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The initial care of newborn infants and subsequent hay fever | Request PDF
Request PDF | The initial care of newborn infants and subsequent hay fever | Patterns of neonatal exposure to microorganisms have changed substantially over the last 100 years, and it has been suggested that this has... | Find, read and cite all the research you need on ResearchGate
The initial care of newborn infants and subsequent hay fever
November 2000
Allergy 55(10):916-22
DOI: 10.1034/j.1398-9995.2000.00480.x
Abstract
Patterns of neonatal exposure to microorganisms have changed substantially over the last 100 years, and it has been suggested that this has influenced the risk of immune-mediated disease. Using a proxy measure, we tested the hypothesis that the initial handling of newborn infants, which is known to affect the pattern of exposure to microorganisms, may alter the risk of developing subsequent atopy, as indicated by hay fever.
Analysis was performed on 5,519 members of the 1970 British Cohort Study, a nationally representative birth cohort. Cohort members with hay fever were identified at intervals up to the age of 26 years. Details of neonatal care and childhood circumstances were recorded prospectively. Those who had spent their first night away from their mother in the communal infant nursery were selected as likely to have experienced atypical exposure compared with infants who remained with their mother. Adjustment was made for potential confounding factors in infancy and childhood by multiple logistic regression analysis.
Unadjusted relative odds (with 95% CI) for developing hay fever among those spending the first night in the communal nursery, when compared with other infants who remained with the mother, were 1.48 (1.23-1.77), P<0.001. Comprehensive adjustment for the potential confounding factors, including feeding practices on the first day of life, markers of social and material circumstances, and region, did not substantially alter this relationship, with adjusted relative odds of 1.31 (1.08-1.59), P=0.005.
While our proxy measure is associated with an increased risk of hay fever, further research is required to confirm that this is due to the pattern of infectious exposure in very early life. The results are consistent with the hypothesis that the first challenges are particularly important in the development of the newborn infant's immune system.
... 24 Nursing away from the mother on the first night of life, clearly an indirect proxy for likely colonisation by nonmaternal organisms, was, however, associated with the later development of atopy in the 1970 UK Birth Cohort.
25
Thus, there is some, admittedly quite limited, evidence that abnormalities in colonisation may have later effects. 12,14,15,[23][24][25] There is much stronger evidence that choice of antibiotics for perinatal use may have significant effects on the developing flora. ...
... 25 Thus, there is some, admittedly quite limited, evidence that abnormalities in colonisation may have later effects. 12,14,15,[23][24]
[25]
There is much stronger evidence that choice of antibiotics for perinatal use may have significant effects on the developing flora. Use of peripartum ampicillin as prophylaxis against group B Streptococcus (GBS) infection resulted in a significant reduction in early-onset neonatal GBS infection in the USA, but at the price of a significant increase in resistant coliform infection. ...
... By contrast, analysis of 5519 members of the 1970 British Cohort study did not identify increased hay fever at 26 years of age in those infants reported to receive prophylactic antibiotics in the first few days of life.
25
These are clearly very preliminary data, and the paucity of studies of long-term outcome of perinatal antibiotic use is striking. While there is an emerging evidence that probiotic use in infancy and early life may have long-term consequences on health, [12][13][14][15]92 the much more common scenario of antibiotic administration to mother or newborn infant remains almost completely unstudied in anything but the short term. ...
Could peripartum antibiotics have delayed health consequences for the infant?
Antibiotics are increasingly prescribed in the peripartum period, for both maternal and fetal indications. Their effective use undoubtedly reduces the incidence of specific invasive infections in the newborn, such as group B streptococcal septicaemia. However, the total burden of infectious neonatal disease may not be reduced, particularly if broad-spectrum agents are used, as the pattern of infections has been shown to alter to allow dominance of previously uncommon organisms. This area has been relatively understudied, and there are almost no studies of long-term outcome. Recent findings suggest that such long-term data should be sought. First, there is evidence that organisms initially colonising the gut at birth may establish chronic persistence in many children, in contrast to prompt clearance if first encountered in later infancy, childhood or adulthood. Second, there is a rapidly advancing basic scientific data showing that individual members of the gut flora specifically induce gene activation within the host, modulating mucosal and systemic immune function and having an additional impact on metabolic programming. We thus review the published data on the impact of perinatal antibiotic regimens upon composition of the flora and later health outcomes in young children and summarise the recent scientific findings on the potential importance of gut flora composition on immune tolerance and metabolism.
... In contrast to the hygiene hypothesis, some studies have demonstrated that infections may instead promote the development of allergies, rather than reduce their risk. An association between viral infection (rhinovirus and respiratory syncytial virus [RSV], primarily) in early infancy and subsequent risk of asthma has in fact been reported among children at high risk [114,
115]
. However, the exact role of RSV remains controversial in this setting [116]. ...
[115]
. A study of over 3000 children in day care conducted in Germany by Cramer and colleagues showed day care attendance is the only risk factor from among 11 possible factors analysed for the development of atopic dermatitis within 2 years (OR: 1.56; 95 % CI: 1.31-1.86). ...
Prevention of food and airway allergy: consensus of the Italian Society of Preventive and Social Paediatrics, the Italian Society of Paediatric Allergy and Immunology, and Italian Society of Pediatrics
Background
Allergic sensitization in children and allergic diseases arising therefrom are increasing for decades.Several interventions, functional foods, pro- and prebiotics, vitamins are proposed for the prevention of allergies and they can’t be uncritically adopted. Objective
This Consensus document was developed by the Italian Society of Preventive and Social Paediatrics and the Italian Society of Paediatric Allergy and Immunology.The aim is to provide updated recommendations regarding allergy prevention in children. Methods
The document has been issued by a multidisciplinary expert panel and it is intended to be mainly directed to primary care paediatricians.It includes 19 questions which have been preliminarily considered relevant by the panel. Relatively to each question, a literature search has been performed, according to the Italian National Guideline Program. Methodology, and a brief summary of the available literature data, has been provided.Many topics have been analyzed including the role of mother’s diet restriction, use of breast/formula/hydrolyzed milk; timing of introduction of complementary foods, role (if any) of probiotics, prebiotics, vitamins, exposure to dust mites, animals and to tobacco smoke. ResultsSome preventive interventions have a strong level of recommendation. (e.g., the dehumidifier to reduce exposure to mite allergens). With regard to other types of intervention, such as the use of partially and extensively hydrolyzed formulas, the document underlines the lack of evidence of effectiveness.No preventive effect of dietary supplementation with polyunsaturated fatty acids, vitamins or minerals has been demonstrated.There is no preventive effect of probiotics on asthma, rhinitis and allergic diseases. It has demonstrated a modest effect, but steady, in the prevention of atopic dermatitis. Conclusions
The recommendations of the Consensus are based on a careful analysis of the evidence available.The lack of evidence of efficacy does not necessarily imply that some interventions may not be effective, but currently they can’t be recommended.
... 28 L'ingresso precoce in comunità come fattore di rischio per lo sviluppo di allergie al contrario rispetto all'ipotesi igienistica, alcuni studi avrebbero dimostrato che le infezioni potrebbero invece favorire lo sviluppo di allergie, piuttosto che ridurne il rischio. È stata, infatti, riportata un'associazione fra infezione virale (principalmente da rhinovirus e virus respiratorio sinciziale o vrS) nella primissima infanzia e rischio successivo di asma, 29,
30
in modo particolare nei soggetti a elevato rischio, sebbene rimanga ancora controverso l'esatto ruolo del vrS. 31 Le infezioni respiratorie, in particolar modo le infezioni di origine virale, e la frequenza al nido, in quanto fattore di rischio per infezione, potrebbero quindi costituire un fattore di rischio, e non di protezione, per lo sviluppo di un fenotipo atopico. ...
... 29 È stato inoltre dimostrato che i neonati che passano la loro prima notte di vita in nursery hanno un maggiore rischio di sviluppare allergia rispetto a chi ha dormito solo con la madre.
30
In uno studio condotto in germania da Cramer e collaboratori e includente oltre 3.000 bambini presso gli asili della germania, la frequenza all'asilo nido è risultata essere l'unico fattore di rischio per lo sviluppo di dermatite atopica entro i due anni, fra gli 11 possibili fattori analizzati (Or: 1,56; IC 95%:1,31-1,86). gli autori concludono che altri fattori ambientali, al di fuori da quelli inclusi nell'ipotesi igienistica, potrebbero spiegare questo risultato. ...
Consensus prevenzione malattie allergiche
Giuseppe DI Mauro
Salvatore Barberi
Obiettivo della Consensus è di definire le evidenze riguardanti il reale impatto che interventi preventivi a differenti livelli, ambientali, comportamentali e nutrizionali, possono avere sulla prevalenza, incidenza
delle allergopatie respiratorie e alimentari.
... Tatsächlich konnte die protektive Rolle eines Kinderkrippenbesuchs während des 1. Lebensjahrs durch zahlreiche weitere Studien bestätigt werden [1, 4,8,
31]
. Offensichtlich kommt es nicht auf den Krippenbesuch allein an, sondern auf das Zeitfenster vor dem 1. Lebensjahr, in dem eine externe virale/bakterielle Stimulation zur Reifung von Parametern des Immunsystems führen kann. ...
... Allerdings war auch hier der protektive Effekt nur in der Gruppe der Einzelkinder aufzeigbar [50]. Im Gegensatz zu den meisten Kinderstudien war bei dieser Erwachsenenstudie [2,4,8,27,
31]
das Asthmarisiko (definiert als "wheeze") für die ehemals Krippen-/Kindergartenkinder erhöht und nicht erniedrigt. Die Autoren spekulierten, dass die höhere mikrobielle Belastung, ausgelöst durch den Krippen-/Kindergartenbesuch, zu mehr Atemwegsinfekten hatte führen können, die die Lunge möglicherweise dauerhaft geschädigt haben. ...
Kindergesundheit und Kinderbetreuung bei unter 3-Jährigen
Knowledge about the health of infants and children in day nursery care facilities in Germany is insufficient. Based on a review of available data we conclude that infants and children under 3 years of age in day nursery are more frequently affected by infections, especially in the upper but also in the lower respiratory tract, than those living at home. Daycare nursery children who grew up as a single child have a clearly lower risk for atopic diseases and allergic sensitization in school age. The available information shows that daycare children are not disadvantaged by persistent health problems compared to children growing up at home. Crowding in daycare is a risk factor for bacterial infections, which diminishes with increasing space per child. Unanswered is the essential question as to which day nursery conditions have a positive or negative impact on child health. These questions of great relevance for child health need to be addressed in further research.
... In this issue of Allergy, Montgomery et al. present results suggesting that neonatal care may have an impact on later development of hay fever
(1)
. Thus, they have found that the odds for developing hay fever among infants spending their ®rst night in a communal nursery, separated from their mothers, are 1.45. ...
... In conclusion, the multitude of effects of microbes on the immune system and the possibly decisive importance of the early colonization of the gut by bacteria for the development of immune responses makes it theoretically possible that early separation of mother and child during the ®rst night after delivery may indeed have long-lasting effects on immune responses, predisposing to hay fever or other atopic diseases. Although Montgomery et al.
(1)
favor this explanation, it should be borne in mind that there may be other explanations of their ®ndings that may be just as likely but are less easily supported by experimental results. For instance, it has been found by Oliveti et al. (2) that poor antenatal care of the mother increases the likelihood of the development of atopy in the child, giving an odds ratio (4.7) that is considerably higher than that (1. ...
Allergy and neonatal care
... In contrast, children exposed to familial infections or normal gut commensals have infectious exposure to a higher dose and longer duration, with an appropriate immune conditioning resulting.
(246)
Crowded conditions are associated with a higher dose of antigen exposure (80;159;244)and this may explain why in some studies of family structure have found a protective effect of higher birth order against IBD. (76) Although there was no statistically significant association between spending the first night in the nursery and later IBD, the increased relative odds, and the consistency in the findings for both CD and UC suggest future studies with larger number of cases be warranted. ...
The epidemiology of inflammatory bowel disease in the United Kingdom: Early environmental associations
Aims: To examine associations between childhood environmental factors and inflammatory bowel disease. Introduction; Recent rises in incidence support environmental factors in the aetiology of inflammatory bowel disease. Studies examining environmental exposures have varying conclusions. Childhood infectious exposures have been proposed. Infections studied including measles have highly controversial conclusions. Atypical infectious patterns such as early or delayed exposure and improved hygiene are hypothesised. Methods: This study used data from the 1970 British Cohort Study, a longitudinal population based birth cohort study of 18,000 children in Great Britain, born in 1970. Data were collected prospectively aged 5, 10 and 16 years. At 26 years, cohort members were questioned about inflammatory bowel disease. Physicians confirmed diagnoses where possible and histology was independently analysed. Factors examined included demographic and perinatal factors, family history, material and cultural circumstances and specific infectious exposures (including measles, other viral infections and vaccinations). Results: The prevalence of inflammatory bowel disease aged 26 years was 49.2 per 10,000 population. 30 subjects reported Crohn's disease and 22 ulcerative colitis. Asian ethnic origins, family history of inflammatory bowel disease and childhood eczema were independent risk factors for inflammatory bowel disease. Passive smoke exposure by age 16 was associated with reduced odds for Crohn's disease. Older siblings and increased maternal parity were associated with increased odds for ulcerative colitis and reduced odds for Crohn's disease. There was no association between measles infection or measles vaccination and inflammatory bowel disease. Conclusions: The study supports the role of childhood environmental factors in inflammatory bowel disease. Measles infection and vaccination in isolation were not risk factors. Additional evidence is required to support the hypothesis that abnormal patterns of infectious exposures in childhood are risks for inflammatory bowel disease. This research should be repeated when more members have developed disease and the study power improved.
... Mikroorganizmami sa jedinec osídľuje už v momente narodenia prechodom cez pôrodné cesty matky a krátko po ňom pri bezprostrednom kontakte dieťaťa s matkou a okolitým svetom, pričom kvalita kolonizácie závisí práve od vonkajších faktorovpozorovali sa napríklad významné rozdiely medzi deťmi narodenými per vias naturales a deťmi rodenými sekciou, resp. medzi deťmi ponechanými po pôrode s matkou a deťmi uloženými hneď po pôrode na novorodeneckej izbe, prípadne v inkubátore
[30]
. Optimálna kolonizácia čreva je nepostrádateľná pre normálny vývoj imunitného systému. ...
Bacterial immunomodulators: A new view on old drugs
Bacterial immunomodulators (autovaccines, lysates, ribosomal products and proteoglycans) comprise a time-tested category of drugs with about half-century history. Their utilisation was empirical initially and their mechanisms of action were detected later in association with progress of clinical and immunological research. Because of not fully described composition these drugs have had also many adversaries, so in some countries they are not registered. After the discovery of interactions between pattern recognition receptors and microbe-associated molecular patterns not only the renaissance of innate immunity started, but also a new era of bacterial immunomodulators may be established.
... Montgomery et al
14
found that newborns spent their first night in a worse hygiene communal nursery were at an increased risk of developing hay fever. The findings suppose that the dysfunction of immune system development is strongly related to early exposure to infectious agents. ...
Association Between Neonatal Urinary Tract Infection and Risk of Childhood Allergic Rhinitis
MEDICINE
Chien-Heng Lin
Wei-Ching Lin
Chia-Hung Kao
The current population-based study investigated the onset of neonatal urinary tract infection (UTI) and the associated risks of allergic rhinitis.
From 2000 to 2005, 3285 children with neonatal UTI and 13,128 randomly selected controls were enrolled from the National Health Insurance Research Database in Taiwan and frequency matched by gender, urbanization of residential area, parental occupation, and baseline year. We compared the risk of allergic rhinitis between the non-UTI and UTI cohorts by performing multivariable Cox regression analysis.
We observed a significant relationship between UTI and allergic rhinitis. This study examined 16,413 patients, among whom 3285 had UTI and 13,128 did not have UTI. The overall incidence rate ratio of allergic rhinitis was 1.41-fold higher in the UTI cohort than in the non-UTI cohort (100.2 vs 70.93 per 1000 person-y). After potential risk factors were adjusted for, the adjusted hazard ratio of allergic rhinitis was 1.32 (95% confidence interval = 1.23–1.41). Regardless of gender, the UTI cohort had a higher risk of allergic rhinitis than that of the non-UTI cohort. The patients with UTI in different follow-up durations were equally susceptible to developing allergic rhinitis compared with those without UTI, especially in follow-up durations shorter than 5 years. Patients with UTI and particular comorbidities such as infections and neonatal jaundice had a significantly increased risk of allergic rhinitis.
UTI in newborns is significantly associated with the development of allergic rhinitis in childhood and might be a risk factor for subsequent childhood allergic rhinitis.
View
Show abstract
... Children exposed to early infections, other than those of the lower respiratory tract, through contact with older siblings or attendance at day care or nursery facilities, prior to 6 months of age, are less likely to develop asthma than their only child, home care peers [20][21]
[22]
[23]. Alternately, daily intake of non-pathogenic bacteria such as Lactobacillus rhamnosus (Lactobacillus GG) to mothers in the final weeks of pregnancy and continuing through 6 months of breastfeeding can halve the incidence of atopy during the first 2 years of an infant's life [24], while direct administration of antigens associated with diseases such as measles, whooping cough, influenza and tuberculosis through either vaccination or natural infection during infancy, is associated with decrease in the incidence of atopic symptoms in older children (13-14 years) [25][26][27][28]. ...
The Role of Human Milk Immunomodulators in Protecting Against Viral Bronchiolitis and Development of Chronic Wheezing Illness
Infants who are breastfed are at an immunological advantage when compared with formula fed infants, evidenced by decreased incidence of infections and diminished propensity for long term conditions, including chronic wheeze and/or asthma. Exclusive breastfeeding reduces the duration of hospital admission, risk of respiratory failure and requirement for supplemental oxygen in infants hospitalised with bronchiolitis suggesting a potentially protective mechanism. This review examines the evidence and potential pathways for protection by immunomodulatory factors in human milk against the most common viral cause of bronchiolitis, respiratory syncytial virus (RSV), and subsequent recurrent wheeze in infants. Further investigations into the interplay between respiratory virus infections such as RSV and how they affect, and are affected by, human milk immunomodulators is necessary if we are to gain a true understanding of how breastfeeding protects many infants but not all against infections, and how this relates to long-term protection against conditions such as chronic wheezing illness or asthma.
... It recently was observed that, after adjustment for several potentially confounding factors, newborns who spent their first night in a communal nursery were at increased risk of developing hay fever (odds ratio = 1.48, 95 percent confidence interval: 1.23, 1.77)
(201)
. The authors speculated that infants in the nursery were more likely to experience lowdose and short-duration exposure to nonfamilial microorganisms. ...
Genetic and Perinatal Risk Factors for Asthma Onset and Severity: A Review and Theoretical Analysis
... T here is accumulating evidence that an inappropriate immune response against normal bowel flora is involved in the etiology of intestinal inflammation in Crohn's disease (CD). 1 This is consistent with the finding that exposures in the early years of life that could disrupt or result in atypical patterns of microbial colonization of the bowel have been associated with an increased risk of subsequent CD.
2,
3 Evidence from animal models indicates that microbial exposures in the birth canal may be espe-cially important for the development of stable homeostasis between host and colonizing flora, as perinatal colonization represents the first major exposure to microorganisms in the gut. 4 In humans, perinatal health events have been associated with an increased risk of inflammatory bowel disease (IBD), where it is plausible that these events involve disruption of perinatal bowel colonization. 5 Here we investigate birth by cesarean section as a putative risk for CD and consider characteristics of delivery mode that may be relevant to patterns of initial bowel colonization. ...
Cesarean section and the risk of pediatric Crohn's disease
| https://www.researchgate.net/publication/12294747_The_initial_care_of_newborn_infants_and_subsequent_hay_fever |
IJMS | Free Full-Text | The Role of Deoxycytidine Kinase (dCK) in Radiation-Induced Cell Death
Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. However, whether dCK plays a role in radiation-induced cell death is less clear. In this study, we genetically modified dCK expression by knocking down or expressing a WT (wild-type), S74A (abrogates phosphorylation) and S74E (mimics phosphorylation) of dCK. We found that dCK could decrease IR-induced total cell death and apoptosis. Moreover, dCK increased IR-induced autophagy and dCK-S74 is required for it. Western blotting showed that the ratio of phospho-Akt/Akt, phospho-mTOR/mTOR, phospho-P70S6K/P70S6K significantly decreased in dCK-WT and dCK-S74E cells than that in dCK-S74A cells following IR treatment. Reciprocal experiment by co-immunoprecipitation showed that mTOR can interact with wild-type dCK. IR increased polyploidy and decreased G2/M arrest in dCK knock-down cells as compared with control cells. Taken together, phosphorylated and activated dCK can inhibit IR-induced cell death including apoptosis and mitotic catastrophe, and promote IR-induced autophagy through PI3K/Akt/mTOR pathway.
The Role of Deoxycytidine Kinase (dCK) in Radiation-Induced Cell Death
by Rui Zhong 1 , Rui Xin 1,2 , Zongyan Chen 1,3 , Nan Liang 1 , Yang Liu 1 , Shumei Ma 1,* and Xiaodong Liu 1,4,*
3
Department Diagnostic Imaging, Weihai Chest Hospital, Weihai 264220, China
4
Department Radiation Oncology, the 2nd Hospitals Affiliated to Jilin University, Changchun 130021, China
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2016 , 17 (11), 1939; https://doi.org/10.3390/ijms17111939
Received: 22 August 2016 / Revised: 12 October 2016 / Accepted: 14 November 2016 / Published: 21 November 2016
(This article belongs to the Collection Programmed Cell Death and Apoptosis )
Abstract
Deoxycytidine kinase (dCK) is a key enzyme in deoxyribonucleoside salvage and the anti-tumor activity for many nucleoside analogs. dCK is activated in response to ionizing radiation (IR)-induced DNA damage and it is phosphorylated on Serine 74 by the Ataxia-Telangiectasia Mutated (ATM) kinase in order to activate the cell cycle G2/M checkpoint. However, whether dCK plays a role in radiation-induced cell death is less clear. In this study, we genetically modified dCK expression by knocking down or expressing a WT (wild-type), S74A (abrogates phosphorylation) and S74E (mimics phosphorylation) of dCK. We found that dCK could decrease IR-induced total cell death and apoptosis. Moreover, dCK increased IR-induced autophagy and dCK-S74 is required for it. Western blotting showed that the ratio of phospho-Akt/Akt, phospho-mTOR/mTOR, phospho-P70S6K/P70S6K significantly decreased in dCK-WT and dCK-S74E cells than that in dCK-S74A cells following IR treatment. Reciprocal experiment by co-immunoprecipitation showed that mTOR can interact with wild-type dCK. IR increased polyploidy and decreased G2/M arrest in dCK knock-down cells as compared with control cells. Taken together, phosphorylated and activated dCK can inhibit IR-induced cell death including apoptosis and mitotic catastrophe, and promote IR-induced autophagy through PI3K/Akt/mTOR pathway.
Keywords:
deoxycytidine kinase (dCK)
;
autophagy
;
apoptosis
;
mitotic catastrophe
;
radiation
1. Introduction
Cell death is a fundamental biological process that has been mediated via intracellular program of biological systems [ 1 , 2 ]. The execution of cell death needs an orchestrated interplay between some important processes: apoptosis, autophagy, necrosis [ 3 ] and mitotic catastrophe [ 4 ]. Apoptosis refers to a constellation of characteristic changes leading directly to cell death [ 5 ]. Over the past few decades, apoptosis has been widely studied, and radiotherapy strategies targeting apoptosis has become one of the most important cancer treatments [ 6 ]. Autophagy is a kind of catabolic process for maintaining cellular homeostasis and supplying substrates for energy generation [ 7 ]. Under stresses, however, autophagy may protect cells or lead to cell death [ 8 ]. Therefore, autophagy is considered a double-edged sword in the process of tumor development.
Other than apoptosis and autophagy, mitotic catastrophe is one of the atypical deaths defined by the Nomenclature Committee on Cell Death (NCCD) [ 9 , 10 ]; it also acts as an oncosuppressive mechanism which can prevent perturbations of the mitotic machinery and genomic instability in response to DNA damage [ 11 ]. A consequence of failure to complete mitosis and accumulation of unrepaired DNA damage can lead to mitotic catastrophe [ 4 ]. The G2 phase checkpoint is important for preventing mitotic cell death. A transient cell cycle will not let cells have enough to repair DNA and then proceed into mitosis, fail to separate, leading to catastrophic cell division [ 12 ].
Deoxycytidine kinase (dCK) is a key enzyme in the deoxyribonucleoside salvage, which is important to maintain normal DNA metabolism. dCK can activate many antiviral and anticancer nucleoside analogs, such as fludarabine, gemcitabine, cladribine and zalcitabine [ 13 ]. dCK can also be responsible for the phosphorylation of deoxycytidine (dC), deoxyadenosine (dA), and deoxyguanosine (dG) to their monophosphate forms [ 14 ] and is also involved in DNA damage repair [ 15 , 16 ]. dCK protein has four phosphorylation sites, Thr-3, Ser-11, Ser-15, Ser-74 [ 17 ]. dCK activity can be increased by Ser-74 phosphorylation [ 18 ] and Thr-3 can promote the stability of dCK [ 17 ]. Radiation and genotoxic drugs such as aphidicolin, etoposide and certain nucleoside analogs can increase dCK kinase activity [ 19 , 20 ]. dCK can activate many nucleoside analogs that have exhibited synergistic activity with radiotherapy to inhibit DNA repair [ 21 ]. Moreover, dCK deficiencies or dCK mutants (G12) can mediate resistance to nucleoside analogs [ 22 , 23 ]. In addition, dCK is used as a biomarker and drug target in clinical application [ 24 ].
Our previous studies have demonstrated that Ataxia-telangiectasia-mutated (ATM) kinase can phosphorylate dCK on Serine 74 to activate it in response to ionizing radiation (IR) treatment and dCK regulates the G2/M checkpoint through interaction with cyclin-dependent kinase 1 in response to DNA damage [
25
]. Ataxia-Telangiectasia Mutated (ATM) could promote IR-induced autophagy via the Akt/mTOR/P70S6K pathway [
26
]. In this study, we focused on further characterization of dCK phosphorylation on S74 in radiation-induced cell death and its possible mechanism. This will provide a new insight for targeting therapy of cancer.
2. Results
2.1. Deoxycytidine Kinase Decreased Radiation-Induced Cell Death
In order to elucidate the roles of dCK in radiation-induced cell death, we established stable HeLa models with dCK shRNA and control shRNA ( Figure 1 A). The colony formation assays demonstrated that dCK knock-down increased radiosensitivity ( Figure 1 B). We transfected either empty vector, wild-type dCK, dCK S74A or S74E plasmid into dCK knock-down cells ( Figure 1 C). The plasmid dCK S74A has a Serine 74 to alanine substitution, which abrogates phosphorylation, and dCK S74E has a Serine 74 to glutamic acid substitution, which mimics phosphorylation. After IR treatment, a CCK-8 assay was conducted to assess cell viability ( Figure 1 D). We found that IR-induced cell death can be reversed by reintroduction of dCK, especially by dCK S74E, which improved survival by 84%, suggesting that dCK has positive effects on radioresistance. To further elucidate the types of cell death occurring, different regulators were used: we inhibited autophagy, apoptosis, necrosis and ferroptosis with 3-methyladenine (3-MA), ZVAD-FMK, Necrostatin-1, Ferrostatin-1, respectively, and induced autophagy by using Rapamycin. Necrostatin-1 and Ferrostatin-1 had no effect on IR-induced cell death, while Rapamycin and ZVAD-FMK decreased the rate of cell death by 19% and 36%, and 3-MA increased the rate of cell death by 25% in dCK knock-down cells, indicating apoptosis contributed to the majority of cell death ( Figure 1 E).
Figure 1.
Deoxycytidine kinase (dCK) decreased radiation-induced cell death. (
A
) Establishment of dCK knock-down cells. Human cervical carcinoma cell line (HeLa) cells were stably transfected with pSUPER control or dCK shRNA. Individual clones were obtained under puromycin selection. Knock-down effects were confirmed by Western blot. Data were presented as mean ± SD of three independent experiments; (
B
) radiosensitivity was assessed by the colony formation assay in both dCK silencing cells and control cells after radiation treatment (0–8 Gy). Data were presented as mean ± SD of three independent experiments. *
p
< 0.05 versus control group or dCK silencing group; (
C
) dCK knock-down HeLa cells were reintroduced with vector control, dCK wild-type, dCK S74A mutant or S74E mutant. Overexpression of different dCK genotypes were shown by Western blot in HeLa cells. Data were presented as mean ± SD of three independent experiments; (
D
) the cells with different dCK genotypes were treated with 8 Gy radiation. Cell viability was analyzed by CCK-8 assay. *
p
< 0.05 versus control group; (
E
) the pSUPER and dCK knock-down cell lines were pretreated with 3-MA (2 mM), rapamycin (200 nM), ZVAD-FMK (10 μM), Necrostatin-1 (10 μM) or Ferrostatin-1 (5 μM) for 1 h, respectively, followed by ionizing radiation (IR) (8 Gy). After 48 h, cells were stained with trypan blue and analyzed by flow cytometry assay. *
p
< 0.05 versus control group.
2.2. dCK Suppressed the Ionizing Radiation (IR)-Induced Apoptosis
To confirm dCK contributed to IR-induced apoptosis, we tested IR-induced apoptosis in HeLa cells (
Figure 2
A). The flow cytometry assay showed that dCK participated in the regulation of apoptosis (
Figure 2
B,C). After IR treatment, a significant increase in apoptosis (141%) was found in the dCK knock-down cells as compared with pSUPER cells (91%). Western blotting showed that in dCK knock-down cells, IR induced more cleaved-caspase3 and less Bcl-2 expression as compared with the control group (
Figure 2
D), suggesting that dCK contributes to the IR-induced apoptosis. We then reintroduced dCK constructs to establish cell models with different dCK genotypes. After 8 Gy irradiation, apoptosis increased by 88% in vector cells, and increased by 50% in dCK-S74A cells. However, apoptosis showed only smaller increases of 29% and 26% in dCK-WT and dCK-S74E cells, suggesting phosphorylated dCK suppresses apoptosis induced by IR (
Figure 2
E).
Figure 2. dCK silencing promoted IR-induced apoptosis. ( A ) Flow cytometry was used to quantify apoptosis in HeLa cells 24 h after radiation. Cells were stained with propidium iodide (PI) and Annexin V-FITC. The positive-stained cells were counted using FACScan; ( B ) apoptosis was detected in both control and dCK knock-down cell lines 24 h after radiation; ( C ) quantitative analysis of ( B ), data were presented as mean ± SD of three independent experiments. * p < 0.05 versus mock group; ( D ) whole-cell lysates were harvested and subjected to Western blot using the indicated antibodies; ( E ) dCK knock-down HeLa cells were reintroduced with vector control, dCK wild-type, dCK-S74A mutation or dCK-S74E mutation and then treated with IR (8 Gy). After 24 h, apoptotic rate was quantified by flow cytometry. * p < 0.05 versus mock group.
2.3. dCK Promoted the IR-Induced Autophagy
Since autophagy inhibitor 3-MA significantly increased IR-induced cell death ( Figure 1 E), we decided to test whether dCK participates in the regulation of radiation-induced autophagy. Flow cytometry was used to test the IR-induced autophagic rate ( Figure 3 A). It showed IR induced autophagy in HeLa cells. Besides that, autophagy induced by IR increased by 397% in pSUPER cells, and only by 134% in dCK knock-down cells, suggesting that dCK could increase IR-induced autophagy ( Figure 3 B). Ammonium chloride (NH4Cl) is a lysosomal inhibitor which can block organelle acidification and enable assessment of autophagic flux [ 27 ]. Western blotting revealed that LC3-II increased in a time-dependent manner ( Figure 3 C), reaching a peak in 72 h with NH4Cl+IR treatment in pSUPER cells, but there was low expression of LC3-II in dCK knock-down cells. In order to investigate whether dCK S74 phosphorylation is associated with IR-induced autophagy, we introduced dCK constructs into the dCK knock-down cells. Western blotting showed that after IR treatment, LC3-II protein levels increased by 44% in dCK-WT cells and by 46% in dCK-S74E cells, but only increased by 9% in dCK-S74A cells and by 16% in the control cells ( Figure 3 D), indicating that dCK S74 phosphorylation is involved in IR-induced autophagy.
Figure 3.
dCK promoted IR-induced autophagy in HeLa cells. (
A
) HeLa cells were treated with mock or IR (8 Gy). Staining of monodansylcadaverine (MDC) was detected by flow cytometry at 24 h after IR treatment; M1 represents fluorescent densities of MDC positive cells; (
B
) both dCK silencing cells and pSUPER cells were treated with 8 Gy radiation; 24 h later, staining of MDC was detected by flow cytometry; M1 represents fluorescent densities of MDC positive cells; (
C
) western blot analysis of microtubule-associated protein 1A/1B-light chain 3 (LC3) expression in the pSUPER and dCK knock down cells 24, 48 and 72 h after 8 Gy radiation. Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) was used as an internal standard; M1 represents fluorescent densities of MDC positive cells; (
D
) dCK knock-down HeLa cells were reintroduced with vector control, dCK wild-type, dCK-S74A mutation and dCK-S74E mutation. 36 h after transfection, cells were exposed to mock or IR (8 Gy). 24 h after IR, cells were harvested and subjected to western blot using the indicated antibodies.
2.4. Suppressing Autophagy Could Increase Apoptosis Induced by ionizing Radiation
To further study the correlation between IR-induced autophagy and apoptosis, the autophagy inhibitors 3-MA and spautin-1 were pretreated for 1 h following IR treatment in pSUPER and dCK knock-down cells. (
Figure 4
A). The result showed that IR increased LC3-II protein by 196% in pSUPER cells and decreased by 55% and 52% in the presence of 3-MA and spautin-1, respectively. In dCK knock-down cells, IR treatment increased LC3-II protein by 12% and decreased LC3-II protein by 7% and 11% in the presence of 3-MA and spautin-1. This suggested that 3-MA and spautin-1 can inhibit IR-induced autophagy. We then used different autophagy regulators to check the change in autophagy flux by flow cytometry (
Figure 4
B).
Figure 4.
Suppressing autophagy could increase apoptosis induced by IR. (
A
) The pSUPER and dCK knock-down cell lines were incubated with spautin-1 (10 μM) or 3-MA (2 mM) for 1 h, and then treated with IR (8 Gy) for 72 h. Western blot analysis was performed to detect MAPLC3-I/II and GAPDH was used as an internal standard; (
B
) the control and dCK knock-down cells were pretreated with 3-MA (2 mM), spautin-1 (10 μM) or rapamycin (200 nM) for 1 h, and then treated with IR (8 Gy). After 24 h, staining of MDC was detected by flow cytometry. Quantitative analysis of autophagic cells was presented as mean ± SD of three independent experiments. *
p
< 0.05 versus mock group; (
C
) the pSUPER and dCK knock-down cell lines were incubated with 3-MA (2 mM), ZVAD-FMK (20 μM) or ZVAD-FMK (20 μM) + 3-MA (2 mM) for 1 h, then treated with IR (8 Gy) and incubated for 24 h. Western blot analysis was performed to detect caspase3 and cleaved-caspase3; GAPDH was used as an internal standard; (
D
) the pSUPER and dCK knock-down cell lines were pretreated with 3-MA (2 mM), ZVAD-FMK (10 μM), 3-MA (2 mM) + ZVAD-FMK (10 μM) for 1 h respectively, and then treated with IR (8 Gy). After 48 h, cells were collected, stained with PI and Annexin V-FITC and analyzed by flow cytometry. *
p
< 0.05 versus control group.
Interestingly, 3-MA and spautin-1 inhibited IR-induced autophagy and rapamycin increased it in both cell lines. After radiation, LC3-II significantly decreased in dCK knock-down cells as Western blot shows (
Figure 4
A), while MDC staining only shows a slight decrease of autophagy in irradiated cells as compared with pSUPER. It might because the different efficacies of the two methods and Western blot is more sensitive than MDC for the detection of autophagy. Given that dCK plays an important role in the induction of both apoptosis and autophagy, we focused on the potential relationship between apoptosis and autophagy. Both 3-MA and ZVAD-FMK were used to inhibit autophagy and apoptosis, respectively. As shown in
Figure 4
C, IR increased cleaved-caspase3 protein by 86% in dCK knock-down cells but only by 25% in control cells. When cells were treated with ZVAD-FMK, cleaved-caspase3/caspase3 decreased in both cell lines. Interestingly, 3-MA pre-treatment caused a notable cleaved-caspase3/caspase3 increase in control and dCK knock-down cells after IR treatment. Furthermore, the ratio of cleaved-caspase3/caspase3 was much lower in the 3-MA + ZVAD-FMK-treated cells than in the 3-MA-treated cells. This suggests that autophagy inhibitor 3-MA may promote apoptosis. IR-induced apoptosis decreased more significantly in dCK knock-down cells (24%) with ZVAD-FMK treatment, and 3-MA increased IR-induced apoptosis by 48%. However, in control cells, 3-MA increased IR-induced apoptosis by 32%, while ZVAD-FMK did not significantly alter apoptosis induced by IR. Moreover, compared with the control group, there was no significant change of cell apoptosis in the 3-MA + ZVAD-FMK group in both cell lines (
Figure 4
D).
2.5. dCK Regulated IR-Induced Autophagy through mTOR Pathway
Cells under stress try first to survive by autophagy and if they notice that it is not possible, they die trough apoptosis. We have demonstrated that activated dCK by IR can increase autophagy (protect cells) and suppress apoptosis. Moreover, suppressing autophagy could increase apoptosis induced by IR. We next want to understand the specific mechanism of autophagy regulated by dCK. It is well known that mTOR serves as the negative regulator of autophagy [
3
]. In our study, Western blot analysis showed that IR treatment significantly decreased levels of phospho-Akt/Akt/GAPDH by 54%, phospho-mTOR/mTOR/GAPDH by 39% and phospho-P70S6K/P70S6K/GAPDH by 31% in the dCK-WT cells (
Figure 5
A,B). Moreover, IR treatment significantly decreased levels of phospho-Akt/Akt/GAPDH by 57%, phospho-mTOR/mTOR/GAPDH by 55% and phospho-P70S6K/P70S6K/GAPDH by 46% in dCK-S74E cells. However, the levels of phospho-Akt/Akt/GAPDH, phospho-mTOR/mTOR/GAPDH, phospho-P70S6K/P70S6K/GAPDH showed only smaller decreases of 8%, 13% and 5%, respectively, in dCK-S74A cells following IR treatment. This suggests that activated dCK could inhibit the Akt/mTOR/P70S6K pathway and promote autophagy with IR treatment. In order to understand how dCK participates in the Akt/mTOR/P70S6K pathway, we conducted a co-localization assay with specific antibodies. The result showed that dCK was co-localized with mTOR, which did not change significantly after IR treatment (
Figure S1
), i.e., the co-immunoprecipitation experiment showed that both inactivated (no IR) and activated (IR) dCK can interact with mTOR despite S74 mutants not being able to interact with mTOR (
Figure 5
C). Together, these results indicate that activated dCK promotes autophagy via the Akt/mTOR/P70S6K pathway in response to IR.
Figure 5.
dCK Serine 74 phosphorylation participated in the regulation of autophagy induced by IR. (
A
) The dCK-complemented cell lines were treated with mock or IR (8 Gy). A total of 24 h after IR, cells were harvested and subjected to Western blot using the indicated antibodies; (
B
) quantitative analysis of (
A
), cells transfected with pSUPER and treated with mock were used as control (100%). Data were presented as mean ± SD of three independent experiments. *
p
< 0.05 versus cells treated with IR only; (
C
) vector control, FLAG-tagged wild-type or S74A dCK were transiently transfected into HeLa cells in which dCK was knocked-down. After 36 h of transfection, the cells were treated with mock or IR (8 Gy). Then, 24 h after IR, cells were harvested and subjected to co-immunoprecipitation using an anti-FLAG antibody. The co-immunoprecipitates were then blotted with indicated antibodies.
2.6. dCK Is Required for the G2/M Cell Cycle Checkpoint and to Protect Cells against Mitotic Catastrophe
Our previous research has shown that dCK is required for G2 arrest [ 25 ]. In this study, we attempt to elucidate cell cycle changes that are associated with cell death. IR-induced G2/M phase arrest increased in a time-dependent manner ( Figure 6 A). Simultaneously, the G2/M phase arrest in dCK knock-down cells was lower than that in control cells after 12 h of IR treatment. In order to investigate whether dCK knock-down induced G2/M checkpoint abrogation, we tested mitotic cells by Histone H3 Ser10 phosphorylation staining. The result showed that the number of mitotic control cells decreased by about 70% 12 h after IR treatment. However, dCK knock-down had a minimal effect on mitotic cell number after 12 h IR treatment ( Figure 6 B). This suggests that dCK is required for activation of the IR-induced G2/M checkpoint. We know that mitotic catastrophe is associated with an abnormal cell cycle checkpoint, centrosomes, spindle and DNA damage. As such, we exposed control and dCK knock-down cells to 8 Gy irradiation and then stained with DAPI to identify mitotic catastrophe by flow cytometry ( Figure 6 C). IR increased polyploidy more significantly in dCK knock-down cells than in control cells (204% versus 56%) in the 12 h IR treatment group. This phenomenon was less obvious in the 24 h IR treatment group. Immediately after DNA damage, there is an early phosphorylation of Ser139 in histone at damage sites which appear quickly and disappear within a few hours [ 28 , 29 ]. Prolonged expression ofγH2AX suggests the abrogation of damage repair [ 30 ] and ERCC1 levels are associated with DNA repair capacity [ 31 , 32 ]. As Figure S2 shows, IR increased levels of H2AX and reduced ERCC1 considerably. ERCC1 expression was slightly lower in dCK knock-down cells as compared with parental cells, which indirectly supported the fact that loss of dCK increased the radiosensitivity by breaking the balance of DNA damage and repair. Overall, the results demonstrate that loss of dCK leads to abrogation of the G2/M checkpoint, thereby enabling abnormal cells to enter the mitosis phase, increasing DNA damage, reducing DNA repair and eventually inducing mitotic catastrophe in response to IR.
Figure 6.
dCK inhibited IR-induced mitotic catastrophe. (
A
) Flow cytometry was used to quantitate the cell G2/M phase with or without IR at 1, 4, 8, 12, and 24 h in isogenic HeLa cells stably expressing control or dCK shRNA. All data are representative of three independent experiments and are shown as the mean ± SD. a
p
< 0.05 versus pSUPER cells treated with IR only, #
p
< 0.05 versus dCK knock-down cells treated with IR only. *
p
< 0.05 versus control group; blue lines are used to compare pSUPER cells treated with or without IR; red lineds are used to compare dCK knock-down cells treated with or without IR; (
B
) isogenic HeLa cell lines with control or dCK shRNA were treated with mock or IR treatment (8 Gy). 12 or 24 h later, cells were harvested and fixed followed by staining for Histone H3 Ser10 phosphorylation and analyzed by flow cytometry. The average and standard deviations of at least triplicate samples are shown. Statistic analysis was done by Student’s
t
-test; *
p
< 0.05 versus cells treated with IR only; (
C
) isogenic HeLa cell lines with control or dCK shRNA were treated with or without IR (8 Gy). After 12 or 24 h, cells were stained by DAPI and detected by flow cytometry. *
p
< 0.05 versus cells treated with IR only.
3. Discussion
It is known that many nucleoside analogs are used in combination with radiotherapy and deoxycytidine kinase (dCK) is required for the anti-tumor activity of these nucleoside analogs [ 21 ]. Moreover, dCK activation can be used as a biomarker for DNA damage response and Ataxia-Telangiectasia Mutated (ATM) function [ 24 ]. However, the roles of dCK in radiation-induced cell death are still unknown.
Given that dCK is activated in response to ionized radiation (IR) and that phosphorylation of dCK is crucial for its enzymatic activity [ 24 , 25 ], we introduced different dCK constructs into dCK knock-down cells. We found the dCK phosphor mimetic S74E was able to inhibit cell death induced by IR, while dCK S74A failed to do so, confirming that dCK S74 had an important role in cell death under IR treatment. We found that loss of dCK increased IR-induced cell death which was associated with autophagy and apoptosis, but was not associated with ferroptosis or necrosis.
Apoptosis is one of the most important mechanisms for cell death. dCK triggers the phosphorylation of cytarabine (Ara-C), CNDAC and other nucleoside analog drugs, which then inhibit tumor growth and promote apoptosis [ 33 , 34 , 35 , 36 ]. Hypoxia-induced dCK expression contributes to apoptosis [ 37 , 38 ]. Caspases are cysteine proteases that mediate apoptosis and Bcl-2 protein can inhibit apoptosis in vitro [ 39 ].To determine whether dCK is involved in IR-induced apoptosis, we detected caspase3 and Bcl-2 expression and discovered that, compared to the control cells, cleaved-caspase3 was increased and Bcl-2 expression was decreased in response to IR in dCK knock-down cells. Moreover, dCK (especially the S74E form) was able to decrease the rate of apoptosis induced by IR, suggesting dCK suppressed IR-induced apoptosis.
Autophagy is a lysosome-dependent self-digestion process [
40
] that promotes cell survival under some stresses, such as nutrient starvation, ROS, hypoxia, DNA damage and the unfolded protein response [
41
]. However when excessive cell damage is beyond the limit of repair under certain physiological conditions, autophagy turns into a programmed cell death mechanism (type II) [
42
]. We provided evidence that autophagy increased noticeably in response to IR in HeLa cells. We confirmed that dCK could increase LC3-II expression in a time-dependent manner in response to IR. It has been reported that dCK was activated in vivo by phosphorylation of Ser-74 [
43
]. We then wondered whether Ser-74 could affect autophagy induced by IR. As expected, IR treatment increased LC3-II expression noticeably in wild-type dCK and dCK-S74E cells, but not in S74A cells and the control cells, indicating that dCK S74 phosphorylation promoted IR-induced autophagy.
Spautin-1 is a specific and potent autophagy inhibitor-1 that can inhibit USP10 and USP13, and promote the degradation of Beclin-1 [
44
]. As an autophagy inhibitor, 3-MA (3-methyladenine) can suppress class III PtdIns 3-kinase [
45
]. We found that dCK increased IR-induced autophagy and this can be inhibited by 3-MA and spautin-1. Rapamycin is TOR (TOR complex 1) inhibitor, which induces autophagy. TOR complex 2 is much less sensitive to inhibition by rapamycin [
46
]. We found that autophagy regulators could cause a corresponding change in the incidence of autophagy and that dCK could change autophagy flux induced by IR. By using 3-MA and ZVAD-FMK to inhibit autophagy or apoptosis and rapamycin to induce autophagy, our data indicated that autophagy inhibition leads to an increase in IR-induced apoptosis in both pSUPER and dCK knock-down cells, which was more significant in pSUPER cells, indicating that dCK promoted IR-induced autophagy which protected cells from apoptosis induced by IR.
Given that dCK was required for autophagy induced by IR, we further investigated the mechanism by which dCK regulates IR-induced autophagy. Several signaling pathways such as mTOR, PI3K, Akt, Beclin-1 and HIF-1 have been reported to be involved in the regulation of autophagy [
47
]. dCK could regulate the migration and invasion through the AKT pathway and seems to be the upstream of AKT [
48
].We hypothesized that dCK-S74 phosphorylation might participate in the autophagy progress and found that the Akt/mTOR/P70S6K pathway could be suppressed obviously by IR in wild-type dCK and dCK-S74E cells. However, dCK-S74A did not change the Akt/mTOR/P70S6K pathway obviously in response to IR. Additionally, we presented data that wild-type dCK interacted with mTOR and the interaction did not change obviously after IR treatment. More interestingly, the S74A or S74E mutant dCK failed to co-immunoprecipitate with mTOR. We checked dCK sequence and found that dCK contained the LIR motif (LC3-interacting region) which was crucial for selective autophagy. If LIR location is close to S74, dCK S74E might be able to recruit LC3 to the LIR motif and S74A could also change the spatial conformation of dCK, consequently interfering with the interaction between dCK and mTOR. These results indicate that activated dCK may inhibit the Akt/mTOR/P70S6K pathway via interaction with mTOR and that dCK S74 participates in regulation of autophagy initiation with IR treatment.
Our previous studies have demonstrated that dCK functions as a critical regulator of the G2/M checkpoint. Cyclin-dependent kinase 1 (Cdk1) is associated with dCK in response to DNA damage. dCK can interact with Cdk1 after IR and the interaction inhibits Cdk1 activity [
25
]. Data presented in this manuscript confirmed that IR could induce G2/M phase arrest; however, silencing dCK resulted in a G2/M checkpoint defect, suggesting that dCK is required for activation of the IR-induced G2/M checkpoint. Besides that, dCK decreased the number of mitotic cells in response to IR, especially after 12 h IR. We know that when DNA is damaged, cells cannot divide completely, leading to significant increases in polyploidy levels and eventually causing mitotic catastrophe [
49
]. Our flow cytometry assay showed that IR-induced polyploidy increased significantly in dCK knock-down cells, especially in the 12 h IR treatment group. Moreover, loss of dCK suppressed DNA repair. As such, dCK has an important role in protecting cells from IR-induced mitotic catastrophe.
4. Materials and Methods
4.1. Cell Line, Antibody and Reagents
Human cervical carcinoma cell line, HeLa, was cultured in Dulbecco’s Modified Eagle Medium (DMEM) (GIBCO, Carlsbad, CA, USA) supplemented with 10% fetal bovine serum (FBS) and 1% penicillin/streptomycin (Invitrogen, Carlsbad, CA, USA) in glass Petri dishes at 37 °C in a 5% CO
2
incubator.
Anti-dCK antibody was purchased from Abcam Inc (Cambridge, MA, USA). Anti-MAPLC3, anti-P-mTOR, anti-P-Akt, anti-P-P70S6K, anti-caspase3, anti-Bcl-2, anti-H2AX and anti-ERCC1 antibodies were purchased from Cell Signaling. Anti-GAPDH was obtained from Santa Cruz Biotechnology (Santa Cruz, CA, USA). The peroxidase-conjugated anti-mouse IgG and peroxidase-conjugated anti-rabbit IgG were purchased at Santa Cruz. Fetal bovine serum (FBS), and Cell Counting Kit-8 (CCK-8) was purchased from Dojin Laboratories (Kumamoto, Japan), 3-Methyladenine (3-MA), NH4Cl, Necrostatin-1, Ferrostatin-1, Rapamycin, Spautin-1 and monodansylcadaverine (MDC) were purchased from Sigma Chemical (St. Louis, MO, USA), ZVAD-FMK was purchased from Selleckchem (Houston, TX, USA), and pSUPER retroviral vector was obtained from OligoEngine (Seattle, WA, USA).
4.2. Radiation
X-ray generator (X-RAD 320ix, Precision X-ray Inc., North Branford, CT, USA) was utilized to deliver radiation at a dose rate of 1.0 Gy/min.
4.3. Plasmids
Wild-type dCK, dCK-S74A, dCK-S74E mutants were gifts from Bo XU (Southern Research Institute, Birmingham, AL, USA). ShRNAs were designed according to “ www.idtdna.com .” ShRNAs were synthesized, denatured, ligated to pSUPER vector at BglII and HindIII sites. The primers used are shown as follows: dCK-WT-F 5′-tcactagtatggccaccccgcccaagagaagc-3′; dCK-WT-R 5′-acgctcgatcacaaagatctcaaaaactctt-3′; dCK-S74A-F 5′-cttacaatggcacagaaaaatggtgg-3′; dCK-S74A-R 5′-ccaccatttttctgtgccattgtaag-3′; dCK-S74E-F 5′-cttacaatggaacagaaaaatggtgg-3′; dCK-S74E-R 5′-ccaccatttttctgttccattgtaag-3′; dCK-shRNAs-F 5′-gatctgtggttcctgaacctgttgttcaagagacaacaggttcaggaaccacttttta-3′; dCK-shRNAs-R 5′-agcttaaaaagtggttcctgaacctgttgtctcttgaacaacaggttcaggaaccaca-3′.
4.4. Establishment of Deoxycytidine Kinase (dCK) Silencing Cells
The pSUPER-dCK and the vector with a scrambled sequence, i.e., pSUPER, were constructed in our lab. Cells were transfected with shRNA vectors to establish the dCK knock-down genotype. Both ShRNA vectors (10 μg) and package vector, Amphopack, were transfected into 293T, then the supernatant containing a pseudovirus particle was retrieved 72 h post-transfection and used to infect HeLa cells. Positive stable clones were selected by growing cells with puromycin (0.8 μg/mL) for 1 week.
4.5. Western Blot Analysis
Cells were harvested and the total proteins were extracted with RIPA (radioimmunoprecipitation) lysis buffer (NaCl (50 mM), HEPES, EGTA (2.5 mM), EDTA (1 mM), dithiothreitol (DTT, 1 mM), NP-40 (1%), NaF (10 mM), SV (1 mM), SDS (0.1%), PMSF (1 mM)), and 1 mL aliquot was mixed with 10 μL protease inhibitor cocktail. Identical amounts (50 μg/lane) of protein samples were subjected to electrophoresis on 8%–15% Tris-glycine SDS polyacrylamide gel, subsequently transferred to nitrocellulose. Membranes were then blocked with 5% skimmed milk in PBS at room for 1 h, incubated with primary antibodies followed by horseradish peroxidase-conjugated secondary antibodies, and visualized with the chemiluminescence system (Santa Cruz, CA, USA). The intensities of protein bands were quantified using image software (Quantity One, Guangzhou, China).
4.6. Co-Immunoprecipitation
Cells were harvested and lysed using RIPA buffer. Whole-cell lysates were incubated with Anti-FLAG-M2 Agarose beads (Sigma, St. Louis, MO, USA) overnight at 4 °C. The samples were then washed with TBST three times, eluted in 2× sample buffer and placed in a boiling water bath for 5 min. Western blot was used to analyze the eluted proteins.
4.7. Immunofluorescence Microscopy Analysis
There were 8 × 10 4 cells seeded into 60 mm Petri dishes using standard culture medium and incubated for 24 h. A total of 24 h after different treatments, cells were washed three times with PBS, and fixed with methanol for 30 min. After washing with PBS, cells were incubated with primary antibodies at 4 °C for one night. Then cells were washed with PBS and stained with a secondary antibody for 1 h. After washing with PBS three times, cells were stained with DAPI for 15 min. Cell images were captured with Leica microsystems.
4.8. Colony Formation Assay
Cells were seeded into six-well plates in triplicate using standard culture medium. After 24 h, cells were irradiated (0, 2, 4, 6 and 8 Gy). Two weeks later, cells were fixed with 4% formaldehyde, and stained with 0.5% crystal violet. Then the number of colonies (more than 50 cells) was counted and normalized to the corresponding non-irradiated control. Cell survival curves were made by the multitarget click model of GraphPad Prism 5.0 (Systat Software, San Jose, CA, USA).
4.9. Cell Counting Kit-8 (CCK-8) Assay
Radiosensitivity was detected by Cell Counting Kit-8 assay (CCK-8, Dojin Laboratories, Kumamoto, Japan). There were 1 × 10 4 cells/well seeded in 96-well plates containing complete medium. After 48 h, following different treatments, cells were incubated with CCK-8 solution (10 μL/well) for 2 h in an incubator. Microplate reader (Synergy HT, Bio-Tek, Winooski, VT, USA) was used to measure the absorbance at 450 nm.
4.10. Flow Cytometry Analysis
Cells were plated into six-well plates and treated with IR; cells were then collected 24 h after IR. For cell cycle analysis, cells were stained with RNase-containing PI (propidium iodide) solution. For polyploidy detection, cells were stained with DAPI. For autophagy detection, cells were stained with MDC. For apoptosis detection, cells were stained with PI and FITC-labeled Annexin-V. For cell death analysis, cells were stained with trypan blue. Stained cells were detected by Flow Cytometry (BD Biosystems, San Jose, CA, USA), data were analyzed with CellQuest (BD Biosciences, San Jose, CA, USA) and FlowJo softwares (Tree Star Inc., Ashland, OR, USA).
4.11. Statistical Analysis
All the data for the statistical analysis are obtained from at least three independent experiments. Statistical evaluations are presented as mean ± SD. The significance of the differences between groups was determined by one-way ANOVA; p < 0.05 was considered significant.
5. Conclusions
In summary, our data demonstrated that dCK could inhibit IR-induced cell death through suppression of apoptosis and mitotic catastrophe and promotion of autophagy. dCK increased autophagy induced by IR via inhibition of the Akt/mTOR/p70 S6K pathway and dCK S74 phosphorylation participated in this regulation. We demonstrated that dCK interacted with mTOR while dCK-S74A failed to do so. Furthermore, dCK was required for the G2/M checkpoint. Loss of dCK inactivated the G2/M checkpoint, allowing cells less time for repair and promoting entry into mitosis, inducing polyploidy increase, and eventually inducing mitotic catastrophe in response to IR.
Supplementary Materials
Supplementary materials can be found at www.mdpi.com/1422-0067/17/11/1939/s1 .
Acknowledgments
We thank Bo XU (Department of Molecular Biology and Biochemistry, Southern Research Institute, Birmingham, AL, USA) for his help with the manuscript. This study was supported by NSFC grant (31370837, 81573082 and 81673092), Provincial Program of Science and Technology of Jilin (20150101142JC), Health and Family Planning Commission of Jilin Province (20142036).
The authors declare no conflict of interest.
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Figure 1. Deoxycytidine kinase (dCK) decreased radiation-induced cell death. ( A ) Establishment of dCK knock-down cells. Human cervical carcinoma cell line (HeLa) cells were stably transfected with pSUPER control or dCK shRNA. Individual clones were obtained under puromycin selection. Knock-down effects were confirmed by Western blot. Data were presented as mean ± SD of three independent experiments; ( B ) radiosensitivity was assessed by the colony formation assay in both dCK silencing cells and control cells after radiation treatment (0–8 Gy). Data were presented as mean ± SD of three independent experiments. * p < 0.05 versus control group or dCK silencing group; ( C ) dCK knock-down HeLa cells were reintroduced with vector control, dCK wild-type, dCK S74A mutant or S74E mutant. Overexpression of different dCK genotypes were shown by Western blot in HeLa cells. Data were presented as mean ± SD of three independent experiments; ( D ) the cells with different dCK genotypes were treated with 8 Gy radiation. Cell viability was analyzed by CCK-8 assay. * p < 0.05 versus control group; ( E ) the pSUPER and dCK knock-down cell lines were pretreated with 3-MA (2 mM), rapamycin (200 nM), ZVAD-FMK (10 μM), Necrostatin-1 (10 μM) or Ferrostatin-1 (5 μM) for 1 h, respectively, followed by ionizing radiation (IR) (8 Gy). After 48 h, cells were stained with trypan blue and analyzed by flow cytometry assay. * p < 0.05 versus control group.
Figure 2. dCK silencing promoted IR-induced apoptosis. ( A ) Flow cytometry was used to quantify apoptosis in HeLa cells 24 h after radiation. Cells were stained with propidium iodide (PI) and Annexin V-FITC. The positive-stained cells were counted using FACScan; ( B ) apoptosis was detected in both control and dCK knock-down cell lines 24 h after radiation; ( C ) quantitative analysis of ( B ), data were presented as mean ± SD of three independent experiments. * p < 0.05 versus mock group; ( D ) whole-cell lysates were harvested and subjected to Western blot using the indicated antibodies; ( E ) dCK knock-down HeLa cells were reintroduced with vector control, dCK wild-type, dCK-S74A mutation or dCK-S74E mutation and then treated with IR (8 Gy). After 24 h, apoptotic rate was quantified by flow cytometry. * p < 0.05 versus mock group.
Figure 3. dCK promoted IR-induced autophagy in HeLa cells. ( A ) HeLa cells were treated with mock or IR (8 Gy). Staining of monodansylcadaverine (MDC) was detected by flow cytometry at 24 h after IR treatment; M1 represents fluorescent densities of MDC positive cells; ( B ) both dCK silencing cells and pSUPER cells were treated with 8 Gy radiation; 24 h later, staining of MDC was detected by flow cytometry; M1 represents fluorescent densities of MDC positive cells; ( C ) western blot analysis of microtubule-associated protein 1A/1B-light chain 3 (LC3) expression in the pSUPER and dCK knock down cells 24, 48 and 72 h after 8 Gy radiation. Glyceraldehyde-3-Phosphate Dehydrogenase (GAPDH) was used as an internal standard; M1 represents fluorescent densities of MDC positive cells; ( D ) dCK knock-down HeLa cells were reintroduced with vector control, dCK wild-type, dCK-S74A mutation and dCK-S74E mutation. 36 h after transfection, cells were exposed to mock or IR (8 Gy). 24 h after IR, cells were harvested and subjected to western blot using the indicated antibodies.
Figure 4. Suppressing autophagy could increase apoptosis induced by IR. ( A ) The pSUPER and dCK knock-down cell lines were incubated with spautin-1 (10 μM) or 3-MA (2 mM) for 1 h, and then treated with IR (8 Gy) for 72 h. Western blot analysis was performed to detect MAPLC3-I/II and GAPDH was used as an internal standard; ( B ) the control and dCK knock-down cells were pretreated with 3-MA (2 mM), spautin-1 (10 μM) or rapamycin (200 nM) for 1 h, and then treated with IR (8 Gy). After 24 h, staining of MDC was detected by flow cytometry. Quantitative analysis of autophagic cells was presented as mean ± SD of three independent experiments. * p < 0.05 versus mock group; ( C ) the pSUPER and dCK knock-down cell lines were incubated with 3-MA (2 mM), ZVAD-FMK (20 μM) or ZVAD-FMK (20 μM) + 3-MA (2 mM) for 1 h, then treated with IR (8 Gy) and incubated for 24 h. Western blot analysis was performed to detect caspase3 and cleaved-caspase3; GAPDH was used as an internal standard; ( D ) the pSUPER and dCK knock-down cell lines were pretreated with 3-MA (2 mM), ZVAD-FMK (10 μM), 3-MA (2 mM) + ZVAD-FMK (10 μM) for 1 h respectively, and then treated with IR (8 Gy). After 48 h, cells were collected, stained with PI and Annexin V-FITC and analyzed by flow cytometry. * p < 0.05 versus control group.
Figure 5. dCK Serine 74 phosphorylation participated in the regulation of autophagy induced by IR. ( A ) The dCK-complemented cell lines were treated with mock or IR (8 Gy). A total of 24 h after IR, cells were harvested and subjected to Western blot using the indicated antibodies; ( B ) quantitative analysis of ( A ), cells transfected with pSUPER and treated with mock were used as control (100%). Data were presented as mean ± SD of three independent experiments. * p < 0.05 versus cells treated with IR only; ( C ) vector control, FLAG-tagged wild-type or S74A dCK were transiently transfected into HeLa cells in which dCK was knocked-down. After 36 h of transfection, the cells were treated with mock or IR (8 Gy). Then, 24 h after IR, cells were harvested and subjected to co-immunoprecipitation using an anti-FLAG antibody. The co-immunoprecipitates were then blotted with indicated antibodies.
Figure 6. dCK inhibited IR-induced mitotic catastrophe. ( A ) Flow cytometry was used to quantitate the cell G2/M phase with or without IR at 1, 4, 8, 12, and 24 h in isogenic HeLa cells stably expressing control or dCK shRNA. All data are representative of three independent experiments and are shown as the mean ± SD. a p < 0.05 versus pSUPER cells treated with IR only, # p < 0.05 versus dCK knock-down cells treated with IR only. * p < 0.05 versus control group; blue lines are used to compare pSUPER cells treated with or without IR; red lineds are used to compare dCK knock-down cells treated with or without IR; ( B ) isogenic HeLa cell lines with control or dCK shRNA were treated with mock or IR treatment (8 Gy). 12 or 24 h later, cells were harvested and fixed followed by staining for Histone H3 Ser10 phosphorylation and analyzed by flow cytometry. The average and standard deviations of at least triplicate samples are shown. Statistic analysis was done by Student’s t -test; * p < 0.05 versus cells treated with IR only; ( C ) isogenic HeLa cell lines with control or dCK shRNA were treated with or without IR (8 Gy). After 12 or 24 h, cells were stained by DAPI and detected by flow cytometry. * p < 0.05 versus cells treated with IR only.
AMA Style
Chicago/Turabian Style
Zhong, Rui, Rui Xin, Zongyan Chen, Nan Liang, Yang Liu, Shumei Ma, and Xiaodong Liu. 2016. "The Role of Deoxycytidine Kinase (dCK) in Radiation-Induced Cell Death" International Journal of Molecular Sciences17, no. 11: 1939.
https://doi.org/10.3390/ijms17111939
Zhong R, Xin R, Chen Z, Liang N, Liu Y, Ma S, Liu X. The Role of Deoxycytidine Kinase (dCK) in Radiation-Induced Cell Death. International Journal of Molecular Sciences. 2016; 17(11):1939.
https://doi.org/10.3390/ijms17111939
Zhong, Rui, Rui Xin, Zongyan Chen, Nan Liang, Yang Liu, Shumei Ma, and Xiaodong Liu. 2016. "The Role of Deoxycytidine Kinase (dCK) in Radiation-Induced Cell Death" International Journal of Molecular Sciences17, no. 11: 1939.
https://doi.org/10.3390/ijms17111939
| https://www.mdpi.com/1422-0067/17/11/1939 |
Debate: Draft Motor Fuel (Composition and Content) (Amendment) (Northern Ireland) Regulations 2022 - 11th Oct 2022 - Tanmanjeet Singh Dhesi extracts
Tue 11th Oct 2022 - Commons - Draft Motor Fuel (Composition and Content) (Amendment) (Northern Ireland) Regulations 2022 debate Tanmanjeet Singh Dhesi contributions to the 11th October 2022 Draft Motor Fuel (Composition and Content) (Amendment) (Northern Ireland) Regulations 2022 debate
Draft Motor Fuel (Composition and Content) (Amendment) (Northern Ireland) Regulations 2022 Debate
Draft Motor Fuel (Composition and Content) (Amendment) (Northern Ireland) Regulations 2022
Tuesday 11th October 2022
General Committees
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Mr Tanmanjeet Singh Dhesi (Slough) (Lab)- Hansard- Copy Link-
It is a pleasure to serve under your chairmanship, Mrs Cummins. I warmly welcome the Minister to her place.
Around a quarter of the UK’s carbon emissions originate from transport, and cars make up a significant proportion of that sector. The last Labour Government set up the renewable transport fuel obligation and introduced E5 petrol in the UK. That was groundbreaking in helping to lower emissions. We must now build on that good work. I am afraid to say that the Government’s measures in these regulations demonstrate a lack of ambition.
At present, E5 fuel in Northern Ireland contains up to 5% ethanol. The regulations will only require E10 petrol to contain at least 5.5% ethanol—a minor increase. The Government have previously stated that the figure is just a minimum, but that argument fails by its own logic. The explanatory memorandum states that the industry would not increase ethanol content to above 5% “without a legislative mandate”. That stands to reason. After all, no supplier would want to be left out in the cold. Following that same logic, what incentive is there for retailers to supply E10 petrol at anything above the 5.5% ethanol, something which the Government clearly view as welcome? I would be extremely grateful if the Minister addressed that particular point. Perhaps she could state the average ethanol content in E10 petrol in the rest of the UK, given that the measure has been in place for many months.
I want to touch on the sourcing of bioethanol. What steps is the Minister taking to ensure that the supply chain does not inadvertently lead to global environmental impacts? Last year, the Government stated that the use of imported bioethanol that could potentially contribute to deforestation was “minimal”. Would the Minister clarify just how minimal the figure is? What safeguards are being put in place to ensure that we do not inadvertently contribute to deforestation through increased demand for ethanol for E10 petrol?
From 2030, new petrol and diesel cars will no longer be sold within the UK. However, given the lifespan of new cars, reducing the environmental impact of petrol will be vital in fighting the climate crisis for many decades to come. As the Climate Change Committee noted, the net zero strategy baseline assumes that manufacturers continue to improve conventional vehicle efficiencies in line with previous regulations and that hybrids with a significant zero-emission range will make up a growing and substantial portion of the new car market, yet the Government’s intention is to require only nominal improvements. What assessment have the Government made of the CCC’s recommendation to incentivise efficiency improvements in conventional vehicles?
We will not oppose the statutory instrument. However, I sincerely hope that for the sake of our environment and our country the Minister will listen very carefully to calls to show far greater ambition in this area.
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Lucy Frazer- Hansard- Copy Link-- Excerpts
I thank the hon. Member for Birmingham, Hall Green for his comments and kind words— [ Interruption. ]I thank the hon. Member for Slough for his comments and kind words at the beginning of his speech. He is absolutely right to say that vehicles on roads are responsible for a significant portion of our CO 2emissions. Transport is responsible for around 24% of carbon in the UK, and 90% of that comes from road emissions, so the hon. Gentleman made a very importantpoint at the outset. He said that we were not ambitious enough, but I remind him that the biofuel supplied under the RTFO saved 5.24 million tonnes of CO 2in 2020—equivalent to taking 2.5 million vehicles off the road—and of course, that is just one aspect of our plan for decarbonisation. In this area, it is important to ensure that we maintain the right balance, as I said in my speech.
The hon. Gentleman mentioned a number of issues that do not directly relate to the statutory instrument, but which are important and are being addressed by Government. He talked about deforestation and the supply chain, but he will know that the Department for Environment, Food and Rural Affairs is looking closely at measures to ensure that we plant enough trees. He also talked about the impact on cars more broadly, but he will know that with our zero-emission vehicle mandate, we are phasing out fuel. He asked whether car manufacturers and suppliers will go above the 5.5% level; I would like to reassure him that the targets for the overall blending levels under the RTFO were increased in 2022, and we will continue to increase them until 2032. For all those reasons, and those I outlined at the beginning of the sitting, I commend the regulations to the Committee.
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Mr Dhesi- Hansard- Copy Link-
On that point, would the Minister outline what incentives are in place for retailers to supply E10 petrol at anything above the 5.5% ethanol level?
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Lucy Frazer- Hansard- Copy Link-- Excerpts
We know that diesel manufacturers are producing it at higher than the 5.5% level. It is in their interest to do so in relation to the environment more broadly, and because we will expand the market. In the long run, those fuels will be cheaper for both consumers and suppliers.
Question put and agreed to.
| https://www.parallelparliament.co.uk/mp/tanmanjeet-singh-dhesi/debate/2022-10-11/commons/general-committees/draft-motor-fuel-composition-and-content-amendment-northern-ireland-regulations-2022 |
JFK Assassination Records - 2018 Additional Documents Release | National Archives
Have a question about JFK Assassination Records? Ask it on HistoryHub! The National Archives is releasing documents previously withheld in accordance with the JFK Assassination Records Collection Act. The vast majority of the Collection (88%) has been open in full and released to the public since the late 1990s. The records at issue are documents previously identified as
JFK Assassination Records - 2018 Additional Documents Release
The National Archives is releasing documents previously withheld in accordance with the JFK Assassination Records Collection Act. The vast majority of the Collection (88%) has been open in full and released to the public since the late 1990s. The records at issue are documents previously identified as assassination records, but withheld in full or withheld in part.Learn more
These releases include FBI, CIA, and other agency documents (both formerly withheld in part and formerly withheld in full) identified by the Assassination Records Review Board as assassination records. The releases to date are as follows:
July 24, 2017: 3,810 documents (read press release )
October 26, 2017: 2,891 documents (read press release )
November 3, 2017: 676 documents (read press release )
November 9, 2017: 13,213 documents (read press release )
November 17, 2017: 10,744 documents (read press release )
December 15, 2017: 3,539 documents * (read press release )
April 26, 2018: 18,731 documents * (read press release )
* Note: There are instances where multiple record identification numbers are associated with the same pdf. This is due to the fact that the files were scanned in batches.
Accessing the Release Files
The table below displays metadata about all the released documents. You can alsodownload the spreadsheet as an Excel file(4.7MB).
To view or download a specific document, follow the link in the "Doc Date" column. The files are sorted by NARA Release Date, with the most recent files appearing first. The previous withholding status (i.e., formerly withheld in part or formerly withheld in full) is identified in the “Formerly Withheld Status” column.
JFK Table
Row Num Record Num NARA Release Date Formerly Withheld Agency Doc Date Doc Type File Num To Name From Name Title Num Pages Originator Record Series Review Date Comments Pages Released
Row Num Record Num NARA Release Date Formerly Withheld Agency Doc Date Doc Type File Num To Name From Name Title Num Pages Originator Record Series Review Date Comments Pages Released 17251 124-10274-10162 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1610 HQ 11/30/2017 17252 124-10274-10359 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1ST NR 1592 HQ 11/30/2017 17253 124-10274-10360 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1ST NR 1597 THUR 1602 HQ 11/30/2017 17254 124-10274-10361 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1604, 1605 HQ JUNE MAIL FOLDER 11/30/2017 17255 124-10271-10310 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1576, 1620, 1638 HQ 11/30/2017 17256 124-10189-10059 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1ST NR 1651, 2ND NR 1651 HQ 11/30/2017 17257 124-10264-10471 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1620 HQ 11/30/2017 17258 124-10264-10473 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1622 THRU 1ST NR 1622 HQ 11/30/2017 17259 124-10264-10478 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1627 THRU 1628 DIRECTOR, FBI HQ 11/30/2017 17260 124-10264-10481 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1631 HQ 11/30/2017 17261 124-10264-10484 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1634 HQ 11/30/2017 17262 124-10264-10487 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1637 THRU 1638 HQ 11/30/2017 17263 124-10264-10496 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1647 HQ 11/30/2017 17264 124-10271-10090 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1671, 1672 HQ 11/30/2017 17265 124-10271-10093 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1668 HQ 11/30/2017 17266 124-10271-10096 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1665 JONES, M. A. HQ 11/30/2017 17267 124-10271-10101 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1660 BAUMGARDNER, F. J. HQ 11/30/2017 17268 124-10271-10103 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1655 THRU 1ST NR 1658 HQ 11/30/2017 17269 124-10271-10084 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1ST NR 1678, 1678 DELOACH, C. D. HQ 11/30/2017 17270 124-10271-10099 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1ST NR 1662, 2ND NR 1662 HQ 11/30/2017 17271 124-10177-10499 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1680, 1681 ELLIFF, JOHN T. HQ 11/30/2017 EBF 17272 124-10184-10082 12/15/2017 In Full 00/00/0000 [ PDF ] 62-HQ-116395 1703X HQ 11/30/2017 17273 124-10188-10051 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1683 THRU 1690 HQ 11/30/2017 17274 124-10188-10054 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1ST NR 1692, 2ND NR 1692 SHAHEEN, MICHAEL E. JR. HQ 11/30/2017 17275 124-10188-10057 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1694, 1ST NR 1694 HQ 11/30/2017 17276 124-10188-10060 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-3RD NR 1694 HQ 11/30/2017 17277 124-10188-10062 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1696 THRU 1ST NR 1698 HQ 11/30/2017 17278 124-10188-10064 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1ST NR 1699 THRU 1705 HQ 11/30/2017 17279 124-10188-10066 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1707 THRU 1714 HQ 11/30/2017 EBF 17280 124-10184-10081 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1683 HQ 11/30/2017 EBF 17281 124-10180-10184 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1702 HQ 11/30/2017 17282 124-10185-10214 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1715 THRU 1740 ELLIFF, JOHN T. HQ 11/30/2017 EBF 17283 124-10269-10340 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-174 DELOACH, C. D. HQ 11/30/2017 17284 124-10273-10101 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1ST NR 1192 THRU 1196X HQ 11/30/2017 17285 124-10186-10045 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1ST NR 1203X LEGAL COUNSEL HQ 11/30/2017 17286 124-10186-10048 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1204X, 1ST NR 1204X ELLIFF, JOHN T. HQ 11/30/2017 17287 124-10186-10049 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1206 THRU 1210X HQ 11/30/2017 17288 124-10186-10051 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1212 HQ 11/30/2017 17289 124-10186-10054 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1214X HQ 11/30/2017 INC 7 MEMOS, 1 LHM, 2 ADMIN PAGES, 8 OF 30 PAGES NAR 17290 124-10186-10055 12/15/2017 In Part 09/30/1963 [ PDF ] PAPER, TEXTUAL DOCUMENT 62-116395-1214X1 AG FBI HQ 11/30/2017 17291 124-10186-10056 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1215, 1215X HQ 11/30/2017 17292 124-10183-10265 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1ST NR 1441 HQ 11/30/2017 17293 124-10183-10269 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-2ND NR 1444, 3RD NR 1444 HQ 11/30/2017 17294 124-10183-10271 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1ST NR 1445 THRU 1447 HQ 11/30/2017 17295 124-10183-10273 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1449 THRU 1452 HQ 11/30/2017 17296 124-10183-10275 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1457 HQ 11/30/2017 17297 124-10183-10277 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1459 THRU 1463 HQ 11/30/2017 17298 124-10183-10279 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1465 THRU 1467 HQ 11/30/2017 17299 124-10183-10281 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1469, 1470 HQ 11/30/2017 17300 124-10183-10283 12/15/2017 In Full 00/00/0000 [ PDF ] 62-116395-1472 THRU 1474 HQ 11/30/2017 INC 9 LTR, 9 MEMO, 6 NEWS ARTIC, 72 OF 117 PAGES NAR
| https://www.archives.gov/research/jfk/release?ftag=YHF4eb9d17&order=Pages%20Released&page=345&sort=asc |
Levels of Model Abstraction. | Download Scientific Diagram
Download scientific diagram | Levels of Model Abstraction. from publication: Using Model-Driven Engineering for Decision Support Systems Modelling, Implementation and Powering | Following the principle of everything is object, software development engineering has moved towards the principle of everything is model, through Model Driven Engineering (MDE). Its implementation is based on models and their successive transformations, which allow starting... | Model Driven Engineering, Decision Support Systems and DSS | ResearchGate, the professional network for scientists.
Levels of Model Abstraction.
Source publication
Using Model-Driven Engineering for Decision Support Systems Modelling, Implementation and Powering
Full-text available
Apollinaire Bamana Batoure
Kolyang
Following the principle of everything is object, software development engineering has moved towards the principle of everything is model, through Model Driven Engineering (MDE). Its implementation is based on models and their successive transformations, which allow starting from the requirements specification to the code's implementation. This engi...
Context in source publication
Context 1
... thus deduce an architecture with four abstraction levels, in addition to the description of the instances of the real world. This relationship is illustrated by Figure 1, adapted from the MDA Guide, version 2 [12]. More concretely, a model represents, through a system, a field reality. ...
Citations
... This section presents a brief overview of some approaches that make use MDA viewpoints in the data warehouse life cycle. Firstly, by utilizing the multidimensional partitioning approach and a multidimensional and spatio-temporal design pattern, which will direct the generation of the data schema, Batoure
[8]
use modeldriven engineering to coordinate the overall process of modelling, implementing, and powering a decision system. On the other hand, Srai et al. [9] proposed a fact-dimension model. ...
Modeling and automatic generation of data warehouse using model-driven transformation in business intelligence process
The work presented in this paper focuses on the modeling and implementation of business intelligence processes, specifically how to apply model-driven architecture (MDA) throughout the entire development process of a data warehouse to automatically generate the multidimensional schema. As a result, this work specifies different rules for automating the process of obtaining an online analytical processing (OLAP) cube and implementing it using a collection of metamodels and automatic transformations. The data warehouse relational and OLAP cube models are then created using a model transformation from the conceptual model (class diagram). Finally, the XML file and SQL code are generated for creating the OLAP cubes and relational data warehouse, respectively. Using transformation languages like query-view-transformation (QVT) and Acceleo, all model transformations are performed.
... This archetype is the generic prototype on which the data schema to be produced is modelled on. Model transformations are also used to move from the multidimensional annotation model (MetaModelAM) to the data mart model (MetaModelMD), as defined in the Computational level (CIM) actions of Model-Driven Engineering (MDE)
[34]
. These transformations allow us to specified which multidimensional element is related to which one, and with which role to play in the overall scheme of the decision-support system. ...
APPLYING MULTIDIMENSIONAL CANONICAL PARTITIONING (MCP) APPROACH TO DESIGN URBAN DECISION-SUPPORT SYSTEM
The design of decision-support systems remains a challenge because no method has yet been approved, although several approaches have been proposed. Multidimensional Canonical Partitioning (MCP) is a supply-driven approach to design decision-support systems, previously proposed. In this approach, decision systems are designed from Entity/Relationship (E/R) schema. The schema provided as input is reduced to a flat relation, if it is not already the case, by using universal relations assumption. The design approach uses two main algorithms. The first is a greedy type heuristic algorithm, and the second a matching algorithm. The approach has six steps. In this paper, we implement algorithms used in the design approach. We then propose a graphical interface as a tool for implementing the approach. The tool, called PaCaM, is intended to be used by decision-support systems designers. We after all apply the design approach on urban transactional systems.
| https://www.researchgate.net/figure/Levels-of-Model-Abstraction_fig1_343999801 |
[RFC,v1,12/19] rtw88: sdio: Add HCI implementation for SDIO based chipsets - Patchwork
[RFC,v1,12/19] rtw88: sdio: Add HCI implementation for SDIO based chipsets
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From: Martin Blumenstingl <martin.blumenstingl@googlemail.com>
To: linux-wireless@vger.kernel.org
Cc: Yan-Hsuan Chuang <tony0620emma@gmail.com>,
Kalle Valo <kvalo@kernel.org>,
Ulf Hansson <ulf.hansson@linaro.org>,
linux-kernel@vger.kernel.org, netdev@vger.kernel.org,
linux-mmc@vger.kernel.org, Chris Morgan <macroalpha82@gmail.com>,
Nitin Gupta <nitin.gupta981@gmail.com>,
Neo Jou <neojou@gmail.com>, Pkshih <pkshih@realtek.com>,
Jernej Skrabec <jernej.skrabec@gmail.com>,
Martin Blumenstingl <martin.blumenstingl@googlemail.com>
Subject: [RFC PATCH v1 12/19] rtw88: sdio: Add HCI implementation for SDIO
based chipsets
Date: Wed, 28 Dec 2022 00:30:13 +0100
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X-Mailing-List: linux-mmc@vger.kernel.org Series rtw88: Add SDIO support | expand [RFC,v1,00/19] rtw88: Add SDIO support [RFC,v1,01/19] rtw88: mac: Use existing interface mask macros in rtw_pwr_seq_parser() [RFC,v1,02/19] rtw88: pci: Change type of rtw_hw_queue_mapping() and ac_to_hwq to enum [RFC,v1,03/19] rtw88: pci: Change queue datatype from u8 to enum rtw_tx_queue_type [RFC,v1,04/19] rtw88: Move enum rtw_tx_queue_type mapping code to tx.{c,h} [RFC,v1,05/19] mmc: sdio: add Realtek SDIO vendor ID and various wifi device IDs [RFC,v1,06/19] rtw88: rtw8821c: Add support for parsing the RTL8821CS (SDIO) efuse [RFC,v1,07/19] rtw88: rtw8822b: Add support for parsing the RTL8822BS (SDIO) efuse [RFC,v1,08/19] rtw88: rtw8822c: Add support for parsing the RTL8822CS (SDIO) efuse [RFC,v1,09/19] rtw88: hci: Add an optional power_switch() callback to rtw_hci_ops [RFC,v1,10/19] rtw88: mac: Add support for the SDIO HCI in rtw_pwr_seq_parser() [RFC,v1,11/19] rtw88: mac: Add support for the SDIO HCI in the TX/page table setup [RFC,v1,12/19] rtw88: sdio: Add HCI implementation for SDIO based chipsets [RFC,v1,13/19] rtw88: mac: Add support for SDIO specifics in the power on sequence [RFC,v1,14/19] rtw88: main: Add the rpwm_addr and cpwm_addr for SDIO based chipsets [RFC,v1,15/19] rtw88: main: Reserve 8 bytes of extra TX headroom for SDIO based cards [RFC,v1,16/19] rtw88: ps: Increase LEAVE_LPS_TRY_CNT for SDIO based chipsets [RFC,v1,17/19] rtw88: Add support for the SDIO based RTL8822BS chipset [RFC,v1,18/19] rtw88: Add support for the SDIO based RTL8822CS chipset [RFC,v1,19/19] rtw88: Add support for the SDIO based RTL8821CS chipset
Add a sub-driver for SDIO based chipsets which implements the following
functionality:
- register accessors for 8, 16 and 32 bits for all states of the card
(including usage of 4x 8 bit access for one 32 bit buffer if the card
is not fully powered on yet - or if it's fully powered on then 1x 32
bit access is used)
- checking whether there's space in the TX FIFO queue to transmit data
- transfers from the host to the device for actual network traffic,
reserved pages (for firmware download) and H2C (host-to-card)
transfers
- receiving data from the device
- deep power saving state
The transmit path is optimized so DMA-capable SDIO host controllers can
directly use the buffers provided because the buffer's physical
addresses are 8 byte aligned.
The receive path is prepared to support RX aggregation where the
chipset combines multiple MAC frames into one bigger buffer to reduce
SDIO transfer overhead.
Co-developed-by: Jernej Skrabec <jernej.skrabec@gmail.com> Signed-off-by: Jernej Skrabec <jernej.skrabec@gmail.com> Signed-off-by: Martin Blumenstingl <martin.blumenstingl@googlemail.com> ---
drivers/net/wireless/realtek/rtw88/Kconfig | 3 +
drivers/net/wireless/realtek/rtw88/Makefile | 3 +
drivers/net/wireless/realtek/rtw88/debug.h | 1 +
drivers/net/wireless/realtek/rtw88/mac.h | 1 -
drivers/net/wireless/realtek/rtw88/reg.h | 10 +
drivers/net/wireless/realtek/rtw88/sdio.c | 1242 +++++++++++++++++++
drivers/net/wireless/realtek/rtw88/sdio.h | 175 +++
7 files changed, 1434 insertions(+), 1 deletion(-)
create mode 100644 drivers/net/wireless/realtek/rtw88/sdio.c
create mode 100644 drivers/net/wireless/realtek/rtw88/sdio.h
> Add a sub-driver for SDIO based chipsets which implements the following
> functionality:
> - register accessors for 8, 16 and 32 bits for all states of the card
> (including usage of 4x 8 bit access for one 32 bit buffer if the card
> is not fully powered on yet - or if it's fully powered on then 1x 32
> bit access is used)
> - checking whether there's space in the TX FIFO queue to transmit data
> - transfers from the host to the device for actual network traffic,
> reserved pages (for firmware download) and H2C (host-to-card)
> transfers
> - receiving data from the device
> - deep power saving state
>
> The transmit path is optimized so DMA-capable SDIO host controllers can
> directly use the buffers provided because the buffer's physical
> addresses are 8 byte aligned.
>
> The receive path is prepared to support RX aggregation where the
> chipset combines multiple MAC frames into one bigger buffer to reduce
> SDIO transfer overhead.
>
> Co-developed-by: Jernej Skrabec <jernej.skrabec@gmail.com>
> Signed-off-by: Martin Blumenstingl <martin.blumenstingl@googlemail.com>
Reviewed-by: Ulf Hansson <ulf.hansson@linaro.org>
> ---
> drivers/net/wireless/realtek/rtw88/Kconfig | 3 +
> drivers/net/wireless/realtek/rtw88/Makefile | 3 +
> drivers/net/wireless/realtek/rtw88/debug.h | 1 +
> drivers/net/wireless/realtek/rtw88/mac.h | 1 -
> drivers/net/wireless/realtek/rtw88/reg.h | 10 +
> drivers/net/wireless/realtek/rtw88/sdio.c | 1242 +++++++++++++++++++
> drivers/net/wireless/realtek/rtw88/sdio.h | 175 +++
> 7 files changed, 1434 insertions(+), 1 deletion(-)
> create mode 100644 drivers/net/wireless/realtek/rtw88/sdio.c
> create mode 100644 drivers/net/wireless/realtek/rtw88/sdio.h
>
> diff --git a/drivers/net/wireless/realtek/rtw88/Kconfig b/drivers/net/wireless/realtek/rtw88/Kconfig
> index 651ab56d9c6b..cdf9cb478ee2 100644
> --- a/drivers/net/wireless/realtek/rtw88/Kconfig
> +++ b/drivers/net/wireless/realtek/rtw88/Kconfig
> @@ -16,6 +16,9 @@ config RTW88_CORE
>
> +config RTW88_SDIO
> + tristate
> +
> config RTW88_USB
> tristate
>
> diff --git a/drivers/net/wireless/realtek/rtw88/Makefile b/drivers/net/wireless/realtek/rtw88/Makefile
> index fe7293ee87b4..892cad60ba31 100644
> --- a/drivers/net/wireless/realtek/rtw88/Makefile
> +++ b/drivers/net/wireless/realtek/rtw88/Makefile
> @@ -59,5 +59,8 @@ rtw88_8821cu-objs := rtw8821cu.o
> obj-$(CONFIG_RTW88_PCI) += rtw88_pci.o
> rtw88_pci-objs := pci.o
>
> +obj-$(CONFIG_RTW88_SDIO) += rtw88_sdio.o
> +rtw88_sdio-objs := sdio.o
> +
> obj-$(CONFIG_RTW88_USB) += rtw88_usb.o
> rtw88_usb-objs := usb.o
> diff --git a/drivers/net/wireless/realtek/rtw88/debug.h b/drivers/net/wireless/realtek/rtw88/debug.h
> index 066792dd96af..a9149c6c2b48 100644
> +++ b/drivers/net/wireless/realtek/rtw88/debug.h
> @@ -24,6 +24,7 @@ enum rtw_debug_mask {
> RTW_DBG_ADAPTIVITY = 0x00008000,
> RTW_DBG_HW_SCAN = 0x00010000,
> RTW_DBG_STATE = 0x00020000,
> + RTW_DBG_SDIO = 0x00040000,
>
> RTW_DBG_ALL = 0xffffffff
> };
> diff --git a/drivers/net/wireless/realtek/rtw88/mac.h b/drivers/net/wireless/realtek/rtw88/mac.h
> index 3172aa5ac4de..58c3dccc14bb 100644
> --- a/drivers/net/wireless/realtek/rtw88/mac.h
> +++ b/drivers/net/wireless/realtek/rtw88/mac.h
> @@ -7,7 +7,6 @@
>
> #define RTW_HW_PORT_NUM 5
> #define cut_version_to_mask(cut) (0x1 << ((cut) + 1))
> -#define SDIO_LOCAL_OFFSET 0x10250000
> #define DDMA_POLLING_COUNT 1000
> #define C2H_PKT_BUF 256
> #define REPORT_BUF 128
> diff --git a/drivers/net/wireless/realtek/rtw88/reg.h b/drivers/net/wireless/realtek/rtw88/reg.h
> index 8852b24d6c2a..4ea2c6b491e9 100644
> --- a/drivers/net/wireless/realtek/rtw88/reg.h
> +++ b/drivers/net/wireless/realtek/rtw88/reg.h
> @@ -185,6 +185,9 @@
> (((x) & BIT_MASK_TXDMA_VIQ_MAP) << BIT_SHIFT_TXDMA_VIQ_MAP)
> #define REG_TXDMA_PQ_MAP 0x010C
> #define BIT_RXDMA_ARBBW_EN BIT(0)
> +#define BIT_RXSHFT_EN BIT(1)
> +#define BIT_RXDMA_AGG_EN BIT(2)
> +#define BIT_TXDMA_BW_EN BIT(3)
> #define BIT_SHIFT_TXDMA_BEQ_MAP 8
> #define BIT_MASK_TXDMA_BEQ_MAP 0x3
> #define BIT_TXDMA_BEQ_MAP(x) \
> @@ -283,10 +286,17 @@
> #define REG_H2C_TAIL 0x0248
> #define REG_H2C_READ_ADDR 0x024C
> #define REG_H2C_INFO 0x0254
> +#define REG_RXDMA_AGG_PG_TH 0x0280
> +#define BIT_SHIFT_DMA_AGG_TO_V1 8
> +#define BIT_EN_PRE_CALC BIT(29)
> #define REG_RXPKT_NUM 0x0284
> #define BIT_RXDMA_REQ BIT(19)
> #define BIT_RW_RELEASE BIT(18)
> #define BIT_RXDMA_IDLE BIT(17)
> +#define REG_RXDMA_STATUS 0x0288
> +#define REG_RXDMA_DPR 0x028C
> +#define REG_RXDMA_MODE 0x0290
> +#define BIT_DMA_MODE BIT(1)
> #define REG_RXPKTNUM 0x02B0
>
> #define REG_INT_MIG 0x0304
> diff --git a/drivers/net/wireless/realtek/rtw88/sdio.c b/drivers/net/wireless/realtek/rtw88/sdio.c
> new file mode 100644
> index 000000000000..0e637ff2293f
> --- /dev/null
> +++ b/drivers/net/wireless/realtek/rtw88/sdio.c
> @@ -0,0 +1,1242 @@
> +// SPDX-License-Identifier: GPL-2.0 OR BSD-3-Clause
> +/* Copyright (C) 2021 Martin Blumenstingl <martin.blumenstingl@googlemail.com>
> + * Copyright (C) 2021 Jernej Skrabec <jernej.skrabec@gmail.com>
> + *
> + * Based on rtw88/pci.c:
> + * Copyright(c) 2018-2019 Realtek Corporation
> + */
> +
> +#include <linux/module.h>
> +#include <linux/mmc/host.h>
> +#include <linux/mmc/sdio_func.h>
> +#include "sdio.h"
> +#include "reg.h"
> +#include "tx.h"
> +#include "rx.h"
> +#include "fw.h"
> +#include "ps.h"
> +#include "debug.h"
> +
> +#define RTW_SDIO_INDIRECT_RW_RETRIES 50
> +
> +static bool rtw_sdio_is_bus_addr(u32 addr)
> +{
> + return (addr & RTW_SDIO_BUS_MSK) != 0;
> +}
> +
> +static bool rtw_sdio_bus_claim_needed(struct rtw_sdio *rtwsdio)
> +{
> + return !rtwsdio->irq_thread ||
> + rtwsdio->irq_thread != current;
> +}
> +
> +static u32 rtw_sdio_to_bus_offset(struct rtw_dev *rtwdev, u32 addr)
> +{
> + switch (addr & RTW_SDIO_BUS_MSK) {
> + case WLAN_IOREG_OFFSET:
> + addr &= WLAN_IOREG_REG_MSK;
> + addr |= FIELD_PREP(REG_SDIO_CMD_ADDR_MSK,
> + REG_SDIO_CMD_ADDR_MAC_REG);
> + break;
> + case SDIO_LOCAL_OFFSET:
> + addr &= SDIO_LOCAL_REG_MSK;
> + addr |= FIELD_PREP(REG_SDIO_CMD_ADDR_MSK,
> + REG_SDIO_CMD_ADDR_SDIO_REG);
> + break;
> + default:
> + rtw_warn(rtwdev, "Cannot convert addr 0x%08x to bus offset",
> + addr);
> + }
> +
> + return addr;
> +}
> +
> +static void rtw_sdio_writel(struct rtw_sdio *rtwsdio, u32 val,
> + u32 addr, int *ret)
> +{
> + u8 buf[4];
> + int i;
> +
> + if (!(addr & 3) && rtwsdio->is_powered_on) {
> + sdio_writel(rtwsdio->sdio_func, val, addr, ret);
> + return;
> + }
> +
> + *(__le32 *)buf = cpu_to_le32(val);
> +
> + for (i = 0; i < 4; i++) {
> + sdio_writeb(rtwsdio->sdio_func, buf[i], addr + i, ret);
> + if (*ret)
> + return;
> + }
> +}
> +
> +static u32 rtw_sdio_readl(struct rtw_sdio *rtwsdio, u32 addr, int *ret)
> +{
> + u8 buf[4];
> + int i;
> +
> + if (!(addr & 3) && rtwsdio->is_powered_on)
> + return sdio_readl(rtwsdio->sdio_func, addr, ret);
> +
> + for (i = 0; i < 4; i++) {
> + buf[i] = sdio_readb(rtwsdio->sdio_func, addr + i, ret);
> + if (*ret)
> + return 0;
> + }
> +
> + return le32_to_cpu(*(__le32 *)buf);
> +}
> +
> +static u8 rtw_sdio_read_indirect8(struct rtw_dev *rtwdev, u32 addr, int *ret)
> +{
> + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv;
> + u32 reg_cfg, reg_data;
> + int retry;
> + u8 tmp;
> +
> + reg_cfg = rtw_sdio_to_bus_offset(rtwdev, REG_SDIO_INDIRECT_REG_CFG);
> + reg_data = rtw_sdio_to_bus_offset(rtwdev, REG_SDIO_INDIRECT_REG_DATA);
> +
> + rtw_sdio_writel(rtwsdio, BIT(19) | addr, reg_cfg, ret);
> + if (*ret)
> + return 0;
> +
> + for (retry = 0; retry < RTW_SDIO_INDIRECT_RW_RETRIES; retry++) {
> + tmp = sdio_readb(rtwsdio->sdio_func, reg_cfg + 2, ret);
> + if (!ret && tmp & BIT(4))
> + break;
> + }
> +
> + if (*ret)
> + return 0;
> +
> + return sdio_readb(rtwsdio->sdio_func, reg_data, ret);
> +}
> +
> +static int rtw_sdio_read_indirect_bytes(struct rtw_dev *rtwdev, u32 addr,
> + u8 *buf, int count)
Patch
diff --git a/drivers/net/wireless/realtek/rtw88/Kconfig b/drivers/net/wireless/realtek/rtw88/Kconfig index 651ab56d9c6b..cdf9cb478ee2 100644 --- a/drivers/net/wireless/realtek/rtw88/Kconfig +++ b/drivers/net/wireless/realtek/rtw88/Kconfig @@ -16,6 +16,9 @@ config RTW88_CORE config RTW88_PCI
tristate +config RTW88_SDIO + tristate + config RTW88_USB
tristate diff --git a/drivers/net/wireless/realtek/rtw88/Makefile b/drivers/net/wireless/realtek/rtw88/Makefile index fe7293ee87b4..892cad60ba31 100644 --- a/drivers/net/wireless/realtek/rtw88/Makefile +++ b/drivers/net/wireless/realtek/rtw88/Makefile @@ -59,5 +59,8 @@ rtw88_8821cu-objs := rtw8821cu.o obj-$(CONFIG_RTW88_PCI) += rtw88_pci.o
rtw88_pci-objs := pci.o +obj-$(CONFIG_RTW88_SDIO) += rtw88_sdio.o +rtw88_sdio-objs := sdio.o + obj-$(CONFIG_RTW88_USB) += rtw88_usb.o
rtw88_usb-objs := usb.o diff --git a/drivers/net/wireless/realtek/rtw88/debug.h b/drivers/net/wireless/realtek/rtw88/debug.h index 066792dd96af..a9149c6c2b48 100644 --- a/drivers/net/wireless/realtek/rtw88/debug.h +++ b/drivers/net/wireless/realtek/rtw88/debug.h @@ -24,6 +24,7 @@ enum rtw_debug_mask { RTW_DBG_ADAPTIVITY = 0x00008000,
RTW_DBG_HW_SCAN = 0x00010000,
RTW_DBG_STATE = 0x00020000, + RTW_DBG_SDIO = 0x00040000, RTW_DBG_ALL = 0xffffffff
}; diff --git a/drivers/net/wireless/realtek/rtw88/mac.h b/drivers/net/wireless/realtek/rtw88/mac.h index 3172aa5ac4de..58c3dccc14bb 100644 --- a/drivers/net/wireless/realtek/rtw88/mac.h +++ b/drivers/net/wireless/realtek/rtw88/mac.h @@ -7,7 +7,6 @@ #define RTW_HW_PORT_NUM 5
#define cut_version_to_mask(cut) (0x1 << ((cut) + 1)) -#define SDIO_LOCAL_OFFSET 0x10250000 #define DDMA_POLLING_COUNT 1000
#define C2H_PKT_BUF 256
#define REPORT_BUF 128 diff --git a/drivers/net/wireless/realtek/rtw88/reg.h b/drivers/net/wireless/realtek/rtw88/reg.h index 8852b24d6c2a..4ea2c6b491e9 100644 --- a/drivers/net/wireless/realtek/rtw88/reg.h +++ b/drivers/net/wireless/realtek/rtw88/reg.h @@ -185,6 +185,9 @@ (((x) & BIT_MASK_TXDMA_VIQ_MAP) << BIT_SHIFT_TXDMA_VIQ_MAP)
#define REG_TXDMA_PQ_MAP 0x010C
#define BIT_RXDMA_ARBBW_EN BIT(0) +#define BIT_RXSHFT_EN BIT(1) +#define BIT_RXDMA_AGG_EN BIT(2) +#define BIT_TXDMA_BW_EN BIT(3) #define BIT_SHIFT_TXDMA_BEQ_MAP 8
#define BIT_MASK_TXDMA_BEQ_MAP 0x3
#define BIT_TXDMA_BEQ_MAP(x) \ @@ -283,10 +286,17 @@ #define REG_H2C_TAIL 0x0248
#define REG_H2C_READ_ADDR 0x024C
#define REG_H2C_INFO 0x0254 +#define REG_RXDMA_AGG_PG_TH 0x0280 +#define BIT_SHIFT_DMA_AGG_TO_V1 8 +#define BIT_EN_PRE_CALC BIT(29) #define REG_RXPKT_NUM 0x0284
#define BIT_RXDMA_REQ BIT(19)
#define BIT_RW_RELEASE BIT(18)
#define BIT_RXDMA_IDLE BIT(17) +#define REG_RXDMA_STATUS 0x0288 +#define REG_RXDMA_DPR 0x028C +#define REG_RXDMA_MODE 0x0290 +#define BIT_DMA_MODE BIT(1) #define REG_RXPKTNUM 0x02B0
#define REG_INT_MIG 0x0304 diff --git a/drivers/net/wireless/realtek/rtw88/sdio.c b/drivers/net/wireless/realtek/rtw88/sdio.c new file mode 100644 index 000000000000..0e637ff2293f --- /dev/null +++ b/drivers/net/wireless/realtek/rtw88/sdio.c @@ -0,0 +1,1242 @@ +// SPDX-License-Identifier: GPL-2.0 OR BSD-3-Clause +/* Copyright (C) 2021 Martin Blumenstingl <martin.blumenstingl@googlemail.com> + * Copyright (C) 2021 Jernej Skrabec <jernej.skrabec@gmail.com> + * + * Based on rtw88/pci.c: + * Copyright(c) 2018-2019 Realtek Corporation + */ + +#include <linux/module.h> +#include <linux/mmc/host.h> +#include <linux/mmc/sdio_func.h> +#include "sdio.h" +#include "reg.h" +#include "tx.h" +#include "rx.h" +#include "fw.h" +#include "ps.h" +#include "debug.h" + +#define RTW_SDIO_INDIRECT_RW_RETRIES 50 + +static bool rtw_sdio_is_bus_addr(u32 addr) +{ + return (addr & RTW_SDIO_BUS_MSK) != 0; +} + +static bool rtw_sdio_bus_claim_needed(struct rtw_sdio *rtwsdio) +{ + return !rtwsdio->irq_thread || + rtwsdio->irq_thread != current; +} + +static u32 rtw_sdio_to_bus_offset(struct rtw_dev *rtwdev, u32 addr) +{ + switch (addr & RTW_SDIO_BUS_MSK) { + case WLAN_IOREG_OFFSET: + addr &= WLAN_IOREG_REG_MSK; + addr |= FIELD_PREP(REG_SDIO_CMD_ADDR_MSK, + REG_SDIO_CMD_ADDR_MAC_REG); + break; + case SDIO_LOCAL_OFFSET: + addr &= SDIO_LOCAL_REG_MSK; + addr |= FIELD_PREP(REG_SDIO_CMD_ADDR_MSK, + REG_SDIO_CMD_ADDR_SDIO_REG); + break; + default: + rtw_warn(rtwdev, "Cannot convert addr 0x%08x to bus offset", + addr); + } + + return addr; +} + +static void rtw_sdio_writel(struct rtw_sdio *rtwsdio, u32 val, + u32 addr, int *ret) +{ + u8 buf[4]; + int i; + + if (!(addr & 3) && rtwsdio->is_powered_on) { + sdio_writel(rtwsdio->sdio_func, val, addr, ret); + return; + } + + *(__le32 *)buf = cpu_to_le32(val); + + for (i = 0; i < 4; i++) { + sdio_writeb(rtwsdio->sdio_func, buf[i], addr + i, ret); + if (*ret) + return; + } +} + +static u32 rtw_sdio_readl(struct rtw_sdio *rtwsdio, u32 addr, int *ret) +{ + u8 buf[4]; + int i; + + if (!(addr & 3) && rtwsdio->is_powered_on) + return sdio_readl(rtwsdio->sdio_func, addr, ret); + + for (i = 0; i < 4; i++) { + buf[i] = sdio_readb(rtwsdio->sdio_func, addr + i, ret); + if (*ret) + return 0; + } + + return le32_to_cpu(*(__le32 *)buf); +} + +static u8 rtw_sdio_read_indirect8(struct rtw_dev *rtwdev, u32 addr, int *ret) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + u32 reg_cfg, reg_data; + int retry; + u8 tmp; + + reg_cfg = rtw_sdio_to_bus_offset(rtwdev, REG_SDIO_INDIRECT_REG_CFG); + reg_data = rtw_sdio_to_bus_offset(rtwdev, REG_SDIO_INDIRECT_REG_DATA); + + rtw_sdio_writel(rtwsdio, BIT(19) | addr, reg_cfg, ret); + if (*ret) + return 0; + + for (retry = 0; retry < RTW_SDIO_INDIRECT_RW_RETRIES; retry++) { + tmp = sdio_readb(rtwsdio->sdio_func, reg_cfg + 2, ret); + if (!ret && tmp & BIT(4)) + break; + } + + if (*ret) + return 0; + + return sdio_readb(rtwsdio->sdio_func, reg_data, ret); +} + +static int rtw_sdio_read_indirect_bytes(struct rtw_dev *rtwdev, u32 addr, + u8 *buf, int count) +{ + int i, ret; + + for (i = 0; i < count; i++) { + buf[0] = rtw_sdio_read_indirect8(rtwdev, addr + i, &ret); + if (ret) + break; + } + + return ret; +} + +static u32 rtw_sdio_read_indirect32(struct rtw_dev *rtwdev, u32 addr, int *ret) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + u32 reg_cfg, reg_data, val; + int retry; + + reg_cfg = rtw_sdio_to_bus_offset(rtwdev, REG_SDIO_INDIRECT_REG_CFG); + reg_data = rtw_sdio_to_bus_offset(rtwdev, REG_SDIO_INDIRECT_REG_DATA); + + rtw_sdio_writel(rtwsdio, BIT(19) | BIT(17) | addr, reg_cfg, ret); + if (*ret) + return 0; + + for (retry = 0; retry < RTW_SDIO_INDIRECT_RW_RETRIES; retry++) { + val = sdio_readb(rtwsdio->sdio_func, reg_cfg + 2, ret); + if (!ret && (val & BIT(4))) + break; + } + + if (!*ret) + val = rtw_sdio_readl(rtwsdio, reg_data, ret); + + return val; +} + +static u8 rtw_sdio_read8(struct rtw_dev *rtwdev, u32 addr) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + bool direct, bus_claim; + int ret; + u8 val; + + bus_claim = rtw_sdio_bus_claim_needed(rtwsdio); + direct = rtw_sdio_is_bus_addr(addr); + + if (bus_claim) + sdio_claim_host(rtwsdio->sdio_func); + + if (direct) { + addr = rtw_sdio_to_bus_offset(rtwdev, addr); + val = sdio_readb(rtwsdio->sdio_func, addr, &ret); + } else { + val = rtw_sdio_read_indirect8(rtwdev, addr, &ret); + } + + if (bus_claim) + sdio_release_host(rtwsdio->sdio_func); + + if (ret) + rtw_warn(rtwdev, "sdio read8 failed (0x%x): %d", addr, ret); + + return val; +} + +static u16 rtw_sdio_read16(struct rtw_dev *rtwdev, u32 addr) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + bool direct, bus_claim; + u8 buf[2]; + int ret; + u16 val; + + bus_claim = rtw_sdio_bus_claim_needed(rtwsdio); + direct = rtw_sdio_is_bus_addr(addr); + + if (bus_claim) + sdio_claim_host(rtwsdio->sdio_func); + + if (direct) { + addr = rtw_sdio_to_bus_offset(rtwdev, addr); + buf[0] = sdio_readb(rtwsdio->sdio_func, addr, &ret); + if (!ret) + buf[1] = sdio_readb(rtwsdio->sdio_func, addr + 1, &ret); + val = le16_to_cpu(*(__le16 *)buf); + } else if (addr & 1) { + ret = rtw_sdio_read_indirect_bytes(rtwdev, addr, buf, 2); + val = le16_to_cpu(*(__le16 *)buf); + } else { + val = rtw_sdio_read_indirect32(rtwdev, addr, &ret); + } + + if (bus_claim) + sdio_release_host(rtwsdio->sdio_func); + + if (ret) + rtw_warn(rtwdev, "sdio read16 failed (0x%x): %d", addr, ret); + + return val; +} + +static u32 rtw_sdio_read32(struct rtw_dev *rtwdev, u32 addr) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + bool direct, bus_claim; + u8 buf[4]; + u32 val; + int ret; + + bus_claim = rtw_sdio_bus_claim_needed(rtwsdio); + direct = rtw_sdio_is_bus_addr(addr); + + if (bus_claim) + sdio_claim_host(rtwsdio->sdio_func); + + if (direct) { + addr = rtw_sdio_to_bus_offset(rtwdev, addr); + val = rtw_sdio_readl(rtwsdio, addr, &ret); + } else if (addr & 3) { + ret = rtw_sdio_read_indirect_bytes(rtwdev, addr, buf, 4); + val = le32_to_cpu(*(__le32 *)buf); + } else { + val = rtw_sdio_read_indirect32(rtwdev, addr, &ret); + } + + if (bus_claim) + sdio_release_host(rtwsdio->sdio_func); + + if (ret) + rtw_warn(rtwdev, "sdio read32 failed (0x%x): %d", addr, ret); + + return val; +} + +static u32 rtw_sdio_to_write_address(struct rtw_dev *rtwdev, u32 addr) +{ + if (!rtw_sdio_is_bus_addr(addr)) + addr |= WLAN_IOREG_OFFSET; + + return rtw_sdio_to_bus_offset(rtwdev, addr); +} + +static void rtw_sdio_write8(struct rtw_dev *rtwdev, u32 addr, u8 val) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + bool bus_claim; + int ret; + + addr = rtw_sdio_to_write_address(rtwdev, addr); + bus_claim = rtw_sdio_bus_claim_needed(rtwsdio); + + if (bus_claim) + sdio_claim_host(rtwsdio->sdio_func); + + sdio_writeb(rtwsdio->sdio_func, val, addr, &ret); + + if (bus_claim) + sdio_release_host(rtwsdio->sdio_func); + + if (ret) + rtw_warn(rtwdev, "sdio write8 failed (0x%x): %d", addr, ret); +} + +static void rtw_sdio_write16(struct rtw_dev *rtwdev, u32 addr, u16 val) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + bool bus_claim; + int ret; + + addr = rtw_sdio_to_write_address(rtwdev, addr); + bus_claim = rtw_sdio_bus_claim_needed(rtwsdio); + + if (bus_claim) + sdio_claim_host(rtwsdio->sdio_func); + + sdio_writeb(rtwsdio->sdio_func, val, addr, &ret); + if (!ret) + sdio_writeb(rtwsdio->sdio_func, val >> 8, addr + 1, &ret); + + if (bus_claim) + sdio_release_host(rtwsdio->sdio_func); + + if (ret) + rtw_warn(rtwdev, "sdio write16 failed (0x%x): %d", addr, ret); +} + +static void rtw_sdio_write32(struct rtw_dev *rtwdev, u32 addr, u32 val) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + bool bus_claim; + int ret; + + addr = rtw_sdio_to_write_address(rtwdev, addr); + bus_claim = rtw_sdio_bus_claim_needed(rtwsdio); + + if (bus_claim) + sdio_claim_host(rtwsdio->sdio_func); + + rtw_sdio_writel(rtwsdio, val, addr, &ret); + + if (bus_claim) + sdio_release_host(rtwsdio->sdio_func); + + if (ret) + rtw_warn(rtwdev, "sdio write32 failed (0x%x): %d", addr, ret); +} + +static u32 rtw_sdio_get_tx_addr(struct rtw_dev *rtwdev, size_t size, + enum rtw_tx_queue_type queue) +{ + u32 txaddr; + + switch (queue) { + case RTW_TX_QUEUE_BCN: + case RTW_TX_QUEUE_H2C: + case RTW_TX_QUEUE_HI0: + txaddr = FIELD_PREP(REG_SDIO_CMD_ADDR_MSK, + REG_SDIO_CMD_ADDR_TXFF_HIGH); + break; + case RTW_TX_QUEUE_VI: + case RTW_TX_QUEUE_VO: + txaddr = FIELD_PREP(REG_SDIO_CMD_ADDR_MSK, + REG_SDIO_CMD_ADDR_TXFF_NORMAL); + break; + case RTW_TX_QUEUE_BE: + case RTW_TX_QUEUE_BK: + txaddr = FIELD_PREP(REG_SDIO_CMD_ADDR_MSK, + REG_SDIO_CMD_ADDR_TXFF_LOW); + break; + case RTW_TX_QUEUE_MGMT: + txaddr = FIELD_PREP(REG_SDIO_CMD_ADDR_MSK, + REG_SDIO_CMD_ADDR_TXFF_EXTRA); + break; + default: + rtw_warn(rtwdev, "Unsupported queue for TX addr: 0x%02x\n", + queue); + return 0; + } + + txaddr += DIV_ROUND_UP(size, 4); + + return txaddr; +}; + +static int rtw_sdio_read_port(struct rtw_dev *rtwdev, u8 *buf, size_t count) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + u32 rxaddr = rtwsdio->rx_addr++; + int ret; + + ret = sdio_memcpy_fromio(rtwsdio->sdio_func, buf, + RTW_SDIO_ADDR_RX_RX0FF_GEN(rxaddr), count); + if (ret) + rtw_warn(rtwdev, + "Failed to read %lu byte(s) from SDIO port 0x%08x", + count, rxaddr); + + return ret; +} + +static int rtw_sdio_check_free_txpg(struct rtw_dev *rtwdev, u8 queue, + size_t count) +{ + unsigned int pages_free, pages_needed; + + if (rtw_chip_wcpu_11n(rtwdev)) { + u32 free_txpg; + + free_txpg = rtw_sdio_read32(rtwdev, REG_SDIO_FREE_TXPG); + + switch (queue) { + case RTW_TX_QUEUE_BCN: + case RTW_TX_QUEUE_H2C: + case RTW_TX_QUEUE_HI0: + case RTW_TX_QUEUE_MGMT: + /* high */ + pages_free = free_txpg & 0xff; + break; + case RTW_TX_QUEUE_VI: + case RTW_TX_QUEUE_VO: + /* normal */ + pages_free = (free_txpg >> 8) & 0xff; + break; + case RTW_TX_QUEUE_BE: + case RTW_TX_QUEUE_BK: + /* low */ + pages_free = (free_txpg >> 16) & 0xff; + break; + default: + rtw_warn(rtwdev, "Unknown mapping for queue %u\n", queue); + break; + } + + /* add the pages from the public queue */ + pages_free += (free_txpg >> 24) & 0xff; + } else { + u32 free_txpg[3]; + + free_txpg[0] = rtw_sdio_read32(rtwdev, REG_SDIO_FREE_TXPG); + free_txpg[1] = rtw_sdio_read32(rtwdev, REG_SDIO_FREE_TXPG + 4); + free_txpg[2] = rtw_sdio_read32(rtwdev, REG_SDIO_FREE_TXPG + 8); + + switch (queue) { + case RTW_TX_QUEUE_BCN: + case RTW_TX_QUEUE_H2C: + case RTW_TX_QUEUE_HI0: + /* high */ + pages_free = free_txpg[0] & 0xfff; + break; + case RTW_TX_QUEUE_VI: + case RTW_TX_QUEUE_VO: + /* normal */ + pages_free = (free_txpg[0] >> 16) & 0xfff; + break; + case RTW_TX_QUEUE_BE: + case RTW_TX_QUEUE_BK: + /* low */ + pages_free = free_txpg[1] & 0xfff; + break; + case RTW_TX_QUEUE_MGMT: + /* extra */ + pages_free = free_txpg[2] & 0xfff; + break; + default: + rtw_warn(rtwdev, "Unknown mapping for queue %u\n", queue); + return -EINVAL; + } + + /* add the pages from the public queue */ + pages_free += (free_txpg[1] >> 16) & 0xfff; + } + + pages_needed = DIV_ROUND_UP(count, rtwdev->chip->page_size); + + if (pages_needed > pages_free) { + rtw_dbg(rtwdev, RTW_DBG_SDIO, + "Not enough free pages (%u needed, %u free) in queue %u for %zu bytes\n", + pages_needed, pages_free, queue, count); + return -EBUSY; + } + + return 0; +} + +static int rtw_sdio_write_port(struct rtw_dev *rtwdev, struct sk_buff *skb, + enum rtw_tx_queue_type queue) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + bool bus_claim; + size_t txsize; + u32 txaddr; + int ret; + + txaddr = rtw_sdio_get_tx_addr(rtwdev, skb->len, queue); + if (!txaddr) + return -EINVAL; + + txsize = sdio_align_size(rtwsdio->sdio_func, skb->len); + + ret = rtw_sdio_check_free_txpg(rtwdev, queue, txsize); + if (ret) + return ret; + + if (!IS_ALIGNED((unsigned long)skb->data, RTW_SDIO_DATA_PTR_ALIGN)) + rtw_warn(rtwdev, "Got unaligned SKB in %s() for queue %u\n", + __func__, queue); + + bus_claim = rtw_sdio_bus_claim_needed(rtwsdio); + + if (bus_claim) + sdio_claim_host(rtwsdio->sdio_func); + + ret = sdio_memcpy_toio(rtwsdio->sdio_func, txaddr, skb->data, txsize); + + if (bus_claim) + sdio_release_host(rtwsdio->sdio_func); + + if (ret) + rtw_warn(rtwdev, + "Failed to write %lu byte(s) to SDIO port 0x%08x", + txsize, txaddr); + + return ret; +} + +static void rtw_sdio_init(struct rtw_dev *rtwdev) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + + rtwsdio->irq_mask = REG_SDIO_HIMR_RX_REQUEST | REG_SDIO_HIMR_CPWM1; +} + +static void rtw_sdio_rx_aggregation(struct rtw_dev *rtwdev, bool enable) +{ + u8 size, timeout; + + if (enable) { + if (rtwdev->chip->id == RTW_CHIP_TYPE_8822C) { + size = 0xff; + timeout = 0x20; + } else { + size = 0x6; + timeout = 0x6; + } + + /* Make the firmware honor the size limit configured below */ + rtw_write32_set(rtwdev, REG_RXDMA_AGG_PG_TH, BIT_EN_PRE_CALC); + + rtw_write8_set(rtwdev, REG_TXDMA_PQ_MAP, BIT_RXDMA_AGG_EN); + + rtw_write16(rtwdev, REG_RXDMA_AGG_PG_TH, size | + (timeout << BIT_SHIFT_DMA_AGG_TO_V1)); + + rtw_write8_set(rtwdev, REG_RXDMA_MODE, BIT_DMA_MODE); + } else { + rtw_write32_clr(rtwdev, REG_RXDMA_AGG_PG_TH, BIT_EN_PRE_CALC); + rtw_write8_clr(rtwdev, REG_TXDMA_PQ_MAP, BIT_RXDMA_AGG_EN); + rtw_write8_clr(rtwdev, REG_RXDMA_MODE, BIT_DMA_MODE); + } +} + +static void rtw_sdio_enable_interrupt(struct rtw_dev *rtwdev) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + + rtw_write32(rtwdev, REG_SDIO_HIMR, rtwsdio->irq_mask); +} + +static void rtw_sdio_disable_interrupt(struct rtw_dev *rtwdev) +{ + rtw_write32(rtwdev, REG_SDIO_HIMR, 0x0); +} + +static u8 rtw_sdio_get_tx_qsel(struct rtw_dev *rtwdev, struct sk_buff *skb, + u8 queue) +{ + switch (queue) { + case RTW_TX_QUEUE_BCN: + return TX_DESC_QSEL_BEACON; + case RTW_TX_QUEUE_H2C: + return TX_DESC_QSEL_H2C; + case RTW_TX_QUEUE_MGMT: + if (rtw_chip_wcpu_11n(rtwdev)) + return TX_DESC_QSEL_HIGH; + else + return TX_DESC_QSEL_MGMT; + case RTW_TX_QUEUE_HI0: + return TX_DESC_QSEL_HIGH; + default: + return skb->priority; + } +}; + +static int rtw_sdio_setup(struct rtw_dev *rtwdev) +{ + /* nothing to do */ + return 0; +} + +static int rtw_sdio_start(struct rtw_dev *rtwdev) +{ + rtw_sdio_rx_aggregation(rtwdev, false); + rtw_sdio_enable_interrupt(rtwdev); + + return 0; +} + +static void rtw_sdio_stop(struct rtw_dev *rtwdev) +{ + rtw_sdio_disable_interrupt(rtwdev); +} + +static void rtw_sdio_deep_ps_enter(struct rtw_dev *rtwdev) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + bool tx_empty = true; + u8 queue; + + if (!rtw_fw_feature_check(&rtwdev->fw, FW_FEATURE_TX_WAKE)) { + /* Deep PS state is not allowed to TX-DMA */ + for (queue = 0; queue < RTK_MAX_TX_QUEUE_NUM; queue++) { + /* BCN queue is rsvd page, does not have DMA interrupt + * H2C queue is managed by firmware + */ + if (queue == RTW_TX_QUEUE_BCN || + queue == RTW_TX_QUEUE_H2C) + continue; + + /* check if there is any skb DMAing */ + if (skb_queue_len(&rtwsdio->tx_queue[queue])) { + tx_empty = false; + break; + } + } + } + + if (!tx_empty) { + rtw_dbg(rtwdev, RTW_DBG_PS, + "TX path not empty, cannot enter deep power save state\n"); + return; + } + + set_bit(RTW_FLAG_LEISURE_PS_DEEP, rtwdev->flags); + rtw_power_mode_change(rtwdev, true); +} + +static void rtw_sdio_deep_ps_leave(struct rtw_dev *rtwdev) +{ + if (test_and_clear_bit(RTW_FLAG_LEISURE_PS_DEEP, rtwdev->flags)) + rtw_power_mode_change(rtwdev, false); +} + +static void rtw_sdio_deep_ps(struct rtw_dev *rtwdev, bool enter) +{ + if (enter && !test_bit(RTW_FLAG_LEISURE_PS_DEEP, rtwdev->flags)) + rtw_sdio_deep_ps_enter(rtwdev); + + if (!enter && test_bit(RTW_FLAG_LEISURE_PS_DEEP, rtwdev->flags)) + rtw_sdio_deep_ps_leave(rtwdev); +} + +static void rtw_sdio_tx_kick_off(struct rtw_dev *rtwdev) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + + queue_work(rtwsdio->txwq, &rtwsdio->tx_handler_data->work); +} + +static void rtw_sdio_link_ps(struct rtw_dev *rtwdev, bool enter) +{ + /* nothing to do */ +} + +static void rtw_sdio_interface_cfg(struct rtw_dev *rtwdev) +{ + u32 val; + + rtw_read32(rtwdev, REG_SDIO_FREE_TXPG); + + val = rtw_read32(rtwdev, REG_SDIO_TX_CTRL); + val &= 0xfff8; + rtw_write32(rtwdev, REG_SDIO_TX_CTRL, val); +} + +static void rtw_sdio_power_switch(struct rtw_dev *rtwdev, bool on) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + + rtwsdio->is_powered_on = on; +} + +static struct rtw_sdio_tx_data *rtw_sdio_get_tx_data(struct sk_buff *skb) +{ + struct ieee80211_tx_info *info = IEEE80211_SKB_CB(skb); + + BUILD_BUG_ON(sizeof(struct rtw_sdio_tx_data) > + sizeof(info->status.status_driver_data)); + + return (struct rtw_sdio_tx_data *)info->status.status_driver_data; +} + +static void rtw_sdio_tx_skb_prepare(struct rtw_dev *rtwdev, + struct rtw_tx_pkt_info *pkt_info, + struct sk_buff *skb, + enum rtw_tx_queue_type queue) +{ + const struct rtw_chip_info *chip = rtwdev->chip; + unsigned long data_addr, aligned_addr; + size_t offset; + u8 *pkt_desc; + + pkt_desc = skb_push(skb, chip->tx_pkt_desc_sz); + + data_addr = (unsigned long)pkt_desc; + aligned_addr = ALIGN(data_addr, RTW_SDIO_DATA_PTR_ALIGN); + + if (data_addr != aligned_addr) { + /* Ensure that the start of the pkt_desc is always aligned at + * RTW_SDIO_DATA_PTR_ALIGN. + */ + offset = RTW_SDIO_DATA_PTR_ALIGN - (aligned_addr - data_addr); + + pkt_desc = skb_push(skb, offset); + + /* By inserting padding to align the start of the pkt_desc we + * need to inform the firmware that the actual data starts at + * a different offset than normal. + */ + pkt_info->offset += offset; + } + + memset(pkt_desc, 0, chip->tx_pkt_desc_sz); + + pkt_info->qsel = rtw_sdio_get_tx_qsel(rtwdev, skb, queue); + + rtw_tx_fill_tx_desc(pkt_info, skb); + chip->ops->fill_txdesc_checksum(rtwdev, pkt_info, pkt_desc); +} + +static int rtw_sdio_write_data(struct rtw_dev *rtwdev, + struct rtw_tx_pkt_info *pkt_info, + struct sk_buff *skb, + enum rtw_tx_queue_type queue) +{ + int ret; + + rtw_sdio_tx_skb_prepare(rtwdev, pkt_info, skb, queue); + + ret = rtw_sdio_write_port(rtwdev, skb, queue); + dev_kfree_skb_any(skb); + + return ret; +} + +static int rtw_sdio_write_data_rsvd_page(struct rtw_dev *rtwdev, u8 *buf, + u32 size) +{ + struct rtw_tx_pkt_info pkt_info = {}; + struct sk_buff *skb; + + skb = rtw_tx_write_data_rsvd_page_get(rtwdev, &pkt_info, buf, size); + if (!skb) + return -ENOMEM; + + return rtw_sdio_write_data(rtwdev, &pkt_info, skb, RTW_TX_QUEUE_BCN); +} + +static int rtw_sdio_write_data_h2c(struct rtw_dev *rtwdev, u8 *buf, u32 size) +{ + struct rtw_tx_pkt_info pkt_info = {}; + struct sk_buff *skb; + + skb = rtw_tx_write_data_h2c_get(rtwdev, &pkt_info, buf, size); + if (!skb) + return -ENOMEM; + + return rtw_sdio_write_data(rtwdev, &pkt_info, skb, RTW_TX_QUEUE_H2C); +} + +static int rtw_sdio_tx_write(struct rtw_dev *rtwdev, + struct rtw_tx_pkt_info *pkt_info, + struct sk_buff *skb) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + enum rtw_tx_queue_type queue = rtw_tx_queue_mapping(skb); + struct rtw_sdio_tx_data *tx_data; + + rtw_sdio_tx_skb_prepare(rtwdev, pkt_info, skb, queue); + + tx_data = rtw_sdio_get_tx_data(skb); + tx_data->sn = pkt_info->sn; + + skb_queue_tail(&rtwsdio->tx_queue[queue], skb); + + return 0; +} + +static void rtw_sdio_tx_err_isr(struct rtw_dev *rtwdev) +{ + u32 val = rtw_read32(rtwdev, REG_TXDMA_STATUS); + + rtw_write32(rtwdev, REG_TXDMA_STATUS, val); +} + +static void rtw_sdio_rx_skb(struct rtw_dev *rtwdev, struct sk_buff *skb, + u32 pkt_offset, struct rtw_rx_pkt_stat *pkt_stat, + struct ieee80211_rx_status *rx_status) +{ + memcpy(IEEE80211_SKB_RXCB(skb), rx_status, sizeof(*rx_status)); + + if (pkt_stat->is_c2h) { + skb_put(skb, pkt_stat->pkt_len + pkt_offset); + rtw_fw_c2h_cmd_rx_irqsafe(rtwdev, pkt_offset, skb); + return; + } + + skb_put(skb, pkt_stat->pkt_len); + skb_reserve(skb, pkt_offset); + + rtw_rx_stats(rtwdev, pkt_stat->vif, skb); + + ieee80211_rx_irqsafe(rtwdev->hw, skb); +} + +static void rtw_sdio_rxfifo_recv(struct rtw_dev *rtwdev, u32 rx_len) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + const struct rtw_chip_info *chip = rtwdev->chip; + u32 pkt_desc_sz = chip->rx_pkt_desc_sz; + struct ieee80211_rx_status rx_status; + struct rtw_rx_pkt_stat pkt_stat; + struct sk_buff *skb, *split_skb; + u32 pkt_offset, curr_pkt_len; + size_t bufsz; + u8 *rx_desc; + int ret; + + bufsz = sdio_align_size(rtwsdio->sdio_func, rx_len); + + skb = dev_alloc_skb(bufsz); + if (!skb) + return; + + ret = rtw_sdio_read_port(rtwdev, skb->data, bufsz); + if (ret) { + dev_kfree_skb_any(skb); + return; + } + + while (true) { + rx_desc = skb->data; + chip->ops->query_rx_desc(rtwdev, rx_desc, &pkt_stat, + &rx_status); + pkt_offset = pkt_desc_sz + pkt_stat.drv_info_sz + + pkt_stat.shift; + + curr_pkt_len = ALIGN(pkt_offset + pkt_stat.pkt_len, + RTW_SDIO_DATA_PTR_ALIGN); + + if ((curr_pkt_len + pkt_desc_sz) >= rx_len) { + /* Use the original skb (with it's adjusted offset) + * when processing the last (or even the only) entry to + * have it's memory freed automatically. + */ + rtw_sdio_rx_skb(rtwdev, skb, pkt_offset, &pkt_stat, + &rx_status); + break; + } + + split_skb = dev_alloc_skb(curr_pkt_len); + if (!split_skb) { + rtw_sdio_rx_skb(rtwdev, skb, pkt_offset, &pkt_stat, + &rx_status); + break; + } + + skb_copy_header(split_skb, skb); + memcpy(split_skb->data, skb->data, curr_pkt_len); + + rtw_sdio_rx_skb(rtwdev, split_skb, pkt_offset, &pkt_stat, + &rx_status); + + /* Move to the start of the next RX descriptor */ + skb_reserve(skb, curr_pkt_len); + rx_len -= curr_pkt_len; + } +} + +static void rtw_sdio_rx_isr(struct rtw_dev *rtwdev) +{ + u32 rx_len; + + while (true) { + if (rtw_chip_wcpu_11n(rtwdev)) + rx_len = rtw_read16(rtwdev, REG_SDIO_RX0_REQ_LEN); + else + rx_len = rtw_read32(rtwdev, REG_SDIO_RX0_REQ_LEN); + + if (!rx_len) + break; + + rtw_sdio_rxfifo_recv(rtwdev, rx_len); + } +} + +static void rtw_sdio_handle_interrupt(struct sdio_func *sdio_func) +{ + struct ieee80211_hw *hw = sdio_get_drvdata(sdio_func); + struct rtw_dev *rtwdev = hw->priv; + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + u32 hisr; + + rtwsdio->irq_thread = current; + + hisr = rtw_read32(rtwdev, REG_SDIO_HISR); + + if (hisr & REG_SDIO_HISR_TXERR) + rtw_sdio_tx_err_isr(rtwdev); + if (hisr & REG_SDIO_HISR_RX_REQUEST) { + hisr &= ~REG_SDIO_HISR_RX_REQUEST; + rtw_sdio_rx_isr(rtwdev); + } + + rtw_write32(rtwdev, REG_SDIO_HISR, hisr); + + rtwsdio->irq_thread = NULL; +} + +static int __maybe_unused rtw_sdio_suspend(struct device *dev) +{ + return 0; +} + +static int __maybe_unused rtw_sdio_resume(struct device *dev) +{ + return 0; +} + +SIMPLE_DEV_PM_OPS(rtw_sdio_pm_ops, rtw_sdio_suspend, rtw_sdio_resume); +EXPORT_SYMBOL(rtw_sdio_pm_ops); + +static int rtw_sdio_claim(struct rtw_dev *rtwdev, struct sdio_func *sdio_func) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + int ret; + + sdio_claim_host(sdio_func); + + ret = sdio_enable_func(sdio_func); + if (ret) { + rtw_err(rtwdev, "Failed to enable SDIO func"); + goto err_release_host; + } + + ret = sdio_set_block_size(sdio_func, RTW_SDIO_BLOCK_SIZE); + if (ret) { + rtw_err(rtwdev, "Failed to set SDIO block size to 512"); + goto err_disable_func; + } + + rtwsdio->sdio_func = sdio_func; + + rtwsdio->sdio3_bus_mode = mmc_card_uhs(sdio_func->card); + + sdio_set_drvdata(sdio_func, rtwdev->hw); + SET_IEEE80211_DEV(rtwdev->hw, &sdio_func->dev); + + sdio_release_host(sdio_func); + + return 0; + +err_disable_func: + sdio_disable_func(sdio_func); +err_release_host: + sdio_release_host(sdio_func); + return ret; +} + +static void rtw_sdio_declaim(struct rtw_dev *rtwdev, + struct sdio_func *sdio_func) +{ + sdio_claim_host(sdio_func); + sdio_disable_func(sdio_func); + sdio_release_host(sdio_func); +} + +static struct rtw_hci_ops rtw_sdio_ops = { + .tx_write = rtw_sdio_tx_write, + .tx_kick_off = rtw_sdio_tx_kick_off, + .setup = rtw_sdio_setup, + .start = rtw_sdio_start, + .stop = rtw_sdio_stop, + .deep_ps = rtw_sdio_deep_ps, + .link_ps = rtw_sdio_link_ps, + .interface_cfg = rtw_sdio_interface_cfg, + + .power_switch = rtw_sdio_power_switch, + + .read8 = rtw_sdio_read8, + .read16 = rtw_sdio_read16, + .read32 = rtw_sdio_read32, + .write8 = rtw_sdio_write8, + .write16 = rtw_sdio_write16, + .write32 = rtw_sdio_write32, + .write_data_rsvd_page = rtw_sdio_write_data_rsvd_page, + .write_data_h2c = rtw_sdio_write_data_h2c, +}; + +static int rtw_sdio_request_irq(struct rtw_dev *rtwdev, + struct sdio_func *sdio_func) +{ + int ret; + + sdio_claim_host(sdio_func); + ret = sdio_claim_irq(sdio_func, &rtw_sdio_handle_interrupt); + sdio_release_host(sdio_func); + + if (ret) { + rtw_err(rtwdev, "failed to claim SDIO IRQ"); + return ret; + } + + return 0; +} + +static void rtw_sdio_indicate_tx_status(struct rtw_dev *rtwdev, + struct sk_buff *skb) +{ + struct rtw_sdio_tx_data *tx_data = rtw_sdio_get_tx_data(skb); + struct ieee80211_tx_info *info = IEEE80211_SKB_CB(skb); + struct ieee80211_hw *hw = rtwdev->hw; + + /* enqueue to wait for tx report */ + if (info->flags & IEEE80211_TX_CTL_REQ_TX_STATUS) { + rtw_tx_report_enqueue(rtwdev, skb, tx_data->sn); + return; + } + + /* always ACK for others, then they won't be marked as drop */ + ieee80211_tx_info_clear_status(info); + if (info->flags & IEEE80211_TX_CTL_NO_ACK) + info->flags |= IEEE80211_TX_STAT_NOACK_TRANSMITTED; + else + info->flags |= IEEE80211_TX_STAT_ACK; + + ieee80211_tx_status_irqsafe(hw, skb); +} + +static void rtw_sdio_process_tx_queue(struct rtw_dev *rtwdev, + enum rtw_tx_queue_type queue) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + struct sk_buff *skb; + int ret; + + while (true) { + skb = skb_dequeue(&rtwsdio->tx_queue[queue]); + if (!skb) + break; + + ret = rtw_sdio_write_port(rtwdev, skb, queue); + if (ret) { + skb_queue_head(&rtwsdio->tx_queue[queue], skb); + break; + } + + if (queue <= RTW_TX_QUEUE_VO) + rtw_sdio_indicate_tx_status(rtwdev, skb); + else + dev_kfree_skb_any(skb); + } +} + +static void rtw_sdio_tx_handler(struct work_struct *work) +{ + struct rtw_sdio_work_data *work_data = + container_of(work, struct rtw_sdio_work_data, work); + struct rtw_dev *rtwdev = work_data->rtwdev; + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + bool has_more_tx_data; + int queue; + + if (!rtw_fw_feature_check(&rtwdev->fw, FW_FEATURE_TX_WAKE)) + rtw_sdio_deep_ps_leave(rtwdev); + + do { + has_more_tx_data = false; + + for (queue = RTK_MAX_TX_QUEUE_NUM - 1; queue >= 0; queue--) { + rtw_sdio_process_tx_queue(rtwdev, queue); + + if (!skb_queue_empty(&rtwsdio->tx_queue[queue])) + has_more_tx_data = true; + } + } while (has_more_tx_data); +} + +static void rtw_sdio_free_irq(struct rtw_dev *rtwdev, + struct sdio_func *sdio_func) +{ + sdio_release_irq(sdio_func); +} + +static int rtw_sdio_init_tx(struct rtw_dev *rtwdev) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + int i; + + rtwsdio->txwq = create_singlethread_workqueue("rtw88_sdio: tx wq"); + if (!rtwsdio->txwq) { + rtw_err(rtwdev, "failed to create TX work queue\n"); + return -ENOMEM; + } + + for (i = 0; i < RTK_MAX_TX_QUEUE_NUM; i++) + skb_queue_head_init(&rtwsdio->tx_queue[i]); + rtwsdio->tx_handler_data = kmalloc(sizeof(*rtwsdio->tx_handler_data), + GFP_KERNEL); + if (!rtwsdio->tx_handler_data) + goto err_destroy_wq; + + rtwsdio->tx_handler_data->rtwdev = rtwdev; + INIT_WORK(&rtwsdio->tx_handler_data->work, rtw_sdio_tx_handler); + + return 0; + +err_destroy_wq: + destroy_workqueue(rtwsdio->txwq); + return -ENOMEM; +} + +static void rtw_sdio_deinit_tx(struct rtw_dev *rtwdev) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + int i; + + for (i = 0; i < RTK_MAX_TX_QUEUE_NUM; i++) + skb_queue_purge(&rtwsdio->tx_queue[i]); + + flush_workqueue(rtwsdio->txwq); + destroy_workqueue(rtwsdio->txwq); + kfree(rtwsdio->tx_handler_data); +} + +int rtw_sdio_probe(struct sdio_func *sdio_func, + const struct sdio_device_id *id) +{ + struct ieee80211_hw *hw; + struct rtw_dev *rtwdev; + int drv_data_size; + int ret; + + drv_data_size = sizeof(struct rtw_dev) + sizeof(struct rtw_sdio); + hw = ieee80211_alloc_hw(drv_data_size, &rtw_ops); + if (!hw) { + dev_err(&sdio_func->dev, "failed to allocate hw"); + return -ENOMEM; + } + + rtwdev = hw->priv; + rtwdev->hw = hw; + rtwdev->dev = &sdio_func->dev; + rtwdev->chip = (struct rtw_chip_info *)id->driver_data; + rtwdev->hci.ops = &rtw_sdio_ops; + rtwdev->hci.type = RTW_HCI_TYPE_SDIO; + + ret = rtw_core_init(rtwdev); + if (ret) + goto err_release_hw; + + rtw_dbg(rtwdev, RTW_DBG_SDIO, + "rtw88 SDIO probe: vendor=0x%04x device=%04x class=%02x", + id->vendor, id->device, id->class); + + ret = rtw_sdio_claim(rtwdev, sdio_func); + if (ret) { + rtw_err(rtwdev, "failed to claim SDIO device"); + goto err_deinit_core; + } + + rtw_sdio_init(rtwdev); + + ret = rtw_sdio_init_tx(rtwdev); + if (ret) { + rtw_err(rtwdev, "failed to init SDIO TX queue\n"); + goto err_sdio_declaim; + } + + ret = rtw_chip_info_setup(rtwdev); + if (ret) { + rtw_err(rtwdev, "failed to setup chip information"); + goto err_destroy_txwq; + } + + ret = rtw_register_hw(rtwdev, hw); + if (ret) { + rtw_err(rtwdev, "failed to register hw"); + goto err_destroy_txwq; + } + + ret = rtw_sdio_request_irq(rtwdev, sdio_func); + if (ret) + goto err_unregister_hw; + + return 0; + +err_unregister_hw: + rtw_unregister_hw(rtwdev, hw); +err_destroy_txwq: + rtw_sdio_deinit_tx(rtwdev); +err_sdio_declaim: + rtw_sdio_declaim(rtwdev, sdio_func); +err_deinit_core: + rtw_core_deinit(rtwdev); +err_release_hw: + ieee80211_free_hw(hw); + + return ret; +} +EXPORT_SYMBOL(rtw_sdio_probe); + +void rtw_sdio_remove(struct sdio_func *sdio_func) +{ + struct ieee80211_hw *hw = sdio_get_drvdata(sdio_func); + struct rtw_dev *rtwdev; + + if (!hw) + return; + + rtwdev = hw->priv; + + rtw_unregister_hw(rtwdev, hw); + rtw_sdio_disable_interrupt(rtwdev); + rtw_sdio_declaim(rtwdev, sdio_func); + rtw_sdio_free_irq(rtwdev, sdio_func); + rtw_sdio_deinit_tx(rtwdev); + rtw_core_deinit(rtwdev); + ieee80211_free_hw(hw); +} +EXPORT_SYMBOL(rtw_sdio_remove); + +void rtw_sdio_shutdown(struct device *dev) +{ + struct sdio_func *sdio_func = dev_to_sdio_func(dev); + struct ieee80211_hw *hw = sdio_get_drvdata(sdio_func); + const struct rtw_chip_info *chip; + struct rtw_dev *rtwdev; + + if (!hw) + return; + + rtwdev = hw->priv; + chip = rtwdev->chip; + + if (chip->ops->shutdown) + chip->ops->shutdown(rtwdev); +} +EXPORT_SYMBOL(rtw_sdio_shutdown); + +MODULE_AUTHOR("Martin Blumenstingl"); +MODULE_AUTHOR("Jernej Skrabec"); +MODULE_DESCRIPTION("Realtek 802.11ac wireless SDIO driver"); +MODULE_LICENSE("Dual BSD/GPL"); diff --git a/drivers/net/wireless/realtek/rtw88/sdio.h b/drivers/net/wireless/realtek/rtw88/sdio.h new file mode 100644 index 000000000000..7339e35f808a --- /dev/null +++ b/drivers/net/wireless/realtek/rtw88/sdio.h @@ -0,0 +1,175 @@ +/* SPDX-License-Identifier: GPL-2.0 OR BSD-3-Clause */ +/* Copyright (C) 2021 Martin Blumenstingl <martin.blumenstingl@googlemail.com> + * Copyright (C) 2021 Jernej Skrabec <jernej.skrabec@gmail.com> + */ + +#ifndef __REG_SDIO_H_ +#define __REG_SDIO_H_ + +#include "main.h" + +/* I/O bus domain address mapping */ +#define SDIO_LOCAL_OFFSET 0x10250000 +#define WLAN_IOREG_OFFSET 0x10260000 +#define FIRMWARE_FIFO_OFFSET 0x10270000 +#define TX_HIQ_OFFSET 0x10310000 +#define TX_MIQ_OFFSET 0x10320000 +#define TX_LOQ_OFFSET 0x10330000 +#define TX_EPQ_OFFSET 0x10350000 +#define RX_RX0FF_OFFSET 0x10340000 + +#define RTW_SDIO_BUS_MSK 0xffff0000 +#define SDIO_LOCAL_REG_MSK 0x00000fff +#define WLAN_IOREG_REG_MSK 0x0000ffff + +/* SDIO Tx Control */ +#define REG_SDIO_TX_CTRL (SDIO_LOCAL_OFFSET + 0x0000) + +/*SDIO status timeout*/ +#define REG_SDIO_TIMEOUT (SDIO_LOCAL_OFFSET + 0x0002) + +/* SDIO Host Interrupt Mask */ +#define REG_SDIO_HIMR (SDIO_LOCAL_OFFSET + 0x0014) +#define REG_SDIO_HIMR_RX_REQUEST BIT(0) +#define REG_SDIO_HIMR_AVAL BIT(1) +#define REG_SDIO_HIMR_TXERR BIT(2) +#define REG_SDIO_HIMR_RXERR BIT(3) +#define REG_SDIO_HIMR_TXFOVW BIT(4) +#define REG_SDIO_HIMR_RXFOVW BIT(5) +#define REG_SDIO_HIMR_TXBCNOK BIT(6) +#define REG_SDIO_HIMR_TXBCNERR BIT(7) +#define REG_SDIO_HIMR_BCNERLY_INT BIT(16) +#define REG_SDIO_HIMR_C2HCMD BIT(17) +#define REG_SDIO_HIMR_CPWM1 BIT(18) +#define REG_SDIO_HIMR_CPWM2 BIT(19) +#define REG_SDIO_HIMR_HSISR_IND BIT(20) +#define REG_SDIO_HIMR_GTINT3_IND BIT(21) +#define REG_SDIO_HIMR_GTINT4_IND BIT(22) +#define REG_SDIO_HIMR_PSTIMEOUT BIT(23) +#define REG_SDIO_HIMR_OCPINT BIT(24) +#define REG_SDIO_HIMR_ATIMEND BIT(25) +#define REG_SDIO_HIMR_ATIMEND_E BIT(26) +#define REG_SDIO_HIMR_CTWEND BIT(27) +/* the following two are RTL8188 SDIO Specific */ +#define REG_SDIO_HIMR_MCU_ERR BIT(28) +#define REG_SDIO_HIMR_TSF_BIT32_TOGGLE BIT(29) + +/* SDIO Host Interrupt Service Routine */ +#define REG_SDIO_HISR (SDIO_LOCAL_OFFSET + 0x0018) +#define REG_SDIO_HISR_RX_REQUEST BIT(0) +#define REG_SDIO_HISR_AVAL BIT(1) +#define REG_SDIO_HISR_TXERR BIT(2) +#define REG_SDIO_HISR_RXERR BIT(3) +#define REG_SDIO_HISR_TXFOVW BIT(4) +#define REG_SDIO_HISR_RXFOVW BIT(5) +#define REG_SDIO_HISR_TXBCNOK BIT(6) +#define REG_SDIO_HISR_TXBCNERR BIT(7) +#define REG_SDIO_HISR_BCNERLY_INT BIT(16) +#define REG_SDIO_HISR_C2HCMD BIT(17) +#define REG_SDIO_HISR_CPWM1 BIT(18) +#define REG_SDIO_HISR_CPWM2 BIT(19) +#define REG_SDIO_HISR_HSISR_IND BIT(20) +#define REG_SDIO_HISR_GTINT3_IND BIT(21) +#define REG_SDIO_HISR_GTINT4_IND BIT(22) +#define REG_SDIO_HISR_PSTIMEOUT BIT(23) +#define REG_SDIO_HISR_OCPINT BIT(24) +#define REG_SDIO_HISR_ATIMEND BIT(25) +#define REG_SDIO_HISR_ATIMEND_E BIT(26) +#define REG_SDIO_HISR_CTWEND BIT(27) +/* the following two are RTL8188 SDIO Specific */ +#define REG_SDIO_HISR_MCU_ERR BIT(28) +#define REG_SDIO_HISR_TSF_BIT32_TOGGLE BIT(29) + +/* HCI Current Power Mode */ +#define REG_SDIO_HCPWM (SDIO_LOCAL_OFFSET + 0x0019) +/* RXDMA Request Length */ +#define REG_SDIO_RX0_REQ_LEN (SDIO_LOCAL_OFFSET + 0x001C) +/* OQT Free Page */ +#define REG_SDIO_OQT_FREE_PG (SDIO_LOCAL_OFFSET + 0x001E) +/* Free Tx Buffer Page */ +#define REG_SDIO_FREE_TXPG (SDIO_LOCAL_OFFSET + 0x0020) +/* HCI Current Power Mode 1 */ +#define REG_SDIO_HCPWM1 (SDIO_LOCAL_OFFSET + 0x0024) +/* HCI Current Power Mode 2 */ +#define REG_SDIO_HCPWM2 (SDIO_LOCAL_OFFSET + 0x0026) +/* Free Tx Page Sequence */ +#define REG_SDIO_FREE_TXPG_SEQ (SDIO_LOCAL_OFFSET + 0x0028) +/* HTSF Informaion */ +#define REG_SDIO_HTSFR_INFO (SDIO_LOCAL_OFFSET + 0x0030) +#define REG_SDIO_HCPWM1_V2 (SDIO_LOCAL_OFFSET + 0x0038) +/* H2C */ +#define REG_SDIO_H2C (SDIO_LOCAL_OFFSET + 0x0060) +/* HCI Request Power Mode 1 */ +#define REG_SDIO_HRPWM1 (SDIO_LOCAL_OFFSET + 0x0080) +/* HCI Request Power Mode 2 */ +#define REG_SDIO_HRPWM2 (SDIO_LOCAL_OFFSET + 0x0082) +/* HCI Power Save Clock */ +#define REG_SDIO_HPS_CLKR (SDIO_LOCAL_OFFSET + 0x0084) +/* SDIO HCI Suspend Control */ +#define REG_SDIO_HSUS_CTRL (SDIO_LOCAL_OFFSET + 0x0086) +/* SDIO Host Extension Interrupt Mask Always */ +#define REG_SDIO_HIMR_ON (SDIO_LOCAL_OFFSET + 0x0090) +/* SDIO Host Extension Interrupt Status Always */ +#define REG_SDIO_HISR_ON (SDIO_LOCAL_OFFSET + 0x0091) + +#define REG_SDIO_INDIRECT_REG_CFG (SDIO_LOCAL_OFFSET + 0x0040) +#define REG_SDIO_INDIRECT_REG_DATA (SDIO_LOCAL_OFFSET + 0x0044) + +/* Sdio Address for SDIO Local Reg, TRX FIFO, MAC Reg */ +#define REG_SDIO_CMD_ADDR_MSK GENMASK(16, 13) +#define REG_SDIO_CMD_ADDR_SDIO_REG 0 +#define REG_SDIO_CMD_ADDR_MAC_REG 8 +#define REG_SDIO_CMD_ADDR_TXFF_HIGH 4 +#define REG_SDIO_CMD_ADDR_TXFF_LOW 6 +#define REG_SDIO_CMD_ADDR_TXFF_NORMAL 5 +#define REG_SDIO_CMD_ADDR_TXFF_EXTRA 7 +#define REG_SDIO_CMD_ADDR_RXFF 7 + +#define RTW_SDIO_BLOCK_SIZE 512 +#define RTW_SDIO_ADDR_RX_RX0FF_GEN(_id) (0x0e000 | ((_id) & 0x3)) + +#define RTW_SDIO_DATA_PTR_ALIGN 8 + +struct sdio_func; +struct sdio_device_id; + +struct rtw_sdio_tx_data { + u8 sn; +}; + +struct rtw_sdio_work_data { + struct work_struct work; + struct rtw_dev *rtwdev; +}; + +struct rtw_sdio { + struct sdio_func *sdio_func; + + u32 irq_mask; + u8 rx_addr; + bool sdio3_bus_mode; + bool is_powered_on; + + void *irq_thread; + + struct workqueue_struct *txwq; + + struct sk_buff_head tx_queue[RTK_MAX_TX_QUEUE_NUM]; + struct rtw_sdio_work_data *tx_handler_data; +}; + +extern const struct dev_pm_ops rtw_sdio_pm_ops; + +int rtw_sdio_probe(struct sdio_func *sdio_func, + const struct sdio_device_id *id); +void rtw_sdio_remove(struct sdio_func *sdio_func); +void rtw_sdio_shutdown(struct device *dev); + +static inline bool rtw_sdio_is_sdio30_supported(struct rtw_dev *rtwdev) +{ + struct rtw_sdio *rtwsdio = (struct rtw_sdio *)rtwdev->priv; + + return rtwsdio->sdio3_bus_mode; +} + +#endif
patchwork patch tracking system | version v2.2.6 | about patchwork
| https://patchwork.kernel.org/project/linux-mmc/patch/20221227233020.284266-13-martin.blumenstingl@googlemail.com/ |
JPM | Free Full-Text | Association between Statin Use and Risk of Parkinson& rsquo;s Disease: Evidence from 18 Observational Studies Comprising 3.7 Million Individuals
The potential impact of statins on the risk of Parkinson’s disease (PD) is still controversial; therefore, we conducted a comprehensive meta-analysis of observational studies to examine the effect of statin use on the risk of PD. We searched electronic databases, such as PubMed, EMBASE, Scopus, and Web of Science, for articles published between 1 January 2000 and 15 March 2022. Cohort studies which examined the association between statins and PD risk in the general population were also included. Two authors assessed the data and extracted all potential information for analysis. Random effects meta-analyses were performed to measure the risk ratio (RR) and 95% confidence intervals (CIs). Eighteen cohort studies including 3.7 million individuals with 31,153 PD participants were identified. In statin users, compared with non-users, the RR for PD was 0.79 (95% CI: 0.68–0.91). In a subgroup analysis of PD, this association was observed with medium and high quality, and the studies were adjusted for age, gender, and smoking status. When the data were stratified according to the duration of exposure, long-duration statin use was associated with a decreased risk of PD (RR = 0.49; 95% CI: 0.26–0.92). There was no significant decrease in the risk of PD in short-term statin users (RR = 0.94; 95% CI: 0.67–1.31). Moreover, no significant difference in the reduction in the risk of PD was observed between men (RR = 0.80; 95% CI: 0.75–0.86) and women (RR = 0.80; 95% CI: 0.75–0.86). Although our findings confirm a reduction in the PD risk associated with statin treatment and suggest that statins play a clinically favorable role, these findings should be interpreted with caution. Future randomized control trials with an ad hoc design are needed to confirm the potential utility of statins in reducing the risk of PD.
Association between Statin Use and Risk of Parkinson’s Disease: Evidence from 18 Observational Studies Comprising 3.7 Million Individuals
by
Chieh-Chen Wu 1,2 ,
Md. Mohaimenul Islam 3 ,
An-Jen Lee 1,4 ,
Chun-Hsien Su 2,5 ,
Yung-Ching Weng 1 ,
Chih-Yang Yeh 6 ,
Hsun-Hua Lee 7,8,9,10,*,† and
Ming-Chin Lin 6,10,11,*,†
Southeast Asian, Cross-Strait and Overseas Student Institute, Ming Chuan University, Taipei 333, Taiwan
5
Graduate Institute of Sport Coaching Science, College of Kinesiology and Health, Chinese Culture University, Taipei 11114, Taiwan
6
Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, Taipei 106339, Taiwan
7
Department of Neurology, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
8
Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
9
Dizziness and Balance Disorder Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan
10
Department of Neurosurgery, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235041, Taiwan
11
Taipei Neuroscience Institute, Taipei Medical University, Taipei 110301, Taiwan
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
J. Pers. Med. 2022 , 12 (5), 825; https://doi.org/10.3390/jpm12050825
Received: 22 April 2022 / Revised: 11 May 2022 / Accepted: 16 May 2022 / Published: 19 May 2022
(This article belongs to the Special Issue Personalized Diagnosis, Treatment, and Prognosis of Parkinson’s Disease )
Versions Notes
Abstract
:
The potential impact of statins on the risk of Parkinson’s disease (PD) is still controversial; therefore, we conducted a comprehensive meta-analysis of observational studies to examine the effect of statin use on the risk of PD. We searched electronic databases, such as PubMed, EMBASE, Scopus, and Web of Science, for articles published between 1 January 2000 and 15 March 2022. Cohort studies which examined the association between statins and PD risk in the general population were also included. Two authors assessed the data and extracted all potential information for analysis. Random effects meta-analyses were performed to measure the risk ratio (RR) and 95% confidence intervals (CIs). Eighteen cohort studies including 3.7 million individuals with 31,153 PD participants were identified. In statin users, compared with non-users, the RR for PD was 0.79 (95% CI: 0.68–0.91). In a subgroup analysis of PD, this association was observed with medium and high quality, and the studies were adjusted for age, gender, and smoking status. When the data were stratified according to the duration of exposure, long-duration statin use was associated with a decreased risk of PD (RR = 0.49; 95% CI: 0.26–0.92). There was no significant decrease in the risk of PD in short-term statin users (RR = 0.94; 95% CI: 0.67–1.31). Moreover, no significant difference in the reduction in the risk of PD was observed between men (RR = 0.80; 95% CI: 0.75–0.86) and women (RR = 0.80; 95% CI: 0.75–0.86). Although our findings confirm a reduction in the PD risk associated with statin treatment and suggest that statins play a clinically favorable role, these findings should be interpreted with caution. Future randomized control trials with an ad hoc design are needed to confirm the potential utility of statins in reducing the risk of PD.
Keywords:
statins
;
Parkinson’s disease
;
meta-analysis
;
observational studies
1. Introduction
Parkinson’s disease (PD) is one of the major causes of death and disability globally [ 1 ]. More than 6.1 million individuals currently live with PD, compared with 2.1 million in 1990 [ 2 ]. Previous global burden studies have reported that prevalence and death rates vary across different countries, similar to what is reported for dementia [ 3 ]. There is growing evidence concerning different risk and protective factors, but age is the most important risk factor for PD. However, previous research highlights that a variety of occupational and environmental factors, such as pesticide exposure [ 4 , 5 , 6 , 7 , 8 , 9 ], metals [ 6 , 8 , 10 , 11 ], exposure to farm animals, and living on a farm [ 12 ], also appear to be associated with PD.
Statins, which are also called HMG-CoA reductase inhibitors, are considered a mainstay therapy in the management of dyslipidemia. They also have proven cardiovascular benefits, including illness and mortality reduction [ 13 , 14 , 15 , 16 ]. Statins are mainly recommended for patients who need to bring their cholesterol down to the normal range. Statins are considered a safe medication even for long-term use. Growing evidence has shown the beneficial effect of statins on cancer risk reduction [ 17 , 18 ], cancer survival [ 19 ], and dementia risk reduction [ 20 ]. However, there has been recent literature on the use of statin to decrease the risk of PD. These studies include geographically diverse prospective cohorts and different types of statins (lipophilic and hydrophilic). The precise mechanism of this significant reduction is still unknown, but several biological mechanisms have been proposed to explain a possible relationship between statin use and the risk of PD. These include a reduction in the production of tumor necrosis factor-alfa (TNF), as well as a reduction in dopamine 3,4-dihydroxyphenylacetic acid and homovanillic acid [ 21 ].
The potential effect of statin therapy on PD risk reduction is not conclusive. To our knowledge, six meta-analyses have evaluated the association between statins and the risk of PD [ 22 , 23 , 24 , 25 , 26 , 27 ], but these studies had limited power to draw solid conclusions. However, it is important to mention that previous meta-analyses have used a relatively modest sample size and have not provided substantial subgroups and sensitivity analyses. We therefore carried out an updated systematic review and meta-analysis of observational studies examining the association between statin use and the risk of PD. We believe that the clarification of the magnitude of the risk of PD associated with statins might have important clinical implications for future strategies for the prevention and treatment of PD.
2. Methods
We conducted this systematic review and network meta-analysis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [ 28 ].
2.1. Data Sources and Search Strategies
Popular electronic databases, such as PubMed, Embase, Scopus, and Web of Science, were searched for articles published between 1 January 2000 and 15 March 2022. Database searches were conducted by two experts’ independent authors with predefined strategies, and disagreements were resolved by the principal investigator. The following keywords were used to search articles: “statin(s)” OR “HMG-CoA reductase inhibitor(s)” OR “lipid-lowering drug(s)” OR “lipid-lowering agent(s)” OR “simvastatin” OR “atorvastatin” OR “pravastatin” OR “Fluvastatin” OR “rosuvastatin” OR lovastatin” AND (“Parkinson disease” OR “Parkinson’s disease” OR “PD”). Moreover, the reference lists of the included studies and previous reviews were screened for more studies that could potentially be included.
2.2. Eligibility Criteria
The criteria for the inclusion of a potential study are as follows: (1) the study was an observational study (case–control and cohort study); (2) all or a subset of the participants had a history of PD; (3) the study evaluated statin therapies through a comparison between statin users and non-users; (4) the treatment duration was at least three months. Studies were excluded if they were published as reviews or case reports, or if they were not in English.
2.3. Data Extraction
A standard protocol was used to extract data from the included studies. The same two authors extracted data regarding study characteristics (author, publication year, country, study design, length of follow-up, total number of participants, number of PD patients, outcomes), patient characteristics (gender, mean/median age in years), inclusion criteria for statin users, inclusion criteria for PD patients, and adjusted variables such as the comorbidity and concomitant drug use.
2.4. Study Quality Assessment
Since all of the included studies were observational studies, the risk of bias in the included studies was assessed using the Newcastle–Ottawa Scale (NOS) [ 29 ]. The NOS contains eight items, categorized into three domains up to a maximum of nine points for the least risk of bias: (1) selection of study (four points); (2) comparability (two points); and (3) ascertainment of exposure (case–control study)/outcomes (cohort study) (three points) for the observational epidemiological studies, respectively. We considered a study as high, medium, and low if the total scores were 9, 7–8, and less than 7.
2.5. Statistical Analysis
The primary outcome of interest was the PD risk. We calculated a random-effects estimate based on the DerSimoneon and Laird method [
30
]. This is a simple and widely used method, due to the virtue that it is always qualitatively consistent with the heterogeneity test based on the Q statistic. The standard errors of the study-specific estimates were adjusted to incorporate a measure of the extent of variation (τ
2
), or heterogeneity (I
2
), among the intervention effects observed in different studies [
31
]. The relative risk (RR) with a 95% CI was used to measure the association of use of statins vs. no use of statins with PD. All
p
values were obtained from 2-sided tests, and effect sizes were considered statistically significant at
p
< 0.05. All effect sizes included in the pooled analyses were taken from a fully adjusted multivariable model.
Subgroup analyses were also conducted to assess possible sources of heterogeneity and to determine whether several confounding and clinical factors were associated with any significant differences in the outcome. Those factors were the (a) study design; (b) regional impact; (c) quality of a study; (d) study year; € whether the study was adjusted for age, gender, and smoking status; and (f) the various type(s) of statins used in the study. We assessed the heterogeneity among the studies using a
p
-value calculated using χ
2
statistics and I
2
statistics. The I
2
values were categorized into four groups: of 0%~29%, 30%~49%, 50%~74%, and 75%~100%, representing unimportant, moderate, substantial, and considerable inconsistency, respectively [
32
,
33
]. We drew a forest plot to visually represent the effect size of each study and the pooled analyses. Finally, we calculated the publication risk bias using Egger’s test and presented the funnel plot asymmetry visually.
3. Results
3.1. Study Identification
Figure 1 presents the overall process of study selection using a PRISMA diagram. Our initial search yielded 842 articles, and 361 were removed because they were duplicates. Next, 457 articles were excluded after title and abstract screening. We further screened the reference lists of 24 articles to obtain more potential articles, but no additional articles were identified. A full-text review of 24 articles was conducted. Finally, 18 articles were included in our study [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 ].
3.2. Study Characteristics and Quality Assessment
Table 1 shows the characteristics of the included studies. Among the 18 included studies, 10 were cohort studies and 8 were case–control studies. Nine of the studies were from North America, five were from Asia and four were from Europe. The study sample size ranged from 230 to 2,004,692 individuals in total. The studies included 3.7 million individuals with 31,153 PD patients. The average NOS score was 7.33, with an interquartile range (IQR) of 6–9.
3.3. Statin Use and PD Risk
Eighteen studies assessed the association between statin therapy and the risk of PD. Statin use was significantly associated with decreased risk of PD compared with the absence of statin use; the pooled RR was 0.79 (95% CI: 0.68–0.91, p = 0.001). Significant heterogeneity was present across the studies (Q = 149.02, p < 0.001, I 2 = 82.05%) in the random-effect models ( Figure 2 ).
3.4. Subgroup Analysis
To make the findings more robust, we performed subgroup analyses using various study features (e.g., the influence of study design) and clinical factors (e.g., adjusted for age) ( Table 2 ). Ten cohort and eight case–control studies compared the risk of PD for statin users and non-statin users. The pooled RRs for cohort and case–control studies were 0.75 (95% CI: 0.62–0.91, p = 0.004) and 0.85 (95% CI: 0.70–1.04, p = 0.09). There was significant heterogeneity among the studies (Q = 98.14, p < 0.001, and I 2 = 90.83% and (Q = 35.35, p < 0.001, and I 2 = 80.19, respectively).
Nine studies from North America evaluated the impact of statin therapy on the risk of PD. The overall pooled RR was 0.81 (95% CI: 0.60–1.09,
p
= 0.17), with significant heterogeneity among the studies (Q = 85.20,
p
< 0.001, I
2
= 90.61%). However, the pooled RRs for studies from Europe and Asia were 0.85 (95% CI: 0.79–0.92,
p
< 0.001, number of studies, n = 4) and 0.71 (95% CI: 0.57–0.90,
p
= 0.005, n = 5), respectively.
The overall pooled RRs for the risk of PD for high and moderate-quality methodologies were 0.79 (95% CI: 0.64–0.97,
p
= 0.02, n = 10) and 0.79 (95% CI: 0.63–0.98,
p
= 0.03, n = 8), respectively. Fourteen studies were adjusted for age when evaluating the risk of PD among statin users compared to non-users. The pooled RR for studies that adjusted for age was 0.80 (95% CI: 0.66–0.97,
p
= 0.02). Moreover, thirteen studies adjusted for gender and ten studies adjusted for smoking status to assess the risk of PD with statin use. The pooled RRs were 0.84 (95% CI: 0.69–1.03,
p
= 0.06) and 0.79 (95% CI: 0.62–0.97,
p
= 0.02), respectively.
Six studies examined the risk of PD with simvastatin; the pooled RR was 0.67 (95% CI: 0.53–0.84,
p
= 0.001), with a significant heterogeneity (Q = 111.29,
p
< 0.001, I
2
= 93.71%). The pooled RRs for studies using atorvastatin, lovastatin, and pravastatin were 0.73 (95% CI: 0.59–0.90,
p
= 0.003, n = 5), 0.89 (95% CI: 0.65–1.21,
p
= 0.46, n = 3), and 1.09 (95% CI: 0.65–1.84,
p
= 0.72), respectively.
3.5. Sensitivity Analysis
To assess whether gender, the nature of the statins used, or the duration of statin usage substantially influenced the main findings, we calculated the summary effect size and heterogeneity of the main analysis. The pooled RRs for PD risk in male and female users were 0.62 (95% CI: 0.39–0.98,
p
= 0.04, n = 4, Q = 34.44,
p
< 0.001, I
2
= 88.38%) and 0.47 (95% CI: 0.30–0.73,
p
= 0.001, n = 3, Q = 8.86,
p
< 0.001, I
2
= 66.16%), respectively. The pooled RRs for PD risk for lipophilic and hydrophilic statin users were 0.86 (95% CI: 0.56–1.34,
p
= 0.52, n = 4, Q = 39.51,
p
< 0.001, I
2
= 92.40%) and 1.03 (95% CI: 0.86–1.23,
p
= 0.69, n = 4, Q = 2.78,
p
= 0.42, I
2
= 0%), respectively. Furthermore, we assessed the impact of the duration of statin therapy and the risk of PD. Six studies examined the impact of shorter-duration statin use, defined as the use of statins for <1 year, on the risk of PD, and the pooled RR was 0.94 (95% CI: 0.67–1.31,
p
= 0.73), with a significant heterogeneity (Q = 39.97,
p
< 0.001, I
2
= 87.47%). In contrast, for longer-duration statin use, defined as the use of statin use for >5 years, the pooled RR was 0.49 (95% CI: 0.26–0.92,
p
= 0.02, n = 2), with no significant heterogeneity (Q = 1.27,
p
= 0.25, I
2
= 21.59%).
3.6. Publication Bias
We drew a funnel plot to assess publication bias and did not find any significant bias ( Figure 3 ). In addition, there was no obvious publication bias, assessed by the trim-and-fill method for PD risk.
4. Discussion
The present meta-analysis, comprising 18 observational studies with 3.7 million individuals, revealed that statin use was associated with a 19% reduced risk of PD. Our findings should be interpreted with caution because there was significant heterogeneity among the studies and because observational studies are unable to determine whether the association is causal or if there are any other confounding factors. However, for the studies that adjusted for age, gender, and smoking status, the use of statins significantly reduced the risk of PD. Moreover, the use of statins for >5 years significantly decreased the risk of PD, whereas there was no statistically significant decrease in PD among short-term (<1 year) statin users. Furthermore, the use of lipophilic statins was associated with a decreased risk of PD, but there was no association between hydrophilic statin and PD risk. The primary findings of our study are consistent with the previous meta-analyses; that is, overall, the use of statins is associated with a decreased risk of PD.
The previous meta-analysis suggests that statins may be beneficial for reducing the risk of PD [ 22 , 23 , 24 , 25 ]. Additionally, both our current study (adjusted RR = 0.79; 95% CI: 0.68–0.91) and previous work by Poly et al. [ 27 ] found that statins appear to have strong protective effects against PD (RR = 0.70; 95% CI: 0.58–0.84). However, compared to the study by Poly et al., we added five studies and had more subjects. Moreover, we have provided more comprehensive subgroups and sensitivity analyses to determine whether there is an association between these subgroups and any factors that affect the association. This study included a higher number of studies and estimated the pooled risk ratio using the adjusted effect size from each study; therefore, the association between statin use and PD risk reduction cannot be ruled out.
The exact mechanism describing how statins affect PD risk reduction has not been clearly elucidated, but several possible pathological mechanisms have been proposed. A preclinical study of the PD model showed that statins protected dopamine-containing neurons in the substantia nigra and striatum in the brain of 6-OHDA-lesioned rats. This finding presents an N-methyl-d-aspartate (NMDA) modulatory effect, providing a new paradigm to ameliorate anti-inflammatory activity in PD [ 51 ]. Previous studies reported that statins regulate tumor necrosis factor (TNF-a) and matrix metallopeptidase-9 (MMP-9) through NMDA receptor-mediated anti-inflammatory mechanisms [ 52 , 53 ], which ultimately provide neuroprotection against dopaminergic neurodegeneration [ 54 ]. Several animal studies have revealed that statin use could attenuate cholesterol metabolites, which help to inhibit α-synuclein aggregation and reduce the toxic effect in dopaminergic neurons [ 55 , 56 ]. Moreover, an in vitro study reported that statins impede neurotoxicity and apoptosis by decreasing reactive oxygen species (ROS) production [ 57 ]. Furthermore, a lipopolysaccharide (LPS)-induced rat model of PD demonstrates that statins reduce the risk of PD by promoting neuronal repair and regeneration [ 58 ]. Statins also reduce oxidative stress and improve substantia nigra function.
In the subgroup analysis stratified by region, we found a reduced risk of PD with statin therapy in all subgroups, although there was a non-significant reduced risk of PD in patients from North America. This finding can be partially explained by the different races in this region. In support of this finding, previous studies have documented statin response variation among races [ 59 , 60 ]. The specific reasons for this finding are unclear; lifestyle factors such as diet [ 61 , 62 ] and exercise [ 63 ] could contribute to the wide confidence interval in the North American group. Age, gender, and smoking status are considered potential confounding factors for PD; however, our study results show that the use of statins was associated with a decreased risk of PD when the analysis was adjusted for these confounding factors. Moreover, the subgroup analysis of high and moderate-quality studies showed a significantly reduced PD risk because these studies adjusted all potential variables during the effect size calculation.
As for individual statin use, simvastatin and atorvastatin showed a reduced risk of PD, whereas pravastatin showed no association with the risk of PD. The classification of statins can be a possible explanation for these variations. Pravastatin is a hydrophilic statin that is distributed mainly in the liver. Lipophilic statins (e.g., simvastatin, atorvastatin) are widely distributed in all tissues [ 64 ] and can cross the blood–brain barrier; they potentially affect the central nervous system [ 65 ]. Our subgroup analysis shows that simvastatin was more protective than atorvastatin because simvastatin is more lipophilic than atorvastatin [ 66 ]. Previous studies have reported that simvastatin is superior at crossing the blood–brain barrier and provides more neuroprotective effects than atorvastatin [ 66 , 67 ].
Our updated meta-analysis has several strengths and limitations. First, this is the most comprehensive meta-analysis performed on this subject; it comprises 18 observational studies with more than 3 million people. Second, our study contains broad subgroup and sensitivity analyses which can be helpful in making a fruitful clinical decision in the real-world clinical setting. Third, our study shows the impact of different types of statins such as atorvastatin and pravastatin on the risk of PD. It also shows the relationship between duration of statin use and PD risk. There were several limitations that need to be addressed. First, there was significant heterogeneity among the studies in the main and subgroup analyses. However, this heterogeneity can be explained by the different study designs, durations, and qualities and by regional effects. Second, our study was unable to show the impact of the statin dose on the risk of PD due to a lack of data. Third, all the included studies were observational studies. As such, there might be several potentially confounding factors, and the findings should be considered with caution.
5. Conclusions
The findings of our updated meta-analysis show a significant PD risk reduction due to statin use. Moreover, the long-term use of statins (>5 years) significantly reduced the risk of PD. As the findings are mainly based on limited observational studies, there may be several potential confounding factors and different definitions of statin users and exposure. Therefore, our results should be used with caution; there is not enough statistical power to confirm or refute these observed associations. A study with a large sample size, high-quality methodology, and long follow-up (more than ten years) is needed to either confirm or refute these findings. Moreover, biological studies are required to verify whether a given association is causal or observed. Until higher-quality evidence is available, statins should only be prescribed for their original purpose (reducing cardiovascular risk); they should not be repurposed for PD risk reduction.
Author Contributions
Conceptualization: C.-C.W. and M.M.I.; Methodology: M.M.I.; software, C.-C.W.; validation: A.-J.L., C.-H.S., Y.-C.W. and C.-Y.Y.; formal analysis: M.M.I., H.-H.L.; investigation: H.-H.L., M.-C.L.; resources: C.-C.W. data curation: C.-C.W. and M.M.I.; writing—original draft preparation: M.M.I.; writing—review and editing, M.-C.L.; visualization: M.M.I.; supervision: M.-C.L. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by the Ministry of Science and Technology, Taiwan (grant number: 108-2314-B-038-053-MY3) and supported from Taipei Medical University, Taiwan (grant number: 108-FRP-02).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. PRISMA diagram of the study selection process.
Figure 1. PRISMA diagram of the study selection process.
Figure 2. Association between statin use and PD risk [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].
Figure 2. Association between statin use and PD risk [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].
Figure 3. Funnel plot for the detection of possible bias of publication on the effect of statin use on PD risk.
Figure 3. Funnel plot for the detection of possible bias of publication on the effect of statin use on PD risk.
Table 1. Basic characteristics of included studies [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].
Table 1. Basic characteristics of included studies [ 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ].
Study Publication Year Study Duration Study Type Population PD Cases Definition of Statin Use Identification of Statin Users Country Quality Score De Lau 2006 1990–2004 Co 6465 87 Medical record ATC Netherland 8 Huang 2007 2002–2004 C-C 236 124 Medical record ATC USA 7 Wolozin 2007 2003–2005 Co 1,226,198 5107 Database ATC USA 6 Becker 2008 1994–2005 C-C 7274 3637 Medical records ATC UK 9 Samii 2008 1997–2003 C-C 23,780 4756 Medical records ATC Canada 6 Wahner 2008 2001–2007 C-C 654 312 Self-report ATC USA 7 HippisleyCox 2010 2002–2008 Co 2,004,692 3553 Database ATC UK 6 Ritz 2010 2001–2006 C-C 11,582 1931 Medical report ATC Denmark 7 Gao 2012 1994–2006 Co 129,006 644 Self-report ATC USA 7 Friedman 2013 2000–2007 Co 87,971 824 Database ATC Israel 8 Lee 2013 2001–2008 Co 43,810 1886 Database ATC China 9 Huang 2015 1987–2008 Co 15,291 56 Medical records ATC USA 6 Lin 2016 1996–2008 Co 50,432 651 Database ATC China 8 Shalaby 2016 2009–2014 C-C 230 108 Self-report ATC USA 7 Liu 2017 2008–2012 C-C 4644 2322 Database ATC USA 7 Jong 2019 2002–2015 Co 76,043 1427 Database ATC USA 8 Chang 2020 1996–2013 Co 48828 692 Database ATC Taiwan 8 Kim 2022 2002–2015 C-C 15,130 3036 Database ATC South Korea 8
Note: C-C = case–control study; Co = cohort study; ATC = Anatomical Therapeutic Chemical Classification System.
Table 2. Subgroup analysis.
Table 2. Subgroup analysis.
Study No of Studies Pooled Estimates Test of Heterogeneity RR (95% CI) p -Value Q Value p Value I 2 (%) All studies 18 0.79 (0.68–0.91) 0.001 149.02 <0.001 82.05 Study design Cohort 10 0.75 (0.62–0.91) 0.004 98.14 <0.001 90.83 Case–control 8 0.85 (0.70–1.04) 0.09 35.35 <0.001 80.19 Region North America 9 0.81 (0.60–1.09) 0.17 85.20 <0.001 90.61 Europe 4 0.85 (0.79–0.92) <0.001 2.26 <0.001 0 Asia 5 0.71 (0.57–0.90) 0.005 42.86 <0.001 90.66 Adjusted for age Yes 14 0.80 (0.66–0.97) 0.02 125.79 <0.001 89.66 No 4 0.75 (0.61–0.92) 0.006 21.36 <0.001 85.96 Adjusted for gender Yes 13 0.84 (0.69–1.03) 0.06 102.57 <0.001 88.30 No 5 0.69 (0.58–0.82) <0.001 21.91 <0.001 81.74 Adjusted for smoking status Yes 10 0.78 (0.62–0.97) 0.02 86.14 <0.001 89.14 No 8 0.79 (0.65–0.96) 0.02 56.60 <0.001 87.63 Quality of Studies Medium 10 0.79 (0.64–0.97) 0.02 59.85 <0.001 84.96 High 8 0.79 (0.63–0.98) 0.03 88.93 <0.001 92.12 Statin type Simvastatin 6 0.67 (0.53–0.84) 0.001 111.29 <0.001 93.71 Atorvastatin 5 0.73 (0.59–0.90) 0.003 32.80 <0.001 81.71 Lovastatin 3 0.89 (0.65–1.21) 0.46 6.26 0.005 81.02 Pravastatin 3 1.09 (0.65–1.84) 0.72 6.56 0.08 54.30 Study year ≤5 3 0.68 (0.28–1.65) 0.39 37.41 <0.001 94.65 ≤10 7 0.76 (0.66–0.88) <0.001 18.61 0.005 67.77 >10 8 0.88 (0.69–1.11) 0.29 87.86 <0.001 92.03
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Percent Without Health Insurance Data for Kansas and Washington - Health Insurance on the Open Data Network
The percent without health insurance of Kansas was 6.90% for under 19, all races, both sexes and at or below 400% of poverty in 2014. The percent without health insurance of Washington was 6.20% for under 19, all races, both sexes and at or below 400% of poverty in 2014.API
Percent Uninsured API
Percent Uninsured by Income Level API
Percent Uninsured by Race API
The Small Area Health Insurance Estimate (SAHIE) estimates health insurance coverage from the American Community Survey (ACS).
Above charts are based on data from theSmall Area Health Insurance Estimate|ODN Dataset|API- Notes:1. ODN datasets and APIs are subject to change and may differ in format from the original source data in order to provide a user-friendly experience on this site.2. To build your own apps using this data, see the ODN Dataset and API links.3. If you use this derived data in an app, we ask that you provide a link somewhere in your applications to the Open Data Network with a citation that states: "Data for this application was provided by the Open Data Network" where "Open Data Network" links to http://opendatanetwork.com. Where an application has a region specific module, we ask that you add an additional line that states: "Data about REGIONX was provided by the Open Data Network." where REGIONX is an HREF with a name for a geographical region like "Seattle, WA" and the link points to this page URL, e.g. http://opendatanetwork.com/region/1600000US5363000/Seattle_WA
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Access to Healthcare
Percent of population 18-64 years of age with no health insurance coverage by race/ethnicity in New Orleans and the United States
WA-APCD Quality and Cost Summary Report: Hospital Quality
WA-APCD - Washington All-Payer Claims Database The WA-APCD is the state’s most complete source of health care eligibility, medical claims, pharmacy claims, and dental claims insurance data. It contains claims from more than 50 data suppliers, spanning commercial, Medicaid, and Medicare managed care. The WA-APCD has historical claims data for five years (2013-2017), with ongoing refreshes scheduled quarterly. Workers' compensation data from the Washington Department of Labor & Industries will be added in fall 2018. Download the attachment for the data dictionary and more information about WA-APCD and the data.
WA-APCD Quality and Cost Summary Report: Facility Cost
WA-APCD - Washington All Payers Claims Database The WA-APCD is the state’s most complete source of health care eligibility, medical claims, pharmacy claims, and dental claims insurance data. It contains claims from more than 50 data suppliers, spanning commercial, Medicaid, and Medicare managed care. The WA-APCD has historical claims data for five years (2013-2017), with ongoing refreshes scheduled quarterly. Workers' compensation data from the Washington Department of Labor & Industries will be added in fall 2018. Download the attachment for the data dictionary and more information about WA-APCD and the data.
WA-APCD Quality and Cost Summary Report: County Cost
WA-APCD - Washington All-Payer Claims Database The WA-APCD is the state’s most complete source of health care eligibility, medical claims, pharmacy claims, and dental claims insurance data. It contains claims from more than 50 data suppliers, spanning commercial, Medicaid, and Medicare managed care. The WA-APCD has historical claims data for five years (2013-2017), with ongoing refreshes scheduled quarterly. Workers' compensation data from the Washington Department of Labor & Industries will be added in fall 2018. Download the attachment for the data dictionary and more information about WA-APCD and the data.
WA-APCD Quality and Cost Summary Report: ACH Quality
WA-APCD - Washington All-Payer Claims Database The WA-APCD is the state’s most complete source of health care eligibility, medical claims, pharmacy claims, and dental claims insurance data. It contains claims from more than 50 data suppliers, spanning commercial, Medicaid, and Medicare managed care. The WA-APCD has historical claims data for five years (2013-2017), with ongoing refreshes scheduled quarterly. Workers' compensation data from the Washington Department of Labor & Industries will be added in fall 2018. Download the attachment for the data dictionary and more information about WA-APCD and the data.
Number Of People Without Health Insurance All States 2005-2012
WA-APCD Quality and Cost Summary Report: Practice Quality
WA-APCD - Washington All-Payer Claims Database The WA-APCD is the state’s most complete source of health care eligibility, medical claims, pharmacy claims, and dental claims insurance data. It contains claims from more than 50 data suppliers, spanning commercial, Medicaid, and Medicare managed care. The WA-APCD has historical claims data for five years (2013-2017), with ongoing refreshes scheduled quarterly. Workers' compensation data from the Washington Department of Labor & Industries will be added in fall 2018. Download the attachment for the data dictionary and more information about WA-APCD and the data.
MCG Group Health Plan Rates
Montgomery County offers medical, prescription, vision and dental plans for our employees, their families and their partners. Employees can choose between two Point-of-Service (POS) plans with CareFirst Blue Cross and Blue Shield (BCBS) and two Health Maintenance Organizations (HMO’s) with United HealthCare and Kaiser; two prescription plans with Caremark; National Vision Administrators (NVA) plan and two PPO and DHMO dental plans with United Concordia. The dataset contains all available plan rates, provider websites and contact numbers. In addition, this information is also available on the Office of Human Resources (OHR) website at https://www.montgomerycountymd.gov/HR/Benefits/EmployeeMedical.html#1 Update Frequency : Annually
Patient Characteristics Survey (PCS): 2017
The number of persons described by survey year (2017) reported in OMH Region‐specific totals (Region of Provider) and three demographic characteristics of the client served during the week of the survey: sex (Male, Female, and Unknown), Transgender (No, Not Transgender; Yes, Transgender and Unknown), age (below 17 (Child), 18 and above(Adult) and unknown age) and race (White only, Black Only, Multi‐racial, Other and Unknown race) and ethnicity (Non‐Hispanic, Hispanic, Client Did Not Answer and Unknown). Persons with Hispanic ethnicity are grouped as “Hispanic,” regardless of race or races reported.
Pierce County, WA -- COVID Risk Index Score
Population over 60 (S0101), Women Who Had a Birth in the Past 12 Months (B13002), Below Poverty Level (B17015), No Health Insurance (B27001), Household Receiving SNAP Assistance (S2201), No Internet Access (B28002), Total Population (B01003) and Language at Home (C16001)
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Investigating Bioequivalence Between Single-dose Liraglutide Administered Subcutaneously With Two Different Pen-injectors - Full Text View - ClinicalTrials.gov
Investigating Bioequivalence Between Single-dose Liraglutide Administered Subcutaneously With Two Different Pen-injectors
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT02207348 Recruitment Status :
Completed First Posted : August 4, 2014 Last Update Posted : December 9, 2016
Sponsor:
Novo Nordisk A/S
Information provided by (Responsible Party):
Novo Nordisk A/S
Study Details
Study Description
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Brief Summary:
This trial is conducted in Europe. The aim of this trial is to investigate bioequivalence between single-dose liraglutide administered subcutaneously with two different pen-injectors.
Condition or disease Intervention/treatment Phase Metabolism and Nutrition Disorder Obesity Drug: liraglutide Phase 1
Study Design
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Layout table for study information Study Type : Interventional
(Clinical Trial) Actual Enrollment : 24 participants Allocation: Randomized Intervention Model: Crossover Assignment Masking: None (Open Label) Primary Purpose: Treatment Official Title: A Randomised, Open-label, Single-centre, Two-period, Cross-over Trial Investigating Bioequivalence Between Single-dose Liraglutide Administered Subcutaneously With Two Different Pen-injectors Study Start Date : August 2014 Actual Primary Completion Date : September 2014 Actual Study Completion Date : September 2014
Resource links provided by the National Library of Medicine
Drug Information available for: Liraglutide
Genetic and Rare Diseases Information Center resources: Oculocerebral Syndrome With Hypopigmentation
U.S. FDA Resources
Arms and Interventions
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Arm Intervention/treatment Experimental: Liraglutide 0.6 mg s.c. with FlexPen® Drug: liraglutide Each subject will receive two single doses of 0.6 mg liraglutide (one with each of the two pen-injectors) Experimental: Liraglutide 0.6 mg s.c. with the PDS290 pen-injector Drug: liraglutide Each subject will receive two single doses of 0.6 mg liraglutide (one with each of the two pen-injectors)
Outcome Measures
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Primary Outcome Measures
:
Area under the liraglutide plasma concentration time curve from 0 to last quantifiable observation (tz) after single dose [ Time Frame: 0-72 hours following administration of 0.6 mg liraglutide ]
Maximum observed liraglutide plasma concentration after single dose [ Time Frame: 0-72 hours following administration of 0.6 mg liraglutide ]
Secondary Outcome Measures
:
Number of treatment emergent adverse events (TEAEs) [ Time Frame: From baseline to follow-up (up to 3 weeks). Baseline is defined as time of first trial drug administration at Visit 2 ]
Eligibility Criteria
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Layout table for eligibility information Ages Eligible for Study: 18 Years to 60 Years (Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Male or female, age 18-60 years (both inclusive) at the time of signing informed consent
Body mass index (BMI) greater than or equal to 27.0 and less than 35.0 kg/m^2
Bodyweight up to 130.0 kg (inclusive)
HbA1c (glycosylated haemoglobin) below 6.5%
Exclusion Criteria:
Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using an adequate contraceptive method. Only highly effective methods of birth control are accepted (i.e. one that results in less than 1% per year failure rate when used consistently and correctly such as implants, injectables, combined oral contraceptives, some intrauterine devices), or sexual abstinence or vasectomised partner
History or presence of cancer, or any clinically significant cardiovascular, respiratory, metabolic, renal, hepatic, gastrointestinal, endocrine (incl. diabetes), haematological, dermatological, venereal, neurological, psychiatric diseases or other major disorders that might have impact on the trial, as judged by the investigator
Use of any prescription or non-prescription medication, except for paracetamol, acetylsalicylic acid, contraceptives and vitamins (but including mega-dose vitamin therapy, as judged by the investigator) within 2 weeks before the trial defined as screening
Significant history of alcoholism or drug/chemical abuse within 1 year from screening, or a positive result of the urine drug screen or alcohol breath test, or consuming more than 21 units of alcohol per week (one unit of alcohol equals about 250 mL of beer or lager, one glass of wine (120 mL), or 20 mL spirits)
Smoking more than 5 cigarettes, or the equivalent, per day and unable to refrain from smoking during the in-house periods
| https://clinicaltrials.gov/ct2/show/NCT02207348 |
Efficacy of Physiotherapy Techniques on Irritable Bowel Syndrome (IBS). Pilot Study. - Full Text View - ClinicalTrials.gov
Efficacy of Physiotherapy Techniques on Irritable Bowel Syndrome (IBS). Pilot Study. (IBS)
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT04486469 Recruitment Status :
Completed First Posted : July 24, 2020 Last Update Posted : July 24, 2020
Sponsor:
IBS Group, Alcalde
Information provided by (Responsible Party):
IBS Group, Alcalde
Study Details
Study Description
Brief Summary:
Introduction and State of Question Irritable Bowel Syndrome can be classified as a functional digestive disorder characterized by abdominal pain, bloating, and changes in the frequency and consistency of bowel movements. Recent studies endorse the use of physical therapies for its symptomatic treatment. With the present study investigators wanted to verify the effectiveness of physiotherapy techniques in order to alleviate or eliminate the symptoms of Irritable Bowel Syndrome.
Material and Methods Investigators have carried out an uncontrolled pilot clinical trial in a sample of 24 patients diagnosed with Irritable Bowel Syndrome in two hospitals in the Region of Murcia. Among the measurement tools used, we highlight the use of the IBS-Severity Scale, IBS-QoL, STAI and spirometry tests.
Condition or disease Intervention/treatment Phase Irritable Bowel Syndrome Other: Physical Therapy Group Not Applicable
Detailed Description:
Scope of treatment: From the Digestive System Services, patients who meet the criteria described above, will be referred to the Rehabilitation Services of the Virgin of Arrixaca and Reina Sofía University Hospital, and then, to the physiotherapy unit. At the same time, the researcher will contact these patients to manage the appointments proposed in physiotherapy. The physical treatment to be applied individually has a duration of 40 min per session, establishing a maximum of 8 sessions and a minimum of 3 sessions. This treatment is described below: the first three weeks: (3 days / week)
Performing direct physical treatment on the diaphragm, using stretching, followed by teaching exercises for re-education of the abdomen and diaphragm. (20 min):
A) Direct physical treatment on the diaphragm. It refers to the stretching of the xiphoid and costal portions. With the patient in the supine position and the hips flexed 90º, investigator take advantage of the abdominal-diaphragmatic respiration in its expiratory component to stretch these portions, trying to penetrate with fingertips over the xiphoid and costal edge and maintaining the position with each gain, performing a maximum of 3 winnings.
B) Abdomino-diaphragmatic reeducation: With the patient in the supine position and the hips flexed 90º, investigator will place the hands in the abdominal area and ask pacient to try to push the hands upwards taking air with the belly. Once the patient have become aware investigator will put up some resistance to the movement. Investigator will avoid possible compensations by controlling the expansion of the rib cage if necessary. Next investigator will ask patient to associate movements of the pelvic scale during breathing. In inspiration, investigator will ask patient to slightly push the sacrum on the stretcher and in ESP, then investigator will ask patient to bring the pelvis back tightening the buttocks as trying to retain defecation. (10min)
Transcutaneous retrograde electrostimulation: L1-L4 (2hz-10hz) rectangular asymmetric biphasic at the level of the dermatome. From the anterior inferior iliac spine to a pubic symphysis. Second canal from the greater trochanter to the saphenous veins. (30 min). For this, investigator use the TENS STIM-PRO T-800 device. European Certificate of Conformity (CE 2460). The investigator use program of acupuncture TENS according to the Sjound and Erikson theory of endorphin release, with a neuromodulating objective. Parameters of this program: 2 Hz and 180ms, for 30 min. Investigator should increase the intensity measured in Milli-Amps until it produces contraction for a few seconds, then lower it until the contraction is no longer visible. This therapy can be applied during manual therapy treatment, be it diaphragmatic stretching, abdominal massage and diaphragmatic reeducation.
Connective Tissue Massage or Dicke (10 min): Investigator place the patient sitting on the table and ask that the lumbar area and gluteal and sacral area be discovered. Without the help of oils or creams, investigator have to make three strokes with the help of the ulnar edge of the hand and the 3rd and 5th finger. This therapy may arise that the patient has to go to the bathroom before, during or after treatment due to the activation of the renal system through stimulation of the cuti-visceral reflex.
Massage with direct maneuvers on the abdomen: It is a massage specially indicated to facilitate intestinal mobility and transit in the large intestine. For its realization investigator can apply creams or oils. The direction of the maneuvers will be clockwise. It is important to apply the not pain rule. Investigator will start with a superficial friction, followed by a spiral massage in the intestinal area. Next, perform 6 very slow strokes adding small pressures on the ascending, transverse and descending colon respectively and repeating this maneuver 3 times. (10min)
Layout table for study information Study Type : Interventional
(Clinical Trial) Actual Enrollment : 24 participants Allocation: N/A Intervention Model: Single Group Assignment Intervention Model Description: 24 patients diagnosed with Irritable Bowel Syndrome Masking: None (Open Label) Masking Description: The patients were cited for individual sessions in a close space so they did not know if they all received the same treatment. Primary Purpose: Treatment Official Title: Efficacy of Physiotherapy Techniques on Irritable Bowel Syndrome Actual Study Start Date : September 30, 2019 Actual Primary Completion Date : May 30, 2020 Actual Study Completion Date : June 24, 2020
Arms and Interventions
Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information
Arm Intervention/treatment Experimental: Subjects with Irritable bowel syndrome Experimental group is formed with 24 patients diagnosed with IBS treated in the digestive system service of the Virgen de la Arrixaca and Reina Sofía General University Hospitals. Other: Physical Therapy Group Performing direct physical treatment on the diaphragm, using stretching, followed by teaching exercises for re-education of the abdomen and diaphragm. Transcutaneous retrograde electrostimulation: L1-L4 (2hz-10hz) rectangular asymmetric biphasic at the level of the dermatome. From the anterior inferior iliac spine to a pubic symphysis. Second canal from the greater trochanter to the saphenous veins. (30 min). Parameters of this program: 2 Hz and 180ms. Connective Tissue Massage or Dicke Massage with direct maneuvers on the abdomen: The direction of the maneuvers will be clockwise. We will perform 6 very slow strokes adding small pressures on the ascending, transverse and descending colon respectively and repeating this maneuver 3 times. (10 minutes)
Outcome Measures
Primary Outcome Measures
:
"Change from Baseline IBS-Severity Index at month"- [ Time Frame: "up to four weeks" ]
The severity questionnaire is divided into 3 sections. The first is the main one, and collects information about the severity. It contains 4 questions, each with a maximum score of 100 using visual analog scales, out of a maximum score of 500.
"Change from Baseline IBS-QoL score at month"- [ Time Frame: "up to four weeks" ]
It is a self-administered questionnaire, which is usually answered in about 10 min. This consists of 34 items with a value of 5 points each, which collect information on the quality of life of patients affected with IBS. This questionnaire is classified into 8 main areas: dysphoria, interference with activity, body image, health concern, avoidance of food, social relationships, sexual scale and relationships.
"Change from Baseline Trait Anxiety Inventory (STAI) score at month" [ Time Frame: "up to four weeks" ]
It is divided into two subscales (AE and AR). The AE scale consists of 20 sentences that the subject scores from 0 to 3 and defines how he feels in a "specific moment". Trait anxiety (AR) signals an anxious predisposition to perceive situations as threatening. The AR scale consists of 20 sentences, shows how the subject feels in "general".
"Change from Baseline Simple spirometry parameters at month" [ Time Frame: "up to four weeks" ]
It is a diagnostic test that allows the detection of respiratory pathologies of an obstructive or restrictive nature, as well as making a differential diagnosis in patients at risk. This device allows investigator to measure the following parameters: Forced Vital Capacity (FVC), Forced Expiration Volume in one second (FEV1), calculate the Tifenneau Index of the examinee by means of the ratio between FEV1 and FVC. It also allows to measure the Peak of Maximum Expiratory Flow (PEF), 25% of FVC flow (FEF25), among others possible.The measurement of these parameters will be carried out with the help of the CONTEC SP10W digital spirometer, with a European Conformity certificate (CE-0123). Electromagnetic Compatibility (EMC): Group I, class B. ¾ Class B (Electromagnetic system, which is marketed for use in a residential environment. Its limits are stricter than industrial devices). Medical devices - covered by directive, 93/42 / EEC. Classification of medical device IIa.
Secondary Outcome Measures
:
"Change from Baseline Setpoint Abdominal Pain in IBS-Severity Index at month" [ Time Frame: "up to four weeks" ]
Setpoint of the severity scale that measures the subjective sensation of abdominal pain with a visual scale.
"Change from Baseline Setpoint funcional bloating in IBS-Severity Index at month" [ Time Frame: "up to four weeks" ]
Setpoint of the severity scale that measures the subjective sensation of bloating
"Change from baseline of bowel movements at month" [ Time Frame: "up to four weeks" ]
Maximum number of bowel movements in one week
Eligibility Criteria
Information from the National Library of Medicine
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
Layout table for eligibility information Ages Eligible for Study: 36 Years to 50 Years (Adult) Sexes Eligible for Study: All Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria:
Over 18 years
Collaborating patients
Patients Diagnosed with IBS from the Digestive System Services of the Virgen de la Arrixaca and Reina Sofía Hospital in Murcia in Outpatient Consultations.
Accept and sign the informed consent
Degree of Severity in the IBS-Severity index from Moderate to Serious (greater than 175p.)
Frequency of abdominal pain in 2 out of 10 days in the IBS-SI
Exclusion Criteria:
Patients with fear or phobia of electricity
Restrictive diaphragmatic respiratory pathologies in your medical history, either due to neurological or traumatic causes.
Patients with pacemakers, or diagnosed with heart disease or arrhythmias.
Presence of developing scars, burns, allergies, wounds or infections in the thigh and lower back application areas.
undiagnosed pain
Neoplasms
Deep venous thrombosis
Pregnancy
Elimination criteria:
Worsening of symptoms after abdominal massage
Failure to attend sessions of 2 or more days followed by treatment
Layout table for location information Spain Jose Luis Gil Alcalde Murcia, Spain, 30003
Layout table for additonal information Responsible Party: IBS Group, Alcalde ClinicalTrials.gov Identifier: NCT04486469 History of Changes Other Study ID Numbers: IBSGroupAlcalde First Posted: July 24, 2020 Key Record Dates Last Update Posted: July 24, 2020 Last Verified: July 2020 Individual Participant Data (IPD) Sharing Statement: Plan to Share IPD: Yes Supporting Materials: Study Protocol Statistical Analysis Plan (SAP) Clinical Study Report (CSR) Time Frame: Are available for 6 months Access Criteria: Those researchers who carry out physiotherapy studies for Irritable Bowel Syndrome
Layout table for additional information Studies a U.S. FDA-regulated Drug Product: No Studies a U.S. FDA-regulated Device Product: No
Privacy
Accessibility
U.S. Department of Health and Human Services
| https://clinicaltrials.gov/show/NCT04486469 |
64090e217d1ad705ea385088d1668401367bf1cbb4f7e9dc05672c0a99f734c8_optim.pdf
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| DH-XVR5816S-I3
DH-XVR5816S-I3
16 Channels Penta-brid 5M-N/1080P 2U 8HDDs WizSense Digital Video Recorder
· H.265+/H.265 dual-stream video compression. · Supports 16-channel AI-Coding. · Supports HDCVI/AHD/TVI/CVBS/IP video inputs. · Max 24 channels IP camera inputs, each channel up to 8MP; Max 128 Mbps incoming bandwidth. · Up to 4 channels video stream (analog channel) Perimeter Protection. · Up to 16 channels video stream (analog channel) SMD Plus. · Up to 2 channels video stream (analog channel) human face recognition. · IoT & POS functionalities.
Launched by Dahua Technology, WizSense is a series of AI products and solutions that adopt independent AI chip and deep learning algorithm. It focuses on human and vehicle with high accuracy, enabling users to fast act on defined targets. Based on Dahua's advanced technologies, WizSense provides intelligent, simple and inclusive products and solutions.
Series Overview Dahua Technology, a world-leading video-centric smart IoT solution and service provider, debuted its new XVR series, XVR5000-I3 Series featuring max.full-channel SMD Plus to benefit customers from AI upgrade (The number of channels differs depending on the model. Please refer to the specifications below for information on the number of channels.). This series has been developed to reduce false-alarm rates and the cost of human surveillance, thus bringing great value to customers in search of products with accurate human/vehicle alarm to raise the security level of various indoor and outdoor facilities.
Functions
Face Recognition Dahua Face Recognition technology extracts the features of captured faces and compares them with that in face database to recognize the person identity.
*Face Recognition takes effect when Face is selected in AI Mode.
Perimeter Protection Automatically filters out false alarms caused by animals, rustling leaves, bright lights, etc. Enables system to act secondary recognition for the targets. Improves alarm accuracy.
*Perimeter Protection takes effect when IVS&SMD is selected in AI Mode.
SMD Plus With intelligent algorithm, Dahua Smart Motion Detection technology can categorize the targets that trigger motion detection and filter the motion detection alarm triggered by non-concerned targets to realize effective and accurate alarm.
*SMD Plus takes effect when SMD or IVS&SMD is selected in AI Mode.
Scheduled AI This technology allows multiple AI functions to be set for one channel based on time frames, eliminating the need to manually configure the system to switch between functions each time. Scheduled AI greatly increases efficiency and widens the number of scenarios that the device can be used in.
Smart Dual Illuminators With Smart Dual Illuminators technology, you can select Smart Illumination Mode for the system to automatically switch between IR mode and white light mode. It allows white light to be turned on when a target is detected by the SMD Plus/Perimeter Protection function of AI-enabled XVR. This significantly reduces light pollution at night. Together with other modes, including IR Mode and White Light Mode, the smart dual illumination technology can meet the requirements of a wide variety of scenes.
One-click Arming/Disarming With just one click, you can enable or disable alarm linkages to show messages, send emails, output audio alarms and more, through the mobile app and platform.
Customizable Alarm Audio Designed for your convenience, the TiOC alarm can be customized to meet your needs. It is flexible, allowing you to directly upload your customized audio through the mobile app and XVR.
AI Coding Compared with H.265/H.264, AI coding can reduce more than 50% bit rate and storage requirements without loss of decoding compatibility, providing clear human and vehicle details.
Audio over Coax The integrated design can reduce wiring troubles which makes it much more cost-effective and convenient for installation.
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Technical Specification System
Main Processor
Embedded Processor
Operating System
Embedded Linux
Operating Interface
Web; Local GUI
Perimeter Protection
Perimeter Performance of AI by Camera (Number of Channels)
Face Detection
Advanced Model: 2 channels, 10 IVS for each channel General Model: 4 channels, 10 IVS for each channel
Face Attributes
Gender; age group; glasses; expressions; face mask; beard
Face Detection Performance of AI by Recorder (Number of Channels)
Face Recognition
2 channels (up to 12 face images/s)
Face Database Capacity
Up to 10 face databases with 10,000 face images in total. Name, gender, birthday, address, certificate type, cerificate No., countries®ions and state can be added to each face image
Face Recognition Performance of AI by Recorder (Number of Channels)
2 channels
SMD Plus
SMD Plus by Recorder
16 channels: Secondary filtering for human and motor vehicle SMD Plus, reducing false alarms caused by leaves, rain and lighting condition change
Audio and Video
Analog Camera Input Camera Input
IP Camera Input
Encoding Capacity
16 BNC ports, CVI access by default, supports HDCVI/ AHD/TVI/CVBS auto-detect
1. CVI: 5 MP@25/30 fps; 4 MP@25/30 fps; 1080p@25/30 fps, 720p@50/60 fps; 720p@25/30 fps. 2. TVI: 5 MP@25/30 fps; 4 MP@25/30 fps; 3 MP@25/30 fps; 1080p@25/30 fps; 720p@25/30 fps. 3. AHD: 5 MP@25/30 fps; 4 MP@25/30 fps; 3 MP@25/30 fps; 1080p@25/30 fps; 720p@25/30 fps.
Up to 24 channels of IPC access 8 IP channels by default + 16 channels (analog channels are converted to IP channels) incoming bandwidth: 128 Mbps, recording bandwidth: 128 Mbps and outgoing bandwidth: 128 Mbps *After IP channels are added beyond the existing channels, the AI Function (IVS, SMD, FACE) will be disabled.
Main stream: All channels 5M-N@(1 fps10 fps); 4M-N@ (1 fps15 fps); 1080p@(1 fps15 fps); 1080N@(1 fps 25/30 fps); 720p@(1 fps25/30 fps); 960H@(1 fps25/30 fps); D1@(1 fps25/30 fps); CIF@(1 fps25/30 fps) Sub stream: D1@(1 fps15 fps); CIF@(1 fps15 fps)
Dual-stream Video Frame Rate Video Bit Rate Audio Sampling Audio Bit Rate
Yes
PAL: 1 fps25 fps NTSC: 1 fps30 fps 32 kbps6144 kbps 8 kHz, 16 bit 64 kbps
Video Output Multi-screen Display
2 HDMI, 1 VGA, 1 TV Resolution VGA/HDMI2: 1920 × 1080, 1280 × 1024, 1280 × 720 HDMI1: 3840 × 2160, 1920 × 1080, 1280 × 1024, 1280 × 720 It changes to 1920 × 1080, 1280 × 1024, 1280 × 720 when Face or IVS&SMD is selected in AI Mode. *Heterogeneous video sources output for HDMI2 is configurable.
When IP extension mode not enabled: 1/4/8/9/16 When IP extension mode enabled: 1/4/8/9/16/25
Third-party Camera Access
ONVIF; Panasonic; Sony; Axis; Arecont; Pelco; Canon; Samsung
Compression Standard
Video Compression
AI Coding; H.265+; H.265; H.264+; H.264
Audio Compression
Network
Network Protocol Mobile Phone Access
G.711a; G.711u; PCM
HTTP; HTTPS; TCP/IP; IPv4; RTSP; UDP; SMTP; NTP; DHCP; DNS; DDNS; P2P iOS; Android
Interoperability
ONVIF 21.06; CGI
Browser
Chrome, IE9 or later, Firefox
Network Mode
Recording Playback
Multi-address mode,Fault Tolerance,Load Balance
Record Mode Recording Playback Backup Method Playback Mode
Storage
General, motion detection; intelligent; alarm; POS
1/4/9/16 It changes to 1/4/9 split when Face or IVS&SMD is selected in AI Mode
USB device and network
Instant playback, general playback, event playback, tag playback, smart playback (face and motion detection)
Disk Group
Yes
Alarm
General Alarm Anomaly Alarm Intelligent Alarm
Motion detection; video loss; tampering; local alarm
No disk; storage error; disk full; camera offline; IP conflict; MAC conflict
Face detection; face recognition; perimeter protection
Alarm Linkage
Ports
Record; snapshot (panoramic); IPC external alarm output; access controller; voice prompt; buzzer; log; preset; email
TV Output Audio Input Audio Output
Yes
16-channel BNC (external) 16-channel BNC (coaxial audio)
1-channel BNC
Two-way Talk
1-channel BNC
Alarm Input
16 channels
Alarm Output
6 channels
HDD Interface
8 SATA ports,up to 16TB, the maximum HDD capacity varies with environment temperature
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eSATA RS-232 RS-485 USB HDMI VGA Network Port
General
Power Supply Power Consumption Net Weight Gross Weight Product Dimensions
Packaging Dimensions Operating Temperature Operating Humidity Installation
Certifications
1 1 port, for PC Communication & Keyboard 1 port, for PTZ control 4 (2 front USB 2.0 ports, 2 rear USB 3.0 ports) 2 1 2 (10/100/1000 Mbps Ethernet port, RJ-45)
100240 VAC, 50±2% Hz <15 W (without HDD) 6.72 kg (14.81 lb) 9.32 kg (20.55 lb) 2U, 439.9 mm × 463 mm × 94.9 mm (17.32" × 18.23" × 3.73") (W × D × H) 570.0 mm × 570.0 mm × 226.0 mm (22.44" × 22.44" × 8.90") (W × D × H) 10 °C to +55 °C (14 °F to +131 °F) 10%90% (RH) Rack or desktop CE: CE-LVD: EN 60950-1/IEC 60950-1 CE-EMC: EN 61000-3-2, EN 61000-3-3, EN 55032, EN 50130, EN 55024 FCC: Part 15 Subpart B
Ordering Information
Type
Model
16 Channels WizSense XVR
DH-XVR5816S-I3
Description 2U DIGITAL VIDEO RECORDER
Dimensions (mm[inch])
<>
<>
<> <>
Panels
4
68
12
15
12 3
5
7 9 10 11 13 14 16
1 Ground 3 Power Switch 5 VIDEO IN 7 MIC OUT 9 VIDEO OUT 11 Network Ports 13 VGA Port 15 eSATA Port
2 Power Input 4 AUDIO IN 6 MIC IN 8 AUDIO OUT 10 RS-232 Port 12 Alarm In/Out 14 HDMI Ports 16 USB Ports
Rev 002.000
© 2022 Dahua. All rights reserved. Design and specifications are subject to change without notice. The images, specifications and information mentioned in the document are only for reference, and might differ from the actual product.
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Processes | Free Full-Text | An Agricultural Products Supply Chain Management to Optimize Resources and Carbon Emission Considering Variable Production Rate: Case of Nonperishable Corps
The management of the man& ndash;machine interaction is essential to achieve a competitive advantage among production firms and is more highlighted in the processing of agricultural products. The agricultural industry is underdeveloped and requires a transformation in technology. Advances in processing agricultural products (agri-product) are essential to achieve a smart production rate with good quality and to control waste. This research deals with modelling of a controllable production rate by a combination of the workforce and machines to minimize the total cost of production. The optimization of the carbon emission variable and management of the imperfection in processing makes the model eco-efficient. The perishability factor in the model is ignored due to the selection of a single sugar processing firm in the supply chain with a single vendor for the pragmatic application of the proposed research. A non-linear production model is developed to provide an economic benefit to the firms in terms of the minimum total cost with variable cycle time, workforce, machines, and plant production rate. A numerical experiment is performed by utilizing the data set of the agri-processing firm. A derivative free approach, i.e., algebraic approach, is utilized to find the best solution. The sensitivity analysis is performed to support the managers for the development of agricultural product supply chain management (Agri-SCM).
An Agricultural Products Supply Chain Management to Optimize Resources and Carbon Emission Considering Variable Production Rate: Case of Nonperishable Corps
by
Mohammed Alkahtani 1,* ,
Muhammad Omair 2 ,
Qazi Salman Khalid 2 ,
Ghulam Hussain 3 and
Biswajit Sarkar 4,*
Department of Industrial Engineering, College of Engineering, King Saud University, P.O. Box 800, Riyadh 11421, Saudi Arabia
3
Faculty of mechanical engineering, GIK Institute of Engineering Sciences & Technology, Topi 23460, Pakistan
4
Department of Industrial Engineering, Yonsei University, 50 Yonsei-ro, Sinchon-dong, Seodaemun-gu, Seoul 03722, Korea
*
Authors to whom correspondence should be addressed.
Processes 2020 , 8 (11), 1505; https://doi.org/10.3390/pr8111505
Received: 18 September 2020 / Revised: 4 November 2020 / Accepted: 11 November 2020 / Published: 20 November 2020
(This article belongs to the Special Issue Expanding the Horizons of Manufacturing: Towards Wide Integration, Smart Systems and Tools )
Abstract
The management of the man–machine interaction is essential to achieve a competitive advantage among production firms and is more highlighted in the processing of agricultural products. The agricultural industry is underdeveloped and requires a transformation in technology. Advances in processing agricultural products (agri-product) are essential to achieve a smart production rate with good quality and to control waste. This research deals with modelling of a controllable production rate by a combination of the workforce and machines to minimize the total cost of production. The optimization of the carbon emission variable and management of the imperfection in processing makes the model eco-efficient. The perishability factor in the model is ignored due to the selection of a single sugar processing firm in the supply chain with a single vendor for the pragmatic application of the proposed research. A non-linear production model is developed to provide an economic benefit to the firms in terms of the minimum total cost with variable cycle time, workforce, machines, and plant production rate. A numerical experiment is performed by utilizing the data set of the agri-processing firm. A derivative free approach, i.e., algebraic approach, is utilized to find the best solution. The sensitivity analysis is performed to support the managers for the development of agricultural product supply chain management (Agri-SCM).
Keywords:
agri-supply chain management
;
variable production rate
;
optimal resources
;
imperfect production
;
eco-efficient production
1. Introduction
Owing to the escalating awareness of resource depletion, climate change, and increasing population, firms in the agriculture domain need to redesign their current supply chain models by taking economic and environmental impacts into account [
1
]. The life cycle of products held in inventory and processing produce a major concern of perishability among agri-products throughout the supply chain. Therefore, replenishment strategies, product supply, and processing indicators are crucial to consider in the research models. The global market for perishable goods, such as refrigerated products and prepared meals, is growing due to changing lifestyles and overall decreasing tariffs. Owing to their common fragility and limited lifetime, handling those goods is far more complex and includes much higher risks compared to non-perishable products [
2
]. However, this work deals with the sugar processing from sugarcane as a raw material in local industry with outsourcing operation as a non-perishable product because of the long life of raw sugarcane. Also, the supply chain considers a small portion of the whole network, i.e., a single sugar processing firm with a single outsourcing vendor.
It is evident that the incidence of the uncertain factors is unforeseeable, which may induce a number of decision-making mistakes through the application of a traditional supply chain, thus incurring a high cost and unclean production environment [
3
]. Moreover, variable demand alters the former assumptions in which demand follows a discrete known distribution for different agri-products [
4
]. To cover up the deficit caused by the positive and negative surges in agri-product demand, an intelligent variable production model should be integrated within the supply chain. Moreover, controllable production will result in cleaner production as it will optimize the resources without losses and wastes. Because it is estimated that, by 2050, the overall production of food should increase by approx. 70% in order to feed the increasing global population [
5
]. Hence, the best utilization of resources in a supply chain is a key factor for cleaner agri-production.
Production technology has played a vital role in the upgradation agriculture supply chain and has been a limelight for governments and agri-business sectors. In the basic production model, the assumption of constant production rate was observed predominantly. Later on, the variable machine production rate was also included by considering optimal production costs in manufacturing systems. Although variable production rate remained the point of interest for researchers many years ago through its effects on machine tool cost with increasing production rate [ 6 , 7 ]. However, Moutaz Khouja (1995) [ 8 ] was among the pioneers to extend the basic production model and consider production rate as a decision variable for the volume flexibility of production. The model suggested the volume-flexibility of manufacturing systems for larger sized lots with a lesser production rate. Moreover, an increased production rate decreases the repeatability [ 9 ] of a robot and affects the quality, as discussed by [ 10 ].
This research contributes to transforming the idea of an intelligent, green supply chain production into a mathematical model. The aim of the model is to represent tangible analysis of human-machine interaction and imperfect production system in order to optimize use of resources and minimize wastes. The inclusion of carbon emission cost as an eco-efficient attribute along with the variable production rate, satisfying agribusiness firms’ demand, is also a limelight of this work, which is hardly observed in previous literature. Further, the impact of this work is extended to quantify production loss due to improper human-machine correspondence. The investigation provides a plan of action for agri-product manufacturing managers to invest in favor of optimized production with effective resource utilization, which ultimately leads to less rejection in a production environment.
The article is structured in a well possible way i.e., background and challenges to the agricultural supply chain management (agri-SCM) are discussed in this section. In Section 2 , the literature is well represented from author contributions, which are presented in consideration of the research gap. Section 3 covers the detailed mathematical formulation of controllable production rate, labor-machine interaction, inventory management, and eco-friendly agri-SCM. The solution method, i.e., algebraic approach application, is also given in Section 3 . Afterwards, Section 4 deals with the numerical experiment, which consists of the required data for performing the experiment using the proposed SCM model. The numerical results are also explained and illustrated significantly in Section 4 along the sensitivity analysis of the SCM model to mathematically check the significant cost parameters with respect to the total cost are also performed. In Section 5 , conclusion of the research study is discussed.
2. Research Reviews
In a cleaner production environment, prime attention is given to the reduction of production and associated costs. Fluctuation in agri-products’ raw materials, fuel prices and falling sale rates drive the agribusiness firms to incorporate technologies and processes which controls expenses. In order to fulfill the requirements of the future generations, the agri-product supply chain should eliminate existing wastefulness and lay emphasis over green defective free production. Such resource waste elimination requires decision assisted tools that covers intrinsic characteristics of an agri-based product. Furthermore, a green agri-product supply chain needs more than only economic validation objective (profit), thus, it should be also able to handle eco-efficient objective. Hence, the decision assisted tool requires the evaluation of both the economic and environmental aspects simultaneously. For this purpose, mathematical optimization is fairly viable to discover best values from the domain and set a better trade-off for managerial insights [
11
], and for establishing eco-efficient results-based system [
12
]. The detailed author contributions are given in
Table 1
.
Table 1. Author Contribution.
In the agricultural supply chain, most of the work is found in the logistic of food supply [ 13 ], food safety [ 14 ], and imperfect information system. As there is a desirable need to encounter the requirements of lean manufacturing, supervision of scraps and reworks due to the significant concerns for production systems [ 15 , 16 , 17 ]. In this aspect, Agri-SCM should be integrated with imperfect and green production. From the perspective of solution methodology, Minjung Kwak (2015) [ 18 ] recommended a mixed-integer linear-programming (MILP) model that optimizes the re-manufacturing plan in order to validate both the environmental and economic benefits of products. Some researchers have taken carbon footprint into account for development of cleaner production SCM models. For instance, Xiao et al. (2016) [ 19 ] optimized SCM cost via minimizing carbon footprint of both the retailers and manufacturers. In this domain, Chia-Chin Wu and Ni-Bin Chang (2004) [ 20 ] presented a grey theory model for uncertain conditions which reflects environmental impact by taking the production planning tax into account. Wang et al. (2011) [ 21 ] established a bi-objective model that evaluates the associated costs with environmental plans along a green SCM. Additionally, [ 22 ] suggested an electricity monitoring-system that considers a multi-objective linear-programming model taking carbon footprint into account by electricity usage as a supply of energy. As referred earlier, (Banasik (2019) [ 1 ]) that work included model development of an uncertain eco-efficient supply chain, however, their model lacks integration of imperfect production.
The effect of the workers’ cost on production and inventory is a significant aspect to cleaner production and can be analyzed in numerous models. Most of the researchers, i.e., [ 23 , 24 , 25 ] studied an imperfect production environment to assist the managers in dealing with poor quality products. Though, very few studies have analyzed the cause to reduce an imperfect production in the setup. A number of factors that affect the production flow and cause imperfection include reworks, rejections, and scraps etc. The management and planning of imperfect production in the model provide a cleaner production int the system and wastes are managed with modeling of the imperfect production [ 26 ]. In another study, Sarkar et al. (2018) [ 27 ] developed a global sustainable supply chain model with constant production rate having short-term production period in which synchronize mechanism is used to set the cycle time for each production stage. Tiwari et al. (2018) [ 28 ] presented a green production quantity model with random imperfect quality products, service level constraints, and failure in reworking. These are depending on the combined efficiency of the machines and workers. Further, the role of controllable production is effective in dealing with imperfect production.
Moutaz Khouja and Abraham Mehrez (1994) [ 29 ] proved the deterioration in quality of product with increase in production rates in an economic production inventory model. He reassessed Rosenblatt [ 30 ] work with an assumption of quality function. In another study, Khouja et al. [ 31 ] further extended his earlier model by assuming that the production rate had a probability to shift production system from in control to the out-of-control state. Later on, Somkiat Eiamkanchanalai and Avijit Banerjee (1999) [ 32 ] advanced the work and established model that determines both the optimal production cycle length and variable production rate for a single item. Giri et al. (2005) [ 33 ] introduced a flexible production rate EPQ model that addressed the issue of higher stress level of the human-machine interaction with the increase of production rate. In this EPQ model, the unit production cost was stated as a function of the production rate, under general failure and overhaul time. Moreover, [ 34 ] presented an EPQ model where the production cycle consisted of multiple runs at various production rates. The author revealed that the production rates should take values between demand rate and production rate that reduces the production cost. Later on, Shib Sankar Sana (2010) [ 35 ] studied unit production cost as a function of product reliability and variable production rate in imperfect production system. Giri et al.’s (2005) [ 33 ] model was later extended with stochastic demand by [ 36 ], sampling in inspection by [ 37 ], and stochastic repair time by [ 38 ]. Also, Zanoni (2014) [ 39 ] examined the case of energy consumption in two stage production system where production depends on the variable production rate.
Production inventory outsourcing policy was studied by [
45
] for a firm with Markovian in-house production capacity that faced independent stochastic demand operating with outsourcing operation. Also, Pablo Biswas and Bhaba R Sarker (2008) [
15
] proposed a manufacturing process whereby finished goods are produced along with a proportion of undesirable defective products and scrap. As the system is not always perfect, some scrap is produced during the manufacturing and/or rework processes. According to Wang et al. (2013) [
46
], when the outsourcing quantity and wholesale price are decision variables, the competitive contract manufacturer sets a wholesale price sufficiently low to allow both parties to coexist in the market, and the original equipment manufacturer outsources its entire production to contract manufacturer. Bettayeb et al. (2014) [
47
] presented a risk-based approach for quality control of complex discrete manufacturing processes to prevent massive scraps. The advancement targeted from this work is the proposal of a model, aiming at the quality control allocation of the products and an understandable algorithm to prevent the production of excessive amount of scrap.
This research deals with the agri-product supply chain management (Agri-SCM). Abundant work on variable production models on realistic case scenarios exists. Particularly, most of the research on eco-efficient (reducing carbon emission) supply chain assumes deterministic demands and constant production rate, and hardly flexible productivity is taken into account. Further, technology development urges for intelligent models in which man-machine interactions are optimized in order to attain minimal wastes. Such intelligent models can hardly be seen in the literature. Additionally, to assert an efficient green production through the supply chain, imperfect production plays a vital role to cut down the cost and reduce the consumption of extra resources. Moving forward, it is worth mentioning that no traces related to agri-products supply chain with intelligent eco-efficient model is found. This work contributes to the latest literature by: (1) providing a centralized, two-echelon supply chain model with variable production rates, (2) presenting an intelligent model in which human–machine interactions are optimized, (3) carbon emission cost and imperfect production are integrated with the proposed model to assure a cleaner production environment, and (4) Agri-SCM with deteriorated products is introduced.
3. Method and Materials
3.1. Research Modeling
This human–machine interface is more significant in the supply chain management of agricultural products. The research contributes to transform the theoretical idea into a mathematical model with an aim to represent the tangible analysis of the imperfect production system in supply chain management. The model is based on Agri-SCM for deteriorated agri-product by considering controllable production rate from the interaction of the human and workers. The flow diagram of the Agri-SCM is illustrated in
Figure 1
. This research deals with the two-echelon Agri-SCM and covers the agri-food processing firm, where the vendor is involved into few operations because of capacity limitation. The first stage includes the basic food operations, second stage is dedicated to the vendor operations, and the third stage is the finishing stage. The raw material in manufacturing firms is first processed through the basic cleaning operations. Then, the semi-finished parts are outsourced to the vendor firm. The inspection operations are carried out by the vendor, where the parts are sorted as good and defective. In order to compensate for the rejection to meet the required demand, the same quantity of rejections is ordered to manufacture from the first stage of the processing firm. The good agri-products are further delivered to the final stage for further processing and packaging.
Figure 1. The inventory diagram of the agricultural supply chain management (Agri-SCM).
3.1.1. Assumptions
The following assumptions were used for the proposed model.
The mathematical model is based on multiple types of agri-product. The constant and variable production rate with given demand is considered in respectively to avoid shortages [ 17 ].
The unit production cost is taken as [see for reference: [ 8 ] f ( p ) = C + g p + b P . Here, C is the unit cost of raw material, g represents the per unit cost component that is reduced as the production rate increases, and b P is the unit cost component that increases in the production rate (e.g., tools costs) [ 48 , 49 ].
The agri-product processing firm outsources few operations due to limited resources. The imperfect products are produced, for which reworking is done and inspection cost is incurred. The rejected products are disposed and recycled.
The model is applicable for non-perishable crop because it considers only a sugar processing firm with outsourcing operation.
The processing firm consisting the combination of labor and equipment/machines to process the agri-product.
Management of imperfection and carbon emission is considered to make the Agri-SCM a cleaner and eco-effective model.
3.1.2. Notation
The decision variables and the parameters used in the proposed mathematical modeling are denoted by the notations enlisted comprehensively in Appendix A .
3.2. Model Formulation
The inventory diagram of the imperfect agri-food processing firm with vendor/supplier is shown as in
Figure 1
, where the cycle time of production is given on the x-axis and inventory is given on the y-axis. The upper portion is showing the inventory of the agri-product processing firm, while the lower portion is associated with the vendor inventory. The objective of the research is to minimize the total cost of Agri-SCM, and the formulation of the cycle time of the processing firm is prerequisite to calculate the total cost (TC). Cycle time is taken as a decision variable in the production model, which is dependent upon the production rates of processing firm. The production rate of the processing firm, i.e.,
P j a
and
P j c
for first and final stage is relying on the production rate of the machines (
ε j a
and
ε j c
). In order to meet the customer demand and no shortages in the processing firm, the production rates are considered as a variable (i.e.,
ε j a *
and
ε j c *
) to take an advantage of flexible production, where,
ε j a * ∈ [ ε j a − m i n * , ε j a − m a x * ]
and
ε j a * ∈ [ ε j c − m i n * , ε j c − m a x * ]
. The total cost of production is the sum of Agri-processing firm and vendor cost as given in Equation (1) and their formulations are further represented as following.
Total cost of production = Agri-processing cost + Vendor cost
(1)
3.2.1. Agri-Processing Cost
The total cost associated with the manufacturer include the cost related to the first stage and final stage of the processing firm, where the basic cost includes setup, production, labor, holding, carbon emission, and stress, as expressed in Equation (2).
Total cost of agri-processing = Setup cost + processing cost + Labor cost + Holding cost + Carbon emissions cost
(2)
The breakup of the agri-processing cost is necessary to understand each cost clearly. That is the reason all the costs are described mathematically and theoretically in Equations (3)–(10) as follows.
3.2.2. Setup Cost
The incurred cost is subject to the initial cost required to operate the production setup. Generally, it may contain setup cost, substitution, and tool setting cost. Further, this is fixed nature cost, independent of quantities, though time dependent. The expression is given in Equation (3).
S C = ∑ j = 1 J A j
(3)
3.2.3. Production Cost
Explicitly, cost incurred in the processing, which is largely dependent on quantity and variable in nature. The cost is accumulation of all costs utilized on resources that are required to manufacture a product. It contains the processing and machining cost, utilities needed for machines, and labor cost. Further, it is linked with the manufacturing processes of initial stage manufacturing. and are the production rates of the initial stage processing plant and machines respectively. Lastly, the production cost is the summation of all the costs linked with the raw materials, production, and tool-die cost [
50
]. The expression is given as in Equation (4).
M C = ∑ j = 1 J ( C r m + T D m a j P j a + g m a j P j a ) P j a t 1 j + ( T D m c j P j c + g m c j P j c ) Q j c
(4)
3.2.4. Holding Cost
Holding cost is the basic cost need to understand the basic production model, which is variable and dependent upon the variable inventory at any instant of time. This is the carrying cost of holding inventory. Holding cost depends on production of semi-finished and finished goods used as stock. It is incurred on production and crashing quantities in the proposed model and includes costs such as wedges, warehouse rent, and insurance. It also depends on the holding time of the product in inventory. The holding cost will be applied on the inventory supported by manufacturing firm, outsourcing operations. The average inventory is calculated as the ratio of the sum of inventories in the form of area under the curve to the cycle time of the production, which is expressed as in Equation (7). The cycle time and inventory levels of the processing firm are calculated by a step-by-step procedure gives in
Appendix B
.
T o t a l I n v e n t o r y = A r e a 123 + A r e a 10,11,12 + A r e a 11,12,13
(5)
= Q j 2 2 P j a + ( Q j − u ) 2 2 P j c ( 1 − D j P j c ) + ( Q j + u ) 2 2 D j ( 1 − D j P j c ) 2
(6)
H C m j = ∑ j = 1 J h m j [ Q j 2 2 P j a + ( Q j − u ) 2 2 P j c ( 1 − D j P j c ) + ( Q j + u ) 2 2 D j ( 1 − D j P j c ) 2 ] .
(7)
3.2.5. Carbon Emission Costs
The model optimized the carbon emission cost as a function of production rate to develop an eco-friendly and eco-effective agri-product SCM. The carbon emission in the agri-processing firm depends upon the source of energy consumed by the equipment/machines. The cost of carbon is incurred by the state government to support the global warming issue. The cost of carbon emission is generated during the life cycle production, which is given as in Equation (9), where
A
is the emissions function parameter (ton.year/unit),
B
is the emissions function parameter (ton year/unit), and
C
is the emissions function parameter (ton/unit) [
51
].
C a r b o n e m i s s i o n c o s t ( C E C j ) = C o s t o f c a r b o n e m i s s i o n i n m a n u f a c t u r i n g ( C E M )
(8)
= ∑ j = 1 J γ 2 [ ( A P j a 2 − B P j a + C ) P j a t 1 j + ( A P j c 2 − B P j c + C ) Q j c ]
(9)
3.2.6. Labor Cost
The cost is associated with the utilization of the workforce in the agri-SCM. The wages paid to the workers on the basis of the level of the skilled. Here, the cost is incurred to reflect the importance of the unskilled workers to understand the importance of the human factor in the processing firm. The labor cost is calculated on the basis of the machines required in the agri-product processing firm, which is expressed in Equation (10).
L a b o r c o s t ( L C ) = ∑ j = 1 J L j W j
(10)
The number of machines required and the amount of labor required in the processing firm are given in Equations (11) and (13), where l
aj
, and l
cj
are the labor rate or the number of labors working on each machine.
K j = K j a + K j c
(11)
N u m b e r o f l a b o r s = L a b o r r a t e × N u m b e r o f m a c h i n e s × P r o d u c t i o n t i m e
(12)
L j = l a j ρ K j a + l c j ρ K j c
(13)
3.2.7. Stress and Workers’ Efficiency
The efficiency of the processing firm depends upon the efficiency of the workers to fulfill the customer demand before deadline. The labor-machine coordination in the processing firm is very important for effective and efficient processing firm. The relationship between the average worker’s stress and efficiency is expressed as given in Equation (15), where
m
is scale factor,
ρ 0
is the workers’ efficiency affected by stress, and
ρ 1
is the efficiency due to the effect of another factor. Therefore, the total efficiency of the worker will be
ρ
[
52
,
53
].
ρ 0 = e − s / m ,
(14)
ρ = ρ 1 ρ 0 .
(15)
3.2.8. Stress Level and Defective Rate
The relationship is developed between the defective rate and averages stress among worker, where the defective rate is considered as a function of stress having a significant impact on the processing firm. The increasing rate of average stress among workers increases the defective rate. That is the reason, the expression for defective is the sum of initial and variable defective rate as expressed in the Equation (16), where variable defective rate is a function of stress among workers,
α 0
is the initial defective rate,
τ
and,
ϵ
are the scaling factors, and
s
is average stress among worker [
53
]. The analysis of workers’ stress on the production system has already been analysed by the research work of Omair et al. [
53
]. Therefore, the formulation has been incorporated in this study. However, the analysis of workplace stress on the production system is not highlighted.
α j = α 0 + τ ( s ) ϵ .
Now, the mathematical form of the total cost of the agri-processing firm is expressed as in Equation (17).
T C a j = ∑ j = 1 J [ A j + ( C r m + T D m a j P j a + g m a j P j a ) P j a t 1 j + ( T D m c j P j c + g m c j P j c ) Q j c + L j W j + h m j [ Q j 2 2 P j a + ( Q j − u ) 2 2 P j c ( 1 − D j P j c ) + ( Q j + u ) 2 2 D j ( 1 − D j P j c ) 2 ] + γ 2 [ ( A P j a 2 − B P j a + C ) P j a t 1 j + ( A P j c 2 − B P j c + C ) Q j c ] + s S C j ] .
The costs related to the manufacturer in the first and final stages of production are calculated, and the costs associated with the vendor are given in the next section.
3.3. Vendor Cost
The semi-finished agri-products are delivered to the vendor for processing few operations. The cost of vendor is the sum of the costs associated with the production, holding, inspection, and recycling of the processes is given in Equation (18). These costs are expressed in the Equations (19)–(24).
Vendor cost = Production cost + Holding cost + Inspection cost + Reworking cost + Scrap recycle cost + Buffer cost
3.3.1. Production Cost of Outsourcing
The expression for production cost is utilized from the research work done by [
50
] except the cost of raw material, because of receiving the semi-finished products from the manufacturer. The expression is given in Equation (19).
M C O = ∑ j = 1 J [ ( T D o j P j b ( 1 − α j ) + g o j P j b ( 1 − α j ) ) P j b ( 1 − α j ) t 2 j ] .
(19)
3.3.2. Holding Cost of Vendor
The holding cost of outsourcing operations is obtained by the sum of inventories calculated from Appendix B . The expression for calculating the total cost of production is expressed in Equation (22).
T o t a l I n v e n t o r y = A r e a 456 + A r e a 5678 + A r e a 689
= Q j 2 ( 1 − α j ) 2 P j b + α j ( 1 − α j ) Q j 2 P j b + α j 2 Q j 2 ( 1 − α j β j ) 2 P j b ,
H C = ∑ j = 1 J [ h o j [ Q j 2 ( 1 − α j ) 2 P j b + α j ( 1 − α j ) Q j 2 P j b + α j 2 Q j 2 ( 1 − α j β j ) 2 P j b ] ] .
3.3.3. Inspection Cost
Inspection of the agri-product is carried out by the vendor, where the products are checked according to the quality control dimensions. The parts are categorized into good and rejected. The total inspection cost of the production is the sum of the fixed and variable inspection cost in the processing, as expressed in Equation (23).
I C j = ∑ j = 1 J [ θ j + ψ j a P j a t 1 j + ψ j b P j b t 2 j ]
3.3.4. Recycling Cost/Disposal Cost
Recycling cost is considered in the agri-processing firm. It is not concerned with the recycling of the agri-product after deteriorated but it is the cost incurred on rejected/defective or imperfect agri-product. The customer/user is not the part of the proposed agricultural supply chain management (Agri-SCM) that is the reason, the perishability factor is not considered. Here, recycling cost is the cost incurred on disposing the imperfect/defective not due to deterioration or perishability factor. These products are bio-waste and further utilized into other byproducts, i.e., fertilizers, bio-fuel, feeds, etc., in the processing expressed as in the equation given below.
R C j = γ 1 P j b t 2 j α j β j
The mathematical expression to sum all the costs equations is represented as given in Equation (24).
T C v j = ∑ j = 1 J [ ( T D o j P j b ( 1 − α j ) + g o j P j b ( 1 − α j ) ) P j b ( 1 − α j ) t 2 j + Q j 2 ( 1 − α j ) 2 P j b + α j ( 1 − α j ) Q j 2 P j b + α j 2 Q j 2 ( 1 − α j β j ) 2 P j b + θ j + ψ j a P j a t 1 j + ψ j b P j b t 2 j + γ 1 P j b t 2 j α j β j ]
The production system of agri-product processing firm is analyzed by the formulation of mathematical model. The mathematically model is based on the cycle time of production. The objective of the proposed model is to minimize the total cost
( T C s j )
of processing firm. The total cost per cycle is given in Equation (26).
T o t a l c o s t = A g r i − p r o c e s s i n g c o s t + M R ( V e n d o r c o s t )
(25)
T C j = ∑ j = 1 J 1 T j [ A j + ( C r m + T D m a j P j a + g m a j P j a ) P j a t 1 j + ( T D m c j P j c + g m c j P j c ) Q j c + L j W j + h m j [ Q j 2 2 P j a + ( D j T j ) 2 2 P j c ( 1 − D j P j c ) + ( Q j + u ) 2 2 D j ( 1 − D j P j c ) 2 ] + γ 2 [ ( A P j a 2 − B P j a + C ) P j a t 1 j + ( A P j c 2 − B P j c + C ) Q j c ] + s . S C j + M R [ ( T D o j P j b ( 1 − α j ) + g o j P j b ( 1 − α j ) ) P j b ( 1 − α j ) t 2 j + Q j 2 ( 1 − α j ) 2 P j b + α j ( 1 − α j ) Q j 2 P j b + α j 2 Q j 2 ( 1 − α j β j ) 2 P j b + θ j + ψ j a P j a t 1 j + ψ j b P j b t 2 j + R j α j Q j ( 1 − α j β j ) + γ 1 P j b t 2 j α j β j ] ]
(26)
where,
L j = L j a + L j c
Q j = T j D j ( Ω ) 1 − α j 2 β j
t 1 j = T j D j K j a ε j a ( 1 − α j 2 β j )
t 2 j = T j D j P j b ( 1 − α j 2 β j )
t 4 j = T j D j K j c ε j c
t 5 j = ( T j D j 1 − α j 2 β j − u ) ( K j c ε j c − D j D j K j c ε j c )
The SCM mathematical model is non-linear by minimizing total cost of SCM, where the decision variables are ( T j , L j a , L j c , K j a , K j c , P j a , and P j c ) .
3.4. Solution Algorithm
The variability in the proposed Agri-SCM model make the model non-linear in nature. The decision variables considered are relying on the decisions of the production planning. Analytically, the proposed model is optimized with the help of improved methodology called algebraic function, which is based on quadratic equation. There are four decision variables, i.e., cycle time (
T j
), machines (
K ja
,
K jc
), production rate (
ε ja
,
ε jc
), and labors (
L ja
,
L jc
) to optimize the non-linear imperfect production model. The algebraic method consists of a positive expression type, and can be rewritten as:
f ( x ) = a 1 x + a 2 / x + a 3 = a 1 x ( x 2 + a 2 / a 1 − 2 x a 2 / a 1 + 2 x a 2 / a 1 ) + a 3
(27)
f ( x ) = a 1 x ( x 2 + a 2 / a 1 − 2 x a 2 / a 1 ) + 2 a 1 a 2 / a 1 + a 3
f ( x ) = a 1 x ( x − a 2 / a 1 ) 2 + 2 a 2 a 1 + a 3
Since the quadratic expression is non-negative and a 1 is positive, it is always minimized for x = a 2 / a 1 , which reaches the minimum at f ( x ) = 2 a 2 / a 1 + a 3 .
In the first step of solution algorithm, by using algebraic function methodology, the form of decision variable
T j
can be written as given in Equation (30).
T C s j ( T j , K j a , K j c , L j a , L j c , ε j a , ε j c ) = 1 T j [ A j + ( C r m + T D m a j P j a + g m a j P j a ) P j a t 1 j + ( T D m c j P j c + g m c j P j c ) Q j c + L j W j + h m j [ Q j 2 2 P j a + ( D j T j ) 2 2 P j c ( 1 − D j P j c ) + ( Q j + u ) 2 2 D j ( 1 − D j P j c ) 2 ] + γ 2 [ ( A P j a 2 − B P j a + C ) P j a t 1 j + ( A P j c 2 − B P j c + C ) Q j c ] + s . S C j + M R [ ( T D o j P j b ( 1 − α j ) + g o j P j b ( 1 − α j ) ) P j b ( 1 − α j ) t 2 j + Q j 2 ( 1 − α j ) 2 P j b + α j ( 1 − α j ) Q j 2 P j b + α j 2 Q j 2 ( 1 − α j β j ) 2 P j b + θ j + ψ j a P j a t 1 j + ψ j b P j b t 2 j + R j α j Q j ( 1 − α j β j ) + γ 1 P j b t 2 j α j β j ] ]
The Equation (30) can be written as in Equation (31)
= 1 T j [ A j + s . S C j + θ j + M R × T D o j P j b ( 1 − α j ) ] + T j [ h m j [ D j 2 2 P j a ( 1 − α j β j ) 2 + 1 2 P j c ( D j 1 − α j 2 β j − α j β j D j 1 − α j 2 β j ) 2 ( 1 − D j P j c ) + ( D j 1 − α j 2 β j − α j β j D j 1 − α j 2 β j ) 2 ( 1 − D j P j c ) 2 ] + M R [ ( D j 1 − α j 2 β j ) 2 1 − α j 2 P j b + α j ( 1 − α j ) P j b ( D j 1 − α j 2 β j ) 2 + α j 2 ( 1 − α j β j ) 2 P j b ( D j 1 − α j 2 β j ) 2 ] ]
Our assumptions are given as in Equations (32) and (33).
A 1 = ∑ j = 1 J [ A j + s . S C j + θ j + M R × T D o j P j b ( 1 − α j ) ]
(32)
A 2 = ∑ j = 1 J [ h m j [ D j 2 2 P j a ( 1 − α j β j ) 2 + 1 2 P j c ( D j 1 − α j 2 β j − α j β j D j 1 − α j 2 β j ) 2 ( 1 − D j P j c ) + ( D j 1 − α j 2 β j − α j β j D j 1 − α j 2 β j ) 2 ( 1 − D j P j c ) 2 ] + M R [ ( D j 1 − α j 2 β j ) 2 1 − α j 2 P j b + α j ( 1 − α j ) P j b ( D j 1 − α j 2 β j ) 2 + α j 2 ( 1 − α j β j ) 2 P j b ( D j 1 − α j 2 β j ) 2 ] ] ,
In the algebraic function approach, the constant term becomes neglected and equal to zero. Therefore, the cost function can be given as in Equation (34).
T C s j ( T j * , K j a , K j c , L j a , L j c , ε j a , ε j c ) = A 1 T j + A 2 T j
= ( A 1 T j ) 2 + ( A 2 T j ) 2 ,
= ( A 1 T j − A 2 T j ) 2 + 2 A 1 A 2 .
By the algebraic approach, in Equation (36), having the square term as a maximum value, the square will be zero, i.e.,
( A 1 T j − A 2 T j ) 2 = 0 ,
A 1 T j − A 2 T j = 0 ,
A 1 T j = A 2 T j ,
T j * = A 1 A 2
By putting the value of in Equation (34). The Equation (41) is obtained as.
T C s j ( T j * , K j a , K j c , L j a , L j c , ε j a , ε j c ) = ∑ j = 1 J A 1 T j * + A 2 T j * .
In the second step, the production rate of each machine in the first stage (
) and final stage (
ε j c
) of the production system are also calculated by using algebraic approach. First of all, to find optimal (
ε j c
), the
T C s j
can be converted into the form given as in the following equation:
T C s j ( T j * , K j a , K j c , L j a , L j c , ε j a , ε j c ) = ε j c [ T D m c j K j c D j − B K j c γ 2 D j ] + 1 ε j c [ g m c j D j K j c + l c j D j W j ρ + h m j ( Q j − u ) 2 2 K j c T j * − ( Q j + u ) 2 h m j K j c T j * ] + [ − h m j T j * { ( Q j − u ) 2 2 K j c D j ( ε j c ) 2 + ( Q j + u ) 2 2 D j D j ρ K j c ε j c } + γ 2 T j * D T A ( K j c ε j c ) 2 ] + [ γ 2 D j ε j a + ( Q j + u ) 2 2 D j T j * h m j + l a j D j W j ρ ε j a ( 1 − α j 2 β j ) ]
R 1 = ε j c [ T D m c j K j c D j − B K j c γ 2 D j ]
R 2 = 1 ε j c [ g m c j D j K j c + l c j D j W j ρ + h m j ( Q j − u ) 2 2 K j c T j * − ( Q j + u ) 2 h m j K j c T j * ]
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Warsaw on the Rise | Travel| Smithsonian Magazine
A new crop of skyscrapers symbolizes the Polish capital's effort to rebuild its downtrodden image
Warsaw on the Rise
Designed by Polish-American Daniel Libeskind, the Zlota 44 building, which is under construction, may lift the city's profile. Tomas van Houtryve
It was as a student in Paris looking for a cheap travel adventure during Christmas break that I got my first glimpse of Warsaw. I had signed up with a couple of friends for a trip into Poland’s Tatra Mountains, and our second-class compartment on the night train was oppressively overheated until, shortly after midnight, cars holding Red Army officers were added in East Berlin, and the heat ceased entirely for the rest of us.
Shivering and miserable, I disembarked before dawn at a bleak platform swept by fine needles of icy snow, backlit by large military-style floodlights on lofty stanchions. It was 1961. The air smelled of low-octane gasoline, the signature scent of urban Eastern Europe in those days. Warszawa, the big station signs read. The atmosphere was eerily gulag.
Many trips over the years only confirmed my initial impression: gray, patched together and woebegone, Warsaw was an ugly misfit compared with the timeless beauties of Rome, Paris and Stockholm or, closer by, the three fabulous Austro-Hungarian gems of Vienna, Prague and Budapest.
There was good reason for Warsaw’s pitiable state. Before World War II, it had been a parklike city, a picture postcard of old-world Central European architecture on a human scale. But beginning in 1939, in the war’s opening days, the city suffered grievously from Nazi shelling and the terror bombing that targeted residential areas. The Nazis would destroy the Jewish ghetto, and more than 300,000 of its residents would die of starvation or disease or in death camps. As the war ground toward its final act, Hitler—enraged by the Polish Home Army’s general insurrection, during which more than 200,000 Poles were killed—ordered Warsaw to be physically erased. Over three months in 1944, the Nazis expelled the city’s 700,000 remaining residents and leveled nearly all of what still stood: incendiary and dynamite squads moved from building to building, reducing them to rubble or, at best, charred shells.
No other city in Europe—not even Berlin or Stalingrad—was taken down so methodically. Rebuilding in haste with the poor materials and primitive equipment available in the dreary postwar days of Soviet domination, Varsovians reclaimed a bit of their history by painfully recreating, stone by stone, the beautiful Old Town section, the elegant Royal Route leading to it, the Market Square and the Royal Castle. But the rest of the city grew into a generally undistinguished low-rise sprawl, some of it the patched-up remains of the rare buildings that escaped complete destruction, some re-creations of what had existed before, but mostly quick-lick solutions for a returning population in desperate need of shelter, offices and workshops. Little did anyone suspect that half a century later Warsaw’s agony would serve as an unexpected advantage over other major European cities: since it was no longer an open-air museum of stately mansions, cathedrals and untouchable historical monuments, the city could be molded into a dashing showcase of contemporary architecture.
In the meantime, though, postwar Poland was threadbare, excruciatingly poor, trammeled by the economic absurdities of Marxist ideology and totally in thrall to the Soviet Union. Between 1952 and 1955, Moscow dispatched several thousand Russian workers to give Warsaw its “Eiffel Tower”: the Joseph Stalin Palace of Culture and Science, a massive confection of tan stonework 42 stories high. At 757 feet, it is the tallest building in Poland (and is still the eighth highest in the European Union) and resembles an oversize wedding cake. It was billed as a fraternal gift from the Soviet people, but it sent a different message: we are bigger than you will ever be, and we are here forever. Big Brother, indeed.
I can’t count the number of Poles who told me the old saw about the palace’s observation platform being the most popular site in Warsaw because it’s the only spot from which you couldn’t see the palace. Even when Stalin’s name was lifted three years after the murderous despot died, Varsovians detested the palace for the political statement it made and for its gaudy hugeness. After 1989, the year the Berlin Wall came down, signaling Communism’s fall, younger citizens began to view it with the sort of grudging acceptance that one might feel toward a doddering but harmless old relative.
But what to do about it? In the euphoria of the early days of freedom from the Soviets, many assumed the palace would soon meet a wrecker’s ball. But it is in the very heart of downtown Warsaw—in a way it was the heart of downtown Warsaw—and it contains offices, theaters, shops, museums, a swimming pool, a conference center, even a nightclub. It had its uses. The answer was a cold war-style compromise: peaceful coexistence.
Under the Communist regime, construction had begun on the first rival to the palace: a 40-story, glass-fronted hotel and office building completed in 1989. By then, Eastern Europe was changing with dizzying speed. In Warsaw, five decades of repressed entrepreneurial energies had been released like an explosion, and soon shiny new buildings were mushrooming from one end of the city to the other. Seizing the freedom to speculate, developers threw up office and apartment blocks of dubious quality, inevitably heavy on the basic glass box cliché. Before, people had worried about what to do with the palace; now they worried about what was happening around it.
Poland, the biggest and most populous of the USSR’s former European satellites, was taking to capitalism like a Labrador pup to a muddy puddle, and the largely underdeveloped country was a good bet for future profits. Eager to secure a foothold and capitalize on low wages and high levels of skill, foreign firms rushed in. Company headquarters of a quality that would not be out of place in New York or Frankfurt began going up.
By 2004, when Polish membership in the European Union was sealed (the nation had joined NATO in 1999), the flow of foreign capital had turned into a flood. Warsaw boomed. Lech Kaczynski, mayor from 2002 to 2005, parlayed his headline-grabbing ways into the nation’s presidency. (Kaczynski died in a plane crash last April.) The current mayor, an economist and former academic named Hanna Gronkiewicz-Waltz, set out to reshape the mutilated city’s downtown area, promising not simply to modernize the city but turn it into Central and Eastern Europe’s principal financial address.
“We will change the downtown,” she declared after taking over in 2006. “In the Parade Square area, skyscrapers will be built, which will become our city’s new pride.” Everyone knew what that meant: the square is home to the palace. The time had come to bring on the “starchitects.”
Gronkiewicz-Waltz knew that she could not turn Warsaw into a futuristic never-never land like Dubai or Abu Dhabi—there was too much urban history to cherish and too little oil underfoot to pay for vastly ambitious projects—but international architects and promoters could make the city’s heart glitter. “Warsaw must grow up if it wants to compete with other big European cities,” the mayor said. She meant “up” literally.
One illustrious architect had already made his mark on the city. Norman Foster’s sober Metropolitan Building, inaugurated in 2003, was a mere seven stories high but something to behold: three cornerless, interconnected wedges, each with its own entryway, their facades punctuated by protruding granite fins that seemed to change color according to the brightness of the sky and the position of the sun. It proved to be a surprise hit with ordinary Varsovians—even parents with bored children. With a crowd-pleasing circular courtyard filled with shops, restaurants, shade trees and a fountain, the building boasts amusement park flair. A ring of 18 water jets set into the granite pavement and activated by high-pressure pumps sends spurts to varying heights, leading to a socko 32-foot burst.
But the Metropolitan was only the beginning. “We intend to build skyscrapers, yes,” says Tomasz Zemla, deputy director of Warsaw’s Department of Architecture and City Planning. “To be honest, we want to show off.”
An architect himself, Zemla presides over the city’s future in a spacious, high-ceilinged office in the central tower of the Palace of Culture and Science. “We need to get the chance to compete with Prague, Budapest and maybe even Berlin,” he says, “because it is our ambition to become an important financial center in this part of Europe. Capital in Poland is very dynamic, very strong.” As for the palace, he continues, “We can’t let it be the most important building anymore. You know, it’s still the only really famous building in Poland. Children see it as the country’s image. We need to compete with that. We have to show our ideas. We have to do bigger and better.”
To anyone who roamed the barren city in the ‘60s, ‘70s and ‘80s searching vainly for a decent café or restaurant—endlessly importuned by hustlers on the sidewalks, prostitutes in hotel lobbies and pettifogging officials at the airport—today’s Warsaw is an astonishing contrast. The city teems with shops, cafés, bars, restaurants and consumer services. A passion for trade has bred an orgy of commercial graphics—taxis and buses virtually disappear under advertisements, entire building fronts are hidden by roll-down canvas billboards. Young men and women on the crowded sidewalks chatter in the chewy syllables of their Slavic tongue, inevitably larded with Americanisms and computerese like the beguiling zupgradowac(to improve), derived from “upgrade.” Just across the street from the palace, the Zlote Tarasy (Golden Terraces) mall, opened in 2007, provides shelter from the elements under an enormous, impudently weird, silvery blanket of undulating triangular glass panes (like some ectoplasmic creature from the deep heaving up and down to catch its breath). In a vast central space escalators zoom the iPod generation to every chain store and fast-food joint that the world’s marketing geniuses could dream of. Dour, drab old Warsaw is turning into a polychrome butterfly.
Among the first starchitects to seriously challenge the dominance of the Palace of Culture was Helmut Jahn of Chicago, creator of One Liberty Place in Philadelphia and the spectacular Sony Center in Berlin. His elegantly classical Residential Tower Warsaw, 42 floors of apartments and commercial space, is now under construction just a block behind the old Soviet rock pile.
Zlota’s stop-and-start progress is typical of the obstacles facing any ambitious administration in a hurry, but Warsaw had the further bad luck to be in full stride when the world banking crisis hit and credit dried up. Suddenly the grandest project of all—Zaha Hadid’s Lilium Tower—was menaced.
Hadid, an Iraqi-born British architect, planned a structure that would dominate the skyline once and for all—the first building in Warsaw to be higher than the palace. Her proposed tower of some 850 feet is destined for a site opposite the main railroad station. Gracefully curved, bowed outward in the middle and tapering at the top and bottom, Lilium’s four wings inescapably evoke horticultural images. There’s not a square line visible, and the building makes a stunning contrast to the palace’s plodding right angles and heavy decorations.
“I love that shape,” says Zemla, before extolling all three of his pet projects: “They’re beautiful.” Unfortunately, though, he and the rest of Warsaw will have to wait to see the Lilium grow. For the moment, the developers have put the project on hold until the economy improves.
Inevitably, some people would dispute Gronkiewicz-Waltz’s belief that skyscrapers are the ticket. Disdaining the race for postmodern glamour, an articulate minority calls for the city to seek instead to recapture the homey atmosphere of Middle Europe before World War II, sometimes idealized as a place of comfortable, easy living, of cobbled streets with friendly little shops, open-air markets and tree-shaded sidewalk cafés.
“When we got our freedom in 1989, I thought we would finally have real quality architecture for human society’s needs,” says Boleslaw Stelmach, an architect specializing in building in historic areas. “Instead, I found myself working in a huge office, not doing architecture but producing buildings like a factory. Well, I would rather see wiser than taller.”
Certainly Warsaw of the late ‘30s was a place of sharp intellectual activity, avant-garde theater, poetry readings, Chopin recitals and the like, but some critics of the skyscraper movement go further than Stelmach and overly romanticize the city’s past. The old Warsaw was not necessarily a civic paragon. There were also poverty, discord and social injustice—the same dark underside as any urban center.
Still, Warsaw’s long history of oppression by Russians and Germans, the terrible efficiency of its destruction and its dogged persistence in reclaiming the past make it a place apart: a city that has been obliged to reinvent itself. Even as the aesthetes and the philistines argue about what it should become, that reinvention continues. Remarkably enough, a sensible compromise seems to be falling into place.
“Yes, the center of Warsaw is going to be skyscraper city,” says Dariusz Bartoszewicz, a journalist specializing in urban matters at the Gazeta Wyborcza. “That’s its destiny. Twenty or 30 of them will be built for sure. Not in the next five years, but over time. It will happen.”
At the city’s fringes, a second wave of innovative design is beginning to reshape the Vistula River’s largely undeveloped banks. The Warsaw University Library is not only low, a mere four stories high, but meant to disappear. Topped by a 108,000-square-foot roof garden and draped with climbing plants whose greenery melds into the green of oxidized copper panels on the building’s facade, this ultramodern repository for two million books is what happens when architects are willing to share glory with a gardener.
The lead architect, Marek Budzynski, is a renowned university professor, but the landscape architect, Irena Bajerska, was virtually unknown until she was brought onto the design team. Her garden has become so popular it is now part of the regular Warsaw tourist routes. Bajerska beams and points out the young couples suited up in their tuxedos, white dresses and veils posing within her foliage for formal wedding photographs, while kids romp on the winding paths and retirees take their ease, reading newspapers and enjoying views of the city and the river.
Across the street, low-rise, riverfront apartment buildings are going up, and a series of planned projects, beginning with the Copernicus Science Center, next to the library, will perpetuate the human-scale development along the riverbank: bicycle, pedestrian and bridle paths, pleasure boat wharves and reconstruction of the Royal Gardens below historic Old Town.
“Warsaw is now in the middle of great, great things going on,” Wojciech Matusik assures me as he sips a drink in the posh bar of the Bristol Hotel, a five-minute walk from Norman Foster’s Metropolitan Building. Formerly the city’s director of planning, Matusik was once in charge of development, a position that allowed him to anticipate much of what is happening today.
I had frequented the Bristol in the ‘70s when it was a shabby, down-at-the-heels palace way past its prime (and I had known Matusik when he was a modestly paid functionary). Now renovated, the Bristol is one of Warsaw’s finest hotels, and Matusik, elegantly tailored, today a real estate consultant, is right at home. The man and the hotel have both prospered, and illustrate the distance Warsaw has come since I first passed through here 50 years ago.
“The past is very heavy here,” said Bogna Swiatkowska, a young woman who founded an organization to bring art and artists to public places. “So much happened here—World War II, the ghetto, the uprising and everything after. We live with ghosts in Warsaw, but it’s a very special place with wonderful, talented, creative people. Now it’s time to get rid of the ghosts, make our peace with the past, and think about the future.”
Rudolph Chelminskiis author of The Perfectionist: Life and Death in Haute Cuisine.Tomas van Houtryve, a photographer on his first assignment for Smithsonian, lives in Paris.
Before World War II, Warsaw had been a parklike city, a picture postcard of old-world Central European architecture on a human scale. Guilbert Gates
Debates about Warsaw's future are rooted in its destruction by the Nazis. Shown here is the ghetto c. 1945, with the Church of St. Augustine. Stanislaw Dabrowiecki / CAF / PAP / Corbis
"Skyscrappers will be built," Mayor Hanna Gronkiewicz-Waltz says. Critics argue for building on an intimate scale, like the prewar city. Tomas van Houtryve
Construction cranes may loom, as shown here from the roof garden of the Warsaw University Library, but not all innovations are high-rise. Tomas van Houtryve
In Warsaw, decades of repressed entrepreneurial zeal was released with Communism's fall in 1989. Tomas van Houtryve
"It is our ambition to become an important financial center in this part of Europe," says Warsaw planner Tomasz Zemla. Tomas van Houtryve
The Soviet-era palace, shown from the pool of the Intercontinental Hotel pool, casts a shadow over downtown. Tomas van Houtryve
Architect Boleslaw Stelmach decries the skyscraper trend, preferring "wiser" development. Tomas van Houtryve
Along the banks of the Vistula River is the area of Warsaw rebuilt after World War II. Tomas van Houtryve
Zamkowy Square in Old Town Warsaw. After World War II, Varsovians recreated, stone by stone, the beautiful Old Town section of their city. Tomas van Houtryve
The Palace of Culture and Science looms behind pedestrians as they cross a bridge above the roof of the Warsaw University Library. Tomas van Houtryve
A 108,000-square-foot roof garden tops the Warsaw University Library. The gardens have become a popular tourist attraction in the city. Tomas van Houtryve
| https://www.smithsonianmag.com/travel/warsaw-on-the-rise-43615/?c=y&page=1 |
Stefania Malmsten
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<title > Stefania Malmsten </title >
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<title >
<![CDATA[ Adidas Marathon magazine ]]>
</title >
<link >
https://fontsinuse.com/uses/49739/adidas-marathon-magazine
</link >
<description >
<![CDATA[
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/49739/adidas-marathon-magazine"><img src="https://assets.fontsinuse.com/static/use-media-items/175/174575/upto-700xauto/63593f83/MH_Adidas_Marathon_Mag_sid_1_omslag_alt1.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/typefaces/90014/ll-bradford"><img src="https://assets.fontsinuse.com/static/samples/6/5224/440/4/5c13e120/ll-bradford.png"/></a><br/><a href="https://fontsinuse.com/typefaces/90015/ll-bradford-mono"><img src="https://assets.fontsinuse.com/static/samples/6/5225/440/4/5c13e20b/ll-bradford-mono.png"/></a><br/><br/><p>Adidas is the main sponsor of <a href="https://www.stockholmmarathon.se/">Stockholm Marathon</a>. In conjunction with the 2022 race, Adidas wanted to pay tribute to the runners and running clubs that they work with in the form of a magazine. Together with editor and sneaker freak Carmilla Floyd, Malmsten Hellberg created a large format 32-page magazine. The publication was typeset in <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/90014/ll-bradford">LL Bradford</a></strong> (incl. <strong><a href="https://fontsinuse.com/typefaces/90015/ll-bradford-mono">Mono</a></strong>) throughout and was printed in high speed heatset in Sundsvall, Sweden. It was handed out to all participants when they collected their number bib.</p><br/><a href="https://fontsinuse.com/uses/49739/adidas-marathon-magazine"><img src="https://assets.fontsinuse.com/static/use-media-items/175/174662/upto-700xauto/6350186c/MH_Adidas_MarathonMag_intag2.gif"/></a><br/><br/><i><b class="">Source: <span class="fiu-attribution__sourceUrl"><a href="https://malmstenhellberg.com/adidas-marathon-magazine/" target="_blank" rel="noopener">malmstenhellberg.com</a></span> </b><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/49739/adidas-marathon-magazine"><img src="https://assets.fontsinuse.com/static/use-media-items/175/174576/upto-700xauto/6350186c/MH_Adidas_Marathon_Mag_sid_2-3.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/49739/adidas-marathon-magazine"><img src="https://assets.fontsinuse.com/static/use-media-items/175/174577/upto-700xauto/6350186c/MH_Adidas_Marathon_Mag_sid_8-9.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/49739/adidas-marathon-magazine"><img src="https://assets.fontsinuse.com/static/use-media-items/175/174578/upto-700xauto/6350186d/MH_Adidas_Marathon_Mag_sid_18-19.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/49739/adidas-marathon-magazine"><img src="https://assets.fontsinuse.com/static/use-media-items/175/174579/upto-700xauto/6350186d/MH_Adidas_Marathon_Mag_sid_22-23.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/49739/adidas-marathon-magazine"><img src="https://assets.fontsinuse.com/static/use-media-items/175/174580/upto-700xauto/6350186d/MH_Adidas_Marathon_Mag_sid_28-29.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/49739/adidas-marathon-magazine">Fonts In Use</a><hr/>
</description >
<guid >
https://fontsinuse.com/uses/49739/adidas-marathon-magazine
<pubDate > Wed, 26 Oct 2022 14:08:49 +0000 </pubDate >
<author > Stefania Malmsten </author >
</item >
<item >
<title >
<![CDATA[
À ma sœur ! (2001) movie poster for NonStop Entertainment
</title >
<link >
https://fontsinuse.com/uses/49720/a-ma-soeur-2001-movie-poster-for-nonstop-ente
</link >
<description >
<![CDATA[
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/49720/a-ma-soeur-2001-movie-poster-for-nonstop-ente"><img src="https://assets.fontsinuse.com/static/use-media-items/175/174508/upto-700xauto/634eb322/MH_Nonstop_AMasoeur_Poster_2400x1600.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/typefaces/146185/vtc-carrie"><img src="https://assets.fontsinuse.com/static/samples/9/8108/440/4/607adf22/vtc-carrie.png"/></a><br/><a href="https://fontsinuse.com/typefaces/47238/ivar-text"><img src="https://assets.fontsinuse.com/static/samples/5/4049/440/4/5a00305a/ivar-text.png"/></a><br/><br/><p><cite><a href="https://en.wikipedia.org/wiki/Fat_Girl">À ma sœur !</a></cite> is a drama written and directed by Catherine Breillat, starring Anaïs Reboux and Roxane Mesquida. It can be seen as part of the “New French Extremity” – a wave of transgressive films by French directors at the turn of the 21st century (a term coined by Artforum critic James Quandt). Malmsten Hellberg designed the poster and title treatment. Another assignment for quality film distributor <a href="https://fontsinuse.com/tags/25889/nonstop-entertainment">NonStop Entertainmen</a>t in their series of films by female directors that finally get a theatrical release in Sweden. The title is set in <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/146185/vtc-carrie">VTC Carrie</a></strong>, from Vocal Type (named after women’s suffrage leader <a href="https://en.wikipedia.org/wiki/Carrie_Chapman_Catt">Carrie Chapman Catt</a>), accompanied by <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/47238/ivar-text">Ivar Text</a></strong> from Letters from Sweden.</p><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/49720/a-ma-soeur-2001-movie-poster-for-nonstop-ente">Fonts In Use</a><hr/>
</description >
<guid >
https://fontsinuse.com/uses/49720/a-ma-soeur-2001-movie-poster-for-nonstop-ente
</guid >
<pubDate > Thu, 20 Oct 2022 08:47:50 +0000 </pubDate >
<author > Stefania Malmsten </author >
</item >
<item >
<title >
<![CDATA[
Jane B. par Agnès V. (1988) movie poster for NonStop Entertainment
</title >
<link >
https://fontsinuse.com/uses/47328/jane-b-par-agnes-v-1988-movie-poster-for-nons
</link >
<description >
<![CDATA[
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/47328/jane-b-par-agnes-v-1988-movie-poster-for-nons"><img src="https://assets.fontsinuse.com/static/use-media-items/165/164449/upto-700xauto/62986e7c/MH_Nonstop_JaneB_Poster_2400x1600_01.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/typefaces/34807/louize"><img src="https://assets.fontsinuse.com/static/samples/4/3500/440/4/58e7dbcc/louize.png"/></a><br/><br/><p><em>Jane B. par Agnès V.</em> is a French docudrama directed by Agnès Varda 1988, starring French-English actress Jane Birkin. The film mixes interviews with Birkin about her past and current life with small vignettes where she takes on roles that she or Varda are interested in seeing her play.<br />
<br />
This is another poster assignment for quality film distributor <a href="https://fontsinuse.com/tags/25889/nonstop-entertainment">NonStop Entertainment</a> in their series of films by female directors that finally get a theatrical release in Sweden. The typeface <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/34807/louize">Louize</a> </strong>from French foundry 205TF, used in one weight only, is a contemporary interpretation of Augustaux, itself allegedly the first revival in the history of typography.</p><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/47328/jane-b-par-agnes-v-1988-movie-poster-for-nons">Fonts In Use</a><hr/>
</description >
<guid >
https://fontsinuse.com/uses/47328/jane-b-par-agnes-v-1988-movie-poster-for-nons
</guid >
<pubDate > Mon, 06 Jun 2022 08:34:54 +0000 </pubDate >
<author > Stefania Malmsten </author >
</item >
<item >
<title >
<![CDATA[ Nordens Paris by Susanna Strömquist ]]>
</title >
<link >
https://fontsinuse.com/uses/43737/nordens-paris-by-susanna-stroemquist
</link >
<description >
<![CDATA[
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/43737/nordens-paris-by-susanna-stroemquist"><img src="https://assets.fontsinuse.com/static/use-media-items/152/151540/upto-700xauto/619a6743/MH_NM_NKs_Franska_bok_2400x1600_01.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Helena Bonnevier</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/typefaces/117680/blanchard-commercial-classics"><img src="https://assets.fontsinuse.com/static/samples/10/9205/440/4/619b62a7/blanchard-commercial-classics.png"/></a><br/><a href="https://fontsinuse.com/typefaces/113132/caslon-ionic"><img src="https://assets.fontsinuse.com/static/samples/7/6277/440/4/5e20888f/caslon-ionic.png"/></a><br/><a href="https://fontsinuse.com/typefaces/117689/antique-no-6-commercial-classics"><img src="https://assets.fontsinuse.com/static/samples/10/9203/440/4/619b5bf8/antique-no-6-commercial-classics.png"/></a><br/><a href="https://fontsinuse.com/typefaces/92/lyon"><img src="https://assets.fontsinuse.com/static/samples/1/100/440/4/570e1fed/lyon.png"/></a><br/><br/><p><cite>Nordens Paris</cite> (“Paris of the North”), by fashion journalist Susanna Strömquist, is a book about the French couture atelier at department store Nordiska Kompaniet 1902–1966, and the result of extensive research; in NK’s archive at Nordiska museet; through interviews and close studies of garments; in the archives of Chanel, Dior, Balenciaga and others. The publication tells the story of the leading establishment for women’s fashion in the Nordic countries during the golden age of haute couture, with newly photographed images of the garments and never before seen black-and-white fashion images from Nordiska museet's archives.</p>
<p>The book is printed on Fedrigoni paper in Italy with gilded edges. Three typefaces from the Commercial Classics collection of Commercial Type – <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/117680/blanchard-commercial-classics">Blanchard</a></strong>, <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/113132/caslon-ionic">Caslon Ionic</a></strong> and<strong> <a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/31431/antique-no-6">Antique No. 6</a></strong> – are used throughout and paired with <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/92/lyon">Lyon</a></strong> from the same foundry, for body text.</p><br/><a href="https://fontsinuse.com/uses/43737/nordens-paris-by-susanna-stroemquist"><img src="https://assets.fontsinuse.com/static/use-media-items/152/151541/upto-700xauto/619a674a/MH_NM_NKs_Franska_bok_2400x1600_02.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Helena Bonnevier</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/43737/nordens-paris-by-susanna-stroemquist"><img src="https://assets.fontsinuse.com/static/use-media-items/152/151542/upto-700xauto/619a6755/MH_NM_NKs_Franska_bok_2400x1600_04.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Helena Bonnevier</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/43737/nordens-paris-by-susanna-stroemquist"><img src="https://assets.fontsinuse.com/static/use-media-items/152/151543/upto-700xauto/619a6760/MH_NM_NKs_Franska_bok_2400x1600_05.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Helena Bonnevier</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/43737/nordens-paris-by-susanna-stroemquist"><img src="https://assets.fontsinuse.com/static/use-media-items/152/151544/upto-700xauto/619a6767/MH_NM_NKs_Franska_bok_2400x1600_06.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Helena Bonnevier</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/43737/nordens-paris-by-susanna-stroemquist"><img src="https://assets.fontsinuse.com/static/use-media-items/152/151545/upto-700xauto/619a676f/MH_NM_NKs_Franska_bok_2400x1600_07.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Helena Bonnevier</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/43737/nordens-paris-by-susanna-stroemquist">Fonts In Use</a><hr/>
</description >
<guid >
https://fontsinuse.com/uses/43737/nordens-paris-by-susanna-stroemquist
</guid >
<pubDate > Mon, 29 Nov 2021 11:27:06 +0000 </pubDate >
<author > Stefania Malmsten </author >
</item >
<item >
<title >
<![CDATA[ Nordens Paris / Paris of the North exhibition ]]>
</title >
<link >
https://fontsinuse.com/uses/43744/nordens-paris-paris-of-the-north-exhibition-1
</link >
<description >
<![CDATA[
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/43744/nordens-paris-paris-of-the-north-exhibition-1"><img src="https://assets.fontsinuse.com/static/use-media-items/152/151585/upto-700xauto/619b61e0/MH_NM_NKs_Franska_utsta%CC%88llning_2400x1600_07.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/typefaces/113132/caslon-ionic"><img src="https://assets.fontsinuse.com/static/samples/7/6277/440/4/5e20888f/caslon-ionic.png"/></a><br/><a href="https://fontsinuse.com/typefaces/117680/blanchard-commercial-classics"><img src="https://assets.fontsinuse.com/static/samples/10/9205/440/4/619b62a7/blanchard-commercial-classics.png"/></a><br/><a href="https://fontsinuse.com/typefaces/117689/antique-no-6-commercial-classics"><img src="https://assets.fontsinuse.com/static/samples/10/9203/440/4/619b5bf8/antique-no-6-commercial-classics.png"/></a><br/><a href="https://fontsinuse.com/typefaces/31744/caslon-doric"><img src="https://assets.fontsinuse.com/static/samples/1/917/440/4/570e2075/caslon-doric.png"/></a><br/><a href="https://fontsinuse.com/typefaces/39222/lab-grotesque"><img src="https://assets.fontsinuse.com/static/samples/2/1756/440/4/570e2103/lab-grotesque.png"/></a><br/><br/><p><a href="http://www.nordiskamuseet.se/utstallningar/nordens-paris"><cite>Nordens Paris</cite></a> / <a href="http://www.nordiskamuseet.se/en/utstallningar/paris-north"><cite>Paris of the North</cite></a> is an exhibition presented by Nordiska museet in Stockholm. It shows the French Couture atelier at Nordiska Kompaniet – the leading establishment for women’s fashion in the Nordic countries during the golden age of haute couture. Malmsten Hellberg has designed exhibition graphics in close collaboration with exhibition designer Marcia Harvey Isaksson. The graphic design follows <a href="http://fontsinuse.com/uses/43737/nordens-paris-by-susanna-stroemquist">the book that is produced in connection with the exhibition</a> with grey, black and gold and typefaces from Commercial Classics, featuring <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/113132/caslon-ionic">Caslon Ionic</a></strong>, <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/117680/blanchard-commercial-classics">Blanchard</a></strong>, <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/117689/antique-no-6-commercial-classics">Antique No 6</a></strong>, and <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/31744/caslon-doric">Caslon Doric</a> Wide</strong>. <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/39222/lab-grotesque">Lab Grotesque</a></strong> (<a target="_self" class="entity-link" href="https://fontsinuse.com/foundry/55/letters-from-sweden">Letters from Sweden</a>) was added for captions where we needed a typeface with good legibility in small sizes.</p><br/><a href="https://fontsinuse.com/uses/43744/nordens-paris-paris-of-the-north-exhibition-1"><img src="https://assets.fontsinuse.com/static/use-media-items/152/151581/upto-700xauto/619b61ea/MH_NM_NKs_Franska_utsta%CC%88llning_2400x1600_02.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/43744/nordens-paris-paris-of-the-north-exhibition-1"><img src="https://assets.fontsinuse.com/static/use-media-items/152/151580/upto-700xauto/619fe238/MH_NM_NKs_Franska_utsta%CC%88llning_2400x1600_01.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/43744/nordens-paris-paris-of-the-north-exhibition-1"><img src="https://assets.fontsinuse.com/static/use-media-items/152/151583/upto-700xauto/619b60c1/MH_NM_NKs_Franska_utsta%CC%88llning_2400x1600_04.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/43744/nordens-paris-paris-of-the-north-exhibition-1"><img src="https://assets.fontsinuse.com/static/use-media-items/152/151584/upto-700xauto/619b60c8/MH_NM_NKs_Franska_utsta%CC%88llning_2400x1600_05.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Hendrik Zeitler / Nordiska museet</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/43744/nordens-paris-paris-of-the-north-exhibition-1"><img src="https://assets.fontsinuse.com/static/use-media-items/152/151586/upto-700xauto/619b611c/MH_NM_NKs_Franska_utsta%CC%88llning_2400x1600_08.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/43744/nordens-paris-paris-of-the-north-exhibition-1">Fonts In Use</a><hr/>
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</description >
<guid >
https://fontsinuse.com/uses/43744/nordens-paris-paris-of-the-north-exhibition-1
</guid >
<pubDate > Mon, 29 Nov 2021 11:26:37 +0000 </pubDate >
<author > Stefania Malmsten </author >
</item >
<item >
<title >
<![CDATA[
Ellen Sundberg – Ett bloss för Bodil Malmsten album art
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</title >
<link >
https://fontsinuse.com/uses/41899/ellen-sundberg-ett-bloss-foer-bodil-malmsten-
</link >
<description >
<![CDATA[
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/41899/ellen-sundberg-ett-bloss-foer-bodil-malmsten-"><img src="https://assets.fontsinuse.com/static/use-media-items/146/145109/upto-700xauto/61252b20/MH_Teg_Ellen_Sundberg_2400x1600_01.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>LP front cover.</p><br/><a href="https://fontsinuse.com/typefaces/45939/styrene-b"><img src="https://assets.fontsinuse.com/static/samples/4/3579/440/4/590f7b4c/styrene-b.png"/></a><br/><a href="https://fontsinuse.com/typefaces/45938/styrene-a"><img src="https://assets.fontsinuse.com/static/samples/4/3578/440/4/590f7b42/styrene-a.png"/></a><br/><a href="https://fontsinuse.com/typefaces/7180/farnham"><img src="https://assets.fontsinuse.com/static/samples/4/3046/440/4/57f35873/farnham.png"/></a><br/><br/><p>Musical interpretations by artist Ellen Sundberg of the late writer Bodil Malmsten's (mother of the designer Stefania Malmsten) poetry, published by independent publisher <a href="http://www.tegpublishing.se/katalog/ett-bloss-bodil-malmsten/">Teg</a> on LP, CD and digital formats. Ellen and Bodil never met but come from the same small village in northern Sweden. They both “own” their first names in a way. <a href="http://fontsinuse.com/search/advanced?v=2&match0=all&typefaces0=45938,45939"><strong>Styrene</strong></a> worked well here. <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/7180/farnham">Farnham</a></strong> was previously used for <a href="http://fontsinuse.com/uses/13894/samlade-dikter-collected-poems-by-bodil-malms">Bodil Malmsten’s collected poems</a>, also designed by the studio.</p>
<p>[<a href="http://www.discogs.com/Ellen-Sundberg-Ett-Bloss-För-Bodil-Malmsten/release/18669127">More info on Discogs</a>]</p><br/><a href="https://fontsinuse.com/uses/41899/ellen-sundberg-ett-bloss-foer-bodil-malmsten-"><img src="https://assets.fontsinuse.com/static/use-media-items/146/145113/upto-700xauto/611fc7fe/MH_Teg_Ellen_Sundberg_2400x1600_02x.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>LP back cover.</p><br/><a href="https://fontsinuse.com/uses/41899/ellen-sundberg-ett-bloss-foer-bodil-malmsten-"><img src="https://assets.fontsinuse.com/static/use-media-items/146/145111/upto-700xauto/611fc803/MH_Teg_Ellen_Sundberg_2400x1600_03.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>LP with label.</p><br/><a href="https://fontsinuse.com/uses/41899/ellen-sundberg-ett-bloss-foer-bodil-malmsten-"><img src="https://assets.fontsinuse.com/static/use-media-items/146/145112/upto-700xauto/611fc664/MH_Teg_Ellen_Sundberg_2400x1600_04.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Insert.</p><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/41899/ellen-sundberg-ett-bloss-foer-bodil-malmsten-">Fonts In Use</a><hr/>
</description >
<guid >
https://fontsinuse.com/uses/41899/ellen-sundberg-ett-bloss-foer-bodil-malmsten-
</guid >
<pubDate > Thu, 26 Aug 2021 08:36:28 +0000 </pubDate >
<author > Stefania Malmsten </author >
</item >
<item >
<title >
<![CDATA[
Daughters of the Dust (1991) movie poster for NonStop Entertainment
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</title >
<link >
https://fontsinuse.com/uses/36584/daughters-of-the-dust-1991-movie-poster-for-n
</link >
<description >
<![CDATA[
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/36584/daughters-of-the-dust-1991-movie-poster-for-n"><img src="https://assets.fontsinuse.com/static/use-media-items/126/125115/upto-700xauto/5fa42800/MH_Nonstop_DotD_Poster_2400x1600_01.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/typefaces/31397/dapifer"><img src="https://assets.fontsinuse.com/static/samples/2/1288/440/4/57860f02/dapifer.png"/></a><br/><br/><p>With the release of <em>Daughters of the Dust</em> in 1991, Julie Dash was the first female African-American director to receive theatrical distribution across the USA. Her film shows three generations of Gullah-women on the island Saint Helena, off the coast of South Carolina in the early 1900s. With cinematography and production design by artists Arthur Jafa and Kerry James Marshall, respectively, the film has created a strong legacy.</p>
<p>This is our third poster for quality film distributor <a href="http://fontsinuse.com/tags/25889/nonstop-entertainment">NonStop Entertainment</a> in a series of films by female directors. <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/31397/dapifer">Dapifer</a></strong> (semibold and black) by <a target="_self" class="entity-link" href="https://fontsinuse.com/type_designers/92/joshua-darden">Joshua Darden</a> is used throughout.</p><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/36584/daughters-of-the-dust-1991-movie-poster-for-n">Fonts In Use</a><hr/>
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https://fontsinuse.com/uses/36584/daughters-of-the-dust-1991-movie-poster-for-n
<title >
<![CDATA[
Wanda (1970) movie poster for NonStop Entertainment
<link >
https://fontsinuse.com/uses/36582/wanda-1970-movie-poster-for-nonstop-entertain
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/36582/wanda-1970-movie-poster-for-nonstop-entertain"><img src="https://assets.fontsinuse.com/static/use-media-items/126/125112/upto-700xauto/5fa4244a/MH_Nonstop_Wanda_Poster_2400x1600_01.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/typefaces/31744/caslon-doric"><img src="https://assets.fontsinuse.com/static/samples/1/917/440/4/570e2075/caslon-doric.png"/></a><br/><a href="https://fontsinuse.com/typefaces/47921/ivar-display"><img src="https://assets.fontsinuse.com/static/renders/57/47921/400/4/6422c371/ivar-display.png"/></a><br/><a href="https://fontsinuse.com/typefaces/110189/swedish-gothic"><img src="https://assets.fontsinuse.com/static/renders/74/110189/400/4/5fafa9fa/swedish-gothic.png"/></a><br/><br/><p><a href="http://www.nonstopentertainment.com/wanda"><em>Wanda</em></a> is an independent American film from 1970, written and directed by Barbara Loden who also stars in the title role; her first and only film. Set in the anthracite coal region of eastern Pennsylvania, this road movie focuses on Wanda, who goes on the run with a bank robber.</p>
<p>This is our second poster for quality film distributor <a href="http://fontsinuse.com/tags/25889/nonstop-entertainment">NonStop Entertainment</a> in a series of films by female directors (the first being <a href="http://fontsinuse.com/uses/30924/jeanne-dielman-23-quai-du-commerce-1080-bruxe"><em>Jeanne Dielman, 23, Quai du Commerce, 1080 Bruxelles</em></a>) that finally gets theatrical release in Sweden. <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/31744/caslon-doric">Caslon Doric</a> Condensed </strong>was perfect for the short title, along with <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/47921/ivar-display">Ivar Display</a></strong> and <strong><a target="_self" class="entity-link" href="https://fontsinuse.com/typefaces/110189/swedish-gothic">Swedish Gothic</a></strong> (both from <a target="_self" class="entity-link" href="https://fontsinuse.com/foundry/55/letters-from-sweden">Letters from Sweden</a>.</p><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/36582/wanda-1970-movie-poster-for-nonstop-entertain">Fonts In Use</a><hr/>
https://fontsinuse.com/uses/36582/wanda-1970-movie-poster-for-nonstop-entertain
Jeanne Dielman, 23, Quai du Commerce, 1080 Bruxelles movie posters for NonStop Entertainment
https://fontsinuse.com/uses/30924/jeanne-dielman-23-quai-du-commerce-1080-bruxe
https://fontsinuse.com/uses/30924/jeanne-dielman-23-quai-du-commerce-1080-bruxe
<![CDATA[ Greta Knutson-Tzara ]]>
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/26224/greta-knutson-tzara"><img src="https://assets.fontsinuse.com/static/use-media-items/88/87806/upto-700xauto/5cd0356c/MH_Portfolio_Norrkopings_Kunstmuseum_2400x1600_1.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Emil Fagander / Art and Theory</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/typefaces/80197/schnyder"><img src="https://assets.fontsinuse.com/static/samples/5/4614/440/4/5b05515d/schnyder.png"/></a><br/><a href="https://fontsinuse.com/typefaces/92/lyon"><img src="https://assets.fontsinuse.com/static/samples/1/100/440/4/570e1fed/lyon.png"/></a><br/><a href="https://fontsinuse.com/typefaces/10534/atlas-grotesk"><img src="https://assets.fontsinuse.com/static/samples/1/516/440/4/570e2034/atlas-grotesk.png"/></a><br/><br/><p>Years of research made it possible for <a href="http://www.norrkopingskonstmuseum.se/in-english/">Norrköping Art Museum</a> to mount the first retrospective of Swedish artist <a href="http://en.wikipedia.org/wiki/Greta_Knutson">Greta Knutson-Tzara</a> (1899–1983). <a href="http://www.malmstenhellberg.com">Malmsten Hellberg</a> has designed a 208-page-book for the exhibition, published by Art and Theory.</p>
<p>In the heyday of modernism, Greta Knutson-Tzara was a member of the avant-garde in Paris; a painter, sculptor and writer who was influenced by her times but always sought to develop her own approach. After divorcing the poet Tristan Tzara, she went back to being Greta Knutson. Her two different names are used in the book, and her name is set in different widths of <a href="http://Schnyder"><strong>Schnyder</strong></a> throughout. In addition to headlines in Schnyder, body text is set in <a href="http://fontsinuse.com/typefaces/92/lyon"><strong>Lyon</strong></a>. The captions, table of contents etc. are set with <strong><a href="http://fontsinuse.com/typefaces/80197/schnyder">Atlas Grotesk</a></strong>. The book comes in a bilingual edition, in Swedish and English languages.</p><br/><a href="https://fontsinuse.com/uses/26224/greta-knutson-tzara"><img src="https://assets.fontsinuse.com/static/use-media-items/88/87804/upto-700xauto/5cd0356c/MH_Portfolio_Norrkopings_Kunstmuseum_2400x1600_3.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Emil Fagander / Art and Theory</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/26224/greta-knutson-tzara"><img src="https://assets.fontsinuse.com/static/use-media-items/88/87805/upto-700xauto/5cd0356c/MH_Portfolio_Norrkopings_Kunstmuseum_2400x1600_4.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Emil Fagander / Art and Theory</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/26224/greta-knutson-tzara">Fonts In Use</a><hr/>
<guid >
https://fontsinuse.com/uses/26224/greta-knutson-tzara
</item >
<item >
<title >
<![CDATA[ Per B Sundberg (IKEA) ]]>
</title >
https://fontsinuse.com/uses/23879/per-b-sundberg-ikea
</link >
<![CDATA[
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/23879/per-b-sundberg-ikea"><img src="https://assets.fontsinuse.com/static/use-media-items/78/77436/upto-700xauto/5bebe4cf/MH_IKEA_Per_B_Sundberg_2400x1600_Cover.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Ola Bergengren/IKEA</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Cover, typeset in <strong>Marr Sans</strong> Ultra Black.</p><br/><a href="https://fontsinuse.com/typefaces/32744/marr-sans"><img src="https://assets.fontsinuse.com/static/samples/2/1528/440/4/570e20dd/marr-sans.png"/></a><br/><a href="https://fontsinuse.com/typefaces/92/lyon"><img src="https://assets.fontsinuse.com/static/samples/1/100/440/4/570e1fed/lyon.png"/></a><br/><br/><p>Published by IKEA in three languages, along with the limited edition collection “Föremål” – a collaboration with artist and ceramicist <a href="http://en.wikipedia.org/wiki/Per_B._Sundberg">Per (Pelle) B Sundberg</a> featuring skull-shaped vases, dog-candleholders and more.</p>
<p>The book, designed by Malmsten Hellberg, with photography by Ola Bergengren, Märta Thisner and Tina Axelsson, shows the making of the collection in the studio and on travels along with unique images of Pelle’s works from museums, private collections and pizza restaurants.</p>
<p>Body text is set in <a href="http://fontsinuse.com/typefaces/92/lyon"><strong>Lyon</strong></a> Text. Headlines are set in <a href="http://fontsinuse.com/typefaces/32744/marr-sans"><strong>Marr Sans</strong></a> Ultra Black and Marr Sans Cond Bold. Captions are set in Marr Sans Regular.</p><br/><a href="https://fontsinuse.com/uses/23879/per-b-sundberg-ikea"><img src="https://assets.fontsinuse.com/static/use-media-items/78/77434/upto-700xauto/5bebe5ca/MH_IKEA_Per_B_Sundberg_2400x1600_Inlay_01.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Ola Bergengren/IKEA</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Table of contents in the English edition. Typeset in Marr Sans Cond Bold, Marr Sans Ultra Black and Lyon Text.</p>
<p></p><br/><a href="https://fontsinuse.com/uses/23879/per-b-sundberg-ikea"><img src="https://assets.fontsinuse.com/static/use-media-items/78/77432/upto-700xauto/5bebe5d6/MH_IKEA_Per_B_Sundberg_2400x1600_Inlay_07.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Ola Bergengren/IKEA</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Chapter opening in the English edition. Typeset in Marr Sans Ultra Black and Marr Sans Regular. Photo: Ola Bergengren/IKEA.</p><br/><a href="https://fontsinuse.com/uses/23879/per-b-sundberg-ikea"><img src="https://assets.fontsinuse.com/static/use-media-items/78/77435/upto-700xauto/5bebe5ec/MH_IKEA_Per_B_Sundberg_2400x1600_Inlay_15_GB.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Ola Bergengren/IKEA</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Spread in the English edition. Typeset in Lyon Text. Photo: Märta Thisner/IKEA.</p><br/><a href="https://fontsinuse.com/uses/23879/per-b-sundberg-ikea"><img src="https://assets.fontsinuse.com/static/use-media-items/78/77433/upto-700xauto/5bebe5f6/MH_IKEA_Per_B_Sundberg_2400x1600_Inlay_SE_3.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Ola Bergengren/IKEA</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Spread in the Swedish edition. Typeset in Marr Sans Cond Bold.</p><br/><a href="https://fontsinuse.com/uses/23879/per-b-sundberg-ikea"><img src="https://assets.fontsinuse.com/static/use-media-items/78/77437/upto-700xauto/5bebe603/MH_IKEA_Per_B_Sundberg_2400x1600_Inlay_DE_3.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Ola Bergengren/IKEA</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Spread in the German edition, typeset in Marr Sans Cond Bold.</p><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/23879/per-b-sundberg-ikea">Fonts In Use</a><hr/>
<guid >
https://fontsinuse.com/uses/23879/per-b-sundberg-ikea
<author > Stefania Malmsten </author >
</item >
<item >
<title >
<![CDATA[ That Summer (2017) opening titles ]]>
https://fontsinuse.com/uses/23349/that-summer-2017-opening-titles
<![CDATA[
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/23349/that-summer-2017-opening-titles"><img src="https://assets.fontsinuse.com/static/use-media-items/76/75293/upto-700xauto/5bb35532/MH_That_Summer_Story_2400x1600_2.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/typefaces/7180/farnham"><img src="https://assets.fontsinuse.com/static/samples/4/3046/440/4/57f35873/farnham.png"/></a><br/><br/><blockquote>
<p><span>Peter Beard discusses his work as a photographer, artist and diarist before reminiscing about his attempt to make a documentary in the summer of 1972 with his friend Lee Radziwill (younger sister of Jacqueline Kennedy Onassis), focusing on their childhood and the 20th-century history of East Hampton. — <a href="http://www.imdb.com/title/tt7057306/plotsummary?ref_=tt_ov_pl">IMDb</a></span></p>
</blockquote>
<p><em>That Summer</em> is a documentary feature film produced by Story and Louverture films. It uncovers footage lost for decades shot by Peter Beard, Andy Warhol and Jonas Mekas, and features Lee Radziwill and the Beales of Grey Gardens, Big Edie and Little Edie. Now re-edited and directed by Göran Hugo Olsson.</p><br/><a href="https://fontsinuse.com/uses/23349/that-summer-2017-opening-titles"><img src="https://assets.fontsinuse.com/static/use-media-items/76/75294/upto-700xauto/5bb35535/MH_That_Summer_Story_2400x1600_4.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/23349/that-summer-2017-opening-titles"><img src="https://assets.fontsinuse.com/static/use-media-items/76/75295/upto-700xauto/5bb47141/MH_That_Summer_Story_2400x1600_5.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/23349/that-summer-2017-opening-titles"><img src="https://assets.fontsinuse.com/static/use-media-items/76/75296/upto-700xauto/5bb35540/MH_That_Summer_Story_2400x1600_6.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/23349/that-summer-2017-opening-titles"><img src="https://assets.fontsinuse.com/static/use-media-items/76/75297/upto-700xauto/5bb35542/MH_That_Summer_Story_2400x1600_7.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/23349/that-summer-2017-opening-titles"><img src="https://assets.fontsinuse.com/static/use-media-items/76/75291/upto-700xauto/5bb3437f/MH_That_Summer_Story_2400x1600_8.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/23349/that-summer-2017-opening-titles">Fonts In Use</a><hr/>
<guid >
https://fontsinuse.com/uses/23349/that-summer-2017-opening-titles
<item >
<title >
<![CDATA[ Hitta hem by Ola Andersson ]]>
</title >
<link >
https://fontsinuse.com/uses/18221/hitta-hem-by-ola-andersson
<![CDATA[
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/18221/hitta-hem-by-ola-andersson"><img src="https://assets.fontsinuse.com/static/use-media-items/56/55978/upto-700xauto/598b2e07/MH_Hitta-Hem_2400x1600_01.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Soft cover book with matte varnish. Headlines in Mercury Display, text in Mercury text.</p><br/><a href="https://fontsinuse.com/typefaces/7534/mercury"><img src="https://assets.fontsinuse.com/static/samples/1/394/440/4/570e201f/mercury.png"/></a><br/><br/><p><cite>Hitta hem</cite> (<cite>Find your way home</cite>) is a book about Stockholm, published by <a href="http://dokument.org/product/hitta-hem-stockholm-och-bostadsbristen-2/">Dokument Press</a> and with nocturnal photography by <a href="http://www.perkristiansen.se/">Per Kristiansen</a> where architect and writer Ola Andersson delivers the definitive solution to the housing situation. The soft cover book has flaps and a foldout section in the middle. All set in Mercury.</p><br/><a href="https://fontsinuse.com/uses/18221/hitta-hem-by-ola-andersson"><img src="https://assets.fontsinuse.com/static/use-media-items/56/55979/upto-700xauto/598d65ef/MH_Hitta-Hem_2400x1600_02.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Soft cover book with flaps. Headlines in Mercury Display, text in Mercury Text.</p><br/><a href="https://fontsinuse.com/uses/18221/hitta-hem-by-ola-andersson"><img src="https://assets.fontsinuse.com/static/use-media-items/56/55980/upto-700xauto/598d65f6/MH_Hitta-Hem_2400x1600_03.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/18221/hitta-hem-by-ola-andersson"><img src="https://assets.fontsinuse.com/static/use-media-items/56/55981/upto-700xauto/598b2ac0/MH_Hitta-Hem_2400x1600_04.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/18221/hitta-hem-by-ola-andersson">Fonts In Use</a><hr/>
<guid >
https://fontsinuse.com/uses/18221/hitta-hem-by-ola-andersson
</guid >
<author > Stefania Malmsten </author >
<title >
<![CDATA[ I am Dublin film poster ]]>
https://fontsinuse.com/uses/18220/i-am-dublin-film-poster
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/18220/i-am-dublin-film-poster"><img src="https://assets.fontsinuse.com/static/use-media-items/56/55977/upto-700xauto/598b29d1/MH_Story_Dublin_2400x1600_01.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p><span><span><span><span>Poster 70x100 cm, printed with Pantone 286 on uncoated coloured paper.</span></span></span></span></p><br/><a href="https://fontsinuse.com/typefaces/32445/duplicate-ionic"><img src="https://assets.fontsinuse.com/static/samples/2/1695/440/4/570e20f9/duplicate-ionic.png"/></a><br/><br/><p><span><span><span><span>Poster for a short documentary about Ahmed, living in hiding in Sweden. Directed by David Aronowitsch and produced by Story. Through the Dublin Regulation the EU has created a group of young people drifting around Europe. The so-called Dublin-cases are deprived of rights and thrown out from country to country in Europe. The content and the title of the film, rather than the limited budget, suggested a typographic solution. </span></span></span></span></p><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/18220/i-am-dublin-film-poster">Fonts In Use</a><hr/>
<guid >
https://fontsinuse.com/uses/18220/i-am-dublin-film-poster
<author > Stefania Malmsten </author >
</item >
<title >
<![CDATA[ 10-gruppen — Patterns and People, for IKEA ]]>
</title >
https://fontsinuse.com/uses/17126/10-gruppen-patterns-and-people-for-ikea
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/17126/10-gruppen-patterns-and-people-for-ikea"><img src="https://assets.fontsinuse.com/static/use-media-items/53/52786/upto-700xauto/5931d860/MH_IKEA_Avsiktlig_2400x1600_Cover_5.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Covers of English, Portuguese and Danish editions. Type set in Lyon Display.</p><br/><a href="https://fontsinuse.com/typefaces/92/lyon"><img src="https://assets.fontsinuse.com/static/samples/1/100/440/4/570e1fed/lyon.png"/></a><br/><br/><p>This book is published by IKEA of Sweden in 16 languages, along with the limited edition collection <a href="http://www.ikea.com/ms/en_AA/ikea-collections/avsiktlig/index.html">AVSIKTLIG</a>, where members of the legendary textile collective Ten Swedish Designers (known in Swedish as <a href="http://ikea.today/without-past-future-makes-no-sense/">10-gruppen</a>) are joined by young textile designers from IKEA. The book is divided into 10 chapters with photography from the making of the collection along with prints from the archives of 10-gruppen.</p><br/><a href="https://fontsinuse.com/uses/17126/10-gruppen-patterns-and-people-for-ikea"><img src="https://assets.fontsinuse.com/static/use-media-items/53/52787/upto-700xauto/592fc7a7/MH_IKEA_Avsiktlig_2400x1600_Inlay_3.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Contents spread in the English edition. Type set in Lyon Display.</p><br/><a href="https://fontsinuse.com/uses/17126/10-gruppen-patterns-and-people-for-ikea"><img src="https://assets.fontsinuse.com/static/use-media-items/53/52788/upto-700xauto/592fc7a2/MH_IKEA_Avsiktlig_2400x1600_Inlay_4_PL.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Text spread in the Polish edition. Type set in Lyon Text.</p><br/><a href="https://fontsinuse.com/uses/17126/10-gruppen-patterns-and-people-for-ikea"><img src="https://assets.fontsinuse.com/static/use-media-items/53/52789/upto-700xauto/592fc7b4/MH_IKEA_Avsiktlig_2400x1600_Inlay_4_PT.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Text spread in the Portuguese edition. Type set in Lyon Text.</p><br/><a href="https://fontsinuse.com/uses/17126/10-gruppen-patterns-and-people-for-ikea"><img src="https://assets.fontsinuse.com/static/use-media-items/53/52790/upto-700xauto/592fc7c1/MH_IKEA_Avsiktlig_2400x1600_Inlay_7.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Chapter start in the English edition. Type set in Lyon Display and Lyon Text.</p><br/><a href="https://fontsinuse.com/uses/17126/10-gruppen-patterns-and-people-for-ikea"><img src="https://assets.fontsinuse.com/static/use-media-items/53/52791/upto-700xauto/5931d667/MH_IKEA_Avsiktlig_2400x1600_Inlay_13.jpeg"/></a><br/><br/><i><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/><p>Image spread. Type set in Lyon Text. Photo by Erik Wåhlström/IKEA.</p><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/17126/10-gruppen-patterns-and-people-for-ikea">Fonts In Use</a><hr/>
<guid >
https://fontsinuse.com/uses/17126/10-gruppen-patterns-and-people-for-ikea
</guid >
<author > Stefania Malmsten </author >
<title >
<![CDATA[ Samlade dikter (Collected poems) by Bodil Malmsten ]]>
<link >
https://fontsinuse.com/uses/13894/samlade-dikter-collected-poems-by-bodil-malms
<description >
<![CDATA[
Contributed by <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a><br/><a href="https://fontsinuse.com/uses/13894/samlade-dikter-collected-poems-by-bodil-malms"><img src="https://assets.fontsinuse.com/static/use-media-items/42/41673/upto-700xauto/577e1532/MH_BM_Samlade_dikter_2400x1600_01.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__is-own">Photo: <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a></span>. </span><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Helena Karlsson/Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/typefaces/7180/farnham"><img src="https://assets.fontsinuse.com/static/samples/4/3046/440/4/57f35873/farnham.png"/></a><br/><br/><p>Everything in this collection, published by <a href="http://www.albertbonniersforlag.se/Bocker/Lyrik/S/samlade-dikter5/">Albert Bonniers Förlag</a>, is set in <a href="https://fontsinuse.com/typefaces/7180/farnham"><strong>Farnham</strong></a>. The title is printed on a plastic transparent dust jacket to create a shadow play. Orange end papers. Cover photo collage by Jenny Källman.</p><br/><a href="https://fontsinuse.com/uses/13894/samlade-dikter-collected-poems-by-bodil-malms"><img src="https://assets.fontsinuse.com/static/use-media-items/42/41674/upto-700xauto/577e1532/MH_BM_Samlade_dikter_2400x1600_02.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__is-own">Photo: <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a></span>. </span><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Helena Karlsson/Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/13894/samlade-dikter-collected-poems-by-bodil-malms"><img src="https://assets.fontsinuse.com/static/use-media-items/42/41675/upto-700xauto/577e1532/MH_BM_Samlade_dikter_2400x1600_03.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__is-own">Photo: <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a></span>. </span><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Helena Karlsson/Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><a href="https://fontsinuse.com/uses/13894/samlade-dikter-collected-poems-by-bodil-malms"><img src="https://assets.fontsinuse.com/static/use-media-items/42/41676/upto-700xauto/577e1532/MH_BM_Samlade_dikter_2400x1600_05.jpeg"/></a><br/><br/><i><span class=""><span class="fiu-attribution__is-own">Photo: <a href="/contributors/9116/malmsten-hellberg">Stefania Malmsten</a></span>. </span><span class=""><span class="fiu-attribution__credits fiu-text--captioning">Helena Karlsson/Malmsten Hellberg</span>. </span><span class="">License: <span class="fiu-attribution__license">All Rights Reserved</span><span>. </span></span></i><br/><br/>This post was originally published at <a href="https://fontsinuse.com/uses/13894/samlade-dikter-collected-poems-by-bodil-malms">Fonts In Use</a><hr/>
<guid >
https://fontsinuse.com/uses/13894/samlade-dikter-collected-poems-by-bodil-malms
</guid >
<author > Stefania Malmsten </author >
</item >
</channel >
| https://fontsinuse.com/contributors/9116/malmsten-hellberg.rss |
Symmetry | Free Full-Text | Analysis of Symmetric Electromagnetic Components Using Magnetic Group Theory
We discuss a method of analysis of symmetric electromagnetic components with magnetic media based on magnetic group theory. In this description, some of the irreducible corepresentations assume complex values exp(iθ) with the real parameter θ. A possible physical interpretation of this parameter is given. We demonstrate the application of the symmetry-adapted linear combination method combined with the corepresentation theory to the problem of current modes in an array of magnetized graphene elements where Faraday and Kerr effects can exist. The elements are described by the magnetic symmetry C4 or C4v(C4). The scattering matrix of the array and its eigensolutions are defined and analyzed and some numerical simulations are presented as well. An example of a waveguide described by symmetry C4v(C2v) with a specific type of degeneracy is also discussed.
Analysis of Symmetric Electromagnetic Components Using Magnetic Group Theory
by Victor Dmitriev 1 , Dimitrios C. Zografopoulos 2,* and Luis P. V. Matos 1
1
Department of Electrical Engineering, Federal University of Pará, Augusto Correa 01, Guama, Belem 66075-110, Pará, Brazil
2
Consiglio Nazionale delle Ricerche, Istituto per la Microelettronica e Microsistemi (CNR-IMM), 00133 Rome, Italy
*
Author to whom correspondence should be addressed.
Symmetry 2023 , 15 (2), 415; https://doi.org/10.3390/sym15020415
Received: 11 January 2023 / Revised: 20 January 2023 / Accepted: 31 January 2023 / Published: 3 February 2023
Abstract
We discuss a method of analysis of symmetric electromagnetic components with magnetic media based on magnetic group theory. In this description, some of the irreducible corepresentations assume complex values exp ( i θ ) with the real parameter θ . A possible physical interpretation of this parameter is given. We demonstrate the application of the symmetry-adapted linear combination method combined with the corepresentation theory to the problem of current modes in an array of magnetized graphene elements where Faraday and Kerr effects can exist. The elements are described by the magnetic symmetry C 4 or C 4 v ( C 4 ) . The scattering matrix of the array and its eigensolutions are defined and analyzed and some numerical simulations are presented as well. An example of a waveguide described by symmetry C 4 v ( C 2 v ) with a specific type of degeneracy is also discussed.
Keywords:
magnetic group theory
;
corepresentations
;
electromagnetic metasurface
;
graphene
1. Introduction
Symmetry and group theoretical methods play essential roles in quantum mechanics, solid-state physics, crystallography, and photonics (see, for example, [ 1 , 2 , 3 , 4 ]). These methods are helpful in obtaining a deeper understanding of physical problems, predicting new solutions, and speeding up numerical calculations [ 5 ].
In electrical engineering and electromagnetic problems, the range of applications of group-theoretical methods is very large, starting from symmetric electric circuits [ 6 ] and waveguides [ 7 ] to parity-time (PT) symmetric systems consisting of both optical loss and gain [ 8 ]. A review of the application of group theory to optics and photonics is presented in [ 9 ]. In the area of metamaterials [ 10 ], for example, the author used the concept of symmetry-adapted linear combination (SALC) of eigensolutions to find longitudinal current modes in metamaterials based on ring resonators. An extended version of this approach was suggested in [ 11 ] with an example of a symmetric graphene array, and for this structure, the authors considered both the longitudinal and vertical currents in the structure.
Magneto-optical effects are used in many photonic components. These components include isolators, circulators, routers, sensors, modulators, magnetometers, etc. A review of the magnetoplasmonic effects and devices is given in [ 12 ] and a review of magnetically controllable metasurfaces can be found in [ 13 ]. Graphene magnetic structures, particularly with the Faraday effect, have been investigated in several works both theoretically [ 14 , 15 , 16 , 17 ] and experimentally [ 18 , 19 ].
The symmetry description of magnetic structures requires the inclusion, along with unitary operators, of some nonunitary ones, which present a combination of unitary operators with the time reversal (see, for instance, [ 1 , 20 , 21 , 22 , 23 , 24 ]). Magnetic group theory and the theory of corepresentations have been used for PT symmetry-breaking systems [ 8 , 25 , 26 ] and topological magnetic materials [ 27 ].
The theory of nonmagnetic groups is a common tool used in classical electromagnetic theory. However, a few works have analyzed the theory of magnetic groups. In some cases, the symmetry description of a magnetic structure can be reduced to nonmagnetic groups, but the complete description in terms of magnetic groups can give valuable additional information, which is the main aim of this work.
As an illustrative example, we chose an array of graphene elements magnetized by a DC magnetic field. In the mathematical description, the magnetic field bias leads to algebra with antiunitary operators of the corresponding group. We apply the SALC approach to the 2D description of the structure where the magnetic group theory is used instead of the classical point group theory. As a result, corepresentations with a free real phase parameter appear. We discuss the physical meaning of this parameter. Another example, namely, a waveguide with a special type of degeneracy due to magnetic symmetry is also given. The 3D description of the Faraday effect by the scattering matrix and its eigensolutions calculated with the help of the magnetic group theory was developed. We discuss several special cases of the scattering matrix solutions. Some numerical results illustrating the theoretical analysis are presented as well.
2. The Problem Description
We shall consider a free-standing infinite array of graphene elements shown in
Figure 1
. A linearly polarized–normally incident wave with frequency
ω
is described by the electric field
E i
and by the wave vector
β
(
β = ω / c
), i.e.,
E i = x ^ E 0 exp [ i ( β z − ω t ) ]
.
B 0 ‖ β
is a uniform DC magnetic field,
θ F
and
θ K
are the angles of the Faraday and Kerr rotations, respectively. Four ports (1, 2, 3, 4) are defined as shown in
Figure 1
and used below in the circuit theory analysis. A square graphene element is placed symmetrically in a square unit cell. The unit cell of the periodic structure with the associated elements of symmetry is presented in
Figure 2
a. The center of Cartesian coordinates coincides with the center of the unit cell.
Figure 1. Array of free-standing square graphene elements where x , y , z is the Cartesian coordinate system; E i , E t , and E r are the electric fields of the incident, transmitted, and reflected waves, respectively, and β is the wave vector. B 0 is the DC magnetic field and θ F and θ K are the angles of Faraday and Kerr rotation, respectively. Ports 1, 2, 3, and 4 are used in the circuit theory description. A unit cell (dotted line square) is shown in the center of the array.
Figure 2. Square graphene element (solid line square) in a unit cell (dotted line square) of the investigated metasurface: ( a ) elements of geometrical symmetry of group C 4 v and ( b ) current basis j n ( n = 1 , ⋯ , 10 ) .
In the group-theoretical analysis, we do not take into account the translational symmetry of the array, i.e., we work in the long-wave approximation. Such an approximation is fulfilled for sufficiently small dimensions of the unit cell compared to the wavelength of the incident wave, i.e., when the graphene squares and the period have sub-wavelength dimensions. In our case, the period of the array is several times smaller than the electromagnetic wavelength in free space.
Below, we present some numerical results obtained by the eigenfrequency and full-wave simulations using the finite-element method (FEM) implemented in the commercial electromagnetic solver COMSOL Multiphysics
®
. Floquet boundary conditions on four sides of the unit cells, namely along the
x
- and
y
-axis, are used to simulate the periodic structure in the
x y
-plane. In the vertical direction (
z
-axis), the computational domain is limited by two perfectly matched layers backed by scattering boundary conditions in the case of the eigenfrequency analysis. Full-wave simulations were performed by implementing four ports as defined in
Figure 1
, corresponding to the two linear polarizations of the normally-impinging plane wave at the excitation (ports 1 and 2) and transmission (ports 3 and 4).
The side of the unit cell, i.e., the period of the array, used in numerical calculus is
A = 9
µm and the side of the graphene square is
a = 6
µm. Since the dimensions of the unit cell are subwavelength, no diffraction occurs in the periodic array, hence there is no need to define additional ports. The physical parameters of graphene are given in
Appendix A
. Graphene’s Drude-type dispersion was naturally implemented in full-wave FEM simulations. In the eigenfrequency analysis, an iterative scheme taking into account graphene’s dispersion was employed for the calculation of the complex eigenfrequencies.
3. Definition of the 4 × 4 Scattering Matrix
In optical and microwave problems, different types of matrix methods are used, for example, classical
2 × 2
Jones and
4 × 4
Mueller matrix techniques, or the
4 × 4
matrix technique of Teitler and Henvis [
28
] and Berreman [
29
]. In our case, we shall use a more convenient tool that is suitable for our group-theoretical treatment. In the long-wave approximation, one can calculate the structure of the scattering matrix
S ¯
using point symmetry arguments. Notice that this description is valid for the far-field region. The reflected
E r
and incident
E i
waves are connected by the matrix
S ¯
:
E r = S ¯ · E i ,
(1)
i.e., the
4 × 4
scattering matrix can be defined as follows:
E 1 r E 2 r E 3 r E 4 r = S ¯ E 1 i E 2 i E 3 i E 4 i ,
(2)
where ports 1 and 3 are oriented in the
x
-direction and ports 2 and 4 in the
y
-direction (see
Figure 1
). Ports 1 and 2 and ports 3 and 4 are placed symmetrically with respect to the array plane, i.e., at equal distance from the array.
The scattering matrix of the 4-port must be invariant under any operation of the corresponding group of symmetry [
23
]. For the unitary operators, we use the commutation relations,
R ¯ · S ¯ = S ¯ · R ¯ ,
(3)
and for the antiunitary ones,
R ¯ · S ¯ = S ¯ t · R ¯ ,
(4)
where
R ¯
is the 4D representation of a symmetry operator of the group [
23
],
t
in (
4
) means transposition. For our purposes, in (
3
) and (
4
), it is sufficient to use only generators of the corresponding group. Notice that in the scattering matrix description, its structure depends on all of the possible resonant and non-resonant modes, i.e., in our case, it includes left-handed (LH) and right-handed (RH) rotating modes of the graphene current, necessary for the Faraday effect.
4. Symmetry Analysis, Nonmagnetic Case, C 4 v Symmetry
4.1. Description of C 4 v Symmetry
In the following, we will use the Schoenflies system of notations of the group elements of symmetry operations, and the notations of the groups [ 4 ]. Notice that the notations of the group elements and the notations of the groups themselves may coincide. For example, symbol C 4 denotes the operation of the rotation about an axis by π / 2 , but it also may denote the group C 4 , consisting of four elements (see below).
In a nonmagnetic case, the DC magnetic field
B 0
equals zero. Firstly, we shall restrict our consideration by 2D point symmetry. The square unit cell with the square graphene resonator is described by the group
C 4 v
, which consists of eight elements:
e is the unit element;
σ x and σ y are reflections in the planes x = 0 , y = 0 , respectively;
σ x y and σ x ( − y ) are reflections in the planes passing through the waveguide axis z and the axes x y and x ( − y ) , respectively;
C 2 are rotations by π about the axis z ;
C 4 and C 4 − 1 are rotations about the axis z by π / 2 and − π / 2 , respectively.
Strictly speaking, the whole group in the nonmagnetic case is C 4 v + T + T C 4 v , where T is the time reversal (see Appendix A ). However, the elements T C 4 v are usually omitted because they do not provide new information.
Now we shall consider the effects of the symmetry operators on the wave vector
β
and DC magnetic field
B 0
, which are parallel to the planes
σ x
,
σ y
,
σ x y
, and
σ x ( − y )
. The unit element
e
and the rotations
C 2
,
C 4
, and
C 4 − 1
preserve the sign of
β
and
B 0
. The reflection operators
σ x
,
σ y
,
σ x y
, and
σ x ( − y )
also preserve the sign of
β
(it is a polar vector) but change the sign of
B 0
because
B 0
is an axial one (see
Table 1
). The DC magnetic field is uniform with a fixed direction, which means that in the magnetic case, the elements
σ x
,
σ y
,
σ x y
, and
σ x ( − y )
cannot exist. These planes are transformed in the antiplanes
T σ x
,
T σ y
,
T σ x y
, and
T σ x ( − y )
(
Appendix A
). The antiplanes leave
B 0
invariant (see a discussion in
Section 6.1
). For the same reason, the pure time reversal operator
T
in the magnetic case cannot also be an element of the group because it changes the sign of
B 0
.
Table 1. Effects of the symmetry operators on the wave vector β and on DC magnetic field B 0 .
4.2. SALCs
Group C 4 v possesses five irreducible representations (IRs) presented in Table 2 . Four of them, namely, A 1 , A 2 , B 1 , and B 2 , are one-dimensional (1D), and E is two-dimensional (2D) IR. The relatively high symmetry and the presence of 2D IRs will allow us to discuss the group-theoretical approach more profoundly. The discussion will be conducted in terms of the 2D current densities j n ( n = 1 , ⋯ , 10 ) in the graphene resonator, which are shown in Figure 2 b. The unit vectors { j 1 , ⋯ , j 8 } and { j 9 , j 10 } belong to orthogonal subspaces; therefore, they can be considered separately.
Table 2. Irreducible representations of group C 4 v and possible modes of the square unit cell.
By applying successively the projection operator ( A9 ) of Appendix B to the unit vectors j n , one can obtain the desired SALCs. A simple example of such calculus is given in Appendix D . In the case of C 4 v symmetry, eight projection operators exist because there are four 1D representations and one 2D. However, for the 2D IR, one can use only diagonal elements. Therefore, the number of operators is reduced to six. Moreover, due to the symmetry C 4 , one can use in calculus only four vectors j n , say, j 1 and j 2 , and j 9 and j 10 . Thus, using Table 2 and Table 3 , the SALCs can be easily calculated. They are presented in Table 4 .
Table 3. The basis set change according to the group C 4 v .
Table 4. Eigenmodes of the graphene square with C 4 v symmetry in terms of vectors j n (see Figure 2 b) and the calculated structures of currents and the magnetic field H z .
Due to the 2D nature of the currents in the graphene and the framework of edge surface plasmon polaritons (SPPs) with exponential dependence of the eigenmode fields along the axis
z
, not all of the modes predicted by symmetry can be realized in the square graphene resonator, such as
A 2
,
Q x
, and
Q y
. Numerical simulations presented in
Table 4
demonstrate that the possible eigenmodes correspond to the IRs
A 1
(radial mode),
B 1
and
B 2
(quadrupole modes), and
E
(dipole modes). We do not consider higher angular modes, such as hexapole and octopole ones, and higher modes defined by variations of the field along the radial coordinate. Notice that the circular mode
A 2
, which was not found in the numerical analysis of the SPP eigenfrequencies, can describe, for example, a magnetic dipole resonance in a dielectric resonator [
30
]. The quadrupole modes
Q x
and
Q y
can also exist in dielectric structures [
31
].
The 1D radial A 1 and 1D quadrupole modes B 1 and B 2 are symmetry-protected dark modes, i.e., they cannot be excited by a plane wave with normal incidence without symmetry breaking [ 32 , 33 ]. In order to excite the dark modes, one needs to reduce C 4 v symmetry in a special manner. Notice that the unique bright mode is the dipole one belonging to the IR E . Its excitation is polarization-independent because its IR is 2D (see Appendix D ).
In contrast to the all-dielectric metasurfaces [ 34 ], the imaginary parts of the calculated numerically eigenfrequencies A 1 , B 1 , and B 2 (they are presented in the fourth column of Table 4 ), in this case, are not zero. However, this is not related to the coupling with external incident fields. The imaginary parts are conditioned by the intrinsic losses in graphene. Notice that the imaginary parts of the resonant frequencies of the dipole modes are higher than those for other modes because they include (along with resistive losses) the effect of coupling with the incident wave.
5. Symmetry Analysis, Magnetic Case, C 4 symmetry
5.1. SALCs
We start our discussion on magnetic structures with a lower symmetry
C 4
. In order to reduce the symmetry
C 4 v
, the square graphene patch is cut off at the corners. Possible geometry of the graphene patch possessing symmetry
C 4
is shown in
Figure 3
. If the field
B 0 = 0
, the group of symmetry of the unit cell with the patch is
C 4
of the first category (it is called nonmagnetic group), i.e., it contains the time reversal operator. When the field
B 0 ≠ 0
, the group of symmetry of the unit cell is
C 4
of the second category (magnetic group), and this group does not have the time reversal operator. The IRs of
C 4
are given in
Table 5
. The symmetry degeneration of group
C 4 v
in
C 4
is presented in
Appendix C
, see
Table A3
.
Figure 3. Graphene element (solid line figure) with C 4 symmetry in a square unit cell, B 0 is the DC magnetic field.
Table 5. Irreducible representations of the C 4 group.
In groups
C 4
and
C 4
, there are only 1D representations, but the IRs
B 1
and
B 2
are complex conjugates. Two of these representations define the complex conjugate pair of eigenvectors. Without the DC magnetic field, i.e., in the corresponding group of the first category
C 4
when symmetry, with respect to the time reversal, exists, such a pair can be considered as one representation
E
with a dimensionality of two. Therefore, we have a specific two-fold degeneracy. If the system is under the DC magnetic field, the symmetry with respect to time reversal is removed, and the two complex conjugate representations correspond to different eigenvalues.
The sense of polarization rotation for the mode Γ B 1 and also for the mode Γ B 2 (see Table 6 )) defined with respect to B 0 , does not depend on the direction of the wave propagation. The Faraday effect is defined by the sum of the RH rotating dipole mode of the ICR Γ B 1 and the LH rotating dipole of the ICR Γ B 2 .
Table 6. Eigenmodes of the graphene element shown in Figure 3 with C 4 symmetry in terms of vectors j n and calculated structure of currents. The dotted arrow in a RH- or LH-rotated dipole mode means a vector multiplied by the imaginary unit i , i.e., it has the phase shift π / 2 .
5.2. Scattering Matrix
In a nonmagnetic group
C 4
, the time reversal operator is a member of the group, and it corresponds to the reciprocity of an object independently of other symmetry elements. In the circuit theory description, this is equivalent to the symmetry of the scattering matrix
S ¯
with respect to the main diagonal.
In both cases, the nonmagnetic group
C 4
and magnetic group
C 4
, one can choose as a generator the four-fold rotation
C 4
. In the 3D symmetry of the diffraction problem, we add in calculus the symmetry plane
z = 0
, which is
σ z
(see
Figure 1
). This plane exists in both nonmagnetic and magnetic cases. Using (
3
), one comes to the matrices for the nonmagnetic (
S ¯ = S ¯ t
) and magnetic (
S ¯ ≠ S ¯ t
) cases, respectively:
S ¯ C 4 n m = S 11 0 S 13 0 0 S 11 0 S 13 S 13 0 S 11 0 0 S 13 0 S 11 , S ¯ C 4 m = S 11 S 12 S 13 S 14 − S 12 S 11 − S 14 S 13 S 13 S 14 S 11 S 12 − S 14 S 13 − S 12 S 11 .
(5)
The matrix
S ¯ C 4 n m
has the simplest form with two complex parameters. The numerical values of
S i j
depend on the parameters and dimensions of the graphene square and the chosen distance between the ports. Ports 1 and 2, as well as 3 and 4, are decoupled from each other.
Matrix
S ¯ C 4 m
for the magnetic case has four complex parameters. In contrast to the nonmagnetic case, ports 1 and 2, and also 3 and 4 are coupled in a nonreciprocal fashion. The same is true for coupling between ports 1 and 4, and also 2 and 3. Thus, the matrix
S ¯ C 4 m
describes a nonreciprocal structure, where nonreciprocity is related to the angular rotation of fields. However, the coupling between ports 1 and 3 and also between 2 and 4 is reciprocal. Analyzing the matrix for the magnetic case, one can see that in this symmetry Faraday and Kerr effects are possible. With the incident wave
E 1
, the angle of Faraday rotation
θ F
can be calculated from
Figure 1
as follows:
tan θ F = E 4 / E 3
, and the angle of Kerr rotation
θ K
is defined by
tan θ K = E 2 / E 1
. In the following, we will not discuss the details of polarization characteristics.
6. Symmetry Analysis, Magnetic Case, C 4 v ( C 4 ) Symmetry
6.1. ICRs
The magnetic group of symmetry of the square graphene element magnetized normally to its plane by the field B 0 (see Figure 1 and Figure 2 a) is C 4 v ( C 4 ) . One can consider the transition from the nonmagnetic to magnetic states from the point of view of the reduction of the symmetry of the system by the DC magnetic field.
The group C 4 v ( C 4 ) of the third category belongs to case a) described in Appendix C , i.e., due to the Herring criterion of reducibility of corepresentations [ 35 ] (see ( A8 ) of Appendix B ), no new degeneracy is introduced by this corepresentation (an example of such degeneracy is given in Appendix E ). Comparing Table 2 and Table 7 below, we see that under applied DC magnetic field, four planes of symmetry convert into antiplanes and the unitary C 4 subgroup contains only rotations.
Table 7. Irreducible corepresentations of the C 4 v ( C 4 ) group.
The antireflection operators T σ x , T σ y , T σ x y , and T σ x ( − y ) , where T is the restricted time reversal operator [ 21 ] (see Appendix B ), change the sign of β , because β is a polar odd in the time vector. However, B 0 is an axial odd in time vector and therefore the combined antireflection produces a double change of the sign preserving the sign of the field B 0 . Therefore, the antireflection operators transform the forward-traveling wave into the backward-traveling one and the backward wave propagates in the same environment as the forward wave ( B 0 is preserved), see Table 1 .
To calculate the ICRs of the given magnetic group, the method of Wigner (see Appendix C ) can be used. For our problem, it is straightforward to calculate ICR from the representations of the unitary subgroup C 4 = { e , C 2 , C 4 − 1 , C 4 } listed in Table 5 . The calculated ICRs for the C 4 v ( C 4 ) group are written in Table 7 . In the complex number called phase-function s = exp ( i θ ) , the parameter θ can assume any real value. The two signs in the ICRs ± s or ∓ s of Table 7 for the antiunitary elements correspond to two possible solutions, but these solutions are equivalent.
In our problem, a physical interpretation of parameter
s
can be as follows. There are several scenarios where a backward wave can exist. For example, (a) the array is situated between two sources, (b) the array is in a resonator with a standing wave, (c) the array is placed on a dielectric substrate, and reflections at the interface between the dielectric and air appear. The unitary part of
C 4 v ( C 4 )
in 2D space
x 0 y
gives the symmetry relations for the currents produced, for example, by the forward wave, but the antiunitary elements define relations for the currents produced by the backward wave. If the 3D symmetry is not given, the waves traveling in the opposite directions arrive at the array with arbitrary phases and this explains the undefined parameter
θ
. In a 3D symmetry with the plane of symmetry
σ z
, the forward and backward waves travel the same way from the sources to the array and arrive at the array with the same phases; therefore, one can set
θ = 0
and
s = 1
. This gives constructive interference to the waves. However, in 3D geometry without
σ z
,
θ
is not defined. This problem can be solved by Maxwell’s equations with the corresponding boundary conditions.
6.2. SALCs
The TEM plane wave E i = x ^ E 0 exp [ i ( β z − ω t ) ] with normal incidence excites all the currents j n (for example, j 9 = x ^ exp ( − i ω t + ϕ ) ) in a graphene square with the same phase ϕ and this phase can be set to zero. The harmonic time dependence of the unit currents exp ( − i ω t ) is preserved for the given and time-reversed quantities [ 21 ]. Therefore, the complex conjugation of the antiunitary elements in Table 8 can be omitted.
Table 8. The basis set change according to the C 4 v ( C 4 ) group.
Using the projection operator of ( A9 ) in Appendix B , Table 7 and Table 8 , we calculate and present in Table 9 the eigenmodes of graphene square with C 4 v ( C 4 ) symmetry in terms of vectors j n . We used in calculus the upper signs in the ICRs of the antiunitary elements presented in Table 7 . The numerically calculated structure of the currents and the magnetic field H z are given in the last column of Table 9 .
Table 9. Eigenmodes of the graphene square with C 4 v ( C 4 ) symmetry in terms of vectors j n (see Figure 2 b), the calculated structures of the currents, and the magnetic field H z . T σ x is the antiplane of the symmetry. The dotted arrow in the LH or RH rotated dipole mode means a vector multiplied by the imaginary unit i , i.e., a phase shift of π / 2 . The sense of polarization rotation for the modes Γ B 1 and Γ B 2 is defined with respect to B 0 . The resonance frequency for the LH mode is ω − and for the RH mode is ω + .
The obtained results can be interpreted as follows. Let us consider, for example, the ICR
Γ B 1
. It is known from the theory of magnetic groups that antiunitary elements can be obtained by multiplying any chosen antiunitary element by all the elements of the unitary subgroup. In our case, this can be written as
T σ x
(
e , C 2 , C 4 − 1 , C 4
)=(
T σ x , T σ y , T σ x y
,
T σ x ( − y )
). The antiunitary element
T σ x
changes the direction wave of propagation, i.e.,
T σ x β = − β
and reflects the currents in the plane
σ x
, changing their directions, preserving the LH or RH sense of rotation due to the combined effects of
σ x
and
T
. Therefore, the antiunitary elements add to the current structure of group
C 4
discussed in
Section 5.1
, the currents with the same structure but for the wave propagating in the opposite direction. In the plane of the array, the sum of these currents related by the multiplier
s = exp ( i θ )
appears. With
s = − i
, the current structure of the ICRs
Γ B 1
corresponds to the constructive interference. For the ICR
Γ B 2
, the constructive interference is produced by the parameter
s = i
.
In the third column of Table 9 , we present a schematic illustration of the mathematical expression for the currents given in the second column. For example, for the ICR Γ B 1 the RH rotating current mode is produced by the forward wave (the first square). By reflection in the antiplane T σ x (this element is a member of the C 4 v ( C 4 ) group) one obtains the RH rotating current mode corresponding to the backward wave (the second square) with the same orientation of B 0 .
The Faraday effect is defined by a sum of the RH rotating dipole mode of ICR
Γ B 1
with the resonance frequency
ω +
and the LH rotating dipole of IR
Γ B 2
with the resonance frequency
ω −
. The central frequency of this effect is defined approximately as
ω F = ( ω + + ω − ) / 2
.
The splitting of the dipole resonance by the DC magnetic field B 0 obtained by numerical calculus in eigenfrequency analysis of COMSOL software is demonstrated in Figure 4 . These results are confirmed by full-wave analysis assuming an x -polarized incident plane wave in Figure 5 where due to the application of B 0 , two dimples in the transmission curve stemming from the resonances of the LH and RH rotating modes appear.
Figure 4. Dependence of the resonant frequencies of the radial and quadrupole modes on the DC magnetic field B 0 and splitting of the dipole resonance by the magnetic field, calculated by eigenfrequency analysis.
Figure 5. Transmission spectra of the investigated graphene element array for different values of the DC magnetic field, calculated by full-wave simulations.
6.3. Scattering Matrix, Eigenvalues, and Eigenvectors
The calculated scattering matrices for the nonmagnetic and magnetic cases are, respectively:
S ¯ C 4 v n m = S 11 0 S 13 0 0 S 11 0 S 13 S 13 0 S 11 0 0 S 13 0 S 11 , S ¯ C 4 v ( C 4 ) m = S 11 S 12 S 13 S 14 − S 12 S 11 − S 14 S 13 S 13 S 14 S 11 S 12 − S 14 S 13 − S 12 S 11 .
(6)
Comparing ( 5 ) and ( 6 ), one can see that despite the different symmetries of the unit cells, the scattering matrices have the same structure.
Now we calculate the eigenvalues of the matrix
S ¯ C 4 v ( C 4 ) m
by solving the equation
S ¯ · V = λ V ,
(7)
where
V
is an eigenvector and
λ
is an eigenvalue of the matrix
S ¯
.
The calculated eigenvalues are
λ 1 = ( S 11 + S 13 ) + i ( S 12 + S 14 ) , λ 2 = ( S 11 + S 13 ) − i ( S 12 + S 14 ) , λ 3 = ( S 11 − S 13 ) + i ( S 12 − S 14 ) , λ 4 = ( S 11 − S 13 ) − i ( S 12 − S 14 ) ,
(8)
where
λ 1
and
λ 2
(and also
λ 3
and
λ 4
) are complex conjugated. From (
8
), one can obtain the relations between the scattering matrix elements and the eigenvalues:
S 11 = 1 4 ( λ 1 + λ 2 + λ 3 + λ 4 ) ,
S 12 = 1 4 i ( λ 1 − λ 2 + λ 3 − λ 4 ) ,
S 13 = 1 4 ( λ 1 + λ 2 − λ 3 − λ 4 ) ,
S 14 = 1 4 i ( λ 1 − λ 2 − λ 3 + λ 4 ) .
The calculated normalized eigenvectors
V m
corresponding to eigenvalues
λ m ( m = 1 , 2 , 3 , 4 )
are as follows:
V 1 = 1 2 1 i − 1 − i ; V 2 = 1 2 1 − i − 1 i ; V 3 = 1 2 1 i 1 i ; V 4 = 1 2 1 − i 1 − i .
(9)
In every vector
V m
, the first two elements present the RH or LH circular polarized wave entering port 1 and port 2, i.e., from one side of the array, and the other two elements describe the wave entering from the other side of the array, i.e., from port 3 and port 4. These eigenvectors can be used in theoretical and experimental investigations of this and other structures with the same symmetry. Notice that the excitation of only port 1 is determined by the sum of eigenvectors (
9
), i.e.,
V 1 + V 2 + V 3 + V 4 = ( 1 , 0 , 0 , 0 ) t .
(10)
One can simplify further the obtained matrices (
6
). Using the unitary conditions [
36
]
S ¯ · ( S ¯ * ) t = I ¯ 4 = ( S ¯ * ) t · S ¯ ,
(11)
where
I ¯ 4
is the
4 × 4
unit matrix,
t
means transposition,
*
denotes complex conjugation, one comes to the scattering matrices for the matched nonmagnetic structure without losses:
S ¯ n m = 0 0 1 0 0 0 0 1 1 0 0 0 0 1 0 0 .
(12)
Let us apply this to the magnetic case. The unitary condition (
11
) for
S ¯ C 4 v ( C 4 ) m
in (
6
) leads to the following system of equations:
| S 11 | 2 + | S 12 | 2 + | S 13 | 2 + | S 14 | 2 = 1 , S 11 S 12 * − S 12 S 11 * + S 13 S 14 * − S 14 S 13 * = 0 , S 11 S 13 * + S 12 S 14 * + S 13 S 11 * + S 14 S 12 * = 0 , S 11 S 14 * − S 12 S 13 * + S 13 S 12 * − S 14 S 11 * = 0 , S 12 S 13 * − S 11 S 14 * + S 14 S 11 * − S 13 S 12 * = 0 , S 12 S 14 * + S 11 S 13 * + S 14 S 12 * + S 13 S 11 * = 0 , S 13 S 14 * − S 14 S 13 * + S 11 S 12 * − S 12 S 11 * = 0 .
(13)
In the following, we shall consider an ideally matched array with | S 11 | = 0 .
In a general case,
| S 12 | ≠ 0
,
| S 13 | ≠ 0
and
| S 14 | ≠ 0
, and
| S 13 | | S 14 | sin ( ϕ 13 − ϕ 14 ) = 0 , | S 12 | | S 14 | cos ( ϕ 12 − ϕ 14 ) = 0 , | S 13 | | S 12 | sin ( ϕ 13 − ϕ 12 ) = 0 .
(14)
These three simultaneous equations cannot be solved in the used approximations of lossless and ideally matched four-port. In order to resolve this problem, one can put an additional restriction on the matrix elements, such as
| S 12 | = 0
,
| S 13 | = 0
, or
| S 14 | = 0
. Considering, for example,
S 12 = 0
, then
S 13 = k exp ( i ϕ 13 )
,
S 14 = 1 − k 2 exp ( i ϕ 14 )
,
ϕ 13 = ϕ 14 + n π
and the scattering matrix
S ¯ C 4 v ( C 4 ) m
acquires the following form:
S ¯ m = 0 0 k ± 1 − k 2 0 0 ∓ 1 − k 2 k k ± 1 − k 2 0 0 ∓ 1 − k 2 k 0 0 ,
(15)
where we have omitted the overall phase multiplier. This matrix is defined by one scalar parameter. It describes a nonreciprocal directional coupler with the Faraday effect. It should be noted that our results follow from general symmetry considerations and with the above approximations in the matrix calculus, one loses the effect of possible ellipticity in the transmitted wave. Moreover, in cases of lossless media and ideal matching of the four-port, the symmetry analysis does not permit the Kerr and the Faraday effects to co-exist. Removing these restrictions allows one to consider both the Kerr and the Faraday effects with possible ellipticity of polarization characteristics of the transmitted and reflected waves.
7. Conclusions
We demonstrated the application of group-theoretical methods to electromagnetic structures with magnetic media. The discussed methods are general and can be applied to electromagnetic structures with different geometries, physical parameters, and physical effects. Using the symmetry approach, we calculated and analyzed the scattering matrix of the discussed array of graphene elements. The eigenvalues and eigenvectors of this matrix are defined. The SALC method was extended here to structures described by magnetic groups with antiunitary elements. We clarified the physical meaning of the parameter
exp ( i θ )
in the irreducible corepresentations. Considering a square waveguide with ferrite media magnetized by a quadrupole DC magnetic field, we demonstrated the existence of a special degeneracy related to magnetic symmetry. This degeneracy is defined by the Herring test. Most of the discussion was related to the electric currents in graphene. However, it can also be fulfilled in terms of electromagnetic fields. We believe that the presented results and developed methods can be useful in the design and optimization of new electromagnetic components with magnetic media.
Author Contributions
Conceptualization, V.D. and L.P.V.M.; formal analysis, V.D., L.P.V.M. and D.C.Z., methodology, V.D. and L.P.V.M.; software, D.C.Z.; visualization, all authors; writing—original draft preparation, V.D. and L.P.V.M.; writing—review and editing, all authors; supervision, V.D.; funding acquisition, V.D. and D.C.Z. All authors have read and agreed to the published version of the manuscript.
Funding
This work was supported by the CNR-FAPESP biennial (2022–2023) bilateral project StReAM “Strongly Resonant All-dielectric Metasurfaces based on quasi-dark and toroidal modes”. V.D. thanks also the Brazilian Agency National Council of Technological and Scientific Development (CNPq) for financial support. D.C.Z. acknowledges the support of the project ECS00000024 “Ecosistemi dell’Innovazione”—Rome Technopole of the Italian Ministry of University and Research, public call n. 3277, PNRR-Mission 4, Component 2, Investment 1.5, financed by the European Union, Next GenerationEU.
Data Availability Statement
The data presented in this study are available from the corresponding author upon reasonable request.
Conflicts of Interest
The authors declare no conflict of interest.
Appendix A. Graphene Parameters
The optical properties of graphene can be determined by the surface conductivity
σ s
, which describes the interaction between graphene with electromagnetic radiation and can be given by Drude’s semi-classical model [
37
]:
σ s = 2 D π i ω − 1 / τ ( ω + i / τ ) 2 ,
(A1)
where
D = 2 σ 0 ϵ F / ℏ
is the Drude weight,
σ 0 = e 2 / ( 4 ℏ )
is the minimum conductivity of graphene,
ϵ F = 0.5
eV is the Fermi energy of graphene,
ℏ
is the reduced Planck’s constant,
e
is the electron charge,
τ = 1
ps is the relaxation time,
γ = 1 / τ = 10 12
1/s and
ω
is frequency of the incident electromagnetic wave.
Application of the external magnetic field
B 0
leads to the circulation of charge carriers in graphene in cyclotron orbits due to the Lorentz force. In this case, the 2D conductivity tensor of graphene with non-zero off-diagonal components can be described by [
37
]
[ σ s ] = σ x x − σ x y σ x y σ x x ,
(A2)
σ x x = 2 D π 1 / τ − i ω ω B 2 − ( ω + i / τ ) 2 ,
(A3)
σ x y = − 2 D π ω B ω B 2 − ( ω + i / τ ) 2 ,
(A4)
where
ω B = e B 0 v F 2 / ϵ F
is the cyclotron frequency,
v F ≈ 10 6
m/s is the Fermi velocity, and
σ x x = σ y y
and
σ y x = − σ x y
are the longitudinal (diagonal) and transverse (off-diagonal) parts, respectively. For the device operating the THz frequency range, we consider only the intraband contributions for the calculation of the components of the graphene conductivity tensor [
σ s
]. The influence of interband transitions can be neglected, since the condition
ℏ ω < < 2 ϵ F
is satisfied [
38
].
Appendix B. Elements of Magnetic Group Theory
Time reversal operator . The time reversal T , which changes the sign of the time, and its combination with geometrical symmetry elements are called the antiunitary operators [ 1 ]. The time reversal operator reverses the direction of currents, magnetic fields, and the Poynting vector. In the frequency domain, it also conjugates electromagnetic quantities and this property can be shown easily by the Fourier transform of the time-reversed quantities [ 21 ].
It should be stressed that due to causality, the time-reversal symmetries in physical processes do not exist. Moreover, the dissipative processes are not time-reversible. A modified version of this operator called the restricted time reversal operator was suggested in [ 21 ]. It is not applied to the dissipative terms of the electromagnetic quantities preserving thus the passive or active nature of the media.
Categories of magnetic groups
. The magnetic groups can be divided into three categories. The group of the first category
G
presents a unitary subgroup
H
and products of the time reversal with the elements of
H
. The magnetic groups of the second category
G
do not contain time reversal
T
. The notations of the groups of the first category and those of the second category coincide. In order to distinguish them, we use the bold-face type for the groups of the second category.
The groups of the third category G ( H ) , which are the most interesting for us, have the so-called antiunitary elements, which present the product of T and the geometrical symmetry elements. We call these elements antielements (for example, antiplane of symmetry). The group of the third category can be described as H + T H ′ . These groups can be defined also in a different way, namely, G = H + B H , where B is any antiunitary element of group G . A description of these categories of magnetic groups is given in Table A1
Table A1. Content of magnetic groups of symmetry.
Table A1. Content of magnetic groups of symmetry.
First Category Second Category Third Category G = H + T H G G ( H ) = H + T H ′ , H ′ ≠ H including T without T T only in combination with rotation-reflections
Co-representations
. Wigner [
1
] introduced in the group theory the so-called corepresentations where the term “corepresentation” reminds one of the complex conjugate signs in the matrix multiplication scheme [see (
A7
) below]. The corepresentations are defined as follows:
Γ ( u ) = Δ ( u ) 0 0 Δ * ( a 0 − 1 u a 0 ) ,
(A5)
Γ ( a j ) = 0 Δ ( a a 0 ) Δ * ( a 0 − 1 a ) 0 ,
(A6)
where
a 0
and
a
are antiunitary elements,
u
is a unitary one,
Δ
is an irreducible representation of
H
.
Homomorphism scheme
. The multiplication scheme for corepresentations in the group of the third category, for
u i , u j
unitaries and
a i , a j
anti-unitaries, is as follows:
Γ ( u i ) Γ ( u j ) = Γ ( u i u j ) , Γ ( u i ) Γ ( a j ) = Γ ( u i a j ) , Γ ( a i ) Γ * ( u j ) = Γ ( a i u j ) Γ ( a i ) Γ * ( a j ) = Γ ( a i a j ) .
(A7)
Herring rule
. This rule [
35
] defines three special cases:
∑ a χ ( a 2 ) = | H | c a s e ( a ) − | H | c a s e ( b ) 0 c a s e ( c )
(A8)
where
| H | = | M | / 2
is the subgroup order,
χ ( a 2 )
is the character of corepresentation
a 2
, where
a
is an antiunitary element. This rule permits determining the reducibility of the corepresentation. For our purposes, this rule can be read as follows. In case (a), no new degeneracy is introduced; in case (b), the degeneracy of
Γ i
is doubled, i.e., a given representation appears twice and the eigenvectors are different and orthogonal but the eigenvalues are identical; in case (c), the representation
Γ i
is degenerate with the representation
Γ j
, i.e., a pair of different eigenvectors has the same eigenvalue. Hence, in case (a), we may discuss the problem of the degeneracy of group
G ( H )
, investigating only the unitary subgroup
H
. In case (b), the degeneracy of one of the eigenvalues appears, though this degeneracy is absent in subgroup
H
. In case (c), the degeneracy of two different eigenvectors exists, though it is also not predicted by subgroup
H
(see
Appendix E
).
Projection operator
. In order to obtain SALCs in the case of a magnetic group of the third category, we use the projection operator [
39
], which for 2D ICR is written as follows:
P Δ i j = 1 | G | ∑ u Γ i j ( u ) u + 1 | G | ∑ a Γ i j * ( a ) a ,
(A9)
where the summation in the first sum is over the unitary elements
u
, and in the second sum is over the antiunitary ones
a
,
Γ i j
are elements of the corepresentation.
Appendix C. Splitting of IR E of C 4 v in C 4
The field B 0 removes the degeneracy which exists in the square non-magnetized structure due to the representation E . In order to find the representations of the C 4 group, which are contained in the representation E of C 4 v , we write out the characters (i.e., traces of the IR) of Table 2 for IR E corresponding to the operations of the C 4 group. It is presented in Table A2 .
Table A2. Characters of the irreducible representation E of group C 4 v .
Table A2. Characters of the irreducible representation E of group C 4 v .
C 4 v e C 2 C 4 C 4 − 1 E 2 −2 0 0
The number of times
n Γ i
a given IR
Γ i
appears in the reducible representation is defined by the following relation:
n Γ i = 1 | G | ∑ u i χ ( u i ) χ I R ( u i ) * ,
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陈天石--中国科学院计算技术研究所
陈天石 研究员
研究方向： 计算机体系结构；计算智能
所属部门：
导师类别： 博导计算机系统结构（客座）
联系方式：
个人网页： http://novel.ict.ac.cn/tchen
简 历：
陈天石，男， 1985 年 6 月生，江西南昌人。2005年毕业于中国科学技术大学少年班，获理学学士学位（数学与应用数学）； 2010 年毕业于中国科学技术大学计算机学院，获工学博士学位（计算机软件与理论）。同年进入中国科学院计算技术研究所工作，历任助理研究员（2010）、副研究员（2013）和研究员（2016）。研究方向为计算机体系结构和计算智能。在 IEEE/ACM Transactions 、 Theoretical Computer Science 、ASPLOS、 ISCA 、MICRO、 HPCA 、 IJCAI 、 AAAI 、 SPAA 、 DATE 等重要期刊和会议上发表论文数十 篇。2015年获 国家自然科学基金委员会优秀青年基金项目（优青）支持。
主要论著：
代表性期刊论文（ * 通讯作者）：
-Tianshi Chen, Shijin Zhang, Shaoli Liu, Zidong Du, Tao Luo, Yuan Gao, Junjie Liu, Dongsheng Wang, Chengyong Wu, Ninghui Sun, Yunji Chen, and Olivier Temam, "A Small-Footprint Accelerator for Large-Scale Neural Networks," ACM Transactions on Computer Systems, in press.
-Tianshi Chen , Qi Guo, Olivier Temam, Yue Wu, Yungang Bao, Zhiwei Xu, and Yunji Chen, "Statistical Performance Comparisons of Computers," IEEE Transactions on Computers , in press .
-Qi Guo, Tianshi Chen, Zhi-Hua Zhou, Olivier Temam, Ling Li, Depei Qian, and Yunji Chen, "Robust Architectural Design Space Modeling," ACM Transactions on Design Automation of Electronic Systems, in press.
-Shaoli Liu, Tianshi Chen, Ling Li, Xi Li, Mingzhe Zhang, Chao Wang, Haibo Meng, Xuehai Zhou, and Yunji Chen, "FreeRider: Non-local Adaptive Network-on-Chip Routing with Packet-Carried Propagation of Congestion Information," IEEE Transactions on Parallel and Distributed Systems, in press.
- Jun He, Tianshi Chen, and Xin Yao, " On the Easiest and Hardest Fitness Functions," IEEE Transactions on Evolutionary Computation , in press.
- Qi Guo, Tianshi Chen*, Yunji Chen, Rui Wang, and Huanhuan Chen, Weiwu Hu, and Guoliang Chen, "Pre-Silicon Bug Forecast," IEEE Transactions on Computer-Aided Design of Integrated Circuits and Systems , vol. 33, no. 33, pp. 451-463, 2014.
- Tianshi Chen , Yunji Chen, Qi Guo, Zhi-Hua Zhou, Ling Li, and Zhiwei Xu, "Effective and Efficient Microprocessor Design Space Exploration Using Unlabeled Design Configurations," ACM Transactions on Intelligent Systems and Technology , vol. 5, no. 1, Article 20, 2013.
- Weishan Dong, Tianshi Chen, Peter Tino, and Xin Yao, "Scaling Up Estimation of Distribution Algorithms For Continuous Optimization," IEEE Transactions on Evolutionary Computation , vol. 17, no. 6, 2013.
- Yunji Chen, Tianshi Chen*, Ling Li, Ruiyang Wu, Daofu Liu, and Weiwu Hu, "Deterministic Replay Using Global Clock," ACM Transactions on Architecture and Code Optimization , vol. 10, no. 1, Article 1, 2013.
- Yunji Chen, Tianshi Chen, Ling Li, Lei Li, Liang Yang, Menghao Su and Weiwu Hu, "LDet: Determinizing Asynchronous Transfer for Post-silicon Debugging," IEEE Transactions on Computers , vol. 62, no. 9, pp. 1732-1744, 2013.
- Yunji Chen, Lei Li, Tianshi Chen*, Ling Li, Lei Wang, Xiaoxue Feng, and Weiwu Hu, "Program Regularization in Memory Consistency Verification," IEEE Transactions on Parallel and Distributed Systems , vol. 23, no. 11, pp. 2163-2174, 2012.
- Weiwu Hu, Yunji Chen, Tianshi Chen*, Cheng Qian, and Lei Li, "Linear Time Memory Consistency Verification," IEEE Transactions on Computers , vol. 61, no. 4, pp. 502-516, 2012.
- Tianshi Chen , Ke Tang, Guoliang Chen, and Xin Yao, "A Large Population Size Can be Unhelpful in Evolutionary Algorithms," Theoretical Computer Science , vol. 436, 2012.
- Tianshi Chen , Ke Tang, Guoliang Chen, and Xin Yao, "Analysis of Computational Time of Simple Estimation of Distribution Algorithms," IEEE Transactions on Evolutionary Computation , vol. 14, no. 1, pp. 1-22, 2010. （ 2010 年度最佳论文奖提名）
- Tianshi Chen , Jun He, Guoliang Chen, and Xin Yao, "Choosing Selection Pressure for Wide-gap Problems," Theoretical Computer Science , vol. 411, no. 6, pp. 926-934, 2010.
- Tianshi Chen , Jun He, Guangzhong Sun, Guoliang Chen, and Xin Yao, "A New Approach to Analyzing Average Time Complexity of Population-based Evolutionary Algorithms on Unimodal Problems," IEEE Transactions on Systems, Man, and Cybernetics: Part B , vol. 39, no. 5, pp. 1092-1106, 2009.
代表性会议论文：
-Shijin Zhang, Zidong Du, Lei Zhang, Huiying Lan, Shaoli Liu, Ling Li, Qi Guo, Tianshi Chen, and Yunji Chen, "Cambricon-X: An Accelerator for Sparse Neural Networks," In Proceedings of 49th IEEE/ACM International Symposium on Microarchitecture (MICRO'16), 2016. （ CCF A 类会议）
-Shaoli Liu, Zidong Du, Jinhua Tao, Dong Han, Tao Luo, Yuan Xie, Yunji Chen, and Tianshi Chen, "Cambricon: An Instruction Set Architecture for Neural Networks," In Proceedings of 43rd ACM/IEEE International Symposium on Computer Architecture (ISCA'16), 2016. （ CCF A 类会议；同行评议最高分）
-Daofu Liu, Tianshi Chen, Shaoli Liu, Jinhong Zhou, Shengyuan Zhou, Olivier Temam, Xiaobing Feng, Xuehai Zhou, and Yunji Chen, "PuDianNao: A Polyvalent Machine Learning Accelerator," In Proceedings of 20th International Conference on Architectural Support for Programming Languages and Operating Systems (ASPLOS'15), 2015. （ CCF A 类会议；第一指导老师）
-Yunji Chen, Tao Luo, Shaoli Liu, Shijin Zhang, Liqiang He, Jia Wang, Ling Li, Tianshi Chen, Zhiwei Xu, Ninghui Sun, and Olivier Temam, "DaDianNao: A Machine-Learning Supercomputer," In Proceedings of 47th IEEE/ACM International Symposium on Microarchitecture (MICRO'14), 2014. （ 最佳论文奖 ； CCF A 类会议）
- Tianshi Chen , Zidong Du, Ninghui Sun, Jia Wang, Chengyong Wu, Yunji Chen, and Olivier Temam, "DianNao: A Small-Footprint High-Throughput Accelerator for Ubiquitous Machine-Learning," In Proceedings of 19th International Conference on Architectural Support for Programming Languages and Operating Systems (ASPLOS 2014) , 2014. （ 最佳论文奖 ； CCF A 类会议）
- Tianshi Chen , Qi Guo, Ke Tang, Olivier Temam, Zhiwei Xu, Zhi-Hua Zhou, and Yunji Chen, "ArchRanker: A Ranking Approach to Design Space Exploration," In Proceedings of 41th ACM IEEE International Symposium on Computer Architecture (ISCA'14) , 2014. （ CCF A 类会议）
- Tianshi Chen , Yunji Chen, Qi Guo, Olivier Temam, Yue Wu, and Weiwu Hu, "Statistical Performance Comparisons of Computers," In Proceedings of 18th International Symposium on High-Performance Computer Architecture (HPCA-18) , New Orleans, Louisiana, 2012. （ CCF A 类会议）
- Tianshi Chen , Yunji Chen, Marc Duranton, Qi Guo, Atif Hashmi, Mikko Lipasti, Andrew Nere, Shi Qiu, Michele Sebag, and Olivier Temam, "BenchNN: On the Broad Potential Application Scope of Hardware Neural Network Accelerators," In Proceedings of 2012 International Symposium on Workload Characterization (IISWC'12) , San Diego, California, 2012. （最佳论文奖提名）
- Qi Guo, Tianshi Chen, Yunji Chen, Zhi-Hua Zhou, Weiwu Hu, and Zhiwei Xu, "Effective and Efficient Microprocessor Design Space Exploration Using Unlabeled Design Configurations," In Proceedings of 22nd International Joint Conference on Artificial Intelligence (IJCAI'11) , Barcelona, Spain, 2011. （ CCF A 类会议；第一指导老师）
- Lei Li, Tianshi Chen, Yunji Chen, Ling Li, Cheng Qian, and Weiwu Hu, "Brief Announcement: Program Regularization in Verifying Memory Consistency," In Proceedings of 23rd ACM Symposium on Parallelism in Algorithms and Architectures (SPAA'11) , San Jose, California, 2011. （ CCF B 类；第一指导老师）
- Qi Guo, Tianshi Chen, Haihua Shen, Yunji Chen, Yue Wu and Weiwu Hu, "Empirical Design Bugs Prediction for Verification," In Proceedings of 2011 Design, Automation and Test in Europe Conference (DATE'11) , Grenoble, France, 2011. （ CCF B 类会议；第一指导老师）
- Ke Tang, Rui Wang, and Tianshi Chen, "Towards Maximizing The Area Under The ROC Curve For Multi-class Classification Problems," In Proceedings of 25th AAAI Conference on Artificial Intelligence (AAAI'11) , San Francisco, USA, 2011. （ CCF A 类会议）
- Qi Guo, Tianshi Chen, Haihua Shen, Yunji Chen, and Weiwu Hu, "On-the-fly Reduction of Stimuli for Functional Verification," In Proceedings of 19th IEEE Asian Test Symposium (ATS'10), Shanghai, China, 2010. （第一指导老师）
- Yunji Chen, Weiwu Hu, Tianshi Chen, and Ruiyang Wu, "LReplay: A Pending Period Based Deterministic Replay Scheme," In Proceedings of 37th ACM IEEE International Symposium on Computer Architecture (ISCA'10) , 2010. （ CCF A 类会议）
- Yunji Chen, Yi Lv, Weiwu Hu, Tianshi Chen, Haihua Shen, Pengyu Wang, and Hong Pan, "Fast Complete Memory Consistency Verification," In Proceedings of 15th International Symposium on High-Performance Computer Architecture (HPCA-15) , 2009. （ CCF A 类会议；中国大陆研究机构首次发表 HPCA 论文）
- Tianshi Chen , Per Kristian Lehre, Ke Tang, and Xin Yao, "When Is an Estimation of Distribution Algorithm Better than an Evolutionary Algorithm," In Proceedings of 2009 IEEE Congress on Evolutionary Computation (CEC'09) , Trondheim, Norway, 2009.
- Tianshi Chen , Ke Tang, Guoliang Chen, and Xin Yao, "Rigorous Time Complexity Analysis of Univariate "> Proceedings of 2009 IEEE Congress on Evolutionary Computation (CEC'09) , Trondheim, Norway, 2009.
- Tianshi Chen , Ke Tang, Guoliang Chen, and Xin Yao, "On the Analysis of Average Time Complexity of Estimation of Distribution Algorithms," In Proceedings of 2007 IEEE Congress on Evolutionary Computation (CEC'07) , Singapore, 2007, pp. 453-460.
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Boyar Branch Post Office, Murshidabad 26, West Bengal
Boyar Post Office, Murshidabad
Boyar post office is located at Boyar, Murshidabad of West Bengal state. It is a branch office (B.O.). A Post Office (PO) / Dak Ghar is a facility in charge of sorting, processing, and delivering mail to recipients. POs are usually regulated and funded by the Government of India (GOI). Pin code of Boyar PO is742226. This Postoffice falls under Murshidabad postal division of the West Bengal postal circle. The related head P.O. for this branch office is Raghunathganj head post office and the related sub-post office (S.O.) for this branch office is Sagardighi post office.
Boyar dak ghar offers all the postal services like delivery of mails & parcels, money transfer, banking, insurance and retail services. It also provides other services including passport applications, P.O. Box distribution, and other delivery services in Boyar.
Types of Post Offices
Post offices are basically classified into 3 types, namely – Head Post Office, Sub-Post Office including E.D. Sub-Office and Branch Postoffice. Boyar P.O. is a Branch Post Office. So far as the public is concerned, there is basically no difference in the character of the service rendered by Sub-Post Offices and Head-Post Offices except in regard to a few Post Office Savings Bank (SB) transactions. Certain Sub Post Offices do not undertake all types of postal business. Facilities are generally provided at Branch Post Offices for the main items of postal work like delivery and dispatch of mails, booking of registered articles and parcels accepting SB deposits and effecting SB withdrawals, and issue and payment of money orders, though in a restricted manner.
Post Office Type Head Post Office Sub-Post Offices including E.D. Sub-Offices Branch Post Office
Boyar Post Office & Its Pin Code
Branch Office Information
Boyar Post Office Services
Mail Services
Parcels
Retail Services
Premium Services
Speed Post
India Post Speed Post Tracking
Tracking System
India Post Tracking Number Formats
Express Parcel Post
Media Post
Greetings Post
Logistics Post
ePost Office
Financial Services
Savings Bank (SB) Account
Recurring Deposit (RD) Account
Monthly Income Scheme (MIS)
Monthly Public Provident Fund (PPF)
Time Deposit (TD)
Senior Citizen Saving Scheme (SCSS)
National Savings Certificate (NSC)
Kisan Vikas Patra (KVP)
Sukanya Samriddhi Accounts (SSA)
Post Office Timings
India Post Tracking
Boyar Post Office Recruitment
Location Map
Contact Details
About India Post
Boyar Post Office & Its Pin Code
Often Post Offices are named after the town / village / location they serve. The Boyar Post Office has the Postal Index Number or Pin Code 742226. A Pincode is a 6 digit post code of postal numbering system used by India Post. The first digit indicates one of the regions. The first 2 digits together indicate the sub region or one of the postal circles. The first 3 digits together indicate a sorting / revenue district. The last 3 digits refer to the delivery post office type.
<table><tbody><tr><th> P.O. Name</th><td> Boyar PO</td></tr><tr><th> Pincode</th><td> 742 226</td></tr></tbody></table>
The first digit of 742226 Pin Code '7' represents the region, to which this Post Office of Boyar belongs to. The first two digits of the Pin Code '74' represent the sub region, i.e, West Bengal. The first 3 digits '742' represent the post-office revenue district, i.e, Murshidabad. The last 3 digits, i.e, '226' represent the Boyar Delivery Branch Office.
Branch Office Information
The Boyar Post Office is a branch office. The Delivery Status for this PO is that it has delivery facility. Postal division name for this Dak Ghar is Murshidabad, which falls under Calcutta region. The circle name for this PO is West Bengal and it falls under Murshidabad Taluka and Murshidabad District. The state in which this Dakghar is situated or located is West Bengal. The related head postoffice is Raghunathganj post office and the related sub post office is Sagardighi post-office. The phone number of Boyar post office is unavailable at present.
<table><tbody><tr><th> PO Type</th><td> Branch Office</td></tr><tr><th> Delivery Status</th><td> Delivery</td></tr><tr><th> Postal Division</th><td> Murshidabad</td></tr><tr><th> Postal Region</th><td> Calcutta</td></tr><tr><th> Postal Circle</th><td> West Bengal</td></tr><tr><th> Town / City / Tehsil / Taluka / Mandal</th><td> Murshidabad</td></tr><tr><th> District</th><td> Murshidabad</td></tr><tr><th> State</th><td> West Bengal</td></tr><tr><th> Related Sub PO</th><td> Sagardighi Sub Office</td></tr><tr><th> Related Head PO</th><td> Raghunathganj Head Post Office</td></tr></tbody></table>
Boyar Post Office Services
Traditionally the primary function of Boyar post office was collection, processing, transmission and delivery of mails but as of today, a Post Office offers many other vital services in addition to its traditional services. The additional services provided by a Dak Ghar include – Mail Services, Financial Services, Retail Services and Premium Services.
Mail Services
Mail Services are the basic services provided by Boyar P.O. Mails and mail services include all or any postal articles whose contents are in the form of message which may include Letters, Postcards, Inland letter cards, packets or parcels, Ordinary mails etc.
Parcels
Mail Service also includes transmission and delivery of Parcels. A parcel can be anything ranging from a single written letter or anything addressed to an addressee. No parcel shall be by any chance be in a shape, way of packing or any other feature, such that it cannot be carried or transmitted by post or cause serious inconvenience or risk. Every parcel (including service parcels) that needs to be transmitted by post must be handed over at the window of the post office. Any parcel found in a letter box will be treated and charged as a registered parcel. Delivery services are provided by some selected delivery and branch post offices. This dakghar have the facility of delivery, thus the people of Boyar and nearby localities can avail all the types of mail services.
Retail Services
Post offices in India serve in various ways and Boyar Post Office offer most of the retail services. They offer the facility to accept or collect constomer bills like telephone or mobile bills, electricity bills for Government and private organizations through Retail Post. Some of the aditional agency services that Post offices offers through retail services are as follows - Telephone revenue collection, e-Ticketing for Road Transport Corporations and Airlines, Sale of UPSC forms, university applications, Sale of Passport application forms, Sale of Gold Coins, Forex Services, Sale of SIM and recharge coupons, Sale of India Telephone cards, e-Ticketing of Railway tickets etc. The postal customers of Boyar can pay their bills and avail other retail services from this Dak Ghar.
Premium Services
Most of the premium services can be availed by the Boyar peoples and nearby living people. The premium services provided by Boyar Post Office are - Speed Post, Business Post, Express Parcel Post, Media Post, Greeting Post, and Logistics Post.
Speed Post
Speed Post is a time bound service in express delivery of letters and parcels. The max weight up to which an article or parcel be sent is 35 kgs between any two specified stations in India. Speed Post delivers 'Value for money' to everyone and everywhere, delivering Speed Post upto 50 grams @ INR 35 across the country and local Speed Post upto 50 grams @ INR 15, excluding applicable Service Tax. Kindly check official website for updated Speed Post service charges.
India Post Speed Post Tracking
Speed Post offers a facility of on-line tracking and tracing that guarantees reliability, speed and customer friendly service. Using a 13 digit barcode that makes a Speed Post consignment unique and identifiable. A web-based technology (www.indiapost.gov.in/speednettracking.aspx) helps the Boyar customers track Speed Post consignments from booking to delivery.
Tracking System
Except Speed Post, India Post also allows people to track their order information for certain products like Parcels, Insured letters, Speed Post, Registered Post, Electronic Money Orders (EMO) and Electronic value payable parcel (EVPPs) etc. The tracking number is available on the receipt given at Boyar Post Office. Using the tracking number postal customers can find out the date and time of dispatch of an article at various locations. The time of booking and the time of delivery of article.
India Post Tracking Number Formats
Different types of postal service have different kinds of tracking number formats. The tracking number for Express Parcel is a 13 digit alphanumeric format. The format for Express Parcel is XX000000000XX. The tracking number for a Registered Mail is a 13 digit alphanumeric number and its format is RX123456789IN. But a Electronic Money Order (EMO) has a 18 digit tracking number and its format is 000000000000000000. For domestic Speed Post (EMS) there is a 13 digit alphanumeric tracking number with the format EE123456789IN.
<table><tbody><tr><th> Bharatiya Dak Ghar Seva</th><th> Tracking Number Format</th><th> Number of Digits</th></tr><tr><td> Electronic Money Order (eMO)</td><td> 000000000000000000</td><td> 18</td></tr><tr><td> Express Parcel</td><td> XX000000000XX</td><td> 13</td></tr><tr><td> International EMS Artilces to be delivered in India</td><td> EE123456789XX</td><td> 13</td></tr><tr><td> Registered Mail</td><td> RX123456789IN</td><td> 13</td></tr><tr><td> Speed Post (EMS) Domestic</td><td> EE123456789IN</td><td> 13</td></tr></tbody></table>
Express Parcel Post
In Express Parcel Post, the Boyar postal customer gets time bound delivery of parcels. These parcels will be transmitted through air or any other fastest mean available at that time. Minimum chargeable weight for which Express Parcel consignments will be booked is 0.5 Kg. Maximum weight of Express Parcel consignments which shall be booked across the Post Office counter by a retail customer shall be 20 Kg and maximum weight that can be booked by corporate customer is 35 kgs.
Media Post
India Post offers a unique way or concept to help the Indian corporate organisations and the Government organizations reach potential customers through media post. Through media post people can advertise on postcards, letters, aerogramme, postal stationary etc. Customers get to see the logo or message of the respective corporate or government organizations. The Aerogramme even gives the organizations the opportunity to make their product have a global impact.
Greetings Post
Greeting Post is yet another innovative or unique step by India Post. It consists of a card with an envelope with pre-printed and pre attached postage stamp on the envelope. The stamp on the envelope is a replica of the design that appears upon the card but in miniature form. Thus there is no need affix postage stamps on the envelope implicitly saving your time of going to post offices and standing in the queue. All the rules and that are applicable for the postage dues will also be applicable to the Greeting Post.
Logistics Post
Logistics Post manages the entire transmission and distribution side of the parcels. It deals with collection of goods, storage of goods, carriage and distribution of the various parcels or goods, from order preparation to order fulfilment. And that too at the minimum possible price. Logistics Post services provides the Boyar postal customer with cost-effective and efficient distribution across the entire country.
ePost Office
The advent of internet made communication very rapid through emails. But, the internet has not yet reached most of the rural parts of India. To change this division between rural & urban life, and to get the benefit of internet technology to Boyar people's lives, Indian Postal Department has introduced e-post. e-post is a service in which personalized handwritten messages of customers are scanned and sent as email through internet. And at the destination address office, these messages are again printed, enveloped and delivered through postmen at the postal addresses. E-post centres are established in the Post Offices, covering a large geographical area including major cities and districts. These e-post centres are well equipped with internet connection, scanners, printers and other necessary hardware equipment. However, this e-post service doesn’t particularly need a e-post centre, but can this facility can be availed at any normal Post Office or you can visit www.epostoffice.gov.in to access postal services on your desktop, laptop or even on mobile. If a message is booked at Boyar post office, the post is scanned and sent to an e-post centre by e-mail and a mail received at e-post centre is printed and sent to nearby Post Office for dispatch.
A Boyar customer can also avail these services of an e-post, at his/ her home. All he/ she has do is to register as a user at www.epostoffice.gov.in website. After registration, a user can use e-post by scanning and sending messages, printing and receive messages. The message to be scanned must not be written in a paper not more A4. There is no limit for sending number of sheets of messages in e-post.
E-Post Office offers certain services like – Philately, Postal Life Insurance, Electronic Indian Postal Order, Information Services, Track & Trace and Complaints & Guidelines services.
Philately
Philately service deals with collection, sale and study of postage stamps. Philately includes lot of services Philately Information, Stamp issue Program, Stamps List and Buy Stamps service.
Postal Life Insurance (PLI)
A service offered by the Government to pay a given amount of money on the death of an individual to his prescribed nominee. The amount may also be paid to the person himself, in case he survives that maturity period. The two services offered under Postal Life Insurance are – Pay Premium service and PLI information.
Electronic Indian Postal Order
eIPO or Electronic Indian Postal Order is a facility to purchase an Indian Postal Order electronically by paying a fee on-line through e-Post Office. This service is launched by the Department of Posts, Ministry of Communications & IT, Government of India.
eIPO can now be used by Indian Citizens living in India for paying online fee, whoever seeks information under the RTI Act, 2005. eIPO offers 2 types of services – eIPO information and payment of online fees.
Information Services
This helps Boyar customers to get information regarding certain products like – Pin Code search, Speed post, Banking, Insurance, Business Post, Logistics Post, IMTS and many more other services.
Track & Trace
The track & trace service is very helpful as it aids in getting information of our valuables. Track & Trace service offers 5 different services – Pin Code search, EMO tracking, Speed Post tracking, WNX tracking and International mail service.
Complaints & Guidelines
Using e-post office service Boyar postal costumer can access services based on – complaint registration, complaint status and guidelines on complaints.
<table><tbody><tr><th> ePost Office Website</th><td> www.epostoffice.gov.in</td></tr></tbody></table>
Financial Services
The customers of Boyar can enjoy the various savings schemes available in this post office that prove to be highly beneficial for the people living in Boyar area. The Financial service offered by PO includes Savings and Postal Life Insurance (PLI). There are various options available to save and invest with post-offices. The commonly used ones include - Savings account, Recurring Deposit, Monthly Income Scheme, Monthly Public Provident Fund, Time Deposit, Senior Citizen Saving Scheme, National Savings Certificate, Kisan Vikas Patra and Sukanya Samriddhi Yojana. Post Office also offers Insurance product through Postal Life Insurance (PLI) and Rural Postal Life Insurance (RPLI) schemes that offer low premium and high bonus.
Post Office Financial Services Kisan Vikas Patra (KVP) Monthly Income Scheme (MIS) Monthly Public Provident Fund (PPF) National Savings Certificate (NSC) Recurring Deposit (RD) Account Savings Bank (SB) Account Senior Citizen Saving Scheme (SCSS) Sukanya Samriddhi Accounts (SSA) Time Deposit (TD)
Savings Bank (SB) Account
A Savings bank account serves the need of regular deposits for its customers as well as withdrawals. Cheque facility is also avail by Boyar postal consumers.
Recurring Deposit (RD) Account
A post office offers a monthly investment option with handsome return at the time period with an option to extend the investment period. Insurance facility is also available with certain conditions.
Monthly Income Scheme (MIS)
MIS offers a fixed investment technique for five or more years with monthly interest payment to the account holder. There is also a facility of automatic crediting of interest to SB account of the Boyar postal customer.
Monthly Public Provident Fund (PPF)
This service offers intermittent deposits subject to a particular limit for a time period of 15 years with income tax exemptions, on the investment. It also offers loan and withdrawal facilities for the postal customers.
Time Deposit (TD)
Fixed deposit option for periods ranging from one, two, three to five years with facility to draw yearly interest offered at compounded rates. Automatic credit facility of interest to SB account.
Senior Citizen Saving Scheme (SCSS)
Offers fixed investment option for senior citizens for a period of five years, which can be extended, at a higher rate of interest that are paid in quarterly instalments.
National Savings Certificate (NSC)
NSC is offered with a fixed investment for 5 or 10 years on certificates of various denominations. Pledging facility available for availing loan from Banks.
Kisan Vikas Patra (KVP)
Kisan Vikas Patra is a saving certificate scheme in which the amount Invested doubles in 110 months (i.e. 9 years & 2 months). It is available in denominations of Rs 1,000, 5000, 10,000 and Rs 50,000. Minimum deposit is Rs 1000/- and there is no maximum limit. The KVP certificate can be purchased by any adult for himself or on the behalf of a minor. This certificate can also be transferred from one account holder to another and from one post office to another. This certificate can be en-cashed only after 2 and 1/2 years from the date of issue.
Sukanya Samriddhi Accounts (SSA)
Sukanya Samriddhi Account Yojana offers a small deposit investment for the girl children as an initiative under 'Beti Bachao Beti Padhao' campaign. This yojana is to facilitate girl children proper education and carefree marriage expenses. One of the main benefits of this scheme is that it is very affordable and offers one of the highest interest rates. Currently its interest rate is set as 8.6% per annum that is again compounded yearly. The minimum deposit allowed in a financial year is INR. 1000/-and Maximum is INR. 1,50,000/-. Subsequent deposits can be made in multiples of INR 100/-. Deposits can be made all at a time. No limit is set on number of deposits either for a month or a financial year. A legal Guardian can open an account in the name of a Girl Child. Account can be closed only after completion of 21 years of the respective child. The normal Premature closure allowed is after completion of 18 years only if that girl is getting married.
Post Office Timings
The official working hours of Post Offices vary from one another, but the general Post Office opening time starts from 09:00 AM or 10:00 AM and the closing time is 06:00 PM or 07:00 PM respectively. The working days are from Monday to Saturday, Sunday being a holiday. This doesn't include the public holidays or the extended working hours. You can verify the working hours of Boyar Branch Post Office from the official resources.
India Post Tracking
Online tracking of India Post allowed Boyar people to access their postal article tracking information and confirm the delivery of their postal article by using the tracking number assigned to them at the time of Booking. They can find the tracking number on the Postal acknowledgement handed over to them at the Boyar Branch Post Office counter at the time of postal article booking. Following items can track through the www.indiapost.gov.in/articleTracking.aspx official website.
Business Parcel
Business Parcel COD
Electronic Money Order (e-MO)
Electronic Value Payable Parcel (eVPP)
Express Parcel
Express Parcel COD
Insured Letter
Insured Parcel
Insured Value Payable Letter
Insured Value Payable Parcel
International EMS
Registered Letter
Registered Packets
Registered Parcel
Registered Periodicals
Speed Post
Value Payable Letter
Value Payable Parcel
The India Post tracking system is updated at regular intervals to give the Boyar postal customers with the most up to date information available about the location and status of their postal article. They'll be able to find out the following:
When their postal article was booked
When their postal article was dispatched at various locations during its Journey
When their postal article was received at various locations during its Journey
When their postal article was delivered, or
When a delivery intimation notice was issued to notify the recipient that the postal article is available for delivery
Boyar Post Office Recruitment
For latest Boyar post office recruitment kindly visit www.indiapost.gov.in/recruitment.aspx.
Location Map
Boyar Branch Post Office is located in Boyar, Murshidabad.
Contact Details
All the queries or complaints regarding Bill Mail Service, Booking Packets, Business Post, Direct Post, Flat Rate Box, Indian Postal Orders, Inland Letters, Instant Money Orders, Insurance of Postal Articles, Insurance of Postal Parcels, Letters, Logistics Posts, MO Videsh, Money Orders, Parcels, Post Office Savings Bank, Postal Life Insurance, Postcards, Registration of Postal Articles, Registration of Postal Parcels, Rural Postal Life Insurance, Saving Certificates, Small Saving Schemes, Speed Post, Value Payable Post etc. services in Boyar Post Office, can be resolved at Boyar Branch Post Office. You can send letters to "Postmaster, Boyar Branch Post Office, Boyar, Murshidabad, West Bengal, India, Pincode: 742 226". The official website of the Berhampur University Sub Office is www.indiapost.gov.in.
Boyar Branch Office
Address: Boyar Branch Post Office, Boyar, Murshidabad, West Bengal, India
Pin Code: 742226
Website: www.indiapost.gov.in
About India Post
India Post is a government-operated postal system, which is part of the Ministry of Communications and Information Technology of the Government of India. It has the largest Postal Network in the India with over 154882 Post Offices. There are around 139182 Post Offices in the rural India and 15700 Post Offices in urban India. The individual post office serves an area of 21.22 Sq. Km. and a population of 8221 people. The slogan of India Post is Dak Seva Jan Seva. There are 25464 departmental post offices and 129418 extra-departmental branch post offices in India.
Boyar Post Office Summary
<table><tbody><tr><th> Dak Ghar Name</th><td> Boyar Branch Post Office</td></tr><tr><th> Pincode</th><td> 742226</td></tr><tr><th> Dakghar Type</th><td> Branch Office</td></tr><tr><th> Post Office Delivery Status</th><td> Delivery Branch Office</td></tr><tr><th> Postal Division</th><td> Murshidabad</td></tr><tr><th> Postal Region</th><td> Calcutta</td></tr><tr><th> Postal Circle</th><td> West Bengal</td></tr><tr><th> Location</th><td> Boyar</td></tr><tr><th> Town / City / Tehsil / Taluka / Mandal</th><td> Murshidabad</td></tr><tr><th> District</th><td> Murshidabad</td></tr><tr><th> State</th><td> West Bengal</td></tr><tr><th> Country</th><td> India</td></tr><tr><th> Related Sub Office</th><td> Sagardighi Sub Office</td></tr><tr><th> Related Head Office</th><td> Raghunathganj Head Post Office</td></tr><tr><th> Website</th><td> www.indiapost.gov.in</td></tr><tr><th> ePost-office Web Site Address</th><td> www.epostoffice.gov.in</td></tr><tr><th> Speed Post Tracking Website</th><td> www.indiapost.gov.in/speednettracking.aspx</td></tr><tr><th> Recruitment Web Site Address</th><td> www.indiapost.gov.in/recruitment.aspx</td></tr></tbody></table>
| https://www.postoffices.co.in/westbengal-wb/boyar-murshidabad-26/amp/ |
(PDF) Autochthonous v. Accreted Terrane development of continental margins: A revised in situ tectonic history of the Antarctic Peninsula
PDF | The allochthonous terrane accretion model previously proposed for the geological development of the Antarctic Peninsula continental margin arc is... | Find, read and cite all the research you need on ResearchGate
Autochthonous v. Accreted Terrane development of continental margins: A revised in situ tectonic history of the Antarctic Peninsula
August 2015
Journal of the Geological Society 172(6)
DOI: 10.1144/jgs2014-110
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CC BY 3.0
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Abstract and Figures
The allochthonous terrane accretion model previously proposed for the geological development of the Antarctic Peninsula continental margin arc is reviewed in light of recent data and the geology is reinterpreted as having evolved as an in situ continental arc. This is based upon the following factors: (1) the presence of Early Palaeozoic basement and stratigraphic correlation of sequences between the autochthonous and previously proposed allochthonous terranes; (2) isotopic evidence for similar deep crustal structure across the different terranes; (3) ocean island basalt magmas and deep marine sedimentary rocks formed during continental margin extension within the previously proposed accretionary wedge sequence (i.e. not formed against an active oceanic arc); (4) the distribution of magnetic susceptibility measurements and aeromagnetic data locating the palaeo-subduction zone along the west of the Peninsula; (5) a lack of clear palaeomagnetic distinction between the terranes. The following alternative tectonic history is proposed: (1) amalgamation and persistence of Gondwana; (2) subsequent silicic large igneous province magmatism and extension; (3) development and history of Andean subduction until its cessation in the Cenozoic. A number of features in the Antarctic Peninsula correlate with those of other circum-Pacific margins, supporting a global evaluation of allochthonous v. autochthonous margin development to aid our understanding of crustal growth mechanisms.
Time–space plot summarizing the stratigraphy within each proposed domain of the Antarctic Peninsula. Symbols as in Figure 1. Sed, depositional age of sedimentary rocks; Vol, magmatic age of volcanic rocks; Int, emplacement age of non-metamorphosed intrusive rocks; Met, protolith age of metamorphic rocks; PLE, Palmer Land Event (Vaughan et al. 2012a). Units for the Western Domain are as follows. Sed: LeMay Group, Sinnemurian–Albian (Thomson & Tranter 1986; Holdsworth & Nell 1992); Fossil Bluff Group, Kimmeridgian– Albian (Butterworth et al. 1988); Adelaide Is., c. 150–113.9 Ma (Thomson 1972; Riley et al. 2012a). Vol: Alexander Is., 157–152 Ma (Macdonald et al. 1999), 80–46 Ma (McCarron 1997) and 2.5–0.5 Ma (Hole 1988); Adelaide Is., 76–39.2 Ma (Griffiths & Oglethorpe 1998; Riley et al. 2012a); South Shetland Is., 135–22.6 Ma (Smellie et al. 1998; Haase et al. 2012) and 2.4–0.1 Ma (Pankhurst & Smellie 1983). Int: Alexander Is., 75–56 Ma (McCarron 1997); Adelaide Is., 60–44 Ma (Pankhurst 1982; Griffiths & Oglethorpe 1998; Riley et al. 2012a). Units for the Central Domain are as follows. Vol: arc magmatism, 153–86 Ma (Rex 1976; Leat & Scarrow 1994); alkali magmatism, 3.1–0.1 Ma (Ringe 1991). Int: 267–8.9 Ma (Ringe 1991; Millar et al. 2002). Met: 422–178 Ma (Pankhurst 1983; Millar et al. 2002). Units for the Eastern Domain are as follows. Sed: Fitzgerald and Erehwon Beds, Pre-Late Palaeozoic to Latest Permian (Laudon 1991); Trinity Peninsula Group, Latest Carboniferous to Mid-Triassic (Smellie & Millar 1995; Riley et al. 2011b; Bradshaw et al. 2012); Latady Group and Mt Hill Fm, 185–140 Ma (Meneilly et al. 1987; Hunter & Cantrill 2006); Larsen Basin, 167 Ma to Paleocene–Eocene (Hathway 2000; Hunter et al. 2005). Vol: Chon Aike Group, 188–178 and 172–162 Ma (Pankhurst et al. 2000); arc magmatism, <162 to 35 Ma (Rex 1976); alkali magmatism, 6.5–0.5 Ma (Rex 1976). Int: 256–54 Ma (Rex 1976; Riley et al. 2012b). Met: 487–175 Ma (Gledhill et al. 1982; Riley et al. 2012b). …
Age and calculated palaeopole latitudes for the Eastern and Western domains (Kellogg & Reynolds 1978; Longshaw & Griffiths 1983; Kellogg & Rowley 1989; Grunow 1993; Poblete et al. 2011). α 95 plotted as palaeolatitude error. …
εNd i and magmatic ages from Millar et al. (2001) for intrusive and volcanic rocks on the Antarctic Peninsula plotted according to their domain. ED, Eastern Domain; CD, Central Domain; WD, Western Domain; FI, felsic intrusions; II, intermediate intrusions; MI, mafic intrusions; V, volcanic rocks. …
Aeromagnetic anomaly map of the Antarctic Peninsula from Ferraccioli et al. (2006) combining improved resolution (indicated by square outline) and previous data. EPLSZ, East Palmer Land Shear Zone; PMA, Pacific Margin Anomaly. Grey dashed lines show other proposed thrust faults of Vaughan & Storey (2000). Figure reproduced with permission from F. Ferraccioli, British Antarctic Survey. …
Illustrative tectonic reconstruction for Palmer Land highlighting the key events in the autochthonous development of the Antarctic Peninsula. …
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Alex Burton-Johnson
Discover the world's research
... The western and eastern boundaries are the Hero (HFZ) and Shackleton (SFZ) fracture zones, respectively (Fig. 1B). The continental margins offshore the northern Antarctic Peninsula have been active since the breakup of Gondwana during the Mesozoic
(Burton-Johnson & Riley, 2015;
Jordan et al., 2020). Cenozoic tectonics of the region was significantly affected by the convergence of the former Phoenix and Antarctic Plates (Henriet et al., 1992;Eagles et al., 2009;Jordan et al., 2020). ...
Deep‐water sedimentary systems and tectono–sedimentary interactions on the oblique convergent margin in Antarctica
Article
Feb 2023
Shan Liu
Chupeng Yang
Shaoru Yin
Zijun Liang
Active continental margins are tectonic sites with complex sedimentary processes. Tectono–sedimentary interactions occur over geological time and determine the modern morphology of the margin. However, such interactions have been poorly documented in high‐latitude regions. This study focuses on deep‐water sedimentary systems on the South Shetland convergent margin, which is the only remaining active continental margin in Antarctica. Numerous gullies, twenty canyons, and three contourite drifts are identified by interpreting bathymetry, oceanography and reflection seismic data. Heavy mineral contents of a gravity core, located at a downslope elongated mounded drift, show the asynchronous interplay of downslope and alongslope processes. The rest of the margin is dominated by turbidity currents. Variations in the slope gradient control thalweg profiles and sinuosity of canyons. Tectonic‐resulted morphology restricts the distribution of contourite drifts. Earthquakes triggered by underplating and tectonic compression may induce slope instability at the lower flank of the plastered drift. Tectonic uplift influences the amount of sediments transported by ice sheets and controls the shelf stacking pattern. The mixed turbidite–contourite system transitions to separated canyon and drift systems from passive to active continental margins under the influence of the tectonic‐related morphology. A systematic comparison has been made among several convergent margins with similar tectonic settings. Results suggest that submarine canyons on these shelf‐slope systems have similar morphological features and are comparable in size. Coarse sediment input and steep continental slopes (mean slope 7–10°) control the canyon morphology on these margins. Therefore, this research has important implications for furthering the current understanding of sedimentary systems on high‐latitude convergent margins and tectono–sedimentary interactions.
... The geological evolution of the Antarctic Peninsula is dominated by an active margin setting during the late Palaeozoic, Mesozoic and Cenozoic resulting from the subduction of the Phoenix Plate beneath the Antarctic Peninsula along southwestern margin of Gondwana (e.g., Burton-Johnson and
Riley, 2015;
Bastias et al., 2020;Jordan et al., 2020;Bastias et al., 2021;Bastias et al., 2022). During the early Mesozoic the breakup of Gondwana occurred, which caused the separation of the Antarctic Peninsula from Patagonia and Africa by the opening of the Weddell Sea in the South Atlantic (e.g., Ghidella et al., 2002;König and Jokat, 2006). ...
The South Shetland Islands, Antarctica: Lithostratigraphy and geological map
Jan 2023
Joaquin Bastias
David Chew
Camila Villanueva
Ricardo Jaña
Over the last few decades, numerous geological studies have been carried out in the South Shetland Islands, which have greatly contributed to a better understanding of its geological evolution. However, few attempts have been conducted to correlate the geological units throughout this archipelago. We present herein a review of the literature available in the South Shetland Islands, which we use to propose a lithostratigraphical correlation that constitutes a coherent stratigraphy for the main Mesozoic and Cenozoic rocks of the South Shetland Islands along with a new geological map. The lithostratigraphical correlation shows that the geological and environmental evolution comprises three main stages: 1) deep marine sedimentation from ∼164 to 140 Ma, 2) subaerial volcanism and sedimentation with a proliferation of plants and fauna from ∼140 to 35 Ma and 3) glacial and interglacial deposits from ∼35 Ma. The lithostratigraphical correlation also shows a broad geographical trend of decreasing age of volcanism from southwest to northeast, which has been previously suggested. However, this spatial age trend is disrupted by the presence of Eocene magmatism in Livingston Island, located in the centre of the archipelago. We suggest that the migration of volcanism occurred from the Late Cretaceous until the early Eocene. Subsequently, enhanced magmatic activity took place from the mid-Eocene until the Miocene, which we associate with processes related with the waning of subduction. Constraining the protolith age of the metamorphic complex of Smith Island remains challenging, yet holds key implications for the tectonic and accretionary evolution of the Antarctic Peninsula. The rocks recording the glaciation of this sector of Antarctica are well exposed in the northern South Shetland Islands and hold critical information for understanding the timings and processes that lead to the greenhouse to icehouse transition at the end of the Eocene. Finally, contemporaneous rocks to the breakup of Antarctic Peninsula from Patagonia that led to the opening of the Drake Passage and the development of the Scotia Sea are exposed in the centre and north of the South Shetland archipelago. Better constraints on the age and tectonic settings on these units may lead to further understanding the paleobiogeographical evolution of the region, which may have played an important role for speciation as a land bridge between South America and Antarctica. The dataset containing the geological map and associated information is shared as a shapefile or KML file.
... During the full glacial stages MIS 6 and 2 (Jouzel et al., 1989), we find low smectite/(chlorite + illite), quartz/feldspar, Ti/Al, and Si/Al ratios associated with high χMS terr values, and Fe-rich chlorite, Ti/Ca and Fe/Ca ratios (Figs. 3, 4 and 6). These features are consistent with basic to intermediate and undifferentiated parent rocks in the southern South America and on the Antarctic Peninsula
(Burton-Johnson and Riley, 2015;
Diekmann et al., 2000;Hillenbrand et al., 2009;Marinoni et al., 2008). Detritus from metamorphic and basic lithologies generally contains large amounts of magnetite minerals, which result in high χMS terr , Ti/Ca and Fe/Ca ratios (Dearing, 1994;Diekmann et al., 2000). ...
Late Quaternary terrigenous sediment supply in the Drake Passage in response to Patagonian and Antarctic ice dynamics
Article
| https://www.researchgate.net/publication/280713048_Autochthonous_v_Accreted_Terrane_development_of_continental_margins_A_revised_in_situ_tectonic_history_of_the_Antarctic_Peninsula |
Hormonal Effect on the Osmotic, Electrolyte and Nitrogen Balance in Terrestrial Amphibia
Zoological Science publishes articles, reviews and editorials that cover the broad and increasingly interdisciplinary field of zoology.
Hormonal Effect on the Osmotic, Electrolyte and Nitrogen Balance in Terrestrial Amphibia
Zoological Science, 12(1):1-11 (1995). https://doi.org/10.2108/zsj.12.1
Abstract
Two main hormones regulate water balance in amphibian. First, mesotocin (MT) acting as a diuretic agent, and second arginine vasotocin (AVT) being an anti-diuretic hormone. In addition, prolactin (PRL), aldosterone, corticosterone, angiotensin II and atriunatriuretic hormones, play a role too in regulating water and ion balance. The hormones affect the epidermis and bladder permeability to water and ions as well as the kidney through the control of the glomerular filtration rate (GFR). The main questions concern the presence and action of these hormones during the amphibian's life history. Are they present in both larval and adult stages? Are these hormones being synthesized in both aquatic and terrestrial adult phases? Under what circumstances are they being stored or released? Would the target organs (epidermis, bladder, kidney) respond in a similar way during all periods? The problem is the fact that under most circumstances an amphibian while in an aquatic environment responds physiologically differently than when on land. Only partial information concerning hormone presence, release and control of water balance is available at the moment, and even that is fragmentary and based on only a very small number of amphibian species.
INTRODUCTION
Amphibians are unique among the vertebrates as they live part of their lives in water and part on land. The proportion of time they spend in each environment varies among the various species even within one genus. Thus, some terrestrial amphibians spend as little as 2% of their lifetime in water until they metamorphose and during their breeding season ( Salamandra[217]), whereas others may spend up to 5% in water. Moreover, some return to water (to breed) at certain intervals and for various length of time. This requires different mechanisms for maintaining their water, electrolyte and nitrogen balance under such extremely different environments. Thus, being aquatic requires diuresis and enables ammonotelism, whereas terrestrial life requires antidiuresis and ureotelism or even uricotelism. Moreover, the hormones regulating these functions need to be available (secreted and in circulation) at all times because they are essential whenever required. On the other hand, each such hormone must not function as a regulating agent continuously all the time, only when necessary. This would also imply some preparedness on behalf of specific organs in order to respond to hormonal action only at a certain definite period. In a previous paper we have discussed the effects of hormones on ion, and water balance in the aquatic amphibians. These included larval forms as well as the aquatic phase of terrestrial amphibians, and the completely aquatic amphibians [217].
In the present paper an attempt will be made to evaluate our present knowledge about three aspects of endocrine control in terrestrial amphibians: water, ion and nitrogen balance.
ENDOCRINE CONTROL
Various aspects of the endocrine control of water balance in amphibians were reviewed by Heller [92], Jorgensen [122], Sawyer and Sawyer [183], Sawyer [179], Heller [93,94], Bentley [17,18], Warburg [213], Scheer et al.[185], Pang [171], Alvarado [3], Goldenberg and Warburg [80], Bentely [22], Warburg [214], Warburg and Rosenberg [217], Olivereau et al.[170], Hourdry [104], and Hanke and Kloas [89]. It was known that neurohypophysial hormones are involved in regulating the water balance. This so called “Brunn effect” caused a weight increase due to water uptake by the animal following injections of pituitary extracts (see Belhradek and Huxley [11]). Jorgensen et al.[125] found that this hormone was liberated during dehydration (in Bufo bufo). Both the par distalis and pars nervosa seem to be involved [55]. The pre-optic neurohypophysial system is responsible for anti-diuretic reaction of the bladder of Bufo bufo[124]. No effect was seen in transport of ions in the larvae of Ambystoma[130].
Some of the data available at the present time is summarized here (seeTable 1).
Table 1
Endocrine control of water, ion and nitrogen balance in amphibia
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A. The hydrins
These peptides found recently in aquatic and terrestrial amphibians are involved specifically in water and electrolyte regulation of amphibians [177]. Hydrin 2 (vasotocinyl-Gly) is found in terrestrial species ( Bufo regularis, B. marinusand B. viridis,see Acher et al.[1]).
They were also shown to affect the secretory action in the granulated glands of the dorsal skin of Xenopus[139].
B. Arginine vasotocin (AVT)
Presence of AVT in hypophysis
AVT was located in the neurohyphophysis of Rana catesbeiana[16] more precisely in the median eminence and the neural lobe of Rana ridibunda[167], and other anuran species [166]. AVT perikarya were localized in the nucleus preopticus of Bufo japonicus[118]. In the tadpole the amounts were a quarter of those found in adult frogs [24]. AVT concentration rose after dehydration due to a decrease in blood volume not because of increased osmolality [169]. Dehydration also affected the levels of AVT in the ventral preoptic brain area in the newt Taricha granulosa[229]. There is evidence of seasonal effect on AVT levels which appear to be higher during the breeding season of the newts in spring [230]. Perhaps because of the breeding activity of the male. Nothing is known about AVT levels in the aquatic anurans ( Xenopus, Pipa, Discoglossus), or urodeles ( Necturus, Siren, Amphiuma). Nor do we know about levels of AVT in amphibians from xeric habitats ( Bufo, Neobatrachus, Scaphiopus). Finally, is there a change in AVT levels when the tadpole or larvae metamorphose and emerge onto land, or when the adult urodele (newt) returns to water to breed?
AVT effect on water balance
Weight increase (as a result of water uptake) was studied in several amphibian species following treatment with AVT. In tadpoles or larvae it was more pronounced towards metamorphic climax ( Rana catesbeiana, [24], and Ambystoma tigrinum, [5]). However, the response was noticeable already in the 2-limbed tadpole of Rana ridibunda[79], or in the metamorphosing Salamandralarva [215], (seeFig. 1). No effect was noticeable in the young tadpole of Bufo bufo[106]. The response to AVT in Rana ridibundatadpoles or juveniles was much lower than to oxytocin (OXY) [79]. In adult frogs the water uptake was about 50% of the body weight ( Hyla hyla), or 5% in Pelobates cultripes[95]. In adult Hyla arboreawater uptake following treatment with AVT was remarkable, twice as much as when treated with OXY. On the other hand, in both Pelobates syriacusand Bufo viridis, it was considerably lower than the uptake following treatment with OXY [211]. A similar pattern was observed in Salamandra salamandraand Triturus vittatus(aquatic phase). The terrestrial phase of the newt ( T. vittatus), responded to AVT in much the same way as to OXY [212]. Elliott [68], described an increase in water uptake in Bufo melanostictus. Similarly, Cree [59,60] found increased water retention in two terrestrial liopelmatid frogs but not in a semi-aquatic species. On the other hand, the aquatic amphibians ( Siren, Amphiuma, Discoglossus, see [95]), or the aquatic phase of the newt ( Notophthalmus viridescenssee Brown et al.[36]), did not respond to AVT by taking up water. Although some effect was noticed later in Sirenand Amphiuma[19]. In the newt Triturus cristatus, the level of activity of alkaline phosphatase was reduced by AVT [65]. It was twice higher in the aquatic phase compared with the terrestrial phase.
Fig. 1
Water retention response in Rana ridibundaand Salamandra salamandratadpoles, juveniles and adults, 1hr after being treated with AVT. Note the major response in juveniles of both species. The response of Salamandralarvae and adults is much less apparent.
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“In vitro” effect of AVT on water movement across the epidermis
In the aquatic phase of the newt Notophthalmus viridescens, no water movement across the isolated skin was noticeable in response to AVT [33]. On the other hand, Litoria aurea, showed an increased cutaneous water uptake [61]. Similarly, in Crinia georgiana, AVT caused greater water uptake through the skin than in Bufo marinus[27]. The osmotic permeability through the ventral pelvic epidermis of Bufo bufoincreased following treatment by AVT [54]. This was shown also in Bufo boreasby Kent [129]. AVT caused an increase in skin permeability in Rana temporariaand R. esculenta, but reduced the permeability of Bufo viridis[147]. No effect on water passage across the epidermis of Scaphiopus couchiwas noticeable [98].
“In vitro” effect of AVT on water movement across the urinary bladder
In the aquatic urodele, Necturus maculosus, the bladder was not affected by AVT [18], nor was there any effect in Xenopus[20], or in Amphiumaor Siren[19]. Some effect was noticeable in the bladder of Notophthalmus viridescens[33]. Similarly, in Rana cancrivorathe bladder responded to AVT [53]. In Salamandraan increase of 14% in body weight was noted following treatment with AVT [26]. This was not seen when the bladder was ligatured. An increased bladder resorption was noted in Taricha[43]. In the hylid Litoria aureaAVT caused a reduction in the rate of urine accumulation [61].
AVT effect on kidney function
The weight gain observed “in vivo” in larvae of Ambystoma tigrinumappears to be the result of an antidiuretic response due to reduced GFR [4,193]. In the aquatic urodele, Necturus maculosus[71,73,74], there is an antidiuretic response. In Sirenand Amphiumathis response is caused by a 50% decrease in GFR [19]. In the newt, Taricha, GFR is reduced by 84% [43], and in Rana catesbeianaby 80% [174].
There is evidence for increased tubular reabsorption [12,20,69,70,184], or an effect on the number of functional glomeruli in Bufo marinus[112]. Pang et al.[174], found no evidence for a tubular effect by AVT, whereas Garland et al.[74] found changes in the permeability of the distal tubules in response to AVT. Recently, Uchiyama [204,205] found that the connecting and distal tubules contain V 2 type receptors to AVT. On the other hand there seems to be a decrease in GFR [182], and a glomerular antidiuresis in both Necturusand Rana catesbeiana[174]. Finally, in the spadefoot toad, Scaphiopus couchi[98], and in the frog Litoria aurea[61], evidence was found for reduced GFR when treated with AVT. There is also a lower rate of urine excretion in Bufo marinus[182], Rana catesbeiana[209], and Rana esculenta[115,116]. Morel and Jard [154], Jard and Morel [116], and Jard [115] found that AVT caused antidiuresis in Rana esculentaby stimulating Na +(and water) reabsorption through the renal tubules, and causing a decline in GFR.
AVT effect on ion balance
AVT caused sodium accumulation in larval Ambystoma[6], and caused sodium uptake in Rana catesbeianatadpoles and Ambystomalarvae [4,123]. AVT was not found to affect sodium influx in Ambystoma tigrinumlarvae [23].
In the aquatic urodele Necturus, sodium transport was affected by AVT [10]. However in Amphiumaand Sirenno effect of AVT on sodium balance was noticeable [21,28]. Some effect on sodium transport was noticeable in Xenopus[14]. However, no effect was noticeable in the SCC of Ambystomalarvae or Necturus[25]. The renal output of Na +and K +increased as a result of AVT [109].
C. Arginine Vasopressin (AVP), Mesotocin (MT) and Oxytocin (OXY)
Arginine Vasopressin (AVP)
Whereas some amphibians: the aquatic Desmognathus[39], and littoral Rana cancrivora[64], did not respond to AVP, others: Bufo melanostictus[64], and Notophthalmus[33] showed an increased water uptake. In some amphibians AVP caused an increase in water uptake either through the epidermis ( Notophthalmus, [33]), or by an increase in water reabsorbed through the bladder ( Notophthalmus, [33] or Aneides, [97]). On the other hand in Bufo marinus, AVP caused a sodium and water transfer across the bladder [15]. No effect was observed in Scaphiopus couchi[99].
AVP was also reported to cause reduced urine production in Plethodon[39], possibly due to a decrease in GFR in Notophthalmus, [33].
Mesotocin (MT)
Mesotocin (MT) was found to be present in amphibians [2], and was located in the median eminence of the neural lobe [167], and in the serum of Rana esculenta[168]. MT caused weight gain in Tarichadue to integumental osmosis [43].
MT caused diuresis in Rana catesbeianaadults [152], possibly due to increased GFR (in Ambystoma tigrinumlarvae [192,195]). It was found to increase urine production in Calyptocephalellaand Necturus[72].
Oxytocin (OXY)
Most experiments were conducted with oxytocin (OXY), a hormone not occurring naturally in Amphibia. The animals responded to this hormone by gaining weight (water), or by increasing the permeability of skin or urinary bladder to water.
OXY effect “in vivo” on water balance
The 2-limbed tadpole of Rana ridibundawas found to respond to OXYby weight increase. This response reached its peak in the juvenile stage but was still noticeable in the adult ([77],Fig. 2). In Bufo viridis, the response was significant towards metamorphic climax reaching a peak at the juvenile stage [77]. In the adult Bufo viridisand Pelobates syriacusthe response to OXY was significant although less than in juveniles ([211],Fig. 2). It also caused water uptake in Bufo melanostictus[68], and increased the cutaneous water uptake in Bufo marinus[9], and in Bufo bufo[108].
Fig. 2
Water retention response in Rana ridibunda, Bufo viridis, Pelobates syriacusand Salamandra salamandra, tadpoles, juveniles and adults 1hr after being treated with OXY. Note the extremely high response of juvenile Ranaand Bufoand the comparatively high response of Salamandralarvae.
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In Rana ridibunda, the response to OXY has shown a seasonal pattern: high in summer and lower in winter [77,88]. In Rana temporariaand Bufo marinusosmotic water transport following treatment with OXY was greater in the winter (cold) months as compared with the summer (warm) months [88]. Rana catesbeianaresponded to OXY in a similar fashion with a peak at metamorphic climax (Stage XXII, [5]).
Already the premetamorphic larvae of Salamandra salamandraresponded to OXY ([216],Fig. 2). The response reached its peak upon metamorphosis. It was still noticeable in the juveniles, and to some extent in the adults ([211],Fig. 2). Both the terrestrial phase of the newt ( Triturus vittatus), and to some extent its aquatic phase, as well as the aquatic phase of Notophthalmus viridescens, have shown some response to OXY ([33,212],Fig. 3).
Fig. 3
The response of the aquatic and terrestrial phases of the newt, Triturus vittatusto OXY and PRL. The terrestrial phase was more responsive to treatment with these hormones.
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In the adult Bufo arenarum, OXY caused an increase in GFR [209], although apparently not changing the number of glomeruli or their size [208], but by its affect on the reabsorption in the glomeruli of Rana pipiens[184]. No effect of OXY was noticed by Stiffler et al.[195] in Ambystomalarvae. In Rana esculentaoxytocin had a clear antidiuretic effect [154].
OXY effect “in vitro” on water movement through isolated bladder and epidermis
The effect of OXY on the isolated urinary bladder of Rana catesbeianatook the form of enhancing water permeability [181], and increasing reabsorption in Rana pipiens[184]. No such effect was noticeable in the bladder of adult Rana ridibunda[211]. However, SCC across the bladder of Rana esculentaincreased [13]. On the other hand OXY caused water movement through the isolated bladder of Bufo viridis, Pelobates syriacus, Hyla arborea, Salamandra salamandraand Triturus vittatus[211,212].
Finally, the water movement across the isolated epidermis showed a marked effect of OXY in adult Rana ridibunda, Pelobates syriacus, Salamandra salamandraand Triturus vittatusas well as Xenopus, but no response in Bufo viridis[211,212].
D. Prolactin (PRL)
Presence of Prolactin
Prolactin-producing-cells were located in the hypophysis of the newt, Triturus cristatus[210]. They are confined to the ventral region of the hypophysis in Cynops[148]. Purified PRL in the newt Cynops pyrrhogastershowed a molecular weight of 23,000, similarly, in Bufo japonicus[149,224,226]. In Xenopustwo forms of prolactin were isolated. In bullfrog tadpoles PRL-like hormone was regulated by dopamine [132]. PRL levels increased markedly towards metamorphic climax in Rana catesbeiana[161,128,227]. In Bufo japonicusPRL levels drop when emerging on land [110]. Thus PRL appears to have anti -metamorphic activities [134,163]. The levels increased from 18 ng/ml at stage X to 98–169 ng/ml at stages XXIII-XXV [224]. The neotenic axolotl ( Ambystoma tigrinum) has more PRL than either larvae or adults [165]. More PRL is released during winter (breeding season) in the newt Triturus cristatus[145]. Similarly, in Bufo japonicusthe high PRL levels were related to breeding in spring [110]. When Xenopuswas kept outside the water PRL was synthesized, but was not released [85]. PRL binding was highest in kidney except for the aquatic amphibians [218].
Renal binding of PRL sites increased during metamorphic climax [219], but was reduced in dehydrated Xenopus[85]. Dehydration caused a drop in PRL binding sites in the kidney and epidermis of Xenopus[86,157].
PRL effect on water balance
The role of PRL in osmoregulation was reviewed by Bern [29] and Brown and Brown [35]. PRL affects water movement into the amphibian. This response was noticeable in Rana ridibundatadpoles just before metamorphosis reaching its peak in the juveniles ([78],Fig. 4). Similarly, in Bufo viridis, already the 4-limbed tadpole responded to PRL, but the largest effect was noticeable in the juveniles ([78],Fig. 4). In Taricha torosa, PRL caused a lower rate of water uptake [34], partly due to a decreased rate of integumental permeability. In Xenopustoo, PRL caused increased water uptake [188]. In Ambystoma tigrinumlarvae PRL caused an increase in body water [175]. In the salamander larva ( Salamandra salamandra) PRL affected water retention already in the 1-week old larva, and more so in the juvenile salamanders ([216],Fig. 4). In adult Rana ridibundaand Bufo viridis, PRL has shown a more pronounced effect than in adult Salamandra(Fig. 4). Likewise in bullfrog tadpoles PRL caused water retention [41]. PRL also affects permeability of the toad bladder [63], and caused a lowering of the rate of urine production in Taricha torosa[34].
Fig. 4
The response to PRL of Rana ridibunda, Bufo viridis, Pelobates syriacusand Salamandra salamandralarval and postmetamorphic forms, after 1hr. Note the very low response of Ranaand Pelobatestadpoles and Salamandraadults. The highest response can be seen in the juvenile stage.
<here is a image 8fc5b1195d20ccf0-63a4ae95e7112bbb>
PRL effect on electrolyte balance
PRL also affects the ion movement. Thus it increased the ion absorbing capacity of Ambystomagills [221], and affected the sodium transport across the epidermis of Rana temporaria[105]. It caused an increased sodium content in the axolotl Ambystoma tigrinum[175], in A. gracile[31], and in Rana catesbeiana[66]. In other amphibians: Rana pipiens, Taricha torosa, [62], Desmognathus[37] Ambystoma tigrinum[222]. PRL had no effect on Na +levels. PRL restored sodium levels in hypophysectomized Necturus maculosus[172]. It depressed sodium transport across isolated skin of Triturus cristatus[144,146], and in both Tarichaand the terrestrial red eft of Notophthalmus[40,42,44,45], but did not affect sodium transport in tadpoles of Rana catesbeiana. Short circuit current (SCC) increased at metamorphic climax or by treatment with PRL [67]. This was shown also “in vitro” in Bufo marinusbladder [189].
In adult DesmognathusPRL caused sodium (and Ca 2+) retention [220]. Similarly, in the axolotl ( Ambystoma mexicanum, [221]). However, in bullfrog tadpoles PRL caused a decrease in plasma Na +[41]. In adult, Triturus cristatusnewts, PRL caused a reduction in sodium transport across the integument [144], and affected SCC [145]. In the aquatic (breeding) phase of the newt, Cynops pyrrhogaster, PRL caused a decrease in trans-epithelial transport, TEP [200]. Transport increased greately at stage XXI-XXII in the bullfrog tadpoles [196,197,199]. The effect on SCC was greater in bullfrog tadpoles at stage XXV during spring-summer [198].
PRL effect on water drive
PRL caused the 2nd metamorphosis (water drive) to occur in Notophthalmus viridescens[81,152], and in the salamander Hynobius retardatus[155]. PRL caused increase in serum osmolality and thus may provide a cause for the newt's movement into the water [156]. By causing accumulation of mucopolysaccharides in the tissue PRL caused water retention which affected a rise in specific gravity, thus enabling the newt to stay in water.
PRL also stimulated courtship behaviour in hypophysectomized newts [76].
PRL effect on mucus formation
PRL functions to release granules in the gland [103]. Thus it caused increased mucus production in the axolotl Ambystoma tigrinum[223], in A. gracile, [31], and in Notophthalmus[32]. It stimulated mucopolysaccaharide synthesis in Triturus pyrrhogaster[131]. The effect of PRL on mucus secretion may be indirect through its effect on testosterone. Testosterone caused the formation of mucus glands in the epidermis and PRL enhanced its action [164]. PRL caused a change from granular to smooth skin in Taricha torosa[82,91]. These changes may be related to the role of the skin in protection from evaporative water loss.
PRL effect on nitrogen balance
PRL stimulated arginase activity in Bufo bufo[47,84,85]. PRL antagonized the urea increase (caused by thyroxine) in Rana catesbeianatadpoles [14], but did not affect the ammonia excretion. PRL caused a decrease in urea excretion in the premetamorphic tadpoles of Rana catesbeiana, but did not affect urea excretion in metamorphosing tadpoles [150].
E. The thyroid hormones
Thyroid hormone excretion is largely related to the stages of metamorphic cycles [140], as well as temperature dependant because iodine uptake by the gland is increased with temperature [52,138]. Thus December frogs showed a low iodine uptake. Kuhn et al.found that hormone levels change seasonally peaking in March [201].
Green and Matty [83], reported an increase in sodium transport through the ventral epidermis and bladder of Bufo bufofollowing application of thyroxine. This could not be confirmed by Taylor and Barker [202].
There are reports that thyroxine caused a rise in urea excretion in the axolotl, Ambystoma mexicanum[187], or that T 3caused increased urea excretion in Rana catesbeiana[8]. Similar findings were previously reported by Munro [158], and Jaffe and Geschwind [114]. There is also a report that thyroid hormone caused increased ammonia production in Rana catesbeianatadpoles (Stages VIII-XII) [151].
F. Other hormones
The effect of corticosteroids on amphibians has been recently reviewed by Hourdry [164], and Hanke and Kloas [89].
Corticosterone levels in the plasma increase towards metamorphic climax (Stages XXI-XXIV) [113,228]. Similarly, in Ambystoma tigrinumplasma corticosterone levels were low in premetamorphic stages increasing at midmetamorphosis and peaking towards metamorphic climax [50]. In either Xenopusand Bufo arenarum, both corticosterone and aldosterone reached their peak at metamorphic climax [51,121]. Similarly, levels of aldosterone increased in Ranatowards metamorphic climax [133].
The interrenal cells appear to be more active during summer [119,120]. In Hyla arboreacirculating corticosteroids peaked in late spring [141]. Thyroid hormones may be involved in elevating aldosterone levels at metamorphic climax [133,134]. Other effective groups of peptides stimulating corticosteroid hormones include AVT, ureotensins and angiotensin II [89].
The pituitary gland seems to affect aldosterone secretion [11]. Both AVT and MT enhanced aldosterone levels in hypophysectomized Xenopus. In the plasma of Rana pipiens, aldosterone levels are only 10% of corticosterone levels [127]. Changes in either osmolality or sodium concentration of plasma (in Rana) affected the interrenal secretion [90]. Apparently corticosterone levels declined significantly in dehydrated Rana pipiens[126]. Corticosterone caused a drop in the water content of Xenopustadpoles [142]. An increase in water uptake was caused by ACTH in the aquatic phase of Notophthalmus viridescens, Taricha granulosa[36]. At the same time ACTH and corticosterone restored the decline in sodium levels [206]. Corticosterone also caused a decline in sodium efflux in Ambystoma tigrinum[46]. Thus it caused sodium retention in neotenous Ambystoma gracile[31], but no effect on sodium levels in Rana pipiens, [62], and in Desmognathus[37]. In Taricha torosa, ACTH caused sodium retention [38].
Aldosterone stimulated sodium transport through the urinary bladder of Bufo marinus[58]. The short circuit current (SCC) through Necturusbladder [18,58], and through Bufo viridisskin [159], was similarly affected by aldosterone. Aldosterone stimulated reabsorption of sodium and secretion of K +in Ambystoma tigrinum[96,194]. It thus caused elevated levels in plasma sodium [96], and sodium retention in Triturus[190]. Aldosterone also stimulated sodium influx through the skin of Bufo bufo[107], or through either skin or gills of Ambystoma tigrinumlarvae [6,7]. It did not affect water balance in Xenopus[142]. Nor did it affect sodium levels in Rana pipiens, Taricha torosa[62], or in Bufo marinus[153].
Finally, corticesterone caused an increase in urea levels of Xenopustadpoles [142], Rana catesbeianatadpoles [150], or the axolotl [186]. This rise in urea levels in the serum could be due to reduced urea excretion. Urea excretion rose as a result of either aldosterone or cortisol treatment [187]. In Rana catesbeianatadpoles ACTH caused increased urea excretion [150], and in Rana pipiensaldosterone enhanced urea production in spring and summer [117].
Angiotensin II (AII), synthesized in several organs (kidney, ovary, pituitary) induces physiological effects that maintain kidney function [162,176,191]. In Anura, AII causes tubular antidiuretic and antinatriuretic effects in the kidney [56], and increased water flow through the skin [57]. Treatment with AII caused a water response in, and increased water absorption through the skin of Bufo punctatus, B. woodhouseiand Scaphiopus couchi[101,102,203]. Atrial natriuretic peptides (ANP) are peptides localized in the atrial cardiocytes of several vertebrate classes [48,49,75]. These peptides have been demonstrated immunohistochemically also in amphibian auricles and vetricles ([160,178],Fig. 5). It was established that ANP is an osmo-mineral regulating hormone causing diuresis and natriuresis in amphibians [135136–137]. In its action it counteracts the effects of AVP, AVT and AII. It causes an increase in GFR, decreased aldosterone and catecholamine production by the adrenal (interrenal), and inhibits secretion of hypophysial hormones [30,87]. In Rana, ANP was shown to inhibit adreno-corticotropic hormone-stimulated adreno-steroid secretion in vitro[143]. The distribution of ANP-like material was followed in cardiocytes of larvae, metamorphosing and adult Bufo[100,207].
Fig. 5
Atriunatriuretic (ANP) reaction in the heart of a 2-legged Pelobates syriacustadpole (a, ×400), and a tadpole with tail stump just prior to meatmorphic climax (b, ×400). The asterisk (star) depicts the site of immunoreaction. No reaction was observed in controls (c, × 1,000). The ANP cell contains a large number of small secretion granules (d, ×5,000).
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CONCLUSIONS
In the terrestrial amphibians a number of hormones are present and affect water and ion balance. These are largely AVT, MT and PRL as well as other hormones. In the aquatic stages, aside from PRL, the other hormones are not active as regulators. During that period PRL is the main regulating hormone. In the aquatic adult amphibian, these hormones although present are not actively regulating. The most interesting aspect is in the adult aquatic phase which may last several weeks in urodeles. Here too the hormones although presumably present are not active. There is a need to focus on the dynamic of hormone synthesis, storage and release during the aquatic and terrestrial phases of amphibians. To what extent are water, ion and nitrogen balance affected by changes in the hormonal balance?
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‘Effective inefficiency’: cellular control of protein trafficking as a mechanism of post-translational regulation in: Journal of Endocrinology Volume 190 Issue 1 ()
The great writer and polyglot, W Somerset Maugham said, ‘I’ll give you my opinion of the human race in a nutshell...their heart’s in the right place, but their head is a thoroughly inefficient organ.’ If his words are applied to trafficking of the human pituitary gonadotropin-releasing hormone receptor, it turns out that he was more right than he knew. Paradoxically, the inefficiency of receptor trafficking to the plasma membrane can bring regulatory advantages to cells. Understanding the mechanism by which cells recognize correctly folded proteins in health and disease opens doors to new therapeutic approaches and provides a more accurate view of mechanisms of normal cell function than is presently available.
‘Effective inefficiency’: cellular control of protein trafficking as a mechanism of post-translational regulation
in Journal of Endocrinology
Authors:
P Michael Conn
P Michael Conn
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Jo Ann Janovick
Jo Ann Janovick
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Shaun P Brothers
Shaun P Brothers
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Paul E Knollman
Paul E Knollman
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DOI:
https://doi.org/10.1677/joe.1.06771
Volume/Issue:
Volume 190: Issue 1
Article Type:
Article Commentary
Page Range:
13–16
Online Publication Date:
24 Mar 2006
Copyright:
Society for Endocrinology 2006
The great writer and polyglot, W Somerset Maugham said, ‘I’ll give you my opinion of the human race in a nutshell...their heart’s in the right place, but their head is a thoroughly inefficient organ.’ If his words are applied to trafficking of the human pituitary gonadotropin-releasing hormone receptor, it turns out that he was more right than he knew. Paradoxically, the inefficiency of receptor trafficking to the plasma membrane can bring regulatory advantages to cells. Understanding the mechanism by which cells recognize correctly folded proteins in health and disease opens doors to new therapeutic approaches and provides a more accurate view of mechanisms of normal cell function than is presently available.
Abstract
The great writer and polyglot, W Somerset Maugham said, ‘I’ll give you my opinion of the human race in a nutshell...their heart’s in the right place, but their head is a thoroughly inefficient organ.’ If his words are applied to trafficking of the human pituitary gonadotropin-releasing hormone receptor, it turns out that he was more right than he knew. Paradoxically, the inefficiency of receptor trafficking to the plasma membrane can bring regulatory advantages to cells. Understanding the mechanism by which cells recognize correctly folded proteins in health and disease opens doors to new therapeutic approaches and provides a more accurate view of mechanisms of normal cell function than is presently available.
Misfolding of protein mutants in disease
Often, mutant proteins lose function in cells. Loss of activity frequently results from misfolding but, until recently, it was believed to be solely explained by loss of protein function.Mutations were viewed to cause loss of receptor–ligand binding (or effector coupling) or loss of substrate binding by enzymes, for example. Frequently, however, misfolded proteins are identified as defective by the cell’s quality control system (QCS) and are retained by the endoplasmic reticulum (ER) for proteasomal destruction or for reprocessing, rather than trafficked to the normal site associated with function. This change in thinking – that mutants are often misrouted yet otherwise competent proteins – is a striking counterpoise to the former view that non-functioning mutants always have an intrinsic defect in the ability to perform. This newer view (Ulloa-Aguirre et al. 2003,2004 a,Castro-Fernandez et al. 2005,Conn & Janovick 2005) acknowledges that the criteria for recognition of misfolded proteins by the cellular QCS is purely physical and does not always consider the ability of a protein to function. This is true because the chaperones of the QCS recognize general errors of folding, such as exposure of hydrophobic regions in an aqueous environment, rather than specific defects of individual proteins, such as failure of receptors to recognize ligands.
This observation also presents the possibility that mutants can be restored to function by pharmacological chaperones (‘pharmacoperones’), small molecules that enter the cell and rescue misfolded mutants by promoting correct folding, allowing them to pass the QCS and become correctly routed (Conn et al.2002 ,Janovick et al.2002 ,2003 a,Leaños-Miranda et al. 2002 ).
Misfolding and retention of GnRHR in normal cell function
Recent observations (Knollman et al. 2005,Janovick et al. 2006) suggest that cells also use the technique of misfolding and misrouting as an effective post-translational regulatory mechanism to decrease the efficiency of movement of wild type (WT) proteins to their normal site of function and potentially provides a protein reserve to call upon when needed and without the need for transcription or translation. In this model, a WT receptor is delicately balanced between expression at the plasma membrane and retention in the ER. Consequently, even modest mutations can tip this balance and have a dramatic effect on plasma membrane expression. Accordingly, these rodent receptors that interfere with human gonadotropin-releasing hormone receptor (GnRHR) plasma membrane expression frequently do not have any impact on rat or mouse GnRHR, since, although about 90% homologous, these rodent mutants traffic to the plasma membrane with much higher efficiency than the human counterpart.
It was surprising to find that there is a strong and convergent pressure for what initially appears to be a wasteful process in light of the high metabolic cost of this form of regulation. Intentionally destroying a potentially functional protein is a curious regulatory approach; proteins regulated in this manner must be created to be delicately balanced between function (plasma membrane) and destruction (ER). The observed convergent evolution suggests that the advantages of this process outweigh the disadvantages.
Convergent evolution of decreased efficiency of expression of the GnRHR at the plasma membrane
Nature’s experiments on GnRHRs – premammals
Evidence (Lin et al.1998 ,Janovick et al.2003 b ) from comparing premammals (fish, reptiles, and birds) with the mammalian class and the primate order suggests that there is an ever- decreasingnet efficiency of expression and maintenance of the GnRHR as the complexity of reproduction has increased. In premammalian groups, a long carboxyl terminal tail on the molecule (Fig. 1) is associated with high expression, since it not only acts to route the structure to the membrane, but also to diminish the rate of turnover. These animals produce large numbers of offspring (or eggs) at a low metabolic cost per unit, with relatively low survival. In contrast, in light of the greater ‘per unit’ cost and time needed to produce mammalianoffspring, it is not surprising that this latter process would be regulated more precisely.
As mammals put more metabolic energy into the production of small numbers of offspring, the GnRHR solidifies a role as an analog-to-digital converter, integrating brain signals into a response of gonadotropin release. Levels of the mammalian GnRHR are well known to fluctuate cyclically and in rapid response to specific stimuli.
Among mammals, the observation that rat and mouse GnRHRs are highly expressed at the plasma membrane, while a smaller proportion of the synthesized human GnRHRs reach the plasma membrane, attracted our attention.
Nature’s experiments on GnRHRs – rats versus mice
Despite its small size, nature has performed many experiments on the GnRHR. A good example of this is the difference between rat and mouse GnRHR. Even though these species are closely related, they differ in routing and in the dominant-negative (DN) effect, whereby a co-expressed mutant receptor causes WT receptor to be retained in the ER (Leaños-Miranda et al. 2003,2005Brothers et al.2004 ,Knollman et al.2005 ).
The difference in both routing and the DN effect appears to be mediated primarily by Ser 216in the rat GnRHR (Gly 216in the mouse). These studies (Knollman et al. 2005) establish the relation between the DN effect and altered receptor trafficking and reveal that a change as modest as gain or loss of –CH 2–OH (i.e. the chemical difference between Gly and Ser) can dramatically alter routing.
Nature’s experiments on GnRHRs – within mammals
Compared with other G-protein coupled receptors (GPCR), the GnRHR is relatively small in mammals – 327 amino acids in rats and mice, and 328 in most other mammals. This minimalist structure is the result of the absence of the extensive extracellular amino and carboxyl terminals found in other members of this super-family. The carboxyl terminal quite literally terminates in the plasma membrane and does not extend into the intracellular space as is common for other GPCRs.
There appears yet another difference, however. An ‘extra’ amino acid is inserted at position 191 in all mammalian GnRHRs cloned to date except rats and mice. This extra amino acid explains why rats and mice have 327 and other mammals have 328 amino acids. Removal of this ‘extra’ amino acid from the human sequence results in a dramatic increase in plasma membrane expression.
We came to realize (Janovick et al. 2006) that in primates, Lys 191(Glu 191in most other mammals) is part of a complex motif that, taken as whole, results in decreased efficiency of expression (Conn et al.2002 ,Janovick et al.2002 ,Ulloa-Aguirre et al.2004 b ,Castro-Fernandez et al. 2005). This evolutionary progression that resulted in progressively diminished plasma membrane expression was intriguing and suggested an explanation of the ability of pharmacoperones to increase the expression of human (partially expressed) but not rat (more fully expressed) GnRH receptors at the plasma membrane.
The observation of agents which promoted the folding of the human GnRHR (hGnRHR) into a shape that passed the cellular QCS suggested that there was a percentage of receptors that were not initially destined to be expressed at the plasma membrane. The presence of the ‘extra’ amino acid in position 191 apparently decreased the efficiency of formation of a specific Cys bridge (Janovick et al. 2006) required for the human GnRHR to pass the cellular QCS. The consideration that there existed WT human GnRHR that were actually misfolded proteins was curious, since it meant that the cell was ‘intentionally’ synthesizing misfolded receptors – ones that would cost metabolic energy to make, but would not be used!
Glu 191is less effective than the primate Lys 191in decreasing plasma membrane GnRHR expression, another observation showing the progressive restriction of plasma membrane expression (Knollman et al. 2005).
The observation then is that nature is progressively decreasing the percentage of the GnRHR expressed at the plasma membrane as the complexity of the reproductive process increases. This approach costs energy, since not all the synthesized receptor is actually used. Nonetheless, there must be a selective advantage, since nature is effecting a solution to an as-yet unclear problem from different and functionally converging directions.
Nature’s experiments on GnRHRs – the primate receptor
Nearly 200 mutants and 2 years after we began the search, we learned the basis of the complex motif involved in restricting expression of the hGnRHR – an unusual motif of nonsequential amino acids that enabled Lys 191to destabilize the Cys 14–Cys 200bridge in the hGnRHR required for correct folding – and produce a percentage of misfolded, and hence, misrouted receptors (Janovick et al.2006 ).
What is the advantage?
It is clear that nature is using multiple approaches to restrict expression of GnRHR concurrent with increased reproductive complexity and metabolic investment per offspring. One feature of mammals is the occurrence of cyclicity of the GnRHR (Savoy-Moore et al.1980 ,Marian et al.1981 ) and the ability to regulate trafficking to the plasma membrane may provide the selective advantage that explains the advantage of this process. The ability to control the presence of a key integrator of the reproductive process without the need to synthesize it de novoallows the animal to optimize the time of reproduction, thus minimizing waste of a fertilized egg and protecting a costly investment indeed. Until the precise mechanism becomes clear, this is hypothetical, of course.
Other proteins use a similar process
Other receptors appear to show inefficient plasma membrane expression and misfolding frequently causes misrouting as well, even if mediated by alternate means (Castro-Fernandez et al.2005 ). The human δ opioid receptor is an example, since permeable agonists and antagonists also facilitate post-translational processing and increased export of the ligand-stabilized receptor from the ER to the cell surface (Petäjä-Repo et al. 2002 ). Other reports indicate that other receptors (GluR1, alpha 1D adrenoreceptor, odorant, and LH receptors) are likewise inefficiently expressed at the plasma membrane (Saito et al.2004 ,Uberti et al. 2004,Petrovska et al. 2005,Pietila et al. 2005), and this suggests that restricted trafficking may be a more commonly occurring means of regulating protein availability than is presently appreciated.
Conclusions
Nature has left a clear trail, progressively diminishing the expression of the GnRHR with increased complexity and cost/unit of production of offspring. This inefficiency has been an effective mechanism for exerting tighter control on the reproductive process. The observation that other proteins, receptors, ion channels, and enzymes, are not fully expressed at their normal locus of action suggests that this mechanism of post-translational regulation may be a common event.
<here is a image c0871638e11cbd16-72f7f30eae9b46e1
Figure 1
GnRHR schematic, summarizing features that regulate plasma membrane expression. Circles represent amino acids. The image shows the carboxyl tail (solid green circles) present in birds, fish, and reptiles but lost in mammals. The solid red circle shows position 191 that frequently contains a Glu 191in mammals but is replaced by Lys 191in primates; in rats and mice this amino acid is absent. Two Cys–Cys bridges are shown. The Cys 14–Cys 200(yellow) association must form for proper routing to the plasma membrane in most mammals and it is formalized by a covalent bond in primates; the formation of this association is destabilized by Glu 191(many mammals) or Lys 191(primates). Precise alignment of the cysteines (less than one water molecule (shown) in spacing) is regulated by alignment of the amino terminal (brown outline) with the second extracellular loops (ECL2, red outline). Twisting of the fourth and fifth transmembrane segments (green outline) controls the positioning of ECL2 and mutations in these regions (TMS4 and 5) and are frequently among the relatively rare unrescuable mutants. The graphic at the bottom is a phyllogram of the evolutionary relations between a wide diversity of species. The confocal images are cells expressing a fluorescent chimera of WT GnRHR (green). Normally, receptor is present at the plasma membrane and in the ER (stained blue); in the presence of pharmacoperone, its level at the plasma membrane is enhanced.
Citation: Journal of Endocrinology 190, 1;10.1677/joe.1.06771
Figure 1
GnRHR schematic, summarizing features that regulate plasma membrane expression. Circles represent amino acids. The image shows the carboxyl tail (solid green circles) present in birds, fish, and reptiles but lost in mammals. The solid red circle shows position 191 that frequently contains a Glu 191in mammals but is replaced by Lys 191in primates; in rats and mice this amino acid is absent. Two Cys–Cys bridges are shown. The Cys 14–Cys 200(yellow) association must form for proper routing to the plasma membrane in most mammals and it is formalized by a covalent bond in primates; the formation of this association is destabilized by Glu 191(many mammals) or Lys 191(primates). Precise alignment of the cysteines (less than one water molecule (shown) in spacing) is regulated by alignment of the amino terminal (brown outline) with the second extracellular loops (ECL2, red outline). Twisting of the fourth and fifth transmembrane segments (green outline) controls the positioning of ECL2 and mutations in these regions (TMS4 and 5) and are frequently among the relatively rare unrescuable mutants. The graphic at the bottom is a phyllogram of the evolutionary relations between a wide diversity of species. The confocal images are cells expressing a fluorescent chimera of WT GnRHR (green). Normally, receptor is present at the plasma membrane and in the ER (stained blue); in the presence of pharmacoperone, its level at the plasma membrane is enhanced.
Citation: Journal of Endocrinology 190, 1;10.1677/joe.1.06771
The authors congratulate the Society for Endocrinology on the occasion of their Diamond Jubilee. This work was supported by NIH grants HD-19899, RR-00163, TW/HD-00668 and HD-18185.
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Factors Influencing Choice Of Teacher Supervisory Approaches Employed By Headteachers In Public Secondary Schools In Nyeri South District, Nyeri County, Kenya | Afribary
ABSTRACT Since the declaration of Education for All (EFA) in Jomtien (Thailand) in 1990, quality education has been high in the agenda of the internat...
Factors Influencing Choice Of Teacher Supervisory Approaches Employed By Headteachers In Public Secondary Schools In Nyeri South District, Nyeri County, Kenya
MUMERO GEOFFREY KINYUA 110 PAGES (23726 WORDS) Art Education Dissertation
Overview
ABSTRACT
Since the declaration of Education for All (EFA) in Jomtien (Thailand) in 1990, quality education has been high in the agenda of the international community. This has created the need to improve the quality of education in many developed and developing countries. In response to international commitments to EFA goals, the Government of the Republic of Kenya is committed to improving the quality of education in secondary schools. For example, the Kenya Education Staff Institute (KESI) on its part is strengthening capacities of education managers through in-service training to improve school governance for increased productivity. In spite of the Headteachers executing teacher supervisory role in their schools, and in addition to the schools having well qualified pupils from primary schools, adequate teaching/learning resources and supportive parents and stakeholders, academic performance of the public secondary schools in some selected secondary schools have been below average. This study therefore sought to establish factors influencing the choice of teacher supervisory approaches employed by headteachers in public secondary schools in Nyeri South District. The objectives of the study will be to: determine the prevailing teacher supervisory approach employed by Headteachers in public secondary schools in Nyeri South District; establish Headteachers‟ characteristics influencing the choice of supervisory approach; establish in-school factors influencing teacher supervisory approach employed by Headteachers in public secondary schools; and establish measures that can be put in place to improve teacher supervision in public secondary schools in Nyeri South District. The findings of the study may help the head teachers to evaluate their supervisory practices and make the necessary modifications so as to enhance education outcomes. The findings may also provide the Ministry of Education with information on the status of teacher supervision in public secondary schools and hence stimulate necessary adjustments in supervisory programmes to improve the quality of education. The study will be guided by McGregor‟s (1960) Theory. The study used descriptive survey design targeting all the 33 headteachers and teachers in all the public secondary schools in Nyeri South District. Stratified sampling was used to select 15 schools; each strata representing provincial and district schools. Purposive sampling was used to select 15 headteachers from the sampled schools. A questionnaire designed for the headteachers and another one for teachers were used as the main tools for data collection. Prior to the actual data collection procedure, a pilot study was carried out to pre-test the data collection procedure. The researcher sought the assistance of research experts, experienced graduates, lecturers and experienced supervisors in order to help improve validity of the instrument. Cronbach‟s coefficient Alpha technique was used for measuring reliability. The study revealed that majority (73.3%) of the teachers rated headteachers supervisory practices as bureaucratic whereas headteachers (93.3%) rated themselves as both bureaucratic and professional. Regarding professional qualifications, it emerged that the choice of teachers‟ supervisory approaches among headteachers did
vi
not differ across their professional qualifications at p
KINYUA, M
(2021). Factors Influencing Choice Of Teacher Supervisory Approaches Employed By Headteachers In Public Secondary Schools In Nyeri South District, Nyeri County, Kenya. Afribary. Retrieved from https://afribary.com/works/factors-influencing-choice-of-teacher-supervisory-approaches-employed-by-headteachers-in-public-secondary-schools-in-nyeri-south-district-nyeri-county-kenya
MLA 8th
KINYUA, MUMERO
"Factors Influencing Choice Of Teacher Supervisory Approaches Employed By Headteachers In Public Secondary Schools In Nyeri South District, Nyeri County, Kenya" Afribary. Afribary, 27 May. 2021, https://afribary.com/works/factors-influencing-choice-of-teacher-supervisory-approaches-employed-by-headteachers-in-public-secondary-schools-in-nyeri-south-district-nyeri-county-kenya. Accessed 10 May. 2023.
MLA7
KINYUA, MUMERO
. "Factors Influencing Choice Of Teacher Supervisory Approaches Employed By Headteachers In Public Secondary Schools In Nyeri South District, Nyeri County, Kenya". Afribary, Afribary, 27 May. 2021. Web. 10 May. 2023. < https://afribary.com/works/factors-influencing-choice-of-teacher-supervisory-approaches-employed-by-headteachers-in-public-secondary-schools-in-nyeri-south-district-nyeri-county-kenya >.
Chicago
KINYUA, MUMERO
. "Factors Influencing Choice Of Teacher Supervisory Approaches Employed By Headteachers In Public Secondary Schools In Nyeri South District, Nyeri County, Kenya" Afribary (2021). Accessed May 10, 2023. https://afribary.com/works/factors-influencing-choice-of-teacher-supervisory-approaches-employed-by-headteachers-in-public-secondary-schools-in-nyeri-south-district-nyeri-county-kenya
| https://afribary.com/works/factors-influencing-choice-of-teacher-supervisory-approaches-employed-by-headteachers-in-public-secondary-schools-in-nyeri-south-district-nyeri-county-kenya |
The Oxford Oratory
A sanctuary in the midst of the city
The Oxford Oratory is a vibrant centre of Catholic life. Our church is open every day: join us for Mass, pop in for some quiet prayer, or come and discover more at one of our groups. Our historic church of St Aloysius has been a key feature in the lives of the city’s Catholics for 150 years, attracting people of all ages and from every walk of life. We use beauty to raise hearts and minds to God, faithful to the traditions of St Philip Neri and St John Henry Newman.
The Oratory Prayer Book is now shipping internationally!
We’ve made it even easier to buy the Oratory Prayer Book from anywhere in the world.
And we’ve made it easier to order multiple copies too — in the UK and worldwide.
Order your copy here:https://tinyurl.com/opb-buy
If you have one, we’d love to hear what you think about it. Let us know in the comments, or tag a photo of your prayer book in the wild with #oratoryprayerbook
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Worship
What does it actually mean to worship God? In the New Testament, the word we most often translate as ‘worship’ doesn’t mean to reverence another in some abstract sense. It always involves some kind of bodily action. When we think about the magi visiting the Holy Family, we sometimes convey this motion by describing them — after they fall to their knees — as ‘doing homage’. But it’s actually that same word here we might translate elsewhere as ‘worship’. It’s just that we recognise the need to describe the bodily sign of their submission and adoration of the new born King with something that sounds a bit more physical.
The word we usually translate as ‘worship’ ( proskuneo) comes literally from a root meaning ‘to make yourself like a dog before the other person’. It originally meant prostrating yourself on the floor to show your humble submission before another. By the time of the New Testament, people wouldn’t necessarily have had the root of this word in mind whenever they used it,* but the word still carries with it the idea of doing something with your body to express your worship.
The feast of Corpus Christi is all about this kind of bodily worship. It’s tied to the fact that we are not pure spirits, but that we are human beings, body and soul. To worship God is not just a spiritual act. The right worship of God does not consist in simply having the right kinds of thoughts towards him. But the worship of God involves the humble submission of our entire human being, body and soul, before the God who is greater than all of us.
And ever since the Incarnation, we do this not just before an abstract spirit. Because, from the moment of the Incarnation, God really does have a human body, that we can worship, that we fall down on our knees before, like the magi and the Canaanite woman, and so many others in the Gospel who kneel down and worship Christ. When we worship God, we kneel before God who is present in the flesh, under the appearances of bread and wine, in our churches all over the world.
Corpus Christi is a joyful celebration of Christ’s presence among us, and it gives us an opportunity to think about how we respond to that gift. All this talk of kneeling and worship might not sound so joyful, but one of the great paradoxes of Christianity is that we find our greatest freedom in the humble service of God. Our greatest joy really should be found in finding ways to express this loving worship. So at least once a year, it is no bad thing to think about how we express with our own bodies that worship of God’s body, and what ways we can find to worship him even more perfectly.
This Sunday, we will carry Christ’s Body through the streets of our city. We have a chance to demonstrate to the world our love, our joyful service, our worship of him, through our presence. The procession leaves our church at 2:30pm. Make sure you are there.
But we should also think about the more ordinary things, like making sure we show that worship whenever we are in his presence. We should show through our behaviour in church that we believe him to be there: by genuflecting before him in the tabernacle of the church, and by keeping the church quiet and prayerful.
We show our worship above all by kneeling down before him — like all those people in the Gospel — for the moment of Holy Communion. And we allow the priest to place the Host on our tongues, so that we don’t handle unnecessarily what is holy and precious, and no particles of Our Lord’s Body are ever dropped or lost through carelessness.
We continue that worship in our prayers of thanksgiving after Communion and once the Mass has ended. We certainly never leave church during Communion. And we might think of ways of extending the time we spend with Christ present in the Blessed Sacrament: by attending Mass during the week sometimes, or visiting him during the times each week when his Body is exposed solemnly on the altar for Adoration, or even just by visiting an empty church, where he is waiting for us to show him our worship.
Our Lord is hidden there, waiting for us to come and visit him, and make our request to him. See how good he is! He is there in the Sacrament of his love, sighing and interceding incessantly with his Father for sinners. To what outrages does he not expose himself, that he may remain in the midst of us! He is there to console us; and therefore we ought often to visit him. How pleasing to him is the short quarter of an hour that we steal from our occupations, from something of no use, to come and pray to him, to visit him, to console him for all the outrages he receives! When he sees pure souls coming eagerly to him, he smiles upon them. They come with that simplicity which pleases him so much, to ask his pardon for all sinners, for the outrages of so many ungrateful men. What happiness do we not feel in the presence of God, when we find ourselves alone at his feet before the holy tabernacles! ‘Come, my soul, redouble thy fervour; thou art alone adoring thy God. His eyes rest upon thee alone.’
— St John Mary Vianney
* One exception is that I do think Christ had this root meaning in mind when he spoke to the Canaanite woman in Matthew 15:21–28. He wasn’t randomly insulting her by comparing her to a dog, but drawing attention to the fact that she was making herself like a dog before him — i.e. worshipping him — because she recognised him to be God. In other words, he was acknowledging her worship as proof of her faith and humility.
On Saturday, Fr Rupert led Men’s Oratory on a walking pilgrimage to Islip, birthplace of St Edward the Confessor. #oxfordoratory
Congratulations to Elizabeth who was received into the Church yesterday evening on the Feast of the Visitation. #oxfordoratory
Congratulations to Livi, baptised on the vigil of Pentecost.
“Therefore, Lord, we pray: graciously accept this oblation of our service, that of your whole family, which we make to you also for those to whom you have been pleased to give the new birth of water and the Holy Spirit, granting them forgiveness of all their sins; order our days in your peace, and command that we be delivered from eternal damnation and counted among the flock of those you have chosen. Through Christ our Lord. Amen.”
#oxfordoratory
Courtesy
I recall how, as a child at school, we were sometimes made to learn poetry. At the time I hated it, and baulked at the idea of having to commit to memory The Ancient Mariner, and in fact, never did. But one poem which did touch me, was Belloc’s Courtesy. It began:
Of Courtesy, it is much lessThan Courage of Heart or Holiness,Yet in my Walks it seems to meThat the Grace of God is in Courtesy.
The poet goes on to tell us how, on one occasion he visited the ‘monks’ at Storrington in Sussex, and that ‘They took me straight into their Hall’where he ‘saw Three Pictures on a wall, And Courtesy was in them all.’
He then tells us the subject of those paintings:
The first the Annunciation;The second the Visitation;The third the Consolation,Of God that was Our Lady’s Son.
The first was of St. Gabriel;On Wings a-flame from Heaven he fell;And as he went upon one kneeHe shone with Heavenly Courtesy.
Our Lady out of Nazareth rode —It was Her month of heavy load;Yet was her face both great and kind,For Courtesy was in Her Mind.
The third it was our Little Lord,Whom all the Kings in arms adored;He was so small you could not seeHis large intent of Courtesy.
Today is the feast of the Visitation, when we celebrate how our Lady made the long and uncomfortable journey to see her older kinswoman, Elizabeth, and her husband Zachariah, who lived in the hill country of Judah. Courtesy seems to me to be a perfect description of what this moment is all about. Imagine the cordial welcome extended to Mary by the older woman, solicitous for her health and how both women were eager to share with one another the joy of the forthcoming births of their sons. Our Lady had herself gone to visit her older cousin, not simply because she wanted to ‘be there’ for her, but because she wanted to share her own good news, which was not hers alone but for her people and, ultimately for the entire world.
This is something Elizabeth seemed to know already! Her enthusiastic greeting is wonderful when she cries out ‘Oh that I should be visited by the Mother of my Lord’. Her unborn son joins in the greeting, kicking and letting his mother know that he too is part of this exciting thing that is happening. Elizabeth’s gracious words: ‘Blessed art thou among women and blessed is the fruit of thy womb’ have been enshrined in our prayer to the Virgin, incorporated with the Angelic Salutation: ‘Hail Mary, full of grace!’
And if today’s feast is about courtesy (so much more than stiff politeness or polished manners, but a warm and real concern for the wellbeing and interest of the other) then it is also about joy. Mary’s presence, together with that of her Divine Son, transformed the home of Elizabeth and Zachariah. ‘Elizabeth was filled with the Holy Spirit’ because of it. St Jose Maria puts it thus: ‘Mary brought joy to her cousin’s home, because she “brought” Christ’. Dame Julian liked to call Jesus ‘our courteous Lord,’ no doubt on account of his gracious dealings with us, flowing from his ‘large intent of Courtesy’!
Julian writes in her Showings:
And this is a supreme friendship of our courteous Lord, that he protects us so tenderly whilst we are in our sins; and furthermore he touches us most secretly, and shows us our sins by the sweet light of mercy and grace. But when we see ourselves so foul, then we believe that God may be angry with us because of our sins. Then we are moved by the Holy Spirit through contrition to prayer, and we desire with all our might an amendment of ourselves to appease God’s anger, until the time that we find rest of soul and ease of conscience. And then we hope that God has forgiven us our sin; and this is true. And then our courteous Lord shows himself to the soul, happily and with the gladdest countenance, welcoming it as a friend, as if it had been in pain and in prison, saying: My dear darling, I am glad that you have come to me in all your woe. I have always been with you, and now you see me loving, and we are made one in bliss.
So sins are forgiven by grace and mercy, and our soul is honourably received in joy, as it will be when it comes into heaven, as often as it comes by the operation of grace of the Holy Spirit and the power of Christ’s Passion.
Even though we have just changed all the light bulbs, our church looks its best when we don’t need to use them.
#oxfordoratory
The flag goes up on feast days!
#oxfordoratory
Blessings with St Philip’s relic after Vespers on Thursday.
#oxfordoratory
Look down from heaven, Holy Father, from the loftiness of that mountain to the lowliness of this valley; from that harbour of quietness and tranquillity to this calamitous sea. And now that the darkness of this world hinders no more those benignant eyes of thine from looking clearly into all things, look down and visit, O most diligent keeper, this vineyard which thy right hand planted with so much labour, anxiety and peril. To thee then we fly; from thee we seek for aid; to thee we give our whole selves unreservedly. Thee we adopt for our patron and defender; undertake the cause of our salvation, protect thy clients. To thee we appeal as our leader; rule thine army fighting against the assaults of the devil. To thee, kindest of pilots, we give up the rudder of our lives; steer this little ship of thine, and, placed as thou art on high, keep us off all the rocks of evil desires, that with thee for our pilot and our guide, we may safely come to the port of eternal bliss.
#oxfordoratory
Our celebrations for St Philip began with First Vespers last night and continue with Masses today. Here St Philip’s relic and altar are incensed during Vespers.
#oxfordoratory
Our new longer term temporary digital organ was hoisted up to the gallery this week in time for First Vespers of Our Holy Father St Philip. Catch up on our YouTube channel if you missed it, and join us for the Solemn Mass at 6pm this Friday.
#oxfordoratory
Vessel of the Holy Spirit
This year the novena in preparation for the feast of Our Holy Father St Philip corresponds almost exactly with the novena of novenas, the first novena, the nine days of prayer between the Ascension and Pentecost when we wait once more with the Apostles for the outpouring of the Holy Spirit. And this is most appropriate, as St Philip was, more than anything else, a man of the Spirit — as we say in his litany, he is the “vessel of the Holy Spirit”. The story of his life, which we read during the novena, really begins with his singular experience of the Spirit on the Vigil of Pentecost 1544 in the catacomb of St Sebastian when the Spirit descended like a ball of fire, entering his mouth and then into his heart. After that experience — Philip’s own Pentecost — his life would never be the same again.
Behind his holiness of life, and his preaching, and his miracles, and his founding of our Institute, there is something fundamental we can learn from St Philip — conveniently for this time in the Church’s liturgical calendar, something about the Holy Spirit. St Philip’s life shows us what happens when we do not simply possess the Holy Spirit, but allow ourselves to be possessed by him. We all have the Holy Spirit dwelling in us — all of us who have been baptised and confirmed. He is in us as much as he was in St Philip Neri, as much as he was in the Apostles at Pentecost. But we are very good at closing ourselves to the Spirit — we, through our sins and our selfishness, our attachments and our self-will, block him out; we ignore his prompting and are deaf to his call, we partition him away into a little forgotten compartment in our souls. Or we make of him a very petty little thing indeed, our God — a God who always agrees with what we say, who wants us to do precisely what we want to do, and makes me right and everyone else wrong.
But this is not the Holy Spirit whom we worship; this is not the awesome power of Almighty God, who hovered over the waters at creation, who raised Jesus from the dead, who came down on the Apostles and Our Lady in the Upper Room, who wonderfully penetrated the heart of St Philip, and who gives power and authority to the Church. The Holy Spirit blows where he wills; his ways are not always our ways; and if we give ourselves to him and allow him to possess us completely — as St Philip did — then we will find that he will do more for us than we ask or even imagine; do more through us and with us. St Philip wanted to be a layman — the Spirit called him to the priesthood; he wanted to be a martyr, the Spirit made him a martyr not of blood, but of charity; Philip wanted to preach the Gospel to the pagans in the Indies, the Holy Spirit had other plans. He wanted to be a humble, hidden servant of the Church, living at San Girolamo and doing what good he could, but the Spirit gave him the gift of preaching and teaching and working miracles and reading men’s hearts and winning souls, and brought him to the Vallicella, and through him founded the Congregation of the Oratory, spread, as it now is, across the world. St Philip loved to be unknown — the Holy Spirit moulded and fashioned and transformed him into one of the most popular saints, the Apostle of Rome. St Philip wanted to reform the hearts and souls of those men and women he met — the Spirit used him to reform the very heart of the Church herself.
It is not enough to have the Holy Spirit — it is not enough even to think we are serving God or doing great things in his honour. We must allow ourselves to be led by the Spirit, formed and transformed by the Spirit. We must be prepared to give up our own desires and plans — even the good ones — and be taken over by the Holy Spirit to be used for his own purposes. If we do this, if we open up to the Spirit who dwells in our hearts, then the life of St Philip Neri, and indeed of all the saints, shows us that the Spirit will do great things for, in, and through us. St Philip, Vessel of the Holy Spirit and Sweetest of Fathers. Pray for us.
A Prayer of Our Holy Father St Philip:
My Lord Jesus, I want to love you but you cannot trust me. If you do not help me, I will never do any good. I do not know you; I look for you but I do not find you. Come to me, O Lord. If I knew you, I would also know myself. If I have never loved you before, I want to love you truly now. I want to do your will alone; putting no trust in myself, I hope in you, O Lord.
The Paschal Candle has been lit for Masses since the Easter Vigil to represent Christ’s presence among us, as with his disciples for forty days. After the Gospel of the Solemn Mass yesterday, it is extinguished to symbolise his ascension into heaven.
#oxfordoratory
Look up to heaven
On Monday this week some of the Fathers and Brothers spent the day erecting and moving scaffolding — with all due health and safety measures observed — in order to change and improve the lighting on the sanctuary of our church. It is already a great boon for us to see more clearly the beautiful decoration which adorns that focal point of the whole building, as well as being a great help for the priest reading from the missal. Tomorrow as we celebrate the feast of the Ascension, our eyes are directed upwards once more as Our Risen Lord ascends to heaven and for a moment like the Apostles we gaze upwards as he is taken from our sight.
How very much more clearly do we see when we make that effort to lift up our eyes towards the Lord. We not only contemplate his glory but from that vantage point are able to see all things in their fullness, seeing them from the perspective of heaven. Prayer, the lifting of the mind and heart to God, enables us to understand and to see clearly, all those other things of life in which we are otherwise immersed. That daily shifting our focus from the things of this world to the vantage point of heaven is that great encouragement for our daily striving for God, so that where Christ goes we too may follow him.
It is often an effort for us to pull ourselves out of the daily round in order to lift up our heads and our hearts to the things of heaven, but if we are to have the desire for heaven to drive us on, it is essential that we always keep our goal before us. Not only in prayer, but all those things which form the way we see things must have heaven as their vantage point and aim. Monsignor Knox wrote:
In all ages, in all countries, the world acts as a solvent to Catholic piety; breathes an air in which Catholic piety languishes. Man’s intellect always wants to approach things from the human side, from the side from which they can be known by man; shirks and burkes discussion of things from the side of reality, from the side which relates them to God. Man’s art and literary genius is constantly concerned with man at his most human level, his passions, his craven fears, the rebellion of his will against the order in which he lives. All that breathes a poison, for which writers who care about the truth as it is in God have to provide an antidote; they must fight, they must react, but still more they must see things, they must record things, from that higher standpoint which is God’s. You must, sometimes, give the lungs of your soul an airing on these heights, even if the atmosphere of it is more rare, is breathed with more effort, than the other. Or else, the miasma of the modern world will get you down, will weaken your resistance; you will be a prey to the germs of infidelity, to the infection of bad example. And you will forget your Friend.
As the Church invites us then on the Ascension to gaze up towards heaven, to contemplate Our Lord, Risen and Ascended, it is perhaps a good time for us to think on the place we give to the things of heaven in our life each day — not only in terms of the time we give to heaven, but also in terms of what we strive for, on what really all our efforts are in fact based.
And from our gazing upon heaven, we can then go on like the Apostles, down from that mountain and into the world — to teach the Good News and make disciples of all nations, keeping ever in mind that he whom we meet on those heights of prayer is with us always, even to the end of time.
Q: How many Oratorians does it take to change a lightbulb?A: “Change”?
Actually the real answer turns out to be three, plus one very helpful volunteer and a lot of scaffolding. The sanctuary lighting is all working at full brightness again!
#oxfordoratory
Monday 15 May 2023
Congratulations to David who was baptised on Saturday!
#oxfordoratory
Saturday 13 May 2023
One of this month’s relics on display is St Philip’s own copy of Jacapone da Todi’s “Laude”, which St Philip has written his name in. The story of how it was rediscovered in our church — only days before the first Fathers of the Oratory arrived here from Birmingham — is extraordinary. You might find it hard to believe, unless you heard it straight from the priest who found them, who is now the Bishop of Leeds. Read his account from his St Philip’s day sermon on our website:
www.oxfordoratory.org.uk/blog/post/1335-solemnity-of-our-holy-father-saint-philip
The novena to St Philip begins on Tuesday after the evening Mass. You will be able to place your own prayer intentions for the novena in St Philip’s chapel over the weekend.
There will be Solemn Choral Vespers on Thursday 25 May at 6:30pm.
We will welcome Fr Robert Ombres OP from Blackfriars to preach at the Solemn Mass for the feast day itself on Friday 26 May at 6pm.
#oxfordoratory
Friday 12 May 2023
May Music
Sunday 7 MaySolemn Mass 11:005th Sunday of EasterMissa Simile est regnum caelorum LoboJubilate Deo universa terra PalestrinaCaro mea vere est cibus Guerrero
Sunday 14 MaySolemn Mass 11:006th Sunday of EasterMissa Regina caeli PalestrinaBenedicite gentes PalestrinaPortio mea White
Thursday 18 MaySolemn Mass 18:00The Ascension of the LordMissa Ascendens Christus VictoriaAscendit Deus PhilipsO Rex gloriae Marenzio
Sunday 21 MaySolemn Mass 11:007th Sunday of EasterMissa Jam Christus astra ascenderat PalestrinaViri Galilaei PalestrinaEgo sum panis vivus Palestrina
Thursday 25 MaySolemn Vespers 18:30Our Holy Father St Philip NeriDeus in adjutorium PadillaMagnificat primi toni VictoriaPangamus Nerio SewellO salutaris hostia LalouxTantum ergo WidorAlleluia GabrieliRespice de caelo Sewell
Friday 26 MaySolemn Mass 18:00Our Holy Father St Philip NeriMissa Papae Marcelli PalestrinaIn spiritu humilitatis CroceJubilate Deo a8 G Gabrieli
Sunday 28 MaySolemn Mass 11:00PentecostMissa De la Batalla GuerreroConfirma hoc deus LassusLoquebantur variis linguis Palestrina
The Oratory
25 Woodstock Road
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G.R. No. 163878
SECOND DIVISION
G.R. No. 163878 December 12, 2006
FAR EAST BANK AND TRUST COMPANY,
petitioner,
vs.
SHEMBERG MARKETING CORPORATION, MACKIE INDUSTRIES CORPORATION, BENSON INDUSTRIES, INC., KAMARO ENTERPRISES CORP., POLYSACCHARIDE CORP., PRIME CRAFTS, INC., CEBU UNITED POLYMER CORP., SHEMBERG NATURES CRAFT INC., MARY U. DACAY
1
, HENRY U. DACAY, BENSON U. DACAY, RAMON U. DACAY AND ERNESTO U. DACAY, JR.,
respondents.
D E C I S I O N
SANDOVAL-GUTIERREZ, J .:
Before us is a petition for review on certiorari assailing the Decision 2
and Resolution
3
of the Court of Appeals dated February 16, 2004 and May 28, 2004 in CA-G.R. SP No. 67270.
Far East Bank & Trust Company (FEBTC), petitioner, is a domestic banking corporation organized and existing under Philippine laws. It is now managed and operated by the Bank of the Philippine Islands with main office in Makati City.
Shemberg Marketing Corporation, Mackie Industries Corporation, Benson Industries Incorporated, Kamaro Enterprises Corporation, Polysaccharide Corporation, Prime Crafts Incorporated, Cebu United Polymer Corporation, Shemberg Natures Craft Inc., respondents herein, are all duly registered domestic corporations based in Pakna-an, Mandaue City. The individual respondents, all surnamed Dacay, are directors and corporate officers of the said corporations.
Respondents are the registered owners of several realties located in Mandaue City described as follows:
LOT NOS. AREA (in square meters) REGISTERED OWNER(S) TRANSFER CERTIFICATES OF TITLE (TCT) NOS.2209-A6,384Henry Dakay, Benson Dakay, Ernesto Dakay, Jr., Ramon Dakay1423122306,677Mackie Industries Corp.(19073)-5795-22315,563Mackie Industries Corp.(T-21005)-6216223216,139Mackie Industries Corp.(T-19451)-592922078,847Mackie Industries Corp.(T-19208)-5857311,224Shemberg Marketing Corp.260792266-A3,112Shemberg Marketing Corp.1994271,322Shemberg Marketing Corp.2693843,685Shemberg Marketing Corp.26080
Prior to 1998, respondents entered into several credit transactions with petitioner secured by several real estate mortgages, thus:
DATES OF MORTGAGE MORTGAGORS SIGNATORIES AMOUNTSDecember 6, 1977Mackie Industries Corp.Mary U. Dacay P3,000,000.00February 21, 1979Mackie Industries Corp.Ernesto Dakay, Sr., and Mary U. Dakay P500,000.00March 21, 1979Mackie Industries Corp.Ernesto Dakay, Sr., and Mary U. Dacay P1,000,000.00June 25, 1982Mackie Industries Corp.Mary U. Dacay P292,000.00October 27, 1982Shemberg Marketing Corp.Mary U. Dacay P3,708,000.00August 14, 1984Shemberg Marketing CorporationErnesto Dacay, Jr., Benson Dacay, Ramon Dacay, Mary Dacay, Ernesto Dacay, Sr., and Henry U, Dacay P10,000,000.00May 7, 1990Shemberg Marketing Corp,Benson Dakay P3.976.000.00May 10, 1990Shemberg Marketing Corp. & Mackie Industries Corp.Henry Dakay, Benson Dakay, Rosemary Tan Dakay, Ernesto Dakay, Jr., and Ramon Dakay P1,565,000.00September 25, 1991Mackie Industries Corp., Henry Dakay, Benson Dakay, Ernesto Dakay, Ramon Dakay, and Mario DakayHenry Dakay, Benson Dakay, Ernesto Dakay, and Ramon Dakay, P1,927,500.00July 27, 1992Mackie Industries Corp. & Shemberg Marketing Corp.Henry Dakay, Benson Dakay, Rosemary Tan Dakay, Ernesto Dakay, Jr., Ramon Dakay, and Mario Dakay P227,313.00November 23, 1995Mackie Industries Corp. & Shemberg Marketing Corp, Henry Dakay, Ramon Dakay, and Mario DakayHenry Dakay, Benson Dakay, Ernesto Dakay, Jr., and Ramon Dakay P13,040,000.00
In their respective mortgage contracts, duly annotated on respondents’ titles, the parties stipulated that upon failure or refusal of the mortgagor to pay the obligations when due, the entire principal, interest, penalties and other charges shall be immediately demandable and payable without need of notice or demand; and the mortgagee shall have the absolute discretion to foreclose the mortgage extrajudicially pursuant to Act No. 3135, as amended.
Pursuant to the parties’ agreements, petitioner released to respondents the principal amounts of the loans as evidenced by various promissory notes, thus:
Note Nos. Dates Amounts SignatoriesTLC-2-060-970509April 8, 1997 P4,700,000.00Mary U. DacayTLC-2-060-970518July 31, 1997 P3,500,000.00Mary U. DacayTLC-2-060-970115September 8, 1997 P11,000,000.00Mary U. DacayTLC-2-060-970153December 4, 1997 P5,000,000.00Mary U. DacayTLC-2-060-970155December 15, 1997 P10,000,000.00Mary U. DacayTLC-2-060-970156December 15, 1997 P10,000,000.00Mary U. DacayTLC-2-060-970157December 15, 1997 P5,000,000.00Mary U. DacayTLC-2-060-985002January 12, 1998 P13,290,000.00Mary U. DacayTLC-1-060-98512February 6, 1998 P8,270,000.00Mary U. DacayTLC-2-060-98563February 27, 1998 P9,342,899.00Mary U. DacayTLC-2-060-985640March 20, 1998 P6,632,500.00Mary U. DacayHenry U. DacayTLC 2-060-986024April 27, 1998 P19,450,000.00Mary U. DacayTLC 2-060-986025April 27, 1998 P13,968,990.00Mary U. DacayTLC 2-060-986026April 27, 1998 P8,558,000.00Mary U. DacayTLC 2-060-986029April 28, 1998 P7,216,000.00Mary U. DacayTLC 2-060-986030April 28, 1998 P37,600,000.00Mary U. DacayTLC 2-060-986031April 28, 1998 P16,436,000.00Mary U. DacayTLC 2-060-986032April 28, 1998 P20,658,860.00Mary U. DacayTLC-2-060-986297July 20, 1998 P13,691,490.00Mary U. DacayTLC-2-060-986298July 20, 1998 P14,511,807.04Mary U. DacayTLC-2-060-986299July 20, 1998 P74,109,900.00Mary U. DacayTLC-2-060-986300July 20, 1998 P98,094,243.30Mary U. DacayTLC-2-060-970161December 29, 1998 P5,239,000.00Ernesto Dacay, Jr. Mary U. Dacay
However, respondents failed to pay the loans which matured on February 14, 2001. Thus, petitioner sought to foreclose the mortgages extrajudicially.
On February 28, 2001, respondents filed with the Regional Trial Court, Branch 56, Mandaue City, a Complaint
4
for Declaratory Relief, Injunction, Damages, Annulment of Promissory Notes, Documents, and Contracts against petitioner, docketed as Civil Case No. MAN-4045. The complaint alleges that prior to 1998, respondents obtained credit accommodations from petitioner. The latter required respondents’ representatives to sign "standard pre-printed bank forms in fine print, such as Credit Line Agreements (CLA), Promissory Notes (PN), Real Estate Mortgages (REM), Chattel Mortgages (CM), Trust Receipts (TR), Surety Agreements (JSS) and other bank forms and documents." Respondents complied since they trusted petitioner. However, it tuned out that petitioner’s employees filled the blanks with "false and inaccurate entries." Respondents deny and dispute the genuineness and due execution of the documents and pray for the following reliefs:
1. Immediately upon filing, to issue
ex parte
a 72-hour temporary restraining order and thereafter upon summary hearing, to issue a temporary restraining order for a maximum period of twenty (20) days restraining and enjoining defendants, their agents, representatives or any other persons acting on their behalf from doing or proceeding with the following:
a) proceeding with the auction sale of the properties under the REMs,
b) execution of Certificate of Sale;
c) registering Certificate of Sale with the Registry of Deeds;
d) execution of the Deed of Final Sale and other consolidation documents;
e) publication of Notices of Sale;
f) posting of Notices of Sale;
g) using the questioned documents, like the TRs, to seek administrative, civil, or criminal remedies;
h) disturbing the status quoprior to the litigation.
2. After due notice and hearing, a Preliminary Injunction be issued upon posting of a bond enjoining defendant, its employees, agents, representatives, or any other persons acting on its behalf from doing the above acts complained against;
3. After trial, it is prayed that judgment be rendered in favor of plaintiffs and against defendant as follows:
a) Declaring null and void the CLA, REMs, CMs, PNs, JSS, TRs, and other related documents, the notices of sale, the entire foreclosure proceedings, including the auction sale, the amount claimed by the bank to be the outstanding account, the amount claimed by the bank to be the principal, the interest unilaterally imposed by the bank, the penalties imposed by the bank and the PNs made basis for default and foreclosure;
b) Declaring the CLA, REMs, CMs, PNs, JSS, TRs, and other related documents as without consideration, invalid, inoperative, ineffective, unenforceable, null and void and to cancel the same;
c) To make the injunction permanent;
d) To order the bank to comply with its commitments, assurances and representations to help in the rehabilitation of the Dacay Group and the restructuring of its obligations, if any;
e) To award to plaintiffs moral damages of
P
300,000.00, exemplary damages of
P
200,000.00, attorney’s fees of
P
200,000.00 plus
P
1,000.00 per billable hour, and litigation expenses of
P
300,000.00;
f) Declaring that the defendant cannot validly do, perform or suffer to be done the acts complained of.
On March 9, 2001, the trial court issued an Order
5
granting respondents’ prayer for the issuance of a temporary restraining order (TRO), thus:
In resolving the petition for the issuance of a TRO the court, without going into the merits of the case has taken into consideration:
a) the fact that petitioners/plaintiffs are presently in the process of rehabilitating their business concerns and for which purpose, a consortium of banks/creditors has been put into existence and that Far East Bank and Trust Company (FEBTC) even had initially approved and led such effort as indicated by the participation of one of its Senior Vice Presidents Ricardo G. Lazatin;
b) the admission by respondent/defendant, in open court, that it has already initiated foreclosure proceedings against petitioners/plaintiffs and that it has in fact scheduled on March 30, 2001 the auction sale of petitioners’ properties subject matter of the foreclosure proceedings, as well as the consequent damage resultant thereto;
c) the purpose of a temporary restraining order (TRO) which is merely to suspend proceedings until there may be an opportunity to inquire whether any injunction should be granted.
WHEREFORE, foregoing premises considered and in the interest of substantial justice, the defendant is hereby ordered to cease and desist and/or its agents, representatives or any other person acting in its behalf to immediately stop foreclosure proceedings of plaintiffs’ properties subject matter of the said foreclosure proceedings, including but not being limited to publication for foreclosure and subsequent auction sale of the said properties.
SO ORDERED.
Petitioner filed its Answer with Affirmative Defenses, Counterclaim, and Vigorous Opposition to the Order directing the issuance of a TRO and/or preliminary mandatory injunction. Likewise, petitioner filed a Motion to Dismiss Based On Affirmative Defenses alleging that: (1) the venue is improperly laid; (2) the trial court did not acquire jurisdiction over the case for non-payment of proper docket fees; (3) there is non-joinder of indispensable parties; and (4) the trial court has no jurisdiction to enjoin the foreclosure proceedings.
On March 27, 2001, the trial court issued an Order
6
denying petitioner’s motion to dismiss, thus:
This resolves defendant’s Motion to Dismiss.
Defendant in his motion insists that the case should be dismissed on the following affirmative defenses: (a) venue is improperly laid; (b) lack of jurisdiction considering the non-payment of docketing fees; (c) non-joinder of indispensable parties and (d) lack of jurisdiction or authority to enjoin foreclosure proceedings.
VENUE
Records show that the office address of plaintiffs is in Mandaue City. In fact, defendant’s annexes to its answer (Annex "I" and "L") admit that plaintiffs’ business address and principal place of business are at Pakna-an, Mandaue City. Likewise similarly situated are the properties sought to be foreclosed. Apparently, foregoing considered, venue has been properly laid.
JURISDICTION
It is to be noted that the question of jurisdiction has not been raised by defendant except with the cause of action regarding annulment of mortgages on defendant’s insistence that the tax declaration attached is not the latest. Considering however that annulment of mortgage is incapable of pecuniary estimation the court feels that jurisdiction is proper.
What determines the nature of an action and the court which has jurisdiction over it are the allegations made by the plaintiff.
Sandel v. Court of Appeals, 262 SCRA 101,
A court’s jurisdiction cannot be made to depend upon defenses set up in the answer or in a motion to dismiss but upon the allegations of the complaint.
Sandel v. Court of Appeals, 262 SCRA 101,
INDISPENSABLE PARTY
Evidence has not been introduced, to the satisfaction of the court that indeed Far East Bank and Trust Company (FEBTC) no longer exists and BPI has taken over its assets and liabilities. Besides, the commercial linkage was between FEBTC and Shemberg as records show.
AUTHORITY
It is an inherent power of the court concomitant to its very existence to issue provisional remedies, like injunction, to protect the rights and interest of parties pending litigation.
Premises considered, the court feels and finds no basis to grant defendant’s motion. Accordingly, the Motion to Dismiss is, as it is hereby, DENIED.
SO ORDERED.
Likewise on the same day, March 27, 2001, the trial court issued another Order
7
directing the issuance of a writ of preliminary injunction in favor of respondents, thus:
WHEREFORE, let a writ of injunction issue enjoining defendant, its employees, agents or representatives, and all those who may be acting in their behalf, from:
(1) Taking further actions to foreclose the real estate and chattel mortgage collaterals of plaintiffs;
(2) To maintain the status quo during the pendency of the proceedings and to refrain from performing the acts complained of including but not being limited to the publication and notice of sale, conducting any foreclosure auction sale and other similar acts which will violate the status quo.
The Clerk of Court is hereby directed to issue the writ prayed for.
Plaintiffs are ordered to put a bond of One Million Pesos (
P
1,000,000.00)
SO ORDERED.
Petitioner then filed with the trial court the following: (a) Motion to Resolve the Motion to Dismiss; (b) Motion to Dissolve Preliminary Mandatory Injunction; (c) Motion for Reconsideration of the Order Dated March 27, 2001; and (d) Opposition to the Sufficiency of Bond.
On August 16, 2001, the trial court issued the following Order: 8
For consideration by the court are the defendant’s (1) Motion for Reconsideration of the Denial of the Motion to Dismiss and (2) the Motion for Reconsideration of the Grant of Preliminary Mandatory Injunction.
After a careful and exhaustive consideration of the arguments adduced in Movant’s Motion for Reconsideration of the Denial of its Motion to Dismiss, the court finds that the arguments advanced for consideration had already been treated and passed upon by this court.
The same finding also holds true with respect to defendant’s Motion for Reconsideration of the Grant of Preliminary Mandatory Injunction.
Accordingly, both motions are hereby DENIED.
SO ORDERED.
Petitioner then filed with the Court of Appeals a petition for certiorari, prohibition, and mandamus, docketed as CA-G.R. SP No. 67270, contending that the trial court acted with grave abuse of discretion amounting to lack or excess of jurisdiction in issuing the following: (1) Order dated March 9, 2001 granting respondents’ prayer for a TRO; (2) Order dated March 27, 2001 ordering the issuance of a writ of preliminary injunction; (3) Order also dated March 27, 2001 denying its motion to dismiss; and (4) Order dated August 16, 2001 denying its motion for reconsideration of the Order denying its motion to dismiss and motion for reconsideration of the Order granting respondents’ application for a preliminary injunction.
On February 16, 2004, the Court of Appeals promulgated its Decision dismissing the petition for certiorari.
The appellate court held that as the trial court has jurisdiction over the case, its orders or decisions upon all questions therein, cannot be corrected by the extraordinary writ of certiorari.
Petitioner filed a motion for reconsideration but it was denied by the Court of Appeals in its Resolution of May 28, 2004.
Hence, the instant petition raising the following issues: (a) whether the trial court has jurisdiction over Civil Case No. MAN-4045; and (b) whether petitioner bank is entitled to the writs of certiorari, prohibition, and mandamus.
On the
first issue
, petitioner contends that in real actions, the assessed value of the property or if there is none, the estimated value thereof, must be alleged in the complaint, and shall serve as the basis for computing the fees. Nowhere in the complaint in Civil Case No. MAN-4045 did respondents allege the assessed values of their realties. Hence, there is no adequate basis for computing the proper filing fees. It necessarily follows that the fees paid are deficient. The trial court, therefore, did not acquire jurisdiction over the case.
Respondents counter that a perusal of the complaint in Civil Case No. MAN-4045 shows that the suit primarily involves cancellation of mortgages, an action incapable of pecuniary estimation. Consequently, petitioner’s contention that there is a deficiency in the payment of docket fees is without merit.
A court acquires jurisdiction over a case only upon the payment of the prescribed fees.
9
The importance of filing fees cannot be gainsaid for these are intended to take care of court expenses in the handling of cases in terms of costs of supplies, use of equipment, salaries and fringe benefits of personnel, and others, computed as to man-hours used in the handling of each case.
10
Hence, the non-payment or insufficient payment of docket fees can entail tremendous losses to the government in general and to the judiciary in particular.
Is an action for cancellation of mortgage incapable of pecuniary estimation?
Under Section 19 (1) of Batas Pambansa Blg. 180, as amended by Republic Act No. 7691, Regional Trial Courts have sole, exclusive, and original jurisdiction to hear, try, and decide "all civil actions in which the subject of the litigation is incapable of pecuniary estimation."
In
Singsong v. Isabela Sawmill
,
11
this Court laid the test for determining whether the subject matter of an action is incapable of pecuniary estimation, thus: Ascertain the nature of the principal action or remedy sought. If the action is primarily for recovery of a sum of money, the claim is considered capable of pecuniary estimation. Whether the trial court has jurisdiction would depend upon the amount of the claim.
However, where the basic issue is something other than the right to recover a sum of money, where the money claim is only incidental or a consequence of the principal relief sought, the action is incapable of pecuniary estimation
.
Here, the primary reliefs prayed for by respondents in Civil Case No. MAN-4045 is the cancellation of the real estate and chattel mortgages for want of consideration. In
Bumayog v. Tumas
,
12
this Court ruled that where the issue involves the validity of a mortgage, the action is one incapable of pecuniary estimation. In the more recent case of
Russell v. Vestil
,
13
this Court, citing
Bumayog
,
14
held that an action questioning the validity of a mortgage is one incapable of pecuniary estimation. Petitioner has not shown adequate reasons for this Court to revisit
Bumayog
and
Russell
. Hence, petitioner’s contention can not be sustained. Since respondents paid the docket fees, as computed by the clerk of court, consequently, the trial court acquired jurisdiction over Civil Case No. MAN-4045.
Concerning to the
second issue,
it should be noted that CA-G.R. SP No. 67270 is a petition for certiorari, prohibition, and mandamus alleging that the trial court acted with grave abuse of discretion amounting to lack or excess of jurisdiction in issuing the following Orders: (1) Order dated March 9, 2001 granting respondents’ prayer for a TRO; (2) Order dated March 27, 2001, directing the issuance of a writ of preliminary injunction; (3) Order also dated March 27, 2001 denying petitioner’s motion to dismiss; and (4) Order dated August 16, 2001 denying petitioner’s motion for reconsideration of the denial of the motion to dismiss and motion for reconsideration of the grant of preliminary injunction.
This Court holds that the Court of Appeals did not commit grave abuse of discretion in issuing the questioned Orders.
There is grave abuse of discretion where the acts complained of amount to an evasion of positive duty or a virtual refusal to perform a duty enjoined by law, or to act at all in contemplation of law, as where the power is exercised in an arbitrary and despotic manner by reasons of passion or personal hostility.
15
It is such whimsical and capricious exercise of judgment as is equivalent to lack of jurisdiction.
The Court of Appeals found that the trial court acted in fair, reasonable, and expeditious manner, thus:
Thus, on the 6
th
of March 2001, His Honor held a hearing on the application for temporary restraining order. He conducted at least three trial-type hearings on the 19
th
, 20
th
, and 23
rd
of March 2001, complete with direct examination, cross-examination, re-direct examination, re-cross examination and marking and offer of exhibits vis-à-vis the application for the issuance of a writ of preliminary injunction. Four witnesses testified during the hearings – two for the Dacay Group and two for the bank. Both parties were even required to submit memoranda.
Indeed, the records are bereft of any indication that the trial court committed grave abuse of discretion in issuing the challenged Orders. Verily, the Court of Appeals correctly held that certiorari will not lie, the sole office of the writ being to correct grave abuse of discretion. Where a court has jurisdiction over the person and the subject matter of the action, as in the instant case, its decisions on all questions arising from the case are but exercises of such jurisdiction.
16
If its findings are not correct, these would at best be questions of law, not abuse of discretion correctible by the extraordinary remedy of certiorari.
17
WHEREFORE,
this Court
DENIES
the petition. The assailed Decision and Resolution of the Court of Appeals in CA-G.R. SP No. 67270 are
AFFIRMED
. Costs against petitioner, now the Bank of the Philippine Islands.
SO ORDERED.
Puno, C.J., Chairperson, Corona, and Azcuna,Garcia, JJ.,concur.
Footnotes
1Also spelled "Dakay" in some parts of the record.
2 Rollo, pp. 419-444. Penned by Associate Justice Renato C. Dacudao and concurred in by Presiding Justice Cancio C. Garcia (now a member of this Court) and Associate Justice Danilo B. Pine (retired).
3 Ibid, pp. 522-523.
4 Id. at 317-349.
5 Id., pp. 385-386.
6 Id., pp. 387-388.
7 Id., pp. 389-394.
8 Id.,pp. 410.
9 Manchester Development Corporation v. Court of Appeals,G.R. No. 75919, May 7, 1987, 149 SCRA 562.
10 Pilipinas Shell Petroleum Corp. v. Court of Appeals, G.R. No. 76119, April 10, 1989, 171 SCRA 674, 680.
11G.R. No. 27343, February 28, 1979, 88 SCRA 623.
12106 Phil. 715 (1959).
13G.R. No. 119347, March 17, 1999, 304 SCRA 738.
14 Supra.
15 Ala-Martin v. Sultan, G.R. No. 117512, October 2, 2001, 366 SCRA 316, 321, citing Azores v. Securities and Exchange Commission,252 SCRA 387 (1996).
16 Platinum Tours and Travel, Inc. v. Panlilio,G.R. No. 133365, September 16, 2003, 411 SCRA 142, 146.
17 Okabe v. Gutierrez,G.R. No. 150185, May 27, 2004, 429 SCRA 685, 705, citing Lalican v. Vergara,276 SCRA 518 (1997).
| https://lawphil.net/judjuris/juri2006/dec2006/gr_163878_2006.html |
Australia's iconic black swans have a worrying immune system deficiency, new genome study finds | Australasian Science Magazine
Conor O'Reagan/Unsplash For years, scientists have known bird flu kills every black swan it infects.
Australia's iconic black swans have a worrying immune system deficiency, new genome study finds
Conor O'Reagan/Unsplash
For years, scientists have known bird flu kills every black swan it infects. This means if the disease made it to the Australian continent, it would be an existential threat to this iconic Aussie species.
A new study
published today in Genome Biology
finally reveals the gene contributions that make black swans particularly prone to falling victim to infectious diseases.
The relative geographic isolation of the black swan (
Cygnus atratus
) may have resulted in a limited immune toolbox, making them more susceptible to the infectious avian diseases Australia
has been largely shielded from
.
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Mute swans are the iconic white species found throughout the Northern Hemisphere, while black swans are native to Australia. Paul Wishart/Shutterstock
A DNA puzzle
Unlike mallard ducks (
Anas platyrhynchos
) and the white-coloured mute swan (
Cygnus olor
), the black swan is extremely sensitive to highly pathogenic avian influenza or HPAI, commonly known as “bird flu”.
In May 2021 a collaborative effort between University of Western Australia and University of Queensland mapped the DNA puzzle of the black swan, which was released open-source
through DNA Zoo
.
To understand whether the geographically-isolated black swan has a different immune gene repertoire compared to its relatives, for the past two years we have worked on comparing the black swan genome to that of the closely related – yet genetically distinct – Northern Hemisphere mute swans. This work was done by a large team of scientists from Australia, New Zealand, Sweden, Germany, Japan, USA and UK.
Harnessing the power of high-performance computing, we mapped and compared tens of thousands of genes between the two species, to better understand why black swans fall victim to the virus so easily while mute swans do not. Such work is akin to finding a needle in a haystack.
Our work has now provided insights into how these species diverge genetically in response to the deadly bird flu and other viruses in the same family.
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Black swans aren’t just a different colour from the white ones – the differences in genome run much deeper. Parwinder Kaur , Author provided
Some missing genes
Notably, we found the black swan showed undetectable gene expression in toll-like receptor (TLR-7), a class of proteins responsible for the immune system’s reaction to foreign viruses. In other words, they have the gene for it, but it’s not turning on for some reason.
https://images.theconversation.com/files/505700/original/file-20230121-8...
1200w,
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Dr Parwinder Kaur pictured with a black swan in Matilda Bay, Perth. The birds are the subject of a major collaboration in genome comparison studies. Parwinder Kaur , Author provided
The TLR-7 family has been extensively studied in humans, as it is known to play a role in virus and tumour cell recognition. A 2021 study showed TLR-7 is crucial to the pattern recognition receptors (the molecules that can detect pathogens)
of SARS-CoV-2 in humans
.
In infected endothelial cells – the cells lining blood vessels and the heart – of the black swan, we found a dysregulated (abnormal) pro-inflammatory response. When the immune system reacts to a threat, some inflammatory response is normal, but it’s possible it can cause a more severe reaction if dysregulated.
Risking a wipe-out
Our work has also found the black swan genome was contractive. This means that from their last common ancestor with mute swans, black swans lost more genes in total than they gained.
Specifically, 39 immune-related gene families of the black swan were contractive as compared to the mute swan. This could be because being relatively isolated in Australia, they were less exposed to infectious bird diseases.
The data gathered by this sequencing project indicate the immune system of the black swan is more susceptible to any avian viral infection if it were to arrive in its native habitat. In other words, bird flu could even risk wiping out this species.
Now that we understand the potential underlying mechanism for black swans’ susceptibility to bird flu – and given TLR-7 is such an extensively studied gene in humans – there are several ways we can save our precious swans.
One way would be to look for natural variation that exists for this particular gene family in different black swan populations across Australia, Tasmania and New Zealand. There are likely to be individuals with higher resistance to bird flu, and we could use them to develop a strategic breeding program for this species.
Otherwise – and a more expensive path – would be to develop immunotherapy treatments, such as we have developed for humans. The good news is we now know what could be done to protect these swans.
Tags:
Online Feature
| https://www.australasianscience.com.au/article/science-and-technology/australias-iconic-black-swans-have-worrying-immune-system-deficiency- |
PEOPLE v. JOAQUIN VELEZ
GR No. L-30038, (1974-07-18)
DIVISION
[ GR No. L-30038, Jul 18, 1974 ]
PEOPLE v. JOAQUIN VELEZ +
DECISION
157 Phil. 23
SECOND DIVISION
[ G.R. No. L-30038, July 18, 1974 ]
THE PEOPLE OF THE PHILIPPINES, PLAINTIFF AND APPELLEE, VS. JOAQUIN VELEZ, ALEJANDRO VELEZ AND ANTONIETO VELEZ, ACCUSED, JOAQUIN VELEZ AND ALEJANDRO VELEZ, ACCUSED AND APPELLANTS. D E C I S I O N
AQUINO, J.:
Joaquin Velez and Alejandro Velez appealed from the decision of the Court of First Instance of Northern Samar, Laoang Branch, convicting them and their brother, Antonieto Velez, of murder, sentencing each of them (Joaquin and Alejandro) to
reclusion
perpetua
and ordering them to indemnify solidarily the heirs of Narciso Becuna in the sum of P6,000 and to pay the costs (Criminal Case No. 3591).
Alejandro died during the pendency of the appeal. The case against him was dismissed insofar as his criminal liability was concerned (Resolution of September 19, 1972).
Antonieto did not appeal his sentence of ten (10) years and one (1) day of
prision mayor
to seventeen (17) years, four (4) months and one (1) day of
reclusion temporal.
This case presents the ever-recurring situation of a victim who was allegedly assaulted by two or more persons, usually relatives or members of a group. One assailant assumes responsibility for the killing but pleads self-defense. The others offer alibis or contend
that they had no complicity in the killing.
The judgment of conviction was based on the following facts:
At around three o'clock in the afternoon of June 24, 1966 Narciso Becuna, upon the invitation of Joaquin Velez, was playing a card game called
monte
in the latter's house (the house of his father Ciriaco) at Barrio P. Rebadulla, Catubig, Northern Samar. Velez acted as
banker or dealer. Narciso was the bettor. Ernesto Becuna, the seventeen-year-old brother of Narciso, was a spectator.
Later, Alejandro Velez and Antonieto Velez, the brothers of Joaquin, and one Damaso Mercader arrived and participated in the game. Since Narciso was winning, he agreed to be the dealer or banker. The others were bettors. The game lasted until the next day, June
25th. At around six o'clock in the morning of that day, Agripino Baldostamo arrived and had a private talk about sawn lumber with Alejandro. Baldostamo watched the game. Narciso was winning.
Inasmuch as Narciso had not eaten anything since the game started, he suggested at around seven o'clock in the morning that the game be suspended so that he could eat and then the game would be resumed thereafter. The Velez brothers, who had already eaten, objected to the
cessation of the game. Narciso, who was assailed by the pangs of hunger, was adamant. Alejandro left, saying that he had to go home. Narciso made another deal. Antonieto, Joaquin and Mercader placed their bets. Narciso won.
He collected his winnings, picked up the cards, arranged them and placed them on the table. He stood up and made a motion to leave the house. Joaquin, who was much discombobulated by his losses, uttered the ominous threat that their lives would be involved if Narciso
stopped playing. Joaquin forthwith ran to the kitchen. He was followed by Antonieto.
Suspecting that their lives were in jeopardy, Narciso and Ernesto jumped out through the window and ran. After they had traversed a distance of about twenty arms' length, they encountered Alejandro who, to all appearances, had been waiting for them. Alejandro was
armed with a bolo (sondang). Narciso stopped and stepped backward. Ernesto took refuge in a grassy place. As Narciso backed out, Joaquin appeared from behind. He was holding a barbed harpoon (gata-ao) more than a meter long, which he plunged into
Narciso's back and then tried to pull out. While Joaquin was trying to extricate the harpoon which got stuck because of its hooks, Alejandro stabbed Narciso with his sondang. Narciso fell to the ground. Antonieto, also armed with a sondang, slashed the
prostrate Narciso in the abdomen. Alejandro and Antonieto repeatedly stabbed him while Joaquin was pulling out the harpoon. Narciso died in consequence of his numerous wounds.
His cadaver was dragged to the house of Joaquin, which was really the house of his father, Ciriaco Velez. The body was brought to the town. The autopsy conducted on June 26th by Doctor Antonio S. Daiz, the municipal health officer, disclosed that the twenty-six-year
old victim sustained fourteen (14) wounds. Two were fatal: (a) the stab wound in the chest, piercing the cavity, cutting the fifth rib and muscles thereof and the diaphragm and piercing the lower lobe of the let lung, probably caused by a bolo and (b) the wound at
the back, penetrating the chest cavity, cutting the rib near the tip of the scapula and piercing the base portion of the left lung, the left side of the diaphragm and the superior portion of the stomach. Due to the presence of satellite wounds around the big penetrating
wound, Doctor Daiz concluded that a barbed harpoon-like instrument was used in inflicting that wound. The cause of death was shock due to massive internal hemorrhage coming from the two fatal wounds and the other twelve wounds (Exhs. A and A-2).
On July 22, 1966 the following developments in the case transpired: (1) the statements of Baldostamo and Ernesto Becuna, identifying the three Velez brothers as the killers, were sworn to before the Municipal Judge: (2) the Chief of Police filed a complaint for
murder against them on the basis of those statements; (3) the Municipal Judge conducted a preliminary examination; (4) a warrant was issued for the arrest of the Velez brothers and (5) they were confined in jail (Exh. C; 1-18 Record). The Chief of Police certified that
Antonieto had surrendered before the warrant of arrest was issued (Exh. B-1).
Alejandro and Antonieto waived the second stage of the preliminary investigation. Joaquin, twenty-four years old, presented witnesses to prove his alibi. The Municipal Court commissioned Cereal P. Rebadulla to make a house-to-house inquiry in Barrio P. Rebadulla so
as to ascertain whether Joaquin was a resident of that barrio. The commissioner in his report found that Joaquin, who was engaged in planting coconuts and sawing lumber, used to reside in his father's house in the barrio but he did not permanently live therein. That
house was near the houses of Antonieto and Alejandro (Exhs. D, 1, 1-B).
The Municipal Court did not give credence to Joaquin's alibi. The case was remanded to the Court of First Instance, where on September 15, 1966 the Fiscal filed against the Velez brothers an information charging them with the murder of Narciso Becuna.
The trial court convicted the Velez brothers on the assumption that they conspired or ganged up against Narciso. On the other hand, the theory of the defense is that only Antonieto and Narciso played
monte,
that they quarrelled and that Antonieto killed Narciso in
self-defense. Joaquin and Alejandro interposed alibis.
The following summation of the evidence for the defense, if juxtaposed with the prosecution's version, will show which factual recital is more credible:
According to Antonieto, at around seven o'clock in that morning of June 25th, Narciso arrived at his house and proposed that they play monte. Antonieto rejected the suggestion because the game was prohibited. Narciso quieted his apprehension by reminding him that the
barrio captain was Narciso's grandfather.
So, they played
monte.
Narciso, who had a five-peso bill, acted as banker. Antonieto won four pesos. When Antonieto gave Narciso a one-peso bill as change, the latter lost his temper, tore the bill and threw the cards at Antonieto. Narciso assumed
a squatting position and was poised to draw his bolo (depang) but Antonieto pushed him out of the house through the door. Narciso fell to the ground. Antonieto immediately closed the door and tied it with a piece of rope and wire. Narciso challenged Antonieto
to come out and fight.
Narciso tried to destroy the door's shutter which was made of woven bamboo (bagacay). Aware that Narciso could smash the door and reenter the house, Antonieto got hold of a harpoon and went out of the house through the kitchen. He outflanked Narciso and stabbed him
with the harpoon on the left side of his back.
According to the defense's version, Narciso, with the harpoon sticking in his back, tried to stab Antonieto by swinging his bolo backward. Antonieto twisted the harpoon thereby causing Narciso to fall to the ground. Fearing that Narciso might be able to pull out the
harpoon, Antonieto stabbed him several times and stopped only when he realized that Narciso had already been immobilized. He looked around and saw Maria Tosing (Tusing) but Ernesto and Baldostamo were not around. He immediately went to the poblacion and surrendered
to a policeman at the municipal building.
Pedmina Baldoza, a sister of the Velez brothers, and Maria Tosing, a neighbor, corroborated Antonieto's story.
On the other hand, Alejandro's alibi was that at about five o'clock in that morning of June 25th, he had gone to Barrio Nagbobtac in order to buy palay. He went to the house of Monica de Asis which was near Elisa Becuna's house, to inquire about persons selling
palay. Monica mentioned Emiliano Pluma. While Alejandro was at Monica's house; it rained and he chatted with her and her husband.
At about eight o'clock that morning, Pedro Becuna, Narciso's father, informed his daughter that Narciso was killed in Barrio P. Rebadulla by Antonieio. Alejandro returned at around nine o'clock to Barrio P. Rebadulla, which is about two kilometers away from Barrio
Nagbobtac. He saw Narciso's remains in the yard of Ciriaco Velez's house.
He went to his own house nearby and informed his wife that they would have to leave the vicinity and go to the town because Narciso's relatives, who had home-made shotguns, might retaliate and wreak reprisals on members of the Velez family. At noontime, he went to the
poblacion. He was afraid of the Becunas. He remembered that Julito Becuna had shot on December 24, 1963 Juan Tosara, the brother-in-law of the Velez brothers. Monica de Asis corroborated Alejandro's testimony.
Alejandro explained that Ernesto Becuna implicated him because he allegedly harbored a grudge against Alejandro. Ernesto had threatened to stab Alejandro with a bolo when the latter asked Ernesto to comply with promise to saw lumber. Alejandro further explained that
Baldostamo testified against him because he had asked Baldostamo to deliver nipa palms which had already been paid for.
Joaquin, the third accused, testified that in that morning of June 25th he was in Barrio Tongodnon where he had allegedly been residing since 1963. He had married Celia Turbana, a native of that barrio which is about seven kilometers away from Barrio P. Rebadulla.
The distance could be covered in two hours.
From June 24th up to the afternoon of June 25th, Joaquin, with Juan Tosing (Tusing) and Ireneo Sending, were weeding the upland ricefield of Clemente Placa, the barrio captain of Tongodnon. Joaquin came to know of the killing after Antonieto sent word to him while he
(Antonieto) was already incarcerated. Placa and Tosing corroborated Joaquin's testimony.
Ignacio Asebuche, a guard of the sub-provincial jail, testified that from June 23rd up to about ten o'clock in that morning of June 25th, he and prosecution witness Baldostamo, who was his friend and is a cousin of his brother's wife, were in Barrio Vigo, attending the
fiesta. Later, Baldostamo accompanied Clemente Becuna to Barrio P. Rebadulla to view the remains of Narciso Becuna who was reported to have been killed. From Barrio Vigo, it would take two hours to walk to Barrio P. Rebadulla.
Ruben L. Roxas, appellants' counsel
de oficio,
true to the noble art of advocacy and aware that the accused should be zealously defended according to the merits of his case, even if the advocate cannot expect any monetary reward, conscientiously studied the case and
submitted two well-written briefs based on the voluminous record.
He (a) assailed the testimonies of the prosecution witnesses, Ernesto Becuna and Baldostamo, (b) contended that, even under the prosecution's version, the killing could not be characterized as murder and (c) argued that the testimonies of the defense witnesses should be given
credence.
The trial court noted that Antonieto's plea of self-defense "is not supported by convincing and credible evidence" and that inconsistencies vitiate the testimonies of the witness for the defense. It also regarded the testimonies of Ernesto Becuna and Agripino Baldostamo as
"positive, clear and convincing".
Appellants' counsel brands Ernesto and Baldostamo as coached prosecution witnesses as allegedly shown by the similarity in phraseology of their testimonies and in the sequence of the episodes described by them. But, as pointed out by the Solicitor General, the wording of
the declarations of Ernesto and Baldostamo is alike because the same interpreter translated their answers. For that matter, their testimonies followed the pattern of their sworn statements at the preliminary examination. A scrutiny of their testimonies does not
support the conclusion that the same were rehearsed and fabricated. Being eyewitnesses of the same occurrence, it is not surprising that their testimonies dovetailed and coincided in vital particulars.
It is contended that Ernesto and Baldostamo erred in stating that the
monte
game was played in Joaquin's house when in truth it was played in the house of his father, Ciriaco. That error does not impair their credibility. It is not unusual that the father's
house is regarded in the community as the son's house, especially if the son is still young and goes often to his father's house and although the son resides in another barrio (Exh. D).
Another discrepancy pointed by appellants' counsel is that Baldostamo testified that he saw Joaquin's wife and child in Ciriaco's house on that morning of June 25, 1966, whereas, Ernesto was positive that he did not see any woman and child in that house. That inconsistency
refers to a trivial detail. It cannot destroy the probative value of their consistent testimonies on how the Velez brothers assaulted Narciso.
The appellants regard it as improbable that Narciso's decision to stop the game in order that he could eat had provoked the Velez brothers to encompass his death. What the prosecution's evidence shows is that when Narciso decided to stop the game the Velez brothers were
already in a fractious frame of mind as a result of their losses. Narciso's refusal to continue the game meant that they would not be able to recover their losses. That was the proverbial last straw which caused their anger to explode and to trigger their murderous
inclinations.
The appellants contend that the nature and location of the wounds indicate that there was a struggle or "grappling" between Narciso and Antonieto and that they had a face-to-face encounter. That contention is conjectural or speculative. If there was a struggle and if
Narciso was armed with a "file" or bolo, it was strange that Antonieto did not sustain any wound, whereas, the victim suffered fourteen wounds, two of which were fatal. One fatal wound was at the back. It was caused by a harpoon. To all appearances, it was
inflicted in a treacherous manner.
The defense did not prove that Narciso committed any unlawful aggression which imperilled Antonieto's life. The fact that Narciso had been convicted of frustrated homicide and was a parolee (Exh. 3) would not mean that he was the aggressor. Antonieto's tortuous story
as to how he defended himself against Narciso's supposed aggression has a patina of artificiality that readily evokes disbelief.
As to the trial court's refusal to give credence to the alibis of Joaquin and Alejandro, it may be argued that Antonieto's failure to appeal and his conformity to the trial court's rejection of his plea of self-defense rendered the alibis untenable. Those defenses were
interlinked. If there was no self-defense, then the obvious conclusion is that the witnesses for the appellants were not telling the truth. That, in turn, would mean that the prosecution's version is the true recital of the circumstances surrounding Narciso's
killing. Alibis can be concocted with facility.
Appellants' counsel considers it incongruous that Antonieto Was given the benefit of voluntary surrender to the authorities while the same mitigating circumstance was not appreciated in favor of Alejandro and Joaquin. As previously noted, on July 22, 1966 a warrant for the
arrest of the Velez brothers was issued. It was returned by the Chief of Police on that same date with the report that Alejandro and Joaquin "surrendered to the Office of the Chief of Police" (Exhs. B-1 and C). According to the police blotter, "the persons of
Alejandro Velez and Joaquin Velez" "surrendered" "after learning that they were involved and accused in connection with the death of the late Ernesto Becuna" (Sic, Exh. 4-B).
While the record seems to indicate that there was voluntary surrender because the Chief of Police and the police blotter euphemistically used the word "surrender", the truth is that, as admitted by Joaquin, he was actually arrested while buying rice in the poblacion (218
tsn). Alejandro did not testify that he surrendered voluntarily. He yielded because of the warrant of arrest. Hence, voluntary surrender to the authorities is not mitigating (
People vs. Conwi,
71 Phil. 595;
People vs. Adlawan
, 83 Phil. 194;
People vs. Saturnino,
96 Phil. 868).
It results that the trial court did not err in accepting the prosecution's version as worthy of belief and in concluding that the guilt of appellant Joaquin Velez had been proven beyond reasonable doubt.
The manner in which Alejandro, Joaquin and Antonieto assaulted Narciso and their conduct sometime before the encounter, show that they had hatched a conspiracy to assassinate him. They left Narciso and Ernesto in the place where the
monte
game was played.
Later, when they confronted Narciso outside the house, they were all armed with deadly weapons. They waited for Narciso outside the house like Apache Indians poised to ambush their quarry. They orchestrated their efforts in their concerted assault on Narciso for the
purpose of attaining their common objective of liquidating him.
The conspiracy among the Velez brothers is easily discernible from their conduct. The rule is that "if it is proven that two or more persons aimed by there acts towards the accomplishment of the same unlawful object, each doing a part so that their acts, although
apparently independent, were in fact connected and cooperative, indicating closeness of personal association and concurrence of sentiment, a conspiracy may be inferred though no actual meeting among them is proven. (Underhill, Criminal Evidence, 4th Ed. by Niblack, pp.
1402-3;
People vs. Carbonel,
48 Phil. 868, 875).
Treachery is aggravating. The Velez brothers, in way laying Narciso, employed a mode of attack, which was deliberately designed by them to insure his death without any risk arising from the defense which he could have made. He was unarmed. He was not able to
make any defense at all.
Abuse of superiority is also aggravating considering that three assailant took advantage of their combined strength to overpower the victim. That circumstance is absorbed in treachery which qualifies the killing as murder.
Premeditation, which was alleged in the information, is not aggravating. The interval between the time when Joaquin uttered the warning that the lives of the players of
monte
were endangered and the time when the assault took place was not sufficient to afford the
Velez brothers full opportunity for meditation and reflection and to allow their consciences to overcome the resolution of their will to kill Narciso had they desired to hearken to the warnings thereof (
U.S. vs. Gil,
13 Phil. 530, 547).
There being no generic aggravating and mitigating circumstances the trial court properly imposed the penalty of
reclusion perpetua
which is the medium period of the penalty for murder (Arts. 64[1] and 248, Revised Penal Code).
The indemnity of P6,000 should be raised to P12,000.
WHEREFORE,
the trial court's judgment as to Joaquin Velez is affirmed with the modification that the indemnity should be raised to P12,000. The trial court's pronouncement that he should be credited with only one-half of his preventive imprisonment was correct when
its judgment was rendered in 1968. That holding was superseded by Republic Act No. 6127 which took effect on June 17, 1970 and which gives the accused full-time credit for his preventive imprisonment as long as the conditions indicated in that law are satisfied.
Costs against the appellant.
SO ORDERED.
Zaldivar, (Chairman), Fernando, Barredo,
and
Fernandez, JJ.,
concur.
Antonio, J.,
took no part.
tags
| https://lawyerly.ph/juris/view/c51c0 |
92136cfe152a654b3a6a2074e2dffccd3a73bea72de94db855968d585cdb64ae_optim.pdf
Velp Scientifica MULTISTIRRER6 Magnetic Stirrer, 100-240V/50-60Hz | B3126470 - GLOBALindustrial.ca
Instruction Manual for VELP SCIENTIFICA models including: F203A0177 Multistirrer 6 and 15 Magnetic Stirrers, F203A0177, Multistirrer 6 and 15 Magnetic Stirrers, 6 and 15 Magnetic Stirrers, Magnetic Stirrers
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Velp Scientifica MULTISTIRRER15 Magnetic Stirrer, 100-240V 50-60Hz | B3126471 - GLOBALindustrial.ca
Velp Scientifica MULTISTIRRER6 Magnetic Stirrer, 100-240V/50-60Hz | B3126470 - GLOBALindustrial.ca
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VELP SCIENTIFICA
VELP SCIENTIFICA F203A0177 Multistirrer 6 and 15 Magnetic Stirrers Instruction Manual
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B3126470 MANUAL
Instruction Manual Manuale di istruzioni Manuel d'instructions Manual de instrucciones Bedienungsanleitung
MULTISTIRRER 6 & 15 Magnetic Stirrers
F203A0177, F203A0178
General Information / Informazioni Generali / Informations Générales / Información General / Allgemeine Hinweise /
Before using the unit, please read the following instruction manual carefully. Prima dell'utilizzo dello strumento si raccomanda di leggere attentamente il seguente manuale operativo. Avant d'utiliser l'instrument, il est recommandé de lire attentivement le présent manuel d'instructions. Antes de utilizar el instrumento, le recomendamos que lea con atención el siguiente manual de funcionamiento. Bitte lesen Sie vor Inbetriebnahme des Geräts diese Bedienungsanleitung sorgfältig durch.
Do not dispose of this equipment as urban waste, in accordance with EEC directive 2002/96/CE. Non smaltire l'apparecchiatura come rifiuto urbano, secondo quanto previsto dalla Direttiva 2002/96/CE. Ne pas recycler l'appareil comme déchet solide urbain, conformément à la Directive 2002/96/CE. No tirar el aparato en los desechos urbanos, como exige la Directiva 2002/96/CE. Dieses Gerät unterliegt der Richtlinie 2002/96/EG und darf nicht mit dem normalen Hausmüll entsorgt werden. EEC 2002/96/CE
This unit must be used for laboratory applications indoor only. The manufacturer declines all responsibility for any use of the unit that does not comply with these instructions. If the product is used in a not specified way by the manufacturer or with non specified accessories, product's safety may be compromised.
Questo strumento deve essere utilizzato solo per applicazioni di laboratorio per uso interno. La società produttrice declina ogni responsabilità sull'impiego non conforme alle istruzioni degli strumenti. Se il prodotto viene utilizzato in un modo non specificato o con accessori non specificati dal costruttore stesso, la sicurezza del prodotto potrebbe essere compromessa.
Cet instrument ne peut être utilisé pour les applications de laboratoire à l'intérieur seulement. Le fabriquant décline toute responsabilité en cas d'utilisation non conforme aux instructions concernant ces instruments. Si le produit est utilisé d'une manière non spécifiée par le fabricant ou accessoires non spécifiés, la sécurité du produit peut être compromise.
Este dispositivo sólo debe utilizarse para aplicaciones de laboratorio para uso interno. El fabricante declina toda responsabilidad por el uso no conforme a las instrucciones de los dispositivos. Si se utiliza el producto de una manera no especificada o con accesorios no especificados de el fabricante, la seguridad del producto puede estar comprometida.
Dieses Gerät muss nur für Laboranwendungen verwendet werden. Der Hersteller lehnt jede Haftung für unsachgemäße Verwendung oder Nichtbeachtung dieser Bedienungsanleitung ab. Wenn das Produkt in einer Weise
1
verwendet wird, die nicht vom Hersteller oder mit unsachgemäßer Zubehör angegeben, kann das Produkt die Sicherheit beeinträchtigt werden.
This unit has been designed and manufactured in compliance with the following standards: Lo strumento è stato progettato e costruito in accordo con le seguenti norme: L'instrument a été conçu et fabriqué conformément aux normes suivantes: El dispositivo se ha sido diseñado y fabricado de acuerdo con las siguientes normas: Das Gerät wurde in Übereinstimmung mit folgenden Normen entwickelt und gebauht:
Safety requirements for electrical equipment for measurement, control and for laboratory use Prescrizioni di sicurezza per apparecchi elettrici di misura, controllo e per l'utilizzo in laboratorio Règles de sécurité pour appareils électriques de mesurage, de régulation et de laboratoire Prescripciones de seguridad para equipos eléctricos de medición, control y su uso en laboratorio Sicherheitsbestimmungen für elektrische Mess-, Steuer-, Regel- und Laborgeräte
IEC/EN 61010-1 IEC/EN 61010-2-051
Electrical equipment for laboratory use General requirement - Canadian electrical code
UL 61010-1 CAN/CSA-C22.2 No.61010-1
VELP reserves the right to modify the characteristics of its products with the aim to constantly improving their quality. Nell'impegno di migliorare costantemente la qualità dei prodotti, VELP si riserva la facoltà di variarne le caratteristiche. Dans le but d'améliorer constamment la qualité de ses produits, VELP se réserve le droit d'apporter des modifications aux caractéristiques de ceux-ci. VELP se reserva el derecho de modificar las características de sus productos con el objetivo de mejorar constantemente su calidad. VELP behält sich zum Zwecke der ständigen Verbesserung der Produktqualität das Recht auf Änderung der Geräteeigenschaften vor. VELP
Safety Regulations / Norme di Sicurezza / Consignes de Securité / Advertencias de Seguridad / Sicherheitshinweise /
The plug disconnects the instrument. Therefore, place the instrument where it can be quickly disconnected. La spina è il mezzo di disconnessione dell'apparecchio. Pertanto, non posizionare l'apparecchio in modo che sia difficile azionare il mezzo di disconnessione. Le bouchon est le moyen de déconnexion de l'appareil. Par conséquent, placer l'appareil où il peut être rapidement débranché. El tapón es el medio de desconexión del dispositivo. No coloque el dispositivo en una forma que es difícil de desconectar. Der Stecker trennt das Gerät. Daher Stellen Sie das Instrument, wo es schnell getrennt werden kann.
Place the power supply in the way to avoid liquid spills directly on it. / Posizionare l'alimentatore in modo da evitare fuoriuscite di liquido direttamente su di esso. / Placez le bloc d'alimentation de manière à éviter les déversements de liquide
directement dessus. / Coloque la fuente de alimentación en el camino para evitar derrames de líquidos directamente sobre
ella. / Stellen Sie das Netzteil so auf, dass keine Flüssigkeiten direkt darauf gelangen. /
The stirred solution may release toxic, dangerous or poisonous gases. Adequate safety measures must be taken, in accordance with the safety regulations in force, including the presence of hood and personal protective equipment (masks, gloves, goggles, etc.). Le sostanze agitate potrebbero emanare gas tossici e/o pericolosi e/o velenosi. Adeguate misure di sicurezza devono essere prese, in accordo con le normative di sicurezza dei prodotti in lavorazione e/o vigenti nei laboratori, compresa la presenza di cappe aspiranti e mezzi di protezione individuale (maschere, guanti, occhiali, camici, ecc.). La solution agité peut libérer gaz toxiques ou dangereux. Des mesures de sécurité adéquates doivent être prises, en conformité avec les règlements de sécurité en vigueur, compris la présence de la hotte de laboratoire et équipements de protection individuelle (masques, gants, lunettes, etc.).
2
Las sustancias agitados pueden emitir tóxicos o peligrosos gas. Medidas de seguridad adecuadas deben ser adoptadas, de acuerdo con las normas de seguridad vigentes en los laboratorios, incluyendo la presencia de la campana de humos y el equipo de protección personal (mascarillas, guantes, gafas, etc.) Die erregt Lösung kann giftige oder gefährliche Gase freigeben. Angemessene Sicherheitsmaßnahmen zu treffen, werden in Übereinstimmung mit den geltenden Sicherheitsvorschriften, einschließlich der Anwesenheit Dunstabzug und persönliche Schutzausrüstungen (Masken, Handschuhe, Schutzbrille, etc.).
Position the instrument on a flat surface, with a distance from the wall of 30 cm (at least). / Posizionare lo strumento su superfici piane, ad una distanza dalle pareti di almeno 30 cm. / Positionner l'appareil sur une surface plat, avec une distance de la paroi de 30 cm (au moins). / Coloque la unidad sobre una superficie plana, con una distancia de la pared de 30 cm (por lo menos). / Stellen Sie das Gerät auf einer ebenen Fläche mit einem Abstand zur Wand von 30 cm (mindestens)./ 30
Do not use with explosive and dangerous materials for which the equipment is not designed. The stirrer must not be used in explosive atmospheres. Vietato l'uso con materiale esplosivo e pericoloso per cui l'apparecchio non è progettato. L'agitatore non può essere impiegato in atmosfere esplosive. Ne pas utiliser avec des matières explosives et dangereuses pour lesquelles l'équipement n'est pas conçu. L'agitateur ne peut pas être utilisé dans des atmosphères explosives. No debe utilizarse con materiales explosivos y peligrosos para los que el equipo no está diseñado. El agitador no puede ser utilizado en ambientes explosivos. Nicht mit explosivem Material zu verwenden, für die das Gerät nicht ausgelegt ist. Das Gerät kann nicht in explosionsgefährdeten Bereichen eingesetzt werden.
It is responsibility of the user appropriately decontaminate the instrument in case of dangerous substances fall on or in it. It is also responsibility of the user to use safety substances for cleaning or decontaminating, which do not react with internal parts of the instrument or with the material contained in it. In case of doubts on the compatibility of a cleaning solution, contact the manufacturer or local distributor. È responsabilità dell'utilizzatore un'appropriata decontaminazione in caso di versamento di sostanze pericolose sul o dentro l'apparecchio. È inoltre responsabilità dell'utilizzatore l'uso di sostanze decontaminanti o per la pulizia che non producano pericolo a causa di reazioni con parti dell'apparecchio o con il materiale in esso contenuto. In caso di dubbio sulla compatibilità di un agente pulente o decontaminante, contattare il produttore o un distributore locale. Est responsabilité de l'utilisateur la décontamination en cas de déversement de matières dangereuses sur ou à l'intérieur de l'équipement. Est responsabilité de l'utilisateur à utiliser des substances qui ne produisent pas de danger pour le nettoyage ou de décontamination, qui ne réagissent pas avec les parties internes de l'appareil ou avec la matière qu'il contient. En cas de doute sur la compatibilité d'une solution de nettoyage, contactez le fabricant ou le distributeur local. Es responsabilidad del usuario una descontaminación adecuada en caso de derrame de sustancias peligrosas en o dentro el equipo. Es responsabilidad del usuario también utilizar sustancias que no producen peligro para limpiar o descontaminar, que no reaccionan con las partes internas del instrumento o con el material contenido en él. En caso de duda sobre la compatibilidad de una solución de limpieza, póngase en contacto con el fabricante o el distribuidor local. Der Benutzer ist dafür verantwortlich, für die ordnungsgemäße Dekontamination beim Freiwerden gefährlicher Stoffe auf oder im Inneren des Geräts. Der Benutzer ist dafür verantwortlich, für die Reinigung oder Dekontaminierungsmitteln, die nicht mit internen Teile des Gerätes oder mit dem Material in ihm enthaltenen reagieren. Im Zweifelsfall über die Vereinbarkeit einer Reinigungslösung den Hersteller, den Vertreiber oder den Händler.
Do not use with explosive and dangerous materials for which the equipment is not designed. The stirrer must not be used in explosive atmospheres, in bain-marie and to stir combustible liquids that have a low combustion temperature. The minimum fire point of flammable solution is 200 °C. Only small amounts (< 50 ml) of flammable liquid can be used with the device. Vietato l'uso con materiale esplosivo e pericoloso per cui l'apparecchio non è progettato. L'agitatore non può essere impiegato in atmosfere esplosive, a bagno maria e per agitare liquidi combustibili a bassa temperatura di combustione. Il minimo fire point delle sostanze infiammabili è 200 °C. Solo piccole quantità (< 50 ml) di liquido infiammabile possono essere utilizzate con l'apparecchio. Ne pas utiliser avec des matières explosives et dangereuses pour lesquelles l'équipement n'est pas conçu. L'agitateur ne peut pas être utilisé dans des atmosphères explosives, dans un bain d'eau et pour remuer les combustibles liquides avec la température de combustion bas. Le point minimale de feu de solution inflammable est de 200 °C. Seules de petites quantités (<50 ml) de liquide inflammable peuvent être utilisés avec l'appareil. No debe utilizarse con materiales explosivos y peligrosos para los que el equipo no está diseñado. El agitador no puede ser utilizado en ambientes explosivos, en baño de agua y para agitar combustibles con una baja temperatura de combustión. El punto mínimo de inflamación de las sustancias inflamables es de 200 °C. Sólo cantidades pequeñas (<50 ml) de líquido inflamable pueden ser utilizade con el dispositivo.
3
Nicht mit explosivem Material zu verwenden, für die das Gerät nicht ausgelegt ist. Das Gerät kann nicht in explosionsgefährdeten Bereichen eingesetzt werden, in einem Wasserbad und rühren für flüssige Brennstoffe mit niedrigen Verbrennungstemperatur. Die minimale Brennpunkt von brennbaren Lösung beträgt 200 °C. Nur geringe Mengen (<50 ml) von brennbaren Flüssigkeit kann mit dem Gerät verwendet werden. 200<50 In case of black-out, once the power is back the device will restart automatically. In caso di black-out lo strumento riparte automaticamente. En cas de panne de blackout, l'appareil redémarre automatiquement dès que l'alimentation est de retour. En caso de blackout, el dispositivo se reiniciará automáticamente. Im Falle einer Ohnmacht, wird das Gerät automatisch neu gestartet, sobald die Stromversorgung wiederhergestellt ist.
4
Contents / Indice / Index / Índice / Inhalt /
1. INTRODUCTION .............................................................................................................................................................. 6 2. ASSEMBLY AND INSTALLATION................................................................................................................................... 6 3. OPERATING CONTROLS ............................................................................................................................................... 6 4. MAINTENANCE ............................................................................................................................................................... 6 5. TECHNICAL DATA .......................................................................................................................................................... 7 6. ACCESSORIES / SPARE PARTS ................................................................................................................................... 7
1. INTRODUZIONE .............................................................................................................................................................. 8 2. MONTAGGIO ED INSTALLAZIONE ................................................................................................................................ 8 3. CONTROLLI DI FUNZIONAMENTO................................................................................................................................ 8 4. MANUTENZIONE............................................................................................................................................................. 8 5. CARATTERISTICHE TECNICHE .................................................................................................................................... 9 6. ACCESSORI / PARTI DI RICAMBIO ............................................................................................................................... 9
1. INTRODUCTION ............................................................................................................................................................ 10 2. MONTAGE ET INSTALLATION ..................................................................................................................................... 10 3. CONTRÔLES DES OPÉRATIONS ................................................................................................................................ 10 4. ENTRETIEN ................................................................................................................................................................... 10 5. CARACTÉRISTIQUES TECHNIQUES .......................................................................................................................... 11 6. ACCESSOIRES / PIECES DE RECHANGE.................................................................................................................. 11
1. INTRODUCCIÓN ........................................................................................................................................................... 12 2. MONTAJE E INSTALACIÓN.......................................................................................................................................... 12 3. CONTROLES DE FUNCIONAMIENTO ......................................................................................................................... 12 4. MANTENIMIENTO ......................................................................................................................................................... 12 5. CARACTERÍSTICAS TÉCNICAS .................................................................................................................................. 13 6. ACCESORIOS / REFACCIONES .................................................................................................................................. 13
1. EINFÜHRUNG ............................................................................................................................................................... 14 2. MONTAGE UND INSTALLATION.................................................................................................................................. 14 3. BEDIENUNGSELEMENTE ............................................................................................................................................ 14 4. WARTUNG ..................................................................................................................................................................... 14 5. TECHNISCHE MERKMALE........................................................................................................................................... 15 6. ZUBEHÖR / ERSATZTEILE .......................................................................................................................................... 15
1. ................................................................................................................................................................................ 16 2. ..................................................................................................................................................................... 16 3. ......................................................................................................................................................................... 16 4. ................................................................................................................................................................................ 16 5. ......................................................................................................................................................................... 17 6. / ...................................................................................................................................................................... 17
7. WIRING DIAGRAM / SCHEMA ELETTRICO / SCHEMA ELECTRIQUE / ESQUEMA ELECTRICO / SCHALTPLAN /
................................................................................................................................................................................ 18
8. DECLARATION OF CONFORMITY / DICHIARAZIONE DI CONFORMITA / DECLARATION DE CONFORMITE /
DECLARACIÓN DE CONFORMIDAD / KONFORMITÄTSERKLÄRUNG /
...................................... 18
9. DECLARATION OF CONFORMITY ........................................................................................................................ 19
5
1. Introduction
EN
MULTISTIRRER is able to stir up to 6 beakers having a maximum diameter of 85 mm (MULTISTIRRER 6) or up to 15 beakers having a maximum diameter of 64 mm (MULTISTIRRER 15) at the same time. The stirrer stays cold even after several days of continuous operation. This feature makes it particularly appreciated in microbiology and biochemistry. Epoxy painted metal structure, with stainless steel cover, is studied and tested in order to give to the instrument an excellent resistance to the attack of chemical agents and to corrosion in general. The stirring speed can be set within a range of 80 1500 rpm using the knob on the front panel. The Stirrer led shows when the stirring is running.
NOTE: it's important to choose the most suitable magnetic stirring bar related to the quantity and the liquid to be stirred as well as to the type of the beaker. For MULTISTIRRER 6 is suggested the stirring bar A00001056 (6x35 mm); for MULTISTIRRER 15 the A00001057 (6x20 mm).
2. Assembly and installation
Upon receipt and after having removed the packaging, please check the integrity of the instrument. The box includes:
· Magnetic stirrer MULTISTIRRER
· Switching VELP 100-240V/12V without plug
· Plug for power supply
· Instruction manual
2.1 Electrical connection After having unpacked the instrument, place the unit on the laboratory bench. Before connecting the instrument to the power supply, make sure that the values on the rating plate correspond to those of the power supply. Connect the unit to the power supply using the transformer supplied. Ensure that the socket and the relative cut-off device conform to current safety norms and easy to reach.
2.2 Start-up Rotate the speed knob completely to the left. Place the flasks containing the sample and a suitable magnetic stirring bar on the stirring plate. Then, set the speed by turning the speed knob.
3. Operating controls
Turn the stirring speed knob on the front panel in order to start the stirring function. It is possible to select speeds between 80 and 1500 rpm. When the led is lighted it means that the stirring is on.
4. Maintenance
No routine or extraordinary maintenance is necessary apart from periodically cleaning the unit as described in this manual. In compliance with the product guarantee law, repairs to our units must be carried out in our factory, unless previously agreed otherwise with local distributors. The instrument must be transported in its original packaging and any indications present on the original packaging must be followed (e.g. palletized). It is the responsibility of the user, to properly decontaminate the unit in case of hazardous substances remaining on the surface or interior of the device. If in doubt about the compatibility of a cleaning or decontamination product, contact the manufacturer or distributor.
4.1 Cleaning Disconnect the unit from the power supply and use a cloth dampened with an non-inflammable non-aggressive detergent.
6
5. Technical data
Power Admitted power supply Dimensions (WxHxD) Weight (with plug) Speed range Stirring capacity Operating mode Construction material Environmental ambient temperature Storage temperature range Pollution degree Overvoltage category Sound level Max humidity Altitude
MULTISTIRRER 6: 12 Vdc 3,6 W MULTISTIRRER 15: 12 Vdc 9 W
0.5 A / 100-240 V / 50-60 Hz (+/-10%)
230x51.5x370 mm
MULTISTIRRER 6: 1,75 kg
MULTISTIRRER 15: 2,1 kg
80 ÷ 1500 rpm
MULTISTIRRER 6: 6x400 ml
MULTISTIRRER 15: 15x250 ml
Continuous
Epoxy painted metal structure and stainless steel
5 - 40 °C (41 - 104°F)
-10... + 60 °C (14 - 140°F)
2
II
35 dBa
80%
Up to 2000 m.
6. Accessories / Spare parts
A00001055 A00001057 10000231
Thermostating bath for samples Stirring bar 6x20mm Foot
A00001056 10005266 10003081
Stirring bar 6x35mm Knob 26D blue Power supply 100-240V/12V no plug
7
1. Introduzione
IT
L'agitatore magnetico multiposizione MULTISTIRRER, è capace di agitare contemporaneamente fino a 6 contenitori aventi un diametro massimo di 85mm (MULTISTIRRER 6), o fino a 15 contenitori aventi un diametro massimo di 64mm (MULTISTIRRER 15). Anche dopo diversi giorni di funzionamento in continuo la piastra di agitazione rimane sempre fredda. Questa caratteristica lo rende molto apprezzato in microbiologia e biochimica. La struttura in alluminio verniciata con apposite vernici, in concomitanza con il coperchio in acciaio inox, garantiscono un'elevata resistenza agli agenti chimici. Tramite la manopola posta sulla plancia frontale è possibile programmare la velocità (80 - 1500 rpm) in modo analogico. Il led stirrer indica il funzionamento dell'agitazione.
NOTA: E' opportuno scegliere l'ancoretta magnetica più adeguata in relazione alla quantità e qualità di liquido in lavorazione nonché al tipo di contenitore utilizzato. Per MULTISTIRRER 6 l'ancoretta che soddisfa la maggior parte delle applicazioni è la A00001056 (6x35 mm), mentre per il MULTISTIRRER 15 la A00001057 (6x20 mm).
2. Montaggio ed installazione
Verificare l'integrità dello strumento al ricevimento. Gli elementi contenuti nell'imballo sono i seguenti:
· Agitatore MULTISTIRRER
· Cavo di alimentazione 100-240V/12V
· Manuale di istruzioni
· Spina UE
2.1 Collegamento alla rete elettrica Dopo avere rimosso l'unità dall'imballo, posizionarla su una superficie piana. Prima di collegare l'unità alla rete di alimentazione elettrica, assicurarsi che i dati di targa dell'unità corrispondano a quelli disponibili. Assicurarsi che sia la presa di corrente che il relativo dispositivo di sezionamento siano conformi alle norme di sicurezza e di facile accessibilità.
2.2 Avvio Posizionare la manopola della velocità sulla battuta di sinistra. Collocare il contenitore con il liquido e la barretta magnetica adatta sulla superfice di appoggio dell'agitatore. Regolare la velocità di agitazione con l'apposita manopola.
3. Controlli di funzionamento
L'avvio dell'agitazione si effettua mediante la relativa manopola. E' possibile selezionare velocità comprese tra 80 e 1500 giri al minuto. Il led acceso indica il funzionamento dell'agitazione.
4. Manutenzione
La manutenzione ordinaria e straordinaria non è prevista salvo la pulizia periodica dello strumento come descritto in questo manuale. In conformità alla legge sulla garanzia dei prodotti, le riparazioni dei nostri strumenti devono essere eseguite presso la nostra sede, salvo accordi diversi con i distributori locali. Il trasporto dello strumento tramite spedizionieri, corrieri o altro, deve essere effettuato utilizzando l'imballo originale antiurto di cui lo strumento è dotato quando spedito da nuovo. Seguire le istruzioni eventualmente riportate sullo stesso (es. pallettizzare). È responsabilità dell'utente procedere alla decontaminazione dell'unità nel caso in cui sostanze pericolose rimangano sulla superficie o all'interno del dispositivo. In caso di dubbi sulla compatibilità di un prodotto per la pulizia o la decontaminazione, contattare il produttore o il distributore.
4.1 Pulizia La pulizia dello strumento deve essere eseguita, dopo aver staccato l'alimentazione, con un panno inumidito con detergenti non infiammabili e non aggressivi.
8
5. Caratteristiche tecniche
Potenza Alimentazione Dimensioni (lxhxp) Peso (con alimentatore) Velocità impostabile Capacità di agitazione Modalità operativa Struttura Temperatura ambiente ammessa Temperatura di stoccaggio ammessa Umidità ammessa Grado di inquinamento Categoria di sovratensione Livello sonoro Umidità massima Altitudine
MULTISTIRRER 6: 12 Vdc 3,6 W MULTISTIRRER 15: 12 Vdc 9 W
0.5 A / 100-240 V / 50-60 Hz (+/-10%)
230x51.5x370 mm
MULTISTIRRER 6: 1,75 kg
MULTISTIRRER 15: 2,1 kg
80 ÷ 1500 rpm
MULTISTIRRER 6: 6x400 ml
MULTISTIRRER 15: 15x250 ml
Continua
Metallica con verniciatura epossidica
5 - 40 °C (41 - 104°F)
-10... + 60 °C (14 - 140°F)
80%
2
II
35 dBa
80%
Fino a 2000 m.
6. Accessori / Parti di ricambio
A00001055 A00001057 10000231
Vaschetta per termostatazione Ancoretta magnetica 6x20mm Piedino
A00001056 10002097 10003081
Ancoretta magnetica 6x35mm Manopola 26D blu Alimentatore 100-240V/12V no spina
9
1. Introduction
FR
MULTISTIRRER est capable de remuer jusqu'à 6 béchers ayant un diamètre maximal de 85 mm (MULTISTIRRER 6), ou jusqu'à 15 béchers ayant un diamètre maximal de 64 mm (MULTISTIRRER 15). L'agitateur reste froid, même après jours d'utilisation continue. Cette caractéristique lo rend apprécié en microbiologie et biochimie. La structure en epoxy métal, avec couvercle en acier, est étudié à fournir une excellente résistance à l'attaque d'agents chimiques et à la corrosion. La vitesse d'agitation peut être réglée de 80 à 1500 rpm. La LED indique lorsque l'agitation est en marche.
NOTE: il est important de choisir le barreau magnétique plus approprié lié à la quantité et le liquide à agiter ainsi que le type de bêcher. Pour MULTISTIRRER 6 le barreau magnétique qui satisfait nombreuses applications est A00001056 (6x35mm), pour MULTISTIRRER 15 est A00001057 (6x20mm).
2. Montage et installation
Lors de la réception et après avoir enlevé l'emballage, contrôler que l'instrument est intègre La fourniture comprend:
· MULTISTIRRER Agitateur magnetique
· Câble d'alimentation100-240V/12V
· Fiche UE pour alimentateur
· Manuel d'instructions
2.1 Raccordement au réseau électrique Après avoir ôté l'instrument de son emballage, le positionner correctement sur un banc de laboratoire. Avant de brancher l'instrument au réseau d'alimentation électrique, vérifier que les données de la plaque de l'instrument correspondent aux données disponibles à la prise d'alimentation.
2.2 Mise en marche Positionnez le bouton de réglage de la vitesse sur butée gauche. Disposez le réservoir avec le liquide et le barreau d'agitation magnétique adéquat sur l'emplacement d'installation de l'agitateur. Régler la vitesse d'agitation.
3. Contrôles des opérations
Le bouton placé sur le devant de l'instrument permet de régler de façon rapide la vitesse d'agitation entre 80 et 1500 rpm. Le voyant indique que l'appareil est en opération.
4. Entretien
Aucun entretien ordinaire ou extraordinaire n'est prévu excepté le nettoyage périodique de l'instrument comme décrit dans le présent manuel. Conformément à la loi sur la garantie des produits, les réparations de nos instruments doivent être effectuées dans nos ateliers, sauf accords différents avec les distributeurs locaux. L'instrument doit être transporté dans son emballage d'origine et les indications présentes sur l'emballage d'origine doivent être suivies (par exemple palettisér). Il est de la responsabilité de l'utilisateur de décontaminer correctement l'unité en cas de substances dangereuses restant sur la surface ou à l'intérieur de l'appareil. En cas de doute sur la compatibilité d'un produit de nettoyage ou de décontamination, contactez le fabricant ou le distributeur.
4.1 Nettoyage Le nettoyage de l'instrument doit être effectué après avoir débranché l'appareil, à l'aide un chiffon légèrement imbibé de détergent non inflammable et non agressif.
10
5. Caractéristiques techniques
Puissance Alimentateur externe Dimensions (LxHxP) Poids Ecart de réglage vitesse Volume d'agitation Fonctionnement permis Châssis Température admise - Milieu environnant Température admise - Stockage Humidité admise Degré de Pollution Catégorie de surtension Niveau de bruit Humidité admise Altitude
MULTISTIRRER 6: 12 Vdc 3,6 W MULTISTIRRER 15: 12 Vdc 9 W
0.5 A / 100-240 V / 50-60 Hz (+/-10%)
230x51.5x370 mm
MULTISTIRRER 6: 1,75 kg
MULTISTIRRER 15: 2,1 kg
80 ÷ 1500 rpm
MULTISTIRRER 6: 6x400 ml
MULTISTIRRER 15: 15x250 ml
Continu
Epoxy métal
5 - 40 °C (41 - 104°F)
-10... + 60 °C (14 - 140°F)
80%
2
II
35 dBa
80%
Up to 2000 m.
6. Accessoires / Pièces de rechange
A00001055 A00001057 10000231
Bain de thermorégulation Barreau magnetique 6x20mm Pied
A00001056 10005266 10003081
Barreau magnetique 6x35mm Bouton 24D bleu Alimentation 100-240V / 12V sans prise
11
1. Introducción
ES
MULTISTIRRER es capaz de agitar hasta 6 muestras en vasos con diámetro máximo 85 mm (MULTISTIRRER 6) o hasta 15 en vasos de 64 mm (MULTISTIRRER 15), al mismo tiempo. Se mantiene frío, y puede ser utilizado en continuo, una característica muy apreciada en microbiología y bioquímica. La estructura metálica recubierta con pintura epoxi, con cubierta de acero, ofrece una excelente resistencia a los ataques de agentes químicos y a la corrosión. La velocidad de agitación se puede ajustar (80 - 1500 rpm) utilizando el pomo en el panel frontal. El led muestra cuando la agitación se está ejecutando.
NOTA: es importante elegir la barrita de agitación magnética más adecuada según la cantidad, el líquido que se agita y al tipo de vaso. La barrita de agitación magnética que satisface la mayor parte de la aplicación de el MULTISTIRRER 6 es la A00001056 (6x35mm); para el MUTLRISTIRRER 15 es la A00001057 (6x20mm).
2. Montaje e instalación
l recibir el producto, quitar el embalaje y comprobar la integridad del aparato. El suministro incluye:
· Agitador magnético MULTISTIRRER
· Alimentador 100-240V/12V sin clavija
· Clavija UE para alimentador
· Manual de instrucciones
2.1 Conexión a red eléctrica Colocar el aparato en una superficie plana. Asegúrarse que las características de la placa corresponden y que la toma de corriente cumplia con las normas de seguridad y accesibilidad.
2.2 Encendido Verificar que el pomo de la velocidad es ajustado al mínimo (completamente a la izquierda). Colocar un recipiente no magnético para contener la muestra su el aparato y una barrita magnética. El pomo permite de ajustar la velocidad.
3. Controles de funcionamiento
La agitación comenza torneando el pomo. Se puede seleccionar la velocidad, entre 80 y 1500 rpm. El LED indica que la agitación es activa.
4. Mantenimiento
El mantenimiento ordinario y extraordinario no está previsto excepto para la limpieza periódica del aparato como se describe en este manual. De acuerdo con la ley de garantía del producto, las reparaciones de nuestros aparatos se deben llevar a cabo en nuestras instalaciones, a menos que se acuerde otra cosa con los distribuidores locales. El equipo debe transportarse sólo en su embalaje original y todas las indicaciones presentes en el embalaje original debe seguirse (por ejemplo, paletizado). Es responsabilidad del usuario descontaminar la unidad en el caso de que haya restos de sustancias peligrosas tanto en la superficie como en el interior del equipo. En caso de duda sobre la compatibilidad de los productos a usar para limpieza y/o descontaminacion, contacte con su distribuidor o con fabricante.
4.1 Limpieza La limpieza del aparato debe llevarse a cabo, después de desconectar la alimentación, con un paño húmedo con detergentes no inflamables y no agresivos.
12
5. Características técnicas
Potencia Alimentacion Dimensiones (LxHxP) Peso Ámbito de ajuste velocidad Capacidad de agitación Funcionamiento permitido Estructura Temperatura admitida - Almacenamiento Temperatura admitida - Ambiente Humedad admitida Grado de contaminacion Categoria de sobratension Nivel de ruido Humedad admitida Altitud
MULTISTIRRER 6: 12 Vdc 3,6 W MULTISTIRRER 15: 12 Vdc 9 W
0.5 A / 100-240 V / 50-60 Hz (+/-10%)
230x51.5x370 mm
MULTISTIRRER 6: 1,75 kg
MULTISTIRRER 15: 2,1 kg
80 ÷ 1500 rpm
MULTISTIRRER 6: 6x400 ml
MULTISTIRRER 15: 15x250 ml
Continuo
Metálica recubierta con pintura epoxi
5 - 40 °C (41 - 104°F)
-10... + 60 °C (14 - 140°F)
80%
2
II
35 dBa
80%
Max 2000 m.
6. Accesorios / Refacciones
A00001055 A00001057 10000231
Baño termostato Barrita magnética 6x20mm Pie
A00001056 10005266 10003081
Barrita magnética6x35mm Pomo Fuente de alimentación 100-240V / 12V sin enchufe
13
1. Einführung
DE
MULTISTIRRER 6 kann bis 6 Becher (maximalen Durchmesser von 85 mm) rühren; MULTISTIRRER 15 bis 15 Becher (maximalen Durchmesser von 64 mm). Sehr geschätzt in der Mikrobiologie und der Biochemie. Die Aluminium-Struktur mit Sonderlackierung in Verbindung mit Edelstahlabdeckung lackiert, gewährleisten eine hohe Beständigkeit gegenüber Chemikalien. Der Geschwindigkeitsbereich ist von 80 bis 1500 rpm und kann einstellbar sein durch den Knopf auf der Vorderseite. Die LED leucht, wenn das Rühren läuft.
HINWEIS: es ist wichtig, die richtige Magnetstäbchen bezogen nach der Menge der Flüssigkeit und dem Becherglas. Die häufigste Magnetstäbchen sind A00001056 (6x35mm).
2. Montage und Installation
Bitte überprüfen Sie nach dem Auspacken den einwandfreien Zustand des Gerätes. Im Lieferumfang sind enthalten:
· Magnetrührer MULTISTIRRER
· Netzteil 100-240V/12V ohne Stecker
· EU-Stecker für Netzteil
· Bedienungsanleitung
2.1 Anschluss an das Stromnetz Bitte stellen Sie das Gerät auf einer stabilen, waagerechten Oberfläche auf. Prüfen Sie bitte vor dem Anschluß an das Stromnetz, dass der Netzschalter ausgeschaltet ist und der Drehknopf auf Linksanschlag steht. Dann können Sie das Gerät mit der Anschlußleitung an das Stromnetz anschließen.
2.2 Inbetriebnahme Setzen Sie das Gefäß bzw. den Badaufsatz mit Flüssigkeit und passendem Magnetrührstäbchen auf die Stellfläche des Magnetrührers auf. Für Start und Steuerung der Schüttelbewegung bedienen Sie sich des Drehknopfes.
3. Bedienungselemente
Die gewünschte Drehzahl können Sie mit dem Drehknopf für die Drehzahl gemäß der Skala auf der Frontblende einstellen (80 - 1500 rpm). Wenn die LED leuchtet ist, das Rührwerk eingeschaltet ist.
4. Wartung
Abgesehen von einer regelmäßigen Reinigung gemäß der nachfolgenden Hinweise benötigt das Gerät keine gewöhnliche oder außergewöhnliche Wartung. In Übereinstimmung mit dem Produkthaftungsgesetz müssen Reparatureingriffe an den Geräten in unserem Hause durchgeführt werden, soweit keine anderweitigen Vereinbarungen mit den örtlichen Händlern getroffen werden. Das Gerät muss in der Originalverpackung transportiert werden. Es liegt in der Verantwortung des Benutzers, das Gerät ordnungsgemäß zu dekontaminieren, falls gefährliche Substanzen auf der Oberfläche oder im Inneren des Geräts verbleiben. Wenn Sie Zweifel an der Verträglichkeit eines Reinigungs- oder Dekontaminationsprodukts haben, wenden Sie sich an den Hersteller oder Händler.
4.1 Reinigung Trennen Sie das Gerät zur Reinigung vom Stromnetz und verwenden Sie ein weiches Tuch mit einem sanften, nicht entzündlichen Reiniger.
14
5. Technische merkmale
Leistung Stromversorgungseingang Außenmaße (BxHxT) Gewicht Geschwindigkeitsbereich Rührmenge Betriebsarten Gehäuse Zulässige Temperatur - Betrieb Zulässige Temperatur - Aufbewahrung Zulässige Feuchtigkeit Verschmutzungsgrad Überspannungskategorie Geräuschpegel Zulässige Feuchtigkeit Max. Betriebshöhe
MULTISTIRRER 6: 12 Vdc 3,6 W MULTISTIRRER 15: 12 Vdc 9 W
0.5 A / 100-240 V / 50-60 Hz (+/-10%)
230x51.5x370 mm
MULTISTIRRER 6: 1.75 kg
MULTISTIRRER 15: 2.1 kg
80 ÷ 1500 rpm
MULTISTIRRER 6: 6x400 ml
MULTISTIRRER 15: 15x250 ml
Dauerbetrieb
Epoxy lackiertem Metall
5 - 40 °C
-10... + 60 °C
Max. 80%
2
II
35 dBa
80%
Up to 2000 m.
6. Zubehör / Ersatzteile
A00001055 A00001057 10001372
Temperierung Bad Magnetstäbchen 6x20mm Fuß
A00001056 10005266 10003081
Magnetstäbchen 6x35mm Drehknopf Netzteil 100-240V / 12V ohne Stecker
15
1.
CN
MULTISTIRRER 6 85 MULTISTIRRER 6) 15 64 MULTISTIRRER 15 80-1500rpm
MULTISTIRRER 6 A000010566x35 MULTISTIRRER 15 A000010576x20
2.
: · MULTISTIRRER · · VELP 100-240V/12V ·
2.1 2.2 .
3.
80 1500 / LED
4.
4.1
16
5.
( x x )
6. /
A00001055 A00001057 10000231
6x20mm
MULTISTIRRER 6: 12 Vdc 3,6 W MULTISTIRRER 15: 12 Vdc 9 W
0.5 A / 100-240 V / 50-60 Hz (+/-10%)
230x51.5x370
MULTISTIRRER 6: 1,75 kg
MULTISTIRRER 15: 2,1 kg
80 ÷ 1500 rpm
MULTISTIRRER 6: 6x400 ml
MULTISTIRRER 15: 15x250 ml
5 - 40 °C (41 - 104°F)
-10 - + 60 °C (14 - 140°F)
2
II
35 dBa
80% 2000
A00001056 10005266 10003081
6x35mm 26D 100-240V/12V
17
7. Wiring diagram / Schema elettrico / Schéma électrique / Esquema eléctrico / Schaltplan /
MULTI
1. External power supply / Alimentatore di rete / Alimentateur de réseau / Alimentador de red / Netzteil /
2. Socket of the instrument / Presa strumento / Prise instrument / Toma aparato / Geräteanschlussdose /
3. Electronic board / Scheda elettronica / Fiche électronique / Tarjeta electrónica / Steckkarte / 4. Potentiometer for speed regulation / Potenziometro regolazione velocità / Potentiomètre réglage vitesse /
Potenciómetro ajuste velocidad / Potentiometer zur Geschwindigkeitsregelung / 5. Electric motor (6 or 15) / Motore elettrico (6 o 15) / Moteur électrique (6 ou 15) / Motor eléctrico (6 o 15) /
Elektromotor (6 oder 15) / 6 15
8. Declaration of conformity / Dichiarazione di conformità / Déclaration de conformité / Declaración de conformidad / Konformitätserklärung /
We, the manufacturer VELP Scientifica, under our responsibility declare that the product is manufactured in conformity with the following standards: Noi, casa costruttrice VELP Scientifica, dichiariamo sotto la ns. responsabilità che il prodotto è conforme alle seguenti norme:Nous, VELP Scientifica, déclarons sous notre responsabilité que le produit est conforme aux normes suivantes: Nosotros casa fabricante, VELP Scientifica, declaramos bajo nuestra responsabilidad que el producto es conforme con las siguientes normas: Der Hersteller, VELP Scientifica, erklärt unter eigener Verantwortung, dass das Gerät mit folgenden Normen übereinstimmt: VELP Scientifica
EN 61010-1 EN 61010-2-05
EN 61326-1
2015/863/EU (RoHS III)
2012/19/EU (WEEE)
and satisfies the essential requirements of the following directives: / e soddisfa i requisiti essenziali delle direttive: / et qu'il satisfait les exigences essentielles des directives: / y cumple con los requisitos esenciales de las directivas: / und den Anforderungen folgender Richtlinien entspricht: /
- Machinery directive 2006/42/EC / Macchine 2006/42/EC / Machines 2006/42/EC / Máquinas 2006/42/EC / Maschinen 2006/42/EC / 2006/42/EC - Electromagnetic compatibility directive 2014/30/EU / Compatibilità elettromagnetica 2014/30/EU / Compatibilité électromagnétique 2014/30/EU / Compatibilidad electromagnética 2014/30/EU / Elektromagnetische Verträglichkeit
2014/30/EU / 2014/30/EU
- plus modifications / più modifiche / plus modifications / más sucesivas modificaciones / in der jeweils gültigen Fassung /
18
9. Declaration of conformity
We, the manufacturer VELP Scientifica, under our responsibility declare that the product is manufactured in conformity with the following regulations:
S.I. 2016/1101
Electrical Equipment (Safety) Regulations 2016
S.I. 2016/1091
Electromagnetic Compatibility Regulations 2016
according to the relevant designated standards:
EN 61010-1
Safety requirements for electrical equipment for measurement, control, and laboratory use Part 1: General requirements
EN 61010-2-051 Particular requirements for laboratory equipment for mixing and stirring
EN 61326-1
Electrical equipment for measurement, control and laboratory use - EMC requirements Part 1: General requirements
and satisfies the essential requirements of regulations:
S.I. 2008/1597
Supply of Machinery (Safety) Regulations 2008
S.I. 2012/3032
Restriction of the Use of Certain Hazardous Substances in Electrical and Electronic Equipment Regulations 2012
S.I. 2013/3113
Waste Electrical and Electronic Equipment Regulations 2013
plus modifications.
19
Thank you for having chosen VELP!
Established in 1983, VELP is today one of the world's leading manufacturer of analytical instruments and laboratory equipment that has made an impact on the world-wide market with Italian products renowned for innovation, design and premium connectivity. VELP works according to ISO 9001, ISO14001 and OHSAS 18001 Quality System Certification. Our instruments are manufactured in Italy according to the IEC 1010-1 and CE regulation.
Our product lines:
Analytical instruments Elemental Analyzers Digestion Units Distillation Units Solvent Extractors Fiber Analyzers Dietary Fiber Analyzers Oxidation Stability Reactor Consumables
Grazie per aver scelto VELP!
Fondata nel 1983, VELP è oggi tra i leader mondiali nella produzione di strumenti analitici e apparecchiature da laboratorio grazie ai suoi prodotti italiani rinomati per innovazione, design e connettività. VELP opera secondo le norme della Certificazione del Sistema Qualità ISO 9001, ISO14001 e OHSAS 18001. Tutti i nostri strumenti vengono costruiti in Italia in conformità alle norme internazionali IEC 1010-1 e alle regole della marcatura CE.
Le nostre Linee di prodotti:
Analytical Instruments Analizzatori Elementari Digestori e Mineralizzatori Distillatori Estrattori a Solventi Estrattori di Fibra Estrattori di Fibra Dietetica Reattore di Ossidazione Consumabili
Laboratory Equipment Magnetic Stirrers Heating Magnetic Stirrers Heating Plates Overhead stirrers Vortex mixers Homogenizers COD Thermoreactors BOD and Respirometers Cooled Incubators Flocculators Overhead Shakers Turbidimeter Radiation Detector Open Circulating Baths Pumps
Laboratory Equipment Agitatori Magnetici Agitatori Magnetici Riscaldanti Piastre Riscaldanti Agitatori ad Asta Agitatori Vortex Omogeneizzatori Termoreattori COD BOD e Analizzatori Respirometrici Frigotermostati e Incubatori Flocculatori Mescolatore Rotativo Torbidimetro Rilevatore di Radiazioni Bagni Termostatici Pompe
www.velp.com
VELP Scientifica Srl 20865 Usmate (MB) ITALY Via Stazione, 16 Tel. +39 039 62 88 11 Fax. +39 039 62 88 120
Distributed by:
20
We respect the environment by printing our manuals on recycled paper. Rispettiamo l'ambiente stampando i nostri manuali su carta riciclata.
10003556/B2
References
Velp Scientifica, Analytical Instruments, Elemental Analyzers, Digestion Units, Distillation Units, Solvent Extractors, Fiber Analyzers, Dietary Fiber Analyzers, Oxidation Stability Reactor, Consumables Laboratory Equipment, Magnetic Stirrers, Heating Magn
Microsoft Word 2019 | https://manuals.plus/m/92136cfe152a654b3a6a2074e2dffccd3a73bea72de94db855968d585cdb64ae_pdf |
PCSK9 Inhibitors: A Revolution in Lipid Lowering Therapy - Breaking Down Barriers to Access - American College of Cardiology
PCSK9 Inhibitors: A Revolution in Lipid Lowering Therapy - Breaking Down Barriers to Access
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the ninth and final member of a class of pro-proteins. Mapped to the short arm of chromosome 1 in 2003 by Abifadel, this pro-protein is unique among its class. Though like others from this group it is released from the hepatocyte as a zymogen and requires auto cleavage to endow it with activity, it differs insofar as its prosegment subsequently binds to the molecule's enzymatic site. Thus, in its active form PCSK9 is strictly a binding protein. It plays no role in catalysis. And it is in its binding that PCSK9 plays a dominant part in LDL metabolism.
PCSK9 binds almost exclusively to the LDL receptors (LDLR) residing in clatharin coated pits on hepatocytes. Its role in LDL metabolism is fascinating and consequential. When bound to an LDLR, PCSK9 leads to the intracellular destruction of the LDLR along with the receptor's intended cargo, an LDL particle. As the LDLR is intended to make approximately 150 trips in and out of the hepatocyte, bringing 150 LDL particles to their demise, cutting short the lifespan of the LDLr leads to a dramatic rise in circulating LDL-C levels.
Our growing understanding of LDL-C has created a shift from the 'LDL Hypothesis' to the 'LDL Truth.' Higher LDL-C levels do cause more heart attacks, strokes, and death while lower LDL-C levels cause the opposite effect. Numerous lines of evidence, such as multiple confirmatory Randomized Controlled Trials (RCT) and Mendelian Randomization Studies (MR), have proved this to be true. Consequently, Abifadel's discovery catalyzed a surge of research to create a therapeutic solution which would lower PCSK9 levels, lower LDL-C, and concomitantly presumably lower cardiovascular events.
In 2007, scientists from Pfizer and Amgen independently published PCSK9's crystal structure; in 2010, Regeneron/Sanofi and Amgen began human clinical trials with fully human monoclonal antibodies (mAb) to PCSK9, and in 2015 alirocumab and evolocumab were approved by the FDA. These drugs rapidly bind all circulating PCSK9, essentially removing PCSK9 from involvement in LDL metabolism and thereby intensively and predictably lowering LDL-C levels in the blood. Disturbingly, their approval was not met with the celebratory response one might have anticipated. Instead, battles have ruled the day.
Even before their FDA approval, organizations such as the Institute for Clinical and Economic Review (ICER) and papers in powerful journals such as the Journal of the American Medical Associationprojected that these novel and costly fully human monoclonal antibodies would bankrupt our healthcare system. 1,2They projected a 1.2-billion-dollar cost in the first year following their release. Insurance companies were proactive. They armed themselves with complex prior authorization (PA) requirements, burdensome step therapy demands, and approval processes that have been shown to be capricious. As a result, the PCSK9 mAb cost to our nation was a mere 83 million dollars in year one, about 1.2% of predicted. Translation: far fewer people received these FDA approved medications than had been predicted, and, accordingly, far fewer people were better protected against cardiovascular events. The last two years represent an unfortunate time in modern medicine. Doctors possess a long-awaited superb, novel therapeutic; yet, they are unable to appropriately provide it to their patients.
Some of the evidence demonstrating illogical payer processes stem from two posters and one paper. 3-5These data reveal that regardless of statin therapy, the use of ezetimibe, or even dual anti-platelet therapy--prescriptions that are pathognomonic for clinical ASCVD--approval rates are unaffected. Additionally, final approval rates are abysmally low, 30.5% in commercial insurance and 58% in Medicare recipients. Higher approval rates and shorter times to approval in Medicare beneficiaries implies an impact from Federal oversight, and a high level of reversals from 'denied' to 'approved' implies improper adjudication. Knowles et al. demonstrated similar findings of frequent PCSK9i denials in high risk, 'appropriate' patients. One of the most egregious discoveries was in those with familial hypercholesterolemia (FH) and extremely high LDL-C. Of the 237 presumptive FH patients who had an LDL-C value >190 mg/dL despite evidence of statin-based LLT, 63% of prescriptions for PCSK9 inhibitors were rejected. In comparison, 9% of prescriptions for ezetimibe were rejected in a similar patient population.
Looking closer at who bears the brunt of insurance restrictions, one need search no further than the drugs' package inserts (PI). These medications have been FDA approved for patients with FH (a common high-ASCVD-risk monogenic LDL disorder occurring in 1/250 individuals worldwide) or clinical ASCVD on maximally tolerated statin therapy yet requiring greater LDL reduction. Parsing the PI, five definitions require clarification: FH (both heterozygous and homozygous), clinical ASCVD, maximally tolerated statin therapy, and requiring greater reduction in LDL-C.
To elucidate these definitions and ease the burden on patients, clinicians, and yes, even payers, the American Society for Preventive Cardiology (ASPC) convened a group of experts from various organizations – the FH Foundation, American Association of Clinical Endocrinologists, the National Lipid Association, and the American College of Cardiology. Multiple Town Halls provided an opportunity to understand the nuances of PCSK9 mAb access issues and find solutions to these problems. Ultimately the group's findings and recommendations were published in Clinical Cardiology, the official journal of the ASPC. 6
An example of one such definition is: "Maximally tolerated statin therapy is defined as the highest tolerated intensity and frequency of a statin, even if the dose is zero..." The document also contains single page PA and Appeal letters. The letters and their five consensus definitions have been constructed to simplify and thereby improve access to these drugs. I highly recommend utilizing the paper and its two attachments as a resource when prescribing this class of medication. To date, they have helped numerous clinicians obtain these medications for suitable patients.
Finally, FOURIER (Further Cardiovascular Outcomes Research With PCSK0 Inhibition in Subjects With Elevated Risk) recently shed light on the efficacy of evolocumab, and by extension the potential impact of inappropriate PCSK9i denials. 7FOURIER evaluated 27,564 individuals with prior ASCVD, comparing evolocumab to placebo. A 59% LDL-C reduction with evolocumab resulted in a 20% decrease in MI, CVA, or CV death in the 2-year trial. Through a landmark analysis, a 25% reduction in these endpoints was found in year two. Such results are comparable to what was anticipated from the findings in the Cholesterol Treatment Trialists' Collaboration (CTTC). Thus, FOURIER demonstrated what many lipidologists had anticipated, a proportionate reduction in cardiovascular events in line with a given reduction in LDL-C.
In sum, three points should be emphasized. First, LDL-C is causally related to ASCVD. Higher LDL-C levels cause more events, and diminishing LDL-C reduces such events. Second, FOURIER proved that evolocumab, a PCSK9i, on top of maximally tolerated statin therapy statistically significantly lowers the combined risk of heart attack, stroke and CV death. And finally, clinicians must often advocate on behalf of their patients to gain access to the PCSK9 mAb. Using the Clinical Cardiologypaper previously cited can help us accomplish this, and in so doing, help us to help our patients.
PCSK9 Inhibitors: A Revolution in Lipid Lowering Therapy: Breaking Down Barriers to Access PCSK9, an integral aspect of LDL-C metabolism. PCSK9 inhibitors: intensive and predictable therapies to lower LDL-C. PCSK9 inhibitors: fully human monoclonal antibodies to PCSK9. PCSK9 inhibitors are costly and extreme barriers have been erected to limit their use. FDA indications for PCSK9 inhibitors are clear and can be understood by reading http://onlinelibrary.wiley.com/doi/10.1002/clc.22713/pdf . Download the prior authorization and appeals letters from above-cited paper to gain access for appropriate patients.
References
ICER draft report on effectiveness, value, and pricing benchmarks for PCSK9 inhibitors for high cholesterol posted for public comment. Institute for Clinical and Economic Review website. https://icerreview.org/announcements/pcsk9-draft-report-release . Accessed 15 March 2017.
Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA 2016;316:743-53.
Baum SJ, Chen C, Rane PB. Time to approval in patients requesting access to PCSK9i therapy by payer type. Presented at AMCP 2017.
Baum S, Chen C, Rane PB. Characteristics of patients approved and denied access to PCSK9i Therapy by Payers. Presented at American College of Cardiology Scientific Sessions 2017.
Knowles JW, Howard WB, Karayan L, et al. Access to non-statin lipid lowering therapies in patients at high-risk of atherosclerotic cardiovascular disease. Circulation 2017;135:2204-6.
Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
Keywords: Hyperlipoproteinemia Type II, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Blood Platelets, Chromosomes, Human, Pair 1, Antibodies, Monoclonal, Receptors, LDL, Nerve Tissue Proteins, Transcription Factors, Drosophila Proteins, Cholesterol, Stroke, Proprotein Convertases, Myocardial Infarction, Enzyme Precursors, Hepatocytes, Lipids, Catalysis, Subtilisins, Dyslipidemias
| https://www.acc.org/latest-in-cardiology/articles/2017/07/20/13/30/pcsk9-inhibitors-a-revolution-in-lipid-lowering-therapy?w_nav=LC%3Fpage=4%2C0 |
In-Gauge and En-Gage: Understanding Occupants' Behaviour, Engagement, Emotion, and Comfort Indoors with Heterogeneous Sensors and Wearables v1.0.0
The project aims to understand occupants’ behaviour, engagement, emotion, and comfort indoors with heterogeneous sensors and wearables.
In-Gauge and En-Gage: Understanding Occupants' Behaviour, Engagement, Emotion, and Comfort Indoors with Heterogeneous Sensors and Wearables
Nan Gao, Max Marschall, Jane Burry, Simon Watkins, Flora Salim
Published: Feb. 13, 2023. Version:
1.0.0
When using this resource, please cite:(show more options) Gao, N., Marschall, M., Burry, J., Watkins, S., & Salim, F. (2023). In-Gauge and En-Gage: Understanding Occupants' Behaviour, Engagement, Emotion, and Comfort Indoors with Heterogeneous Sensors and Wearables (version 1.0.0). PhysioNet.https://doi.org/10.13026/srm3-7z33.
Additionally, please cite the original publication:
Gao, N., Marschall, M., Burry, J. et al. Understanding occupants’ behaviour, engagement, emotion, and comfort indoors with heterogeneous sensors and wearables. Sci Data 9, 261 (2022). https://doi.org/10.1038/s41597-022-01347-w
Please include the standard citation for PhysioNet:(show more options) Goldberger, A., Amaral, L., Glass, L., Hausdorff, J., Ivanov, P. C., Mark, R., ... & Stanley, H. E. (2000). PhysioBank, PhysioToolkit, and PhysioNet: Components of a new research resource for complex physiologic signals. Circulation [Online]. 101 (23), pp. e215–e220.
Abstract
We conducted a field study at a K-12 private school in the suburbs of Melbourne, Australia. The datasets contained two elements: (1) In-Gauge dataset: we conducted a 5-month longitudinal field study using two outdoor weather stations, as well asindoor weather stationsin 17 classrooms andtemperature sensorson the vents of occupant-controlled room air-conditioners; these were collated into individual datasets for each classroom at a 5-minute logging frequency, including additional data on occupant presence. (2) En-Gage dataset: we tracked 23 students and 6 teachers in a 4-week cross-sectional study En-Gage, using wearable sensors to log physiological data(electrodermal activity,heart rate,blood column pulse,skin temperature,3-axis acceleration), as well as daily surveys to query the occupants'thermal comfort,learning engagement,emotionsandseating behaviours. Overall, the combined dataset could be used to analyse the relationships between indoor/outdoor climates and students' behaviours/mental states on campus, which provide opportunities for the future design of intelligent feedback systems to benefit both students and staff.
Background
How can indoor spaces be designed in ways that increase occupant well-being while decreasing energy consumption? Answering this question requires a holistic understanding of indoor climates, occupant comfort and behaviour, as well as the dynamic relationships between these different aspects. The present study sits within a context of research that aims to gain insights by examining these themes using mixed methods of data capture within operational buildings. More specifically, the study contains two separate assays, each relating to a distinct body of existing research.
The first assay is a 5-month longitudinal field study using outdoor and indoor weather stations as well as sensors to determine the use of occupant-controlled room air-conditioners. This assay was undertaken to contribute knowledge to the research field of occupant behaviour modelling in building performance simulation. During the design of buildings, engineers often use simulations to predict the indoor environmental quality and energy consumption of design options in order to inform decision-making. There are often large discrepancies between simulated and actual building performance[1].
The second assay is a four-week study tracking 23 students and six teachers, using wearable sensors to log physiological data as well as self-report from participants at school. Studying student engagement, emotions, and daily behaviours has attracted increasing interest to address problems such as low academic performance and disaffection. Sensor-based physiological and behaviour recordings provide great opportunities to unobtrusively measure students' behaviours and emotional changes in classroom settings. In previous studies, various physiological signals, such as electrodermal activity (EDA) and heart rate variability (HRV), and environmental data have been explored to assess emotional arousal[2]and engagement levels[3]. Existing datasets in affective computing either provide limited scope for understanding emotion responses in real-world settings or only consider a particular type of annotation to meet their research goals (e.g., stress level and mental workload).
Methods
For the In-Gauge dataset, the longitudinal study was conducted for a 5.5-month period from the end of 2019 to early 2020, using the indoor and outdoor weather stations as well as temperature sensors attached to air-conditioning outlets.
For the En-Gage dataset, we used wearable sensors (i.e.,Empatica E4 wristbands) as well as the same weather stations in the first longitudinal study. The two studies are located on the same campus, and the timelines of the two studies were partly overlapped. As a result, the collected data (i.e., weather information and occupant behaviours) in the longitudinal study can benefit the cross-sectional study or vice versa.
In the study, we tracked participants using Empatica E4 wristbands to measure physiological data, as well as daily surveys to query their thermal comfort, learning engagement and emotions while at school. Overall, we have collected 488 survey responses and 1415.56 hours of wearable data from all participants. During the data collection, one representative student was selected in each of the three Form classes. Their job was to distribute wristband sensors each morning, collect them after school and remind participants to complete the online surveys at the appropriate times. We anonymised the student's data by assigning each student an identity number (ID). Occupancy schedules were obtained from the individual classroom schedules provided by the school. These schedules can be used to represent the actual occupancy patterns of the building, although slight deviations from the planned schedule are to be expected in a school setting due to sickness and other circumstances.
Removal of Protected Health Information (PHI). We have de-identified the dates in the released data, and only kept the index of the week, weekday, day of the data collection, and time of the day. Specifically, we renamed the subfolders under the Raw_wearable_data folderusing the index of week/weekday to indicate different days. We have also removed the date information in the survey responses, class tables and longitudinal data.
Data Description
The data contains wearable sensor data (electrodermal activity,heart rate,blood volume pulse,skin temperature,3-axisacceleration data), environmental data and self-report data (student engagement,emotion,thermal comfort,seating behaviours) collected from a field study in a K-12 high school.
The In-Gauge dataset consists of comma-separated variable (CSV) files - one for each classroom. Each classroom's spreadsheet contains time-related information and outdoor weather conditions (these are obviously identical for all classrooms). Furthermore, each classroom has information on its own indoor climate, whether or not it is occupied according to the class schedule, and information on whether its room air-conditioner is in heating or cooling mode.
For the En-Gage dataset, we have provided two versions: the original raw data by week/weekday and organised data based on the different class groups of the participants. The En-Gage dataset includes physiological signals measured using the Empatica E4 as well as self-reported data from the student and teacher participants.
Overall, the Longitudinal folder refers to the In-Gauge dataset and the other folders refer to the En-Gage datasets. Some useful notes for both datasets are provided below:
Longitudinal foldercontains all data pertaining to the longitudinal field study. It consists of 16 CSV files (one for each classroom). The CSV file names correspond to the classroom names. Each CSV file has a single header line and each of the following rows contains the following timestamped data at a resolution of 5 minutes per row.
Participant_class_info foldercontains demographic information on the background questionnaires and th e class schedule. Note that for several survey questions, we adopted the 5-point Likert scale: -2 = 'strongly disagree', -1 = 'somewhat disagree', 0 = 'neither agree nor disagree', 1 = 'somewhat agree' and 2 = 'strongly agree'.
Survey foldercontains 2 files: Student_survey.csv and Teacher_survey.csv. Student_survey.csv contains the 488 survey responses from student participants and Teacher_survey.csv contains 22 survey responses by teachers.
Raw_wearable_data folderincludes 20 sub-folders named with the index of week and weekday (e.g., 'Week1_4' indicates Thursday on Week 1), containing the raw wearable data for each day during the 4-week data collection. In each sub-folder, there are multiple sessions from different participants. Some participants provided more than 1 session on the same day. The name of each session consists of two parts connected by an underscore: a random string and the participant ID. For example, the session named 'kgarvl_17' indicates the data is provided by participant 17. There are 6 CSV files in each session, and each of these (except IBI.csv) records the time and the sample rate expressed in Hz. It is worth noting that all the timestamps were removed except the time of the day.
Class_wearable_data foldercontains 221 sub-folders representing 221 different classes during which the wearable data were recorded. Each sub-folder is named by the unique 'Class_id' as shown in the Class_table.csv. Each sub-folder includes further sub-folders named by the unique participant id or simply the label 'teacher'. These contain data from the wristband sensors for each participant in this class. There are 6 CSV files in each sub-folder: ACC.csv, EDA.csv, BVP.csv, HR.csv, IBI.csv, and TEMP.csv. The format of these files is identical to the ones in the Raw_wearable_data folder.
Usage Notes
Our datasets include the outdoor/indoor/wearable sensing data and the self-report occupants’ thermal comfort, learning engagement, and emotions while at school. This dataset is the first publicly available dataset for studying the daily behaviours and engagement of high school students using heterogeneous sensing. For the longitudinal outdoor and indoor sensing data, the most straightforward potential usage is to derive predictive models of how occupants operate room air-conditioning units. Our dataset could potentially be useful to examine the relationships between indoor/outdoor climates and physiological signals of occupants, which provide opportunities for the future design of intelligent feedback systems to benefit both students and staff on campus.
Specifically, various data mining (e.g., segmentation, clustering) and modelling techniques could be explored to build prediction models for measuring occupants' mental states using sensor-based physiological and behavioural recordings in buildings. This could be further used for various applications in future studies: (1) Monitoring signs of disengagement and negative emotions of students. Measuring the study engagement and emotions of students is beneficial to both teachers and students. Teachers will be able to improve their teaching strategies to create the right learning environment, improve the learning experience for students and re-engage students with low engagement. Students will be able to self-track their learning engagement and emotions, which could promote their self-regulation and reflective learning. (2) Studying peer effects in educational settings. It could be helpful to explore group-wise seating behaviours and their relationship to perceived engagement and physiological synchrony. (3) Providing comfortable indoor environments for occupants. It is possible to mitigate the negative effects of hot weather on student learning by using air conditioning, and teachers could ventilate classrooms timely to prevent excess carbon dioxide from affecting students' concentration.
Release Notes
Initial release version 1.0.0 of the dataset.
The detailed data descriptor of In-Gauge and En-Gage can be found in Scientific Data[7]. The dataset has been used in publications to predict student engagement in classes[3], analyse the classroom seating experience[6]and investigate the reliability of self-report surveys[4]. Compared to previous versions[5], the current release has added information related to the week, weekday, and day of the data collection.
Ethics
The data collection was approved by the Science, Engineering and Health College Human Ethics Advisory Network (SEH CHEAN) of RMIT University. The project was also approved by the principal of the school in which the study was conducted. Written informed consent was obtained from participants and guardians of minors prior to data collection.
Acknowledgements
This research is supported by the Australian Government through the Australian Research Council's Linkage Projects funding scheme (project LP150100246 in partnership with Aurecon). This paper is also a contribution to the IEA EBC Annex 79.
Conflicts of Interest
We declare no conflicts of interest.
References
Haldi, F., & Robinson, D. (2011). The Impact of Occupants' Behaviour on Building Energy Demand. Journal of Building Performance Simulation, 4(4), 323-338.
Di Lascio, E., Gashi, S., & Santini, S. (2018). Unobtrusive assessment of students' emotional engagement during lectures using electrodermal activity sensors. Proceedings of the ACM on Interactive, Mobile, Wearable and Ubiquitous Technologies, 2(3), 1-21.
Gao, N., Shao, W., Rahaman, M. S., & Salim, F. D. (2020). n-Gage: Predicting in-class Emotional, Behavioural and Cognitive Engagement in the Wild. Proceedings of the ACM on Interactive, Mobile, Wearable and Ubiquitous Technologies, 4(3), 1-26.
Gao, N., Saiedur Rahaman, M., Shao, W., & Salim, F. D. (2021, September). Investigating the Reliability of Self-report Data in the Wild: The Quest for Ground Truth. In Adjunct Proceedings of the 2021 ACM International Joint Conference on Pervasive and Ubiquitous Computing and Proceedings of the 2021 ACM International Symposium on Wearable Computers (pp. 237-242).
Gao, N., Marschall, M., Burry, J., Watkins, S., & Salim, F. (2021). In-Gauge and En-Gage Datasets. Figshare.
Gao, N., Rahaman, M. S., Shao, W., Ji, K., & Salim, F. D. (2022). Individual and Group-wise Classroom Seating Experience: Effects on Student Engagement in Different Courses. arXiv preprint arXiv:2112.12342.
Gao, N., Marschall, M., Burry, J. et al. Understanding Occupants’ Behaviour, Engagement, Emotion, and Comfort Indoors with Heterogeneous Sensors and Wearables. Sci Data 9, 261 (2022). https://doi.org/10.1038/s41597-022-01347-w. Accessed on 9/6/2022.
Access
Access Policy:Anyone can access the files, as long as they conform to the terms of the specified license.
License (for files):Open Data Commons Attribution License v1.0
Discovery
DOI:https://doi.org/10.13026/srm3-7z33
Topics: heart rate electrodermal activity environmental sensing thermal comfort modelling physiological signals occupant behaviour sensing emotion sensing human behavoural modelling smart building
Project Website:https://www.nature.com/articles/s41597-022-01347-w
Corresponding Author
Files
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Download the ZIP file(5.1 GB)
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wget -r -N -c -np https://physionet.org/files/in-gauge-and-en-gage/1.0.0/
Folder Navigation: <base> / class_wearable_data / 164 / 14
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ACC.csv (download) 2.4 MB 2022-08-24
BVP.csv (download) 3.4 MB 2022-08-24
EDA.csv (download) 227.4 KB 2022-08-24
HR.csv (download) 37.3 KB 2022-08-24
IBI.csv (download) 3.1 KB 2022-08-24
TEMP.csv (download) 199.2 KB 2022-08-24
| https://www.physionet.org/content/in-gauge-and-en-gage/1.0.0/class_wearable_data/164/14/ |
amazing Apiaceae (the umbellifers) | North American Rock Garden Society
amazing Apiaceae (the umbellifers)
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NARGS member Tim Ingram mentioned his interest in Lomatium, a North American genus of umbellifers.See:http://nargs.org/smf/index.php?topic=662.0;topicseen
The plant family Apiaceae is huge, with 347 plant genera, with many species of interest for rock gardens, so let me start up this topic with links to another North American genus, Cymopterus.
I share an enthusiasm for rock-garden-sized Apiaceae, and have long admired both Lomatium and Cymopteris when I've seen them both in photos and during my Western American travels years ago... some are truly superb. Here are some selected links to photos of Western American species of Cymopterus.
fruiting heads on Cymopterus cinerariushttp://calphotos.berkeley.edu/cgi/img_query?enlarge=0000+0000+0908+0697flowering Cymopterus cinerarius, fantastic foliagehttp://calphotos.berkeley.edu/cgi/img_query?enlarge=0000+0000+0908+0696 Cymopterus gilmaniihttp://calphotos.berkeley.edu/cgi/img_query?enlarge=0000+0000+1210+1537
Cymopteris globosushttp://calphotos.berkeley.edu/cgi/img_query?enlarge=0000+0000+0306+0913 Cymopterus multinervatushttp://calphotos.berkeley.edu/cgi/img_query?enlarge=0000+0000+1004+0875
Some Apiaceae that I've seen photos of, in places such as Kazakhstan, and in New Zealand and Australia, show these are fantastic foliage plants, with strangely beautiful flowers.
Comments
Re: amazing Apiaceae (the umbellifers)
Really remarkable plants, Mark! I didn't know such treasures existed. Now you have given me a problem - shall I ignore them or look out for seed?! And I have several years to retirement. . . .
Re: amazing Apiaceae (the umbellifers)
I was very pleased to see seedlings of Cymopterus --I think its planosus, but would have to check--they were sown in spring last year, early enough for some cold strat, but maybe not enough-- I got one seedling, which I think didn't survive, so I thought that seed was done for, and didn't even put the pot with others that were overwintering outside.. well, there are at least several coming up now :)
Re: amazing Apiaceae (the umbellifers)
I have encountered Cymopterus globosus in it's native haunts. The flowers have rather thick petals very densly packed. The immature fruiting bodies feel like dense, bumpy rubber balls.
Re: amazing Apiaceae (the umbellifers)
John, what do you call such a plant? Showy? Beautiful? Spectacular? Anyway it is a remarkable plant :)
Re: amazing Apiaceae (the umbellifers)
My interest in these plants is being rapidly reignited. Thanks for the images and websites. I have also grown Shoshonea in the past, but didn't look after it well enough. There are some wonderful Mediterranean species adapted to similar but not so winter cold conditions - Athamanta turbith is probably my favourite. Another, Thapsia maxima, has large broad pleated leaves and a football size head of yellow flowers only to about a metre high. It is an extraordinary and fascinating family once you get into it!
Re: amazing Apiaceae (the umbellifers)
Weiser wrote:
I have encountered Cymopterus globosus in it's native haunts. The flowers have rather thick petals very densly packed. The immature fruiting bodies feel like dense, bumpy rubber balls.
seriously cool, and at a glance, un-Apiaceae looking!
Tim, agreed, very cool family :)There is another I've been looking at, I think a Lomatium, which is a metre or so tall, plus Anthriscus and others, and I have Heracleum growing naturally here--so they do have lots of appeal/potential besides the regular rock garden :)
Re: amazing Apiaceae (the umbellifers)
Hoy wrote:
John, what do you call such a plant? Showy? Beautiful? Spectacular? Anyway it is a remarkable plant :)
Strangely, remarkably, cool??? Comes to mind.
Re: amazing Apiaceae (the umbellifers)
Tim wrote:
My interest in these plants is being rapidly reignited. Thanks for the images and websites. I have also grown Shoshonea in the past, but didn't look after it well enough. There are some wonderful Mediterranean species adapted to similar but not so winter cold conditions - Athamanta turbith is probably my favourite. !
Fascinating plants being shown!I can verify that Athamanta turbith ssp. haynaldiiis reliably hardy in this zone 3 area, even without snow cover. I believe Rick grows it in zone 4(?) too. Shoshonea pulvinatawintered over last year here in a trough... no real record yet, but so far, so good!
Re: amazing Apiaceae (the umbellifers)
I currently only grow only two Lomatiums but there are many around. I like the short matted types with gray leaves.Lomatium austiniae (syn. L. plummerae)Lomatium nevadense var nevadense. The flowers always look like they have been peppered. It's the dark purple staymens that give this effect.
Re: amazing Apiaceae (the umbellifers)
Weiser wrote:
I currently only grow only two Lomatiums but there are many around. I like the short matted types with gray leaves.Lomatium austiniae (syn. L. plummerae)
Lomatium nevadense var nevadense. The flowers always look like they have been peppered. It's the dark purple staymens that give this effect.
Both cool!
Re: amazing Apiaceae (the umbellifers)
A few umbels flowering in our garden at the moment. Athamanta turbith grows on a raised bed along with Lomatium columbianum, and still stands as my favourite of the family in the garden. I think of it as like a symphony of green and white; simple but very beautiful. Later the small seeds are silvery-grey and attractive in themselves. I was introduced to it at the Chelsea Physic Garden in London, where I often went to sell plants.
The second, Laserpitium siler, came on the recommendation of a Landscape Architect friend from Belgium, who used it in his planting schemes. It is a tough plant, used to the severe cold of northern and central Europe, slow to establish but very perennial, and with rather distinctive open heads of flowers and greyish foliage.
Thirdly, probably one of the best plant introductions of recent years, Anthriscussylvestris'Ravenswing', the black-leaved cow parsley (or Queen Anne's Lace). This self-sows under the apple trees with others such as Aquilegias and Brunnera, and they make a fine picture at the moment, even in one of the driest springs we have had for years.
Re: amazing Apiaceae (the umbellifers)
All nice, the last combination especially :)I have some Raven's Wing seedlings, looking forward to seeing them grow up :) You don't find the Brunnera too vigorous in its selfsowing? a gardener in Manitoba was recently telling a tale of woe regarding all-green leafed seedlings of an expired B 'Jack Frost'....
Re: amazing Apiaceae (the umbellifers)
Amazing scenes, Tim! You have a fabulous garden! :o
Mmmm, Lomatium- another genus to try! Thanks for opening our eyes to that one, John!
Cohan, Brunnera macrophyllaself sows in moderation here... enough to start giving some seedlings away after a few years. It's hard to imagine that anyone would find its relatively modest habit excessive though (if I'm interpreting your comment correctly), in comparison to the truly rampant seeding of so many other species!
Re: amazing Apiaceae (the umbellifers)
Skulski wrote:
Cohan, Brunnera macrophyllaself sows in moderation here... enough to start giving some seedlings away after a few years. It's hard to imagine that anyone would find its relatively modest habit excessive though (if I'm interpreting your comment correctly), in comparison to the truly rampant seeding of so many other species!
Good to know, Lori, I haven't grown them, but sort of admired some of the variegated types, at least;-- the person in Manitoba was giving a warning (coldzone yahoo group, mostly western Canadian members) that this plant must be deadheaded ifyou were going to grow it at all, or planted by itself far from anything else! I think part of the problem was that the variegated parent died, leaving only green seedlings, and they were coming up in the middle of some more valued plants...lol
Re: amazing Apiaceae (the umbellifers)
Well, that seems like a veryextreme view, based on what I've seen, and on never having heard a similar complaint. ???
Re: amazing Apiaceae (the umbellifers)
That's good, Lori, since I was kind of thinking about it--if I run across a cheap plant somewhere..lol
Re: amazing Apiaceae (the umbellifers)
Off topic but...Cohan, if you ever have a reason to visit Calgary, you should let me know in advance... Having a mature perennial garden (that is in a constant state of flux due to needing more alpine beds!), I have many plants that I'd be happy to share! I tend not to divide many things, but I have lots of seedlings, offsets, etc., often blooming-size plants, that I pot up to give away.
Re: amazing Apiaceae (the umbellifers)
Thanks, Lori, I'll let you know if we are going that way and my driver is amenable to a stop...lol
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Re. Brunnera. With me this self-sows hugely and seems to grow as well in full sun as shade. Because I have so many seedlings I have decided to use it as ground cover under our rows of fruit trees - but we have a big garden of around 1 and 1/2 acres.
I neglected to say that Anthriscussylvestris'Ravenswing' was discovered and introduced by Prof. John Richards of Primula fame. If a nurseryman had found it they could have made a fortune!
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Well, live and learn! :)
Here's Shoshonea pulvinatain a trough, wintered over from last year - a tiny thing at present. I've only seen it in photos... I expect the flower stems will elongate, unless this is some particularly dwarfish form?? I got it from Beaver Creek, at last year's CRAGS spring plant sale.
Re: amazing Apiaceae (the umbellifers)
Skulski wrote:
Well, live and learn! :)
Here's Shoshonea pulvinatain a trough, wintered over from last year - a tiny thing at present. I've only seen it in photos... I expect the flower stems will elongate, unless this is some particularly dwarfish form?? I got it from Beaver Creek, at last year's CRAGS spring plant sale.
Cute!
Re: amazing Apiaceae (the umbellifers)
Skulski wrote:
Well, live and learn! :)
Here's Shoshonea pulvinatain a trough, wintered over from last year - a tiny thing at present. I've only seen it in photos... I expect the flower stems will elongate, unless this is some particularly dwarfish form?? I got it from Beaver Creek, at last year's CRAGS spring plant sale.
I would hardly guessed that this is a Apiaceae!
Here Brunnera makes runners and selfsow but not much.
Re: amazing Apiaceae (the umbellifers)
A selection of my umbellifers:
1. Lomatium nudicaule: of the 10 or so I’ve tried, 5 have survived and this is the easiest and the only one to have flowered and seeded itself.2). L. californicum (survived one winter and then died in the subsequent more severe winter)3-6. I’m not sure which 2 species these are, but they’ve proven reliably hardy here having survived 4 or 5 winters. Just contrast the leaves of these with nudicaule … The possibilities are L.dissectum, utriculatum and triternatum (there are two pictures of each). Any suggestions?7. Lovage, Levisticum officinale is one of the grandest umbellifers and looks particularly smart when blanched in springtime (it then doesn’t taste unlike celery and much milder than unblanched)8. Laser trilobum (I also grow Laserpitium siler and latifolium, all 3 reliably hardy here, down to about -23C)9. Angelica keiskei – surprised me to see that the sap is yellow!10. Angelicasylvestris“Vicar’s Mead” is also a nice foliage plant (like the Anthriscus) – here with Trillium camtschacensis and Hylomecon japonicum
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Very nice, Stephen. Ahh, I was thinking about what to plant in a big area where we removed a huge old lilac last fall... Angelicawould be suitably statuesque! Lots of great ideas in your photos... lovage is worth growing for its appearance alone (aside from using the leaves for flavouring) - I should get myself another one.Here are a couple more fairly interesting umbellifers:
Peucedanum ostruthium'Daphnis' - I don't have many variegated plants but I am fond of this one (though, strangely, I have few good photos of it):
Pleurospermum szechenyii:http://www.efloras.org/florataxon.aspx?flora_id=2&taxon_id=200015840
Re: amazing Apiaceae (the umbellifers)
Lori, does the Pleurospermum remain that colour, or is that just spring foliage?
Some of these remind of several local umbellifers I am fond of, I'll have to dig up pictures--such as the very charming, subtle Sweet Cicely (blunt-fruited; Osmorhiza depauperata) which is common in the woods here.. I sent seed to Stephen, hopefully he gets some babies :)
Re: amazing Apiaceae (the umbellifers)
cohan wrote:
Lori, does the Pleurospermum remain that colour, or is that just spring foliage?
It's actually dark purple throughout the season.
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Lori: I've overwintered Peucedanum ostruthium 'Daphnis' (nice pictures) for the first time this year! Nice Pleurospermum too!
Cohan: I wonder what happened to the Osmorhiza you sent me (it was in the fall wasn't it?). I haven't noticed them germinating (my pots are in a bit of disarray as a cat got into my cold frame with winter stratified seeds and labels were everywhere... I have otherwise Osmorhiza longistylis (picture) and O. claytonii:
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Lori--then wow!
Stephen, it may have been mid-winter when I sent the seed, though I'm not sure, I might have a pm record of it.. if it does not appear eventually, let me know, I can get more seed this year...
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Great to see those various umbels. Stephen you have had better success with Lomatiums than me - I have grown nudicaule and californicum and a few others but had them on a gritty raised bed that may have been too dry and well drained, they never really got going well. I used to sell a few Laser trilobum on the nursery which shows there are gardeners who have a fascination with these plants - you could hardly call it showy. Lori's photo of Shoshonea is nice; this is definitely a plant I will try again - it is reminiscent of Olymposciadumcaespitosum, which still grows on my raised bed and on the shady side of this, in deep grit, I have at last succeeded in getting Bolaxgummiferato grow (this is a wonderful cushion plant often seen at the Shows and which I must have tried three or four times to date - its relative Azorella trifurcata is much easier and has made a lovely vivid green mat).
Re: amazing Apiaceae (the umbellifers)
The latest umbel to flower - Orlayagrandiflora- an annual species that more than lives up to its name. I am not sure how many gardeners grow it but it flowers just at the right time for the Chelsea Show and is often used on displays there. This and Ammi majus are both superb dry meadow plants mixed with poppies and the like.
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There are so many of these umbellifers that I don't know and never heard of, but I'm paying attention ;) The Orlaya is pretty, the genus name sounding like it should be a town inFloridaor a brand of potato chips :D
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I didn't know what it was or what it's family might be when I saw it in seed in the Uppsala (Sweden) botanics a couple of years ago. Good to see it in flower!
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That certainly seems like strange seed pods for the family.
I have tried to grow Orlaya from seed from another acquaintance in another garden forum. She gave me so many seeds that I planted them in a pot and directly in soil outside. Nothing ever showed, even in future years.Any special insights/experiences on this one?
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With me Orlaya self seeds well, except when the rabbits discover it! Generally umbel seed should be sown pretty fresh and will germinate after a period of winter cold. Orlaya is a Mediterranean annual and should germinate with autumn rains if sown early enough, making strong overwintering plants. It sounds like you were just unlucky.
Umbel seeds are marvellously varied and quite a few have hooked spines like Orlaya, especially in dry habitats.
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I have grown Orlaya at my summerhouse for many years but I have to sow it regularly.
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Thanks, Tim. Perhaps I will try again sometime.
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It is not such an unusual one as some of those shown here, but Myrrhis odoratais looking nice right now...
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Tim wrote:
With me Orlaya self seeds well, except when the rabbits discover it! Generally umbel seed should be sown pretty fresh and will germinate after a period of winter cold. Orlaya is a Mediterranean annual and should germinate with autumn rains if sown early enough, making strong overwintering plants. It sounds like you were just unlucky.
Umbel seeds are marvellously varied and quite a few have hooked spines like Orlaya, especially in dry habitats.
No chance of it self seeding in the wet north west or surviving the winter. Here it is a tender annual which needs to be sown in a warm propagator in spring and grown on in individual pots for planting out now which is what I have just done.Small country vastly varied climate.It is a lovely plant
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Here's an update on Peucedanum ostruthium'Daphnis'... I've gained a bit more appreciation for it since this thread started, and it really is an attractive thing:
Re: amazing Apiaceae (the umbellifers)
Skulski wrote:
It is not such an unusual one as some of those shown here, but Myrrhis odoratais looking nice right now...
It is a very nice plant and the seeds taste like "King of Denemark" ( a kind of sweeties) but it is one of the worst weeds here - I have it many places >:( ;)
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I've just planted seedlings of "Bald Cicely", my name for a variety of Myrrhisodoratawhich is completely hairless - also an excellent spring vegetable...
This is what Gerard had to say on the matter in 1597 (Kew Gardens):
Re: amazing Apiaceae (the umbellifers)
Delighted to see Tim's Orlaya: one of my favorites. It has been self sowing a bit more every year and starting to make quite a show for me. Unlike many spring annuals, it hangs in there through the summer and reblooms when we get the odd shower in summer. I recall seeing something like these here and there all over Greece in April and May. It is a must have in my opinion. I keep stumblng on whole genera that seem to be twins to Orlaya from all over Eurasia. The only one I have a picture of is from Central Asia, I photographed it last September...here goes:
1) Overall shot of Orlaya grandiflorain my dry garden2) Closeup of the same3) Semenovia sp photographed near the Observatory near treeline above Almaty in Kazakhstan Tian Shan...growing with what looks like Veronicaspicata, but is not, I believe.
Love them umbels!
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When I first became interested in these plants I was persuaded by the Hardy Plant Society to write one of their booklets on the family. Umbellifers have always been of interest to knowledgeable gardeners in the UK (such as Graham Stuart Thomas and Alan Bloom, both of whom wrote about them). Recently though they have been grown a lot more widely, especially in more naturalistic gardens, and they must always have an appeal even to non-gardeners because they are so recognisable. Even so it is only the very few that are grown in gardens. Looking back through this thread, and with the host of amazing North American umbels which are hardly grown anywhere, I am keen to learn a lot more about them and hopefully put this together in a more comprehensive book on the family (a bit of a tall order since it is such a large family!). There are quite a few nurserypeople I know with a fascination in the family - for example Marina Christopher who used to work with John Coke at Green Farm Plants, and who values them especially for the very wide range of pollinators they attract, and Graham Gough at Marchants Nursery and John-Pierre Jolivot in France.
I would be very grateful for any information from members of the NARGS who grow umbels (there is quite bit already on this thread already which is really helpful and stimulating) or even more who have experience of seeing them in the wild. I aim to try more of the North American species from seed since these are virtually unknown in cultivation. There are also quite a few alpine species in particular that have been introduced from South America.
I think the diversity of the family would surprise many even botanically minded gardeners and the long historical uses of umbels in medicine and as foods have given them such enduring interest. It may be quite a long project but there has been very little written on the family from a gardening perspective. Many thanks in advance.
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TimHere is one you will not see every day, Cymopterus globosus. I have only come across this little desert Spring Parsely one time, on a low, very cobbled hill in eastern Nevada. The flower heads feel like a moist, dense rubber ball when you squeeze them. I can't find a lot of information about it but it is a uniqui little guy. I hope some day to find it in seed.
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Cymopteris globosus is an amazing plant. I thought it rang a bell, and sure enough, I posted a CalPhotos link to this species and several other fantastic Cymopteris here:http://nargs.org/smf/index.php?topic=662.msg8397#msg8397
Glad to be reminded of such unique plants as the NARGS Seedex opening approaches.
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Some of the Cymopterusreally are extraordinary! It is interesting how little they are known in comparison even with many of alpine umbels of South America and New Zealand. Mind you they must be really difficult to grow in the garden in many cases; I have always thought them very like bulbs with their early flowering habit and summer aestivation. I have tried a few of these from seed and had good germination (in some cases in the fridge!), but haven't yet managed to grow them on successfully. They must be good candidates for a sand or crevice bed. (There is a glorious example on the Alplains list - Cymopterus planosus- who would not want to grow a plant like that!!).
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Two pix: the first is good old Lomatiumdissectum: big, variable, easy in the garden. Here photographed on the West Elk Mts. in mid July in aspenwoods at about 8000-9000'.
The second is more problematical: Oreoxishumilisonly grows on Pikes peak. I believe it is proposed for endangered species status. It is very cute and probably quite growable. Too this a few days after the last picture.
I spent the day with my girlfriend at the Stanford Mall (quite the shopping center): I cannot remember the name of the manufacturer, but there was an exquisite set of China at Bloomingdale's featuring all manner of Umbelliferae. Very appropriate to this string...
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Wow, Oreoxishumilisis a beauty! Found a link from 2009 concerning endangered species status, with disappointing news. PK, hopefully you'll be collecting seed on it sometime (before it does get listed) and grow them at DBG.
USDA list 4 secies of Oreoxishttp://plants.usda.gov/java/profile?symbol=OREOX
Oreoxis humilisIn the following USDA Forest Service documents, the range is given as only Colorado.http://www.fs.fed.us/r2/projects/scp/assessments/oreoxishumilis.pdfhttp://www.fs.fed.us/wildflowers/rareplants/profiles/critically_imperile......and listed as only Colorado in this U.S. Fish and Wildlife Service document entitled " Endangered Species Act Protections for 165 Petitioned Species Not Warranted":http://www.fws.gov/mountain-prairie/pressrel/09-04.html
...curiously the UDSA Plant Profile includes New Mexico in its range, probably a mistake:http://plants.usda.gov/java/profile?symbol=ORHU
Oreoxis alpina(and O. bakeri):http://www.swcoloradowildflowers.com/Yellow%20Enlarged%20Photo%20Pages/o...... O. alpinaon the NARGS Wiki:http://www.nargs.org/nargswiki/tiki-browse_image.php?imageId=2960
Oreoxis bakerihttp://www.flickr.com/photos/12803916@N00/3936911951/
Oreoxis trotteri:http://www.scribd.com/doc/35623196/Oreoxis-trotteri-Utah-Rare-Plants
Re: amazing Apiaceae (the umbellifers)
I like the look of them. Do they go dormant in the summer months?
Here we have Lomatium nevadense var nevadense a more wild spread miniature species. Easy from seed and summer dormant.
http://plants.usda.gov/java/profile?symbol=LONEN
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It's good to hear that they are easy from seed. Does that mean they don't need conditioning (stratification) or would you recommend it?
I've tried Lomatium columbianuma couple of times now with no germination at room temp, or stratified in the cold room, or over the winter outdoors - very frustrating! I wonder if the seeds have limited longevity? Then again, I seem to have problems germinating Apiaceae in general... what's the trick?
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LoriI just scattered the seed and let nature take care of the rest. I think stratification will not hurt them. We are so hot and dry in the summer that the seedlings can't sprout so have to wait for spring. It takes a couple of years for them to reach flowering size.
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Okay then, by scattering them outside, they are being stratified (exposed to varying temperatures)... good to know. Thank you!
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Really like that Oreoxisand the further details from Mark - these small umbels have the same appeal that the larger herbaceous species have, even if a lot more tricky to grow. I have always sown umbellifer seed in the cooling days of autumn (if I get the seed early enough), so it gets a spell of warm and moist weather, with cooler nights, and then a winter stratification. Usually then germination is pretty good in spring. However, I have had seed sown late and stratified in the fridge germinate still at 4°C in the dark (similarly with eriogonums). This year plants of Lomatium columbianumin our garden set lots of seed so I hope for good germination next year. I find the foliage of these plants irresistable.
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Very helpful to read your germination experiences too, Tim. Thanks.
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NARGS seed of Lomatium columbianum from 2007 germinated mid-June here (I just sowed the seed in a pot and stratified in a cold frame outside). However, I lost it the following winter. I have succeeded with 3 or 4 Lomatium species of about 14 species that I've tried here!
Re: amazing Apiaceae (the umbellifers)
cohan wrote:
Some of these remind of several local umbellifers I am fond of, I'll have to dig up pictures--such as the very charming, subtle Sweet Cicely (blunt-fruited; Osmorhiza depauperata) which is common in the woods here.. I sent seed to Stephen, hopefully he gets some babies :)
Unfortunately, there were no babies, perhaps next spring?
Re: amazing Apiaceae (the umbellifers)
Lori wrote:
Here's an update on Peucedanum ostruthium'Daphnis'... I've gained a bit more appreciation for it since this thread started, and it really is an attractive thing:[attachthumb=1]
Yes, very nice, but it might also be a bit thuglike too - I've noticed it spread quite far in one season, worth keeping an eye on!
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The dry (on top of cold, I suppose) conditions here have seemed to keep it in check so far, but I will certainly watch it.
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Tim: your picture of Lomatium columbianum is stunning: but white! I have seen this in full bloom in the Columbia River gorge where it is incredibly beautiful (deep rose purple red flowers): your foliage is the same silvery blue, but you must have an albino! I never saw white flowered ones in nature...you may or not be aware this is quite a rare plant in nature. So having an albino (even rarer) is something special. But you need the purple phase too! Most lomatiums are yellow, so white and purple are very cool!
Re: amazing Apiaceae (the umbellifers)
I thought the white flowers were the Athamantha turbith... ? ???
Re: amazing Apiaceae (the umbellifers)
Yes - sorry, I have the two plants growing next to each other and the picture was taken after the Lomatiumhad flowered.
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Kelaidis wrote:
Tim: your picture of Lomatium columbianum is stunning: but white!
I thought the white was the Athamanta turbith(?)
Edited to say:You both posted as I was doing mine, I guess. Isn't it interesting that you and I, Lori, chose the same wording...
Re: amazing Apiaceae (the umbellifers)
Well, guess we've cleared thatup... :D
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Lots more beauties- love them all-- the Oreoxis is very cute! I think I have a few Cymopterus seedlings-- some I think came up second spring..Alplains has a lot of these, have to check there for Oreoxis...
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Stephenb wrote:
cohan wrote:
Some of these remind of several local umbellifers I am fond of, I'll have to dig up pictures--such as the very charming, subtle Sweet Cicely (blunt-fruited; Osmorhiza depauperata) which is common in the woods here.. I sent seed to Stephen, hopefully he gets some babies :)
Unfortunately, there were no babies, perhaps next spring?
Cohan: I now have lots of babies of depauperata, just a long gestation period!
Re: amazing Apiaceae (the umbellifers)
Great to know :) these have been emerging in the woods here the last few weeks, always great to see those pretty leaves :)
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This is Athamanta turbithflowering again this summer on a raised bed, and it still holds pride of place in my affection for umbels; such a delicate and beautiful plant. The aquilegia is triternata, but unfortunately this has crossed with other more vigorous species close by in the garden and a lot of very different specimens have appeared on the bed as well.
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A handsome and elegant Apiaceae, Tim!Here's another kind of flowers: Bupleurum longifolium from seed a couple of years ago.
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The Athamanta looks good! I have a small plant and am yet to see what the fuss is about...
Lomatium urticulatum (I think it's this species, but please correct me if wrong) flowered for the first time this year, in the first picture with L. nudicaule:
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Great contrast between those two Stephen - nudicauleis so distinct but urticulatumresembles so many other species! I'm aiming to gather more information on umbels over this coming autumn/winter so will have to quiz you on what you grow! The number of people who grow these American species must be pretty much counted on one hand.
Trond - that longifoliumis very striking. I have grown it but it never seems long lived. Wonderful flower arrangers plant!
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Please do, Tim - I'll collect what seed I can...
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No new ones - I remain totally unable to grow umbellifers from seed! >:( - just some of the old ones in bloom: Athamanta turbith ssp. haynaldii:
Pimpinella major'Rosea':
Peucedanum ostruthium'Daphnis':
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Lori wrote:
No new ones - I remain totally unable to grow umbellifers from seed! >:( - just some of the old ones in bloom:
I have exactly two seedlings of Cymopterus (planosus, I think) from Alplains seed two years ago...lol.. several Angelicas from StephenB did nothing for me, but Anthriscus Ravenswing from Kristl did germinate well, and I have a couple doing well in ground- tried a drier spot which died over winter and a wetter spot which is doing well, no sign of flowers yet, though!
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This umbellifer, Angelicasylvestris, was very busy starting flowering before the umbel had cleared from the sheath. The first picture is from yesterday, the other from today.
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Trond - Angelica sylvestrisisn't seen too much in gardens, much less than the culinary A. archangelica, but has sported to produce deep purple leaved forms like Anthriscus sylvestris'Ravenswing'. Rather stunning specimens, but because they are biennial they come and go and don't self-seed with the freedom of cow parsley.
Cohan - will be interested to know how you get on with the Cymopterus- so far I have germinated quite a number but not managed to grow them on well. I think they need the same treatment as many bulbs - so really summer dry as they aestivate naturally. The smaller species are the most striking but the larger probably the ones easiest to grow. Are they grown at Denver at all I wonder?
Lori - if I have my own seed I sow it in the autumn and usually get good germination the following spring. I think the oily nature of the seed tends to make it more hydrophobic as it dries out and older seed can be really slow and difficult to come up, if at all. Late sown seed I often put in the fridge for 4 to 6 weeks and this has been quite good for Lomatiumand Cymopterus, in fact they sometimes begin to germinate in the fridge as I have also found with Eriogonum. I am aiming to write something on the family so really want to learn a lot more about the American species.
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Tim wrote:
Trond - Angelica sylvestrisisn't seen too much in gardens, much less than the culinary A. archangelica, but has sported to produce deep purple leaved forms like Anthriscus sylvestris'Ravenswing'. Rather stunning specimens, but because they are biennial they come and go and don't self-seed with the freedom of cow parsley.
Tim, I haven't planted Asylvestrisbut I haven't removed it either ;)
Both Asylvestrisand archangelica are native here and archangelica is a weed. I remove hundreds every year but let some grow as they are important for some butterfly caterpillars and the plant belongs to the shore.Purple leaved forms had been interesting though!
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Is Angelicasylvestristhen the same as Anthriscussylvestris?AnthriscussylvestrisRavenswing is not that large here yet, but assuming I get flowers and seeds, I'll have to make sure to replant some on purpose!
The Cymopterus I have was, I think, sown in 2010, though I think I was too late in spring to get adequate cold stratification, and they germinated last year.. still in the pot and still very tiny.. if I get the bed intended for dryland North Americans finished soon enough (working in that general area- building the alpine stretch now, then a sort of steppe area in front of it) I will plant them out this year..Can't say I have any great insight to special treatment for them, other than that they will get a highly drained area, and the overall design will hopefully create a bit of a heat sink... Our greatest precip is usually from late May or early June until early to mid July, so time will tell how dry summer plants will do here! I'm hoping our generally cool spring/early summer will be the growing period for that sort of plant and they wont mind the moisture then.... a long hot dry summer is not going to happen here, at least not in recent years' patterns!
Re: amazing Apiaceae (the umbellifers)
No, Angelicasylvestrisand Anthriscussylvestrisare two different plants. They all (including Angelica archangelica) grow here and are a bit weedy.
Another umbellifer here, and much more refined and elegant, is the annual Torilis japonica (it is native despite the epithet).
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There's also the variegated Angelica archangelica 'Corinne Tremaine'. Anyone had successs with that one? I've sown seed twice, but the resultant plants have been very weak and haven't survived.
We also have an heirloom Angelica archangelica ssp archangelica v. Majorum, Voss Angelica, a traditional cultivated selection with filled (solid) leaf stalks. You can read about it here:http://www.skogoglandskap.no/filearchive/angelica_fossaa.pdf
Re-Cymopterus - I bought several species from Alplains this year but I was probably also a bit late like Cohan and only one seedling has appeared so far...
Re: amazing Apiaceae (the umbellifers)
Truth be known quite a number of umbels are weedy!! But they can be very beautiful, like Selinum wallichianumfrom the Himalayas, which flowers later into the summer and has the most fine foliage of all, or very different, like Thapsia maxima(below) from the south-west Mediterranean. The most extraordinary must be the eryngiums - this one, bourgatii, is widely grown but also very free seeding. The larger colouring flowers with long spiky bracts are actually on a single plant that grew earlier than the rest and could be an interesting variant. I have this planted in a bulb bed which it effectively takes over after the bulbs have flowered and are dying down - I am trying to weed it out of more alpine areas!
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Nice, Tim.
Here's Eryngium alpinumin bud:
Re: amazing Apiaceae (the umbellifers)
I'm very envious Lori because I've never been able to grow alpinumvery well and you really don't see it in gardens so much. Those bracts are wonderfully dissected and quite soft compared to most eryngos.
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I liked the foliage of Eryngium bourgatiibetter than the flowers when I grew it. Doesn't seem to be very zone 4 winter hardy. They only lasted two or three seasons from seed.
Eryngium amethystinumhas flowers nearing full size, but haven't turned color yet.
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I've had something I've been referring to as Eryngium x zabelliifor many years now... I'm sort of wondering if it may not be E. bourgatii- I'll have to pay closer attention to it this year.Love that Bupleurum longifolium, Trond!It's disappointing that a couple of Angelicasp. used to generally be available as potted plants around here but not so for the last few years. I was hoping to find one at a nursery to fill some of the big gaps left by shrub removal.Tim, your mention of Selinumreminds me that I did grow Selinum tenuifoliumfor a few years; it never did bloom, oddly enough, but I did enjoy the foliage. I must try these again.Interesting thread... I'm realizing that many plants that I would not have suspected to be, are actually umbellifers!
Astrantia major:
Astrantia carniolica'Rubra'... or so it is supposed to be - I was just reading recently that this is supposed to be a dwarf astrantia, and my plants certainly are not!
amazing Apiaceae (the umbellifers)
Tim: I remember being struck by Selinum wallichianum the first time I saw it in the botanical garden in Århus, Denmark, but it hasn't found a permanent place in my garden as it isn't edible enough. ;)
Heracleums are so common that we tend to ignore them, but they are attractive plants if we care to look! I've also grown Heracleum sphondylium "Hoggin' the Limelight", a yellow leaved form, but it died on me. I'd also like to get hold of Heracleum maximum "Washington Limes".
Re: amazing Apiaceae (the umbellifers)
Angelicasylvestris"Vicar's Mead" and Angelicaatropurpurea.
Re: amazing Apiaceae (the umbellifers)
Stephen,does Vicar's Mead come true from seed and stay pink? I have often noticed pink coloration on newly emerged umbels but they always fade to white.
Re: amazing Apiaceae (the umbellifers)
I didnt realise Astrantias and Eryngiums were umbellifers- interesting! Still love the purple Angelicas- and quite lovely foliage on the Selinums as well...
One of my favourite of the natives is the very delicate Cicuta bulbifera -bulbous water hemlock.. I thought perhaps it was inappropriate to cultivate it, but then as long as I'm not mixing it with water parsnips, I don't see an issue ;D - I don't think twice about growing other poisonous plants such as Zigadenus.. Maybe I will collect some bulbils this year..
Re: amazing Apiaceae (the umbellifers)
Hoy wrote:
Stephen,does Vicar's Mead come true from seed and stay pink? I have often noticed pink coloration on newly emerged umbels but they always fade to white.
I've only gown it once (from NARGS seed). As far as I remember it remained pink throughout and also seemed to be a lower more compact plant than the wild plant, one of which is seen below. I think the reason I didn't grow it again is that the seed didn't mature - I had the plant on the north side of my house - it might have benefitted from a sunnier location.
Re: amazing Apiaceae (the umbellifers)
Angelica gigas is another garden worthy Angelica, but I've lost this one too as it didn't produce seed last summer...
Re: amazing Apiaceae (the umbellifers)
No sign of losing Angelica grayi (Gray's Angelica) though as it's turned out to be perennial and is now 10 years old. However, I've never checked it's identity. Anyone have a key to North American Angelica?
Re: amazing Apiaceae (the umbellifers)
Like the Angelica gigaswith monarda and lily - all these plants struggle in our summer dry garden, though might have done better this year (which was actually spring 'very dry' and summer 'quite cool and moist'). The pictures of Selinumshow what a very lovely plant it is with those dark stems. And I am interested in Angelica grayi- I've not grown this, but until now I have tended to assume all angelicas are monocarpic. Do you get many wasps pollinating A. gigas? Umbels are great for all sorts of insects but some seem to especially attract different types.
| https://www.nargs.org/comment/12838 |
Muraglitazar, a Novel Dual (α/γ) Peroxisome Proliferator–Activated Receptor Activator, Improves Diabetes and Other Metabolic Abnormalities and Preserves β-Cell Function in db/db Mice | Diabetes | American Diabetes Association
Muraglitazar, a novel dual (α/γ) peroxisome proliferator–activated receptor (PPAR) activator, was investigated for its antidiabetic properties and its effects o
Muraglitazar, a Novel Dual (α/γ) Peroxisome Proliferator–Activated Receptor Activator, Improves Diabetes and Other Metabolic Abnormalities and Preserves β-Cell Function in db/db Mice
Thomas Harrity
;
Thomas Harrity
1 Department of Metabolic Diseases Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey
Peter T. Cheng
Narayanan Hariharan
Accepted:
September 26 2005
Muraglitazar, a novel dual (α/γ) peroxisome proliferator–activated receptor (PPAR) activator, was investigated for its antidiabetic properties and its effects on metabolic abnormalities in genetically obese diabetic db/dbmice. In db/dbmice and normal mice, muraglitazar treatment modulates the expression of PPAR target genes in white adipose tissue and liver. In young hyperglycemic db/dbmice, muraglitazar treatment (0.03–50 mg · kg −1· day −1for 2 weeks) results in dose-dependent reductions of glucose, insulin, triglycerides, free fatty acids, and cholesterol. In older hyperglycemic db/dbmice, longer-term muraglitazar treatment (30 mg · kg −1· day −1for 4 weeks) prevents time-dependent deterioration of glycemic control and development of insulin deficiency. In severely hyperglycemic db/dbmice, muraglitazar treatment (10 mg · kg −1· day −1for 2 weeks) improves oral glucose tolerance and reduces plasma glucose and insulin levels. In addition, treatment increases insulin content in the pancreas. Finally, muraglitazar treatment increases abnormally low plasma adiponectin levels, increases high–molecular weight adiponectin complex levels, reduces elevated plasma corticosterone levels, and lowers elevated liver lipid content in db/dbmice. The overall conclusions are that in db/dbmice, the novel dual (α/γ) PPAR activator muraglitazar 1) exerts potent and efficacious antidiabetic effects, 2) preserves pancreatic insulin content, and 3) improves metabolic abnormalities such as hyperlipidemia, fatty liver, low adiponectin levels, and elevated corticosterone levels.
Peroxisome proliferator–activated receptor (PPAR)γ and PPARα are ligand-activated nuclear hormone receptors that regulate the transcription of genes involved in carbohydrate and lipid metabolism pathways (1–4). Activation of PPARγ, which is predominantly expressed in adipose tissue, results in insulin-sensitizing antidiabetic effects (5,6). Activation of PPARα, which is highly expressed in the liver, results in the lowering of triglycerides and the elevation of plasma HDL cholesterol levels (7,8). In addition, both PPARγ and PPARα selective activators have been demonstrated to suppress vessel wall inflammatory activity and reduce atherosclerosis in experimental animal models through complementary mechanisms (9,10). Since type 2 diabetic patients often develop dyslipidemia and other metabolic abnormalities, eventually resulting in atherosclerotic coronary heart disease, an agent that simultaneously activates both PPARγ and PPARα has the potential to be useful for the treatment of these patients (11,12).
The discovery and preliminary biological and pharmacokinetic properties of muraglitazar (BMS-298585), a novel oxybenzylglycine dual (α/γ) PPAR activator, have been recently described (13). Muraglitazar binds with high affinity to both human PPARγ and PPARα ligand binding domain protein (IC 50for binding = 0.19 and 0.25 μmol/l, respectively) and potently transactivates full-length human PPARγ- or PPARα-mediated reporter gene activity (EC 50for transactivation = 0.11 and 0.32 μmol/l, respectively). We assessed the effects of muraglitazar treatment on diabetes and other metabolic abnormalities in genetically obese, diabetic, and hyperlipidemic db/dbmice. Untreated db/dbmice exhibit progressive deterioration of glycemic control and develop insulin deficiency and loss of pancreatic insulin content (14–17). In these mice, the clinically used PPARγ selective activators (e.g., rosiglitazone and piogitazone) have been reported to show antidiabetic effects, and the PPARα selective activators (e.g., gemfibrozil) have been reported to lower plasma triglyceride levels and also show some improvement in insulin sensitivity (14–17). Furthermore, we assessed the effects of muraglitazar treatment on diet-induced hyperglycemia and hyperlipidemia in C57BL/6J mice (diet-induced obese [DIO]) (18)
RESEARCH DESIGN AND METHODS
Compounds.
Muraglitazar and rosiglitazone were synthesized by BMS Medicinal Chemistry. Fenofibric acid was purchased from Sigma (St. Louis, MO).
Mice.
db/dbmice (C57BL/6ks lepr −/−) and age-matched lean normal C57BL/6J or Swiss Webster mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and housed under controlled temperature (23°C) and lighting (12 h of light between 6 a.m.and 6 p.m.) with free access to water and standard mouse diet (18% protein rodent diet no. 2018; Harlan). The db/dbmice were prebled, and those within a narrow range of fasted glucose levels were selected for studies to minimize variability between control and drug-treated groups. C57BL/6J mice on experimental diet were fed research diet no. 12327, which contains 40% sucrose/40% fat by calorie (Research Diets, New Brunswick, NJ) for 12 weeks before the start of the experiment and were maintained on this diet for the duration of the experiment. Mice were dosed daily by oral gavage in a vehicle composed of 20% polyethylene glycol (vol/vol), 5% N-methyl pyrrolidone, and 75% 10 mmol/l phosphate buffer, pH 7.4. Bristol-Myers Squibb study guidelines were strictly followed in the investigations.
Gene expression profiling.
Lean normal mice or db/dbmice that were treated with vehicle or compounds, respectively, were killed, and their inguinal white adipose tissue (WAT) and liver were harvested. Total RNA was isolated from WAT or liver samples using RNeasy (Qiagen, Valencia, CA). For Northern blot analysis, 15 μg RNA was subjected to MOPS-formaldehyde gel electrophoresis. The gels were blotted to nylon membranes and hybridized to 32P-cDNA probes according to standard procedures. The radioactivity in the hybridized bands was counted on an Instant Imager (Packard Instruments, Meridian, CT). Alternatively, SYBR-Green PCR analysis was carried out (Applied Biosystems, Foster City, CA). Oligonucleotide primers were designed using Primer Express, and RT-PCRs were carried out (primer sequences and protocol available upon request). The mRNA levels of target genes were normalized to control glyceraldehyde-3-phosphate dehydrogenase mRNA levels. WAT RNA samples from vehicle- and compound-treated mice were also analyzed by Affymetrix microarray for changes in gene expression pattern (protocol available upon request).
Triglyceride/VLDL secretion assay.
C57BL/6J mice that were treated with vehicle or compounds for 7 days were fasted overnight and intravenously injected with Triton-WR1339 (250 mg/kg) 1 h after the final dosing. The injection of Triton prevents the degradation of triglyceride-rich VLDL (triglyceride/VLDL) particles in plasma, resulting in an accumulation of triglycerides. The secretion rate (typically 0.16–0.20 mg · min −1· 100 g body wt −1, linear for 5 h after Triton administration) was determined by calculating the amount of triglycerides accumulated 2.5 h after the Triton injection/100 g body wt. Triglyceride levels were determined using a Roche Cobas blood chemistry analyzer.
Acyl coenzyme-A oxidase activity.
The db/dbmice that were treated with vehicle or compounds for 14 days were killed, and their liver was harvested. Liver acyl coenzyme-A oxidase activity (ACO) activity [(slope of the rate of A 502increase after addition of substrate − the slope of the background rate)/mg protein] was measured according to a published method (19).
Plasma chemistry analysis.
About 50 μl tail vein blood from overnight-fasted or ad libitum–fed mice was collected in EDTA-coated tubes. Plasma glucose, triglyceride, free fatty acid (FFA), cholesterol, and HDL cholesterol levels were determined using a Roche Cobas blood chemistry analyzer; insulin, adiponectin, and corticosterone levels were determined by mouse enzyme-linked immunosorbent assay kits (Linco Research, St. Charles, MO). Corticosterone levels were assessed at 10 a.m.during regular 12-h diurnal light cycle. ED 50to normalization is calculated as the midpoint of the dose-response activity curve using a four-parameter-fit equation.
High–, medium–, and low–molecular weight adiponectin complexes.
The high–molecular weight (HMW), medium–molecular weight (MMW), and low–molecular weight (LMW) adiponectin complexes in db/dbmouse plasma were detected according to the method described by Waki et al. (20). A total of 0.5 μl db/dbmouse plasma samples were diluted (1:12) and incubated for 1 h at room temperature in reducing sample buffer (3% SDS, 50 mmol/l Tris-HCl, pH 6.8, 10% glycerol, 5% 2-mercaptoethanol, and 10 mmol/l dithiothreitol) or nonreducing sample buffer (3% SDS, 50 mmol/l Tris-HCl, pH 6.8, and 10% glycerol) and subjected to SDS-PAGE under reducing/heat-denaturing conditions (samples were heated at 95°C for 10 min) or nonreducing/nonheat-denaturing conditions, according to the standard Laemmli’s method with Criterion precast Tris-HCl 4–15% gel (Bio-Rad, Hercules, CA). For immunoblotting, proteins separated by SDS-PAGE were transferred to nitrocellulose membranes, blocked with StartingBlock (Tris-buffered saline) Blocking Buffer (Pierce, Rockford, IL), and then incubated with 1:5,000 diluted anti-mouse adiponectin globular domain monoclonal antibody (Chemicon, Temecula, CA) in Tris-buffered saline with 0.1% Tween-20 for 1 h at room temperature. After washing, the membranes were incubated with goat anti-mouse IRDye 800 (1:10,000) (Rockland, Gilbersville, PA) for 1 h at room temperature and then washed thoroughly. The membrane was scanned with the Odyssey Imaging System (Li-Cor, Lincoln, NE).
Oral glucose tolerance test.
The db/dbmice, which were on a 2-week dosing regimen, were fasted overnight on day 13. On day 14, an oral dose of vehicle alone or compound was given in the morning, and blood samples were collected from the tail vein for determination of baseline values ( t= 0 min). The mice were then gavaged with an oral bolus of glucose (2 g/kg), and additional blood samples were collected at regular intervals ( t= 15, 30, 60, and 90 min) for glucose and insulin measurement. Homeostasis model assessment index values were calculated using the following equation: (the product of the fasting insulin levels [mU/l] × fasting glucose levels [mmol/l]/22.5).
Pancreatic insulin content.
Pancreata were harvested from overnight-fasted vehicle- and drug-treated mice, placed in liquid N 2, then stored at −20°C. Pancreata were homogenized in acid-ethanol (75% ethanol, 23.5% water, and 1.5% c-HCl in 1.8 ml volume) with a polytron homogenizer. The homogenates were stored at 4°C for 28 h and then centrifuged at 1500 gfor 30 min at 4°C. The supernatants were diluted (1:20,000), and insulin levels were determined by enzyme-linked immunosorbent assay (21).
Liver lipid analysis.
Liver triglyceride levels were determined using a Wako Kit (no. 997-69801). Frozen liver pieces were homogenized in saline and brought to a concentration of 0.05 mg/1 ml. Twenty microliters of the sample were solubilized with 20 μl deoxycholate (1.6% wt/vol in water), and 1 ml of the Wako reagent was added. The mixture was incubated at 37°C for 15 min, and the absorbance was read at 505 nm.
Statistical analysis.
Unpaired, two-tailed Student’s ttests were performed for comparisons between compound-treated and vehicle control groups. Differences were considered significant at P< 0. 05.
RESULTS
Muraglitazar modulates PPAR target gene expression in mice.
As previously described, muraglitazar potently stimulates full-length human PPARγ- and PPARα-mediated reporter gene expression (EC 50for PPARγ and PPARα transactivation = 0.11 and 0.32 μmol/l, respectively;13) The ability of muraglitazar to transactivate full-length mouse PPARγ or PPARα receptor has not been determined. However, in a chimeric Gal4/mouse PPAR-mediated reporter gene assay, muraglitazar shows mouse PPARγ agonist activity at levels comparable with its human PPARγ activity (EC 50for mouse PPARγ = 0.09 μmol/l for muraglitazar and 0.08 μmol/l for the PPARγ selective activator rosiglitazone; the PPARα selective activator fenofibric acid was inactive) and mouse PPARα agonist activity that is weaker than its human PPARα activity (observed EC 50for mouse PPARα = 23.8 μmol/l for muraglitazar and 16.3 μmol/l for fenofibric acid; rosiglitazone was inactive). The disparity between the mouse and human PPARα activity is likely due to mouse/rodent-specific differences in the interactions of muraglitazar with several amino acid residues that are altered between mouse and human PPARα ligand binding domains (22).
The effects of muraglitazar treatment on the expression of PPAR target genes in WAT and liver were determined in db/dband normal mice. In db/dbmice, muraglitazar treatment (10 mg · kg −1· day −1for 2 weeks) increases mRNA levels of fatty acid binding protein aP2, GLUT4 glucose transporter, and lipoprotein lipase in WAT and stimulates both mRNA and activity levels of ACO and suppresses apolipoprotein CIII mRNA levels in liver (Fig. 1A and B). Microarray analysis of WAT RNA from muraglitazar- or rosiglitazone (10 mg · kg −1· day −1for 7 days)-treated db/dbmice shows that expression levels of genes that are implicated in 1) adipocyte differentiation, 2) insulin signaling and glucose metabolism, 3) fatty acid transport, 4) fatty acid oxidation, 5) triglyceride synthesis, and 6) energy expenditure are modulated by both muraglitazar and rosiglitazone treatment (Table 1). Both muraglitazar and rosiglitazone treatment (10 mg · kg −1· day −1for 3 days) stimulate aP2 and lipoprotein lipase mRNA levels and suppress 11β-hydroxy steroid desaturase 1 mRNA levels in normal mouse WAT (Fig. 1C). Muraglitazar, but not rosiglitazone, stimulates ACO mRNA levels in normal mouse liver (Fig. 1D). Finally, in normal mice, muraglitazar treatment (3, 10, and 30 mg · kg −1· day −1for 7 days) dose dependently inhibits triglyceride/VLDL secretion from the liver without promoting liver weight increase (Fig. 1E and F). Fenofibrate treatment (30, 50, and 100 mg · kg −1· day −1) also inhibits triglyceride/VLDL secretion (Fig. 1E and F). However, this effect is accompanied by dose-dependent increases in liver weight, which is a known fibrate-induced phenomenon in rodents (23). Rosiglitazone treatment (3, 10, and 30 mg · kg −1· day −1), by contrast, does not inhibit triglyceride/VLDL secretion (Fig. 1E and F). The gene expression data thus demonstrate that muraglitazar treatment results in modulation of PPAR target gene expression in WAT and liver. The PPARα agonist activity of muraglitazar may have contributed to the differences in the expression levels of various PPAR target genes in WAT and liver as well as inhibition of VLDL secretion in muraglitazar-treated compared with rosiglitazone-treated mice.
Muraglitazar treatment ameliorates diabetes and hyperlipidemia and increases pancreatic insulin content in db/db mice.
Muraglitazar was investigated in three separate studies for 1) dose-dependent lowering of fasted and fed glucose, insulin, FFA, triglyceride, and cholesterol levels in young hyperglycemic db/dbmice (∼8-week-old males; 0.03–50 mg · kg −1· day −1orally for 2 weeks), 2) effect on time-dependent deterioration of glycemic control and plasma insulin levels in older db/dbmice (∼12-week-old females; 30 mg · kg −1· day −1for 4 weeks), and 3) improvements in hyperglycemia and glucose tolerance and effect on pancreatic insulin content in severely hyperglycemic db/dbmice (∼10-week-old females with fasting plasma glucose >500 mg/dl; 10 mg · kg −1· day −1for 2 weeks; rosiglitazone at 10 mg · kg −1· day −1was used as a positive control in the study).
In study 1, muraglitazar treatment results in dose-dependent lowering of both fasted (day 7 data shown, similar data were also obtained after 14 days) and fed (on day 15) plasma glucose, FFA, insulin, triglyceride, and cholesterol levels (Fig. 2A–E). Amelioration of hyperglycemia in the presence of reduced plasma insulin levels suggests that insulin sensitivity has been improved in muraglitazar-treated young db/dbmice. As previously observed with PPARα activators in rodents, the cholesterol-lowering effect of muraglitazar is restricted to a reduction of the HDL cholesterol fraction (data not shown) (24). The ED 50to normalization of glucose and triglyceride levels in fasted animals on day 14 are 0.1 and 0.2 mg · kg −1· day −1, respectively, and in fed animals on day 15 are 0.5 and 1.3 mg · kg −1· day −1, respectively. As observed with PPARγ activators (4), muraglitazar-treated mice (at 10 and 50 mg · kg −1· day −1) experience a trend toward increased body weight gain in comparison with the vehicle-treated mice (Fig. 2F).
In study 2, the vehicle- and muraglitazar-treated db/dbmice were monitored weekly for changes in fasting glucose and insulin levels. As shown inFig. 3A and B, the vehicle-treated control db/dbmice show poor glycemic control throughout the duration of the study. The vehicle-treated db/dbmice also show signs of further deterioration of glycemic control (higher fasting plasma glucose levels) and some β-cell exhaustion (significant drop in plasma insulin levels) by the end of the 4-week treatment period (Fig. 3B and C). By contrast, the muraglitazar-treated mice show time-dependent improvement in glycemic control (fasting glucose levels are reduced to the levels observed in lean normal mice) and maintain reduced, but stable, plasma insulin levels during the entire 4-week period (Fig. 3A–C). Muraglitazar-treated mice also show significant improvements in other metabolic parameters such as fasted FFA (−49%), fed glucose (−60%), fasted triglyceride (−31%), and fed triglyceride (−47%) levels (Fig. 3D–F).
In study 3, at the end of the 2-week treatment period, the db/dbmice were fasted overnight and, after collecting baseline ( t= 0 min) plasma samples, were challenged with an oral bolus of glucose. Muraglitazar treatment results in significant reduction of baseline fasting plasma glucose (−51%), insulin (−55%), and FFA (−33%) levels as well as homeostasis model assessment index (−63%) (Table 2). When challenged with an oral bolus of glucose, muraglitazar-treated animals exhibit a reduced glucose excursion (indicating increased tolerance to glucose) and lower plasma insulin levels compared with vehicle-treated animals (Fig. 4A and B). The increased glucose tolerance, along with the concomitantly lowered insulin levels and reduced homeostasis model assessment index, indicate that insulin sensitivity has been improved in muraglitazar-treated mice. Rosiglitazone treatment also results in improved glycemic control; however, the effects are less pronounced than with muraglitazar at the same dose (Table 2,Figs. 4A and B). In addition to improvements in insulin sensitivity and glycemic control, pancreatic insulin content is increased by about fourfold by both muraglitazar and rosiglitazone treatment (Fig. 4C), which is suggestive of some preservation of β-cell function. Neither drug shows any significant impact on the weight of the pancreas in this study (Fig. 4D).
Muraglitazar treatment lowers hyperglycemia and hyperlipidemia in DIO-mice.
C57BL/6J mice, when maintained on a diet high in fat and sucrose (DIO-mice), develop mild hyperglycemia and high plasma triglyceride and cholesterol levels (18). Consistent with its antidiabetic and lipid-lowering effects in db/dbmice, muraglitazar treatment (10 mg · kg −1· day −1for 2 weeks) lowers fasting glucose, triglyceride, and cholesterol levels of DIO-mice to the levels observed in mice on normal standard diet (Table 3).
Muraglitazar treatment increases low plasma adiponectin levels, increases HMW adiponectin complex levels, and lowers elevated corticosterone levels in db/db mice.
As in some type 2 diabetic patients, db/dbmice exhibit abnormally low plasma adiponectin levels and high plasma corticosterone (the murine counterpart to cortisol in humans) levels compared with age-matched normal C57BL/6J mice. Diminished adiponectin levels and elevated corticosterone levels serve as biomarkers of tissue insulin resistance and increased hepatic glucose production (20,25–30). Adiponectin exists as HMW, MMW, and LMW complexes in plasma (20,25,28). In patients and in animal models, increased levels of HMW adiponectin complex have been associated with improved insulin sensitivity (20,25,28).
In older hyperglycemic db/dbmice, muraglitazar treatment (study 2) elevates plasma adiponectin levels and lowers plasma corticosterone levels to the levels observed in normal mice (Fig. 5A and B). In severely hyperglycemic db/dbmice, muraglitazar treatment (study 3) elevates their plasma adiponectin levels above the levels observed in lean normal mice and significantly lowers plasma corticosterone levels (Fig. 5C and D). By comparison, rosiglitazone treatment elevates adiponectin levels to the levels observed in normal mice and lowers corticosterone to the levels comparable with muraglitazar-treated levels in this study (Fig. 5C and D). Furthermore, immunoblot analysis shows that in muraglitazar-treated db/dbmice (10 mg · kg −1· day −1for 2 weeks), their plasma total adiponectin levels as well as HMW adiponectin complex levels are substantially increased compared with the vehicle-treated mice (Fig. 5E and F).
Muraglitazar treatment lowers liver lipid content in db/db mice.
Obese patients with insulin resistance and type 2 diabetes frequently suffer from nonalcoholic fatty liver condition (31,32). Elevated lipid content in the liver has been implicated in hepatic insulin resistance, glucose overproduction, and increased VLDL synthesis and secretion (30,31). The db/dbmice on a normal diet accumulate lipids (primarily triglycerides) in the liver and develop hepatic steatosis. In these mice, muraglitazar treatment (50 mg · kg −1· day −1for 2 weeks) results in significant reductions of liver triglycerides content (76 ± 3 mg/g liver tissue in muraglitazar-treated vs. 100 ± 10 mg/g liver tissue in vehicle-treated mice).
DISCUSSION
Muraglitazar is a novel dual (α/γ) PPAR activator that selectively binds to and activates human PPARγ and human PPARα (13,33–37). The in vivo pharmacological data in lean normal mice and in db/dbmice demonstrate that muraglitazar modulates the expression of PPAR target genes implicated in the regulation of glucose and lipid metabolic pathways in WAT and in liver. The in vivo data also demonstrate that muraglitazar is a potent and efficacious antidiabetic and lipid-lowering agent in db/dbmice. In young hyperglycemic db/dbmice, muraglitazar lowers both fasted and fed glucose and triglyceride levels to the levels commonly observed in lean normal mice. In addition, muraglitazar treatment reduces fasted and fed insulin, FFA, and cholesterol levels. In older db/dbmice, longer-term muraglitazar treatment prevents time-dependent deterioration of glycemic control and development of insulin deficiency. In severely hyperglycemic db/dbmice, muraglitazar treatment markedly reduces fasted plasma glucose and insulin levels as well as glucose excursion. In these animals, muraglitazar also increases the insulin content in the pancreas. Muraglitazar treatment elevates the low plasma adiponectin levels, increases the HMW adiponectin complex levels, and reduces the elevated plasma corticosterone levels of db/dbmice. Muraglitazar treatment also significantly lowers triglyceride content in db/dbmouse liver. Finally, in DIO-mice, muraglitazar treatment normalizes diet-induced mild hyperglycemia and hyperlipidemia, which corroborates the glucose and lipid-lowering effects in db/dbmice. Muraglitazar treatment did not cause hypoglycemia in mice under the experimental conditions used.
The antidiabetic and lipid-lowering effects induced by muraglitazar treatment may result from one or more of the following PPAR-mediated mechanisms: 1) improved insulin action and enhanced glucose uptake in adipose tissue and skeletal muscle, 2) increased fatty acid uptake and storage in adipose tissue, 3) reduced plasma FFA levels, 4) increased plasma total adiponectin and HMW adiponectin complex levels, 5) suppression of glucose overproduction by liver, 6) enhanced VLDL catabolism in the plasma, and 7) reduced triglycerides/VLDL synthesis/secretion in the liver (1–4,25,38–39). The HDL cholesterol lowering in muraglitazar-treated mice is most likely the result of a rodent-specific PPARα-mediated mechanism that suppresses the production of apolipoprotein A1 (a major protein component of HDL particles) in the liver (24). In humans, muraglitazar, like other human PPARα activators (e.g., fenofibrate, gemfibrozil), has demonstrated plasma HDL cholesterol–raising effects (7,8,40–42).
The trend toward increased weight gain in muraglitazar-treated db/dbmice is probably due to a combination of effects including 1) enhanced adipogenesis, 2) retention of calories that would otherwise be lost due to glucosuria, and 3) water retention due to the alleviation of the glucose-driven osmotic diuresis and/or increased plasma or extracellular fluid volume (43,44). The liver triglyceride-lowering effect of muraglitazar is possibly due to reduced plasma FFA and lipid levels, which would limit fatty acid substrate availability for lipid biosynthesis in the liver. Reduced lipid content in the liver will lower hepatic insulin resistance, glucose overproduction, and increased VLDL synthesis (31,32).
In muraglitazar-treated db/dbmice, the improvement in insulin sensitivity and the concomitant reduction in plasma glucose and FFA levels are anticipated to 1) lower insulin secretory demand on β-cells and 2) prevent apoptosis of β-cells, respectively. These effects may help to prevent deterioration of β-cell function, loss of pancreatic insulin content, development of insulin deficiency, and deterioration of glycemic control in muraglitazar-treated db/dbmice.
The increase in both total adiponectin levels and HMW adiponectin complex levels are expected to stimulate fatty acid oxidation in liver and skeletal muscle as well as enhance insulin sensitivity and glucose uptake in skeletal muscle (20,25–28). Interestingly, an inverse correlation has been recently described between plasma adiponectin levels and the rate of incidence of myocardial infarction in men irrespective of their glycemic status (47). The reduction of corticosterone levels by muraglitazar is likely due to reduced metabolic stress and/or PPAR-mediated suppression of the 11β-hydroxy steroid desaturase 1 gene expression in WAT and liver. The reduced corticosterone levels may suppress hepatic glucose overproduction and enhance glucose uptake in peripheral tissues (29,30).
In conclusion, the novel dual (α/γ) PPAR activator muraglitazar 1) exerts potent and efficacious insulin-sensitizing antidiabetic effects, 2) prevents time-dependent deterioration of glycemic control and development of insulin deficiency, 3) increases pancreatic insulin content and, 4) improves other metabolic abnormalities such as hyperlipidemia, fatty liver, low adiponectin levels, and high corticosterone levels in db/dbmice. In the clinical setting, muraglitazar treatment (0.5–20 mg for 28 days) lowers glucose, insulin, triglyceride, FFA, and apolipoprotein CIII levels and increases HDL cholesterol levels in type 2 diabetic patients (40–42). These clinical data emphasize the utility of db/dbmice as a useful model for evaluating antidiabetic properties and antidyslipidemic properties of novel PPAR activators. However, the weak mouse PPARα activity, relative to its human PPARα activity, for muraglitazar may suggest that its antidyslipidemic effects are probably underrepresented in db/dbmice. Finally, since type 2 diabetes patients often suffer from dyslipidemia and other metabolic abnormalities, thus putting them at high risk for cardiovascular disease, muraglitazar, with its dual (α/γ) PPAR activity, has the potential to be useful for the treatment of these patients.
FIG. 1.
Effect of muraglitazar on PPAR target gene expression and VLDL secretion in mice. Aand B: WAT and liver: db/dbmice. Mice (8-week-old males, three to four animals per group) were treated with vehicle alone or muraglitazar (10 mg · kg −1· day −1for 2 weeks). ACO activity was determined in liver homogenates. Cand D: WAT and liver: normal mice. Mice (8-week-old males, three to four animals per group) were treated with vehicle alone, muraglitazar, or rosiglitazone (10 mg · kg −1· day −1for 3 days). Eand F: Inhibition of triglycerides/VLDL secretion and liver weight change in normal mice. Mice (8-week-old females, five animals per group) were administered vehicle alone, muraglitazar, or rosiglitazone (3, 10, or 30 mg · kg −1· day −1) or fenofibrate (30, 50, and 100 mg · kg −1· day −1) for 7 days. At the end of the treatment period, mice were fasted overnight and injected with Triton-WR1339. The triglyceride/VLDL secretion rate was determined by the amount of triglycerides accumulated in the plasma 2.5 h after Triton injection. Liver weight is presented as percent body weight. (RNA data are presented as a percentage compared with vehicle-treated animals, which were defined as 100% [dotted line]). For WAT, tissue samples from three to four animals were pooled for RNA preparation. Data are presented as means ± SE. *Difference between vehicle- and muraglitazar-treated groups, P< 0.05. Feno, fenofibrate, Mura, muraglitazar, Rosi, rosiglitazone. Glut-4 mediates insulin-stimulated glucose uptake, aP2 binds to fatty acids, lipoprotein lipase promotes triglyceride lipolysis, and 11β-HSD1 suppresses insulin sensitivity in adipocytes; ACO stimulates peroxisomal fatty acid oxidation in hepatocytes; and ApoCIII inhibits VLDL catabolism in plasma.
FIG. 1.
Effect of muraglitazar on PPAR target gene expression and VLDL secretion in mice. Aand B: WAT and liver: db/dbmice. Mice (8-week-old males, three to four animals per group) were treated with vehicle alone or muraglitazar (10 mg · kg −1· day −1for 2 weeks). ACO activity was determined in liver homogenates. Cand D: WAT and liver: normal mice. Mice (8-week-old males, three to four animals per group) were treated with vehicle alone, muraglitazar, or rosiglitazone (10 mg · kg −1· day −1for 3 days). Eand F: Inhibition of triglycerides/VLDL secretion and liver weight change in normal mice. Mice (8-week-old females, five animals per group) were administered vehicle alone, muraglitazar, or rosiglitazone (3, 10, or 30 mg · kg −1· day −1) or fenofibrate (30, 50, and 100 mg · kg −1· day −1) for 7 days. At the end of the treatment period, mice were fasted overnight and injected with Triton-WR1339. The triglyceride/VLDL secretion rate was determined by the amount of triglycerides accumulated in the plasma 2.5 h after Triton injection. Liver weight is presented as percent body weight. (RNA data are presented as a percentage compared with vehicle-treated animals, which were defined as 100% [dotted line]). For WAT, tissue samples from three to four animals were pooled for RNA preparation. Data are presented as means ± SE. *Difference between vehicle- and muraglitazar-treated groups, P< 0.05. Feno, fenofibrate, Mura, muraglitazar, Rosi, rosiglitazone. Glut-4 mediates insulin-stimulated glucose uptake, aP2 binds to fatty acids, lipoprotein lipase promotes triglyceride lipolysis, and 11β-HSD1 suppresses insulin sensitivity in adipocytes; ACO stimulates peroxisomal fatty acid oxidation in hepatocytes; and ApoCIII inhibits VLDL catabolism in plasma.
FIG. 2.
Effect of muraglitazar on plasma glycemic and lipid parameters and body weight in young hyperglycemic db/dbmice. A– E: db/dbmice (8-week-old males, five animals per group) were administered vehicle alone or muraglitazar (0.03–50 mg · kg −1· day −1for 2 weeks). Plasma samples were collected after 7 or 14 days (fasted overnight; 14-day data not shown), and 15 days (fed) and analyzed for glycemic and lipid parameters. Fasted cholesterol data are from 14-day treated mice (cholesterol levels were not determined for 0.03-mg · kg −1· day −1group). Animals were weighed pre- and posttreatment ( F). Data are presented as means ± SE. *Difference between vehicle- and muraglitazar-treated groups, P< 0.05. Fasted values in C57BL/6J mice: glucose = 100–125 mg/dl, triglycerides = 75–100 mg/dl, FFAs = 0.5–1.0 meq/l, insulin = 0.5–1.0 ng/ml, and cholesterol = 75–100 mg/dl. Vh, vehicle.
FIG. 2.
Effect of muraglitazar on plasma glycemic and lipid parameters and body weight in young hyperglycemic db/dbmice. A– E: db/dbmice (8-week-old males, five animals per group) were administered vehicle alone or muraglitazar (0.03–50 mg · kg −1· day −1for 2 weeks). Plasma samples were collected after 7 or 14 days (fasted overnight; 14-day data not shown), and 15 days (fed) and analyzed for glycemic and lipid parameters. Fasted cholesterol data are from 14-day treated mice (cholesterol levels were not determined for 0.03-mg · kg −1· day −1group). Animals were weighed pre- and posttreatment ( F). Data are presented as means ± SE. *Difference between vehicle- and muraglitazar-treated groups, P< 0.05. Fasted values in C57BL/6J mice: glucose = 100–125 mg/dl, triglycerides = 75–100 mg/dl, FFAs = 0.5–1.0 meq/l, insulin = 0.5–1.0 ng/ml, and cholesterol = 75–100 mg/dl. Vh, vehicle.
FIG. 3.
Effect of long-term treatment of muraglitazar on time-dependent deterioration of glycemic control and insulin deficiency in old hyperglycemic db/dbmice. db/dbmice (12-week-old females, five animals per group) were administered vehicle alone or muraglitazar (30 mg · kg −1· day −1for 4 weeks). At the end of each week, the vehicle- and muraglitazar-treated animals were fasted overnight and bled, and the plasma glucose and insulin levels were determined. A: Pretreatment of fasted blood glucose. Band C: Fasted plasma glucose and insulin levels. Dand F: Fasted plasma FFA and triglyceride levels (day 28). Eand F: Fed plasma glucose and triglyceride levels (day 29). Data are presented as means ± SE. *Difference between vehicle- and drug-treated groups, P< 0.05.
FIG. 3.
Effect of long-term treatment of muraglitazar on time-dependent deterioration of glycemic control and insulin deficiency in old hyperglycemic db/dbmice. db/dbmice (12-week-old females, five animals per group) were administered vehicle alone or muraglitazar (30 mg · kg −1· day −1for 4 weeks). At the end of each week, the vehicle- and muraglitazar-treated animals were fasted overnight and bled, and the plasma glucose and insulin levels were determined. A: Pretreatment of fasted blood glucose. Band C: Fasted plasma glucose and insulin levels. Dand F: Fasted plasma FFA and triglyceride levels (day 28). Eand F: Fed plasma glucose and triglyceride levels (day 29). Data are presented as means ± SE. *Difference between vehicle- and drug-treated groups, P< 0.05.
FIG. 4.
Effect of muraglitazar on glucose tolerance, plasma insulin levels, and pancreatic insulin content in severely hyperglycemic db/dbmice. db/dbmice (∼10-week-old females, five animals per group) were administered vehicle alone, muraglitazar, or rosiglitazone (10 mg · kg −1· day −1for 2 weeks). At the end of treatment, animals were fasted overnight, and baseline ( t= 0 min) plasma glucose and insulin levels were determined ( Aand B). Animals were then given a bolus of glucose, and blood samples were drawn after 15, 30, 60, and 90 min, and plasma glucose and insulin levels were determined ( Aand B). At the termination of the study, mice were fasted overnight, pancreata were harvested and weighed, and pancreatic insulin content ( C) was determined. Weight of pancreas is presented as percent of body weight ( D). Data are presented as means ± SE. *Difference between vehicle- and drug-treated groups, P< 0.05. Mura, muraglitazar; Rosi, rosiglitazone.
FIG. 4.
Effect of muraglitazar on glucose tolerance, plasma insulin levels, and pancreatic insulin content in severely hyperglycemic db/dbmice. db/dbmice (∼10-week-old females, five animals per group) were administered vehicle alone, muraglitazar, or rosiglitazone (10 mg · kg −1· day −1for 2 weeks). At the end of treatment, animals were fasted overnight, and baseline ( t= 0 min) plasma glucose and insulin levels were determined ( Aand B). Animals were then given a bolus of glucose, and blood samples were drawn after 15, 30, 60, and 90 min, and plasma glucose and insulin levels were determined ( Aand B). At the termination of the study, mice were fasted overnight, pancreata were harvested and weighed, and pancreatic insulin content ( C) was determined. Weight of pancreas is presented as percent of body weight ( D). Data are presented as means ± SE. *Difference between vehicle- and drug-treated groups, P< 0.05. Mura, muraglitazar; Rosi, rosiglitazone.
Close modal
FIG. 5.
Effect of muraglitazar treatment on plasma adiponectin, HMW adiponectin complex, and corticosterone levels in db/dbmice. A– D: Plasma adiponectin and corticosterone levels were determined by enzyme-linked immunosorbent assay. Aand B: Treated with vehicle alone or muraglitazar (30 mg · kg −1· day −1for 4 weeks). Cand D: Treated with vehicle alone, muraglitazar, or rosiglitazone (10 mg · kg −1· day −1for 2 weeks). Eand F: Immunoblot analysis for adiponectin and adiponectin complex. Plasma samples (0.5 μl) from vehicle- and muraglitazar-treated db/dbmice (10 mg · kg −1· day −1for 2 weeks, three animals per group; plasma samples were from an independent study) were analyzed by reducing/denaturing (for total adiponectin) and nonreducing/nondenaturing gel electrophoresis (for adiponectin complex) followed by immunoblotting. Data are presented as means ± SE. *Difference between vehicle- and drug-treated groups, P< 0.05. Plasma adiponectin and corticosterone concentration in normal mice is 25 ± 3 and 400 ± 50 ng/ml, respectively. Mura, muraglitazar; Rosi, rosiglitazone.
FIG. 5.
Effect of muraglitazar treatment on plasma adiponectin, HMW adiponectin complex, and corticosterone levels in db/dbmice. A– D: Plasma adiponectin and corticosterone levels were determined by enzyme-linked immunosorbent assay. Aand B: Treated with vehicle alone or muraglitazar (30 mg · kg −1· day −1for 4 weeks). Cand D: Treated with vehicle alone, muraglitazar, or rosiglitazone (10 mg · kg −1· day −1for 2 weeks). Eand F: Immunoblot analysis for adiponectin and adiponectin complex. Plasma samples (0.5 μl) from vehicle- and muraglitazar-treated db/dbmice (10 mg · kg −1· day −1for 2 weeks, three animals per group; plasma samples were from an independent study) were analyzed by reducing/denaturing (for total adiponectin) and nonreducing/nondenaturing gel electrophoresis (for adiponectin complex) followed by immunoblotting. Data are presented as means ± SE. *Difference between vehicle- and drug-treated groups, P< 0.05. Plasma adiponectin and corticosterone concentration in normal mice is 25 ± 3 and 400 ± 50 ng/ml, respectively. Mura, muraglitazar; Rosi, rosiglitazone.
TABLE 1
Effect of muraglitazar and rosiglitazone on WAT gene expression in db/dbmice
Genes . Muraglitazar . Rosiglitazone . Potential role in adipocytes .
GATA3 0.3 0.7 ↑ differentiation
Glut-4 2.2 1.8 ↑ glucose uptake
Phosphatidylinositol 3-kinase (p170) 1.6 4.0 ↑ insulin sensitivity
Glucocorticoid receptor 0.65 0.78 ↑ insulin sensitivity
11β-Hydroxy steroid desaturase 1 0.7 0.78 ↑ insulin sensitivity
Fatty acid transport protein 2.7 2.5 ↑ fatty acid transport
Keratinocyte fatty acid binding protein 2.2 NC ↑ fatty acid availability
Adipophilin 6.0 NC ↑ fatty acid into fat droplets
Sterol regulatory element–binding protein 1c 1.9 NC ↑ fatty acid synthesis
Diacyl glycerol kinase 2.1 NC ↑ triglyceride synthesis
Glycerol 3-PO4 dehydrogenase 1.5 NC ↑ triglyceride synthesis
Glycerol 3-PO4 acyl transferase 1.5 NC ↑ triglyceride synthesis
Glycerol kinase 6.3 2.9 ↑ triglyceride synthesis
PPARγ-coactivator 1α 1.8 2.7 ↑ energy expenditure
Uncoupling protein 1 97.1 16.2 ↑ energy expenditure
AMP kinase-α subunit 31.3 15.8 ↑ insulin sensitivity/ fatty acid oxidation/
Long-chain fatty acid CoA dehydrogenase 2.3 NC ↑ fatty acid oxidation
3 hydoxyacyl CoA dehydrogenase 2.7 2.5 ↑ fatty acid oxidation
Long-chain fatty acid CoA oxidase 2.0 1.5 ↑ fatty acid oxidation
Genes . Muraglitazar . Rosiglitazone . Potential role in adipocytes . GATA3 0.3 0.7 ↑ differentiation Glut-4 2.2 1.8 ↑ glucose uptake Phosphatidylinositol 3-kinase (p170) 1.6 4.0 ↑ insulin sensitivity Glucocorticoid receptor 0.65 0.78 ↑ insulin sensitivity 11β-Hydroxy steroid desaturase 1 0.7 0.78 ↑ insulin sensitivity Fatty acid transport protein 2.7 2.5 ↑ fatty acid transport Keratinocyte fatty acid binding protein 2.2 NC ↑ fatty acid availability Adipophilin 6.0 NC ↑ fatty acid into fat droplets Sterol regulatory element–binding protein 1c 1.9 NC ↑ fatty acid synthesis Diacyl glycerol kinase 2.1 NC ↑ triglyceride synthesis Glycerol 3-PO4 dehydrogenase 1.5 NC ↑ triglyceride synthesis Glycerol 3-PO4 acyl transferase 1.5 NC ↑ triglyceride synthesis Glycerol kinase 6.3 2.9 ↑ triglyceride synthesis PPARγ-coactivator 1α 1.8 2.7 ↑ energy expenditure Uncoupling protein 1 97.1 16.2 ↑ energy expenditure AMP kinase-α subunit 31.3 15.8 ↑ insulin sensitivity/ fatty acid oxidation/ Long-chain fatty acid CoA dehydrogenase 2.3 NC ↑ fatty acid oxidation 3 hydoxyacyl CoA dehydrogenase 2.7 2.5 ↑ fatty acid oxidation Long-chain fatty acid CoA oxidase 2.0 1.5 ↑ fatty acid oxidation
Data are fold level compared with vehicle control (defined as 1). db/dbmice (8-week-old males, three mice per group) were treated with vehicle, muraglitazar, or rosiglitazone (3 mg · kg −1· day −1for 7 days). WAT RNA samples were analyzed by Affymetrix microarray chip. Genes that are implicated in metabolic pathways, whose expression levels are altered, are listed. NC, no change.
TABLE 2
Effect of muraglitazar on glycemic parameters in severely hyperglycemic db/dbmice
Treatment . Glucose (mg/dl) . Insulin (ng/ml) . Homeostasis model assessment (mU/l × mmol/l) . FFA (meq/l) . Vehicle 649 ± 57 12.2 ± 3.21 425 ± 59 1.23 ± 0.16 Muraglitazar (10 mg/kg) 317 ± 52 (−51%) * 5.43 ± 0.55 (−55%) * 159 ± 32 (−63%) * 0.82 ± 0.07 (−33%) * Rosiglitazone (10 mg/kg) 454 ± 49 (−30%) * 8.27 ± 1.46 (−32%) * 256 ± 42 (−39%) * 0.86 ± 0.10 (−30%) *
Treatment . Glucose (mg/dl) . Insulin (ng/ml) . Homeostasis model assessment (mU/l × mmol/l) . FFA (meq/l) . Vehicle 649 ± 57 12.2 ± 3.21 425 ± 59 1.23 ± 0.16 Muraglitazar (10 mg/kg) 317 ± 52 (−51%) * 5.43 ± 0.55 (−55%) * 159 ± 32 (−63%) * 0.82 ± 0.07 (−33%) * Rosiglitazone (10 mg/kg) 454 ± 49 (−30%) * 8.27 ± 1.46 (−32%) * 256 ± 42 (−39%) * 0.86 ± 0.10 (−30%) *
Data are means ± SE (percentage change). db/dbmice (10-week-old females, five animals per group) were administered vehicle alone, muraglitazar, or rosiglitazone (10 mg · kg −1· day −1for 2 weeks). At the end of the dosing regimen, animals were fasted overnight and their baseline ( t= 0 min) plasma glucose, insulin, and FFA levels and homeostasis model assessment value were determined.
*
Difference between vehicle- and drug-treated groups, P< 0.05.
TABLE 3
Effect of muraglitazar on diet-induced hyperglycemia and hyperlipidemia in DIO-mice
Treatment . Glucose (mg/dl) . Triglycerides (mg/dl) . Cholesterol (mg/dl) . Vehicle 143 ± 5 150 ± 5 196 ± 7 Muraglitazar (10 mg/kg) 112 ± 4 (−22%) * 107 ± 6 (−29%) * 106 ± 5 (−46%) *
Treatment . Glucose (mg/dl) . Triglycerides (mg/dl) . Cholesterol (mg/dl) . Vehicle 143 ± 5 150 ± 5 196 ± 7 Muraglitazar (10 mg/kg) 112 ± 4 (−22%) * 107 ± 6 (−29%) * 106 ± 5 (−46%) *
Data are means ± SE (percentage change). DIO-mice (8-week-old females, five animals per group) were administered vehicle alone or muraglitazar (10 mg · kg −1· day −1for 2 weeks). At the end of the dosing regimen, animals were fasted overnight, plasma samples were collected, and glucose, triglyceride, and cholesterol levels were determined.
*
Difference between vehicle- and drug-treated groups, P< 0.05.
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| https://diabetesjournals.org/diabetes/article/55/1/240/12383/Muraglitazar-a-Novel-Dual-Peroxisome-Proliferator?searchresult=1 |
BCM-HGSC | Eric Boerwinkle, Ph.D. | page 6
Associate Director, Baylor College of Medicine Human Genome Sequencing Center Contact information eboerwin@bcm.edu Other positions Dean, UTHealth School of Public Health M. David Low Chair in Public Health Kozmetsky Family Chair in Human Genetics Professor, Human Genetics Center and Dept. of Epidemiology Research interests The research interests of Dr. Boerwinkle encompass the
Eric Boerwinkle, Ph.D.
Associate Director, Baylor College of Medicine Human Genome Sequencing Center
Contact information
eboerwin@bcm.edu (link sends e-mail)
Other positions
Dean, UTHealth School of Public HealthM. David Low Chair in Public HealthKozmetsky Family Chair in Human GeneticsProfessor, Human Genetics Center and Dept. of Epidemiology
Research interests
The research interests of Dr. Boerwinkle encompass the genetic analysis of the common chronic diseases in humans, including coronary artery disease, hypertension, and non-insulin dependent (type II) diabetes.
Dr. Boerwinkle received his B.S. in Biology from the University of Cincinnati in 1980, an M.A. in Statistics (1984), and M.S. and Ph.D. in Human Genetics (1985) from the University of Michigan, Ann Arbor where he served as Senior Research Associate in the Department of Human Genetics from 1985-1986. He joined the University of Texas-Houston Center for Demographic/ Population Genetics in 1986 as a Research Assistant and became Assistant Professor in the same year. In 1991 he joined the Department of Human Genetics at the School of Public Health, University of Texas-Houston Health Science Center as Associate Professor, in 1996 was promoted to Professor, and in 1997, Director of the Human Genetics Center. He became a faculty member of the Institute of Molecular Medicine in 1996 and became Professor and Director of the Research Center for Human Genetics.
Dr. Boerwinkle is a member of the American Diabetes Association and the American Society of Human Genetics. The research interests of Dr. Boerwinkle encompass the genetic analysis of common chronic diseases in humans, including coronary artery disease, hypertension, and non-insulin dependent (type II) diabetes. This work includes localizing genes which contribute to disease risk, identification of potentially functional mutations within these genes, testing these candidate functional mutations in experimental systems, defining the impact of gene variation on the epidemiology of disease, and determining the extent to which these genes interact with environmental factors to contribute to disease risk. Activities include both statistical analysis and laboratory work. A large part of Dr. Boerwinkle's current research effort consist of localizing genes contributing to disease risk using modern genome-wide mapping methods. Success depends on keeping up with the latest genomic technical advances. The laboratory is set-up and operating as a high through-put sequencing and genotyping facility in which speed, accuracy and efficiency are monitored continuously. However, we are constantly seeking out more efficient methods to collect and manage genetic information.
Dr. Boerwinkle and colleagues have completed the world's first genome-wide analyses for a variety of CAD risk factors, including diabetes and hypertension. These investigations have lead to the identification of novel susceptibility genes in both cases. Dr. Boerwinkle is particularly interested in methods for identifying potentially functional mutations within a gene region. This seemingly simple objective is made difficult because the functional mutations are expected to have small effects and are imbedded in a sea of silent genetic variation. Once nearly all of the variation is catalogued directly by DNA sequencing, individuals are genotyped for each variable site. Both novel and traditional statistical methods are applied to relate the array of genetic information to a wealth of phenotypic data. This algorithm generates "candidate functional mutations" that are then tested in an in vitro or mouse model system. Once a functional mutation has been identified, Dr. Boerwinkle's group evaluates the ability of the variable site to predict the onset of disease (e.g. myocardial infarction or stroke) above and beyond traditional risk factors. This work is carried out as part of multiple prospective studies of cardiovascular disease and its risk factors in tens of thousands of individuals representing the major American ethnic groups.
Finally, he is working on experimental designs for studying genotype by environment interaction in humans. In particular, we are working on the extent to which interindividual variation in lipid lowering and anti-hypertensive medications are influenced by genetic factors. The practical objective of the research is to use genetic information to identify individuals at increase risk of disease and to design more efficacious interventions. Genetic studies are defining, at the molecular level, novel mechanisms of disease risk, onset and progression. Dr. Boerwinkle and collaborators address the localization of genes which contribute to disease risk in cardiovascular diseases, hypertension and diabetes. The methodology used involves screening of families having the disease and linking the presence of disease with known markers of the human genome. In this manner, the genomic region in which relevant mutations are located can be mapped and the relevant DNA sequenced. By assessing the structural change the mutation may have caused in the gene product (protein), it is possible to infer how it may affect biological function. In order to determine experimentally whether a mutation is functional, it is necessary to introduce the mutated gene into an animal, usually a mouse, and assess its biological effects on the animal's phenotype.
Dr. Boerwinkle has participated in multiple notable discoveries since joining the Institute. Only two will be highlighted here. First, Dr. Boerwinkle's group has completed the first ever genome-wide search for genes contributing to inter-individual blood pressure levels. This initial effort has lead to the identification of an important gene (an adrenergic receptor) which influences blood pressure levels and the risk to hypertension. This is the first time that such a genome-wide approach has led to the identification of a susceptibility gene to a major cardiovascular disease risk factor. Second, Dr. Boerwinkle has participated in similar efforts to identify genes contributing to the risk of developing non-insulin dependent (type II) diabetes. In this case, however, there were no genes in the region that were suspects for the disease. A team of collaborating investigators have painstakingly characterized the genetic region and identified the mutated gene (in this case a protease). This is the first time that anyone has ever positionally cloned a gene contributing to any common chronic disease. This work is of obvious potential clinical importance. It may lead to improved prediction of those at increased risk of disease and the design of more efficacious intervention strategies. The technologies and information from the human genome project provide new tools for lessening the burden of ill-health. Dr. Boerwinkle's accomplishments in developing an internationally recognized team of investigators targeting the genetics of cardiovascular disease and its risk factors ensures a productive future and further discoveries.
Publications
2020
Hahn J , Fu Y-P , Brown MR , Bis JC , de Vries PS , Feitosa MF , et al. . Genetic loci associated with prevalent and incident myocardial infarction and coronary heart disease in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. PLoS One. 2020;15(11):e0230035. PubMed DOI Google Scholar Tagged
Longchamps RJ , Castellani CA , Yang SY , Newcomb CE , Sumpter JA , Lane J , et al. . Evaluation of mitochondrial DNA copy number estimation techniques. PLoS One. 2020;15(1):e0228166. PubMed DOI Google Scholar Tagged
2019
Chen N , Caruso C , Alonso A , Derebail VK , Kshirsagar AV , A Sharrett R , et al. . Association of sickle cell trait with measures of cognitive function and dementia in African Americans. eNeurologicalSci. 2019;16:100201. PubMed DOI Google Scholar Tagged
Kunkle BW , Grenier-Boley B , Sims R , Bis JC , Damotte V , Naj AC , et al. . Author Correction: Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat Genet. 2019;51(9):1423-1424. PubMed DOI Google Scholar Tagged
Davies G , Lam M , Harris SE , Trampush JW , Luciano M , W Hill D , et al. . Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function. Nat Commun. 2019;10(1):2068. PubMed DOI Google Scholar Tagged
Turcot V , Lu Y , Highland HM , Schurmann C , Justice AE , Fine RS , et al. . Publisher Correction: Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity. Nat Genet. 2019;51(7):1191-1192. PubMed DOI Google Scholar Tagged
He KY , Li X , Kelly TN , Liang J , Cade BE , Assimes TL , et al. . Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data. Hum Genet. 2019;138(2):199-210. PubMed DOI Google Scholar Tagged
Yu B , Flexeder C , McGarrah RW , Wyss A , Morrison AC , North KE , et al. . Metabolomics Identifies Novel Blood Biomarkers of Pulmonary Function and COPD in the General Population. Metabolites. 2019;9(4). PubMed DOI Google Scholar Tagged
Kowalski MH , Qian H , Hou Z , Rosen JD , Tapia AL , Shan Y , et al. . Use of >100,000 NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium whole genome sequences improves imputation quality and detection of rare variant associations in admixed African and Hispanic/Latino populations. PLoS Genet. 2019;15(12):e1008500. PubMed DOI Google Scholar Tagged
Noordam R , Bos MM , Wang H , Winkler TW , Bentley AR , Kilpeläinen TO , et al. . Multi-ancestry sleep-by-SNP interaction analysis in 126,926 individuals reveals lipid loci stratified by sleep duration. Nat Commun. 2019;10(1):5121. PubMed DOI Google Scholar Tagged
Hansen AW , Murugan M , Li H , Khayat MM , Wang L , Rosenfeld J , et al. . A Genocentric Approach to Discovery of Mendelian Disorders. Am J Hum Genet. 2019;105(5):974-986. PubMed DOI Google Scholar Tagged
Liang J , Cade BE , He KY , Wang H , Lee J , Sofer T , et al. . Sequencing Analysis at 8p23 Identifies Multiple Rare Variants in DLC1 Associated with Sleep-Related Oxyhemoglobin Saturation Level. Am J Hum Genet. 2019;105(5):1057-1068. PubMed DOI Google Scholar Tagged
Sarnowski C , Leong A , Raffield LM , Wu P , de Vries PS , DiCorpo D , et al. . Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program. Am J Hum Genet. 2019;105(4):706-718. PubMed DOI Google Scholar Tagged
Yee SWah , Stecula A , Chien H-C , Zou L , Feofanova EV , van Borselen M , et al. . Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies. PLoS Genet. 2019;15(9):e1008208. PubMed DOI Google Scholar Tagged
Chiang T , Liu X , Wu T-J , Hu J , Sedlazeck FJ , White S , et al. . Atlas-CNV: a validated approach to call single-exon CNVs in the eMERGESeq gene panel. Genet Med. 2019;21(9):2135-2144. PubMed DOI Google Scholar Tagged
Agha G , Mendelson MM , Ward-Caviness CK , Joehanes R , Huan T , Gondalia R , et al. . Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease. Circulation. 2019;140(8):645-657. PubMed DOI Google Scholar Tagged
Sung YJu , Fuentes Lde Las , Winkler TW , Chasman DI , Bentley AR , Kraja AT , et al. . A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure. Hum Mol Genet. 2019;28(15):2615-2633. PubMed DOI Google Scholar Tagged
Pehlivan D , Bayram Y , Gunes N , Akdemir ZCoban , Shukla A , Bierhals T , et al. . The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance. Am J Hum Genet. 2019;105(1):132-150. PubMed DOI Google Scholar Tagged
Naj AC , Lin H , Vardarajan BN , White S , Lancour D , Ma Y , et al. . Quality control and integration of genotypes from two calling pipelines for whole genome sequence data in the Alzheimer's disease sequencing project. Genomics. 2019;111(4):808-818. PubMed DOI Google Scholar Tagged
Wang Z , Zhu C , Nambi V , Morrison AC , Folsom AR , Ballantyne CM , et al. . Metabolomic Pattern Predicts Incident Coronary Heart Disease. Arterioscler Thromb Vasc Biol. 2019;39(7):1475-1482. PubMed DOI Google Scholar Tagged
| https://www.hgsc.bcm.edu/people/boerwinkle-e?f%5Bauthor%5D=20616&page=5 |
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Bore Kevelaer, depth 60m: Middle Miocene
, Germany
List of taxa
Where & when
Geology
Taphonomy & methods
Metadata & references
Taxonomic list
Rotaliidae
Gyroidina soldanii 1 specimen
Hoeglundina elegans 1 specimen
Elphidiidae
Elphidium inflatum 5 specimens
Elphidium ungeri 4 specimens
Bagginidae
Cancris auriculus Fichtel and Moll 1798 3 specimens
Asterigerinidae
Asterigerina guerichi 17 specimens
A. gürichi staeschi
Cibicididae
Cibicides lobatulus 3 specimens
incl. 1 specimen C. lobatulus var. ornatus
Cibicides aknerianus 2 specimens
Cibicides ungerianus 1 specimen
Cibicides pseudoungerianus (Cushman 1922) 9 specimens
Cibicides dutemplei (dOrbigny 1846) 27 specimens
Planulidae
Planulina austriaca 1 specimen
Uvigerinidae
Uvigerina semiornata 6 specimens
U. semiornata for. semiornata
Uvigerina acuminata 2 specimens
Nonionidae
Cribrononion subnodosum 5 specimens
Nonion boueanum 3 specimens
Nonion affine 2 specimens
Nonion (Porosononion) soldanii 1 specimen
Spiroplectamminidae
Spiroplectammina carinata (d'Orbigny 1846) 93 specimens
Globothalamea
- Rotaliida
- Chilostomellidae
Sphaeroidina bulloides d'Orbigny 1826 2 specimens
Tubothalamea
- Miliolida
- Miliolidae
Quinqueloculina akneriana 1 specimen
Sigmoilina tenuis 1 specimen
Textulariidae
Textularia gramen dOrbigny 1846 10 specimens
Bigenerina nodosaria 6 specimens
Valvulinidae
Martinottiella communis Huang et al. 2019 4 specimens
Nodosariata
- Polymorphinida
- Polymorphinidae
Pseudopolymorphina subnodosa 2 specimens
incl. 1 specimen P. subnodosa for. rugosa
Globulina gibba 15 specimens
Guttulina problema (d'Orbigny 1826) 2 specimens
Nodosariata
- Nodosariida
- Nodosariidae
Lenticulina (Lenticulina) calcar 4 specimens
Lenticulina (Robulus) cultrata 6 specimens
Lenticulina (Lenticulina) inornata 2 specimens
Lenticulina (Robulus) similis 1 specimen
Lenticulina (Robulus) ornata 1 specimen
Marginulina hirsuta 1 specimen
Lagena globosa 2 specimens
Nodosaria bacillum 9 specimens
Dentalina intermittens 1 specimen
Dentalina pauperata (d'Orbigny 1846) 1 specimen
Dentalina konincki Reuss 1861 6 specimens
Lenticulina (Robulus) vortex (Fichtel and Moll 1798) 1 specimen
Glandulinidae
Glandulina ovula 3 specimens
Anthozoa
- Scleractinia
- Flabellidae
Flabellum sp. Lesson 1831 12 specimens
Gymnolaemata
- Cheilostomata
- Lunulitidae
Lunulites voigti Wienrich 1999 3 specimens
Lunulites burdigalensis Wienrich 1999 1 specimen
Gymnolaemata
- Cheilostomata
- Membraniporidae
Reussirella haidingeri Wienrich 1999 12 specimens
Polychaeta
- Sabellida
- Serpulidae
Ditrupa cornea Wienrich 1999 2 specimens
Bivalvia
- Pectinida
- Pectinidae
Aequipecten angelonii Wienrich 1999 1 specimen
Bivalvia
- Arcida
- Arcidae
Scapharca (Scapharca) diluvii (Lamarck 1805) Wienrich 1999 4 specimens
Bivalvia
- Arcida
- Limopsidae
Limopsis (Pectunculina) anomala Wienrich 1999 4 specimens
synonym of Limopsis
Limopsis (Pectunculina) lamellata (Lehmann 1885) Wienrich 1999 3 specimens
Limopsis (Limopsis) aurita (Brocchi 1814) Wienrich 1999 31 specimens
Bivalvia
- Pholadida
- Corbulidae
Corbula (Varicorbula) gibba (Oliva 1792) Wienrich 1999 58 specimens
C. (V.) gibba gibba
Bivalvia
- Cardiida
- Veneridae
Venus (Ventricoloidea) multilamella (Lamarck 1818) Wienrich 1999 14 specimens
V. (V.) multilamella multilamella
Gouldia minima (Montagu 1803) Wienrich 1999 4 specimens
recombined as Gouldia (Gouldia) minima
Bivalvia
- Cardiida
- Cardiidae
Parvicardium straeleni Wienrich 1999 4 specimens
Habecardium subturgidum Wienrich 1999 1 specimen
spelled with current rank as Laevicardium (Habecardium)
H. subturgidum subturgidum
Bivalvia
- Carditida
- Carditidae
Cyclocardia sp. Conrad 1867 Wienrich 1999 4 specimens
Bivalvia
- Carditida
- Astartidae
Astarte (Astarte) radiata (Nyst and Westendorp 1839) Wienrich 1999 9 specimens
Astarte radiata fa. radiata 1 specimen, Astarte radiata fa. convexior 7 specimens, Astarte radiata fa. goldfussi 1 specimen
Bivalvia
- Protobranchia
- Nuculanidae
Nuculana (Saccella) westendorpi (Nyst and Westendorp 1839) Wienrich 1999 11 specimens
recombined as Saccella westendorpi
Nuculana (Jupiteria) curvirostris de Cserna 1961 Wienrich 1999 4 specimens
Bivalvia
- Protobranchia
- Yoldiidae
Yoldia (Yoldia) glaberrima (von Münster 1837) Wienrich 1999 3 specimens
Portlandia (Yoldiella) pygmaea Wienrich 1999 4 specimens
original and current combination Yoldiella
Bivalvia
- Protobranchia
- Nuculidae
Nucula (Lamellinucula) comta (Goldfuss 1837) Wienrich 1999 1 specimen
Nucula (Nucula) nucleus (Linnaeus 1758) Wienrich 1999 1 specimen
Gastropoda
- Opisthobranchia
Roxania utriculus Wienrich and Janssen 2007 10 specimens
Gastropoda
- Opisthobranchia
- Retusidae
Retusa (Cylichnina) elongata Wienrich and Janssen 2007 1 specimen
Volvulella (Volvulella) acuminata Wienrich and Janssen 2007 7 specimens
Gastropoda
- Opisthobranchia
- Cylichnidae
Scaphander grateloupi Wienrich and Janssen 2007 1 specimen
Cylichna (Cylichna) pseudoconvoluta Wienrich and Janssen 2007 8 specimens
Gastropoda
- Heterostropha
- Pyramidellidae
Syrnola hoernesi Wienrich and Janssen 2007 1 specimen
Chrysallida (Pyrgulina) pygmaea (Grateloup 1838) Wienrich and Janssen 2007 6 specimens
incl. 5 specimens Chrysallida pygmaea f. belgica
Chrysallida (Parthenina) cimbrica Wienrich and Janssen 2007 1 specimen
Turbonilla (Mormula) cf. miomutiniensis Wienrich and Janssen 2007 1 specimen
sensu ANDERSON
Turbonilla (Turbonilla) koeneniana Wienrich and Janssen 2007 3 specimens
sensu JANSSEN
Pyramidella (Voluspa) elata Wienrich and Janssen 2007 1 specimen
Pyramidella (Voluspa) plicosa Wienrich and Janssen 2007 7 specimens
Odostomia (Megastomia) tuexeni Wienrich and Janssen 2007 1 specimen
Turbonilla (Pyrgolampros) pseudoterebralis Wienrich and Janssen 2007 4 specimens
original and current combination Pyrgolampros
sensu JANSSEN
Turbonilla (Pyrgolampros) undulata Wienrich and Janssen 2007 1 specimen
original and current combination Pyrgolampros
sensu JANSSEN
Gastropoda
- Heterostropha
- Architectonicidae
Architectonica (Pseudotorinia) obtusa sensu lato Wienrich and Janssen 2007 1 specimen
original and current combination Pseudotorinia
Gastropoda
- Heterostropha
- Ringiculidae
Ringicula (Ringiculina) buccinea (Sowerby 1823) Wienrich and Janssen 2007 516 specimens
Gastropoda
- Heterostropha
- Acteonidae
Acteon (Acteon) informal sp. 2 Montfort 1810 Wienrich and Janssen 2007 1 specimen
spelled as 'Actaeon'
Gastropoda
- Trochidae
Calliostoma (Ampullotrochus) ? laureatum Wienrich 2001 1 specimen
Gastropoda
- Cerithiidae
Bittium (Bittium) tenuispina Wienrich 2001 2 specimens
Bittium (Bittium) spina (Partsch 1856) Wienrich 2001 6 specimens
recombined as Bittium spina
Gastropoda
- Turritellidae
Turritella subangulata Wienrich 2001 101 specimens
Gastropoda
- Rissoidae
Alvania (Alvania) basisulcata Wienrich 2001 1 specimen
Gastropoda
- Triphoridae
Norephora (Norephora) fritschi Wienrich 2001 1 specimen
Gastropoda
- Naticidae
Naticidae indet. Guilding 1834 Wienrich 2001 53 specimens
Natica tigrina sensu lato (Röding 1798) Wienrich 2001 1 specimen
recombined as Cochlis tigrina
Euspira staringi Wienrich 2001 25 specimens
Gastropoda
- Eulimidae
Niso (Niso) terebellum Wienrich 2001 7 specimens
Gastropoda
- Epitoniidae
Amaea (Scalina) subreticula Wienrich 2001 1 specimen
original and current combination Scalina
Gastropoda
- Cassidae
Semicassis (Echinophoria) bicoronata Wienrich 2001 3 specimens
original and current combination Echinophoria
Gastropoda
- Triviidae
Trivia (Trivia) cf. westfalica (Schilder 1929) Wienrich 2001 1 specimen
original and current combination Trivia westphalica
Gastropoda
- Aporrhaidae
Aporrhais (Aporrhais) alata Wienrich 2001 29 specimens
Gastropoda
- Xenophoridae
Xenophora deshayesi (Michelotti 1847) Wienrich 2001 11 specimens
Gastropoda
- Neogastropoda
- Costellariidae
Orthosurcula steinvorthi Wienrich and Janssen 2007 2 specimens
Gastropoda
- Neogastropoda
- Cancellariidae
Babylonella fusiformis Wienrich 2001 18 specimens
Trigonostoma (Ventrilia) pouwi Wienrich 2001 2 specimens
original and current combination Ventrilia
Sveltia varicosa Wienrich 2001 1 specimen
S. varicosa paucicostata
Gastropoda
- Neogastropoda
- Columbellidae
Anachis (Costoanachis) hosiusi Wienrich 2001 4 specimens
Mitrella (Macrurella) nassoides Wienrich 2001 5 specimens
Gastropoda
- Neogastropoda
- Fasciolariidae
Streptodictyon sexcostatus Wienrich 2001 78 specimens
? Exilifusus attenuatus Wienrich 2001 1 specimen
Aquilofusus festivus Wienrich 2001 1 specimen
Gastropoda
- Neogastropoda
- Nassariidae
Nassarius bocholtensis Wienrich 2001 93 specimens
Nassarius tenuistriatus Wienrich 2001 46 specimens
Gastropoda
- Neogastropoda
- Muricidae
Lyrotyphis (Eotyphis) fistulosus Wienrich 2001 52 specimens
Gastropoda
- Neogastropoda
- Raphitomidae
Raphitoma aff. praehispida Wienrich and Janssen 2007 2 specimens
Favriella sinuosula Wienrich and Janssen 2007 1 specimen
Metuonella grippi Wienrich and Janssen 2007 9 specimens
Mioawateria andersoni Wienrich and Janssen 2007 1 specimen
Teretia anceps Wienrich and Janssen 2007 4 specimens
Gastropoda
- Neogastropoda
- Clathurellidae
Pleurotomoides luisae Wienrich and Janssen 2007 2 specimens
Gastropoda
- Neogastropoda
- Borsoniidae
Bathytoma jugleri Wienrich and Janssen 2007 8 specimens
Genota ramosa (Basterot 1825) Wienrich and Janssen 2007 1 specimen
synonym of Genota valeriae
Asthenotoma pannoides Wienrich and Janssen 2007 50 specimens
Asthenotoma pannus Wienrich and Janssen 2007 6 specimens
Gastropoda
- Neogastropoda
- Drilliidae
Splendrillia selenkae Wienrich and Janssen 2007 7 specimens
Gastropoda
- Neogastropoda
- Conidae
Conus (Conolithus) antediluvianus sensu lato Wienrich and Janssen 2007 21 specimens
spelled with current rank as Conus (Conolithes)
Gastropoda
- Neogastropoda
- Terebridae
Strioterebrum hoernesi Wienrich and Janssen 2007 14 specimens
Strioterebrum ronaldi Wienrich and Janssen 2007 3 specimens
Gastropoda
- Neogastropoda
- Mangeliidae
Sorgenfreispira tenella ( Conrad 1848 ) Wienrich and Janssen 2007 2 specimens
Benthomangelia aff. obtusangula Wienrich and Janssen 2007 2 specimens
Gastropoda
- Neogastropoda
- Turridae
Perrona obliquiplicatula Wienrich and Janssen 2007 1 specimen
Gemmula (Gemmula) zimmermanni Wienrich and Janssen 2007 78 specimens
Fusiturris aquensis Wienrich and Janssen 2007 3 specimens
Fusiturris duchastelii Wienrich and Janssen 2007 48 specimens
F. duchastelii flexiplicata
Unedogemmula boreoturricula sensu lato Wienrich and Janssen 2007 17 specimens
Unedogemmula hanseata sensu lato Wienrich and Janssen 2007 4 specimens
Unedogemmula stoffelsii sensu lato Wienrich and Janssen 2007 1 specimen
Inquisitor borealis sensu lato Wienrich and Janssen 2007 9 specimens
Boreodrillia hosiusi Wienrich and Janssen 2007 14 specimens
Nitidiclavus maitrejus Wienrich and Janssen 2007 3 specimens
Gastropoda
- Neogastropoda
- Ancillariidae
Ancilla (Baryspira) obsoleta (Brocchi 1814) Wienrich 2001 1 specimen
recombined as Amalda obsoleta
Gastropoda
- Neotaenioglossa
- Calyptraeidae
Calyptraea (Calyptraea) chinensis (Linnaeus 1758) Wienrich 2001 1 specimen
Scaphopoda
- Dentaliida
- Dentaliidae
Pseudantalis aturensis Wienrich 1999 6 specimens
spelled with current rank as Dentalium (Pseudantilis)
Lentigodentalium pseudomutabile Wienrich 1999 73 specimens
see common names
Geography Country: Germany State/province: North Rhein-Westfalia Coordinates: 51.6° North, 6.3° East (view map) Paleocoordinates: 51.8° North, 4.8° East Basis of coordinate: estimated from map Geographic resolution: small collection Time Period: Neogene Epoch: Miocene 10 m.y. bin: Cenozoic 5 Key time interval: Middle Miocene Age range of interval: 15.97000 - 11.60800 m.y. ago Stratigraphy Local section: Kevelaer Local bed: 60 m Local order: top to bottom Stratigraphic resolution: bed Stratigraphy comments: Reinbek-Bislicher stage Lithology and environment Primary lithology: fine,brown,gray,green unlithified sandstone Environment: marine indet. Taphonomy Modes of preservation: body Size of fossils: macrofossils,mesofossils,microfossils Collection methods and comments Collection methods: core,mechanical,peroxide,sieve,field collection Reason for describing collection: taxonomic analysis Collection method comments: well drilling, 1994 Metadata Database number: 62889 Authorizer: M. Aberhan Enterer: S. Nurnberg Modifier: S. Nurnberg Research group: marine invertebrate,micropaleontology Created: 2006-08-01 04:19:26 Last modified: 2007-06-28 05:46:44 Access level: the public Released: 2006-08-01 04:19:26 Creative Commons license: CC BY Reference information
Primary reference: 18176 . G. Wienrich. 1997. Die Fauna des marinen Miozäns von Kevelaer (Niederrhein). Band 1 Foraminiferen, Anthozoen. Backhuys Publishers, Leiden 1 :1-187 [M. Aberhan/S. Nurnberg/S. Nurnberg]
Secondary references: 17884 G. Wienrich. 1999. Die Fauna des marinen Miozäns von Kevelaer (Niederrhein). Band 2 Bivalvia, Scaphopoda, Cephalopoda, Bryozoa, Annelida, Brachiopoda. Backhuys Publishers, Leiden 2 :188-384 [M. Aberhan/S. Nurnberg/S. Nurnberg] 24758 G. Wienrich. 2001. Die Fauna des marinen Miozäns von Kevelaer (Niederrhein). Gastropoda bis Cancellariidae 3 :385-639 [M. Aberhan/S. Nurnberg/M. Uhen] 25284 G. Wienrich and R. Janssen. 2007. Die Fauna des marinen Miozäns von Kevelaer (Niederrhein). Band 4 Gastropoda ab Mitridae. Backhuys Publishers BV Leiden 4 :643-954 [M. Aberhan/S. Nurnberg/S. Nurnberg] | https://paleobiodb.org/classic/displayCollResults?a=basicCollectionSearch&collection_no=62889 |
History of The First International by G. M. Stekloff
History of The First International by G. M. Stekloff
Chapter Thirteen. The London Conference of 1871 The Bakuninists
Although the International played only an indirect part in the Commune, nevertheless, after its suppression, a persecution of the Workingmen’s Association was set on foot throughout Europe. The counter-revolutionary government of France was responsible for the first step in this persecution. The Thiers ministry was not content with inflicting ruthless punishment on the Communards who had remained in the homeland; it had the effrontery to demand of the governments abroad the summary extradition of the refugees who had found an asylum in foreign parts; this demand was acquiesced in only by the Belgian and by the Spanish governments. On March 14, 1872, the Dufaure law was passed in France. This law threatened with severe penalties any individual who should be a member of the International.
But the governmental persecutions were as nothing when compared with the internal strife which was disrupting the International. To the extant conflict between the Marxists and the Bakuninists, there was now superadded the friction brought about by the influx of numberless refugees, especially into Switzerland and Great Britain. The tense mood and the anger of these refugees naturally brought a feeling of discord into the local sections of the International. To this must be added the acute poverty which, despite the help forth coming from the General Council, and from local socialists, reigned supreme in the colonies of refugees.
The French refugees in Geneva, led by Maion and Lefrançais, now adhered to the Bakuninist Alliance. In August, 1871, the Genevese branch of the Alliance, having been boycotted by the other branches, declared itself dissolved; but with the help of the French refugees, it speedily re-organised itself as “the section of propaganda and of social revolutionary activity.” The General Council refused to recognise the new organisation, regarding it as still nothing more than an offshoot of the Alliance, and as a focus for the old intrigues. The French branch in London likewise gave the General Council a good deal of trouble. In order to create, in London, a body that should seriously represent the French proletarian movement, the General Council appealed to many of the Communard refugees. Thus, among the internationalists, Charles Longuet, Theiss, Seraillier, etc., were approached; among the Blanquists, Vaillant, Arnaud, Ranvier, Cournet, etc. All these men, in so far as they recognised the necessity for the seizure of political power by the workers, were supporters of the General Council against the Bakuninists.
Since it had been impossible to convene the International congress at the agreed time (owing, as we have seen, to the Franco-German war and to the suppression of the Commune), the General Council decided, with the consent of the majority of the federations, to call a conference in London. [249]This conference was held from September 17 to 23, 1871. It consisted of twenty-three persons, thirteen of whom were members of the General Council, seven of them being the corresponding secretaries, Marx (for Germany), Engels (for Italy), Eccarius (for the U.S.), Hales (for Britain), Rochat (for Holland), Cohn (for Denmark) and Zabicki (for Poland), these seven all had votes, but the remaining six members of the General Council were present only in a consultative capacity; these were Serraillier, Vaillant, Bastelica (the representatives of the Paris Commune), Mottershead, Frankel, and Jung; there were six Belgian delegates, De Paepe, Verrycken, Steens, Coenen, Fluse, and Herman; two Swiss delegates, Utin and Peret; and one Spanish delegate Anselmo Lorenzo; the twenty third delegate, described by Guillaume as “an unknown person with no mandate,” came from Bordeaux.
The most urgent question before the conference was the imminence of a split in the international. It is true that the conference decided certain other questions, for instance: concerning the formation of separate working women’s branches although both sexes were still to participate as members of the ordinary branches; concerning the need for an earnest attempt to collect statistics about the position of the workers in all lands; concerning a carefully planned international organisation of trade-union leagues, whose executives were to keep in touch with the General Council; concerning the need for propaganda among agricultural workers in order to induce them to join the International. But these were subordinate questions, and it was not they which made the conference important in the history of the International. The struggle with anarchism (the influence of which increased day by day), threatening the complete destruction of the International; the strengthening of the organisation of the International and of the General Council; the checking of the centrifugal forces which were germinating within the International; and, finally, a definite decision upon the fiercely disputed topic of participation in the political struggle such were the main concerns of the London Conference.
The conference approved the inclusion of representatives of the French refugees (Communards) in the General Council. But, in order to defend itself from influx of spurious delegates, the General Council urged upon the conference the necessity of restricting the number of co-opted representatives from the various countries. They ought to be co-opted on a basis of proportional representation. The central committees of the different countries were to appoint the federal councils or committees; the local branches, sections, or groups, and their committees, must henceforward be named branches, sections, and groups of the International with the addition of the name of the town or locality in which their activities were centred. In addition they were forbidden to admit to their ranks any sectarian organisations going by such names as positivist, mutualist, collectivist, or communist societies, or independent groups of “sections of propaganda,” and so forth, which arrogated to themselves special aims outside the general aim of all the branches of the International. [250]An exception to this rule was made in favour of those countries where the undisguised organisation of branches of the International was rendered impossible by governmental persecution. It was decided that in such cases the local groups of the International could adopt special names, but on no account were the branches of the International to be organised as secret societies. [251]
In addition, the conference discussed the question of the Bakuninist Alliance. Starting from the fact that the Genevese section of the Alliance (the only one which did not function in secret) had declared itself dissolved (this event was communicated to the General Council in a letter from the secretary, Zhukoffsky, dated August 10, 1871), and also taking into consideration the above-mentioned regulation concerning the affiliation of local groups and sections of a sectarian character working for ends outside the general aims of the International, and, further, recalling the decision of the Basle Congress which had granted the General Council the right to affiliate or to refuse to affiliate to the ranks of the international any society or group, pending an appeal to the next general congress – the London Conference declared “the question of the Alliance of the Socialist Democracy to be settled.” [252]
But the General Council could hardly have supposed that by a purely formal pronouncement of this sort it had once and for all defeated “the enemy within the gates” of the International. The further course of events was to show that the anarchists, far from laying down their arms after the London Conference, began thenceforward to wage open war against the International. Their action in this matter was to lead to the disruption of the International Workingmen’s Association.
One of the most important centres of Bakuninist propaganda was, as I have already pointed out, the Jura Federation in Switzerland. The London Conference discussed the question of this Federation. Locle and La Chaux-de-Fonds were the foci of this organisation, which claimed the title of Federation of Romand Switzerland. The Jura Federation conducted a savage campaign against the old Romand Federation whose centre was at Geneva, and which continued to stand by the General Council. Dealing with the split in the Swiss sections, the delegates, above all, challenged the Jura attempt to discredit the competence of the London Conference. They declared that this conference possessed wider competence than the General Council, in such matters. Now, the Basle Congress had resolved that, should dissensions arise in the various national sections, the General Council should have the right to settle such disputes; its decision could be appealed against at the next congress; and the general congress had the last word in the matter. Passing on to deal with the second contention of the Jura Federation (that it had received no invitation to attend the special conference which was to meet in London on September 17th) the London Conference declared that Jung, the corresponding secretary for Switzerland, had not issued an invitation to the committee of the Jura sections for the following reasons: “In flagrant violation of the decision of the General Council on June 28th, 1870, this committee... continues to call itself the committee of the Romand Federation. The committee has the right to appeal to the next general congress against the decision of the General Council, but it has not the right to ignore such a decision.” Having done so, the committee had no legal status in relation to the General Council, and the corresponding secretary had been well-advised not to issue an invitation. The General Council recognised the Genevese committee as the nucleus of the Romand Federation. The conference then declared that, in view of the persecutions launched against the International, it was of supreme importance that unity and a spirit of solidarity should animate the workers. It further urged the “valiant workers” of the highland branches to rally to the Romand Federation. If this amalgamation could not be effected, the Federation of the highland branches must take the name of the Jura[ Jurassian] Federation.The conference further declared that, henceforward, the General Council should denounce and repudiate all the journals unwarrantably giving themselves out to be organs of the International, and which, by following the example of the “Progrès” of Locle, and “Solidarité” of La Chaux-de-Fonds, should publicly discuss in their columns questions which ought rightly to be dealt with only in the privacy of the local committees, the federal committees, or the General Council, or in the private sessions of the federal or general congresses.
In order to strengthen the British branches of the International, the congress resolved that the General Council should advise the London branches to form a federal committee for London which, after having communicated with the provincial branches and with the affiliated societies, and after having received their adhesion, should be recognised by the General Council as the federal council of England.
The Conference declared that the German workers had done their duty during the Franco-German war. It sent fraternal thanks to the members of the Spanish federation for their work in organising the International, dissociated itself from the “Nechaeff conspiracy,” which had fraudulently usurped and exploited the name of the International, [253]and commissioned Utin to publish a summary account of the Nechaeff trial. [254]Finally, it was left to the discretion of the General Council to summon the next international congress at a time and place which would seem most appropriate. If the congress could not be summoned, then the General Council was to call a conference which should act in its stead.
The fundamental question of the political strugglewas also discussed at the conference. The political struggle had assumed a peculiarly aggressive character after the Paris Commune, and had made plain the need for creating an independent political party of the workers. Such a party was already taking shape in Germany, and its initial activities, as we have seen, had met with considerable success. The anarchists were not impressed by this success, but, on the contrary, they redoubled their efforts to combat any political achievements, and regarded political action as a divergence from the right proletarian path. Inasmuch as the conference in general had had to fight the anarchists on the organisational and other fields, it could not fail to discuss the question of the political struggle.
In view of the wording of the Address and Provisional Rules of the International Workingmen’s Association, and also of the decision of the Lausanne Congress, to the effect that the social emancipation of the workers is inseparable from their political emancipation and from the conquest of political power; and in view of the unbridled activities of the reactionaries, who were forcibly suppressing all the efforts of the workers to achieve their own liberation, and were by brute force maintaining class distinctions and the consequent political dominance of the propertied classes – the London Conference decided that, against the collective power of the propertied classes, the proletariat could only act as a class by forming itself into a distinct political party opposed to all the old political parties that had been formed by the propertied classes; that this formation of a proletarian political party was an indispensable preliminary to the triumph of the social revolution and to the achievement of its supreme end, the abolition of classes; that the union of working-class forces which had already been achieved by means of the industrial struggle, must also serve as a lever which the working masses could use in their struggle against the political power of the landlords and capitalists. For these reasons, the conference reminded the members of the International that, in the fighting activities of the working class, industrial action and political action must always go hand in hand.
The Bakuninists did not consider themselves vanquished. On the contrary, they were so convinced that the General Council had decided to pass from the defensive to the attack, that they boldly took up the gauntlet. On November 12, 1871, they held a congress at Sonvillier which was attended by the Swiss sections of the Alliance. Fourteen delegates (among whom were Guillaume, Spichiger, and Schwitzguébel) represented eight sections. The Genevese Section of Propaganda and Social Revolutionary Action, though not forming part of the Alliance, sent two delegates who were accepted as members of the congress. One was Jules Guesde (who, though at the time we are now dealing with, he inclined to the anarchism of the political refugees, subsequently founded the Marxist Parti Ouvrier in France), and Nicholas Zhukoffsky, a Russian refugee and friend of Bakunin. The congress declared that the old Romand Federation was dissolved (which pronouncement did not, it need hardly be said, prevent the Federation from continuing to exist!); that the anarchist sections were its legitimate successor; and that the new body should be named the Jura Federation – precisely what had been proposed at the London Conference. The congress then drew up the rules of the new federation, founding them upon the principle of full autonomy of the branches.
The most important result of the congress was the issue of a “Circular to all the Federations of the International Workingmen’s Association.” In this document the federations of the international were urged to join hands with the Jura Federation in order to insist upon the calling of the general congress as soon as possible. The power placed in the hands of the General Council, by the resolutions passed at the International congresses, had corrupted it, and had tempted it into dangerous paths. The General Council was composed of men who had been led, in the ordinary course of affairs, to try to impose their special program on the International, and to make the Association adopt their personal views. These men had come to regard any opinion which did not coincide with their own as “heretical.” Thus there had gradually come to be established a sort of orthodoxy, with headquarters in London, whose representatives were the members of the General Council. The natural result of this state of things had been that the General Council met with opposition. Irresistible logic drove the Council to try and break this opposition. Conflicts had ensued, and cabals had been formed. The General Council had become a focus of intrigue, and, at last, war had been declared within the Association. During the two years which had elapsed since the Basle Congress, the General Council had been left to its own devices. The Franco-German war had served as an excuse for not calling the international congress in 1870; in 1871 this congress had been replaced by a “secret conference” convened by the General Council. This conference could not be said to represent the International, seeing that many sections, the Jura Federation among others, had not been invited. The conference had passed resolutions which seriously infringed the general rules of the International, resolutions tending to make of the International a hierarchical and authoritarian organisation of disciplined sections entirely under the control of the General Council which might at its pleasure refuse to admit them to affiliation or might hold up their activities. To crown all, the London Conference had decided that the General Council was to fix the date and place of the next international congress or of the conference which was to replace it.
“This decision threatens us with the complete suppression of the international congresses ... and their replacement, at the behest of the General Council, by secret conferences similar to the one just held in London ... We do not wish to charge the General Council with bad intentions. The persons who compose it are the victims of a fatal necessity: they wanted, in all good faith, and in order that their particular doctrines might triumph, to introduce into the International the authoritarian spirit; circumstances have seemed to favour such a tendency, and we regard it as perfectly natural that this school, whose ideal is the conquest of political power by the working class, should believe that the International, after the recent course of events, must change its erstwhile organisation and be transformed into a hierarchical organisation guided and governed by an executive. But though we may recognise that such tendencies and facts exist, we must nevertheless fight against them in the name of the social revolution for which we are working, and whose program is expressed in the words, ‘Emancipation of the workers by the workers themselves,’ independently of all guiding authority, even though such authority should have been consented to and appointed by the workers themselves. We demand that the principle of the autonomy of the sections shall be upheld in the International, just as it has been heretofore recognised as the basis of our Association; we demand that the General Council, whose functions have been tampered with by the administrative resolutions of the Basle Congress, shall return to its normal function, which is to act as a correspondence and statistical bureau. The unity which the Council is endeavouring to establish by means of centralisation and dictatorship, we shall realise by means of a free federation of autonomous groups. The society of the future will be nothing more than a universalisation of the organisation which the International will have adopted as its own. Our task is to make such an organisation coincide as closely as possible with our ideals. How could we expect an equalitarian and free society to issue from an authoritarian organisation? Such a thing would be impossible. The International, that germ of the human society of the future, must be ..... a faithful representation of our principles of freedom of federation; it must reject any principle which may tend towards authoritarianism and dictatorship.”
Thus we see that the circular confirms our supposition that in the case of each of the conflicting sections of the International, there was an intimate association between program and organisational structure. The Jura circular emphasises the tact that the communist program of the Marxists, and in especial its recognition of the need for the conquest of political power by the working class, must inevitably lead to the creation of a centralised and disciplined organisation (which the Jura Federation calls “hierarchical”), administered and guided by an executive styled by the name of the General Council. The anarchist program, on the other hand, rejecting any kind of centralisation for the organisation as a whole, likewise refused to allow of any proposal for centralisation to be included in the rules of the organisation. It advocated complete autonomy alike for individuals and for groups, and it therefore recommended that a similar autonomy should be granted to the branches of the International.
The congress decided to have the circular printed and sent to all the countries where branches of the International were in existence. It was further resolved to publish a “Memoir” which should enlighten the other national sections of the International as to the events which had led to the split in the old Romand Federation, and explain the reasons for some of the conflicts raging within the ranks of the Association itself. This “Memoir of the Jura Federation” did not see the light of day until two years had elapsed, that is to say, not until after the split in the International had become an established fact.
In addition to sending the Sonvillier circular to every national section of the International, Bakunin and his friends Guillaume, Zhukoffsky, Bastelica, and others, kept up a lively correspondence with comrades of their way of thinking in Italy, Spain, Belgium, Switzerland, and elsewhere. The results of the agitation against the General Council and its tactics soon made themselves felt in many lands. [255]In Spain, [256]the first groups of internationalists were formed in the years 1868 and 1809, as the result of a visit paid to that country by the Italian deputy Fanelli, one of the founders of the Bakuninist Alliance. The first group was formed in Madrid in 1868; the second was formed in Barcelona in 1869. The program adopted by these groups was anarchist, the first Spanish internationalists being under the impression that the Bakuninist program was the program of the International itself. When the legal organisation of the Alliance was dissolved, and when it was proposed that the local groups should affiliate to the International, some of the Spanish Bakuninists demurred to such a submission, and entered into correspondence with the members of the Genevese section of the Alliance (which section was secretly acting as the centre of the Alliance). In 1870, after the Basle Congress, during the course of which they had become intimate friends of Bakunin, Farga-Pellicer, and Sentiñon, aided by friends in Barcelona, founded a secret group which adopted the name and the program of the Bakuninist Alliance of the Socialist Democracy. This group became the focus of anarchist propaganda in Spain. Similar groups were soon formed in Madrid, Valencia, Seville, Cordova, and so forth.
In addition to the groups affiliated to the Alliance and led by Mora, there also existed in certain towns the usual sections of the International. As the struggle between the Bakuninists and the General Council became more acute, so the conflicts between the anarchist groups and the sections of the International in Spain grew more bitter likewise. When, at the end of 1877, Marx’s son-in-law Lafargue visited Spain, matters came to a head. Lafargue, recognising that anarchism spelt ruin to the working-class movement, declared open war against it. He got into touch with the Spanish Federal Council of the International, which had been elected by the Valencia Congress of the Spanish branches in September, 1871, and he found an active collaborator in one of the members of the council, Jose Mesa, who acted as editor of the official organ of the International in Spain, the “Emancipacion.”
The persecution which was let loose on the Spanish internationalists in January 1872 by the Sagasta ministry, did not succeed in stemming the growth of the International in the Iberian peninsula, though it exacerbated the conflict within the organisation. In view of the threatening attitude of the government, the Federal Council realised that the secret organisation known as the Alianza must be immediately dissolved if the work of the International was to be continued. The local federation of Madrid, in which the anarchists formed a majority, excluded from its ranks six members of the staff of the “Emancipacion,” who, besides being collaborators on this paper, were likewise members of the Spanish Federal Council. In April, 1872, the Spanish federation held its annual congress at Saragossa. An endeavour was made to patch up the internal quarrels by proposing that two old time members be re-elected to the Federal Council, and by urging the Madrid federation and the “Emancipacion” to settle their differences. But, in spite of this conciliatory attitude, strife continued. Lafargue and his friends still demanded the expulsion of the members of the secret Alianza from the ranks of the International. When the Federal Council, which was at this time transferred to Valencia, refused to interfere in the matter, Lafargue and his colleagues founded a new Madrid federation, which was not recognised by the Spanish Federal Council, but which was recognised by the General Council in London. Henceforward there existed two hostile organisations in Spain; the preponderant current of opinion being in favour of anarchism. [257]
Bakunin had been in close touch with the secret brotherhoods in Italy, [258]ever since the middle sixties. His polemic with Mazzini [259]after the Commune of Paris, strengthened the bonds which already existed between him and the younger Italian revolutionists, who had been greatly disenchanted with bourgeois-republican idealism, and were endeavouring to join up with the working-class world. After the congress of November 1, 1871, held in Rome by the Mazzinist party, many of the internationalists expressed themselves dissatisfied with its conclusions. Among those who voiced a protest against the congress were Carlo Cafiero (who was at that time a Marxist and in correspondence with Engels), Alberto Tucci, and De Montel. The veteran Garibaldi took up the cudgels in favour of the new current of opinion, exclaiming: “The International is the sun of the future!” As a counterblast to the petty-bourgeois Mazzinist organisations, there was formed at Bologna on December 4, 1871, a society calling itself “Il Fascio operaio” (unification of labour). These Fasci operaie soon spread to many towns throughout Italy. It was here that Andrea Costa, then a student at the Bologna university, began his political career. This young man was destined to play an important part in the development of the socialist movement in Italy. He at first held anarchist views, from these he passed to accept the Marxist theories, and, finally became a champion of class-collaboration.
The Sonvillier circular appeared in several Italian newspapers accompanied by sympathetic commentary. But the majority of the Italian internationalists, not being sufficiently informed as to the details of the fight between the General Council and the Bakuninists, knew not to whose side they were to rally. The Fascio operaio which had been inaugurated at the Bologna conference of December, 1871 to fight the Mazzinist party, now held a second conference in the same town on March 17, 1872. The delegates considered the question, whether the Fascio operaio should recognise the leadership of the General Council in London, or that of the Jura Federation. [260]The conference came to the decision that both the General Council and the Jura Federation were no more than corresponding and statistical bureaux, and instructed the Facio branches to get into touch with both bodies. But gradually the balance went in favour of Bakuninism, which was more accordant with the social conditions prevailing in the Italy of those days. On August 4, 1872, a conference of the twenty branches of the International in Italy took place at Rimini. Hitherto they had worked independently of one another, but they now decided to form an Italian Federation. The delegates declared that the London Conference of September, 1871, had tried to force the Association into accepting an authoritarian gospel which was “part of the program of the German communists”; that the reactionary attitude of the General Council had aroused the revolutionary antagonism of the Belgians, the French, the Spanish, the Slavs, the Italians, and sections of the Swiss workers. The conference proposed that the General Council should be suppressed, and that a revision of the general rules of the organisation should be undertaken. Finally it was also decided not to send any delegates to the Hague Congress, which had just been convened by the General Council.
In Belgium, likewise, the internationalists were beginning to turn their sympathies towards the antagonists of the General Council. The annual congress of the Belgian federation took place an December 24 and 25, 1871, in Brussels. The Congress started with a discussion of the problem which was at that time agitating the whole International. After long deliberation, a resolution was adopted protesting against the calumnies spread abroad by a reactionary press with the object of representing the International Workingmen’s Association as “a despotic society subject to a discipline and to a word of command issued from headquarters, and applied to all the members by means of a hierarchical decree.” The resolution went on to declare that the International, desiring to react against despotism and centralisation, had always believed in attuning its organisation to its principles, and that a General Council had never been anything more than a centre for correspondence and information. The Belgian federation invited all other national federations to make a similar declaration. It concluded by declaring that a revision of the general rules was essential, and empowered the Belgian federal council to draft new rules, which could be placed on the agenda of the forthcoming international congress.
This resolution was so ambiguous that both parties to the dispute were able to count it an asset and a triumph. On the one hand, it clearly affirmed the principles of autonomy and decentralisation of the branches and the federations, and declared that the General Council was nothing more than an information bureau. In this way the Belgians proved their solidarity with the Jura Federation. On the other hand, the resolution did not accuse the General Council or the London Conference of laving infringed the principle of autonomy; and the supporters of the General Council were therefore entitled to consider the resolution a victory for their side. In actual fact, however, the Belgians had no intention of rallying to the support of the General Council, as was shown by the subsequent course of events. Their sympathy with the anarchist outlook was further demonstrated in their resolve to revise the general rules of the Association. At the following congress of the Belgian Federation held in Brussels on July 14, 1872, the federal council submitted its draft of the general rules to discussion. Among other recommendations it was proposed to suppress the General Council as a useless and even dangerous institution. The majority of the delegates, however, considered that such a measure would be too drastic, and favoured a suggestion made by the Liege branch that that the General Council should be re-organised. The powers of that body were to be curtailed, and it would have no right to interfere in the private affairs of the individual branches.
Everywhere, a tendency towards decentralisation was making itself felt. In certain ways the International was still scoring points. It could register a spread of socialist ideas, as, for instance, in Denmark, where, since 1871, several branches had been formed; and in Sweden, to which country the movement had spread in 1872. On the other hand, the antagonism to the General Council was steadily growing, and appeared even in Great Britain which hitherto had been one of the firmest supporters of the Council.
Down to the time of the London Conference, Great Britain had had no federal council; the part that such a body should have played, was undertaken by the General Council in London. The latter had pronounced itself against the formation of a special British federal council, because it believed that the imminent social revolution in Europe would start in industrial England. In the “confidential communication” of the General Council, Marx, rebutting the Bakuninist accusation that the General Council was wholly opposed to the inauguration of a special federal council for Great Britain, declared that, from time to time, the same proposal had been brought forward by some of the British members of the General Council, but that almost invariably it had been unanimously rejected.
At the meeting of the General Council on January 1, 1870, a resolution (Guillaume says it was penned by Marx, and the statement is presumably correct) was passed, and was sent to the Federal Committee of Romand Switzerland in Geneva. Part of this resolution runs as follows: “Although the initial revolutionary impetus will probably come from France, England will have to be the lever which will bring about a really serious economic revolution. England is the only country in which peasants no longer exist, and where the ownership of the land is concentrated in very few hands. It is the only country where the capitalist method – that is to say, where associated labour upon a large scale under capitalist entrepreneurs – has made itself master of nearly the whole of production. It is the only country where the large majority of the population consists of wage labourers. It is the only country where the class struggle and the organisation of the working class by the trade unions have attained a fair degree of maturity and universality. Britain, thanks to its domination of the world market, is the only country in which every change in economic conditions exercises an immediate influence all over the world. Though it be true that landlordism and capitalism have their roots in this country, it is here that the material conditions requisite for their destruction are ripest. The General Council being in the fortunate position of having its hand upon this great lever of the proletarian revolution, how foolish, we might almost say, how criminal, it would be to allow that lever to pass under the control of purely British hands! The English have all the materials requisite for the social revolution; what they lack is the spirit of generalisation and revolutionary fervour. [261]
Only the General Council can supply this lack; and only the General Council, therefore, can quicken the genuinely revolutionary movement in Britain, and consequently throughout the world ....
“If we were to form a federal council in Britain, apart from the General Council, what would be the immediate result? Sandwiched between the General Council of the International and the General Council of the trade unions, the federal council would have no authority whatever, but the General Council would forfeit the power of handling the great lever ... Britain must not simply be treated as one country among several. It must receive special treatment as the metropolis of capitalism.” [262]
It is clear that Marx was aware of the possibility of conflicts arising between the central committee of an international workers’ party (which in his view was or should be represented by the General Council), and the future central committee of a British labour party (which, again according to Marx, would be formed from the British federal council). The need for working from one centre and of operating the same lever, i.e., the British working class, would lead the two bodies, declared Marx, to perform the same tasks, and in such circumstances they would have to depend upon the same basic source of power and influence, and must inevitably come into collision in the course of their operations. The danger would grow more menacing as the divergence of opinions on the political held increased between the General Council and the British federal council; between the opposing embodiments of internationalism on the one hand and nationalism on the other. In consequence of the opportunism of the leaders of the working-class movement of those days (an opportunism Marx was quick to detect), the probability of such a conflict became almost a certainty. While the conflicts that might arise between the two centres appeared in general so undesirable and so dangerous to the cause of revolution, the danger seemed all the more threatening in the case of Great Britain, which, in consequence of the advanced development of capitalism within its borders, appeared to Marx to be the most important motive force propelling society towards a revolutionary change.
But when, after the fall of the Paris Commune, it became clear that the first step must be the creation of an independent political workers’ party, and that the centre of gravity of the proletarian movement was being transferred to the continent, then Marx was the foremost in recognising that it was necessary to set up, in Great Britain as elsewhere, a federal council, which might prove to be the germ of the British workers’ party. The London Conference, therefore, decided in favour of forming a British federal council.
The resolution was carried into effect at the end of October, 1871, when a temporary committee was set up in London under the chairmanship of Maltman Barry and with John Hales acting as secretary. As soon as the local branches of the International in Britain and the General Council had approved of the rules drawn up by the temporary committee, a permanent federal council was elected. The first activities of the new body were crowned with success. Many new branches were formed, [263]and ever increasing numbers of trade unionists rallied to the International. In Ireland, too, the international soon had its branches, in the defence of which the General Council took up a decidedly militant attitude towards the British Government. [264]However, the Irish organisations did not form a constituent part of the British Federation. They were directly under the control of the General Council. Still, as events were to show, all endeavours for the creation of an independent workers’ party in Great Britain, competent to confront the bourgeoisie both the economic and the political fields, proved unsuccessful during this epoch.
I have already shown that the British workers contemplated the International with a severely practical eye. They looked upon it as an organisation capable of preventing the importation of cheap foreign labour, and able to assist in the struggle for electoral rights and the introduction of reform legislation. As Marx observed: “The trade unions ... will hold aloof from the International until they fall upon evil times. Then they will come rushing to the International for help.” [265]And, indeed, when strikes took place, the International actively supported the strikers and prevented the introduction of strike-breakers from abroad. But the International did not prove strong enough to wean the British proletariat from bourgeois outlooks and to unite it for the general political struggle. Content with their victories in the industrial arena, and fearful lest a rupture with the bourgeoisie should expose their organisations to reprisals, the British workers, and especially their leaders, were already in those days consolidating themselves into a moderate and cautious working-class bureaucracy which acknowledged the need for joint political action with the liberal bourgeoisie. Concerning such leaders of the movement, Marx declared at the Hague Congress of the International, that it might be reckoned an honour not to be a recognised leader of the workers seeing that all the “recognised leaders” were to be found supporting the liberal party. As typical leaders we may mention Odger and his friends who, in order to please the bourgeois hypocrites, resigned from the International as a demonstration against the “horrors” of the Paris Commune. [266]
Odger and Co. were merely the first rats to forsake a ship which they considered both incommodious and risky. The Act of 1871, which, as we have already learned, had legalised the trade unions but had at the same time imposed grave penalties on those who should promote strikes, was hailed by leaders such as Applegarth as a tremendous victory, for it enabled them to take a rest, and to transfer their energies to peaceful organisation. This was the beginning of the era of “class-collaboration” which characterised the whole period of “working-class liberalism.”
Since British manufacturers still continued to flood the world market, the capitalists found it an easy task to capture the working-class aristocracy, which at that time was organised in craft unions. In addition, there was a revival of industrial activity following upon the crisis of 1866. The latter had greatly sharpened the conflict between workers and employers, had led to frequent strikes, and turned the workers towards the International; but the industrial revival had the effect of a soothing syrup as far as the British proletariat was concerned. In those days it was still possible to hope for a few improvements in the workers’ lot without resorting to strikes, and such a possibility was not long in turning the leaders of the trade-union movement away from the more forcible methods of fighting.
The workers’ organisations, which were mainly composed of members of the working-class aristocracy, became more and more corroded with opportunism. The trade-union leaders, who not long since had been fairly radical in outlook, were not slow to change their tone and to adopt a more conservative attitude than that of the broad masses of trade unionists. It not infrequently happened that the workers struck in defiance of the wishes of their leaders, who, for their part, did their utmost to prevent the strike, and to cut it short. With the growth of the unions and the accumulation of trade-union funds, and with the development of a trade-union bureaucracy imbued with a conservative outlook and inspired by a philosophy of class collaboration, an antagonistic attitude towards strikes became increasingly manifest. Other methods were preferred, such as peaceful negotiation, courts of arbitration, mediation, etc., etc. The trade-union leaders adopted the point of view of the capitalists, namely that wages must be determined by the amount of profit and the general state of the market. Hence arose the idea of the “sliding scale” of wages, an idea which embodied the triumph of bourgeois political economy over proletarian political economy.
Adaptation to bourgeois outlooks was not only apparent in the realm of economics, but likewise in the realm of politics. The notion of the seizure of power by the working class, which had been promulgated by the Chartists, was now quite forgotten. Not only was the fight for universal suffrage abandoned, but even the thought of creating an independent workers’ party which should defend the general interests of the working class in the face of a united bourgeoisie was no longer entertained. The idea of running independent labour candidates in opposition to the extant bourgeois parties of conservatives and liberals almost fell through. The very few representatives of the workers who by a turn of fate were returned to parliament, slavishly licked the boots of the bourgeoisie, and usually came to form a part (and not even as a rule the most advanced part) of the liberal party. Some were actually working-class conservatives! In a word, they were part and parcel of the bourgeois order.
The bourgeoisie, following suit, now began to change its attitude towards the workers, or rather towards the leaders of the proletariat, who, by their tactics of class collaboration, had won the gratitude of the governing class. Formerly the capitalists had been used to treat all the workers as outlaws, pariahs, and serfs. Assured of the pliability of the working-class aristocracy and of the “reasonableness” of its leaders, they began to allow these leaders a very restricted share in social life. The trade-union chiefs, who until recently had been regarded as dangerous revolutionists, now came to participate in the institutions of capitalist society, not as delegates of the workers, but as nominees of the Government. They became members of school boards, sat as poor law guardians, took part in royal commissions, and were appointed to governmental posts. Thus the appearance of present-day leaders of the Labour Party, such as Henderson and Thomas, in the role of privy councillors is nothing so very new after all. The adaptation of labour leaders to the bourgeois regime is not without its precedent, and may be traced back to the late sixties of the nineteenth century. Lucraft, who had left the General Council in so melodramatic a manner, now took his seat on a school board side by side with Lord Lawrence. Another trade-union leader, Applegarth, who was a member of the General Council, was in 1872 appointed a member of the royal commission on the Contagious Diseases Acts, being thus the first British working man to be styled by the sovereign as “our Trusty and Well-beloved.” In fact, the ground was already being prepared for the possibility that labour leaders might become “His Majesty’s ministers.” We see, therefore, how correct was Marx’s somewhat acrimonious declaration about the “so-called leaders” of the British working class. The words which were uttered when Odger made his exit from the General Council may even more aptly be applied to the other leaders
“He made use of the International in order to win the confidence of the working class, and he left the ranks of the Association as soon as he was convinced that the principles upon which the organisation was founded would be a stumbling block in the way of his political career.”
At first the leaders of the workers accommodated themselves to bourgeois life in the industrial and political fields; this was followed by a further adaptation on the ideological plane – in the realm of ideas. By utilising the whole of their powerful apparatus for corrupting the minds of the people, the governing class set about perverting the labour leaders, instilling into them the spirit of hypocrisy, of servility, of spiritual aridity, and forcing them to bow before the conventional “proprieties” of the bourgeois world. The representitives of the workers this became “respectable,” “decorous,” “honourable,” “sane,” citizens, entitled to style themselves “Mr.,” and as such they were admitted into the front ranks of capitalist society, where they became the watch-dogs of the existing order. The International, which they had never been prepared to use as a battering-ram, could henceforward only be a drag on their movements, and could serve only to “compromise” them in the eyes of the bourgeoisie. Any pretext would do to sever their connexion.
In such circumstances, and in view of the turncoat policy of the working-class leaders, the attempt to create in Great Britain a workers’ party that should be independent of all other political parties, a party inspired with revolutionary zeal, was foredoomed to failure. The attempt was actually made, and at first there seemed to be some prospect of success, for, although the leaders went over to the enemy, the masses (those sections of the masses which had been influenced by the ideology of the International) did not immediately follow the example of the leaders by deserting the International Workingmen’s Association.
The first congress of the British Federal Council of the International met at Nottingham on July 21, 1872. It declared that an independent working-class party was essential to the conduct of the political struggle of the proletariat; it produced a program which, generally speaking, was inspired with socialist ideas; and it urged the trade unions to join the new workers’ party and the International. Furthermore, the congress expressed its agreement with the resolutions of the London Conference; and it protested against the rumours current in the bourgeois press concerning a split in the International. In these respects, the first steps of the British federation were fairly successful. Nevertheless, certain tendencies became obvious at the Nottingham Congress which threatened to split the International. Thus, during the discussion concerning the rules for the British federation, which were in general based upon those of the International as a whole, Hales proposed an amendment to the effect that the British Federal Council might eater into direct relationships with the federations of other lands and ignore the General Council. [267]The amendment was adopted in spite of a certain amount of opposition. Another resolution adopted by the Nottingham Congress was aimed directly at the General Council (although the proposers formally denied that such was their intention). This motion was to curtail the powers of the General Council in the matter of the exclusion of such sections of the International as had infringed the rules and constitution of that organisation. [268]All this only goes to prove that the British federation had joined the ranks of the opponents to the General Council.
Even more dangerous was the marked divergence of views between the British Federal Council and the General Council in the matter of program and tactics – the real difference being, here as always, upon matters of organisation. The leading part in the British Federal Council was played (as it had been played at the Nottingham Congress) by the trade-union leaders, who in subsequent years were successful in reversing the natural course of evolution by making the proletariat adopt “working-class liberalism”; at the same time they paved the way for their own migration into the liberal camp. Hales, Eccarius, Burnett, and others, though they were working in the British Federal Council, and gave to that body such influence as it possessed, differed but little in essence from Allen, Odger, Lucraft, and Applegarth. The members of the latter group differed from those of the former in that they accomplished their evolution more rapidly, and earlier left their “revolutionary” chrysalis in order to become “liberal” butterflies. The others were bound to tread the same path in due time. Their exit from the International marked a definite stage in their bourgeois metamorphosis, but the causes of that metamorphosis were deep-rooted in their nature.
In the very earliest days of the activity of the first Federal Council, it received a delegation from the bourgeois-democratic Land and Labour League, asking the council for aid in the cause of republican democracy. Upon the proposal of Hales, the Federal Council acceded to the request of the delegation. The incident is characteristic, inasmuch as, to the very last, the British Federal Council could never properly differentiate itself from the League in question, and from similar bodies of a non-proletarian type. For this very reason, the Federal Council could do nothing to counteract bourgeois influences in the trade unions; nor could it offer any serious opposition to the liberal trend in the trade unions, whose leaders were now rubbing shoulders with the bourgeois liberals in various organisations working for electoral reform. Even Eccarius, a veteran from the days of the Communist League, a sometime Marxist, came at last to support these dubious activities of the British Federal Council, and began to preach collaboration with the bourgeois democrats in order to promote working-class parliamentary candidatures. In these circumstances, what was to be expected of the other working-class leaders, breathing a “liberal-labour” atmosphere and poisoned by its fumes? When the effects of the industrial crisis wore off and the ferment among the labouring masses subsided, these leaders entered the fold of the “Great Liberal Party” which they regarded as the only source of salvation.
Contents|Marxists Internet Archive
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JFK Assassination Records - 2022 Additional Documents Release | National Archives
Have a question about JFK Assassination Records? Ask it on HistoryHub! The National Archives and Records Administration (NARA) is processing previously withheld John F. Kennedy assassination-related records to comply with President Joe Biden’s Memorandum for the Heads of Executive Departments and Agencies on the Temporary Certification Regarding Disclosure of Information in
JFK Assassination Records - 2022 Additional Documents Release
The National Archives and Records Administration (NARA) is processing previously withheld John F. Kennedy assassination-related records to comply with President Joe Biden’sMemorandum for the Heads of Executive Departments and Agencies on the Temporary Certification Regarding Disclosure of Information in Certain Records Related to the Assassination of President John F. Kennedy, requiring disclosure of releasable records by December 15, 2022. The National Archives has posted records online to comply with these requirements.
Accessing the Release Files
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JFK Table
Row Num Record Num NARA Release Date Formerly Withheld Doc Date Doc Type File Num To Name From Name Title Num Pages Originator Record Series Review Date Comments Pages Released
Row Num Record Num NARA Release Date Formerly Withheld Doc Date Doc Type File Num To Name From Name Title Num Pages Originator Record Series Review Date Comments Pages Released
4202 104-10101-10205 12/15/2022 Redact 12/13/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE: SENDING HMMS 3283 POUCH 8420. 1 CIA JFK 03/09/2022 JFK33 : F8 : 20040108-1032785 : 1
4203 104-10101-10207 12/15/2022 Redact 12/13/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MULTIPLE ADDRESSEES DIRECTOR BOOK CABLE:NEAR EAST-AFRICA BRIEF 5 CIA JFK 11/30/2022 JFK33 : F8 : 1997.05.15.17:39:56:903106 : 5
4204 104-10101-10208 12/15/2022 Redact 12/14/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A WITHHELD DIRECTOR CABLE:REF A SUSPICIONS CONFIRMED WITH SEVERAL VARIATION PP NUMBERS - PLANNING DEBRIEFINGS? 1 CIA JFK 07/04/2022 JFK33 : F8 : 1997.05.15.17:42:47:170106 : 1
4205 104-10101-10211 12/15/2022 Redact 12/14/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MERIDA INFO MEXICO CITY DIRECTOR CABLE:OPERATIONAL APPROVAL FOR LIHACK-ONE CANNOT BE OBTAINED UNTIL 1 CIA JFK 07/04/2022 JFK33 : F8 : 1997.05.15.18:05:13:340106 : 1
4206 104-10101-10214 12/15/2022 Redact 12/16/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A SANTIAGO, MERIDA INFO MEXICO CITY DIRECTOR CABLE:CONCUR PASSING SANITIZED VERSION 1 CIA JFK 11/30/2022 JFK33 : F8 : 1997.05.15.18:17:05:983106 : 1
4207 104-10101-10215 12/15/2022 Redact 12/14/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MULTIPLE ADDRESSEES DIRECTOR BOOK CABLE:20 DECEMBER IS 46TH ANNIVERSARY OF FOUNDING OF SOVIET STATE SECURITY ORGANIZATION. 3 CIA JFK 05/07/2021 JFK33 : F8 : 1997.05.15.18:21:47:170106 : 3
4208 104-10101-10216 12/15/2022 Redact 12/16/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MULTIPLE ADDRESSEES DIRECTOR BOOK MESSAGE:NEAR EAST-AFRICA BRIEF 2 CIA JFK 12/01/2022 JFK33 : F8 : 1997.05.15.18:24:39:890106 : 2
4209 104-10101-10220 12/15/2022 Redact 12/17/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:HQS RECOMMENDS REPLACEMENT FIVE ROBOT STAR CAMERAS 1 CIA JFK 03/09/2022 JFK33 : F8 : 1997.05.15.18:37:55:810106 : 1
4210 104-10101-10221 12/15/2022 Redact 12/17/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A OTTAWA INFO OTHERS DIRECTOR CABLE:40 H.P. OUTBOARD MOTOR MODEL R.D.S. SERIAL NUMBER 2 CIA JFK 05/07/2021 JFK33 : F8 : 1997.05.15.18:42:26:936106 : POOR LEGIBILITY IN PARTS 2
4211 104-10101-10223 12/15/2022 Redact 12/17/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A SAO PAULO INFO MULTIPLE ADDRESSEES DIRECTOR CABLE:REF REPORTED THAT HEMISPHERIC MEETING OF COMMUNISTS TO TAKE PLACE 1 CIA JFK 04/04/2022 JFK33 : F8 : 1997.05.15.18:49:23:780106 : 1
4212 104-10101-10227 12/15/2022 Redact 12/17/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MULTIPLE ADDRESSEES DIRECTOR BOOK CABLE:FYI: ACTION INTENDED PARA 2 REF WAS UNATTRIBUTABLE SURFACING 1 CIA JFK 05/07/2021 JFK33 : F8 : 1997.05.15.19:08:24:920106 : 1
4213 104-10101-10228 12/15/2022 Redact 12/17/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY INFO CARACAS DIRECTOR CABLE:MR. ( ) MAY CONTINUE ON TO CARACAS. 1 CIA JFK 05/09/2022 JFK33 : F8 : 1997.05.15.19:10:23:856106 : 1
4214 104-10101-10230 12/15/2022 Redact 12/17/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:NO TRACES CORBEA 1 CIA JFK 07/04/2022 JFK33 : F8 : 1997.05.15.19:15:20:216106 : 1
4215 104-10101-10231 12/15/2022 Redact 12/18/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A CARACAS INFO MEXICO CITY DIRECTOR CABLE: ( ) SCHEDULED LEAVE MEXI FOR CARA DIRECT GUEST FLIGHT 19 DEC. 1 CIA JFK 05/09/2022 JFK33 : F8 : 1997.05.19.15:32:24:590106 : 1
4216 104-10101-10232 12/15/2022 Redact 12/18/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MULTIPLE ADDRESSEES DIRECTOR BOOK MESSAGE:NEAR EAST-AFRICA BRIEF. 2 CIA JFK 11/21/2022 JFK33 : F8 : 1997.05.19.16:01:44:750106 : 2
4217 104-10101-10233 12/15/2022 Redact 12/18/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:APPRECIATE REF D ASSISTANCE. 1 CIA JFK 11/21/2022 JFK33 : F8 : 1997.05.19.16:04:18:310106 : 1
4218 104-10101-10234 12/15/2022 Redact 12/18/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:IDEN 1 CIA JFK 03/09/2022 JFK33 : F8 : 1997.05.19.16:05:57:560106 : 1
4219 104-10101-10236 12/15/2022 Redact 12/11/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE: APPRECIATE MATERIAL FORWARDED IN REF. CAN COPY OF NEGS 2 CIA JFK 03/09/2022 JFK33 : F8 : 20040108-1032788 : 2
4220 104-10101-10237 12/15/2022 Redact 12/19/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:FOLLOWING HQS TRACES VLADIMIR PETROVICH TIKHONOV 1 CIA JFK 03/09/2022 JFK33 : F8 : 1997.05.19.16:20:00:390106 : 1
4221 104-10101-10238 12/15/2022 Redact 12/18/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:NO TRACES PETERSON HDQS FILES. ASSUME ODENVY DOING 1 CIA JFK 11/21/2022 JFK33 : F8 : 1997.05.19.16:23:23:950106 : 1
4222 104-10101-10239 12/15/2022 Redact 12/19/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MULTIPLE ADDRESSEES DIRECTOR BOOK MESSAGE:REUTERS, UPI, AP REPORT FROM MOSCOW 18 DECEMBER THAT APPROX FIVE HUNDRED AFRICAN STUDENTS GATHERED 4 CIA JFK 05/07/2021 JFK33 : F8 : 1997.05.19.16:27:06:043106 : PORTIONS ILLEGIBLE 4
4223 104-10101-10241 12/15/2022 Redact 12/19/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY INFO JMWAVE DIRECTOR CABLE:CONCUR HANDLING CONDITIONS AMBARB/53 OUTLINED IN REFS 1 CIA JFK 03/09/2022 JFK33 : F8 : 1997.05.19.16:31:28:436106 : 1
4225 104-10101-10244 12/15/2022 Redact 12/19/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:STAFFER IDENTIFYING SELF AS RICHARDSON PHONED 1 CIA JFK 11/21/2022 JFK33 : F8 : 1997.05.19.16:40:55:216106 : PORTIONS ILLEGIBLE 1
4226 104-10101-10246 12/15/2022 Redact 12/19/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:IN MEETINGS WITH HDQS REPS, MEXI ( ) REP STATED HAD DISCUSSED WITH 1 CIA JFK 05/07/2021 JFK33 : F8 : 1997.05.19.16:45:37:340106 : 1
4227 104-10101-10247 12/15/2022 Redact 12/19/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:PLEASE ADVISE IF SAMBORA LEGEND COMPLETED AND ALL 1 CIA JFK 05/07/2021 JFK33 : F8 : 1997.05.19.16:57:00:623106 : 1
4228 104-10101-10248 12/15/2022 Redact 12/19/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:HQS DESIRES MEXI UNDERTAKE EFFORT PROVIDE REPORT ON 2 CIA JFK 05/07/2021 JFK33 : F8 : 1997.05.19.17:00:30:310106 : 2
4229 104-10101-10249 12/15/2022 Redact 12/25/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MULTIPLE ADDRESSEES DIRECTOR BOOK MESSAGE:WORLD BRIEF 8 CIA JFK 05/07/2021 JFK33 : F8 : 1997.05.19.17:04:04:873106 : 8
4230 104-10101-10250 12/15/2022 Redact 12/19/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MULTIPLE ADDRESSEES DIRECTOR BOOK MESSAGE:LATIN AMERICA BRIEF. 7 CIA JFK 11/23/2022 JFK33 : F8 : 1997.05.19.17:07:33:280106 : 7
4231 104-10101-10252 12/15/2022 Redact 12/19/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:APPRECIATE REF BUT PREFER NOT MAKE COLD APPROACH TO SUBJ ON 1 CIA JFK 03/09/2022 JFK33 : F8 : 1997.05.19.17:29:49:373106 : 1
4232 104-10101-10253 12/15/2022 Redact 12/20/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE: ALTHOUGH TAKE MUCH BETTER ON TAPES WHERE PUMP OFF, GENERAL AUDIDBILITY 1 CIA JFK 03/09/2022 JFK33 : F8 : 20040108-1032789 : 1
4233 104-10101-10254 12/15/2022 Redact 12/20/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MULTIPLE ADDRESSEES DIRECTOR BOOK MESSAGE:NEAR EAST-AFRICA BRIEF. 2 CIA JFK 11/21/2022 JFK33 : F8 : 1997.05.19.17:35:17:280106 : 2
4234 104-10101-10255 12/15/2022 Redact 12/20/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MULTIPLE ADDRESSEES DIRECTOR BOOK CABLE:FOLLOWING, AS WELL AS EARLIER, CABLES THIS SERIES INTENDED 5 CIA JFK 05/07/2021 JFK33 : F8 : 1997.05.19.17:38:17:560106 : 5
4235 104-10101-10256 12/15/2022 Redact 12/21/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MULTIPLE ADDRESSEES COMMUNICATIONS BOOK MESSAGE:NOW ACTIVE MEMBER AXANET AND AUTHORIZED HANDLE ODYOKE 1 CIA JFK 05/07/2021 JFK33 : F8 : 1997.05.19.17:45:40:390106 : 1
4236 104-10101-10257 12/15/2022 Redact 12/20/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:INTERVIEW WITH ( ) REVEALS FOLLOWING: 4 CIA JFK 05/07/2021 JFK33 : F8 : 1997.05.19.17:48:46:793106 : 4
4237 104-10101-10258 12/15/2022 Redact 12/20/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:SOV DIP COURIER VLADIMIR V. BYKOV AND LEONID V. MILOVIDOV 1 CIA JFK 11/23/2022 JFK33 : F8 : 1997.05.19.17:51:12:263106 : PORTIONS ILLEGIBLE 1
4238 104-10101-10259 12/15/2022 Redact 12/20/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY INFO WAVE DIRECTOR CABLE:REF INFO MUCH APPRECIATED. REQUEST STATION OBTAIN 1 CIA JFK 04/04/2022 JFK33 : F8 : 1997.05.19.17:53:37:483106 : 1
4239 104-10101-10261 12/15/2022 Redact 12/20/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A RIO DE JANEIRO AND OTHERS DIRECTOR CABLE: IN VIEW INDEFINITE PLANS, CONFLICT OF INFO AND PRESSURE 1 CIA JFK 11/23/2022 JFK33 : F8 : 20040108-1032790 : 1
4240 104-10101-10262 12/15/2022 Redact 12/20/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:CONCURS PARA FOUR REF A WHICH CROSSED REF B. 1 CIA JFK 05/07/2021 JFK33 : F8 : 1997.05.19.18:08:13:750106 : 1
4241 104-10101-10263 12/15/2022 Redact 12/20/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A JMWAVE, MEXICO CITY DIRECTOR CABLE:HQS CONCURS BETTER PAY BRIBE RATHER THAN ALERT GOM.. 1 CIA JFK 07/04/2022 JFK33 : F8 : 1997.05.19.18:10:06:716106 : 1
4242 104-10101-10264 12/15/2022 Redact 12/21/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:SUBJECT BORN 13 MARCH 1930, SANTIAGO DE CUBA IS LISTED AS COMMUNIST 1 CIA JFK 03/09/2022 JFK33 : F8 : 1997.05.19.18:12:23:983106 : 1
4243 104-10101-10267 12/15/2022 Redact 12/21/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXI INFO MANI, HONG DIRECTOR CABLE:REQUEST TRACES HENRY YAMADA, CIT US, PDOB CALIFORNIA 1923, JAPAN 1946-48 1 CIA JFK 11/21/2022 JFK33 : F8 : 1997.05.19.18:20:47:936106 : 1
4244 104-10101-10268 12/15/2022 Redact 12/22/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A MEXICO CITY DIRECTOR CABLE:LETTER SENT SPECIAL DELIVERY. GUIDANCE REQUESTED REF WILL 1 CIA JFK 11/23/2022 JFK33 : F8 : 1997.05.19.18:22:21:403106 : 1
4245 104-10101-10272 12/15/2022 Redact 11/14/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 201-289248 MEXICO CITY DIRECTOR REASSIGNMENT FITNESS REPORT 1 CIA JFK 11/23/2022 JFK33 : F7 : 1996.11.01.20:27:14:793075 : 1
4246 104-10101-10273 12/15/2022 Redact 11/01/1963 [ PDF ] PAPER - TEXTUAL DOCUMENT 201-289248 MEXICO CITY DIRECTOR TRACE FRANKLIN FISHER 1 CIA JFK 07/04/2022 JFK33 : F7 : 1996.11.01.21:49:43:950075 : 1
4248 104-10102-10013 12/15/2022 Redact 08/03/1962 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A DIRECTOR WITHHELD LENGTHY MEETING 1 AND 2 AUG STATED FIRMLY DETERMINED RETURN CUBA IN EFFORT OVERTHROW REGIME. 3 CIA JFK 06/21/2022 JFK34 : F7 : 1993.07.19.16:13:50:810270 : 3
4249 104-10102-10014 12/15/2022 Redact 08/17/1962 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A DIRECTOR PARIS TWO LENGTHY SESSIONS ON 16 AUG 4 CIA JFK 05/07/2021 JFK34 : F7 : 1993.07.19.16:17:32:280270 : 4
4250 104-10102-10043 12/15/2022 Redact 04/20/1977 [ PDF ] PAPER - TEXTUAL DOCUMENT 80T01357A HOPKINS, CHRIS, LAD/TASK FORCE IDENTIFICATION OF SENSITIVE SOURCE. 1 CIA JFK 05/07/2021 JFK34 : F7 : 1993.07.19.17:13:49:750270 : 1
| https://www.archives.gov/research/jfk/release2022?ftag=MSF0951a18&order=Record%20Series&page=84&sort=asc |
68hc12 | Freescale's new roadmap - 9s12 not looking good?| page 3
posts 21-30 - They're going to introduce a new line of RISC 8 bit MCU's: http://www.embedded.com/showArticle.jhtml?articleID=181502582 some quotes: " The...
Freescale's new roadmap - 9s12 not looking good?
> The LPC2* have no non-intrusive debugging capability like BDM. For
> me, that's a strong reason, because I have some
"hard realtime"
> applications which I can't debug with interrupt driven methods. So I
> needed an emulator...
What is "non-intrusive"? The LPC2103 definitely has JTAG based
in-circuit debugger interface, much like the OnCE on the Motorola
MCORE chips or the BDM on the MPC8xx chips. So what's the
difference between the HC12 BDM and those?
Thanks,
Zoltan
it's called 9S12C32 and it's around $6 (1K)-- been out there about 3
years now. oh, and the bus speed is 25Mhz. somebody even made a
"stamp-killer" with it: read
http://www.seanet.com/%7Ekarllunt/binload.htm
--- In 68HC12@68HC..., BobGardner@... wrote:
>
> I've thought for years that an HC11F1 with 32K of flash on chip
would have
> been a mega avr killer. There are a few things the
hc11 has that the
avrs
> dont.... swi, rti, illegal opcode trap, von neuman
achetecture so
you dont need
> extra const char print librbray functions. It
already ran at 20mhz
clock...
> darn avr only runs at 16mhz still.... they havent
pushed their
20mhz process
> into their mega cpus yet.... I bet all you guys
would design in a
new 32k flash
> hc11 next month if it came out wouldnt you?
>
>
>
>
mculater12 wrote:
[HC11F1 successor]
> it's called 9S12C32 and it's around $6 (1K)--
been out there about 3
the C32 has no external memory interface and/or less I/O.
Oliver
--
Oliver Betz, Muenchen
Zoltan wrote:
[The LPC2* have no non-intrusive debugging capability like BDM]
> What is "non-intrusive"? The LPC2103
definitely has JTAG based
> in-circuit debugger interface, much like the OnCE on the Motorola
> MCORE chips or the BDM on the MPC8xx chips. So what's the
> difference between the HC12 BDM and those?
Probably I'm not well informed. I heared that there should be some
devices with extended debug possibilities, but AFAIK you can't read
LPC2103 memory without interrupting the running application.
Can you tell me which ARM7 devices support real "background" memory
access working without the help of a interrupt driven target monitor
firmware?
And which debugger (hardware + software, pricing) supports this
feature?
BTW: _much_ more pins are needed for the ARM7 debug interface!
Maybe the limitations I mentioned are no more valid, this could
facilitate a switch to small ARM7. Yesterday I learned that the
S12GC16 costs more than twice the amount of a LPC2102 (>3,6EUR@1000
vs. 1,8EUR at even smaller quantities)! Annoying that they need two
supply voltages and don't work at 5V.
Oliver
--
Oliver Betz, Muenchen
"Oliver Betz" <list_ob@list...> wrote:
> Zoltan wrote:
>
> [The LPC2* have no non-intrusive debugging capability like BDM]
>
> > What is "non-intrusive"? The LPC2103 definitely has JTAG
based
> > in-circuit debugger interface, much like the OnCE on the Motorola
> > MCORE chips or the BDM on the MPC8xx chips. So what's the
> > difference between the HC12 BDM and those?
>
> Probably I'm not well informed. I heared that there should be some
> devices with extended debug possibilities, but AFAIK you can't read
> LPC2103 memory without interrupting the running application.
I do not think you can - that's why I said it was like the MCORE and
the MPC8xx debug port. Like those chips, it works by allowing you to
issue arbitrary CPU instructions through the debug port and have a
special register to transfer data between the chip and the debug SW.
Actually you can't read the memory even with the 683xx and HC16 BDM
while the code is running, as far as I know. You have to halt the chip
for that, although you do not need to use the CPU core to access the
memory.
> Can you tell me which ARM7 devices support real
"background" memory
> access working without the help of a interrupt driven target monitor
> firmware?
I don't think any does. You can have 'watchpoints' where the on-chip
debug HW checks all bus cycles against accessing an address but if you
want to actually read/write memory or registers, you have to halt the
core. You don't need any target resident SW for that, but it is not
real-time. I'll check if the watchpoint stuff can actually tell you
what the new value of the watched location is without halting the
core, but I doubt it.
> And which debugger (hardware + software, pricing)
supports this
> feature?
Well, the devkits and tools vary in price, USB based debug pods
and (limited) compiler for Windows are around US $200 - $300.
If you go to the Philips website and look up the 2103 they have
a handful of links to devkit, debug pod and SW vendors. I have
no clue if there's gdb/Linux support for any of those pods, of
course gcc happily compiles for ARM.
> BTW: _much_ more pins are needed for the ARM7
debug interface!
No quastion about that - you can hardly beat a 1-wire interface :-)
Don't get me wrong, I don't want to convert you from HC12 to ARM,
I just didn't know what you meant by non-intrusive, that's all.
On the other hand, those ARM chips are really cheap.
> Maybe the limitations I mentioned are no more
valid, this could
> facilitate a switch to small ARM7. Yesterday I learned that the
> S12GC16 costs more than twice the amount of a LPC2102 (>3,6EUR@1000
> vs. 1,8EUR at even smaller quantities)! Annoying that they need two
> supply voltages and don't work at 5V.
Yes, that's a drawback. The MCORE is quite nice in that sense, it runs
from 3.3V but it's 5V tolerant and the A/D section actually runs from
5V and of course converts between 0 and 5V. A tad more expensive than
the HC12, though, around $15 in quantities for a 33MHz 256K FLASH 32K
RAM part (MMC2114). Comes with or without external bus, too. An other
cool but orphaned Motorola part :-(
Zoltan
Zoltan wrote:
[LPC2* non-intrusive debugging capability?]
> I do not think you can - that's why I said it was
like the MCORE and
> the MPC8xx debug port. Like those chips, it works by allowing you to
I see.
[...]
> Don't get me wrong, I don't want to convert you
from HC12 to ARM,
I didn't think you want to convince me. I only wanted to be sure that
my knowledge about LPC2* debug capabilities is still correct, as I'm
considering to use them, but still had no application justifying the
switch.
Working with the HC12 since several years now, I have to say that the
background memory access is priceless. Especially in small and/or
"hard realtime" devices it's extremly useful that you simply attach
four wires and get reasonable access to the CPU. If I understand
correctly, the coldfire BDM is even better.
Well, if I save enough money buying ARM7, I can pay the longer debug
time and/or buy an emulator.
Oliver
--
Oliver Betz, Muenchen
--- In 68HC12@68HC..., "hc08jb8" <hc08jb8@...> wrote:
> If given a choice between ColdFire and the ARM9s
> which would be a safe bet?
In my mind it depends on your application. I've used ARM7's from both
Atmel and Philips and they are terrific. But I seriously HATE
programming in ARM assembly language. The ARM chips have a lot of
modes, and many modes have differing sets of shadow registers. And the
pipeline makes it hard to work out memory offsets. I find myself
getting frustrated any time I write a small asm routine for Arm.
The 68K/Coldfire devices have a very sweet assembler programming
model. Motorola studied the PDP-11, which was loved by everyone back
then, and made some improvements to come up with the basics. I really
think this is an ideal model: as close as I'm likely to see in my
lifetime. The key word they had in mind during its design is
"orthogonal". Everything is consistant and the opcodes work the same
on all the registers and there's not many special cases in the form of
limits. You never hear someone say: "that looks like it should work,
but it doesn't". With the 68K, if it looks like it should work, it
almost always DOES.
My only concern is about which family Freescale will move towards in
the 32 bit space for the future. I have never used Arm9's, but I might
someday. I'm also impressed by the very new Arm Cortex M-8 core
(Freescale is using the A-8 in some future designs, I think, but I
could be wrong). The Cortex has the Thumb-2 instuction set, which is a
much nicer 16 bit instruction set for Arm devices than the original
Thumb instructions.
If you're going to code in C (which I guess is the case), then the
issue of ugly vs sweet internal programming models isn't relevant for
you. ARMs give you a lot of horsepower for a given number of
electrons, which is why they are so popular. I don't know if I'd use a
Freescale Arm device, though - I am more than a little disappointed in
their marketing of Arm devices. I get the feeling that the people in
charge don't personally like Arm, and they're only using it because of
strong demand by some specific big customers. The Arm core is
something you license from the Arm company, and Freescale/Motorola
historically always prefers to roll their own designs.
I also have no experience with PowerPC, so I don't want to leave you
with the impression that this is not a good option. I really don't
know if this is a good contenter for the future.
Eric
not quite true-- the 68HC11F1 has 68 pins, 1K RAM, and
non-multiplexed memory interface, vs. the 9S12C32 available in 80-pin
QFP, with 2K RAM and multiplexed memory interface
--- In 68HC12@68HC..., "Oliver Betz" <list_ob@...> wrote:
>
> mculater12 wrote:
>
> [HC11F1 successor]
>
> > it's called 9S12C32 and it's around $6 (1K)-- been out there about 3
>
> the C32 has no external memory interface and/or less I/O.
>
> Oliver
> --
> Oliver Betz, Muenchen
>
--- In 68HC12@68HC..., "Oliver Betz" <list_ob@...> wrote:
> Well, if I save enough money buying ARM7, I can
pay the longer debug
> time and/or buy an emulator.
You guys are right about JTAG debugging on the ARM being less good
than BDM. But the overall costs of ARM dev boards has been dropping a
lot, and they're now quite cheap. Perhaps cheaper than a Coldfire
board/BDM combo.
$300 can get you a nice dev board that uses the lpc2148 USB-enabled
ARM chip, along with a USB JTAG debug device. And it comes with a 32K
limited version of the IAR Embedded Workshop, which is good enough for
many purposes.
I got a cool little lpc2103 dev board disguised as a Christmas tree
with a set of blinking LEDs under program control, and a 2 line LCD
screen. The cost was about $20, including postage from Sweden to the
US. This kind of power in a fully assembled board is incredible at
this price. I guess some Europeans would have needed to pay a high tax
on it, but it's still a great deal. These devices were connected to a
PC serial port, and a Java program on the PC connected them to the
Internet, thereby creating a large Christmas tree network where people
could exchange greetings over the holidays. This was made by
EmbeddedArtists.
To use gcc/gdb you'll need a JTAG device with an open API. Amontec
makes a USB device with an open API, but most gcc uses use a Wiggler
clone by Olimex, which is a cheap PC parallel port device.
But I am not recommending that people flock away from the hc12. I
still like it best, especially if I have to write assembler routines
(everyone hates Arm assembly code - even the company reps I've talked
to). And I'll look into the new Coldfire devices - that might be a
great way to do 32 bits.
Eric
Good day Eric,
> 6812 came from the 6811, which came from the 6801,
which came from the
> 6800. So if you want to take this approach the 6800 comes from the
Indeed, I do not wish to belabor this issue. My only point was that the
HC12 was a migratory path taken by the users of the HC11 et all and
therefore had a lot more people familiar with the overall architecture. The
CF had its origins with the 68000, but this too came much later than the
6800/6801 et all, hence the familiarity would not be as large.
>(a guy in my micros class in college built one of
these in a
> shoebox - it was the coolest thing to play with back then).
>
I hate to say it, but I used to "play" a lot with the 6800 derivatives
when
I was in school. In fact, I still have my old 6809 lab project somewhere...
Given the limited amount of memory (EPROM/RAM) we still were able to make
some cool devices (rudimentary voice recognition, HVAC controllers, printer
muxes, etc)
>This is good news, but my point is that FREESCALE does not have such a
>forum because they think there isn't much interest
in 68K/Colfire.
I think that you should talk to other Freescale employees and disti FAEs.
The CF family has a tremendous following with an amazing feature set and
architecture. We have several products based on the CF family and are
starting to migrate a lot of the lower 8 (and 16) bit designs to the CF
family.
As I said in my earlier post, you should really check out the variety of CF
derivatives... All sorts of speeds and features.
> You might be too young to remember the famous Motorola BBS that was
> popular before the Internet became popular. This
was largely
Sadly, I do remember... I guess I am not too young...In fact, I used those
BBSes often.
> Ditto for this forum, but Freescale set up their own hc12 forum, anyway.
I wish I could answer this, but I cannot. Perhaps someone from Freescale
can answer.
> How many of these have Coldfire boards that were
introduced within the
> past 12 months? I'm sure some of them do, but my google searching
> showed that most 68K/Coldfire hardware and software in the marketplace
> tends to be several years old. I'd love to be wrong on this!
Check out my previous post's links... There are a variety of designs that
have been released within the last year. The two CF parts that has me most
excited are:
1. MCF5213... which to me is a HC12 eater
Price and Performance kicks!
2. MCF5329... Ethernet, LCD interface, DDR interface, QSPI, etc
This part rocks!
Also, I think that there is a lot of vendors that do not sell their CF
designs openly...i.e. they sell end-products as opposed to being embedded
solution vendors.
I know that this is true for both my client's and my firm's designs. In
fact, given the 9S12's future rumblings, my client is most likely migrating
to the MCF5213.
> What happened to the cool 68332 chip? It was the best thing going a
> few years ago (maybe 5 or 6 - the older I get the
faster the calendar
> moves for some reason).
Yes, the '332 was (is) awesome. This chip actually dates back to the early
90's ( I know we did a design around 1992/93 with the 332). Consequently,
Freescale considers this to be a mature part and is not high on the priority
scale with adding new features, etc. In fact, as an indicator to the
68332's interest, its Yahoo list (
http://groups.yahoo.com/group/68300/
)
shows very little activity...perhaps a few posts every few months.
Anyway, I think that if you really look at the CF family and implement a
design with it, you will find it to be a very rich and rewarding experience
from both a hardware and software perspective. In my opinion after having
designed both hardware and software (firmware) for the old 6800's, HC11's,
HC08's, HC16s, 68332s, and CFs (5272, 5282, 5213, 5329, etc), I find that
the CF family the best to work with....I know that statement sounds corny,
but it is true... and for those that may be wondering...No, I do not work
for Freescale!
Enough said!
Have a great evening!
Cheers,
Sam
| https://www.embeddedrelated.com/showthread/68hc12/13497-3.php |
Viewpoint: What’s the NEWS? Supporting the identification of the deteriorating patient | British Journal of General Practice
Life & Times
Viewpoint: What’s the NEWS? Supporting the identification of the deteriorating patient
Alison Tavaré
British Journal of General Practice 2020; 70 (695): 291. DOI: https://doi.org/10.3399/bjgp20X709398
Alison Tavaré
Bristol and Primary Care Clinical Lead, West of England Academic Health Science Network. South Plaza, Marlborough Street, Bristol BS1 3NX. Email:
Roles: GP
Article
Figures & Data
Info
PDF
Surgery to stabilise my spine sorted the pain and power was restored to my leg. I was re-admitted feeling vaguely unwell and with a CRP of 600, but that had returned to normal and I arrived home, admittedly with a PICC line in place, but relishing the peace and the contrast to a busy Nightingale Ward.
I remember doors swinging as the F1 ran onto the ward, but this was followed by a very disjointed conversation when I kept saying ‘I feel really, really ill’and being told ‘you can’t have an infection as you have a low temperature and low white cell count’.
My bewildered and non-medical husband watched as his confident and experienced GP wife transformed into an anxious, timid patient whispering ‘you don’t have to have a raised temperature to be sick’.
I remember my heart felt as if it were about to explode, but seeing the cardiac trolley at the end of the bed and knowing the team would not have to go far when I arrested was an odd kind of comfort.
Again something changed; I became very calm as I knew death was imminent and resigned to the inevitable. There was a grey tunnel over my husband’s shoulder and as I gently moved towards it, I told my husband I was about to die but that I loved him, our sons, and my family. Apparently I started to look very pale, and luckily the F1 returned to the ward and put up some fluids; although I still felt very unwell the feeling of doom ebbed away. I spent hours in theatre having the pus washed out and the spinal scaffolding replaced.
Although sepsis was one of the diagnoses on my discharge summary very few people knew what had happened as any discussion provoked vivid and distressing flashbacks.
However, the following year, clinicians at my local trust were raising awareness of sepsis and I offered to share my experience. In preparation I reviewed my notes; there was mention of recent surgery and the PICC line, but as I suspected the provisional diagnosis was a panic attack. Seeing my severely ischaemic electrocardiogram and the evidence that my perception I had been in peri-arrest was correct made me cry. National Early Warning Scores (NEWS) had not been in use at that time but I noted the individual observations, which included both a marked tachycardia and tachypnoea.
My very private experience has now become much more public. I am involved in raising awareness of sepsis and improving the identification and management of the deteriorating patient. As part of this I learned about NEWS and with curiosity I looked again at my observations; my NEWS was 6, or 9 if the NEWS2 update was used and my confusion included. 1There is increasing evidence that the higher the NEWS on admission, the more likely the patient is to die. 2
So why does NEWS matter? As a GP I use NEWS alongside clinical judgement when arranging admissions, so supporting secondary care colleagues deciding where patients should be seen, by whom, and with what urgency. However, I feel strongly that NEWS also protects me as a clinician; if a patient unexpectedly has a high NEWS it makes me think ‘have I missed something?’ Sepsis and an overwhelming feeling of doom undoubtedly made me anxious, so the F1 did not intentionally make a mistake but instead the diagnosis was informed by my behaviour and not my physiology. If NEWS had been in place, a NEWS of 9 would have led to immediate escalation and it is unlikely I would have progressed to peri-arrest.
We all want to do the best for our patients, so think about spreading the NEWS and if it helps you sleep better at night what’s not to like?
© British Journal of General Practice 2020
REFERENCES
1.
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Royal College of Physicians (RCP)
National Early Warning Score (NEWS) 2: Standardising the assessment of acute-illness severity in the NHS London RCP 2017
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| https://bjgp.org/content/70/695/291 |
Entropy | Free Full-Text | Nature of Heat and Thermal Energy: From Caloric to Carnot’s Reflections, to Entropy, Exergy, Entransy and Beyond
The nature of thermal phenomena is still elusive and sometimes misconstrued. Starting from Lavoisier, who presumed that caloric as a weightless substance is conserved, to Sadi Carnot who erroneously assumed that work is extracted while caloric is conserved, to modern day researchers who argue that thermal energy is an indistinguishable part of internal energy, to the generalization of entropy and challengers of the Second Law of thermodynamics, the relevant thermal concepts are critically discussed here. Original reflections about the nature of thermo-mechanical energy transfer, classical and generalized entropy, exergy, and new entransy concept are reasoned and put in historical and contemporary contexts, with the objective of promoting further constructive debates and hopefully resolve some critical issues within the subtle thermal landscape.
by Milivoje M. Kostic
Department of Mechanical Engineering, Northern Illinois University, DeKalb, IL 60115, USA
Entropy 2018 , 20 (8), 584; https://doi.org/10.3390/e20080584
Received: 11 July 2018 / Revised: 3 August 2018 / Accepted: 6 August 2018 / Published: 7 August 2018
(This article belongs to the Special Issue Nature of Heat and Entropy: Fundamentals and Applications for Diverse and Sustainable Future )
Abstract
The nature of thermal phenomena is still elusive and sometimes misconstrued. Starting from Lavoisier, who presumed that caloric as a weightless substance is conserved, to Sadi Carnot who erroneously assumed that work is extracted while caloric is conserved, to modern day researchers who argue that thermal energy is an indistinguishable part of internal energy, to the generalization of entropy and challengers of the Second Law of thermodynamics, the relevant thermal concepts are critically discussed here. Original reflections about the nature of thermo-mechanical energy transfer, classical and generalized entropy, exergy, and new entransy concept are reasoned and put in historical and contemporary contexts, with the objective of promoting further constructive debates and hopefully resolve some critical issues within the subtle thermal landscape.
Keywords:
entransy
;
entropy
;
exergy
;
heat
;
Carnot work potential
1. Introduction—From Caloric to Carnot’s Reflections
There is a need to “shed more light onto dissipative heat”. It is the goal of this treatise to contribute to that aspiration. Richard Feynman once stated, “It is important to realize that in physics today, we have no knowledge what energy is” [
1
]. This statement has a deeper connotation, since we tend to simplify, pre-judge, and proclaim definite meanings of the fundamental concepts, or to discredit new ones. Heat and thermal energy are more subtle and elusive than many other forms of energies. Nature is, and so is heat, what it is, no more and no less. In fact, all other forms of energies are ultimately dissipating in thermal heat, the omnipresent and universal phenomena, quantified with perpetual and irreversible generation of thermal displacement, i.e., entropy. Science and technology have evolved over time on many scales and levels, so that we now have the advantage to look at related historical developments more comprehensively than the pioneers. The fundamental laws of thermodynamics, and especially the issues related to thermal energy and entropy, including the Second law challenges, have been of primary interest and the topic of this author’s past presentations and recent writings. Long-contemplated reflections on some critical issues of thermoscience concepts, from unpublished presentations and selected citations with updates, are presented here to hopefully contribute to further discussions and encourage due debate.
There are many puzzling issues surrounding thermodynamics and the nature of heat, including subtle definitions and ambiguous meanings of very fundamental concepts. In modern times, there is a tendency by some authors to unduly discredit thermal energy as being indistinguishable from other internal energy types. Romer [
2
] argues that “Heat is not a noun”, and proposes to remove it from the dictionary. Ben-Naim [
3
] titles his book “A Farewell to Entropy”, while Leff [
4
] in a series of articles entitled “Removing the Mystery of Entropy and Thermodynamics”, argues surprisingly, that “Entropy can be introduced and understood without ever mentioning heat engines”, and against the “thermal energy” concept in favor of more modern and well-defined “internal energy”.
The nature of heat was intriguing since the introduction of caloric and still is an elusive concept. Lavoisier proposed that “heat is a subtle, weightless substance called caloric”, with the assumption of “conservation of caloric”. The “caloric” was not obviously conserved during dissipative “heat generation” processes, such as drilling, and similarly, so that “caloric theory” has been discredited, regardless of ingenious developments. Caloric was not also conserved in heat engines, as mistakenly assumed by Sadi Carnot [
5
]. In fact, the caloric theory is invaluable to modern calorimetric property measurements, and it should only be objectively re-evaluated and augmented with contemporary thermal developments.
Sadi Carnot (1824) laid ingenious foundations for the Second Law of thermodynamics and discovery of entropy before the First law of energy conservation was even known (Joule, 1843, and Helmholtz, 1847), and long before thermodynamic concepts were established in the second half of the nineteenth century. In the historical context, it is hard to comprehend now, how Carnot then, at age 28, ingeniously and thoroughly explained the critical concepts of reversible thermo-mechanical processes and the limits of converting heat to work at inception of the heat engines’ era, when the nature of heat was not fully understood. Note that Carnot erroneously assumed that the same caloric (heat) passes through the engine and extracts (produces) work by lowering its temperature, similar to how the same water flow passes through the water-wheel and produces work by lowering its elevation potential. This error (violating energy conservation), considering the knowledge at the time, in no way diminishes Carnot’s ingenious reasoning and conclusions about limiting, reversible processes and its accurate limitations of heat to work conversion [
6
].
2. Nature of Thermo—Mechanical Energy Transfer
It is widely believed that thermal heat conduction and mechanical work transfer are “massless” phenomena. However, based on existing observations of atomic electron-shell interactions and well-established phenomena and theories, including Einstein’s mass-energy equivalence [
7
] and thermal radiation, it is reasoned here that for a conduction heat transfer (e.g., through a wall) or mechanical work transfer (e.g., a rotating shaft), there has to be underlying electromagnetic energy transfer (i.e., via photon “on-contact” diffusive annihilation/reemission and propagation) and commensurate mass-transfer (
m
=
E/c
2
) through material systems involved, from a mass-energy source to a sink system, as depicted on
Figure 1
, and detailed in its caption. Ironically, Lavoisier was correct that caloric is a substance, but not weightless. More details were presented [
8
] and will be published after updates are finalized.
Figure 1.
Electromagnetic nature of thermo-mechanical mass-energy transfer due to photon diffusive re-emission and propagation. Based on atomic electron-shell interactions and the Einstein mass-energy equivalence, during “believed-massless” heat conduction or mechanical work transfer there has to be electromagnetic, photonic mass-energy propagation through involved material structures from a mass-energy source to a sink system. Steady-state, mass-energy transfer is depicted through heat conduction plate (at Figure top) and rotating shaft (at Figure bottom). Energy transfer (i.e., Einstein’s mass-energy equivalency transfer,
E ˙ t r = m ˙ t r c 2
) has to be electromagnetic by photon transfer, either as photon electromagnetic waves on-long range through space/vacuum (
Q ˙ r a d = m ˙ r a d c 2 )
, or photon “on-contact” transfer (annihilation/reemission) within material structures, e.g., through heat conduction plate (at Figure top) and turbine shaft work (at Figure bottom), since it is neither gravitational nor nuclear (strong or weak) interaction. Otherwise, Einstein’s mass-energy equivalency and the fundamental force/interactions will be violated. Thermal conduction is due to chaotic thermal electron-shell collisions and may be enhanced by free-electrons or crystal-lattice structure vibration (phonons), both phenomena due to underlining photon propagation (similar to electro-chemical phenomena). The mechanical work transfer is due to electron-shell directional pushing/twisting as the most efficient (“focused”) energy transfer (i.e., mechanical super conductor). If it is fully investigated and understood, it has potential for development of hybrid synthetic-materials with superior thermal conductivity such as diamond and others, for critical and new applications [
8
].
3. Nature of Heat and Thermal Energy
Denying the existence of thermal energy is the same as denying the existence of its transfer (heat transfer) [ 9 , 10 ]. Some consider the Thermodynamic internal energy to be the thermal energy, although the former represents all energy types stored as the kinetic and potential energies of the constituent microstructure, namely, the thermal and mechanical-elastic energies in simple compressible substances, in addition to the chemical and nuclear internal energies. In more complex system structure there are more energy types. The stored system heat increases the system thermal energy that is distinguished from the system internal, mechanical (elastic) energy. For example, the heating or compressing an ideal gas with the same amount of energy will result in the same temperatures and internal energies, but different states, with different volumes and entropies, and similar for other material substances, see Figure 2 [ 9 , 10 ]. Reversible heat transfer and caloric heat transfer, without work interactions, are introduced as limiting processes of heat-work interactions. It is reasoned and deduced, that the thermal energy is distinguishable, regardless of its coupling with the other internal energy forms, and thus paving the way to further illuminate other critical concepts, including thermodynamic entropy, entropy-generation, the Second law of energy degradation, and the new entransy concept.
Figure 2. Thermal and mechanical internal energies are distinguishable parts of the thermodynamic internal energy, the former increasing the thermal and the latter increasing the mechanical part of the internal energy, resulting in different states, regardless that the internal energies are the same, as illustrated by 1 kJ heating or 1 kJ compressing of ideal gas ( A ), or a spring ( B ).
Heat is a unique and universal concept representing energy transfer of thermal random-motion and its interactions, while all other energy transfers are classified as different types of work. The “thermal energy” or “stored heat” represents stored energy of relevant thermal motion and interactions due to thermal heat transfer or heat-generation, i.e., dissipation-conversion of all other energy types to thermal heat. The term “thermal heat” represents here the holistic meaning of both, the heat as transfer of the stored thermal energy and the stored thermal energy itself.
There is an important peculiarity about spontaneous heat transfer processes such as within simple heat exchangers (without forced flow work): no heat conversion to work like in heat engine, and no other heat generation from work dissipation, but only the Carnot’s “thermal work-potential dissipation” to heat itself at lower temperature—resulting in the conservation of thermal energy, i.e., conservation of thermal heat [ 9 , 10 , 11 ]. Just like the original caloric—the thermal energy is conserved on its own, but spontaneously degraded to a lower temperature (dissipation of thermal work-potential, and dissipation of entransy), since it cannot be spontaneously reversed back to higher temperatures. Such processes, without work interactions, are called here as “caloric processes” or “caloric heat transfer”. The “reversible heat transfer“, could also be defined as limiting process when the heat source and heat sink are at a finite temperature difference, accomplished by an ideal Carnot cycle so that thermal work-potential is extracted (instead of being dissipated into heat, such as in the above “caloric processes”), while adjusting temperature levels so that “reversible heat transfer” takes place at infinitesimally small temperature difference at each temperature level (dT→0) [ 9 , 10 , 11 ], see Figure 3 . Therefore, the Carnot principle defines both: thermal work-potential and reversible heat transfer.
Figure 3. During a spontaneous caloric heat transfer process between two thermal reservoirs, the work potential, W Rev , is completely dissipated into heat at a lower temperature, Q Diss , which after being added to the reduced reversible heat at lower temperature, Q Rev , will result in conserved heat or thermal energy, Q Cal = Q Rev + Q Diss = constant , with increased, generated entropy in the amount of dissipated work potential per relevant absolute temperature [ 9 , 10 ].
The stored system heat increases the system’s “thermal energy” and entropy, the former is distinguished from the other internal-energy types (e.g., mechanical elastic energy). A related manuscript is being updated, to quantify the thermal energy within the system internal energy [ 10 ].
4. Entropy: Thermal (Chaotic-Dynamic) Displacement
What is the underlying nature of “entropy” and why does it always increase? Why is entropy so intriguing and mysterious, unique and universal, as if it is a miraculous property of natural, material systems? How does it encompass and quantify all processes at all natural space and time scales, governed by the Second law of thermodynamics? And many other elusive and debatable issues, as if entropy is among the deepest unresolved mysteries in nature, defying our common sense [
11
]. Entropy is the most used and often abused concept in science, but also in philosophy and society. Further confusions are produced by some attempts to generalize entropy with similar, but not the same concepts in other disciplines. Von Neumann once remarked that “whoever uses the term ‘entropy’ in a discussion always wins since no one knows what entropy really is, so in a debate one always has the advantage”.
Carnot paved the way for his followers to define and prove that entropy is a state function, a material property conserved in ideal, reversible cycles (Clausius Equality—definition of entropy property), that entropy could not be destroyed since it will imply more efficient than ideal cycles (and ideal processes), but is always generated (locally and globally, thus overall increased) due to dissipation of any and all work potentials to heat, causing generation of entropy in irreversible cycles (Clausius Inequality—definition of entropy generation); thereby, quantifying all reversible and irreversible processes and providing generalization of the Second law of thermodynamics [
5
,
6
]. Note that Carnot erroneously assumed that the same caloric (heat) passes through the engine and extracts (produces) work by lowering its temperature, similar to how the same water flow passes through the water-wheel and produces work by lowering its elevation potential. This error, considering the knowledge at the time, in no way diminishes Carnot’s ingenious reasoning and conclusions about limiting, reversible processes and its accurate limitations of heat to work conversion [
6
].
Entropy is related to thermal motion of a system microstructure, the latter gives rise to all thermal phenomena and related properties, namely, temperature, thermal or heat capacity, thermal energy and entropy, among others, see
Figure 4
. Due to conversion of thermal energy to other energy forms, such as mechanical work in heat engine, and also spontaneous and unavoidable dissipation of all other energy forms to thermal energy via so called heat generation, additional issues and sometimes confusions arise. However, entropy is a well-defined material system macro-property, precisely measured, and tabulated and/or correlated, for practical use in engineering and science. Entropy should be further reasoned, refined and explained for what it is, and not be misrepresented as something it might be or is not [
11
].
Figure 4. Entropy is not a space disorder, nor form, nor functional disorder. Entropy is a thermal motion disorder. No thermal motion, no entropy! Expanding entropy to any type of disorder or information is a source of many misconceptions.
5. Maxwell’s Demon and Second Law Challenges
A demonic being, introduced by Maxwell, to miraculously create thermal non-equilibrium by taking advantage of non-uniform distribution of molecular velocity in equilibrium, and thereby violate the Second law of thermodynamics, has been among the most intriguing and elusive wishful concepts for 150 years now. Maxwell and his followers focused on “effortless gating” a molecule at a time, but overlooked simultaneous interference of other chaotic molecules, while the demon exorcists tried to justify impossible processes with misplaced “compensations” by work of measurements and gate operation, and information storage and memory erasure with entropy generation. It is reasoned phenomenologically and deduced by this author that a Maxwell’s demon operation, against natural forces and without due work effort, is not possible, since it would be against the physics of the chaotic thermal motion, the latter without consistent molecular directional preference for selective timing to be possible [
12
]. Maxwell’s demon (MD) would have miraculous useful effects, but also some catastrophic consequences.
The most crucial fact, that the integral, chaotic and simultaneous interactions of all thermal particles on the MD’s operation, has been overlooked, but focus on a single, opportunistic particle motion is emphasized, as if the other thermal particles would not interfere, see
Figure 5
. Due effort to suppress such forced interference of other thermal particles would amount to required, major “due-work” to establish a macro non-equilibrium, which is independent and in addition to auxiliary “gate-work” of MD to observe molecules and operate a gate. The former, thermodynamic due-work, is unavoidable and substantial, while the latter, MD’s operational work, could be infinitesimally small if the MD’s operation is perfected to near-reversible actions, thus making delusion of the Second law violation.
Figure 5. Maxwell’s demon (MD) operates its gate. MD opens the gate to “wishfully pass” a higher speed molecule from L to H (see dashed arrow line in L ) and lower speed in reverse. However, considering the chaotic and fast, simultanious molecular thermal motion (most molecules are faster than sound speed), it is probable that the same or even higher speed molecule from H will pass back to L in that time period (or collide with an oncoming molecule, see dashed arrow line in H ). Even higher speed molecules may pass back from H to L , and more probably so if MD was “successful by chance” to separate more high speed molecules into H . Therefore, “just opening the gate” would “more equalize than separate” by speed.
Landauer [ 13 ] and his followers, recognizing that the information and storage work suggested by Szilard [ 14 ] and his followers is inadequate, introduced additional fallacies to save the Second law. They stated that any MD’s miraculous work gain and related entropy reduction is compensated by follow-up memory information-erasure with entropy generation. However, a fundamental law cannot be selectively violated and then “saved” by compensation elsewhere later, see Figure 6 . Entropy cannot be destroyed by MD, locally or at a time, and “compensated” by generation elsewhere or later. It would be equivalent to allow rivers to spontaneously flow uphill and compensate it by more downhill flow later. We cannot pick-and-choose to violate a fundamental law and compensate it later elsewhere. Entropy is generated everywhere and always, at any scale without exception, and cannot be destroyed by any means at any scale [ 6 , 11 ]. Impossibility of entropy reduction by destruction should not be confused with local entropy decrease due to entropy outflow with heat (thermodynamic entropy is associated with thermal motion or heat only).
Figure 6.
Destruction of entropy is impossible and cannot be “compensated” elsewhere or at later time. “Entropy of an isolated, closed system (or universe) is always increasing”, is a necessary but not sufficient condition of the Second Law of thermodynamics. Entropy cannot be destroyed, locally or at a time, and “compensated” by generation elsewhere or later. It would be equivalent to allow rivers to spontaneously flow uphill and compensate it by more downhill flow elsewhere or later. Entropy is generated everywhere and always, at any scale without exception, and cannot be destroyed by any means at any scale. Impossibility of entropy reduction by destruction should not be confused with local entropy decrease due to entropy outflow with heat [
12
].
6. Exergy and Entransy, and Beyond
Exergy, as work potential of a system in non-equilibrium with regard to a so-called, reference “dead-state”, is well defined in classical textbooks and references. Here, some selected challenges will be discussed.
Irreversible versus reversible process towards mutual equilibrium is presented on
Figure 7
. The isolated, combined system (parts
A
and
B
) is initially at non-equilibrium (
T B
<
T A
). The mutual work-potential (
W Rev
) is fully dissipated with related entropy generation (
S AB,Gen
) during the irreversible process leading to mutual equilibrium at
T AB
=
T AB,Irr
.
S A B , G e n = ∫ T i n i t i a l ( A + B ) T f i n a l ( A B ) δ Q G e n T = m A c A l n T A B T A + m B c B l n T A B T B
(1)
Figure 7. Irreversible (solid lines) versus reversible process (dashed lines) towards mutual equilibrium. System A and B , each at constant volume, in thermal contact but isolated from the rest of surrounding.
If, during a reversible process, the work-potential is extracted and entropy conserved, it will lead to another mutual equilibrium at
T AB,Rev
with entropy changes, but without entropy generation:
Δ S A , R e v = ∫ T A T A B , R e v m A c A · d T T = m A c A l n T A B , R e v T A = − m B c B l n T A B , R e v T B = − Δ S B , R e v
(2)
If the reversible work potential is extracted from the combined system
A + B
, see dashed lines on
Figure 7
, it will come to a different mutual equilibrium at
T AB,Rev
(Equation (2)), smaller than in spontaneous irreversible case at
T AB
=
T AB,Irr
, since the work potential will dissipate within the combined system instead of being extracted out, i.e.,:
T A B , R e v = e x p [ m A · c A · l n T A + m B · c B · l n T B m A · c A + m B · c B ] versus T A B = T A B , I r r = m A · c A · T A + m B · c B · T B m A · c A + m B · c B > T A B , R e v
(3)
Note (on
Figure 7
) that the mutual work-potential
W Rev
and entropy generation
S AB,Gen
are not related, and thus not dependent on any reference, surrounding dead-state (
P o , T o
), since the combined system (
A + B
) is isolated from its surrounding. However, it is capable of producing (extracting) work due to its initial non-equilibrium. That work-potential is completely dissipated (heat generation within) after coming spontaneously (irreversibly) in mutual equilibrium. Actually, the required condition for spontaneous process is the existence of “mutual, non-equilibrium work potential”. The “exergy” is “hypothetical work-potential” if a system reversibly comes to equilibrium by interacting with an arbitrary reference dead-state system (i.e., surrounding). Exergy is useful for comparison, and practical if our systems are coming in equilibrium with such a reference surrounding (i.e., the case with many engineering processes and the Earth’s surroundings, i.e., environment).
Note also that boundary heat transfer (
Q Bry
) at finite temperature difference may be considered as reversible at boundary temperature
T Bry
, and that the irreversibility takes place within the system when the boundary heat is received at a lower system temperature
T Sys
, thus resulting in generated heat and the remaining reversible heat at the system level (heat totality, such as original caloric, conserved). This may be perplexing, since it depends where the irreversibility takes place (whether the temperature gradients are within a layer close to the boundary on the system or surrounding’s sides, or within the system), but if properly accounted for, it will result in the same outcome.
Furthermore, the irreversibility is related to a process, not a system
per se
. For example, if the (sub)system
B
is heated from
T B
to
T AB
, instead with system
A
, but with another system
B
+
with variable temperature, always infinitesimally higher than A’s, then such a process would be reversible (in limit) and without (or infinitesimally small) entropy generation. The
entropy
(a system property) is subtle and so is irreversible
entropy generation
(a process quantity), that it becomes the property after the process is finished.
The irreversible work loss, i.e., work dissipation to generated heat (
W Loss
=
W Diss
=
Q Gen
) and entropy generation (
S Gen
) are function of the initial and final process states’ properties only, and not of any other reference dead-state, as it might allude at first, since the combined system (
A
+
B
) is isolated from the surrounding, i.e., it comes to mutual equilibrium, and does not interact with the surrounding.
Similarly, for example, with reference to a surrounding dead-state at
T o
&
P o
, the exergy of heat
Q
1
from a reservoir at temperature
T
1
is
E x
1
= Q
1
(1
− T o /T
1
) and at state 2 would be
E x
2
= Q
2
(1
− T o /T
2
). It appears that the exergy difference,
E x
1
− E x
2
, is a function of
T o
. However, for reversible cycle,
Q
2
/T
2
= Q
1
/T
1
(Carnot ratio equality), the relevant quantities are correlated, so the above is reduced to:
E x 1 − E x 2 = Q 1 (1 − T o / T 1 ) − Q 2 (1 − T o / T 2 ) = Q 1 (1 − T o / T 1 ) − ( Q 1 · T 2 / T 1 )(1 − T o / T 2 ) = ( Q 1 / T 1 )( T 1 − T 2 )
(4)
This is an interesting and deceptive outcome: the change of exergy of heat is not the function of dead-state temperature
T o
. Therefore, it is unnecessary to use exergy (which is based on a hypothetical reference, surrounding dead-state,
T o
,
P o
). Furthermore, for isolated processes without interaction with the surrounding, it may be inappropriate, to use exergy difference, since actual work-loss is relative to mutual equilibrium state reached between the two isolated sub/systems, as demonstrated above (there is no
T o
and
P o
in the above expressions). It may be the case for all thermal processes with no net-entropic, nor net-volumetric interactions with the surrounding. It requires further discussions and clarifications.
Entropy is generated when work potential is lost (i.e., dissipated) into “generated heat transfer” (randomly equi-partitioned) into the thermal energy at given absolute temperature within the space occupied by the system, or when expansion (elastic) work potential is lost (i.e., energy randomly redistributed within enlarged volume, as in the free expansion, instead of being extracted as work (volume displacement against the surrounding or load pressure). Therefore, heat is thermal energy transfer due to temperature gradient, while work is other than thermal energy transfer due to other energy-potential gradients, such as pressure, elevation, voltage, gravity, electro-magnetic, electro-chemical, etc.
The entropy unit is not “exactly the same” as for the specific heat, since entropy increase at constant volume is equal to the thermal energy increase per absolute temperature level (important), as opposed to per temperature difference for specific heat at constant volume. Entropy also increases with volume increase at constant temperature and during adiabatic expansion unless the latter is reversible (i.e., isentropic; entropy increase due to volume expansion is balanced with equal decrease due to work extraction and the corresponding internal energy reduction). Therefore, during reversible change of volume (mechanical, not thermal process) there is no change of entropy due to change of volume, but only due to boundary heat transfer if any.
A new property, based on physical analogy between electrical conduction, represented by the Ohm’s law (the electrical charge
Q v e = I·t = E e
/
V
), and heat conduction, is introduced from
Q v h = Z tr
/
T = E vh
/
T = G
/
T
(as concept-in-general, if electrical charge and heat are transferred at constant voltage and temperature, respectively), thus, in principle, defining a new physical quantity, “entransy” [
15
,
16
,
17
,
18
], i.e.,:
G ≡ E v h ≡ Z t r = Q v h T
(5)
Note that designation of “stored heat” (
Q v h
), has been utilized for stored heat as thermal energy within the material system, For the new quantity, entransy different symbols have been used in subsequent publications.
The entransy has been defined as a state property, as a function of ”stored heat”. Although the real system specific heat is function of temperature, the entransy has been regrettably and unnecessarily restricted for constant specific heat systems. It is suggested that entransy be defined instead, as integral quantity for variable specific heat for incompressible systems and/or constant volume processes
C v
=
f
(
P
,
T
) ≈
f
(
T
), i.e.,
G = ∫ MC v TdT
Correlations between entransy G , reversible heat Q REV , entransy dissipation or loss G LOSS , and Carnot work-potential loss W LOSS is presented on Figure 8 .
Figure 8. Correlation between entransy G , reversible heat Q REV , entransy dissipation or loss G LOSS , and Carnot work-potential loss W LOSS , during 1-D steady-state heat conduction caloric process 1–2 with conserved heat transfer Q .
Furthermore, the “entransy of work”,
G W
, is also essential to be defined for processes when thermal heat is converted to work, such as in heat engines. The work entransy could be defined using the entransy balance for reversible, Carnot cycle relationship, and considering that there is no entransy loss in an ideal reversible process, i.e.,
G IN = G OUT
or
G
1
= G W + G
2
(notation in [
18
]):
G W = G 1 − G 2 = G 1 (1 − ( T 2 2 / T 1 2 )) or dG W = (1 − ( T 2 2 / T 1 2 ))· dG 1
(7)
In another publication [ 19 ], the work entransy, G W , was derived by algebraic manipulation as G W = WT 1 = ( Q 1 − Q 2 ) T 1 = Q 1 ( T 1 − T 2 ). However, this definition is not appropriate since it does not satisfy condition that entransy loss is zero for reversible processes. There is a need for further interpretations of the entransy concept and possible refinements [ 18 ].
7. Challenges and Concluding Remarks
Starting from Clausius till nowadays, the obvious but in general not quantified thermal energy, is “lumped” into well-quantified internal energy, provided in Thermodynamic data tables. Some (or many) argue that subtle “thermal energy” is not definable, but the “internal thermal energy” is manifested as heat transfer due to temperature difference. It is argued here and elsewhere (related manuscripts being finalized by this author) that heat (and anything else for that matter) could be transferred only if it exists as stored quantity in kind, in the first place. It is self-evident in caloric processes and quantified by the caloric quantities that the “thermal energy” is stored heat (directly related to the system heat capacity),
U Th
≡
Q Stored
, and heat is the thermal energy transfer,
Q
≡
U Th,transfer
, [
10
].
The Second law is not about disorder and probability
per se
(or any other math or physics “tools”
per se
used to describe it), but about spontaneous, forced-tendency (natural process-forcing displacement) of mass-energy redistribution in certain, irreversible direction (process driving force), from higher to lower energy-potential (mass-energy density in space). Spontaneity implies forced-directionality and in turn irreversibility. No spontaneous, irreversible process could ever be completely reversed or undone. For example, the driving force for the life and processes on Earth is the irreversible dissipation of energy from the Sun.
It is hard to believe that a serious scientist, who truly comprehends the Second law and its essence, would challenge the concept based on incomplete and elusive facts. Sometimes, highly respected scientists in their fields, do not fully comprehend the essence of the Second law of thermodynamics. The Second law “challengers” need to demonstrate and quantify destruction of entropy to challenge the universal validity of the Second law. It has been reasoned and thus proven that destruction of entropy, i.e., violation of the Second law, is against the forced tendency of natural processes and thus impossible, leaving “
No Hope
” for the challengers [
11
]. After all, the “Wishful Maxwell’s demon” could not be realized since its introduction in 1867. Therefore, before “the Second law violation” claims are stated, the reliable criteria for the Second law violation, including proper definition and evaluation of entropy, should be established based on full comprehension of the fundamental natural Laws.
A critical treatise of “Entransy concept and controversies” within elusive thermal landscape, has been given recently by this author [
18
]. Regardless of entransy redundancy, being derived from other physical quantities, it does not diminish its usefulness and uniqueness in thermal analysis and optimization. Despite the need for further development and clarifications of the new concept, it is argued in [
18
] that the entransy, due to its unique nature, may contribute to better comprehension of often obscured thermal phenomena. It would be unjust and premature, based on limited and subjective claims, to discredit entransy as if the “already established” concepts and methodologies are perfect, and do not need alternatives and innovations, as if further progress is not needed.
As the fundamental laws of nature and thermodynamics are expended from simple systems in physics and chemistry, to different space and time scales and to much more complex systems in biology, life and intelligent processes, there are more challenges to be comprehended and understood.
Funding
This research received no external funding.
Conflicts of Interest
The author declares no conflict of interest.
References
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Carnot, S. Reflections on the Motive Power of Heat ; Thurston, R.H., Translator; Chapman & Hall, Ltd.: London, UK, 1897; Available online: https://sites.google.com/site/professorkostic/energy-environment/sadi-carnot (accessed on 20 March 2018).
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Figure 1. Electromagnetic nature of thermo-mechanical mass-energy transfer due to photon diffusive re-emission and propagation. Based on atomic electron-shell interactions and the Einstein mass-energy equivalence, during “believed-massless” heat conduction or mechanical work transfer there has to be electromagnetic, photonic mass-energy propagation through involved material structures from a mass-energy source to a sink system. Steady-state, mass-energy transfer is depicted through heat conduction plate (at Figure top) and rotating shaft (at Figure bottom). Energy transfer (i.e., Einstein’s mass-energy equivalency transfer, E ˙ t r = m ˙ t r c 2 ) has to be electromagnetic by photon transfer, either as photon electromagnetic waves on-long range through space/vacuum ( Q ˙ r a d = m ˙ r a d c 2 ) , or photon “on-contact” transfer (annihilation/reemission) within material structures, e.g., through heat conduction plate (at Figure top) and turbine shaft work (at Figure bottom), since it is neither gravitational nor nuclear (strong or weak) interaction. Otherwise, Einstein’s mass-energy equivalency and the fundamental force/interactions will be violated. Thermal conduction is due to chaotic thermal electron-shell collisions and may be enhanced by free-electrons or crystal-lattice structure vibration (phonons), both phenomena due to underlining photon propagation (similar to electro-chemical phenomena). The mechanical work transfer is due to electron-shell directional pushing/twisting as the most efficient (“focused”) energy transfer (i.e., mechanical super conductor). If it is fully investigated and understood, it has potential for development of hybrid synthetic-materials with superior thermal conductivity such as diamond and others, for critical and new applications [ 8 ].
Figure 2. Thermal and mechanical internal energies are distinguishable parts of the thermodynamic internal energy, the former increasing the thermal and the latter increasing the mechanical part of the internal energy, resulting in different states, regardless that the internal energies are the same, as illustrated by 1 kJ heating or 1 kJ compressing of ideal gas ( A ), or a spring ( B ).
Figure 3. During a spontaneous caloric heat transfer process between two thermal reservoirs, the work potential, W Rev , is completely dissipated into heat at a lower temperature, Q Diss , which after being added to the reduced reversible heat at lower temperature, Q Rev , will result in conserved heat or thermal energy, Q Cal = Q Rev + Q Diss = constant , with increased, generated entropy in the amount of dissipated work potential per relevant absolute temperature [ 9 , 10 ].
Figure 4. Entropy is not a space disorder, nor form, nor functional disorder. Entropy is a thermal motion disorder. No thermal motion, no entropy! Expanding entropy to any type of disorder or information is a source of many misconceptions.
Figure 5. Maxwell’s demon (MD) operates its gate. MD opens the gate to “wishfully pass” a higher speed molecule from L to H (see dashed arrow line in L ) and lower speed in reverse. However, considering the chaotic and fast, simultanious molecular thermal motion (most molecules are faster than sound speed), it is probable that the same or even higher speed molecule from H will pass back to L in that time period (or collide with an oncoming molecule, see dashed arrow line in H ). Even higher speed molecules may pass back from H to L , and more probably so if MD was “successful by chance” to separate more high speed molecules into H . Therefore, “just opening the gate” would “more equalize than separate” by speed.
Figure 6. Destruction of entropy is impossible and cannot be “compensated” elsewhere or at later time. “Entropy of an isolated, closed system (or universe) is always increasing”, is a necessary but not sufficient condition of the Second Law of thermodynamics. Entropy cannot be destroyed, locally or at a time, and “compensated” by generation elsewhere or later. It would be equivalent to allow rivers to spontaneously flow uphill and compensate it by more downhill flow elsewhere or later. Entropy is generated everywhere and always, at any scale without exception, and cannot be destroyed by any means at any scale. Impossibility of entropy reduction by destruction should not be confused with local entropy decrease due to entropy outflow with heat [ 12 ].
Figure 7. Irreversible (solid lines) versus reversible process (dashed lines) towards mutual equilibrium. System A and B , each at constant volume, in thermal contact but isolated from the rest of surrounding.
Figure 8. Correlation between entransy G , reversible heat Q REV , entransy dissipation or loss G LOSS , and Carnot work-potential loss W LOSS , during 1-D steady-state heat conduction caloric process 1–2 with conserved heat transfer Q .
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A phase
of research to describe clinical trials that gather preliminary data on whether a drug works in people who have a certain condition/disease
(that is, the drug's effectiveness). For example, participants receiving the drug may be compared to similar participants receiving a different treatment, usually an inactive substance (called a placebo
) or a different drug. Safety continues to be evaluated, and short-term adverse events
are studied.
Phase 3
A phase
of research to describe clinical trials that gather more information about a drug's safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. These studies typically involve more participants.
Phase 4
A phase
of research to describe clinical trials occurring after FDA has approved a drug for marketing. They include postmarket requirement and commitment studies that are required of or agreed to by the study sponsor. These trials gather additional information about a drug's safety, efficacy, or optimal use.
Phase Not Applicable
Describes trials without FDA-defined phases
, including trials of devices or behavioral interventions.
Placebo
An inactive substance or treatment that looks the same as, and is given in the same way as, an active drug or intervention/treatment
being studied.
Placebo comparator arm
An arm type
in which a group of participants receives a placebo
during a clinical trial.
Primary completion date
The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure
. Whether the clinical study ended according to the protocol
or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "estimated" primary completion date is the date that the researchers think will be the primary completion date for the study.
Primary outcome measure
In a clinical study's protocol
, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment
. Most clinical studies have one primary outcome measure, but some have more than one.
Primary purpose
The main reason for the clinical trial
. The types of primary purpose are: treatment, prevention, diagnostic, supportive care, screening, health services research, basic science, and other.
Principal investigator (PI)
The person who is responsible for the scientific and technical direction of the entire clinical study.
Protocol
The written description of a clinical study. It includes the study's objectives, design, and methods. It may also include relevant scientific background and statistical information.
Quality control (QC) review
National Library of Medicine (NLM) staff perform a limited review of submitted study records
for apparent errors, deficiencies, or inconsistencies. NLM staff identify potential major and advisory issues and provide comments directly to the study sponsor or investigator. Major issues identified in QC review must be addressed or corrected (see First submitted that met QC criteria
and Results first submitted that met QC criteria
). Advisory issues are suggestions to help improve the clarity of the record. NLM staff do not verify the scientific validity or relevance of the submitted information. The study sponsor or investigator is responsible for ensuring that the studies follow all applicable laws and regulations.
Randomized allocation
A type of allocation
strategy in which participants are assigned to the arms
of a clinical trial by chance.
Recruitment status
Not yet recruiting: The study has not started recruiting participants. Recruiting: The study is currently recruiting participants. Enrolling by invitation: The study is selecting its participants from a population, or group of people, decided on by the researchers in advance. These studies are not open to everyone who meets the eligibility criteria but only to people in that particular population, who are specifically invited to participate. Active, not recruiting: The study is ongoing, and participants are receiving an intervention or being examined, but potential participants are not currently being recruited or enrolled. Suspended: The study has stopped early but may start again. Terminated: The study has stopped early and will not start again. Participants are no longer being examined or treated. Completed: The study has ended normally, and participants are no longer being examined or treated (that is, the last participant's last visit has occurred). Withdrawn: The study stopped early, before enrolling its first participant. Unknown: A study on ClinicalTrials.gov whose last known status was recruiting; not yet recruiting; or active, not recruiting but that has passed its completion date, and the status has not been last verified within the past 2 years.
Registration
The process of submitting and updating summary information about a clinical study and its protocol
, from its beginning to end, to a structured, public Web-based study registry
that is accessible to the public, such as ClinicalTrials.gov.
Removed location countries
Countries that appeared under listed location countries
but were removed from the study record
by the sponsor or investigator.
Reporting group
A grouping of participants in a clinical study that is used for summarizing the data collected during the study. This grouping may be the same as or different from a study arm or group.
Responsible party
The person responsible for submitting information about a clinical study to ClinicalTrials.gov and updating that information. Usually the study sponsor or investigator.
Results database
A structured online system, such as the ClinicalTrials.gov results database, that provides the public with access to registration and summary results information for completed or terminated clinical studies. A study with results available on ClinicalTrials.gov is described as having the results "posted." Note:
The ClinicalTrials.gov results database became available in September 2008. Older studies are unlikely to have results available in the database.
Results delayed
Indicates that the sponsor or investigator submitted a certification
or extension request
.
Results first posted
The date on which summary results information was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review
has concluded. There is typically a delay between the date the study sponsor or investigator first submits summary results information (the results first submitted date) and the results first posted date. Some results information may be available at an earlier date if Results First Posted with QC Comments
.
Results first posted with QC comments
The date on which summary results information was first available on ClinicalTrials.gov with quality control review comments from the National Library of Medicine (NLM) identifying major issues that must be addressed by the sponsor or investigator. As of January 1, 2020, initial results submissions for applicable clinical trials (ACTs) that do not meet quality control review criteria
will be publicly posted on ClinicalTrials.gov with brief standardized major comments. Accordingly, the Results First Posted with QC Comments date may be earlier than the Results First Posted date for an ACT with summary results information that is not consistent with NLM quality control review criteria.
Results first submitted
The date on which the study sponsor or investigator first submits a study record
with summary results information. There is typically a delay between the results first submitted date and when summary results information becomes available on ClinicalTrials.gov (the results first posted
date).
Results first submitted that met QC criteria
The date on which the study sponsor or investigator first submits a study record
with summary results information that is consistent with National Library of Medicine (NLM) quality control (QC) review
criteria. The sponsor or investigator may need to revise and submit results information one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
Results returned after quality control review
The date on which the National Library of Medicine provided quality control (QC) review
comments to the study sponsor or investigator. The sponsor or investigator must address major issues identified in the review comments. If there is a date listed for results returned after quality control review, but there is not a subsequent date listed for results submitted to ClinicalTrials.gov
, this means that the submission is pending changes by the sponsor or investigator.
Results submitted to ClinicalTrials.gov
Indicates that the study sponsor or investigator has submitted summary results information for a clinical study to ClinicalTrials.gov but the quality control (QC) review
process has not concluded.
The results submitted date indicates when the study sponsor or investigator first submitted summary results information or submitted changes to summary results information. Submissions with changes are typically in response to QC review comments from the National Library of Medicine (NLM). If there is a date listed for results submitted to ClinicalTrials.gov, but there is not a subsequent date listed for results returned after quality control review
, this means that the submission is pending review by NLM.
Secondary outcome measure
In a clinical study's protocol
, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Serious adverse event
An adverse event
that results in death, is life-threatening, requires inpatient hospitalization or extends a current hospital stay, results in an ongoing or significant incapacity or interferes substantially with normal life functions, or causes a congenital anomaly or birth defect. Medical events that do not result in death, are not life-threatening, or do not require hospitalization may be considered serious adverse events if they put the participant in danger or require medical or surgical intervention to prevent one of the results listed above.
Sex
A type of eligibility criteria
that indicates the sex of people who may participate in a clinical study (all, female, male). Sex is a person's classification as female or male based on biological distinctions. Sex is distinct from gender-based eligibility
.
Sham comparator arm
An arm type
in which a group of participants receives a procedure or device that appears to be the same as the actual procedure or device being studied but does not contain active processes or components.
Single group assignment
A type of intervention model
describing a clinical trial in which all participants receive the same intervention/treatment.
Sort studies by
In Advanced Search, the Sort studies by option is used to change the order of studies listed on the Search Results page. You can sort by Relevance or Newest First: Relevance: Studies that best match your search terms appear higher in the search results list. This is the default display for all searches. Newest First: Studies with the most recent First posted dates appear higher in the search results list.
Sponsor
The organization or person who initiates the study and who has authority and control over the study.
State
In the search feature, the State field is used to find clinical studies with locations in a specific state within the United States. If you choose United States in the Country
field, you can search for studies with locations in a specific state.
Statistical analysis plan (SAP)
The written description of the statistical considerations and methods for analyzing the data collected in the clinical study
.
Status
Indicates the current recruitment status
or the expanded access status
.
Study completion date
The date on which the last participant in a clinical study was examined or received an intervention/treatment
to collect final data for the primary outcome measures
, secondary outcome measures
, and adverse events
(that is, the last participant's last visit). The "estimated" study completion date is the date that the researchers think will be the study completion date.
Study design
The investigative methods and strategies used in the clinical study.
Study documents
Refers to the type of documents that the study sponsor or principal investigator may add to their study record
. These include a study protocol
, statistical analysis plan
, and informed consent form
.
Study IDs
Identifiers that are assigned to a clinical study by the study's sponsor
, funders, or others. They include unique identifiers from other trial study registries
and National Institutes of Health grant numbers. Note: ClinicalTrials.gov assigns a unique identification code to each clinical study registered on ClinicalTrials.gov. Also called the NCT number
, the format is "NCT" followed by an 8-digit number (for example, NCT00000419).
Study record
An entry on ClinicalTrials.gov that contains a summary of a clinical study's protocol information, including the recruitment status
; eligibility criteria; contact information; and, in some cases, summary results. Each study record is assigned a ClinicalTrials.gov identifier, or NCT number
.
Study registry
A structured online system, such as ClinicalTrials.gov, that provides the public with access to summary information about ongoing and completed clinical studies.
Study results
A study record
that includes the summary results posted in the ClinicalTrials.gov results database
. Summary results information includes participant flow
, baseline characteristics
, outcome measures
, and adverse events
(including serious adverse events
).
Study start date
The actual date on which the first participant was enrolled in a clinical study. The "estimated" study start date is the date that the researchers think will be the study start date.
Study type
Describes the nature of a clinical study
. Study types include interventional studies
(also called clinical trials), observational studies
(including patient registries
), and expanded access
.
Submitted date
The date on which the study sponsor or investigator submitted a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria.
Title
The official title of a protocol
used to identify a clinical study or a short title written in language intended for the lay public.
Title acronym
The acronym or initials used to identify a clinical study (not all studies have one). For example, the title acronym for the Women's Health Initiative is "WHI."
U.S. Agency for Healthcare Research and Quality (AHRQ)
An agency within the U.S. Department of Health and Human Services. AHRQ's mission is to produce evidence to make health care safer, higher quality, more accessible, equitable, and affordable, and to work within the U.S. Department of Health and Human Services and with other partners to make sure that the evidence is understood and used.
U.S. Food and Drug Administration (FDA)
An agency within the U.S. Department of Health and Human Services. The FDA is responsible for protecting the public health by making sure that human and veterinary drugs, vaccines and other biological products, medical devices, the Nation's food supply, cosmetics, dietary supplements, and products that give off radiation are safe, effective, and secure.
Unknown
A type of recruitment status
. It identifies a study on ClinicalTrials.gov whose last known status was recruiting; not yet recruiting; or active, not recruiting but that has passed its completion date, and the status has not been verified within the past 2 years. Studies with an unknown status are considered closed studies.
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Study has passed its completion date and status has not been verified in more than two years. | https://www.clinicaltrials.gov/ct2/results?term=mesothelioma+AND+Pleural+Mesothelioma+AND+Pleural+AND+Malignant&recrs=abc&lupd_s=06%2F03%2F2022&lupd_d=30 |
SAE MOBILUS
Development of an Engine-Based Catalytic Converter Poisoning Test to Assess the Impact of Volatile ZDDP Decomposition Products from Passenger Car Engine Oils
Technical Paper
2007-01-4079
ISSN: 0148-7191 , e-ISSN: 2688-3627
DOI: https://doi.org/10.4271/2007-01-4079
Published October 29, 2007 by SAE International View list of content related to the publisher(s) in United States
Sector:
Automotive Content related to Automotive
Event: Powertrain & Fluid Systems Conference and Exhibition Technical Paper presented at Powertrain & Fluid Systems Conference and Exhibition
Language: English
Abstract
An engine test has been developed to assess the impact of volatile phosphorus from passenger car engine oils on catalytic converter efficiency. The ten-day, steady-state, catalyst aging test was established to promote the production and consumption of volatile phosphorus species contained in crankcase vapors that are evacuated and combusted via the PCV system. A system for sampling, analyzing and identifying crankcase vapors led to a greater understanding of the phosphorus-based poisoning mechanism. Catalytic converter conversion efficiency was assessed through an engine-based system that swept catalyst inlet temperature from low to high while using a constant flow of controlled exhaust gas. The test results indicate correct ranking of field-tested oils that have catalyst poisoning data.
Recommended Content
Technical Paper Oxidation Stability of Some Phosphorus - Free Fully Formulated Crankcase Oils Technical Paper Development of High Performance Three-Way-Catalyst Technology to Lower NOx Emission Technical Paper The Effects of a Heated Catalyst on the Unsteady Gas Dynamic Process
Authors
Gregory H. Guinther Works by Gregory H. Guinther - Afton Chemical Corporation Content by authors affiliated with Afton Chemical Corporation
Michael M. Danner Works by Michael M. Danner - Afton Chemical Corporation Content by authors affiliated with Afton Chemical Corporation
Topic
Catalytic converters Content related to Catalytic converters
Crankcases Content related to Crankcases
Catalysts Content related to Catalysts
Hazardous materials Content related to Hazardous materials
Citation
Guinther, G. and Danner, M., "Development of an Engine-Based Catalytic Converter Poisoning Test to Assess the Impact of Volatile ZDDP Decomposition Products from Passenger Car Engine Oils," SAE Technical Paper 2007-01-4079, 2007, https://doi.org/10.4271/2007-01-4079 .
Also In
SAE 2007 Transactions Journal of Fuels and Lubricants Number: V116-4 ; Published: 2008-08-15
References
Spearot, J.A. Caracciolo, F. SAE 770637 Engine Oil Phosphorus Effects on Catalytic Converter Performance in federal Durability and High-Speed Vehicle Tests
Heck, R.M. Farrauto, R.J. Catalytic Air Pollution Control: Commercial Technology John Wiley & Sons, Inc. New York 1995
Williamson, W.B. Perry, J. Goss, R.L. Gandhi, H.S. Beason, R.E. SAE 841406 Catalyst Deactivation due to Glaze Formation from Oil-derived Phosphorus and Zinc
Kristen, U. Mueller, K. Chasan, D. Gandhi, H.S. Perry, J. Beckwith, E.C. SAE 872080 Use of a Novel Non-Phosphorus Antiwear Additive for Engine Oils
Drury, C. Whitehouse, S. SAE 940745 The Effect of Lubricant Phosphorus Level on Exhaust Emissions in a Field Trial of Gasoline Engine Vehicles
Inoue, K. Kurahashi, T. Negishi, T. Akiyama, K. Arimura, K. Tasaka, K. SAE 920654 Effects of Phosphorus and Ash Contents of engines on Deactivation of Monolithic Three-Way Catalysts and oxygen Sensors
Culley, S.A. McDonnell, T.F. SAE 952344 The Impact of Passenger Car Motor Oil Phosphorus Levels on Engine Durability, oil Degradation, and Exhaust Emissions in Field Trial
Culley, S.A. McDonnell, T.F. Ball, D.J. Kirby, C.W. Hawes, S.W. SAE 961898 The Impact of Passenger Car Motor Oil Phosphorus Levels on automotive Emissions Control systems
Selby, T.W. Proceedings of 13 th International Colloquium Tribology - Lubricants, Materials, and Lubrication Technische Akademie Esslingen Stuttgart/Ostifildern, Germany January 15-17 2002 Development and Significance of the Phosphorus Emission Index of Engine Oils
Selby, T.W. Bosch, B.J. Fee, D.C. J. ASTM International October 2005 2 9 Phosphorus Additive Chemistry and its effects on the Phosphorus Volatility of engine Oils
Ueda, F. Sugiyama, S. Arimura, K. Hamaguchi, S. Akiyama, K. SAE 940746 Engine Oil Additive Effects on Deactivation of Monolithic Three-Way Catalysts and Oxygen Sensors
Johnson, M.D. McCabe, R.W. Hubbard, C.P. Riley, M.J. Kirby, C.W. Ball, D.J. Tripp, G. McDonnell, T.F. Lam, W.Y. SAE 2002-01-2680 Effects of Engine Oil Formulation Variables on Exhaust Emissions in Taxi Fleet Service
Yilmaz, E. Tian, T. Wong, V.W. Heywood, J.B. SAE 2004-01-2909 The Contribution of Different Oil Consumption Sources to Total Oil Consumption in a Spark Ignition Engine
Burton, D. Joyner, R. MELCat Doc 6100, Eurpoacat 4 September 1999 Optimisation of the Preparation of Ceria/Zirconia Mixed Oxides by a Statistical Approach
Xu, L. McCabe, R. Hubbard, C. Dennis, R. Tabron, J. Norman, K. SAE 2007-01-1072 Impact of Oil Consumption Modes and Pathways on Oil-Derived Catalyst Deposits
Kumar, S. Ferrari, V. Burk, P.L. Deeba, M. Rogalo, J. SAE 2003-01-3735 Influence of Phosphorus Poisoning on TWC Catalysts
Devlin, M.T. Guevremont, J. Sheets, R.M. Loper, J.T. Guinther, G.H. Thompson, K. Jao, T.C. RSC Additives 2007 April 2007 London, UK “Effect of Metal-Free Phosphorus Antiwear Compounds on Passenger Car Emissions and Fuel Economy”
| https://saemobilus.sae.org/content/2007-01-4079/ |
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| https://lasp.colorado.edu/maven/sdc/public/data/sites/site-20180109T001245/anc/eng/usm4/sci_anc_usm415_062_068.drf |
The Gender-Biased Fertility Behavior: Evidence from Southeast Asian Countries | ScienceGate
This paper explores the existence of son preference and gender-based fertility behavior among Southeast Asian mothers. Using census data of te ...
The Gender-Biased Fertility Behavior: Evidence from Southeast Asian Countries
Economic Alternatives ◽
10.37075/ea.2021.2.05 ◽
2021 ◽
Vol 27 (2) ◽
pp. 235-261
Keyword(s):
Census Data ◽
Cohort Analysis ◽
Southeast Asian ◽
This paper explores the existence of son preference and gender-based fertility behavior among Southeast Asian mothers. Using census data of ten countries (Cambodia, China, India, Indonesia, Malaysia, Myanmar, Nepal, Philippines, Thailand, and Vietnam) over the years 1970-2014 and a sample of over 18 million observations, I show that having a first-born girl is associated with 0.16 more children in the household, equivalent to 7.2 percent rise from the mean. The marginal effects are quite robust across various specifications and subsamples. The effects are larger for countries with a lower human development index and individuals with lower education. A birth cohort analysis shows that the effects are significantly smaller for later cohorts implying that son preference fertility behavior has diminished over time.
The Transition of Son Preference: Evidence from Southeast Asian Countries
ECONOMICS ◽
10.2478/eoik-2021-0010 ◽
2021 ◽
Vol 9 (1) ◽
pp. 43-67
Author(s):
Nahid Tavassoli
Keyword(s):
Census Data ◽
Cohort Analysis ◽
Southeast Asian ◽
Fertility Behavior ◽
Son Preference ◽
The Mean ◽
Lower Education ◽
Gender Based ◽
And Gender ◽
Asian Mothers
Abstract
This paper explores the existence of son preference and gender-based fertility behavior among Southeast Asian mothers. Using census data of ten countries (Cambodia, China, India, Indonesia, Malaysia, Myanmar, Nepal, Philippines, Thailand, and Vietnam) over the years 1970-2014 and a sample of over 18 million observation, I show that having a first-born girl is associated with 0.16 more children in the household, equivalent to 7.2 percent rise from the mean. The marginal effects are quite robust across various specifications and subsamples. The effects are larger for countries with lower human development index and individuals with lower education. A birth cohort analysis show that the effects are significantly smaller for later cohorts implying that son preference fertility behavior has diminished over time.
Impact of Gender and Locality Differences upon Professional Attitude of Physical Education Professionals
Global Physical Education & Sports Sciences Review ◽
10.31703/gpessr.2020(iii-i).04 ◽
2020 ◽
Vol III (I) ◽
pp. 21-26
Author(s):
Faheemullah Khan ◽
Abdurrehman
Keyword(s):
Physical Education ◽
Sampling Technique ◽
Natural Attitude ◽
Education Professionals ◽
Professional Attitude ◽
Demographic Difference ◽
The Mean ◽
Gender Based ◽
And Gender ◽
The Impact
Professional attitude has a key role in performing any duty. If a person lacks positive professional attitude or has natural attitude towards his/her profession then it creates many problems. So there for positive professional attitude has fruitful results in performing any task. This study was initiated to know the impact of demographic difference, locality and gender upon professional attitude of physical education professionals. Total 125 participants participated in this study which was selected through purposive sampling technique. Consents of 77 male and 48 female were taken for the purpose of gender based difference impact and in which 50 were from rural and 75 were from urban setup. It was for locality wise difference. Data was collected through questionnaire and was analyzed by using SPSS. The concluded results shown that gender differences has no significant impact upon professional attitude of physical education professionals and similarly locality is also has no significant impact upon professional attitude of physical education professionals. Both groups were found same in locality basis and gender basis. The mean score of both groups were found significantly same.
Global Journal of Guidance and Counseling in Schools Current Perspectives ◽
10.18844/gjgc.v5i2.463 ◽
2016 ◽
Vol 5 (2) ◽
pp. 67-71
Author(s):
Mualla Yılmaz ◽
Meral Altiok ◽
Zeliha Yaman ◽
Sevgi Seyrek ◽
Yagmur Surmeli ◽
...
Keyword(s):
Emotional Intelligence ◽
University Students ◽
Personal Information ◽
Male Students ◽
Physical Sciences ◽
The Mean ◽
Emotional Intellegence ◽
Gender Based ◽
And Gender ◽
The University
This study was conducted to determine the status of university students' emotional intelligence. The sample of this descriptive research is composed of students who have stuidied at a four year university. They are selected according to criteria of faculty and gender based on the random sampling. The data was collected using "Personal Information Form", Bar-On Emotional Intellegent Inventory. Mean, standard deviation, Independent Samples t-test, one way ANOVA tests were used for the evaluation. This study, female university students' emotional intelligence total scale and all of subscale of the mean scores were determined to be higher than male students. The emotional intellegence of the university students who are training in physical sciences was determined to be higher than that of students studying in other sections. The emotional intellegence of the university students who are training in the first class was determined to be higher than the students studying in other classes. Results: In this study, female university students' emotional intelligence total scale and all of subscale of the mean scores were determined to be higher than male students. The emotional intellegence of the university students who are training in physical sciences was determined to be higher than that of students studying in other sections. The emotional intellegence of the university students who are training in the first class was determined to be higher than the students studying in other classes. Keywords: University, student, emotional intelligence
AGE AND GENDER DIFFERENCES IN MODIFIED FEMORAL NECK-SHAFT
ANGLE: AN MRI BASED OBSERVATIONAL STUDY
10.36106/ijsr/8420737 ◽
2020 ◽
pp. 1-4
Author(s):
Najamul Huda ◽
Ankur Agarawal* ◽
Man Mohan Sharma ◽
Saurabh Agarwal
Keyword(s):
Femoral Neck ◽
Age Group ◽
Age And Gender ◽
Neck Shaft Angle ◽
Mri Scans ◽
Shaft Angle ◽
The Mean ◽
Gender Based ◽
And Gender
Background: Femoral neck-shaft angle has its importance in describing biomechanics of hip. Measurement methods like plain radiography and
CT scans have its limitations. The modied neck-shaft angle (mNSA) drawn on MRI scans is less susceptible to rotational effects and is more
reliable for getting normal values. The present study was undertaken to assess the neck shaft angle on MRI and establish differences according to
age and gender. Methods: Total 200 adults were recruited and equally distributed under four study cohorts according to age and gender. MRI of hip
joint was analysed and mNSA was measured using pre-dened axial lines and landmarks. Results: The mean age of the participants was
49.76±18.184 years (18 to 87 years). The mean mNSA was 147.855o. Males had signicantly higher mean mNSA (149.93±6.61)o than females
(145.78±5.71)o. Though the younger age group (<60 years) had higher mNSA values (148.32±6.65) than older (> 60years) age group
(147.3900±6.35), the difference was not statistically signicant. Conclusions: We conclude that gender-based variation exists in the population
with the higher values of mNSAin males as compared to females in any age group. The age based difference is also present, but it is not signicant.
Neck shaft angle calculated on the MRI has the advantage that it is unaffected by rotation of the hip and is radiation free. The orthopaedic surgeons
can use the mNSAfor the diagnosis and planning surgeries around hip, for designing implants and prosthesis. It can also be of help for the forensic
anthropologists and to the anatomists. Multicentric studies may be undertaken to include a larger population.
Linking Systematic Review, Best Practice and Gender-based Analysis Methods to Identify Promising Practices in Smoking Cessation for Pregnant Women
PsycEXTRA Dataset ◽
10.1037/e511852013-001 ◽
2011 ◽
Author(s):
Nancy Poole ◽
Lorraine Greaves ◽
Phoebe Long
Keyword(s):
Systematic Review ◽
Smoking Cessation ◽
Pregnant Women ◽
Best Practice ◽
Promising Practices ◽
Gender Based ◽
And Gender
Detection of Circulating Tissue Factor and Factor VII in a Normal Population
Thrombosis and Haemostasis ◽
10.1055/s-0038-1650365 ◽
1996 ◽
Vol 75 (05) ◽
pp. 772-777 ◽
Cited By ~ 30
Author(s):
Sybille Albrecht ◽
Matthias Kotzsch ◽
Gabriele Siegert ◽
Thomas Luther ◽
Heinz Großmann ◽
...
Keyword(s):
Tissue Factor ◽
Normal Population ◽
Mean Value ◽
Factor Vii ◽
Significant Difference ◽
Age Dependent ◽
The Mean ◽
Highly Correlated ◽
And Gender
SummaryThe plasma tissue factor (TF) concentration was correlated to factor VII concentration (FVIIag) and factor VII activity (FVIIc) in 498 healthy volunteers ranging in age from 17 to 64 years. Immunoassays using monoclonal antibodies (mAbs) were developed for the determination of TF and FVIIag in plasma. The mAbs and the test systems were characterized. The mean value of the TF concentration was 172 ± 135 pg/ml. TF showed no age- and gender-related differences. For the total population, FVIIc, determined by a clotting test, was 110 ± 15% and the factor VIlag was 0.77 ± 0.19 μg/ml. FVII activity was significantly increased with age, whereas the concentration demonstrated no correlation to age in this population. FVII concentration is highly correlated with the activity as measured by clotting assay using rabbit thromboplastin. The ratio between FVIIc and FVIIag was not age-dependent, but demonstrated a significant difference between men and women. Between TF and FVII we could not detect a correlation.
pp. 105-112
Keyword(s):
Gender Based Violence ◽
And Gender ◽
Israeli Occupation
This sample of photos from 16 August–15 November 2019 aims to convey a sense of Palestinian life during this quarter. The images capture Palestinians across the diaspora as they fight to exercise their rights: to run for office, to vote, and to protest both Israeli occupation and gender-based violence.
Vol 33 ◽
Author(s):
Jong Kun Kim ◽
Jai In Park ◽
Mei Hua Lee
Keyword(s):
Son Preference ◽
Gender Consciousness ◽
Author(s):
Lyn Snodgrass
Keyword(s):
South Africa ◽
Black Women ◽
South African ◽
African Women ◽
Gender Based Violence ◽
Political Issues ◽
Race And Gender ◽
And Gender ◽
South African Women
This article explores the complexities of gender-based violence in post-apartheid South Africa and interrogates the socio-political issues at the intersection of class, ‘race’ and gender, which impact South African women. Gender equality is up against a powerful enemy in societies with strong patriarchal traditions such as South Africa, where women of all ‘races’ and cultures have been oppressed, exploited and kept in positions of subservience for generations. In South Africa, where sexism and racism intersect, black women as a group have suffered the major brunt of this discrimination and are at the receiving end of extreme violence. South Africa’s gender-based violence is fuelled historically by the ideologies of apartheid (racism) and patriarchy (sexism), which are symbiotically premised on systemic humiliation that devalues and debases whole groups of people and renders them inferior. It is further argued that the current neo-patriarchal backlash in South Africa foments and sustains the subjugation of women and casts them as both victims and perpetuators of pervasive patriarchal values.
Author(s):
Ana Maria Vega Gutierrez
Keyword(s):
Gender Based Violence ◽
Gender Based ◽
And Gender ◽
Religious Reasons
| https://www.sciencegate.app/document/10.37075/ea.2021.2.05 |
STATE v. SOMMERS | 569 P.2d 1110 (1977) | 2d111011674 | Leagle.com
MAUGHAN Justice Based on stipulated facts defendant was tried and convicted by the court of an attempt to receive stolen property...2d111011674
STATE v. SOMMERS
No. 15066.
View Case
Cited Cases
569 P.2d 1110 (1977)
STATE of Utah, Plaintiff and Respondent,
v.
Don Leon SOMMERS, Defendant and Appellant.
Supreme Court of Utah. https://leagle.com/images/logo.png
September 16, 1977.
September 16, 1977.
Attorney(s) appearing for the Case
A.W. Lauritzen, Logan, for defendant and appellant.
Robert B. Hansen, Atty. Gen., Earl F. Dorius, Asst. Atty. Gen., R. Paul VanDam, Salt Lake County Atty., John T. Nielsen, Deputy Salt Lake County Atty., Salt Lake City, for plaintiff and respondent.
Supreme Court of Utah.
MAUGHAN, Justice:
Based on stipulated facts, defendant was tried and convicted by the court of an attempt to receive stolen property. Defendant appeals therefrom. We affirm the trial court.
The stipulated facts include a transcript of a conversation overheard by means of a "bugging" device between defendant and
[569 P.2d 1111]
an undercover agent by the name of Archuletta. It was stipulated that defendant had been under investigation by the police for some time in regard to his purchase of stolen property. In fact, on prior occasions, Archuletta had sold stolen property to defendant.
A colored television set, owned by Skaggs, Inc., was taken by Archuletta to defendant's place of business. Archuletta represented the television set had been stolen from Skaggs' loading dock the previous day. The conversation was replete with representations that the merchandise was stolen. Defendant purchased it for $40. The conversation further indicated defendant was interested in purchasing stolen meat, tools, appliances, gloves, and clothes. Defendant stated he did not want guns or other items with serial numbers, and he presently did not want any stereos. Subsequently, the police obtained a search warrant, seized the subject television set, and prosecution was thereafter commenced.
On appeal, defendant contends that Section 76-4-101(3)(b), U.C.A. 1953, as enacted 1973, is void on its face as a violation of the due process clause of the Fourteenth Amendment of the Constitution of the United States. Specifically, this provision under the attempt statute, in the Inchoate Offenses chapter, negates the defense of impossibility, viz:
(3) No defense to the offense of attempt shall arise: ... (b) Due to factual or legal impossibility if the offense could have been committed had the attendant circumstances been as the actor believed them to be.
Defendant urges the preclusion of the defense of impossibility under this statute violates the right of fundamental fairness implied in the due process clause.
In Duncan v. Louisiana 1the court stated:
The test for determining whether a right extended by the Fifth and Sixth Amendments with respect to federal criminal proceedings is also protected against state action by the Fourteenth Amendment has been phrased in a variety of ways in the opinions of this Court. The question has been asked whether a right is among those `fundamental principles of liberty and justice which lie at the base of all our civil and political institutions,' [Citations]; whether it is `basic in our system of jurisprudence,' [Citation]; and whether it is `a fundamental right, essential to a fair trial,' [Citations]...
In footnote 14, the court observed that in the more recent cases, the question has been whether a procedure was necessary to an Anglo-American regime of ordered liberty.
In the A.L.I., Model Penal Code, Tentative Draft No. 10 (1960), under Article 5, Inchoate Crimes, the "impossibility" defense was rejected. Section 76-4-101 adhered to this principle advocated by that Code. In the Introduction to Article 5: Inchoate Crimes, the A.L.I., cited the major functions of the penal law:
... Finally, and quite apart from these considerations of prevention, when the actor's failure to commit the substantive offense, as when the bullet misses in attempted murder or when the expected response to solicitation is withheld, his exculpation on that ground would involve inequality of treatment that would shock the common sense of justice. Such a situation is unthinkable in any mature system, designed to serve the proper goals of penal law... .2
Thus to exculpate defendant solely on the ground the television set he purchased was not, in fact, stolen property would shock the common sense of justice. The defense of impossibility is not a fundamental right essential to an Anglo-American regime of ordered liberty. The express abolition of such a defense advances the fundamental principles of liberty and justice which support all of our civil and political institutions.
[569 P.2d 1112]
Defendant's assertion that he was convicted of the crime of conjuring up malevolent thoughts is without merit. His conviction was predicated on proof of his criminal purpose implemented by an overt act strongly corroborative of such purpose.
He further contends the trial court erred in its ruling that an entrapment had not occurred. He asserts that he was entrapped as a matter of law by the active governmental participation in consummating the crime.
Section 76-2-303(1), U.C.A. 1953, as enacted 1973, provides that conduct merely affording a person an opportunity to commit an offense does not constitute an entrapment.
The conduct of undercover agent, Archuletta, merely gave defendant an opportunity to commit the offense. There are no facts of record indicating the police used methods creating a substantial risk the offense would be committed by one not otherwise ready to commit it.
ELLETT, C.J., and CROCKETT, WILKINS and HALL, JJ., concur.
FootNotes
1.391 U.S. 145, 148-149, 88 S.Ct. 1444, 1447, 20 L.Ed.2d 491 (1968).
2. At p. 25, A.L.I., Model Penal Code, Tentative Draft No. 10 (1960).
| https://www.leagle.com/decision/19771679569p2d111011674 |
Origin of variable propensity for anomalous slip in body-centered cubic metals | Request PDF
Request PDF | Origin of variable propensity for anomalous slip in body-centered cubic metals | Many transition metals crystalizing in the body-centered cubic (bcc) structure exhibit anomalous slip on low-stressed {110} planes at low... | Find, read and cite all the research you need on ResearchGate
Article
Origin of variable propensity for anomalous slip in body-centered cubic metals
October 2022
Modelling and Simulation in Materials Science and Engineering30(8)
DOI: 10.1088/1361-651X/ac9b79
Authors:
<here is a image 688769de17f32eb0-3fd74517e681b69e>
Roman Gröger
The Czech Academy of Sciences
Abstract
Many transition metals crystalizing in the body-centered cubic (bcc) structure exhibit anomalous slip on low-stressed {110} planes at low homologous temperatures, which cannot be reconciled with the Schmid law. Specifically, for uniaxial loading in the center of the [001] - [011] - [-111] stereographic triangle, this is manifested by 1/2[111] and 1/2[1-1-1] screw dislocations moving on low-stressed (0-11) planes. While the anomalous slip is often attributed to non-planar cores of 1/2<111> screw dislocations or to the tendency for their networks to glide easily, it remains unclear why it dominates the plastic deformation in some bcc metals, whereas it is weak or even absent in others. Using molecular statics simulations at 0 K, we demonstrate that the anomalous slip in bcc metals is intimately linked with the stability of <100> junctions between two intersecting 1/2<111> screw dislocations under stress (for example, 1/2[111] and 1/2[1-1-1] screws giving rise to the [100] junction). Our atomic-level studies show that in nearly all bcc metals of the 5th and 6th groups these junctions cannot be broken by the applied stress and the three dislocations can only move on the common {110} plane (in the above example on the (0-11) plane). On the other hand, these junctions are found to be unstable in alkali metals, tantalum, and iron, where the application of stress results in unzipping of the two dislocations and their further glide on the planes predicted for isolated dislocations. These results also suggest that the experimentally observed increased propensity for the anomalous slip in further stages of plastic deformation may be explained by reduced curvatures of 1/2<111> screw dislocations in dense networks.
<here is a image 175d1bd4b7439d95-754927124da715c1>
Anomalous slip in body-centred cubic metals
Article
Full-text available
Sep 2022
NATURE
<here is a image 5c536061a01059ae-bcf0ec8de01d2158> Daniel Caillard
<here is a image d222874ebca8adc3-b4aeea658847794d> Baptiste Bienvenu
<here is a image 5d1204d966b15bde-c2785a5e1675d22d> Emmanuel Clouet
Crystal strength and plastic flow are controlled by the motion and interaction of dislocations, the line defects carrying atomic shear increments. Whereas, in most crystals, deformation develops in the crystallographic planes in which the glide force acting on dislocations is maximum, plasticity in body-centred cubic metals is more complex. Slip systems in which the resolved shear stress is not the highest can dominate at low temperature, leading to anomalous slip. Using in situ tensile tests in a transmission electron microscope we show that anomalous slip arises from the high mobility of multi-junctions, that is, junctions between more than two dislocations, which glide at a velocity several orders of magnitude larger than single dislocations. These multi-junctions result from the interaction of a simple binary junction with a gliding dislocation. Although elasticity theory predicts that these binary junctions should be unstable in crystals with a weak elastic anisotropy such as tungsten, both experiments and atomistic simulations reveal that such junctions can be created under dynamic conditions, in agreement with the existence of anomalous slip in almost all body-centred cubic metals, including tungsten.
Screw dislocation core structure in the paramagnetic state of bcc iron from first-principles calculations
Article
Full-text available
Sep 2020
Luis Casillas-Trujillo
<here is a image d0bb97c482e4c006-d8421c445a70d156> Davide Gambino
<here is a image 8d4d687450b6e2c2-dedf043ce06a82bf> Björn Alling
Lisa Ventelon
Iron-based alloys are widely used as structural components in engineering applications. This calls for a fundamental understanding of their mechanical properties, including those of pure iron. Under operational temperatures the mechanical and magnetic properties will differ from those of ferromagnetic body-centered-cubic iron at 0 K. In this theoretical work we study the effect of disordered magnetism on the screw dislocation core structure and compare with results for the ordered ferromagnetic case. Dislocation cores control some local properties such as the choice of glide plane and the associated dislocation mobility. Changes in the magnetic state can lead to modifications in the structure of the core and affect dislocation mobility. In particular, we focus on the core properties of the 12〈111〉 screw dislocation in the paramagnetic state. Using the noncollinear disordered local moment approximation to address paramagnetism, we perform structural relaxations within density functional theory. We obtain the dislocation core structure for the easy and hard cores in the paramagnetic state, and compare them with their ferromagnetic counterparts. By averaging the energy of several disordered magnetic configurations, we obtain an energy difference between the easy- and hard-core configurations, with a lower, but statistically close, value than the one reported for the ferromagnetic case. The magnetic moment and atomic volume at the dislocation core differ between paramagnetic and ferromagnetic states, with possible consequences on the temperature dependence of defect-dislocation interactions.
Ab initio modeling of dislocation core properties in metals and semiconductors
Article
Full-text available
Oct 2016
ACTA MATER
<here is a image ab84bd9a80319902-1e1d0459f5a77dea> David Rodney
Lisa Ventelon
<here is a image 5d1204d966b15bde-c2785a5e1675d22d> Emmanuel Clouet
<here is a image 576bbae4601ab024-3438193c64a84016> Francois Willaime
Dislocation cores, the regions in the immediate vicinity of dislocation lines, control a number of properties such as dislocation mobility, cross-slip and short-range interactions with other defects. The quantitative modeling of dislocation cores requires an electronic-level description of atomic bonding. Ab initio quantum mechanical calculations of dislocation cores based on the density functional theory have progressed rapidly thanks to the steady increase in computing capacities and the development of dedicated numerical methods and codes. Our aim in this overview paper is, after a description of the methodology regarding in particular the boundary conditions, to review the new and unexpected results obtained on dislocation cores from first principles, including the identification of unforeseen stable and metastable cores and the quantitative evaluation of both interaction energies and energy pathways, in pure metals and alloys of different crystallography (FCC, BCC, HCP) as well as semiconductors. We also identify key challenges to be explored in this rapidly growing field.
Origin of Anomalous Slip in Tungsten
Article
Full-text available
Jul 2014
PHYS REV LETT
<here is a image 5b06b704201f5b29-87a379f257b8b27b> Cecile Marichal
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Kinshuk Srivastava
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> D. Weygand
<here is a image fb90c7760c9390a6-885639987b48589e> Helena van swygenhoven
Low-temperature deformation of body-centered cubic metals shows a significant amount of plastic slip on planes with low shear stresses, a phenomenon called anomalous slip. Despite progress in atomistic modeling of the consequences of complex stress states on dislocation mobility, the phenomenon of anomalous slip remained elusive. Using in situ Laue microdiffraction and discrete dislocation dynamics in micrometer sized tungsten single crystals, we demonstrate the occurrence of significant anomalous slip. It occurs as a consequence of cross kinks, topological configurations generated by prior dislocation interactions. This clearly identifies anomalous slip as a multidislocation process and not a property of isolated dislocations. The cross-kink mechanism also explains the ambiguous reporting of anomalous slip traces in the past and directs us to ways of including anomalous slip in continuum crystal plasticity formulations.
Ab initio modeling of the two-dimensional energy landscape of screw dislocations in bcc transition metals
Article
Full-text available
Jan 2014
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Lucile Dezerald
Lisa Ventelon
<here is a image 5d1204d966b15bde-c2785a5e1675d22d> Emmanuel Clouet
<here is a image 576bbae4601ab024-3438193c64a84016> Francois Willaime
A density functional theory (DFT) study of the 1/2⟨111⟩ screw dislocation was performed in the following body-centered cubic transition metals: V, Nb, Ta, Cr, Mo, W, and Fe. The energies of the easy, hard, and split core configurations, as well as the pathways between them, were investigated and used to generate the two-dimensional (2D) Peierls potential, i.e. the energy landscape seen by the dislocation as a function of its position in the (111) plane. In all investigated elements, the nondegenerate easy core is the minimum energy configuration, while the split core configuration, centered in the immediate vicinity of a ⟨111⟩ atomic column, has a high energy near or above that of the hard core. This unexpected result yields 2D Peierls potentials very different from the usually assumed landscapes. The 2D Peierls potential in Fe differs from the other transition metals, with a monkey saddle instead of a local maximum located at the hard core. An estimation of the Peierls stress from the shape of the Peierls barrier is presented in all investigated metals. A strong group dependence of the core energy is also evidenced, related to the position of the Fermi level with respect to the minimum of the pseudogap of the electronic density of states.
| https://www.researchgate.net/publication/364428516_Origin_of_variable_propensity_for_anomalous_slip_in_body-centered_cubic_metals |
PEOPLE v. SMITH | 63 Cal.2d 779 (1966) | al2d7791758 | Leagle.com
MOSK J. Defendants Leaman Smith Barbara Walker and Donald Castner appeal from judgments entered upon jury verdicts finding them...al2d7791758
PEOPLE v. SMITH
Docket No. Crim. 8547.
View Case
Cited Cases
Citing Case
63 Cal.2d 779 (1966)
409 P.2d 222
48 Cal. Rptr. 382
THE PEOPLE, Plaintiff and Respondent,
v.
LEAMAN RUSSEL SMITH, BARBARA RUTH WALKER and DONALD E. CASTNER, Defendants and Appellants.
Supreme Court of California. In Bank. https://leagle.com/images/logo.png
January 4, 1966.
January 4, 1966.
Attorney(s) appearing for the Case
Burton Marks and George V. Denny III, under appointment by the Supreme Court, and Erling J. Hovden, Public Defender, Wilbur F. Littlefield and James L. McCormick, Deputy Public Defenders, for Defendants and Appellants.
Thomas C. Lynch, Attorney General, William E. James, Assistant Attorney General, and Norman H. Sokolow, Deputy Attorney General, for Plaintiff and Respondent.
Supreme Court of California. In Bank.
[63 Cal.2d 784]
MOSK, J.
Defendants Leaman Smith, Barbara Walker, and Donald Castner appeal from judgments entered upon jury verdicts finding them guilty of conspiracy to commit forgery and burglary (Count I), the murder of Charles Monaghan (Count II), the murder of Robert Endler (Count III), the attempted murder of Stephen Suzuki (Count IV), and the attempted murder of Endel Jurman (Count V). The jury found the murders to be of the first degree, and fixed the penalty therefor at life imprisonment for Mrs. Walker and Castner, and death for Smith. The appeal of the latter is automatic. (Pen. Code, § 1239, subd. (b).) 1
[1a]
During the two months preceding February 1, 1964, Smith arranged for the printing of large numbers of blank checks purportedly issued by the Colgate-Palmolive Company and the Alka-Seltzer Miles Laboratories Company. With the assistance of Castner and Anderson, Smith placed false account numbers on the checks by a silk-screen process, made the checks payable to fictitious payees, signed them with the names of fictitious makers who were purportedly authorized officers of the issuing companies, prepared fictitious driver's licenses appearing to identify Smith as the person named as payee, and cashed a number of these checks at stores in the Los Angeles area.
In the late afternoon of February 1, 1964, Smith and Mrs. Walker left the house where they lived together, and proceeded to drive along West Pico Boulevard and nearby streets. Smith attempted with mixed success to cash fraudulent Alka-Seltzer checks at eight or nine liquor stores and food markets on the way. When the owner of one of the liquor stores refused to cash a check that Smith had presented, Mrs. Walker said, "Why don't you cash that check, it's a good check."
About 8:15 p.m. Smith and Mrs. Walker arrived at the Sears, Roebuck store on West Pico Boulevard. They went to the cashier's department and Smith presented one of the Alka-Seltzer checks to be cashed, together with a fictitious
[63 Cal.2d 785]
driver's license purporting to identify him as the payee, "Thomas B. Conway." On turning the license over, the cashier's suspicions were aroused when she found it did not have the usual seal of the State of California stamped on the reverse side. A call went out for the store security officer, Mr. Winters; while awaiting his arrival, the cashier explained the delay to Smith by pretending that the check was being cleared through Telecredit. Smith stated that he "couldn't wait that long," but the cashier retained the check and license and reported that the Telecredit line was busy. Mr. Winters then arrived, and out of the presence of Smith and Mrs. Walker the cashier gave the check and license to him and explained her reasons for believing they were not genuine.
At Mr. Winters' request, Smith and Mrs. Walker accompanied him to an inner office. He asked Smith if he had any further identification, and Smith said he did not. Smith then stated he wanted the check and license returned to him and wanted to leave. Mr. Winters replied he would first have someone examine the check and license; in the presence of Smith and Mrs. Walker, Mr. Winters telephoned the Wilshire Detective Bureau, located next door to Sears, and asked that a detective be sent over.
A few minutes later Police Officers Monaghan, Endler, and Jurman, all in plain clothes, arrived in the office. Mr. Winters showed them the check and license and told them he suspected they were not genuine. Smith asked the officers, "Are you cops?" and Officer Endler answered, "Yes." Smith and Mrs. Walker appeared to speak to each other, but their words were inaudible to the others present.
2
The police officers then separated Smith and Mrs. Walker, conducting the latter to a chair in the outer office. Mr. Winters attempted to reach Telecredit to verify the check, when Smith suddenly drew a gun from under his coat. Officer Monaghan shouted, "Look out, he has a gun," and a shot rang out. Mr. Winters and the officers ducked, and Smith stood waving his gun and saying, "Get out of my way, I'm coming through" or "I'm coming out." Officer Endler had been shot point-blank in the head; when found after the shooting, his gun was still in its holster. Officer Monaghan drew his gun and pushed Mr. Winters, who
[63 Cal.2d 786]
was unarmed, behind him on the floor. Mr. Winters' view was then blocked, but he heard another shot and saw Officer Monaghan bleeding profusely from the head. Officer Jurman attempted to stop Smith, but Smith shot him in the chest and arm. At some point in this melee Smith also fired in the direction of two employees crouching by a counter and wounded one, Mr. Suzuki. Smith then ran out of the office and down a main aisle of the store, brandishing his gun and shouting, "Don't move, anybody, don't move." He left via the parking lot and escaped in his car.
Additional police arrived on the scene and found Officers Monaghan and Endler dead from gunshot wounds of the head, and Officer Jurman and employee Suzuki alive but suffering from other gunshot wounds. Throughout the shooting and escape Mrs. Walker had remained seated in the chair where she had been placed earlier. Officer Bradshaw took possession of her purse, opened it and found a loaded .25-caliber pistol in a holster. Officer Bradshaw then arrested and handcuffed Mrs. Walker, and turned her over to Officer Sinclair, his superior. A further examination of Mrs. Walker's purse disclosed a driver's license in her wallet with her photograph on it but issued to the name "Barbara J. Snyder," and scraps of paper bearing the names and addresses of defendants Castner and Anderson. In a separate, zippered compartment of the purse were found four other driver's licenses, each bearing the same photograph of Smith but issued to a different fictitious name and address; six forged Alka-Seltzer checks; and a driver's license and social security card in a fictitious name ("Larry Parker") previously used by Smith in passing the Colgate-Palmolive checks. 3
After leaving the Sears parking lot Smith abandoned his car on a side street and took a taxi to a bar, where he telephoned Castner. Phillips, who lived with Castner, testified that the latter answered the call about 9:15 p.m., and became "visibly shook and nervous." After hanging up, Castner ran around the apartment pouring photographic solutions down the drain and packing other equipment, including an enlarger, into Phillips' car. They drove to the bar and had a round of drinks with Smith, then all three returned to Phillips'
[63 Cal.2d 787]
car. As they entered Smith said, "Turn on the radio, I have shot someone." They heard a news broadcast stating that two policemen had been killed at the Sears store and two persons had been wounded. Smith told Phillips and Castner that he and Mrs. Walker had gone into Sears to cash a check and there had been "some trouble." At Smith's direction they drove to an alley and dumped the equipment into a trash can, then continued to the railroad freight yard where Smith left them. Phillips and Castner drove on to the apartment of a friend, Johnny Holloway; the three went to a bar, and Castner told Holloway that if anyone should ask, they had been with him all evening. Smith was arrested in Chicago on a fugitive warrant four days later, still in possession of the gun that had been used to kill Officers Monaghan and Endler.
Mrs. Walker testified in her own defense. She was five or six months pregnant at the time of trial, had three children by a prior marriage, and was 21 years old. Her schooling had not progressed beyond the sixth or seventh grade, and she could barely read or write. Smith met her in Chicago where she was working as a waitress, and brought her to California in the middle of January 1964. Through Smith she met Castner and Phillips, but she had never seen Anderson until he appeared in court. Smith told her to call him "Jim Snyder," and to describe him as a sales promotion man for Colgate-Palmolive. He told her he carried a gun for protection because he often had large amounts of money on his person. He told her that the various checks he cashed were his own pay checks, and she had no knowledge that they were fictitious. She had no part in preparing any of the checks involved in this case, and Smith had made it very clear to her that she was to keep out of his "business." He gave her a driver's license made out to "Barbara J. Snyder" for the purpose of proving her age when they went to bars or nightclubs together. He often opened her purse, and told her she need not use the zippered compartment. Before they went out on the evening of February 1 he turned his back on her and put something in that compartment, which was later found to contain the additional fictitious checks and driver's licenses. When they reached the Sears parking lot Smith said he planned to buy a dress for her and told her to carry the .25-caliber automatic in her purse for him. She obeyed, as she had in the past, and they entered the store. She did not know he was still armed; during the shooting and the confusion
[63 Cal.2d 788]
following it, she made no move to escape; and thereafter she fully cooperated with the police in their efforts to identify and apprehend "Jim Snyder."
Smith took the stand and corroborated Mrs. Walker's testimony as to her ignorance of his "business." 4As for himself, he made in effect a judicial confession of all the crimes charged against him. He admitted conceiving the idea of the check forging operation, and described his participation therein during December 1963 and January 1964. As to the events of February 1, he admitted stopping on the way to Sears with Mrs. Walker at a number of liquor stores and food markets for the express purpose of cashing fictitious checks. He admitted presenting such a check at the cashier's department of Sears; and although he testified that he "didn't intend to kill anyone," his own description of the ensuing events discloses an unmistakable intent to shoot his way out of his predicament regardless of the cost in human lives. 5
We shall consider the contentions of each appellant generally in the order presented.
[63 Cal.2d 789]
Challenges to prospective jurors. Smith first contends that the trial court erred in sustaining the People's challenges for cause to a group of prospective jurors who stated that although they could vote for a verdict of guilty of first-degree murder, their moral scruples would prevent them from thereafter voting to fix the penalty at death. Penal Code section 1074, subdivision 8, provides that a challenge for implied bias may be taken "If the offense charged be punishable with death, the entertaining of such conscientious opinions as would preclude his finding the defendant guilty; in which case he must neither be permitted nor compelled to serve as a juror." (Italics added.) Smith argues that the scruples of the prospective jurors here involved would not have precluded such a finding of guilt but would only have precluded a vote to impose the death penalty. The same argument was considered at length and rejected in People v. Riser (1956) 47 Cal.2d 566 , 573-576 [ 305 P.2d 1 ]. Smith urges that the result should be otherwise today because of the enactment since Riser of Penal Code section 190.1, providing for separate guilt and penalty trials and allowing a new jury to be empaneled for the latter phase "for good cause shown."
[2]
The point is without merit. The enactment of section 190.1 can in no way be construed as evidence of legislative intent to overrule our decision in
Riser,
which has since been cited in two further decisions of this court rejecting the argument here advanced by Smith. (
People
v.
Shipp
(1963)
59 Cal.2d 845
, 853 [
31 Cal.Rptr. 457
,
382 P.2d 577
];
People
v.
Love
(1961)
56 Cal.2d 720
, 726 [
16 Cal.Rptr. 777
, 17 Cal.Rptr. 481,
366 P.2d 33
].) On the contrary, a full quotation of the relevant sentence of section 190.1
6
discloses a directive of the Legislature that whenever possible the same jury shall serve at both phases of the trial for reasons of continuity and economy of effort. This directive of the Legislature neither denies the defendant due process of law nor favors the prosecution over the defense. (
People
v.
Gilbert
(1965)
ante,
pp. 690, 712 [
47 Cal.Rptr. 909
,
408 P.2d 365
].)
Smith's prior felony convictions.
The indictment charged Smith with six prior convictions of felony in various states and federal courts. Smith denied these allegations, and at the
[63 Cal.2d 790]
close of the People's case in chief on the guilt phase the prosecuting attorney introduced into evidence, without objection by Smith, documentary proof of the prior convictions charged. Smith then took the witness stand in his own defense. In the course of cross-examination the prosecuting attorney asked Smith if he had been convicted of each of the charged felonies and had served a term of imprisonment therefor, identifying each by the date and place of conviction and the name of the crime. Smith contends that such questions exceeded the allowable scope of cross-examination for impeachment purposes.
The contention is without merit.
[3]
A defendant who testifies in his own behalf may be impeached by proof he has suffered one or more prior convictions of felony in this state or elsewhere. (Code Civ. Proc., §§ 2051, 2065.)
[4]
While the courts will be zealous to insure that the prosecuting attorney is not permitted to delve into the details and circumstances of the prior crime (
People
v.
David
(1939) 12 Cal.2d 639, 646 [86 P.2d 811];
People
v.
Wynn
(1941) 44 Cal.App.2d 723, 731-733 [112 P.2d 979]), simple questions designed to identify the particular felony involved in the conviction are allowable. Thus the name or nature of the crime may be asked (
People
v.
David
(1939)
supra,
12 Cal.2d 639, 646;
People
v.
Miller
(1961)
196 Cal.App.2d 171
, 176 [
16 Cal.Rptr. 408
]), and an inquiry into the place and date of the conviction is harmless as such details will appear in any event on the face of the record of judgment (
People
v.
Tubby
(1949)
34 Cal.2d 72
, 79 [
207 P.2d 51
]; cf.
People
v.
Muchupoff
(1926) 79 Cal.App. 306, 310-312 [249 P. 240]).
Smith contends that the prosecuting attorney in the present case was allowed to go beyond these limits and ask him the actual terms of imprisonment he served on each prior conviction. Inquiry into "the length of time served and conditions or circumstances surrounding the parole of a defendant" is improper (
People
v.
Wynn
(1941)
supra,
44 Cal.App.2d 723, 732; accord,
People
v.
Hollander
(1961)
194 Cal.App.2d 386
, 396 [
14 Cal.Rptr. 917
]), but here no such questions were asked.
[5]
The prosecuting attorney did not inquire how long defendant spent in prison under the prior convictions, but simply asked in each case "Did you serve a term of imprisonment in the State [or federal] prison for that?" Only once was the actual term mentioned, and then it was volunteered by Smith. As to certain of the prior crimes the inquiry
[63 Cal.2d 791]
was proper for the purpose of establishing whether, upon conviction, Smith should be adjudged an habitual criminal. (Pen. Code, § 644.) While the prosecutor in some instances asked the same question as to other priors that are not listed in the statutory definition of habitual criminality, we note that the rule excluding such a question is not as rigid as Smith implies. The matter turns in large part on the good faith of the prosecutor (see People v. Linyard (1957) 151 Cal.App.2d 50 , 54-55 [ 311 P.2d 57 ]); and where, as here, the questions are brief and to the point, and there is no indication of a deliberate attempt by the prosecutor to prejudice the defendant in the eyes of the jury, it is within the trial court's discretion to allow the inquiry. No abuse of that discretion is shown here.
[6]
Smith also complains that the court failed to give appropriate limiting instructions upon request at the time the foregoing questions were asked. The court replied that it would give such instructions "when the proper time comes," and proceeded to do so in its charge to the jury at the close of the guilt phase. In particular, the court on defendant's request carefully instructed as to the limited purposes for which the evidence of Smith's prior convictions could be considered by the jury, and warned the jury that "You must not use this evidence in determining the defendant's guilt or innocence of the other charges, nor must you permit yourself to be influenced against the defendant because he may have suffered a prior felony conviction." Such instructions adequately protected Smith's substantive rights.
[1b]
Proof and instructions relating to conspiracy.
The prosecution advanced two theories to warrant a verdict of first-degree murder against Smith: that the killings of Officers Monaghan and Endler were deliberate and premeditated, or that they occurred in the perpetration of burglary, i.e., during Smith's entry into Sears with the intent to commit the felony of forgery. (Pen. Code, §§ 189, 459, 470.) There was ample evidence to support a first-degree murder conviction of Smith on either or both of these grounds, and the court gave corresponding proper instructions.
There was also ample evidence that Smith and Castner, and possibly Anderson in addition, were guilty of forgery and conspiracy to commit forgery. Yet rather than ask for an indictment on these simple and provable charges, the prosecution apparently sought to use the fact of the common forgery
[63 Cal.2d 792]
operation as a means to ensure first-degree murder convictions of everyone in any way connected with these events. For this purpose, of course, a charge of conspiracy merely to commit forgery would have been insufficient because it would not have involved the felony-murder doctrine. To bring that doctrine into play, the prosecution charged instead that Smith, Castner, Anderson, and Mrs. Walker had committed a compound crime entitled "conspiracy to commit forgery and burglary." The evidence is thin indeed that such a conspiracy ever existed here. Rather, the jury's verdict on Count I may well have been based on the not unnatural surmise that if several persons conspire to prepare fictitious checks, they probably also intend to pass them for profit in stores or other business establishments. It is true that Smith himself clearly intended to pass these checks in stores, and he admitted as much on the witness stand. But other than mere association and opportunity to conspire, there is little evidence from which the jury could justifiably have believed beyond a reasonable doubt that Castner, Anderson, or Mrs. Walker participated in the burglarious plans of Smith.
At this time, however, we need not finally determine whether the evidence of conspiracy to commit burglary is so inadequate as to require reversal on that ground alone. Anderson is not a party to this appeal; and as will appear, the judgments as to Castner and Mrs. Walker must be reversed in any event because of the admission into evidence of statements obtained in violation of the rules of Escobedov. Illinois(1964)378 U.S. 478[84 S.Ct. 1758, 12 L.Ed.2d 977], and Peoplev. Dorado,(1965)62 Cal.2d 338[42 Cal.Rptr. 169,398 P.2d 361]. For the purpose of discussing Smith's contentions on the subject of conspiracy, we will assume arguendo that the evidence is sufficient in this regard. 7
[7]
Smith complains that the court erred in sustaining an objection to the following question asked of him by his counsel: "Mr. Smith, when you entered any establishment that you did enter for the purpose of cashing one of these checks, did you
[63 Cal.2d 793]
have any knowledge that when you entered that store or that establishment, that that would constitute a crime of burglary in California?" It is urged that this question was essential to Smith's defense because he proposed to testify he was ignorant of the law of burglary in California and therefore "had no intent" to commit that crime. To state the argument is to refute it. It is true, as we held in
People
v.
Marsh
(1962)
58 Cal.2d 732
, 743-744 [
26 Cal.Rptr. 300
,
376 P.2d 300
], that to sustain a conviction of conspiracy there must be proof that the accused entered into the criminal agreement with the specific intent to commit the substantive crime; but it is also the rule that the specific intent necessary to commit burglary is simply the felonious design with which the accused enters the building, i.e., "with intent to commit grand or petit larceny or any felony" therein. (Pen. Code, § 459;
People
v.
Sears
(1965)
62 Cal.2d 737
, 745-746 [
44 Cal.Rptr. 330
,
401 P.2d 938
]; see generally 25 So.Cal.L.Rev. 75, 88-91.) Here, proof of that intent on Smith's part was conclusively established by his judicial confession that he entered the stores in question for the sole purpose of cashing checks he knew had been forged. He admitted knowing it was unlawful to pass such forged checks; and whether or not he also knew which precise statute or code section he was violating when he entered the stores with this intent is, as the trial court ruled, irrelevant.
[8]
In short, the law recognizes honest purpose, not dishonest ignorance of the law, as a defense to a charge of committing a crime requiring "specific intent."
[9]
As we said in
Marsh
(at p. 743 of 58 Cal.2d, quoting from
People
v.
Bucchierre
(1943) 57 Cal.App.2d 153, 163 [134 P.2d 505]), "The association of persons with an honest intent is not conspiracy, and one of the tests on a conspiracy trial is, did the accused act in ignorance without criminal intent? In other words, did they honestly entertain a belief that they were not committing an unlawful act?" This is a far different question from the one here asked of Smith, and had it been asked, he admittedly could not have answered it in the affirmative.
[10]
Smith contends that any conspiracy to commit forgery or burglary terminated as a matter of law when he and Mrs. Walker were "placed into custody by police officers." Once again the facts do not support his contention. At the time of the shooting neither Smith nor Mrs. Walker had been placed under arrest; and although the store personnel had expressed doubts about the validity of the check and license presented by Smith, the matter was still under investigation
[63 Cal.2d 794]
when Smith suddenly drew his gun and began firing.
[11]
It has long been settled, of course, that "whether or not the act committed was the ordinary and probable effect of the common design or whether it was a fresh and independent product of the mind of one of the conspirators, outside of, or foreign to, the common design, is a question of fact for the jury [citations], and if there be any evidence to support the finding of the jury on this question, its determination is conclusive." (
People
v.
Kauffman
(1907) 152 Cal. 331, 335 [92 P. 861].)
Directly in point are Kauffmanand a number of later decisions (e.g., Peoplev. Boss(1930) 210 Cal. 245 [290 P. 881]; Peoplev. Wells(1960)187 Cal.App.2d 324[9 Cal.Rptr. 384]; Peoplev. Corkery(1933) 134 Cal.App. 294 [25 P.2d 257]; see also Peoplev. Ketchel(1963)59 Cal.2d 503, 523-524 [30 Cal.Rptr. 538,381 P.2d 394]), which hold that each conspirator is bound by the acts of a confederate in furthering the common design of the conspiracy by escaping or resisting arrest, even though such acts may have been "dictated by the exigencies of the moment. "Smith contends that these decisions are no longer good law because of Grunewaldv. United States(1957)353 U.S. 391[77 S.Ct. 963, 1 L.Ed.2d 931, 62 A.L.R.2d 1344]. That case, however, is not in point, for it and its predecessors ( Krulewitchv. United States(1949)336 U.S. 440[69 S.Ct. 716, 93 L.Ed. 790], and Lutwakv. United States(1953)344 U.S. 604[73 S.Ct. 481, 97 L.Ed 593]) held only that "after the central criminal purposes of a conspiracy have been attained, a subsidiary conspiracy to concealmay not be implied from circumstantial evidence showing merely that the conspiracy was kept a secret and that the conspirators took care to cover up their crime in order to escape detection and punishment." (Italics added.) (353 U.S. at pp. 401-402.)
Here, the events had not progressed as far as in Grunewald,for Smith was not attempting to conceal a successfully completed crime but to escape arrest for an unfinished crime that was on the brink of being uncovered in his presence. His acts were clearly part of the res gestae of the offense, and Grunewaldin no way affects the settled rules of liability for such conduct.
Smith contends that the instructions on conspiracy and various other theories of the case were contradictory and confusing. It would unduly prolong this opinion to discuss the particulars of Smith's contention; we have examined the instructions and conclude that taken together, as the jury was
[63 Cal.2d 795]
charged to do, they fairly state the law governing this somewhat complicated multiple trial.
Procedure at the penalty phase.Smith contends that in this phase the People should not be permitted to open and close either the presentation of evidence or the arguments to the jury. This point has more than once been rejected by this court. ( Peoplev. Love(1961) supra,56 Cal.2d 720, 725; Peoplev. Corwin(1959)52 Cal.2d 404, 407 [340 P.2d 626].) Equally without merit are Smith's contentions that the penalty phase instruction we proposed in Peoplev. Morse(1964)60 Cal.2d 631, 648 [36 Cal.Rptr. 201,388 P.2d 33], is improper ( Peoplev. Jacobson(1965) ante,pp. 319, 332 [46 Cal.Rptr. 515,405 P.2d 555]), and that the court should have instructed the jurors that if they had a reasonable doubt as to which penalty was proper they should resolve that doubt in favor of life imprisonment ( Peoplev. Howk(1961)56 Cal.2d 687, 697-699 [16 Cal.Rptr. 370,365 P.2d 426]).
[12a]
Questions of search and seizure.
Shortly after the commission of the crimes on the evening of February 1 police officers entered the house at the rear of 2962 Veteran Avenue, Los Angeles, where Smith and Mrs. Walker lived together, and removed therefrom certain items of evidence. Defendants objected to the introduction of these items on the ground of illegal search and seizure, and the matter was heard at length in the absence of the jury. At the outset the prosecution stipulated that the entry and search were made without a warrant, thereby assuming the burden of showing proper justification. (
Tompkins
v.
Superior Court
(1963)
59 Cal.2d 65
, 67 [
27 Cal.Rptr. 889
,
378 P.2d 113
].)
Officer Sinclair testified that he arrived at Sears within minutes after the shooting and took charge of Mrs. Walker. He explained, "We were seeking the identity of the man who had accompanied her into Sears." In Mrs. Walker's purse he found her driver's license bearing the address, 2962 Veteran Avenue. He asked her if the latter was her address, and she said it was. He asked her who lived with her at that address, and she said that Lee did, the man who had come into the store with her (i.e., defendant Leaman Smith). The officer then asked her if Lee would go back to that address, and she answered, "I suppose he will. His clothes are there." Officer Sinclair then asked her, "You don't mind if we go and wait for him?" and Mrs. Walker replied, "No. I hope you catch him." Officer Sinclair instructed two uniformed policemen
[63 Cal.2d 796]
to stake out the Veteran Avenue premises and stop anyone who tried to enter or leave.
Officer Sinclair then conducted Mrs. Walker next door to the Wilshire station where he questioned her further, his purpose being "To attempt to identify the man that shot the officers." She said she didn't know his real name, but that he had told her to call him "Jim Snyder." She gave a physical description of Smith, and Officer Sinclair caused this description to be broadcast over police radio, then sent Officer Denver, a plainclothesman, to the Veteran Avenue address. Officer Denver was instructed to "take up a position" at that address "to apprehend the suspect wanted, if he should arrive there; and also to obtain whatever information I could which would assist to identify the suspect or to determine his present whereabouts." When Denver arrived, Officers Germann and Ruedy had already entered the house.
At the Wilshire station Officer Sinclair asked Mrs. Walker if she had any pictures of "this Jim Snyder." She said there were pictures of him at the Veteran Avenue house, and he asked her if it would be all right for the police to pick them up. She said she didn't mind if they did so, and repeated, "I hope you catch him." Officer Sinclair then asked her if there was anything else in the house to identify "Jim Snyder," and she answered that there might be "something in a bag or some bags."
Officer Sinclair then spoke by telephone to Officer Denver at the Veteran Avenue house and instructed him to pick up the pictures of "Jim Snyder" and "anything else that might aid in identifying him." Being aware, moreover, that the entire shooting incident had arisen out of an attempt by" Jim Snyder" to pass an Alka-Seltzer check of doubtful validity, Officer Sinclair spoke to Officer Denver a second time and told him generally to bring in all identifying evidence in "a forgery case or shooting case." In the ensuing search the officers found and removed a photograph of Smith and Mrs. Walker, a box of .38-caliber ammunition, a box of .25-caliber ammunition, a toy pistol, a packet of Colgate-Palmolive checks, a packet of Alka-Seltzer checks, a checkwriter, a typewriter, five partially-completed California driver's licenses, and several receipts. After hearing the foregoing testimony the court held the search to be lawful and overruled defendants' objections to the evidence seized. This ruling was correct. 8
[63 Cal.2d 797]
It will be remembered that the shootings took place in front of numerous eyewitnesses, some of them police officers. Although "Jim Snyder" escaped from the scene, the manhunt began immediately. It was reasonable for the police to believe he might stop at his house before continuing his flight, to obtain clothes, money, or ammunition. This belief, in fact, was shared by his mistress, who communicated it to the police at that time.
[13]
To make an arrest, a peace officer may break open the door or window of the house in which he has reasonable grounds for believing the suspect to be, "after having demanded admittance and explained the purpose for which admittance is desired." (Pen. Code, § 844.) But compliance with the latter section "is not required if the officer's peril would have been increased or the arrest frustrated had he demanded entrance and stated his purpose." (
People
v.
Maddox
(1956)
46 Cal.2d 301
, 306 [
294 P.2d 6
].)
[12b]
It was with this kind of danger in mind that Officer Germann took reasonable precautions in entering the house on Veteran Avenue. He had received a radio message instructing him to stake out that house, and informing him that the suspect had just killed two policemen at the Sears store. Failing to obtain a key from the adjacent house of the landlord, Officer Germann approached the suspect's residence while "covered" by his fellow officers. He shone a flashlight into various rooms, saw no one, tried the doors and found them locked, then slipped in through an unlocked window and crawled to the door which he opened for his partner, Officer Ruedy. With drawn guns the policemen then searched the house for the suspect or "for any evidence of the suspect's having been there and gone."
[14]
The law recognizes that fresh pursuit of a fleeing suspect who has committed a grave offense and remains dangerous to life and limb may constitute "exceptional circumstances" sufficient to justify a search without a warrant. (
Johnson
v.
United States
(1948)
333 U.S. 10
, 14-15 [68 S.Ct. 367, 92 L.Ed. 436];
McDonald
v.
United States
(1948)
335 U.S. 451
, 454-455 [69 S.Ct. 191, 93 L.Ed. 153];
id.
at pp. 459-460 [concurring opinion of Jackson, J.];
Brinegar
v.
United States
(1949)
338 U.S. 160
, 183 [69 S.Ct. 1302, 93 L.Ed. 1879] [dissenting opinion of Jackson, J., quoted with approval in
People
v.
Schader
(1965)
62 Cal.2d 716
, 724 [
44 Cal.Rptr. 193
,
401 P.2d 665
];
People
v.
Gilbert
(1965)
ante,
pp. 690, 706-707 [
47 Cal.Rptr. 909
,
408 P.2d 365
].)
[63 Cal.2d 798]
[12c]
Nor were the police required at that point to abandon their search for "Jim Snyder" or his true identity. They were not compelled to close their eyes to the contents of the house, and their ensuing search was incidental to the purpose of their entry. While in the house, it was not unreasonable for the officers to look about them for evidence that would identify the suspect, thus far known to them only by one of his several aliases, or that would enable them to pick up his trail. The evidence obtained by that search was properly admitted.
The second ground of the trial court's ruling was that Mrs. Walker had given valid consent to the entry and search. ( Peoplev. Burke(1956)47 Cal.2d 45, 49 [301 P.2d 241]; Peoplev. Michael(1955)45 Cal.2d 751, 753 [290 P.2d 852].) Mrs. Walker now argues that her consent was limited to an entry for the single purpose of retrieving the pictures of Smith, but the record shows a much broader permission given by her to Officer Sinclair. That officer testified, for example, "I asked her this many times, if she minded if we went to the 2962 Veteran Avenue address to try to find something to identify Jim Snyder,and she always replied that she didn't mind; she hoped we caught him." (Italics added.)
[15]
Mrs. Walker also contends that her consent was involuntary and was given only "because of assertion of authority by police officers." While permission obtained by means of such an assertion of authority is constitutionally inadequate (
People
v.
Shelton
(1964)
60 Cal.2d 740
, 746 [
36 Cal.Rptr. 433
,
388 P.2d 665
], and cases cited), there is no showing of a compulsion of this type in the present case. It is true that Mrs. Walker was under arrest at the time; but that fact, although relevant (
People
v.
Shelton, supra,
at p. 745), is "not conclusive" (
Castenada
v.
Superior Court
(1963)
59 Cal.2d 439
, 443 [
30 Cal.Rptr. 1
,
380 P.2d 641
]). "It cannot be said as a matter of law that consent given by a defendant is involuntary because it is given while he is under arrest." (
People
v.
Fischer
(1957)
49 Cal.2d 442
, 448 [
317 P.2d 967
].) Rather, the question is one of fact "to be determined in the light of all the circumstances." (
People
v.
Michael
(1955)
supra,
45 Cal.2d 751
, 753; accord,
People
v.
Bilderbach
(1965)
62 Cal.2d 757
, 762-763 [
44 Cal.Rptr. 313
,
401 P.2d 921
].) Here, the record shows no reluctance on Mrs. Walker's part to cooperate with the police; as noted above, on several occasions she even expressed the hope that Smith would be apprehended. Furthermore, in her
[63 Cal.2d 799]
testimony at the trial she reiterated her consent and did not claim that it had been other than voluntary. Taken as a whole, the record supports the trial court's conclusion that "I am satisfied that Barbara Walker gave consent to the entry to assist in identifying and capturing Smith."
[16]
Apparently on Smith's behalf, Mrs. Walker argues that her consent was not binding on Smith, cooccupant with her of the premises at 2962 Veteran Avenue. She relies on such cases as
People
v.
Shelton
(1964)
supra,
60 Cal.2d 740
, 745, and
Tompkins
v.
Superior Court
(1963)
supra,
59 Cal.2d 65
, 68-69; but those and similar decisions are distinguishable in that they dealt with situations in which one joint occupant, away from the premises, purported to authorize police officers to enter and search the premises over the express objection of another joint occupant who was actually on the premises at the time. Here, by contrast, Mrs. Walker's cooccupant was not only absent; he was in full flight and had virtually abandoned the premises. In these circumstances there is no impediment to invoking the rule that a search is not unreasonable if made with the consent of a cooccupant of the premises who, by virtue of his relationship or other factors, the officers reasonably and in good faith believe has authority to consent to their entry. (
People
v.
Gorg
(1955)
45 Cal.2d 776
, 783 [
291 P.2d 469
]; accord,
People
v.
Guyette
(1964)
231 Cal.App.2d 460
-465 [
41 Cal.Rptr. 875
];
People
v.
Kinard
(1962)
210 Cal.App.2d 85
, 87 [
26 Cal.Rptr. 377
];
People
v.
Ortiz
(1962)
210 Cal.App.2d 489
, 498 [
26 Cal.Rptr. 677
];
People
v.
Rogers
(1962)
207 Cal.App.2d 261
, 266 [
24 Cal.Rptr. 341
]; and cases cited in
Bielicki
v.
Superior Court
(1962)
57 Cal.2d 602
, 608, fn. 1 [
21 Cal.Rptr. 552
,
371 P.2d 288
].)
This is not a case in which, as in
Stoner
v.
California
(1964)
376 U.S. 483
[84 S.Ct. 889, 11 L.Ed.2d 856], consent was purportedly given by one who was not a cooccupant but who had merely a limited right of entry for certain specific purposes (i.e., a hotel clerk). Here, Mrs. Walker was Smith's mistress, and at the time of the crimes was living with him in the Veteran Avenue house. We have held that a valid consent may be given by a defendant's wife (
People
v.
Ingle
(1960)
53 Cal.2d 407
, 416 [
2 Cal.Rptr. 14
,
348 P.2d 577
]), and numerous cases have taken the logical step of including within this rule consent given by a defendant's mistress (e.g.,
People
v.
Nelson
(1963)
218 Cal.App.2d 359
, 362-363 [
32 Cal.Rptr. 675
];
People
v.
Smith
(1960)
183 Cal.App.2d 670
,
[63 Cal.2d 800]
671 [ 6 Cal.Rptr. 866 ]; People v. Howard (1958) 166 Cal.App.2d 638 , 651 [ 334 P.2d 105 ]; cf. People v. Triche (1957) 148 Cal.App.2d 198 , 203-204 [ 306 P.2d 616 ]).
Finally, Mrs. Walker complains that various items taken by the police from the automobile that Smith drove on the evening of February 1, and introduced into evidence over objection, were obtained by an illegal search and seizure. The car was found parked on a side street on February 3, and an inventory of its contents was taken later that day at the Wilshire police station; it was stipulated that the inventory was made without a search warrant. Mrs. Walker seeks to bring this case within the authority of Prestonv. United States(1964)376 U.S. 364, 366-367 [84 S.Ct. 881, 11 L.Ed.2d 777], and Peoplev. Burke(1964)61 Cal.2d 575, 578-580 [39 Cal.Rptr. 531,394 P.2d 67], but both decisions are distinguishable on the same ground. In each, the defendants were arrested in or near their automobile because of their suspicious conduct in the immediate vicinity; although a search of the car at that place and time would have been permissible as an incident to the arrest, the police did not do so; instead, the defendants were taken to the police station and their car was conveyed to a garage and impounded, where at a subsequent time it was searched and its contents seized. On these facts both this court (in Burke) and the United States Supreme Court (in Preston) held that the delayed search of the car could not be justified as incidental to the arrest because it was "too remote" in time and place.
In the present case, however, the People do not attempt to justify this search as incidental to an arrest, i.e., the ground relied on in
Burke
and
Preston.
In distinction to those cases, here the car was abandoned property when it was found by the police.
[17]
Smith had rented it from Avis Rent-A-Car some two weeks prior to February 1, under a fictitious name, and had equipped it with stolen license plates. Smith himself testified that after using the car to escape from the Sears parking lot he abandoned it on a side street, parking it between two other cars to prevent a quick check on its license plates. As we know, he then hailed a taxi, met Castner and Phillips in a bar, and left the city by freight train, finally being arrested in Chicago four days later. It may reasonably be inferred from such conduct that Smith had abandoned any interest he possessed in either the car or its contents, the latter being mainly liquor and groceries purchased by Smith on the way to Sears to facilitate cashing his fictitious checks.
[63 Cal.2d 801]
In these circumstances the controlling decision is Abel v. United States (1960) 362 U.S. 217 [80 S.Ct. 683, 4 L.Ed.2d 668]. There, the defendant was arrested in his hotel room; he was allowed to pack and take whatever he desired with him; then he vacated the room, paid his bill, and left in custody of the arresting officers. After his departure F.B.I. agents searched the room he had vacated, with permission of the management but without a search warrant, and found in the wastebasket incriminating evidence that was subsequently used against him at his trial. The United States Supreme Court upheld the legality of this search on the ground that "at the time of the search petitioner had vacated the room. The hotel then had the exclusive right to its possession, and the hotel management freely gave its consent that the search be made. Nor was it unlawful to seize the entire contents of the wastepaper basket, even though some of its contents had no connection with crime. So far as the record shows, petitioner had abandoned these articles. He had thrown them away. So far as he was concerend, they were bona vacantia. There can be nothing unlawful in the Government's appropriation of such abandoned property. See Hester v. United States, 265 U.S. 57 , 58 [44 S.Ct. 445, 68 L.Ed.2d 898]." ( Id. at p. 241.)
The analogy between the vacating of a rented hotel room and the abandonment of a rented automobile is persuasive. Here, as in Abel,the property in question was bona vacantiaas far as Smith was concerned. The police therefore were free to seize and search the vehicle without fear of infringing any of Smith's constitutional rights. (For a case applying this rule to the search of an abandoned "getaway" car, see Peoplev. Harper(1962)26 Ill.2d 85[185 N.E.2d 865, 868].)
[18, 19a]
Extrajudicial statements of Mrs. Walker and Castner.
During the night of February 1-2 Mrs. Walker and Castner were separately interrogated at the Wilshire police station. Although the interrogation of Mrs. Walker was directed in part to discovering the identity of a third suspect still at large, the investigation had nevertheless focused on Castner and her as probable participants in the crimes. Each was under arrest and in custody at that time, and the police had undertaken a process of interrogations that lent itself to eliciting incriminating statements. The inquiry had thus reached the accusatory stage as to Mrs. Walker and Castner (cf.
People
v.
Mathis
(1965)
ante,
pp. 416, 431-432 [
46 Cal.Rptr. 785
,
[63 Cal.2d 802]
406 P.2d 65 ]), and they were constitutionally entitled to be informed of their right to counsel and their right to remain silent. ( Escobedo v. Illinois (1964) supra, 378 U.S. 478 ; People v. Dorado (1965) supra, 62 Cal.2d 338 .)
[20]
The record does not show that Mrs. Walker was informed of her rights in this regard, and under
People
v.
Stewart
(1965)
62 Cal.2d 571
, 580-581 [
43 Cal.Rptr. 201
,
400 P.2d 97
], we will not presume in the face of a silent record that the necessary warning was given.
[21]
As to Castner, the Attorney General makes much of the fact that this defendant had some acquaintance with law books and some awareness of his privilege against self-incrimination, yet he confessed nevertheless. But we are dealing here not merely with an informed citizen's knowledge of the existence of a privilege against self-incrimination, but with a criminal suspect's right to effective, practical aid of counsel at a crucial point in the prosecution against him. The officer who conducted the interrogation of Castner admitted on the witness stand that as many as four times during the questioning, including once at the outset, Castner specifically asked to be allowed to consult with an attorney; the officer testified that Castner was not allowed to do so, and was told that he could seek legal advice "as soon as we are through talking to him." In such circumstances no waiver of the constitutional right to counsel will be presumed. (
People
v.
Mathis
(1965)
supra, ante,
pp. 416, 432;
People
v.
Modesto
(1965)
62 Cal.2d 436
, 446 [
42 Cal.Rptr. 417
,
398 P.2d 753
].)
[19b]
It follows that the admission into evidence of the statements of Mrs. Walker and Castner constituted error under
Escobedo
v.
Illinois, supra,
and
People
v.
Dorado, supra.
The final question to be determined is whether such errors were prejudicial. (Cal. Const., art. VI, § 4 1/2;
People
v.
Watson
(1956)
46 Cal.2d 818
, 836 [
299 P.2d 243
];
Fahy
v.
Connecticut
(1963)
375 U.S. 85
, 86-87 [84 S.Ct. 229, 11 L.Ed.2d 171].) It is true, as the Attorney General emphasizes, that Mrs. Walker's statements do not amount to outright confessions, and that she steadfastly denied any knowledge of or participation in a conspiracy to commit forgery or burglary or both. But her statements were not wholly exculpatory, as were those involved in
People
v.
Mathis
(1965)
supra, ante,
pp. 416, 432-433, and
People
v.
Hillery
(1965)
62 Cal.2d 692
, 712-713 [
44 Cal.Rptr. 30
,
401 P.2d 382
]. In the present case, by contrast, the interrogation of February 1 began with
[63 Cal.2d 803]
the admission by Mrs. Walker, relating to her presence in Sears with Smith on the night of the crimes, that she "came in there with him to cash a check." She went on to admit she knew he was using false names, had no regular job, forged her California driver's license, and carried a gun whenever he went out. She also admitted having seen Smith and Castner working over blank checks in their house, using a silk screen. The Attorney General seeks to minimize the effect of these and similar admissions by Mrs. Walker, pointing out that she thereafter took the witness stand and repeated in her testimony the gist of her extrajudicial statements. But when Mrs. Walker testified, the only substantial evidence that had been introduced connecting her with the conspiracy was the reading of her statement of February 1 to the jury and the playing of the tape-recording of that same statement. Her testimony was therefore "impelled by the erroneous admission of that evidence and cannot be segregated therefrom to sustain the judgment." ( People v. Davis (1965) 62 Cal.2d 791 , 796 [ 44 Cal.Rptr. 454 , 402 P.2d 142 ]; accord People v. Clark (1965) 62 Cal.2d 870 , 881-882 [ 44 Cal.Rptr. 784 , 402 P.2d 856 ].) Moreover, the prosecution thought enough of her statements to use one in rebuttal and to refer to the contents of others a number of times in closing argument to the jury, as evidence of her asserted consciousness of guilt and knowledge of the conspiracy.
Castner's statement constituted a full confession of the crime of check forgery, and strong evidence of his participation in a conspiracy to commit such forgery. He admitted that he had placed the account numbers on the checks by means of a silk-screen process, explaining how suspicion was allayed by using only nonunion printing shops to print the blanks; he admitted that he had provided all the equipment and materials to print the account numbers; he acknowledged that he had no authority from either Colgate-Palmolive or Alka-Seltzer to print its checks, and that when he did so he knew someone was "going to be hurt" and a "lot of money" lost. The Attorney General concedes that Castner's statement was "generally incriminating," as indeed it was. Moreover, since Castner chose not to take the witness stand this statement constituted the primary prosecution evidence, apart from the testimony of accomplices, connecting him with the crimes charged.
In view of the meager amount of properly admitted evidence
[63 Cal.2d 804]
of participation by either Mrs. Walker or Castner in a conspiracy to commit burglary, the use of their extrajudicial statements obtained in violation of Escobedo and Dorado must be held prejudicial error. 9 That error, however, did not taint Smith's judgment of conviction. The jury was carefully instructed that each extrajudicial statement was limited to the defendant making it, and that statements of a defendant-accomplice must be corroborated and should be viewed with distrust. More importantly, the independent evidence of Smith's guilt was overwhelming: not only was he positively identified by numerous eyewitnesses, but he took the stand himself and in effect made a detailed judicial confession of all the crimes charged. In the premises there is no reasonable possibility that the error in admitting the statements of Mrs. Walker and Castner might have contributed to Smith's conviction. (Cal. Const., art. VI, § 4 1/2; Fahy v. Connecticut (1963) 375 U.S. 85 , 86-87 [84 S.Ct. 229, 11 L.Ed.2d 171]; People v. Watson (1956) 46 Cal.2d 818 , 836 [ 299 P.2d 243 ]; People v. Gilbert (1965) ante, pp. 690, 702 [ 47 Cal.Rptr. 909 , 408 P.2d 365 ].)
The judgment as to Smith is affirmed. The judgments as to Castner and Mrs. Walker are reversed.
Traynor, C.J., McComb, J., Peters, J., Tobriner, J., Peek, J., and Burke, J., concurred.
The petition of appellant Smith for a rehearing was denied February 2, 1966.
FootNotes
1. A fourth defendant, Dennis Anderson, was originally charged in all five counts; his motion to dismiss for lack of probable cause (Pen. Code, § 995) was granted as to each count except Count I (conspiracy), and he obtained a severance.
Count VI of the indictment charged a fifth defendant, Clifford Phillips, with being an accessory after the fact (Pen. Code, § 32). In the course of trial, however, the court ruled that a corpus delicti of the charge against him had not been proved, and hence testimony of his statements to the police were inadmissible. The court then granted the People's motion to dismiss as to Phillips for the purpose of calling him as a witness for the prosecution. (Pen. Code, § 1099.)
2. Smith testified that he asked Mrs. Walker, "Are you ready?" Mrs. Walker denied this on the witness stand; she testified, rather, that he asked her to give him the gun she had in her purse and that she refused to do so despite his repeated urging.
3. With Mrs. Walker's consent the police then went to the house where she and Smith lived together, and found further evidence of Smith's identity and of check forging operations. The circumstances surrounding this search and seizure will be discussed more fully at the appropriate point below.
4. He testified, for example, that "I didn't think she was intelligent enough to put up the front, you might say, that was necessary to pass checks; and her memory was so bad that she couldn't remember hardly even the names that I was using, much less the one that she should be using."
5. Thus Smith testified that after separating him from Mrs. Walker, Mr. Winters began to frisk him "and I just pulled the gun out and jerked loose from his arm and told him, `Don't move.' And he backed up into a position right along here, and I was standing up here. (Indicating) So I started to go out this door, and I looked; and somewhere right along here, there was an officer with a gun. (Indicating) There was some more people out here on the floor, but I couldn't tell exactly who was who at the time. So I shot from out here. (Indicating) And I came back in this way. And as I turned around, Mr. Endler was pushing the left side of his coat back as if he were going for his gun, and I hollered, `Don't move,' and I shot again, and I continued on past here and came out this door. (Indicating) I don't even recall this table being in front of the door; but I do remember coming past here, and I looked back down through this window, and an officer who has now been identified as Mr. Jurman was back down in this position still with the gun in his hand. (Indicating.) So I shot again through here (indicating) and I came down this way and down here. (Indicating) Now, I am not really certain in my own mind even whether Mr. Monaghan shot at me from over here or I shot first, I don't really know; but I don't remember running into this gate at all. But I do know that when I came out that gate, that I had to continue this way to get back out the same direction that I had came in (indicating)."
While testifying that he could not remember firing the shot that wounded Mr. Suzuki, Smith admitted that in making good his escape "I continued on running down this hall (indicating), hollering, `Don't move! Don't move!' every time I would see someone."
6. "If the defendant was convicted by a jury, the trier of fact
shall be the same jury
unless, for good cause shown, the court discharges that jury in which case a new jury shall be drawn to determine the issue of penalty." (Italics added.)
7. If the evidence on Count I is legally insufficient, of course, it is insufficient as to all three defendants convicted on that count, including Smith. But such a determination could not benefit the latter, who remains under two valid sentences of death. The conspiracy theory of Count I added nothing to the prosecution's proof that Smith, the actual killer of Officers Monaghan and Endler, was guilty of first-degree murder on Counts II and III. In particular, even if the jury found that Smith entered the Sears store in furtherance of the alleged conspiracy to commit burglary, that same entry was an act of burglary sufficient to call into play the felony-murder rule.
8. Although the attack on the ruling is made in Mrs. Walker's brief, we discuss its merits because it is also relevant to Smith's appeal.
9. Because of this disposition we need not reach a contention raised by Mrs. Walker concerning the adequacy of the court's answer to a question of law asked by the jury during its deliberations.
| https://www.leagle.com/decision/196684263cal2d7791758 |
ACP - Saharan dust aerosol over the central Mediterranean Sea: PM10 chemical composition and concentration versus optical columnar measurements
Special issue:
Desert dust and its impact on air quality and climate
Saharan dust aerosol over the central Mediterranean Sea: PM 10 chemical composition and concentration versus optical columnar measurements
M. Marconi ,
D. M. Sferlazzo ,
S. Becagli ,
C. Bommarito ,
G. Calzolai ,
M. Chiari ,
A. di Sarra ,
C. Ghedini ,
J. L. Gómez-Amo ,
F. Lucarelli ,
D. Meloni ,
F. Monteleone ,
S. Nava ,
G. Pace ,
S. Piacentino ,
F. Rugi ,
M. Severi ,
and R. Udisti
Abstract.This study aims to determine the mineral contribution to PM 10in the central Mediterranean Sea, based on 7 yr of daily PM 10samplings made on the island of Lampedusa (35.5° N, 12.6° E).The chemical composition of the PM 10samples was determined by ion chromatography for the main ions, and, on selected samples, by particle-induced X-ray emission (PIXE) for the total content of crustal markers. Aerosol optical depth measurements were carried out in parallel to the PM 10sampling.The average PM 10concentration at Lampedusa over the period June 2004–December 2010 is 31.5 μg m −3, with low interannual variability. The annual means are below the EU annual standard for PM 10, but 9.9% of the total number of daily data exceeds the daily threshold value established by the European Commission for PM (50 μg m −3, European Community, EC/30/1999).The Saharan dust contribution to PM 10was derived by calculating the contribution of Al, Si, Fe, Ti, non-sea-salt (nss) Ca, nssNa, and nssK oxides in samples in which PIXE data were available. Cases in which crustal content exceeded the 75th percentile of the crustal oxide content distribution were identified as elevated dust events. Using this threshold, we obtained 175 events. Fifty-five elevated dust events (31.6%) displayed PM 10higher than 50 μg m −3, with dust contributing by 33% on average.The crustal contribution to PM 10has an annual average value of 5.42 μg m −3, and reaches a value as high as 67.9 μg m −3(corresponding to 49% of PM 10) during an intense Saharan dust event.The crustal content estimated from a single tracer, such as Al or Ca, is in good agreement with the one calculated as the sum of the metal oxides. Conversely, larger crustal contents are derived by applying the EU guidelines for demonstration and subtraction of exceedances in PM 10levels due to high background of natural aerosol. The crustal aerosol amount and contribution to PM 10showed a very small seasonal dependence; conversely, the dust columnar burden displays an evident annual cycle, with a strong summer maximum (monthly average aerosol optical depth at 500 nm up to 0.28 in June–August). We found that 71.3% of the dust events identified from optical properties over the atmospheric column display a high dust content at the ground level. Conversely, the remaining 28.7% of cases present a negligible or small impact on the surface aerosol composition due to the transport processes over the Mediterranean Sea, where dust frequently travels above the marine boundary layer, especially in summer.Based on backward trajectories, two regions, one in Algeria–Tunisia, and one in Libya, are identified as main source areas for intense dust episodes occurring mainly in autumn and winter. Data on the bulk composition of mineral aerosol arising from these two source areas are scarce; results on characteristic ratios between elements show somewhat higher values of Ca / Al and (Ca + Mg) / Fe (2.5 ± 1.0, and 4.7 ± 2.0, respectively) for Algeria–Tunisia than for Libyan origin (Ca / Al = 1.9 ± 0.7 and (Ca + Mg) / Fe = 3.3 ± 1.1).
How to cite.
Marconi, M., Sferlazzo, D. M., Becagli, S., Bommarito, C., Calzolai, G., Chiari, M., di Sarra, A., Ghedini, C., Gómez-Amo, J. L., Lucarelli, F., Meloni, D., Monteleone, F., Nava, S., Pace, G., Piacentino, S., Rugi, F., Severi, M., Traversi, R., and Udisti, R.: Saharan dust aerosol over the central Mediterranean Sea: PM
10
chemical composition and concentration versus optical columnar measurements, Atmos. Chem. Phys., 14, 2039–2054, https://doi.org/10.5194/acp-14-2039-2014, 2014.
| https://acp.copernicus.org/articles/14/2039/2014/ |
Anti-Glass patterns and real motion perception: Same or different mechanisms? | JOV | ARVO Journals
Research Article
Anti-Glass patterns and real motion perception: Same or different mechanisms?
Maria Michela Del Viva ; Monica Gori
Author Affiliations
Maria Michela Del Viva
Dipartimento di Psicologia, Università di Firenze,Firenze, Italy Istituto di Neuroscienze, CNR,Pisa, Italy michela@in.cnr.it
Monica Gori
Istituto Italiano di Tecnologia,Genoa, Italy Dipartimento di Informatica Sistemistica e Telematica,Genoa, Italy monica.gori@unige.it
Journal of Vision February 2008, Vol.8, 1. doi: https://doi.org/10.1167/8.2.1
Abstract
A sequence of anti-Glass patterns, composed by dot pairs with opposite luminance polarity, elicits a clear perception of motion in the direction of the white dot of the pair. This effect can be reversed by introducing a delay in the presentation of white dots, suggesting a faster processing of light dots as a cause of the motion signal (M. M. Del Viva, M. Gori, & D. C. Burr,2006). If this hypothesis is correct, anti-Glass patterns should interact with real motion signals. In this study, we compare the motion induced by these stimuli to test whether they are analyzed by the same motion mechanism. We found that motion induced by anti-Glass patterns annuls real motion, when they are presented simultaneously in the same display and moving in opposite directions. By lowering the contrast of one of them, motion toward the stimulus with higher contrast prevails. We also found sub-threshold summation of motion induced by anti-Glass patterns and real motion, when presented simultaneously and moving in the same direction.These findings indicate that anti-Glass patterns and moving stimuli are processed by the same, contrast-dependent motion mechanism and lend further support to the proposed explanation of the effect.
Introduction
Glass patterns (Glass, 1969 ; Glass & Switkes, 1976 ) are arrays of randomly positioned dot pairs oriented along global patterns. They carry a powerful sense of global spatial structure, and their properties have been widely investigated (Cardinal & Kiper, 2003 ; Dakin & Bex, 2001 ; Kurki, Laurinen, Peromaa, & Saarinen, 2003 ; Seu & Ferrera, 2001 ; Wilson & Wilkinson, 1998 ; Wilson, Wilkinson, & Asaad, 1997 ). Glass patterns have been shown to activate early visual areas as V1 and V2 (Hegdé & Van Essen, 2000 ; Movshon, Smith, & Kohnet, 2003 ; Smith, Bair, & Movshon, 2002 ) as well as brain regions in the ventral pathway (Tanaka, 1992 ; Wilkinson et al., 2000 ).
Displaying a succession of such patterns (dynamic patterns), with dipoles randomly repositioned at each screen refresh, conveys a compelling sense of global motion along the dominant orientation of the patterns, even though the stimulus itself contains no physical motion information (Ross, Badcock, & Hayeset, 2000 ). The direction of perceived motion is ambiguous because the structure is perfectly symmetrical (see Movie 1 ). Presence and direction of perceived motion depend on distance of dots within the dipole (Ross et al., 2000 ). A recent electrophysiological study on monkeys (Krekelberg, Dannenberg, Hoffmann, Bremmer, & Rosset, 2003 ) showed that Glass patterns activate brain regions in the dorsal pathway devoted to real and apparent motion processing (Britten & van Wezel, 1998 ; Duffy & Wurtz, 1991 ; Krekelberg, Vatakis, & Kourtzi, 2005 ; Mikami, Newsome, & Wurtz, 1986a ; Morroneet al., 2000 ; Newsome & Pare, 1988 ; Tanaka, Fukada, & Saito, 1989 ; Zeki, Watson, & Frackowiak, 1993 ). Psychophysical results are in agreement with electrophysiology (Ross, 2004 ), showing that perceived direction and speed of global motion is influenced by the presence of Glass patterns.
_video_
Movie 1
Motion illusion induced by sequence of Glass patterns. Motion direction is ambiguous.
A variant of the Glass stimulus is given by “anti-Glass” patterns, using dot pairs of opposite luminance polarity (anti-pairs). These create a weaker sense of global structure than regular Glass patterns, sometimes in a direction orthogonal to the global orientation (Dakin, 1997 ; Glass & Switkes 1976 ) and are harder to distinguish from randomly oriented dipoles (Prazdny, 1986 ). They are able to destroy the apparent global structure of Glass patterns when added to them (Barlow & Olshausen, 2004 ; Burr & Ross, 2006 ).
In a previous publication (Del Viva, Gori, & Burr, 2006 ), it was shown that uncorrelated sequences of anti-Glass patterns produce a clear perception of motion, but unlike the motion caused by Glass patterns, the motion from anti-Glass is always in a specific direction: from the dark to the light dot (see Movie 2 ). Motion directionality could be reversed by delaying the presentation of light dots by 5 ms. Control experiments showed that this latency was generated neither by luminance nor contrast asymmetry, like other illusions of contrast induced motion perception (Backus & Oruç, 2006 ; Conway, Kitaoka, Yazdanbakhsh, Pack, & Livingstone, 2005 ) nor by biphasic temporal impulse response functions for light increments and decrements (Brooks, van der Zwan, & Holden, 2003 ). It was therefore hypothesized that the illusory motion could result from a delayed processing of the dark dots due to differential delays in the primate on and off systems, presumably at retinal level (Chichilnisky & Kalmar, 2002 ; Ueno, Kondo, Niwa, Terasaki, & Miyake, 2004 ).
_video_
Movie 2
Motion illusion induced by a sequence of anti-Glass patterns. Motion direction is defined by dot polarity.
If the above explanation is correct, anti-Glass patterns and real motion should evoke similar activity in direction-selective neurons (such as in V1 cells), implying that anti-Glass should interact with real motion signals.
Current study
In this study, we compared the sensitivity of the human global motion system to anti-Glass patterns and to real optic-flow motion. Since anti-Glass motion is perceived in the direction opposite to time ordering (Del Viva et al., 2006 ) as in “reverse-phi motion” (Anstis, 1970 ), we also compared anti-Glass with reversing-contrast moving dots to demonstrate that they are two special cases of the same phenomenon. For this purpose, we devised a rotational optic-flow stimulus, made locally of reversing-contrast dots, whose properties have not yet been studied.
We first matched the motion and the anti-Glass stimuli for speed and contrast. Speed matching was obtained by manipulating the distance between dots of anti-Glass pairs and the displacement of moving dots. The time interval was kept constant, according to the assumption that the motion effect of anti-Glass is due to a fixed latency (Del Viva et al., 2006 ).
Finally, we combined anti-Glass patterns and real motion stimuli in the same display to study the relationship between the processing of the two signals by varying their relative strength. Stimulus strength was adjusted either by varying the proportion of dots of each stimulus or their luminance contrast. The motivation for these two types of manipulations was the suggestion from previous studies that they test different stages of motion analysis: a first contrast-dependent local stage and a second coherence-dependent global stage (Morrone, Burr, & Vaina, 1995 ). Measuring the contrast sensitivity of the global motion system to the combined stimuli sheds light on the level at which they are integrated.
General methods
Stimuli
Anti-Glass patterns
Stimuli were sequences of circularly arranged anti-Glass patterns, each composed by 70 anti-pairs, made of dots with opposite luminance polarity with respect to the background (see Figure 1A and Movie 2 ). Each pair was randomly positioned within an annulus, delimited by r max = 13° and r min = 3.5°, and was oriented tangentially to produce coherent circular patterns. The position of pairs was randomly updated every 6 video frames (30 ms = duration), so that dots were uncorrelated in space and time, providing no motion signals. Five different patterns were displayed in each trial, for a total presentation time of 150 ms.
Figure 1
(A) Example of anti-Glass stimuli used in this study. The position of pairs is updated randomly every 6 video frames ( t 1 = duration = 30 ms). (B) Schematic representation of the anti-Glass stimulus during time t 1 that corresponds to 6 video frames (frame-rate 200 Hz). Dots are presented simultaneously (left), but the stimulus is perceived as moving in the direction of the white dot (right). (C) Left: schematic representation of the reversing-contrast stimulus during time t 1 . Right: motion is perceived in the opposite direction (reverse-phi motion).
Figure 1
(A) Example of anti-Glass stimuli used in this study. The position of pairs is updated randomly every 6 video frames ( t 1 = duration = 30 ms). (B) Schematic representation of the anti-Glass stimulus during time t 1 that corresponds to 6 video frames (frame-rate 200 Hz). Dots are presented simultaneously (left), but the stimulus is perceived as moving in the direction of the white dot (right). (C) Left: schematic representation of the reversing-contrast stimulus during time t 1 . Right: motion is perceived in the opposite direction (reverse-phi motion).
Motion
Motion stimuli were arrays of 70 random dots that moved coherently along circular trajectories around the screen center. In contrast-reversing stimuli, all dots switched polarity during motion from white to black (see Figure 1C ) because white dots are assumed to be processed faster than dark dots (Del Viva et al., 2006 ). In same-polarity motion stimuli, 50% of the dots were black and 50% were white to match the global luminance of anti-Glass and reverse-phi, and polarity was maintained during motion. Moving dots stayed in a given position for 15 ms before being displaced abruptly, with a total lifetime of 30 ms. After 30-ms dots, position was updated randomly and total presentation time was 150 ms. As in the anti-Glass stimulus, dots were confined within an annulus delimited by r max = 13° and r min = 3.5°.
Apparatus
The background luminance was 61 cd/m 2 , maximum luminance was 140 cd/m 2 (white), and minimum luminance was lower than 1 cd/m 2 (black). All stimuli were programmed with Matlab and displayed on a gamma-corrected Clinton Monoray monitor (frame rate 200 Hz, 640 × 480 pixel) via a VSG 2/3 board (Cambridge Research System). The whole display subtended 26° × 26° of visual angle at a viewing distance of 57 cm, and a single dot subtended 0.3° All experiments were carried out in a completely dark room.
Observers
Three observers participated to the experiments, one of the authors (M.G.) and two observers (F.B. and L.B.), naive to the aims of the study. All observers had normal or corrected to normal visual acuity and no history of visual disorders.
Dependence on speed
Stimuli and procedures
In anti-Glass patterns, coherence discrimination thresholds were measured by degrading the circular patterns by replacing a fraction of the 70 pairs with spatially uncorrelated pairs with random orientation (noise). The degree of coherence was kept constant throughout each trial sequence. Relative position of all light and dark dots was randomly assigned on each trial. In motion stimuli, coherence discrimination thresholds were measured by degrading the coherent circular flow by replacing a fraction of the 70 pairs with dots moving in random directions (noise).
For all stimuli, motion direction was randomized between trials, and the proportion of signal and noise pairs was varied from trial to trial according to a QUEST staircase procedure (Watson & Pelli, 1983 ). The subject's task was to indicate the direction of perceived motion, in a two-alternative forced-choice procedure (2AFC) with a single temporal presentation.
Thresholds for moving stimuli were measured for displacements (center to center) from 0.05° to 1°, while for anti-Glass the lowest distance was 0.4°, corresponding to a two-pixel separation between dot boundaries. Note that since dot separation was the same for all pairs, local angular rotation speed decreased with the inverse of the distance from the center of the screen. While these stimuli did not exactly simulate real global motion, they were able to activate global motion detectors.
Contrast of dark and light dots was 100%. For each stimulus and distance, data were collected in 2 sessions of 4 blocks, each composed of 100 trials. For every condition and subject, a cumulative maximum likelihood fit was performed off-line with data obtained in all sessions, based on a Weibull ( 1951 ) psychometric function. Thresholds were defined as the coherence level yielding 75% correct discrimination. Student's t -tests with significance level of 0.05 were used to compare measured thresholds.
Results and discussion
Figure 2A shows psychometric curves as a function of coherence for anti-Glass stimuli, obtained for different distances between dots within the pair. The horizontal line drawn at chance level separates perception in the direction of white dot (probabilities 0.5–1) from perception in the direction of black dot (probabilities 0–0.5). All subjects perceived a clear direction of motion for distances between 0.4° and 0.7°. In this range, all psychometric curves lie in the upper half of probability range, meaning that motion was always perceived in the direction from the black to the white dot (see Figure 1B ). For all subjects, the best performance was obtained for 0.4° separation, corresponding to a coherence threshold of 63%. This separation has been used for anti-Glass patterns in all other experiments in this paper.
Figure 2
Spatiotemporal properties of stimuli. (A) Probability of motion discrimination in the direction of the white dot as a function of coherence of anti-Glass. Different red symbols represent different distances between dots in the pair. (B) Probability of motion discrimination in the direction of the white dot as a function of coherence of reversing-contrast moving dots (reverse-phi motion). (C) Probability of motion discrimination in the physical direction as a function of coherence of same-polarity moving dots. Different green and black symbols represent different displacements for same-polarity and reverse-phi motion. The red curve replot anti-Glass data in panel A. The horizontal line indicates chance level.
Figure 2
Spatiotemporal properties of stimuli. (A) Probability of motion discrimination in the direction of the white dot as a function of coherence of anti-Glass. Different red symbols represent different distances between dots in the pair. (B) Probability of motion discrimination in the direction of the white dot as a function of coherence of reversing-contrast moving dots (reverse-phi motion). (C) Probability of motion discrimination in the physical direction as a function of coherence of same-polarity moving dots. Different green and black symbols represent different displacements for same-polarity and reverse-phi motion. The red curve replot anti-Glass data in panel A. The horizontal line indicates chance level.
Black curves in Figure 2B represent probability of response in the direction of the white dot as a function of coherence, for different displacements of contrast-reversing moving dots corresponding to different speeds. All subjects perceived motion in the direction of the dot presented first (white dot, see also Figure 1C ), in accord to the reverse-phi motion illusion (Anstis, 1970 ). The red curve is the performance obtained with anti-Glass patterns with 0.4° separation. The best match to the anti-Glass curve was obtained for the same experimental conditions (0.4°, squares). Both stimuli yielded perception of motion in the direction of the white dot with very similar psychometric curves and comparable coherence thresholds: anti-Glass = (63 ± 7%), reverse-phi motion = (63 ± 11%) ( p = 0.82). In the rest of the study, we will use this reversing-contrast stimulus.
Green curves in Figure 2C represent probability of responses in the physical direction of motion as a function of coherence, for different displacements of same-polarity moving dots. The best match with the anti-Glass curve (replottedin red) was obtained for 0.1° (triangles); coherence thresholds of these two conditions were not significantly different: anti-Glass = (63 ± 7%) and regular motion = (48 ± 11%) ( p = 0.35). The curve obtained for the same displacement (0.4°, circles) was very far from the anti-Glass curve: anti-Glass = (63 ± 7%) and regular motion = (29 ± 3%) ( p = 0.015). This shows that perception of regular motion is stronger than anti-Glass or reverse-phi motion in the same conditions, although it is still possible to find experimental conditions that yield comparable performances. We will use this condition for same-polarity moving dots in the rest of the paper.
The translation of distances into speeds, necessary to compare our results with others, is not straightforward because spatiotemporal properties of our reverse-phi, real motion, and anti-Glass stimuli are quite different; therefore, a common definition of velocity is not obvious. The integration time during the computation of speed for anti-Glass is uniquely determined by the 3- to 5-ms delay (Δ t ) found between processing of black and white dots (Del Viva et al., 2006 ). Under this assumption, the velocity v = Δ x /Δ t of optimal stimuli is 0.4°/Δ t > 80°/s. In our moving stimuli, Δ t = 0, and such an abrupt displacement (Dirac delta) generates a broad spectrum of velocities activating simultaneously many detectors, tuned also to very high speeds, so we need to make a reasonable assumption about integration time. Since the delay between the onset of the first and the second dot is 15 ms, and this is shorter than typical integration times, we assume Δ t = 15 ms, which should correspond to the lag between peak activation of the neural units responding to the two-frame stimulus, whatever the time course of the response. Under this assumption, reverse-phi that best matches anti-Glass move at ≈27°/s (Δ x = 0.4°), and best-matched motion stimulus has a velocity of ≈7°/s (Δ x = 0.1°).
The results presented above show that dynamic anti-Glass patterns give rise to perception of motion in the direction of black to white, for a wide range of distances.
Assuming the definition of velocity given above, the estimated speed range of anti-Glass motion is from 80°/s to 140°/s. In this range, motion from anti-Glass is always perceived in the direction of dots that are processed faster, even though presented simultaneously, consistent with “reverse-phi motion” (Anstis, 1970 ).
Under our conditions, coherence sensitivities (defined as 1/threshold) for anti-Glass (1.6) matching reversing-contrast (1.66) and regular optic flow (2) were quite low in comparison with those found for regular optic flow (10) (Burr & Santoro, 2001 ; Morrone et al., 1995 ). This discrepancy may be due to substantial differences between stimuli: lower speed (7°/s in our stimuli vs. 13°/s in theirs), lower density (0.25/cm 2 in our stimuli vs. 2.5–5/cm 2 in theirs), and dot life-time (30 ms in our stimuli vs. 200 ms in theirs).
The maximum displacement allowing perception of reverse-phi motion (0.4°) is also larger than the previously found 0.17° (Sato, 1989 ), but again very different experimental conditions and stimuli (such as pattern duration, dot size and number, stimulus size, etc.) can account for the discrepancy.
Contrast thresholds
Stimuli and procedures
We measured motion direction discrimination as a function of Michelson contrast, in 100% coherent anti-Glass patterns, reversing-contrast, and regular moving dots, with the same spatiotemporal characteristics of the first experiment.
Contrast was varied from trial to trial with the method of constant stimuli . Subjects indicated the direction of perceived motion, in a two-alternative forced-choice procedure (2AFC) with a single temporal presentation. For each experimental condition, data were collected in 2 sessions of 4 blocks, each composed of 100 trials and all data were fitted (maximum likelihood fit) using a Weibull ( 1951 ) psychometric function. Thresholds were defined as the contrast level yielding 75% correct discrimination. Luminance of light and dark dots corresponding to Michelson contrast 7%, 9%, 13%, and 17% were 65 and 56, 67 and 55, 69 and 51, and 73 and 48 cd/m 2 , respectively. Student's t -tests with significance level of 0.05 were used to compare thresholds.
Results and discussion
Figure 3A shows the probability of observing motion in the direction of the light dot as a function of Michelson contrast, for both reverse-phi motion and anti-Glass (black and red curves, respectively). The two stimuli yield very similar results, with motion perception becoming less pronounced with decreasing contrast, but always in the direction of the lighter dot. Even at contrasts as low as 13%, more than 75% of presentations were perceived to move toward the lighter dots. Direction discrimination thresholds for the two stimuli were not statistically different (anti-Glass = (11.9 ± 1.2%), reverse-phi motion = (11.4 ± 1.0%), p = 0.76) and so were detection thresholds (anti-Glass = (4.2 ± 0.6%), reverse-phi motion = (4.1 ± 0.6%), p = 0.92), shown by arrows.
Figure 3
Contrast dependency of stimuli. (A) Probability of motion discrimination in the direction of the white dot as a function of Michelson contrast for anti-Glass patterns (red) and reverse-phi motion (black). Arrows indicate detection thresholds for motion (black) and anti-Glass (red). (B) Probability of motion discrimination in the physical direction as a function of Michelson contrast for same-polarity moving dots (green). The red curve is the same as in panel A. Arrows indicate detection thresholds for motion (green) and anti-Glass (red). Coherence of all stimuli was 100%. The horizontal line indicates chance level.
Figure 3
Contrast dependency of stimuli. (A) Probability of motion discrimination in the direction of the white dot as a function of Michelson contrast for anti-Glass patterns (red) and reverse-phi motion (black). Arrows indicate detection thresholds for motion (black) and anti-Glass (red). (B) Probability of motion discrimination in the physical direction as a function of Michelson contrast for same-polarity moving dots (green). The red curve is the same as in panel A. Arrows indicate detection thresholds for motion (green) and anti-Glass (red). Coherence of all stimuli was 100%. The horizontal line indicates chance level.
Figure 3B shows the probability of observing motion in the physical direction as a function of Michelson contrast for both same-polarity motion and anti-Glass (green and red curves, respectively, already shown in Figure 3A ). The curves overlap, implying a motion perception with similar contrast dependence for the two stimuli. Direction discrimination thresholds (anti-Glass = (11.9 ± 1.2%), regular motion = (8.7 ± 1.6%), p = 0.18) and detection thresholds (shown by arrows) (anti-Glass = (4.2 ± 0.6%), regular motion = (4.0 ± 0.1%), p = 0.52) were not statistically different.
Overall, contrasts thresholds of reverse-phi and regular motion are comparable and the latter are in agreement with those found in optic flow (Burr & Santoro, 2001 ; Morrone et al., 1995 ).
Annulling motion with anti-Glass patterns
The consistency between speed and contrast dependence of anti-Glass and real motion raises the possibility of processing by a common directional motion mechanism. To test this hypothesis, we presented real motion stimuli and anti-Glass patterns simultaneously in the same display, trying to annul the motion induced by anti-Glass patterns with reversing-contrast or same-contrast moving dots, perceived as moving in the opposite direction. We studied the perception of the resulting motion as a function of the relative strength of the two stimuli, determined by the proportion of dots of each stimulus and their contrast
Stimuli and procedures
Stimuli were combinations of moving dots, either reversing-contrast or same contrast, with anti-Glass patterns. All stimuli had the same spatiotemporal characteristics found in the first experiment. All dots moved coherently along circular trajectories around the screen center, and all anti-Glass pairs were oriented tangentially, so that we always had coherent circular motion. The relative position of light and dark dots was such that anti-Glass motion was perceived in the direction opposite to real motion. Given that dots in anti-Glass were presented simultaneously, moving dots in each single frame were half of the number of anti-Glass dots. The number of moving and anti-Glass dots was thus paired in two frames.
First, we measured motion direction discrimination for this combined stimulus by varying the proportion of anti-Glass pairs with respect to moving dots, keeping constant the total number of dots. For example, we could have 80% moving dots (56 × 2 frames) and 20% anti-Glass pairs (14 dipoles). The proportion of moving dots, and consequently of anti-pairs, was varied from trial to trial according to the method of constant stimuli, randomizing all conditions. The subject's task was to indicate the direction of perceived motion, in a two-alternative forced-choice procedure (2AFC) with a single temporal presentation. In this measurement, contrast of anti-Glass and moving stimuli were 100%.
Then, we repeated the above measurement by setting different contrast values for motion and anti-Glass. Since Michelson contrast yielding chance level was different for our subjects (see Figure 3 ), some conditions were different between observers (see caption of Figure 4 ). Luminance of light and dark dots were 80 and 40 cd/m 2 for 30% contrast and 68 and 53 cd/m 2 for 10% contrast (for other values, see the previous section). For each experimental condition, data were collected from each subject in 2 sessions of 5 blocks, each composed of 200 trials. For each subject, the proportion of moving dots matching anti-Glass (annulling point) was measured by a maximum likelihood fit to an erf function, performed off-line with the data obtained in all sessions.
Figure 4
(A) Anti-Glass against reverse-phi motion. Curves represent either the probability of motion discrimination in the direction of reverse-phi (left ordinate) as a function of fraction of moving dots (lower abscissa), or the probability of motion discrimination in the direction of anti-Glass (right ordinate) as a function of fraction of anti-Glass pairs (upper abscissa). The number of anti-Glass plus moving dots is constant: ▴, contrast anti-Glass and reverse-phi = 100%; •, contrast anti-Glass = 30%, contrast reverse-phi = 100%;, contrast anti-Glass = 13%, contrast reverse-phi = 100%;, contrast anti-Glass = 10%, contrast reverse-phi = 100%;, contrast anti-Glass = 100%, contrast reverse-phi = 30%;, contrast anti-Glass = 100%, contrast reverse-phi = 13%;, contrast anti-Glass = 100%, contrast reverse-phi = 10%. (B) Anti-Glass against motion. Motion discrimination in the direction of moving dots (left ordinate)—or anti-Glass (right ordinate)—as a function of fraction of moving dots (lower abscissa)—or anti-pairs (upper abscissa). The number of anti-Glass plus moving dots is constant., contrast anti-Glass and motion = 100%;, contrast anti-Glass = 30%, contrast motion = 100%;, contrast anti-Glass = 13%, contrast motion = 100%;, contrast anti-Glass = 100%, contrast motion = 30%;, contrast anti-Glass = 100%, contrast motion = 13%.
Figure 4
(A) Anti-Glass against reverse-phi motion. Curves represent either the probability of motion discrimination in the direction of reverse-phi (left ordinate) as a function of fraction of moving dots (lower abscissa), or the probability of motion discrimination in the direction of anti-Glass (right ordinate) as a function of fraction of anti-Glass pairs (upper abscissa). The number of anti-Glass plus moving dots is constant: ▴, contrast anti-Glass and reverse-phi = 100%; •, contrast anti-Glass = 30%, contrast reverse-phi = 100%;, contrast anti-Glass = 13%, contrast reverse-phi = 100%;, contrast anti-Glass = 10%, contrast reverse-phi = 100%;, contrast anti-Glass = 100%, contrast reverse-phi = 30%;, contrast anti-Glass = 100%, contrast reverse-phi = 13%;, contrast anti-Glass = 100%, contrast reverse-phi = 10%. (B) Anti-Glass against motion. Motion discrimination in the direction of moving dots (left ordinate)—or anti-Glass (right ordinate)—as a function of fraction of moving dots (lower abscissa)—or anti-pairs (upper abscissa). The number of anti-Glass plus moving dots is constant., contrast anti-Glass and motion = 100%;, contrast anti-Glass = 30%, contrast motion = 100%;, contrast anti-Glass = 13%, contrast motion = 100%;, contrast anti-Glass = 100%, contrast motion = 30%;, contrast anti-Glass = 100%, contrast motion = 13%.
Results and discussion
Figure 4A shows the probability to perceive motion in the direction of reverse-phi (left ordinate) as a function of fraction of reversing-contrast moving dots. The same curves, if read in the opposite direction, represent the probability to perceive motion in the direction of anti-Glass (right ordinate) as a function of fraction of anti-pairs (upper abscissa) because the sum of moving dots and anti-Glass pairs was kept constant. When reversing-contrast and anti-Glass dots had the same contrast (100%, green triangles), perception of motion shifted gradually from one direction to the other when varying the proportion of dots in each stimulus. When the number of dots was equal, subjects could not tell the direction of motion: the mean annulling point, averaged over subjects, was (49.9 ± 1%). In this condition, subjects reported a percept of random noise without motion in either direction. Psychometric curves were symmetrical end-to-end, indicating that similar quantities of anti-Glass and moving dots produced the same amount of motion percept.
In further measurements, we lowered the contrast of reverse-phi stimuli (squares); in this case, a higher number of moving dots were needed to perceive motion in their direction. The same applied to anti-pairs (circles).
In other words, an increase in the proportion of dots can compensate for the lower contrast of a given stimulus down to levels close to the discrimination thresholds (13% for F.B. and L.B.; 10% for M.G.). The psychometric curves are symmetrical when the parameters of the two stimuli are swapped, indicating complete equivalence.
In experiments performed with same-polarity moving dots and anti-Glass patterns with 100% contrast ( Figure 4B , green triangles), perception of motion was annulled when the fraction of moving dots was (19 ± 4%). Again, in the annulling condition, the subjects reported a perception of dots moving in random directions. The results indicate that real motion prevails on anti-Glass motion. As in the previous experiment, the strength of each stimulus could be modulated by varying its contrast.
Anti-Glass patterns can annul perception of real motion in the opposite direction, indicating that these two stimuli are processed by the same directional mechanism. However, anti-Glass patterns and contrast-reversing dots give rise to identical perception of motion while same-polarity moving dots are more effective than anti-Glass. The lack of a perception of transparency in the annulling conditions is in agreement with the results of studies performed with real motion stimuli in opposite directions (Qian & Andersen, 1994 ). In our experiment, the vertical displacement between opposing random dots fields (about 0.1°) and the distances covered during motion (0.4° anti-Glass and reverse-phi; 0.1° motion) are in agreement with corresponding values (less than 0.12° and 0.4°, respectively) reported by Qian and Andersen ( 1994 ) in order to expect integration rather than transparency.
Contrast dependency of the annulment point suggests that the common mechanism could be located at low level in the visual system, as it is known that perceived local motion is more dependent on contrast than perceived global motion (Morrone et al., 1995 ; Shioiri, Ito, Sakurai, & Yaguchi, 2002 ), and that MT neurons are less effective in signaling absolute levels of contrast than LGN or V1 neurons (Sclar, Maunsell, & Lennie, 1990 ). To further test the interactions between stimuli as a function of contrast, we performed a sub-threshold summation experiment.
Sub-threshold summation
Stimuli and procedure
Stimuli were anti-Glass pairs superimposed on moving dots, either reversing-contrast or same contrast. The relative position of light and dark dots was such that anti-Glass motion and real motion were expected to be perceived in the same direction. Spatiotemporal characteristics of stimuli were those found in the first experiment, and their coherence was 100%. The number of moving and anti-Glass dots was paired in two frames as in previous experiments. We measured direction discrimination thresholds by varying simultaneously the contrast of anti-Glass and motion stimuli of the same amount (i.e., 7% and 7%, etc.). Contrast was varied from trial to trial according to a QUEST staircase procedure (Watson & Pelli, 1983 ). For each condition, data were collected in 2 sessions of 3 blocks, each composed of 200 trials, and all data were fitted (maximum likelihood fit) with a Weibull ( 1951 ) psychometric function. Thresholds were defined as the contrast level yielding 75% correct discrimination. Student's t -tests with significance level of 0.05 were used to compare mean thresholds.
Results and discussion
Red-filled circles in Figure 5 represent the probability of perceiving motion in the direction of the white dot as a function of contrast of anti-Glass, obtained with 70 anti-Glass pairs presented alone (same data of Figure 3 ). The blue curve, obtained by adding 70 contrast-reversing moving dots to the 70 anti-pairs, is shifted leftward: thresholds shift from (11.9 ± 1.2%) to (7.8 ± 0.3%) ( p = 0.019). This indicates that motion is perceived at contrasts well below the individual thresholds for anti-Glass or motion.
Figure 5
Sub-threshold summation. Probability of motion discrimination in the direction of anti-Glass (toward white dot) as a function of contrast of anti-Glass. Red filled circles: stimulus composed by 70 anti-Glass pairs (also shown in Figure 3 ). Blue: stimulus composed by 70 anti-Glass pairs and 70 reversing-contrast moving dots. Cyan: stimulus composed by 70 anti-Glass pairs and 70 same-polarity moving dots. Red hollow circles: stimulus composed by 140 anti-Glass pairs.
Figure 5
Sub-threshold summation. Probability of motion discrimination in the direction of anti-Glass (toward white dot) as a function of contrast of anti-Glass. Red filled circles: stimulus composed by 70 anti-Glass pairs (also shown in Figure 3 ). Blue: stimulus composed by 70 anti-Glass pairs and 70 reversing-contrast moving dots. Cyan: stimulus composed by 70 anti-Glass pairs and 70 same-polarity moving dots. Red hollow circles: stimulus composed by 140 anti-Glass pairs.
Following Meese and Harris (
2001
), we employed the Minkowsky metric to evaluate the degree of summation in our experiment
ν c o m p o u n d = ( ν s t i m A k + ν s t i m B k ) 1 k ,
(1)
where
ν
compound
is the sensitivity for the compound stimulus (anti-Glass + reverse-phi motion) and
ν
stimA
and
ν
stimB
are the sensitivities of individual stimuli. The exponent
k
is the degree of summation:
k
= 1 for linear summation,
k
= 2 for quadratic summation, and
k
= 3 to 4 for probability summation between independent mechanisms (Graham,
1989
). For our experiment, we found
k
= 1.67 ± 0.24, indicating a sub-threshold summation intermediate between linear and quadratic, excluding probability summation between independent channels.
The curve for real motion plus anti-Glass (cyan curve) is also shifted significantly toward left: thresholds shift from (11.9 ± 1.2%) to (5.8 ± 0.6%) ( p = 0.009). In this case, we obtain k = 1.27 ± 0.08, again indicating sub-threshold summation intermediate between linear and quadratic.
As a control, we measured contrast thresholds from 140 anti-Glass pair (hollow circles) and compared with thresholds obtained with 70 pairs (thresholds shift from (11.9 ± 1.2%) to (7 ± 0.5%), p = 0.015). The results are indistinguishable from those obtained with motion plus anti-Glass (reverse-phi + anti-Glass: p = 0.24; regular motion + anti-Glass: p = 0.23), thus showing that the sub-threshold summation happens in exactly the same way between different and same stimuli.
These facts demonstrate that there must be a neural motion mechanism where the two stimuli are added together in an almost-linear way before a thresholding effect occurs.
Local motion
Although the annulling and the sub-threshold summation experiments do not rule out the possibility of two different populations of local motion detectors, they show that if there are two such populations, their outputs are integrated in a global motion perception. The fact that the global integration is so good strongly suggests, but does not prove, that the same type of local motion detector is responsible for reporting a motion signal for both anti-Glass and real motion. If these stimuli at local level had similar properties, this could constitute further evidence in favor of low-level motion mechanisms of the same type.
We investigated this issue by measuring motion direction discrimination as a function of displacement and as a function of contrast of a single moving dot, a single contrast reversing dot, an anti-Glass pair, a Glass pair.
Stimuli and procedure
Dots were positioned in the center of the screen, each subtending 0.3° of visual angle.
Moving and reversing-contrast dots
Direction of motion could be either leftward or rightward, randomized between trials. We presented two-frame motion, each frame lasting 15 ms, for a total duration of 30 ms. Direction discrimination was measured as a function of displacement (from 0.4° to 1.25°), and during this measurement, the dot contrast was kept constant (100%). Direction discrimination was measured also as function of contrast (from 5% to 30%). During this measurement, displacement was kept constant (0.4°).
Glass and anti-Glass
The dipole was oriented horizontally, and the relative position of black and white dots in anti-Glass was randomized between trials. Total duration of the stimulus was 30 ms. Direction discrimination was measured as a function of displacement (from 0.4° to 1.25°), and during this measurement, dot contrast was kept constant (100%). Direction discrimination was measured also as function of contrast (from 5% to 30%). During this measurement displacement was kept constant (0.4°).
In both measurements, dot displacement and contrast were varied from trial to trial according to the method of constant stimuli, randomizing all conditions. The subject's task was to indicate the direction of perceived motion, in a two-alternative forced-choice procedure (2AFC) with a single temporal presentation. Correct direction was defined as
physical direction for regular motion;
opposite to physical direction for reverse-phi;
toward white dot for anti-Glass; and
toward left for Glass.
We ran 100 trials for each subject for each condition. Two of the previous subjects participated to all experiments. Two other naive subjects (N.G. and B.P.) discriminated the direction of local motion only for a displacement of 0.4°.
Results and discussion
The upper part of Figure 6A shows the probability of perceiving the correct direction of motion for all stimuli, for a displacement of 0.4°, which is optimal for anti-Glass (see Experiment 1). All subjects detected equally well motion direction of all stimuli, except the Glass pair where, as expected, direction was ambiguous.
Figure 6
Local motion with different stimuli. (A) Upper panels. From left: motion direction discrimination (probability of correct responses) for dot distance of 0.4° of four subjects for a single moving dot, a single contrast reversing moving dot, one anti-Glass pair, one Glass pair. Definition of correct response (labels above graphs) depends on the kind of stimulus. Lower panels. Motion direction discrimination as a function of distance for one moving dot, one contrast reversing moving dot, one anti-Glass pair (two subjects). Contrast was 100%. (B) Motion direction discrimination as a function of contrast for one moving dot, one contrast reversing moving dot, one anti-Glass pair (two subjects). Dot distance was 0.4°. Definition of correct response is the same as in panel A.
Figure 6
Local motion with different stimuli. (A) Upper panels. From left: motion direction discrimination (probability of correct responses) for dot distance of 0.4° of four subjects for a single moving dot, a single contrast reversing moving dot, one anti-Glass pair, one Glass pair. Definition of correct response (labels above graphs) depends on the kind of stimulus. Lower panels. Motion direction discrimination as a function of distance for one moving dot, one contrast reversing moving dot, one anti-Glass pair (two subjects). Contrast was 100%. (B) Motion direction discrimination as a function of contrast for one moving dot, one contrast reversing moving dot, one anti-Glass pair (two subjects). Dot distance was 0.4°. Definition of correct response is the same as in panel A.
All local stimuli yielded very similar direction discrimination, also when displacement was varied in the whole interval used in global motion tests, as shown in lower panels of Figure 6A , dropping dramatically beyond 0.7°. Results for Glass are not shown because they always gave 50% correct discrimination.
This experiment demonstrates that detection of local motion of dots and anti-Glass is perfectly equivalent when varying their spatial displacement. From this experiment, it is also possible to figure out a lower limit for spatial frequency tuning of detectors for local anti-Glass and real motion: The maximum value is obtained for 0.4° displacement for all stimuli, which correspond to a spatial frequency 2.5 cycles/deg, the lowest detectable in this experiment.
Figure 6B shows the probability of perceiving correct direction of motion for all stimuli, for a displacement of 0.4°, as a function of contrast. All psychometric curves overlap perfectly, meaning that contrast sensitivity of local motion system is the same for all three stimuli presented here. Mean direction thresholds, defined as 75% of psychometric functions, are (12.3 ± 0.7%) for anti-Glass, (12.5 ± 0.9%) for reversing-contrast motion, and (11.2 ± 0.6%) for regular motion. These values are not much higher than those found for the global stimuli.
General discussion
Glass and anti-Glass patterns are ideal stimuli to investigate properties of local and global integration mechanisms as well as form and motion processing. Results presented in this paper help to elucidate the relationships between these two stimuli.
The goal of this paper is to study the motion illusion induced by anti-Glass patterns, and we have shown that perception of global motion induced by anti-Glass patterns is comparable to that obtained with real motion, either contrast-reversing or not, indicating that anti-Glass patterns stimulate the same directional motion mechanisms. We also found that a single moving point, either contrast-reversing or not, elicits comparable motion perception to an anti-Glass pair if motion is matched for duration and distance. The close similarities observed at local level between these two types of motion and the contrast dependency of global motion perception strongly suggest that the two kind of motions are encoded at low levels by the same type of motion system (Morrone et al., 1995 ; Sclar et al., 1990 ), rather than by local different mechanisms combined at a higher level by a non-selective motion detector (Albright, 1992 ).
Overall, we can conclude that, at least in the spatiotemporal range explored here, anti-Glass are treated by the human visual system in the same way as real motion and reverse-phi stimuli. In particular, anti-Glass and reverse-phi motion are perceived in the direction opposite to the temporal processing of dots, thus proving to be two special cases of the same phenomenon. The powerful motion experience generated by really moving objects cannot be equated to the perception of this illusion that is perceived for short time intervals that probably never occur in natural situations. From the results of our experiments, we conjecture that there exist a set of local motion detectors tuned to these spatiotemporal parameters that process all stimuli, illusory or not. In addition to these detectors, there are many others tuned to a broader range of speed values, triggered by slower motion or by objects moving over larger areas, that we experience in everyday life. In this respect, anti-Glass motion is real motion, but not all real motion is equivalent to anti-Glass motion perception.
Overall, perception of form and apparent motion in Glass and anti-Glass patterns could be described within a general framework of visual networks (Van Essen, 1995 ; Van Essen, Anderson, & Felleman, 1992 ) that hypothesize a hierarchical analysis of form and motion, realized in two stages. In an early stage, visual features are analyzed in parallel by local orientation units (Hubel & Wiesel, 1962 ; Hubel & Wiesel, 1977 ) and local motion detectors with a preferred motion direction (Movshon, Adelson, Gizzi, & Newsome, 1985 ; Hubel, 1989 ; Tovèe, 1994 ), widely found in early visual areas. The output from local orientation mechanisms is integrated at a higher level by neurons with larger receptive fields, responsible for perception of complex structures located, for example, in visual areas V4 or IT (Tanaka, 1992 ; Wilkinson et al., 2000 ). Similarly, outputs from motion detectors selective to specific directions are integrated by neurons with larger receptive fields located in global motion areas such as MT, MSTd, or STS (Britten & van Wezel, 1998 ; Duffy & Wurtz, 1991 ; Mikami et al., 1986a ; 1986b ; Movshon et al., 1985 ; Tanaka et al., 1989 ).
Different perceptions elicited by Glass and anti-Glass patterns can thus be explained by a substantial difference of neural structures involved in the initial stage of analysis. Glass patterns could undergo initial local form integration along dipoles due to local orientation detectors, performed by early visual areas such as V1 or V2 (Movshon et al., 2003 ; Smith et al., 2002 ). This initial stage could be followed by global form integration (Wilkinson et al., 2000 ) and integration along flow trajectories performed by global motion areas (Krekelberg et al., 2003 ).
Anti-Glass patterns are not expected to elicit local form perception in early visual areas: Mean activation of local orientation units should be null if two identical dots with opposite luminance are presented simultaneously in their receptive field (Glass & Switkes, 1976 ). Some evidence showing there is no difference between detection of circular anti-Glass and random oriented pairs also demonstrates scarce involvement of global form areas (Wilson, Switkes, & De Valois, 2004 ).
On the other hand, results presented in this study strongly suggest the involvement of low-level contrast-dependent local motion detectors that can be modelled by Reichardt ( 1961 ) detectors, possibly localized in early visual areas such as V1 or V2 (Hubel, 1989 ; Movshon et al., 1985 , 2003 ; Tovèe, 1994 ) (see Figure 7 ). The input to these motion detectors could be provided by sub-cortical neurons, where a temporal delay in the processing of the dark dots is generated, maybe due to differential temporal processing between the primate on and off systems (Chichilnisky & Kalmar, 2002 ; Ueno et al., 2004 ) ( Figure 7 ). Anti-Glass patterns appear to move in the direction opposite to the temporal processing of dots, like reverse-phi motion stimuli (Anstis, 1970 ), and produce the same motion perception of reverse-phi. Recordings from direction-selective cells in monkey V1 (Conway & Livingstone, 2003 ), as well as correlation of motion energy models (Adelson & Bergen, 1985 ) and Reichardt models (van Santen & Sperling, 1985 ), can account for motion and reverse-phi motion, even though it is still unclear how neurons accomplish this. These low-level local motion detectors could extract direction of motion of anti-Glass patterns before it is integrated along complex motion trajectories in global motion areas (Heeger et al., 1999 ; Qian & Andersen, 1994 ).
Figure 7
Descriptive model of motion generated by anti-Glass patterns. Dots in the anti-Glass pairs are presented simultaneously to the visual system. A sub-cortical delay (∼3 ms) between on and off pathways causes a latency in the processing of the dark dot with respect to the white. This latency can generate a motion signal in cortical direction-selective neurons, indistinguishable from that elicited by contrast-reversing real motion. The vector sign of velocity is inverted like in reverse-phi motion.
Figure 7
Descriptive model of motion generated by anti-Glass patterns. Dots in the anti-Glass pairs are presented simultaneously to the visual system. A sub-cortical delay (∼3 ms) between on and off pathways causes a latency in the processing of the dark dot with respect to the white. This latency can generate a motion signal in cortical direction-selective neurons, indistinguishable from that elicited by contrast-reversing real motion. The vector sign of velocity is inverted like in reverse-phi motion.
Glass pattern sequences made of dots with same-polarity (i.e., Ross et al., 2000 ) are not expected to stimulate these directional detectors because there cannot be a delay between dots with same luminance. This could be the reason why they produce perception of motion without any sense of direction. The question regarding how same-polarity Glass patterns produce global sense of motion without producing local or global direction is beyond the scope of this work. In fact, our experiments lead to think that the mechanisms causing motion perception in anti-Glass stimuli are very different from those responsible for motion perception in Glass stimuli. For the latter, dipoles could be interpreted by the visual system as motion streaks (Geisler, 1999 ) and therefore could be sufficient to trigger motion perception. An alternative explanation could rely on the existence of connections between global form and global motion integration areas (Kourtzi & Kanwisher, 2000 ; Krekelberg et al., 2003 ; Van Essen, 1995 ) that might guarantee unity of perception and provide a system able to cope with complex environments with multiple objects in motion.
Acknowledgments
We thank David Burr for helpful discussions. This research was supported by the Italian MURST 2005 grant.
Commercial relationships: none.
Corresponding author: Monica Gori.
Email: monica.gori@unige.it.
Address: Istituto Italiano di Tecnologia, via Morego 30, 16163 Genoa, Italy.
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Figure 1
(A) Example of anti-Glass stimuli used in this study. The position of pairs is updated randomly every 6 video frames ( t 1 = duration = 30 ms). (B) Schematic representation of the anti-Glass stimulus during time t 1 that corresponds to 6 video frames (frame-rate 200 Hz). Dots are presented simultaneously (left), but the stimulus is perceived as moving in the direction of the white dot (right). (C) Left: schematic representation of the reversing-contrast stimulus during time t 1 . Right: motion is perceived in the opposite direction (reverse-phi motion).
Figure 1
(A) Example of anti-Glass stimuli used in this study. The position of pairs is updated randomly every 6 video frames ( t 1 = duration = 30 ms). (B) Schematic representation of the anti-Glass stimulus during time t 1 that corresponds to 6 video frames (frame-rate 200 Hz). Dots are presented simultaneously (left), but the stimulus is perceived as moving in the direction of the white dot (right). (C) Left: schematic representation of the reversing-contrast stimulus during time t 1 . Right: motion is perceived in the opposite direction (reverse-phi motion).
Figure 2
Spatiotemporal properties of stimuli. (A) Probability of motion discrimination in the direction of the white dot as a function of coherence of anti-Glass. Different red symbols represent different distances between dots in the pair. (B) Probability of motion discrimination in the direction of the white dot as a function of coherence of reversing-contrast moving dots (reverse-phi motion). (C) Probability of motion discrimination in the physical direction as a function of coherence of same-polarity moving dots. Different green and black symbols represent different displacements for same-polarity and reverse-phi motion. The red curve replot anti-Glass data in panel A. The horizontal line indicates chance level.
Figure 2
Spatiotemporal properties of stimuli. (A) Probability of motion discrimination in the direction of the white dot as a function of coherence of anti-Glass. Different red symbols represent different distances between dots in the pair. (B) Probability of motion discrimination in the direction of the white dot as a function of coherence of reversing-contrast moving dots (reverse-phi motion). (C) Probability of motion discrimination in the physical direction as a function of coherence of same-polarity moving dots. Different green and black symbols represent different displacements for same-polarity and reverse-phi motion. The red curve replot anti-Glass data in panel A. The horizontal line indicates chance level.
Figure 3
Contrast dependency of stimuli. (A) Probability of motion discrimination in the direction of the white dot as a function of Michelson contrast for anti-Glass patterns (red) and reverse-phi motion (black). Arrows indicate detection thresholds for motion (black) and anti-Glass (red). (B) Probability of motion discrimination in the physical direction as a function of Michelson contrast for same-polarity moving dots (green). The red curve is the same as in panel A. Arrows indicate detection thresholds for motion (green) and anti-Glass (red). Coherence of all stimuli was 100%. The horizontal line indicates chance level.
Figure 3
Contrast dependency of stimuli. (A) Probability of motion discrimination in the direction of the white dot as a function of Michelson contrast for anti-Glass patterns (red) and reverse-phi motion (black). Arrows indicate detection thresholds for motion (black) and anti-Glass (red). (B) Probability of motion discrimination in the physical direction as a function of Michelson contrast for same-polarity moving dots (green). The red curve is the same as in panel A. Arrows indicate detection thresholds for motion (green) and anti-Glass (red). Coherence of all stimuli was 100%. The horizontal line indicates chance level.
Figure 4
(A) Anti-Glass against reverse-phi motion. Curves represent either the probability of motion discrimination in the direction of reverse-phi (left ordinate) as a function of fraction of moving dots (lower abscissa), or the probability of motion discrimination in the direction of anti-Glass (right ordinate) as a function of fraction of anti-Glass pairs (upper abscissa). The number of anti-Glass plus moving dots is constant: ▴, contrast anti-Glass and reverse-phi = 100%; •, contrast anti-Glass = 30%, contrast reverse-phi = 100%;, contrast anti-Glass = 13%, contrast reverse-phi = 100%;, contrast anti-Glass = 10%, contrast reverse-phi = 100%;, contrast anti-Glass = 100%, contrast reverse-phi = 30%;, contrast anti-Glass = 100%, contrast reverse-phi = 13%;, contrast anti-Glass = 100%, contrast reverse-phi = 10%. (B) Anti-Glass against motion. Motion discrimination in the direction of moving dots (left ordinate)—or anti-Glass (right ordinate)—as a function of fraction of moving dots (lower abscissa)—or anti-pairs (upper abscissa). The number of anti-Glass plus moving dots is constant., contrast anti-Glass and motion = 100%;, contrast anti-Glass = 30%, contrast motion = 100%;, contrast anti-Glass = 13%, contrast motion = 100%;, contrast anti-Glass = 100%, contrast motion = 30%;, contrast anti-Glass = 100%, contrast motion = 13%.
Figure 4
(A) Anti-Glass against reverse-phi motion. Curves represent either the probability of motion discrimination in the direction of reverse-phi (left ordinate) as a function of fraction of moving dots (lower abscissa), or the probability of motion discrimination in the direction of anti-Glass (right ordinate) as a function of fraction of anti-Glass pairs (upper abscissa). The number of anti-Glass plus moving dots is constant: ▴, contrast anti-Glass and reverse-phi = 100%; •, contrast anti-Glass = 30%, contrast reverse-phi = 100%;, contrast anti-Glass = 13%, contrast reverse-phi = 100%;, contrast anti-Glass = 10%, contrast reverse-phi = 100%;, contrast anti-Glass = 100%, contrast reverse-phi = 30%;, contrast anti-Glass = 100%, contrast reverse-phi = 13%;, contrast anti-Glass = 100%, contrast reverse-phi = 10%. (B) Anti-Glass against motion. Motion discrimination in the direction of moving dots (left ordinate)—or anti-Glass (right ordinate)—as a function of fraction of moving dots (lower abscissa)—or anti-pairs (upper abscissa). The number of anti-Glass plus moving dots is constant., contrast anti-Glass and motion = 100%;, contrast anti-Glass = 30%, contrast motion = 100%;, contrast anti-Glass = 13%, contrast motion = 100%;, contrast anti-Glass = 100%, contrast motion = 30%;, contrast anti-Glass = 100%, contrast motion = 13%.
Figure 5
Sub-threshold summation. Probability of motion discrimination in the direction of anti-Glass (toward white dot) as a function of contrast of anti-Glass. Red filled circles: stimulus composed by 70 anti-Glass pairs (also shown in Figure 3 ). Blue: stimulus composed by 70 anti-Glass pairs and 70 reversing-contrast moving dots. Cyan: stimulus composed by 70 anti-Glass pairs and 70 same-polarity moving dots. Red hollow circles: stimulus composed by 140 anti-Glass pairs.
Figure 6
Local motion with different stimuli. (A) Upper panels. From left: motion direction discrimination (probability of correct responses) for dot distance of 0.4° of four subjects for a single moving dot, a single contrast reversing moving dot, one anti-Glass pair, one Glass pair. Definition of correct response (labels above graphs) depends on the kind of stimulus. Lower panels. Motion direction discrimination as a function of distance for one moving dot, one contrast reversing moving dot, one anti-Glass pair (two subjects). Contrast was 100%. (B) Motion direction discrimination as a function of contrast for one moving dot, one contrast reversing moving dot, one anti-Glass pair (two subjects). Dot distance was 0.4°. Definition of correct response is the same as in panel A.
Figure 6
Local motion with different stimuli. (A) Upper panels. From left: motion direction discrimination (probability of correct responses) for dot distance of 0.4° of four subjects for a single moving dot, a single contrast reversing moving dot, one anti-Glass pair, one Glass pair. Definition of correct response (labels above graphs) depends on the kind of stimulus. Lower panels. Motion direction discrimination as a function of distance for one moving dot, one contrast reversing moving dot, one anti-Glass pair (two subjects). Contrast was 100%. (B) Motion direction discrimination as a function of contrast for one moving dot, one contrast reversing moving dot, one anti-Glass pair (two subjects). Dot distance was 0.4°. Definition of correct response is the same as in panel A.
Figure 7
Descriptive model of motion generated by anti-Glass patterns. Dots in the anti-Glass pairs are presented simultaneously to the visual system. A sub-cortical delay (∼3 ms) between on and off pathways causes a latency in the processing of the dark dot with respect to the white. This latency can generate a motion signal in cortical direction-selective neurons, indistinguishable from that elicited by contrast-reversing real motion. The vector sign of velocity is inverted like in reverse-phi motion.
Figure 7
Descriptive model of motion generated by anti-Glass patterns. Dots in the anti-Glass pairs are presented simultaneously to the visual system. A sub-cortical delay (∼3 ms) between on and off pathways causes a latency in the processing of the dark dot with respect to the white. This latency can generate a motion signal in cortical direction-selective neurons, indistinguishable from that elicited by contrast-reversing real motion. The vector sign of velocity is inverted like in reverse-phi motion.
| https://jov.arvojournals.org/article.aspx?articleid=2158184&resultClick=1 |
Reply to Frachon: Amphetamine Derivatives and the Risk of Pulmonary Arterial Hypertension: A Missing Chapter of the Story? | American Journal of Respiratory and Critical Care Medicine
Reply to Frachon: Amphetamine Derivatives and the Risk of Pulmonary Arterial Hypertension: A Missing Chapter of the Story?
Gérald Simonneau 1 , 2 , 3 x Gérald Simonneau Search for articles by this author, and Marc Humbert 1 , 2 , 3 x Marc Humbert Search for articles by this author, + Author Affiliations 1Université Paris-Sud, Université Paris-SaclayLe Kremlin-Bicêtre, France 2AP-HP, Hôpital BicêtreLe Kremlin-Bicêtre, Franceand 3INSERM UMR_S 999, Hôpital Marie LannelongueLe Plessis Robinson, France
https://doi.org/10.1164/rccm.201712-2483LE PubMed: 29272591
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Full Text
From the Editorialists:
In the most recent update of the classification for drug- and toxin-induced pulmonary arterial hypertension, several anorectic agents sharing with amphetamines the same phenylethylamine structure are listed as “definite” risk factors (aminorex, benfluorex, dexfenfluramine, and fenfluramine) (1). Among them, benfluorex has some specificities that should be emphasized. Benfluorex has been approved in Europe as an agent for the treatment of diabetes and as a hypolipidemic agent but, surprisingly, not as an anorectic substance. However, benfluorex shares similar structural and pharmacological characteristics with dexfenfluramine and fenfluramine, and these drugs all form norfenfluramine as a metabolite. Given its properties, benfluorex would obviously be expected to have toxic effects similar to the fenfluramine derivatives. Despite these scientific facts, benfluorex was not subjected to the same restrictions as the fenfluramine derivatives in 1997 in France, at least in part because it was not recognized as an anorectic agent. This drug was thus marketed until 2009, and it is likely that it was, regrettably, used between 1998 and 2009 as a replacement for the withdrawn fenfluramine derivatives.
The first case of pulmonary arterial hypertension in a patient treated with benfluorex was declared in June 1999 by the French Reference Center of pulmonary hypertension to the French pharmacovigilance authorities (2). This was followed by several reports of pulmonary arterial hypertension and valvular heart disease occurring in patients exposed to benfluorex (3–6). Benfluorex use was suspended in France on November 30, 2009, and definitively withdrawn from the French market on July 20, 2010, more than 12 years after the ban of other fenfluramine derivatives (2). This sad French section of the anorexigen chapter further underscores the unacceptable cardiovascular risks of the amphetamine derivatives and suggests that closely related illicit substances, such as methamphetamines, may have similar consequences, as reported by Zamanian and colleagues (7,8).
References
<table><tbody><tr><td> 1.</td><td> Simonneau G, Gatzoulis MA, Adatia I, Celermajer D, Denton C, Ghofrani A, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013;62: D34– D41.Crossref,Medline, Google Scholar</td></tr><tr><td> 2.</td><td> Bensadon A-C, Marie E, Morelle A.Enquête sur le MEDIATOR. 2011 [accessed 2017 Dec 14]. Available from:http://www.igas.gouv.fr/IMG/pdf/Synthese_MEDIATOR.pdf. Google Scholar</td></tr><tr><td> 3.</td><td> Boutet K, Frachon I, Jobic Y, Gut-Gobert C, Leroyer C, Carlhant-Kowalski D, et al. Fenfluramine-like cardiovascular side-effects of benfluorex. Eur Respir J 2009;33: 684– 688.Crossref,Medline, Google Scholar</td></tr><tr><td> 4.</td><td> Frachon I, Etienne Y, Jobic Y, Le Gal G, Humbert M, Leroyer C. Benfluorex and unexplained valvular heart disease: a case-control study. PLoS One 2010;5: e10128.Crossref,Medline, Google Scholar</td></tr><tr><td> 5.</td><td> Humbert M, Savale L, Chaumais MC, Sitbon O, Simonneau G. Benfluorex (Mediator) et hypertension pulmonaire: rapport provisoire du centre de référence de l’hypertension pulmonaire sévère Hôpital Antoine Béclère. 2011[accessed 2017 Dec 14]. Available from:www.syndicardio.com/IMG/pdf/rapport_mediatoretHTAP09avril2011.pdf. Google Scholar</td></tr><tr><td> 6.</td><td> Savale L, Chaumais MC, Cottin V, Bergot E, Frachon I, Prevot G, et al. Pulmonary hypertension associated with benfluorex exposure. Eur Respir J 2012;40: 1164– 1172.Crossref,Medline, Google Scholar</td></tr><tr><td> 7.</td><td> Zamanian RT, Hedlin H, Greuenwald P, Wilson DM, Segal JI, Jorden M, et al. Features and outcomes of methamphetamine-associated pulmonary arterial hypertension. Am J Respir Crit Care Med 2018;197: 788– 800.Abstract,Medline, Google Scholar</td></tr><tr><td> 8.</td><td> Simonneau G, Humbert M. Amphetamine derivatives and the risk of pulmonary arterial hypertension: a new chapter of the story [editorial]. Am J Respir Crit Care Med 2018;197: 704– 706.Abstract,Medline, Google Scholar</td></tr></tbody></table>
Originally published in press as DOI:10.1164/rccm.201712-2483LEon December 22, 2017 Author disclosuresare available with the text of this letter atwww.atsjournals.org.
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| https://www.atsjournals.org/doi/10.1164/rccm.201712-2483LE |
Blood MxA protein as a marker for respiratory virus infections in young children
Toivonen L, Schuez-Havupalo L, Rulli M, Ilonen J, Pelkonen J, Melen K, Julkunen I, Peltola V, Waris M. Blood MxA protein as a marker for respiratory virus infections in young children. J Clin Virol. 2015 Jan;62:8-13. doi: 10.1016/j.jcv.2014.11.018. Epub 2014 Nov 18.
Blood MxA protein as a marker for respiratory virus infections in young children
Laura Toivonen, Linnea Schuez-Havupalo, Maris Rulli, Jorma Ilonen, Jukka Pelkonen, Krister Melen, Ilkka Julkunen, Ville Peltola, Matti Waris, Laura Toivonen, Linnea Schuez-Havupalo, Maris Rulli, Jorma Ilonen, Jukka Pelkonen, Krister Melen, Ilkka Julkunen, Ville Peltola, Matti Waris
Abstract
Background:Type I interferon induced MxA response can differentiate viral from bacterial infections, but MxA responses in rhinovirus or asymptomatic virus infections are not known.
Objective:To study MxA protein levels in healthy state and during respiratory virus infection of young children in an observational prospective cohort.
Study design:Blood samples and nasal swabs were collected from 153 and 77 children with and without symptoms of respiratory infections, respectively. Blood MxA protein levels were measured by an enzyme immunoassay and PCR methods were used for the detection of respiratory viruses in nasal swabs.
Results:Respiratory viruses were detected in 81% of symptomatic children. They had higher blood MxA protein levels (median [interquartile range]) than asymptomatic virus-negative children (695 [345-1370] μg/L vs. 110 [55-170] μg/L; p < 0.001). Within asymptomatic children, no significant difference was observed in MxA responses between virus-positive and virus-negative groups. A cut-off level of 175 μg/L had 92% sensitivity and 77% specificity for a symptomatic respiratory virus infection. Rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, coronavirus, and human metapneumovirus infections were associated with elevated MxA responses. Asymptomatic virus-negative children vaccinated with a live virus vaccine had elevated MxA protein levels (240 [120-540] μg/L), but significantly lower than children with an acute respiratory infection, who had not received vaccinations (740 [350-1425] μg/L; p<0.001).
Conclusion:Blood MxA protein levels are increased in young children with symptomatic respiratory virus infections, including rhinovirus infections. MxA is an informative general marker for the most common acute virus infections.
Keywords:Interferon; MxA protein; Respiratory virus infection; Rhinovirus; Rotavirus vaccine; STEPS study.
Figures
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Fig. 1
Blood MxA protein levels in children according to virus detection and presence of symptoms, and in asymptomatic adults. Boxes show median and IQR, and whiskers show 10th and 90th percentiles. Values below the sensitivity limit of 10 μg/L are presented as 7 or 5 μg/L. Values above different groups indicate the ratios of values above the cut-off level of 175 μg/L.
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Fig. 2
Blood MxA protein levels in relation to the duration of fever or respiratory symptoms before MxA measurement. All symptomatic children with recorded duration of symptoms for 1–14 days and with ( n= 103) or without ( n= 21) detected virus are included. Spearman's rho −0.193; p0.032; correlation line (– – –); 175 μg/L cut-off (- - -).
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Fig. 3
Blood MxA protein levels in symptomatic virus-positive children according to detected viruses. Boxes show median and IQR, and whiskers show 10th and 90th percentiles. Values above different groups indicate the ratios of values above the cut-off level of 175 μg/L. HBoV, human bocavirus; RV, rhinovirus; CoV, coronavirus; HMPV, human metapneumovirus; PIV, parainfluenza virus (types 1–3); RSV, respiratory syncytial virus; Flu, influenza virus (A or B). A single case with adenovirus is not presented.
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Fig. 4
Blood MxA protein levels and virus findings in the same individuals during the healthy state and during a respiratory infection. Median and IQR values are shown above the groups; p0.001 by the Mann–Whitney Utest. HBoV, human bocavirus; RV, rhinovirus; HMPV, human metapneumovirus; CoV, coronavirus; PIV2, parainfluenza virus type 2; RSV, respiratory syncytial virus; FluA, influenza A virus.
References
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Simon A., Fäh J., Haller O., Staeheli P. Interferon-regulated Mx genes are not responsive to interleukin-1, tumor necrosis factor, and other cytokines. J Virol. 1991;65:968–971.
Ronni T., Matikainen S., Lehtonen A., Palvimo J., Dellis J., Van Eylen F. The proximal interferon-stimulated response elements are essential for interferon responsiveness: a promoter analysis of the antiviral MxA gene. J Interferon Cytokine Res. 1998;18:773–781.
Kotenko S.V., Gallagher G., Baurin V.V., Lewis-Antes A., Shen M., Shah N.K. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003;4:69–77.
Holzinger D., Jorns C., Stertz S., Boisson-Dupuis S., Thimme R., Weidmann M. Induction of MxA gene expression by influenza A virus requires type I or type III interferon signaling. J Virol. 2007;81:7776–7785.
Haller O., Kochs G. Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. J Interferon Cytokine Res. 2011;31:79–87.
Ronni T., Melén K., Malygin A., Julkunen I. Control of IFN-inducible MxA gene expression in human cells. J Immunol. 1993;150:1715–1726.
Maria N.I., Brkic Z., Waris M., van Helden-Meeuwsen C.G., Heezen K., van de Merwe J.P. MxA as a clinically applicable biomarker for identifying systemic interferon type I in primary Sjogren's syndrome. Ann Rheum Dis. 2014;73:1052–1059.
Roers A., Hochkeppel H.K., Horisberger M.A., Hovanessian A., Haller O. MxA gene expression after live virus vaccination: a sensitive marker for endogenous type I interferon. J Infect Dis. 1994;169:807–813.
Halminen M., Ilonen J., Julkunen I., Ruuskanen O., Simell O., Mäkelä M.J. Expression of MxA protein in blood lymphocytes discriminates between viral and bacterial infections in febrile children. Pediatr Res. 1997;41:647–650.
Mäkelä M.J., Halminen M., Ruuskanen O., Puhakka T., Pirhonen J., Julkunen I. Lack of induction by rhinoviruses of systemic type I interferon production or enhanced MxA protein expression during the common cold. Eur J Clin Microbiol Infect Dis. 1999;18:665–668.
Selvaggi C., Pierangeli A., Fabiani M., Spano L., Nicolai A., Papoff P. Interferon lambda 1-3 expression in infants hospitalized for RSV or HRV associated bronchiolitis. J Infect. 2014;68:467–477.
Mäkelä M.J., Puhakka T., Ruuskanen O., Leinonen M., Saikku P., Kimpimäki M. Viruses and bacteria in the etiology of the common cold. J Clin Microbiol. 1998;36:539–542.
Miller E.K., Lu X., Erdman D.D., Poehling K.A., Zhu Y., Griffin M.R. Rhinovirus-associated hospitalizations in young children. J Infect Dis. 2007;195:773–781.
Mackay I.M., Lambert S.B., Faux C.E., Arden K.E., Nissen M.D., Sloots T.P. Community-wide, contemporaneous circulation of a broad spectrum of human rhinoviruses in healthy Australian preschool-aged children during a 12-month period. J Infect Dis. 2013;207:1433–1441.
Lagström H., Rautava P., Kaljonen A., Räihä H., Pihlaja P., Korpilahti P. Cohort profile: Steps to the healthy development and well-being of children (the STEPS Study) Int J Epidemiol. 2013;42:1273–1284.
Peltola V., Waris M., Osterback R., Susi P., Ruuskanen O., Hyypia T. Rhinovirus transmission within families with children: incidence of symptomatic and asymptomatic infections. J Infect Dis. 2008;197:382–389.
Waris M., Osterback R., Lahti E., Vuorinen T., Ruuskanen O., Peltola V. Comparison of sampling methods for the detection of human rhinovirus RNA. J Clin Virol. 2013;58:200–204.
Vallittu A.M., Erälinna J.P., Ilonen J., Salmi A.A., Waris M. MxA protein assay for optimal monitoring of IFN-beta bioactivity in the treatment of MS patients. Acta Neurol Scand. 2008;118:12–17.
Bellingan G., Maksimow M., Howell D.C., Stotz M., Beale R., Beatty M. The effect of intravenous interferon-beta-1a (FP-1201) on lung CD73 expression and on acute respiratory distress syndrome mortality: an open-label study. Lancet Respir Med. 2014;2:98–107.
Ruuskanen O., Waris M., Kainulainen L. Treatment of persistent rhinovirus infection with pegylated interferon alpha 2a and ribavirin in patients with hypogammaglobulinemia. Clin Infect Dis. 2014;58:1784–1786.
Osterback R., Tevaluoto T., Ylinen T., Peltola V., Susi P P., Hyypiä T. Simultaneous detection and differentiation of human rhino- and enteroviruses in clinical specimens by real-time PCR with locked nucleic Acid probes. J Clin Microbiol. 2013;51:3960–3967.
Koskenvuo M., Möttönen M., Waris M., Allander T., Salmi T.T., Ruuskanen O. Human bocavirus in children with acute lymphoblastic leukemia. Eur J Pediatr. 2008;167:1011–1015.
Forster J., Schweizer M., Schumacher R.F., Kaufmehl K., Lob S. MxA protein in infants and children with respiratory tract infection. Acta Paediatr. 1996;85:163–167.
Chieux V., Hober D., Chehadeh W., Harvey J., Alm G., Cousin J. MxA protein in capillary blood of children with viral infections. J Med Virol. 1999;59:547–551.
Nakabayashi M., Adachi Y., Itazawa T., Okabe Y., Kanegane H., Kawamura M. MxA-based recognition of viral illness in febrile children by a whole blood assay. Pediatr Res. 2006;60:770–774.
Bartlett N.W., Slater L., Glanville N. Defining critical roles for NF-(B p65 and type I interferon in innate immunity to rhinovirus. EMBO Mol Med. 2012;4:1244–1260.
Jartti T., Jartti L., Peltola V., Waris M., Ruuskanen O. Identification of respiratory viruses in asymptomatic subjects: asymptomatic respiratory viral infections. Pediatr Infect Dis J. 2008;27:1103–1107.
Chorazy M.L., Lebeck M.G., McCarthy T.A., Richter S.S., Torner J.C., Gray G.C. Polymicrobial acute respiratory infections in a hospital-based pediatric population. Pediatr Infect Dis J. 2013;32:460–466.
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Source:PubMed
| https://ichgcp.net/clinical-trials-registry/publications/156845-blood-mxa-protein-as-a-marker-for-respiratory-virus-infections-in-young-children |
(PDF) Increased Participation and Decreased Performance in Recreational Master Athletes in “Berlin Marathon” 1974–2019
PDF | The aspect of participation and performance trends in marathon running has been investigated mainly in marathons held in the United States of... | Find, read and cite all the research you need on ResearchGate
Increased Participation and Decreased Performance in Recreational Master Athletes in “Berlin Marathon” 1974–2019
DOI: 10.3389/fphys.2021.631237
Abstract and Figures
The aspect of participation and performance trends in marathon running has been investigated mainly in marathons held in the United States of America (e.g., “New York City Marathon,” “Boston Marathon”), but not for the fastest course in the world, the “Berlin Marathon” held in Berlin, Germany. This study aimed to examine trends in participation and performance in the “Berlin Marathon” on all its previous 46 editions from 1974 to 2019, the largest dataset ever studied in this event with 696,225 finishers (after data cleaning). Athletes in all age groups increased their participation, except for male athletes aged 20–49 years and athletes of both sexes above 79 years of age. This overall increase in participation was more pronounced in women, but still, there are more men than women participating in “Berlin Marathon” nowadays. All age group athletes decreased their performance across years overall, whereas the top ten recreational athletes improved their performance over the years. Our findings improved the knowledge about the evolution of male and female marathoners across calendar years, especially for the fastest marathon race in the world, the “Berlin Marathon.”
| Number of participants in "Berlin Marathon" from 1974 to 2019 by sex and age groups. …
| Race time of men and women in "Berlin Marathon" across calendar years. …
| Race time of men and women in "Berlin Marathon" across age groups. …
Jaume I University, Spain
University of Calgary, Canada
*Correspondence:
Beat Knechtle
beat.knechtle@hispeed.ch
Specialty section:
This article was submitted to
Exercise Physiology,
a section of the journal
Frontiers in Physiology
Received: 19 November 2020
Accepted: 14 May 2021
Published: 28 June 2021
Citation:
Reusser M, Sousa CV , Villiger E,
Alvero Cruz JR, Hill L, Rosemann T ,
Nikolaidis PT and Knechtle B (2021)
Increased Participation
and Decreased Performance
in Recreational Master Athletes
in “Berlin Marathon” 1974–2019.
Front. Physiol. 12:631237.
doi: 10.3389/fphys.2021.631237
Decreased Performance in
Recreational Master Athletes in
“Berlin Marathon” 1974–2019
Marlen Reusser 1 , Caio Victor Sousa 2 , Elias Villiger 1 , José Ramón Alvero Cruz 3 , Lee Hill 4 ,
Thomas Rosemann 1 , Pantelis T. Nikolaidis 5 and Beat Knechtle 1,6 *
1 Institute of Primary Care, University of Zurich, Zurich, Switzerland, 2 Bouvé College of Health Sciences, Northeastern
University, Boston, MA, United States, 3 Dpto de Fisiología Humana, Histología, Anatomia, Patológica y Educación Física y
Deportiva Universidad de Málaga, Málaga, Spain, 4 Division of Gastroenterology & Nutrition, Department of Pediatrics,
McMaster University, Hamilton, ON, Canada, 5 Exercise Physiology Laboratory , Nikaia, Greece, 6 Medbase St. Gallen Am
Vadianplatz, St. Gallen, Switzerland
The aspect of participation and performance trends in marathon running has been
investigated mainly in marathons held in the United States of America (e.g., “New Y ork
City Marathon,” “Boston Marathon”), but not for the fastest course in the world, the
“Berlin Marathon” held in Berlin, Germany . This study aimed to examine trends in
participation and performance in the “Berlin Marathon” on all its previous 46 editions
from 1974 to 2019, the largest dataset ever studied in this event with 696,225 finishers
(after data cleaning). Athletes in all age groups increased their participation, except
for male athletes aged 20–49 years and athletes of both sexes above 79 years of
age. This overall increase in participation was more pronounced in women, but still,
there are more men than women participating in “Berlin Marathon” nowadays. All age
group athletes decreased their performance across years overall, whereas the top ten
recreational athletes improved their performance over the years. Our findings improved
the knowledge about the evolution of male and female marathoners across calendar
years, especially for the fastest marathon race in the world, the “Berlin Marathon.”
Keywords: marathon, running, participation, performance, age of peak performance, performance decline, sex
differences in endurance
INTRODUCTION
The inaugural modern marathon event was first held during the 1896 Summer Olympic
games and was refined to the official distance of 42.195 km for the 1908 Olympic Games
in London ( Burfoot, 2007 ; Wilcock, 2008 ). However , these races were only for men. The
women’ s marathon event was added to the official program nearly 99 years later, during
the 1984 Los Angeles Olympic Games ( Burfoot, 2007 ). In the 1970s and 80s – in line
with the upcoming fitness trend – a skyrocketing boom of these marathon events occurred
( V alentine, 1982 ; Maffetone et al., 2017 ; Knechtle et al., 2018 ) and marathon races have become
more and more popular all over the world ( Vitti et al., 2020 ). The largest participation
numbers so far were reached in 2016, with approximately nine million runners crossing
Reusser et al. Participation and Performance in “Berlin Marathon” 1974–2019
finish lines all over the world ( The State of Running, 2019 ).
A total of 12% of those finishers were marathoners ( The State of
Running, 2019 ), and most of them were age group athletes ( Rüst
et al., 2013 ; Lara et al., 2014 ).
With such participation numbers and demographic diversity,
marathon running provides scientifically interesting samples
for research in endurance sport ( Stones and Baker, 2020 ).
Further analyses of these data can contribute to, e.g., a
better understanding of aging processes and consecutively age-
related performance declines ( Leyk et al., 2007 ; Reaburn and
Dascombe, 2008 ; T ayrose et al., 2015 ), differences between the
sexes regarding physiology and performance ( Rüst et al., 2013 ;
Knechtle and Nikolaidis, 2018 ; Nikolaidis et al., 2018, 2019c ),
the influence of lifestyle ( Leyk et al., 2009, 2010 ), environmental
( Nielsen, 1996 ; El Helou et al., 2012 ; Maffetone et al., 2017 ;
Knechtle et al., 2019 ) and demographic factors ( Knechtle et al.,
2017 ; Maffetone et al., 2017 ; Nikolaidis et al., 2017 ; Knechtle and
Nikolaidis, 2018 ) on performance and a better understanding of
motivational factors for running of different cohorts and decades
( Krouse et al., 2011 ; Nikolaidis et al., 2019b ).
The “Berlin-Marathon, ” for the first time in 2019, marked
the final race of the “World Marathon Majors, ” a series of six
of the largest and most renowned marathons in the world and
popularly known as the “Marathon’ s Champion’ s Le ague” ( World
Marathon Majors, 2021 ). This may be a deserved position as
today, the “Berlin Marathon” ranks third in the world regarding
the size of the runner field and is the fastest course among
the city marathons worldwide in men’ s racing and third fastest
in women’ s ( Berlin Marathon, 2021 ). Seven of the ten fastest
men’ s marathon times and numerous world records were set
during the “Berlin-Marathon” ( Berlin Marathon, 2021 ). Among
those records is the current men’ s world record, achieved in
2018 by the Kenyan Eliud Kipchoge in a time of 2:01:39 ( World
Athletic Records, 2021 ). The current course record for women in
“Berlin-Marathon” was set by Kipchoge’ s countrywomen Gladys
Cherono in 2018 (2:18:11 h) ( BMW Berlin Marathon, 0000 ). This
running time is close to the current world record for “women
only marathon” (as is also “Berlin Marathon” since 2011) set by
Mary Jepkosgei in 2017 in the “London Marathon” with a time of
2:17:01 1 .
More recently, research has tended to focus primarily on
marathon races held in the United States, with the “ New York
City Marathon, 2021 ” – the largest marathon race nowadays –
being one of the most investigated ( Jokl et al., 2004 ; Santos-
Lozano et al., 2015 ; Zavorsky et al., 2017 ; Nikolaidis et al.,
2018 ). Alongside the “ New York City Marathon, 2021 ” is the
“ Boston Marathon, 2021 ” generating the next most scientific
interest ( Maffetone et al., 2017 ; Knechtle et al., 2018, 2020 ).
Most studies conducted on those two marathon events (the
“ New York City Marathon, 2021 ” and the “ Boston Marathon,
2021 ”) have demonstrated increasing participation rates over
the last two decades (more pronounced in women than in
men) and a concomitant increase in mean race times (i.e.,
decreased performance) across calendar years ( Jokl et al., 2004 ;
1 www.worldathletics.org/records/by-discipline/road-
running/marathon/outdoor/women
Mathews et al., 2012 ; Nikolaidis et al., 2018 ; Knechtle et al.,
2020 ). Even though the “Berlin-Marathon” is one of the fastest
and most popular marathon events in the world, there has not
been any complete analysis of participation and performance
trends on all its 46 previous editions. Therefore, it is interesting
to see whether the above-mentioned consensus about the
development of participation rates and running times found
in American marathon events would also be applicable for
European Marathon races such as the “Berlin Marathon.”
Much of the current research on participation and
performance in marathon racing also was done with regard
only at a short period of time or limited participation group.
For example, Ahmadyar et al. (2015, 2016) studied elderly
marathoners ( > 75 years of age) in the four largest marathon
events nowadays in the time period from 1990 to 2014 and
2004 to 2011. Knechtle et al. (2018) analyzed participation and
performance for all editions of “Boston Marathon” from 1879 to
2017, but only in male runners. Jokl et al. (2004) included runners
of all age groups and both sexes in their analysis of the “New York
City Marathon, ” but only analyzed the time period between 1983
and 1999 ( Jokl et al., 2004 ). Mathews et al. (2012) studied the
mortality among marathon runners in the United States, and
thereby analyzed a variety of events throughout the United States
but could only include data from 2000 to 2009 in their study.
More recently, an interesting perspective that investigated the
motivation for running in the “Athens Classic Marathon” was
done by Nikolaidis et al. but only focused on the 2017 edition
( Nikolaidis et al., 2019b ). Therefore, by analyzing the full data of
the “Berlin Marathon” since its inaugural event in 1974, we hope
to provide valuable new information to the above-mentioned
ongoing research.
Furthermore, the current study aims to contribute to the
growing literature on women’ s participation in endurance sports.
Previously, women were barred from participating in sporting
events primarily based on Victorian area myths about endurance
exercise and the fragility of the female body ( Wrynn, 2014 ; Hill,
2017 ). It has taken several decades for women to be permitted the
same sporting opportunities as their male counterparts, and even
still, equity has not been achieved ( Capranica et al., 2013 ). The
first time women were permitted to officially run a marathon race
occurred during the 1972 “Boston Marathon” ( Thibault et al.,
2010 ; Knechtle et al., 2020 ). In 2018, for the first time in history,
equal participation between men and women in running events
was achieved with women representing 50.24% of runners at
events all around the world ( The State of Running, 2019 ). Race
organizers at the “Berlin-Marathon” in its 46th edition (2019) set
its focus for the first time officially on the women’ s race ( Berlin
Marathon, 2021 ).
Although progress toward equal opportunity has been
consistent for female athletes, sports science research focusing on
women is still sorely lacking. Only 4% of the present research
in sport sciences is conducted exclusively on female athletes,
whereas 27% of those studies are conducted exclusively on
male athletes ( Women in Sports are Often Underrepresented
in Science, 2016 ; Costello et al., 2014 ). Further, an analysis of
1,382 articles published from 2011 to 2013 showed that female
participation rate per article was around 36 percent (added up
Frontiers in Physiology | www.frontiersin.org 2 June 2021 | Volume 12 | Article 631237
Reusser et al. Participation and Performance in “Berlin Marathon” 1974–2019
in this analysis was a total of more than six million participants)
( Women in Sports are Often Underrepresented in Science, 2016 ).
As physiology and biomechanics properties differ between the
sexes, it is not applicable to transfer study results found in a
predominantly male population to a female population, which –
as mentioned – accounts for more than half of the athletic
population currently competing in running ( Women in Sports
are Often Underrepresented in Science, 2016 ; Lewis et al., 1986 ).
To optimize female performances and health in sport, we need
to include women in our analyses in order to better understand
the peculiarities that may exist in physiology. Therefore, we are
happy to enrich the existing pool of knowledge with more data
on female participation and performance in marathon racing.
T aken together, our understanding of the characteristics of
participation and performance are well known for only a handful
of important marathon events ( Jokl et al., 2004 ; Mathews et al.,
2012 ; Santos-Lozano et al., 2015 ; Maffetone et al., 2017 ; Zavorsky
et al., 2017 ; Nikolaidis et al., 2018, 2019c ; Knechtle et al., 2020 )
and/or limited periods or participation groups ( Jokl et al., 2004 ;
Mathews et al., 2012 ; Ahmadyar et al., 2015, 2016 ; Nikolaidis
et al., 2019b ). Drawing general conclusions out of these limited
data, which can be important for the above-mentioned research
fields in sport, epidemiological and medical sciences, should be
done cautiously.
The aims of the present study were, therefore, (i) to analyze
the changes in participation and performance trends of age group
marathon runners in the “Berlin-Marathon” for all its previous
editions, (ii) to compare the sex differences in performance as
a function of age across the years, and (iii) by this to provide
one more complete analysis on participation and performance
of female athletes in the history of a significant event in
order to allow best possible future findings of particularities
in female sports physiology. Based upon existing evidence, we
hypothesized that for “Berlin-Marathon” between 1974 and 2019,
the participation of all age groups would grow, with more
substantial growth in female participation and, therefore, a
narrowing sex gap in participation. Further, we hypothesized
the performance of top age group athletes would improve over
calendar years, whereas the performance of the average age
groupers would decrease.
MA TERIALS AND METHODS
Ethics Approval
The institutional review board of St Gallen, Switzerland,
approved this study (EKSG 01/06/2010). Since the study involved
the analysis of publicly available data, the requirement for
informed consent was waived.
Participants
To test our hypothesis, data (i.e., first and last name, sex,
age, calendar year, and running time) on all successful female
and male finishers in the “Berlin-Marathon” since 1974, the
inauguration year of the “Berliner Volksmarathon, ” was obtained
from the official race website ( BMW Berlin Marathon, 0000 ). To
compete in the “Berlin-Marathon, ” athletes must be 18 years old
or older but must not meet specific time standards ( BMW Berlin
Marathon, 0000 ). Starting places are limited and assigned via
raffle. Initially, 884,927 finishers were considered in our analysis.
The Race
The “Berlin-Marathon” takes place from mid to end of
September, depending on several logistical factors. The course
builds one large loop through the historic city of Berlin, with
the finish line lying almost under the “Brandenburger Tor.”
Berlin lies 34 meters above sea-level, the average temperature in
September is about 14.9 ◦ Celsius and average humidity about 75%
( Klimatabelle, 2021 ) and the total elevation of the course is only
50 meters ( Berlin Marathon, 2021 ).
Data Analysis
First and last name, sex, age, calendar year , and running time on
all successful female and male finishers in the “Berlin-Marathon”
from 1974 to 2019 were obtained from the official race website
( BMW Berlin Marathon, 0000 ). We cleaned the dataset removing
runners with missing or questionable (unreliable) information on
race time, i.e., race time under 2 h or over 6 h. With respect to
age stratification, finishers were classified in 10-year age groups
(e.g., 20–29 years to 70–79 years) to analyze performance and
participation. We compared top ten age group runners to the age
group average in order to highlight differences in performance
over calendar years between those groups and both sexes. Further,
we compared top five age group runners of each age-category to
average age group runners of the same age category to examine
performance declines during aging.
Statistical Analysis
All statistical procedures were carried out using the Statistical
Package for the Social Sciences (SPSS version 26. IMB, IL,
United States) and GraphPad Prism (version 8.4.2. GraphPad
Software LLC, CA, United States). The Shapiro-Wilk and Levene ’ s
tests were applied for normality and homogeneity, respectively.
Six General Linear Models (two-way ANOV A) were used as
follows: model 1 – all participants by sex and calendar year;
model 2 – top ten athletes in each race by sex and calendar
year; model 3 – all participants by age group and sex; model
4 – top five athletes in each age group in each race by age
group and sex; model 5 – all men participants by age group and
calendar year; model 6 – all women participants by age group
and calendar year. When interactions were found ( p < 0.05),
pairwise comparisons were applied to identify the differences
more accurately. Calendar years without sex or age information
were removed from the analysis. For performance analysis,
age groups, or calendar years with less than five participants
were removed. Applying those criteria, the calendar years 1976
to 1984, 1994 to 1998, and 2019 had to be removed from
the performance × years for men and women analysis, the
calendar years 1976 to 1978, 1980 to 1981, 1994 to 1998 and
2019 had to be removed from the performance × years × age
group analysis for men and the calendar years 1974 to
1984, 1994 to 1998 and 2019 had to be removed from the
performance × years × age group analysis for women. For the
participation × year analysis for both sexes (total participants)
Reusser et al. Participation and Performance in “Berlin Marathon” 1974–2019
FIGURE 1 | Number of participants in “Berlin Marathon” from 1974 to 2019 by sex and age groups.
we had to remove the years 1976 to 1984, 1994 to 1998 and
2019, for the participation × sex × age analysis, we had to
remove the years 1974, 1976 to 1978, 1980 to 1981, 1994 to
1998 and 2019 for men and the years 1974, 1976 to 1984, 1994
to 1998 and 2019 for women. The level of significance utilized
was p ≤ 0.05.
RESUL TS
The total number of athletes ever registered in the 46 editions
of the “Berlin-Marathon” between 1974 and 2019 was 884,927
finishers. After filtering out invalid data regarding our criteria,
696,225 finishers were included for the final analysis. The number
of athletes participating in the “Berlin-Marathon” increased
from only 236 men and 8 women in 1974 to 28,373 men
and 12,268 women in 2018 ( Figure 1 ). Moreover, all a ge
groups increased their participation, except for male athletes
aged 20–49 years and athletes of both sexes above 79 years
old ( Figure 1 ).
The first two ANOV A models (model 1 and 2) to analyze
performance showed a significant effect on sex, year, and
interaction sex × year ( T able 1 ). However, pairwise comparisons
and the linear trend show that model 1 tends to increase race
time across calendar years. In contrast, in model 2, which only
included the top ten athletes in each race, race time has a
decreasing trend across calendar years ( Figure 2 ).
Models 3 and 4 showed significant effects on sex, age group,
and interaction sex × age group ( T able 1 ). Both models showed
similar performance trends across age groups, with the lowest
race times between 20 and 39 years old, and slight increases across
each next age group ( Figure 3 ).
Models 5 and 6 showed significant effects for age group, year,
and an interaction age group × year ( T able 1 ). Both men and
women showed similar performance trends among all age groups,
with increasing race time across calendar years ( Figure 4 ).
DISCUSSION
The main aims of this study were (i) to analyze the changes in
participation and performance trends of age group marathon
runners in the “Berlin-Marathon” for all its previous editions,
(ii) to compare the sex differences in performance as a function
of age across the years, and (iii) by this to provide one
more complete analysis on participation and performance of
female athletes in the history of a significant event in order
to allow best possible future findings of particularities in
female sports physiology. The main findings were that (i)
the number of finishers increased for both women and men
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Reusser et al. Participation and Performance in “Berlin Marathon” 1974–2019
TABLE 1 | ANOV A results of performance analysis in “Berlin marathon” in different models.
Factor F p -value
Model 1 Sex 294.5 < 0.001
Year 29.0 < 0.001
Sex × Calendar year 85.4 < 0.001
Model 2 (T op ten athletes) Sex 91.6 < 0.001
Year 3.4 0.001
Sex × Calendar year 12.8 < 0.001
Model 3 Sex 280.4 < 0.001
Age group 155.3 < 0.001
Sex × Age group 19.9 < 0.001
Model 4 (T op five athletes in each age group) Sex 29.5 0.001
Age group 38.7 < 0.001
Sex × Age group 13.1 < 0.001
Model 5 (Men) Age group 208.3 < 0.001
Calendar year 80.0 < 0.001
Age group × Calendar year 7.6 < 0.001
Model 6 (Women) Age group 100.4 < 0.001
Calendar year 39.2 < 0.001
Age group × Calendar year 1.8 < 0.001
FIGURE 2 | Race time of men and women in “Berlin Marathon” across calendar years.
runners over the decades, (ii) this increase in participation
was more pronounced in women than in men, and (iii) all
age group athletes decreased their overall performance, whereas
the top ten recreational athletes improved their performance
over the years.
Participation T rends
The first important finding was that the number of finishers
increased for both women and men runners over the decades,
which supports our first hypothesis. In the first edition of the
“Berliner Volksmarathon” in 1974, only 236 men and 8 women
took part, and by 2018 there were 28,373 men and 12,268
women participating. The increase in participation in recent
years was more pronounced in women, whereas men of the age
groups 20 – 49 years showed a slight decrease in participation
numbers in the last two decades. This narrowing of the gender
gap in participation has been previously reported in well-
studied city marathons such as the “New York City Marathon”
( Hunter and Stevens, 2013 ; Nikolaidis et al., 2018 ) and the
“Boston Marathon” ( Knechtle et al., 2020 ). Some researchers
even predicted a closing of the gender gap in participation
in the marathon; however, it has n o t appeared yet for the
large city marathons such as the “New York City Marathon”
( Jokl et al., 2004 ; Knechtle et al., 2020 ; Vitti et al., 2020 )
and after analysis of the present study, neither in the “Berlin-
Marathon” so far.
Still, an extensive but not officially validated research of
Andersen et al. showed that in 2018 – “for the first time in
history” – there were more female than male runners competing
worldwide (50.24% women) ( The State of Running, 2019 ).
Reusser et al. Participation and Performance in “Berlin Marathon” 1974–2019
FIGURE 3 | Race time of men and women in “Berlin Marathon” across age groups.
FIGURE 4 | Race time of men and women in “Berlin Marathon” in age groups across calendar years.
The analysis by Andersen and colleagues covered 96% of US-
based running race results, 91% of the race results from the
EU, Canada, and Australia and a “big portion” from A sian,
Africa, and South America. Andersen et al. analyzed not only
marathon races, but all types of running events. This may
be the crucial point: Women seemed to be more engaged
in shorter running events. Moreover, it was noted that the
longer events were, women were less likely to participate
showing a decreased number of starters in relation to men.
However, further investigation in worldwide participation in
running events of different distances considering demographical
conditions of the participants is required. However, also an
analysis of running races from one single country would
be of interest.
A significant observation described previously by Nikolaidis
et al. (2018) found that women, in general, start and stop racing at
a younger age than men. That men-to-women-ratio in the older
age groups compared to their younger counterparts could be
explained through the existence of historical and social barriers
( Vitti et al., 2020 ). Pointing in the same direction are the findings
of Andersen et al., who – by comparing sex participation rates
for running events between different countries – found a clear
correlation between “general gender equality” and equality in
participation rates ( The State of Running, 2019 ). When taking
into account the historical perspective of women’ s competitive
sports, female athletes have been subjected to a variety of
discriminatory practices and gender-based social barriers, many
of which are still ongoing ( Costello et al., 2014 ). The 2012
Summer Olympic Games were an important milestone, whereby
every participating country’ s delegation included at least one
female competitor ( Costello et al., 2014 ), albeit a positive step,
but far from what is required for a true closing of the gender gap.
However, it must be noted that some countries have been
successful in improving women’ s participation rates and some
have even tipped the scales completely. Higher participation
rates in running events for women than for men have been
Reusser et al. Participation and Performance in “Berlin Marathon” 1974–2019
observed with Iceland on the top of the board (59%), followed
by the United States (58%) and Canada (57%) ( The State of
Running, 2019 ). Switzerland (16%) and Italy (19%) are among
the countries with the least female participation in running
events ( The State of Running, 2019 ). In the case of Switzerland,
this participation rate seems to contradict to the fact that 49%
of the regularly running population in Switzerland (which is
about one-third of the Swiss population) are women ( Sport
Schweiz 2020, 2020 ). This finding may be quite surprising,
given the mentioned country’ s apparent progressiveness, but
not so, if one considers the repeated international criticism on
Switzerland’ s gender policy ( Human Rights Switzerland, 2021 ).
When examining sports such as road cycling, the gender gap
in Switzerland seems even more prominent (in 2019, only
14% of the licensed road cyclists in Switzerland were women)
( personal and unpublished written communication with Stefania
Ratano, the responsible for members and license s at the Swiss
national cycling federation “Swis s Cycling, ” mid of June 2020 ). This
possible correlation between actual and effective “general gender
equality” and participation rates in endurance events could be an
interesting subject for future research.
Performance T rends
As expected, performance in all age group athletes decreased,
whereas the top ten age group athletes improved their finishing
times across calendar years. This tendency was found for the
“Boston Marathon” already ( Maffetone et al., 2017 ; Knechtle
et al., 2019, 2020 ). Vitti et al. (2020) analyzed 1.2 Million runs
“during half a century” in the “New York City Marathon” and
described the phenomenon of “the faster get faster and the
slower get slower.” They stated that nowadays, more women,
more recreational and more elderly runners participate in most
of the marathons worldwide, while in the 1970s, participation
was limited to mainly elite male runners ( Vitti et al., 2020 ).
Knechtle et al. (2018) who analyzed men’ s participation and
performance in the Boston Marathon from 1897 to 2017
commentated the same way: There is more variability on
performance introduced by the increased number of age group
runners in marathon running. We also see these changes in the
marathoners’ community over the years as an important factor
that explains why “the slower get slower.”
The factors that influence the improvement in running times
of the already fast marathoners seem to be more complex and
multi-factorial. Historically, marathon running training, pre-race
preparation, nutrition, fluids and equipment were significantly
different than what is available today ( Ineos 1:59 Running
Challenge, 2019 ; Joyner et al., 2020 ). Special attention should
be given to recent advancements in running shoe technology
and as a result, improved running times by professional runners,
who primarily wear them ( Carbon Fiber Racing Shoe Battle,
2020 ). In 2017 “Nike” released the first carbon fiber shoe,
triggering a technology advancement race between commercial
shoe companies ( Carbon Fiber Racing Shoe Battle, 2020 ).
Independent tests showed significantly lower oxygen uptake by
runners at higher running speeds wearing carbon sole “Nike”
shoes ( Carbon Fiber Racing Shoe Battle, 2020 ; Hoogkamer et al.,
2018 ; Hunter et al., 2019 ).
Therefore, improvements in “running economy” seem to be
crucial for the constantly dropping running times. This is also
seen in analyses of East-African runners, who comprise most
of today’ s elite in big-city-marathons ( World Athletic Records,
2021 ). Those runners, who originate from specific regions in
Kenya and Ethiopia ( Scott et al., 2003 ; Onywera, 2009 ), show
a profile that allows them to run with an exceptional high
running economy ( Weston et al., 2000 ; Lucia et al., 2006 ;
Kong and De Heer, 2008 ; Mooses and Hackney, 2017 ). This
outstanding running economy is seen as one of the important
factors for the dominance of East-African runners ( Weston
et al., 2000 ; Kong and De Heer, 2008 ; Mooses and Hackney,
2017 ). Still, even if the reasons for Kenyan and Ethiopian
apparent dominance in endurance running races have been
deeply analyzed, there remains no clear consensus on what
contributes to their dominance ( Hamilton, 2000 ). So, one part
of the explanation why the “faster” become faster, could be a
growing participation rate of mentioned African ethnicities in
the big city marathons during the last decades ( Vitti et al., 2020 ).
Still, extensive research about worldwide participation rates in
marathon running for the last decades split up in ethnicities or
countries of origins are missing.
Not all studies conducted on a large population of endurance
athletes find improving race times of the “fast athletes” and
slowing race times of recreational athletes in the past though.
Research conducted on elite and master Ironman triathletes
e.g., showed improving race times for both these groups of
athletes during the last decades while also the average age of
the athletes augmented ( Lepers et al., 2013 ; Gallmann et al.,
2014 ). Regarding at these results, the importance of interaction
of age of a certain study population and age of peak performance
in endurance sport has to be underlined. Future studies need
to take into consideration the current ideas about age of peak
performance (see below) in a certain discipline and changing age
of participations over decades of analysis.
Athletes in the age groups 20–29 years and 30–39 years
showed the fastest race times in the “Berlin-Marathon” for both
sexes, as well as the top five were the fastest in those two age
groups. For the following older age groups, we constated slight
increases in race times. Above the age of 60 years, the increase in
average race time was more pronounced, with a greater decline of
performance for top five age group athletes than for the average
age group. All those findings account for both sexes, with only
minor differences in-between.
There is no consensus about the precise age of peak
performance and the dynamics of the age-related performance
decline in endurance sport in the current scientific literature
( Lara et al., 2014 ; Zavorsky et al., 2017 ; Nikolaidis et al.,
2018, 2019a ; Jäckel et al., 2020 ). Depending on the discipline
(“locomotion models”) ( Jäckel et al., 2020 ), the study population
(recreational athletes versus top age group athletes ( Lepers and
Cattagni, 2012 ; Zavorsky et al., 2017 ) versus top professional
athletes ( Knechtle et al., 2018, 2019 ) and other factors like
research period ( Leyk et al., 2007 ; Lara et al., 2014 ; Knechtle et al.,
2018 ), the outcomes are different. For example, Jäckel et al. (2020)
stated a progressive running performance decline for recreational
half-ironman triathletes after the age of 50 years. The same was
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Reusser et al. Participation and Performance in “Berlin Marathon” 1974–2019
constated for age group marathoners by Zavorsky et al. (2017)
who examined data from the New York City, Boston and
Chicago marathons, in addition to Leyk et al. (2007) who
examined 69 marathons and 65 half-marathons performed
between 2003 and 2005 in Germany. At the same time, Käch
et al. (2018) , who investigated recreational Ironman triathletes,
reported a much earlier decline in running performance starting
at about 30–34 years in women and 35–39 years in men.
Reaburn et al. summarized the same for recreational runners
( Reaburn and Dascombe, 2008 ). Their review reported that the
declines in performance are curvilinear from age 35 years until
approximately the age of 60–70 years ( Reaburn and Dascombe,
2008 ). Additionally, Lepers et al. (2010) showed that elite
triathletes maintained their performance up to the fourth or fifth
decade of life, i.e., a curvilinear decline from 50 years onward
in Olympic Triathlon World Championships and from 45 years
onward in the “Ironman Hawaii.”
Also, there is the question of sex and age of peak performance,
which is important for athletes and coaches to plan a career ( Allen
and Hopkins, 2015 ). In contrast to existing findings reporting a
higher age of peak marathon performance in women compared to
men ( Nikolaidis et al., 2018 ), it was found that women achieved
their best marathon race time ∼ 5 years earlier in life than men
by analyzing all finishers of the “New York City Marathon”
between 2006 and 2016 ( Nikolaidis et al., 2018 ). More data from
big events over large periods of time is needed to discuss those
questions and find consensus about the age of peak performance
and the dynamics of the age-related performance decline in
endurance sport.
Limitations
Several limitations of this study should be noted. First, the
data obtained for the “Berlin Marathon” database only included
finishing times, gender and age of the participants. Other factors,
such as training volume and intensity, previous experience,
ethnicity and physiological variables (VO 2 max, lactate threshold,
and running economy) were not recorded. Still, those other
factors are known to affect endurance running performance, and
therefore some part of the variance in endurance performance
explained by age may actually be related to those ( Lara et al.,
2014 ). For this reason, the outcomes found in this investigation
should be reinforced by collecting experimental data. Second,
there are limited participation places for the “Berlin Marathon, ”
which are allocated by raffle. Information about the year of
installment of the raffle and places distributed per year and sex
since then are not available 2 . If there had been a distribution
key respecting the sex of participants, it consecutively must
have had an influence on sex ratios found in finisher reports
and thereby on our results. At the same time, drawing lots
shouldn’t influence mean running times because the sample
sizes in “Berlin Marathon” are large enough to ensure an evenly
distributed composition of the runners. In the present study, we
only considered finishing numbers but neither registration nor
starting numbers, which are not accessible to public “(see text
2 www.bmw-berlin-marathon.com/en/your-registration/registration-
information/general/
footnote 2)”. By this, we cannot exclude to actually report more
on the ability of participants to make it to the finish line within the
limit of 6 h, than on the actual trend to participate and register
for the “Berlin Marathon.” We do not expect the latter to differ
by much, still those analyses would be needed to confirm our
findings. Third, sex and age data are unavailable for the years 1976
to 1984, 1994 to 1998 and 2019. For those years, the analyses are
missing between sexes, age groups, and sex ratio. Therefore, our
analysis on that subject is not fully complete. Nevertheless, the
available data allows us to see trends and make statistically reliable
statements on sex ratios. Further, the way the platform of “Berlin
Marathon” displays the data about participants has changed
throughout the years, so as how they store data ( BMW Berlin
Marathon, 0000 ). For some years, we suspect that they calculated
the age of each participant as “current year – year of birth.”
This can generate a problem with participants with missing data
because they would enter as 90 + years old, and we excluded this
age group from our analysis. Finally, in order to make statements
about age of peak performance and the dynamics of age-related
performance declines in marathon running, data should be split
up into rather small age group fragments. The present work
analyzed age groups in 10-year intervals, which doesn’t allow us
to draw conclusions regarding this issue.
CONCLUSION
This study tested the hypothesis that for “Berlin-Marathon” over
all its previous 46 editions (1974–2019), participation of age
group athletes would increase, the over-all performance of age
group athletes would decrease and top age-group performances
would improve over calendar years. Participation for female
and male runners increased, with a stronger increase in female
participation and thereby narrowing sex gap in participation,
the fastest age group women and men became faster across
years and average age group performance decreased. This is the
largest dataset ever studied in this event and provides valuable
information in the ongoing research about characteristics in
participation and performance in large city marathons. Future
studies might investigate the influence of other parameters
such as country of origin, training volume, training years and
motivation of athletes to understand how training and life of
athletes can be planned best to achieve maximal performance.
DA T A A VAILABILITY ST ATEMENT
The raw data supporting the conclusions of this article will be
made available by the authors, without undue reservation.
AUTHOR CONTRIBUTIONS
MR and BK designed the study. EV collected the data.
CS performed the statistical analyses. JA, LH, TR, and PN
contributed by writing and editing a part of the manuscript. All
authors read and approved the final manuscript.
Frontiers in Physiology | www.frontiersin.org 8 June 2021 | Volume 12 | Article 631237
Reusser et al. Participation and Performance in “Berlin Marathon” 1974–2019
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Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Copyright © 2021 Reusser, Sousa, V illiger, Alvero Cruz, Hill, Rosemann, Nikolaidis
and Knechtle. This is an open-access article distributed under the terms of
the Creative Commons Attribution L icense (CC BY). The use, distribution or
reproduction is permitted which does not comply with these terms.
... In Europe in particular, the Berlin Marathon held in Berlin, Germany, is a benchmark as a popular sporting event for recreational runners. The number of endurance runners who crossed the finish line in the first edition of the Berlin Marathon in 1974 was only 236 men and 8 women, in contrast to the remarkable increase in 2018 when there was a participation of 28,373 men and 12,268 women
(12)
. Moreover, another characteristic of the evolution undergone during this process of expansion of longdistance events among recreational runners in Europe is that the average times at the end of the half marathon have been getting slower. ...
... Moreover, another characteristic of the evolution undergone during this process of expansion of longdistance events among recreational runners in Europe is that the average times at the end of the half marathon have been getting slower. That is, over time, there are more runners who are slower
(12)
. However, the runners at the top of the Berlin Marathon rankings have also been breaking records and improving their performance (12). ...
... That is, over time, there are more runners who are slower (12). However, the runners at the top of the Berlin Marathon rankings have also been breaking records and improving their performance
(12)
. In summary, for the Berlin Marathon the evolution has been that more and more recreational runners are slower and more and more professional runners are faster. ...
Biomechanical assessment and efficacy of the implementation of running retraining programs in long distance runners
Thesis
Full-text available
Running as an activity to improve health and personal performance has become increasingly widespread among the popular population. This popular phenomenon of running is due to, among other factors, the satisfaction of physical and psychological health needs, the achievement of goals, tangible rewards, social influences and easy availability. However, today, runners suffer injuries at a high rate despite scientific and technological advances in running, training control, technique and footwear. Progress in describing the biomechanical characteristics of these runners is necessary in terms of injury prevention and performance improvement. Footstrike pattern has been associated with risk factors for running injuries and running economy in endurance runners. However, few studies have been carried out in real competition situations or on mass populations. In addition, previous studies have demonstrated, separately, the effects of barefoot running and increasing cadence with similar results, such as the alteration of spatiotemporal parameters, lower limb kinematics, postural balance and walking foot motion. However, there is uncertainty in the evaluation of these programmes in the same study population with similar training loads. General aim. To analyse biomechanical indicators of human running locomotion, under natural and non-invasive conditions (in competition), and its optimisation through the implementation of running retraining programs in recreational endurance runners.
... The total number of athletes registered in the 13 VM editions between 2007 and 2019 (the year of the last edition before the lockdown due to the COVID-19 pandemic) was 71,575 finishers, with 59,819 males (82.3%) and 12,656 females (17.7%). Figure 1a shows the numbers of participants in the 13 editions, with a significant increase (p < 0.001) in the female participation, which increased from 14% in 2007 to
22
The ratio (ratio-y F/M) between female and male participants by year, obtained as the number of female participants over the number of males, showed a linear and significant increase (Figure 1b), from a minimum value in 2007 (ratio-y = 0.16) to a maximum in 2019 (ratio-y = 0.29) (p < 0.001). Figure 1c shows the distribution of participants by age category over the 13 editions of VM. ...
... Since the analyses in each age category included the running speeds of both winners and the last classified participants (who kept a walking pace), these results are more of social and cultural relevance than of sporting interest, as reported by Reusser and collaborators
[22]
. The details of the analysis of AD during the 13 VM editions showed a trend towards a decline in men's performance almost in every age category, from 30 years old onwards, while in women this decline was limited to the 30-35-year age category. ...
Performance Analysis on Trained and Recreational Runners in the Venice Marathon Events from 2007 to 2019
Full-text available
Davide Zuccon
Diego Guidolin
Laura Astolfi
The Venice Marathon (VM) has gained fame and prestige over time. It is part of a group of marathons that are recognized worldwide. The aims of this study were to describe the attractiveness of the event over the years according to the gender and age of participants, and to investigate their performances according to gender and age differences in the group of all finishers over 23 years old (AD), along with the best 10% performance (TOP) over a 13-year period. Methods: We conducted a retrospective analysis of VM race data from 2007 to 2019; the data were collected from the free Timing Data Service website and statistically analyzed. Results: In total, 82.3% of participants were male and 17.7% were female. A significant total increase in female participation was observed over the 13 editions of the VM. Linear regression analysis of AD speeds for each category showed a significant decrease in the youngest categories. Among the TOP athletes, the 40-year age category showed increased performance of both males and females. Analyzing the mean speed by age (AD13 and TOP13), there was a breakpoint in the speed decrease in AD13 in the age categories of 50 years in males and 55 years in females, while in TOP13 the breakpoints were in the 55- and 45-year age categories in males and females, respectively. Conclusion: The results obtained confirmed the reduction in running speed with age, as well as the definition of the VM as an example of a recreational marathon in which the participation of runners over 40 years will increase in the future, and for which specific adaptations will be required.
... Among long-distance events, the marathon is one of the most symbolic races globally and has increased participation of all age groups and both sexes
[14,
15]. For instance, The TCS New York City Marathon, named after the major sponsor Tata Consultancy Services, is the premier event of New York Road Runners (NYRR) and the largest marathon in the world. ...
... Marathon running is highly popular with an increase in the number of races and participants, especially the number of master marathoners and female runners
[14]
. Many marathon runners suffer from gastrointestinal disorders due to dehydration and electrolyte imbalance [61][62][63][64][65]. ...
Exercise-Associated Hyponatremia in Marathon Runners
Article
Full-text available
Mark Klingert
Pantelis Theo Nikolaidis
Katja Weiss
Beat Knechtle
Exercise-associated hyponatremia (EAH) was first described as water intoxication by Noakes et al. in 1985 and has become an important topic linked to several pathological conditions. However, despite progressive research, neurological disorders and even deaths due to hyponatremic encephalopathy continue to occur. Therefore, and due to the growing popularity of exercise-associated hyponatremia, this topic is of great importance for marathon runners and all professionals involved in runners’ training (e.g., coaches, medical staff, nutritionists, and trainers). The present narrative review sought to evaluate the prevalence of EAH among marathon runners and to identify associated etiological and risk factors. Furthermore, the aim was to derive preventive and therapeutic action plans for marathon runners based on current evidence. The search was conducted on PubMed, Scopus and Google Scholar using a predefined search algorithm by aggregating multiple terms (marathon run; exercise; sport; EAH; electrolyte disorder; fluid balance; dehydration; sodium concentration; hyponatremia). By this criterion, 135 articles were considered for the present study. Our results revealed that a complex interaction of different factors could cause EAH, which can be differentiated into event-related (high temperatures) and person-related (female sex) risk factors. There is variation in the reported prevalence of EAH, and two major studies indicated an incidence ranging from 7 to 15% for symptomatic and asymptomatic EAH. Athletes and coaches must be aware of EAH and its related problems and take appropriate measures for both training and competition. Coaches need to educate their athletes about the early symptoms of EAH to intervene at the earliest possible stage. In addition, individual hydration strategies need to be developed for the daily training routine, ideally in regard to sweat rate and salt losses via sweat. Future studies need to investigate the correlation between the risk factors of EAH and specific subgroups of marathon runners.
... Evaluation of the broad economic, urban, tourist, social and sporting effects of city marathons on their host cities has attracted more attention since the beginning of the new millennium Not surprisingly, this international phenomenon has received significant attention from academic and industry researchers of very different disciplines such as sports and leisure economics (Cobb and Olberding 2007;Coleman 2004;Coleman and Ramchandani 2010;DeSchriver et al. 2022;Foster et al. 2021;Frick et al. 2019;Gratton et al. 2006), sport and event management (Huang et al. 2015; Llopis-Goig and Paramio-Salcines 2021; Paule-Koba 2020a; Shipway and Jones 2008; Thomson et al. 2019;Wicker et al. 2012), economics and business administration (García-Vallejo et al. 2020), sport history (Cooper 1992(Cooper , 1998, sociology (Capsi and Llopis-Goig 2021;Scheerder et al. 2015), tourism (Gibson et al. 2012;Melo et al. 2021), health science
(Reusser et al. 2021
) and even cultural studies (Suozzo 2002(Suozzo , 2006. In this process, city marathons have been consolidated as major tourist destinations by attracting large numbers of elite and amateur runners from outside the host city and abroad (e.g., Gibson et al. 2012;Hallmann and Wicker 2012;Heere et al. 2019;Huang et al. 2015;Park et al. 2019;Wicker et al. 2012). ...
... Most of the research on the managerial aspects, impacts and legacies of marathons on their host cities are based, not surprisingly, with the U.S. at the forefront (Cobb and Olberding 2007;Cooper 1992Cooper , 1998Fickenscher 2006Fickenscher , 2011Martin and Hall 2020;Miller and Washington 2017;Suozzo 2002Suozzo , 2006, followed by Britain (Coleman 2004;Coleman and Ramchandani, 2010;Gratton et al. 2006;Shipway and Jones 2008), Germany
(Reusser et al. 2021;
Wicker et al. 2012), China (Huang et al. 2015;Qiu et al. 2020), Greece (Papanikos 2015) or Spain ( Over the years, more financial data on some of the leading world city marathons have been made public. Indeed, from a comparative economic impact perspective on urban marathons, it has been reported that the direct economic impact of The SalleBank Chicago Marathon in Chicago was estimated to be USD 90 million in 2001 (Suozzo 2002) (a figure that in the 2013 Chicago Marathon was increased to more than USD 253 million in business activity as an independent study conducted by University of Illinois at Urbana-Champaign's Regional Economics Applications Laboratory estimated (Bank of America 2022)). ...
Key Strategic Decisions and Their Influences on the Management and Success of the Bank of America Chicago Marathon and the Marathon Valencia Trinidad Alfonso
Full-text available
Juan Luis Paramio-Salcines
Ramón Llopis-Goig
City marathons have evolved and grown exponentially in type and popularity, in their managerial complexity, and in terms of their financial impact on their host cities and the attraction of corporate sponsors. Most of the research on city marathons has focused on evaluating their broad economic, urban, tourist, social, sporting, and symbolic effects on host cities. However, less attention has been paid to analyzing key strategic decisions that could account for the evolution and growth of specific marathons and their influences on their management and success. This article, which addresses the cases of the Bank of America Chicago Marathon and the Marathon Valencia Trinidad Alfonso, examines those key strategic decisions that have been taken from their inaugural first editions to present and how effective they have been as regards the management and success of both races. Results show that the international success of both events –in terms of sporting participation, performance, and economic impact– is closely related to critical key decisions taken to improve the design and management of the event; the synergies between the political, business and sporting spheres that the organizational leadership of both races has favored their implementation and, as a consequence, the support received from sponsors. This factor has not only provided both races with financial stability, but it has also contributed to improving how both marathons are managed.
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Show abstract
... For example, Gallman et al. 39 analyzed the results of the top ten elite athletes, whereas we analyzed all successful finishers of adult age group categories. In many studies on performance trends in marathon races, a phenomenon was observed that "the faster get faster and the slower get slower"
[40]
[41][42][43] . It is important to note that we analyzed data from multiple races, with differences in drafting rules, weather conditions, and track specifications, and not one specific race over a period of time, what may have impacted the results. ...
This study aims to investigate vegetarian and mixed diet type prevalences among distance runners at running events around the world and associations with running-related patterns and performance. Following a cross-sectional approach, linear regression analyses were carried out to identify potential associations among body mass index (BMI), diet type, and average best performance times of half-marathon and marathon events for males and females. From a sample of 3835 runners who completed an online questionnaire, 2864 all-distance runners (age: 37 years; 57% females) were included in inferential analyses and categorized into dietary subgroups according to self-reports: 994 vegans (34.7%), 598 vegetarians (20.9%), and 1272 omnivores (44.4%). Significant associations were identified between kind of diet and best average time to finish (i) half-marathons in females where vegans (p = 0.001) took longer than omnivores, (ii) half-marathons in males where vegans (p < 0.001) and vegetarians (p = 0.002) took longer than omnivores, and (iii) marathons in males where vegans (p < 0.001) and vegetarians (p = 0.043) averaged slower than omnivores. Increased units of BMI (+1.0) in males influenced best runtimes: 2.75 (3.22–2.27) min slower for HM and 5.5 (5.69–4.31) min slower for M. The present study did not take detailed confounders into account such as runner motives or training behaviors; however, the results may provide valuable insight for running event organizers, nutrition experts, coaches, and trainers advising runners who adhere to a general diet type regarding the basic question of who participates in running events around the world.
Importance:
Higher amounts of physical activity are associated with increased longevity. However, whether different leisure time physical activity types are differentially associated with mortality risk is not established.
Objectives:
To examine whether participation in equivalent amounts of physical activity (7.5 to <15 metabolic equivalent of task [MET] hours per week) through different activity types is associated with mortality risk and to investigate the shape of the dose-response association.
Design, setting, and participants:
Participants in this cohort were respondents from the National Institutes of Health-AARP Diet and Health Study who completed the follow-up questionnaire between 2004 and 2005. This questionnaire collected data on weekly durations of different types of physical activities. Mortality was ascertained through December 31, 2019.
Exposures:
MET hours per week spent participating in the following activities: running, cycling, swimming, other aerobic exercise, racquet sports, golf, and walking for exercise.
Main outcomes and measures:
All-cause, cardiovascular, and cancer mortality. Separate multivariable-adjusted Cox proportional hazards regression models were fitted to estimate hazard ratios (HRs) and 95% CIs of mortality for each of the 7 types of leisure time physical activities, as well as the sum of these activities.
Results:
A total of 272 550 participants (157 415 men [58%]; mean [SD] age at baseline, 70.5 [5.4] years [range, 59-82 years]) provided information on types of leisure time activity, and 118 153 (43%) died during a mean (SD) follow-up of 12.4 (3.9) years. In comparison with those who did not participate in each activity, 7.5 to less than 15 MET hours per week of racquet sports (HR, 0.84; 95% CI, 0.75-0.93) and running (HR, 0.85; 95% CI, 0.78-0.92) were associated with the greatest relative risk reductions for all-cause mortality, followed by walking for exercise (HR, 0.91; 95% CI, 0.89-0.93), other aerobic activity (HR, 0.93; 95% CI, 0.90-0.95), golf (HR, 0.93; 95% CI, 0.90-0.97), swimming (HR, 0.95; 95% CI, 0.92-0.98), and cycling (HR, 0.97; 95% CI, 0.95-0.99). Each activity showed a curvilinear dose-response association with mortality risk; low MET hours per week of physical activity for any given activity type were associated with a large reduction in mortality risk, with diminishing returns for each increment in activity thereafter. Associations were similar for cardiovascular and cancer mortality.
Conclusions and relevance:
This cohort study of older individuals found differences between different types of leisure time activities and mortality risk, but there were significant associations between participating in 7.5 to less than 15 MET hours per week of any activity and mortality risk.
June 2019 · International Journal of Environmental Research and Public Health
Pantelis Theo Nikolaidis
Jose Ramon Alvero Cruz
Elias Villiger
[...]
Beat Knechtle
The variation of marathon race time by age group has been used recently to model the decline of endurance with aging; however, paradigms of races (i.e. marathon running) mostly from USA have been examined so far. Therefore, the aim of the present study was to examine the age of peak performance (APP) in a European race, the ‘Berlin Marathon’. Race times of 387,222 finishers (women, n=93,022; men, ... [Show full abstract] n=294,200) in this marathon race from 2008 to 2018 were examined. Men were faster by +1.10 km.h-1 (10.74±1.84 km.h-1 versus 9.64±1.46 km.h-1, p<0.001, η2=0.065, medium effect size) and older by +2.1 years (43.1±10.0 years versus 41.0±9.8 years, p<0.001, η2=0.008, trivial effect size) than women. APP was 32 years in women and 34 years in men using 1-year age groups, and 30-34 years in women and 35-39 years in men using 5-year age groups. Women’s and men’s performance at 60-64 and 55-59 age groups, respectively, corresponded to ~90% of the running speed at APP. Based on these findings, it was concluded that - although APP occurred earlier in women than men - the observed age-related differences indicated that the decline of endurance with aging might differ by sex.
Keywords: aerobic capacity; ageing; age of peak performance; exercise; gender
The “New York City Marathon”: participation and performance trends of 1.2M runners during half-centu...
March 2019 · Research in Sports Medicine An International Journal
Ambra Vitti
Pantelis Theo Nikolaidis
Elias Villiger
[...]
Beat Knechtle
The aim of the present study was to examine trends in participation, performance, age and nationality during a ~ 50-years period in the largest dataset ever studied in the “New York City Marathon”. We analysed 1,174,331 finishers (women, n= 349,145, age 39.7 ± 8.7 years; men, n= 825,186, 41.7 ± 9.2 years). The overall participation increased across calendar years for all nationalities, and this ... [Show full abstract] increase was more pronounced in women, which resulted in a decreasing men-to-women ratio. Men were faster and older than women. Ethiopians and Kenyans were the fastest and youngest in women and men, respectively. Japanese were the slowest and Germans were the oldest in both sexes. Race time increased across years. Coaches and fitness trainers should be aware of these trends and should emphasize the development of training programs for older and slower runners.
Increase in participation but decrease in performance in age group mountain marathoners in the 'Jung...
Beat Knechtle
Thomas Johannes Rosemann
Christoph Alexander Rüst
Matthias Alexander Zingg
Participation and performance trends for age group marathoners have been investigated for large city marathons such as the 'New York City Marathon' but not for mountain marathons. This study investigated participation and trends in performance and sex difference in the mountain marathon 'Jungfrau Marathon' held in Switzerland from 2000 to 2014 using single and mixed effects regression analyses. ... [Show full abstract] Results were compared to a city marathon (Lausanne Marathon) also held in Switzerland during the same period. Sex difference was calculated using the equation ([race time in women] - [race time in men]/[race time in men] × 100). Changes in sex differences across calendar years and were investigated using linear regression models. In 'Jungfrau Marathon', participation in all female and male age groups increased with exception of women in age groups 18-24 and men in age groups 30-34, 40-44 and 60-64 years where participation remained unchanged. In 'Lausanne Marathon', participation increased in women in age groups 30-34 to 40-44 years. In men, participation increased in age groups 25-29 to 44-44 years and 50-54 years. In 'Jungfrau Marathon' runners became slower across years in age groups 18-24 to 70-74 years. In 'Lausanne Marathon', runners became slower across years in age groups 18-24 and 30-34 to 65-69 years, but not for 25-29, 70-74 and 75-79 years. In 'Jungfrau Marathon', sex difference increased in age groups 25-29 (from 4 to 10 %) and 60-64 years (from 3 to 8 %) but decreased in age group 40-44 years (from 12 to 6 %). In 'Lausanne Marathon', the sex difference showed no changes. In summary, participation increased in most female and male age groups but performance decreased in most age groups for both the mountain marathon 'Jungfrau Marathon' and the city marathon 'Lausanne Marathon'. The sex differences were lower in the 'Jungfrau Marathon' (~6-7 %) compared to the 'Lausanne Marathon' where the sex difference was ~10-12 % from age groups 18-24 to 55-59 years. These unexpected findings might be a typical Swiss phenomenon. Future studies need to investigate whether this trend can also be found in other endurance sports events held in Switzerland and other mountain marathons held in other countries.
Article
Full-text available
Elite Marathoners Run Faster With Increasing Temperatures in Berlin Marathon
July 2021 · Frontiers in Physiology
Beat Knechtle
Elias Villiger
Pantelis Theo Nikolaidis
[...]
David Valero
The influence of environmental conditions has been investigated for different marathon races, but not for the Berlin Marathon, the fastest marathon race course in the world. The aim of this study was to investigate the potential influence of environmental conditions such as temperature, precipitation, sunshine, and atmospheric pressure on marathon race times in the Berlin Marathon since its first ... [Show full abstract] event in 1974–2019. A total of n = 882,540 valid finisher records were available for analysis, of which 724,135 correspond to male and 158,405 to female runners. We performed analyses regarding performance levels considering all finishers, the top 3, the top 10, and the top 100 women and men. Within the 46 years of Berlin marathons under study, there was some level of precipitation for 18 years, and 28 years without any rain. Sunshine was predominant in 25 of the events, whilst in the other 21, cloud cover was predominant. There was no significant trend with time in any of the weather variables (e.g., no increase in temperature across the years). Overall runners became slower with increasing temperature and sunshine duration, however, elite runners (i.e., top 3 and top 10) seemed to run faster and improved their race times when the temperature increased (with women improving more than men). Top 10 women seemed to benefit more from increasing temperatures than top 10 males, and male top 100 runners seemed to benefit more from increasing temperatures than female top 100 runners. In the top three sub-group, no differences were observed between male and female correlations. In summary, in marathoners competing in the Berlin Marathon between 1974 and 2019, increasing temperatures and sunshine duration showed a different effect on different performance levels where overall runners (i.e., the general mass of runners) became slower with increasing temperature and sunshine duration, but elite runners (i.e., top 3, top 10) became faster with increasing temperatures where sex differences exist.
| https://www.researchgate.net/publication/352789042_Increased_Participation_and_Decreased_Performance_in_Recreational_Master_Athletes_in_Berlin_Marathon_1974-2019 |
Nanomaterials | Free Full-Text | Tunable Terahertz Wavefront Modulation Based on Phase Change Materials Embedded in Metasurface
In the past decades, metasurfaces have shown their extraordinary abilities on manipulating the wavefront of electromagnetic wave. Based on the ability, various kinds of metasurfaces are designed to realize new functional metadevices based on wavefront manipulations, such as anomalous beam steering, focus metalens, vortex beams generator, and holographic imaging. However, most of the previously proposed designs based on metasurfaces are fixed once design, which is limited for applications where light modulation needs to be tunable. In this paper, we proposed a design for THz tunable wavefront manipulation achieved by the combination of plasmonic metasurface and phase change materials (PCMs) in THz region. Here, we designed a metal-insulator-metal (MIM) metasurface with the typical C-shape split ring resonator (CSRR), whose polarization conversion efficiency is nearly 90% for circular polarized light (CPL) in the range of 0.95~1.15 THz when PCM is in the amorphous state, but the conversion efficiency turns to less than 10% in the same frequency range when PCM switches into the crystalline state. Then, benefiting from the high polarization conversion contrast of unit cell, we can achieve tunable wavefront manipulation by utilizing the Pancharatnam–Berry (PB) phase between the amorphous and crystalline states. As a proof-of-concept, the reflective tunable anomalous beam deflector and focusing metalens are designed and characterized, and the results further verify their capability for tunable wavefront manipulation in THz range. It is believed that the design in our work may pave the way toward the tunable wavefront manipulation of THz waves and is potential for dynamic tunable THz devices.
Background:
Tunable Terahertz Wavefront Modulation Based on Phase Change Materials Embedded in Metasurface
by Ming Zhang , Peng Dong , Yu Wang , Baozhu Wang , Lin Yang , Ruihong Wu , Weimin Hou * and Junyao Zhang
School of Information Science and Engineering, Hebei University of Science and Technology, Shijiazhuang 050018, China
Author to whom correspondence should be addressed.
Nanomaterials 2022 , 12 (20), 3592; https://doi.org/10.3390/nano12203592
Received: 3 September 2022 / Revised: 26 September 2022 / Accepted: 10 October 2022 / Published: 13 October 2022
(This article belongs to the Section Nanophotonics Materials and Devices )
Abstract
:
In the past decades, metasurfaces have shown their extraordinary abilities on manipulating the wavefront of electromagnetic wave. Based on the ability, various kinds of metasurfaces are designed to realize new functional metadevices based on wavefront manipulations, such as anomalous beam steering, focus metalens, vortex beams generator, and holographic imaging. However, most of the previously proposed designs based on metasurfaces are fixed once design, which is limited for applications where light modulation needs to be tunable. In this paper, we proposed a design for THz tunable wavefront manipulation achieved by the combination of plasmonic metasurface and phase change materials (PCMs) in THz region. Here, we designed a metal-insulator-metal (MIM) metasurface with the typical C-shape split ring resonator (CSRR), whose polarization conversion efficiency is nearly 90% for circular polarized light (CPL) in the range of 0.95~1.15 THz when PCM is in the amorphous state, but the conversion efficiency turns to less than 10% in the same frequency range when PCM switches into the crystalline state. Then, benefiting from the high polarization conversion contrast of unit cell, we can achieve tunable wavefront manipulation by utilizing the Pancharatnam–Berry (PB) phase between the amorphous and crystalline states. As a proof-of-concept, the reflective tunable anomalous beam deflector and focusing metalens are designed and characterized, and the results further verify their capability for tunable wavefront manipulation in THz range. It is believed that the design in our work may pave the way toward the tunable wavefront manipulation of THz waves and is potential for dynamic tunable THz devices.
Keywords:
metasurfaces
;
terahertz (THz) region
;
Graphical Abstract
1. Introduction
Metasurfaces, artificially designed two-dimensional metamaterials [ 1 ], can flexibly manipulate the wavefront of beam to change the propagation of beam [ 2 ]. Therefore, the metasurfaces have been widely investigated and developed in wavefront modulation devices, such as anomalous beam deflection [ 3 ], light focusing [ 4 ], vortex beams generator [ 5 ], holographic imaging [ 6 , 7 , 8 ], and polarization conversion [ 9 ]. Compared with the three-dimensional metamaterials, the metasurfaces are composed of planar meta-atoms with specific electromagnetic response in a certain order, which has less thickness, lower ohmic losses, simpler design and manufacturing process. Through the interaction between electromagnetic waves and meta-atoms, metasurfaces can fully utilize and manipulate the abrupt phase changes of beam to control wavefront [ 10 ]. These characteristics grant metasurfaces many great potential applications. With continuous in-depth research of terahertz technology, various metasurface devices that manipulate THz wavefronts have been increasingly proposed [ 11 , 12 , 13 ]. However, the functions and capabilities of the most metasurfaces are fixed when their design is complete, and thus, they are difficult to apply in fickle situations and not suitable for applications that needs tunable wavefront manipulation [ 14 ].
In recent years, metasurfaces combined with phase change materials (PCMs) to achieve dynamic photonic devices have become a research hotspot [ 15 , 16 ]. Phase change material (PCM) is a promising and earth-abundant alternative to the next-generation nonvolatile optical devices, offering a new avenue to realize tunable wavefront manipulation. GeSbTe (GST) alloys as typical phase change materials have been used for many years in optical disk storage [ 17 , 18 ] and have been introduced to reconfigurable photonic devices recently. Compared to phase change material VO 2 [ 19 ], GST [ 20 ] has greater advantages in stability, conversion rate [ 21 ], and non-volatility [ 22 ]. GST can be converted between two states (usually amorphous and crystalline state) or the intermediate states by external excitation (such as thermal [ 23 ], electrical [ 24 ], and optical excitation [ 25 ]). The transformation of PCMs between the amorphous and crystalline states will bring significant difference in optical and electrical properties. In addition, the GST exhibits high refractive index and contrast and lower absorption loss in THz region [ 21 , 26 , 27 ], which enables it to be integrated into THz devices to achieve tunable functions. GST alloys are ideal materials for switchable or reconfigurable devices, such as thermal emitters [ 28 ], Fresnel zone plates [ 29 ], and absorbers [ 30 ]. Furthermore, several works [ 31 , 32 , 33 ] have shown great potential of GST in dynamic wavefront manipulation. Among them, PCMs are integrated in THz switchable metalens, optical vortex generators and beam steering verified tunable wavefront manipulation [ 34 , 35 ], and experimental verifications were carried out. However, the designs of terahertz tunable metasurfaces are complex [ 36 ] and difficult to extend to other types of photonic devices, which hinders the further development of THz tunable metadevices.
In this work, the phase change material GST was embedded into the plasmonic metasurface to realize tunable wavefront manipulation of THz waves. The design in our work is technically challenging as it requires high contrast of polarization conversion between two states. We utilized the genetic algorithm (GA) to optimize the geometric parameters of the unit cell and to obtain high contrast response in two states. The design was a metal-insulator-metal (MIM) configuration with the typical C-shape split ring resonator (CSRR). The unit cell shows high circular polarization conversion efficiency near 90% at amorphous state but low conversion efficiency less than 10% at crystalline state at a frequency of 0.95~1.15 THz. To verify the capability of the proposed design for tunable wavefront manipulation, we designed tunable anomalous beam deflector and focusing metalens by rigorously arranging unit cell with PB phase. In amorphous state, these two metadevices can deflect and focus THz beams with high efficiency. However, in crystalline state, the metadevices act as conventional reflective mirrors. Furthermore, both metadevices show broadband characteristics. It is believed that the tunable metasurface will be further developed in the field of THz beam manipulation.
2. Design and Methods
The split-ring resonator is a kind of magnetic metamaterial. In 1981, Hardy described the magnetic split-ring resonance of a hollow cylinder with a linear notch at about 1 GHz [
37
]. Metal ring is equivalent to the inductance to produce an induced electromagnetic field in a variable magnetic field perpendicular to it, and the gap of split-ring regarded as capacitance is introduced to produce resonance. Therefore, the incident changing electric field forms magnetic field polarization on the metal ring, which causes induced circulation on the metal ring, and the charge accumulates at a gap between both ends, so that the electric field energy is accumulated at the ring. Now, this design is used as a prototype of many metadevice units in metasurface research.
The schematic diagram of the metasurface for tunable wavefront manipulation is shown in
Figure 1
. The unit cell is a metal-insulator-metal (MIM) configuration with CSRR. The materials of the top-layer CSRR array and bottom metal reflective ground are pure copper, and the intermediate dielectric layer is phase change material GST. In addition, the bottom metal reflection plate plays a role in reflecting the transmitted light, and the GST dielectric layer plays a role in regulating the dielectric constant to change the electromagnetic response of the metasurface. According to the different lattice state (crystalline and amorphous state) of the GST, metasurface can exhibit different electromagnetic response (cross-polarization or co-polarization reflection) for the circular polarization light (CPL).
For such an anisotropic unit cell, if left-handed or right-handed circular polarization light
E
/
L
is incident to metasurface from −
z
direction, the scattering light
E
S
R
/
L
can be described as [
38
].
E
S
R
/
L
=
t
o
e
2
E
/
o
−
t
e
2
exp
(
∓
i
2
φ
)
L
/
R
(1)
The first term in Formula (1) represents the transmitted light having the same handedness as the incident light, and the second term represents the scattering light having the opposite handedness with respect to the incident light and attaching a Pancharatnam- Berry (PB) phase of ∓2
φ
(“−“ for right-handed and “+” for left-handed circularly polarized incident light), where
t
o
and
t
e
are the coefficients of incident linearly polarized light along the long axis and short axis of anisotropic structure, respectively [
2
]. Benefitting from the significant differences of dielectric constant of GST in two states, we can control the
t
o
and
t
e
to make the scattering light only have the cross-polarized or co-polarized part by adjusting the geometric parameters of unit cell. As illustrated in
Figure 1
, when GST is in amorphous state, the incident left-handed or right-handed circular polarization light is converted to its cross polarization by metasurface. Meanwhile, scattering light will produce an additional abrupt phase, and the value of the phase is a function of the rotation angle
φ
of the CSRR. When GST is in crystalline state, the handedness of scattering light is the same as incident circular polarized light. When the CSRR rotates from 0 to π, the phase can be tuned from 0 to 2π for the opposite handedness. Moreover, the geometrical shape of each unit cell remains essentially unchanged, only changing the rotate angle
φ
with respect to the
x
-axis, so the transmission amplitude remains almost unchanged. Based on this characteristic, phase is adjusted according to different rotation angles of the CSRR, so as to manipulate the wavefront of THz waves. Meanwhile, by adjusting the lattice state of GST, one designed metasurface can achieve two functions.
The real and imaginary part of permittivity of GST in amorphous state and crystalline state are shown in
Figure 2
a. The permittivity is fitted to the range of 0.1~2 THz from the measured data of visible light and infrared by CST 2018 software (CST, Germany) utilizing enough measurements, and the result is consistent with the previous papers [
39
,
40
]. Meanwhile, the measurement values were measured by spectroscopic ellipsometer (SENTECH SE850 and SENDIRA) in visible and infrared bands [
41
]. In the wide frequency region, we can see that the real part of the permittivity of GST shows significant difference between amorphous and crystalline states. The imaginary part of the permittivity in both states is close to 0, reflecting excellent feature of low absorption loss of GST, which is vital for metadevices with high efficiency. The material of pure copper was loaded from the library, whose electric conductivity is 5.96 × 10
7
s/m. Periodic boundary conditions were applied in the
x
and
y
directions while perfectly matched layer boundary condition was used in the
z
direction.
Numerical simulations are performed using the finite element method (FEM) in a commercial software package CST Microwave Studio 2018. Meanwhile, we used genetic algorithm to optimize the geometric parameters of the unit cell and to obtain the flat response with frequency and 2π phase shift. By optimizing the geometric parameters, the unit cell can realize different polarization conversion between amorphous and crystalline states. The main operators of genetic algorithm are selection, crossover, and mutation and genetic algorithm is also widely used in optimization, planning, design, etc. Although CST Microwave Studio (CST) software has its own genetic algorithm optimization function, it is found that its function is relatively fixed and lacks flexibility through our attempts, and it is not convenient to process the simulation results data. Here we used the co-simulation of MATLAB R2016b software (MathWorks, USA) and CST 2018 software, which means MATLAB and CST can establish communication links. Then the genetic algorithm code program is written by MATLAB. The process of executing the program is to control CST modeling and simulation, and the simulation results data can also be accessed by MATLAB, which is automatic and efficient (more detailed setup of simulation is presented in
Appendix A
).
After the rough model of the metasurface unit cell is determined, a set of optimal parameters needs also to be simulated to determine the final unit structure. In order to avoid a lot of time and energy consumption by manual parameter setting, we use genetic algorithm to automatically optimize a set of optimal parameters, and just need to focus on the final result. Meanwhile, the optimal parameters represent the final unit structure showing high polarization conversion efficiency and wide working band-width. As is illustrated in
Figure 2
, the unit cell shows high circular polarization conversion efficiency near 90% at amorphous state but low conversion efficiency less than 10% at crystalline state in the frequency of 0.95~1.15 THz. In the initial population, each unit cell is determined by five parameters of [p, h, α, Rin, Rout] (
Figure 1
). The fitness function is shown as
F
(
X
)
=
[
w
1
,
w
2
,
w
3
,
w
4
]
∗
[
∑
i
=
1
1001
f
(
0.9
≤
x
≤
1.0
)
∑
i
=
1
1001
f
(
0.8
≤
x
<
0.9
)
∑
i
=
1
1001
f
(
0.7
≤
x
<
0.8
)
∑
i
=
1
1001
f
(
0.6
≤
x
<
0.7
)
]
X
=
{
p
,
h
,
α
,
n
,
R
u
t
,
(2)
where
f(x)
is used to judge the polarization conversion efficiency
x
represents a certain point in the dataset, and [
w
1
,
w
2
,
w
3
,
w
4
] are the weight coefficients. According to the requirement of this work, the weight coefficients are [
1
,
4
,
7
,
12
].
a, where the trend of mean fitness is incremental.
Figure 3
a shows the fitness value of the optimal individual has not changed since the 5th generation, that is, the optimal individual has been obtained in the 5th generation. After 7 generations of iterations, the stability of the optimal results is fully verified. The parameters of optimized individual are shown in
Figure 3
b and the result is [55 μm, 20 μm, 65°, 10 μm, 14 μm] [
42
].
Normally incident plane wave with left circular polarization was used to excite the metasurface. The cross-polarized and co-polarized reflectance of the scattered light under the amorphous and crystalline state were recorded, which is shown in
Figure 2
b,c. In the region of 0.95~1.15 THz, and when GST is in amorphous state, cross-polarization reflectance is nearly 90%, at the same time, co-polarization reflectance is close to 0. On the contrary, when GST is in crystalline state, cross-polarization reflectance is close to 0, and the co-polarization reflectance is more than 90%.
Figure 3
c shows the relationship of reflectance and phase shift with respect to the orientation angles. R
cross_a
and PS represent the cross-polarized reflectance and phase shift at 1.1 THz in amorphous state. We can see that when
φ
is varied, the phase shift is very consistent with the PB phase of 2
φ
, and cross-polarized reflectance in amorphous state R
cross_a
maintains high efficiency. We can also see that the unit cells keep low cross-polarized reflectance in crystalline state at same frequency from the red line of R
cross_c
. The significant difference in spectral response between the two states exhibits the capability of the designed metasurface to achieve tunable wavefront manipulation.
In addition, we calculate the polarization conversion ratio (PCR = R
cross
/(R
cross
+ R
co
)) to characterize the operating bandwidth.
Figure 4
a shows the simulated PCR of two states, in the region of 0.95~1.15 THz, respectively. PCR is more than 90% in amorphous state, even close to 100% in 0.95~1.1 THz, and less than 10% in crystalline state. So, the operating bandwidth of the tunable metasurface is 0.95~1.15 THz (defined as PCR exceeding 90% in amorphous state and below 10% in crystalline state). To further explore the physical mechanism of different responses of unit cell in GST two states, the reflective phase difference between two LP components along the
x
and
y
directions are calculated as depicted in
Figure 4
b. For a unit cell illuminated by normally incident linearly polarized light with a polarization angle of 45°, a phase difference with a slight variation in the region of 0.9
π
~1.1
π
exists, which is a requirement to convert circularly polarized light to its cross-polarization state. This result shows the operating bandwidth of 0.97~1.14 THz in amorphous state. However, the phase difference between two orthogonal components in crystalline state cannot meet the condition of polarization conversion resulting in the most deflection of co-polarization.
In order to further reveal the physical mechanism of the unit cell producing opposite electromagnetic responses in GST two states, we illustrate the instantaneous electric field distributions and surface current under normal incidence. Figure 5 a,b illustrated the opposite electromagnetic responses of the two devices under different states. In amorphous state, the designed unit cell can realize the circular polarization conversion. In crystalline state, the unit cell works as a mirror-like device. Figure 5 c,d shows the distributions of electric field E x at a resonant frequency of 1.1 THz in the xy plane, respectively. The direction of arrow represents the vibration direction of electric field vector. It is obvious that the electric fields are highly localized in the opening of the split ring in both states. The vibration direction of electric field vector rotates at the opening of the split ring in amorphous state, but in crystalline state, the electric field directions on both sides of the opening of the split ring are opposite. The different electric field distributions lead to diametrically opposite polarization conversion efficiencies in the two states. Figure 5 e,f show the distributions of surface current at a resonant frequency of 1.1 THz in the xy plane, and the direction of arrow represents the direction of surface current. In amorphous state, the surface currents have the same circulating direction along the split ring, corresponding to the symmetric resonance mode. Since the direction of the surface current in the amorphous state is the same as that on the split-ring resonator, the incident circularly polarized light will be deflected along the direction of the surface current to realize polarization conversion. But in crystalline state, the surface currents exhibit both counterclockwise and clockwise directions along the split ring, corresponding to the asymmetric resonance mode. The asymmetric resonance mode induces the magnetic resonance [ 43 , 44 ]. Therefore, the components of the incident circularly polarized light deflecting along the left and right sides of the split ring resonator will repeal by implication, and THz waves are simply specular reflected. The much larger refractive index of GST suppresses the transversal coupling. Thus, the unit cell exhibits a weak anisotropy and low polarization conversion efficiency. Based on this characteristic, the tunable wavefront manipulation can be realized by appropriately arranging the unit cell.
3. Characterization
According to the design and analysis of the above unit cell, wavefront manipulation can be achieved only by arranging the unit cell with specific requirements. Therefore, metasurfaces can be designed for various metadevices. To demonstrate the tunable wavefront manipulation, we designed and simulated two reflective tunable metadevices. The phase gradient induced by a linear change of orientation with the coordinates produces a helicity-dependent transverse wave vector. Thus, the planar anisotropic metasurface can deflect the propagation direction of THz beams under the normal right- and left-hand polarized incidence. The designed metadevice consists of periodic arrays of 15 unit cells with an incremental rotation angle of
π
/15, and the rotation is clockwise along the
x
-axis, as shown in
Figure 6
a,b. In the simulations, the two-dimensional beam deflector was periodically extended along
x
-axis and
y
-axis by setting the boundary condition as periodic. When GST is in amorphous state, the metadevice exhibits an anomalous beam deflector with design angle
θ r
, where the deflection angle
θ r
is described by the generalized Snell law [
45
,
46
]
sin
θ
r
=
λ
2
π
d
+
sin
θ
i
(3)
where
λ
is the operating wavelength,
d
is the distance between unit cells. Δ
ϕ
is the phase gradient between each unit cell, which is determined by the number of abrupt phase sampling points, so
θ r
can be manually adjusted by the number of unit cells. Here, the designed anomalous deflection angle
θ r
= 19.36°. In
Figure 6
a,b, we show the reflection intensity of the metadevice at the frequency of 1.1 THz in amorphous and crystalline states, respectively. When GST is in amorphous state, the deflection angle
θ r
is 18°, which is close to the theoretical value, and the reflection intensity is more than 80%. When GST is in crystalline state, the beam deflector is equivalent to an ordinary mirror. Thus, according to conventional deflection law, deflection angle
θ r
equals to the incident angle
θ i
(i.e.,
θ r
=
θ i
= 0°), and the reflection intensity exceeds 95%.
Figure 6
c,d show the instantaneous normalized electric field distribution under normal incidence light of left-handed circularly polarized (LCP). The results further confirmed the anomalous deflection in amorphous GST and normal specular deflection in crystalline GST of the metadevices, which also exhibits its capability of the tunable wavefront manipulation.
To demonstrate the bandwidth feature, the anomalous beam deflector was simulated under the illumination of LCP light at the frequency ranging from 0.95~1.15 THz. Normalized far-field radiation patterns in two states are presented in
Figure 7
. From
Figure 7
a, the incidence lights in the GST amorphous state are deflected anomalously at the angle of 22.57°~18.48° in the whole frequency range.
Figure 7
b shows that incidence lights in GST crystalline state are deflected in the conventional mirror in the same frequency band. These two figures show that the reflection intensity of amorphous and crystalline state is roughly more than 80% and 90% in the whole frequency range, respectively. The results further indicate the broadband characteristics of anomalous beam deflector designed by this paper and make the metadevice more convenient for application.
To further demonstrate the ability of tunable wavefront manipulation, the unit cells are arranged to construct a reflective tunable focusing metalens. The area of metalens is 1155 × 1155 μm
2
, and the focal length is set as 500 μm. To focus light correctly, the model of focusing metalens is composed of central unit cell clockwise rotation along
x
-axis and
y
-axis, respectively. The phase difference on the metadevice can be expressed as [
47
]
Φ
(
x
,
y
)
−
Φ
(
O
)
=
2
π
λ
(
x
2
2
+
f
2
−
f
)
(4)
where
Φ
(
x,y
) represents the phase distribution of the unit cells with respect to center
O
.
λ
is the operating wavelength, and
f
represents design focal length of the focusing metalens.
Figure 8
a–d show the distribution of electric field intensity on
y
= 0 μm plane and
z
= 500 μm focal plane in both GST states, respectively. When GST is in amorphous state, as shown in
Figure 8
a,b, 1.05 THz LCP light wavefront becomes spherical after the phase is manipulated and beam is reflected by focusing metalens, so most of the right-handed circularly polarized (RCP) light is focused to a point. When GST is in crystalline state, owing to when the LCP light passes through the focusing metalens, reflected light always has a certain RCP light component. Therefore, as shown in
Figure 8
c,d, RCP light also has a weak focus when it is reflected by focusing metalens. However,
Figure 8
e shows the difference of focusing intensity between amorphous and crystalline states of GST is obvious and more than 40 times contrast. This not only verifies the tunable wavefront manipulation ability of focusing metalens, but also verifies capability of the design and realizes beam focusing.
When the frequency of incident circularly polarized light changes, to make focusing metalens cover 0~2π phase, the rotation angle
φ
of unit cells should be changed, to constitute different metalens for different incidence light frequencies. In this paper, we redesign focusing metalenses for LCP light with the frequency of 1 THz, 1.1 THz, and 1.15 THz. As shown in
Figure 9
, in GST amorphous state, LCP light on these four metalenses has cross-polarization, and the spherical wavefront constituted by additional phase makes the beam to focus to a point. When GST is in crystalline state, four metalenses behave as mirror-like reflector. The results exhibit the tunable and broadband characteristics of the focusing metalens.
4. Conclusions
In this paper, the tunable wavefront manipulation of terahertz electromagnetic wave is realized via the combination of plasmonic metasurface with phase change material GST. The optimization of enabling wavefront manipulation in one state and suppressing it in another state is sophisticated and require elaborate design to make a balance between the two states. The design in our work is technically challenging as it requires high contrast of polarization conversion between the two states. We utilized genetic algorithm (GA) to optimize the geometric parameters of the unit cell and to obtain the high contrast response in two states. By embedding the GST into a typical MIM structure, the CSRR shows that when GST changes from crystalline to amorphous at 0.95~1.15 THz, the cross-polarization reflectance changes from less than 10% to nearly 90%, which indicates high polarization conversion contrast and wide operating bandwidth. The same basic structure could be redesigned for other NIR and MIR spectral bands, where GST exhibits low absorption losses and high refractive index contrast. Moreover, on the basis of the proposed method, independent beam manipulation in more than two different states can be further achieved. Then, reflective tunable anomalous beam deflector and focusing metalens based on PB phase are designed to demonstrate the capability of tunable wavefront manipulation. The two metadevices show obvious contrast in EM response in amorphous and crystalline state. Moreover, the wavefront manipulation achieved by the anisotropy structure based on PB phase can be extended to apply for other types of dynamic photonic devices, such as dynamic hologram imaging and dynamic vortex beam generators. The designed metasurfaces-based devices show great advantages in THz region manipulation and solve the problems of complex design and large volume of traditional THz manipulation system. Therefore, it is believed that the design in our work may pave the way toward the tunable wavefront manipulation of THz electromagnetic waves applied in beam-steering and beam-shaping applications.
We thank Xiaoran Zhang for helping with drawing the figures.
Conflicts of Interest
The authors declare no conflict of interest.
Appendix A
Details of Simulation Set-Up
Numerical analysis of metasurfaces was carried out using the finite element method (FEM) in a commercial software package CST Microwave Studio 2018 that integrates time domain and frequency domain solver. Considering that the simulation of metasurface model takes a lot of time and the unit cell has polarization-independent characteristics, we only simulated the situation of incident LCP light. As shown in
Figure A1
a, the C-shape split ring, dielectric material GST, and metallic ground plane domains were assigned, and the rest of simulation domain is normal vacuum. The incident and reflected light enter and exit from the top Zmax port of the unit cell, and the S-parameter is distinguished by Zmax (1) and Zmax (2). Moreover, in the frequency range of 0.8~1.2 THz, the lower
z
distance and upper
z
distance of background are set as 1 μm and 500 μm, respectively. Furthermore, the
x
and
y
directions of boundary conditions are unit cell, and that of
z
direction is set as open. Since the thickness of bottom copper plate is several times thicker than the electromagnetic wave penetration depth considered in this work, the transmittance of incident light is essentially zero. Then, the Zmax port is used as the source and excitation port, and the polarization reflectance and abrupt phase change are characterized by calculating the S-parameter. The number of tetrahedrons utilizing the meshing method of surface is about 2.5 thousand (
Figure A1
b). When the tunable anomalous beam deflector and tunable focusing metalens are simulated, the boundary conditions in
z
direction are all set as open, and in
x
and
y
directions are periodic (anomalous beam deflector) or open (focusing metalens). Here, the number of grids is about 1.3 million or 6.7 million (
Figure A1
c), which takes about 30 min or 2 h of simulation time, respectively.
Figure A1. Simulation set-ups show in ( a ) the metallic ground plane, GST, C-shape split ring and vacuum domains, ( b ) the meshes used in the simulations of unit cell, and ( c ) the meshes sets in the whole tunable anomalous beam deflector and its mesh view in xoz plane.
Figure A1. Simulation set-ups show in ( a ) the metallic ground plane, GST, C-shape split ring and vacuum domains, ( b ) the meshes used in the simulations of unit cell, and ( c ) the meshes sets in the whole tunable anomalous beam deflector and its mesh view in xoz plane.
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Figure 1. The schematic diagram of the metasurface for tunable wavefront manipulation. The insets are the top view and 3D illustration of unit cell with its geometric parameters. The geometric parameters of the unit cell: period p , the thickness of GST h , the opening angle α , the rotate angle with respect to the x -axis φ = 0° initially, the inner radius R in , the outer radius R out , the thicknesses of the top-layer CSRR and the bottom metal reflector plate are 0.2 μm and 10 μm, respectively.
Figure 1. The schematic diagram of the metasurface for tunable wavefront manipulation. The insets are the top view and 3D illustration of unit cell with its geometric parameters. The geometric parameters of the unit cell: period p , the thickness of GST h , the opening angle α , the rotate angle with respect to the x -axis φ = 0° initially, the inner radius R in , the outer radius R out , the thicknesses of the top-layer CSRR and the bottom metal reflector plate are 0.2 μm and 10 μm, respectively.
Figure 2. Schematic diagram of genetic algorithm. The genetic algorithm optimizes the CSRR unit structure with high polarization conversion efficiency and wide working band-width. ( a ) The real and imaginary parts of permittivity of GST in two states, A and C represent the amorphous and crystalline states, respectively. The simulated results of cross-polarization and co-polarization reflectance in amorphous state ( b ) and crystalline state ( c ).
Figure 2. Schematic diagram of genetic algorithm. The genetic algorithm optimizes the CSRR unit structure with high polarization conversion efficiency and wide working band-width. ( a ) The real and imaginary parts of permittivity of GST in two states, A and C represent the amorphous and crystalline states, respectively. The simulated results of cross-polarization and co-polarization reflectance in amorphous state ( b ) and crystalline state ( c ).
Figure 3. ( a ) The variation of fitness value with generation in the optimization. ( b ) The values of the parameters for the best optimized individual. ( c ) Simulated cross-polarization reflectance and phase shift as a function of rotation angle φ in amorphous state and cross-polarization reflectance in crystalline state. The deep yellow line corresponds to the vertical axis on the right, and the unit with different rotation angles in the inset represent different phase shifts.
Figure 4. ( a ) The PCR with respect to the frequency in two states. ( b ) The calculated phase difference between the two orthogonal polarizations in two states (the dark yellow and grey band represent the slight variation of phase difference of π).
Figure 4. ( a ) The PCR with respect to the frequency in two states. ( b ) The calculated phase difference between the two orthogonal polarizations in two states (the dark yellow and grey band represent the slight variation of phase difference of π).
Figure 5. ( a , b ) The schematic diagram of opposite electromagnetic responses of unit cell in amorphous and crystalline states. ( c , d ) The top view of the electric field Ex distributions under the illumination of LCP in amorphous and crystalline states. The arrows represent the direction of the electric field. ( e , f ) The top view of the surface currents distributions under the illumination of LCP in amorphous and crystalline state. The arrows represent the direction of the surface current.
Figure 5. ( a , b ) The schematic diagram of opposite electromagnetic responses of unit cell in amorphous and crystalline states. ( c , d ) The top view of the electric field Ex distributions under the illumination of LCP in amorphous and crystalline states. The arrows represent the direction of the electric field. ( e , f ) The top view of the surface currents distributions under the illumination of LCP in amorphous and crystalline state. The arrows represent the direction of the surface current.
Figure 6. Simulated cross-polarization and co-polarization reflection intensity as a function of orientation angle φ in amorphous states ( a ) and crystalline states ( b ), where the insets are the simulated polar. The distributions of electric field Ex in the periodic unit cell under the illumination of LCP at the resonant wavelength of 1.1 THz in amorphous ( c ) and crystalline ( d ) states (the blue and red band represent the slight variation of phase).
Figure 6. Simulated cross-polarization and co-polarization reflection intensity as a function of orientation angle φ in amorphous states ( a ) and crystalline states ( b ), where the insets are the simulated polar. The distributions of electric field Ex in the periodic unit cell under the illumination of LCP at the resonant wavelength of 1.1 THz in amorphous ( c ) and crystalline ( d ) states (the blue and red band represent the slight variation of phase).
Figure 7. Normalized far-field radiation patterns of anomalous beam deflector when incidence light frequencies in 0.95~1.15 THz. The deflection angle and reflection intensity of the device in GST amorphous state ( a ) and crystalline state ( b ).
Figure 7. Normalized far-field radiation patterns of anomalous beam deflector when incidence light frequencies in 0.95~1.15 THz. The deflection angle and reflection intensity of the device in GST amorphous state ( a ) and crystalline state ( b ).
Figure 8. Under illumination of 1.05 THz LCP light, the sectional views of GST in amorphous ( a , b ) and crystalline ( c , d ) on focal plane z = 500 μm and plane y = 0 μm of the focusing metalens. ( e ) Electric field intensity distribution of z = 500 μm sectional view along x -axis in GST two states.
Figure 8. Under illumination of 1.05 THz LCP light, the sectional views of GST in amorphous ( a , b ) and crystalline ( c , d ) on focal plane z = 500 μm and plane y = 0 μm of the focusing metalens. ( e ) Electric field intensity distribution of z = 500 μm sectional view along x -axis in GST two states.
Figure 9. The focus situation of four reflective focusing metalenses at four frequencies in different GST states.
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Mathematics | Free Full-Text | Solving Optimization Problems Using an Extended Gradient-Based Optimizer
This paper proposes an improved method for solving diverse optimization problems called EGBO. The EGBO stands for the extended gradient-based optimizer, which improves the local search of the standard version of the gradient-based optimizer (GBO) using expanded and narrowed exploration behaviors. This improvement aims to increase the ability of the GBO to explore a wide area in the search domain for the giving problems. In this regard, the local escaping operator of the GBO is modified to apply the expanded and narrowed exploration behaviors. The effectiveness of the EGBO is evaluated using global optimization functions, namely CEC2019 and twelve benchmark feature selection datasets. The results are analyzed and compared to a set of well-known optimization methods using six performance measures, such as the fitness function’s average, minimum, maximum, and standard deviations, and the computation time. The EGBO shows promising results in terms of performance measures, solving global optimization problems, recording highlight accuracies when selecting significant features, and outperforming the compared methods and the standard version of the GBO.
Solving Optimization Problems Using an Extended Gradient-Based Optimizer
by Ahmed A. Ewees 1,2
1
College of Computing and Information Technology, University of Bisha, Bisha 61922, Saudi Arabia
2
Department of Computer, Damietta University, Damietta 34511, Egypt
Mathematics 2023 , 11 (2), 378; https://doi.org/10.3390/math11020378
Received: 10 December 2022 / Revised: 30 December 2022 / Accepted: 7 January 2023 / Published: 11 January 2023
Abstract
:
This paper proposes an improved method for solving diverse optimization problems called EGBO. The EGBO stands for the extended gradient-based optimizer, which improves the local search of the standard version of the gradient-based optimizer (GBO) using expanded and narrowed exploration behaviors. This improvement aims to increase the ability of the GBO to explore a wide area in the search domain for the giving problems. In this regard, the local escaping operator of the GBO is modified to apply the expanded and narrowed exploration behaviors. The effectiveness of the EGBO is evaluated using global optimization functions, namely CEC2019 and twelve benchmark feature selection datasets. The results are analyzed and compared to a set of well-known optimization methods using six performance measures, such as the fitness function’s average, minimum, maximum, and standard deviations, and the computation time. The EGBO shows promising results in terms of performance measures, solving global optimization problems, recording highlight accuracies when selecting significant features, and outperforming the compared methods and the standard version of the GBO.
Keywords:
feature selection
;
gradient-based optimizer
;
Lévy flight
MSC:
68T20
1. Introduction
Nowadays, data volumes are increasing daily, massively, and rapidly; data include many features and attributes, and some of these attributes may be irrelevant or redundant. However, such data should be saved, processed, and retrieved with reasonable computational time and effort. Therefore, using data processing techniques in terms of volume and compatibility is essential; one of these techniques is the feature selection strategy, which is used to select the essential sub-features. In this context, searching for the best attributes in many features is considered a challenge. Therefore, many feature selection models have been proposed to help solve that problem. For instance, the authors of [
1
] proposed a modified version of the salp swarm algorithm (SSA) called DSSA to reduce the features of different benchmark datasets; the results showed the effectiveness of the DSSA and good classification accuracy compared to the other methods. Another work was performed by the authors of [
2
]; they introduced a feature selection stage to detect facial expressions from a real dataset using the sine–cosine algorithm (SCA); their method reduced the feature number by 87%.
Furthermore, the authors of [ 3 ] applied the particle swarm optimization (PSO) and fuzzy rough set to reduce the feature set of benchmark datasets. The obtained feature sets were evaluated using the decision tree and naive Bayes classifiers; the results showed their effectiveness at evaluating the selected features. The e-Jaya optimization algorithm was also effectively utilized by the authors of [ 4 ] to select the essential features in the group of essays to grade them in less time with more accuracy. In this context, the feature selection was applied in medical applications, such as [ 5 ]; it was applied to help classify the influenza A virus cases; the results showed good performances compared to the classic methods. The whale optimization algorithm (WOA) was also applied in feature selection by the authors of [ 6 ]. In that study, the WOA was enhanced by a pooling mechanism. The performance of the enhanced WOA was evaluated using two experiments: global optimization and feature selection. It was also evaluated in detecting the coronavirus disease (COVID-19). The results showed the efficiency of the enhanced WOA in solving different problems. More applications for feature selection can be found here [ 7 , 8 , 9 , 10 , 11 ].
From this insight, this paper proposes a new method for feature selection. The proposed method, called EGBO, improves the gradient-based optimizer (GBO) using expanded and narrowed exploration behaviors of the Aquila optimizer (AO) [ 12 ]. The effectiveness of the EGBO was evaluated using seven well-known benchmark feature selection datasets and compared with some optimization algorithms.
The gradient-based optimizer is a recent optimization algorithm that was motivated by the gradient-based Newton method [ 13 ]. It has been successfully applied to several applications, such as identifying the parameters of photovoltaic systems [ 14 ]. The GBO was also applied by [ 15 ] to predict the infected, recovered, and death cases for the COVID-19 pandemic in the US. On the other hand, the aquila optimizer (AO) is a recent optimization algorithm; it simulates the hunting behaviors of the Aquila proposed by [ 12 ]. The AO was used in several applications, such as forecasting oil production [ 16 ] and forecasting China’s rural community population [ 17 ]. Furthermore, the authors of [ 18 ] applied the GBO to identify the parameters in photovoltaic models. Their method’s performance was evaluated using the single-diode, double-diode, and three-diode models as well as the photovoltaic module model. The results showed that their method obtained the best results and it was highly competitive with the compared technologies. On the same side, the authors of [ 19 ] used an improved version of the GBO, called IGBO, for parameter extraction of photovoltaic models. The IGBO used two strategies to identify the adaptive parameters: adaptive weights and chaotic behavior. The results showed competitive performance compared to the other methods. Furthermore, the GBO was also modified and called GBOSMA by the authors of [ 20 ]. They applied the slime mould algorithm (SMA) as a local search to improve the GBOSMA to explore the search space; the experimental results demonstrated the superiority of their method. In this regard, the difference between the GBOSMA and this paper can be summarized as follows; the GBOSMA uses a probability to apply the operator of the SMA, whereas this paper extends the local search operator of the GBO using the expanded and narrowed exploration behaviors of the AO algorithm.
From the above studies, the GBO was used in different applications and showed promising results; it also has some advantages, such as ease of use and not having many predefined parameters that need to be optimized. However, it may show slow convergence in some cases and can be trapped in local optima; therefore, this paper introduces a new version of the GBO called EGBO to improve the local search phase of the standard GBO method.
The rest of this paper is arranged as follows: Section 2 describes the methods and materials used in this paper. Section 3 describes the proposed method. The experiments and results are presented in Section 4 . Section 5 concludes the paper and lists future works.
2. Gradient-Based Optimizer
This section introduces a brief description of the gradient-based optimizer (GBO). The GBO is an optimization algorithm proposed by [ 13 ]. The optimization process of the GBO contains two main phases: gradient search rule (GSR) and local escaping operator (LEO). These phases are explained in the following subsections.
2.1. Gradient Search Rule (GSR)
The GSR is used to promote the GBO exploration. The following equations are applied to perform the GSR and to update the position
(
l
)
.
X
1
n
l
=
x
n
l
−
r
a
n
d
n
×
ρ
1
×
2
Δ
x
×
x
n
l
(
X
w
o
r
s
t
−
X
b
e
s
t
+
ε
)
+
r
a
n
d
×
ρ
2
×
(
X
b
e
s
t
−
x
n
l
)
ρ
1
=
2
×
r
a
n
d
×
α
−
α
(2)
α
=
|
β
×
sin
(
3
π
2
+
sin
(
β
×
3
π
2
)
)
|
(3)
β
=
β
min
+
(
β
max
−
β
min
)
×
(
1
−
(
l
L
)
3
)
2
(4)
where
β
min
=
0.20
and
β
max
=
1.20
.
l
and
L
denote the current and total iterations.
ε
is a random value
∈
[
0
,
0.1
]
.
r
a
n
d
n
denotes a normally distributed number.
ρ
2
is computed using Equation (
5
).
ρ
2
=
2
×
r
a
n
d
×
α
−
α
(5)
Δ
x
=
r
a
n
d
(
1
:
N
)
×
∣
s
t
e
p
∣
(6)
s
t
e
p
=
(
X
b
e
s
t
−
x
r
1
l
)
+
δ
2
(7)
δ
=
2
×
r
a
n
d
×
(
|
x
r
1
l
+
x
r
2
l
+
x
r
3
l
+
x
r
4
l
4
−
x
n
l
|
)
(8)
where
r
1
,
r
2
,
r
3
,
r
4
and
r
a
n
d
denote random numbers
∈
[
1
,
N
]
. In this stage, the
X
2
n
l
is computed as in Equation (
9
).
X
2
n
l
=
X
b
e
s
t
−
r
a
n
d
n
×
ρ
1
×
2
Δ
x
×
x
n
l
(
y
p
n
l
−
y
q
n
l
+
ε
)
+
r
a
n
d
×
ρ
2
×
(
x
r
1
l
−
x
r
2
l
)
(9)
y
p
n
=
r
a
n
d
×
(
[
z
n
+
1
+
x
n
]
2
+
r
a
n
d
×
Δ
x
)
y
q
n
=
r
a
n
d
×
(
[
z
n
+
1
+
x
n
]
2
−
r
a
n
d
×
Δ
x
)
After that, the solution of the next loop
X
n
m
+
1
is computed, as in Equation (
12
) based on
X
1
n
l
and
X
2
n
l
and the current solution
X
n
l
.
X
n
m
+
1
=
r
a
×
(
r
b
×
X
1
n
l
+
(
1
−
r
b
)
×
X
2
n
l
)
+
(
1
−
r
a
)
×
X
3
n
l
(12)
X
3
n
l
=
X
n
l
−
ρ
1
×
(
X
2
n
l
−
X
1
n
l
)
2.2. Local Escaping Operator (LEO)
The LEO is applied to improve the efficiency of the GBO algorithm. This phase starts if a random number (
p
r
) exceeds
0.5
. It also uses another random number (
p
r
2
) to update the solutions using Equation (
14
) if
p
r
2
>
0.5
; otherwise, it will update the solution using Equation (
15
).
X
n
l
+
1
=
X
n
l
+
1
+
f
1
×
(
u
1
×
X
b
e
s
t
−
u
2
×
x
k
l
)
+
f
2
×
ρ
1
×
(
u
3
×
(
X
2
n
l
−
X
1
n
l
)
+
u
(
x
r
1
l
−
x
r
2
l
)
)
/
2
X
n
l
+
1
=
e
s
t
+
f
1
×
(
u
1
×
X
b
e
s
t
−
u
2
×
x
)
+
f
2
×
ρ
1
×
(
u
3
×
(
X
2
n
l
−
X
1
n
+
u
2
×
(
x
r
1
l
−
x
r
2
l
)
)
/
2
(15)
where
x
m
,
x
r
2
m
, and
x
k
m
are random solutions.
f
1
and
f
2
are random numbers.
u
1
,
u
u
3
are generated as in Equations (
16
)–(
18
).
u
1
=
{
2
×
r
a
n
d
i
f
λ
1
1
o
t
h
e
r
w
i
s
e
u
2
=
{
r
a
n
d
i
f
<
0.5
1
o
t
h
e
r
w
i
s
e
(17)
u
3
=
{
r
a
n
d
i
f
λ
1
<
0.5
1
o
t
h
e
r
w
i
s
e
(18)
where
r
a
n
d
and
λ
1
are generated randomly
∈
[
0
,
1
]
.
x
k
l
in computed as in Equation (
19
).
x
k
l
=
L
2
×
x
p
l
+
(
1
−
L
2
)
×
x
r
a
n
d
(19)
where
L
2
is a binary variable generated randomly. Algorithm 1 shows the structure of the GBO.
Algorithm 1 Gradient-based optimizer. 1: Define the global parameters L , N , and D , as well as the initial population, X . 2: Compute the fitness function for population X . 3: Select the best solution X b e s t m and the worst one X w o r s t m . 4: Start the main optimization process. 5: for l =1 to L do 6: for n = 1: N do 7: for i = 1: D do 8: Generate the random variables to apply GSR. 9: Update the current position using the GSR phase. 10: end for 11: Generate the random variables to apply LEO. 12: if r a n d ( ) < 0.5 then 13: Update the current position using the LEO phase. 14: end if 15: Update the best and worst positions. 16: end for 17: end for 18: Return the best result.
3. Proposed Method
This section explains the structure of the proposed EGBO method. The EGBO aims to improve the exploration phase of the standard GBO by using Lévy flight as well as the expanded and narrowed exploration behaviors of the AO algorithm [ 12 ]. In this regard, the local escaping operator of the GBO is extended to include the expanded and narrowed exploration behaviors. This modification adds more flexibility and reliability to the GBO to explore different hidden areas in the search space, reflecting on effectively reaching the optimal point.
The EGBO starts by generating its population as in Equation (
20
), then evaluates it to determine the best solutions.
X
=
r
(
N
,
D
)
×
(
l
b
−
u
b
)
+
l
b
(20)
where
N
and
D
denote the population size and dimension, respectively, of the given problem.
r
is a random function.
l
b
and
u
b
denote the lower and upper bounds.
Then, the GSR is applied to accelerate the convergence behavior. After that, the local escaping operator phase is used to maintain the current solution. In this stage, a random variable (
r
a
n
d
) is checked to run the improvement phase. This phase runs an expanded or narrowed exploration (using a random variable). Therefore, if
r
a
n
d
2
(
)
>
0.5
, run the expanded exploration; else, run the narrowed exploration.
The EGBO uses Equation (
21
) to apply the expanded exploration as follows:
X
=
X
b
e
s
t
×
(
1
−
l
L
)
+
(
X
a
−
X
b
e
s
t
)
×
r
a
n
d
(
)
(21)
where
X
b
e
s
t
denotes the best solution so far.
l
and
L
denote the current and total iterations.
X
a
is the average of the current solution, and it is calculated as:
X
a
=
1
N
(
∑
i
=
1
N
x
Furthermore, the EGBO uses Equation (
23
) to apply the narrowed exploration. It also applies the Lévy flight distribution to update the solutions as follows:
X
=
X
b
e
s
t
×
L
v
y
(
D
)
+
X
r
y
−
q
)
×
r
a
n
d
(
)
(23)
where
L
v
y
(
D
)
applies the Lévy flight distribution as in Equations (
24
) and (
25
).
X
r
is a random solution.
L
v
y
(
D
)
=
s
×
u
×
σ
(24)
σ
=
(
Γ
(
1
+
β
3
)
×
s
i
n
e
(
π
β
3
2
)
0.010
and
β
3
=
1.50
.
u
and
δ
denote random numbers ∈ [0,1].
y
and
q
are two variables that simulate the spiral shape, and they are calculated as in Equations (
26
)–(
28
), respectively.
y
=
c
o
s
(
θ
)
,
q
=
r
×
s
i
n
(
θ
)
(26)
r
=
r
U
×
d
1
,
d
1
=
1
,
2
,
⋯
,
D
(27)
θ
=
−
ω
×
+
θ
1
,
θ
1
=
3
×
π
2
(28)
where
r
0
is a random value
∈
[
0
,
10
.
U
=
0.005650
and
ω
=
0.0050
, these values are selected based on the recommendation of the AO study [
12
].
After that, the best solution is determined and saved using the fitness function. This sequence is repeated until the stop condition is reached. Finally, the best result is presented. Algorithm 2 shows the pseudo-code of the proposed EGBO method.
Algorithm 2 Pseudo-code of the proposed EGBO method.
1:
First: Define the global parameters
L
,
N
, and
D
, as well as the initial population
X
.
2:
Perform the fitness function to evaluate the population to define the best solution
X
b
e
s
t
and the worst one
X
w
o
r
s
t
.
3:
Second: Start the main processing.
4:
for
l
=
1
do
5:
for
n
=
1
:
N
do
6:
for
i
=
1
:
D
do
7:
Generate random variables.
8:
Update the current position using the GSR phase.
9:
end for
10:
Start the LEO phase
11:
if
r
a
n
d
<
0.5
then
12:
Compute the solution using the LEO phase.
13:
if
r
a
n
d
<
0.5
then
14:
if
r
a
n
d
<
0.5
then
15:
Apply the expanded exploration.
16:
else
17:
Apply the narrowed exploration.
18:
end if
19:
end if
20:
end if
21:
Update the best and worst positions.
22:
end for
23:
end for
24:
Return the best result.
4. Experiment and Results
In this section, the proposed EGBO is evaluated in two experiments; the first is global optimization, and the second is feature selection. All results of the proposed EGBO are compared to six algorithms: GBO, particle swarm optimization (PSO) [ 21 ], genetic algorithms (GA) [ 22 ], differential evolution (DE) [ 23 ], dragonfly algorithm (DA) [ 24 ], and moth-flame optimization (MFO) [ 25 ]. These algorithms are selected because they have shown stability and good results in the literature. They have different behaviors in exploring the search space; for instance, the PSO uses the particle’s position and velocity, whereas the GA uses three phases: selection, crossover, and mutation.
The parameters of all algorithms were set as mentioned in their original paper, whereas the global parameters were as follows: the search agents’ numbers = 25 and the maximum iteration number = 100. The number of the fitness function evaluation is set to 2500 as a stop condition, and each algorithm is applied with 30 independent runs.
4.1. First Experiment: Solving Global Optimization Problem
In this section, the proposed EGBO method is assessed using CEC2019 [ 26 ] benchmark functions to solve global optimization functions and the results are compared to some well-known algorithms. This experiment aims to evaluate the proposed EGBO in solving different types of test functions.
The comparison is performed using a set of performance measures: the mean (Equation (
29
)), min, max, and standard deviations (Equation (
30
)) of the fitness functions, and the computation times for all algorithms. All experimental results are listed in
Table 1
,
Table 2
,
Table 3
,
Table 4
and
Table 5
.
m
e
a
n
=
1
N
∑
i
=
1
N
(
f
i
)
(29)
S
t
1
N
∑
i
=
1
N
(
f
i
−
f
^
)
2
(30)
where
f
is the produced fitness value and
f
^
denotes the mean value of
f
.
N
indicates the size of the sample.
Table 1 tabulates the results of the mean of the fitness function measure. In that table, the proposed EGBO outperformed the other methods in six out of ten functions (i.e., F1–F5, F9); therefore, it was ranked first. The GA was ranked second by obtaining the best values in two functions, F7 and F8. The GBO came in the third rank with the best values in three functions, F1–F3, followed by the MFO. The rest of the algorithms were ordered: the AO, DE, DA, and PSO, respectively. Figure 1 illustrates the average fitness function values for all methods over all functions.
The results of the standard deviation measure are reported in Table 2 to show the stability of each method. In this measure, the smallest value indicates good stability behavior within the independent runs. The results show that the proposed EGBO showed the best stability in 70% of the functions compared to the other methods followed by the DE and GBO. The GA, AO, and MFO came in the fourth, fifth, and sixth ranks.
The results of the max measure are listed in Table 3 . In this table, the worst value of each algorithm for each function is recorded. As seen in the table, the worst values of the proposed EGBO were better than the compared methods in six out of ten functions (i.e., F1–F3, F5, and F8–F9). The GA was ranked second by obtaining the best values in both F6 and F10. The MFO and GBO came in the third and fourth ranks, followed by the DE and AO.
Furthermore, the results of the min measure are presented in Table 4 . In this measure, the best values so far obtained by each algorithm are recorded. As seen in the results, the proposed EGBO obtained the best values in four out of ten functions (i.e., F1, F2, F5, and F9) and obtained good results in the rest of the functions. The GA ranked second by obtaining the minimum values in F4 and F8 functions. The GBO came in third, followed by the MFO, DA, D, PSO, and AO.
The computation time is also considered in Table 5 . In this measure, the MFO algorithm was the fastest among all methods, followed by the PSO and AO. The EGBO consumed an acceptable computation time in each function and was ranked fourth, followed by GBO, GA, and DE. The slower algorithm was the DA; it recorded the longest computation time in each function. Figure 2 illustrates the average computation times for all methods over all functions.
Moreover, Figure 3 illustrates the convergence curves for all methods during the optimization process. From this figure, it can be seen that the proposed EGBO can effectively maintain the populations to converge toward the optimal value as shown in F1, F4, F5, and F9. The PSO, GBO, and MFO also showed second-best convergence. In contrast, the DA algorithm showed the worst convergence in most functions.
Furthermore, Table 6 records the Wilcoxon rank-sum test as a statistical test to check if there is a statistical difference between the EGBO and the compared algorithms at a p -value < 0.05. The results, as recorded in Table 6 , show significant differences between the proposed EGBO and the compared algorithms, especially with MFO, DA, DE, and AO, which indicates the effectiveness of the EGBO in solving global optimization problems.
In light of the above results, the proposed EGBO method can effectively solve global optimization problems and provide promising results compared to the other methods. Therefore, in the next section, it will be evaluated in solving different feature selection problems.
4.2. Second Experiment: Solving Feature Selection Problem
In this part, the proposed EGBO method is assessed in solving different feature selection problems using twelve well-known feature selection datasets from [ 27 ]; Table 7 lists their descriptions.
The performance of the proposed method is evaluated by five measures, namely fitness value (Equation (
31
)), accuracy (Acc) as in Equation (
32
), standard deviation (Std) as in Equation (
30
), number of selected features, and the computation time for each algorithm. The results are recorded in
Table 8
,
Table 9
,
Table 10
,
Table 11
,
Table 12
and
Table 13
.
f
(
x
i
(
t
)
)
=
ξ
E
x
t
−
ξ
c
C
)
,
where
E
x
i
(
t
)
∈
[
0
,
1
]
is used to balance the number of the selected features and the classification error.
c
and
C
are the current and ’all-feature’ numbers, respectively.
A
c
c
u
r
a
c
y
(
A
T
P
1
T
N
T
P
1
T
N
F
P
1
where the number of positive classes correctly classified is (
T
P
1
), whereas the number of negative classes correctly classified is (
T
N
1
). Both
F
P
1
and
F
N
1
are the numbers of positive and negative classes incorrectly classified, respectively.
Table 8 shows the results of the fitness function values for all algorithms over all datasets. These results indicate that the proposed EGBO obtained the best fitness value among the compared algorithms and performed well in all datasets. The DE obtained the second-best results in 75% of the datasets. The PSO came in third, followed by GBO, GA, DA, AO, and MFO. Figure 4 illustrates the average of this measure over all datasets, which shows that the EGBO obtained the smallest average among all methods.
The stability results of all algorithms are listed in Table 9 . As in that table, the proposed EGBO showed the most stable algorithm in 7 out of 12 datasets: glass, tic-tac-toe, waveform, clean1data, SPECT, Zoo, and heart. The GA and DE ranked second and third for stability, respectively, followed by PSO, DA, and GBO.
reports the number of selected features in each dataset. From
Table 10
, we can see that the EGBO chose the smallest number of features in 9 out of 12 datasets and showed good performance in the remaining datasets. The GBO was ranked second, followed by MFO, AO, DE, PSO, and GA. In this regard, the small number of features is sometimes the best; therefore, we used the classification accuracy measure to evaluate the obtained feature by each algorithm.
Consequently, the classification accuracy measure was used to evaluate the proposed method’s ability to classify the samples of each dataset correctly. The results of this measure were recorded in Table 11 . This table shows that the EGBO ranked first; it outperformed the other methods and obtained high-accuracy results in all datasets. The DE came in the second rank, whereas the PSO obtained the third, followed by the GBO, GA, DA, and AO. In contrast, the MFO recorded the worst accuracy measures in most datasets.
The computation times for all methods were also measured. Table 12 records the time consumed by each algorithm. By analyzing the results, we can note that all algorithms consumed similar times to some extent. In detail, the EGBO was the fastest in 59% of the datasets, followed by PSO, MFO, DE, GBO, and DA, respectively, whereas the GA and AO recorded the longest computation time.
Furthermore, an example of the convergence curves for all methods is illustrated in Figure 5 . In this figure, a sample of the datasets is presented, which shows that the proposed EGBO method converged to the optimal values faster than the compared algorithms, which indicates the good convergence behaviors of the EGBO when solving feature selection problems.
In addition, Table 13 shows the Wilcoxon rank-sum test as a statistical test to check if there is a statistical difference between the proposed method and the other algorithms at a p -value < 0.05. From this table, we can see that there are significant differences between the proposed methods and the other algorithms in most datasets, indicating the EGBO’s effectiveness in solving different feature selection problems.
From the previous results, the proposed EGBO method outperformed the compared algorithms in most cases in solving global optimization problems and selecting the most relative features. These promising results can be attributed to a few reasons, e.g., the local escaping operator of the GBO was extended to include the expanded and narrowed exploration behavior, which added more flexibility and reliability to the traditional GBO algorithm. This extension increased the ability of the GBO to explore more areas in the search space, reflecting on effectively reaching the optimal point. On the other hand, although the EGBO obtained good results in most cases, it failed to show the best results in the computation time measure, namely in the global optimization experiment. This defect can be due to the traditional GBO consuming a relatively longer time than the compared algorithm when performing an optimization task. Therefore, this defect can be studied in future work. Generally, the exploration behaviors used in the EGBO increased the performance of the traditional algorithm in terms of performance measures.
5. Conclusions
This paper proposed a new version of the gradient-based optimizer (GBO), called EGBO, to solve diverse optimization problems, namely global optimization and feature selection. The local search of the EGBO was improved and expanded using expanded and narrowed exploration behaviors to increase the ability of the GBO to explore broad areas in the search space. The effectiveness of the EGBO was checked and evaluated using CEC2019 as global optimization functions and twelve benchmark feature selection datasets. The results were analyzed and compared to a set of well-known optimization algorithms using six performance measures. The EGBO showed promising results in solving global optimization problems, recording the highlight accuracy, selecting the most significant features, and outperforming the compared methods and the traditional version of the GBO in terms of performance measures. However, the computation time of the EGBO needs to be improved. In future works, the EGBO will be evaluated and applied in parameter estimation, image segmentation, and classifier optimization. In addition, the complexity of the EGBO will be maintained, and its initial population will be improved using chaotic maps to add more diversity to the search space.
Funding
This research received no external funding.
Data Availability Statement
The data presented in this study are openly available in [ 26 , 27 ].
Conflicts of Interest
The author declares no conflict of interest.
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Figure 1. Average fitness function values for all methods in all functions.
Figure 1. Average fitness function values for all methods in all functions.
Figure 2. Average computation times for all methods in all functions.
Figure 2. Average computation times for all methods in all functions.
Figure 3. Convergence curves for the proposed EGBO and the compared methods.
Figure 3. Convergence curves for the proposed EGBO and the compared methods.
Figure 4. Average of the fitness function values for all methods.
Figure 4. Average of the fitness function values for all methods.
Figure 5. Example of the convergence curves for the proposed EGBO and the compared methods.
Figure 5. Example of the convergence curves for the proposed EGBO and the compared methods.
Table 1. Results of the average measure of the fitness function values.
Table 1. Results of the average measure of the fitness function values.
Table 2. Results of the Std measure of the fitness function values.
Table 2. Results of the Std measure of the fitness function values.
EGBO GBO PSO GA MFO DA DE AO F1 3.23 × 10 3 6.44 × 10 3 3.17 × 10 12 8.14 × 10 10 4.80 × 10 10 9.09 × 10 10 6.23 × 10 10 1.74 × 10 4 F2 2.79 × 10 − 5 6.89 × 10 − 5 4.73 × 10 3 2.51 × 10 1 1.77 × 10 − 2 7.29 × 10 1 5.83 × 10 − 1 8.72 × 10 − 2 F3 6.76 × 10 − 11 3.36 × 10 − 9 4.44 × 10 − 4 1.06 × 10 − 6 2.61 × 10 − 4 7.28 × 10 − 4 4.27 × 10 − 5 3.75 × 10 − 5 F4 3.73 × 10 1 6.89 × 10 1 2.54 × 10 3 8.82 × 10 1 3.16 × 10 2 7.30 × 10 2 1.34 × 10 1 1.43 × 10 3 F5 7.45 × 10 − 2 1.14 × 10 − 1 7.45 × 10 − 1 1.21 × 10 − 1 1.62 × 10 − 1 2.41 × 10 − 1 9.31 × 10 − 2 2.19 × 10 − 1 F6 8.67 × 10 − 1 5.07 × 10 − 1 9.32 × 10 − 1 1.05 × 10 0 1.60 × 10 0 1.70 × 10 0 5.43 × 10 − 1 8.56 × 10 − 1 F7 1.96 × 10 2 2.38 × 10 2 2.32 × 10 2 1.87 × 10 2 2.06 × 10 2 3.03 × 10 2 1.26 × 10 2 2.64 × 10 2 F8 3.57 × 10 − 1 6.77 × 10 − 1 8.36 × 10 − 1 7.76 × 10 − 1 6.22 × 10 − 1 6.22 × 10 − 1 3.74 × 10 − 1 5.90 × 10 − 1 F9 2.62 × 10 − 1 5.56 × 10 − 1 2.40 × 10 2 6.62 × 10 − 1 8.12 × 10 − 1 5.91 × 10 1 3.13 × 10 − 1 1.29 × 10 2 F10 6.56 × 10 − 2 1.44 × 10 − 1 1.54 × 10 − 1 7.52 × 10 − 2 1.20 × 10 − 1 1.33 × 10 − 1 6.65 × 10 − 2 1.08 × 10 − 1
Table 3. Results of the max measure of the fitness function values.
Table 3. Results of the max measure of the fitness function values.
EGBO GBO PSO GA MFO DA DE AO F1 5.23 × 10 4 6.21 × 10 4 1.70 × 10 13 3.26 × 10 11 1.97 × 10 11 4.12 × 10 11 3.05 × 10 11 1.23 × 10 5 F2 1.73 × 10 1 1.73 × 10 1 2.55 × 10 4 1.52 × 10 2 1.74 × 10 1 3.80 × 10 2 1.94 × 10 1 1.76 × 10 1 F3 1.27 × 10 1 1.27 × 10 1 1.27 × 10 1 1.27 × 10 1 1.27 × 10 1 1.27 × 10 1 1.27 × 10 1 1.27 × 10 1 F4 1.81 × 10 2 3.27 × 10 2 1.03 × 10 4 3.49 × 10 2 1.76 × 10 3 2.96 × 10 3 1.15 × 10 2 5.80 × 10 3 F5 1.29 × 10 0 1.53 × 10 0 4.68 × 10 0 1.52 × 10 0 1.81 × 10 0 2.00 × 10 0 1.73 × 10 0 2.83 × 10 0 F6 1.32 × 10 1 1.30 × 10 1 1.25 × 10 1 9.20 × 10 0 9.86 × 10 0 1.16 × 10 1 1.13 × 10 1 1.33 × 10 1 F7 8.28 × 10 2 9.41 × 10 2 9.81 × 10 2 7.85 × 10 2 7.31 × 10 2 1.37 × 10 3 8.64 × 10 2 1.22 × 10 3 F8 6.45 × 10 0 6.84 × 10 0 7.00 × 10 0 6.49 × 10 0 6.80 × 10 0 6.93 × 10 0 7.13 × 10 0 6.84 × 10 0 F9 3.62 × 10 0 4.95 × 10 0 1.08 × 10 3 5.12 × 10 0 6.12 × 10 0 2.48 × 10 2 4.02 × 10 0 5.26 × 10 2 F10 2.07 × 10 1 2.08 × 10 1 2.08 × 10 1 2.03 × 10 1 2.04 × 10 1 2.06 × 10 1 2.05 × 10 1 2.08 × 10 1
Table 4. Results of the min measure of the fitness function values.
Table 4. Results of the min measure of the fitness function values.
EGBO GBO PSO GA MFO DA DE AO F1 3.93 × 10 4 3.98 × 10 4 1.39 × 10 12 2.10 × 10 9 1.06 × 10 10 1.85 × 10 9 5.11 × 10 10 4.43 × 10 4 F2 1.73 × 10 1 1.73 × 10 1 5.12 × 10 3 1.73 × 10 1 1.73 × 10 1 1.74 × 10 1 1.76 × 10 1 1.74 × 10 1 F3 1.27 × 10 1 1.27 × 10 1 1.27 × 10 1 1.27 × 10 1 1.27 × 10 1 1.27 × 10 1 1.27 × 10 1 1.27 × 10 1 F4 2.80 × 10 1 3.53 × 10 1 6.45 × 10 2 1.80 × 10 1 5.82 × 10 1 9.83 × 10 1 5.32 × 10 1 6.61 × 10 2 F5 1.05 × 10 0 1.06 × 10 0 1.63 × 10 0 1.06 × 10 0 1.19 × 10 0 1.24 × 10 0 1.42 × 10 0 1.87 × 10 0 F6 9.57 × 10 0 1.11 × 10 1 8.87 × 10 0 5.53 × 10 0 4.40 × 10 0 5.86 × 10 0 9.14 × 10 0 9.81 × 10 0 F7 6.34 × 10 1 1.52 × 10 1 1.45 × 10 2 3.02 × 10 1 6.13 × 10 1 1.42 × 10 2 3.83 × 10 2 2.37 × 10 2 F8 5.17 × 10 0 4.51 × 10 0 3.83 × 10 0 3.61 × 10 0 4.19 × 10 0 4.00 × 10 0 5.44 × 10 0 4.77 × 10 0 F9 2.56 × 10 0 2.63 × 10 0 3.67 × 10 0 2.59 × 10 0 2.75 × 10 0 2.89 × 10 0 2.70 × 10 0 4.67 × 10 1 F10 2.05 × 10 1 2.01 × 10 1 2.03 × 10 1 2.01 × 10 1 2.00 × 10 1 2.00 × 10 1 2.03 × 10 1 2.04 × 10 1
Table 5. Results of the computation times of the fitness function values.
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PEOPLE v. ELY CABILES
GR No. 113785, (1995-09-14)
DIVISION
[ GR No. 113785, Sep 14, 1995 ]
PEOPLE v. ELY CABILES +
DECISION
318 Phil. 250
SECOND DIVISION
[ G.R. No. 113785, September 14, 1995 ]
PEOPLE OF THE PHILIPPINES, PLAINTIFF-APPELLEE, VS. ELY CABILES (AT LARGE), ACCUSED. RUDY ESPARRAGUERRA AND ROGELIO ESPARRAGUERRA, ACCUSED-APPELLANTS. D E C I S I O N
PUNO, J.:
Rudy Esparraguerra, Rogelio Esparraguerra and Ely Cabiles were charged with Robbery with Homicide before the Regional Trial Court,
[1]
Branch L, of San Jacinto, Masbate. The Information
[2]
against them, dated
October 1, 1991, reads:
"That on or about July 27, 1991, in the evening thereof, at
Barangay
Sowa, Municipality of San Fernando, Province of Masbate, Philippines, within the jurisdiction of this Honorable Court, the said accused confederating together and mutually helping one another
with intent of (sic) gain, violence and intimidation upon person, did then and there willfully, unlawfully and feloniously demand money from one Violeta Angustia y Mitra, box and then hogtied her, with intent to kill, hack (her) with a bolo hitting her neck, thereby inflicting
wound which directly caused her instantaneous death, willfully, unlawfully and feloniously take, steal and rob away cash (in the) amount of One Thousand (P1,000.00) Pesos, belonging to Violeta Angustia y Mitra, to the damage and prejudice of the latter in the amount
aforementioned.
"That apart from the aforementioned aggravating circumstances, the following also concurrently attended in the commission of the crime; that the crime was committed in an uninhabited place; that it was committed with insult or in disregard on account of her sex.
"CONTRARY TO LAW."
Only accused Rudy and Rogelio Esparraguerra were arrested. They entered a plea of "not guilty"
[3]
and underwent trial. Ely Cabiles, on the other hand, remains at large.
The victim, Violeta Angustia, was a fish vendor. At the time of the incident, she was a resident of
sitio
Sowa in San Fernando, Masbate. Her house is about 200 meters away from the
poblacion
proper of
b
arangay
Sowa. Accused Ely Cabiles and
Rogelio Esparraguerra (both accused reside in
barangay
Sowa) were her barriomates. The other accused, Rudy Esparraguerra, younger brother of Rogelio, resides in
barangay
Talisay (also in San Fernando, Masbate), which is about four (4) kilometers away from
Violeta's house in
sitio
Sowa.
In essence, the prosecution
[4]
tried to establish the following facts:
On July 27, 1991, Violeta visited her daughter, Salvacion Almoguera, at the latter's house in Buenavista, San Fernando, Masbate. Violeta borrowed P1,000.00 cash from her daughter who readily gave the money to her. That same day, Violeta was to return to her house in
sitio
Sowa. At that time, she was allegedly tipsy. Concerned with her mother's safety, Salvacion decided to accompany her mother to
sitio
Sowa.
[5]
Salvacion and Violeta left Buenavista at about 5:00 p.m. and trekked the trail leading towards Sowa. Along the way, they had to occasionally stop because Violeta was getting weak.
[6]
Soon after, it became dark. It was, however, a moonlit night.
The two women passed the
poblacion
proper of
barangay
Sowa at approximately 7:30 p.m. Suddenly, accused-appellants Rogelio and Rudy Esparraguerra and their uncle and co-accused Ely Cabiles, appeared from nowhere and blocked the trail leading to
sitio
Sowa.
Salvacion, who was only a few meters behind her mother, recognized the three (3) men. She knew all of them since childhood.
[7]
Rogelio demanded money from Violeta saying, "Give me the money." Violeta refused. Her response infuriated Rogelio. He forcibly took the money from Violeta and boxed her shoulders. She lurched. Thereafter, Ely Cabiles approached Violeta and twisted her
arms towards her back. While she was in that defenseless position, Rudy drew a
bolo
and hacked Violeta, hitting her neck (just below the chin) in the process.
[8]
Salvacion was shocked by what transpired. Initially, she thought that the accused were only joking. During the hacking incident, she stood motionless at a distance of about two (2) meters behind her mother and about five (5) meters away from Rudy. Upon seeing
the tragic fate of her mother, she came to her senses and ran back to her house in Buenavista. She immediately informed her husband of the incident. For fear that the three (3) men would harm her, Salvacion and her husband locked the doors and windows of their
house.
[9]
The news about the death of Violeta spread in
barangay
Sowa in the early morning of July 28, 1991. Soon after, people started to gather at the crime scene. Among those who came to view the victim's body was Reynaldo Capisnon, a resident of
barangay
Sowa.
Apparently, that fateful evening, at around 6:00 p.m., Reynaldo Capisnon encountered Ely Cabiles and the Esparraguerra brothers along the trail leading to
barangay
Sowa. Reynaldo was on his way home after working in his farm some 150 meters away from the crime
scene. At that time, Reynaldo was carrying a
bolo
which he used in clearing his farm. For no apparent reason, Rogelio grabbed Reynaldo's
bolo
and attempted to hack him. Fortunately, Reynaldo managed to escape. He immediately went home. He
did not inform his wife or the authorities of the incident.
[10]
The following day (July 28), at around 7:00 a.m., Reynaldo was told by his neighbors that a dead body was recovered within the vicinity of
barangay
Sowa. Thereafter, Reynaldo and his neighbors proceeded to the crime scene. When they arrived, there was a crowd at the
scene. Reynaldo viewed the victim's body. He also saw Salvacion Almoguera. She was holding a
bolo
stained with blood. Reynaldo immediately recognized the
bolo
as his because he himself made its handle and put a distinguishing mark
thereon. He asked Salvacion to give it to him for safekeeping. She agreed.
[11]
The victim's body was examined by Dr. Jesus Camposano, Rural Health Physician of Ticao District Hospital, in Masbate, on July 28, 1991. His postmortem examination revealed that the victim sustained, among others, contusion on her left shoulder and a 10-centimeter hacking
wound in her neck which caused her death.
[12]
Accused-appellants proffered the defense of denial and alibi. They claimed they were in their respective houses during the commission of the crime.
Rogelio Esparraguerra averred that he worked in the farm of Hilario Barruga from 7:00 a.m. until 4:00 p.m. of July 27, 1991. Thereafter, he went home and rested. He and his family had supper at 7:00 p.m. Rogelio claimed he did not see his younger brother Rudy
nor his uncle Ely that evening. Rogelio and his wife slept at around 9:00 p.m.
The following day, at about 7:00 a.m., Rogelio again worked at Hilario's farm. Allegedly, Hilario hired him to work in his farm from July 24, 1991, to July 28, 1991.
Rosevita Esparraguerra, wife of Rogelio, corroborated her husband's testimony. She claimed, further, that she learned of Violeta's death from her neighbors at around 8:00 a.m. of July 28, 1991. She and her neighbors went to the crime scene which was only about a
kilometer from their house. According to Rosevita, she wanted to see Violeta's body because her father and Violeta were cousins. Rosevita denied having seen Salvacion Almoguera and Reynaldo Capisnon at the crime scene. However, she admitted that she stayed
thereat only for a brief moment. She went home thereafter. She admitted that, prior to the incident, they never had any misunderstanding with the victim and her family.
For his part, Rudy Esparraguerra alleged that, during the hacking incident on July 27, 1991, he stayed home with his wife, Milagros, who was then four (4) months pregnant. Allegedly, she had a miscarriage that night.
Rudy alleged that, on July 27, 1991, at around 3:00 p.m., Milagros felt pain in her stomach. An hour later, she started to bleed. The bleeding became more profuse at 6:00 p.m. She then asked Rudy to fetch a
hilot (
comadrona
). He left at once and
returned home with the
hilot
, Adelina Baldeo, at around 6:30 p.m. Adelina attended to the needs of Milagros but failed to save the fetus.
That same evening, Rudy sought the help of spouses Felixberto Bartolay and Socorro Cabiles whose house is about ten (10) meters away from his house. Socorro is Rudy's mother, while Felixberto is his stepfather. Felixberto and Socorro went to Rudy's house at about 7:00
p.m.
While Adelina was attending to Milagros, Rudy, Felixberto and Socorro drank liquor. Adelina went home at 10:00 p.m. Felixberto and Socorro left an hour later.
Milagros Esparraguerra and Felixberto Bartolay corroborated Rudy's testimony.
To destroy the alibi put up by accused-appellants, the prosecution presented the testimonies of Hilario Barruga and Adelina Baldeo.
Hilario Barruga denied that Rogelio worked for him from July 24, 1991, until July 28, 1991. According to Hilario, Rogelio worked for him on July 14 and 15, 1991. Hilario allegedly encircled said calendar dates to help him remember the dates when he started planting
his crops.
For her part, Adelina Baldeo confirmed that Milagros had a miscarriage sometime in July, 1991. However, she averred that the miscarriage happened on July 5, 1991, not July 27, 1991. In support of her allegation, Adelina submitted notebook containing the information
relative to the child births she had attended to. Her testimony was corroborated by Imelda Almoguera, the supervising midwife of Adelina Baldeo.
After trial, accused-appellants were found guilty as charged by the court
a quo
. They were sentenced to
reclusion perpetua
and ordered to pay the heirs of the victim, Violeta Angustia, civil indemnity in the amount of P50,000.00.
[13]
Hence, the appeal. Accused-appellants contend that:
THE TRIAL COURT ERRED IN CONVICTING THE ACCUSED-APPELLANT DESPITE FAILURE OF THE PROSECUTION TO PROVE THEIR GUILT BEYOND REASONABLE DOUBT.
We affirm the judgment of conviction.
Salvacion Almoguera positively identified accused-appellants as the culprits. She testified as follows:
[14]
"PROSECUTOR RAPSING:
"Q: At about 5:00 (P.M.) of July 27, 1991, do you remember where you were?
"A: Yes, sir.
"Q: Where were you?
"A: I was walking with my late mother?
x x x x x x x x x
"Q: Where were you walking?
"A: Going to Sitio Sowa.
x x x x x x x x x
"Q: Of San Fernando, Masbate?
"A: Yes, sir.
"Q: You said you were walking with your mother, who is your mother please?
"A: Violeta Mitra Angustia.
"Q: While walking with your mother, do you remember of any incident that took place?
"A: Yes, sir.
x x x x x x x x x
"A: While I and my mother were walking, and upon arrival at Barangay Sowa, San Fernando, Masbate, all of a sudden this Rogelio, Rudy and Ely Cabiles appeared.
"Q: You mean Ely Cabiles, Rudy Esparraguerra and Rogelio Esparraguerra, the accused in this case?
"A: Yes, sir.
"Q: And what happened thereafter?
"A: One of the accused, Rogelio Esparraguerra, demanded the money of my mother saying, "Give me the money."
"Q: And what did your mother do upon the demand of Rogelio with your mother's money?
"A: She refused to give the money.
"Q: And what happened after that?
"A: Rogelio boxed my mother twice on both her shoulder.
"Q: What happened next?
"A: She was out balanced.
"Q: You mean, your mother, Violeta?
"A: Yes, sir.
"Q: And what happened after?
"A: Ely approached my mother and held her two hands behind her back.
"Q: What happened?
"A: Rudy pulled out his bolo and hacked my mother on her neck.
x x x x x x x x x
"Q: After your mother (was) hacked by Rudy Esparraguerra, what happened next.
"A: Upon seeing that my mother was hacked by Rudy, I ran towards our house.
"COURT:
Do you remember what part of his body was hacked?
"A: On the neck.
"Q: On the left or right?
"A: (Witness pointing to her upper throat below the chin).
x x x x x x x x
"Q: You said, Mrs. Witness, that after your mother Violeta was hacked at the neck by Rudy Esparraguerra, you ran away, where did you go?
"A: To our house at Buenavista.
"Q: Upon reaching your house, what did you do?
"A: I and my husband closed the door and the windows of our house.
x x x x x x x x x
"Q: And what happened to your mother after that?
"A: She died."
Accused-appellants, however, find the prosecution's version of the crime at bar incredible. They aver that Salvacion's allegation -- that she was with her mother during the hacking incident -- does not inspire belief because it would be unwise for them as the alleged
assailants, to leave her unharmed if, indeed, she had witnessed the incident. Further, accused-appellants fault Salvacion for her failure to report the crime to the authorities or seek help from her neighbors that same evening. Accused-appellants, therefore, insist that
Salvacion was not around at the time of the incident.
We are not persuaded.
Accused-appellants' argument hinges on the credibility of Salvacion Almoguera as an eyewitness. It is settled that the findings of the trial court on the credibility of witnesses should not be disturbed because the latter is in a better position to decide the question,
having observed the deportment of the witnesses and their manner of testifying during the trial, unless certain facts of value have been plainly overlooked which, if considered, might affect the outcome of the case.
[15]
Indeed, the trial court's assessment on whose story should be believed goes beyond what the witnesses declare at the trial a privilege which the appellate court does not usually enjoy. Absent any compelling reason to overturn the trial court's findings, the same
must be respected. We adhere to this rule, especially since the court
a quo
observed that Salvacion testified in a forthright and direct manner.
[16]
Moreover, she mentioned the minutiae of the incident, indicating her sincerity and truthfulness in
the narration of events.
[17]
The probative value of Salvacion's testimony is not diminished by her failure to report the incident to the authorities that tragic evening. What she did after the killing of her mother was an act of self-preservation. At that time, she believed that
accused-appellants had followed her. She testified thus:
[18]
"PROSECUTOR RAPSING: (continuing)
"Q: You testified, Mrs. Witness, that upon seeing Rudy hack the neck of your mother, you ran away and upon reaching your home, you and your husband closed the windows and the doors of your house, why, Mrs. Witness?
"(SALVACION):
"A: Because I thought that they were following me.
"COURT:
"Q: More or less what time was that?
"(WITNESS):
"A: More or less 8:30 o'clock (sic) in the evening."
On cross-examination,
[19]
she further testified as follows:
"ATTY. BAILON:
"Q: So we are now certain that the place of Buenavista is very much farther from the house of your mother to the place of the incident.
"(SALVACION):
"A: Yes, sir.
"Q: And you told us that when you saw the accused hack your mother, you ran to your house at Buenavista.
"A: Yes, sir.
"Q: Why did you run to your house at Buenavista which is very far, rather than (go to) the house of your mother which is very near?
"A: Because they were guarding the place?
"Q: Who were guarding the place?
"A: The three accused, Rudy, Rogelio and Ely.
"Court:
"Q: How did you know that?
"A: Because the dogs were barking.
"Q: Aside from that, why did you know that they were barking?
"A: Because I was afraid that I might be killed by them and I don't want to be killed."
We are not convinced by accused-appellants that Salvacion would falsely accuse them of a very grave offense such as the case at bar. Considering her relationship with the victim she would be more interested in securing the conviction of the guilty, and that would deter her from
implicating persons other than the culprits, otherwise, the latter would go free.
[20]
Accused-appellants' defense of alibi is not worthy of belief. We have repeatedly ruled that alibi is a weak defense as it is easy to concoct and fabricate. It becomes weaker in the face of the positive identification of an accused by an eyewitness with no improper
motive to falsely testify.
[21]
More. It is not sufficient for an accused to allege that he was away from the scene of the crime at the time of its commission. He must also present clear and convincing proof that it is physically impossible for him to be at the
locus criminis
while
the crime was in progress. That physical impossibility is not present in this case.
[22]
The records show that Rogelio's residence is about a kilometer away from the crime scene.
[23]
On the other hand, Rudy's house in
barangay
Talisay
is about four (4) kilometers away from the house of the victim in
sitio
Sowa.
[24]
As a fish vendor, Rudy peddled fish not only in Talisay but also in the other nearby
barangays
of San Fernando, Masbate, such as Buenavista and
Sowa.
[25]
Thus, it was not physically impossible for both accused-appellants to be at the crime scene and commit the crime on July 27, 1991.
Accused-appellants also argue that, as per the testimony of Salvacion Almoguera, the main motive of the assailants was to rob the victim. Thus, they suggest that whoever killed the victim must have had previous knowledge that the victim was carrying cash at the time of the
incident. In their case, no such evidence was adduced against them.
Jurisprudence tells us that the prosecution need not prove motive on the part of the accused when they have been positively identified as the perpetrators of the crime.
[26]
In robbery with homicide cases, the prosecution need only to prove these
elements:
[27]
(a) the taking of personal property with violence or intimidation against persons; (b) that the property taken belongs to another; (c) the taking be done with
animo lucrandi;
[28]
and (d) on the occasion of the
robbery or by reason thereof, homicide (used in its generic sense) was committed. These elements had been established by the prosecution when Salvacion testified in open court that accused-appellants, acting in unison, demanded money from her mother, forcibly took the same
against her will and then hacked her to death.
We now come to the allegation in the information that the aggravating circumstances of disregard of sex and uninhabited place attended the commission of the crime.
Well settled is the rule that the aggravating circumstance that the crime was committed with insult or in disregard of the respect due the offended party on account of his rank, age or sex,
[29]
may be taken into account only in crimes against persons or
honor, when in the commission of the crime, there is some insult or disrespect shown to rank, age or sex. It is not proper to consider this aggravating circumstance in crimes against property. Robbery with homicide is primarily a crime against property and not
against persons. Homicide is a mere incident of the robbery, the latter being the main purpose and object of the criminal. It is thus erroneous to take this aggravating circumstance into account in robbery with homicide.
[30]
As regards the aggravating circumstance of uninhabited place (
despoblado
), we have ruled that the term uninhabited place refers not to the distance of the nearest house to the
locus criminis
. The more important consideration is whether the place of commission
affords a reasonable possibility for the victim to receive some help.
[31]
Further, before it could be appreciated against the accused, it must be established that solitude was purposely sought or taken advantage of to facilitate the commission of the
crime.
[32]
We find that this circumstance was not satisfactorily proven in this case.
Robbery with homicide is punishable by two (2) indivisible penalties,
reclusion perpetua
to death. Since the alleged aggravating circumstances were not duly established, we agree with the court
a quo
that the lesser penalty of
reclusion perpetua
should be
imposed against accused-appellants.
[33]
IN VIEW WHEREOF
, the assailed decision of the Regional Trial Court (Branch L) of San Jacinto, Masbate, in Criminal Case 453, finding accused-appellants ROGELIO ESPARRAGUERRA AND RUDY ESPARRAGUERRA guilty beyond reasonable doubt of the crime of Robbery With Homicide, is
AFFIRMED. No costs.
SO ORDERED.
Narvasa, C.J., (Chairman), Regalado, Mendoza,
and
Francisco, JJ.,
concur.
[1]
Presided by Judge Manuel S. Pecson.
[2]
Rollo
, p. 4.
[3]
Certificate of Arraignment, dated February 4, 1992, Original Records, p. 20.
[4]
The prosecution presented the following witnesses,
viz
: Salvacion Almoguera, the lone eyewitness and daughter of the victim; Dr. Jesus Camposano; Reynaldo Capisnon; and rebuttal witnesses Adelina Baldeo, Hilario Barruga and Imelda
Almoguera.
[5]
TSN, March 3, 1992, pp. 15-19.
[6]
Ibid
.
[7]
Ibid
, p. 11.
[8]
TSN, March 3, 1992, pp. 6-7.
[9]
Ibid
, pp. 9-10, 27.
[10]
TSN, April 8, 1992, pp. 3, 9, 18; Exhibit "E".
[11]
Ibid
, pp. 11-13, 23-24.
[12]
TSN, April 7, 1992, pp. 131-141; see also Exhibit "B", Original Records, p. 64.
[13]
Original Records, pp. 358, 366.
[14]
TSN, March 3, 1992, pp. 5-9.
[15]
People
vs
. Balanag, G.R. No. 103225, September 15, 1994, 236 SCRA 474.
[16]
RTC Decision, dated February 2, 1993, p. 8.
[17]
People
v
. Bañez, G.R. No. 95456, September 18, 1992, 214 SCRA 109.
[18]
TSN, March 3, 1992, pp. 10-11.
[19]
Ibid
, pp. 26-27.
[20]
People
v
. Pugal, G.R. No. 90637, October 29, 1992, 215 SCRA 247, 262; People
v
. Hasiron, G.R. No. 100797, October 15, 1992, 214 SCRA 586, 594.
[21]
People
vs
. Javier, G.R. No. 104729, February 3, 1994, 229 SCRA 638.
[22]
People
vs
. De la Cruz, G.R. No. 102063, January 20, 1993, 217 SCRA 263, 283, 293; People
vs
. Pugal, G.R. No. 90637, October 20, 1992, 215 SCRA 247, 263.
[23]
TSN, August 4, 1992, p. 61.
[24]
Ibid
, p. 45.
[25]
Ibid
, pp. 47, 65.
[26]
People
vs
. Canceran, G.R. No. 104866, January 31, 1994, 229 SCRA 581.
[27]
See Articles 293 and 294, Revised Penal Code.
[28]
Unless the contrary appears,
animo lucrandi
or intent to gain is presumed when one takes the property belonging to another against his will, whether force or violence was employed. The unlawful taking with violence or intimidation against
the "owner" of the property being the natural and proper motive for the perpetration of the act (See United States
vs
. Alabot, No. 13052, October 4, 1918, 38 Phil 698, citing United States
vs
. San Pedro, 4 Phil 405).
[29]
Article 14 (3) of the Revised Penal Code.
[30]
People
v
s
. Ga, G.R. No. 49831, June 27, 1992, 186 SCRA 790, 798; People
v
. Collado, 196 SCRA 519.
[31]
People
vs
. Desalisa, G.R. No. 95262, January 4, 1994, 229 SCRA 35.
[32]
Article 14 (6) of the Revised Penal Code.
[33]
cf. Article 63 (2) of the Revised Penal Code. Parenthetically, even if the alleged aggravating circumstances had been established, the imposable penalty is still
because death penalty cannot be imposed under Section 19 (1),
Article III of the 1987 Constitution.
tags
| https://lawyerly.ph/juris/view/c81bf |
Nanomaterials | Free Full-Text | Lung Toxicity Analysis of Nano-Sized Kaolin and Bentonite: Missing Indications for a Common Grouping
Kaolin and bentonite (nanoclay NM-600) are nanostructured aluminosilicates that share a similar chemical composition, platelet-like morphology, and high binding capacity for biomolecules. To investigate if these material-based criteria allow for a common grouping, we prepared particle suspensions of kaolin and bentonite with a similar hydrodynamic diameter and administered them to NR8383 alveolar macrophages in vitro and also to a rat lung using quartz DQ12 as a reference material. Bentonite was far more bioactive in vitro, indicated by a lower threshold for the release of enzymes, tumor necrosis factor α, and H2O2. In addition, in the lung, the early effects of bentonite exceeded those of kaolin and even those of quartz, due to strongly increased numbers of inflammatory cells, and elevated concentrations of total protein and fibronectin within the bronchoalveolar lavage fluid. The pro-inflammatory effects of bentonite decreased over time, although assemblies of particle-laden alveolar macrophages (CD68 positive), numerous type-2 epithelial cells (immunopositive for pro-surfactant protein C), and hypertrophic lung epithelia persisted until day 21. At this point in time, kaolin-treated lungs were completely recovered, whereas quartz DQ12 had induced a progressive inflammation. We conclude that bentonite is far more bioactive than equally sized kaolin. This argues against a common grouping of aluminosilicates, previously suggested for different kaolin qualities.
Background:
Lung Toxicity Analysis of Nano-Sized Kaolin and Bentonite: Missing Indications for a Common Grouping
by Martin Wiemann 1,* , Antje Vennemann 1 and Wendel Wohlleben 2
1
IBE R&D Institute for Lung Health gGmbH, 48149 Münster, Germany
2
BASF SE, Advanced Materials Research, 67056 Ludwigshafen, Germany
*
Author to whom correspondence should be addressed.
Nanomaterials 2020 , 10 (2), 204; https://doi.org/10.3390/nano10020204
Received: 20 December 2019 / Revised: 20 January 2020 / Accepted: 22 January 2020 / Published: 24 January 2020
(This article belongs to the Special Issue Lung Cell Toxicity of Metal-containing Nanoparticles )
Abstract
O
2
. In addition, in the lung, the early effects of bentonite exceeded those of kaolin and even those of quartz, due to strongly increased numbers of inflammatory cells, and elevated concentrations of total protein and fibronectin within the bronchoalveolar lavage fluid. The pro-inflammatory effects of bentonite decreased over time, although assemblies of particle-laden alveolar macrophages (CD68 positive), numerous type-2 epithelial cells (immunopositive for pro-surfactant protein C), and hypertrophic lung epithelia persisted until day 21. At this point in time, kaolin-treated lungs were completely recovered, whereas quartz DQ12 had induced a progressive inflammation. We conclude that bentonite is far more bioactive than equally sized kaolin. This argues against a common grouping of aluminosilicates, previously suggested for different kaolin qualities.
Keywords:
nanotoxicology
;
aluminosilicate
;
alveolar macrophage
;
intratracheal instillation
Graphical Abstract
1. Introduction
Kaolin (Al
2
Si
2
O
5
(OH)
4
) and bentonite (Al
2
H
2
Na
2
O
13
Si
4
) are platelet-like aluminosilicates (or mixed Si-Al-oxides), which are a challenging group of particles for risk assessment. Their chemical sum formula places them in the substance class of silicates, but their physical structure and biopersistence differ from pure silicates. Solubility studies on mineral fibers have shown that at acidic pH, mixed Si-Al-oxides have a significantly higher biodissolution rate and reduced biopersistence rate than pure Si-oxides [
1
]. In addition, the release of Al
3+
ions may raise concerns, as recently considered by the European Chemicals Agency (ECHA) for the read-across of aluminum salts [
2
,
3
]. The toxicity assessment of aluminosilicates should, therefore, be based on a common evaluation of material properties, solubility data, and biological effects. Here, we investigate whether or not the high degree of structural and chemical similarity justifies an allocation of kaolin and bentonite to the same group of nanomaterials (NMs) according to current concepts also comprising in vitro and in vivo testing [
4
].
Kaolin is a natural aluminosilicate nanomaterial and may, therefore, be found at a low level in the ambient air. The material is used in megaton quantities for paper production but is also used by the chemical, pharmaceutical, and cosmetics industries for ceramic, rubber, plastic, and paint production [ 5 ]. Effects on kaolin mining workers have been studied in early case reports [ 6 ], and a low incidence of pneumoconiosis after prolonged exposure was reported [ 7 , 8 , 9 ]. Long-term workers exposed to 95% kaolin and low (<1%) quartz concentrations (mean lung burden of 63 mg/g tissue) exhibited a moderate interstitial fibrosis [ 10 ] such that kaolin appeared far less toxic than, e.g., quartz DQ12. Effects of kaolin on human lung were also suggested by animal experiments, although high doses were used in these studies: Sahu et al. [ 11 ] instilled 5 mg per mouse lung and detected “dirty white patches” and histological lesions but no signs of tumor formation. A mild fibrogenic effect of kaolin was reported by Rosmanith et al. (1989) and Wagner et al. (1986, 1987) [ 10 , 12 , 13 ] who also noted bronchoalveolar hyperplasia after inhalation. Under severe overload conditions and repeated instillation administration, kaolin with a particle size of 2 μm was found to induce a tumor formation [ 14 ]. Clearance from the lung of kaolin and other clay minerals mainly relies on physical mechanisms and also on solubilization [ 5 ].
Bentonite particles consist of highly colloidal and plastic clays mainly composed of montmorillonite and low, variable traces of quartz, cristobalite, and feldspar. Similar to kaolin, bentonite comes in flat, platelet-like particles. The basal molecular structure of bentonite comprises two (tetrahedral) silica sheets that enclose an (octahedral) alumina sheet in between [
5
]. The material is industrially used as a binding foundry sand in molds, as grease, or as an absorbing material in wastewater. As part of many consumer products, it is also incorporated in ceramics, and serves as a stabilizer or extender in adhesives, paints, cosmetics, and medicines [
5
]. Bentonite forms thixotropic gels with water and is used as a clarifying agent in wine making [
15
] or vegetable oil as a bonding agent. Considering its widespread use, the exposure to bentonite of the general population is low. However, the occupational exposure to bentonite mining dust may be higher, and several studies have investigated the effects of bentonite on the lung. Bentonite and montmorillonite (with low quartz content) caused a transient local inflammation, edema, and increased lung weight [
16
].
According to their similar chemical structure, and their platelet-like morphology with opposite charges of lateral and edge surfaces, kaolin and bentonite may induce similar biologic effects inside the lung. However, a direct comparison of the bioactivity of kaolin and bentonite nanomaterials has not yet been carried out for similarly sized materials at the nano level. Of note, the particle size-distribution is of pivotal importance for both in vivo and in vitro testing, as it determines lung deposition, biodistribution or, in terms of deposition and gravitational settling, the availability to interact with cells. Here, we compare the effects of kaolin and bentonite suspensions with mean particle sizes being highly similar. The bentonite quality used for this study is provided by Joint Research Center (JRC) as a characterized standard nanomaterial (“nanoclay NM-600”) [
17
] but, to the best of our knowledge, has not yet been investigated for its biological properties. A rat alveolar macrophage assay was used to describe in vitro effects. A single concentration was then administered to the rat lung to analyze bronchoalveolar lavage fluid (BALF), lung histology, and particle distribution in lung tissue.
2. Materials and Methods
2.1. Particle Characterization and Preparation of Suspensions
Bentonite (NM-600 Nanoclay, CAS no. 1302-78-9) is a hydrated sodium calcium aluminum magnesium silicate hydroxide with a quartz content of up to 3%. The material was provided by the Joint Research Center (JRC, Ispra, Italy), characterized by JRC [
18
] and also in a previous publication [
4
]. In brief, bentonite as a powder material has a mean particle size of 288 nm (percentile d10: 631 nm, percentile d50: 166 nm, percentile d90: Mean 87 nm). The specific surface size (BET) amounted to 51.9 m
2
/g. A quartz content of up to 3% was supposed. Energy dispersive X-ray spectroscopy (EDX) results showed that a thin layer of the NM-600 bentonite contains (in mass %): Ca (0.29), Fe (1.61), Na (2.85), Mg (1.29), Al (8.61), Si (22.25), O (62.84), and S (0.27).
Kaolin (CAS no. 1332-58-7) was provided and characterized by the NanoGRAVUR consortium [
4
]. A highly similar material (JRC-IRMM385), provided by the NanoDefine consortium (not used here) was characterized by Babick et al. [
19
]. The specific surface size of this type of kaolin (BET) was 24 m
2
/g. Quartz DQ12 and corundum particles had been characterized before and were suspended as described [
20
]. Kaolin and bentonite (2.4 mg/mL) were suspended in distilled pyrogen-free H
2
O (dH
2
O) by vortexing, followed by dispersion with ultrasonic energy for 10 s and 5 x 1 min on ice (300 s), respectively. Therefore, a VibraCell™ (Sonics & Materials, Danbury, CT, USA) was operated at 50 W. The hydrodynamic diameters of all particle suspensions were measured by particle tracking analysis in dH
2
O and also in cell culture media (see below) using a NanoSight LM10 instrument equipped with a blue laser (405 nm), an Andor CCD camera, and NanoSight software (NTA 3.1, Malvern Instruments GmbH, Herrenberg, Germany). The z-potential measurements were carried out with a Zetasizer Nano ZS (Malvern Instruments GmbH, Herrenberg, Germany).
2.2. In Vitro Toxicity Test
The rat alveolar macrophage cell line NR8383 was cultured at 37 °C and 5% CO
2
in 175 cm
2
culture flasks in F-12K medium prepared from powder medium (Sigma-Aldrich, N3520, Germany), supplemented with 15% heat-inactivated fetal calf serum, glutamine (2 mM), and 100 U penicillin and 10 mg/mL streptomycin. Experiments were performed as described with minor modifications [
21
]. In brief, cells were incubated with increasing concentrations of particles in serum-free F-12K medium. Therefore, the aqueous particle stock suspensions were diluted to a working concentration of 360 μg/mL. These aqueous suspensions were further diluted in an equal volume of double-concentrated F-12K cell culture medium or double-concentrated Krebs–Ringer buffer containing 2 mmol/L glucose (KRPG), to achieve cell compatibility of the suspensions. F-12K medium or KRPG were used for all further dilution steps. NR8383 cells (3 × 10
5
per well of a 96-well plate) were incubated with increasing concentrations of particle suspensions prepared in serum-free F-12K medium for 16 h. Supernatants were retrieved and centrifuged at 200×
g
for 10 min. Each supernatant was analyzed for lactate dehydrogenase activity (LDH), glucuronidase activity (GLU), and tumor necrosis factor α (TNFα) using a specific enzyme-linked immunosorbent assay (ELISA) for rat TNF-α (bio-techne, Wiesbaden, Germany). LDH was measured with the Cytotoxicity Detection Kit (Merck KGaA, Darmstadt, Germany) and GLU was measured photometrically using
p
-nitrophenyl-β-D-glucuronide as a substrate. Both enzyme activities were expressed as a % of the positive control value, which was obtained by adding 0.1% triton X-100 to an equal number of non-particle-treated cells. Bioactive TNF-α was measured indirectly via induction of apoptosis/necrosis in L-929 fibroblasts in the presence of actinomycin D and was expressed as % killing activity [
22
]. The release of H
2
O
2
was measured 90 min after the addition of particles, which were suspended in KRPG. H
2
O
2
concentration was determined quantitatively using resorufin as a detection reagent in the presence of horseradish peroxidase. All assays were run in 96-well plates and repeated three times. Vehicle-treated cells were used as negative controls. Cell-free wells were processed in the same way and used to exclude particle interference.
2.3. Animal Experiments
The animal experiments were conducted at the animal facility of the University Clinics of Essen, Germany and ethically approved by LANUV (Dortmund, Germany, Accession No. 84-02.04.2022.A157). Female Wistar rats, strain WU, weighing 200–250 g (Charles River Laboratories, Sulzfeld, Germany), were maintained in a 12 h lights-on lights-off environment. Food and water were provided ad libitum. Particles used for intratracheal instillation experiments were suspended as described for in vitro experiments in dH
2
O at a concentration of 2.4 mg/mL. All instillation fluids were prepared on the day of the experiment. The animals (
n
= 5 per group) were anaesthetized with isoflurane and received 500 μL of instillation fluid (containing 1.2 mg (
w
/
v
) of either kaolin, bentonite, or quartz DQ12) intratracheally under visual control. After three and 21 days, the animals were deeply anaesthetized with a mixture of ketamine and xylazine. Citrate blood (1 mL) was retrieved from the left ventricle, and blood cell analysis was carried out with a Sysmex KX21N (Sysmex GmbH, Hamburg, Germany). The animals were then bled from the
Aorta descendens
and BALF was prepared from the right lung by repeated washing with 0.9% NaCl (5 × 3 mL). Thereafter, the left lung was filled with 3 mL cryomatrix (Thermo Shandon Ltd., Runcorn, UK), excised, and snap-frozen in liquid nitrogen.
BALF was centrifuged (200 ×g, 4 °C, 10 min), cell pellets were re-suspended, and cells were counted with a Coulter counter (model Z2, Beckman Coulter GmbH, Krefeld, Germany). The cell viability was determined by trypan blue testing. Differential cell counts of at least 400 cells per animal were obtained after May-Grünwald and Giemsa staining of cytospin preparations, as described [ 23 ]. The total BALF protein was measured with the Lowry method, using bovine serum albumin as a standard. Fibronectin was detected by a specific ELISA [ 24 ].
2.4. Immunocytochemistry and Microscopy
Cryo-sections (7 μm) were cut from the left lung, dried onto glass slides, and stored at −20 °C. Frozen sections were post-fixed with 3.7% phosphate-buffered formaldehyde for 10 min. Sections were rinsed in phosphate-buffered saline (PBS), followed by quenching of endogenous peroxidase with 1% H
2
O
2
in PBS for 10 min and treated with 3% bovine serum albumin (fraction V) for 1 h at room temperature. An anti-CD68 antibody (AbDSerotec, diluted 1:100 in PBS, 1% BSA) and an anti-pro-surfactant protein C antibody (antibodies-online, diluted 1:400 in PBS, 1% BSA) was used to label alveolar macrophages and type-2 epithelial cells, respectively. Rabbit anti-nitrotyrosin antibody (Merck Millipore No.: 06284, diluted 1:200) was used to label nitrosylated proteins. Bound specific antibodies were labelled with biotinylated anti-mouse IgG (Jackson Immuno Research Labs, West Grove, PA, USA) to detect CD68, and biotinylated anti-rabbit IgG (Vector Laboratories, Burlingame, CA, USA) to detect surfactant protein C and nitrotyrosine. Avidin-biotin horse radish peroxidase-based detection systems (Vector Laboratories, No.: PK-4001) followed by substrate staining (Vector blue for CD68 and nitrotyrosine, Vector laboratories, No.: SK-4700) and AEC for surfactant protein C (Vector Laboratories, No.: SK-4205) were used. Nitrosylated tissue was prepared as a positive control by bathing sections in a mixture of 1 mM NaNO
2
/1 mM H
2
O
2
in 100 mM sodium acetate, pH 5. All sections were finally rinsed in phosphate buffered saline (PBS) and cover slipped with aqueous mounting medium (Immu-Mount, Fisher Scientific GmbH, Schwerte, Germany). Micrographs were taken with a Retiga 2000R camera and Q capture imaging software (Q Imaging Corporation, Surrey, BC, Canada) mounted on an Olympus BX51 microscope (Olympus Germany GmbH, Hamburg, Germany). Unstained and immuno-stained sections were also viewed with enhanced dark field microscopy (DFM) using an appropriate DFM condenser (CytoViva Inc., Auburn, AL, USA). Polarization microscopy was carried out with two perpendicularly oriented linear polarizing filters, which were inserted into the optical path of the microscope.
2.5. Statistics
At least three independent repetitions of in vitro experiments were carried out. Results for each concentration were compared to non-particle treated controls by two-way analysis of variance (ANOVA) and Dunnets’s multiple comparisons test, using GraphPad Prism 6.01. Particle size data were compared using an unpaired t-test. In vivo results are based upon five animals per group; all data are expressed as mean ± standard deviation (SD). BALF data were compared pair-wise to the vehicle control group by one-way ANOVA and post-hoc Dunnett’s multiple comparison test. For all experiments, p ≤ 0.05 was considered significant.
3. Results
3.1. Particle Size after Ultrasonic Dispersion
Aqueous kaolin and bentonite suspensions were subjected to differential ultrasonic treatment (kaolin: 10 s; bentonite: 300 s). This led to similar, non-significantly different mode values, ranging from 100 to 350 nm ( Figure 1 ). Table 1 shows that the transfer from H 2 O to KRPG elicited a slight agglomeration, with the mode values of kaolin and bentonite suspensions remaining similar and not significantly different. The transfer of the aqueous dispersions into the F-12K medium led to a more pronounced agglomeration of both aluminosilicates. While the bentonite agglomerate reached hydrodynamic diameters of 350 nm ( Table 1 ), kaolin agglomerates were larger and no longer measurable with optical particle tracking; agglomerates were, however, partly visible with phase contrast optics (see below). A de-agglomeration of kaolin could be achieved by an additional 10 s lasting ultrasonication, and these values are shown in Table 1 for comparison. In line with these observations, the z-potential of bentonite and kaolin was strongly negative in H 2 O and KRPG, and became less negative in the F-12K medium ( Table 1 ).
Figure 1. Particle size distribution of kaolin and bentonite particles dispersed in distilled H 2 O as analyzed with optical particle tracking. Kaolin and bentonite were dispersed for 10 and 300 s, respectively (see Method section for details).
Table 1. Hydrodynamic particle diameter and z-potential of kaolin and bentonite.
3.2. In Vitro Study
The in vitro toxicity of kaolin and bentonite was measured with the alveolar macrophage assay in comparison to corundum and quartz DQ12. Under cell-free conditions, corundum and quartz DQ12 appeared as microscopically visible particles at the bottom of the culture vessel due to gravitational settling (not shown). Precipitates of kaolin and bentonite particles and/or agglomerates were visible as well (
Figure 2
). Of note, the morphology of both aluminosilicates differentially dispersed by ultrasonic treatment (see above) appeared highly similar. By contrast, a brief 10 s lasting ultrasonic treatment of bentonite led to numerous large bentonite particles that could not be phagocytized by the cells (
Figure 2
c) and whose effects were not further investigated. Both aluminosilicates, as well as corundum and quartz DQ12 particles (not shown), were largely engulfed by the NR8383 cells during the 16 h lasting incubation period (
Figure 2
b,f), and at least high concentrations of kaolin and bentonite led to visible signs of cytotoxicity such as low contrast and/or a granular appearance of the cells (
Figure 2
b,f).
Figure 2.
Gravitationally settled kaolin and bentonite particles, and uptake by NR8383 cells after 16 h. (
a
,
c
,
e
) Settled particles in cell-free control wells. (
b
,
d
,
f
) NR8383 cells incubated for 16 h with the same particles as shown above. (a,b) Kaolin (180 µg/mL) after ultrasonic dispersion for 10 s. (c,d) Bentonite (180 µg/mL) after ultrasonic dispersion for 10 s. (e,f) Bentonite (180 µg/mL) after ultrasonic dispersion for 300 s. Filled arrows point to dark, particle-filled cells (b), or deteriorated cells with granular appearance (f). Filled asterisks mark areas where settled, non-ingested particle agglomerates are visible (b,f). Open arrows (d) show largely uncompromised cells; open asterisks (d) mark areas that had been cleared from particulate matter by phagocytosing cells.
In vitro effects of all particles are shown in Figure 3 and Table 2 . Corundum particles elicited nearly no cytotoxicity but induced a moderate dose-dependent formation of H 2 O 2 . By contrast, quartz DQ12 was strongly cytotoxic as indicated by the release of LDH and GLU. The pro-inflammatory effect of quartz DQ12 was reflected by a strong induction of TNFα, although the formation of H 2 O 2 was typically low. The findings for corundum and quartz DQ12 are in accord with historical records.
Figure 3. Dose-dependent effects of corundum, quartz DQ12, bentonite, and kaolin on NR8383 alveolar macrophages in vitro. Cultures of 3 × 10 5 cells per well were incubated with particle concentrations, as indicated by the graphs. After 16 h, culture supernatants were assessed for ( a ) activity of lactate dehydrogenase (LDH) in percent of triton X-100 lysed control cells, ( b ) activity of glucuronidase (GLU) in percent of triton X-100 lysed control cells, ( c ) extracellular H 2 O 2 , and ( d ) tumor necrosis factor α (TNFα), measured by a specific enzyme-linked immunosorbent assay or, in the case of bentonite, by the lysis of L929 fibroblasts. The black line in (c) shows H 2 O 2 release upon 180 µg/mL zymosan (positive control). Values are means ± SD from three independent experiments.
Table 2. In vitro effects of corundum, quartz DQ12, kaolin, and bentonite on NR8383 macrophages.
Kaolin elicited dose-dependent effects on NR8383 alveolar macrophages in vitro, which were highly similar to those of quartz DQ12 with respect to the release of LDH, GLU, and TNFα, while H 2 O 2 formation was increased ( Figure 3 , Table 2 ).
Effects of bentonite were more pronounced. The dose−response curves for the release into the medium of LDH, GLU, TNFα, and H 2 O 2 were much steeper and shifted leftward. Interestingly, we found clear maximum values for the activities of LDH and GLU at a concentration of 45 µg/mL. Based on the significant low adverse effect concentration measured for LDH ( Table 2 ), bentonite was 4-times more cytotoxic than kaolin.
3.3. In Vivo Study
A single dose of 1.2 mg per rat lung was chosen to compare the effects of bentonite, kaolin, and quartz DQ12 in vivo. This dose had been successfully used to obtain significant changes in previous experiments with quartz DQ12 as a positive control [ 23 ]. The same dose may also be estimated from the most effective concentration of kaolin in vitro (180 µg/mL, i.e., 36 µg/well), which calculates to a mean cellular dose of 120 pg/cell (36 µg divided by 3 × 10 5 cells per well). If multiplied by 10 7 , which is a typical number of alveolar macrophages in the non-compromised rat lung [ 25 ], a dose of 1.2 mg is obtained. Considering the even higher bio-activity of bentonite in vitro, we expected significant changes in BALF and, at least in part, also in the lung histology. Main results are shown in Figure 4 , Figure 5 and Figure 6 and values are shown in Tables S1–S3 .
Figure 4. In vivo effects of kaolin, bentonite, and quartz DQ12 on lung and peripheral blood. Analysis of the bronchoalveolar lavage fluid (BALF) and of white blood cells (WBC) in peripheral blood (5 animals per group) 3 and 21 days after intratracheal instillation of 1.2 mg (all particles). The vehicle control (CTR) received 0.5 mL H 2 O only. ( a ) Differential cell counts revealed changes in the numbers of eosinophils (EO), neutrophilic granulocytes (PMN), and alveolar macrophages (AM). ( b ) Number of WBC in citrate blood. ( c ) Concentration of total protein in BALF. ( d ) Concentration of fibronectin in BALF. *: p < 0.05, **: p < 0.01, ***: p < 0.001.
Figure 5. Detection of polarizing particles in quartz DQ12, kaolin, and bentonite-laden rat lungs. Cryo-sections investigated by polarization microscopy (polarizers 90° crossed). Animals were intratracheally instilled with vehicle ( a , CTR), or 1.2 mg of either quartz DQ12 ( b ), kaolin ( c ), or bentonite ( d ), and were sacrificed after 21 days. Bright particulate matter occurred in discrete macrophage-like cells facing the alveolar lumen. In bentonite-treated lungs ( d ), particles were less concentrated and occurred with alveolar septa.
Figure 6.
Distribution of alveolar macrophages (AM) and pro-surfactant protein C positive type-2 epithelial cells (AEC-II) in rat lungs treated with kaolin, bentonite, or quartz DQ12. Animals were intratracheally instilled with vehicle (CTR;
a
,
b
), or 1.2 mg of either quartz DQ12 (
c
,
d
), kaolin (
e
,
f
), or bentonite (
g
,
h
) and sacrificed after 21 days (a,h). Alveolar macrophages (AM) and AEC-II were indirectly stained with antibodies against CD68 (blue) and anti-pro-surfactant protein c antibodies (red). Figure parts b, d, f, and h represent the white boxes in a, c, e, and g. Assemblies of AM and increased expression of pro-surfactant protein c are evident in quartz DQ12-treated (c,d) and bentonite-treated lungs (g,h). Hypertrophic epithelia are seen in bentonite-treated (g), but not in quartz DQ12-treated, lungs.
3.3.1. Quartz DQ12
Quartz DQ12 was used as a positive control and elicited typical increases in the numbers of lavagable alveolar macrophages (AM), and neutrophilic granulocytes (PMN) relative to vehicle control ( Figure 4 a). Effects were significantly different from the control on day 3 and became further augmented on day 21, especially with respect to increased numbers of neutrophilic granulocyte (PMN), indicating the typical quartz-driven progressive inflammation. Low amounts of eosinophils (EO) on day 3 were accompanied by non-significant changes in white blood cell numbers in 2/5 animals ( Figure 4 b). Total protein ( Figure 4 c) and fibronectin concentrations ( Figure 4 d) were also significantly elevated. Quartz DQ12 particles occurred mainly in alveolar macrophages ( Figure 5 b), and the histological examination of hematoxylin eosin (HE)-stained tissue confirmed that quartz DQ12-treated lungs, in contrast to the control lungs, exhibited pronounced assemblies of enlarged or partially deteriorated CD68-positive AM within the lung parenchyma ( Figure 6 d). DQ12 particles in the lung were hardly detectable by brightfield or enhanced darkfield microscopy ( Figure S1 ). However, typical birefringent particles not seen in control animals appeared in AM under polarized light ( Figure 5 ). Quartz DQ12 treatment also increased the number and staining intensity of pro-surfactant protein C (pSP-C) positive type-2 epithelial cells ( Figure 6 ). The pSP-C positive cells occurred throughout the lung parenchyma with no spatial relation to regions crowded by AM. Overall, the changes upon 1.2 mg quartz DQ12 were deemed typical for the early response of the rat lung for this fibrogenic type of quartz.
3.3.2. Kaolin
Kaolin induced an increase in AM and EO counts in BALF, highly similar to quartz DQ12, but, in contrast to the latter, had nearly no effect on PMN counts ( Figure 4 , Table S1 ). The fibronectin and total protein concentrations were elevated in BALF on day 3; all effects had fully recovered on day 21. At this point, in time kaolin was localized in AM ( Figure 5 ), and no structural changes in the lung parenchyma ( Figure S1 ) and in the numbers of CD68-positive AM or pSP-C positive cells were noted ( Figure 6 ). Overall, 1.2 mg kaolin induced a transient macrophage-based hypercellularity in the rat lung, but, unlike quartz DQ12, elicited neither a (progressive) inflammation nor a structural change of the lung parenchyma.
3.3.3. Bentonite
In contrast to kaolin, bentonite had a very strong effect on the rat lung on day 3. Even compared to quartz DQ12 positive control, AM and PMN counts were 1.15- and 3.1-fold higher, respectively. In addition, the increases in total protein and fibronectin in BALF outscored the values of quartz DQ12 by far ( Figure 4 ), indicating lung cell damage and/or epithelial leakage. Lung biopsy revealed numerous opaque and even petechia-like sites at the outer lung surface ( Figure S2 ) on day 3. Interestingly, these macroscopic signs of damage and also most other inflammatory markers had decayed down to the control level on day 21, except for the still increased AM counts, which were confirmed by histology on days 3 and 21 ( Figure S1 ). In contrast to quartz DQ12-treated lungs, alveolar septae in bentonite-laden lungs appeared hypertrophic with beginning hyperplasia. Numerous pSP-C-positive type-2 cells were found close to assemblies of CD68 positive AM ( Figure 6 ). Interestingly, the CD68 staining intensity of many alveolar macrophages was low in bentonite-laden lungs. Weakly CD68-positive cells with bubble-like inclusions were also found within alveolar septae and appeared equivalent to similar formations seen in HE-stained tissue ( Figure S1 , Figure 6 ). By means of polarization microscopy, but hardly by DFM ( Figure S1 ), birefringent particles were seen in alveolar macrophages. Unlike quartz DQ12 or kaolin treatment, bentonite particles also appeared within alveolar septae ( Figure 5 ). Therefore, a staining for immunoreactive nitrotyrosin was carried out, showing immunopositive areas in alveolar septae not seen in controls ( Figure S4 ). Overall, bentonite elicited a very strong, though transient, inflammation of the lung along with beginning structural changes of the lung epithelium.
4. Discussion
In this paper, we produced aqueous suspensions from kaolin and bentonite powders with a highly similar particle size distribution down to the nanosize, to better compare the bioactivity of both aluminosilicates. Under these conditions, bentonite was about fourfold more bio-active than kaolin in the alveolar macrophage assay with respect to cytotoxicity and TNFα induction. In addition, in the rat lung, bentonite was far more bio-active as it elicited a pronounced, though transient, inflammation, which outscored the early effects of quartz DQ12 on day 3 but, in contrast to the latter, was not progressively inflammogenic. The effects of kaolin were moderate, transient, and resembled a typical foreign body reaction.
In principle, these findings are in line with earlier studies, which were, however, not specially designed to compare nano fractions of similarly sized particles. In macrophage-like P388D
1
cells, bentonite in the presence of 4% serum was more cytotoxic than kaolin [
26
]. In addition, RAW267.4 cells in the presence of 10% serum were lysed by ≥25 µg/mL bentonite but were resistant against 100 µg/mL kaolin [
27
]. Considering the serum-mediated attenuation of silica toxicity, these findings are in line with our findings on NR8383 macrophages, which were lysed upon 11.25–22.5 µg/mL bentonite and 45–90 µg/mL kaolin, respectively. Bentonite (100 µg/mL) was also readily cytotoxic for primary neurons under serum-free conditions, but not for cultured NIE-115 cells in the presence of 10% serum [
28
]. Bowman and co-workers suggested that the toxicity of bentonite requires a direct contact of particles and cells because toxic effects were not observed when cells and particles were separated by a membrane [
27
]. Overall, bentonite is more cytotoxic than kaolin for NR8383 alveolar macrophages and many other cells.
The comparatively strong effect of kaolin on NR8383 cells found here differs from earlier findings, which demonstrated a cytotoxicity of 100 µg/mL kaolin on NR8383 cells after 5 days only [ 29 ]. Again, the low cytotoxicity of kaolin in that study may be explained by the presence of 10% serum, known to mitigate the in vitro response of silica [ 30 , 31 ]. However, the attenuated cytotoxicity described by Gao and co-workers [ 29 ] is in line with the moderate in vivo response seen here in the rat lung for kaolin, suggesting that the milieu of the inner lung surface mainly composed of lung surfactant and lung lining fluid mitigates kaolin effects. Especially, dipalmitoylphosphatidylcholine (DPPC), the major phospholipid of the lung surfactant, inhibited cytotoxic effects of quartz and kaolin [ 29 ]. The lower toxicity of kaolin compared to quartz, as found here in vivo, has also been documented in cell studies [ 26 ]. However, bentonite particles bind to proteins and surfactant components as well [ 32 ], but for bentonite, a protein and/or lipid corona formation was not sufficient to inhibit inflammatory effects. Interestingly, the CD68 staining intensity of many alveolar macrophages was low in bentonite-laden lungs (c.f. Figure 6 h), suggesting beginning cell damage upon bentonite inclusion. Meanwhile, there is compelling evidence that the toxicity of silica material, including quartz and amorphous silica as well, is linked up with the steric organization of superficially located silanol groups responsible for membranolytic activity, cell surface receptor interaction, and proteasome activation [ 31 ]. As kaolin and bentonite share tetrahedric SiO 2 layers at their outer surface [ 33 ], a silica-like bioactivity may be expected for both aluminosilicates, whereby bentonite with its larger BET surface (51.9 vs. 24 m 2 /g) should be about twice as reactive. Furthermore, a bolus administration of particles with a large surface may adsorb high amounts of lung surfactant compromising normal lung function [ 34 ]. Such a disturbance of the inner lung milieu may especially apply for bentonite, which adsorbs proteins faster and more effectively than kaolin (Haase, personal communication). Adsorption of proteins by bentonite may also explain the biphasic responses observed here for the activities of LDH and GLU in cell culture supernatant. It may be speculated that these enzymes are bound and inactivated by bentonite and that this effect is especially evident under serum-free conditions.
The direct comparison of in vitro and in vivo results is always impeded by different observation periods (16 h in vitro versus 3 or even 21 days in vivo), different dose rates (kaolin agglomerated in F-12K medium and settled completely), and by the fact that the lung is a dynamic and open system into which cell populations such as monocytes and PMN may invade from the blood stream. Nevertheless, the pronounced cytotoxic effects found for bentonite in vitro seem to be reflected by the elevated concentrations of total protein (2.8-fold of control) and of fibronectin in BALF (6.8-fold of control) on day 3. These proteins may originate from the damaged or leaky lung epithelia, as suggested by histology (see Figure 6 g), but also from deteriorated macrophages, which, in a compromised lung, are known to contain fibronectin [ 35 ]. Quartz DQ12 elicited less pronounced increases in total protein and fibronectin (1.7- and 3.5-fold of control, respectively) and this difference appears in accordance with its lower bio-activity in vitro. In addition, the pro-inflammatory effect of bentonite indicated by high PMN counts was 3.1-fold larger than the quartz DQ12-induced recruitment of PMN on day 3, possibly reflecting the discrepancy in TNFα expression in vitro, although PMN invasion appears to involve several mediators [ 36 ]. Interestingly, the in vitro assays partly overestimated the effects of kaolin in the lung, especially when compared to the effects of quartz DQ12: While all in vitro dose–response curves of quartz DQ12 and kaolin were largely congruent, in vivo only elevated AM counts, and the concentration of fibronectin was nearly identical, whereas PMN counts and the total protein concentration were far lower and hardly different from the vehicle control. Considering the histological pictures of the lung ( Figure 5 c and Figure 6 e), it appears that kaolin does not compromise the lung epithelium known to be involved in the recruitment of PMN from the blood [ 37 ]. Overall, the in vitro in vivo comparison shows that the alveolar macrophage assay is a valuable tool to predict early effects of (nano)particles on the alveolar macrophage population but has its limitations if complex biological processes are to be predicted.
There were also some differences between kaolin and bentonite concerning particle localization in lung tissue. The detection of small silica particles in lung tissue even by enhanced darkfield microscopy was cumbersome due to the high transparency of silica (
Figure S1
). However, crystalline quartz alters the plane of polarized light and is, therefore, detectable by polarization microscopy. Here, also kaolin and bentonite particles were visualized as bright objects under the polarization microscope, possibly because their layer structure changes the plane of the polarized light. By this approach, quartz DQ12, kaolin, and bentonite particles were detected in macrophage-like cells. Only bentonite particles were found also within alveolar septae, suggesting their uptake into epithelial cells or interstitial macrophages. This finding is in line with an earlier study on the subcellular localization of bentonite (sized 0–2 µm) in the rat lung [
38
], showing that epithelial cells within so-called “storage foci” contained numerous stacked, lamellar particles identified as bentonite by energy-dispersive X-ray analysis. Interestingly, many of these inclusions were not surrounded by membranes and were located in close contact to unrestrained cytoplasmic organelles and cytosolic components. Of note, this situation was obtained three or six months post-administration of bentonite. Given the acute cytotoxicity and acute lung toxicity of this aluminosilicate, and also the unexpected recovery from effects in the lung as seen here, we hypothesize that bentonite, by contacting cells and/or tissue fluids, transforms into a biocompatible material over time. The biocompatible stage may require an equilibrium to be reached for water adsorption, ion exchange processes, and protein and/or lipid corona formation. Further equilibration experiments followed by macrophage testing is required to better understand bentonite’s mode of action.
Aside from differences based on surface size, surfactant binding, and protein adsorption, the layered structure of montmorillonite, the major constituent of bentonite, differs from that of kaolinite as it bears the gippsite layer between two silica sheets. This feature enables the material to adsorb high amounts of H 2 O, leading to a so-called “expanding lattice” with a variable thickness of 0.96 to 2.14 nm [ 33 ]. While this process may disturb the water balance and osmolarity of ingesting cells or tissues exposed to dry bentonite, it may be less relevant in our experiments with well-dispersed, H 2 O-equilibrated materials. However, the special arrangement of the gippsite layer structure of montmorillonite also allows for a considerable ion exchange capacity [ 33 ], which amounts to 184 mEq for bentonite but only to 4 mEq for kaolin [ 27 ]. Ion exchange of bentonite seems to be driven by Si and Al ions leaving the lattice and being replaced by Ca 2+ , Na + , and Mg 2+ ions entering the bentonite nanostructure. It is tempting to speculate that these changes take place at least in part within alveolar macrophages and/or epithelial cells (c.f. Figure 5 ) and that they contribute to ionic instability and eventually to cytotoxicity seen in NR8383 cells. In addition, tissue hypertrophy and/or swelling in the vicinity of bentonite-triggered alveolar macrophage assemblies may be caused by local osmotic effects emanating from bentonite particles (c.f. Figure 6 g). Local ionic imbalances around bentonite particles may therefore be of importance for the toxic potential of this aluminosilicate and, especially, an unbalanced retrieval of Ca 2+ and/or Mg 2+ ions may destabilize a cell. As larger differences in the z-potential of kaolin and bentonite were not found ( Table 1 ), this parameter appears of minor importance. Further studies are in progress to identify the transformation of aluminosilicates in situ.
Interestingly, an unproportional release of Al and Si ions has been demonstrated from kaolin and bentonite flushed by a pH 4.5 phagolysosomal simulation fluid (Keller et al., this special issue), with Si ions being released faster than Al ions. In comparison to kaolin, the bentonite dissolution rate of 33 ng/cm²/h (calculated dissolution halftime: 1.7 d) was much faster than the dissolution rate of kaolin (9.8 ng/cm²/h, calculated dissolution halftime: 12.3 d), and both were categorized as “partially dissolving,” such that the toxicity of both ions and particles needs to be considered. Al ions are known to act geno- and neurotoxic [
39
] and their local release from aluminosilicates, which is about five times faster from bentonite compared to kaolin (Keller et al., this special issue), may contribute to cytotoxic effects in the lung as well. Although the administration of 46.6 µg Al
3
(SO
4
)
2
to the rat lung had no adverse effect on BALF parameters [
40
], and even 500–1000 µM Al
3+
were needed to observe a growth retarding effect on smooth muscle cells [
41
], a contribution of Al ions to bentonite toxicity cannot completely be ruled out, if local concentrations reach high values.
A further effect of bentonite and kaolin may be based on oxidative damage, and this may be attributed to the edges of the aluminosilicate lattice. Of note, a platelet-like kaolin fostered the generation of radical oxidative species and genotoxic events in vitro, whereas a more spherical kaolin had lower effects [
42
]. Here, the bentonite-treated NR8383 cells produced more H
2
O
2
than kaolin-treated cells, which is in line with an earlier study measuring particle-induced chemiluminescence [
43
]. In another study [
4
], we employed the ferric reduction ability of serum (FRAS) assay and two electron paramagnetic resonance (EPR) assays, and found that the oxidative power of bentonite outscored that of kaolin and several other silica nanoparticles about 4–8 fold. On the other hand, the carbonylation of cell proteins, providing a measure for accumulated oxidative damage inside cells, was similar or even slightly more augmented by kaolin than by bentonite (on a mass per volume basis, Bahl et al., manuscript submitted). To put these differences into perspective, we recall that the two nanoforms of kaolin differed much less, with very similar dissolution kinetics (9.8 and 7.8 ng/cm²/h respectively, Keller et al., this Special Issue), similar oxidative damage (13 and 16 nmol TEU/m² respectively), and similar NR8383 reactivity. Thus, by the same criteria that identify the two nanoforms of kaolin as to be similar, bentonite is clearly dissimilar. Overall, bentonite proved to be the more reactive nanomaterial in many assays and, therefore, has a high capacity to cause protein damage. Indeed, we obtained first evidence for an increase in nitrosylated proteins in bentonite-treated lungs (
Figure S3
). Further studies should investigate if nitrosylated sites are co-localized with bentonite particles in the tissue.
5. Conclusions
The paper shows that, despite highly similar composition, plate-like structure, and adsorption properties, nano-sized bentonite is far more bioactive than size-matched kaolin, and this finding strongly argues against a common grouping of both aluminosilicates. Combining the findings from the literature and also from recent studies on reactivity and solubility (see Keller et al., this Special Issue), this difference may be due to differences in ion exchange capacity, oxidative potential, specific surface area, and dissolution, as all these properties were more pronounced for bentonite compared to kaolin. The unexpectedly fast recovery found for bentonite-treated lungs may rely on a transition of bentonite from a cytotoxic to a cell-compatible material. Together, transformation and dissolution processes of aluminosilicates are highly relevant for the field of nanotoxicology and deserve further attention.
Supplementary Materials
The following are available online at https://www.mdpi.com/2079-4991/10/2/204/s1 , Table S1: Differential cell counts in bronchoalveolar lavage fluid [x 106]. Table S2: Total protein in bronchoalveolar lavage fluid. Table S3: Fibronectin in bronchoalveolar lavage fluid. Figure S1: Histologic and dark field aspects of rat lungs treated with kaolin, bentonite or quartz DQ12. Figure S2: Macroscopic inspection of bentonite-treated lungs. Figure S3: Detection of nitrosylated proteins in the bentonite-treated and control lung tissue.
Author Contributions
A.V. and M.W. conceived, designed and performed the experiments on cells and animals and tissue sections; W.W. initiated the study, wrote parts of the paper and contributed to the discussion. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by the German Federal Ministry of Education and Research (BMBF), grant number 03XP0002.
Acknowledgments
The authors would like to thank the NanoGRAVUR consortium for providing and characterizing the nanomaterials.
Conflicts of Interest
M.W. and A.V. declare no conflict of interest. W.W. is an employee of the BASF, a company producing and selling nanomaterials.
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Figure 1. Particle size distribution of kaolin and bentonite particles dispersed in distilled H 2 O as analyzed with optical particle tracking. Kaolin and bentonite were dispersed for 10 and 300 s, respectively (see Method section for details).
Figure 2. Gravitationally settled kaolin and bentonite particles, and uptake by NR8383 cells after 16 h. ( a , c , e ) Settled particles in cell-free control wells. ( b , d , f ) NR8383 cells incubated for 16 h with the same particles as shown above. (a,b) Kaolin (180 µg/mL) after ultrasonic dispersion for 10 s. (c,d) Bentonite (180 µg/mL) after ultrasonic dispersion for 10 s. (e,f) Bentonite (180 µg/mL) after ultrasonic dispersion for 300 s. Filled arrows point to dark, particle-filled cells (b), or deteriorated cells with granular appearance (f). Filled asterisks mark areas where settled, non-ingested particle agglomerates are visible (b,f). Open arrows (d) show largely uncompromised cells; open asterisks (d) mark areas that had been cleared from particulate matter by phagocytosing cells.
Figure 3. Dose-dependent effects of corundum, quartz DQ12, bentonite, and kaolin on NR8383 alveolar macrophages in vitro. Cultures of 3 × 10 5 cells per well were incubated with particle concentrations, as indicated by the graphs. After 16 h, culture supernatants were assessed for ( a ) activity of lactate dehydrogenase (LDH) in percent of triton X-100 lysed control cells, ( b ) activity of glucuronidase (GLU) in percent of triton X-100 lysed control cells, ( c ) extracellular H 2 O 2 , and ( d ) tumor necrosis factor α (TNFα), measured by a specific enzyme-linked immunosorbent assay or, in the case of bentonite, by the lysis of L929 fibroblasts. The black line in (c) shows H 2 O 2 release upon 180 µg/mL zymosan (positive control). Values are means ± SD from three independent experiments.
Figure 4. In vivo effects of kaolin, bentonite, and quartz DQ12 on lung and peripheral blood. Analysis of the bronchoalveolar lavage fluid (BALF) and of white blood cells (WBC) in peripheral blood (5 animals per group) 3 and 21 days after intratracheal instillation of 1.2 mg (all particles). The vehicle control (CTR) received 0.5 mL H 2 O only. ( a ) Differential cell counts revealed changes in the numbers of eosinophils (EO), neutrophilic granulocytes (PMN), and alveolar macrophages (AM). ( b ) Number of WBC in citrate blood. ( c ) Concentration of total protein in BALF. ( d ) Concentration of fibronectin in BALF. *: p < 0.05, **: p < 0.01, ***: p < 0.001.
Figure 5. Detection of polarizing particles in quartz DQ12, kaolin, and bentonite-laden rat lungs. Cryo-sections investigated by polarization microscopy (polarizers 90° crossed). Animals were intratracheally instilled with vehicle ( a , CTR), or 1.2 mg of either quartz DQ12 ( b ), kaolin ( c ), or bentonite ( d ), and were sacrificed after 21 days. Bright particulate matter occurred in discrete macrophage-like cells facing the alveolar lumen. In bentonite-treated lungs ( d ), particles were less concentrated and occurred with alveolar septa.
Figure 6. Distribution of alveolar macrophages (AM) and pro-surfactant protein C positive type-2 epithelial cells (AEC-II) in rat lungs treated with kaolin, bentonite, or quartz DQ12. Animals were intratracheally instilled with vehicle (CTR; a , b ), or 1.2 mg of either quartz DQ12 ( c , d ), kaolin ( e , f ), or bentonite ( g , h ) and sacrificed after 21 days (a,h). Alveolar macrophages (AM) and AEC-II were indirectly stained with antibodies against CD68 (blue) and anti-pro-surfactant protein c antibodies (red). Figure parts b, d, f, and h represent the white boxes in a, c, e, and g. Assemblies of AM and increased expression of pro-surfactant protein c are evident in quartz DQ12-treated (c,d) and bentonite-treated lungs (g,h). Hypertrophic epithelia are seen in bentonite-treated (g), but not in quartz DQ12-treated, lungs.
Table 1. Hydrodynamic particle diameter and z-potential of kaolin and bentonite.
Value Bentonite Kaolin Bentonite Kaolin Bentonite Kaolin in H 2 O in F-12K Medium in KRPG Mode [nm] 141.0 ± 13.5 165.8 ± 3.9 350.9 ± 51.8 208.9 ± 54 1) 218.5 ± 28.5 200.4 ± 65.4 d10 [nm] 102.8 ± 9.3 131.9 ± 0.9 201.6 ± 9.6 124.9 ± 13.7 1) 174.1 ± 6.4 111 ± 14.9 d50 [nm] 139.8 ± 8.0 185.3 ± 2.7 318.3 ± 12.1 234.2 ± 13.2 1) 262.7 ± 11.2 229.2 ± 14.2 d90 [nm] 190.7 ± 8.8 294.8 ± 1.6 447.9 ± 20.9 327.4 ± 6.0 1) 401.6 ± 9.4 360.5 ± 5.3 z-Potential [mV] −47.4 −30.0 −18.2 −16.7 −31.8 −31.5
Table 2. In vitro effects of corundum, quartz DQ12, kaolin, and bentonite on NR8383 macrophages.
Material LDH [% of CTR] 1) GLU [% of CTR] 1) H 2 O 2 [µmol/L] TNFα [pg/mL] or [% cell eath] 2) µg/mL mean ± SD mean ± SD mean ± SD mean ± SD Corundum 0 26.1 ± 3.6 3.3 ± 0.6 0.5 ± 0.1 7.8 ± 2.3 22.5 24.0 ± 0.6 1.1 ± 1.3 0.2 ± 0.1 8.5 ± 8.5 45 27.1 ± 0.6 1.5 ± 1.4 0.7 ± 0.1 10.9 ± 10.8 90 28.2 ± 2.2 1.4 ± 1.5 1.8 ± 0.1*** 13.0 ± 12.1 180 32.3 ± 0.7** 2.0 ± 1.9 3.4 ± 0.2*** 21.4 ± 25.3 Quartz 0 26.1 ± 3.6 3.3 ± 0.6 0.5 ± 0.1 7.8 ± 2.3 DQ12 22.5 29.9 ± 0.6 3.5 ± 0.3 0.0 ± 0.0 13.3 ± 6.6 45 46.7 ± 0.9*** 6.6 ± 0.2** 0.2 ± 0.2 31.8 ± 3.8 90 82.4 ± 0.3*** 22.1 ± 0.2*** 0.6 ± 0.1 100.7 ± 20.3** 180 103.2 ± 0.2*** 44.1 ± 0.5*** 1.2 ± 0.3*** 104.6 ± 47.1** Kaolin 0 26.1 ± 3.6 3.3 ± 0.6 0.5 ± 0.1 7.8 ± 2.3 2.8 38.0 ± 6.0 4.6 ± 0.4 0.2 ± 0.1 5.625 34.5 ± 9.3 4.4 ± 1.6 0.3 ± 0.1 11.25 31.9 ± 3.2 4.1 ± 0.6 0.5 ± 0.1 22.5 29.0 ± 3.9 4.4 ± 0.4 0.5 ± 0.2 5.6 ± 6.9 45 51.0 ± 8.9*** 8.8 ± 1.7*** 1.1 ± 0.1** 19.5 ± 13.7 90 79.6 ± 2.4*** 21.9 ± 0.7*** 1.9 ± 0.2*** 158.3 ± 101.6*** 180 93.6 ± 3.5*** 32.4 ± 2.0*** 2.1 ± 0.3*** 142.4 ± 81.9*** Bentonite 0 26.1 ± 3.6 3.3 ± 0.6 0.5 ± 0.1 19.1 ± 10.2 2.8 20.0 ± 2.8 4.2 ± 2.5 0.6 ± 0.1 5.625 21.7 ± 0.8 3.8 ± 1.6 1.3 ± 0.1*** 11.25 41.0 ± 3.1* 5.0 ± 0.7 1.7 ± 0.2*** 22.5 70.3 ± 3.1*** 13.9 ± 0.8*** 2.0 ± 0.5*** 70.3 ± 16.4 45 104.7 ± 6.7*** 36.2 ± 2.2*** 1.9 ± 0.1*** 99.1 ± 2.2* 90 97.3 ± 3.9*** 33.2 ± 1.6*** 1.5 ± 0.1*** 100.1 ± 2.1* 180 43.6 ± 1.9** 28.7 ± 1.0*** 1.6 ± 0.1*** 100.8 ± 1.4*
1) Lactate dehydrogenase activity (LDH) and glucuronidase activity (GLU) in % of triton X-100 lysed positive control values (CTR). 2) TNFα values of bentonite treatment represent % cell death of L-929 reporter cells. *: p < 0.05; **: p < 0.01; ***: p < 0.001.
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A CASE OF KAWASAKI DISEASE IN AN EIGHT-YEAR-OLD BOY
Download Citation | A CASE OF KAWASAKI DISEASE IN AN EIGHT-YEAR-OLD BOY | Kawasaki disease is an acute systemic disease characterized by the predominant lesions of middle and small arteries, alongside destructive and... | Find, read and cite all the research you need on ResearchGate
A CASE OF KAWASAKI DISEASE IN AN EIGHT-YEAR-OLD BOY
October 2022
Wiadomości lekarskie (Warsaw, Poland: 1960) 75(10):2544-2548
DOI: 10.36740/WLek202210143
Authors:
Ganna K Kopiyka
Tetiana Y Kravchenko
Olena M Artomova
Krystyna B Soboleva
Abstract
Kawasaki disease is an acute systemic disease characterized by the predominant lesions of middle and small arteries, alongside destructive and proliferative vasculitis development. The aetiology is currently being discussed. Infectious factors are mostly preferred, in addition, autoimmune mechanisms and genetic heredity are considered. The diagnosis of Kawasaki disease is established by clinical signs; laboratory changes are usually taken into account as are ancillary criteria. The article discusses the clinical case of Kawasaki disease in an 8-year-old boy. Given the variety and inconsistency of the clinical symptoms (the child had four of the five mandatory criteria together with prolonged fever), there was a late diagnosis, namely on day 10 of the disease. Due to the high risk of cardiovascular complications in the differential diagnosis of children with fever lasting more than 3 days should be considered Kawasaki disease, followed by mandatory heart echocardiography during the first 10 days of the disease, especially if the fever is accompanied by the increase of acute phase reactants. When treating children with chronic fever without a specific source, the doctor should be wary of Kawasaki disease, as it can clinically simulate acute respiratory viral disease, the onset of diffuse connective tissue disease, and infectious endocarditis, and can have common features and require differential diagnostics with coronavirus associated multisystem inflammatory syndrome.
COVID-19: Multisystem Inflammatory Syndrome in Children (MIS-C)
A novel coronavirus was identified in late 2019 that rapidly reached pandemic proportions. The World Health Organization has designated the disease as COVID-19, which stands for coronavirus disease 2019. In children, COVID-19 is usually mild. However, in rare cases, children can be severely affected, and clinical manifestations may differ from adults. In April of 2020, reports from the United Kingdom documented a presentation in children similar to incomplete Kawasaki disease (KD) or toxic shock syndrome. Since then, there have been reports of similarly affected children in other parts of the world. The condition has been termed multisystem inflammatory syndrome in children (MIS-C). We report a case of a 12-year-old previously healthy boy admitted with fever, generalized skin rash, conjunctivitis, and multiorgan dysfunction with positive COVID-19 polymerase chain reaction (PCR), and diagnosed as MIS-C on the basis of clinical and laboratory criteria. He received intravenous immunoglobulin (IVIG) for two days and other supportive treatment. He improved with defervescence and normalization of acute-phase reactants.
Purpose of review:
Provide the most recent updates on the epidemiology, pathogenesis, and treatment advances in Kawasaki disease.
Recent findings:
Treatment advances in complex, IVIG-refractory cases of Kawasaki disease. Multisystem inflammatory syndrome, a newly reported inflammatory condition with Kawasaki-like features and an association with the 2019 Coronavirus (COVID-19). Kawasaki disease (KD) is a rare systemic inflammatory disease that predominately affects children less than 5 years of age. Pathogenesis of KD remains unknown; the leading theory is that an unknown stimulus triggers an immune-mediated inflammatory cascade in a genetically susceptible child. Classic KD is a clinical diagnosis based on set criteria and excluding other similar clinical entities. Patients who do not fulfill complete diagnostic criteria for KD are often referred to as atypical (or incomplete) KD. The most feared complication of KD is coronary artery abnormality development, and patients with atypical KD are also at risk. Administration of intravenous immunoglobulin (IVIG) and aspirin has greatly reduced the incidence of coronary lesions in affected children. Several other immune-modulating therapies have recently been utilized in complex or refractory cases.
Risk Model Development and Validation for Prediction of Coronary Artery Aneurysms in Kawasaki Disease in a North American Population
Mary Beth Son
Kimberlee Gauvreau
Adriana Tremoulet
Jane W Newburger
Background
Accurate prediction of coronary artery aneurysms ( CAAs ) in patients with Kawasaki disease remains challenging in North American cohorts. We sought to develop and validate a risk model for CAA prediction.
Methods and Results
A binary outcome of CAA was defined as left anterior descending or right coronary artery Z score ≥2.5 at 2 to 8 weeks after fever onset in a development cohort (n=903) and a validation cohort (n=185) of patients with Kawasaki disease. Associations of baseline clinical, laboratory, and echocardiographic variables with later CAA were assessed in the development cohort using logistic regression. Discrimination (c statistic) and calibration (Hosmer‐Lemeshow) of the final model were evaluated. A practical risk score assigning points to each variable in the final model was created based on model coefficients from the development cohort. Predictors of CAAs at 2 to 8 weeks were baseline Z score of left anterior descending or right coronary artery ≥2.0, age <6 months, Asian race, and C‐reactive protein ≥13 mg/ dL (c=0.82 in the development cohort, c=0.93 in the validation cohort). The CAA risk score assigned 2 points for baseline Z score of left anterior descending or right coronary artery ≥2.0 and 1 point for each of the other variables, with creation of low‐ (0–1), moderate‐ (2), and high‐ (3–5) risk groups. The odds of CAA s were 16‐fold greater in the high‐ versus the low‐risk groups in the development cohort (odds ratio, 16.4; 95% CI , 9.71–27.7 [ P <0.001]), and >40‐fold greater in the validation cohort (odds ratio, 44.0; 95% CI, 10.8–180 [ P <0.001]).
Conclusions
Our risk model for CAA in Kawasaki disease consisting of baseline demographic, laboratory, and echocardiographic variables had excellent predictive utility and should undergo prospective testing.
Prediction for Intravenous Immunoglobulin Resistance by Using Weighted Genetic Risk Score Identified From Genome-Wide Association Study in Kawasaki DiseaseCLINICAL PERSPECTIVE
Ho-Chang Kuo
Henry Sung-Ching Wong
Wei-Pin Chang
WC Chang
Background—
Intravenous immunoglobulin (IVIG) is the treatment of choice in Kawasaki disease (KD). IVIG is used to prevent cardiovascular complications related to KD. However, a proportion of KD patients have persistent fever after IVIG treatment and are defined as IVIG resistant.
Methods and Results—
To develop a risk scoring system based on genetic markers to predict IVIG responsiveness in KD patients, a total of 150 KD patients (126 IVIG responders and 24 IVIG nonresponders) were recruited for this study. A genome-wide association analysis was performed to compare the 2 groups and identified risk alleles for IVIG resistance. A weighted genetic risk score was calculated by the natural log of the odds ratio multiplied by the number of risk alleles. Eleven single-nucleotide polymorphisms were identified by genome-wide association study. The KD patients were categorized into 3 groups based on their calculated weighted genetic risk score. Results indicated a significant association between weighted genetic risk score (groups 3 and 4 versus group 1) and the response to IVIG (Fisher’s exact P value 4.518×10⁻⁰³ and 8.224×10⁻¹⁰, respectively).
Conclusions—
This is the first weighted genetic risk score study based on a genome-wide association study in KD. The predictive model integrated the additive effects of all 11 single-nucleotide polymorphisms to provide a prediction of the responsiveness to IVIG.
Aspirin Dose and Prevention of Coronary Abnormalities in Kawasaki Disease
Zoe Fortier-Morissette
Samuel Blais
Rosie Scuccimarri
Background:
Acetylsalicylic acid (ASA) is part of the recommended treatment of Kawasaki disease (KD). Controversies remain regarding the optimal dose of ASA to be used. We aimed to evaluate the noninferiority of ASA at an antiplatelet dose in acute KD in preventing coronary artery (CA) abnormalities.
Methods:
This is a multicenter, retrospective, nonrandomized cohort study including children 0 to 10 years of age with acute KD between 2004 and 2015 from 5 institutions, of which 2 routinely use low-dose ASA (3-5 mg/kg per day) and 3 use high-dose ASA (80 mg/kg per day). Outcomes were CA abnormalities defined as a CA diameter with a z score ≥2.5. We assessed the risk difference of CA abnormalities according to ASA dose. All subjects received ASA and intravenous immunoglobulin within 10 days of fever onset.
Results:
There were 1213 subjects included, 848 in the high-dose and 365 in the low-dose ASA group. There was no difference in the risk of CA abnormalities in the low-dose compared with the high-dose ASA group (22.2% vs 20.5%). The risk difference adjusted for potential confounders was 0.3% (95% confidence interval [CI]: -4.5% to 5.0%). The adjusted risk difference for CA abnormalities persisting at the 6-week follow-up was -1.9% (95% CI: -5.3% to 1.5%). The 95% CI of the risk difference of CA abnormalities adjusted for confounders was within the prespecified 5% margin considered to be noninferior.
Conclusions:
In conjunction with intravenous immunoglobulin, low-dose ASA in acute KD is not inferior to high-dose ASA for reducing the risk of CA abnormalities.
870 Impact of Paediatric Multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS-TS) on Critical Care – an HDU experience
Conference Paper
Aug 2022
Lekha Sridhar
ChinKien Eyton-Chong
Rachel Hoi Khoon Tan
Background
Alder Hey is a tertiary children’s hospital in North-West England with co-located Intensive Care and High Dependency units, covering North West England, North Wales and Isle of Man.PIMS-TS is a new multisystem inflammatory condition which has led to an increased demand on critical care beds. Some children presenting with PIMS-TS need haemodynamic support in the form of inotropes, which would traditionally need an PICU bed.
Aim
Review of all patients managed on Critical Care with PIMS-TS.
Methods
All patients in the region were discussed in a PIMS-TS multidisciplinary meeting attended by Paediatrics, Infectious Diseases, Rheumatology, Cardiology and Critical Care daily. Patients across the region needing haemodynamic support or cardiology evaluation were highlighted as, in need of either HDU or PICU bed and transferred by the North West & Wales Paediatric Transport Service (NWTS).This is a retrospective analysis of all children admitted to HDU or PICU with a diagnosis of PIMS-TS, from October 2020-December 2021.
Results
Thirty (10%) patients were admitted to HDU from the 300 patients discussed over the 15month period. 16 (53%) of patients were female. Mean age was 10 years (range 3-17). Median length of stay (LOS) on HDU was 2 days (range 1-8) with a median hospital LOS of 6 days (range 2-10).All patients admitted were monitored appropriately and had full echocardiography assessment.
Twenty nine (97%) patients admitted to HDU required inotropic support, twelve (40%) patients required a single agent and seventeen (57%) required double agents with a combination of adrenaline, noradrenaline and milrinone.
Median fluid resuscitation was 40mls/kg (range 20-70mls/kg).
Eight patients (27%) were escalated to PICU for either invasive ventilation (4) or higher inotropic requirements of 0.2micrograms/kg/minute. There were no adverse events.
Conclusion
Most children with PIMS-TS have low to moderate haemodynamic instability that can be safely managed on HDU with appropriate monitoring and agreed limits to vasopressor therapy. Our experience in managing with these patients successfully and safely in a high dependency setting has helped in the use of a critical care bed efficiently, thus reducing dependency on the availability of a PICU bed.
Treatment Intensification in Patients With Kawasaki Disease and Coronary Aneurysm at Diagnosis
Article
May 2019
Audrey Dionne
Jane C. Burns
Nagib S Dahdah
Kevin G Friedman
Background:
Coronary artery aneurysms (CAA) are a serious complication of Kawasaki disease. Treatment with intravenous immunoglobulin (IVIg) within 10 days of fever onset reduces the risk of CAA from 25% to <5%. Corticosteroids and infliximab are often used in high-risk patients or those with CAA at diagnosis, but there are no data on their longer-term impact on CAA.
Methods:
Retrospective multicenter study including children who had CAA with a z score ≥2.5 and <10 at time of diagnosis and who received primary therapy with IVIg alone or in combination with either corticosteroids or infliximab within 10 days of onset of fever.
Results:
Of 121 children, with a median age of 2.8 (range 0.1-15.5) years, 30 (25%) received primary therapy with corticosteroids and IVIg, 58 (48%) received primary therapy with infliximab and IVIg, and 33 (27%) received primary therapy with IVIg only. Median coronary z scores at the time of diagnosis did not differ among treatment groups (P = .39). Primary treatment intensification with either corticosteroids or infliximab were independent protective factors against progression of coronary size on follow-up (coefficient: -1.31 [95% confidence interval: -2.33 to -0.29]; coefficient: -1.07 [95% confidence interval: -1.95 to -0.19], respectively).
Conclusions:
Among a high-risk group of patients with Kawasaki disease with CAA on baseline echocardiography, those treated with corticosteroids or infliximab in addition to IVIg had less progression in CAA size compared with those treated with IVIg alone. Prospective randomized trials are needed to determine the best adjunctive treatment of patients who present with CAA.
Efficacy and safety of intravenous immunoglobulin plus prednisolone therapy in patients with Kawasaki disease (Post RAISE): a multicentre, prospective cohort study
Oct 2018
Koichi Miyata
Tetsuji Kaneko
Yoshihiko Morikawa
Masaru Miura
Background:
The RAISE study showed that additional prednisolone improved coronary artery outcomes in patients with Kawasaki disease at high risk of intravenous immunoglobulin (IVIG) resistance. However, no studies have been done to test the steroid regimen used in the RAISE study. We therefore aimed to verify the efficacy and safety of primary IVIG plus prednisolone.
Methods:
We did a multicentre, prospective cohort study at 34 hospitals in Japan. We included patients diagnosed with Kawasaki disease according to the Japanese diagnostic criteria, and excluded those who were treated at other hospitals before being transferred to a participating hospital. Patients who were febrile at diagnosis received primary IVIG (2 g/kg per 24 h) and oral aspirin (30 mg/kg per day) until the fever resolved, followed by oral aspirin (5 mg/kg per day) for 2 months after Kawasaki disease onset. We stratified patients using the Kobayashi score into predicted IVIG non-responders (Kobayashi score ≥5) or predicted IVIG responders (Kobayashi score <5). For predicted non-responders, each hospital independently decided whether to add prednisolone (intravenous injection of 2 mg/kg per day for 5 days) to the primary IVIG treatment, according to their respective treatment policy, and we further divided these patients based on the primary treatment received. The primary endpoint was the incidence of coronary artery abnormalities determined by two-dimensional echocardiography at 1 month after the primary treatment in predicted non-responders treated with primary IVIG plus prednisolone. Coronary artery abnormalities were defined according to the criteria of the Japanese Ministry of Health and Welfare and of the American Heart Association (AHA). This study is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN000007133.
Findings:
From July 1, 2012, to June 30, 2015, we enrolled 2628 patients with Kawasaki disease, of whom 724 (27·6%) were predicted IVIG non-responders who received IVIG plus prednisolone as primary treatment. 132 (18·2%) of 724 patients did not respond to primary treatment. Among patients with complete data, coronary artery abnormalities were present in 40 (incidence rate 5·9%, 95% CI 4·3-8·0) of 676 patients according to the AHA criteria or in 26 (3·8%, 2·5-5·6) of 677 patients according to the Japanese criteria. Serious adverse events were reported in 12 (1·7%) of 724 patients treated with primary IVIG plus prednisolone; two of these patients had hypertension and bacteraemia that was probably related to prednisolone. One patient died possibly due to severe inflammation from the Kawasaki disease itself.
Interpretation:
Primary IVIG plus prednisolone therapy in this study had an effect similar to that seen in the RAISE study in reducing the non-response rate and decreasing the incidence of coronary artery abnormalities. A primary IVIG and prednisolone combination therapy might prevent coronary artery abnormalities and contribute to lowering medical costs.
Funding:
Tokyo Metropolitan Government Hospitals and the Japan Kawasaki Disease Research Center.
Intestinal Involvement in Kawasaki Disease
Jul 2018
J Pediatr
Claudia Colomba
Simona La Placa
Laura Saporito
Antonio Cascio
Objectives:
To describe a case of Kawasaki disease with intestinal involvement and to analyze other published reports to define clinical characteristics, diagnostic issues, and therapeutic approaches of gastrointestinal involvement in Kawasaki disease.
Study design:
A computerized search without language restriction was conducted using PubMed and SCOPUS. An article was considered eligible for inclusion in the systematic review if it reported data on patient(s) with intestinal involvement in Kawasaki disease. Our case was also included in the analysis.
Results:
Thirty-three articles reporting 48 cases of Kawasaki disease with intestinal involvement were considered. Fever, abdominal pain, and vomiting were the most frequent symptoms observed and typical Kawasaki disease signs and symptoms appeared after intestinal complaints in all cases. Plain radiographs, ultrasonography, and computed tomography showed pseudo-obstruction as the most frequent sign of gastrointestinal involvement; 25 patients underwent surgery. Cardiac involvement was documented in 21 cases. All but three patients received medical treatment with immunoglobulin intravenous or aspirin. The outcome was good in 28 patients; 7 patients showed persistence of coronary artery abnormalities; 1 patient developed cyanosis, and later, left hand and forefoot gangrene; 3 patients died.
Conclusions:
The diagnosis and treatment of Kawasaki disease might be delayed if intestinal symptoms appear before the characteristic clinical features of Kawasaki disease, thus, increasing the risk of cardiac complications. Furthermore, patients may undergo unnecessary invasive procedures. Pediatricians and pediatric surgeons, therefore, should consider Kawasaki disease among diagnoses in children with fever, abdominal symptoms, and radiologic findings of pseudo-obstruction.
View
Show abstract
Cardiac Complications, Earlier Treatment, and Initial Disease Severity in Kawasaki Disease
Article
Jun 2017
Joseph Y. Abrams
Ermias Belay
Ritei Uehara
Yosikazu Nakamura
Objectives:
To assess if observed higher observed risks of cardiac complications for patients with Kawasaki disease (KD) treated earlier may reflect bias due to confounding from initial disease severity, as opposed to any negative effect of earlier treatment.
Study design:
We used data from Japanese nationwide KD surveys from 1997 to 2004. Receipt of additional intravenous immunoglobulin (IVIG) (data available all years) or any additional treatment (available for 2003-2004) were assessed as proxies for initial disease severity. We determined associations between earlier or later IVIG treatment (defined as receipt of IVIG on days 1-4 vs days 5-10 of illness) and cardiac complications by stratifying by receipt of additional treatment or by using logistic modeling to control for the effect of receiving additional treatment.
Results:
A total of 48 310 patients with KD were included in the analysis. In unadjusted analysis, earlier IVIG treatment was associated with a higher risk for 4 categories of cardiac complications, including all major cardiac complications (risk ratio, 1.10; 95% CI, 1.06-1.15). Stratifying by receipt of additional treatment removed this association, and earlier IVIG treatment became protective against all major cardiac complications when controlling for any additional treatment in logistic regressions (OR, 0.90; 95% CI, 0.80-1.00).
Conclusions:
Observed higher risks of cardiac complications among patients with KD receiving IVIG treatment on days 1-4 of the illness are most likely due to underlying higher initial disease severity, and patients with KD should continue to be treated with IVIG as early as possible.
Rheumatic diseases clinics of North America
R P Sundel
Kawasaki Disease
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals From the American Heart Association
B W Mccrindle
A H Rowley
J W Newburger
Kawasaki disease epidemic: pitfalls. Italian journal of pediatrics
R Gallizzi
G Corsello
G B Pajno
D W Kimberlin
Recommended publications
Article
Full-text available
Retropharyngeal abscess-like as an atypical presentation of Kawasaki disease: a case report and lite...
April 2023 · Pediatric Rheumatology
Rim Kasem Ali Sliman
Joris M. van Montfrans
Najwan Nassrallah
[...]
Mohamad Hamad Saied
Background
Kawasaki disease (KD) is a systemic inflammatory condition primarily affecting young children. Although 90% of KD patients present with variable head and neck manifestations, especially cervical lymphadenopathy, peritonsillar, retropharyngeal and parapharyngeal involvement are uncommonly reported as initial manifestations of KD.
Case report
Eight-year-old girl with prolonged fever, ... [Show full abstract] clinical and a radiological picture suggestive of retropharyngeal abscess, unresponsive to three changes in the antibiotic regimen and surgical drainage. The disease progressed with the development of additional signs and symptoms as non-purulent conjunctivitis (with uveitis), mucosal involvement (strawberry tongue and cracked lips), edema of her hands and feet, and arthritis. A diagnosis of Kawasaki disease was reached with complete remission after Intravenous Immunoglobulin (IVIG) treatment.
In addition, we present a literature review of similar cases reported in the last thirty years.
Conclusion
Kawasaki disease requires a high index of suspicion and awareness of unusual presentations. It should be kept in mind as one of the differential diagnosis of patients with febrile inflammation of the retropharyngeal and parapharyngeal spaces who do not respond to antibiotic treatment in the relevant clinical context.
Article
Full-text available
An Update on Reports of Atypical Presentations of Kawasaki Disease and the Recognition of IVIG Non-R...
April 2023 · Diagnostics
Cristiano Conte
Francesco Sogni
Donato Rigante
[...]
Susanna Esposito
Kawasaki disease (KD) is an acute vasculitis with an intrinsic risk of severe involvement of coronary arteries. The worldwide spread of KD and the importance of early diagnosis for preventing cardiovascular complications have ascertained the need for updating guidelines for prompt disease recognition and treatment efficacy assessment. All KD patients who comply with the definition of classic or ... [Show full abstract] atypical disease should be treated with intravenous immunoglobulin (IVIG) soon after diagnosis. The objective of our narrative review was to analyze the medical literature about case reports with atypical KD in relation to diagnosis and potential identification of predictors of non-responsiveness to IVIG. Our analysis has shown that the seminal challenge in KD management is the timeliness of diagnosis, although both extreme variability and transience of clinical manifestations make this goal difficult. A non-negligible percentage of patients, especially in the first 6 months of life, might have atypical manifestations of KD, whose painstaking differential diagnosis may be tricky. Many attempts to develop universal scoring systems and detect children at higher risk of IVIG resistance have been rather unsuccessful. Additionally, KD may show different evolutions according to unraveled demographic, genetic, or epigenetic factors. Further research is needed to elucidate all open questions about KD and clarify the long-term outcome of its potential complications.
View full-text
| https://www.researchgate.net/publication/366064170_A_CASE_OF_KAWASAKI_DISEASE_IN_AN_EIGHT-YEAR-OLD_BOY |
UNITED STATES v. GALLAGHE | 183 F.2d 342 (1950) | 3f2d3421429 | Leagle.com
MARIS Circuit Judge. The appellant was indicted on May 16 1941 in the United States District Court for the Eastern District...3f2d3421429
UNITED STATES v. GALLAGHER
No. 9990.
View Case
Cited Cases
Citing Case
183 F.2d 342 (1950)
UNITED STATES
v.
GALLAGHER.
United States Court of Appeals, Third Circuit. https://leagle.com/images/logo.png
Submitted October 3, 1949.
Resubmitted April 20, 1950.
Decided June 21, 1950.
Attorney(s) appearing for the Case
Harry B. Gallagher, pro se.
Alfred E. Modarelli, U. S. Attorney, Newark, N. J.; Grover C. Richman, Jr., Asst. U. S. Attorney, Camden, N. J.; Stuart B. Rounds, Asst. U. S. Attorney, Trenton, N. J., for appellee.
Before BIGGS, Chief Judge, and MARIS, GOODRICH, McLAUGHLIN, KALODNER and HASTIE, Circuit Judges.
United States Court of Appeals, Third Circuit.
MARIS, Circuit Judge.
The appellant was indicted on May 16, 1941 in the United States District Court for the Eastern District of Missouri on two counts. The first count charged him with transporting in interstate commerce a motor vehicle which he then knew to be stolen. The second count alleged that he received the same automobile moving as interstate commerce, knowing it to have been stolen. On June 25, 1946 appellant, being arrested in the District of New Jersey, stated in writing that he had received a copy of the indictment, that he desired to plead guilty to the charges of the indictment, that he waived trial in the district in which the charges were pending and that he consented to the disposition of the case in the District of New Jersey, subject to the approval of the United States Attorney for each district. The appellant was represented by counsel of his choice and the statement was signed by him and subscribed by his attorney as a witness. The whole procedure was in accordance with Criminal Procedure Rule 20, 18 U.S.C.A.
On July 12, 1946 the appellant pleaded guilty to the indictment in question in the District Court for the District of New Jersey and at the same time pleaded guilty to another indictment involving another crime. He was sentenced on the indictment in question for a term of five years, the execution of the sentence being suspended and the appellant being placed on probation for five years. On May 5, 1947 the appellant was brought before the District Court for the District of New Jersey for violation of his probation. The court terminated the probation and resentenced him to a term of five years which he is presently serving in the federal penitentiary at Atlanta, Georgia.
On March 31, 1949 the appellant filed in the District Court for the District of New Jersey a paper entitled "Motion in Arrest of Judgment". The motion was intended by him to be made under Section 2255 of Title 28, United States Code Annotated.
1
As grounds for his motion he asserted that
[183 F.2d 344]
the district court did not have jurisdiction to accept his plea of guilty and to sentence him upon the indictment because the automobile in question had not in fact been stolen but rather had been obtained by false pretenses in that it had been obtained by a purchase involving the delivery of a worthless check. The district court denied the motion. From its action in so doing the appellant took the appeal now before us.
Relief under Section 2255 may be granted only where it appears that "the judgment was rendered without jurisdiction, or that the sentence imposed was not authorized by law or otherwise open to collateral attack, or that there has been such a denial or infringement of the constitutional rights of the prisoner as to render the judgment vulnerable to collateral attack." Motions under this section may not be used to review the proceedings of the trial as upon appeal but merely to test their validity when judged upon the face of the record or by constitutional standards. The purpose of the section was not to confer a broader right of attack upon a judgment and sentence than might be made by habeas corpus but rather to provide that the attack which theretofore might have been made in some other court through resort to habeas corpus must now be made in the court where the sentence was imposed unless it should appear that this remedy was inadequate. 2
Here the appellant, with the advice of counsel, pleaded guilty to the indictment. That plea constituted an admission of his guilt, a waiver of all nonjurisdictional defects and defenses, 3and admitted all the facts averred in the indictment. 4The appellant, therefore, could not be heard to challenge those facts in a habeas corpus proceeding. 5Nor can he do so upon a motion under Section 2255 to set aside the judgment of conviction. 6
[183 F.2d 345]
The basic difficulty with the appellant's contention is that he misapprehends the nature and extent of the jurisdiction of the district court. He appears to think that even though he pleaded guilty to the charge against him the court was without jurisdiction to enter a judgment of conviction because, as he now asserts, he was not in fact guilty of the offense charged. But his plea of guilty was itself a conviction and the court had merely to give judgment and sentence thereon. 7 This the court unquestionably had power to do. For even if the action of the court could be considered as a determination that the facts justified the conviction and this was erroneous, the error would not have been jurisdictional in the sense that it would have deprived the court of the power to hear and determine the case. "Jurisdiction to decide," as Chief Justice Stone said in Pope v. United States, 1944, 323 U.S. 1 , 14, 65 S.Ct. 16, 23, 89 L.Ed. 3, "is jurisdiction to make a wrong as well as a right decision." Moreover a wrong decision upon the merits does not constitute a denial of due process of law if the opportunity of a full hearing is afforded. 8 Such a decision, therefore, does not involve a denial of constitutional rights which may be made the basis of a motion under Section 2255.
A further question is presented by the record and we, therefore, consider it although the appellant has not raised it. This is whether the District Court for the District of New Jersey had venue jurisdiction of the defendant. Criminal Procedure Rule 20 9expressly conferred such jurisdiction upon the district court under the circumstances of this case. Since the rule was adopted by the Supreme Court pursuant to authority granted by Congress the question comes down to whether the rule violates the Constitution. In United States v. Bink, 1947,74 F.Supp. 603, the District Court for the District of Oregon has held it to be unconstitutional. We do not agree.
Section 3231 of Title 18 United States Code,
10
confers general jurisdiction upon all the district courts of all offenses against the laws of the United States. The district court accordingly was vested with jurisdiction of the subject matter involved in the present case. But Section 3231 does not specify the particular district court in which a given offense is to be prosecuted. Venue for this purpose is prescribed by the Constitution and by the Criminal Procedure
[183 F.2d 346]
Rules. The basic provisions are in Article III, Section 2, Clause 3, of the Constitution 11 and in the Sixth Amendment. 12 These provide that the trial of persons accused of crime shall be held in the State and district wherein the crime shall have been committed. In accord with these constitutional provisions Criminal Procedure Rule 18 13 provides that the prosecution shall be had in the district in which the offense was committed except as otherwise permitted by statute or rule.
As we have seen, it is otherwise permitted by Rule 20, but only upon the express written waiver by the accused person, who desires to plead guilty or nolo contendere, of his right to trial in the district in which the prosecution is pending against him and his express written consent to the disposition of the case in the district in which he has been arrested. Since the rule operates only when the accused has expressly waived the venue fixed by the Constitution and Rule 18 the basic question is whether the Constitutional right to trial in the district in which the offense has been committed is a right which may be waived by the accused. In considering this question we assume, without deciding, that the proceedings had in the district court upon the appellant's consent and plea of guilty amounted to a "trial" in the constitutional sense.
The district courts are national courts. Their powers are not necessarily limited by the boundaries of the states in which they sit. There is no constitutional bar which prevents Congress from conferring nation-wide jurisdiction upon them. Indeed in a number of fields it has already done so. 14Accordingly there is no constitutional barrier to the operation of Rule 20 unless it be the venue provisions of Article III, Section 2, clause 3, and of the Sixth Amendment. But we think that the venue specified by these provisions, like other venue provisions, 15is a procedural right, which, while in a broad sense for the protection of the public generally, is in a very special sense a privilege accorded to the individual member of the public who has been accused of crime. Accordingly, as in the case of the other procedural privileges conferred upon accused persons by these particular clauses of the Constitution, 16the venue privilege may be waived by an individual defendant. 17
[183 F.2d 347]
We conclude that Criminal Procedure Rule 20 is not in conflict with the Constitution and that it conferred venue jurisdiction upon the district court in the present case. The court, therefore, had full power to dispose of the appellant's case. No other question having been raised which would support the appellant's motion under Section 2255 to set aside the judgment of conviction, the district court rightly denied the motion.
The order of the district court will be affirmed.
McLAUGHLIN, Circuit Judge (concurring).
In his motion to the District Court appellant swore that he had purchased the automobile in question; that he had not stolen it. If this be so, there is substantial authority that he did not commit the offense to which he had pleaded guilty. Ex parte Atkinson, D.C.E.D.S.C.,84 F.Supp. 300, 304; United States v. Patton, 3 Cir.,120 F.2d 73; Hite v. United States, 10 Cir.,168 F.2d 973; Loney v. United States, 10 Cir.,151 F.2d 1, 4; United States v. O'Carter, D.C., S.D.Iowa,91 F.Supp. 544. Contra, Davilman v. United States, 6 Cir.,180 F.2d 284; Taylor v. United States, 4 Cir.,177 F.2d 194.
Appellant asserts that he mistakenly pleaded guilty to a crime which he had not committed. He says that his attorney, perhaps through inadvertence, advised such course. He may be wrong in his contentions but at least he should be allowed to submit those contentions to the scrutiny of the Court.
Since it is correct that the decisions construing Section 2255 hold it to be a substitute for habeas corpus confined to the trial court, I think it important to note that appellant's claim that he is in prison for an offense of which he is innocent, can and should be heard on an application under Rule 32(d) of the Federal Rules of Criminal Procedure. This reads: "Withdrawal of Plea of Guilty. A motion to withdraw a plea of guilty or of nolo contendere may be made only before sentence is imposed or imposition of sentence is suspended; but to correct manifest injustice the court after sentence may set aside the judgment of conviction and permit the defendant to withdraw his plea."
The inquiry would be to fairly ascertain whether the plea of guilty was "given through ignorance, fear or inadvertence. Such an application does not involve any question of guilt or innocence." Kercheval v. United States,274 U.S. 220, 224, 47 S.Ct. 582, 583, 71 L.Ed. 1009. See also United States v. Colonna, 3 Cir.,142 F.2d 210, 212.
FootNotes
1. "§ 2255. Federal custody; remedies on motion attacking sentence
"A prisoner in custody under sentence of a court established by Act of Congress claiming the right to be released upon the ground that the sentence was imposed in violation of the Constitution or laws of the United States, or that the court was without jurisdiction to impose such sentence, or that the sentence was in excess of the maximum authorized by law, or is otherwise subject to collateral attack, may move the court which imposed the sentence to vacate, set aside or correct the sentence.
"A motion for such relief may be made at any time.
"Unless the motion and the files and records of the case conclusively show that the prisoner is entitled to no relief, the court shall cause notice thereof to be served upon the United States attorney, grant a prompt hearing thereon, determine the issues and make findings of fact and conclusions of law with respect thereto. If the court finds that the judgment was rendered without jurisdiction, or that the sentence imposed was not authorized by law or otherwise open to collateral attack, or that there has been such a denial or infringement of the constitutional rights of the prisoner as to render the judgment vulnerable to collateral attack, the court shall vacate and set the judgment aside and shall discharge the prisoner or resentence him or grant a new trial or correct the sentence as may appear appropriate.
"A court may entertain and determine such motion without requiring the production of the prisoner at the hearing.
"The sentencing court shall not be required to entertain a second or successive motion for similar relief on behalf of the same prisoner.
"An appeal may be taken to the court of appeals from the order entered on the motion as from a final judgment on application for a writ of habeas corpus.
"An application for a writ of habeas corpus in behalf of a prisoner who is authorized to apply for relief by motion pursuant to this section, shall not be entertained if it appears that the applicant has failed to apply for relief, by motion, to the court which sentenced him, or that such court has denied him relief, unless it also appears that the remedy by motion is inadequate or ineffective to test the legality of his detention. As amended May 24, 1949, c. 139, § 114, 63 Stat. 105."
2. Birtch v. United States, 4 Cir., 1949,
173 F.2d 316
; Carvell v. United States, 4 Cir., 1949,
173 F.2d 348
; Taylor v. United States, 4 Cir., 1949,
177 F.2d 194
; Pulliam v. United States, 10 Cir., 1949,
178 F.2d 777
; Davilman v. United States, 6 Cir., 1950,
180 F.2d 284
.
3. Rice v. United States, 5 Cir., 1929,
30 F.2d 681
; Weir v. United States, 7 Cir., 1937,
92 F.2d 634
, 635, 114 A.L.R. 481, certiorari denied 302 U.S. 761, 58 S.Ct. 368, 82 L.Ed. 590; Weatherby v United States, 10 Cir., 1945,
150 F.2d 465
, 466.
4. Lindsay v. United States, 10 Cir., 1943,
134 F.2d 960
, 962, certiorari denied 319 U.S. 763, 63 S.Ct. 1316, 87 L.Ed. 1714; Hood v. United States, 8 Cir., 1946,
152 F.2d 431
, 433; Maye v. Pescor, 8 Cir., 1947,
162 F.2d 641
, 643; Thornburg v. United States, 10 Cir., 1947,
164 F.2d 37
, 39.
5. Birtch v. Hunter, 10 Cir., 1946, 158 F.2d 134 , 136, certiorari denied 331 U.S. 825, 67 S.Ct. 1314, 91 L.Ed. 1841.
6. United States v. Sturm, 7 Cir., 1950, 180 F.2d 413 .
7. Kercheval v. United States, 1927, 274 U.S. 220 , 223, 47 S.Ct. 582, 71 L.Ed. 1009.
8. Central Land Company of West Virginia v. Laidley, 1895,
159 U.S. 103
, 112, 16 S.Ct. 80, 40 L.Ed. 91; Jones v. Buffalo Creek Coal Co., 1917,
245 U.S. 328
, 329, 38 S.Ct. 121, 62 L.Ed. 325; Corrigan v. Buckley, 1926,
271 U.S. 323
, 332, 46 S.Ct. 521, 70 L.Ed. 969.
9. "Rule 20. Transfer From the District for Plea and Sentence
"A defendant arrested in a district other than that in which the indictment or information is pending against him may state in writing, after receiving a copy of the indictment or information, that he wishes to plead guilty or nolo contendere,to waive trial in the district in which the indictment or information is pending and to consent to disposition of the case in the district in which he was arrested, subject to the approval of the United States attorney for each district. Upon receipt of the defendant's statement and of the written approval of the United States attorneys, the clerk of the court in which the indictment or information is pending shall transmit the papers in the proceeding or certified copies thereof to the clerk of the court for the district in which the defendant is held and the prosecution shall continue in that district. If after the proceeding has been transferred the defendant pleads not guilty, the clerk shall return the papers to the court in which the prosecution was commenced and the proceeding shall be restored to the docket of that court. The defendant's statement shall not be used against him unless he was represented by counsel when it was made."
10. "§ 3231. District courts
"The district courts of the United States shall have original jurisdiction, exclusive of the courts of the States, of all offenses against the laws of the United States. * * *"
11. Article III, Section 2, clause 3 of the Constitution:
"The Trial of all Crimes, except in Cases of Impeachment, shall be by Jury; and such Trial shall be held in the State where the said Crimes shall have been committed; but when not committed within any State, the Trial shall be at such Place or Places as the Congress may by Law have directed."
12. The Sixth Amendment:
13. "Rule 18. District and Division
"Except as otherwise permitted by statute or by these rules, the prosecution shall be had in a district in which the offense was committed, but if the district consists of two or more divisions the trial shall be had in a division in which the offense was committed."
14. See, for example, § 5 of the Sherman Act and § 12 of the Clayton Act, which authorize extraterritorial service upon a defendant corporation, 15 U.S.C.A. §§ 5, 22; Chapter X of the Bankruptcy Act, which confers upon the bankruptcy court exclusive jurisdiction of the debtor and its property wherever located, 11 U.S. C.A. § 511; and the Federal Interpleader Act, which authorizes extraterritorial service upon claimants in interpleader, 28 U.S.C.A. § 2361.
15. Panama R. Co. v. Johnson, 1924, 264 U.S. 375 , 385, 44 S.Ct. 391, 68 L.Ed. 748; 28 U.S.C.A. § 1406(b).
16. See United States v. Sorrentino, 3 Cir., 1949, 175 F.2d 721 , certiorari denied 338 U.S. 868, 70 S.Ct. 143, and cases therein cited.
17. Hagner v. United States, 1931, 60 App. D.C. 335,
54 F.2d 446
; Mahaffey v. Hudspeth, 10 Cir., 1942,
128 F.2d 940
, certiorari denied 317 U.S. 666, 63 S.Ct. 76, 87 L.Ed. 535; United States v. Jones, 2 Cir., 1947,
162 F.2d 72
.
| https://www.leagle.com/decision/1950525183f2d3421429 |
Ischemia-reperfusion of the liver impairs the inducibility of microsomal cytochrome P450 system by phenobarbital in rats | Request PDF
Request PDF | Ischemia-reperfusion of the liver impairs the inducibility of microsomal cytochrome P450 system by phenobarbital in rats | Using the animal model of warm ischemia and reperfusion of the liver (male Spraque-Dawley rats) we have shown that during reperfusion the... | Find, read and cite all the research you need on ResearchGate
Ischemia-reperfusion of the liver impairs the inducibility of microsomal cytochrome P450 system by phenobarbital in rats
January 2002
Acta Poloniae Toxicologica10(2):111-122
Authors:
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Ryszard Wiaderkiewicz
Medical University of Silesia in Katowice
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A. Wiaderkiewicz
A. Wiaderkiewicz
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Piotr Czekaj
Medical University of Silesia in Katowice
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
T. Lebda-Wyborny
T. Lebda-Wyborny
Abstract
Using the animal model of warm ischemia and reperfusion of the liver (male Spraque-Dawley rats) we have shown that during reperfusion the cytochrome P450 system in the rat liver is seriously impaired. Protein expression of CYP1A1, CYP2B1/B2 and CYP2E1 afte 24 h of reperfusion was reduced by 30% and their corresponding enzymatic activities (EROD, PROD, MROD) dropped by 50-70%. After stimulation with phenobarbital during reperfusion the expression of CYP2B1/B2 protein was 3 times lower, and their enzymatic PROD activity even 8 times lower, than in the corresponding group not subjected to ischemia/reperfusion. The results indicate that during ischemia and reperfusion detoxification of many xenobiotics that depend on the cytochrome P450 metabolism may be affected.
<here is a image 175d1bd4b7439d95-754927124da715c1>
Phenobarbital-induced expression of cytochrome P450 genes
Article
Full-text available
Feb 2000
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Piotr Czekaj
In contrast to the well-known Ah receptor-mediated regulation of the CYP1A1 gene by polycyclic aromatic hydrocarbons, the molecular mechanism by which phenobarbital (PB) and PB-like inducers affect transcription of CYP genes remains unknown; no receptor for these chemicals has been found to date. However, in the last 5 years PB-responsive sequences have been identified in the 5' flanking regions of several P450 genes. The phenobarbital-responsive enhancer unit (PBRU) of CYP2B gene family members contain two potential nuclear receptor binding sites (NR1 and NR2) that flank a nuclear factor 1 (NF-1) binding motif. The nuclear factors that regulate PBRU activity have not yet been characterized. It seems that PB may activate multiple nuclear orphan receptors to induce various CYP genes. CYP2B and CYP3A genes appear to be targets for the orphan receptors CAR and PXR, respectively. It is also possible that the pleiotropic effects of PB can, in part, be explained by the ability of the CAR-RXR heterodimer to bind to a variety of nuclear receptor binding motifs. The induction of cytochromes P450 may result in interactions between xenobiotics and in the interference of xenobiotic metabolism and endogenous signalling pathways.
Kupffer cell inhibition and its effect on ischemia/reperfusion injury as well as the biotransforming potential of the liver
Article
Jan 1999
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Ryszard Wiaderkiewicz
Anna Wiaderkiewicz
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Danuta Plewka
S Kuśmierski
Kupffer cells are believed to play an important role during ischemia- reperfusion (IR) injury of the liver, mostly by releasing pro-inflammatory factors and oxygen free radical formation. In our study we investigated the effect of pharmacological Kupffer cell inhibition by gadolinium chloride (GdCl3 - a selective Kupffer cell toxicant) on IR injury, as well as the biotransforming potential of the liver intoxicated with the organophosphorous insecticide - chlorfenvinphos. The study was performed on rats divided into 6 groups. Group 1 served as the control. Group 2 rats were subjected to 60 min of ischemia followed by 24 hours of reperfusion (I/R). Group 3 rats received chlorfenvinphos (i.p. - 2 mg/kg body weight) and were sacrificed after 24 hours. Group 4 rats received chlorfenvinphos after 30 min of ischemia and were sacrificed after 24 hours of reperfusion. Group 5 rats were subjected to I/R and GdCl3 was injected (i.v.) prior to reperfusion. Group 6 comprised rats subjected to I/R, treated with GdCl3 as mentioned above and injected with chlorfenvinphos. Liver sections were evaluated morphologically (H and E staining) and histochemically (SDH, LDH, G6Pase, Mg+2 ATPase and AcP activity). We evaluated the total content of cytochromes P450 and b5, activities of their corresponding NADPH and NADH reductases, as well as the presence of CYP1A1, CYP2E1 and CYP2B1/B2 isoforms in the microsomal fraction of the liver. I/R affects all studied enzyme activities and reduces the cytochrome P450 content and activity of its NADPH reductase. Amongst the studied isoforms, CYP2B1/B2 are mostly affected by IR. Intraperitoneal injection of chlorfenvinfos alone caused slight damage to the liver, although dramatically affected all studied parameters in rats subjected to I/R. The injection of gadolinium chloride alone has no effect on the structure nor biotransforming potential of the liver. However, the injection of GdCl3 prior to reperfusion demonstrated a beneficial effect on the activity of marker enzymes and diminished the morphological liver changes caused by I/R.
Cytochrome P450 dependent xenobiotic activation by physiological hydroperoxides in intact hepatocytes
Article
Dec 1997
EUR J DRUG METAB PH
<here is a image c86022ae136e43a9-450c42b23d8494bf> M. Reza Anari
S Khan
S D Jatoe
P J O'Brien
Xenobiotic metabolic activation by intact hepatocytes was recently shown to be enhanced by the addition of nontoxic concentrations of t-butyl hydroperoxide and prevented by cytochrome P450 inhibitors. Furthermore, H2O2 (Km = 103 microM) was found to be highly effective in supporting the human microsomal CYP1A2 catalyzed metabolic activation of the heterocyclic aromatic amine 2-amino-3-methylimidazo (4,5-f) quinoline (IQ) to mutagenic metabolites and the DNA adduct formed was the same as that formed by the mixed-function oxidase catalyzed activation system. In the following, it is shown that the cytotoxicity of other xenobiotics including carcinogenic arylamines and their N-hydroxyarylamine metabolites were markedly enhanced by hydroperoxide addition but not in the presence of cytochrome P450 inhibitors. The CYP1A2 dependent O-demethylation of methoxyresorufin in 3-methylcholanthrene induced hepatocytes was also markedly enhanced when intracellular H2O2 was generated by the mitochondrial monoamine oxidase (MAO) substrates tyramine or kynurenamine. Linoleic acid hydroperoxide also dramatically enhanced the cytotoxicity of phenelzine towards isolated hepatocytes and the microsomal metabolism of phenelzine to form ethylbenzene. The P450 inhibitors phenylimidazole, benzylimidazole prevented the metabolic activation of phenelzine but not lipid peroxidation. These results suggest that linoleic acid hydroperoxide can activate hydrazines via a cytochrome P450 peroxidase catalyzed one electron oxidation to form highly cytotoxic reactive intermediates. Furthermore, increased hydrogen peroxide formation, e.g. as a result of oxidative stress, would also be expected to enhance the metabolic activation of carcinogenic arylamines via the peroxygenase function of CYP1A2.
Inhibition of monooxygenase activities in human hepatocytes by interferons
Article
Jul 1993
TOXICOL IN VITRO
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Teresa Donato
E Herrero
<here is a image 5d01ff5fbd816538-a3e81e5c9f9f583c> Mª José Gómez-Lechón
<here is a image 7e51230d0f19945f-4b1fc4f37159d368> Jose V Castell
The effects of human recombinant interferons alpha and gamma on monooxygenase activities in cultured human hepatocytes have been investigated. Dose-response and time course studies showed that interferons reduced 7-ethoxyresorufin O-deethylase activity of human hepatocytes after a 12-hr incubation with 300 U/ml interferons alpha and gamma (52% and 38% decrease, respectively). A reduction in 7-ethoxyresorufin O-deethylase activity was also observed in HepG2 cells, although in these cells maximal inhibition was observed after 24 hr of treatment with 1000 U/ml (a 41% and 28% decrease with interferon alpha and gamma, respectively). A decrease in activity was also observed in 7-pentoxyresorufin O-depentylase, 7-ethoxycoumarin O-deethylase and testosterone 2alpha- and 6beta-hydroxylase. It is noteworthy that the marked increase in 7-ethoxyresorufin O-deethylase activity detected in human hepatocytes after incubation with 2 mum-3-methylcholanthrene (10-fold over non-treated cells) was reduced by 40% in the presence of interferons (300 U/ml), thus indicating that the inducibility of monooxygenases could be altered by interferon treatment. The inhibitory effect of interferons on 7-ethoxyresorufin O-deethylase was transient and HepG2 cells recovered their normal activity 24 hr after interferon removal from culture medium. This study provides the first direct evidence that interferons down-regulate the level of monooxygenases in human hepatic cells and prevent, in part, their induction by xenobiotics.
[5] Isolation of microsomal subfractions by use of density gradients
Article
Feb 1978
METHOD ENZYMOL
Gustav Dallner
This chapter provides information on the isolation of microsomal subfractions by use of density gradients. To avoid contamination of microsomes by fragments of organelles other than the endoplasmic reticulum (ER), relatively gentle homogenization (4 x 400 rpm) is required. Isolation of rough and smooth microsomes with a sucrose gradient containing cations is an effective and rapid procedure, but both cation-free water and careful maintenance of laboratory animals are required to avoid aggregation. It is possible to carry out density gradient centrifugation using metrizamide gradients because this substance has a low viscosity in aqueous solutions even when gradients with high density are formed. Metrizamide is nonionic, does not inhibit microsomal enzymes, and has no detergent effects on membranes, making this solute advantageous for density gradient centrifugation of microsomal fractions. It appears that deoxycholate liberates membrane fragments, which upon gradient centrifugation equilibrate in different bands. The presence of similar fragments in high concentration within the same band may result in aggregation of these fragments to larger particles.
<here is a image 10f6caeae07305d1-145472182745f952> Michele Gottardi
Andreas Kretschmann
<here is a image b3eb654a69c348e7-e4daeeeb7af8edc8> Nina Cedergreen
| https://www.researchgate.net/publication/287369342_Ischemia-reperfusion_of_the_liver_impairs_the_inducibility_of_microsomal_cytochrome_P450_system_by_phenobarbital_in_rats |
Modeling the Cross Section of Stock Returns Using Sensible Models in a Model Pool | Request PDF
Request PDF | On Jan 1, 2017, I-Hsuan Ethan Chiang and others published Modeling the Cross Section of Stock Returns Using Sensible Models in a Model Pool | Find, read and cite all the research you need on ResearchGate
Modeling the Cross Section of Stock Returns Using Sensible Models in a Model Pool
DOI: 10.2139/ssrn.3064014
Queensland University of Technology
Qing Zhou
Qing Zhou
Combining density forecasts using focused scoring rules
Article
Full-text available
May 2017
<here is a image 3222598839f25e58-a72fddaad10c683d> Anne Opschoor
<here is a image 9d3c359308f320a4-72c58de0ffd478fb> Dick van Dijk
Michel van der Wel
We investigate the added value of combining density forecasts focused on a specific region of support. We develop forecast combination schemes that assign weights to individual predictive densities based on the censored likelihood scoring rule and the continuous ranked probability scoring rule (CRPS) and compare these to weighting schemes based on the log score and the equally weighted scheme. We apply this approach in the context of measuring downside risk in equity markets using recently developed volatility models, including HEAVY, realized GARCH and GAS models, applied to daily returns on the S&P 500, DJIA, FTSE and Nikkei indexes from 2000 until 2013. The results show that combined density forecasts based on optimizing the censored likelihood scoring rule significantly outperform pooling based on equal weights, optimizing the CRPS or log scoring rule. In addition, 99% Value-at-Risk estimates improve when weights are based on the censored likelihood scoring rule.
The Poor Predictive Performance of Asset Pricing Models
Full-text available
Jun 2008
J FINANC QUANT ANAL
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Tim Simin
Thesis (Ph. D.)--University of Washington, 2002 This paper examines the time-series forecast errors of conditional and unconditional asset pricing models for both portfolio and individual firm equity returns. The mean squared forecast error of models is decomposed into separate variance and bias components. A new result concerning model specification and forecasting is also introduced. The results indicate that conditional versions of the models generally produce lower mean squared errors than do unconditional versions for in-sample but not for step-ahead prediction. This holds true even for individual firm data when the instruments are firm specific. Time varying parameter specifications of conditional asset pricing models typically produce mean square forecast errors that are larger then those of fixed parameter specifications. While the models produce relatively unbiased predictions, their one step ahead predictive ability rarely exceeds that of simple benchmarks.
An Inter-Temporal Capital Asset Pricing Model
Feb 1973
ECONOMETRICA
<here is a image 857c041c951327c7-41efb0d5392946a7> Robert C. Merton
An intertemporal model for the capital market is deduced from the portfolio selection behavior by an arbitrary number of investors who act so as to maximize the expected utility of lifetime consumption and who can trade continuously in time. Explicit demand functions for assets are derived, and it is shown that, unlike the one-period model, current demands are affected by the possibility of uncertain changes in future investment opportunities. After aggregating demands and requiring market clearing, the equilibrium relationships among expected returns are derived, and contrary to the classical capital asset pricing model, expected returns on risky assets may differ from the riskless rate even when they have no systematic or market risk.
Model Confidence Sets and forecast combination
Article
Mar 2017
INT J FORECASTING
Jon D. Samuels
Rodrigo Sekkel
A longstanding finding in the forecasting literature is that averaging the forecasts from a range of models often improves upon forecasts based on a single model, with equal weight averaging working particularly well. This paper analyzes the effects of trimming the set of models prior to averaging. We compare different trimming schemes and propose a new approach based on Model Confidence Sets that takes into account the statistical significance of the out-of-sample forecasting performance. In an empirical application to the forecasting of U.S. macroeconomic indicators, we find significant gains in out-of-sample forecast accuracy from using the proposed trimming method.
Hedge Fund Replication: A Model Combination Approach
Article
Jul 2016
Michael S. O'Doherty
N. E. Savin
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Ashish Tiwari
Recent years have seen increased demand from institutional investors for passive replication products that track the performance of hedge fund strategies using liquid investable assets such as futures contracts. In practice, linear replication methods suffer from poor tracking performance and high turnover. We propose a model combination approach to index replication that pools information from a diverse set of pre-specified factor models. Compared with existing methods, the pooled clone strategies yield consistently lower tracking errors, generate less severe portfolio drawdowns, and require substantially smaller trading volume. The pooled hedge fund clones also provide economic benefits in a portfolio allocation context.
Evaluating hedge funds with pooled benchmarks
Jan 2016
Michael S. O'Doherty
N. E. Savin
A. Tiwari
The evaluation of hedge fund performance is challenging given the flexible nature of hedge funds' strategies and their lack of operational transparency. As a result, inference about skill is inevitably contaminated by the error in the benchmark model. To address this concern, we propose a model pooling approach to develop a fund-specific benchmark obtained by pooling a set of diverse attribution models. The weights assigned to the individual models in the pool are based on the log score criterion, an information-theoretic measure of the conditional performance of a model. We illustrate the advantages of a pooled benchmark over alternative approaches, including the Fung and Hsieh [Fung W, Hsieh DA (2004) Hedge fund benchmarks: A risk-based approach. Financial Analysts J. 60:65-80] model, stepwise regression methods, and style-adjusted methods in the contexts of a real-time investment strategy, hedge fund replication, and fund failure prediction.
| https://www.researchgate.net/publication/321087139_Modeling_the_Cross_Section_of_Stock_Returns_Using_Sensible_Models_in_a_Model_Pool |
Crystals | Free Full-Text | Effect of Various Nanoparticles (GaF3, ZnF2, Zn(BF4)2 and Ga2O3) Additions on the Activity of CsF-RbF-AlF3 Flux and Mechanical Behavior of Al/Steel Brazed Joints
In this study, brazing AA6061 to Q235 steel using flame brazing was performed with 70.9 wt.% CsF-0.5 wt.% RbF-28.6 wt.% AlF3 fluxes doped with GaF3, ZnF2, Zn(BF4)2 and Ga2O3 nanoparticles, matched with a Zn-15Al filler metal, and the spreadability of the filler metal and the mechanical properties of brazed joints were investigated at the same time. The results showed suitable amounts of GaF3, ZnF2, Zn(BF4)2 and Ga2O3 doped into the base flux could strengthen the filler metal in wetting and spreading on the surface of aluminum alloy and steel to different degrees. The suitable ranges of GaF3, ZnF2, Zn(BF4)2 and Ga2O3, respectively, were 0.0075& ndash;0.01 wt.%, 0.0075& ndash;0.01 wt.%, 0.0075& ndash;0.01 wt.% and 0.009& ndash;0.01 wt.%, and the maximum spreading area was obtained via doping with GaF3. The shear strength of brazed joints reached the peak at 126 MPa when 0.075 wt.% GaF3 was added. Comparative tests proved that the activity of the CsF-RbF-AlF3 flux doped with GaF3 was the best. The reason was that the CsF-RbF-AlF3-GaF3 flux was competent in removing oxides of the base metal and decreasing the interfacial tension, in virtue of the activity of Ga3+ as well as F& minus;.
Background:
Effect of Various Nanoparticles (GaF 3 , ZnF 2 , Zn(BF 4 ) 2 and Ga 2 O 3 ) Additions on the Activity of CsF-RbF-AlF 3 Flux and Mechanical Behavior of Al/Steel Brazed Joints
by Zhen Yao , Songbai Xue * and Junxiong Zhang
College of Materials Science and Technology, Nanjing University of Aeronautics and Astronautics, Nanjing 210016, China
Author to whom correspondence should be addressed.
Crystals 2020 , 10 (8), 683; https://doi.org/10.3390/cryst10080683
Received: 15 July 2020 / Revised: 1 August 2020 / Accepted: 5 August 2020 / Published: 7 August 2020
(This article belongs to the Special Issue Intermetallic Compound )
Abstract
In this study, brazing AA6061 to Q235 steel using flame brazing was performed with 70.9 wt.% CsF-0.5 wt.% RbF-28.6 wt.% AlF
3
fluxes doped with GaF
3
2
, Zn(BF
4
)
2
and Ga
2
O
3
nanoparticles, matched with a Zn-15Al filler metal, and the spreadability of the filler metal and the mechanical properties of brazed joints were investigated at the same time. The results showed suitable amounts of GaF
3
, ZnF
2
, Zn(BF
4
)
2
and Ga
2
O
3
doped into the base flux could strengthen the filler metal in wetting and spreading on the surface of aluminum alloy and steel to different degrees. The suitable ranges of GaF
3
, ZnF
2
, Zn(BF
4
)
2
and Ga
2
O
3
, respectively, were 0.0075–0.01 wt.%, 0.0075–0.01 wt.%, 0.0075–0.01 wt.% and 0.009–0.01 wt.%, and the maximum spreading area was obtained via doping with GaF
3
. The shear strength of brazed joints reached the peak at 126 MPa when 0.075 wt.% GaF
3
was added. Comparative tests proved that the activity of the CsF-RbF-AlF
3
flux doped with GaF
3
was the best. The reason was that the CsF-RbF-AlF
3
-GaF
3
flux was competent in removing oxides of the base metal and decreasing the interfacial tension, in virtue of the activity of Ga
3+
as well as F
−
.
Keywords:
GaF 3
;
ZnF 2
;
Zn(BF 4 ) 2
;
Ga 2 O 3
;
flux
;
Zn-Al filler metal
;
spreadability
;
mechanical properties
1. Introduction
The increase in joining dissimilar metals has been prompted by the increasing demand for light weights and fuel efficiency in modern industries in recent years [
1
]. The emerging trend towards lightweight, high performance and emissions reduction is leading to the increasing use of multi-material hybrid structures in electric vehicles [
2
]. The hybrid structure of aluminum and steel are superior to conventional materials because of the high mechanical properties of steel and the excellent corrosion resistance of aluminum [
3
]. Naturally, the combination of aluminum alloy and steel shows huge research value and future potential, and has become the subject of many investigators [
4
].
However, it remains an unconquerable problem to get stable brazed joints between aluminum/metals dissimilar to steel because of the formation of brittle and hard intermetallic compounds, like Fe x Al y [ 5 ]. The complexity and randomness of the brazing process makes the design and development of brazing materials more complicated and time-consuming than ordinary materials [ 6 ]. Therefore, it is absolutely imperative to control the formation of Fe-Al intermetallic compounds. EI-Sayed and Naka [ 7 ] found that the maximum bond shear strength of 127 MPa was obtained for an Al-steel joint brazed at 663 K with a 3 s ultrasound application time using a Zn-14Al alloy. It was reported that the shear strength of brazed joints reached the peak at 131 MPa when the Zn–15Al filler metal was added in the joining of lap joints of 6061 aluminum alloy to the 304 stainless steel via a flame brazing process, with the Zn-xAl filler metals matching the CsF-0.5 wt.% RbF-AlF 3 flux [ 8 ]. The interfacial layer in the weld made with the Zn-15Al filler metal was comprised of (FeAl 3 )Zn x and (Fe 2 Al 5 )Zn x [ 9 ].
Nanomaterials have been widely applied due to their unique properties. Joining technology at the nanometer scale has gradually developed with the popularity of nanomaterials, which have broad application prospects in the fields of electronics, aero-space, biology and health care [
10
]. Previous studies have indicated that [
11
] trace amounts of Ga
2
O
3
addition in the CsF-0.5 wt.% RbF-AlF
3
flux could obviously strengthen the Zn-2Al filler metal in its wetting and spreading on the surface of 5052 aluminum alloy and Q235 low-carbon steel. One previous study discussed how the addition of GaF
3
and Ga
2
O
3
nanoparticles influenced the wettability and spreadability of the CsF-AlF
3
flux under the same conditions [
12
].
The influence that adding heavy metal fluoride, ZnF 2 , SnF 2 , CdF 2 , PbF 2 and KBF 4 into the KF-AlF 3 flux has on the spreadability of brazing aluminium was investigated, and adding ZnF 2 could greatly improve the brazing area [ 13 ]. Therefore, the fourth component, ZnF 2 , has been considered for doping into CsF-0.5 wt.% RbF-AlF 3 flux in order to reduce the price in this paper. ZnCl 2 and SnCl 2 were added into the CsF-AlF 3 flux for connecting aluminium alloys [ 14 ]. The joints were bonded soundly when the mass fractions of ZnCl 2 and SnCl 2 are about 4%.
The effect of KBF 4 addition on the microstructure of the Mg-6Zn-1Si alloy has been investigated [ 15 ], and the morphology of the Mg 2 Si phase changed with the addition of 1.5 wt.% KBF 4 . To compare the activity of BF 4 − and its unified positive ions in reducing the variables, Zn(BF 4 ) 2 has been chosen.
In this paper, brazing AA6061 to Q235 steel using flame brazing has been performed with improved CsF-0.5 wt.% RbF-AlF
3
fluxes doped with a GaF
3
, ZnF
2
, Zn(BF
4
)
2
and Ga
2
O
3
nanoparticles-matched Zn-15Al filler metal, and the spreadability of the filler metal and the mechanical properties of the brazed joints were investigated at the same time. XDR analysis was carried out and the reaction mechanism was analyzed. The results could be useful for brazing AA6061 to Q235 steel while choosing a suitable flux.
2. Materials and Methods
The 6061 aluminum alloy and Q235 steel were used in this work as base metals. The compositions of the base metals were listed in
Table 1
and
Table 2
. Zn–15Al alloys were chosen as the filler metal. A CsF-0.5 wt.% RbF-AlF
3
flux was prepared by using commercial CsF-AlF
3
flux and an RbF of AR purity (Zhejiang Xinrui Welding Materials Co., Ltd., Shengzhou, China). CsF-RbF-AlF
3
-GaF
3
fluxes with different compositions of AR purity GaF
3
were confected and the range of GaF
3
was 0.0001–0.125 wt.%. Same amounts of ZnF
2
, and Zn(BF
4
)
2
of AR purity were doped in the same way to obtain CsF-RbF-AlF
3
-ZnF
2
fluxes and CsF-RbF-AlF
3
-Zn(BF
4
)
2
fluxes. Nano Ga
2
O
3
powder in the same range was doped into the CsF-RbF-AlF
3
flux to get the corresponding CsF-RbF-AlF
3
-Ga
2
O
3
fluxes. After mixing into a liquid, the fluxes were then dried to powder with the oven. The chemical compositions of these four nanoparticles doped into the fluxes has been listed in
Table 3
.
Table 1. Chemical composition of 6061 aluminum alloy (wt.%).
Table 2. Chemical composition of Q235 steel (wt.%).
Table 3. Chemical composition of nanoparticles doped into the fluxes (wt.%).
Zn–15Al alloys were extruded into a 2 mm diameter wire as an advanced preparation. SiC paper was used for mechanically polishing the specimens and filler metals. Before brazing, these materials were all degreased with acetone and cleaned by ethanol.
In order to prepare for the spreading test, the base metals were processed into plates of 40 mm × 40 mm × 3 mm. The spreading test was performed according to China’s National Standard GB 11364-2008. The weights of the solder and flux used in the test should be 100 mg and 15 mg, respectively. The filler metals were placed in the center of the base metals covered with the fluxes prepared previously, as in
Figure 1
, and then put into the electrical resistance furnace (Zhejiang Xinrui Welding Materials Co., Ltd., Shengzhou, China). The heating temperature was uniformly set at 530 °C. The holding time of each test was set as 60 s. After spreading, the test boards were cleaned using ultrasonic wave waits and the spreading areas were calculated by the software Image-ro Plus (Image-Pro Plus Version 6.0). To be specific, we photographed the spreading boards with the graduated ruler and imported the image into Image-Pro Plus. By determining the actual scale in the picture and using chromatic aberration to circle the spreading outline, the spreading areas could be calculated. For the credibility of the results, the above tests of each group were repeated 5 times and the spreading areas of each group were averaged. At last, the residues of the fluxes were collected and the components in the residues were analyzed with a Brucker D8 XRD analyzer (Ningbo Institute of Materials Technology & Engineering, Ningbo, China).
Figure 1. Schematic diagram of the spreading test (mm).
For the shear performance tests, the supplied base metals for the brazed joint were processed into plates with the size of 60 mm × 25 mm × 3 mm.
Figure 2
shows the schematic illustration of the brazed joint. The shear performance tests of the AA6061/Q235 brazed joints were carried out in strict accordance with China’s National Standard GB 11363-2008. The equipment was an SAMS-CMT5105 universal tensile testing machine (Nanjing University of Aeronautics and Astronautics, Nanjing, China), and the loading rate in the tensile process was 3 mm/min. The test results for each group of samples were all averaged from 5 samples. The brazing temperature was detected and controlled at around 530 °C.
Figure 2. Schematic illustration of the brazed joint (mm).
3. Results and Discussion
3.1. The Spreadability and Wettability of Zn-15Al Filler Metal
The influence of GaF
3
, ZnF
2
, Zn(BF
4
)
2
and Ga
2
O
3
particles, doped into CsF-0.5 wt.% RbF-AlF
3
fluxes, on the spreadability of the Zn-15Al filler metal was studied via spreading tests performed on the surface of the 6061 aluminum alloy and the Q235 steel. The results were as follows.
The relationships between the concentrations of GaF
3
, ZnF
2
, Zn(BF
4
)
2
and Ga
2
O
3
and the spreading areas on the 6061 aluminum alloy are shown in
Figure 3
a. While the content of GaF
3
was 0.01 wt.%, the spreading area was maximized to 329 mm
2
, which was 65% larger than the area without any addition. With 0.0075 wt.%-doped ZnF
2
, the spreading area was maximized at 312 mm
2
, and showed a 56% increase compared with the results derived without adding ZnF
2
. While the content of Zn(BF
4
)
2
was 0.0075 wt.%, the spreading area was maximized at 304 mm
2
, and was 52% larger than the area without any addition. With 0.009 wt.%-doped Ga
2
O
3
, the spreading area was maximized at 321 mm
2
and showed a 61% increase compared with the results derived without adding Ga
2
O
3
.
Figure 3. Spreading areas of Zn-15Al filler metal ( a ) 6061 aluminum alloy; ( b ) Q235 steel.
Figure 3
b showed that the spreadability of the Zn-15Al filler metal over Q235 steel was clearly improved with GaF
3
doped into the CsF-RbF-AlF
3
flux, compared to others. While the content of GaF
3
was 0.0075 wt.%, the spreading area was maximized at 189 mm
2
. With 0.01 wt.%-doped ZnF
2
, the spreading area was maximized at 155 mm
2
. While the content of Zn(BF
4
)
2
was 0.01 wt.%, the spreading area was maximized at 149 mm
2
. With 0.01 wt.%-doped Ga
2
O
3
, the spreading area was maximized at 161 mm
2
. With the addition of GaF
3
, the spreading areas over Q235 steel underwent a 105% increase, compared with the results derived without adding GaF
3
(92 mm
2
), and this substance showed clear advantages over ZnF
2
, Zn(BF
4
)
2
and Ga
2
O
3
.
The pictures of the best spreadings of Zn-15Al alloys on AA6061 and Q235, with CsF-RbF-AlF 3 flux doped with different additions, are shown in Figure 4 . Taking the test results from two kinds of base metal together, it could be concluded that the suitable ranges of GaF 3 , ZnF 2 , Zn(BF 4 ) 2 and Ga 2 O 3 in the CsF-RbF-AlF 3 flux respectively were 0.0075–0.01 wt.%, 0.0075–0.01 wt.%, 0.0075–0.01 wt.% and 0.009–0.01 wt.%, and the maximum spreading area of all the tests was obtained via doping with GaF 3 .
Figure 4. Spreading boards of Zn-15Al filler metal on base metals with CsF-RbF-AlF 3 flux doped with different additions: ( a – d ) 6061 aluminum; ( e – h ) Q235 low-carbon steel.
3.2. The Mechanical Properties of Brazed Joints
The variation of brazed joint shear strength was shown in Figure 5 . It could be seen that the addition of GaF 3 has a significant impact on the brazed joint shear strength of AA6061/Q235. While the content of GaF 3 was 0.075 wt.%, the shear strength reached a maximum at 126 MPa, which was 110% higher than that achieved without GaF 3 addition (64.5 MPa). While the content of ZnF 2 was 0.01 wt.%, the maximum shear strength was 111 MPa. While the content of Zn(BF 4 ) 2 was 0.01 wt.%, the shear strength reached the top at 105 MPa. While the content of Ga 2 O 3 was 0.01 wt.%, the maximum shear strength was 116 MPa.
Figure 5. Influence of contents of GaF 3 , ZnF 2 , Zn(BF 4 ) 2 and Ga 2 O 3 on shear strength of brazed joints.
It could be seen that, only considering the shear strength of the AA6061/Q235 brazed joints, the addition range should be controlled as 0.0075–0.01 wt.%, and this appropriate addition range coincides with the results of the spreading test. Among the four doped ingredients selected, GaF
3
showed the best performance as regards the mechanical properties of brazed joints. The second-best performance was achieved with Ga
2
O
3
. At the same time, Zn(BF
4
)
2
was inferior to others.
The typical fracture modes of the 6061/Q235 brazed joints were shown in Figure 6 . The fracture of the joint occurred mainly at the interface layer of the brazing joint and the Q235 steel. It demonstrated that the interface layer between the filler metal and the Q235 steel was the weakest area of the whole joint, and that when there were layers of brittle compounds at the interface, the brazed joint would crack at the layers of brittle compounds first.
Figure 6. Typical fracture modes of 6061/Q235 brazed joints: ( a ) Macromorphology of fracture interface; ( b ) Organization of interface before shear tests; ( c ) Microtopography of fracture interface after shear tests.
3.3. Interfacial Effect of Different Particles
3.3.1. Effect of Zn(BF 4 ) 2
The XRD analysis results for the residues of the fluxes on Q235 low-carbon steel are shown in
Figure 7
. In inndividually evaluating the spreadability of the Zn-15Al filler metal, and the mechanical properties of the brazed joints with CsF-RbF-AlF
3
-Zn(BF
4
)
2
over the 6061 aluminum and Q235 steel, it was clear that the addition of Zn(BF
4
)
2
significantly improved the activity of the CsF-RbF-AlF
3
flux, with a 52% increase in spreading area and a 92% increase in shear strength.
Zn ( BF 4 ) 2 → ZnF 2 + 2 BF 3
(1)
Figure 7. X-ray diffraction analysis results of the residues on Q235 low-carbon steel: ( a ) CsF-RbF-AlF 3 -Zn(BF 4 ) 2 ; ( b ) CsF-RbF-AlF 3 -ZnF 2 flux; ( c ) CsF-RbF-AlF 3 - Ga 2 O 3 flux; ( d ) CsF-RbF-AlF 3 -GaF 3 flux.
Zn(BF 4 ) 2 could produce BF 3 as shown Equation (1). BF 3 could react with oxides such as FeO, Fe 2 O, NiO, Cr 2 O 3 and ZnO, thus playing the role of removing the oxide film and promoting the wetting, spreading and flowing of the molten filler metal in the brazed part [ 16 ]. However, BF 3 could not react with oxides such as Al 2 O 3 and MgO on the surface of t he aluminum alloy, thus limiting the activity of the CsF-RbF-AlF 3 -Zn(BF 4 ) 2 flux.
3.3.2. Effect of ZnF 2
It was found in the study [
13
] that adding ZnF
2
to the flux could produce a mass transfer effect, and improve the activity of the flux. This was because the ZnF
2
was reduced by the base metal, and molten Zn has great solubility in aluminum. It was also observed that adding ZnF
2
could reduce the initial temperature of the flux, which was also related to the reduction of the precipitation of molten Zn.
ZnF 2 → Δ Zn ↓ + 2 F −
(2)
F − + Al 2 O 3 → AlF 3 + O 2 −
(3)
F − + Fe 2 O 3 → FeF 3 + O 2 −
(4)
When heated, ZnF 2 would react as shown Equation (2). The F - generated by the reaction would react with the oxide on the surface of the base metals, as shown in Equations (3) and (4), respectively, thus enhancing the membrane removal effect of CsF-RbF-AlF 3 flux. The Zn atoms precipitated from the reaction would react with the aluminum atoms on the surface of the aluminum alloy and the Fe atoms on the surface of steel, and the wetting and spreading would be promoted on the surface of the base metals [ 17 ].
The presence of ZnSiO
3
, ZnFe
2
O
4
, AlPO
4
and FePO
4
in the residue on the one hand indicated that the ZnF
2
in the flux did participate in the reaction, and the Zn atoms from the reduced precipitation participated in the reaction and played a role in improving the activity. On the other hand, it indicated that the enrichment phenomenon of P occurred, which resulted in the formation of compounds such as AlPO
4
and FePO
4
, which also played an important role in the removal of the oxide film from the steel surface.
3.3.3. Effect of Ga 2 O 3
The “skin effect” of high-frequency currents is a well-known natural phenomenon in physics, especially in electromagnetism. However, the “skin effect” of some oxides or halides in brazing has rarely been reported. It was found that [
18
] adding a very small amount of Ga
2
O
3
to the CsF-RbF-AlF
3
flux could increase the brazed area by about 50~90%. Observing the surface of the spreading filler metal via its spectrum showed that much Ga
2
O
3
was enriched at the spreading surface and at the edge of the spreading area. Further, the relative amount of Ga
2
O
3
was higher here than in the middle part, from which it could be concluded that the chemical reaction mechanism resulted from the skin effect of the Ga
2
O
3
, which enabled the Ga
2
O
3
to flow fast and then promote the CsF-RbF-AlF
3
flux flow, so as to improve the spreadablity of the filler metal.
MgO + Ga 2 O 3 → MgGa 2 O 4
(5)
Extremely small amounts of Ga
2
O
3
were enriched to participate in the reaction, and played a nonnegligible role. The appearance of MgGa
2
O
4
indicated that the reaction between the flux and the MgO, which was more stable than Al
2
O
3
, was also liable to react as in Equation (5). However, RbF did not appear as a compound phase in the residue, which indicated that the compound of Rb was diffused-distributed, and acted as catalysis and welding aid. CsF always appeared in the form of Cs
11
O
3
, which indicated that CsF did undergo chemical reactions with Al
2
O
3
and MgO, and replaced the O atoms in Al
2
O
3
and MgO. This result explains why the spreading area increased with the increased addition of Ga
2
O
3
, shown in
Figure 3
.
3.3.4. Effect of GaF 3
From the above it was demonstrated that the CsF-RbF-AlF
3
flux doped with GaF
3
obtained the maximum spreading area, both on 6061 aluminum alloy and Q235 steel, and reached the highest shear strength of 126MPa. The CsF-RbF-AlF
3
flux doped with GaF
3
showed remarkable superiority to that doped with ZnF
2
, Zn(BF
4
)
2
and Ga
2
O
3
.
The mechanism of GaF
3
could be summarized as a “synergistic effect” on the oxide removal of steel. When GaF
3
was doped, the flux could not only remove the oxide films on the surface of the aluminum alloy, but could also remove those on the surface of the steel at the same time, thus making it superior to brazed aluminum-steel heterogeneous materials.
GaF 3 → Ga 3 + + 3 F −
(6)
4 ZnO + 2 GaF 3 → ZnGa 2 O 4 + 3 ZnF 2
(7)
The ionic compound GaF
3
consists of cations Ga
3+
and anions F
−
, and makes it such that Ga
4. Conclusions
It was shown that the CsF-RbF-AlF 3 flux doped with GaF 3 obtained the maximum spreading area, both on 6061 aluminum alloy and Q235 low-carbon steel, and reached the highest shear strength of 126MPa. The above analysis led to the following conclusions:
(1)
The spreading tests indicated that the spreadability of the Zn-15Al filler metal both on Q235 steel and AA6061 alloy was promoted with a CsF-RbF-AlF 3 flux doped with GaF 3 , ZnF 2 , Zn(BF 4 ) 2 and Ga 2 O 3 , and the performance of GaF 3 was the best. The suitable ranges of GaF 3 , ZnF 2 , Zn(BF 4 ) 2 and Ga 2 O 3 respectively were 0.0075–0.01 wt.%, 0.0075–0.01 wt.%, 0.0075–0.01 wt.% and 0.009–0.01 wt.%.
(2)
The shear strength of the brazed joints reached its peak at 126 MPa, when 0.075 wt.% GaF 3 was added. The second-best performance was Ga 2 O 3 . At the same time, Zn(BF 4 ) 2 was inferior to others.
(3)
The fluxes doped with GaF 3 were competent in removing oxides of the base metal and decreasing the interfacial tension, in virtue of the activity of Ga 3+ , which has a “skin effect”, as well as F − . In consequence, the activity of the CsF-RbF-AlF 3 doped with GaF 3 was better than that of others.
Author Contributions
Conceptualization, S.X.; methodology, J.Z.; software, Z.Y.; validation, Z.Y.; formal analysis, Z.Y.; investigation, Z.Y.; resources, S.X.; data curation, Z.Y.; writing—original draft preparation, Z.Y.; writing—review and editing, Z.Y.; visualization, Z.Y.; supervision, S.X.; project administration, S.X.; funding acquisition, S.X. All authors have read and agreed to the published version of the manuscript.
References
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Figure 1. Schematic diagram of the spreading test (mm).
Figure 2. Schematic illustration of the brazed joint (mm).
Figure 3. Spreading areas of Zn-15Al filler metal ( a ) 6061 aluminum alloy; ( b ) Q235 steel.
Figure 5. Influence of contents of GaF 3 , ZnF 2 , Zn(BF 4 ) 2 and Ga 2 O 3 on shear strength of brazed joints.
Figure 6. Typical fracture modes of 6061/Q235 brazed joints: ( a ) Macromorphology of fracture interface; ( b ) Organization of interface before shear tests; ( c ) Microtopography of fracture interface after shear tests.
Figure 7. X-ray diffraction analysis results of the residues on Q235 low-carbon steel: ( a ) CsF-RbF-AlF 3 -Zn(BF 4 ) 2 ; ( b ) CsF-RbF-AlF 3 -ZnF 2 flux; ( c ) CsF-RbF-AlF 3 - Ga 2 O 3 flux; ( d ) CsF-RbF-AlF 3 -GaF 3 flux.
Table 1. Chemical composition of 6061 aluminum alloy (wt.%).
Table 2. Chemical composition of Q235 steel (wt.%).
Table 3. Chemical composition of nanoparticles doped into the fluxes (wt.%).
Yao, Zhen, Songbai Xue, and Junxiong Zhang. 2020. "Effect of Various Nanoparticles (GaF 3, ZnF 2, Zn(BF 4) 2and Ga 2O 3) Additions on the Activity of CsF-RbF-AlF 3Flux and Mechanical Behavior of Al/Steel Brazed Joints" Crystals10, no. 8: 683.
https://doi.org/10.3390/cryst10080683
| https://www.mdpi.com/2073-4352/10/8/683/html |
Historical Markers and War Memorials in Burleson County, Texas
A list of Historical Markers and War Memorials in .
63
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After filtering for Mississippi, 63 entries match your criteria.
Historical Markers and War Memorials in Burleson County, Texas
image/svg+xml
U.S. Census Bureau, Abe.suleiman; Lokal_Profil; HMdb.org; J.J.Prats/dc:title>
https://commons.wikimedia.org/wiki/File:Usa_counties_large.svg
Burleson County, TX (63) Brazos County, TX (67) Lee County, TX (38) Milam County, TX (56) Robertson County, TX (54) Washington County, TX (157) Burleson County (63) Burleson County (63) Brazos County (67) Brazos County (67) Lee County (38) Lee County (38) Milam County (56) Milam County (56) Robertson County (54) Robertson County (54) Washington County (157) Washington County (157)
Caldwell is the county seat for Burleson County
Adjacent to Burleson County, Texas
Brazos County
(67)
►
Lee County
(38)
►
Milam County
(56)
►
Robertson County
(54)
1► Texas, Burleson County, Bryan — 8652 —San Salvador Mission Church—
<table><tbody><tr><td></td><td></td><td colspan=2> San Salvador, a mission of St. Anthony's Catholic Church, Bryan, was named for the patron saint of Cefalu, Sicily, the native village of Italian immigrants who came here in 1894. Religious services were held in homes until 1908, when devout families . . .— — Map (db m187394)HM</td></tr></tbody></table>
2► Texas, Burleson County, Caldwell — 13145 —Brazos Bottom Baptist Church Cemetery—
<table><tbody><tr><td></td><td></td><td colspan=2> Also known as the Old Tunis Cemetery, this burial ground originally served a pioneer area of the fertile Brazos Valley. Graves date from the 1840s, and John and Sarah Wright Echols formally set aside land in 1867 for this graveyard and a Baptist . . .— — Map (db m220019)HM</td></tr></tbody></table>
3► Texas, Burleson County, Caldwell — 7551 —Brazos River Levee—
<table><tbody><tr><td></td><td></td><td colspan=2> Destructive Brazos River floods have often plagued residents of Burleson County. In 1899, a 30-inch rain killed 35 and caused about $9 million in property damage. Again in 1900, 1902 and 1908 Brazos River bottom inhabitants endured serious . . .— — Map (db m135747)HM</td></tr></tbody></table>
4► Texas, Burleson County, Caldwell — 7553 —Burleson County—
<table><tbody><tr><td></td><td></td><td colspan=2> Farmed early as 1744 by Indians under guidance of Spanish missionaries. In 1830, Ft. Tenoxtitlan, guarding Brazos crossing, San Antonio Road, attracted Anglo-Texans, who lived off wild game in early years.
County created and organized in 1846. . . .— — Map (db m129339)HM</td></tr></tbody></table>
5► Texas, Burleson County, Caldwell — 7554 —Burleson County—
<table><tbody><tr><td></td><td></td><td colspan=2> In rich Brazos River basin; had settlers early as 1825. Site in 1830 of Tenoxtitlan, one of 3 forts built by Mexico in Texas, situated above El Camino Real (The King's Highway) crossing on Brazos River. North of the road was Sterling Robertson's . . .— — Map (db m201845)HM</td></tr></tbody></table>
6► Texas, Burleson County, Caldwell — 14275 —Burleson County in World War II—
<table><tbody><tr><td></td><td></td><td colspan=2> During World War II, out of a population of 18,000 close to 1300 men and women from Burleson County joined the military, with 450 who attended Caldwell High School drafted or voluntarily enlisted. Many had never been outside the county before their . . .— — Map (db m125665)HM</td></tr></tbody></table>
7► Texas, Burleson County, Caldwell — 7555 —Burleson County, C.S.A.—
<table><tbody><tr><td></td><td></td><td colspan=2> On Feb. 23, 1861, citizens voted for secession, 422 to 84. On March 1, the "Burleson Guards" organized and offered its services to the state. Most "Guards" were mustered into Co.G, 2nd Texas Infantry Regt., and others served in Walker's Texas . . .— — Map (db m125671)HM</td></tr></tbody></table>
8► Texas, Burleson County, Caldwell — 12471 —Caldwell Masonic Cemetery—
<table><tbody><tr><td></td><td></td><td colspan=2> With more than 2,700 burials, this cemetery is a significant reflection of the heritage of Caldwell and Burleson County. It began as a Masonic cemetery in 1890 when Warren Lodge No. 56 purchased land here for that purpose. There already were at . . .— — Map (db m210791)HM</td></tr></tbody></table>
9► Texas, Burleson County, Caldwell — 7559 —Caldwell National Bank—
<table><tbody><tr><td></td><td></td><td colspan=2> On January 24, 1903, a group of local businessmen under the direction of J. J. Lane and C. C. Nelms met for the purpose of establishing a National Bank. The thirty original stock subscribers who attended pledged $25,000 in organizational capital and . . .— — Map (db m150939)HM</td></tr></tbody></table>
10► Texas, Burleson County, Caldwell — 7562 —Chisholm Cattle Trail— An Arm of the—
<table><tbody><tr><td></td><td></td><td colspan=2> The Chisholm Trail, which was developed following the Civil War, allowed Texas cattle to be driven to railheads in Kansas for shipment to eastern markets. An arm of the celebrated route, reaching from Matagorda County to the main trail near present . . .— — Map (db m135746)HM</td></tr></tbody></table>
11► Texas, Burleson County, Caldwell — 7556 —City of Caldwell—
<table><tbody><tr><td></td><td></td><td colspan=2> In 1840 the Republic of Texas Congress annexed to Milam County all of Washington County north of Yegua Creek and west of the Brazos River. The name Caldwell, which honored Mathew "Old Paint" Caldwell, a noted pioneer and a signer of the Texas . . .— — Map (db m125666)HM</td></tr></tbody></table>
12► Texas, Burleson County, Caldwell — 7557 —City of Caldwell—
<table><tbody><tr><td></td><td></td><td colspan=2> Founded 1840 by Lewis L. Chiles, a veteran of Battle of San Jacinto. Named for Mathew "Old Paint" Caldwell, Indian fighter and signer of the Texas Declaration of Independence. This was county seat, Milam County, in 1845; since 1846 county seat of . . .— — Map (db m204264)HM</td></tr></tbody></table>
13► Texas, Burleson County, Caldwell — 7566 —Cooks Point—
<table><tbody><tr><td></td><td></td><td colspan=2> Founded about 1840 where colonial road from southeast crossed San Antonio Road.
Settler Gabriel Jackson had two-story log cabin-trading post here. Community was named for Silas L. Cooke, who surveyed much land in this vicinity. It is now a . . .— — Map (db m125653)HM</td></tr></tbody></table>
14► Texas, Burleson County, Caldwell — 12724 —Duewall House—
<table><tbody><tr><td></td><td></td><td colspan=2> Rudolph and Anna Duewall established a family farm here in the 1880s upon moving to Burleson County. Their son Edward (1885-1944) and his wife, Lizzie (Herrmann) (1890-1947), continued the farm operations. In 1928, they built this house on the site . . .— — Map (db m210799)HM</td></tr></tbody></table>
15► Texas, Burleson County, Caldwell — 7569 —Early Settlers of Burleson County in the Texas War for Independence—
<table><tbody><tr><td></td><td></td><td colspan=2> When Mexican Dictator Santa Anna revoked national rights, 30 or more men from this sparsely settled area left to resist his armies: in Grass Fight (Nov. 26, 1835), Siege of Bexar (Dec. 5-9) and other actions. While able men were absent, the foe . . .— — Map (db m201851)HM</td></tr></tbody></table>
16► Texas, Burleson County, Caldwell — 7571 —Elizabeth Chapel Methodist Church— One Mile North to Site of—
<table><tbody><tr><td></td><td></td><td colspan=2> First Methodist Church in the county. Began as Sunday School in home of Isaac Addison, early settler. Later moved to home of Mrs. Elizabeth Scott. Organized about 1839 by Robt. Alexander, famous pioneer minister. Soon a small, hand-hewn frame . . .— — Map (db m129340)HM</td></tr></tbody></table>
17► Texas, Burleson County, Caldwell — 7572 —First Baptist Church—
<table><tbody><tr><td></td><td></td><td colspan=2> Originally named Dove Church. Organized May 4, 1843, in home of Laban Rice, one of six charter members. Noted frontier ministers R.E.B. Baylor and Noah Byars presided at founding, and Byars served as first pastor.
First building (1844) stood on . . .— — Map (db m204221)HM</td></tr></tbody></table>
18► Texas, Burleson County, Caldwell — 8629 —First Presbyterian Church— of Caldwell—
<table><tbody><tr><td></td><td></td><td colspan=2> This congregation was organized by the Rev. Hugh Wilson, an early Presbyterian missionary noted for his active work on the Texas frontier. Although the first account of the church appears in an 1850 document, it is likely that the congregation was . . .— — Map (db m204236)HM</td></tr></tbody></table>
19► Texas, Burleson County, Caldwell — 8630 —First United Methodist Church— of Caldwell—
<table><tbody><tr><td></td><td></td><td colspan=2> Congregation, organized 1840, is one of the oldest in Texas. It was one of 12 appointments on Nashville Circuit, Galveston District, Republic of Texas. Early worship was in various temporary structures. Here, in 1841, the Republic gave this church a . . .— — Map (db m204225)HM</td></tr></tbody></table>
20► Texas, Burleson County, Caldwell — 8634 —Fort Tenoxtitlan— "Dream Capital of Texas"— (Site About 8 Miles Northeast) —
<table><tbody><tr><td></td><td></td><td colspan=2> Founded by Mexico as a bulwark against Anglo-American immigration, this fort and its nearby city were twice proposed for the capital of Texas.
Alarmed by the influx of Anglo settlers into Texas, Mexico in 1830 sought to erect a line of forts to . . .— — Map (db m129343)HM</td></tr></tbody></table>
21► Texas, Burleson County, Caldwell — 12738 —John Mitchell—
<table><tbody><tr><td></td><td></td><td colspan=2> Born in Tennessee c. 1836-37, John Mitchell came to Texas in 1846. He began purchasing land in this area in 1870, the same year he married Viney Cox. As a member of both the 12th and 14th Legislatures, Mitchell championed increased educational . . .— — Map (db m125669)HM</td></tr></tbody></table>
22► Texas, Burleson County, Caldwell — 50 —Kings Highway— Camino Real— Old San Antonio Road —
<table><tbody><tr><td></td><td></td><td colspan=2> Marked by the
Daughters of the
American Revolution
and The State of Texas
A.D. 1919— — Map (db m125654)HM</td></tr></tbody></table>
23► Texas, Burleson County, Caldwell — 48 —Kings Highway - Camino Real — Old San Antonio Road— Marker #48— El Camino Real de los Tejas National Historic Trail —
<table><tbody><tr><td></td><td></td><td colspan=2> Kings Highway - Camino Real - Old San Antonio Road.
Marked by The Daughters of The American Revolution and the State of Texas A.D. 1918— — Map (db m222168)HM</td></tr></tbody></table>
24► Texas, Burleson County, Caldwell — 51 —Kings Highway Camino Real — Old San Antonio Road— Marker #51— El Camino Real de los Tejas National Historic Trail —
<table><tbody><tr><td></td><td></td><td colspan=2> Kings Highway Camino Real Old San Antonio Road
Marked by The Daughters of The American Revolution and The State of Texas A.D. 1918— — Map (db m222390)HM</td></tr></tbody></table>
25► Texas, Burleson County, Caldwell — 52 —Kings Highway Camino Real — Old San Antonio Road— Marker #52— El Camino Real de los Tejas National Historic Trail —
<table><tbody><tr><td></td><td></td><td colspan=2> Kings Highway Camino Real Old San Antonio Road
Marked by The Daughters of The American Revolution and The State of Texas A.D. 1918— — Map (db m222393)HM</td></tr></tbody></table>
26► Texas, Burleson County, Caldwell — 53 —Kings Highway Camino Real — Old San Antonio Road— Marker #53— El Camino Real de los Tejas National Historic Trail —
<table><tbody><tr><td></td><td></td><td colspan=2> Kings Highway Camino Real Old San Antonio Road
Marked by The Daughters of The American Revolution and The State of Texas A.D. 1918— — Map (db m222396)HM</td></tr></tbody></table>
27► Texas, Burleson County, Caldwell —Masonic Cemetery— Nov. 11, 1989—
<table><tbody><tr><td></td><td></td><td colspan=2> This Flagpole is dedicated to the war veterans who are buried in the Masonic Cemetery. The Civil War, Spanish American War, World War I, World War II, Korean War and Vietnam. It is made possible through the combined efforts of the Caldwell Cemetery . . .— — Map (db m210795)WM</td></tr></tbody></table>
28► Texas, Burleson County, Caldwell — 8645 —Moseley's Ferry—
<table><tbody><tr><td></td><td></td><td colspan=2> Situated where the Old San Antonio Road crossed the Brazos River, this public ferry was begun by Michael Boren (1806-75) about 1846. The ferry and a settlement nearby were named for Daniel Moseley (1787-1856), who took over the service in 1849 and . . .— — Map (db m68684)HM</td></tr></tbody></table>
29► Texas, Burleson County, Caldwell — 7552 —Near Homesite of Judge Andrew S. Broaddus— (1810 - 1891)—
<table><tbody><tr><td></td><td></td><td colspan=2> Noted pioneer leader. Member Virginia House of Delegates (1844-45). Piloted to Texas (1854) a mile-long wagon train of 200 people, who built Salem Baptist Church - reminder of their Virginia home.
Broaddus debated the Hon. Sam Houston at . . .— — Map (db m125652)HM</td></tr></tbody></table>
30► Texas, Burleson County, Caldwell — 8646 —New Tabor Brethren Church—
<table><tbody><tr><td></td><td></td><td colspan=2> About 1870 this area of Burleson County was settled by Czech-Moravian immigrants in search of fertile land and the religious freedom denied them in their native European homeland. Informal services were held twice a year in the family home of Joseph . . .— — Map (db m220013)HM</td></tr></tbody></table>
31► Texas, Burleson County, Caldwell — 11770 —New Tabor Cemetery—
<table><tbody><tr><td></td><td></td><td colspan=2> New Tabor was settled by Czech and German immigrants in the 1870s and 1880s. It was named for the community of Tabor in Czechoslovakia. In February 1888, Henry Ginzel sold 3 1/4 acres of land for a cemetery to trustees F. Jurcak, G. Hnilica and J. . . .— — Map (db m220014)HM</td></tr></tbody></table>
32► Texas, Burleson County, Caldwell — 7565 —Old City Cemetery—
<table><tbody><tr><td></td><td></td><td colspan=2> Created in 1840 (same year Caldwell was laid out) when lots 3 and 12 were made a "Grave Yard and Church lot" forever.
Town founder Lewis L. Chiles (d.1864) is buried here. Oldest legible stone is for Margarette A. King and infant daughter . . .— — Map (db m201847)HM</td></tr></tbody></table>
33► Texas, Burleson County, Caldwell — 8648 —Providence Cemetery—
<table><tbody><tr><td></td><td></td><td colspan=2> According to oral tradition, this cemetery has served residents of the Providence area since the 1830s. The earliest marked grave is that of Elizabeth Hughes, who died in 1841, but the presence of unmarked graves suggests that the burial ground was . . .— — Map (db m220017)HM</td></tr></tbody></table>
34► Texas, Burleson County, Caldwell — 11771 —Warren Lodge No. 56, A.F. & A.M.—
<table><tbody><tr><td></td><td></td><td colspan=2> Burleson County was established in 1846 with Caldwell as the county seat. By the late 1840s Caldwell had a population of about three hundred. Local Masons began organizing and in October 1848 nine Freemasons petitioned George M. Patrick, Grand . . .— — Map (db m204219)HM</td></tr></tbody></table>
35► Texas, Burleson County, Chriesman — 8655 —Alexander Thomson, Jr.— (August 29, 1785 - June 1, 1863)—
<table><tbody><tr><td></td><td></td><td colspan=2> A leader in Texas colonization, Alexander Thomson, Jr., was born in St. Matthew's Parish, South Carolina, the only son of Alexander and Lucy (Fontaine) Thomson. He later lived in Georgia before moving to Tennessee. There, in 1830, he became a . . .— — Map (db m210613)HM</td></tr></tbody></table>
36► Texas, Burleson County, Chriesman — 7563 —Horatio Chriesman— (Aug. 13, 1797 - Nov. 21, 1878).—
<table><tbody><tr><td></td><td></td><td colspan=2> Colonial statesman, Methodist lay leader, pioneer in Burleson County. Came to Texas in 1822 from Kentucky. Had office of surveyor, Austin's Colony, 1823 - 1836; was a military officer in Indian conflicts and also Army of Gen. Sam Houston during . . .— — Map (db m210617)HM</td></tr></tbody></table>
37► Texas, Burleson County, Chriesman — 7564 —Town of Chriesman— (Originally "Yellow Prairie", 0.5 Mi. E)—
<table><tbody><tr><td></td><td></td><td colspan=2> Settled by Alexander Thomson, Jr., early Texas patriot and partner of the colonizer Sterling C. Robertson. When railroad came through in 1880, the settlers moved to tracks.
Renamed, 1884, after Capt. H.C. Chriesman, surveyor for Stephen F. . . .— — Map (db m210616)HM</td></tr></tbody></table>
38► Texas, Burleson County, Deanville — 7568 —Deanville—
<table><tbody><tr><td></td><td></td><td colspan=2> Founded 1872 by merchant James L. Dean (born 1841) on an arm of Chisholm Cattle Trail. The post office was established 1877. Houston & Texas Central Railroad extended line here in 1913. Sons of Hermnan (O.D.H.S.) Lodge, organized in 1916, sponsors . . .— — Map (db m219432)HM</td></tr></tbody></table>
39► Texas, Burleson County, Deanville — 54 —Kings Highway Camino Real — Old San Antonio Road— Marker #54— El Camino Real de los Tejas National Historic Trail —
<table><tbody><tr><td></td><td></td><td colspan=2> Kings Highway Camino Real Old San Antonio Road
Marked by The Daughters of The American Revolution and The State of Texas A.D. 1918— — Map (db m222400)HM</td></tr></tbody></table>
40► Texas, Burleson County, Deanville — 8651 —St. John's Lutheran Church—
<table><tbody><tr><td></td><td></td><td colspan=2> This church was organized by the Rev. A.H. Falkenberg and 35 charter members in 1910. Services were held in a schoolhouse until a sanctuary, containing an 800-pound bell donated by the family of John B. Luedke, Sr., was built here in 1917. The . . .— — Map (db m219434)HM</td></tr></tbody></table>
41► Texas, Burleson County, Dime Box — 7570 —Site of El Camino Real— (The Old San Antonio Road)—
<table><tbody><tr><td></td><td></td><td colspan=2> Great thoroughfare of early Texas. Following ancient Indian and buffalo paths, sometimes on same course as 1691 "Trail of the Padres", stretches 1,000 miles from Saltillo, Mexico, to present Louisiana. Highway for explorers, traders, smugglers, . . .— — Map (db m176337)HM</td></tr></tbody></table>
42► Texas, Burleson County, Frenstat — 13077 —Frenstat Cemetery—
<table><tbody><tr><td></td><td></td><td colspan=2> In 1884, several Moravian Czech families established farms in this area, naming the community Frenstat, or Friendsted, for Frenštát, Czechoslovakia, Alois and Veronica Polansky deeded 20 acres for a school, church and cemetery in 1887. . . .— — Map (db m219877)HM</td></tr></tbody></table>
43► Texas, Burleson County, Frenstat — 13256 —Our Lady of the Holy Rosary Catholic Church—
<table><tbody><tr><td></td><td></td><td colspan=2> In 1884, Catholic settlers from Czechoslovakia first arrived in this area. They named their settlement Frenstat for the community they had left, Frenstat Rod Radhost, Moravia. By 1887 the Rev. Joseph Chromcik regularly visited Frenstat. That year, . . .— — Map (db m219882)HM</td></tr></tbody></table>
44► Texas, Burleson County, Lyons — 8641 —Lyons—
<table><tbody><tr><td></td><td></td><td colspan=2> An 1878 railway work camp; in 1880 became town of Lyon's Station, named for site donor, W.A. Lyon. Soon had 3 cotton gins, an oil mill, many businesses. In 1894 hosted first auto ever seen in this county, with rides for the daring. Now gateway to . . .— — Map (db m204216)HM</td></tr></tbody></table>
45► Texas, Burleson County, Lyons — 8642 —Lyons Methodist Church—
<table><tbody><tr><td></td><td></td><td colspan=2> Organized at High Prairie (5 mi NW) before 1880. The Rev. John R. Dunn was the first pastor. After the railroad came to Lyons, moved here.
Erected 1887, this is the oldest church building in regular use in this areas. Recorded Texas . . .— — Map (db m204215)HM</td></tr></tbody></table>
46► Texas, Burleson County, Snook — 8653 —Community of Snook— (Originally Located One Mile West)—
<table><tbody><tr><td></td><td></td><td colspan=2> Settled 1880s by Czech immigrants. First called "Sebesta's Corner". In 1895 named "Snook" for John Snook, who helped secure post office. Soon had a one-room school, a "masova schuza" (slaughterhouse), a cooperative store, and lodge for . . .— — Map (db m196633)HM</td></tr></tbody></table>
47► Texas, Burleson County, Snook — 22836 —Dabney Hill Freedom Colony—
<table><tbody><tr><td></td><td></td><td colspan=2> Following Emancipation in 1865, formerly enslaved African Americans established independent communities known as Freedom Colonies or Freedmen's Towns. Between 1865 and 1920, more than 500 of these settlements were established in Texas. These safe . . .— — Map (db m220060)HM</td></tr></tbody></table>
48► Texas, Burleson County, Snook — 8635 —Giesenschlag Cemetery—
<table><tbody><tr><td></td><td></td><td colspan=2> Prussian born Johann Joachim Giesenschlag (1817-80), his wife Anna (Schulze), and their children came to Texas in 1855. Settling first in Washington County, they moved to Burleson County in the 1870s and bought over 1,000 acres here. Giesenschlag . . .— — Map (db m220041)HM</td></tr></tbody></table>
49► Texas, Burleson County, Snook — 13277 —Lone Oak Baptist Church—
<table><tbody><tr><td></td><td></td><td colspan=2> Traveling preachers conducted early worship services in the Lone Oak area and in 1905, local residents organized a Baptist church in 1911. The congregation called the Rev. A.S. Broaddus as pastor. He led the church for the next 42 years, with time . . .— — Map (db m220043)HM</td></tr></tbody></table>
50► Texas, Burleson County, Snook — 13727 —Snook Brethren Church—
<table><tbody><tr><td></td><td></td><td colspan=2> During the 19th century, many families from Bohemia and Moravia emigrated to Texas. They brought their Czech traditions, including beliefs of the Brethren Church, established on religious teachings of reformer Jan Hus. Settlers to this area founded . . .— — Map (db m196635)HM</td></tr></tbody></table>
51► Texas, Burleson County, Snook — 13234 —Snook Cemetery—
<table><tbody><tr><td></td><td></td><td colspan=2> Immigrants from Czechosovakia settled in this area in the 1880s. The community was originally known as Sebesta or Sebesta's Corners, after one of the early families. In the 1890s, residents renamed the settlement Snook in honor of John Snook, the . . .— — Map (db m196636)HM</td></tr></tbody></table>
52► Texas, Burleson County, Somerville — 8638 —1906 Reunion of Hood's Texas Brigade—
<table><tbody><tr><td></td><td></td><td colspan=2> In 1906 Somerville hosted the annual reunion of the Hood's Texas Brigade Association, a group established in 1872 for veterans of the celebrated Confederate unit. For two days, June 27-28, 74 veterans were honored with a celebration which included . . .— — Map (db m74293)HM</td></tr></tbody></table>
53► Texas, Burleson County, Somerville — 8631 —First United Methodist Church of Somerville—
<table><tbody><tr><td></td><td></td><td colspan=2> Organized 1901 by the Rev. H.G. Williams; had 29 charter members, and was in the Lyons Circuit. During first year, held prayer meetings in homes and preaching services in brush arbor lighted by members' lanterns. For weeks, evangelists operated a . . .— — Map (db m204213)HM</td></tr></tbody></table>
54► Texas, Burleson County, Somerville — 8657 —J.L. Woods’ Undertaking Company—
<table><tbody><tr><td></td><td></td><td colspan=2> Jebb Lee Woods (1872-1932) came to Somerville in 1900. He began working for his uncle at the cowboy merchant store, where he sold coffins. In 1911 he became the town undertaker and started the first funeral parlor in the county. The practice of . . .— — Map (db m203939)HM</td></tr></tbody></table>
55► Texas, Burleson County, Somerville —James W. Lauderdale—
<table><tbody><tr><td></td><td></td><td colspan=2> This railroad bell was given in memory of James W. Lauderdale (1854-1914), Burleson County pioneer. He came by covered wagon caravan from Mississippi to Texas. In 1888 he married Florence Brooks. They had four children: Cyrus, Davis, Charles and . . .— — Map (db m74296)HM</td></tr></tbody></table>
56► Texas, Burleson County, Somerville — 8640 —Lake Somerville—
<table><tbody><tr><td></td><td></td><td colspan=2> First shovel of earth for Somerville Dam was turned Sept. 22, 1962, by Lyndon B. Johnson then Vice President of United States.
Dam was built to control flooding on Yegua Creek in the 46 years prior to 1958, Yegua had flooded 43 times, costing . . .— — Map (db m203943)HM</td></tr></tbody></table>
57► Texas, Burleson County, Somerville — 8647 —Oaklawn Cemetery—
<table><tbody><tr><td></td><td></td><td colspan=2> Dating to 1900, this graveyard was first called the Somerville and Lyons Cemetery. Land was purchased by J.W. Lauderdale to establish a cemetery upon the death of his two-year-old son Charles on November 6, 1900. The name was changed to Oaklawn . . .— — Map (db m204214)HM</td></tr></tbody></table>
58► Texas, Burleson County, Somerville — 8636 —Site of the Somerville Harvey House—
<table><tbody><tr><td></td><td></td><td colspan=2> Fred Harvey, a native of England, began operation of his Santa Fe Railroad dining rooms in 1876. In 1900 a Harvey House opened in Somerville, Divisional Headquarters of the Santa Fe Line. The 2-story, galleried structure was 260 ft. long and . . .— — Map (db m74294)HM</td></tr></tbody></table>
59► Texas, Burleson County, Somerville — 8654 —Somerville—
<table><tbody><tr><td></td><td></td><td colspan=2> Located where two branches of the Gulf, Colorado & Santa Fe Railway joined, town was named for Albert Somerville, first president of the railroad. First settlers arrived after town was surveyed about 1883; the post office was permanently established . . .— — Map (db m74295)HM</td></tr></tbody></table>
60► Texas, Burleson County, Somerville — 18443 —Somerville Stadium—
<table><tbody><tr><td></td><td></td><td colspan=2> Emerging from the Great Depression, the Somerville school board partnered with the Works Progress Administration (WPA) to build a football stadium. Known as "The Rock," the stadium was designed by Travis Broesche in the Rustic style of architecture. . . .— — Map (db m117792)HM</td></tr></tbody></table>
61► Texas, Burleson County, Somerville — 12776 —Thomas J. Gary—
<table><tbody><tr><td></td><td></td><td colspan=2> Born on Sept. 16, 1922, in Texas City, Thomas J. Gary, Jr. attended Somerville Junior High in the 1930s. He returned to Texas City and, in 1940, at age 18, enlisted in the U.S. Navy. A seaman second class, Gary was assigned to the USS California, . . .— — Map (db m203910)HM</td></tr></tbody></table>
62► Texas, Burleson County, Somerville — 18442 —Yegua Center at Somerville ISD—
<table><tbody><tr><td></td><td></td><td colspan=2> As the Somerville Independent School District (SISD) emerged from the great depression, the school board filed a Works Progress Administration project proposal on October 3, 1938, to build a gymnasium. The proposal was accepted and construction on . . .— — Map (db m203941)HM</td></tr></tbody></table>
63► Texas, Burleson County, Somerville — 8658 —Yegua Creek—
| https://www.hmdb.org/results.asp?County=Burleson%20County&FilterState=Mississippi&Search=County&State=Texas&nu=4 |
Molecules | Free Full-Text | Synthesis of Bis(1,2,3-Triazole) Functionalized Quinoline-2,4-Diones
Derivatives of 3-(1H-1,2,3-triazol-1-yl)quinoline-2,4(1H,3H)-dione unsubstituted on quinolone nitrogen atom, which are available by the previously described four step synthesis starting from aniline, were exploited as intermediates in obtaining the title compounds. The procedure involves the introduction of propargyl group onto the quinolone nitrogen atom of mentioned intermediates by the reaction of them with propargyl bromide in N,N-dimethylformamide (DMF) in presence of a potassium carbonate and the subsequent formation of a second triazole ring by copper catalyzed cyclisation reaction with azido compounds. The products were characterized by 1H, 13C and 15N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments (1H–1H gs-COSY, 1H–13C gs-HSQC, 1H–13C gs-HMBC) with 1H–15N gs-HMBC as a practical tool to determine 15N NMR chemical shifts at the natural abundance level of 15N isotope.
Synthesis of Bis(1,2,3-Triazole) Functionalized Quinoline-2,4-Diones †
Roman Kimmel 1 ,
Damijana Urankar 2 ,
Stanislav Kafka 1,* and
Janez Košmrlj 2,*
1
Department of Chemistry, Faculty of Technology, Tomas Bata University in Zlin, 760 01 Zlin, Czech Republic
2
Faculty of Chemistry and Chemical Technology, University of Ljubljana, SI-1000 Ljubljana, Slovenia
*
Authors to whom correspondence should be addressed.
†
Dedicated to Professor Oldřich Paleta on his 80th birthday.
Molecules 2018 , 23 (9), 2310; https://doi.org/10.3390/molecules23092310
Received: 25 June 2018 / Revised: 28 August 2018 / Accepted: 4 September 2018 / Published: 10 September 2018
Abstract
:
Derivatives of 3-(1
H
H
,3
H
)-dione unsubstituted on quinolone nitrogen atom, which are available by the previously described four step synthesis starting from aniline, were exploited as intermediates in obtaining the title compounds. The procedure involves the introduction of propargyl group onto the quinolone nitrogen atom of mentioned intermediates by the reaction of them with propargyl bromide in
N
,
N
-dimethylformamide (DMF) in presence of a potassium carbonate and the subsequent formation of a second triazole ring by copper catalyzed cyclisation reaction with azido compounds. The products were characterized by
1
H,
13
C and
15
N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments (
1
H–
1
H gs-COSY,
1
H–
13
C gs-HSQC,
1
H–
13
C gs-HMBC) with
1
H–
15
N gs-HMBC as a practical tool to determine
15
N NMR chemical shifts at the natural abundance level of
15
N isotope.
Keywords:
click chemistry
;
azido group
;
quinoline-2,4(1 H ,3 H )-diones
;
propargyl group
;
bis(1,2,3‑triazole)
Graphical Abstract
1. Introduction
The 1,4-disubstituted-1,2,3-triazole heterocyclic motif has become an exceedingly popular structure finding applications in a broad range of areas including materials, biomaterials, metallopharmaceuticals, supramolecular chemistry, chemical sensing and catalysis, to name just a few [ 1 ]. In coordination and organometallic chemistry, for example, it became an important ligand scaffold, not only because of simplicity and reliability in its preparation, but also due to a variety of coordination modes offering [ 2 , 3 , 4 , 5 , 6 ]. Owing to the discovery of copper(I)-catalyzed 1,3-cycloaddition of terminal alkynes with organic azides, the CuAAC click reaction, the preparation of 1,4-disubstituted-1,2,3-triazole is facilitated in mild and modular fashion [ 7 , 8 ]. Although this “click triazole” has become a part of a broad range of molecules, its association with quinoline-2,4-diones remains largely underdeveloped. Apart from our recent publication on 3-(1 H -1,2,3-triazol-1-yl)quinoline-2,4(1 H ,3 H )-dione derivatives ( 1 , Figure 1 ) [ 9 ], to the best of our knowledge, other 1,2,3-triazole functionalized quinoline-2,4-diones are unprecedented.
As part of our endeavor in quinoline-2,4-dione chemistry [ 10 ] as well as functional click triazoles [ 11 , 12 ] and their applications [ 13 ], we became interested in the synthesis of bis(1,2,3-triazole) functionalized quinoline-2,4-diones 2 that may potentially serve as functional scaffolds in coordination chemistry, molecular sensing and biochemistry. It is noteworthy that many compounds with the quinoline-2,4-dione structure were isolated from fungi, bacteria and plants, possessing broad range of interesting biological activities in vitro and in vivo [ 10 ]. Herein we report an approach to quinoline-2,4-diones unsymmetrically substituted with two click triazoles, an extensive 1 H, 13 C, and 15 N NMR spectral analyses, and a preliminary investigation of their chelating properties towards arene-ruthenium.
2. Results and Discussion
We reasoned that the desired bis(1,2,3-triazole) functionalized quinoline-2,4-diones 2 could be obtained via previously described 3-(1 H -1,2,3-triazol-1-yl)quinoline-2,4(1 H ,3 H )-dione derivatives 1 as synthetic intermediates ( Scheme 1 ). The latter were prepared in a four-step reaction sequence starting from aniline, which upon treatment with diethyl 2-methylmalonate and diethyl 2-phenylmalonate initially afforded the corresponding 4-hydroxyquinolin-2(1 H )-ones 3a and 3b [ 14 ]. Chlorination with sulfuryl chloride into 3-methyl- and 3-phenyl-3-chloroquinolin-2,4(1 H ,3 H )-diones 4a [ 15 ] and 4b [ 16 ], followed by the nucleophilic displacement of the chlorine atoms with sodium azide, gave 3-methyl- and 3-phenyl- substituted 3-azidoquinoline-2,4(1 H ,3 H )-diones 5a and 5b [ 16 ]. Then we began with copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC).
Although a large variety of reaction conditions have been developed for the CuAAC reaction [
17
,
18
], our previous work in this field has shown that for 3-azidoquinoline-2,4(1
H
,3
H
)-diones a combination of copper(II) sulfate pentahydrate and elemental copper (CuSO
4
/Cu
0
) in dimethyl sulfoxide (DMSO) provided results that were superior to other combinations. Adopting those previous results in this work some additional optimizations of the reaction conditions were carried out with
5a
and phenylacetylene (
6a
) as the model substrates. Screening through the reaction solvents indicated that
N
,
N
-dimethylformamide (DMF) is even more efficient than DMSO, providing the desired target compound
1a
in shorter reaction times. The influence of the amount of granular copper to the course of the reaction between
5a
and equimolar amount of
6a
in DMF was also briefly investigated. While keeping the loading of CuSO
4
·5H
2
O constant at 10 mol % relative to
5a
, the amount of the elemental copper was varied from 380 mol % to 100 mol %. The results are summarized in
Table 1
.
Based on the above, in a general procedure, a mixture of 3-azidoquinoline-2,4(1
H
,3
H
)-dione (
5
, 1.0 mmol), a slight excess of terminal alkyne
6
(1.05 mmol), CuSO
4
⋅5H
2
O (0.12 mmol), and granular copper (2.0 mmol) in DMF (2.3 mL) was stirred at room temperature, in the presence of air. In addition to phenylacetylene (
6a
), propargyl alcohol (
6b
) was selected as the acetylene partner. The reactions were completed within 30 min. As indicated in
Table 2
, the products
1
were obtained in excellent yields. By using a more standard CuSO
4
∙5H
2
O
/l
-ascorbic acid catalyst in CH
2
Cl
2
/water biphasic system, the cycloaddition between
5a
and
6a
required substantially longer reaction time (48 h) to achieve a similar yield of the product
1a
as compared to the above CuSO
4
/Cu
0
/DMF conditions (Entries 1 and 2).
Prior to the introduction of propargyl group at the N1 nitrogen atom of the quinoline-2,4(1 H ,3 H )-dione ring in 1 , the primary hydroxyl groups at 1c and 1d were protected by acetylation by using acetic anhydride in pyridine as shown in Scheme 2 . The corresponding acetates 1e and 1f were obtained in 84–85% yields.
Alkylation of compounds 1a , b , e , f with propargyl group was carried out by using 1.5 equivalent of propargyl bromide ( 6c ) and 3 equivalents of potassium carbonate in DMF. These reactions proceeded smoothly within 45 min at room temperature. The yields are given in Table 3 .
Although N -alkylation of the lactam group usually takes place preferentially in quinoline-2,4(1 H ,3 H )-diones [ 10 ], the competitive O -alkylation has been documented in similar systems [ 19 ]. The N1 position of thus introduced propargyl group in 7 was confirmed by 2D NMR spectroscopy in particular by the presence of the long-range correlations between the propargyl methylene protons and carbon atoms C-8a and C-2 in the 1 H- 13 C HMBC spectra (in 7a , c , d ) as well as N1 nitrogen atom in the 1 H– 15 N gs -HMBC spectrum (in 7a ).
As the last step of the reaction sequence shown in
Scheme 1
, monotriazoles
7
were submitted to a second cycloaddition with selected azides
8
to give the expected bis-triazoles
2
. Benzyl azide (
8a
), azidobenzene (
8b
) and tetrazolo[1,5-
a
]pyridine (
8c
) were selected as the reaction partners. Whereas benzyl azide (
8a
) and azidobenzene (
8b
) readily reacted into the desired products
2a
,
b
,
d
,
e
,
g
,
h
,
j
,
k
at room temperature, tetrazolo[1,5-
a
]pyridine (
8c
), a synthetic equivalent for 2-azidopyridine (
8c’
), required harsher reaction conditions (
Table 4
). This can be explained by the tetrazolyl form in which compound
8c
exists predominantly at room temperature [
11
]. As the proportion of the azido isomer increases at elevated temperature, the reactions with
8c
were conducted at 100 °C, to afford compounds
2c
,
f
,
i
,
l
in good yields.
In this case too, some standard click catalyst/solvent combinations were briefly evaluated. The cycloaddition between acetylene
7c
and benzyl azide (
8a
) with CuSO
4
∙5H
2
O/Na-ascorbate (or
l
-ascorbic acid) pair in CH
2
Cl
2
/water and
t
-BuOH/water solvent systems required prolonged reaction times, providing lower yields of the product
2d
as compared to the CuSO
4
/Cu
0
/DMF conditions (compare Entries 4–7). In the case of
t
-BuOH/water the presence of water in the reaction mixture turned the reactants and products into a gummy material that stuck to the reaction vessel and the magnetic stirring bar, impeding the reaction from going to completion, as already noticed for click reactions with highly hydrophobic reagents [
20
].
In principle, the “click-propargylation-click” reaction sequence at 3-azidoquinoline-2,4-diones
5
could be altered, providing the target bis-(1,2,3-triazole) functionalized products
2
via bifunctional azidoethynyl quinoline-2,4-dione intermediate
9
as shown in
Scheme 3
. This would allow orthogonal sequential synthetic strategies for accessing bis(1,2,3-triazole) functionalized materials [
21
]. We briefly explored this possibility by treating 3-azido-1-propargylquinoline-2,4-dione derivative
9a
with phenylacetylene (
6a
) or benzyl azide (
8a
) under the above mentioned CuSO
4
/Cu
0
/DMF conditions. The corresponding monotriazoles
7a
(16%) and
10a
(42%), respectively, were obtained in moderate yields.
The compounds 2a – l were characterized by 1 H, 13 C and, with the exception of 2a , g , h , also by 15 N NMR spectroscopy. The corresponding resonances were assigned on the basis of gradient-selected 2D NMR experiments including 1 H– 1 H gs -COSY, 1 H– 13 C gs -HSQC, 1 H– 13 C gs -HMBC and 1 H– 15 N gs -HMBC. For the atom numbering scheme, see Figure 2 . Some characteristic spectral features are discussed below.
The 13 C and 15 N chemical shifts for triazole rings A and D ( Table 5 and Table 6 ) are in a good agreement with those reported previously [ 11 ].
To preliminarily assess the applicability of bis-triazole compounds 2 as ligands, we decided to examine their coordination abilities to arene-ruthenium. NMR experiment was designed in which compound 2b and equimolar amount of ruthenium (0.5 equiv of [RuCl(μ-Cl)(η 6 - p -cymene)] 2 ) were mixed in CDCl 3 in NMR tube at room temperature. CDCl 3 was selected as the reaction solvent in place of the coordinative DMSO- d 6 to avoid possible interference with the metal center ( Scheme 4 ). The reaction mixture was monitored by time dependent 1 H NMR spectroscopy indicating an instant change in the resonances for 2b and p -cymene ligands upon mixing to form a new set of resonances that remained unchanged over several days. As shown in Figure 3 and Figure 4 , both proton and carbon NMR resonances were severely broadened suggesting the presence of a dynamic process in the solution, presumably an equilibrium with the starting ligand, which can result from a relatively weak ligand-to-metal interaction. Unfortunately, broad NMR resonances prevented an unambiguous structure determination of the product [Ru–Cym]- 2b through the 2D NMR techniques due to overlap as well as lack of several indicative crosspeaks in the spectra, especially in 1 H– 15 N gs -HMBC. Nevertheless, the analysis of the available NMR data tentatively suggested the coordination of both 1,2,3-triazole rings to the Ru–Cym unit as indicated in Scheme 4 . Although the coordination properties of the 1,2,3-triazole nitrogen atom N2 are weak, some of us have previously shown that such chelates can be greatly stabilized through an assistance of auxiliary ligand [ 22 ].
Attempts to unambiguously determine the structure of [Ru–Cym]-
2b
by variable temperature NMR techniques, as well as to grow crystals suitable for X-ray, failed. All of the above also applies to compounds
2g
and
2h
that were also preliminarily tested in [Ru–Cym] coordination.
3. Materials and Methods
3.1. General Experimental Methods
The reagents and solvents were used as obtained from the commercial sources. Compounds 3a [ 14 ], 3b [ 14 ], and 5b [ 15 ], as well as benzyl azide ( 8a ) [ 23 ], azidobenzene ( 8b ) [ 11 ], and tetrazolo[1,5- a ]pyridine ( 8c ) [ 24 ] were prepared as described in the literature. Column chromatography was carried out on Fluka Silica gel 60 (particle size 0.063–0.2 mm, activity acc. Brockmann and Schodder 2–3). Melting points were determined on the microscope hot stage, Kofler, PolyTherm, manufacturer Helmut Hund GmbH, Wetzlar and are uncorrected. TLC was carried out on pre-coated TLC sheets ALUGRAM ® SIL G/UV 254 for TLC, MACHEREY-NAGEL. NMR spectra were recorded with a Bruker Avance III 500 MHz NMR instrument operating at 500 MHz ( 1 H), 126 MHz ( 13 C) and 51 MHz ( 15 N) at 300 K. Proton spectra were referenced to TMS as internal standard, in some cases to the residual signal of DMSO- d 5 (at δ 2.50 ppm) or CHCl 3 (at δ 7.26 ppm). Carbon chemical shifts were determined relative to the 13 C signal of DMSO- d 6 (39.52 ppm) or CDCl 3 (77.16 ppm). 15 N chemical shifts were extracted from 1 H– 15 N gs -HMBC spectra (with 20 Hz digital resolution in the indirect dimension and the parameters adjusted for a long-range 1 H– 15 N coupling constant of 5 Hz) determined with respect to external nitromethane and are corrected to external ammonia by addition of 380.5 ppm. Nitrogen chemical shifts are reported to one decimal place as measured of the spectrum, however, the data should not be considered to be more accurate than ±0.5 ppm because of the digital resolution limits of the experiment. Chemical shifts are given on the δ scale (ppm). Coupling constants ( J ) are given in Hz. Multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) or br (broadened). Infrared spectra were recorded on FT-IR spectrometer Alpha (Bruker Optik GmbH Ettlingen, Ettlingen, Germany) using samples in potassium bromide disks and only the strongest/structurally most important peaks are listed. Electron impact mass spectra (EI) were recorded on a Shimadzu QP–2010 instrument at 70 eV. HRMS spectra were recorded with Agilent 6224 Accurate Mass TOF LC/MS system with electrospray ionization (ESI). Elemental analyses (C, H, N) were performed with FlashEA1112 Automatic Elemental Analyser (Thermo Fisher Scientific Inc., Waltham, MA, USA).
3.2. General Procedure for the Synthesis of 3-Chloroquinoline-2,4(1H,3H)-Diones 4 ( Scheme 1 )
The 3-Chloroquinoline-2,4(1 H ,3 H )-diones 4a [ 15 ] and 4b [ 16 ], were prepared from 4‑hydroxyquinolin-2(1 H )-ones 3a [ 14 ] and 3b [ 14 ], respectively, according to the procedures described in the literature.
3-Chloro-3-methylquinoline-2,4(1 H ,3 H )-dione (4a).
Compound
4a
(19.71 g, 94.0 mmol, 94%) was prepared from
3a
(17.52 g, 100 mmol). Yellow crystals, m.p. 178–181 °C (benzene), m.p. [
15
] 172 °C (acetic acid—water);
R
f
= 0.52 (30% ethyl acetate in chloroform);
1
H NMR (500 MHz, CDCl
3
)
δ
1.99 (s, 3H), 7.06 (d, 1H,
J
= 8.0 Hz), 7.22 (dd, 1H,
J
= 7.6, 7.6 Hz), 7.59–7.66 (m, 1H), 8.02 (d, 1H,
J
= 7.7 Hz), 9.41 (s, 1H);
13
C NMR (126 MHz, CDCl
3
)
δ
21.2, 62.8, 116.7, 118.1, 124.5, 129.1, 136.8, 139.6, 169.2, 188.4; IR (cm
−1
):
ν
3203, 3072, 3004, 2940, 1709, 1674, 1614, 1600, 1486, 1439, 1379, 1239, 770, 440; MS (EI)
m
/
z
(%): 212 (4, [M + 3]
+
), 211 (33, [M (
37
Cl)]
+
), 210 (17, [M + 1]
+
), 209 (100, [M (
35
Cl)]
+
), 208 (18), 175 (15), 174 (36), 146 (68), 128 (17), 120 (18), 119 (59), 92 (32), 91 (15); HRMS (ESI+):
m
/
z
calcd for C
10
H
9
ClNO
2
+
[M + H]
+
210.0316, found 210.0313. Anal. Calcd for C
10
H
8
ClNO
2
(209.63): C, 57.30; H, 3.85; N, 6.68%. Found: C, 57.18; H, 3.83; N, 6.61%.
3-Chloro-3-phenylquinoline-2,4(1 H ,3 H )-dione (4b).
Compound
4b
(26.08 g, 96.0 mmol, 96%) was prepared from
3b
(23.73 g, 100 mmol). Pale yellow needles, m.p. 182–185 °C (benzene), m.p. [
16
] 178–180 °C (ethanol);
R
f
= 0.57 (30% ethyl acetate in chloroform).
1
H NMR (500 MHz, CDCl
3
)
δ
7.04 (d, 1H,
J
= 8.0 Hz, H-8), 7.18 (ddd, 1H,
J
= 7.8, 7.4, 0.7 Hz, H-6), 7.33–7.39 (m, 3H, H‑3
C
, H‑4
C
, H‑5
C
), 7.51–7.54 (m, 2H, H-2
C
, H-6
C
), 7.55 (ddd, 1H,
J
= 7.3, 6.5, 1.5 Hz, H-7), 7.97 (dd, 1H,
J
= 7.8, 1.2 Hz, H-5), 9.82 (s, 1H, H-1);
13
C NMR (126 MHz, CDCl
3
)
δ
74.9 (C-3), 116.9 (C-8), 118.7 (C-4a), 124.7 (C-6), 127.4 (C-2
C
, C-6
C
), 129.1 (C-5), 129.2 (C-3
C
, C-5
C
), 129.8 (C-4
C
), 134.6 (C-1
C
), 137.0 (C-7), 139.4 (C-8a), 168.8 (C-2), 187.9 (C-4); IR (cm
−1
):
ν
3201, 3138, 3082, 2992, 2926, 1716, 1680, 1613, 1595, 1485, 1365, 755, 743, 690; MS (EI)
m
/
z
(%): 273 (7, [M (
37
Cl)]
+
), 271 (21, [M (
35
Cl)]
+
), 238 (12), 237 (80), 236 (100), 218 (10), 120 (63), 119 (19), 92 (34), 89 (10), 77 (12), 76 (10), 65 (14), 63 (10); HRMS (ESI+):
m
/
z
calcd for C
15
H
11
ClNO
2
+
[M + H]
+
272.0473, found 272.0480. Anal. Calcd for C
15
H
10
ClNO
2
(271.70): C, 66.31; H, 3.71; N, 5.16%. Found: C, 66.07; H, 3.62; N, 5.29%.
3.3. General Procedure for the Synthesis of 3-Azidoquinoline-2,4(1H,3H)-Diones 5 ( Scheme 1 )
To a stirred solution of the 3-chloroquinoline-2,4(1
H
,3
H
)-dione
4
(40 mmol) in DMF (200 mL), sodium azide (3.90 g, 60 mmol) was added in small portions during 10 min. The reaction mixture was stirred in darkness for additional 2 h and then poured into ice-water (1.5 L). The precipitated solid was filtered, washed with water and dried at 50 °C in darkness, which afforded product
5
, pure according to TLC and
1
H NMR spectrum, which was crystallized from benzene.
3-Azido-3-methylquinoline-2,4(1 H ,3 H )-dione (5a).
Compound
5a
(8.47 g, 39.2 mmol, 98%) was prepared from
4a
(8.39 g, 40.0 mmol). Colorless needles, m.p. 158–161 °C (benzene, 87% yield of recrystallization);
R
f
= 0.30 (30% ethyl acetate in chloroform).
1
H NMR (500 MHz, CDCl
3
)
δ
1.86 (s, 3H, CH
3
), 7.11 (d, 1H,
J
= 8.0 Hz, H-8), 7.22 (dd, 1H,
J
= 7.4, 7.4 Hz, H-6), 7.60–7.67 (m, 1H, H-7), 7.98 (d, 1H,
J
= 7.3 Hz, H-5), 9.86 (s, 1H, H-1);
13
C NMR (126 MHz, CDCl
3
)
δ
23.6 (CH
3
), 70.0 (C-3), 116.9 (C-8), 118.0 (C-4a), 124.6 (C-6), 128.6 (C-5), 137.2 (C-7), 140.0 (C-8a), 171.6 (C-2), 191.7 (C-4); IR (cm
−1
):
ν
3202, 3078, 3005, 2936, 2108, 1708, 1682, 1614, 1598, 1485, 1392, 1284, 1156, 755, 612; MS (EI)
m
/
z
(%): 217 (0.24, [M + 1]
+
), 216 (2, [M]
+
), 147 (15), 120 (11), 119 (100), 92 (35), 91 (11), 64 (12); HRMS (ESI+):
m
/
z
calcd for C
10
H
9
N
3-Azido-3-phenylquinoline-2,4(1 H ,3 H )-dione (5b). Compound 5b (10.90 g, 39.2 mmol, 98%) was prepared from 4b (10.87 g, 40.0 mmol). Colorless needles, m.p. 186–189 °C (benzene, 96% yield of recrystallization); m.p. [ 9 ] 173–181 °C (benzene); R f = 0.33 (38% ethyl acetate in petroleum ether); 1 H NMR (500 MHz, CDCl 3 ) δ 6.98 (d, 1H, J = 8.1 Hz, H-8), 7.16 (dd, 1H, J = 7.6, 7.6 Hz, H-6), 7.38–7.43 (m, 3H, H-3 C , H-4 C , H-5 C ), 7.48–7.53 (m, 2H, H-2 C , H-6 C ), 7.54 (ddd, 1H, J = 7.7, 7.7, 1.6 Hz, H-7), 7.93 (dd, 1H, J = 7.8, 1.6 Hz, H-5), 9.30 (s, 1H, H-1); 13 C NMR (126 MHz, CDCl 3 ) δ 78.0 (C-3), 116.7 (C-8), 119.5 (C-4a), 124.6 (C-6), 127.3 (C-2 C , C-6 C ), 128.6 (C-5), 129.8 (C-3 C , C-5 C ), 130.4 (C-4 C ), 132.6 (C-1 C ), 136.9 (C-7), 139.4 (C-8a), 170.2 (C-2), 189.9 (C-4); 15 N NMR (51 MHz, CDCl 3 ) δ 133.4 (N-1); IR (cm −1 ): ν 3244, 2105, 1718, 1705, 1685, 1611, 1484, 1356, 1256, 877, 773, 744, 702, 611, 525; MS (EI) m / z (%): 250 (7, [M − N 2 ] + ), 236 (8, [M − N 3 ] + ), 147 (28), 120 (14), 119 (100), 104 (15), 92 (32), 77 (10), 76 (10), 64 (14); HRMS (ESI+): m / z calcd for C 15 H 11 N 2 O 2 + [M − N 2 + H] + 251.0815, found 251.0818. HRMS (ESI−): m / z calcd for C 15 H 9 N 4 O 2 − [M − H] − 277.0731, found 277.0732; calcd for C 15 H 9 N 2 O 2 − [M − N 2 − H] − 249.0670, found 249.0671. Anal. Calcd for C 15 H 10 N 4 O 2 (278.27): C, 64.74; H, 3.62; N, 20.13%. Found: C, 64.54; H, 3.56; N, 20.38%.
3.4. General Procedure for the Synthesis of 3-(1H-1,2,3-Triazol-1-yl)Quinoline-2,4(1H,3H)-Diones 1a–d by Employing CuSO 4 /Cu 0 /DMF Conditions ( Table 2 , Entries 1 and 3–5)
A solution of phenylacetylene ( 6a ) (1.287 g, 12.6 mmol) or propargyl alcohol ( 6b ) (706 mg, 12.6 mmol) in DMF (4 mL) was added dropwise to a vigorously stirred mixture of 3-azidoquinoline-2,4(1 H ,3 H )-dione 5 (12 mmol), CuSO 4 ⋅5H 2 O (300 mg, 1.2 mmol), granular copper (1.5 g, 24 mmol) and DMF (24 mL). The reaction mixture was stirred in darkness for 30 min. Afterward, (NH 4 ) 2 CO 3 (3.5 g, 36 mmol) and water (12 mL) were added to the resulting brown-black suspension and the stirring was continued for 10 min. The reaction mixture was subjected to column chromatography with silica gel (15 g, column diameter of 1 cm) as a stationary phase, and 10% ethanol in chloroform as a mobile phase. Combined fractions containing yellow eluate were washed with saturated aqueous NH 4 Cl (5 × 50 mL), dried (Na 2 SO 4 ), and concentrated under reduced pressure to afford pure products 1a – d , which were recrystallized from ethanol for analyses.
3-Methyl-3-(4-phenyl-1 H -1,2,3-triazol-1-yl)quinoline-2,4(1 H ,3 H )-dione (1a). Colorless solid, m.p. 217–219 °C (ethanol); R f = 0.35 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.15 (s, 3H, CH 3 ), 7.22–7.27 (m, 2H, H-6, H-8), 7.33–7.39 (m, 1H, H-4 B ), 7.45–7.50 (m, 2H, H-3 B , H-5 B ), 7.73–7.79 (m, 1H, H-7), 7.83–7.90 (m, 3H, H-5, H-2 B , H-6 B ), 8.89 (s, 1H, H-5 A ), 11.48 (s, 1H, H-1); 13 C NMR (126 MHz, DMSO- d 6 ) δ 23.1 (CH 3 ), 72.2 (C-3), 117.0 (C-8), 117.4 (C-4a), 122.4 (C-5 A ), 123.5 (C-6), 125.1 (C-2 B , C-6 B ), 127.7 (C-5), 128.0 (C-4 B ), 129.0 (C-3 B , C-5 B ), 130.6 (C-1 B ), 137.3 (C-7), 141.6 (C-8a), 145.8 (C-4 A ), 168.5 (C-2), 190.7 (C-4); IR (cm −1 ): ν 3137, 2911, 1714, 1683, 1612, 1483, 1430, 1386, 1355, 1238, 1023, 808, 759, 690, 594; MS (EI) m / z (%): 319 (2, [M + 1] + ), 318 (8, [M] + ), 117 (14), 116 (100), 102 (12), 89 (14); HRMS (ESI+): m / z calcd for C 18 H 15 N 4 O 2 + [M + H] + 319.1190, found 319.1188. Anal. Calcd for C 18 H 14 N 4 O 2 (318.33): C, 67.91; H, 4.43; N, 17.60%. Found: C, 67.80; H, 4.47; N, 17.89%.
3-Phenyl-3-(4-phenyl-1 H -1,2,3-triazol-1-yl)quinoline-2,4(1 H ,3 H )-dione (1b). Colorless solid, m.p. 280–283 °C (ethanol); m.p. [ 9 ] 274–277 °C (ethanol); R f = 0.37 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 7.12 (d, 1H, J = 8.1 Hz, H-8), 7.16–7.20 (m, 1H, H-6), 7.31–7.37 (m, 1H, H-4 B ), 7.40–7.47 (m, 4H, H-3 B , H-5 B , H-2 C , H-6 C ), 7.49–7.55 (m, 3H, H-3 C , H-4 C , H-5 C ), 7.62–7.67 (m, 1H, H-7), 7.80–7.84 (m, 2H, H-2 B , H-6 B ), 7.86 (dd, 1H, J = 7.8, 1.4 Hz, H-5), 8.49 (s, 1H, H-5 A ), 11.68 (s, 1H, H-1); 13 C NMR (126 MHz, DMSO- d 6 ) δ 80.0 (C-3), 116.7 (C-8), 119.2 (C-4a), 123.4 (C-5 A ), 123.5 (C-6), 125.2 (C-2 B , C-6 B ), 127.6 (C-5), 128.0 (C-4 B ), 128.9 (C-2 C , C-6 C ), 129.0 (C-3 B , C-5 B ), 129.6 (C-3 C , C-5 C ), 129.9 (C-1 C ), 130.5 (C-1 B ), 130.6 (C-4 C ), 137.0 (C-7), 140.5 (C-8a), 145.3 (C-4 A ), 166.8 (C-2), 188.9 (C-4); IR (cm −1 ): ν 3275, 3169, 1721, 1690, 1613, 1595, 1486, 1452, 1353, 854, 771, 756, 699, 666, 607; MS (EI) m / z (%): 381 (2, [M + 1] + ), 380 (8, [M] + ), 247 (13), 237 (15), 236 (56), 220 (13), 218 (13), 120 (11), 117 (10), 116 (100), 102 (15), 92 (10), 89 (15), 77 (14); HRMS (ESI+): m / z calcd for C 23 H 17 N 4 O 2 + [M + H] + 381.1346, found 381.1341. Anal. Calcd for C 23 H 16 N 4 O 2 (380.40): C, 72.62; H, 4.24; N, 14.73%. Found: C, 72.40; H, 4.23; N, 14.90%.
3-(4-(Hydroxymethyl)-1 H -1,2,3-triazol-1-yl)-3-methylquinoline-2,4(1 H ,3 H )-dione (1c). Colorless solid, m.p. 188–189 °C (ethanol); R f = 0.35 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.08 (s, 3H, CH 3 ), 4.55 (d, 2H, J = 5.6 Hz, CH 2 ), 5.28 (t, 1H, J = 5.6 Hz, OH), 7.18–7.25 (m, 2H, H-6, H-8), 7.69–7.76 (m, 1H, H-7), 7.83 (dd, 1H, J = 8.1, 1.4 Hz, H-5), 8.26 (s, 1H, H-5 A ), 11.39 (s, 1H, H-1); 13 C NMR (126 MHz, DMSO- d 6 ) δ 23.1 (CH 3 ), 55.0 (CH 2 ), 71.9 (C-3), 116.9 (C-8), 117.5 (C-4a), 123.3 (C-6), 123.7 (C-5 A ), 127.6 (C-5), 137.1 (C-7), 141.6 (C-8a), 147.4 (C-4 A ), 168.7 (C-2), 190.8 (C-4); IR (cm −1 ): ν 3148, 2992, 2919, 1729, 1682, 1613, 1486, 1378, 1345, 1235, 1189, 1009, 751, 667, 590; MS (EI) m / z (%): 273 (2, [M + 1] + ), 272 (13, [M] + ), 185 (68), 175 (89), 174 (45), 146 (100), 128 (58), 120 (70), 119 (75), 92 (66), 91 (39), 77 (39), 65 (37), 55 (39), 42 (79); HRMS (ESI+): m / z calcd for C 13 H 13 N 4 O 3 + [M + H] + 273.0982, found 273.0981. Anal. Calcd for C 13 H 12 N 4 O 3 (272.26): C, 57.35; H, 4.44; N, 20.58%. Found: C, 57.20; H, 4.42; N, 20.83%.
3-(4-(Hydroxymethyl)-1 H -1,2,3-triazol-1-yl)-3-phenylquinoline-2,4(1 H ,3 H )-dione dimethylformamide solvate (1d·DMF). Colorless solid, m.p. 139–143 °C (ethanol); m.p. [ 9 ] 116–135 °C (benzene); R f = 0.27 (10% ethanol in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 4.53 (d, 2H, J = 5.7 Hz, CH 2 ), 5.22 (t, 1H, J = 5.7 Hz, OH), 7.09 (d, 1H, J = 8.1 Hz, H-8), 7.13–7.18 (m, 1H, H-6), 7.36–7.42 (m, 2H, H-2 C , H-6 C ), 7.47–7.53 (m, 3H, H-3 C , H-4 C , H-5 C ), 7.59–7.65 (m, 1H, H-7), 7.77 (s, 1H, H-5 A ), 7.83 (dd, 1H, J = 7.8, 1.3 Hz, H-5), 11.60 (s, 1H, H-1); 13 C NMR (126 MHz, DMSO- d 6 ) δ 55.0 (CH 2 ), 79.7 (C-3), 116.7 (C-8), 119.2 (C-4a), 123.4 (C-6), 124.8 (C-5 A ), 127.5 (C-5), 128.8 (C-2 C , C-6 C ), 129.6 (C-3 C , C-5 C ), 130.2 (C-1 C ), 130.5 (C-4 C ), 136.9 (C-7), 140.6 (C-8a), 146.8 (C-4 A ), 166.8 (C-2), 189.0 (C-4); IR (cm −1 ): ν 3392, 3136, 2926, 1724, 1692, 1654, 1613, 1485, 1438, 1353, 857, 769, 752, 665, 603; MS (EI) m / z (%): 335 (0.8, [M + 1] + ), 334 (4, [M] + ), 305 (37), 275 (18), 249 (30), 247 (27), 237 (50), 236 (100), 218 (35), 208 (18), 180 (20), 120 (33), 104 (23), 92 (23), 77 (34); HRMS (ESI+): m / z calcd for C 18 H 15 N 4 O 3 + [M + H] + 335.1139, found 335.1138. Anal. Calcd for C 21 H 21 N 5 O 4 (407.42): C, 61.91; H, 5.20; N, 17.19%. Found: C, 61.89; H, 5.24; N, 17.28%.
3.5. Synthesis of Compound 1a by Employing CuSO 4 ∙5H 2 O /l -Ascorbic Acid/CH 2 Cl 2 /Water Conditions ( Table 2 , Entry 2)
To a solution of azide 5a (162 mg, 0.75 mmol) and phenylacetylene ( 6a ) (153 mg, 1.5 mmol) in dichloromethane (8 mL) a solution of l -ascorbic acid (106 mg, 0.60 mmol) in water (4 mL), and a solution of CuSO 4 ∙5H 2 O (15 mg, 0.06 mmol) in water (4mL) were added. The two-phase reaction mixture was stirred in darkness at room temperature for 48 h. The reaction mixture was extracted with chloroform (5 × 30 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, and evaporated to dryness. The residue was dissolved in chloroform (5 mL) and subjected to silica gel (30 g) column chromatography using 38% ethyl acetate in hexane as eluent, affording compound 1a (199 mg, 63 mmol 83%).
3.6. General Procedure for the Synthesis of (1-(2,4-Dioxo-1,2,3,4-Tetrahydroquinolin-3-yl)-1H-1,2,3-Triazol-4-yl)Methyl Acetates 1e,f ( Scheme 2 )
Acetic anhydride (12 mL, 12.9 g, 126 mmol) was added to a light yellow solution of compound 1c or 1d (6 mmol) in pyridine (18 mL) under stirring during 2 min. The reaction mixture was stirred for 1 h, followed by evaporation of volatiles under reduced pressure. The remaining pyridine was removed by co-distillation with ethanol (6 × 40 mL). The residue was triturated with water (300 mL) to form a white precipitate which was collected by filtration on a sintered glass filter with suction, washed with water to neutral and dried to give acetates 1e or 1f . The crude product was recrystallized from the solvent indicated below.
(1-(3-Methyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl)-1 H -1,2,3-triazol-4-yl)methyl acetate (1e). Compound 1e (1.58 g, 5.04 mmol, 84%) was prepared from 1c (1.63 g, 6.0 mmol). Pale yellow solid, m.p. 145–148 °C (ethyl acetate); R f = 0.33 (5% ethanol in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.06 (s, 3H, COCH 3 ), 2.09 (s, 3H, C-3–CH 3 ), 5.16 (s, 2H, CH 2 ), 7.19–7.26 (m, 2H, H-6, H-8), 7.70–7.77 (m, 1H, H-7), 7.83 (dd, 1H, J = 8.0, 1.4 Hz, H-5), 8.45 (s, 1H, H-5 A ), 11.40 (s, 1H, H-1); 13 C NMR (126 MHz, DMSO- d 6 ) δ 20.6 (COCH 3 ), 23.2 (C-3–CH 3 ), 57.1 (CH 2 ), 72.4 (C-3), 116.9 (C-8), 117.5 (C-4a), 123.3 (C-6), 125.8 (C-5 A ), 127.6 (C-5), 137.1 (C-7), 141.4 (C-4 A ), 141.6 (C-8a), 168.6 (C-2), 170.1 (COCH 3 ), 190.7 (C-4); 15 N NMR (51 MHz, DMSO-d 6 ) δ 133.5 (N-1), 248.7 (N-1 A ), 354.1 (N-3 A ), 362.9 (N-2 A ); IR (cm −1 ): ν 3467, 3249, 3148, 2920, 1722, 1685, 1613, 1485, 1439, 1384, 1355, 1239, 1028, 759, 666; MS (EI) m / z (%): 315 (2, [M + 1] + ), 314 (11, [M] + ), 244 (22), 201 (22), 175 (71), 174 (31), 146 (43), 128 (26), 120 (25), 119 (27), 92 (24), 55 (20), 43 (100), 42 (26); HRMS (ESI+): m / z calcd for C 15 H 15 N 4 O 4 + [M + H] + 315.1088, found 315.1087. Anal. Calcd for C 15 H 14 N 4 O 4 (314.30): C, 57.32; H, 4.49; N, 17.83%. Found: C, 57.32; H, 4.59; N, 17.58%.
(1-(2,4-Dioxo-3-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)-1 H -1,2,3-triazol-4-yl)methyl acetate (1f). Compound 1f (1.92 g, 5.1 mmol, 85%) was prepared from 1d (2.01 g, 6.0 mmol). Colorless crystals, m.p. 130–134 °C (ethanol, 80% yield of recrystallization); R f = 0.40 (5% ethanol in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.04 (s, 3H, CH 3 ), 5.13 (s, 2H, CH 2 ), 7.09 (d, 1H, J = 8.1 Hz, H-8), 7.13–7.18 (m, 1H, H-6), 7.35–7.42 (m, 2H, H-2 C , H-6 C ), 7.46–7.54 (m, 3H, H-3 C , H-4 C , H-5 C ), 7.59–7.65 (m, 1H, H-7), 7.83 (dd, 1H, J = 7.8, 1.3 Hz), 8.07 (s, 1H, H-5 A ), 11.62 (s, 1H, H-1); 13 C NMR (126 MHz, DMSO- d 6 ) δ 20.7 (CH 3 ), 57.1 (CH 2 ), 79.9 (C-3), 116.7 (C-8), 119.3 (C-4a), 123.4 (C-6), 127.0 (C-5 A ), 127.5 (C-5), 128.8 (C-2 C , C-6 C ), 129.6 (C-3 C , C-5 C ), 130.0 (C-1 C ), 130.6 (C-4 C ), 136.9 (C-7), 140.5 (C-8a), 140.8 (C-4 A ), 166.8 (C-2), 170.1 (COCH 3 ), 188.8 (C-4); IR (cm–1): ν 3501, 3155, 2920, 1722, 1707, 1686, 1614, 1594, 1484, 1358, 1252, 1229, 1063, 857, 759; MS (EI) m / z (%): 377 (1, [M + 1]+), 376 (6, [M]+), 306 (16), 289 (18), 288 (54), 263 (15), 237 (50), 236 (100), 218 (34), 180 (14), 141 (14), 120 (24), 92 (14), 77 (19), 43 (16); HRMS (ESI+): m / z calcd for C 20 H 17 N 4 O 4 + [M + H] + 377.1244, found 377.1241.
3.7. General Procedure for the Synthesis of 3-(1H-1,2,3-Triazol-1-yl)-1-(prop-2-yn-1-yl)Quinoline-2,4(1H,3H)-Diones 7 ( Table 3 )
The mixture of the appropriate compound 1a , b , e , f (8.00 mmol), potassium carbonate (3.32 g, 24 mmol), and DMF (40 mL) was stirred for 40 min. During this time, the original yellow color of the suspension changed to orange. Afterwards, under continued stirring, an 80% solution of propargyl bromide ( 6c ) in toluene (1.78 g, 12 mmol) diluted with DMF (20 mL) was added dropwise during 1 min and stirring was continued for 90 min. Then the mixture was reduced in vacuo and then toluene (50 mL) was added and the whole evaporated in vacuo at 50 °C. This was repeated seven times in order to remove traces of DMF. The residual light brown solid was suspended in chloroform (100 mL) and the suspension was acidified with 0.5 m HCl, whereas carbon dioxide was evolved owing to decomposition of unreacted potassium carbonate. The formed emulsion was diluted with water, organic phase was separated and aqueous phase was extracted with chloroform (5 × 40 mL). The organic phases were combined, dried (Na 2 SO 4 ), filtered and taken down in vacuo . The residual solid TLC pure product was crystallized from a suitable solvent. The yields of prepared compounds 7 are given in Table 3 .
3-Methyl-3-(4-phenyl-1 H -1,2,3-triazol-1-yl)-1-(prop-2-yn-1-yl)quinoline-2,4(1 H ,3 H )-dione (7a). Colorless crystals, m.p. 187–189 °C (benzene); R f = 0.63 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.16 (s, 3H, CH 3 ), 3.39 (dd, 1H, J = 2.3, 2.3 Hz, C≡CH), 4.90 (dd, 1H, J = 18.1, 2.3 Hz, N-1–CH α ), 4.97 (dd, 1H, J = 18.1, 2.3 Hz, N-1–CH β ), 7.34–7.42 (m, 2H, H-6, H-4 B ), 7.48 (dd, 2H, J = 7.7, 7.7 Hz, H-3 B , H-5 B ), 7.61 (d, 1H, J = 8.4 Hz, H-8), 7.84–7.89 (m, 2H, H-2 B , H-6 B ), 7.89–7.95 (m, 1H, H-7), 8.00 (dd, J = 7.7, 1.5 Hz, H-5), 8.89 (s, 1H, H-5 A ); 13 C NMR (126 MHz, DMSO- d 6 ) δ 23.3 (CH 3 ), 32.7 (N-1–CH 2 ), 72.6 (C-3), 75.4 (C≡ C H), 78.2 ( C ≡CH), 116.7 (C-8), 119.0 (C-4a), 122.5 (C-5 A ), 124.2 (C-6), 125.1 (C-2 B , C-6 B ), 128.1 (C-4 B ), 128.2 (C-5), 129.0 (C-3 B , C-5 B ), 130.5 (C-1 B ), 137.3 (C-7), 140.8 (C-8a), 145.9 (C-4 A ), 167.7 (C-2), 189.7 (C-4); IR (cm −1 ): ν 3261, 3173, 2122, 1713, 1678, 1601, 1469, 1427, 1381, 1368, 1353, 1306, 1189, 769, 754; MS (EI) m / z (%): 357 (2, [M + 1] + ), 356 (8, [M] + ), 259 (10), 128 (11), 117 (16), 116 (100), 102 (17), 90 (11), 89 (16), 77 (10), 76 (10); HRMS (ESI+): m / z calcd for C 21 H 17 N 4 O 2 + [M + H] + 357.1346, found 357.1342. Anal. Calcd for C 21 H 16 N 4 O 2 (356.38): C, 70.77; H, 4.53; N, 15.72%. Found: C, 70.81; H, 4.58; N, 15.82%.
3-Phenyl-3-(4-phenyl-1 H -1,2,3-triazol-1-yl)-1-(prop-2-yn-1-yl)quinoline-2,4(1 H ,3 H )-dione (7b). Colorless crystals, m.p. 232–234 °C (ethanol); R f = 0.69 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, CDCl 3 ) δ 2.34 (dd, 1H, J = 2.4, 2.4 Hz), 4.51 (dd, 1H, J = 17.8, 2.3 Hz), 5.37 (dd, 1H, J = 17.8, 2.3 Hz), 7.23 (dd, 1H, J = 7.6, 7.6 Hz), 7.26 (s, 1H), 7.27–7.31 (m, 1H), 7.32–7.40 (m, 3H), 7.43–7.51 (m, 3H), 7.51–7.56 (m, 2H), 7.62–7.69 (m, 1H), 7.73–7.81 (m, 2H), 8.05 (dd, 1H, J = 7.7, 1.4 Hz); 13 C NMR (126 MHz, CDCl 3 ) δ 33.6, 73.6, 76.9, 79.6, 115.8, 121.0, 122.3, 124.6, 126.0, 128.1, 128.8, 129.0, 129.2, 130.0, 130.1, 130.7, 131.3, 136.9, 140.6, 146.0, 165.8, 187.5; IR (cm −1 ): ν 3197, 2983, 2118, 1716, 1680, 1603, 1468, 1448, 1304, 1039, 870, 760, 752, 694; MS (EI) m / z (%): 419 (13, [M + 1] + ), 418 (75, [M] + ), 390 (43), 287 (22), 286 (31), 285 (89), 276 (25), 275 (100), 274 (28), 259 (70), 248 (46), 235 (53), 145 (52), 116 (95), 44 (99); HRMS (ESI+): m / z calcd for C 26 H 19 N 4 O 2 + [M + H] + 419.1503, found 419.1502. Anal. Calcd for C 26 H 18 N 4 O 2 : C, 74.63; H, 4.34; N, 13.39%. Found: C, 74.45; H, 4.40; N, 13.43%.
(1-(3-Methyl-2,4-dioxo-1-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroquinolin-3-yl)-1 H -1,2,3-triazol-4-yl)methyl acetate (7c). Colorless crystals, m.p. 159–161 °C (ethyl acetate); R f = 0.29 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.06 (s, 3H, COCH 3 ), 2.10 (s, 3H, C-3–CH 3 ), 3.37 (dd, 1H, J = 2.4, 2.4 Hz, C≡CH), 4.84 (dd, 1H, J = 18.1, 2.4 Hz, N-1–CH α ), 4.95 (dd, 1H, J = 18.1, 2.4 Hz, N-1–CH β ), 5.17 (s, 2H, OCH 2 ), 7.37 (dd, 1H, J = 7.5, 7.5 Hz, H-6), 7.58 (d, 1H, J = 8.4 Hz, H-8), 7.87–7.93 (m, 1H, H-7), 7.96 (dd, 1H, J = 7.7, 1.5 Hz, H-5), 8.46 (s, 1H, H-5 A ); 13 C NMR (126 MHz, DMSO- d 6 ) δ 20.6 (CO C H 3 ), 23.4 (C-3–CH 3 ), 32.6 (N-1–CH 2 ), 57.1 (OCH 2 ), 72.8 (C-3), 75.3 (C≡ C H), 78.2 ( C ≡CH), 116.6 (C-8), 119.2 (C-4a), 124.0 (C-6), 126.0 (C-5 A ), 128.0 (C-5), 137.1 (C-7), 140.7 (C-8a), 141.5 (C-4 A ), 167.8 (C-2), 170.1 ( C OCH 3 ), 189.63 (C-4); 15 N NMR (51 MHz, DMSO- d 6 ) δ 134.4 (N1), 247.9 (N-1 A ), 354.0 (N-3 A ), 363.4 (N-2 A ); IR (cm −1 ): ν 3256, 3152, 2122, 1721, 1687, 1604, 1471, 1383, 1306, 1246, 1194, 1053, 1008, 756; MS (EI) m / z (%): 353 (3, [M + 1] + ), 352 (12, [M] + ), 213 (69), 212 (34), 184 (19), 156 (32), 146 (17), 130 (19), 129 (21), 128 (22), 77 (17), 57 (16), 55 (23), 43 (100), 42 (17); HRMS (ESI+): m / z calcd for C 18 H 17 N 4 O 4 + ([M+H] + ): 353.1244, found 353.1246. Anal. Calcd for C 18 H 16 N 4 O 4 (352.34): C, 61.36; H, 4.58; N, 15.90%. Found: C, 61.27; H, 4.64; N, 15.87%.
(1-(2,4-Dioxo-3-phenyl-1-(prop-2-yn-1-yl)-1,2,3,4-tetrahydroquinolin-3-yl)-1 H -1,2,3-triazol-4-yl)methyl acetate (7d). Colorless crystals, m.p. 210–214 °C; R f = 0.66 (5% ethanol in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.05 (s, 3H, COCH 3 ), 3.41 (dd, 1H, J = 2.4, 2.3 Hz, C≡CH), 4.80 (dd, 1H, J = 18.0, 2.3 Hz, N-1–CH α ), 5.09–5.20 (m, 3H, N-1–CH β , OCH 2 ), 7.24–7.32 (m, 3H, H-6, H-2 C , H-6 C ), 7.41–7.51 (m, 4H, H-8, H-3 C , H-4 C , H-5 C ), 7.73–7.79 (m, 1H, H-7), 7.92 (dd, 1H, J = 7.7, 1.5 Hz, H-5), 8.15 (s, 1H, H-5 A ); 13 C NMR (126 MHz, DMSO- d 6 ) δ 20.6 (CO C H 3 ), 33.1 (N-1–CH 2 ), 57.1 (OCH 2 ), 75.5 (C≡ C H), 77.9 ( C ≡CH), 80.0 (C-3), 116.3 (C-8), 120.9 (C-4a), 124.2 (C-6), 127.1 (C-5 A ), 127.8 (C-5), 128.6 (C-2 C , C-6 C ), 129.5 (C-3 C , C-5 C ), 129.9 (C-1 C ), 130.7 (C-4 C ), 136.7 (C-7), 140.0 (C-8a), 140.9 (C-4 A ), 165.8 (C-2), 170.1 ( C OCH 3 ), 187.7 (C-4); IR (cm −1 ): ν 3227, 3152, 2116, 1736, 1715, 1683, 1602, 1467, 1379, 1303, 1251, 1036, 764, 747, 694; MS (EI) m / z (%): 415 (2, [M + 1] + ), 414 (7, [M] + ), 313 (26), 275 (72), 274 (63), 246 (28), 235 (31), 218 (29), 217 (30), 156 (26), 130 (29), 105 (22), 104 (29), 103 (22), 43 (100); HRMS (ESI+): m / z calcd for C 23 H 19 N 4 O 4 + [M + H] + 415.1401, found 415.1403. Anal. Calcd for C 23 H 18 N 4 O 4 : C, 66.66; H, 4.38; N, 13.52%. Found: C, 66.45; H, 4.39; N, 13.35%.
3.8. General Procedure for the Synthesis of Bis-Triazoles 2a,b,d,e,g,h,j,k by Employing CuSO 4 /Cu 0 /DMF Conditions ( Table 4 , Entries 1, 2, 4, 8, 10, 11, 13 and 14)
A solution of azidobenzene ( 8b , 197 mg, 1.65 mmol) or (azidomethyl)benzene ( 8a , 220 mg, 1.65 mmol) in DMF (4 mL) was added to a vigorously stirred mixture of the appropriate N ‑propargylquinoline-2,4(1 H ,3 H )-dione 7 (1.5 mmol), CuSO 4 ∙5H 2 O (38 mg, 0.15 mmol) and granular copper (191 mg, 3.05 mmol) in DMF (5 mL). The reaction mixture was stirred in darkness at room temperature for the time given in Table 4 . The color of the mixture became brown-black. Then, (NH 4 ) 2 CO 3 (432 mg, 4.5 mmol) and water (2 mL) were added to the reaction mixture and the stirring was continued for 10 min. The reaction mixture was poured into a narrow (1 cm in diameter) column of silica gel (15 g). The organic portion was eluted with 10% ethanol in chloroform (approximately 150 mL). The yellow eluate was washed with saturated aqueous NH 4 Cl (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation in vacuo . The TLC pure product thus prepared, with the exception of compounds 2d , e , k , was crystallized from suitable solvent. The yields of prepared compounds 2 are given in Table 4 .
1-((1-Benzyl-1 H -1,2,3-triazol-4-yl)methyl)-3-methyl-3-(4-phenyl-1 H -1,2,3-triazol-1-yl)quinoline-2,4(1 H ,3 H )-dione (2a). Colorless crystals, m.p. 202–204 °C (ethanol); R f = 0.40 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.18 (s, 3H, CH 3 ), 5.24 (d, 1H, J = 16.2 Hz, N-1–CH α ), 5.49 (d, 1H, J = 16.2 Hz, N-1–CH β ), 5.58 (s, 2H, N-1 D –CH 2 ), 7.24–7.29 (m, 2H, H-2 E , H-6 E ), 7.29–7.40 (m, 5H, H-6, H-4 B , H-3 E , H-4 E , H-5 E ), 7.49 (dd, 2H, J = 7.7, 7.7 Hz, H-3 B , H-5 B ), 7.67 (d, 1H, J = 8.5 Hz, H-8), 7.79–7.90 (m, 3H, H-7, H-2 B , H-6 B ), 7.96 (dd, 1H, J = 7.7, 1.4 Hz, H-5), 8.16 (s, 1H, H-5 D ), 8.87 (s, 1H, H-5 A ); 13 C NMR (126 MHz, DMSO- d 6 ) δ 23.4 (CH 3 ), 38.7 (N-1– C H 2 ), 52.8 (N-1 D – C H 2 ), 72.8 (C-3), 116.7 (C-8), 119.1 (C-4a), 122.5 (C-5 A ), 123.8 (C-5 D ), 123.9 (C-6), 125.1 (C-2 B , C-6 B ), 127.9 (C-2 E , C-6 E ), 128.0 (C-4 B ), 128.1 (C-5), 128.1 (C-4 E ), 128.7 (C-3 E , C-5 E ), 129.1 (C-3 B , C-5 B ), 130.6 (C-1 B ), 136.0 (C-1 E ), 137.2 (C-7), 141.5 (C-8a), 142.2 (C-4 D ), 145.9 (C-4 A ), 168.2 (C-2), 190.0 (C-4); IR (cm −1 ): ν 3137, 3128, 1711, 1673, 1600, 1471, 1387, 1051, 768, 761, 718, 694; MS (EI) m / z (%): 490 (2, [M + 1] + ), 489 (6, [M] + ), 289 (13), 145 (17), 144 (16), 117 (11), 116 (44), 91 (100), 90 (10), 89 (12); HRMS (ESI+): m / z calcd for C 28 H 24 N 7 O 2 + [M + H] + 490.1986, found 490.1981. Anal. Calcd for C 28 H 23 N 7 O 2 (489.53) C, 68.70; H, 4.74; N, 20.03. Found: C, 68.71; H, 4.78; N, 20.36.
3-Methyl-3-(4-phenyl-1 H -1,2,3-triazol-1-yl)-1-((1-phenyl-1 H -1,2,3-triazol-4-yl)methyl)quinoline-2,4(1 H ,3 H )-dione (2b). Colorless crystals, m.p. 194–197 °C (benzene); R f = 0.48 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.23 (s, 3H, CH 3 ), 5.33 (d, 1H, J = 16.4 Hz, N-1–CH α ), 5.62 (d, 1H, J = 16.4 Hz, N-1–CH β ), 7.31–7.39 (m, 2H, H-6, H-4 B ), 7.45–7.52 (m, 3H, H-3 B , H-5 B , H-4 E ), 7.55–7.62 (m, 2H, H-3 E , H-5 E ), 7.70 (d, 1H, J = 8.5 Hz, H-8), 7.82–7.91 (m, 5H, H-7, H‑2 B , H-6 B , H-2 E , H-6 E ), 7.98 (dd, 1H, J = 7.7, 1.5 Hz, H-5), 8.75 (s, 1H, H-5 D ), 8.87 (s, 1H, H-5 A ); 13 C NMR (126 MHz, DMSO- d 6 ) δ 23.4 (CH 3 ), 38.7 (N-1– C H 2 ), 73.0 (C-3), 116.8 (C-8), 119.2 (C-4a), 120.2 (C-2 E , C-6 E ), 121.8 (C-5 D ), 122.5 (C-5 A ), 124.0 (C-6), 125.2 (C-2 B , C-6 B ), 128.1 (C-4 B ), 128.1 (C-5), 128.8 (C-4 E ), 129.1 (C-3 B , C-5 B ), 129.9 (C-3 E , C-5 E ), 130.6 (C-1 B ), 136.5 (C-1 E ), 137.3 (C-7), 141.6 (C-8a), 143.3 (C-4 D ), 146.0 (C-4 A ), 168.3 (C-2), 190.0 (C-4); 15 N NMR (51 MHz, DMSO- d 6 ) δ 136.3 (N1), 248.9 (N-1 A ), 255.7 (N-D-1), 347.1 (N-3 A ), 353.4 (N-3 D ), 358.1 (N-2 D ), 363.2 (N-2 A ); IR (cm −1 ): ν 3275, 1721, 1690, 1613, 1485, 1353, 854, 771, 756, 698, 666, 607, 520; MS (EI) m / z (%): 476 (3, [M + 1] + ), 475 (8, [M] + ), 289 (14), 145 (12), 131 (11), 130 (100), 129 (18), 128 (11), 116 (56), 104 (12), 103 (16), 102 (12), 89 (12), 77 (69); HRMS (ESI+): m / z calcd for C 27 H 22 N 7 O 2 + [M + H] + 476.1829, found 476.1825. Anal. Calcd for C 27 H 21 N 7 O 2 (475.50): C, 68.20; H, 4.45; N, 20.62%. Found: C, 68.48; H, 4.53; N, 20.60%.
(1-(1-((1-Benzyl-1 H -1,2,3-triazol-4-yl)methyl)-3-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinolin-3-yl)-1 H -1,2,3-triazol-4-yl)methyl acetate (2d). Colorless powder, m.p. 69–82 °C; R f = 0.42 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, CDCl 3 ), δ 2.09 (s, 3H, COCH 3 ), 2.12 (s, 3H, C-3–CH 3 ), 5.25 (s, 2H, OCH 2 ), 5.33 (s, 2H, N-1-CH 2 ), 5.45 (d, 1H, J = 14.8 Hz, N-1 D –CH α ), 5.51 (d, 1H, J = 14.8 Hz, N-1 D –CH β ), 7.23–7.26 (m, 3H, H-6, H-2 E , H-6 E ), 7.32–7.38 (m, 3H, H-3 E , H-4 E , H-5 E ), 7.55 (s, 1H, H-5 D ), 7.73 (ddd, 1H, J = 8.7, 7.1, 1.6 Hz, H-7), 7.78 (s, 1H, H-5 A ), 7.82 (d, 1H, J = 8.4 Hz, H-8), 8.02 (dd, 1H, J = 7.7, 1.6 Hz, H-5); 13 C NMR (126 MHz, CDCl 3 ) δ 21.1 (CO C H 3 ), 23.5 (C-3– C H 3 ), 39.5 (N-1–CH 2 ), 54.5 (N-1 D –CH 2 ), 57.7 (OCH 2 ), 71.6 (C-3), 116.9 (C-8), 119.2 (C-4a), 123.5 (C-5 D ), 124.2 (C-5 A ), 124.6 (C-6), 128.3 (C-2 E , C-6 E ), 129.0 (C-4 E ), 129.3 (C-3 E , C-5 E ), 129.3 (C-5), 134.4 (C-1 E ), 137.8 (C-7), 141.7 (C-8a), 142.3 (C-4 A ), 142.9 (C-4 D ), 168.2 (C-2), 171.1 ( C OCH 3 ), 189.4 (C-4); 15 N NMR (51 MHz, CDCl 3 ) δ 138.7 (N-1), 248.4 (N-1 A ), 250.4 (N-1 D ), 350.0 (N-3 D ), 355.2 (N-3 A ), 361.6 (N-2 A ), 362.6 (N-2 D ); IR (cm −1 ): ν 3143, 2930, 1739, 1717, 1679, 1602, 1470, 1384, 1243, 1186, 1050, 1028, 765, 721, 664; MS (EI) m / z (%): 486 (0.3, [M + 1] + ), 485 (1, [M] + ), 144 (18), 91 (100), 43 (24); HRMS (ESI+): m / z calcd for C 25 H 24 N 7 O 4 + [M + H] + 486.1884, found 486.1884.
(1-(3-Methyl-2,4-dioxo-1-((1-phenyl-1 H -1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroquinolin-3-yl)-1 H -1,2,3-triazol-4-yl)methyl acetate (2e). Colorless powder, m.p. 78–97 °C; R f = 0.25 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, CDCl 3 ) δ 2.10 (s, 3H, COCH 3 ), 2.20 (s, 3H, C-3–CH 3 ), 5.27 (s, 2H, OCH 2 ), 5.42 (d, 1H, J = 15.8 Hz, N-1–CH α ), 5.52 (d, 1H, J = 15.8 Hz, N-1–CH β ), 7.27–7.30 (m, 1H, H-6), 7.41–7.47 (m, 1H, H-4 E ), 7.49–7.55 (m, 2H, H-3 E , H-5 E ), 7.69–7.74 (m, 2H, H-2 E , H-6 E ), 7.76 (ddd, 1H, J = 8.1, 7.7, 1.6 Hz, H-7), 7.85 (d, 1H, J = 7.3 Hz, H-8), 7.86 (s, 1H, H-5 A ), 8.05 (dd, 1H, J = 7.8, 1.5 Hz, H-5), 8.10 (s, 1H, H-5 D ); 13 C NMR (126 MHz, CDCl 3 ) δ 21.0 (CO C H 3 ), 23.4 (C-3– C H 3 ), 39.5 (N-1-CH 2 ), 57.7 (OCH 2 ), 71.5 (C-3), 116.8 (C-8), 119.2 (C-4a), 120.6 (C-2 E , C-6 E ), 121.7 (C-5 D ), 124.1 (C-5 A ), 124.7 (C-6), 129.1 (C-4 E ), 129.4 (C-5), 129.9 (C-3 E , C-5 E ), 136.9 (C-1 E ), 137.8 (C-7), 141.7 (C-8a), 142.3 (C-4 A ), 143.2 (C-4 D ), 168.3 (C-2), 171.1 ( C OCH 3 ), 189.4 (C-4); 15 N NMR (51 MHz, CDCl 3 ) δ 138.7 (N-1), 248.8 (N-1 A ), 256.3 (N-1 D ), 351.9 (N-3 D ), 355.5 (N-3 A ); IR (cm −1 ): ν 3145, 2926, 1740, 1717, 1681, 1601, 1470, 1384, 1242, 1184, 1046, 761, 691, 664; MS (EI) m / z (%): 472 (0.9, [M + 1] + ), 471 (3, [M] + ), 303 (20), 302 (17), 131 (13), 130 (100), 129 (14), 77 (44), 43 (25); HRMS (ESI+): m / z calcd for C 24 H 22 N 7 O 4 + [M + H] + 472.1728, found 472.1726.
1-((1-Benzyl-1 H -1,2,3-triazol-4-yl)methyl)-3-phenyl-3-(4-phenyl-1 H -1,2,3-triazol-1-yl)quinoline-2,4(1 H ,3H)-dione (2g). Colorless crystals, m.p. 142–145 °C (ethanol); R f = 0.42 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 5.15 (d, 1H, J = 15.8 Hz, N-1–CH α ), 5.62 (s, 2H, N-1 D –CH 2 ), 5.63 (d, 1H, J = 15.8 Hz, N-1–CH β ), 7.22–7.50 (m, 14H, H-6, H-3 B , H-4 B , H-5 B , H-2 C , H-3 C , H-4 C , H-5 C , H-6 C , H-2 E , H-3 E , H-4 E , H-5 E , H-6 E ), 7.68 (d, 1H, J = 7.8 Hz, H-8), 7.73 (ddd, 1H, J = 8.5, 7.1, 1.7 Hz, H-7), 7.80–7.83 (m, 2H, H-2 B , H-6 B ), 7.92 (dd, 1H, J = 7.7, 1.5 Hz, H-5), 8.24 (s, 1H, H-5 D ), 8.51 (s, 1H, H-5 A ); 13 C NMR (126 MHz, DMSO- d 6 ) δ 39.2 (N-1–CH 2 ), 52.8 (N-1 D –CH 2 ), 80.1 (C-3), 116.7 (C-8), 120.9 (C-4a), 123.4 (C-5 A ), 124.0 (C-6), 124.2 (C-5 D ), 125.2 (C-2 B , C-6 B ), 127.9 (C-5), 128.0 (C-4 C , C-2 E , C-6 E ), 128.2 (C-4 B ),128.7 (C-1 C ), 128.8 (C-3 E , C-5 E ), 129.0 (C-3 B , C-5 B ), 129.4 (C-2 C , C-6 C ), 129.8 (C-1 B ), 130.5 (C-3 C , C-5 C , C-4 E ), 136.0 (C-1 E ), 136.8 (C-7), 140.8 (C-8a), 141.9 (C-4 D ), 145.4 (C-4 A ), 166.2 (C-2), 188.2 (C-4); IR (cm −1 ): ν 3434, 3138, 3062, 1716, 1678, 1601, 1468, 1375, 1307, 1035, 870, 761, 724, 695; MS (EI) m / z (%): 552 (1, [M + 1] + ), 551 (3, [M] + ), 289 (23), 236 (11), 145 (18), 144 (17), 116 (31), 104 (10), 91 (100), 89 (11), 77 (16); HRMS (ESI+): m / z calcd for C 33 H 26 N 7 O 2 + [M + H] + 552.2142, found 552.2133. Anal. Calcd for C 33 H 25 N 7 O 2 (551.60): C, 71.86; H, 4.57; N, 17.78%. Found: C, 71.58; H, 4.58; N, 17.73%.
3-Phenyl-3-(4-phenyl-1 H -1,2,3-triazol-1-yl)-1-((1-phenyl-1 H -1,2,3-triazol-4-yl)methyl)quinoline-2,4(1 H ,3 H )-dione (2h). Colorless crystals, m.p. 152–157 °C (ethanol); R f = 0.54 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 5.33 (d, 1H, J = 16.1 Hz, N-1–CH α ), 5.71 (d, 1H, J = 16.1 Hz, N-1–CH β ), 7.25–7.29 (m, 1H, H-6), 7.32–7.48 (m, 8H, H-3 B , H-4 B , H-5 B , H-2 C , H-3 C , H-4 C , H-5 C , H-6 C ), 7.48–7.53 (m, 1H, H-4 E ), 7.58–7.64 (m, 2H, H-3 E , H-5 E ), 7.70 (d, 1H, J = 8.2 Hz, H-8), 7.72–7.77 (m, 1H, H-7), 7.81–7.85 (m, 2H, H-2 B , H-6 B ), 7.88–7.93 (m, 2H, H-2 E , H-6 E ), 7.95 (dd, 1H, J = 7.7, 1.5 Hz, H-5), 8.54 (s, 1H, H-5 A ), 8.83 (s, 1H, H-5 D ); 13 C NMR (126 MHz, DMSO- d 6 ) δ 39.0 (N-1–CH 2 ), 80.3 (C-3), 116.7 (C-8), 120.2 (C-2 E , C-6 E ), 120.9 (C-4a), 122.3 (C-5 D ), 123.5 (C-5 A ), 124.1 (C-6), 125.2 (C-2 B , C-6 B ), 127.9 (C-5), 128.0 (C-4 B ), 128.9 (C-4 E ), 128.9 (C-2 C , C-6 C ), 129.0 (C-3 B , C-3 B ), 129.4 (C-3 C , C-5 C ), 129.9 (C-1 C ), 130.0 (C-3 E , C-5 E ), 130.5 (C-4 C ), 130.6 (C-1 B ), 136.5 (C-1 E ), 136.8 (C-7), 140.7 (C-8a), 142.9 (C-4 D ), 145.4 (C-4 A ), 166.4 (C-2), 188.2 (C-4); IR (cm −1 ): ν 3447, 3142, 3060, 1716, 1679, 1600, 1468, 1449, 1375, 1305, 1040, 871, 758, 693; MS (EI) m / z (%): 538 (1, [M + 1] + ), 537 (3, [M] + ), 366 (14), 262 (10), 236 (17), 145 (29), 131 (10), 130 (100), 129 (19), 128 (11), 118 (10), 116 (38), 104 (14), 103 (17), 102 (13), 90 (12), 89 (15), 77 (71), 51 (12); HRMS (ESI+): m / z calcd for C 32 H 24 N 7 O 2 + ([M+H] + ) 538.1986, found 538.1976. Anal. Calcd for Anal. calcd for C 32 H 23 N 7 O 2 (537.57) C, 71.50; H, 4.31; N, 18.24%. Found: C, 71.22; H, 4.32; N, 17.94%.
(1-(1-((1-Benzyl-1 H -1,2,3-triazol-4-yl)methyl)-2,4-dioxo-3-phenyl-1,2,3,4-tetrahydroquinolin-3-yl)-1 H -1,2,3-triazol-4-yl)methyl acetate (2j). Colorless powder, m.p. 188–194 °C (ethanol); R f = 0.41 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, CDCl 3 ) δ 2.04 (s, 3H, CH 3 ), 5.17 (s, 2H, OCH 2 ), 5.21 (d, 1H, J = 15.6 Hz, N-1–CH α ), 5.43 (d, 1H, J = 14.8 Hz, N-1 D –CH α ), 5.51 (d, 1H, J = 15.6 Hz, N-1–CH β ), 5.55 (d, 1H, J = 14.8 Hz, N-1 D –CH β ), 7.08 (s, 1H, H-5 A ), 7.18 (ddd, 1H, J = 7.5, 7.5, 0.8 Hz, H-6), 7.23–7.29 (m, 4H, H-3 C , H-5 C , H-2 E , H-6 E ), 7.29–7.33 (m, 2H, H-2 C , H-6 C ), 7.34–7.39 (m, 3H, H-3 E , H-4 E , H-5 E ), 7.38–7.44 (m, 1H, H-4 C ), 7.58 (s, 1H, H-5 D ), 7.63 (ddd, 1H, J = 8.4, 7.4, 1.7 Hz, H-7), 7.75 (d, 1H, J = 8.3 Hz, H-8), 7.99 (dd, 1H, J = 7.7, 1.7 Hz, H-5); 13 C NMR (126 MHz, CDCl 3 ) δ 21.0 (CH 3 ), 39.9 (N-1–CH 2 ), 54.5 (N-1 D –CH 2 ), 57.6 (OCH 2 ), 79.6 (C-3), 116.8 (C-8), 120.9 (C-4a), 123.5 (C-5 D ), 124.6 (C-6), 126.4 (C-5 A ), 128.3 (C-2 E , C-6 E ), 128.7 (C-2 C , C-6 C ), 129.0 (C-5), 129.1 (C-4 E ), 129.4 (C-3 E , C-5 E ), 129.7 (C-1 C ), 130.0 (C-3 C , C-5 C ), 131.3 (C-4 C ), 134.5 (C-1 E ), 137.2 (C-7), 140.9 (C-4 A ), 141.1 (C-8a), 142.9 (C-4 D ), 166.6 (C-2), 171.0 ( C OCH 3 ), 187.9 (C-4); 15 N NMR (51 MHz, CDCl 3 ) δ 140.4 (N-1), 249.8 (N-1 A ), 250.4 (N-1 D ), 350.5 (N-3 D ), 356.9 (N-3 A ), 362.9 (N-2 D ), 365.1 (N-2 A ); IR (cm −1 ): ν 3142, 2927, 1740, 1717, 1679, 1602, 1469, 1377, 1244, 768, 749, 714, 697; MS (EI) m / z (%): 548 (0.1, [M + 1] + ), 547 (0.3, [M] + ), 347 (13), 289 (13), 144 (14), 105 (10), 104 (13), 91 (100), 43 (29); HRMS (ESI+): m / z calcd for C 30 H 26 N 7 O 4 + [M + H] + 548.2041, found 548.2032.
(1-(2,4-Dioxo-3-phenyl-1-((1-phenyl-1 H -1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroquinolin-3-yl)-1 H -1,2,3-triazol-4-yl)methyl acetate (2k). Colorless powder, m.p. 93–105 °C; R f = 0.42 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, CDCl 3 ) δ 2.05 (s, 3H, CH 3 ), 5.19 (s, 2H, OCH 2 ), 5.42 (d, 1H, J = 15.7 Hz, N-1–CH α ), 5.55 (d, 1H, J = 15.7 Hz, N-1–CH β ), 7.14 (s, 1H, H-5 A ), 7.20 (ddd, 1H, J = 7.6, 7.6, 0.8 Hz, H-6), 7.38–7.49 (m, 6H, H-2 C , H-3 C , H-4 C , H-5 C , H-6 C , H-4 E ), 7.49–7.55 (m, 2H, H-3 E , H-5 E ), 7.66 (ddd, 1H, J = 8.5, 7.3, 1.7 Hz, H-7), 7.68–7.72 (m, 2H, H-2 E , H-6 E ), 7.76 (d, 1H, J = 8.4 Hz, H-8), 8.03 (dd, 1H, J = 7.8, 1.5 Hz, H-5), 8.05 (s, 1H, H-5 D ); 13 C NMR (126 MHz, CDCl 3 ) δ 21.0 (CH 3 ), 39.8 (N-1-CH 2) , 57.6 (OCH 2 ), 79.6 (C-3), 116.7 (C-8), 120.7 (C-2 E , C-6 E ), 120.9 (C-4a), 121.8 (C-5 D ), 124.7 (C-6), 126.4 (C-5 A ), 128.9 (C-2 C , C-6 C ), 129.1 (C-5), 129.2 (C-4 E ), 129.9 (C-1 C ), 130.0 (C-3 E , C-5 E ), 130.2 (C-3 C , C-5 C ), 131.4 (C-4 C ), 136.9 (C-1 E ), 137.4 (C-7), 140.9 (C-4 A ), 140.9 (C-8a), 143.2 (C-4 D ), 166.9 (C-2), 171.0 ( C OCH 3 ), 187.9 (C-4); 15 N NMR (51 MHz, CDCl 3 ) δ 140.4 (N-1), 249.9 (N-1 A ), 256.3 (N-1 D ), 352.9 (N-3 D ), 357.2 (N-3 A ); IR (cm −1 ): ν 3146, 2962, 1741, 1718, 1681, 1600, 1468, 1376, 1243, 1043, 762, 693, 665, 608; MS (EI) m / z (%): 534 (0.2, [M + 1] + ), 533 (0.6, [M] + ), 366 (12), 365 (11), 262 (12), 131 (11), 130 (100), 129 (19), 128 (12), 104 (14), 103 (16), 99 (18), 77 (62), 44 (17), 43 (52); HRMS (ESI+): m / z calcd for C 29 H 24 N 7 O 4 + [M + H] + 534.1884, found 534.1882.
3.9. General Procedure for the Synthesis of Bis-Triazoles 2c,f,i,l by Employing CuSO 4 /Cu 0 /DMF Conditions ( Table 4 , Entries 3, 9, 12 and 15)
A mixture of the appropriate N -propargylquinoline-2,4(1 H ,3 H )-dione 7 (1.5 mmol), tetrazolo[1,5- a ]pyridine (189 mg, 1.58 mmol), CuSO 4 ∙5H 2 O (38 mg, 0.15 mmol), granular copper (191 mg, 3.05 mmol) and DMF (9 mL) was heated in darkness to 95–105 °C (oil bath) for the time given in Table 4 , whereas the color of the mixture changed from brown-black to dark green. The mixture was then allowed to cool to room temperature. Subsequently, (NH 4 ) 2 CO 3 (432 mg, 4.5 mmol) and water (2 mL) were added and after stirring for 15 min, the mixture was poured into a narrow (1 cm diameter) column of silica gel (15 g). The organic portion was eluted from the column with 10% ethanol in chloroform. The yellow eluate was washed with saturated aqueous NH 4 Cl (50 mL), dried over anhydrous sodium sulfate, filtered, and the solvent was removed by rotary evaporation in vacuo . In the cases of 2c , i , the residue, which was TLC pure compound, was crystallized from suitable solvent. In the cases of 2f , l , the residue was purified by chromatography on silica gel column using chloroform as eluent. The yields of prepared compounds 2 are given in Table 4 .
3-Methyl-3-(4-phenyl-1 H -1,2,3-triazol-1-yl)-1-((1-(pyridin-2-yl)-1 H -1,2,3-triazol-4-yl)methyl)quinoline-2,4(1 H ,3 H )-dione (2c). Colorless crystals, m.p. 188–191 °C (benzene); R f = 0.29 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.23 (s, 3H, CH 3 ), 5.42 (d, 1H, J = 16.5 Hz, N-1–CH α ), 5.58 (d, 1H, J = 16.5 Hz, N-1–CH β ), 7.28–7.40 (m, 2H, H-6, H-4 B ), 7.43–7.51 (m, 2H, H-3 B , H-5 B ), 7.51–7.57 (m, 1H, H-5 E ), 7.64 (d, 1H, J = 8.4 Hz, H-8), 7.78–7.90 (m, 3H, H-7, H-2 B , H-6 B ), 7.99 (d, 1H, J = 7.5 Hz, H-5), 8.07–8.17 (m, 2H, H-3 E , H-4 E ), 8.54–8.61 (m, 1H, H-6 E ), 8.82 (s, 1H, H-5 D ), 8.87 (s, 1H, H-5 A ); 13 C NMR (126 MHz, DMSO- d 6 ) δ 23.4 (CH 3 ), 38.7 (N-1–CH 2 ), 73.0 (C-3), 113.7 (C-3 E ), 116.6 (C-8), 119.3 (C-4a), 120.6 (C-5 D ), 122.5 (C-5 A ), 123.9 (C-6), 124.5 (C-5 E ), 125.2 (C-2 B , C-6 B ), 128.1 (C-4 B ), 128.1 (C-5), 129.1 (C-3 B , C-5 B ), 130.5 (C-1 B ), 137.2 (C-7), 140.3 (C-4 E ), 141.4 (C-8a), 143.2 (C-4 D ), 146.0 (C-4 A ), 148.4 (C-2 E ), 149.0 (C-6 E ), 168.5 (C-2), 189.9 (C-4); 15 N NMR (51 MHz, DMSO- d 6 ) δ 135.8 (N-1), 248.9 (N-1 A ), 260.5 (N-1 D ), 284.9 (N-1 E ), 347.1 (N-3 A ), 356.9 (N-3 D ), 358.6 (N-2 D ), 363.4 (N-2 A ); IR (cm −1 ): ν 3426, 3126, 2972, 1706, 1674, 1601, 1471, 1378, 1310, 1232, 1041, 777, 764; MS (EI) m / z (%): 477 (2, [M + 1] + ), 476 (7, [M] + ), 289 (11), 145 (14), 132 (14), 131 (96), 116 (50), 102 (10), 90 (10), 89 (13), 79 (20), 78 (100), 77 (10), 51 (10); HRMS (ESI+): m / z calcd for C 26 H 21 N 8 O 2 + [M + H] + 477.1782, found 477.1773. Anal. Calcd for C 26 H 20 N 8 O 2 (476.48) C, 65.54; H, 4.23; N, 23.52%. Found: C, 65.68; H, 4.21; N, 23.63%.
(1-(3-Methyl-2,4-dioxo-1-((1-(pyridin-2-yl)-1 H -1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroquinolin-3-yl)-1 H -1,2,3-triazol-4-yl)methyl acetate (2f). Colorless powder, m.p. 69–82 °C; R f = 0.29 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 2.06 (s, 3H, COCH 3 ), 2.18 (s, 3H, C3–CH 3 ), 5.17 (d, 1H, J = 12.7 Hz, O–CH α ), 5.20 (d, 1H, J = 12.7 Hz, O–CH β ), 5.41 (d, 1H, J = 16.5 Hz, N-1–CH α ), 5.53 (d, 1H, J = 16.5 Hz, N-1–CH β ), 7.31 (dd, 1H, J = 7.4, 7.4 Hz, H-6), 7.54 (dd, 1H, J = 8.8, 4.5 Hz, H-5 E ), 7.59 (d, 1H, J = 8.5 Hz, H-8), 7.77–7.83 (m, 1H, H-7), 7.96 (dd, 1H, J = 7.7 Hz, J = 1.6 Hz, H-5), 8.08–8.14 (m, 2H, H-3 E , H-4 E ), 8.47 (s, 1H, H-5 A ), 8.55–8.59 (m, 1H, H-6 E ), 8.82 (s, 1H, H-5 D ); 13 C NMR (126 MHz, DMSO- d 6 ) δ 20.6 (CO C H 3 ), 23.5 (C3– C H 3 ), 38.7 (N-1–CH 2 ), 57.2 (OCH 2 ), 73.3 (C-3), 113.7 (C-3 E ), 116.5 (C-8), 119.4 (C-4a), 120.6 (C-5 D ), 123.8 (C-6), 124.4 (C-5 E ), 126.1 (C-5 A ), 127.9 (C-5), 137.0 (C-7), 140.2 (C-4 E ), 141.3 (C-8a), 141.6 (C-4 A ), 143.2 (C-4 D ), 148.3 (C-2 E ), 148.9 (C-6 E ), 168.6 (C-2), 170.1 ( C OCH 3 ), 189.9 (C-4); 15 N NMR (51 MHz, DMSO- d 6 ) δ 135.3 (N1), 247.6 (N-1 A ), 260.0 (N-1 D ), 284.7 (N-1 E ), 353.4 (N-3 A ), 356.5 (N-3 D ), 361.9 (N-2 D ), 363.7 (N-2 A ); IR (cm −1 ): ν 3152, 1741, 1718 1681, 1600, 1471, 1384, 1314, 1242, 1183, 1038, 782, 756, 663; MS (EI) m / z (%): 473 (0.7, [M + 1] + ), 472 (2, [M] + ), 304 (27), 303 (26), 302 (17), 132 (13), 131 (100), 79 (22), 78 (100), 43 (21); HRMS (ESI+): m / z calcd for C 23 H 21 N 8 O 4 + [M + H] + 473.1680, found 473.1684. Anal. Calcd for C 23 H 20 N 8 O 4 ·½H 2 O (472.46): C, 57.38; H, 4.40; N, 23.27%. Found: C, 57.39; H, 4.36; N, 23.47%.
3-Phenyl-3-(4-phenyl-1 H -1,2,3-triazol-1-yl)-1-((1-(pyridin-2-yl)-1 H -1,2,3-triazol-4-yl)methyl)quinoline-2,4(1 H ,3 H )-dione (2i). Colorless crystals, m.p. 188–192 °C (benzene); R f = 0.50 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, DMSO- d 6 ) δ 5.44 (d, 1H, J = 16.3 Hz, N-1–CH α ), 5.67 (d, 1H, J = 16.3 Hz, N-1–CH β ), 7.26 (dd, 1H, J = 7.5, 7.5 Hz, H-6), 7.32–7.40 (m, 3H, H-4 B , H-2 C , H-6 C ), 7.41–7.52 (m, 5H, H-3 B , H-5 B , H-3 C , H-4 C , H-5 C ), 7.52–7.61 (m, 2H, H-8, H-5 E ), 7.68–7.75 (m, 1H, H-7), 7.78–7.86 (m, 2H, H-2 B , H-6 B ), 7.96 (dd, 1H, J = 7.7, 1.5 Hz, H-5), 8.09–8.16 (m, 2H, H-3 E , H-4 E ), 8.58 (s, 1H, H-5 A ), 8.60 (ddd, 1H, J = 4.8, 1.3, 1.3 Hz, H-6 E ), 8.81 (s, 1H, H-5 D ); 13 C NMR (126 MHz, DMSO- d 6 ) δ 39.1 (N-1– C H 2 ), 80.4 (C-3), 113.7 (C-3 E ), 116.5 (C-8), 120.8 (C-5 D ), 120.9 (C-4a), 123.4 (C-5 A ), 124.0 (C-6), 124.5 (C-5 E ), 125.2 (C-2 B , C-6 B ), 127.9 (C-5), 128.0 (C-4 B ), 128.9 (C-2 C , C-6 C ), 129.0 (C-3 B , C-5 B ), 129.4 (C-3 C , C-5 C ), 130.0 (C-1 C ), 130.5 (C-4 C ), 130.6 (C-1 B ), 136.8 (C-7), 140.2 (C-4 E ), 140.5 (C-8a), 143.0 (C-4 D ), 145.4 (C-4 A ), 148.3 (C-2 E ), 149.0 (C-6 E ), 166.6 (C-2), 188.1 (C-4); 15 N NMR (51 MHz, DMSO- d 6 ) δ 137.5 (N1), 248.7 (N-1 A ), 260.4 (N-1 D ), 284.8 (N-1 E ), 347.2 (N-3 A ), 357.7 (N-3 D ), 367.4 (N-2 A ); IR (cm −1 ): ν 3418, 2973, 1718, 1679, 1596, 1477, 1467, 1450, 1049, 1031, 773, 766, 757, 701; MS (EI) m / z (%): 539 (1, [M + 1] + ), 538 (3, [M] + ), 236 (11), 145 (16), 132 (14), 131 (100), 116 (32), 91 (11), 89 (11), 79 (15), 78 (85), 77 (13); HRMS (ESI+): m / z calcd for C 31 H 23 N 8 O 2 + [M + H] + 539.1938, found 539.1932. Anal. calcd for C 31 H 22 N 8 O 2 (538.19): C, 69.13; H, 4.12; N, 20.81%. Found: C, 68.91; H, 4.17; N, 20.66%.
(1-(2,4-Dioxo-3-phenyl-1-((1-(pyridin-2-yl)-1 H -1,2,3-triazol-4-yl)methyl)-1,2,3,4-tetrahydroquinolin-3-yl)-1 H -1,2,3-triazol-4-yl)methyl acetate (2l). Colorless powder, m.p. 93–102 °C; R f = 0.18 (30% ethyl acetate in chloroform); 1 H NMR (500 MHz, CDCl 3 ) δ 2.05 (s, 3H, COCH 3 ), 5.19 (s, 2H, OCH 2 ), 5.30 (d, 1H, J = 15.8 Hz, N-1–CH α ), 5.71 (d, 1H, J = 15.8 Hz, N-1–CH β ), 7.13 (s, 1H, H-5 A ), 7.19 (dd, 1H, J = 7.5, 7.5 Hz, H-6), 7.36 (dd, 1H, J = 7.3, 4.9 Hz, H-5 E ), 7.38–7.42 (m, 2H, H-3 C , H-5 C ), 7.42–7.48 (m, 3H, H-2 C , H-4 C , H-6 C ), 7.63 (ddd, 1H, J = 8.3, 7.4, 1.6 Hz, H-7), 7.70 (d, 1H, J = 8.4 Hz, H-8), 7.88–7.95 (m, 1H, H-4 E ), 8.02 (dd, 1H, J = 7.8, 1.5 Hz, H-5), 8.15 (d, 1H, J = 8.2 Hz, H-3 E ), 8.47–8.53 (m, 1H, H-6 E ), 8.63 (s, 1H, H-5 D ); 13 C NMR (126 MHz, CDCl 3 ) δ 21.0 (CO C H 3 ), 39.9 (N-1–CH 2 ), 57.6 (OCH 2 ), 79.7 (C-3), 113.9 (C-3 E ), 116.6 (C-8), 121.0 (C-4a), 121.0 (C-5 D ), 124.0 (C-5 E ), 124.6 (C-6), 126.4 (C-5 A ), 128.9 (C-2 C , C-6 C ), 129.1 (C-5), 129.7 (C-1 C ), 130.2 (C-3 C , C-5 C ), 131.3 (C-4 C ), 137.2 (C-7), 139.3 (C-4 E ), 140.9 (C-4 A ), 141.2 (C-8a), 143.0 (C-4 D ), 148.9 (C-6 E ), 149.0 (C-2 E ), 166.6 (C-2), 171.0 ( C OCH 3 ), 187.9 (C-4); 15 N NMR (51 MHz, CDCl 3 ) δ 138.9 (N-1), 249.7 (N-1 A ), 261.2 (N-1 D ), 285.1 (N-1 E ), 355.8 (N-3 D ), 357.1 (N-3 A ); IR (cm −1 ): ν 3155, 2926, 1741, 1718, 1682, 1599, 1470, 1375, 1313, 1243, 1034, 779, 697, 665; MS (EI) m / z (%): 535 (0.4, [M + 1] + ), 534 (0.7, [M] + ), 132 (14), 131 (100), 79 (19), 78 (93), 44 (11), 43 (31); HRMS (ESI+): m / z calcd for C 28 H 23 N 8 O 4 + [M + H] + 535.1837, found 535.1846.
3.10. Synthesis of Bis-Triazole 2d by Employing CH 2 Cl 2 /Water/CuSO 4 ∙5H 2 O/Na-Ascorbate Conditions ( Table 4 , Entry 5)
To a solution of acetylene 7c (132 mg, 0.375 mmol) and azide 8a (52.4 mg, 0.394 mmol) in dichloromethane (6.5 mL) a solution of sodium ascorbate (59.5 mg, 0.3 mmol) in water (5.5 mL), and a solution of CuSO 4 ∙5H 2 O (7.5 mg, 0.03 mmol) in water (1 mL) were added. The two-phase liquid reaction mixture was stirred in darkness at room temperature until the compound 7c reacted completely according to TLC analysis (4 h). The reaction mixture was diluted with water (50 mL) and extracted with chloroform (4 × 30 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, and evaporated to dryness. The residue was dissolved in chloroform (5 mL) and subjected to silica gel (25 g) column chromatography using 67% ethyl acetate in petroleum ether as eluent, affording product 2d (155 mg, 0.32 mmol, 85%).
3.11. Synthesis of Bis-Triazole 2d by Employing t-BuOH/Water/CH 3 CN/CuSO 4 ∙5H 2 O/Na-Ascorbate Conditions ( Table 4 , Entry 6)
To a mixture of acetylene 7c (264 mg, 0.75 mmol), azide 8a (105 mg, 0.79 mmol) and t -BuOH (3.5 mL) a solution of Na-ascorbate (30 mg, 0.15 mmol) in water (2.5 mL), and a solution of CuSO 4 ∙5H 2 O (4 mg, 0.02 mmol) in water (1 mL) were added. The reaction mixture was stirred in darkness at room temperature for 9 h. Then a solution of Na-ascorbate (89 mg, 0.45 mmol) in water (1 mL), and a solution of CuSO 4 ∙5H 2 O (11 mg, 0.044 mmol) in water (1 mL) and t -BuOH (2 mL) were added. The reaction mixture was stirred for additional 20 h. The resulting sticky sediment that formed in the course of the reaction was dissolved by addition of acetonitrile (3 mL) to the reaction mixture. The reaction mixture was stirred for additional 19 h. Although the azide and acetylene coupling partners were still present in the reaction mixture, as judged by TLC analysis, the reaction was stopped by the addition of water (50 mL) and extracted with chloroform (4 × 30 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, and evaporated to dryness. The residue was dissolved in chloroform and subjected to silica gel (35 g) column chromatography using 67% ethyl acetate in petroleum ether as eluent, affording regenerated starting acetylene 7c (48 mg, 0.14 mmol, 18%) and product 2d (295 mg, 0.61 mmol, 81%).
3.12. Synthesis of Bis-Triazole 2d by Employing t-BuOH/Water/CuSO 4 ∙5H 2 O/ l -Ascorbic Acid Conditions ( Table 4 , Entry 7)
To a mixture of acetylene 7c (264 mg, 0.75 mmol) and azide 8a (105 mg, 0.79 mmol) a solution of l -ascorbic acid (13 mg, 0.074 mmol) and CuSO 4 ∙5H 2 O (2 mg, 0.008 mmol) in water (3.5 mL), and t -BuOH (3.5 mL) were added. The reaction mixture was stirred in darkness at room temperature. After 8.5 h and 22 h of stirring additional portions of l -ascorbic acid/CuSO 4 ∙5H 2 O/water/ t -BuOH (40 mg, 0.23 mmol/6 mg, 0.02 mmol/1 mL/1 mL and 53 mg, 0.3 mmol/7.5 mg, 0.03 mmol/1 mL/1 mL, respectively) were added. Although after stirring for additional 23 h (total reaction time 45 h), TLC analysis indicated the presence of azide and acetylene starting compounds, the heterogeneous reaction mixture (a sticky sediment was formed) was diluted with water and extracted with chloroform (5 × 50 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, and evaporated to dryness. The residue was dissolved in chloroform (5 mL) and subjected to silica gel (35 g) column chromatography using 33% ethyl acetate in petroleum ether as eluent, affording regenerated starting acetylene 7c (114 mg, 0.32 mmol, 43%) and product 2d (165 mg, 0.34 mmol 45%).
3.13. 3-Azido-3-methyl-1-(prop-2-yn-1-yl)Quinoline-2,4(1H,3H)-Dione (9a) ( Scheme 3 )
A mixture of the azide 5a (649 mg, 3.0 mmol) and potassium carbonate (1.24 g, 9 mmol) in DMF (15 mL) was stirred at room temperature in darkness for 40 min. Propargyl bromide ( 6c , 80% solution in toluene, 669 mg, 4.5 mmol) diluted with DMF (7 mL) was added dropwise under stirring during 1 min. The reaction mixture was stirred for 6 h, during which time it turned yellow, diluted with cold water (200 mL) and extracted with chloroform (5 × 50 mL). The combined organic layers were dried (Na 2 SO 4 ), filtered, and evaporated to dryness. Trace amounts of DMF were removed by five subsequent co-destilations in vacuo at 50 °C with toluene (30 mL). The residual yellow oil was dissolved in chloroform (5 mL) and chromatographed on column silica gel (35 g) using chloroform as eluent, affording product 9a (717 mg, 2.82 mmol, 94%, dried in vacuo to constant weight) as off-white oily material, that was pure by TLC ( R f = 0.57; chloroform); 1 H NMR (500 MHz, CDCl 3 ) δ 1.79 (s, 3H), 2.29 (dd, 1H, J = 2.5, 2.5 Hz), 4.67 (dd, 1H, J = 17.8, 2.5 Hz), 4.98 (dd, 1H, J = 17.8, 2.5 Hz), 7.26 (ddd, 1H, J = 7.7, 7.4, 0.8 Hz), 7.35 (d, 1H, J = 8.3 Hz), 7.71 (ddd, 1H, J = 8.3, 7.4, 1.7 Hz), 8.02 (dd, 1H, J = 7.7, 1.7 Hz); 13 C NMR (126 MHz, CDCl 3 ) δ 23.6, 32.7, 70.7, 73.4, 77.1, 115.8, 119.6, 124.4, 129.0, 136.9, 140.8, 169.1, 191.1; IR (cm −1 ): ν 3241, 2980, 2138, 2107, 1711, 1678, 1603, 1471, 1383, 1366, 1305, 1285, 1260, 1218, 762; HRMS (ESI+): m / z calcd for C 13 H 11 N 4 O 2 + [M + H] + 255.0877, found 255.0877; calcd for C 13 H 11 N 2 O 2 + [M − N 2 + H] + 227.0815, found 227.0814.
3.14. Synthesis of Triazole 7a from Phenylacetylene ( 6a ) and Compound 9a ( Scheme 3 )
A mixture of compound 9a (286 mg, 1.13 mmol), phenylacetylene ( 6a ) (230 mg, 2.25 mmol), CuSO 4 5H 2 O (28 mg, 0.11 mmol) and granular copper (143 mg, 2.25 mmol) in DMF (5 mL) was stirred in darkness at room temperature for 60 min. To the resulting brown-green suspension (NH 4 ) 2 CO 3 (324 mg, 3.38 mmol) and water (3 mL) were added and stirring was continued for 10 min. The resulting mixture was diluted with 10% ethanol in chloroform (10 mL). The organic layer was separated and the aqueous layer was extracted with chloroform (3 × 10 mL). The combined organic layers were passed through a narrow (1 cm in diameter) column of silica gel (13 g) and the column was subsequently washed with 10% ethanol in chloroform (210 mL) using overpressure to the top of the column. The yellow eluate was washed with saturated aqueous NH 4 Cl (1 × 50 mL) and distilled water (1 × 50 mL), dried (Na 2 SO 4 ), filtered, and evaporated to dryness. Trace amounts of DMF were removed by five subsequent co-destilations in vacuo at 50 °C with toluene (40 mL). The residue was chromatographed on a column of silica gel (30 g) using 38% ethyl acetate in hexane. The resulting white solid (88 mg) was crystallized from benzene affording triazole 7a (66 mg, 0.19 mmol, 16%), which was identified with the compound 7a described above.
3.15. 3-Azido-1-((1-Benzyl-1H-1,2,3-Triazol-4-yl)Methyl)-3-Methylquinoline-2,4(1H,3H)-Dione ( 10a ) ( Scheme 3 )
A mixture of acetylene 9a (254 mg, 1.0 mmol), (azidomethyl)benzene ( 8a ) (266 mg, 2.0 mmol), CuSO 4 ∙5H 2 O (25 mg, 0.1 mmol) and granular copper (127 mg, 2.0 mmol) in DMF (10 mL) was stirred at room temperature for 21 h. Then (NH 4 ) 2 CO 3 (288 mg, 3.0 mmol) and water (3 mL) were added and the stirring was continued for 10 min. The resulting mixture was poured into a narrow (1 cm in diameter) column of silica gel (13 g). The organic portion was eluted with 10% ethanol in chloroform (190 mL). The yellow eluate was washed with saturated aqueous NH 4 Cl (50 mL) and water (50 mL), dried (Na 2 SO 4 ), filtered, and evaporated to dryness. Trace amounts of DMF were removed by six subsequent co-destilations in vacuo at 50 °C with toluene (30 mL). The residue was dissolved in chloroform (5 mL) and chromatographed on silica gel (35 g) column using gradually 38% and 50% ethyl acetate in petroleum ether as mobile phase, affording product 10a (164 mg, 0.42 mmol, 42%) as a white solid, m.p. 42–47 °C; R f = 0.21 (38% ethyl acetate in petroleum ether); 1 H NMR (500 MHz, CDCl 3 ) δ 1.73 (s, 3H), 5.20 (d, 1H, J = 15.6 Hz), 5.31 (d, 1H, J = 15.6 Hz), 5.45 (d, 1H, J = 14.8 Hz), 5.49 (d, 1H, J = 14.8 Hz), 7.16–7.28 (m, 3H), 7.32–7.39 (m, 3H), 7.54 (s, 1H), 7.67 (ddd, 1H, J = 8.3, 7.4, 1.6 Hz), 7.77 (d, 1H, J = 8.4 Hz), 7.96 (dd, 1H, J = 7.7, 1.5 Hz); 13 C NMR (126 MHz, CDCl 3 ) δ 23.6, 39.1, 54.5, 70.6, 116.6, 119.5, 123.5, 124.3, 128.3, 128.8, 129.0, 129.3, 134.3, 137.1, 141.4, 143.0, 169.8, 191.3; IR (cm −1 ): ν 3137, 3033, 2980, 2106, 1713, 1676, 1602, 1489, 1469, 1379, 1336, 1279, 1223, 765, 724; HRMS (ESI+): m / z calcd for C 20 H 18 N 7 O 2 + [M + H] + 388,1516, found 388.1514. Anal. Calcd for C 20 H 17 N 7 O 2 (387.39): C, 62.01; H, 4.42; N, 25.31%. Found: C, 61.74; H, 4.77; N, 25.15%.
4. Conclusions
We have developed a methodology for accessing bis(1,2,3-triazole) functionalized quinoline-2,4-diones in which the triazole heterocycles are present in substituents at positions 1 and 3 of the quinoline scaffold. Preliminary investigation has revealed that these compounds are potential multidentate ligands for arene-ruthenium.
Reference
Supplementary Materials
The following are available online: 1 H NMR and 13 C NMR spectra of all new compounds.
Author Contributions
D.M. performed the experiments. The manuscript was prepared through the contributions of R.K., M.G., D.U., S.K., and J.K.
Funding
The authors acknowledge the financial support from (internal grants No. IGA/FT/2018/007, funded from the resources of specific university research) and the Slovenian Research Agency (Research Core Funding Grant P1-0230, Project J1-8147, and Project J1-9166).
Acknowledgments
Tereza Dostálová and Lovro Kotnik participated in this study in their undergraduate projects. Their contributions are gratefully acknowledged.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of all compounds are available from the authors.
Figure 1. A general structure of 1,2,3-triazole quinoline-2,4-diones 1 ( left ) and the bis(1,2,3-triazole) counterparts 2 ( right ).
Figure 1. A general structure of 1,2,3-triazole quinoline-2,4-diones 1 ( left ) and the bis(1,2,3-triazole) counterparts 2 ( right ).
Scheme 1. Preparation of bis(1,2,3-triazole) functionalized quinoline-2,4-diones 2 .
Scheme 1. Preparation of bis(1,2,3-triazole) functionalized quinoline-2,4-diones 2 .
Scheme 2. Preparation of compounds 1e and 1f .
Scheme 2. Preparation of compounds 1e and 1f .
Scheme 3. An alternative approach to bis(1,2,3-triazole) functionalized quinoline-2,4-diones 2 through a “propargylation-click-click” reaction sequence.
Scheme 3. An alternative approach to bis(1,2,3-triazole) functionalized quinoline-2,4-diones 2 through a “propargylation-click-click” reaction sequence.
Figure 2. Selected ring and atom numbering along with the chemical shift data (mean values rounded up to whole numbers are provided).
Figure 2. Selected ring and atom numbering along with the chemical shift data (mean values rounded up to whole numbers are provided).
Scheme 4. Reaction of 2b with [RuCl(μ-Cl)(η 6 - p -cymene)] 2 with tentatively proposed structure of the [Ru–Cym]- 2b complex.
Scheme 4. Reaction of 2b with [RuCl(μ-Cl)(η 6 - p -cymene)] 2 with tentatively proposed structure of the [Ru–Cym]- 2b complex.
Figure 3. Aromatic region of 1 H NMR spectra of: ( a ) 2b in CDCl 3 , and ( b ) a mixture of 2b (42 mM) and [RuCl(μ-Cl)(η 6 - p -cymene)] 2 (21 mM) in CDCl 3 immediately after dissolution.
Figure 3. Aromatic region of 1 H NMR spectra of: ( a ) 2b in CDCl 3 , and ( b ) a mixture of 2b (42 mM) and [RuCl(μ-Cl)(η 6 - p -cymene)] 2 (21 mM) in CDCl 3 immediately after dissolution.
Figure 4. Aromatic region of 13 C NMR spectra of: ( a ) 2b in CDCl 3 , and ( b ) a mixture of 2b (42 mM) and [RuCl(μ-Cl)(η 6 - p -cymene)] 2 (21 mM) in CDCl 3 .
Figure 4. Aromatic region of 13 C NMR spectra of: ( a ) 2b in CDCl 3 , and ( b ) a mixture of 2b (42 mM) and [RuCl(μ-Cl)(η 6 - p -cymene)] 2 (21 mM) in CDCl 3 .
Table 1. The Effect of Granular Copper to the Conversion of 5a into 1a a .
Table 1. The Effect of Granular Copper to the Conversion of 5a into 1a a .
a Reaction conditions: 5a (1 mmol), phenylacetylene (1 mmol), and CuSO 4 ·5H 2 O (0.1 mmol), DMF (4 mL), rt. The reaction time was determined by thin-layer chromatography (TLC) monitoring of the reaction mixture. b Refers to the yield of isolated pure product. c Complete consumption of 5a was not reached.
Table 2. Preparation of compounds 1 .
Table 2. Preparation of compounds 1 .
Entry Azide 5 R 1 Acetylene 6 R 2 Product 1 Yield a 1 5a Me 6a Ph 1a 95 2 5a Me 6a Ph 1a 83 b 3 5b Ph 6a Ph 1b 86 4 5a Me 6b CH 2 OH 1c 99 5 5b Ph 6b CH 2 OH 1d 98
a Refers to percent yield of pure (by TLC and IR) isolated product. b Employing CuSO 4 ∙5H 2 O /l -ascorbic acid/CH 2 Cl 2 /water conditions, 48 h reaction time.
Table 3. Preparation of compounds 7 .
Table 3. Preparation of compounds 7 .
Entry 1 R 1 R 2 6 Yield of 7 (%) a 1 1a Me Ph 6c 7a , 96 2 1b Ph Ph 6c 7b , 79 3 1e Me CH 2 OAc 6c 7c , 81 4 1f Ph CH 2 OAc 6c 7d , 63
a Refers to percent yield of pure (by TLC and IR) isolated product.
Table 4. Preparation of compounds 2 .
Table 4. Preparation of compounds 2 .
Entry 2 R 1 R 2 R 3 t (°C) Time (h) Yield a (%) 1 a Me Ph Bn 23 1 97 2 b Me Ph Ph 23 1 99 3 c Me Ph 2-Py 100 0.5 93 4 d Me CH 2 OAc Bn 23 0.5 96 5 d Me CH 2 OAc Bn 23 4 85 b 6 d Me CH 2 OAc Bn 23 48 81 c 7 d Me CH 2 OAc Bn 23 45 45 d 8 e Me CH 2 OAc Ph 23 2 92 9 f Me CH 2 OAc 2-Py 100 1 85 10 g Ph Ph Bn 23 1 92 11 h Ph Ph Ph 23 1 94 12 i Ph Ph 2-Py 100 0.75 57 13 j Ph CH 2 OAc Bn 23 2 97 14 k Ph CH 2 OAc Ph 23 0.5 93 15 l Ph CH 2 OAc 2-Py 100 0.5 85
a Refers to percent yield of pure (by TLC and IR) isolated product. b Employing CH 2 Cl 2 /water/CuSO 4 ∙5H 2 O/Na-ascorbate conditions. c Employing t -BuOH/water/CH 3 CN/CuSO 4 ∙5H 2 O/Na-ascorbate conditions. d Employing t -BuOH/water/CuSO 4 ∙5H 2 O/ l -ascorbic acid conditions.
Table 5. Selected 1 H, 13 C and 15 N NMR chemical shifts in ppm for compounds 1 and 7 .
Table 5. Selected 1 H, 13 C and 15 N NMR chemical shifts in ppm for compounds 1 and 7 .
1a 1b 1c 1d 7a 7b 7c 7d Quinolone N1 – – – – – – 134.4 – C2 168.5 166.8 168.7 166.8 167.7 165.8 167.8 165.8 C3 72.2 80.0 71.9 79.7 72.6 79.6 72.8 80.0 C4 190.7 188.9 190.8 189.0 189.7 187.5 189.6 187.7 C4a 117.4 119.2 117.5 119.2 119.0 121.0 119.2 120.9 C5 127.7 127.6 127.6 127.5 128.2 129.2 128.0 127.8 C6 123.5 123.5 123.3 123.4 124.2 124.6 124.0 124.2 C7 137.3 137.0 137.1 136.9 137.3 136.9 137.1 136.7 C8 117.0 116.7 116.9 116.7 116.7 115.8 116.6 116.3 C8a 141.6 140.5 141.6 140.6 140.8 140.6 140.7 140.0 Ring A N1 A – – – – – – 247.9 – N2 A – – – – – – 363.4 – N3 A – – – – – – 354.0 – C4 A 145.8 145.3 147.4 146.8 145.9 146.0 141.5 140.9 C5 A 122.4 123.4 123.7 124.8 122.5 122.3 126.0 127.1 H5 A 8.89 8.49 8.26 7.77 8.89 7.26 8.46 8.15
Table 6. Selected 1 H, 13 C and 15 N NMR chemical shifts in ppm for compounds 2 .
Table 6. Selected 1 H, 13 C and 15 N NMR chemical shifts in ppm for compounds 2 .
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Canada Lynx Lynx canadensis Habitat and Forest Succession in Northern Maine, USA
Wildlife Biology publishes on wildlife science, with the primary focus of enhancing wildlife management practices, from both an ecological and human standpoint.
Canada Lynx
Lynx canadensis
Habitat and Forest Succession in Northern Maine, USA
Christopher L. Hoving, Daniel J. Harrison, William B. Krohn, Walter J. Jakubas, Mark A. McCollough
Author Affiliations +
Christopher L. Hoving, 1,*,**Daniel J. Harrison, 2William B. Krohn, 3Walter J. Jakubas, 4Mark A. McCollough 5 1Christopher L. Hoving*, Department of Wildlife Ecology and Maine Cooperative Fish and Wildlife Research Unit, 5755 Nutting Hall, Rm. 210, Orono, Maine 04469, USA - e-mail: 2Daniel J. Harrison, Department of Wildlife Ecology, 5755 Nutting Hall, Room 210, Orono, Maine 04469, USA - e-mail: 3William B. Krohn, United States Geological Survey, Maine Cooperative Fish and Wildlife Research Unit, 5755Nutting Hall. Room 210, Orono, Maine 04469, USA - e-mail: 4Walter J. Jakubas, Maine Department of Inland Fisheries and Wildlife, 650 State St., Bangor Maine 04401-5654, USA -e -mail: 5Mark A. McCollough, United States Fish and Wildlife Service, 1168 Main Street, Old Town, Maine 04468, USA - e-mail: *Corresponding author: Christopher L. Hoving **Associate Editor: Henrik Andrén
Wildlife Biology, 10(4):285-294 (2004). https://doi.org/10.2981/wlb.2004.034
Abstract
The contiguous United States population of Canada lynx Lynx canadensiswas listed as threatened in 2000. The long-term viability of lynx populations at the southern edge of their geographic range has been hypothesized to be dependent on old growth forests; however, lynx are a specialist predator on snowshoe hare Lepus americanus,a species associated with early-successional forests. To quantify the effects of succession and forest management on landscape-scale (100 km 2) patterns of habitat occupancy by lynx, we compared landscape attributes in northern Maine, USA, where lynx had been detected on snow track surveys to landscape attributes where surveys had been conducted, but lynx tracks had not been detected. Models were constructed a prioriand compared using logistic regression and Akaike's Information Criterion (AIC), which quantitatively balances data fit and parsimony. In the models with the lowest (i.e. best) AIC, lynx were more likely to occur in landscapes with much regenerating forest, and less likely to occur in landscapes with much recent clearcut, partial harvest and forested wetland. Lynx were not associated positively or negatively with mature coniferous forest. A probabilistic map of the model indicated a patchy distribution of lynx habitat in northern Maine. According to an additional survey of the study area for lynx tracks during the winter of 2003, the model correctly classified 63.5% of the lynx occurrences and absences. Lynx were more closely associated with young forests than mature forests; however, old-growth forests were functionally absent from the landscape. Lynx habitat could be reduced in northern Maine, given recent trends in forest management practices. Harvest strategies have shifted from clearcutting to partial harvesting. If this trend continues, future landscapes will shift away from extensive regenerating forests and toward landscapes dominated by polesized and larger stands. Because Maine presently supports the only verified populations of this federally threatened species in the eastern United States, changes in forest management practices could affect recovery efforts throughout that region.
Around 1900, Canada lynx Lynx canadensiswere commonly perceived to inhabit remote ‘primeval’ forests largely unoccupied by people (e.g.Hardy 1907,Seton 1929). This perception has changed little over the last hundred years. Popular literature (e.g.Kobalenko 1997) and a ruling by a federal judge have inferred that lynx require mature forests, and that industrial forest management degrades lynx habitat (United States Department of the Interior 1997). A scientific report recently contended that old growth forests provided temporally stable lynx habitat at the southern edge of their geographic range (Buskirk, Ruggiero, Aubry, Pearson, Squires & McKelvey 2000). Although this hypothesis might be consistent with patterns of habitat occupancy by lynx in the western United States, there is no evidence that lynx require old growth forest in the eastern United States where forests generally are younger, more mesic, diverse and structurally complex.
The Canada lynx is a specialist predator of snowshoe hare Lepus americanus(Saunders 1963,van Zyll de Jong 1966,Nellis, Wetmore & Keith 1972,Parker, Maxwell, Morton & Smith 1983). Although lynx will utilize alternative prey, such as red squirrels Tamiasciurus hudsonicusor Tetraonids (grouse), the percentage of snowshoe hare occurring in lynx scats can be as high as 97% (Parker et al. 1983), and in the core parts of their range, lynx populations cycle with a two to three year time lag behind snowshoe hare populations (Brand & Keith 1979,O'Donoghue, Boutin, Krebs, Zuleta, Murray & Hofer 1998). In the northern boreal forests of Canada and Alaska, USA, lynx are associated with habitats where hare are abundant (Parker et al. 1983,Koehler 1990,Staples 1995), although lynx seem to select slightly more open habitats than hare (O'Donoghue et al. 1998).
Snowshoe hare reach their highest densities in dense shrublands or dense immature forests (Tompkins & Woehr 1979,Pietz & Tester 1983,Orr & Dodds 1982), and select more for high understory density rather than for cover type or plant species (Litvaitis, Sherburne & Bissonette 1985,Long 1995). In Maine, USA, high densities of snowshoe hare are associated with dense regeneration that usually follows complete removal of overstory trees (i.e. clearcutting) at both the stand (Monhey 1986,Lachowski 1997,Fuller 1999) and statewide (Hoving 2001) scales. Because prey densities for lynx are highest in early successional forests, at least in the eastern United States, we predicted that lynx would be more likely to inhabit landscapes with much regenerating forest and little mature or old growth forest.
Habitat relationships can be difficult to quantify for wide-ranging animals; therefore, spatially explicit habitat models have become increasingly popular conservation tools (Turner, Arthaud, Engstrom, Hejl, Liu, Loeb & McKelvey 1995). Mladenoff, Sickley, Haight & Wydeven (1995) used locations of pack territories and unoccupied areas to build a predictive model of habitat occupancy for wolves Canis lupusin Wisconsin, USA, and then applied the model to predict areas in the states of Minnesota, Wisconsin and Michigan that wolves were likely to colonize as their populations expanded. They found that their model correctly predicted the locations of 18 of 23 new pack territories (Mladenoff, Sickley & Wydeven 1999). Logistic regression modeling was also used to predict grizzly bear Ursus arctosactivity in the Swan Mountains of northwestern Montana, USA, relative to human activity, trails, and roads (Mace, Waller, Manley, Ake & Wittinger 1999). Broad-scale data have also been used to explore the habitat relationships of fisher Martes pennantiand interspecific relationships between fishers and marten M. americanain North America (Krohn, Elowe & Boone 1995,Krohn, Zielinski & Boone 1997). Further, Carroll, Zielinski & Noss (1999) used logistic regression to model and map fisher habitat in the northwestern United States.
The objective of our study was to develop and evaluate logistic regression models for Canada lynx in northern Maine, giving special attention to the effects of forest management and forest succession on the probability that lynx would occur in a landscape.
Study area
The 32,566 km 2area considered in this study was delineated as the portion of Maine in which lynx were predicted to occur with > 10% probability based on a broad-scale model incorporating deep annual snowfall (> 268 cm) and low prevalence of deciduous forests (Hoving, Harrison, Krohn, Joseph & O'Brien in press). The state of Maine is located at the extreme northeastern comer of the United States, bordered by the Canadian provinces of Quebec and New Brunswick to the north, the state of New Hampshire to the west, and the Atlantic Ocean to the south and east. Maine is 90% forested. In the northern half of the state, large forest product companies own most of the forest lands. The forests of northern Maine are sub-boreal Acadian Forest; these forests feature high interspersion of spruce-fir and northern hardwood forests (Irland 1999). Typical species include: beech Fagus grandifolia,maple Acerspp., hemlock Tsuga canadensis,birch Betulaspp., spruce Piceaspp., and balsam fir Abies balsamea.The forests are mesic and have a relatively low fire frequency; most natural disturbances are small-scale wind and insect events (Lorimer 1977). Large-scale insect defoliation of mature spmce and fir caused by spruce budworm Choristoneura fumiferanaand industrial forest harvesting are the large-scale disturbance regimes in this region (Hardy, Mainville & Schmitt 1985,Irland 1988). Nearly all of northern Maine has been harvested in the past 150 years, and old growth forests are essentially absent from the landscape (Critical Areas Program 1980). Northern Maine is also the only locality in the eastern United States with a verified population of the federally threatened Canada lynx (United States Fish and Wildlife Service 2000).
Material and methods
In December 1994, the Maine Department of Inland Fisheries and Wildlife (MDEFW) initiated an annual track survey in northern Maine to detect the presence of wolves or lynx. Private contractors used snowmobiles during the winter to record tracks of lynx, bobcats L. rufus,and the relative density of snowshoe hare along transect segments during 1994–1999. Each transect was divided into segments that were approximately 1 km in length, although there was some variation introduced by inconsistent snowmobile odometers. The locations of transects were recorded on copies of a DeLorme atlas (Anon. 1993) at a scale of 1:125,000.
Survey routes and the presence or absence of the aforementioned mammal tracks were digitized into Arc-Info (ESRI, Redlands, California, USA; use of trade names does not imply endorsement). United States Geological Survey (USGS) Digital Line Graphs (DLG) of roads, trails and water bodies were used as background coverages (i.e. digital maps) when digitizing transects. A coverage of township lines at the 1:250,000 scale, available from the Maine Office of Geographic Information Systems (GIS), was also used as a background coverage. Each transect was divided into segments to match the data sheets and maps.
Lynx are highly mobile and have large home ranges, which average about 100 km 2in the southern boreal forest (Aubry, Koehler & Squires 2000). Therefore, lynx tracks occurring on adjacent segments might have resulted from double sampling of an individual lynx. However, tracks separated by > 5.6 km (the radius of a hypothetical, circular 100 km 2home range) were unlikely to represent the same individual. Because lynx exhibit intrasexual territoriality, individual lynx on average will be 5.6 km apart. Some lynx could have been included in the model twice (Type I error). However, using a track separation of > 5.6 km would have increased the risk of not including individual lynx (Type II error). Thus, the 5.6 km separation seemed to best balance issues of pseudoreplication and loss of power, especially given the rarity of the species in this landscape. A subset of transect segments was selected at random to test the spatial distribution of the sampled lynx tracks. These random segments were also separated by at least 5.6 km.
The proportions of each vegetation type within 5.6 km of each selected segment with lynx presence or absence were calculated from the Maine Vegetation and Land Cover map (Hepinstall, Sader, Krohn, Boone & Bartlett 1999). The map was based on a classification of 1991 and 1993 Thematic Mapper (TM) satellite imagery, which was ground-truthed using low-altitude aerial videography, to represent 1993 conditions and was resolute to a 30 m 2grid. This map was generalized to 90 m 2cell size using RESAMPLE in ARC-INFO Grid because of limits on computer processing time, and to match the approximate resolution of field mapping of lynx occurrences.
We developed logistic regression models for the Canada lynx in northern Maine based on presence or absence in the snow track surveys. We evaluated nine a priorimodels that included variables deemed important to lynx or snowshoe hare based on a literature review, rather than using a statistical model to define the relationships. Statistical null hypothesis testing is prevalent in ecological literature, but may be uninformative in some modeling situations, especially when selecting descriptor variables for models (Anderson, Bumham & Thompson 2000). Testing a logistic regression model for lynx against a null model would not result in much new biological insight. The research question was not whether the variables had an effect significantly greater than zero (null hypothesis testing), but rather, which combination of variables best approximated the real biological system (model ranking). The information-theoretic approach is an alternative to model selection via null hypothesis testing (Burnham & Anderson 1998,Anderson et al. 2000). In the information-theoretic approach, models are constructed using different combinations of variables (i.e. different models) that are considered likely to describe the system based on a prioriscientific knowledge. This approach avoids the inclusion of variables that have little or no justification in the model but might give spurious correlations to the pattern of interest.
The Maine Vegetation and Land Cover map delineated 37 vegetation types (Hepinstall et al. 1999). Based on a review of literature, a relatively small subset of types was considered likely to describe lynx habitat: recent clearcut, late regeneration, partial harvest, mature deciduous forest, mature conifer forest and forested wetland. Late regeneration forest was generally clearcut prior to 1991, and had > 50% overhead closure at a height of 1 m. Recent clearcut areas were generally harvested between 1991 and 1993 and contained little vegetation biomass in the overstory or understory. Partial harvest corresponded to a variety of silvicultural practices including improvement thinning, shelterwood and selection harvest. Deciduous species contributed to > 75% of the dominant cover in the mature deciduous forest type, and conifer species contributed to > 75% of the dominant cover in the mature conifer forest type.
The vegetation types were not developed from maps of known stand histories, but were based on reflectance patterns as captured in TM satellite data. Thus, the harvest classes did not represent stands of known age. The differences between early and late regeneration, for example, were structural and represented differences in biomass and reflectance patterns. The harvest classes were tested and corresponded to interpreted aerial videography (seeHepinstall et al. 1999for details on accuracy), but the exact age and specific method of harvest were unavailable. Wetlands were incorporated into the Maine Vegetation and Land Cover map directly from the United States Fish and Wildlife Service, National Wetlands Inventory (Hepinstall et al. 1999). For this analysis, four forested wetland categories (deciduous forested, coniferous forested, deciduous scrub-shrub and coniferous scrub-shrub) were combined into one forested wetland vegetation type. Mean snowfall on each transect segment was also calculated (Hoving 2001).
Of the above variables, nine combinations were considered to have the greatest potential to be biologically meaningful (seeTable 1). One model incorporated variables that predicted snowshoe hare abundance (Hoving 2001): late regeneration, partial harvest, forested wetlands, clearcut and mature deciduous forest. A model similar to a Canada lynx model developed and tested at a coarser and broader spatial scale (Hoving et al. in press) was also considered: mature deciduous forest and mean annual snowfall. A global model that included all variables (late regeneration, partial harvest, forested wetlands, clearcut, mature deciduous forest, mature conifer forest and snowfall) was also considered. A series of progressively simpler models were also considered by removing progressively less important variables based on the literature.
We built nine logistic regression models using the track transect data (Hosmer & Lemeshow 1989,Agresti 1996). Models were ranked according to their second order Akaike's Information Criterion (AIC c) and ΔAIC c(Burnham & Anderson 1998). The AIC cis an AIC corrected for small sample size, and the ΔAIC cis the difference between each model and the model with the lowest AIC c: ΔAIC ci= AIC ci- minimum AIC c. McFadden's p 2(McFadden 1974), Hosmer Lemeshow P (Hosmer & Lemeshow 1989), sensitivity and specificity were calculated using SYSTAT 9.0 (SPSS, Chicago, Illinois, USA). The model with the lowest (i.e. best) mean ΔAIC cwas used to predict habitat at a 90 m 2resolution for northern Maine.
To evaluate the predictive capabilities of the model, track locations from a snow track survey conducted in 2003 were compared to the predicted probabilities of occurrence on the landscape. Surveys were conducted from snowmobiles on snow covered roads. Locations were documented using GPS. Between mid-January and mid-March 2003,1,713 km were surveyed in 20 townships predicted to have a high (> 0.66; N = 4), medium (0.66–0.33; N = 5), and low (< 0.33; N = 11) probability of lynx occurrence in northern Maine.
Table 1.
Model performance in terms of AIC c, AAIC c, McFadden's ρ 2, Hosmer-Lemeshow P, sensitivity and specificity for nine logistic regression models of lynx presence and absence, based on transects where Canada lynx were present and absent in northwestern Maine. Vegetation types 1were derived from the Maine Vegetation and Land Cover map (Hepinstall et al. 1999).
Results
During 1995–1999, 2,664 segments of transect were surveyed for the presence or absence of lynx tracks. Lynx tracks were present on 66 (2.9%) segments, but using our spacing criteria, lynx were considered present on only 13 segments. Although lynx were not detected on 2,598 segments, only 108 segments were considered as absences because of our spacing criteria.
Models with Δ AIC c< 2 can be considered to give a roughly equivalent balance of data fit and parsimony (Burnham & Anderson 1998). Two models had ΔAIC c< 2, and were thus considered equivalent (Table 1). The logistic regression model with the lowest AIC cincorporated clearcut (C), partial harvest (P), late regeneration (L), forested wetlands (F), and mature deciduous (D) forest (hereafter referred to as model CPLFD). A roughly equivalent model (ΔAIC c= 1.4) did not include mature deciduous forest (hereafter referred to as model CPLF). Model parameters, statistics and maps were similar for CPLFD and CPLF. To avoid redundancy we report only the parameters and map for model CPLFD, and note that the effect of mature deciduous forest was weak and ambiguous at this spatial scale.
The CPLFD model fit the data well (McFadden's ρ 2= 0.31), and indicated that lynx were more likely to occur in 100 km 2landscapes with much late regeneration, and relatively little recent clearcut, partial harvest, forested wetland or mature deciduous forest. Proportion of mature conifer and average snowfall in a landscape had no significant association with either lynx presence or absence at this spatial scale. The direction of effects was consistent across models (e.g. late regeneration had a positive effect in all models in which it was considered), regardless of AIC cscore. The Hos-mer Lemeshow P statistic, which is the probability that the data fit a logistic curve (Hosmer & Lemeshow 1989), was moderately high (P = 0.76).
The probability of lynx occurrence (P Iynx) in northern Maine was mapped using the logistic regression model:
where x
C
was the proportion of a 100 km
2
circle centered on a 90 m
2
grid cell that was clearcut between 1991 and 1993, x
P
was the proportion that was partial harvest, x
L
was the proportion that was late regeneration, x
F
was the proportion that was forested wetland, and x
D
was the proportion that was mature deciduous forest.
When the probability of occurrence was calculated for the entire study area (Fig. 1), potential lynx habitat (probability of occurrence > 50%) constituted < 5.5% of the study area. Potential habitat was distributed among several areas north and west of Moosehead Lake, one area of habitat west of Baxter State Park, and a complex in far northern Maine (seeFig. 1). Patches were separated by 25–80 km.
During the 2003 test survey, lynx tracks were present on 156 segments (9% of the 1,713 km surveyed). This represented 23 positive occurrences of lynx when randomly selected at a 5.6 km spacing. Lynx tracks were not present on 1,557 km, which represented 40 absences when randomly selected at a 5.6 km spacing. At a probability threshold of 0.5, the model correctly classified 63.5% of the selected transect segments. Sensitivity (the rate that presence was predicted correctly) was low (0.22), and specificity (the rate absence was predicted correctly) was high (0.88). The 0.5 threshold is not always the best cut-point; this is especially true of logistic regression models (Fielding & Bell 1997). At a probability threshold of 0.2, the correct classification rate was slightly higher (65.1%); sensitivity was moderate at 0.61, and specificity was similar at 0.68. Lynx occurrences that did occur in low probability areas tended to be adjacent to regions where lynx were predicted to occur (seeFig. 1).
Figure 1.
Probabilistic map of lynx occuirence derived from a logistic regression model of lynx presence/absence and the proportions of late regeneration, partial harvest, recent clearcuts, forested wetlands and mature deciduous forest in northern Maine, USA, during 1995–1999. Hatched areas were not included in the study area based on < 10% probability of lynx occupancy based on broader scale models developed for New England and eastern Canada (Hoving 2001). Lines and circled points represent test data from a winter survey in 2003. The circled area represents a concurrent radio telemetry study which was not surveyed in 2003, but where 30 lynx have been captured and monitored since 1999.
Discussion
The model with the lowest AIC cpredicted an independent data set of lynx presence and absence with moderate success. The low sensitivity and bias toward lower thresholds were expected given the modeling methodology and recent changes in the lynx population in Maine. In logistic regression, probabilities tend to be biased toward the larger group (Fielding & Bell 1997). In the present case, absences far outnumbered presences due to the rarity of lynx within the study area.
The population of Canada lynx in northern Maine appears to have increased between the time that the tracks used to build the model were observed (1995–1999) and the time the test data were collected (2003). The proportion of segments with lynx tripled between the two surveys, and litter sizes during 2003 on a concurrent radio telemetry study in northern Maine were larger than any previously recorded in that state (MDIFW, unpubl. data). Because lynx are territorial, an increase in the population would likely result in some lynx using more habitats. This would be reflected in a drop in the sensitivity of the model, and a shift downward in the threshold value. Conversely, a decreasing population size likely would have resulted in a drop in specificity and an increase in the optimal threshold value. Thus, the low sensitivity of the model was consistent with an apparent increase in the lynx population on the study area during the 4–8 year interval separating the model-build and model-test data. Additionally, one of the highest probability areas (up to 94% probability of occurrence) was not surveyed during the model test year to avoid disturbing an on-going telemetry study (seeFig. 1), which may have further reduced our ability to correctly predict occupied habitat during that year. However, that 400 km 2area was known to support resident lynx; 30 non-juvenile lynx and adult females with 39 kittens have been captured and monitored there as part of a companion radio-telemetry study (MDIFW, unpubl. data).
The recent increase in the lynx population may be related to a 10-year lynx-hare population cycle or unusually good habitat conditions for snowshoe hares in regenerating forests created by clearcutting in the 1970s and 1980s. In 2003, lynx populations in the Gaspe region of Quebec were high, which could result in increased emigration from that population into Maine. The extent of dispersal from Quebec to Maine is currently unknown. However, a thorough study of the historic record of lynx observation and harvest in Maine concluded that lynx populations fluctuate, but those snow-shoe hare and lynx data were too sparse to document a regular cycle in Maine (Hoving, Joseph & Krohn 2003).
Lynx in northern Maine occurred most frequently in 100 km 2landscapes with a disproportionately high amount of regenerating forest, predominantly even-aged forests that regenerated following clearcutting. A similar pattern has been reported for lynx on Cape Breton Island (Parker et al. 1983) and other northern boreal forests (Kesterton 1988,Staples 1995,Mowat, Poole & O'Donoghue 2000). Lynx presence was negatively associated with 100 km 2landscapes dominated by recent clearcuts and partial harvests. Snowshoe hare showed the same positive associations with regenerating forest and negative associations with recent clearcuts and partial harvests in 0.46 km 2landscapes (Hoving 2001), which suggests that lynx were exhibiting second order habitat selection (Johnson 1980) based primarily on abundance of principal prey.
Ecological scale can be measured in a variety of different ways (Peterson & Parker 1998), and organisms may show different habitat associations at different scales (Johnson 1980). Within a 506,963 km 2area of eastern North America and at a 1 km 2resolution, Canada lynx were strongly associated with areas of deep snowfall and with 100 km 2landscapes comprised of little deciduous forest (Hoving et al. in press). However, lynx occurrences showed no significant association with snowfall and were weakly associated with deciduous forest within our 32,566 km 2study area within eastern North America. Thus, the broad geographic distribution of lynx in eastern North America is greatly influenced by snowfall, but within areas of similarly deep snowfall, measures of forest succession become more important.
Potential habitat for lynx in northern Maine was rare, occurring on approximately 6% of the 32,566 km 2study area. Furthermore, the patches of potential habitat were disjunct, and separated by 25–80 km. The distances between patches were considerably lower than the mean dispersal distance of 163 ± 209 km for Canada lynx in the Northwest Territories, Canada (Poole 1997). Thus, northern Maine appears to have discontinuous, rather than continuous, habitat for Canada lynx. Indeed, studies at broader spatial scales indicate that potential habitat in northern Maine was at the southern extremity of an international complex of potential habitat in eastern North America that encompasses northern Maine, Quebec and northern New Brunswick (Hoving et al. in press). Given the patchy and fragmented nature of potential habitat in northern Maine, lynx may be sensitive to changes in forest practices.
The proportion of partial harvest (which included thinning, selection cuts and shelterwood cuts) within 100 km 2landscapes was negatively associated with both the presence of lynx and the relative abundance of snow-shoe hare (Hoving 2001). At the scale of the forest stand, hares were one order of magnitude less abundant in one type of partial harvest, 3–4 years post-harvest, relative to regenerating forests (Fuller 1999). Based on our logistic regression model, the negative coefficient for partial harvest was stronger than the positive effect of late regeneration or the negative effects of forested wetland or mature deciduous forest.
Although lynx presence was positively associated with regenerating forest, it was negatively associated with recent clearcuts. Clearcutting was beneficial to lynx at a longer time scale because it produced a dense regenerating forest with abundant snowshoe hare, but clearcutting had a negative effect at shorter time scales. In Maine, lynx occurred in 100 km 2landscapes that experienced relatively intensive (10–20% of a 100 km 2landscape) clearcutting in the past 15–25 years, but relatively little clearcutting 0–15 years prior to our study. Extensive areas of even-aged management may mimic large-scale natural disturbances associated with lynx occurrence in boreal forest landscapes, such as fire or insect outbreaks (Poole, Wakelyn & Nicklen 1996,Paragi, Johnson & Katnik 1997).
During the 1990s there was a dramatic increase in partial harvesting, and an equally dramatic decrease in clearcutting in Maine. In 1989, clearcuts accounted for 45% of the land area harvested and partial harvests for 55% (Maine Forest Service 1995). In 1999, clearcuts accounted for only 3%, whereas partial harvests accounted for 96% of the forest area harvested in Maine (Maine Forest Service 2000). Much of the late regeneration on the landscape in the 1990s was a result of large-scale clearcutting during the 1970s and early 1980s that was associated with salvage harvesting from an epidemic of spruce budworm. Recent trends away from clearcutting in favour of partial harvest could have significant negative consequences on densities of snowshoe hare, and could affect an entire suite of carnivores that depend on hare, including the Canada lynx. Many types of forest practices are included under the term ‘partial harvest’, and these different forms of partial harvesting were not discernable from the Maine Vegetation and Land Cover Map. Therefore, further study is needed to better understand the effects of specific forms of partial harvesting on snowshoe hare and lynx.
In 1997 a federal judge stated that Canada lynx were threatened by “forest clearing and current timber management” (U.S. Department of the Interior 1997), and a recent review of the scientific knowledge of Canada lynx hypothesized that old growth forest may ensure more temporally stable habitat for lynx relative to earlier stages of forest succession (Buskirk et al. 2000). In the western United States, current timber management might reduce habitat suitability for lynx, depending on the structure that regeneration provides in that region. In Maine, however, different forms of timber management had different effects. Lynx were positively associated with 100 km 2landscapes altered by clearcutting 15–25 years previously, but were less likely to use landscapes with partial harvesting or vety recent clearcutting. The proportion of mature conifer forest in the landscape was not a powerful determinant of lynx occurrence, and the influence of mature deciduous forest on lynx occurrence was ambiguous. Although some forest harvest practices seem to harm lynx, some forms of harvesting that promote increased densities of snow-shoe hare may be beneficial.
Canada lynx were sometimes abundant in Maine prior to the large-scale clearcutting of the late twentieth century (Hoving 2001). Though lynx occurred often in old burns (Audubon & Bachman 1852,Thoreau 1893), the pre-settlement frequency of fires appears to have been low in most of Maine (Coolidge 1963,Lorimer 1977) relative to the more conifer dominated boreal forests of Canada and Alaska. However, in extreme northwestern Maine fire frequency was notably higher (C. Cogbill, unpubl. data). Epidemic insect infestations, such as spruce budworm outbreaks, may account for periods of lynx abundance in pre-settlement forest. Spruce budworm outbreaks generally cause extensive mortality in mature balsam fir and lesser mortality in mature spruce (Blais 1985). Outbreaks in Canada appear to be cyclic with a period of 25–100 years, and occur over extensive areas (Blais 1983,Krause 1997). The most recent outbreak affected Ontario, Quebec, Maine, New Brunswick, Nova Scotia and Newfoundland (Hardy et al. 1985) in the 1970s and 1980s. Though there is some disagreement as to the proximate causes and frequency of spruce budworm outbreaks in Maine (Seymour 1992), budworm and spruce bark beetle Dendroctonus rubipennis,which affects mature spruce, likely caused mortality over large parts of Maine (Seymour 1992). Furthermore, snowshoe hare were more abundant in stands defoliated by the spruce budworm relative to mature forest in north-central Maine (Lachowski 1997). Thus, regeneration following periodic mortality of mature forest following insect infestations may have provided extensive areas of snowshoe hare habitat that met the landscape-scale requirements of Canada lynx in the pre-settlement forests of Maine.
Old growth forest does not currently exist as a functional component on the landscape in Maine (Critical Areas Program 1980). As such, this study can determine little about positive or negative associations of Canada lynx with old growth forest. Further, no benchmarks currently exist to evaluate the relative habitat quality of pristine versus managed forests for lynx in the eastern United States.
Trends toward partial harvesting seem to be the most immediate potential threat to the only population of lynx in the eastern United States. Partial harvests represented a large proportion of the annual area of forest logged in Maine when this study was conducted; however, partial harvests represented a small but increasing portion of the overall study area. Although our study was not designed to evaluate population level responses of lynx to partial harvesting, the negative stand-scale effects on snowshoe hares of one form of partial harvesting has been documented (Fuller 1999). Given recent trends toward partial harvest and away from forest management that creates large areas of regenerating forest, we recommend additional study of how different forms of partial harvest regenerate, and the effects through time of partial harvests on snowshoe hare and lynx.
Acknowledgements
Josh Holloway and Ann Winters conducted the 2003 lynx surveys, and Charles Todd, Amy Meehan and Jennifer Vashon were instrumental in providing the data. Mary Kate Beard-Tisdale provided guidance and edited early versions of this paper. Jeffery Hepinstall provided insight on GIS and programming. Matthew Hoyt, Amanda Paradis and Sean Chisolm digitized and transcribed track transect data. This research was funded by the National Council for Air and Stream Improvement, the Maine Department of Inland Fisheries and Wildlife, the Federal Aid in Wildlife Restoration Program, the United States Fish and Wildlife Service, the Maine Cooperative Fish and Wildlife Research Unit, and the University of Maine, Department of Wildlife Ecology. This is a contribution of the Maine Cooperative Fish and Wildlife Research Unit (United States Geological Survey, University of Maine, Maine Department of Inland Fisheries and Wildlife, and Wildlife Management Institute, cooperating), and is Publication No. 2755 of the Maine Agriculture and Forest Experiment Station.
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© WILDLIFE BIOLOGY
Citation
Christopher L. Hoving , Daniel J. Harrison , William B. Krohn , Walter J. Jakubas , and Mark A. McCollough"Canada Lynx Lynx canadensisHabitat and Forest Succession in Northern Maine, USA," Wildlife Biology10(4), 285-294, (1 December 2004). https://doi.org/10.2981/wlb.2004.034
Received: 13 August 2002; Accepted: 2 December 2003; Published: 1 December 2004
Christopher L. Hoving, Daniel J. Harrison, William B. Krohn, Walter J. Jakubas, Mark A. McCollough "Canada Lynx
Lynx canadensis
Habitat and Forest Succession in Northern Maine, USA," Wildlife Biology, 10(4), 285-294, (1 December 2004)
Include:
Format:
| https://complete.bioone.org/journals/wildlife-biology/volume-10/issue-4/wlb.2004.034/Canada-Lynx-Lynx-canadensis-Habitat-and-Forest-Succession-in-Northern/10.2981/wlb.2004.034.full |
JRFM | Free Full-Text | A Survey of the Accounting Industry on Holdings of Cryptocurrencies in Xiamen City, China
This is the first survey conducted in China on the holding of cryptocurrencies. Although cryptocurrencies have existed in the world for more than a decade, because the exchange of cryptocurrencies is banned in China, there is no guidance on the holding of cryptocurrencies in China’s accounting standards. Moreover, although the exchange of cryptocurrencies is prohibited by the Chinese government, holdings of cryptocurrencies by Chinese entities and individuals cannot be prevented. Thus, we conducted a survey in investors’ attitudes towards cryptocurrencies in Xiamen City, a special economic zone (SEZ) and a pilot free trade zone (FTZ) in China. The survey respondents commonly defined cryptocurrencies as investments (45%), inventories (19%), and intangible assets (36%). A total of 84% of respondents stated that the value of a cryptocurrency should be represented by a fair value. These results are similar to those obtained in a survey by The Digital Assets Accounting Consortium (DAAC), but different to the tentative agenda decision of the International Financial Reporting Standards Interpretations Committee (IFRSIC). Additionally, 65% of respondents stated that they prefer to accept cryptocurrencies as cash equivalent currencies, and these cash equivalent currencies were considered to have two main functions: a medium of exchange (56%) and a monetary unit for pricing goods and services (52%).
A Survey of the Accounting Industry on Holdings of Cryptocurrencies in Xiamen City, China
by Huqin Yan 1 , Kejia Yan 2,* and Rakesh Gupta 3
1
Xiamen National Accounting Institute, Xiamen 361005, China
2
School of Management, Xiamen University, Xiamen 361009, China
3
Department of Accounting, Finance and Economics, Griffith University, Nathan 4111, Australia
*
Author to whom correspondence should be addressed.
J. Risk Financial Manag. 2022 , 15 (4), 175; https://doi.org/10.3390/jrfm15040175
Received: 11 January 2022 / Revised: 4 April 2022 / Accepted: 6 April 2022 / Published: 11 April 2022
Abstract
This is the first survey conducted in China on the holding of cryptocurrencies. Although cryptocurrencies have existed in the world for more than a decade, because the exchange of cryptocurrencies is banned in China, there is no guidance on the holding of cryptocurrencies in China’s accounting standards. Moreover, although the exchange of cryptocurrencies is prohibited by the Chinese government, holdings of cryptocurrencies by Chinese entities and individuals cannot be prevented. Thus, we conducted a survey in investors’ attitudes towards cryptocurrencies in Xiamen City, a special economic zone (SEZ) and a pilot free trade zone (FTZ) in China. The survey respondents commonly defined cryptocurrencies as investments (45%), inventories (19%), and intangible assets (36%). A total of 84% of respondents stated that the value of a cryptocurrency should be represented by a fair value. These results are similar to those obtained in a survey by The Digital Assets Accounting Consortium (DAAC), but different to the tentative agenda decision of the International Financial Reporting Standards Interpretations Committee (IFRSIC). Additionally, 65% of respondents stated that they prefer to accept cryptocurrencies as cash equivalent currencies, and these cash equivalent currencies were considered to have two main functions: a medium of exchange (56%) and a monetary unit for pricing goods and services (52%).
Keywords:
survey of cryptocurrencies
;
financial reporting standards interpretations committee
1. Introduction
Since Bitcoin was invented in 2008 (
Nakamoto 2008
), more than 10,707 new cryptocurrencies (
Investing 2022
) have been created (as of March 2022). Generally, a cryptocurrency is a digital currency that is designed to work as a medium of intermediate exchange. Cryptocurrencies are decentralized digital currencies that are not issued by any jurisdictional authority. All transactions of cryptocurrencies are written in a big, distributed ledger that can be copied by every participant assigned to a node of the blockchain network. Cryptocurrencies are secured by encryption hash algorithms, signed with a digital signature, timestamped, and verified by participants to ensure security and prevent fraud (
Silvia 2019
).
Blockchain technology is the supporting technology that underlies cryptocurrencies. Cryptocurrencies are crypto assets, which are digitized by blockchain technology. Crypto assets are the most important financial assets in modern financial markets. Crypto assets impact elements of modern finance including highways, mobile phones, and the Internet. Blockchain technology has led to a revolutionary change to potentially many service industries, including finance and banking. Blockchain technology has become an innovative medium and transaction system with high value ( Boring 2019 ).
On 5–6 March 2019, in London, the International Financial Reporting Standards (IFRS) Interpretations Committee (IFRSIC) held a meeting and discussed how the IFRS standards could apply to the holding of cryptocurrencies. A tentative agenda decision on holdings of cryptocurrencies was published. According to the tentative agenda decision, the IFRSIC ( 2019a ) noted that cryptocurrencies are crypto assets.
A cryptocurrency is a digital currency that is recorded on a distributed ledger. For security, it is encrypted by a mathematical cryptography algorithm. A cryptocurrency is not as legal as a fiat currency issued by a jurisdictional authority or a central bank. Most cryptocurrencies are issued by private companies, which do not have any issuing permissions from the central government. The holders of cryptocurrencies do not have any legal contracts as they usually do in traditional financial markets ( IFRSIC 2019a ).
Based on the tentative agenda decision,
IFRSIC
(
2019a
) proposed that the IAS 2 Inventories accounting standard is the accounting rule that best fits the holding of cryptocurrencies. As in the ordinary course of business, when holders want to sell their crypto assets, the best accounting rule is the IAS 2 Inventories. The
IFRSIC
(
2019a
) also proposed that if the IAS 2 Inventories accounting standard is not appropriate for holdings of cryptocurrencies, another good choice is the IAS 38 Intangible Assets accounting standard. In most cases, IAS 38 will be the best accounting standard for holdings of cryptocurrencies.
After the tentative agenda decision was published by the IFRSIC ( 2019a ), many accounting bodies worldwide, including accounting firms and accountants, made comments to the IFRSIC. As of 15 May 2019, at least 20 comment letters had been received by the IFRSIC ( 2019b, Comment letters ). These comments represent the major opinions of the accounting industry on holdings of cryptocurrencies. This was the first time that the issue of cryptocurrency holding had been a focus of accounting bodies.
However, there have not been any comments from Mainland China. Do the Chinese accounting bodies not care about the issues of cryptocurrency holding?
Actually, since Bitcoin was created in 2008, the trend of cryptocurrency holding by private companies and individuals has been rapidly increasing in China. However, in contrast to the enthusiasm from private companies and individuals about cryptocurrency holding, the Chinese government has set up a number of regulations to prevent the widespread purchase of cryptocurrencies in China. The conflict between the private holding of cryptocurrencies and the government regulations means that no Chinese accounting body has made a statement on the suggestions of the
IFRSIC
(
2019a
). Although the exchange of cryptocurrencies is prohibited by the Chinese government, holdings of cryptocurrencies by Chinese entities and individuals cannot be prevented. Although there are a number of governmental regulations to prevent the exchange of cryptocurrencies in China, when dealt with as a technical problem, it is necessary to consider how to record the holdings of cryptocurrencies in financial statements. As long as some Chinese entities and individuals still hold cryptocurrencies, this will continuously be a question related to accounting standards. On the other hand, even if Chinese accounting bodies do not care about this issue, many international accounting bodies do. If the Chinese accounting bodies do not consider the implications of this issue in China now, it will be a continuous issue in the future. Thus, the motivation of this study was to investigate this issue now in relation to the situation in China.
On 3 December 2013, five Chinese central government regulators, including The People’s Bank of China (PBOC), jointly issued a governmental document named A Circular on Preventing Risks Related to Bitcoin (
CSRC 2013
) in which the Chinese central government regulators warn that no Chinese financial institution can offer its services to Bitcoin. The Chinese central government regulators noted that Bitcoin may be defined as a special virtual commodity in nature, but because it does not have any legal status as fiat currencies do, it must not be used or circulated in circulation markets as a currency in China. The Chinese central government regulators stated that Bitcoin has no central issuer, a limited total volume, no territory restrictions for its use, and anonymous users. In China, Bitcoin is not seen as a real currency although it is called a currency. Because it is not issued by monetary authorities, it does not have the characteristics of currency in terms of legal compensation and mandatory payment. For these reasons, the Chinese central government regulators have asked that the national financial institutions do not provide any bitcoin-related businesses or services. The Chinese central government regulators also require online Bitcoin exchanges to be filed as trading records, and measures must be taken to prevent speculative trading and money-laundering risks associated with bitcoin. The Chinese central government regulators have warned that if individuals use Bitcoin, then any risks related to Bitcoin will be taken by themselves (
Zhu 2013
).
Although Bitcoin-related business is prohibited by the Chinese regulators, many cryptocurrencies were used in China. Along with the development of cryptocurrencies in China, further regulations were published by the Chinese government.
On 4 September 2017, seven Chinese central government regulators, including the PBOC (
CSRC 2017
), again jointly issued a governmental document, named The Announcement on Preventing Financial Risks from Initial Coin Offerings (ICO Rules). Its purpose is to protect investors from financial risks. Under the ICO Rules, ICOs that raise cryptocurrencies are illegal in China. Cryptocurrencies, such as Bitcoin, Ethereum, and others, are considered illegal cryptocurrencies, and their issue and trading are prohibited in China by the Chinese government. If an investor tries to raise money by issuing cryptocurrencies on the black market or selling cryptocurrencies through an irregular trading channel, his or her illegal behavior is prohibited by the Chinese government. Because cryptocurrencies involved in ICOs are not issued by the Chinese official authorities, they are not legally accepted as a fiat currency in China (
LLC 2018
).
On 3 September 2021, eleven top Chinese economic regulators, including the National Development and Reform Commission (
NDRC 2021
), jointly issued a tightened regulation named the Notice on Regulating the Activities of Virtual Currency Mining. According to the notice, because virtual currency mining has many negative impacts on the economy, such as energy wastage and the creation of carbon emissions, which do not promote industrial development or technological improvements, industrial entities will be strictly punished if they engage in mining Bitcoin or other virtual currencies. The main punitive measures are the imposition of high electricity prices on state-owned and private companies undertaking virtual currency mining activities that would otherwise pay household electricity prices.
On 24 September 2021, ten Chinese central government regulators, including the
PBOC
(
2021
), jointly issued a more tightened regulation on virtual-currency trading and speculation, which is named The Notice on Further Preventing and Disposing of the Risk of Hype in Virtual Currency Trading. Based on the new notice, cryptocurrency trading in China was totally cracked down on. Because there was a concern that financial transactions of cryptocurrencies will have big negative impacts on the Chinese economic and financial order, these kinds of activities were made illegal and were banned in the country. According to the notice of the
PBOC
(
2021
), the main negative activities that may result from financial transactions of cryptocurrencies include financial gambling, illegal fund-raising, commercial fraud, pyramid scheme investments, money laundering, and serious threats to the safety of people’s property. Immediately, all cryptocurrency-related business activities were defined as illegal and strictly banned in China.
Although the mining of virtual currency and the trading of cryptocurrencies are banned based on the regulations announced by the Chinese government, in fact, some individuals and companies do hold cryptocurrencies in China. It is thus necessary to do a survey on holdings of cryptocurrencies in China. Except for the regulations, technically, it is necessary to discuss how transactions of cryptocurrencies should be recorded in financial statements. As China’s central bank is developing a digital currency electronic payment (DCEP) system (
Xinhua 2020
), a survey of holdings of cryptocurrencies will provide some useful suggestions for policy makers.
Generally, under the reform and opening up policy, the Chinese government usually prefers to operate and test its new business policies in a special economic zone (SEZ) or in a pilot free trade zone (FTZ). For example, according to the 2020 annual report (
Meitu 2021
), during the year ended 31 December 2021, the company of Meitu
1
had invested 940.88523 units of Bitcoin and 31,000 units of Ethereum, and were accounted as intangible assets approximately US
$
45.1 million and US
$
117.3 million when revaluated by using the prevailing market prices of fair values (
Meitu 2022
). Moreover, on 12 October 2020, the PBOC issued CNY 10 million (about USD 1.47 million) of its first digital currency, known as Digital Renminbi, in Shenzhen (
Xinhua 2020
). These were the first SEZs and FTZs in China. Because the Digital Renminbi is not a cryptocurrency like Bitcoin, we do not discuss it in this paper. However, if a cryptocurrency is used as a reference to the Digital Renminbi, the survey on cryptocurrencies can provide some reference suggestions for the government.
Since the first pilot free trade zone was set up in 2013, China has established 18 pilot FTZs ( CGTN 2019 ). Setting up new pilot FTZs is a strategic policy to improve the degrees of the Chinese reform and opening up in the new era. In China, the pilot FTZs are meant to serve as pioneers of the country’s reform and opening up. For better integration of the domestic economy with international practices, the Chinese government has given some special policies to the pilot FTZs. Before a new opening up policy is implemented in the country, it can be firstly implemented and tested in the pilot FTZs.
Xiamen City became a special economic zone (SEZ) in 1980 and a pilot free trade zone (FTZ) in 2015. Based on the support from the Xiamen City Federation of Social Science Associations (
XMSK 2020
), we conducted survey focusing on the issue of whether it would be possible for the Chinese government to allow people within the SEZ and FTZ of Xiamen City to trade cryptocurrencies. If this is possible, how do we deal with holdings of cryptocurrencies in accounting? To answer these questions, we conducted a survey in Xiamen City. We discuss the majority opinions from the global accounting industry and present the results of the survey conducted in Xiamen City.
2. Literature Review
2.1. Are Cryptocurrencies Intangible Assets, as Defined in IAS 38?
The IFRSIC ( 2019a ) stated that the cryptocurrencies are intangible assets, as defined in IAS 38. If a cryptocurrency is an intangible asset, the basic assessment is that it must meet the requirements of an intangible asset defined in IAS 38. An asset is intangible if it can be separated, sold, or transferred from the holder individually, and it cannot be seen as a monetary item that can give the holder a contractual right to obtain a number of units of currency.
Some accounting bodies have noted that the application of IAS 38 may not be relevant for investors. Because a cryptocurrency is mostly held by investors for the purpose of investment, they have suggested that it is inappropriate to apply IAS 38 to holdings of cryptocurrencies.
Although a cryptocurrency meets the definition in paragraph 8 of IAS 38 for classification as an intangible asset, the purposes of holding a traditional intangible asset and holding a crypto asset for investment are totally different ( Kim 2019 ).
Regarding the tentative agenda decision made by the IFRSIC ( 2019a ) on the application of IAS 38 to holdings of cryptocurrencies, only a few accounting bodies agreed with this conclusion. Many other accounting bodies did not agree with the conclusion of the IFRSIC ( 2019a ). For example, The Digital Assets Accounting Consortium (DAAC) conducted an industry survey for the period from February to April 2019 and found that only 19% of respondents carrying cryptocurrencies answered that holdings of cryptocurrencies are considered intangible assets, whereas as many as 64% of respondents answered no to this question ( Boring 2019 ).
The Taiwan Accounting Research and Development Foundation (ARDF Taiwan) stated that the application of IAS 38 to holdings of cryptocurrencies may not generate relevant information for the investors. When comparing the characteristics and nature of cryptocurrencies and intangible assets, they are not exactly as the same as defined in IAS 38, because cryptocurrencies produce economic benefits through being sold or invested, while general intangible assets produce economic benefits through business operation ( Liu 2019 ).
The Securities and Exchange Commission of Brazil (CVM) stated that if a cryptocurrency is bought for the purposes of investment, trading, or use as a medium of exchange, it can clearly not be considered within the scope of IAS 38 Intangible assets, because the nature of an intangible asset is related to the maintenance of operational activities ( Ferreira and Silva 2019 ).
Generally, intangible assets are usually defined as goodwill or non-liquid assets. When a cryptocurrency is treated as an intangible asset, its true nature may not be easily separated from other intangible assets in financial statements ( Boring 2019 ).
The information produced based on IAS 38 may not be the most useful information for investors, because under IAS 38, the value of holdings of cryptocurrencies might be estimated by a cost-based valuation method that measures the crypto assets’ value in financial statements. If the cost-based method is implemented, then values may be assigned to holdings of cryptocurrencies and recorded in financial statements as historical costs, but this will not provide relevant information about their current market value to investors. If the cost-based revaluation method is implemented, the real value of holding the cryptocurrency in terms of profit or loss will not be reflected when an active market exists and the cost-based revaluation method will need to change (
Hait et al. 2019
).
The Mexican Financial Reporting Standards Board (CINIF) stated that based on IAS 38, a cryptocurrency might be revalued at its purchased cost or at its fair value, because the purchased cost does not reflect the economic value of a cryptocurrency. If the revaluation method is applied to cryptocurrencies, which should be revaluated at fair value, the result of the revaluation should be confirmed as an integrated income. Because the purpose of cryptocurrency holding is speculative in nature, for revaluating in the short term, it might be inappropriate to revalue cryptocurrencies in terms of historical costs and the best revaluation method may be to measure the profit or loss using the fair value (
Cervantes 2019
).
The Canadian Accounting Standards Board (AcSB) noted that the IAS 38 was introduced much earlier than when cryptocurrencies were created. When the paragraphs of the IAS 38 were written, the nature of cryptocurrencies was never considered. When IAS 38 is applied to measure whether holdings of cryptocurrencies are intangible assets, the measurement result will be inappropriate and a fair value will not be achieved ( Mezon 2019 ).
The Canadian Securities Administrators Chief Accountants Committee (CSACAC) explained that intangible assets, as defined in paragraph 9 of IAS 38, are generally held to help an entity to operate its business. However, cryptocurrencies are generally held to help an entity with investment, mostly to produce future profits from sale. Again, the prices of cryptocurrencies are volatile in the market, and cryptocurrencies are often held for speculative purposes in the short-term when they are used for the exchange for goods or services. Based on this analysis, it is inappropriate to see holdings of cryptocurrencies as intangible assets (
Hait et al. 2019
).
The Chamber of Digital Commerce stated that, in general, the application of the IAS 38 Intangible Assets accounting standard for holdings of cryptocurrencies is not appropriate, because the purposes of cryptocurrency holding should be considered when assessing which IFRS accounting standards should be applied (
Boring 2019
). Usually, the purposes of cryptocurrency holding are very different depending on whether the holders are broker-traders or cryptocurrency miners. While a cryptocurrency miner may take out a loan to mine crypto assets and repay this through selling crypto assets, another company’s treasury department may hold cryptocurrencies with a long-term investment objective and sell the remaining cryptocurrencies as a short-term liquid requirement (
Boring 2019
). Because the purposes are different, the accounting standard IAS 38 may not reflect the purposes appropriately.
2.2. Are Cryptocurrencies Inventories, as Defined in IAS 2?
The IFRSIC ( 2019a ) concluded that if cryptocurrencies are held for sale during the ordinary course of business, it is appropriate to apply the IAS 2 Inventories accounting standard. If an entity holds cryptocurrencies for sale during the ordinary course of business, the held cryptocurrencies will be the same as inventories defined in the IAS 2. Conversely, if an entity holds cryptocurrencies that are not for sale in the ordinary course of business, the held cryptocurrencies can be considered intangible assets as described in IAS 38.
The IFRSIC ( 2019a ) also concluded that when an entity acts as a broker-trader of cryptocurrencies and considers cryptocurrencies to be inventory assets similar to the description of commodities in the broker-traders act, it is appropriate to apply paragraph 3(b) of the IAS 2. In these circumstances, it is better to measure the value of inventories at fair value and calculate the profit less costs from the selling prices.
Many accounting bodies have agreed to accept the tentative agenda decision of the IFRSIC ( 2019a ) by applying IAS 2 to holdings of cryptocurrencies so that they are considered inventories.
The Digital Assets Accounting Consortium (DAAC) conducted an industry survey from February to April 2019 and found that 39% of respondents who had crypto assets considered their cryptocurrencies to be inventories ( Boring 2019 ).
The Accounting Standards Board of Japan (ASBJ) stated that because cryptocurrencies do not have any inherent value, their value usually comes from market exchange, if an entity wants to generate cash flow from its holdings of cryptocurrencies, the only way is to sell the cryptocurrencies on the cryptocurrency market. In this situation, it is appropriate to apply IAS 2 ( Kogasaka 2019 ).
Hardidge ( 2019 ) suggested that cryptocurrencies held by broker-traders can be seen as inventories. Under IAS 2, a broker-trader holds cryptocurrencies for the purpose of generating a benefit by selling cryptocurrencies at high prices and buying them at low prices. The price fluctuations are the first consideration for holdings of cryptocurrencies.
Generally, a broker-trader holds cryptocurrencies in an ordinary business to sell them to customers. In some cases, these cryptocurrencies are bought from customers to satisfy the dealers’ sell orders. In other cases, cryptocurrencies are bought from miners to meet customers’ buy orders. In both cases, the cryptocurrencies are bought and sold to generate marginal profits. The characteristics of cryptocurrency holding in this case fits the definition of the IAS 2 inventory; accordingly, these digital assets are held as part of the inventory on the entities’ distributed ledger account ( Boring 2019 ).
Some accounting bodies have noted that it is inappropriate to accept the tentative agenda decision of the IFRSIC ( 2019a ) by applying IAS 2 to the holdings of cryptocurrencies as part of the inventory.
The Taiwan Accounting Research and Development Foundation (ARDF Taiwan) stated that the application of IAS 2 to holdings of cryptocurrencies may not provide relevant information to investors, because when cryptocurrencies are seen as inventory, their value may be estimated based on the purchased cost, and when they are valued using their historical cost, this will not exactly reflect their market economic value ( Liu 2019 ).
Different to cryptocurrency holding by broker-traders, cryptocurrencies held by miners cannot be seen as inventories. When miners get a cryptocurrency reward from mining, the cryptocurrency cannot be seen as inventories under IAS 2 ( Hardidge 2019 ).
2.3. Are Cryptocurrencies Cash, as Defined in IAS 32?
The IFRSIC ( 2019a ) concluded that cryptocurrencies are not cash, because the nature of cryptocurrencies is not currently the same as the nature of cash.
Some accounting bodies prefer to accept that cryptocurrencies are not cash, as concluded by IFRSIC.
Although a cryptocurrency can be used as a medium for exchanging particular goods and services, it is not widely accepted as cash, as defined in the accounting standard IAS 32 Financial Instruments: Presentation. Additionally, although a cryptocurrency can be used as a monetary unit to price goods or services, it is also not widely accepted as cash in terms of the measurement and recording of transactions in financial statements, as defined in IAS 32.
Why are cryptocurrencies not accepted as cash, as defined in IAS 32? Many people are concerned that the prices of cryptocurrencies are highly volatile. Because the prices of cryptocurrencies undergo large fluctuations, they cannot be accepted as a medium or a monetary unit to measure the prices of other goods and services on the market. Conversely, the prices of cryptocurrencies have to be measured by other fiat currencies (
Blockchain 2020
). Based on this, cryptocurrencies’ functions are not the same as those of fiat currencies, because fiat currencies are usually used to measure the prices of goods and services. Moreover, considering their volatile pricing, cryptocurrencies are poorly stored as store value (
Silvia 2019
).
Some other accounting bodies prefer to accept that cryptocurrencies can be considered cash, as defined in IAS 32.
In the first quarter of 2021, Tesla ( 2021 ) purchased an aggregate amount of USD 1.50 billion Bitcoin. This cryptocurrency was firstly accepted as a type of payment for sales and was considered non-cash in accordance with the non-cash consideration guidance included in The US Accounting Standards Codification (ASC) 606 and as intangible asset as defined in ASC 805. Later, in 2022, Tesla ( 2022 ) reassessed the aggregate amount of USD 1.50 billion Bitcoin purchased in 2021 and reclassified it as an investment and also as a liquid alternative to cash in the long term.
The Securities and Exchange Commission of Brazil (CVM) stated that cryptocurrencies are not currently accepted as currency because cryptocurrencies were not entirely considered when the AG3 of IAS 32 was created; however, in some transactions, cryptocurrencies have to be considered cash, because, in fact, cryptocurrencies have been implemented as a medium of exchange and used as monetary units for transactions in some markets ( Ferreira and Silva 2019 ).
The Mexican Financial Reporting Standards Board (CINIF) stated that, in general terms, it is inappropriate for cryptocurrencies to receive accounting recognition according to IAS 2 Inventories or IAS 38 Intangible. Conversely, it is appropriate to define a cryptocurrency as cash, because a cryptocurrency is a digital record that is based on encrypted algorithms and used as a form of payment, and its transfer can only be carried out via electronic means ( Cervantes 2019 ).
Bitcoin, Ethereum, and other cryptocurrencies, although not widely accepted as electronic cash, are accepted by many commercial entities as a payment tool and used to pay for exchanges worldwide. More and more people are preferring to use cryptocurrencies to exchange goods and services, and this trend will continue to accelerate in the future (
Rowland 2019
). As the most popular cryptocurrency today, Bitcoin was created in a peer-to-peer network as an electronic form of cash, which permits payments to be directly transferred from one party to another through the blockchain network. It is targeted to act as a medium of exchange and monetary unit for pricing goods and services and is defined as having the basic function of cash according to IAS 32.
The International Air Transport Association’s (IATA) Industry Accounting Working Group (IAWG) suggested that cryptocurrencies should be treated as cash. Generally, cash has three basic functions: a medium of exchange, a monetary unit for pricing goods and services, and a store value of currency. Although the exchange medium function is an essential element for an asset that acts as cash, it is not essential for an asset acting as cash to have the other two basic functions. Although many sovereign currencies are widely accepted as cash, they cannot be converted into a normal fiat currency and are not able to be widely used as a medium of exchange in the international market. Functional currencies and foreign notes and coins held by an entity are generally reported as cash in accounting statements. Thus, if cryptocurrencies are widely used as a medium of exchange in the market by entities, they should be treated as cash (
Nevo and Cahalan 2019
).
The Taiwan Accounting Research and Development Foundation (ARDF Taiwan) stated that the fundamental function of a cryptocurrency is to act as a medium of exchange, usually for the purpose of exchanging goods, services, or fiat currencies. Although cryptocurrencies do not have any inherent or intrinsic value, entities that hold cryptocurrencies can receive market benefits from their subsequent exchange or sale. This is quite different to the description of intangible assets by IAS 38 or inventories by IAS 2 ( Liu 2019 ).
Different to some accounting bodies that directly agree or disagree that cryptocurrencies are not cash, as concluded by the IFRSIC, some accounting bodies are focused on future trends.
Deloitte agrees that although the conclusion that cryptocurrencies are not cash is accepted now, this will not be the case in the future. While existent accounting standards, such as IAS 38, have been used to assess whether cryptocurrencies act as cash now, this conclusion will be reassessed if the accounting standards catch up with the development of cryptocurrencies in the future. Accordingly, in the future, it will be essential to develop a more robust definition for the accounting standards of cash ( Poole 2019 ).
The Fintech company Brane stated that it is necessary to review and develop the definition of cash in the IFRS standards. There are five ways to assess whether an asset is as a financial asset according to IAS 32. Only Paragraph AG3 of IAS 32 defines the function of cash as being a medium of exchange. This is an incomplete definition for cash, because it does not sufficiently explain the widespread function of an exchange medium when assessing whether a given asset can be considered cash ( Rowland 2019 ).
2.4. Are Cryptocurrencies a Financial Instrument, as Defined in IAS 32?
The IFRSIC ( 2019a ) noted that cryptocurrencies are not monetary items and do not give the holder legal rights as monetary items usually do. Generally, a monetary item can give a holder a contractual right to get a fixed number of units of currency. Based on the tentative agenda decision on holdings of cryptocurrencies of the IFRSIC ( 2019a ), a cryptocurrency is not a financial equity instrument because it cannot give the holder a legal contractual right to receive a fixed interest.
Some accounting bodies accept the conclusion of the IFRSIC ( 2019a ) that a cryptocurrency is not a monetary item.
Rowland ( 2019 ) noted that a smart contract is embedded on the blockchain network for cryptocurrencies. When assessing whether a cryptocurrency is a financial asset, it is very important to consider whether the contractual rights and obligations utilize a consensus protocol coordinated between the holder and the blockchain network of cryptocurrencies.
A financial instrument is defined in IAS 32 as a contract that can give a holder the right to receive a fixed benefit. Silvia ( 2019 ) stated that a cryptocurrency is not a financial instrument because the holders of cryptocurrencies generally do not have any legal contractual right to receive cash or another financial asset as occurs with a traditional financial instrument.
Some accounting bodies do not accept the conclusion of the IFRSIC ( 2019a ) that a cryptocurrency is not a financial instrument, as defined in IAS 32, based on the issuance of cryptocurrencies, because cryptocurrencies do involve a contract between the holder and the blockchain network.
Actually, it is not true that the holder of a cryptocurrency does not have any contract. The truth is that the holder of a cryptocurrency has an electronic contract with the blockchain system through a distributed ledger. The difference between a cryptocurrency and a traditional financial instrument, as defined in IAS 32, is that the contract of the cryptocurrency holder does not contain a legal contractual right to receive a fixed unit of money. This means that the electronic contract does not have any guarantee from the jurisdictional authority.
The Fintech company Brane noted that it is necessary for the IFRSIC to consider the technical attributes of the proof-of-stake consensus protocol (PoS) in the blockchain network when assessing whether a cryptocurrency can or cannot be considered a financial asset (
Rowland 2019
). It is not correct for the IFRSIC to state that the holder of a cryptocurrency does not have any contractual right to receive a number of units of money (
Rowland 2019
). For example, the Bitcoin blockchain network is addressed in a proof-of-work (POW) consensus protocol. Similarly, the Ethereum blockchain network is addressed in a proof-of-stake (POS) consensus protocol. Under both the POW and POS consensus protocol networks, all participants in the blockchain networks are required to agree with these consensus protocols and the related rules when they intend to hold Bitcoin and Ethereum and conduct business on the networks. If an entity decides to participate in the Bitcoin or Ethereum blockchain networks, they accept the network consensus protocols and receive financial reward from holdings of Bitcoin and Ethereum. If an entity enters into the networks, the POW and POS consensus protocols become obligations that the entity has to obey. The POW and POS consensus protocols and their related rules are usually embedded in a smart contract. As soon as the entity accesses the typical networks, the smart contract between the entity and the network is automatically signed. Consequently, every participant’s activities, responsibilities, and obligations on the network are regulated by the smart contract. Similar to the cryptocurrencies of Bitcoin and Ethereum, the consensus protocols of POW and POS are applied by more than 80% of all cryptocurrencies (
Rowland 2019
). It is significant that the smart contracts can be accepted as general contracts, as defined in IAS 32 for financial instruments.
Some accounting bodies suggested that different methods should be used to assess whether a cryptocurrency can be seen as an intangible asset, cash, inventory, or financial instrument in different situations.
The Chamber of Digital Commerce stated that it is more appropriate to use different accounting standards to assess the characteristics of cryptocurrencies based on the purpose of their holding. When the intent is to resell the cryptocurrency, it is appropriate to apply the inventory accounting standard, IAS 2; however, when the intent is to use a cryptocurrency as a financial instrument, then it is appropriate to apply both IAS 32 and IAS 39 ( Boring 2019 ).
2.5. How to Disclose Holdings of Cryptocurrencies in Accounting?
The
IFRSIC
(
2019a
) concluded that an entity may apply the disclosure requirements of the IFRS standards to determine the amount to be recorded in accounting financial statements in three ways. If an entity holds cryptocurrencies for sale in the ordinary course of business, it is appropriate to apply paragraph 36–39 of the IAS 2 Inventory to determine the amount to be displayed in the financial statement. Otherwise, it is appropriate to apply paragraph 118–128 of IAS 38 intangible assets to determine the amount to be displayed in the financial statement. In both cases, because the cost-based method can only measure the historical value of holdings of cryptocurrencies but cannot provide any relevant information for making investment decisions, it is essential to apply paragraphs 91–99 of IFRS 13 Fair Value Measurement to disclose the value of holdings of cryptocurrencies.
The IFRSIC ( 2019a ) noted that when an entity applies paragraph 122 of IAS 1 Presentation of Financial Statements to holdings of cryptocurrencies in accounting, it is necessary to disclose judgements that significantly affect the amounts confirmed in the financial statements.
The
IFRSIC
(
2019a
) also noted that if an entity is applying paragraph 21 of IAS 10 Events to holdings of cryptocurrencies in accounting after the reporting period, it is necessary to disclose any relevant non-adjusting events, including information related to the nature of the event and value of the financial effects. For example, if an entity holds cryptocurrencies and intends to sell them for liquidity, because the disclosed events in the financial statement may influence the decisions of investors, based on the IFRS 13 Fair Value Measurement requirement, it is necessary to disclose significant changes to the fair value that have occurred after the reporting period.
Many accounting bodies agree that the fair value is a good way to measure value when an entity holds cryptocurrencies.
Because a cryptocurrency is usually used as a payment tool or stored for sale, the fair value is the best way to reflect the economic value of holdings of cryptocurrencies ( Cervantes 2019 ).
The Accounting Standards Board of Japan (ASBJ) stated that the best way of revaluating the holdings of cryptocurrencies is to use their fair value through profit or loss (FVTPL), because the FVTPL provides the most relevant information to investors in financial statements ( Kogasaka 2019 ).
Grant Thornton International Ltd. noted that if an entity is not a broker-trader and its holdings of cryptocurrencies are not for sale in the short-run, because the accounting standard defined by the IFRSIC cannot sufficiently reveal the performance of its businesses, FVTPL is the best choice to provide relevant information for investors ( Haygarth 2019 ).
The Mexican Financial Reporting Standards Board (CINIF) stated that the historical cost and net realizable value may not reflect the actual value of holdings of cryptocurrencies, because only the FVTPL can reflect the market value of holdings of cryptocurrencies ( Cervantes 2019 ).
When Tesla ( 2021 ) revaluated its aggregate of USD 1.50 billion Bitcoin purchased in 2021, the sales revenue from contracts with customers was recorded based on the fair value according to current quoted market prices.
The Canadian Securities Administrators Chief Accountants Committee (CSACAC) conducted a survey of 41 Canadian entities with cryptocurrency holdings and/or undergoing related activities and summarized that although there are different accounting practices that can be applied to holdings of cryptocurrencies, most respondents (76%) stated that they prefer to disclose the values of cryptocurrencies in financial statements using fair value through profit and loss ( Hait et al. 2019 ).
In most cases, if an entity holding cryptocurrencies is considered to be a commodity broker-trader, as defined in IAS 2, the alternative accounting standard that can be used is paragraph 11 of IAS 8, which may provide a framework for assessing the concepts of assets, liabilities, income, and expenses ( Hait et al. 2019 ).
Similarly, the Digital Assets Accounting Consortium (DAAC) conducted an industry survey from February to April 2019 and found that 75% of respondents holding cryptocurrencies treated changes in events related to cryptocurrencies at fair value when revaluing their earnings or liquidity from holdings of cryptocurrencies ( Boring 2019 ).
2.6. What Proposals Were Put Forward by Accounting Bodies?
Some accounting bodies suggested that it is essential to change the definition of cryptocurrency from that proposed by the IFRSIC ( 2019a ).
As a Fintech company, Brane stated that the birth of cryptocurrencies was a shock to the traditional financial market. Clearly, cryptocurrencies emerged much later than the formation of IAS 38, and while the blockchain distributed ledger technology and encryption algorithms are rapidly evolving in the accounting area, the IAS 38 only provides a very limited solution to the estimation of the fair value of cryptocurrency holdings. When IAS 38 is applied to holdings of cryptocurrencies, considering the nature of cryptocurrencies, IAS 38 cannot provide a perfect solution and therefore does not appropriately represent the nature of the crypto assets when attempting to accounted for them in financial statements (
Rowland 2019
).
The International Air Transport Association’s (IATA) Industry Accounting Working Group (IAWG) questioned the definition presented by the IFRSIC. Although cryptocurrencies are considered by the IFRSIC as not being issued by a jurisdictional authority, the IAWG confirmed that this is not true. Although cryptocurrencies are not issued by a jurisdictional authority at the moment, they can be transferred to a fiat currency and used as a medium of payment clearing. It is easy to solve this problem if a contract between the holder of cryptocurrencies and the clearing parties is created through the blockchain network. For this reason, the IAWG suggested that the definition of cryptocurrency should be changed (
Nevo and Cahalan 2019
).
Some accounting bodies suggested that it is essential to revise the current IFRS standards.
The IFRS Technical Committee of Chile (TCC) suggested that although holdings of cryptocurrencies are intangible assets, as defined in IAS 38, because this is an implicit assumption but not an explicit assumption, there is a requirement for the accounting standard of IAS 38 to be updated when explicitly defining holdings of cryptocurrencies as intangible assets ( Torres 2019 ).
The Securities and Exchange Commission of Brazil (CVM) stated that an IFRS standard revision of cryptocurrencies is essential. As a new category of asset, when the majority of IFRS standards were created, no cryptocurrencies had been created. Cryptocurrencies are directly constrained by the scope of the current IFRS standards and explained by a tentative agenda decision by
IFRSIC
(
2019a
). If the standards of the IFRS are not revised and updated, some new characteristics of cryptocurrencies will probably be far beyond the scope of the current IFRS standards, meaning that the current IFRS standards will probably not be able to correctly reflect new financial trends related to cryptocurrencies (
Ferreira and Silva 2019
).
The Accounting Standards Committee of Germany (ASCG) noted that the outcome of the tentative agenda decision of the
IFRSIC
(
2019a
) on holdings of cryptocurrencies has led to inappropriate results under all facts and circumstances. Some cryptocurrencies, such as Bitcoin, are accepted as mediums of exchange, which implies that these cryptocurrencies have the basic function of cash. Some cryptocurrencies, such as utility tokens, have limited use within a very specific scope of service, which means that these cryptocurrencies may or may not have the basic function of cash. Some cryptocurrencies may not have any functions of cash at all, which means that these cryptocurrencies do not have any cash functions. To record the holdings of all categorized cryptocurrencies in financial statements appropriately, it is essential to revise and update the standards of the IFRS, including IAS 2 and IAS 38. It is necessary to consider all possible scenarios, as the standard make more sense in some scenarios than in others (
Barckow 2019
).
Some accounting bodies suggested that it is essential to add new projects to the current IFRS standards.
Rowland
(
2019
The Mexican Financial Reporting Standards Board (CINIF) suggested that it is necessary to issue a new standard for cryptocurrencies. Cryptocurrencies are a new kind of asset. They are completely different to the traditional assets explained in the existing accounting standards of the IFRS, including IAS 2 and IAS 38. When the accounting standards of the IFRS were issued, cryptocurrencies had not been created. As cryptocurrencies were created a long time later, the existing accounting standards of the IFRS do not reflect the fair value of cryptocurrencies presented in financial statements. Accordingly, it is necessary to develop the standards of the IFRS and issue new specific paragraphs within the IFRS for cryptocurrencies ( Cervantes 2019 ).
3. A Survey of the Accounting Industry on Holdings of Cryptocurrencies
3.1. Survey Results from the Xiamen City, China
In order to provide meaningful feedback on how to deal with holdings of cryptocurrencies in accounting, we conducted a survey of the industry in Xiamen City, China, from April to September 2020.
First, basic information of the respondents was collected.
During the survey, a total of 1013 valid questionnaires were collected. About 60% of the respondents were male, and the other 40% of the respondents were female ( Table A1 ).
The total of 1013 respondents could be distributed into six different areas ( Figure 1 ): 13% were from government agencies and affiliated institutions, 19% were from state-owned companies, 19% were from foreign-owned companies, 18% were from China and foreign joint companies, 22% were from private companies, and 9% were from other organizations ( Table A2 ).
Figure 1. Respondents for question of which industry are you from?
About 40% of the respondents were from financial-related industries, and the other 60% were from other industries ( Figure 2 , Table A3 ).
Figure 2. Respondents for question of are you working in the financial related industries?
A total of 67% of the respondents held a bachelor’s degree or higher, while the other 33% held a lower degree ( Figure 3 , Table A4 ).
Figure 3. Respondents for question of do you hold a bachelor or higher degree?
A total of 53% of the respondents have experience with operating financial derivatives, including stocks and options, while 47% of the respondents did not have this experience ( Figure 4 , Table A5 ).
Figure 4. Answers for question of do you have any experiences on operating financial derivatives?
Only 31% of the respondents had experience with holdings of cryptocurrencies, while the other 69% did not ( Figure 5 , Table A6 ).
Figure 5. Answers for question of do you have any experiences on holdings of cryptocurrencies?
While 100% of the respondents already knew that Bitcoin is the first-ranking cryptocurrency in the world ( Table A7 ), only 38% of the respondents knew that the Ethereum is the second-ranking cryptocurrency in the world ( Table A8 ).
Second, the survey investigated the characteristics of holdings of cryptocurrencies in China.
In answer to the question of how companies currently account for holdings of cryptocurrencies, 45% of the respondents stated that entities carry crypto assets as investments (13% as cash, 20% as foreign currencies, and 12% as other financial instruments), 36% of the respondents stated that entities carry crypto assets as intangible assets (15% as intangible assets except for goodwill, and 21% as goodwill), and 19% of the respondents stated that entities carry crypto assets as inventories ( Figure 6 and Figure 7 , Table A9 ).
Figure 6. Answers for question of how companies to account for holdings of cryptocurrencies?
Figure 7. Answers for question of how companies to account for holdings of cryptocurrencies?
This survey result is similar to that of the DAAC, where 50% of the respondents answered that entities carry crypto assets as investments, 39% as inventories, and 19% as intangible assets ( Boring 2019 ). However, this result differs from the tentative agenda decision of the IFRSIC, because the conclusion of the IFRSIC does not include investments.
In answer to the question of how to disclose the value of the crypto assets held by entities in accounting, 84% of the respondents stated that entities holding cryptocurrencies should revaluate them at fair value through profit and loss (FVTPL) ( Figure 8 , Table A10 ).
Figure 8. Answers for question of how to disclose the values of cryptocurrencies in accounting?
This survey result has also revealed that the 84% of fair value is composed by four different types of fair value, including 30% of current market exchange price, 11% of selling price, 26% of revaluation price and 17% or other weighted price ( Figure 9 , Table A10 ).
Figure 9. Answers for question of how to disclose the values of cryptocurrencies in accounting?
This percentage of the respondents stated that entities holding cryptocurrencies should revaluate them at FVTPL is much higher than those obtained in the Canadian Securities Administrators Chief Accountants Committee (76%) ( Hait et al. 2019 ) and the DAAC (75%) ( Boring 2019 ).
In answer to the question of whether cryptocurrencies are considered cash (currencies), 65% of the respondents stated that cryptocurrencies are cash, whereas 35% of the respondents stated that cryptocurrencies are not cash ( Figure 10 , Table A11 ).
Figure 10. Answers for question of do you think cryptocurrencies are cash or non-cash currency?
This result is different to that of the tentative agenda decision of the IFRSIC, because the conclusion of the IFRSIC was that cryptocurrencies are not cash.
In answer to the question of what functions of a currency that cryptocurrencies have (if the respondent considers cryptocurrencies to be currencies), 56% of the 1013 respondents stated that cryptocurrencies can be used as a medium of exchange ( Figure 11 ), 52% stated that cryptocurrencies can be used as a monetary unit for pricing goods or services ( Figure 12 ), 36% stated that cryptocurrencies can be used to store currency value, and 18% stated that cryptocurrencies can be used as world currencies ( Table A12 ).
Figure 11. Answers for question of what functions of currency do you think that cryptocurrencies have?
Figure 12. Answers for question of what functions of currency do you think that cryptocurrencies have?
In answer to the question of whether the current accounting standards of the IFRS are appropriate for entities’ holdings of cryptocurrencies, 74% of the respondents answered no, and only 26% of the respondents answered yes ( Figure 13 , Table A13 ).
Figure 13. Answers for question of are the current IFRS standards satisfied holdings of cryptocurrencies?
In answer to the question of whether it is essential to make additions to the current standards of the IFRS for holdings of cryptocurrencies, 64% of the respondents answered yes, and 36% of the respondents answered no ( Figure 14 , Table A14 ).
Figure 14. Answers for question of is it necessary to add new projects to current IFRS standards for holdings of cryptocurrencies?
In answer to the question of whether the distribution ledger recording the trading of cryptocurrencies has greater advantages than the central ledger recording the trading of traditional currencies, 61% of the respondents answered yes, and 39% of the respondents answered no ( Table A15 ).
In answer to the question of whether the distribution ledger in the blockchain will become a trend that substitutes the central ledger in the future, 54% of the respondents answered yes, and 46% of the respondents answered no ( Table A16 ).
In answer to the question of whether the respondent would accept the use of cryptocurrencies by their partners when doing business with them, 58% of the respondents answered yes, while 42% of the respondents answered no ( Table A17 ).
Third, the survey asked questions about the future trends for holdings of cryptocurrencies in China.
In answer to the question of whether the respondent considered exchange platforms of cryptocurrencies on the Internet to be legal in China, 37% answered yes and 63% answered no ( Table A18 ).
In answer to the question of whether the respondent considered that the trading of cryptocurrencies, including Bitcoin, should be legally permitted in China, 52% answered yes and 48% answered no ( Table A19 ).
In answer to the question of whether the respondent thought holdings of cryptocurrencies would become legal in China in the future, 60% answered yes and 40% answered no ( Table A20 ).
In answer to the question of whether the respondent considered it essential for legal exchange platforms to be set for cryptocurrencies and the management of these platforms to be enhanced in China, 62% answered yes and 38% answered no ( Figure 15 , Table A21 ).
Figure 15. Answers for question of do you think that in China it is essential to set legal exchange platforms of cryptocurrencies and enhance platforms’ management?
Fourth, the survey asked questions about future trends for holdings of cryptocurrencies in China’s Xiamen pilot FTZs.
In answer to the question of whether the respondent thought that the legal trade of cryptocurrencies should first be operated and tested in China’s pilot FTZs, 61% answered yes and 39% answered no ( Figure 16 , Table A22 ).
Figure 16. Answers for question of do you think that the legal trade of cryptocurrencies should be firstly permitted to operate and test in China’s Xiamen pilot FTZs?
In answer to the question about the areas that the legal trade of cryptocurrencies should be first operated and tested in China’s Xiamen pilot FTZs, 59% stated that this should occur and agreed to encourage the setup of platforms for the trading of cryptocurrencies, 55% suggested that the government should give permission to entities to hold and use cryptocurrencies, 51% stated that cryptocurrencies should become legal, and 50% stated that cryptocurrencies should be freely traded ( Table A23 ).
In answer to the question of which industry should be selected as the first to use cryptocurrencies in the pilot FTZs, 58% of the respondents chose the financial industry ( Table A24 ).
3.2. Analysis of the Survey Results and Policy Suggestions
When considering all respondents, this survey tended to collect questionnaires from people with higher educational degrees who had already learned about cryptocurrencies, particularly about the first-ranking cryptocurrency, Bitcoin. This survey is tended to collect questionnaires from people who had work experience in government agencies, state-owned companies, financial organizations, and Internet-related companies.
Because the first contractors and holders of cryptocurrencies preferred to access them via the Internet, and because the questionnaire was focused on the concepts of currency and accounting, it was reasonable to target the questionnaire to people with Internet experience and higher educational degrees in computing, banking, accounting, and some other majors.
Regarding the total number questionnaires received and the industries of the respondents, we consider the survey results to be representative in terms of both quantity and quality. Because the respondents were from many different industries, held higher educational degrees, and had good understanding of cryptocurrencies, including Bitcoin, the survey results give a good idea of the real situation of cryptocurrencies in China.
The survey results fit with the enthusiasms of private companies and individuals with holdings of cryptocurrencies in China. Most respondents responded positively when asked about the developing trend of cryptocurrencies and supported the legal operation and testing of holdings in China’s Xiamen pilot free trade zone.
Nearly one-third of the respondents had experience with holdings of cryptocurrencies, despite there being no legal exchange market or policy support in China.
Most of the respondents stated that they define holdings of cryptocurrencies as investments, inventories, or intangible assets and believe that the value of a cryptocurrency holding is best represented by its market fair value. Most of the respondents stated that they consider cryptocurrencies are currencies with two main functions: a medium of exchange and a monetary unit for pricing goods and services. Most of the respondents confirmed that the current IFRS standards do not satisfy the accounting requirements for holdings of cryptocurrencies. Thus, it is necessary to add to current IFRS standards to make them appropriate for holdings of cryptocurrencies. Most respondents stated the distributed decentralized ledger based on blockchain technology recording the transactions of cryptocurrencies has more advantages than the centralized ledger, which records the transactions of traditional currencies and believe that, in the future, the distributed ledger will replace the centralized ledger.
Although most of the respondents already knew that the trade of cryptocurrencies in China is illegal and strictly prohibited by the Chinese government, they still stated that, in the future, the trade of cryptocurrencies is likely to become legal and be permitted by the government; platforms for the exchange of cryptocurrencies will be set up and regulated by the government; and cryptocurrencies will be accepted and used by firms for business.
One-third of the respondents stated that, in Xiamen city, there are a few firms that record cryptocurrencies as assets in financial statements and use them as monetary units in business contracts to price goods and services. Most respondents estimated that, in Xiamen city, there are about 50–100 firms that are focused on doing business related to the development of cryptocurrencies.
Most respondents supported the setting up of exchange platforms for cryptocurrencies in the Xiamen pilot free trade zone, the holding and use of cryptocurrencies by entities, the trading of cryptocurrencies in a legal mode, and the initial operation and testing of legal trading in the financial industry.
From the survey results, we can see that although most respondents presented an optimistic attitude toward the holding, use, and trading of cryptocurrencies, a few respondents presented a negative attitude. This means that for an opening up policy for cryptocurrencies to be developed, namely, the operation and test exchange of cryptocurrencies in the Xiamen pilot FTZ, it is necessary to maintain a prudent attitude and conduct a complete analysis of policies, environments, and risks to avoid financial risks from the trading of cryptocurrencies.
4. Summary
According to the conclusion of the IFRSIC in March 2019, cryptocurrencies can be seen as inventories, as defined in IAS 2, when an entity holds them for sale in the ordinary course of business; otherwise, cryptocurrencies can be seen as intangible assets, as defined in IAS 38. Because the trade of cryptocurrencies is strictly prohibited by the Chinese government, there have been no comments from Mainland China. However, according to our survey, many private companies and individuals are very keen to do business in the area of cryptocurrencies. Generally, under the reform and opening up policy, the Chinese government has preferred to operate and test its new business policies in a special economic zone (SEZ) or a pilot free trade zone (FTZ). Xiamen City became a special economic zone in 1980 and a pilot free trade zone in 2015. Based on support from the Xiamen City Federation of Social Science Associations ( XMSK 2020 ), we conducted a survey in Xiamen City on holdings of cryptocurrencies in China.
The results represents that, the respondents defined holdings of cryptocurrencies as investments (45%), inventories (36%), or intangible assets (19%) and stated that the value of cryptocurrencies can be better represented by the fair value ( Table A9 and Table A10 ). This result is similar to that of DAAC ( Boring 2019 ), but different to the tentative agenda decision of the IFRSIC, as the conclusion of the IFRSIC does not include investment in its definition. More than half of respondents stated that cryptocurrencies are currencies with two main functions: a medium of exchange (56%) and a monetary unit for pricing goods and services (52%) ( Table A12 ). This differs from the tentative agenda decision of the IFRSIC, which concluded that cryptocurrencies can be considered cash. 74% of the respondents stated that the current IFRS standards do not satisfy the accounting requirements of cryptocurrency holding ( Table A13 ). Thus, it is necessary to discuss the current IFRS standards for holdings of cryptocurrencies. 62% respondents stated that they support the setting up of legal exchange platforms for cryptocurrencies in the Xiamen pilot free trade zone in China ( Table A21 ). Our suggestion is to initially support the operation and testing exchange of cryptocurrencies in the Xiamen pilot FTZ but to be careful to avoid financial risks associated with the trading of cryptocurrencies.
Author Contributions
Conceptualization H.Y.; methodology, H.Y.; software, H.Y.; validation, H.Y.; formal analysis, H.Y. and K.Y.; investigation, H.Y.; resources, H.Y.; data curation, H.Y.; writing—original draft preparation, H.Y. and K.Y.; writing—review and editing, H.Y. and K.Y.; visualization, H.Y. and K.Y.; supervision, K.Y. and R.G.; project administration, H.Y. All authors have read and agreed to the published version of the manuscript.
Funding
This research was funded by [Xiamen City Federation of Social Science Associations] grant number [2020-16].
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Not applicable.
Conflicts of Interest
The authors declare no conflict of interest.
Appendix A. Statistics of the Valid Questionnaires on Holdings of Cryptocurrencies in Accounting
Appendix A.1. Statistics from the Questions Related to the Basic Information of the Respondents
Table A1. Are you male or female (single-choice question)?
Table A1. Are you male or female (single-choice question)?
Selections Number of the Respondents Percentages Male 612 60% Female 401 40% Sum 1013 100%
Table A2. Which industry are you from (single-choice question)?
Table A2. Which industry are you from (single-choice question)?
Selections Number of the Respondents Percentages Government agencies 131 13% State owned companies 195 19% Foreign owned companies 197 19% China and foreign joint companies 187 18% Private companies 217 22% Other kind of organizations 86 9% Sum 1013 100%
Table A3. Are you working in the financial related industries (single-choice question)?
Table A3. Are you working in the financial related industries (single-choice question)?
Selections Number of the Respondents Percentages Financial related industries 405 40% Non-financial related industries 608 60% Sum 1013 100%
Table A4. Do you hold a bachelor or higher degree (single-choice question)?
Table A4. Do you hold a bachelor or higher degree (single-choice question)?
Selections Number of the Respondents Percentages Bachelor or higher degree 676 67% Lower degree 337 33% Sum 1013 100%
Table A5. Do you have any experiences on operating financial derivatives (single-choice question)?
Table A5. Do you have any experiences on operating financial derivatives (single-choice question)?
Selections Number of the Respondents Percentages Yes 535 53% No 478 47% Sum 1013 100%
Table A6. Do you have any experiences on holdings of cryptocurrencies (single-choice question)?
Table A6. Do you have any experiences on holdings of cryptocurrencies (single-choice question)?
Selections Number of the Respondents Percentages Yes 318 31% No 695 69% Sum 1013 100%
Table A7. Have you already learned Bitcoin (single-choice question)?
Table A7. Have you already learned Bitcoin (single-choice question)?
Selections Number of the Respondents Percentages Yes 1013 100% No 0 0% Sum 1013 100%
Table A8. Which cryptocurrency have you already learned (multiple-choice question)?
Table A8. Which cryptocurrency have you already learned (multiple-choice question)?
Selections Number of the Respondents Percentages Digital Renminbi (DCEP) 345 34% Ethereum (ETH) 380 38% EOS (EOS) 90 9% Litecoin (LTC) 90 9% XRP (XRP) 79 8% Tether (USDT) 64 6% TRON (TRX) 78 8% Monero (XMR) 92 9% Others 77 8% No (except for Bitcoin) 288 28%
Appendix A.2. Statistics from the Questions of the Characteristics on Holdings of Cryptocurrencies in China
Table A9. How companies to account for holdings of cryptocurrencies (multiple-choice question)?
Table A9. How companies to account for holdings of cryptocurrencies (multiple-choice question)?
Selections Number of the Respondents Percentages Weight Average Sum Investments Currency (Except for foreign currency) 241 24% 13% 45% Foreign currency 354 35% 20% Other financial instruments 210 21% 12% Intangible assets Intangible assets (Except for goodwill) 264 26% 15% 36% Goodwill 384 38% 21% Inventories Inventories 341 34% 19% 19% Sum (The valid questionnaires are 1013) 100% 100%
Table A10. How to disclose the values of cryptocurrencies in accounting (multiple-choice question)?
Table A10. How to disclose the values of cryptocurrencies in accounting (multiple-choice question)?
Selections Number of the Respondents Percentages Weight Average Sum Purchasing price Purchasing price 279 28% 16% 16% Fair value Current market exchange price 513 51% 30% 84% Selling price 186 18% 11% Revaluation price 436 43% 26% Other (Except for purchasing price) 293 29% 17% Sum (The valid questionnaires are 1013) 100% 100%
Table A11. Do you think that cryptocurrencies are cash or non-cash currency (single-choice question)?
Table A11. Do you think that cryptocurrencies are cash or non-cash currency (single-choice question)?
Selections Number of the Respondents Percentages Cash 661 65% Non-cash Currency 352 35% Sum 1013 100%
Table A12. What functions of currency do you think that cryptocurrencies have (multiple-choice question)?
Table A12. What functions of currency do you think that cryptocurrencies have (multiple-choice question)?
Selections Number of the Respondents Percentages A medium of exchange 576 56% A monetary unit in pricing goods or services 534 52% A store of value 375 36% A world currency 185 18%
Table A13. Are the current IFRS standards satisfied holdings of cryptocurrencies (single-choice question)?
Table A13. Are the current IFRS standards satisfied holdings of cryptocurrencies (single-choice question)?
Selections Number of the Respondents Percentages Yes 266 26% No 747 74% Sum 1013 100%
Table A14. Is it necessary to add new projects to current IFRS standards for holdings of cryptocurrencies (single-choice question)?
Table A14. Is it necessary to add new projects to current IFRS standards for holdings of cryptocurrencies (single-choice question)?
Selections Number of the Respondents Percentages Yes 646 64% No 367 36% Sum 1013 100%
Table A15. Do you think that the distribution ledger in blockchain will become a trend and substitute the central ledger in the future (single-choice question)?
Table A15. Do you think that the distribution ledger in blockchain will become a trend and substitute the central ledger in the future (single-choice question)?
Selections Number of the Respondents Percentages Yes 621 61% No 392 39% Sum 1013 100%
Table A16. Do you think that the distribution ledger recording the trading of cryptocurrencies has higher advantages than the central ledger in the future (single-choice question)?
Table A16. Do you think that the distribution ledger recording the trading of cryptocurrencies has higher advantages than the central ledger in the future (single-choice question)?
Selections Number of the Respondents Percentages Yes 543 54% No 470 46% Sum 1013 100%
Table A17. Will you accept that your partners use cryptocurrencies in the business when you are doing business with them (single-choice question)?
Table A17. Will you accept that your partners use cryptocurrencies in the business when you are doing business with them (single-choice question)?
Selections Number of the Respondents Percentages Yes 592 58% No 421 42% Sum 1013 100%
Appendix A.3. Statistics from the Questions of the Future Trend of Holdings of Cryptocurrencies in China
Table A18. Do you think that exchange platforms of cryptocurrencies existed on the Internet are legal in China (single-choice question)?
Table A18. Do you think that exchange platforms of cryptocurrencies existed on the Internet are legal in China (single-choice question)?
Selections Number of the Respondents Percentages Yes 379 37% No 634 63% Sum 1013 100%
Table A19. Do you think that the trading of cryptocurrencies including Bitcoin in China should be legally permitted (single-choice question)?
Table A19. Do you think that the trading of cryptocurrencies including Bitcoin in China should be legally permitted (single-choice question)?
Selections Number of the Respondents Percentages Yes 529 52% No 484 48% Sum 1013 100%
Table A20. Do you think that holdings of cryptocurrencies will become legal in the future in China (single-choice question)?
Table A20. Do you think that holdings of cryptocurrencies will become legal in the future in China (single-choice question)?
Selections Number of the Respondents Percentages Yes 607 60% No 406 40% Sum 1013 100%
Table A21. Do you think that in China it is essential to set legal exchange platforms of cryptocurrencies and enhance platforms’ management (single-choice question)?
Table A21. Do you think that in China it is essential to set legal exchange platforms of cryptocurrencies and enhance platforms’ management (single-choice question)?
Selections Number of the Respondents Percentages Yes 624 62% No 389 38% Sum 1013 100%
Appendix A.4. Statistics from the Questions Related to the Future Trend of Holdings of Cryptocurrencies in China’s Xiamen Pilot FTZs
Table A22. Do you think that the legal trade of cryptocurrencies should be firstly permitted to operate and test in China’s Xiamen pilot FTZs (single-choice question)?
Table A22. Do you think that the legal trade of cryptocurrencies should be firstly permitted to operate and test in China’s Xiamen pilot FTZs (single-choice question)?
Selections Number of the Respondents Percentages Yes 615 61% No 398 39% Sum 1013 100%
Table A23. What do you think that the legal trade of cryptocurrencies should be firstly permitted to operate and test in China’s Xiamen pilot FTZs (multiple-choice question)?
Table A23. What do you think that the legal trade of cryptocurrencies should be firstly permitted to operate and test in China’s Xiamen pilot FTZs (multiple-choice question)?
Selections Number of the Respondents Percentages To set up platforms for the trading of cryptocurrencies 599 59% To allow entities holding and using cryptocurrencies 554 55% To support that cryptocurrency will become legality 516 51% To support that cryptocurrencies will be freedom traded 505 50%
Table A24. Do you think which industry can be selected as the first industry to use cryptocurrencies in the pilot FTZs (multiple-choice question)?
Table A24. Do you think which industry can be selected as the first industry to use cryptocurrencies in the pilot FTZs (multiple-choice question)?
Selections Number of the Respondents Percentages Financial industry 589 58% Foreign trade industry 499 49% IT related industry 449 44% Medicine industry 135 13% Commercial industry 277 27% Other 272 27%
Note
1 Meitu Inc. is the biggest company that holds cryptocurrencies in Xiamen city. It is an artificial intelligence (AI) driven technology company with a total of 246 million monthly active users in the field of computer vision, deep learning, and computer graphics. The Company’s two main subsidiaries are Xiamen Meitu Networks Technology Co., Ltd. and Xiamen MeituEve Networks Services Co., Ltd. From the example of Meitu Inc., we can see that the survey of holdings of cryptocurrencies in accounting is very important in Xiamen city, China. The survey results will really provide some supports to companies when they assess the holdings of cryptocurrencies in accounting.
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Kogasaka, Atsushi. 2019. Comments on the Tentative Agenda Decision Relating to Holdings of Cryptocurrencies from Accounting Standards Board of Japan (ASBJ). Comment Letters on Holdings of Cryptocurrencies, IFRS Interpretations Committee Meeting, June 2019. April 26. Available online: https://www.ifrs.org/content/dam/ifrs/meetings/2019/june/ifric/ap12a-comment-letters.pdf (accessed on 5 September 2020).
Liu, Chi Chun. 2019. Comments on the Tentative Agenda Decision—Holdings of Cryptocurrencies from Taiwan Financial Reporting Standards Committee, Accounting Research and Development Foundation (ARDF). Comment Letters on Holdings of Cryptocurrencies, IFRS Interpretations Committee Meeting, June 2019. May 13. Available online: https://www.ifrs.org/content/dam/ifrs/meetings/2019/june/ifric/ap12a-comment-letters.pdf (accessed on 5 September 2020).
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Meitu. 2021. 2020 Annual Report . Xiamen: Meitu, Inc., Available online: https://corp-static.meitu.com/corp-new/20210426/ew_01357AR-25032021.pdf (accessed on 5 April 2022).
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Mezon, Linda F. 2019. Comments on the Tentative Agenda Decision—Holdings of Cryptocurrencies from Canadian Accounting Standards Board (AcSB). Comment Letters on Holdings of Cryptocurrencies, IFRS Interpretations Committee Meeting, June 2019. Available online: https://www.ifrs.org/content/dam/ifrs/meetings/2019/june/ifric/ap12a-comment-letters.pdf (accessed on 8 May 2020).
Nakamoto, Satoshi. 2008. Bitcoin: A Peer-To-Peer Electronic Cash System. Bitcoin . October 31. Available online: https://bitcoin.org/bitcoin.pdf (accessed on 5 May 2020).
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Poole, Veronica. 2019. Comments on the Tentative agenda decision relating to holdings of cryptocurrencies from Deloitte Touche Tohmatsu Limited. Comment Letters on Holdings of Cryptocurrencies, IFRS Interpretations Committee Meeting, June 2019. Available online: https://www.ifrs.org/content/dam/ifrs/meetings/2019/june/ifric/ap13-ias-19-plan-classification.pdf (accessed on 14 May 2020).
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Torres, Leonardo. 2019. Comments on the Tentative Agenda Decision Relating to Holdings of Cryptocurrencies from IFRS Technical Committee, Universidad de Chile. Comment Letters on Holdings of Cryptocurrencies, IFRS Interpretations Committee Meeting, June 2019. Available online: https://www.ifrs.org/content/dam/ifrs/meetings/2019/june/ifric/ap10-ifrs-15-costs-to-fulfil-a-contract.pdf (accessed on 14 September 2020).
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Figure 1. Respondents for question of which industry are you from?
Figure 2. Respondents for question of are you working in the financial related industries?
Figure 3. Respondents for question of do you hold a bachelor or higher degree?
Figure 4. Answers for question of do you have any experiences on operating financial derivatives?
Figure 5. Answers for question of do you have any experiences on holdings of cryptocurrencies?
Figure 6. Answers for question of how companies to account for holdings of cryptocurrencies?
Figure 7. Answers for question of how companies to account for holdings of cryptocurrencies?
Figure 9. Answers for question of how to disclose the values of cryptocurrencies in accounting?
Figure 10. Answers for question of do you think cryptocurrencies are cash or non-cash currency?
Figure 11. Answers for question of what functions of currency do you think that cryptocurrencies have?
Figure 12. Answers for question of what functions of currency do you think that cryptocurrencies have?
Figure 13. Answers for question of are the current IFRS standards satisfied holdings of cryptocurrencies?
Figure 14. Answers for question of is it necessary to add new projects to current IFRS standards for holdings of cryptocurrencies?
Figure 15. Answers for question of do you think that in China it is essential to set legal exchange platforms of cryptocurrencies and enhance platforms’ management?
Figure 16. Answers for question of do you think that the legal trade of cryptocurrencies should be firstly permitted to operate and test in China’s Xiamen pilot FTZs?
Yan, Huqin, Kejia Yan, and Rakesh Gupta. 2022. "A Survey of the Accounting Industry on Holdings of Cryptocurrencies in Xiamen City, China" Journal of Risk and Financial Management15, no. 4: 175.
https://doi.org/10.3390/jrfm15040175
| https://www.mdpi.com/1911-8074/15/4/175/xml |
Bear Metal Gear? - SCP Foundation
The SCP Foundation's 'top-secret' archives, declassified for your enjoyment.
Bear Metal Gear?
Summary:
Need a co-writer. A bio-mechanical, normal looking bear inhabited by thousands of bear people that doubles as a war machine.
Bear Metal Gear?
Super long, be warned.
I really, really love bears, and this is me channeling it into an SCP. I've been trying to write this SCP for awhile, however my lack of knowledge when it comes to things such as clinical diction and metric measurements hinders my progress. I do have an idea, and I know what I want to do with it. Im just having a tough time writing it. I do have a sandbox article (with major flaws), ask for a link if wanted, but heres the basic idea.
The SCP itself looks pretty normal. It's a white bear (like a pizzly bear.) and it behaves as usual during the day time, say for slow movements and unpredictable halting in movement. However, at night time or any time light is not present, a few strange things happen. The bear slowly comes to a halt and lights in a pattern not too different from a city seen from orbit appear on the surface of the bear's skin near the chest area.
Heres everything more specifically.
1. The BearThe bear is some sort of bear similar to a Pizzly bear in appearance. It's composition is more like an android however, similar to the ones of the Aliens series or Detroit: Become Human. Their exterior is some sort of flexible, artificial skin polymer(?) while the internal organs are highly complex machines. The exterior of the bear on extremely close inspection is dotted with various military installations, especially on its face. The ears and nose act as radar. The nose emits a radar ping channeled through the nostrils to scan for potential threats ahead, while the ears are extremely adept at picking up the quietest noises. The eyes are two highly complex cameras used for seeing, obviously. The brain is a control room of sorts, where the leaders of the military control the bear and gather their data. Is basically a big room with seats and control panels.
The back is the more interesting part. Inside the back is where a lot of the powerful stuff is. Connected to the upper portion of the ribs is a long series of concealed hangars capable of deploying aircraft similar to bombers, fighters and helicopters. Various gun emplacements are hidden too, such as SAMs and energy/laser based gun batteries. The spine is connected to a massive railgun. The spinal railgun slowly emerges from the back and launches an extremely powerful projectile in whatever way the bear is facing. Using it drains a significant amount of energy and it takes at least a minute before it can be used again.
Inside the bear are all the organs and inhabitants. The organs are just basically mechanical counterparts of the normal thing, and act to both keep the bear functional and the residents alive. The residents live inside the rib cage to protect them from outside harm.
So why isnt the bear kicking ass and fighting, because it has been greatly damaged and is trying to repair itself. It is unknown what it's full combat capabilities are, so if it were to become fully operational, it is unknown how much of a threat it could pose.
2. The inhabitantsThe inhabitants themselves are a sort of humanoid-bear species. They arent too different from humans, besides the bear part. Though, compared to a human they would be slightly larger.They are very intelligent and behave in a hive-like manner, though they do possess intelligence and sapience, it is thought to be limited. Individuals do not really have much freedom, and their society is a very sleek, highly advanced technological autocracy, where all are extremely loyal to their government, and are very hostile towards anything they deem a threat.
3. BackstoryThis is still TBD. But I have a few ideas.
1. They were a scientific experiment of sorts that managed to break out of its enclosure.2. They are aliens.3. They do not know their history.
Concerns
I dont know how exactly to write their encounters with foundation personnel. Do they somehow shrink when they touch the bear, is a shrink ray involved? I dont know how to do this without it coming across as… Cheesy or more ridiculous than it already is. I want this to be a fun read, but I want it to be somewhat mature too.
Re: Bear Metal Gear?
Took a quick look at this since it fell to page 5 with no replies.
So… this is pretty over the top and off the walls, but I think it might be doable solely on the fact that I don't think we have anything quite like this on the site yet. You do have a lot of specific details but not too much in the way of narrative, and I think that might be something a co-author can help with.
I'm personally not a huge fan of laundry-listed statistics and features, but something like that might be useful for a GoI-format. MC&D perhaps? Maybe Prometheus Labs, or a cyperpunk wizard faction of the Serpent's Hand. Given how wacky this is and the fact that you're not a super expert at clinical tone, a GoI format seems to be the way to go for this.
If you like the idea and are interested in helping me turn this mess into something good, please shoot me a message or DM me on discord.
I think you'd have much better luck reaching out to authors of your own initiative. Try using theTag Searchtool to look up high-rated Series IV and V articles with tags like "mechanical" or the like that are similar to what you want to accomplish with this premise. Then send (polite!) PMs to the authors of those pieces and ask if they can advise on how to proceed with your concept, and/or if they're interested in co-authoring.
Re: Bear Metal Gear?
Do you mean "over the top" in a negative way, or?I just want to make something so unusual and unique, that it gives everyone a feeling of "What the fuck?" and "That's cool." at the same time. I have my own sort of plans for a narrative (Including multiple logs of them fighting the thing, and messages from the crew inside.) but origin story is still N/A.
I'll try to contact any authors if possible. I just don't want to come across as annoying/irritating to them.
Thank you for your help.
Re: Bear Metal Gear?
Do you mean "over the top" in a negative way, or?
In this case, it's neutral. This is objectively a very detailed anomaly with lots of features.
I just want to make something so unusual and unique, that it gives everyone a feeling of "What the fuck?" and "That's cool." at the same time. I have my own sort of plans for a narrative (Including multiple logs of them fighting the thing, and messages from the crew inside.) but origin story is still N/A.
What is the narrative beyond just fighting?
I'll try to contact any authors if possible. I just don't want to come across as annoying/irritating to them.
Just be polite and don't send repeat messages in the same week or so. IRC chat might be a more reliable place to seek co-authors.
Re: Bear Metal Gear?
Beyond fighting, the narrative is more of things that are going on in the present as opposed to the past.
The species inside (referring to themselves as Ursids) have been operating and living inside this machine for quite some time, and they don’t know how long it’s been. Some time ago, they had suffered lots of damage. The ursids have grown to distrust humans because of this. Not absolute hatred but extreme distrust and caution. There’s about 100 of them living inside (more in “cryo”), and they all serve a military role onboard the bear, so their “culture” is heavily militaristic with a focus on combat skills and propaganda, hence why they all act in a sort of hive-like status under command of an autocrat captain.They have been involved in a war with an SCP Foundation, or at least so they think it’s a war. It’s moreso the containment procedures. They claim to have an equivalent of a nuclear charge, and that they will detonate it should they ever face defeat. So the SCP Foundation has deployed a security force (with non-lethal weaponry) to the bears containment area, and they engage the bear every so often to convince the ursids that they are still in a war and have not been contained in order to keep them from detonating the charge. While it wouldn’t be fatal, it’s just something they don’t want to have to deal with. The main narrative is about the SCP Foundation’s “war” with the bear and trying to get them to surrender, as well as how the war ends.
| https://scp-wiki.wikidot.com/forum/t-12093769/bear-metal-gear |
Secretary Panetta’s First Press Briefing on US Defense Expenditure - Paperblog
As shown in the above video, Secretary of Defense Leon Panetta, who succeeded the position from Robert Gates this June, did the first press briefing on August 4 to warn against further cuts in defense spending.
Secretary Panetta’s First Press Briefing on US Defense Expenditure
As shown in the above video, Secretary of Defense Leon Panetta, who succeeded the position from Robert Gates this June, did the first press briefing on August 4 to warn against further cuts in defense spending. Panetta was expected to be a cost cutter of defense as the Director of the Office of Management and Budget under the Clinton administration. However, wars in Afghanistan, Iraq, and Libya, have led him to abstain from further cut in military budget (“Leon Panetta warns against Pentagon budget cuts”; San Francisco Chronicle; August 5, 2011).
As President Barack Obamaand the Republican Party reached an agreement on debt ceiling, it is time to discuss how much expenditure is to be cut in which area. Defense spending is no exception, and Republicans, notably Senator John Kyl, denounce that Democrat proposal of a 500 billion dollar automatic cut in a decade from 2013 would be irresponsible and weak on defense. In view of the forthcoming presidential election, Republican attack on the proposed defense expenditure reduction is being intensified. Meanwhile, Secretary Panetta spoke against his own party in his first press briefing (“Threatened Defense Cuts in Debt Deal Could Loom Over 2012 Race”; Bloomberg News; August 5, 2011). Also, Panetta urged tax increase and spending cuts in other areas like Medicare and social security for necessary savings. It is quite noteworthy that defense spending has been on the rise since 2001 even without wars in Iraq and Afghanistan. Secretary Panetta says that a drastic cut “would do real damage to our security, our troops and their families, and our military’s ability to protect the nation.” It is expected that military benefits and increasingly sophisticated weaponry system push defense spending upward (“Defense Secretary Leon Panetta warns against more cuts in Pentagon budget”; Washington Post; August 5, 2011).
However, congressional debates are not simply Democrat-Republican duels. Defense budget split the Republican as well. While Tea Party libertarians focus on tax reduction, neoconservatives support strong military power. In view of inter and intra party rifts, Senator John McCain proposed to reduce tax breaks as a preemptive strike against defense cuts (“Defense spending in Washington spotlight”; San Francisco Chronicle; August 7, 2011). Above all, the economy is supposed to be the primary determinant in 2012 election, and it will place significant influence on defense budget debates (“Will Obama be reelected? The economy could hold the answer”; Washington Post; August 6, 2011).
Having seen the overview of Secretary Panetta’s first briefing on defense spending, I would like to mention opinions among national security experts. As the bipartisan agreement on the Debt Ceiling Deal was reached, Resident Fellow Thomas Donnelly and Resident Scholar Gary Schmitt, both at the American Enterprise Institute, argues that it is time to discuss the defense budget. They insist that a weak push on defense will alienate the military, which will eventually hurt conservative bases for the next election. Also, they urge Tea Party libertarians to balance a small government and a strong defense, not to let the country run by a president who prefers to "lead from behind" (“The (Raw) Deal on Defense”; Weekly Standard; August 3, 2011).
Furthermore, I would like to introduce a highly recommended article by Max Boot, Senior Fellow at the Council on Foreign Relations, to refute far left liberals. In this article, Boot articulates his support for Panetta, and makes lucid and strong arguments against a leading advocate for Little Americanism Fareed Zakaria, Editor-at-Large of Time (“Cutting Defense Spending Could Hasten America’s Decline as a World Power”; Commentary; August 4, 2011). Arguing against Zakaria’s recent column calling for a drastic cut of defense spending (“Why defense spending should be cut”; Washington Post; August 4, 2011), Boot makes the case for maintaining US military power from the following points.
Even though including war expenditure for Afghanistan and Iraq, the total cost of national defense accounts for just 5.1% of GDP, which is lower than 8.1% for Social Security and Medicare, and around 7% defense spending during the Cold War. More importantly, Boot criticizes Zakaria for dismissing military benefits and high tech weaponry systems when comparing defense expenditure today and during the Korean War and the Eisenhower era. That is, there is every reason why defense spending soars these days. The vital point in this essay us defense spending cut does not help civilian diplomacy and development aid. He also criticizes Zakaria that foreign aid is no exception under the pressure for expenditure cut. Finally Boot quotes Leon Panetta that a drastic defense spending would be “extraordinarily difficult and very high risk.” Again, I strongly recommend this article to make the case against pacifist liberals like Fareed Zakaria.
Another analysis that needs to be attention is a budget chart created by the Heritage Foundation. As opposed to widely believed notions, it shows that the total budget is likely to increase sharply even excluding defense spending. That is, it is utterly wrong to blame defense expenditure for growing budget deficit (“The Military Isn't the Problem”; Weekly Standard Blog; August 3, 2011). See the chart below.
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As Secretary of Defense Leon Panetta said in the press briefing, there are two vital points to discuss US defense under present fiscal austerity. One is to provide the capability to meet security challenges around the world, such as terrorism, rogue states, and rising powers. The other is to maintain the position of the best armed forces in the world. Secretary Panetta has outlined continuity of US defense from his predecessor Robert Gates. Further talk on defense budget will be done at the super committee at the congress. Watch the process there closer!
| https://en.paperblog.com/secretary-panetta-s-first-press-briefing-on-us-defense-expenditure-53265/ |
Perceptions and miconceptions | Iain Abernethy
Perceptions and miconceptions
Perceptions and miconceptions
A recent thread forced me to review my view of Shotokan as a style of karate and while I was not ultimately moved from my view as the stye as one more concerned with the development of the self, than building fighters per se (sorry Jon), I was forced to look at why I hold certain beliefs and question certain aspects of those views (thanks Jon).
As such I am interested in how people view the various karate styles. I'm not talking about informed opinion, oe worse still, googled repitition, I'm talking about a broad brushstroke 'feeling' about what characterises various styles.
I'll kick off:
Goju Ryu - Close quarter system including, grappling and groundwork.
Wado Ryu - Primarilly stand up fast evasive style with lots of locks and holds. Heavy emphasis on getting out of the way
Shotokan - Very militaristic, powerful style. Big classes, low stances, moving basics, primarily concerned with the development of spirit
Kykoshinkai - Stand up, powerful full contact system. Wholly standup paying scant attention to kata and bunkai. Less emphasis on evasion, more on direct power
Shorin Ryu - Okinawan style so probably featuring more grappling than the Japanese styles
Shoto Ryu - Not realy sure so basically as above for Shorin
None of this is supposed to insult anyone, I'm just interested in peoples basic one-line perceptions of the styles.
O would some power the giftie gie us to see ourselves as others see us.Robert Burns;
What do you think?
Damn, even after my long essay :)
Well, it sparked this discussion at least.
I think anyone posting in this topic is going to have to pick their words carefully. ;)
Seriously, I learned a lot from that Jon. In fact, that's what got me wondering how people see the various styles.
By way of clarification, this is meant to be light-hearted and as I say is meant to be how you see the styles at the most basic level.
Funnily enough, I didn't clarify my own opinions on mainstream shotokan, which are probably close to yours Gavin. I just think they've veered away from the initial intent and it doesn't have to be like that. So, shotokan, as it is taught now in the majority of schools/associations around the world closely matches your description. Though I do think that many of the practitioners would also add that they work on self protection. On that I'd strongly disagree with them.
I'm sitting on the fence because I said why should I feel the need to belong to any of them.
I was just curious about how people see the styles and not belonging doesn't mean you don't have an opinion.
My descriptions of the styles are probably incorrect, and definitely simplistic, but that was what I was looking for! Hopefully, none of the descriptions as I have put them, implies that any is better than any other and is it not just a case of horses for courses anyway?
Why so timid?
I'm starting to feel like I've asked an awkward question and it really wasn't my intention so let me revise it slightly...
As a Goju practitioner, I obviously have an understanding of the system and its practices. What I do not have (hence the Robbie Burns quote) is any idea how Goju is percieved within the wider scheme of things.
So, if you are uncomfortable putting up your topline feel of all of the styles, tell me how you see Goju?
No political agenda here, just curious...
p.s. Jon, I did pick up on your opinion on mainstream and I'm very sure that our views on how things should be done is very closely aligned.
I think Gavin M has gathered together here many of the common perceptions regarding the more commonly practiced karate styles. Clearly these are not being presented as facts and I find it hard to deny that these are commonly held views (whether the holder is willing to change or adapt them when they encounter the real thing is of course another matter.)
I agree that Shotokan is often seen as overly formalised with excessively wide stances, emphasis on power and militaristic overtones in the training.
Wado ryu probably gets its lighter and more nimble characterisation from a direct comparison to Shotokan. As the most common style it often gets used as a benchmark to judge the peculiarities of others. I have noticed however that the preconceptions of Japanese karateka are different to British ones here. Most of the Japanese folks I have talked to seem to see wado as slightly archaic and having overtones of classical Japanese arts due to the presence of idori/ tachi dori and other such in its syllabus.
Goju ryu cant seem to avoid its reputation for being a close in oriented style (which from my own experience is not undeserved at all although a bit of a narrow characterisation) but the other major peculiarity is the emphasis on breathing techniques.
Uechi ryu seems to be well known for its use of the fingers and toes as striking surfaces (one Japanese karateka I know from a different style who had a lot of uechi ryu experience said of it "People with jobs to go to can't do that! we need our hands to do stuff!"). The other thing that is often pointed to is its greater resemblance to Chinese styles.
It seems to me that there are no really widespread opinions on shorin ryu or shito ryu (although I have heard comment on the number of kata used in shito ryu from other stylists). There is one slight misconception though in that shorin ryu is often labelled as the older style that shotokan and thus wado ryu came from. This is not strictly the case as shorin ryu is a name used by many modern Okinawan styles that developed from the shuri te and/ or tomari te lineage. As far as I can tell it was never used before the 20th century.
Kyokushin has a reputation for hard, full contact training and physical conditioning combined with a militaristic and macho attitude. The publicity materials used by the original kokushinkai really do play on this. In the words of another karateka friend of mine from Tokyo "They are a bunch of masochistic nutters!!".
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I'll bite. I stress these are tongue in cheek brief impressions.
Goju Ryu - They like hitting things and lifting weights, and breathing like constipated men, I think they may also pair up.
Wado Ryu - Actually Ju Jitsu with a few Karate kata performed for fun - called Karate by founder for marketing.
Shotokan - Close range effective style now predominantly taught as a long range athletic display.
Kykoshinkai - Tough guys who like hitting each other.
Enshin - Weird guys who don't do head strikes despite their making up the majority of all real attacks, they like hitting each others legs.
Shorin Ryu - Light and whippy short range Karate.
GKR - Sign here please for your creche Karate.
I could write lots more, but as quick snapshots of impressions - that's what I get.
Okay here goes
Goju that I have tried and seen in a few sessions with Jon Law I liked a lot. It seems to have the grappling side to it that I like and need, but it was really only a sampling as he is just too far away to train on a regular basis. I can't find any Goju clubs up here. It seemed more like it was being tailoured to me( rather than in the line type training) when we did the Sanchin classes and ground fighting and I came away thinking thats for me as like up close and personal due to my job.
I do however like the directness of Shotokan and to me it seems a lot harder and more miltaristic in its approach to training ( longer and deeper stances than the Goju stuff with Jon, held for long periods that made my legs burn like hell) but no groundwork at all but I enjoyed it and everyone was brilliant to train with and came away with a real buzz at the end of a class.
Can't comment on other styles as I know nothing about them.
Time to go training.
Hey Dom
Check out this comment I made in reference to to the naha/shuri and tomari distinctions.
e wrote:
Incidentally the root of shotokan is shorin-ryu and, according to the Cook book, shuri-te, tomari-te and naha-te were terms introduced in 1926 to classify the various methods by region in an effort to conceal their chinese roots as karate was spreading in an increasingly nationalistic Japan.
Taken from here:http://www.iainabernethy.co.uk/content/block-%E2%80%93-kick-%E2%80%93-pu...
They are all 20th century distinctions invented to de-Chinese the origins of tode/karate to make it more palatable for a, at that time, nationalistic Japanese public.
Hi,
This is my first post on this board (though, have been reading it with great eagerness for some time!!).
Firstly, awesome question and I've been following your work Sensei Mullholland (and Iain's) for the past few years, in fact, it's because of yours and Iain's work that I 'came back' to Karate - so a HUGE thank you to both of you.
So...my take on it is pretty much as described...Shotokan - very big on style, spirit development, and...looking good (i.e. technique execution) - very little emphasis on practical application. I can say this as this is the school that I practice/study currently (I'm only a low, grade 3rd Kyu) and, yes, it does frustrate the hell out of me at times. That said, I have absorbed as much as I can from the likes of "Four Shades of Black" (absolutely marvellous) and Iain's work and developed my own "out of class" training routine directly from this.
What did I do before? JuJitsu (both stand-up and Groundwork/sports oriented), Krav Maga (sorry!), Judo (in the Army), Aikido (in the Army..yawn) and prior to that, Wado Ryu (very sports oriented 25 years ago) and Wing Chun.
I think that if we all looked at the principles behind the styles/kata etc, then we could make each school/style a little more effective.
Just my thoughts (and sorry for the longer post than I'd hoped!)
Thanks, Andy
Hi All,
I can only comment on what i have come into contact with.
Shotokan . Strict military style training, high enphasis on etiquette, mostly useless outside of dojo.
Goju . traditional hard style maintaining a lot of it's chinese influence.
Kyokushin . Full contact style mostly used in competition, strange breathing noise.
Intersting thread, i am a 'shotokan' man myself yet this is my honest opinion of most dojos. Of course i know that this is not the same for all dojos (hence this forum) but if this is how i feel after 10 years of karate, what does a bigginer think?
Neil
Iain Abernethy
JWT wrote:
Gary
Gavin Mulholland wrote:
I apologise
Gavin Mulholland wrote:
Styles give a sense of belonging and confirmation i.e. “our style does not suffer from the flaws that other styles do”. To say that there are “styles within styles” and that good karate is good karate, bad karate is bad karate, and styles are not trusted definitions of either good or bad, undermines that.
If you have a Shotokan guy, for example, who has bought into the idea that his style is all about long deep stances, and that such stances are always needed to generate power (none of which is true) they could view fluid motion relative to the circumstance as being “not Shotokan”; and hence in their desire to “be Shotokan” they will uphold, support and further the Shotokan stereotype.
However, you’ll also have guys who perhaps better understand stance and the initial Shotokan training methodology who will hold the other view and state that “always low and always static” is not Shotokan. We then get into the age old argument of what the “true Shotokan is”. The bottom line though is that “Shotokan” is both those things and both not those things; depending on who you ask. And let’s not forget that the Funakoshi himself did not want to be called “Shotokan” and strongly objected to “this attempt at classification” (Karate-Do: My Way of Life).
It all gets very confusing and the style terminology becomes, from my perspective, less and less meaningful the more closely it is examined.
Styles are still good for a few gags and wind-ups and the seminars though :-) For example, “ OK, so let’s all try the Shotokan variation … I know it will make you feel unclean but you can always shower afterward”. Or, “ So if we compare the techniques we can see how Bill did it the Shito-Ryu way. Bob did it the Goju-Ryu Way . And I did it right”. And so on. The point I always earnestly make though is that good karate is good karate and no one style has a monopoly on that.
All the best,
Iain
All true.
Dom
Maybe it's not the style that is the shortcoming, although I would suggest it is. Maybe it is an understanding of technique within the style of the man?
Can any definition fit any style anymore?There are a recorded 75 styles claiming to be shotokan all headed by either original students of FUNAKOSHI or those who came shortly after.You study shotokan whose shotokan?It is likely the same could be said of all the founding ryu.
vic
Kyokushinkai, last year I trained with a local class and really enjoyed the full contact sparring and also the different versions of the pinnan kata's. This club also practiced the seated defences as shown in Funakoshi's Kararte Do Kyohan which was also very interesting to practice.
| https://iainabernethy.co.uk/comment/2171 |
Angiotensin-I converting enzyme fatty acid inhibitory fractions from the Korean melania snail Semisulcospira coreana | Request PDF
Request PDF | Angiotensin-I converting enzyme fatty acid inhibitory fractions from the Korean melania snail Semisulcospira coreana | The angiotensin-I converting enzyme (ACE) inhibitory activity of Semisulcospira coreana was investigated. Crude CH2Cl2 and MeOH extracts showed... | Find, read and cite all the research you need on ResearchGate
Angiotensin-I converting enzyme fatty acid inhibitory fractions from the Korean melania snail Semisulcospira coreana
DOI: 10.1007/s10068-015-0089-9
Abstract
The angiotensin-I converting enzyme (ACE) inhibitory activity of Semisulcospira coreana was investigated. Crude CH2Cl2 and MeOH extracts showed 59.3 and 25.6% ACE-inhibitory activities at 5 mg/mL, respectively. After 2 phase separations including n-hexane, 85% aqueous MeOH, n-BuOH, and H2O, the 85% aq. MeOH fraction exhibited the highest ACE-inhibitory activity of 62.1%. The inhibitory activity of 85% aq. EtOH subfraciton 5 (merf5) partially purified using C18 reversed-phase flash chromatography was increased up to 94.6% at 0.5 mg/mL. Typical fatty acids signals observed in 1H NMR and gas chromatography analysis of merf5 and n-BuOH subfractions 6 (burf6) indicated that components of merf5 and burf6 included fatty acids. The fatty acid fractions from S. coreana act as novel ACE inhibitors.
[39]
who found that both SFAs and UFAs from Semisulcospira coreana lipid extracts were involved in ACE inhibitory activities with IC50 values of 0.1 to 0.5 mg/mL. In the literature, the ability of FAs to inhibit ACE activity correlated with high levels of MUFAs and PUFAs such as EPA, DHA, ARA, GLA (gamma-linolenic acid), and LA (linoleic acid) [7]. ...
Lipid Profile, Antioxidant and Antihypertensive Activity, and Computational Molecular Docking of Diatom Fatty Acids as ACE Inhibitors
Article
Full-text available
Jan 2022
Jeeraporn Pekkoh
Kittiya Phinyo
Theera Thurakit
Sirasit Srinuanpan
Diatoms, as single cell eukaryotic microalgae, are rich sources of lipids, which have either beneficial or detrimental effects on the prevention and treatment of many diseases. Gas chromatography-mass spectrometry (GC-MS) identified diatom lipids with high levels of essential fatty acids (EFAs), especially polyunsaturated FAs (PUFAs) containing both omega-3 and omega-6. Nutritional values of FAs indicated possible applications in the pharmaceutical, nutraceutical, and functional food industries. Diatom FAs showed antioxidative potential on harmful radicals by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2’-azino-bis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) scavenging, with high inhibition of the angiotensin-converting enzyme (ACE) that causes cardiovascular disease (CVD) and hypertension. A computational molecular docking simulation confirmed the inhibition mechanisms of FAs on ACE, with comparable levels of binding free energy to chemically synthesized ACE drugs. Findings suggested that diatom lipids showed potential for use as alternative ACE inhibitors or food supplement for CVD prevention.
First de-novo transcriptome assembly, annotation and expression profiles of a freshwater snail (Semisulcospira coreana) fed with chlorella supplement
Article
Feb 2019
MAR GENOM
Sang Yoon Lee
Lee Sangmin
Kim Yikyung
The aim of this study was to develop the transcriptome resource of Semisulcospira coreana that would support development of commercial feeds and physiological studies. We compared mRNA expression in S. coreana to determine gene transcripts that were differentially regulated responding two feeding conditions (with or without chlorella). A total of 13.1 G raw reads were obtained and assembled using the CLC Genomics Workbench v 11.0, resulting in 134,402 transcripts with an average length of 694 bp and N50 of 1058 bp. Subsequently, we performed functional gene annotations using BLASTx NR, Gene Ontology (GO), InterProScan, and Kyoto Encyclopedia of Genes and Genomes (KEGG). We identified differentially expressed antioxidant-related genes and chlorophyllase (CLH) between the control and experimental groups. This data provides the first insight into the physiological response of S. coreana to chlorella ingestion at the transcriptome level and will be the basis for the study of S. coreana gene resources.
Mechanism study of multimode ultrasound pretreatment on the enzymolysis of wheat gluten
Article
Full-text available
Aug 2017
Yanyan Zhang
Jing Li
Suyun Li
Hua Zhang
Background:
Ultrasound pretreatment could improve the angiotensin-I converting enzyme (ACE) inhibitory activity of hydrolysates of wheat gluten (WG). The working mode of ultrasound has an important effect on the enzymatic hydrolysis of protein.
Results:
The results showed that the optimum working mode of ultrasound was alternate dual-frequency mode (20/35 kHz), substrate concentration was 30 g L(-1) , initial temperature of the suspension was 30 °C, ultrasound pretreatment time was 10 min and power density was 150 W L(-1) . Under optimized conditions, ACE inhibitory activity of WG hydrolysates reached to its maximum value in advance. The H0 of WG and the content of small peptides at the beginning of the enzymolysis were improved by the ultrasound pretreatment. The structure of WG was destroyed by the ultrasound pretreatment. The enzymatic residue of ultrasound pretreated WG were damaged greater than control.
Conclusion:
It was concluded that alternate dual-frequency ultrasound pretreatment improved the ACE inhibitory activity. Ultrasonic pretreatment may loosen the tissue of WG aggregate, and help the enzyme alcalase to attack the interior of WG aggregate easily, which resulted in the release of low molecular weight peptides from WG aggregate.
ACE Inhibitory and Antihypertensive Effect of Chitosan Oligosaccharides in SHR
Article
Jan 1998
Sang-Pill Hong
Myung-Hee Kim
Se Wook Oh
Yong-Hyun Kim
Effect of chitosan oligosaccharides on the ACE (angiotensin I converting enzyme) inhibition and antihypertension in SHR (Spontaneously hypertensive rat) was examined. The ACE inhibition activity was observed in all the chitosan oligosaccharides used in this study, and chitosan trimer exhibited the highest inhibitory activity compared with other chitosan oligosaccharides . The results suggested that chitosan trimer was a good inhibitor of ACE in molecular level. When the single oral dose (2.14 mg/kg, similar to dose level of Captopril, known as strong ACE inhibitor) of chitosan trimer was given to 8 or 21 week aged SHR, the blood pressure reduction of both SHRs in 4hrs were , respectively. Therefore, it was suggested that chitosan trimer could be applicable as natural ACE inhibitor related to antihypertension.
| https://www.researchgate.net/publication/276929091_Angiotensin-I_converting_enzyme_fatty_acid_inhibitory_fractions_from_the_Korean_melania_snail_Semisulcospira_coreana |
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SCHUMER, GILLIBRAND, SLAUGHTER ANNOUNCE MONROE COMMUNITY COLLEGE SECURES $550,000 TO MAKE COLLEGE A TOP PHOTONICS TRAINING CENTER - New York Photonics
New York Photonics has been working on getting this designation for over 10 years. It wasn't until Professor Alexis Vogt, PhD came to MCC that it began to move…
SCHUMER, GILLIBRAND, SLAUGHTER ANNOUNCE MONROE COMMUNITY COLLEGE SECURES $550,000 TO MAKE COLLEGE A TOP PHOTONICS TRAINING CENTER
In Manufacturing , New York Photonics , New York State Optics , Optics , Workforce Development News
Tag NYPhotonics
New York Photonics has been working on getting this designation for over 10 years. It wasn’t until Professor Alexis Vogt, PhD came to MCC that it began to move forward. Thank you, Alexis!
SCHOOL AIMS TO MEET GROWING DEMAND FOR SKILLED WORKERS IN UPSTATE NEW YORK
Monroe Community College (MCC), The Only Community College In The Nation Offering An Optics and Photonics Associates Degree, Needed Federal Funds To Expand Facilities, Meet Regional Need For Trained Workers
Over $500K from National Science Foundation (NSF) Is First Step Towards Making MCC the Northeast Regional Center for Optics and Photonics; Schumer, Gillibrand, Slaughter Urged Feds To Approve Funds That Would Support New Equipment, Curriculum & Recruitment
Schumer, Gillibrand, Slaughter: Critical Fed Funds Will Help Build on MCC’s Proven Success in Optics and Photonics
U.S. Senate Minority Leader Charles E. Schumer, Senator Kirsten Gillibrand, and Congresswoman Louise Slaughter (NY25) today announced the National Science Foundation’s (NSF) Advanced Technology Foundation’s Education program has awarded $550,434 for Monroe Community College (MCC). The funding will allow MCC to expand its optics and photonics degree programs, purchase new equipment, as well as develop a new curriculum and expand student outreach. Optics and photonics involves the science and application of light and are key to many industries including manufacturing, telecommunications and medicine.
“MCC is a proven leader in optics and photonics training, and we have an opportunity here to build on that success by creating a top-notch training center that will prepare Upstate New Yorkers for good-paying, middle-class jobs in this burgeoning field,” said Senator Schumer. “This five hundred thousand will enable MCC to expand its optics and photonics degree programs, update its equipment, and put it on track to become the Northeast Regional Center for Optics & Photonics. This grant is the first step in creating a regional center that will ensure all of New York and the entire Northeast has the workforce it needs to attract, build and sustain a strong photonics industry.”
“This federal funding is great news for Monroe Community College and for the entire Rochester community,” said Senator Kirsten Gillibrand . “The Rochester area is already at the center of the American optics and photonics industries, and these funds will help secure MCC’s position as a leading training center for students who want good-paying jobs in these fields. I will continue to do everything I can to make sure our students are prepared to take on the good-paying jobs of the future.”
“We have fought hard these last few months to ensure the National Science Foundation understood the important impact this federal award could have in helping train the next generation advanced manufacturing workforce.” SaidCongresswoman Louise Slaughter.“It was truly a team effort that would not have been possible without the work of Alexis Vogt and the extraordinary leadership of President Kress. I’m proud to have stood with Monroe Community College in support of their proposal every step of the way. This federal award will help Monroe County continue to lead the world in optics and photonics,” said Slaughter.
MCC is currently the only community college in the U.S. with an optics and photonics associate’s degree program, and is looking to become a major training center for this burgeoning field. Schumer, Gillibrand said that MCC hopes to ultimately become the “Northeast Regional Center for Optics & Photonics,” and this federal funding will help start make that expansion possible.
L to R: student Mark Smith; Professor Bill Strong; Professor Alexis Vogt, PhD; MCC President Anne Kress; Congresswoman Louise Slaughter
Additionally this NSF grant is the first step in MCC reaching that goal of becoming a center for photonics training and, eventually, middle-class job growth in this growing industry. Schumer explained that there are currently over 120 optics, photonics and imaging companies that employ over 24,000 people across the Finger Lakes, Southern Tier and Central New York regions. Schumer, Gillibrand said this federal funding would help provide training for over 800 area high school and college students through the proposed OPT IN! program. Schumer said that OPT IN! would put Rochester area students in the best possible position to pursue higher education and compete in the job market. Not only would it allow high school students to earn college credits, Schumer argued that OPT IN! would make it easier for non-traditional students, such as veterans, to transfer from MCC to four-year universities and to complete critical student internships. The grant would also allow MCC to develop new and revised curriculum, and expand online education. Finally, Schumer explained that OPT IN ! would broaden industry and community partnerships aimed at recruitment and education about optics and photonics as a career option.
Dr. Alexis Vogt, Endowed Chair & Associate Professor of Optics at Monroe Community College said, “We are very appreciative of the Senators’ support to help us win this grant. We are now on our way to making Monroe Community College the home of the Northeast Regional Center for Photonics & Optics. This grant to allow MCC to strengthen our region’s optics and photonics workforce and provide students here with employment opportunities in regional high skill, high demand positions. Ultimately this funding gives us the foundation to begin creating a regional center that will ensure all of New York and the entire Northeast has the workforce it needs to attract, build and sustain a strong photonics industry.”
The photonics and optics industry is central to the New York State economy and the Rochester area in particular. According to the Rochester Regional Photonics Cluster (RRPC), these companies generate $3 billion in revenue per year, and support 1-in-14 households in Monroe County. In addition to the one-of-a-kind program at MCC, Rochester is home to the University of Rochester’s Institute of Optics, and the Laboratory for Laser Energetics at Rochester Institute of Technology. Statewide, New York universities educate 60 percent of the nation’s optics Ph.Ds.
Schumer, Gillibrand has long championed optics and photonics in the Rochester area. Earlier this year, Schumer, Gillibrand announced that the NSF awarded a $2 million dollar grant to the University of Rochester’s photonics research program. These funds created new opportunities for AIM Photonics Center outreach in the Rochester community. The University of Rochester was able to create K-12 education materials to teach students about photonics and optics.
A copy of Senator Schumer’s October 2016 letter to the National Science Foundation Director appears below:
Dear Director Cordova,
I am pleased to write in strong support of Monroe Community College (MCC) grant application to the National Science Foundation’s (NSF) Advanced Technological Education (ATE) program to enable MCC to expand its optics and photonics education and training program so that MCC can train more students to fill available high skill, high demand positions at local and regional employers. Currently MCC is the only college in the nation that offers an associate degree program in optics, and yet, in the Rochester region there are now more job openings for these positions than there are graduated students ready to fill these openings. Thus, MCC’s proposal, named the Optics & Photonics Technology INnovation-OPT IN!, will expand MCC’s work by first expanding and enriching its curriculum to train students for today’s cutting-edge photonics fields, and secondly by linking with secondary schools, universities, and employers to create a seamless pipeline for more students to seek a career in photonics.
Currently more than 120 optics, photonics, and imaging companies employ over 24,000 people across the Finger Lakes, Southern Tier and Central New York regions. With an anticipated 3.3% annual employment growth and a workforce that is approaching retirement, the need for skilled optics technicians is outpacing the number of graduates who are prepared to fill positions. Beyond the specific workforce needs of these existing companies, demand for skilled photonics worker will grow further with the establishment in 2015 of the Rochester, NY headquartered federal American Institute for Manufacturing Integrated Photonics (AIM Photonics).
To grow the optics and photonics workforce, the proposed OPT IN! program will impact 850 high school and college students including underrepresented, non-traditional students like our growing veteran student population to help them advance their careers. MCC would expand dual enrollment opportunities for high school students, 2+2 and transfer linkages to four-year universities, student internships, and faculty professional development. Furthermore the program would develop new and revised curriculum, including online curriculum, at MCC’s Optical Systems Technology program to meet current industry standards. And by broadening industry and community partnerships it will foster recruitment, retention, and outreach activities to promote the awareness of optics and photonics as career option.
Again, I am pleased to write in support of this win-win proposal that aims to meet both the needs of a student population seeking the skills needed to gain a career in a high tech industry and for the needs of existing photonics businesses seeking new employees to fill current and future job openings. I appreciate your consideration of this proposal.
Sincerely,
Charles E. Schumer United States Senator
A copy of Congresswoman Slaughter’s October 2016 letter to the National Science Foundation Director appears below:
Dear Director Cordova,
I am writing to express my support for Monroe Community College’s (MCC) proposal entitled “Optics and Photonics Technology Innovation – OPT IN” to the National Science Foundation’s (NSF) Advanced Technological Education (ATE) program.
Starting in 1963, MCC became the first educational institution in the country to offer a two – year Associates degree in optics and continues to set a national example in optics education. Under the leadership of Professor Alexis Voigt, MCC is pursuing two objectives through this proposal: First, MCC will strengthen the existing optics program by updating the curriculum to meet industry needs, including adding an online format to accommodate students balancing employment. The program will also prepare regional high school teachers to teach an “Introduction to Optics” course which will expose younger students to optics and provide them an opportunity to launch an early career. Secondly, I’m pleased this proposal is increasing the program’s outreach efforts to populations underrepresented in the optics industry, such as Women and minorities.
Located within the largest optics and photonics manufacturing region in the world, MCC Optics is playing a central role in providing a qualified workforce to strengthen our nation’s competitiveness in high tech manufacturing. The Rochester region recently secured the federally supported $600 million American Institute for Manufacturing Integrated Photonics (AIM Photonics) that will bring together experts from government, industry, and academia to work together on solving common problems in photonics manufacturing. This collaboration will result in improved technology for our military and spur job creation through the commercialization of new discoveries. These important efforts are sustained by workforce development programs, like MCC Optics, that are producing the qualified workforce needed to keep up with industry demands.
Throughout its history, MCC Optics has demonstrated success in providing students the foundation they need for a productive career in optics while also making significant contributions to the region’s economy. I am proud of the work MCC Optics has done and encourage your full consideration of this proposal.
Sincerely,
Louise M. SlaughterMember of Congress
| https://newyorkphotonics.org/2017/04/21/schumer-gillibrand-announce-monroe-community-college-secures-550000-to-make-college-a-top-photonics-training-center/?ajaxCalendar=1&id=276958139&yr=2023 |
MPRI, Division of L-3 Services, Inc.; LINC Government Services | U.S. GAO
MPRI, Division of L-3 Services, Inc., of Alexandria, Virginia, and LINC Government Services (LGS), of Hopkinsville, Kentucky, protest the award of a...
MPRI, Division of L-3 Services, Inc.; LINC Government Services
B-402548,B-402548.2,B-402548.3,B-402548.4,B-402548.5,B-402548.6 Jun 04, 2010
Highlights
MPRI, Division of L-3 Services, Inc., of Alexandria, Virginia, and LINC Government Services (LGS), of Hopkinsville, Kentucky, protest the award of a contract by the Department of the Army, U.S. Army Materiel Command, to DynCorp International, LLC, of Falls Church, Virginia, under request for proposals (RFP) No. W91CRB-09-R-0009, for Combined Security Transition Command-Afghanistan (CSTC-A), Afghanistan Ministry of Defense (MoD), and Afghan National Army (ANA) mentoring and program support. The protesters challenge the evaluation of proposals.
We sustain MPRI's protest and deny LGS's protest.
View Decision
B-402548; B-402548.2; B-402548.3; B-402548.4; B-402548.5; B-402548.6, MPRI, Division of L-3 Services, Inc.; LINC Government Services, June 4, 2010
DOCUMENT FOR PUBLIC RELEASEThe decision issued on the date below was subject to a GAO Protective Order. This redacted version has been approved for public release.
Decision
Matter of:MPRI, Division of L-3 Services, Inc.; LINC Government Services
File:B-402548; B-402548.2; B-402548.3; B-402548.4; B-402548.5; B-402548.6
Date:June 4, 2010
W. Jay DeVecchio, Esq., Kevin C. Dwyer, Esq., Daniel E. Chudd, Esq., Joshua L. Kaul, Esq., Michael W. Khoo, Esq., and Jason P. Mehta, Esq., Jenner & Block, for MPRI, Division of L-3 Services, Inc.; Joan Kelley Fowler Gluys, Esq., John C. Dulske Esq., and Bryan L. Kost, Esq., Dulske & Gluys, for LINC Government Services, the protesters.
Richard J. Vacura, Esq., Keric B. Chin Esq., and K. Alyse Latour, Esq., Morrison & Foerster, for DynCorp International, LLC, an intervenor.
Debra J. Talley, Esq., and David Scott, Esq., Department of the Army, for the agency.
David A. Ashen, Esq., and John M. Melody, Esq., Office of the General Counsel, GAO, participated in the preparation of the decision.
DIGEST
Protest of cost realism evaluation is sustained where, although agency reasonably determined that protester had failed to adequately support its proposed substantial reduction in labor rates relative to those under its incumbent contract, the extent of the agency's resulting upward adjustment in the labor rates was unreasonable.
DECISION
MPRI, Division of L-3 Services, Inc., of Alexandria, Virginia, and LINC Government Services (LGS), of Hopkinsville, Kentucky, protest the award of a contract by the Department of the Army, U.S. Army Materiel Command, to DynCorp International, LLC, of Falls Church, Virginia, under request for proposals (RFP) No. W91CRB-09-R-0009, for Combined Security Transition Command-Afghanistan (CSTC-A), Afghanistan Ministry of Defense (MoD), and Afghan National Army (ANA) mentoring and program support. The protesters challenge the evaluation of proposals.
We sustain MPRI's protest and deny LGS's protest.
The solicitation contemplated the award of a cost-plus-fixed-fee contract, with a 2'month phase-in, a base period of 2 years, and 1 option year, for the services of qualified personnel to provide dedicated in-depth mentoring, training, subject matter expertise, and programmatic support to CSTC-A staff and the Afghan MoD for the purpose of assisting the MoD and associated Afghan National Army (ANA) forces in assuming full responsibility for their own security needs. Specifically, the solicitation statement of work (SOW) required the contractor to provide personnel to augment military personnel in the Combined Training Assessment Group in assisting ANA in developing programs of instruction; support Task Force Phoenix in mentoring ANA corps and division headquarters; "develop the positions of Minister of Defense, the 1st Deputy Minister, the Chief of the General Staff, the Vice Chief of the General Staff, and the Director of the General Staff and support the individual[s] in the execution of [their] duties"; and mentor and support the ANA in such areas as logistics, intelligence, personnel, military medicine, strategy and policy, operations and communications. SOW sect. VI. In total, the SOW provided for the contractor to provide 275 staff in 5 skill levels or categories, including senior mentor (8 staff), mentor (128), subject matter expert (32), senior trainer (30), and trainer (77), each with specified minimum educational and experience qualifications.
Award was to be made on a "best value basis" considering four evaluation factors: (1) capability (with subfactors for key personnel, management plan, technical approach, quality control and transition plan); (2) performance risk, under which the offeror's past performance was to be evaluated; (3) small business participation; and (4) cost. The capability factor was significantly more important than the remaining factors combined, while the non-cost factors, when combined, were significantly more important than cost.
Five proposals were received. Based on the initial proposals and offerors' oral presentations, the results of the evaluation for the awardee and the two protesters here, were as follows:
DynCorpMPRILGSCAPABILITYExcellentAcceptableGoodKey PersonnelExcellentAcceptableExcellentManagementExcellentAcceptableGoodTechnical ApproachExcellentExcellentAcceptableQuality ControlExcellentGoodGoodTransitionGoodGoodGoodPERFORMANCE RISKLowLowLowSMALL BUSINESSLowModerateModeratePROPOSED COST$[REDACTED]$[REDACTED]$[REDACTED]EVALUATED COST$249.1 million$212.7 Million$235.7 million
Source Selection Decision (SSD) at 2, 8; Source Selection Evaluation Board (SSEB) Report at 3.
DynCorp's proposal was determined to be excellent under the capability evaluation factor. DynCorp, whose experience included contracts to mentor and advise the Iraq Ministries of Defense and Interior, and Iraq Counterterrorism Task Force (Multi-National Security Transition Command-Iraq (MNSTC-I) contract), the Afghanistan national, border, and civil order police (CIVPOL Afghanistan Civilian Advisor Support (CIVPOL-A)), and Iraqi civil police (CIVPOL Iraq Civilian Advisor Support (CIVPOL-I)), received an excellent rating under key personnel on the basis that the "experience of its key personnel in similar environments in Iraq, and those with experience in Afghanistan, indicates that it has a strong understanding of the problems that will be faced supporting CSTC-A." SSD at 4. For example, the agency noted that DynCorp's proposed project manager (PM) was the PM for the DynCorp's MNSTC-I Iraqi security forces mentoring contract, while the caliber of DynCorp's key personnel overall significantly exceeded the requirements as clearly shown through "a career progression in their resumes highlighting their relevant experience."
Id.
DynCorp's proposal likewise received an excellent management plan rating based on the finding that its approach offered such strengths as a demonstrated ability to staff the contract (as shown by a letter of intent, furnished during the oral presentation) for every position under the SOW and its partnership with a recruiting firm; a [REDACTED]. DynCorp's excellent technical approach rating was based on its demonstrating how it would meet the SOW requirements for each staff section; its linking key personnel and their relevant experiences to specific staff functions; and its highlighting experience and successes in similar missions in Iraq, Afghanistan and Liberia, thereby demonstrating an understanding of and ability to accomplish the CSTC-A mission. DynCorp's excellent quality control rating was based on its offering a [REDACTED] and approach to continuously improving performance by systematically measuring and analyzing various performance metrics. Finally, DynCorp's good transition plan rating was based in part on its having a transition team ready to deploy within 72 hours of notice to proceed.
MPRI is the incumbent contractor providing these services. While MPRI's proposal initially received an overall good rating under the capability factor, as well as good ratings under the key personnel and management plan subfactors, these ratings were ultimately downgraded to acceptable on the basis of agency concerns arising from MPRI's proposal of a significant reduction in direct labor rates relative to those under its incumbent contract. In this regard, the Army determined that "[a]ll proposed [MPRI] Key Personnel have significant experience in Muslim environments, and they possess knowledge of the CSTC-A mission." SSD at 8. Further, while the agency questioned under the management plan factor MPRI's proposal to use five of the eight senior mentors as only group leads, rather than in a dual'hatted capacity that would also use them to mentor Afghan officials, the agency nevertheless initially rated MPRI's management plan as good. However, MPRI proposed to reduce its direct labor rates from the current rates under its incumbent contract by between [REDACTED]% percent (for 8 senior mentors) and [REDACTED]% (for 126 mentors), resulting in an overall weighted average reduction of approximately [REDACTED]%. Joint Agency/DynCorp Comments, May 24, 2010, attach. 6. Although MPRI in its proposal generally attributed its proposed reduction in compensation to "updating salaries based on the current market conditions," MPRI Cost Proposal at IV-3, the Army determined that MPRI had "grossly underestimated" its labor costs such that a "direct labor cost growth of approximately [REDACTED]% would occur" as MPRI was forced to increase its labor compensation to the current levels under its incumbent contract. SSD at 8. As noted above, not only did the agency adjust MPRI's evaluated costs upward to account for the expected cost growth in this regard, but in addition, the agency downgraded MPRI's proposal under the capability evaluation factor on the basis that "any attempt by MPRI to execute its Capability proposal for the Costs it proposed" would result in MPRI experiencing "high turnover, a lack of qualified personnel, and/or be[ing] forced to work with personnel of lesser qualifications than those proposed," resulting in a "high risk of performance disruptions, significant lapses in quality of performance, or outright performance failure." SSD at 8.
The downgrading of MPRI's proposal under the key personnel and management plan subfactors resulted in the overall reduction to acceptable under the overall capability factor. MPRI's proposal otherwise received an excellent rating under the technical approach subfactor on account of its exhibiting a "clear understanding of the CSTC-A mission" and including a clear description of how MPRI would perform the SOW; a good rating under the quality control subfactor (notwithstanding the lack of a dedicated quality control manager) on account of such strengths as its tailored quality control process measuring individual and program performance, weekly activity reports to CSTC-A allowing rapid resolution of problem areas, and an annual work plan for each employee and section; and a good rating under the transition subfactor. SSD at 8-9; SSEB Report at 27-31.
LGS's proposal received an overall good rating under the capability factor. LGS's proposal received an excellent rating under the key personnel subfactor on account of the experience of its key personnel in similar environments in Iraq and in Afghanistan, including, for example, its program manager, a retired general officer with two combat tours in Iraq. While LGS's proposal received a good rating under the management plan subfactor on account of such strengths as the program manager being empowered to make decisions and commit corporate resources and a [REDACTED], it received only an acceptable rating under the technical approach subfactor as a result of an evaluated failure to adequately describe its process for mentoring Afghan personnel, substituting instead an over-reliance on prior military experience. LGS's proposal also received good ratings under the quality control subfactor, on account of its [REDACTED], and a good rating under the transition subfactor.
All three of these proposals received low performance risk ratings and acceptable small business subcontracting ratings. Although DynCorp's evaluated cost ($249.1 million) was significantly higher than MPRI's ($212.7 million), the source selection authority (SSA) determined that DynCorp's proposal was "vastly superior" under the capability factor, noting in particular the "inherent risk" in MPRI's proposed reduction in salaries and the fact that five of its eight senior mentors will serve only as team leaders and not also as mentors to Afghan officials. The SSA determined that these considerations outweighed MPRI's lower cost. SSD at 18'20. Likewise, the SSA determined that DynCorp's superiority under the capability factor, including a strong corporate knowledge of and experience in similar mentoring, in contrast to LGS's over-reliance on its leaders' military background, and DynCorp's existing relationship with its subcontractors, offset its higher cost. SSD at 16-17. The agency thus made award to DynCorp, following which MPRI and LGS filed these protests challenging the evaluation.
DISCUSSION
In reviewing protests relating to an agency's evaluation of proposals, we will not reevaluate the proposals; rather, we will review the record to ensure that the evaluation was consistent with the terms of the solicitation and applicable statutes and regulations.
Dell Mktg. LP
, B-400784, Jan. 27, 2009, 2009 CPD para. 35 at 3. We have considered all of MPRI's and JGS's arguments and find that only MPRI's challenge to the evaluation of its labor rates furnishes a basis upon which to question the award to DynCorp. We discuss the protesters' principal arguments below.
Labor Rates
MPRI challenges the agency's cost realism analysis, which resulted in an upward adjustment in its proposed labor rates.
When an agency evaluates proposals for the award of a cost-reimbursement contract, an offeror's proposed costs are not considered controlling because, regardless of the costs proposed, the government is bound to pay all actual, allowable costs. Federal Acquisition Regulation (FAR) sections 15.305(a)(1); 15.404-1(d). Consequently, an agency must perform a cost realism analysis to determine the extent to which an offeror's proposed costs represent what the contract should cost, assuming reasonable economy and efficiency. FAR sect. 15.404'1(d)(2);
Information Ventures, Inc.
, B-297276.2
et al.
, Mar. 1, 2006, 2006 CPD para. 45 at 7;
Hanford Envtl. Health Found.
, B-292858.2, B-292858.5, Apr. 7, 2004, 2004 CPD para. 164 at 8-9. An agency's cost realism analysis requires the exercise of informed judgment, and we will review this judgment only to see that it was reasonable.
Information Ventures, Inc.
,
supra
;
Hanford Envtl. Health Found.
,
supra
. While a realism analysis need not achieve scientific certainty, the methodology employed must provide some measure of confidence that the agency's conclusions about the most probable costs under an offeror's proposal are reasonable and realistic.
Information Ventures, Inc.
,
supra
;
see
Metro Mach. Corp.
, B-295744; B'295744.2, Apr. 21, 2005, 2005 CPD para. 112 at 10-11. Here, we find that the Army's cost realism analysis was not reasonable, and that it resulted in an excessive upward adjustment to MPRI's proposed labor rates.
The record shows that the agency initially reviewed offerors' proposed labor rates for discrepant rates by comparing them to a range of rates for each position calculated based on one standard deviation (OSD) from the average of the five offerors' proposed rates for the position. The agency then further reviewed the rates based on the circumstances of each offeror, adjusting some, but not all, of the rates outside the range, as well as some, but not all, of the rates within the range. The proposed and evaluated rates for the first contract year are set forth below:
Senior Mentor(8 staff)Mentor(128 staff)Subject Matter Expert(32 staff)Senior Trainer(30 staff)Trainer(77 staff)MPRI Proposed/ Evaluated[REDACTED][REDACTED][REDACTED][REDACTED][REDACTED]DynCorp Proposed/ Evaluated[REDACTED][REDACTED][REDACTED][REDACTED][REDACTED]LGS Proposed/ Evaluated[REDACTED][REDACTED][REDACTED][REDACTED][REDACTED]Offeror A Proposed/ Evaluated[REDACTED][REDACTED][REDACTED][REDACTED][REDACTED]Offeror B Proposed/ Evaluated[REDACTED][REDACTED][REDACTED][REDACTED][REDACTED]Average Proposed$35.49$31.49$29.65$27.83$25.72OSD Range$33.02-37.97$28.51-34.46$27.17-32.13$24.99-30.66$23.07-28.38
Cost Realism and Price Analysis Report at 3-15.
As shown by the chart, MPRI's proposed labor rates for [REDACTED] of the labor categories ([REDACTED]) were lower than the OSD range the agency considered realistic, accounting for [REDACTED] of 275 required staff as specified in the SOW. MPRI attributed the rate reduction--on average approximately [REDACTED] percent as compared to its incumbent contract--to "updating salaries based on the current market conditions." MPRI Cost Proposal at IV-3. Based on its realism analysis, the agency determined that the reduction was not justified and adjusted MPRI's rates for all five labor categories upward to the rates under MPRI's current Afghanistan mentoring contract. This actually left three of the five resulting rates higher than the OSD range.
Likewise, notwithstanding that all of DynCorp's proposed rates were within the OSD range, the Army adjusted the rates for all five categories--four upward and one downward--to the levels under DynCorp's MNSTC-I contract (for mentoring of Iraq security forces), which the agency determined to be similar "in customer, scope, and function to the CSTC'A effort." Cost Realism and Price Analysis Report at 7. While LGS's proposed labor rates for [REDACTED] labor categories were above the OSD range, all were accepted without modification for purposes of the cost realism evaluation on the basis that "LGS's hourly wages are competitive and are held to be sufficient."
Id.
at 8. As for Offeror B, "[n]o exceptions were taken to the rates proposed by [Offeror B]. In its common labor categories, all rates are well within the standard deviation range."
Id.
at 14. Finally, although four of Offeror A's five proposed rates fell within the OSD range, its rates were adjusted upward to the levels under MPRI's current contract based on the indication in its proposal that Offeror A "expect[ed] to recruit most, if not all, incumbents, because we will offer to match their current compensation if higher than proposed."
Id.
at 4.
MPRI asserts that the agency unreasonably failed to consider whether MPRI could achieve its proposed rates, and that the adjustment unreasonably increased MPRI's rates above the OSD range and the rates calculated for other offerors.
As an initial matter, we find the agency's rejection of MPRI's proposed labor rates as unsupported to be reasonable. An offeror has the burden of submitting an adequately written proposal, and it runs the risk that its proposal will be evaluated unfavorably when it fails to do so.
Recon Optical, Inc.
, B-310436, B-310436.2, Dec. 27, 2007, 2008 CPD para. 10 at 6. MPRI's proposal generally attributed the [REDACTED]% reduction in its incumbent labor rates to "current market conditions," MPRI Cost Proposal at IV-3, but included no information regarding current market conditions. Further, MPRI's proposed rates not only were significantly lower than its current rates for the same work, but also were significantly lower (by a weighted average of approximately [REDACTED]%) than the rates under DynCorp's MSNTC-I contract (which, as noted, the agency considered to be similar to the current requirement). Finally, MPRI's proposed rates were lower than the average of all offerors' proposed rates for [REDACTED] labor categories; lower than the OSD range for [REDACTED] labor categories, accounting for [REDACTED] of 275 required staff; lower than all of the other proposed rates for the [REDACTED] labor categories; and lower than [REDACTED] of the other proposed rates for [REDACTED].
While we find that the agency reasonably rejected MPRI's proposed labor rates as unrealistc, we agree with MPRI that the extent of the resulting upward adjustment in the rates was unreasonable. In this regard, we review an agency's conclusions about the most probable costs under an offeror's proposal in view of the cost information reasonably available to the agency at the time of its evaluation.
Information Ventures, Inc.
,
supra
;
see
Metro Mach. Corp.
,
supra
. In increasing MPRI's labor rates to the level under its current contract, thereby rejecting any reduction, the agency's realism evaluation assumed rates for MPRI that were higher than the average proposed rate for each of the labor categories; higher than the OSD range for three of the five labor categories; higher than the rates proposed by any offeror for three of the labor categories; and higher than the rates proposed by three of the other offerors for the remaining two categories. The adjusted rates for MPRI also were higher than the rates for three of the five labor categories under DynCorp's similar MSNTC-I contract, which rates DynCorp itself proposed to reduce for this procurement. In some instances, the adjustment left MPRI's rates significantly higher than these other reference points; for example, for the mentor category (128 of 275 required staff), the adjusted rate for MPRI was $[REDACTED], while DynCorp's proposed rate was $[REDACTED] and its MNSTC-I contract rate was $[REDACTED], the average proposed rate was $31.49, and the OSD range was $28.51-$34.46.
The significance of these reference points in determining the realism of MPRI's evaluated rates is highlighted by testimony at the hearing conducted by our Office in this matter, indicating that the SSA and the agency cost analyst performed no analysis of trends in compensation for foreign nationals in Afghanistan and, indeed, were unaware of the rates currently being paid (including those under DynCorp's civilian police mentoring contract) in Afghanistan other than those under MPRI's incumbent contract. Transcript (Tr.) at 78-82, 94, 494-96, 508. In this regard, when asked what the most probable labor rates would be for foreign nationals in Afghanistan, the cost analyst responded that "competition generally dictates what a reasonable price is," that the "market rates" were determined by competition, and that the average of the rates proposed by the five offerors thus represented "a reasonable starting point." Tr. at 514-16, 558-60. The cost analyst then went on to state that MPRI's current contract rates did not represent "the market rates." Tr. at 513. Further, testimony by the chairman of the SSEB (a senior mentor in Afghanistan)--that the offerors were expecting to draw their staff from "a limited number of people, some [of whom] are already doing the same work in Afghanistan, some [of whom] were doing the same work in Iraq . . . ," Tr. at 579-80, 587-88--suggests that there would be no reason to expect widely disparate rates among offerors, since they all are drawing from the same pool of potential employees. We conclude that the record does not support the magnitude of the upward adjustments to MPRI's proposed labor rates, and that the cost evaluation therefore was unreasonable.
MPRI also challenges the downgrading of its technical proposal under the capability factor based on the cost evaluation conclusions. Again, the Army determined that MPRI had "grossly underestimated" its labor costs such that a "direct labor cost growth of approximately [REDACTED]% would occur" as MPRI was forced to increase its labor compensation to the levels under its current contract, with the result that MPRI would experience "high turnover, a lack of qualified personnel, and/or be forced to work with personnel of lesser quality than those proposed." SSD at 8. We agree that the technical evaluation was flawed. While it may be that any reduction in compensation would lead to some additional turnover, it is reasonable to assume that the degree to which MPRI's rates were deemed inadequate determined the extent to which its proposal was downgraded under the capability factor. Thus, since we have found that the inadequacy of MPRI's rates was unreasonably exaggerated in the evaluation--as reflected in the excessive increase in MPRI's proposed rates--we also find that the downgrading of MPRI's technical proposal based on the same flawed cost evaluation results likewise was unreasonable.
We will sustain a protest based on our finding of an evaluation deficiency only where the protester demonstrates a reasonable possibility that it was competitively prejudiced, that is, that, but for the agency's actions, it would have had a substantial chance of receiving the award.
Parmatic Filter Corp.
, B-285288.3, B-285288.4, Mar. 30, 2001, 2001 CPD para. 71 at 11;
see
Statistica, Inc. v. Christopher
, 102 F.3d 1577, 1581 (Fed. Cir. 1996).
The parties have offered alternative methodologies for ascertaining the extent to which MPRI was prejudiced by the agency's unreasonable cost evaluation. The agency and DynCorp suggest that any new adjusted rates should be based on the average of the proposed rates for each labor category. The agency and DynCorp go on to assert that, if such an approach were adopted, DynCorp's evaluated rates--which were based on its MNSTC-I contract rates, which DynCorp indicated in its proposal were excessive for this procurement--likewise should be adjusted. According to the agency and DynCorp, this approach would increase MPRI's evaluated cost advantage by less than $[REDACTED] million--from approximately $36.4 million ($212.7 million for MPRI versus $249.1 million for DynCorp) to approximately $[REDACTED] million ($[REDACTED] million for MPRI versus $[REDACTED] million for DynCorp), Joint Agency/DynCorp Comments, May 24, 2010, at 4-5--and would not have a material impact on the evaluation or source selection.
MPRI, on the other hand, asserts that the extent of prejudice is best captured by a calculation based on accepting MPRI's proposed rates for senior mentor and trainer--since they fell within the OSD range--and adjusting the rates for the remaining three categories upward to the low end of the OSD range. MPRI notes, in this latter regard, that the proposed rates for LGS's subcontractors that fell outside the OSD range were adjusted to the low end of the range. MPRI further asserts that there is no basis for adjusting DynCorp's evaluated rates, since there has been no showing that it was unreasonable for the agency to rely on DynCorp's MNSTC-I contract rates rather than its lower proposed rates (for four of the labor categories). MPRI calculates that this approach--based on a revised evaluated cost of $[REDACTED] million for MPRI, and DynCorp's originally evaluated $249.1 million--would increase its cost advantage to approximately $[REDACTED] million. MPRI Comments, May 24, 2010, at 4-11.
Here, only by accepting the agency's material reevaluation of the cost proposals and declining to accord any weight to the protester's alternative methodology could we conclude that there was no substantial probability of prejudice. However, while in reviewing protests we will take into account post-protest explanations that provide a detailed rationale for contemporaneous conclusions, we generally give little or no weight to reevaluations and judgments prepared in the heat of the adversarial process.
Navistar Defense, LLC; BAE Sys., Tactical Vehicle Sys. LP
, B'401865
et al.
, Dec. 14, 2009, 2009 CPD para. 258 at 6;
Boeing Sikorsky Aircraft Support
, B-277263.2, B'277263.3, Sept. 29, 1997, 97-2 CPD para. 91 at 15. There is no basis for according any significant weight to the agency's reevaluation here, given the possibility and the appearance that the agency may have selected its alternative methodology to ensure no material impact on the original evaluation results. In any case, the agency's position fails to take into account our finding that the flaws in the cost evaluation resulted in an unreasonable evaluation of MPRI's technical proposal. Accordingly, we conclude that MPRI was prejudiced by the agency's actions and sustain the protest on this basis.
PERFORMANCE RISK
LGS and MPRI maintain that DynCorp's proposal should have been evaluated less favorably under the performance risk factor.
We will review a past performance evaluation to ensure that it was reasonable and consistent with the solicitation's stated evaluation criteria and applicable statutes and regulations.
Guam Shipyard
, B-311321, B-311321.2, June 9, 2008, 2008 CPD para. 124 at 3. The evaluation of past performance, by its very nature, is subjective; a protester's disagreement with the agency's judgment does not demonstrate that those judgments are unreasonable.
SDV Telecomms
., B'279919, July 29, 1998, 98-2 CPD para. 34 at 2.
The evaluation of DynCorp's proposal as offering low performance risk was reasonable. In this regard, the solicitation provided for the agency to "conduct a Performance Risk assessment based on the quality of the offeror's recent (within the past 3 years) and relevant past performance as well as proposed major subcontractors, as it relates to the probability of successful accomplishment of the required effort." RFP sect. M, Factor 2, at 66. Offerors were required to identify a minimum of three and a maximum of five contracts; describe for each how the effort is "similar to the requirements of [the] solicitation," the objectives achieved, the reasons for any shortcomings, and any corrective action taken to avoid reoccurrence; and furnish a past performance questionnaire (PPQ) "to the Government/commercial contracting activity and Government/commercial technical representative responsible for the past/current contract. (One (1) Point of Contact (POC) and one (1) contract per questionnaire.)" RFP sect. L, Factor 2, at 58.
DynCorp's proposal cited five prior contracts: the current MNSTC-I contract; the current CIVPOL-A contract with the Department of State (DOS), under which DynCorp provides approximately 615 mentors, advisers and trainers to support the Afghan national, border and civil order police; the current CIVPOL-I DOS contract to mentor Iraqi civil police, under which DynCorp provides approximately 700 advisors; the current DOS contract to mentor Palestinian Authority security forces; and the current DOS contract to implement the African Peacekeeping Force Liberia Security Sector Reform program. Although the record indicates that DynCorp requested PPQs for all five of the contracts,
see
Declaration of DynCorp Director of Business Development, May 21, 2010, the two DOS points of contact identified for the CIVPOL'A and CIVPOL-I contracts did not return completed PPQs.
As discussed, DynCorp's MNSTC-I contract was viewed by the agency as most relevant to the requirement here; indeed, the contracting agency for the MNSTC-I contract described it as identical to the requirement here. MNSTC-I PPQ Response. DynCorp's proposal cited its accomplishments under that contract, and also cited two letters of concern regarding a delay in the contract award, which had resulted DynCorp's losing 90% of its job candidates and had caused initial problems in staffing the contract effort. According to DynCorp, it resolved the staffing problems through aggressive recruitment efforts. Despite these staffing issues, the contracting agency's PPQ response for this contract characterized DynCorp's overall performance as excellent or very good (4 excellent, 18 very good, and 2 satisfactory ratings) under nearly all PPQ evaluation categories; stated that the contract had "low administrative issues" and that the agency was "[v]ery pleased with the management of this contract and its responsiveness to [the government's] changing needs"; and indicated that the agency would recommend DynCorp for other contracts. MNSTC-I PPQ Response.
DOS returned very favorable PPQs for DynCorp's Liberia and Palestinian contracts. Regarding the former, DOS primarily rated DynCorp's performance as excellent (20 excellent and 5 very good ratings), stating that DynCorp performed "all tasks in the SOW in an extremely professional manner" and "under budget." Liberia Security Sector Reform PPQ. Likewise, regarding the latter, while DynCorp described initial difficulties in both recruiting mentors with the exact skill set desired by the customer and in rapidly processing donated equipment, DOS acknowledged no more than "small problems [which] were immediately rectified"; indicated that DynCorp had performed "well"; and specifically rated its performance almost exclusively very good (22 very good and 1 satisfactory rating). Palestinian Authority Mentoring PPQ.
DOS POCs for DynCorp's CIVPOL-A and CIVPOL-I contracts did not respond to DynCorp's request to return a PPQ. However, DynCorp's proposal described the scope of the contracts, and its accomplishments and shortcomings in performing. Specifically, for its CIVPOL-A contract, DynCorp acknowledged that: (1) it had removed three senior managers as a result of customer concern that their management style was impairing the mission, but explained that it had immediately replaced the managers, instituted a new leadership training course, and instituted a 360-degree program for the evaluation of managers by peers and subordinates; and (2) had experienced two drug-related deaths over the past year, but explained that it had increased drug testing procedures and was offering comprehensive psychological services in the event that staff needed support to cope with work challenges. DynCorp Performance Risk Proposal at 7-8. For its CIVPOL-I contract, DynCorp acknowledged that: it had removed four managers as a result of customer concern that their management style was impairing the mission, but explained that it had immediately replaced the managers, instituted a new leadership training course and instituted a 360-degree evaluation program for managers; and (2) had initial trouble implementing a new computer system mandated by the customer, but explained that it had immediately met with the customer's technical staff to develop a solution, with the result that installation of the new network was now ahead of schedule.
Id.
at 9.
The Army assigned DynCorp a low performance risk rating based on its finding that DynCorp had performed contracts similar in size, scope and complexity to the requirement here; in particular, that it had trained senior leaders from 11 different ministries and agencies under its MNSTC-I contract; that it has had a "permanent presence in Afghanistan since 2003," including 5 years mentoring and training the Afghan police; and that its performance had been rated as either exceptional or very good. Performance Risk Assessment Report, DynCorp.
The protesters primarily assert that the agency failed to consider the problems under DynCorp's contracts, and focus in particular on the agency's failure to receive a PPQ for the CIVPOL-A contract.
The evaluation was unobjectionable. As discussed, the agency was aware that DynCorp had encountered problems under its prior contracts. While DynCorp acknowledged shortcomings in its performance under certain contracts, it also explained the measures taken to address the problems. (For example, to address possible concerns about the initial staffing problems under some of its contracts, DynCorp's proposal indicated that it had obtained letters of intent for all 275 required positions, DynCorp Capability Proposal at 1, and it furnished copies of the letters of intent during its oral presentation.) The PPQs received by the agency confirmed that DynCorp's acknowledged shortcomings were not viewed as significant by the contracting activities in question, and that DynCorp instead was considered to be a very good or excellent contractor. The agency ultimately determined that the information DynCorp provided, along with the PPQ ratings, sufficiently supported a low risk rating. The fact that the agency did not receive a PPQ for the CIVPOL-A contract did not render the evaluation unreasonable; there is no requirement that an agency consider all references in evaluating an offeror's past performance.
Sunrise Med. HHG, Inc.
, B'310230, Dec. 12, 2007, 2007 CPD para. 7 at 5. Here, the information available to the agency demonstrated that DynCorp had successfully performed other mentoring contracts in Muslim countries, including the MNSTC-I contract, and had been performing in Afghanistan for a number of years. We conclude that there is no basis for questioning DynCorp's low performance risk rating.
[1]
RECOMMENDATION
We sustain MPRI's protest on the grounds that the cost and technical evaluations were unreasonable, as discussed above. We recommend that the agency reevaluate the proposals using a methodology that reasonably accounts for the likely cost for each offeror to staff its proposed capability approach. If a proposal other than DynCorp's is selected for award, the agency should terminate DynCorp's contract for convenience, and make award to that offeror, if otherwise appropriate. In addition, we recommend that MPRI be reimbursed the costs of filing and pursuing its protest, including reasonable attorneys' fees. 4 C.F.R. sect. 21.8(d)(1) (2010). The protester should submit its certified claim, detailing the time expended and costs, incurred, directly to the contracting agency within 60 days of receiving this decision. 4 C.F.R. sect. 21.8(f)(1).
MPRI's protest is sustained. LGS's protest is denied.
Lynn H. GibsonActing General Counsel
[1]
The protesters point to our decisions holding that some information is simply "too close at hand to require offerors to shoulder the inequities that spring from an agency's failure to obtain and consider information,"
see
,
e.g.
,
Shaw-Parsons Infrastructure Recovery Consultants, LLC; Vanguard Recovery Assistance, J.V.
, B'401679.4
et al.
, Mar. 10, 2010, 2010 CPD para. 77 at 8. However, they have made no showing that there was information here too close at hand for the agency to ignore and that would call into question DynCorp's low performance risk rating.
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Crona, Kristina (Dept. of Mathematics and Statistics) | AU Digital Research Archive
Crona, Kristina (Dept. of Mathematics and Statistics)
Collection Title: Crona, Kristina (Dept. of Mathematics and Statistics)
Description: Kristina Crona is an assistant professor in the Department of Mathematics and Statistics. She researches mathematical evolutionary biology.
Antibiotic resistance landscapes
Fitness landscapes are central in analyzing evolution, in particular for drug resistance mutations for bacteria and virus. We show that the fitness landscapes associated with antibiotic resistance are not compatible with any of the classical models; additive, uncorrelated and block fitness landscapes. The NK model is also discussed. It is frequently stated that virtually nothing is known about fitness landscapes in nature. We demonstrate that available records of antimicrobial drug mutations can reveal interesting properties of fitness landscapes in general. We apply the methods to analyze the TEM family of beta-lactamases associated with antibiotic resistance. Laboratory results agree with our observations. The qualitative tools we suggest are well suited for comparisons of empirical fitness landscapes. Fitness landscapes are central in the theory of recombination and there is a potential for finding relations between the tools and recombination strategies.
Epistasis and entropy
Evolutionary predictability and complications with additivity
Inferring genetic interactions from comparative fitness data
Darwinian fitness is a central concept in evolutionary biology. In practice, however, it is
hardly possible to measure fitness for all genotypes in a natural population. Here, we present
quantitative tools to make inferences about epistatic gene interactions when the fitness landscape
is only incompletely determined due to imprecise measurements or missing observations. We
demonstrate that genetic interactions can often be inferred from fitness rank orders, where all
genotypes are ordered according to fitness, and even from partial fitness orders. We provide a
complete characterization of rank orders that imply higher order epistasis. Our theory applies to all
common types of gene interactions and facilitates comprehensive investigations of diverse genetic
interactions. We analyzed various genetic systems comprising HIV-1, the malaria-causing parasite
Plasmodium vivax, the fungus Aspergillus niger, and the TEM-family of b-lactamase associated with
antibiotic resistance. For all systems, our approach revealed higher order interactions among
mutations.
Polytopes, graphs and fitness landscapes
Darwinian evolution can be illustrated as an uphill walk in a landscape, where the surface consists of genotypes, the height coordinates represent fitness, and each step corresponds to a point mutation. Epistasis, roughly defined as the dependence between the fitness effects of mutations, is a key concept in the theory of adaptation. Important recent approaches depend on graphs and polytopes. Fitness graphs are useful for describing coarse properties of a landscape, such as mutational trajectories and the number of peaks. The graphs have been used for relating global and local properties of fitness landscapes. The geometric theory of gene interaction, or the shape theory, is the most fine-scaled approach to epistasis. Shapes, defined as triangulations of polytopes for any number of loci, replace the well established concepts of positive and negative epistasis for two mutations. From the shape one can identify the fittest populations, i.e., populations where allele shuffling (recombination) will not increase the mean fit- ness. Shapes and graphs provide complementary information. The approaches make no structural assumptions about the underlying fitness landscapes, which make them well suited for empirical work.
Rank orders and signed interactions in evolutionary biology
eLife, Volume 9, January 2020, Article number e51004., Rank orders have been studied in evolutionary biology for almost a hundred years. Constraints on the order in which mutations accumulate are known from cancer drug treatment, and order constraints for species invasions are important in ecology. However, current theory on rank orders in biology is somewhat fragmented. Here, we show how our previous work on inferring genetic interactions from comparative fitness data (Crona et al., 2017) is related to an influential approach to rank orders based on sign epistasis. Our approach depends on order perturbations that indicate interactions. We apply our results to malaria parasites and find that order perturbations beyond sign epistasis are prevalent in the antimalarial drug-resistance landscape. This finding agrees with the observation that reversed evolution back to the ancestral type is difficult. Another application concerns the adaptation of bacteria to a methanol environment.
Rational design of antibiotic treatment plans
Recombination and peak jumping
We find an advantage of recombination for a category of complex fitness landscapes. Recent studies of empirical fitness landscapes reveal complex gene interactions and multiple peaks, and recombination can be a powerful mechanism for escaping suboptimal peaks. However classical work on recombination largely ignores the effect of complex gene interactions. The advantage we find has no correspondence for 2-locus systems or for smooth landscapes. The effect is sometimes extreme, in the sense that shutting off recombination could result in that the organism fails to adapt. A standard question about recombination is if the mechanism tends to accelerate or decelerate adaptation. However, we argue that extreme effects may be more important than how the majority falls., Published as:
Crona K (2018) Recombination and peak jumping. PLoS ONE 13(3): e0193123. https://doi.org/10.1371/journal.pone.0193123
| https://dra.american.edu/islandora/object/auislandora:55264?display=list&f%5B0%5D=mods_typeOfResource_ms%3A%22text%22&limit=50 |
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Abstract
Scientific literature on mammalian terrestrial carnivores in Portugal from 1789 until November 2015 (n = 755 studies).
Note: Relevant studies were identified using several search engines, including Google Scholar (http://scholar.google.com), ISI Web of Knowledge / Web of Science (WoS, www.wokinfo.com), Scientific Electronic Library Online (SciELO, www.scielo.org) and online archives of all Portuguese universities. In each database, several combinations of keywords were used to identify relevant publications for all carnivore species known to occur in Portugal: the scientific and common name (both in Portuguese and English), ‘carnivore’, ‘Portugal’ and ‘Iberian Peninsula’. Reference lists of publications were also used as bibliographic sources. ‘Research Topic’ refers to the publication’s main area of research and was defined as follows: ‘Conservation’ (studies related to human-wildlife conflicts; human perceptions and attitudes towards carnivores; illegal persecution; damages; habitat recovery; conservation action plans; impact of human activities), ‘General Ecology’ (trophic ecology; reproduction; habitat requirements and selection; home ranges; space use; activity; ecological modelling; scent-marking; behavioural responses; social ecology; abundance), ‘Genetics’ (phylogeography, population genetics, non-invasive genetics, hybridization, molecular markers), ‘Health Status’ (parasites, diseases, physiological parameters), ‘Population Status’ (past and present distribution patterns; population size; population trends and dynamics; Population Viability Analysis (PVA); monitoring) and ‘Others’ (palaeontology; ethology; systematics; morphology; anatomy; methodological approaches; etc.). Publications marked in light grey were used to obtain presence records.
(DOCX)
S1 T able. Scientific literature on mammalian terrestrial carnivores in Portugal from 1789 until November 2015 (n=755 studies). Note: Relevant studies were identified
using several search engines, including Google Scholar (http://scholar.google.com), ISI W eb of Knowledge / We b of Science (WoS, www .wokinfo.com), Scientific Electronic
Library Online (SciELO, www.scielo.org) and online archives of all Portuguese universities. In each database, several combinations of keywords were used to identify
relevant publications for all carnivore species known to occur in Portugal: the scientific and common name (both in Portuguese and English), ‘carnivore’, ‘Portugal’ and
‘Iberian Peninsula’. Reference lists of publications were also used as bibliographic sources. ‘Research Topic’ refers to the publication’s main area of research and was defined
as follows: ‘Conservation’ (studies related to human-wildlife conflicts; human perceptions and attitudes towards c arnivores; illegal persecution; damages; habitat recovery;
conservation action plans; impact of human activities), ‘General Ecology’ (trophic ecology; reproduction; habitat requirements and selection; home ranges; space use;
activity; ecological modelling; scent-marking; behavioural responses; social ecology; abundance), ‘Genetics’ (phylogeography, population genetics, non-invasive genetics,
hybridization, molecular markers), ‘Health Status’ (parasites, diseases, physi ological parameters), ‘Population Status’ (past and present distribution patterns; population size;
population trends and dynamics; Population V iability Analysis (PV A); monitoring) and ‘Others’ (palaeontology; e thology; systematics; morphology; anatomy;
methodological approaches; etc.). Publications marked in light grey were used to obtain presence records.
Publication name T ype of Publication Research T opic
Abreu F, Galhardo L (2012) Effects of feeding enrichment in behavior of a f emale otter in captivity. In:
Abstracts of the IV Congresso da Fauna Selvagem W AVES Portugal , 75. Bragança, Portugal. Conference Proceedings General ecology
Abreu MP (1993) A comunidade de carnívoros da Reserva Natural da Serra da Malcata. Uma partilha de
recursos. Faculty of Sciences of the University of Lisbon, Lisbon, Portugal. Thesis General ecology
Abreu P (2003) O Lince-ibérico na nossa Região: um Projecto Interdisciplinar . Instituto da Conservação da
Natureza. Book Conservation
Afonso MR (1997) Abordagem ao estudo do grau de contaminação por mercúrio da bacia do Rio T ejo e
avaliação do possível impacte na população de lontra (Lutra lutra L., 1758). Final degree thesis, Faculty
of Sciences of the University of Lisbon, Lisbon, Portugal.
Thesis Conservation
Alexandre AS (1995) A raposa (V ulpes vulpes silacea Miller , 1907) na região de Onor no Parque Natural de
Montesinho: Ecologia trófica, uso do espaço e uso do tempo. Final Degree thesis, Faculty of Sciences of
the University of Lisbon, Lisbon, Portugal.
Thesis General ecology
Alexandre AS, Cândido AT , Grilo C, Moço G, Petrucci-Fonseca F (1999) Nuevos datos sobre la población
lupina portuguesa a sur del Rio Duero. In: Abstracts of t he Congresso sobre Recuperación del Lobo en
Sierra Morena , Sevilla, Spain.
Conference Proceedings General ecology
Alexandre AS, Cândido A T, Grilo C, Moço G, Petrucci-Fonseca F (1999) Propuesta de conservación del Lobo
al sur del río Duero en Portugal: definición de corredores ecológicos. In: Resúmenes IV Jornadas de la
SECEM , 4. Segovia, Spain.
Conference Proceedings Conservation
Alexandre AS, Cândido A T, Petrucci-Fonseca F (2000) A população lupina portuguesa a sul do Rio Douro.
Galemys 12: 113-122. non-SCI Journals Population Status
Alfonso-Roque MM (1991) Introdução de animais na ilha de S. Miguel (Açores) e eventuais consequências na
helmintofauna de vertebrados terrestres. Garcia de Orta - Série de Zoologia 18: 5–12. non-SCI Journals Health status
Almaça C (1977) A lontra, Lutra lutra, no litoral marítimo. Boletim da LPN 16: 17–19. non-SCI Journals Population Status
Alonso P , V illar Pías J, Pérez Hernández T, Sánchez Quintas M (2012) Evolução recente da população de lobos
presente a SE da Galiza. Apontamentos sobre reprodução e mortalidade. In: Abstracts of the III Iberian
W olf Congress , 39. Lugo, Spain.
Conference Proceedings Population Status
Álvares F (1995) Aspectos da distribuição e ecologia do lobo no noroeste de Portugal. O caso do Parque
Nacional da Peneda-Gerês. Final Degree thesis, Faculty of Sciences of the University of Lisbon Lisbon,
Portugal.
Thesis Population Status
Álvares F (1997) Novos dados sobre a fauna de vertebrados terrestres no Noroeste de Portugal. In: I Encontro
do Norte: Ambiente, Desenvolvimento, Autar quias e Educação , Braga, Portugal. Conference Proceedings Population Status
Álvares F (1997) O Lince-ibérico (Lynx pardinus) no Noroeste de Portugal - Presença Historica e Situação
Actual. Instituto da Conservação da Natureza/Programa Liberne. Technical report Population Status
Álvares F (1998) Consequências da Auto-Estrada Braga-V alença na população lupina do extremo Noroeste de
Portugal. Boletim informativo do Grupo Lobo 13: 1–2. non-SCI Journals Conservation
Álvares F (1999) Andam a soltar lobos?! Boletim informativo do Grupo Lobo 14: 1–3. non-SCI Journals Conservation
Álvares F (1999) Implicações da utilização de veneno direccionado ao lobo na conservação dos ecossistemas.
O exemplo do Noroeste de Portugal. In: Seminário “O envenenamento e o seu efeito na conservação das
espécies selvagens e em especial nas aves”, Mértola, Portugal.
Conference Proceedings Conservation
Álvares F (2000) A realidade e o Mito do lobo. In: Abstracts of the Ciclo de Conferências “O Despertar da
Primavera,” Universidade de Trás-os Montes e Alto Douro, Vila Real, Portugal. Conference Proceedings Conservation
Álvares F (2000) O lobo em Portugal. Situação actual e causas de regressão. In: Abstracts of the Ciclo de
Colóquios 2000/2001: O Lobo na Beira Alta – Sobrevivência ou Extinção , Guarda, Portugal. Conference Proceedings Population Status
Álvares F (2000) O Lobo no Noroeste de Portugal, a vida de um sobrevivente. Tribuna da Nature za 1: 4–7. non-SCI Journals Population Status
Álvares F (2001) O Lobo - Mitos e Realidades. In: Abstract of the I Jornadas Ambientai s do Alto Tâmega e
V e rín , Chaves, Portugal. Conference Proceedings Conservation
Álvares F (2003) A Problemática dos Venenos na Conservação do Lobo e o seu Impacto na Biodiversidade
dos Ecossistemas . Programa Antídoto - Portugal, Lisbon, Portugal. Technical report Conservation
Álvares F (2003) Monitorização do lobo (Canis lupus) na área de influência do Parque Nacional Peneda.-
Gerês: análise do decénio 1994-2003. Relatório Anual de Projecto. Lisbon, Portugal. Technical report Population Status
Álvares F (2004) O lobo no imaginário popular. In: Nunes M (ed) Serra da Aboboreira: a T erra, o Homem e
os Lobos , 135–145. Câmara Municipal de Amarante. Book Conservation
Álvares F (2004) O lobo-ibérico, biologia, ecologia e distribuição. In: Nunes M (ed) Serra da Aboboreira: a
T erra, o Homem e os Lobos , 85–91. Câmara Municipal de Amarante. Book General ecology
Álvares F (2004) Status and Conservation of the Iberian W olf in Portugal. Wolf Print 20: 4–6. non-SCI Journals Population Status
Álvares F (2005) Casos Particulares de Conservação de Carnívoros em Portugal - O Lobo-ibérico, o Gato-
bravo e a Marta . ALDEIA Technical report Conservation
Álvares F (2005) O Mito do l obo: a importância de um grande predador na cultura das comunidades rurais.
Ter ranatur non-SCI Journals Conservation
Álvares F (2006) Espécies Emblemáticas and Desenvolvimento Rural: o potencial do lobo-ibérico e da sua
identidade na cultura popular. In: Actas das Jornadas sobre Biodive rsidade e Mundo Rural: Perspectivas e
Estratégias de Conservação da Fauna Selvagem , ALDEIA/NEBUP .
Conference Proceedings Conservation
Álvares F (20 1 1) Ecologia e conservação do lobo (Canis lupus, L.) no noroeste de Portugal. PhD thesis,
Faculty of Sciences of the University of Lisbon, Lisbon, Portugal. Thesis Conservation
Álvares F (2013) Dinâmica das populações de lobo em ambientes humanizados Colóquio “O lobo ibérico na
Beira Interior”, ATN/Grupo Lobo, Almeida, Portugal, 16 March 2013. Oral. Conference Proceedings Conservation
Álvares F (2013) Etnobiologia: a utilização do lobo na medicina tradicional. In: Rodrigues JB (ed) Entre Lobos
& Pastores , 90–92. CORANE/ALDEIA, Bragança, Portugal. Book Conservation
Álvares F (2013) Meios e procedimentos na luta contra um predador . In: Rodrigues JB (ed) Entre Lobos &
Pastores , 64–66. CORANE/ALDEIA, Bragança, Portugal. Book Conservation
Álvares F (2013) W olf conservation in human-dominated landscapes: ecological and socio-economic
constraints. In: Seminar Series “Colloquium for Applied Ecology and Planning”, Technical University
Munich, Germany, 2013 , Oral.
Conference Proceedings Conservation
Álvares F , Alonso P , Sierra P , Petrucci-Fonseca F (2000) Os fojos dos lobos na Península Ibérica. Sua
inventariação, caracterização e conservação. Galemys 12: 57–77. non-SCI Journals Conservation
Álvares F, Brito JC (2006) Habitat requirements and potential areas of occurrence for the Pine Marten in
North-western Portugal: conservation implications. In: Santos-Reis M, Birks JDS, O’Doherty EC, Proulx
G (eds) Martes in Carnivore Communities: Proceedings of the Fourth International Martes Symposium ,
29–45. Alpha Wildlife Publications, Albert a, Canada.
Book Population Status
Álvares F , Domingues J (2010) Presença histórica do urso em Portugal e testemunhos da sua relação com as
comunidades rurais. AÇAF A on-line : 1–22. non-SCI Journals Others
Álvares F, Domingues J, Sierra P , Primavera P (2011) Cultural dimension of wolves in the Iberian Peninsula:
implications of ethnozoology in conservation biology . Innovation: The European Journal of Social
Science Research 24: 313–331.
non-SCI Journals Conservation
Álvares F, Pereira E, Petrucci-Fonseca F (2000) O lobo no Parque Internacional Gerês-Xurés. Situaçao
populacional, aspectos ecológicos e perspectivas de conservação. Galemys 12: 223–239. non-SCI Journals Conservation
Álvares F, Petrucci-Fonseca F (1996) O lobo no Parque Nacional da Peneda-Gerês - Ecologia e Distribuição.
In: Abstracts of the I Encontro Ecologista sobr e o Lobo Ibérico , Benavente, Zamora, Espanha. Conference Proceedings General ecology
Álvares F , Petrucci-Fonseca F (1997) O lobo no Alto Minho - Problemática da conservação de um predador
numa região f ortemente humanizada. In: Abstracts of the I Encontr o Regional do Norte - Ambiente,
Conference Proceedings Conservation
Desenvolvimento, Autarquias e Educação , 47–48. Associação Portuguesa de Biólogos, Braga, Portugal,.
Álvares F , Petrucci-Fonseca F (2001) S ocial and Ecological Dimemnsions of Human-W olf Conflict in
Northwest Portugal. In: Abstracts of the 8th International Theriological Congress , Sun City , South Africa. Conference Proceedings Conservation
Álvares F, Petrucci-Fonseca F (2002) O papel do Ecoturismo e da Educação Ambiental na conservação de
espécies ameaçadas - O caso do lobo-ibérico no Parque Nacional da Peneda-Gerês. In: Pr oceedings f r om
Congresso Nacional Desenvolvimento Sustentável em Ár eas de Montanha , PNPG, Terras de Bouro,
Portugal.
Conference Proceedings Conservation
Álvares F, Petrucci-Fonseca F (2012) Ecologia trófica e impacto da predação do lobo num sistema com várias
espécies de ungulados domésticos. In: Abstracts of the III Iberian W olf Congress , 31. Lugo, Spain. Conference Proceedings General ecology
Álvares F, Primavera P (2004) The W olf in rural communities’ culture in the North of Portugal. Wolf Print 20:
10–12. non-SCI Journals Conservation
Álvares F , Rio-Maior H, Nakamura M, Petrucci-Fonseca F , Godinho R (2012) Parâmetros populacionais do
lobo no noroeste de Portugal: padrões espácio-temporais e considerações metodológicas. In: Abstracts of
the III Iberian W olf Congress , 33. Lugo, Spain.
Conference Proceedings Population Status
Álvares F , Roque S, Petrucci-Fonseca F (2013) Wolf feeding strategies by wolves in agricultural landscapes:
lessons from two areas in Portugal. In: Potocnik H, Razen N, Mulej J, Jelencic M, B ertoncelj I (eds)
Abstracts of the International Confer ence “W olf Conservation in Human Dominated Landscapes”, 25-28
September 2013 , Oral. University of Ljubljana, Biotechnical Faculty, Postojna, Slovenia.
Conference Proceedings General ecology
Álvares F, Sierra P (2004) Monitorização do lobo (Canis lupus) na área de influência do Parque Nacional da
Peneda-Gerês. Relatório Anual de Projecto. Grupo Lobo/PNPG. Technical report Population Status
Álvares F, Simão R, Alexandre AS, Cândido A T, Petrucci-Fonseca F (1998) W olf monitoring in Portugal with
the selection of key-sites. Importance for the definition of a conservation strategy. In: Reig S (ed)
Abstracts of the Euro-American Mammal Congr ess , 262. Santiago Compostela, Spain.
Conference Proceedings Conservation
Alves AF , Loureiro F, Rosalino LM, Carvalho S, Rei C, Santos-Reis M (2007) Effects of fire on Eurasian
badger’s trophic ecology in cork oak woodlands of SW Portugal. Galemys 19: 251–270. non-SCI Journals General ecology
Álvaro C,Bekker H, Bekker J, Boshamer J, Buys J, Hunia A, Kosten E et al. (2004) Mammal Survey Alvão
Natural Park (Portugal). Society for the Study and Conservation of Mammals, Nijmegen, Netherlands. Technical report Population Status
Alves J (2014) Avaliação da resposta de lince-ibérico (L ynx pardinus, Temminck 1827) à presence humana,
face a difer entes métodos de preparação para reintrodução. MSc thesis, Faculty of Sciences of the
University of Lisbon, Lisbon, Portugal.
Thesis Conservation
Alves JP (2001) The Relationships between Humans and W olves in the Montesinho Natural Park (North-east
of Portugal): From Destruction to Conservation. In: Abstracts of the Canid Bi ology & Conservation: An
International Conference , 26. Oxford, U.K.
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Assemblée Generale , 131–132. Vienne, France. Conference Proceedings Population Status
Ângelo IS (2000) Aspectos da ecologia da raposa (Vulpes vulpes) no Nordeste Algarvio. Final Degree thesis,
Faculty of Sciences of the University of Lisbon Lisbon, Portugal. Thesis General ecology
Anonymous (2005) Plano de ordenamento da Albufeira da Aguieira . Direção de Serviços de Utilizações do Technical report Population Status
Domínio Hídrico.
Antunes MT (1993) Mamíferos em Portugal: extinções desde o Plistocénico Superior . Liberne 43/44: 6–10. non-SCI Journals Others
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processes: the case of b iodiversity conser vation and aquaculture in the Sado estuary (Portugal). In:
Abstracts of the Society for Conservation Biology Annual Meeting , 2. San Jose, USA.
Conference Proceedings Conservation
Ascensão F (2001) Mortalidade de V ertebrados por Atropelamento em Estradas do Alto Alentejo. Faculty of
Sciences of the University of Lisbon, Lisbon, Portugal. Thesis Conservation
Ascensão F (2013) Ecologically scaled responses of forest-dwelling vertebrates to habitat fragmentation. PhD
thesis, Faculty of Sciences of the University of Lisbon, Lisbon, Portugal. Thesis Conservation
Ascensão F, Grilo C, LaPoint S, Tracey J, Clevenger AP , S antos-Reis M (2014) Inter-individual variability of
stone marten behavioral responses to a highway. PLoS ONE 9: e103544. SCI Journals Conservation
Ascensão F, Grilo C, Santos-Reis M (2007) Assessing the Stone Marten’s Patch Occupancy in Fragmented
landscapes and its Relation to Road-Killing Occurences. In: Proceedings of the The 2007 International
Conference on Ecology and T ransportation , 583. Little Rock, Arkansas, U.S.A.
Conference Proceedings Conservation
Ascensão F, Mira A (2006) Factors affecting culvert use by vertebrates along two stretches of road in southern
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Portugal. T echnical report Conservation
Ascensão F , Tracey J, Pinheiro P , Costa M, Matos H, Dias F, Clevenger A, Santos-Reis M, Grilo C (2009)
¿Actúan las autopistas como barreras para los movimientos de la garduña (Martes foina)? Sí, y más de lo
que podría parecer. In: Resúmenes IX Jornadas de la SECEM , Bilbao, Spain.
Conference Proceedings Conservation
Azeda C (2001) Análise dos factor es que condicionam a distribuição da geneta (G enetta genetta Linnaeus,
1758) e do sacarrabos (Herpestes icnheumon Linnaeus, 1758) na região de influência directa das futuras
albufeiras de Alqueva e Pedrógão. Faculty of Sciences of the University of Lisbon, Lisbon, Portugal.
Thesis Population Status
Azinheira C (1998) Ecologia da Lontra (Lutra Lutra L., 1758): Selecção de Habitat. Final degree thesis,
University of Évora, Évora, Portugal. Thesis General ecology
Baeta Neves CM (1967) Sobre a Existência e Extinção do Urso em Portugal. Publicações da Liga para a
Protecção da Natureza : 3–7. non-SCI Journals Population Status
Balestrieri A, Remonti L, Ruiz-González A, Zenato M, Gazzola A, Vergara M et al. (2015) Distribution and
habitat use by pine marten Martes martes in a riparian corridor crossing intensively cultivated lowlands.
Ecological Research 30: 153–162.
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University of Lisbon, Lisbon, Portugal.
Thesis General ecology
Baptista MD (1789) Faunae Conimbricencis Rudimentum. Coimbra, Portugal. Book Population Status
Barbosa AM (2001) Modelação biogeográfica da distribuição da lontra (Lutra lutra) na península Ibérica
com base em factores espaciais, ambientais e humanos. Final Degree thesis, University of Malaga and
University of Porto.
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Barbosa AM, Puerto MA, Figueiredo D, Real R (2012) Modelling disjunct carnivore distributions: the case of
the wolf (Canis lupus) in the Iberian Peninsula. In: Álvares FI , Mata GE (eds) Carnivor es: Spe cies,
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Barbosa AM, Real R (2010) Áreas favoráveis e factores a ter em conta na reintrodução do lince em Portugal.
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conservation inferences. Conservation Biology 24: 1378–1387. SCI Journals Conservation
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Albergaria National Forest (Portugal). In: Abstracts of the 27th Mustelid Coloquium , 43. Lisbon, Portugal. Conference Proceedings General ecology
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Real. MSc thesis, Faculty of Sciences of the University of Lisbon, Lisbon, Portugal. Thesis Conservation
Barrett-Hamilton GEH (1904) Note on an undescribed weasel from the Atlas Mountains, and on the occurrence
of a weasel in the Azores. Annals and Magazine of Natural History 7: 323–325. non-SCI Journals Population Status
Barrinha C (2001) Análise da dieta da lont ra (Lutra lutra Linnaeus, 1758) na área de regolfo de Alqueva e
Pedrógão (SE Portugal). Final Degree thesis, Faculty of Sciences of the University of Lisbon Lisbon,
Portugal.
Thesis General ecology
Barros T, Carvalho J, Pereira MJR, F erreira JP , Fonseca C (2015) Following The T rail: Factors Underlying the
Sudden Expansion of the Egyptian Mongoose (Herpestes ichneumon) in Portugal. PloS one 10: e0133768. SCI Journals Population Status
Barros T , Fonseca C (2009) Estatus y distribución actual del meloncillo (Herpestes ichneumon) en Portugal. In:
Resúmenes IX Jornadas de la SECEM , Bilbao, Spain. Conference Proceedings Population Status
Barros T, Fonseca C (2011) Expansão do sacarrabos Herpestes ichneumon (Linnaeus, 1758) em Portugal.
Galemys 23: 9–15. non-SCI Journals Population Status
Barros T, Gaubert P , Rocha RG, Bandeira V , Souto L, Mira A, Fonseca C (2015) Mitochondrial demographic
history of the Egyptian mongoose (Herpestes ichneumon), an expanding carnivore in the Iberian
Peninsula. Mammalian Biology - Zeitschrift für Säugetierkunde .
SCI Journals Genetics
Barroso I, Carmo P (1998) Conservation of the wolf in Portugal: an administration point of view . In: Reig S
(ed) Abstracts of the Euro-American Mammal Congr ess , 268. Santiago Compostela, Spain. Conference Proceedings Conservation
Barroso I, Llaneza L (2005) W olf status and conservation in the Iberian Peninsula. In: Abstracts of the
Frontiers of W olf Recovery Conference , 26–27. International Wolf Center , Colorado Springs, U.S.A. Conference Proceedings Conservation
Barroso I, Pimenta V (2008) Sistema de Monitorização de Lobos Mortos: Relatorio de Actividades 1999-2008 .
Instituto da Conservação da Natureza. Technical report Population Status
Barroso I, Pimenta V , Santos N, Pimenta C, Godinho R (2012) Sistema de monitorização de lobos mortos em
Portugal: resultados entre 1999 e 2011. In: Abstracts of the III Iberian W olf Congress , 37. Lugo, Spain. Conference Proceedings Population Status
Basto MP (2015) Population and landscape genetics of the stone marten and red fox in Portugal: implications
for conservation management of common carnivores . PhD thesis, Faculty of Sciences of the University of
Lisbon, Lisbon, Portugal.
Thesis Genetics
Basto MP , Matos H, Pinheiro P , Santos-Reis M (2007) Diet of stone martens (Martes foina) in the Iberian
Peninsula: a comparative analysis. In: Hajkova P , Rüziczová O (eds) Abstracts of the 25th Mustelid
Colloquium, 53. Trebon, Czech Republic.
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Díaz-Ruiz F, Delibes-Mateos M, García-Moreno JL, María López-Martín J, Ferreira C, Ferreras P (2013)
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W olf Congress , 42. Lugo, Spain.
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Ferreira AM (1991) Alguns aspectos da ecologia da raposa (V ulpes vulpes silacea Miller , 1907) no Parque
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ibérico. Technical report Conservation
Ferreira C, Alves PC (2005) Impacto da implementação de medidas de gestão do habitat nas populações de
coelho-bravo (Oryctolagus c uniculus algirus) no Par que Natural do Sudoeste Alentejano e Costa
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Ferreira C, Rio-Maior H, Roque S, Petrucci-Fonseca F, Brandão R, Santos N, Álvares F (2012) Hematological
and serum biochemical reference values of free-ranging Iberian wolves in Portugal. In: Abstracts of the III
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Ferreira I, Silva M, Santos N, Rio-Maior H, Nakamura M, Álvares F , Carvalho LMM de (2012) Rastreio
sorológico de alguns agentes de zoonoses em canídeos silvestres no Norte de Portugal. Abstracts of the III
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Ferreira JP (2003) Análise dos factores condicionantes na distribuição de gato-bravo (Felis silvestris) no Sítio
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Ferreira JP (2010) Integrating anthropic factors into wildcat Felis silvestris conservation in Southern Iberia
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Fino F, Torres J, Petrucci-Fonseca F, Segovia J-M, Miquel J, Bacellar F , Feliu C (1995) Helmintofauna de
Canis lupus signatus Cabrera, 1907 (Carnivora: Canidae) en Portugal mediante técnicas coprológicas. In:
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comunidade de carnívoros na Reserva Natural do Paúl do Boquilobo. Faculty of Sciences of the
University of Lisbon, Lisbon, Portugal.
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Florêncio E (1994) Distribuição e ecologia trófica da lontra (Lutra lutra L.) na bacia hidrográfica do rio Technical report Population Status
Almonda . Instituto da Conservação da Natureza, Lisbon, Portugal.
Florêncio E (1995) Distribuição da lontra (Lutra lutra Linnaeus, 1758) em Portugal Continental: Região a
Norte do Rio T ejo . Instituto da Conservação da Natureza, Lisbon, Portugal. Technical report Population Status
Flower E (1971) Lobos em Portugal (1933-1957). Direcção Geral dos Serviços Florestais e Aquícolas, Lisbon Book Population Status
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Fonseca de Ambrósio IS, Marcos AF , Órfão I, Petrucci-Fonseca F (2012) O Centro de Recuperação do Lobo
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Congress , 82. Lugo, Spain.
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Fonseca V, Quaglietta L (2011) Fine-scale spatial genetic structure and dispersal of the Eurasian Otter (Lutra
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Fontes L, Campos A (1998 ) Os Fojos de Lobo da Cabreira. Mínia 6: 73–94. non-SCI Journals Conservation
Fordham DA, Akçakaya HR, Brook BW , Rodríguez A, Alves PC, Civantos E, Triviño M, Watts MJ, Araújo
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Fragoso S (1999) Distribuição e alguns aspectos da ecologia da doninha (Mustela nivalis Linnaeus, 1766) no
Parque Natural das Serras de Aire e Candeeiros. Final Degree thesis, Faculty of Sciences of the
University of Lisbon Lisbon, Portugal.
Thesis Population Status
Fragoso S, Santos-Reis M (1999) Abundancia y uso del espacio por la Comadreja en el Parque Natural Serra
de Aire e Candeeiros (Portugal). In: Resúmenes IV Jornadas de la SECEM , Segovia, Spain. Conference Proceedings General ecology
Fragoso S, Santos-Reis M (2000) Utilização dos recursos tróficos pela doninha no Parque Natural das Serra de
Aire e Candeeiros. Revista de Biologia 18: 23–32. SCI Journals General ecology
Franco I (2000) Aspectos Ecológi cos da Mortalidade de V ertebrados em Rodovias do Interior Alentejano.
Faculty of Sciences of the University of Lisbon, Lisbon, Portugal. Thesis Conservation
Freitas D (1999) A dieta da lontra (Lutra lutra) ao longo da bacia hidrográfic a do rio T ejo . Final Degree
thesis, Faculty of Sciences of the University of Lisbon Lisbon, Portugal. Thesis General ecology
Freitas D, Gomes J, Sales-Luís T , Madruga L, Marques C, Baptista G et al. (2007) Otters and fish farms in the
Sado estuary: ecological and socio-economic basis of a conflict. Hydrobiologia 587: 51–62. SCI Journals Conservation
Freitas D, Sales-Luís T , Santos-Reis M (2003) Evaluación del conflicto entre el hom bre y la nutria (Lutra lutra)
en las piscifactorias de Portugal. In: Resúmenes VI Jornadas de la SECEM , Ciudad Real, Spain. Conference Proceedings Conservation
Freitas D, Santos-Reis M (2005) Ecuaciones de regresión de S parus aurata, Dicentrarchus labrax y Solea
senegalensis en una región del estuario del Sado (Portugal): aplicación al estudio de la dieta de la nutria
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Freitas MC (2014) Assessing the spatial extent of wolf-dog hybridization in real-time and at population level
using non-invasive DNA sampling. MSc thesis, Faculty of Sciences of the University of Porto, Porto,
Portugal.
Thesis Genetics
Galantinho A, Mira A (2005) Influencia del uso del suelo y de la conservación de las líneas de agua en la
abundancia de gineta (Genetta gen etta L., 1758) en Monfurado, Portugal. In: Resúmenes VII Jornadas de
la SECEM , V alencia, Spain.
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Galantinho A, Mira A (2009) The influence of human, livestock, and ecological features on the occurrence of
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Gaubert P , Del Cerro I, Centeno-Cuadros A, Palomares F , Fournier P, Fonseca C, Paillat J-P , Godoy JA (2015)
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SCI Journals Genetics
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Invasions 11: 523–546.
SCI Journals Genetics
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uma contribuição para estudos com amostras não invasivas. MSc thesis, Faculty of Sciences of the
University of Porto, Porto, Portugal.
Thesis Genetics
Godinho R (2013) New insights into the dynamics of hybridization between wolves and dogs. In: Abstracts of
the International Conference “Wolf Conservation in Human Dominated Landscapes”, 25-28 September
2013 , Oral.
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Godinho R, Llaneza L, Blanco JC, Lopes S, Álvares F, García EJ et al. (2011) Genetic evidence for multiple
events of hybridization between wolves and domestic dogs in the Iberian Peninsula. Molecular Ecology
20: 5154–5166.
SCI Journals Genetics
Godinho R, Lopes S, Ferrand N (2007) Estudo da diversidade e estruturação genética das populações de l obo
(Canis lupus) e m Portugal . Rese arch Center in Biodiversity and Genetic Resources/University of Porto,
Porto, Portugal.
Technical report Genetics
Godinho R, López-Bao JV , Castro D, Llaneza L, Lopes S, Silva P, Ferrand N (2015) Real-time assessment of
hybridization between wolves and dogs: combining noninvasive samples with ancestry informative
markers. Molecular Ecology Resources 15: 317–28.
SCI Journals Genetics
Godinho R, Roque S, Castro D, Lopes S, Petrucci-Fonseca F, Álvares F (2012) Molecular ecology of the
isolated and endangered wolf population occurring south of Douro river, Portugal. In: Abstracts of the III
Iberian W olf Congress , 21. Lugo, Spain.
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Gomes C (2010) Comparação de dois métodos de monitorização de carnívoros. Armadilhagem de pêlo vs.
Armadilhagem fotográfica. MSc thesis, Faculty of Sciences of the University of Porto, Porto, Portugal. Thesis Others
Gomes N (1997) Dieta de la nutria (Lutra lutra) en una zona húmeda del Baixo V ouga Lagunar (Ría de A veiro),
y su relación con la abundancia de presas. In: Resúmenes III Jornadas de la SECEM , Castelló d’Empúries,
Gerona, Spain.
Conference Proceedings General ecology
Gomes N (1998) Distribuição e ecologia trófica da lontra (Lutra lutra) na ria de Av eiro. MSc thesis, Faculty
of Sciences of the Unoversity of Porto, Porto, Portugal. Thesis Population Status
Gomes N, Alves P , Henriques J, Ramos A, T avares L (1989) Contribution à l’étude du régime alimentaire de la
loutre (Lutra lutra) au Portugal. Ciência Biológica. Ecology and Systematics 9: 47–54. non-SCI Journals General ecology
Gomes N, Silva E, Pópulo H, Leite M (1999) La utilización de rastros de Nutria (Lutra lutra) para el estudio de
la comunidad de peces del Río P aiva (Cuenca del Río Duero, Portugal). In: Resúmenes IV Jornadas de la
SECEM , Segovia, Spain.
Conference Proceedings General ecology
Gomes P (1988) Análise da estrutura trófica de uma comunidade de mamífer os: estudo comparativo do regime
alimentar de três tipos de predador es (raposa, geneta e complexo toirão/fuínha) no Parque Nacional da
Peneda-Gerês. University of Minho, Braga, Portugal.
Thesis General ecology
Gomes P (1998) Ocupação e Utilização do Espaço pela Geneta. PhD thesis, University of Minho, Braga,
Portugal. Thesis General ecology
Gonçalves A (2015) Antibiotic re sistance in gastrointestinal bacteria isol ated fr om the Iberian lynx and
Iberian wolf: species conservation and public health concerns. PhD thesis, University of Trás-os-Montes
and Alto Douro, Vila Real, Portugal.
Thesis Health status
Gonçalves A, Igrejas G, Radhouani H, Correia S, Pacheco R, Santos T et al. (2013) Antimicr obial resistance in
faecal enterococci and Escherichia coli isolates recovered from Iberian wolf. Letters in Applied
Microbiology 56: 268–74.
SCI Journals Health status
Gonçalves A, Poeta P , Monteiro R, Marinho C, Silva N, Guerra A et al. (2014) Comparative proteomics of an
extended spectrum β-lactamase producing Escherichia coli strain from the Iberian wolf. Journal of
Proteomics 104: 80–93.
SCI Journals Health status
Gonçalves I (2006) Espaços silvestres para animais selvagens, no noroeste de Portugal, com as inquirições de
1258. In: Estudos em Homenagem ao Professor Doutor José Marques , 193–219. Faculty of Arts of the
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Book Conservation
Gonçalves P , Alcobia S, Simões L, Santos-Reis M (2011) Effects of management options on mammal richness
in a Mediterranean agro-silvo-pastoral system. Agroforestry Systems 85: 383–395. SCI Journals Conservation
Gonçalves S (2012) Comparação da dieta da lontra (Lutra lutra) e do visão-americano (Neovison vison)
numa situação de simpatria no NO de Portugal. MSc thesis, Faculty of Sciences of the University of
Lisboa, Lisbon, Portugal.
Thesis General ecology
Grilo AF (2013) Influência de factores locais no uso das galerias ripícolas por carnívoros num ambiente
mediterrânico. MSc thesis, Faculty of Sciences of the University of Lisbon, Lisbon, Portugal. Thesis General ecology
Grilo C (2009) Habitat Connectivity for Carnivores i n Mediterranean Landscapes: Implications for
Conservation Planning. PhD thesis, Faculty of Sciences of the University of Lisbon, Lisbon, Portugal. Thesis General ecology
Grilo C, Ascensão F , Santos-Reis M, Bissonette JA. (2010) Do well-connected landscapes promote road-
related mortality? European Journal of Wildlife Research 57: 707–716. SCI Journals Conservation
Grilo C, Bissonette JA, Santos-Reis M (2008) Response of carnivores to existing highway culverts and
underpasses: implications for road planning and mitigation. Biodiversity and Conservation 17: 1685–1699. SCI Journals Conservation
Grilo C, Bissonette JA, Santos-Reis M (2009) Spatial-temporal patterns in Mediterranean carnivore road
casualties: Consequences for mitigation. Biological Conservation 142: 301–313. SCI Journals Conservation
Grilo C, Cândido A T, Alexandre AS, Moço G, Petrucci-Fonseca F (2002) The isolated Iberian wolf population
in south Douro River (Portugal): Ecology and Threat factors. In: Abstract of the International Congress of
Biodiversity and Management , V ouziers, Ardennes França.
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Grilo C, Cruz M, Bissonette JA, Santos-Reis M (2006) The role of patch size and isolation to carnivore relative
abundance in a oak woodland landscape. In: Abstracts of the 1st European Congress on Conservation
Biology, 1 14. Eger, Hungary .
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Grilo C, Ferreira FZ, Revilla E (2015) No evidence of a threshold in traffic volume affecting road-kill mortality
at a large spatio-temporal scale. Environmental Impact Assessment Review 55: 54–58. SCI Journals Conservation
Grilo C, Moço G, Alexandre A, Cândido AT , Petrucci-Fonseca F (1999) Integração de um modelo ambiental
num sistema de informação geografica para a definição de corredores ecológicos. In: Abstracts of the V
Encontro sobre Sistemas de Informação Geografica. Escola Superior Agrária de Castelo Branco, Castelo
Branco, Portugal.
Conference Proceedings Conservation
Grilo C, Moço G, Cândido A T, A lexandre AS, Petrucci-Fonseca F (2001) Modelação de áreas prioritárias para
a recuperação do lobo-ibérico a sul do rio Douro. In: Proceedings of the VI Encontro Nacional de
Ecologia - Fragmentação de Habitats e Populações , Lisbon, Portugal.
Conference Proceedings Conservation
Grilo C, Moço G, Cândido A T, A lexandre AS, Petrucci-Fonseca F (2002) Bases para a definição de corredores
ecológicos na conservação de uma população marginal e fragmentada: o caso da população lupina a Sul
do rio Douro – 1 a Fase . Centre for Environmental Biology , Lisbon, Portugal.
Technical report Conservation
Grilo C, Moço G, Cândido A T, A lexandre AS, Petrucci-Fonseca F (2002) Bases para a definição de corredores
ecológicos na conservação de uma população marginal e fragmentada: o caso da população lupina a Sul
do rio Douro – 2 a Fase . Centre for Environmental Biology , Lisbon, Portugal.
Technical report Conservation
Grilo C, Moço G, Cândido A T, Alexandre AS, Petrucci-Fonseca F (2002) Challenges for the recovery of the
Iberian wolf in the Douro river south region. Revista de Biologia : 121–133. non-SCI Jour nals Conservation
Grilo C, Roque S, Rio-Maior H, Petrucci-Fonseca F (2003) El lobo ibérico al sur del Río Duero (Portugal):
bases para la definición de una estrategia para su recuperación. In: Resúmenes VI Jornadas de la SECEM ,
84. Ciudad Real, Spain.
Conference Proceedings Conservation
Grilo C, Roque S, Rio-Maior H, Petrucci-Fonseca F (2004) The isolated wolf population South of Dou ro
River: status and action lines for its recovery. W olf Print 20: 13–15. non-SCI Journals Conservation
Grilo C, Santos-Reis M (2011) Monitorização da mortalidade de vertebrados por atropelamento nas estradas
de Portugal. 1º Relatório de Progresso . Center for Environmental Biology , Faculty of Sciences of the
University of Lisbon, Lisbon, Portugal.
Technical report Conservation
Grilo C, Silva C, Baltazar C, Gomes L, Bissonette JA, Santos-Reis M (2007) Patterns of C arnivore Road
Casualties in Southern Portugal. In: International C onfer ence on Ecology and Transportation “Bridging
The Gaps, Naturally,” Little Rock, Arkansas, U.S.A.
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Grilo C, Sousa J, Ascensão F, Matos H, Leitão I, Pinheiro P et al. (2012) Individual Spatial Responses towards
roads: Implications for Mortality Risk. PLoS ONE 7: e43811. SCI Journals Conservation
Guerra AM (2004) Estudo das relações ecológicas entre o lobo-ibérico e equinos e bovinos no Alto Minho:
propostas para a minimização do impacto predatório. Final Degree thesis, Faculty of Sciences of the
University of Lisbon Lisbon, Portugal.
Thesis General ecology
Guerra D, Armua-Fernandez MT , Silva M, Bravo II, Santos N, Deplazes P , Carvalho LMM de (2013) Taeniid
species of the Iberian wolf (Canis lupus signatus) in Portugal with special focus on Echinococcus spp.
International Journal for Parasitology: Parasites and Wildlife 2: 50–53.
SCI Journals Health status
Guzman López-Ocón JN, García González FJ, Garrote Alonso G, Pérez de A yal a Balzola R, Iglesias Llamas C
(2006) El Lince Iberico (Lynx Pardinus) En España Y Portugal. Censo Diagnostico De Sus Poblaciones.
Dirección General para la Biodiversidad, Madrid, Spain.
Book Population Status
Haaften JL V an, Petrucci-Fonseca F , Pereira M (1983) A wolf study in Portugal. In: Pr oceedings of the XVI
Congress of Game Biologists , 550–553. Strbské Pleso, Slovakia. Conference Proceedings General ecology
Henriques JF , T avares PC, Correia-dos-Santos MM, Trancoso MA, Santos-Reis M (2009) Contamination by
heavy metals in aquatic trophic webs: the case of Otter and Red-Swamp Crayfish. In: Abstracts of the 27th
Mustelid Coloquium , 50. Lisbon, Portugal.
Conference Proceedings Health status
Hipólito D (2014) Influência das opções de gestão em recursos-chave para o texugo num ambiente agro-silvo-
pastoril mediterrânico. MSc thesis, Faculty of Sciences of the University of Lisbon, Lisbon, Portugal. Thesis Conservation
Hodge I, Milheiras S (2011) Attitudes towards compensation for wolf damage to livestock in Viana do Castelo,
North of Portugal. Innovation: The European Journal of Social Science Research 24: 333–351. non-SCI Journals Conservation
Inácio Amaro AM, Felgueiras M, Lencastr e M (2012) Representações e atitudes morais face ao lobo ibérico de
alunos do ensino básico e secundário do concelho de Penafiel. In: Abstracts of the III Iberian Wolf
Congress , 77. Lugo, Spain.
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Janeiro C, Ferreira JP, Mira A, Santos-Reis M (2007) Idoneidad y perspectivas de gestión de hábitat para el
lince ibérico Lynx pardinus en el sitio Moura-Barrancos (Alentejo - Portugal). In: Resúmenes VIII
Jornadas de la SECEM , Huelva, Spain.
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Jefferies R, Shaw SE, Willesen J, Viney ME, Morgan ER (2010) Elucidating the spread of the emerging canid
nematode Angiostrongylus vasorum between Palaearctic and Nearctic ecozones. Infection, Genetics and
Evolution 10: 561–568.
SCI Journals Health status
Needs Assessment: A T ool for Environmental Conflict Resolution and Sustainable Organization of Living
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| https://www.researchgate.net/publication/329826782_S1_Table |
Search Results - NHS
First Call 24/7 East Staffordshire;Diabetes Uk Chester And District;Ash-Worth Time Bank Cheshire;Crossroads Together Cheshire East Shropshire & Herefordshire;Shepshed Diabetic Self Help Group;Insulin Dependent Diabetes Trust;Diabetes UK Milton Keynes;Mental Health Advocacy Project;Diabetes UK North West (Main office);Crossroads Together Cheshire West Chester and Merseyside
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First Call 24/7 East Staffordshire
Address & contact detailsTel: 01283 528528Trent and Dove Housing LimitedTrinity SquareHorninglow StreetBurton-on-TrentDerbyshireDE14 1BL77.3 miles away
Information supplied by First Call provides a 24/7 pendant and Telecare alarm service for elderly and vulnerable residents living in the East Staffordshire area to give reassurance and emergency response.
Target group Elderly and vulnerable people and their carers/support workers
Diabetes Uk Chester And District
Address & contact detailsTel: 07702 973 360Chester UniversityCastle DriveChesterCheshireCH1 1SF80.5 miles away
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Target group Everyone interested in Diabetes is welcome and there is no membership fee.
Ash-Worth Time Bank Cheshire
Address & contact detailsTel: 01829 7513981st Floor Post OfficeKelsall Road Ashton HayesAshtonChesterCheshireCH3 8BH82.9 miles away
Information supplied by Our project encourages rural people to take control of their personal wellbeing, participate in social groups, walking, reading, art groups. We have a lending library in our office and are organising holistic therapy sessions to benefit older people, carers, single parents and older people who h... Continue reading overview
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Crossroads Together Cheshire East Shropshire & Herefordshire
Address & contact detailsTel: 0333 323 1990Crossroads TogetherOverton HouseWest streetCongletonCheshireCW12 1JY84.4 miles away
Information supplied by Crossroads Together is a registered charity dedicated to providing information, advice and practical support to unpaid carers of all ages and the people they care for. We provide a range of services including care in the home, carer breaks and a carers information service. We also run a range of ... Continue reading overview
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Shepshed Diabetic Self Help Group
Address & contact detailsTel: 01509 50378486.3 miles away
Information supplied by Shepshed Support Group for people with diabetes, their families and carers.
Local contact for all diabetics and their friends and relatives. Talks by workers in the medical profession, plus talks on general interests.
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Insulin Dependent Diabetes Trust
Address & contact detailsTel: 01604 622837210 Abington AvenueNorthamptonNorthamptonshireNN1 4PR89.3 miles away
Information supplied by The Insulin Dependent Diabetes Trust (IDDT) offers FREE support and information to people with diabetes, their families and health professionals on the issues that are important to them. Our Helpline offers a friendly understanding ear when the going gets tough.
Diabetes can cause serious long-... Continue reading overview
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Diabetes UK Milton Keynes
Address & contact detailsCentrecom Meeting Place602 N RowMilton KeynesBuckinghamshireMK9 3BJ92.8 miles away
Information supplied by The group is run by a committee of volunteers, the majority of whom are living with diabetes themselves. So, while we are unable to offer any medical advice, we are able to understand your condition, provide support and share experiences of living with diabetes, which often is usually beneficial.
Target group Meetings are free to attend and are open to all.
Mental Health Advocacy Project
Address & contact detailsTel: 0151 709 944291 Upper Parliament StreetLiverpoolMerseysideL8 7LB94.9 miles away
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Diabetes UK North West (Main office)
Address & contact detailsTel: 01925 653 281Diabetes UK North WestUnit C, Second Floor, Dalam CourtDalam LaneWarringtonCheshireWA2 7LT96.0 miles away
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Crossroads Together Cheshire West Chester and Merseyside
Address & contact detailsTel: 0333 323 1990Crossroads Together436 Queens DriveLiverpoolMerseysideL13 0AR96.7 miles away
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Commissioner bids to narrow EU-US divisions over Cyprus – POLITICO
WITH tension in Cyprus showing little sign of abating, Foreign Affairs Commissioner Hans van den Broek will meet US Secretary of State Madeleine Albright in Washington next week for talks on the divided island’s faltering peace process.
Commissioner bids to narrow EU-US divisions over Cyprus
WITH tension in Cyprus showing little sign of abating, Foreign Affairs Commissioner Hans van den Broek will meet US Secretary of State Madeleine Albright in Washington next week for talks on the divided island’s faltering peace process.
The meeting is unlikely to produce any surprise new transatlantic initiative. But it will be watched closely in the wake of strong American criticism of the EU’s policy towards Turkey and threats by Ankara to destroy Russian air-defence missiles bought by Nicosia as they make their way to Cyprus by sea.
US special envoy Richard Holbrooke believes the EU made a tactical error last December by failing to offer Turkey the same status as other Union membership candidates.
“The European Union made two decisions in Luxembourg on 13 December. One was to invite Cyprus to begin talks to join the EU. We think that was a good decision,” explained Holbrooke. “The other was not to start a process with Turkey. We think that was a mistake. I don’t see how Cyprus can move forward without Turkey’s support.”
Washington is at present exerting pressure on the Union to offer Turkey a better deal at the Cardiff summit in June.
“It should be possible to reach a formulation where the same conditions apply to all 12 EU applicants, but it is made clear that some countries will take much longer,” said one US diplomat.
Brussels officials are not best pleased by such statements. “It costs the US nothing to make these comments,” said one. “The main risk is creating expectations which cannot be met. If you look at the Luxembourg conclusions carefully, you will see that they are already much more forthcoming than the EU has ever been. I think it is very unlikely we will change them only six months later.”
Union sources add that in the run-up to Turkey’s summer elections Ankara is proving unwilling to compromise on any issues which could cost votes. “It is totally unrealistic to think we’ll get anything out of Turkey before that date,” said the official.
Nonetheless, the EU is considering holding an Association Council with Ankara at the end of next month, and the UK intends to arrange a visit before the end of its Union presidency.
A great deal will be at stake. Although Commission officials and Greek Cypriots are trying to play down Turkish threats to integrate the northern half of the island with the mainland, it is clear that such a move could spell doom for the peace process.
Ankara would be able to reject any form of mediation, claiming Cypriot affairs were an internal matter, and neither France nor Germany would be willing to bring a divided state into the EU.
That could reignite Greek threats to stymie enlargement to central and eastern Europe.
The US is also questioning how strong a role it should play in the search for a solution on Cyprus. “I will return to the island at the beginning of May for some intense negotiations and discussions with the two sides,” said Holbrooke. “Those will be very important in allowing the US to determine what its role is going to be.” But he warned: “The US is not going to spend the rest of the century wandering around trying to create a settlement between sides if they don’t want one.”
| https://www.politico.eu/article/commissioner-bids-to-narrow-eu-us-divisions-over-cyprus/ |
Nutrients | Free Full-Text | MACC1-Dependent Antitumor Effect of Curcumin in Colorectal Cancer
Metastasis is the main reason for the high mortality rate of colorectal cancer (CRC) patients. Despite the whole improvement in the field of cancer medicine, the treatment options for the patient in the late stages are very restricted. Our previous studies have elucidated metastasis-associated in colon cancer 1 (MACC1) as a direct link to metastasis formation. Therefore, we have aimed to inhibit its expression by using natural products, which are recently the center of most studies due to their low side effects and good tolerability. In this study, we have investigated the effect of one of the promising natural products, curcumin, on MACC1 expression and MACC1-induced tumor-promoting pathways. Curcumin reduced the MACC1 expression, restricted the MACC1-induced proliferation, and was able to reduce the MACC1-induced cell motility as one of the crucial steps for the distant dissemination of the tumor. We further showed the MACC1-dependent effect of curcumin on clonogenicity and wound healing. This study is, to our knowledge, the first identification of the effect of curcumin on the restriction of cancer motility, proliferation, and colony-forming ability by using MACC1 as a target.
MACC1-Dependent Antitumor Effect of Curcumin in Colorectal Cancer
by Nazli Güllü 1,2 , Janice Smith 1 , Pia Herrmann 1 and Ulrike Stein 1,2,*
Department Translational Oncology of Solid Tumors, Experimental and Clinical Research Center, Charité—Universitätsmedizin Berlin, and Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straße 10, 13125 Berlin, Germany
German Cancer Consortium (DKTK), Heidelberg, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
Author to whom correspondence should be addressed.
Nutrients 2022 , 14 (22), 4792; https://doi.org/10.3390/nu14224792
Received: 11 October 2022 / Revised: 7 November 2022 / Accepted: 10 November 2022 / Published: 12 November 2022
Abstract
Keywords:
curcumin
MACC1
colorectal cancer
cancer stemness
1. Introduction
Cancer is one of the leading causes of death worldwide. Only in 2020, 19 million patients were diagnosed with cancer. Among them, 40% developed metastasis, and 10 million lost their lives [ 1 ]. One of the most common cancer types is colorectal cancer (CRC) [ 2 ]. Although recent studies report improvements in the early stages, the overall survival rate of patients in the late stages is less than 10% [ 3 ]. Accordingly, it is crucial to identify novel biomarkers that can be used for metastasis prediction and simultaneously as a target of therapeutic interventions to treat patients at high risk for metastasis. One of the remarkable biomarkers, metastasis-associated in colon cancer 1 (MACC1), was discovered in 2009 [ 4 ]. The high expression of this gene drops the metastasis-free survival rate and, correlatively, the overall survival rate of the patients drastically [ 4 ]. Numerous research groups have acquainted its importance as a metastasis inducer, prognostic, and predictive biomarker for more than 20 different tumor entities, including CRC, breast cancer, and hepatocellular carcinoma [ 5 , 6 , 7 , 8 , 9 ]. MACC1 promotes cell death, genome instability, sustaining proliferative signaling, and inflammation. Furthermore, the high expression of MACC1 induces stemness, migration, invasion, and metastasis [ 6 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. These studies center MACC1 as a robust therapeutic target to restrict cancer progression and distant tumor dissemination.
17
18
19
20
Curcumin is the curcuminoid compound of turmeric (Curcuma longa). Its remedial effect was shown for various diseases, such as Alzheimer’s and gastrointestinal disorders [ 21 , 22 , 23 ]. Recent studies also demonstrated curcumin’s inhibitory impact on cancer progression and distant dissemination of tumors [ 24 ]. Curcumin is able to inhibit proliferation and induces apoptosis by increasing the expression of wild-type p53 [ 25 ]. Further studies revealed that curcumin treatment enhances G1/S cell cycle arrest by the downregulation of cyclin D1 [ 26 ]. Moreover, curcumin treatment induces autophagy through the suppression of the AKT/mTOR/p70S6K pathway and the activation of ERK1/2 [ 27 ]. In addition to these, its effect on angiogenesis, cancer stemness, and NFκB signaling was reported in different tumor entities [ 13 , 28 ]. Preliminary studies indicated the potential inhibitory effect of curcumin on prostate cancer metastasis by decreasing the expression of CXCL1 and 2 [ 29 ].
Despite all the studies, curcumin’s entire anti-cancer effects are still unclear. Therefore, in this study, we investigated the effect of curcumin on MACC1-driven tumor progression. To our knowledge, this is the first study showing a relationship between curcumin and MACC1.
2. Materials and Methods
2.1. Cell Lines and Compounds
The CRC cell lines SW620 and HCT116 were used for the experiments. The cells were obtained from the American Type Culture Collection (Manassas, VA, USA) maintained in DMEM and RPMI 1640 (both Thermo Fisher Scientific, Waltham, MA, USA), supplemented with 10% fetal bovine serum (FBS). The cells were preserved at 37 °C with 5% CO 2 in a humidified incubator.
For the experiments, previously by Crispr-Cas9-technology-generated MACC1 knocked-out clones of SW620 and HCT116 were used: SW620/KO-MACC1, HCT116/KO-MACC1 (control: SW620/KO-Control, HCT116/KO-Control).
In addition, various curcumin concentrations (50 μM–1.5 μM) were prepared freshly by diluting the curcumin powder in DMSO. At the same time, as a negative control, the cells were treated with DMSO and named untreated.
2.2. RNA Extraction and Quantitative PCR
The Gene Matrix Universal RNA purification Kit was used to isolate total RNA according to the manufacturer’s instructions (Roboklon, Gdansk, Poland). The extracted RNAs were used either immediately after the extraction or maintained at −80 °C. The concentration and the quality of RNA were assessed with NanoDrop 2000 (Thermo Fisher Scientific, Waltham, MA, USA). The total RNA (50 ng) was reverse transcribed by using the Biozym kit (Biozym, Hessisch Oldendorf, Germany).
For the amplification of the cDNAs, the Syber green format (Biozym, Hessisch Oldendorf, Germany) was used. The amplification protocol was performed for 10 min at 95 °C and 45 cycles of 10 s at 95 °C, 30 s at 60 °C, and 4 s at 72 °C. The gene expressions were normalized to GAPDH. The mean values of the duplicates were calculated using standard curves. The primer sequences were listed in Supplementary Table S1 .
2.3. Protein Extraction and Western Blot
6
2.4. Live Cell Imaging
7.5 × 10 3 cells were seeded in 96-well plates to investigate the curcumin’s effect on cell proliferation. Cells were treated with different curcumin concentrations between 7.5 μM–30 μM. The plates were placed into the IncuCyte system (Essen Bioscience, Ann Arbor, MI, USA). Cell proliferation was assessed every 2 h for 72 h and analyzed using the integrated software (Essen Bioscience, Ann Arbor, MI, USA).
2.5. Viability Assay
Cell viability was detected by using an MTT assay. First, 5 × 10 4 control or curcumin-treated cells were seeded into the 96-well plates. After 24 h or 48 h, the cells were incubated with MTT solution for 2.5 h at 37 °C. Afterward, the medium was removed, and the crystals were dissolved in DMSO. The absorbance was measured at 560 nm using a multi-well plate reader.
2.6. Migration Assay
The migration capability of the cells was determined using the Boyden chamber. The serum-starved cells (6 h 0.5% FBS) were seeded into a 12 mm diameter transwell upper chamber, and 10% FBS-containing medium served as a chemoattractant in the lower chamber. Curcumin was added to both chambers. Subsequently, the cells that migrated towards the down part were collected after 16 h. The collected cells were counted using a Guava live-cell counter (Luminex, Saluggia, Italy).
2.7. Wound Healing Assay
30 × 10 3 cells were seeded into a 96-well plate. After 12 h, the wounds were created with the wound-healing insert (Essen Bioscience, Ann Arbor, MI, USA). The medium was replaced with solvent and various curcumin concentrations. Subsequently, plates were placed into the IncuCyte live-cell-imaging system (Essen Bioscience, Ann Arbor, MI, USA). The wound was visualized every 2 h with the scratch mask of the integrated program. After 48 h, the wound size was compared to the wound size starting day 0.
2.8. Clonogenic Assay
A clonogenicity assay was performed to assess the ability of the single cells to grow into colonies. The 400 cells/well were seeded into 6-well plates and allowed to attach for 24 h. After adding (drug-containing-) fresh medium, they were incubated for 10 days in a humidified incubator at 37 °C with 5% CO 2 . For the analysis and visualization of the colonies, cells were fixed and stained with 1% Formaldehyde and 0.1% crystal violet containing PBS. The colonies were visualized by the FlourChemQ system (Alpha Innotech, Cell Biosciences, Santa Clara, CA, USA), and numbers and areas were determined using a colony plug of integrated AlphaView software version 2.0.1.1. (Alpha Innotech, Cell Biosciences, Santa Clara, CA, USA).
2.9. Statistics
All of the statistical analyses were performed with GraphPad Prism version 9.0 (La Jolla, CA, USA). The comparison of multiple groups was evaluated by one-way analysis of variance ANOVA. p values smaller than 0.05 were considered statistically significant (* = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001).
3. Result
3.1. Curcumin Treatment Reduced the MACC1 Expression
Initially, we determined the effect of curcumin on MACC1 expression. The SW620 cells were treated with various concentrations of curcumin. The endogenous MACC1 expression in the SW620 cells was reduced by 33% under 5 μM curcumin treatment compared to the untreated cells. The 7.5 μM, 15 μM, and 30 μM curcumin treatments decreased the MACC1 expression by 39%, 58%, and 83%, respectively ( Figure 1 A). The MACC1 protein levels dropped under 7.5 μM and higher curcumin treatments compared to untreated cells ( Figure 1 A).
Figure 1. Curcumin treatment reduced the metastasis-associated in colon cancer 1 (MACC1) expression. Colorectal cancer (CRC) cells SW620 and HCT116 cells were treated with various concentrations of curcumin. MACC1 mRNA expression was determined by qRT-PCR, and protein levels were detected with Western blot analysis. MACC1 mRNA and protein levels decreased upon increasing curcumin concentration in both SW620 and HCT116 cells ( A ). The same experiment was performed using the MACC1 knock-out clones, whereas the curcumin treatment did not impact the knock-out clones ( B ). MACC1 mRNAs were normalized with GAPDH. ß-actin has been used as a loading control for the Western blot analysis. Data represent mean ± SEM ( n ≥ 3), * = p < 0.05, ** = p < 0.01, **** = p < 0.0001.
These results were further consolidated in the HCT116 cells. The 7.5 μM curcumin treatment reduced the MACC1 expression by more than 39% ( Figure 1 A). The highest effect was observed at 30 μM curcumin treatment, whereby the MACC1 expression was reduced by more than 75%. The treatment of 7.5 μM and higher curcumin concentrations for 24 h reduced the MACC1 protein level in both cell lines ( Figure 1 B). Although various curcumin concentrations were able to reduce the MACC1 expression, the decrease in the MACC1 mRNA and protein levels is more prominent in treatments with higher curcumin dosages.
3.2. Curcumin Reduced the MACC1-Induced Proliferation Rate and Viability
Figure 2
Figure 2. Curcumin reduced proliferation and viability of CRC cell lines with high or moderate MACC1 expression. CRC cells were treated with various concentrations of curcumin. Every 2 h, the confluency of the cells was assessed by a cell imaging system. Curcumin significantly reduced the proliferation of the cells with high or moderate MACC1 expression (SW620/KO-Control, HCT116/KO-Control) ( A ). Cell viability was determined using the MTT assay. Viability of the CRC cells was reduced upon curcumin treatment in a dose-dependent manner ( B ). Data represent mean ± SEM ( n ≥ 3), * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001.
The same effect was also observed in the HCT116 cells. The HCT116/KO-Control cells proliferated 2.5 times more compared to the MACC1 knock-out cells. The treatment with 30 μM curcumin reduced the proliferation rate by 56%. Further treatment with 7.5 μM and 15 μM reduced the proliferation rate by 19% and 34.84%, respectively, compared to the untreated cells ( Figure 2 A). Especially, the proliferation of the cells with high MACC1 expression was reduced even under treatment of lower curcumin concentrations in both cell lines.
Moreover, the effect of curcumin on viability was investigated. The treatment with 50 μM and lower curcumin concentrations for 24 h and 48 h significantly reduced the viability of the cells ( Figure 2 B and Figure S1 ). The viability of the SW620/KO-Control and the HCT116/KO-Control cells dropped more than 40%.
3.3. Curcumin Treatment Restricted the Migratory Capability of the CRC Cells
In the context of the distant dissemination of the tumor, we investigated the effect of curcumin on the migratory capability of CRC cells. For this, we used the Boyden chamber assay. The high endogenous expression of MACC1 increased the migration rate of the SW620 cells by 22% compared to its MACC1 knock-out clones ( Figure 3 A). SW620/KO-Control cells migrated 66% less under 30 μM curcumin treatment. Similar effects were determined in MACC1 moderately-expressing HCT116 cells. Curcumin treatment reduced the migration rate of the HCT116/KO-Control cells by more than 73% under 30 μM curcumin treatment compared to untreated cells ( Figure 3 A).
Figure 3. Curcumin reduced the cell motility in CRC cell lines with high or moderate MACC1 expression. SW620 and HCT116 cells were treated with 15 μM and 30 μM curcumin, and their impact on the migratory capability was measured by Boyden chamber assay ( A ). The results were further validated by a wound healing assay, and wound size was analyzed and visualized by the IncuCyte live cell imaging system ( B ). Data represent mean ± SEM ( n ≥ 3).
We further complemented the effect of curcumin on directed migration in a wound-healing assay. Once the SW620/KO-Control cells were exposed to curcumin, the wound closed slower compared to the untreated cells, as shown by the representative figures and the corresponding quantification ( Figure 3 B).
3.4. Curcumin Restricted the Colony-Forming Capability of the Cells
Figure 4
Figure 4
Figure 4. Curcumin reduces MACC1-mediated clonogenicity. 400 cells/well were seeded into 6-well plates and were treated with various curcumin concentrations. After 10 days, the cells were fixed and stained with crystal violet. Afterward, the cells were imaged, and the colony numbers were assessed. Data represent mean ± SEM ( n ≥ 3), * = p < 0.05.
4. Discussion
Among all cancer types, CRC accounted for the second most common and third deadliest cancer [ 1 ]. Therefore, it is crucial to establish new treatment opportunities by establishing novel biomarkers that can be used for the stratification of the course of the disease and as a target for the restriction of cancer- and metastasis formation. In this study, we investigated the effect of the natural compound curcumin on reversing the tumor-promoting effect of MACC1 by reducing its expression.
In previous studies, the effect of statins on reducing MACC1 expression was demonstrated [ 30 , 31 ]. Statins (HMG-CoA reductases) are mainly used to reduce cholesterol levels and correlatively treat cardiovascular diseases [ 32 , 33 ]. The current studies broadened the impact of statins and showed their effect on other diseases, such as cancer and Alzheimer`s disease [ 34 , 35 , 36 , 37 ]. The effect of statins on the remission of cancer and on the improvement of the survival rate of CRC patients were revealed in a transatlantic cohort [ 31 ]. However, their effects are broad, and they were involved in various essential pathways. Therefore, it led to severe side effects, and their usage is still under consideration for ALS, HIV, some cardiomyopathic patients, and especially for patients older than 80 years [ 38 , 39 , 40 , 41 ].
We further elucidated the inhibitory effect of saffron on MACC1-dependent proliferation and migration; despite its MACC1-dependent effect, saffron treatment did not reduce MACC1 expression [ 18 ]. Especially due to the high costs and low availability of saffron, we studied further the effect of curcumin on MACC1. Recent studies showed the impact of curcumin on different metastasis-promoting pathways, such as NFκB and MMPs, in various tumors [ 13 , 42 , 43 ]. Most importantly, a wide range of studies showed that curcumin could be tolerated even in high dosages [ 44 ].
The curcumin treatment reduced the MACC1 expression in a concentration-dependent manner in the endogenously high/mild MACC1-expressing SW620/HCT116 cells. The reduction was more prominent under the treatment of the higher dosages (15 μM and 30 μM). To elucidate the MACC1-dependent effect of curcumin, we further treated the MACC1 knock-out clones of the same cells.
Previous studies reported that high MACC1 expression increases the proliferation and viability of a wide range of tumor types, including CRC and breast cancer [ 14 ]. Therefore, we investigated if curcumin reduces MACC1 expression and further reverses MACC1-promoted proliferation and viability. Exposure to various curcumin concentrations reduced the proliferation rate of the CRC cells. However, this reduction was more prominent by the endogenously high/moderate MACC1-expressing cells. Even exposure to lower concentrations (7.5 μM) for 72 h could significantly reduce the proliferation of MACC1-expressing cells. The same effect was not observed by the SW620/KO-MACC1 clones. These results were further validated in viability assay.
The distant dissemination of the tumor requires the motility capability of the cells and the ability to form de novo tumors at a distant site [ 45 , 46 ]. It is known that MACC1 expression increases this process by inducing several pathways, including PI3K/AKT and ß-catenin [ 6 , 16 , 47 , 48 ]. Therefore, we have exposed the cells to various curcumin concentrations, showing that the migration reduced upon treatment. We were aware that curcumin has a general anti-migratory effect [ 49 ]; however, in this study, we demonstrated that this reduction was more prominent in the MACC1-expressing cells. We further observed a similar effect of curcumin on directed migration by a wound-healing assay. MACC1 expression increased the wound-healing rate, but once the cells were treated with curcumin, the MACC1 accelerated wound-healing rate decreased.
We further showed the MACC1-dependent effect of curcumin on clonogenicity. The de novo tumor-forming capability of the cancer cells is essential for metastasis formation. The high level of MACC1 enhances the clonogenicity of the tumor cells. Therefore, to inhibit the MACC1-induced clonogenicity, the cells were treated with various curcumin concentrations for 10 days. Although curcumin generally reduces clonogenicity [ 50 ], it showed an accelerated effect on the moderate/high MACC1-expressing cells compared to MACC1 knock-out clones.
This study successfully demonstrated curcumin’s novel effect on MACC1 expression and the inhibition of MACC1-induced pro-tumorigenic pathways, including proliferation, migration, wound healing, and clonogenicity in established cell lines. However, we do not know how curcumin elicits its effect on MACC1 expression. Previous studies showed that curcumin treatment inhibits ERK phosphorylation, which promotes MACC1 expression [ 6 , 51 ]. This interaction should be further investigated.
Taken together, we illustrated the prominent inhibitory effect of curcumin on MACC1 expression and MACC1-induced phenotypes. In addition, we further revealed the MACC1-dependent anti-proliferative and anti-migratory effects of curcumin. Although the experiments have been conducted in the established cell lines, these promising results can expand in the other models so that curcumin can further supplement the treatment of CRC patients, notably those who cannot tolerate statins and have high MACC1 expression.
5. Conclusions
This is the first study showing the effect of curcumin on reducing MACC1 expression in the established cell lines. In this study, we demonstrated the MACC1-dependent inhibitory effect of a wide range of curcumin concentrations on MACC1-induced viability, proliferation, migration, wound healing, and clonogenicity. This study provides evidence to target MACC1 via natural products to establish new treatment opportunities for the treatment of especially MACC1-driven tumor progression and metastasis.
Supplementary Materials
The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/nu14224792/s1 , Table S1: Primers used for RT-qPCR; Figure S1: Curcumin reduced viability of CRC cell lines with high or moderate MACC1 expression after 48 h.
Author Contributions
U.S. and N.G.: conception and design. N.G., J.S. and P.H.: acquisition and analysis of data. N.G. and U.S.: writing of the manuscript. N.G. and U.S.: critical review of the manuscript. All authors read and approved the final manuscript.
Funding
This work was supported by German Cancer Consortium (DKTK).
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Acknowledgments
We would like to thank Benedikt Kortüm for establishing the SW620 and HCT116 MACC1 knock-out clones and all the members of the Stein lab for their valuable discussion and contributions.
Conflicts of Interest
The authors declare no conflict of interest.
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Figure 1. Curcumin treatment reduced the metastasis-associated in colon cancer 1 (MACC1) expression. Colorectal cancer (CRC) cells SW620 and HCT116 cells were treated with various concentrations of curcumin. MACC1 mRNA expression was determined by qRT-PCR, and protein levels were detected with Western blot analysis. MACC1 mRNA and protein levels decreased upon increasing curcumin concentration in both SW620 and HCT116 cells ( A ). The same experiment was performed using the MACC1 knock-out clones, whereas the curcumin treatment did not impact the knock-out clones ( B ). MACC1 mRNAs were normalized with GAPDH. ß-actin has been used as a loading control for the Western blot analysis. Data represent mean ± SEM ( n ≥ 3), * = p < 0.05, ** = p < 0.01, **** = p < 0.0001.
Figure 2. Curcumin reduced proliferation and viability of CRC cell lines with high or moderate MACC1 expression. CRC cells were treated with various concentrations of curcumin. Every 2 h, the confluency of the cells was assessed by a cell imaging system. Curcumin significantly reduced the proliferation of the cells with high or moderate MACC1 expression (SW620/KO-Control, HCT116/KO-Control) ( A ). Cell viability was determined using the MTT assay. Viability of the CRC cells was reduced upon curcumin treatment in a dose-dependent manner ( B ). Data represent mean ± SEM ( n ≥ 3), * = p < 0.05, ** = p < 0.01, *** = p < 0.001, **** = p < 0.0001.
Figure 3. Curcumin reduced the cell motility in CRC cell lines with high or moderate MACC1 expression. SW620 and HCT116 cells were treated with 15 μM and 30 μM curcumin, and their impact on the migratory capability was measured by Boyden chamber assay ( A ). The results were further validated by a wound healing assay, and wound size was analyzed and visualized by the IncuCyte live cell imaging system ( B ). Data represent mean ± SEM ( n ≥ 3).
Figure 4. Curcumin reduces MACC1-mediated clonogenicity. 400 cells/well were seeded into 6-well plates and were treated with various curcumin concentrations. After 10 days, the cells were fixed and stained with crystal violet. Afterward, the cells were imaged, and the colony numbers were assessed. Data represent mean ± SEM ( n ≥ 3), * = p < 0.05.
MDPI and ACS Style
Güllü, N.; Smith, J.; Herrmann, P.; Stein, U. MACC1-Dependent Antitumor Effect of Curcumin in Colorectal Cancer. Nutrients 2022, 14, 4792.
https://doi.org/10.3390/nu14224792
AMA Style
Güllü N, Smith J, Herrmann P, Stein U. MACC1-Dependent Antitumor Effect of Curcumin in Colorectal Cancer. Nutrients. 2022; 14(22):4792.
https://doi.org/10.3390/nu14224792
Chicago/Turabian Style
Güllü, Nazli, Janice Smith, Pia Herrmann, and Ulrike Stein. 2022. "MACC1-Dependent Antitumor Effect of Curcumin in Colorectal Cancer" Nutrients14, no. 22: 4792.
https://doi.org/10.3390/nu14224792
| https://www.mdpi.com/2072-6643/14/22/4792/html#B3-nutrients-14-04792 |
Microwave Dielectric Properties Measurements Using the Waveguide Reflection Dielectric Resonator
Download Citation | Microwave Dielectric Properties Measurements Using the Waveguide Reflection Dielectric Resonator | Measurements of dielectric properties of the homogeneous and isotropic medium in the microwave frequencies by a waveguide reflection dielectric... | Find, read and cite all the research you need on ResearchGate
Conference Paper
Microwave Dielectric Properties Measurements Using the Waveguide Reflection Dielectric Resonator
June 2007
Conference Record - IEEE Instrumentation and Measurement Technology Conference
DOI: 10.1109/IMTC.2007.379350
Source
IEEE Xplore
Conference: Instrumentation and Measurement Technology Conference Proceedings, 2007. IMTC 2007. IEEE
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Jyh Sheen
Jyh Sheen
Abstract
Measurements of dielectric properties of the homogeneous and isotropic medium in the microwave frequencies by a waveguide reflection dielectric resonator are studied. A dielectric rod sample is put inside of a rectangular cavity made by a microwave waveguide. The sample's dielectric constant and loss tangent are measured at the resonant frequency of the TE<sub>01delta</sub> mode. A simple field model of the waveguide reflection resonator is developed for the measurements of dielectric properties. This field model is developed from that of the parallel-plate dielectric resonator. Reflection signal is measured for the calculations of dielectric properties. The dielectric properties are computed from the resonant frequency, structure dimensions, and unloaded quality factor. The effect of the conductor loss of the metal cavity is studied. The measurement accuracy of dielectric properties is discussed by comparing the results with those measured by other well known techniques.
<here is a image 175d1bd4b7439d95-754927124da715c1>
... Impedance spectrometry has brought important developments with the following important contributions: impedance characterization of cell-electrode interface using an equivalent circuit approach [7]; development of capacitive impedance spectroscopy (CIS) to investigate the electric properties of electrochemical materials [8]; demonstration of cell manipulation and analysis using dielectrophoresis and micro-electrical impedance spectroscopy in chromaffin cells and red blood cells [9]; measurement of impedance in biofluids to examine the impact of the length and concentration of free-floating double-stranded DNA molecules [10]; and using a resonant sensing electrode structure having an external inductor to sense human blood cells [11]. RF and MW signal stimulation have been used in bioprocessing to characterize dielectric properties of materials such as: use of measurement of moisture content in grain and in considering dielectric heating applications of agricultural products [12] ; evaluation of the RF safety of mobile phones in terms of specific absorption rate [13]; development of a microwave nondestructive evaluation to measure dielectric properties of liquids [14]; measurement of the scattering transmission parameters to determine the dielectric properties of wheat, corn and soybeans [15]; and measurement of dielectric properties of homogeneous isotropic medium using microwave frequency signal stimulation
[16]
. ...
Interdigitated arrays for the measurement of electrical and electrochemical characteristics of biological samples.
Conference Paper
Full-text available
Jun 2013
<here is a image 2ec9fe754947f48c-cf4c91243027c0ca> Christian Mendoza-Buenrostro
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Jose Manuel Rodriguez-Delgado
<here is a image 58bb39efd4459820-60c133251e3e79b1> Melissa Rodríguez
<here is a image 1248ba4ebfcf79df-b711b4a752befe3b> Sergio O. Martinez-Chapa
In this work we compared two methodologies for the
characterization of biological samples with two Interdigitated Arrays (IDA’s)
of different size and material. The characteristic measured on the firs IDA
(Figure 1a) corresponds to an impedance measurement of the biological
sample, a change in impedance is detected over an IDA made of cooper
electrodes on a Printed Circuit Board (PCB) [1]. The second measurement
corresponds to the electrochemical characteristics of a biological sample
using an IDA (Figure 1b) made of carbon electrodes over a silicon wafer [2].
Both methodologies were used to characterize the different responses of the
biological sample and measure the responses of IDA’s.
... Impedance spectrometry has brought important developments with the following important contributions: impedance characterization of cell-electrode interface using an equivalent circuit approach [7]; development of capacitive impedance spectroscopy (CIS) to investigate the electric properties of electrochemical materials [8]; demonstration of cell manipulation and analysis using dielectrophoresis and micro-electrical impedance spectroscopy in chromaffin cells and red blood cells [9]; measurement of impedance in biofluids to examine the impact of the length and concentration of free-floating double-stranded DNA molecules [10]; and using a resonant sensing electrode structure having an external inductor to sense human blood cells [11]. RF and MW signal stimulation have been used in bioprocessing to characterize dielectric properties of materials such as: use of measurement of moisture content in grain and in considering dielectric heating applications of agricultural products [12] ; evaluation of the RF safety of mobile phones in terms of specific absorption rate [13]; development of a microwave nondestructive evaluation to measure dielectric properties of liquids [14]; measurement of the scattering transmission parameters to determine the dielectric properties of wheat, corn and soybeans [15]; and measurement of dielectric properties of homogeneous isotropic medium using microwave frequency signal stimulation
[16]
. ...
Characterization of interdigitated electrode structures for water contaminant detection using a hybrid voltage divider and a vector network analyzer
Article
Full-text available
Aug 2012
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Jose Manuel Rodriguez-Delgado
<here is a image 58bb39efd4459820-60c133251e3e79b1> Melissa Rodríguez
<here is a image 2ec9fe754947f48c-cf4c91243027c0ca> Christian Mendoza-Buenrostro
<here is a image 1248ba4ebfcf79df-b711b4a752befe3b> Sergio O. Martinez-Chapa
Interdigitated capacitive electrode structures have been used to monitor or actuate over organic and electrochemical media in efforts to characterize biochemical properties. This article describes a method to perform a pre-characterization of interdigitated electrode structures using two methods: a hybrid voltage divider (HVD) and a vector network analyzer (VNA). Both methodologies develop some tests under two different conditions: free air and bi-distilled water media. Also, the HVD methodology is used for other two conditions: phosphate buffer with laccase (polyphenoloxidase; EC 1.10.3.2) and contaminated media composed by a mix of phosphate buffer and 3-ethylbenzothiazoline-6-sulfonic acid (ABTS). The purpose of this study is to develop and validate a characterization methodology using both, a hybrid voltage divider and VNA T-# network impedance models of the interdigitated capacitive electrode structure that will provide a shunt RC network of particular interest in detecting the amount of contamination existing in the water solution for the media conditions. This methodology should provide us with the best possible sensitivity in monitoring water contaminant media characteristics. The results show that both methods, the hybrid voltage divider and the VNA methodology, are feasible in determining impedance modeling parameters. These parameters can be used to develop electric interrogation procedures and devices such as dielectric characteristics to identify contaminant substances in water solutions.
... MUTs, either rice husk board or rice straw board, is pressed using the dielectric probe as shown inFigure 14. This probe propagates signal into the MUT
[17]
, and the resulting measured reflections are then converted into dielectric properties values via Agilent 85070B software. This system is capable of determining dielectric properties up to 20 GHz. ...
Alternatives for PCB Laminates: Dielectric Properties' Measurements at Microwave Frequencies
Chapter
Full-text available
Oct 2012
<here is a image 0155bc7c6c23039e-12e006513f896cfe> F.h Wee
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Ping Jack Soh
F. Malek
<here is a image 352d984966bb0544-6bfdd9adfa201ab4> H. Nornikman
... MUTs, either rice husk board or rice straw board, is pressed using the dielectric probe as shown inFigure 14. This probe propagates signal into the MUT
[17]
, and the resulting measured reflections are then converted into dielectric properties values via Agilent 85070B software. This system is capable of determining dielectric properties up to 20 GHz. ...
Alternatives for PCB Laminates: Dielectric Properties' Measurements at Microwave Frequencies
Chapter
Full-text available
Oct 2012
<here is a image 0155bc7c6c23039e-12e006513f896cfe> F.h Wee
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Ping Jack Soh
Mohd Fareq Abd Malek
<here is a image 352d984966bb0544-6bfdd9adfa201ab4> H. Nornikman
A study on the properties of complementary frequency selective surfaces for permittivity measurements
This paper presents parametric studies on the geometric and electromagnetic (EM) properties of complementary frequency selective surfaces (CFSS), used in an X-band waveguide for measuring the permittivities of dielectric substrates. This gives understanding of the optimum configuration to be used for the dielectric measurements. The studies were done via simulations using 3D finite-difference timedomain (FDTD) EM software, Empire XPU™ and the results are summarized in this paper.
Application of microwave aquametry in civil engineering and in power generation
The first part of this paper is devoted to microwave moisture-measurement (aquametry), starting with an overview of the work performed by researchers involved in using microwave (or high-frequency electromagnetic) signals for moisture measurement, as well as in non-destructive testing and evaluation (NDT&E) of mainly concrete. A non-contact sensor for concrete (NSC) will be introduced in the second part of this paper, designed to be applied in concrete mixers above the moving mix, using a cross-polarized, active back-scatter. The system is based on microwave free-space, double transmission/reflection type, two-parameter complex vector measurement. A new microwave NDT-method and instrument (sensor for timber, SFT) have also been developed for real-time on-line measurement of the moisture content of timber, the latter intended to be used as fuel in wood-fired power plants (renewable energy source). For direct and inverse modelling, problem-specific software was developed, corresponding to the type of firewood, the moisture content, microwave attenuation and phase shift, etc. After validation, a proposal is given for a multi-frequency, free-space measurement setup.
Comparisons of Microwave Dielectric Property Measurements by Transmission/Reflection Techniques and Resonance Techniques
This review provides a general comparison of the two most commonly used techniques for measurement of complex permittivity at microwave frequencies: transmission/reflection and resonance. The transmission/reflectance techniques are analyzed using distributed and lumped impedance models. The resonance techniques are analyzed using both dielectric and cavity resonance models. The analysis, combined with experimental results, enables us to illustrate the advantages and disadvantages of the various techniques and provide guidance on which techniques to use under particular circumstances. In general, transmission/reflection techniques can be used over a broad band of frequencies, and are suitable for loss measurements on high loss materials. Resonance techniques do not have swept frequency capability, but have higher accuracy for measurement of the real part of permittivity and can measure the loss tangent of low loss materials with high resolution.
Cylindrical Dielectric Resonators and Their Applications in TEM Line Microwave Circuits
Article
Full-text available
IEEE T MICROW THEORY
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Marian . W Pospieszalski
A cylindrical sample of low-loss high epsilon<sub>r</sub> placed between two parallel conducting plates perpendicular to the sample axis forms a microwave resonator. A simple approximate method for predicting the resonant frequencies of the TE modes of this structure is developed. The method becomes exact for the fitting case of this structure which is known as a dielectric post resonator. In all cases, the accuracy of the method is shown to be better than 3.5 percent. The TE<sub>01delta</sub> mode chart presented allows the determination of the resonant frequency and the tuning range of any cylindrical dielectric resonator for which epsilon<sub>r</sub> >or= 10. The properties of the dielectric resonator as a TEM line element are demonstrated experimentally.
A Microwave Dielectric Measurement Technique for High Permittivity Materials
Article
FERROELECTRICS
<here is a image 6fe7d2e653050f34-1cc9778a1f2b37ca> M. T. Lanagan
J. H. Kim
<here is a image 91e9417d54e0d678-7fe0043514df28a7> Charu Dube
R. E. Newnham
A microwave measurement technique has been developed for the characterization of high dielectric constant (100 to 10,000), and high dielectric loss (0.2 to 0.7) materials. The method is based on the frequency dependence of electromagnetic wave transmission through a dielectric slab. It is a useful technique for the dielectric measurement of relaxor ferroelectric materials, and an example is given for the Pb(Mg1/3Nb2/3)O3-PbTiO3 system. The rapid developments in network analysis have made this measurment method possible.
Ba(Zn1/3Nb2/3)O3-Sr(Zn1/3Nb2/3)O3 Solid Solution Ceramics with Temperature-Stable High Dielectric Constant and Low Microwave Loss
Article
Makoto Onoda
Jun Kuwata
Kumiko Kaneta
Shoichiro Nomura
Solid solution ceramics in the
Ba(Zn1/3Nb2/3)O3(BZN)-Sr(Zn1/3Nb2/3)O3
(SZN) system have been studied with a view to finding materials for use
as dielectric resonators at microwave frequency. The relative dielectric
constant and the unloaded Q at 10 GHz are respectively 41 and 5400 for
BZN, and 40 and 2000 for SZN. The temperature coefficient of the
resonant frequency is estimated as 30 ppm/°C for BZN and -38
ppm/°C for SZN. The dielectric constant of 0.3 BZN-0.7 SZN ceramic
is nearly independent of temperature, which gives a very small estimated
temperature coefficient of the resonant frequency of -5 ppm/°C.
Modification to a simple field model of the TE01δ mode of the parallel-plate open dielectric resonator
Article
MICROW OPT TECHN LET
Jyh Sheen
A. S. Bhalla
L. E. Cross
A modification to the field expressions on the simple Itoh and Rudokas model for the TE01δ mode of the parallel-plate open dielectric resonator is given. This modification is justified by the dramatic improvement in the accuracy of resonant frequency prediction. © 1994 John Wiley & Sons, Inc.
Ba2Ti9O20 as a Microwave Dielectric Resonator
Article
J AM CERAM SOC
J. K. PLOURDE
D. F. LINN
H. M. O'BRYAN JR
JOHN THOMSON Jr
Microwave measurements of Ba2Ti9O20 show that this ceramic is uniquely suited for dielectric resonators. (Suitable ceramics should have a high dielectric constant K, a low dielectric loss (high Q), and a low temperature coefficient of resonant frequency, τ.) At 4 GHz, Ba2Ti9O20 resonators have Q >8000, K= 39.8, and τ=2 ppm/°C. Measurements of Q and τ were made on unmetallized ceramic resonator disks positioned in a waveguide; K was measured using a dielectric post resonator technique. From 4 to 10 GHz, Q approaches that for a copper waveguide cavity, whereas the temperature coefficient is typically 8 times lower.
Far Infrared Reflection Spectra of Ba(Zn,Ta)O3-BaZrO3 Dielectric Resonator Material
Article
Kikuo Wakino
MICHIHIRO MURATA
HIROSKI TAMURA
The dielectric ceramic materiala Ba(Zn1/3Ta2/3)O3–BaZrO3 has extremely low dielectric loss at microwave frequencies. To investigate the lattice vibrations of Ba(Zn,Ta)O3 and Ba(Zr, Zn, Ta)O3 solid solutions, far infrared reflection spectra were measured from 50 to 4000 cm−1 using a Fourier transform infrared spectrometer. These data were analyzed according to the classical dispersion theory. The spectra of Ba(Zn,Ta)O3 are well fitted by using the 14 resonant modes, and the spectra of Ba(Zr, Zn, Ta)O3 solid solution are fitted by assuming the normal distribution on resonant frequencies. The damping constant of these materials is discussed, and the values of tan δ calculated from the dispersion parameters agree with the measured values.
Improved High-Q Dielectric Resonator With Complex Perovskite Structure
Article
J AM CERAM SOC
Hiroshi Tamura
Takehiro Konoike
Yukio Sakabe
| https://www.researchgate.net/publication/224715365_Microwave_Dielectric_Properties_Measurements_Using_the_Waveguide_Reflection_Dielectric_Resonator |
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(+)-alpha-pinene (+)-DCA-CC(2-) (-)-DCA-CC(2-) (-)-trans-carveol (10Z)-tricosene (11Z)-icos-11-enoic acid + (11Z,14Z,17Z)-icosatrienoate (13E)-octadecenoic acid (13R)-S-cysteinyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoic acid (13R)-S-cysteinylglycinyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoic acid (13R)-S-glutathionyl-(14S)-hydroxy-(4Z,7Z,9E,11E,16Z,19Z)-docosahexaenoic acid (13S)-hydroxy-(14S,15S)-epoxy-(5Z,8Z,11Z)-icosatrienoic acid (15Z)-phycoviolobilin(2-) (15Z)-tetracosenoate + (17Z)-hexacosenoic acid + (1R,10aS)-1,4,10,10a-tetrahydrophenazine-1,6-dicarboxylate (1R,5aS,6R)-1,4,5,5a,6,9-hexahydrophenazine-1,6-dicarboxylate (1R,6R)-2-(3-carboxylatopropanoyl)-6-hydroxycyclohexa-2,4-diene-1-carboxylate (1S)-1,23,25-trihydroxy-24-oxocalciol (1S)-1,25-dihydroxy-24-oxocalciol (1S,6R)-2-(3-carboxylatopropanoyl)-6-hydroxycyclohexa-2,4-diene-1-carboxylate(2-) (2,3-diphenylcyclopropyl)methyl phenyl sulfoxide (2-aminoethyl)phosphonic acid + (2-aminophenyl)succinate (2-hydroxyphenyl)acetate (2-hydroxyphenyl)acetic acid (2-trans,6-cis)-dodeca-2,6-dienoyl-CoA (20R)-17alpha,20-dihydroxycholesterol (20R,22R)-20,22-dihydroxycholesterol (20S)-20-hydroxypregn-4-en-3-one (20S)-hydroxyvitamin D3 (20S,23)-dihydroxyvitamin D3 (20S,23,24)-trihydroxyvitamin D3 (20S,23,25)-trihydroxyvitamin D3 (20S,24R)-dihydroxyvitamin D3 (20S,24S)-dihydroxyvitamin D3 (23S)-23,25,26-trihydroxycalciol + (24E)-3alpha,7alpha-dihydroxy-5beta-cholest-24-en-26-oyl-CoA (24R)-24,25-dihydroxycalciol (24R,25R)-3alpha,7alpha,24-trihydroxy-5beta-cholestan-26-oyl-CoA (24S)-7alpha,24-dihydroxycholesterol (24S,25)-dihydroxycholesterol (24S,26)-dihydroxycholesterol (24Z),26-hydroxydesmosterol (25R)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-oyl-CoA(4-) (25R)-7alpha,26-dihydroxycholest-4-en-3-one (25R)-cholest-5-ene-3beta,26-diol + (25S)-3alpha,7alpha,12alpha-trihydroxy-5beta-cholestanoyl-CoA (2E)-2-(methoxycarbonylmethyl)but-2-enedioate(2-) (2E)-2-hexenyl isovalerate (2E)-3-(methoxycarbonyl)pent-2-enedioate(2-) (2R,3S)-2,3-dimethylmalate(2-) (2R,3S)-2-methyl-3-propyloxirane (2R,3Z)-phycocyanobilin(2-) (2S)-2-(4-\{[(1R,2S)-2-hydroxycyclopentyl]methyl\}phenyl)propanoic acid (2S)-2-amino-2'-deoxyadenylo-succinate(4-) (2S)-2-isopropyl-3-oxosuccinate(2-) (2S,3R)-3-hydroxybutane-1,2,3-tricarboxylate (2S,3S)-3-hydroxy-2-methylbutanoyl-CoA(4-) (2S,4R)-4-hydroxy-4-methylglutamate(1-) (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate(2-) (2S,4S)-4-hydroxy-4-methylglutamate(1-) (2Z,4E)-2-aminomuconate(2-) (2Z,4E)-2-ammoniomuconate(1-) (3,4-dihydroxyphenyl)acetate (3,4-dihydroxyphenyl)acetic acid + (3E)-2,3,4-trimethylhex-3-enal (3E)-2,6-dimethyloct-3-ene (3E)-phycocyanobilin(2-) (3E)-phycoerythrobilin(2-) (3R,5S)-1-pyrroline-3-hydroxy-5-carboxylic acid (3S)-3-hydroxy-3-methylglutaryl-CoA (3S)-citramalyl-CoA(5-) (3S,4R)-3,4-dihydroxycyclohexa-1,5-diene-1,4-dicarboxylate (3Z)-phycoerythrobilin(2-) (3Z)-phytochromobilin(2-) (3Z,6Z)-dodecadienoyl-CoA (4-hydroxy-3-methoxyphenyl)acetaldehyde (4-hydroxyphenyl)acetaldehyde (4E)-7-methyldec-4-ene (4S,10Z,16R)-phycourobilin(2-) (4Z)-2-oxohept-4-enedioate (4Z,7Z,10Z,13Z,16Z)-docosa-4,7,10,13,16-pentaenoic acid + (4Z,7Z,10Z,13Z,16Z,19Z)-docosahexaenoate + (5-hydroxyindol-3-yl)acetaldehyde (5-hydroxyindol-3-yl)acetate (5-hydroxyindol-3-yl)acetic acid + (5alpha)-androst-3-en-17-one (5aS)-5,5a-dihydrophenazine-1,6-dicarboxylate (5Z)-tetradecenoylcarnitine (5Z,8Z)-octadecadienoic acid (5Z,9E,12S,14Z)-8,11,12,20-tetrahydroxyicosa-5,9,14-trienoic acid (5Z,9E,12S,14Z)-8,11,12-trihydroxyicosa-5,9,14-trienoate (5Z,9E,14Z)-(8xi,11R,12S)-11,12-epoxy-8-hydroxyicosa-5,9,14-trienoate (6E,8Z)-5-oxooctadecadienoic acid (6R)-5,10-methenyltetrahydrofolate + (6R)-5,10-methylenetetrahydrofolate(2-) + (6S)-5,6,7,8-tetrahydrofolate(2-) (6S)-5-formyltetrahydrofolate(2-) (6S)-5-methyltetrahydrofolate(2-) + (6S)-6-ammonio-3,3-dimethyl-2-oxoheptanedioate (7R)-7-(4-carboxylatobutanamido)cephalosporanate (7R)-7-(5-carboxy-5-oxopentanamido)cephalosporanate(2-) (7Z,10Z,13Z,16Z,19Z)-docosapentaenoate + (7Z,10Z,13Z,16Z,19Z)-docosapentaenoic acid + (9E)-10-nitrooctadecenoic acid (9E)-9-nitrooctadecenoic acid (9E,11E)-octadecadienoic acid + (alpha-D-mannosyl)2-beta-D-mannosyl-diacetylchitobiosyldiphosphodolichol (alpha-D-mannosyl)3-beta-D-mannosyldiacetylchitobiosyldiphosphodolichol (alpha-D-mannosyl)4-beta-D-mannosyldiacetylchitobiosyldiphosphodolichol (alpha-D-mannosyl)5-beta-D-mannosyldiacetylchitobiosyldiphosphodolichol (alpha-D-mannosyl)6-beta-D-mannosyl-diacetylchitobiosyldiphosphodolichol (alpha-D-mannosyl)7-beta-D-mannosyl-diacetylchitobiosyldiphosphodolichol (E)-2-((N-methylformamido)methylene) succinate (E)-2-dodecene + (E)-2-octene (E)-3-dodecene (E)-3-octene (E)-4-oxonon-2-enal (E)-dec-3-en-2-ol (E)-hexadec-2-enoyl-CoA(4-) (E,E)-bilirubin anion (Kdo)2-lipid A 1-diphosphate(7-) (E. coli) (Kdo)2-lipid A(6-) (E. coli) (N(omega)-L-arginino)succinate(1-) (R)-2-(carboxylatomethyl)-5-oxo-2,5-dihydro-2-furoate (R)-2-benzylsuccinate (R)-2-ethylmalate(2-) (R)-2-hydroxy-4-methylpentanoate (R)-2-hydroxyadipate(2-) (R)-3,3-dimethylmalate(2-) (R)-3-hydroxybutanoyl-CoA(4-) (R)-3-hydroxybutyrate + (R)-3-hydroxybutyric acid + (R)-3-hydroxylauric acid + (R)-4'-phosphonatopantothenate(3-) (R)-5-diphosphomevalonic acid (R)-5-phosphonatomevalonate(3-) (R)-adrenaline(1+) (R)-icosanoylcarnitine (R)-lactaldehyde (R)-lactic acid + (R)-methylmalonyl-CoA(5-) (R)-mevalonate + (R)-noradrenaline(1+) (R)-oleoylcarnitine (R)-oleoylcarnitine hydrochloride (R)-propane-1,2-diol (R)-S-lactoylglutathionate(1-) (R)-S-lactoylglutathione (S)-2,3-epoxysqualene (S)-2-acetamido-6-oxopimelate(2-) (S)-2-benzylsuccinate (S)-2-hydroxy-3-methylbutyrate (S)-2-hydroxy-3-methylbutyric acid (S)-3-aminoisobutyric acid (S)-3-hydroxybutanoyl-CoA(4-) (S)-3-hydroxydecanoyl-CoA (S)-3-hydroxyhexanoyl-CoA (S)-3-hydroxyisobutyryl-CoA (S)-3-hydroxylauroyl-CoA (S)-3-hydroxyoctanoyl-CoA (S)-3-hydroxypalmitoyl-CoA (S)-3-hydroxytetradecanoyl-CoA (S)-3-sulfonatolactate(2-) (S)-carnitinium (S)-dihydroorotate (S)-dihydroorotic acid (S)-lactaldehyde (S)-lactic acid + (S)-malate(2-) + (S)-methylmalonyl-CoA(5-) (S)-propane-1,2-diol + (Z)-2-octene (Z)-2-penten-1-ol (Z)-3-dodecene (Z)-3-octene (Z)-but-2-ene-1,2,3-tricarboxylate 1,1,3,3-tetramethylurea 1,2,3,4-tetrachlorobutane 1,2-di-[(6Z)-octadecenoyl]-sn-glycero-3-phosphocholine 1,2-diacyl-sn-glycero-3-phosphocholine(1+) + 1,2-dioleoyl-sn-glycero-3-phospho-N,N-dimethylethanolamine 1,2-dioleoyl-sn-glycero-3-phospho-N,N-dimethylethanolamine zwitterion 1,2-dioleoyl-sn-glycero-3-phospho-N-methylethanolamine 1,2-dioleoyl-sn-glycero-3-phospho-N-methylethanolamine zwitterion 1,2-distearoylphosphatidylethanolamine zwitterion + 1,4-butanediammonium + 1,4-dimethylcyclohexane + 1,4-dithiothreitol + 1,5-anhydro-D-glucitol 1-(4Z,7Z,10Z,13Z,16Z,19Z-docosahexaenoyl)-sn-glycero-3-phosphocholine 1-[(10Z,13Z,16Z)-docosatrienoyl]-2-[(9Z,12Z)-hexadecadienoyl]-sn-glycero-3-phospho-1D-myo-inositol 1-[(10Z,13Z,16Z)-docosatrienoyl]-2-hexadecanoyl-sn-glycero-3-phospho-1D-myo-inositol 1-[(10Z,13Z,16Z)-docosatrienoyl]-2-linoleoyl-sn-glycero-3-phospho-1D-myo-inositol 1-[(13Z,16Z)-docosadienoyl]-2-hexadecanoyl-sn-glycero-3-phospho-1D-myo-inositol 1-[(13Z,16Z)-docosadienoyl]-2-linoleoyl-sn-glycero-3-phospho-1D-myo-inositol 1-[(1Z,9Z)-octadecadienyl]-sn-glycero-3-phosphocholine 1-[(8Z,11Z,14Z,17Z)-icosatetraenoyl]-2-[(11Z)-icosenoyl]-sn-glycero-3-phospho-1D-myo-inositol 1-[(8Z,11Z,14Z,17Z)-icosatetraenoyl]-2-[(11Z)-octadecenoyl]-sn-glycero-3-phospho-1D-myo-inositol 1-[(8Z,11Z,14Z,17Z)-icosatetraenoyl]-2-icosanoyl-sn-glycero-3-phospho-1D-myo-inositol 1-[(8Z,11Z,14Z,17Z)-icosatetraenoyl]-2-octadecanoyl-sn-glycero-3-phospho-1D-myo-inositol 1-[(9Z)-hexadecenoyl]-sn-glycero-3-phosphocholine 1-acyl-sn-glycerol 3-phosphate(2-) + 1-acylglycerone 3-phosphate(2-) + 1-alkyl-2-acetyl-sn-glycerol + 1-alkyl-2-acetyl-sn-glycerol 3-phosphate(2-) 1-alkyl-2-acyl-sn-glycero-3-phosphoethanolamine + 1-alkyl-2-acyl-sn-glycerol + 1-alkyl-sn-glycerol 3-phosphate(2-) + 1-alkylglycerone 3-phosphate + 1-alkylglycerone 3-phosphate(2-) + 1-arachidonoyl-sn-glycero-3-phospho-1D-myo-inositol 1-arachidonoyl-sn-glycero-3-phosphoethanolamine 1-bromo-2-propanol 1-carboxylatovinyl carboxylatophosphonate(3-) 1-chlorobutan-2-ol 1-docosene 1-dodecene 1-ethyl-2-propylcyclohexane 1-hexadecanoyl-2-(9-oxononanoyl)-sn-glycero-3-phosphocholine 1-hexadecanoyl-sn-glycero-3-phospho-D-myo-inositol 1-hexadecanoyl-sn-glycero-3-phosphoethanolamine 1-icosapentaenoyl-sn-glycero-3-phosphocholine 1-iodo-2-methylundecane 1-linoleoyl-sn-glycero-3-phosphoethanolamine 1-linoleoyl-sn-glycero-3-phosphoethanolamine zwitterion 1-methyladenosine 1-methylimidazole-4-acetaldehyde 1-methylpyrrolinium 1-O-all-trans-retinoyl-beta-glucuronic acid 1-octadec-9-enoylglycero-3-phosphate 1-octadecylglycero-3-phosphocholine 1-oleoyl-2-arachidonoyl-sn-glycero-3-phospho-1D-myo-inositol 1-oleoyl-sn-glycero-3-phosphoethanolamine 1-palmitoleoyl-2-palmitoyl-sn-glycero-3-phosphocholine 1-pentadecanoyl-2-[(5Z,8Z,11Z,14Z)-eicosatetraenoyl]-sn-glycero-3-phosphocholine 1-pentadecyl-2-acetyl-sn-glycero-3-phosphocholine 1-penten-3-one 1-phenylethylamine + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate(7-) + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate(5-) + 1-phosphatidyl-1D-myo-inositol 3,5-bisphosphate(5-) + 1-phosphatidyl-1D-myo-inositol 3-phosphate(3-) + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate + 1-phosphatidyl-1D-myo-inositol 4-phosphate(3-) + 1-phosphatidyl-1D-myo-inositol 5-phosphate(3-) + 1-phosphatidyl-1D-myo-inositol(1-) + 1-piperideine-2-carboxylate 1-piperideine-6-carboxylate + 1-pyrroline-2-carboxylate 1-pyrroline-5-carboxylate + 1-pyrrolinium + 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphoethanolamine 1-stearoyl-sn-glycero-3-phospho-1D-myo-inositol 1-stearoyl-sn-glycero-3-phosphoethanolamine 10-formyldihydrofolate(2-) 10-formyltetrahydrofolate(2-) 10-hydroxypalmitic acid 10-nonadecenoate 10-nonadecenoic acid + 10-PAHSA 10-PAHSA(1-) 11-cis-retinal + 11-cis-retinol + 11-cis-retinyl palmitate 11-dehydro-thromboxane B2 11-dehydrocorticosterone 11-deoxycorticosterone + 11-deoxycortisol 11-epi-prostaglandin F2alpha + 11-epi-prostaglandin F2alpha(1-) 11-nitro-1-undecene 11-oxo-ETE + 11-oxotestosterone 11-PAHSA 11-PAHSA(1-) 11beta-hydroxyandrost-4-ene-3,17-dione 11beta-hydroxyprogesterone 12(S)-HETE 12(S)-HPETE(1-) 12-HETE + 12-hydroxylauric acid + 12-PAHSA 12-PAHSA(1-) 12alpha-hydroxy-3-oxo-5beta-cholan-24-oic acid + 13(S)-HPODE + 13(S)-HPODE(1-) 13,14-dihydro-15-oxolipoxin A4 13,14-dihydro-15-oxolipoxin A4(1-) 13,14-dihydrolipoxin A4 13,14-dihydrolipoxin A4(1-) 13-cis-retinal 13-cis-retinol + 13-hydroxy-(14R,15S)-epoxy-(5Z,8Z,11Z)-icosatrienoic acid 13-hydroxy-alpha-tocopherol 13-PAHSA 13-PAHSA(1-) 14-demethyllanosterol + 15(S)-HETE 15(S)-HPETE(1-) 15,16-dihydrobiliverdin(2-) 15-dehydro-prostaglandin E1(1-) 15-dehydroprostaglandin A1 15-ketoprostaglandin F1alpha(1-) 15-oxo-beta-bilirubin(2-) 15-oxo-ETE + 16alpha-hydroxydehydroepiandrosterone 16alpha-hydroxygypsogenate(2-) + 16alpha-hydroxypregnenolone 17-phenyl-18,19,20-trinor-prostaglandin D2 17-phenyl-18,19,20-trinor-prostaglandin E2 17alpha-hydroxypregnenolone + 17alpha-hydroxyprogesterone 17beta-estradiol + 17beta-estradiol 3-glucosiduronic acid 17beta-hydroxy-5alpha-androstan-3-one + 17beta-hydroxy-5beta-estran-3-one 18-hydroxycorticosterone 1alpha,23(S),25-trihydroxyvitamin D3 1alpha,2beta,25-trihydroxy vitamin D3 1D-myo-inositol 1,3,4,5-tetrakisphosphate(8-) 1D-myo-inositol 1,3,4-trisphosphate(6-) 1D-myo-inositol 1,4,5,6-tetrakisphosphate(8-) 1D-myo-inositol 1,4,5-trisphosphate(6-) 1D-myo-inositol 1,4-bisphosphate(4-) 1D-myo-inositol 1-phosphate 1D-myo-inositol 1-phosphate(2-) 1D-myo-inositol 3,4,5,6-tetrakisphosphate(8-) 1D-myo-inositol 3,4-bisphosphate 1D-myo-inositol 3-phosphate(2-) 1D-myo-inositol 4-phosphate(2-) 2',3'-cyclic UMP(1-) 2'-deoxyadenosine + 2'-deoxyadenosine 5'-monophosphate(2-) + 2'-deoxycytidine + 2'-deoxycytosine 5'-monophosphate(2-) + 2'-deoxyguanosine + 2'-deoxyguanosine 5'-monophosphate(2-) + 2'-deoxyinosine 2'-deoxyinosine 5'-phosphate(2-) 2'-deoxyinosine-5'-diphosphate 2'-deoxyinosine-5'-monophosphate 2'-deoxyuridine + 2,2'-[(2-amino-2-oxoethyl)imino]diacetate(2-) 2,2'-[(2-azanidyl-2-oxoethyl)imino]diacetate(3-) 2,2'-iminodipropanoate + 2,2-dihydroxy-3-methylbutanoate 2,2-dimethylsuccinate(2-) 2,3,3-trimethylpentane 2,3,4,5-tetrahydrodipicolinate(2-) + 2,3,5,8-tetramethyldecane 2,3,5-trimethylhexane 2,3-bisphosphoglyceric acid + 2,3-bisphosphonato-D-glycerate(5-) 2,3-dihydroxybutanoic acid + 2,3-diketogulonate 2,3-dimethylsuccinate(2-) 2,3-epoxymenatetrenone 2,4,4-trimethylpentane-1,3-diyl bis(2-methylpropanoate) 2,4,6-trimethyldecane 2,4-dihydroxyhept-2-enedioate 2,4-dimethyl-1-heptene 2,4-dimethylfuran 2,4-dimethylhexane 2,4-dimethylpentan-3-amine 2,5-diamino-6-ribosylamino-4(3H)pyrimidinone 5'-triphosphate 2,5-dihydroxybenzaldehyde 2,5-dihydroxybenzoate 2,5-dihydroxybenzoic acid + 2,6,10,14-tetramethylheptadecane 2,6,10,15-tetramethylheptadecane 2,6,8-trimethyldecane 2,6-diaminopimelate(2-) + 2,7,10-trimethyldodecane 2-(2-carboxyethyl)-4-methyl-5-propylfuran-3-carboxylic acid 2-(4-methoxyphenyl)propan-2-ol 2-(4-methyl-1-piperazinyl)ethanamine 2-(acetamidomethylidene)succinate(2-) 2-(beta-D-glucopyranosyluronate)-D-glucuronate(2-) 2-(carboxylatomethyl)-5-oxo-2,5-dihydro-2-furoate(2-) 2-(E)-O-feruloyl-D-galactarate(2-) 2-(omega-methylthio)alkylmalate(2-) + 2-(omega-methylthio)alkylmaleate(2-) + 2-acetamido-2-deoxy-D-glucopyranose 1-phosphate + 2-acetamido-5-oxopentanoate 2-amino-3-(3-oxoprop-1-enyl)but-2-enedioic acid + 2-amino-3-oxoadipic acid 2-amino-3-phosphonopropanoic acid 2-aminoacrylic acid + 2-aminoadipate(2-) 2-aminoethanesulfonate 2-aminomuconate 6-semialdehyde(1-) 2-aminooctanoic acid 2-aminooctanoic acid zwitterion 2-ammonio-2-deoxy-D-glucopyranose + 2-ammonio-2-deoxy-D-glucopyranose 6-phosphate(1-) + 2-arachidonoylglycerol + 2-benzylsuccinate(2-) + 2-butyl-1-octanol + 2-butylfuran 2-carboxy-L-lyxonate 2-cis,6-trans,10-trans-geranylgeranyl diphosphate 2-decaprenyl-6-methoxy-1,4-benzoquinone 2-decaprenyl-6-methoxy-3-methyl-1,4-benzoquinone 2-decaprenyl-6-methoxyphenol 2-dehydro-L-gluconic acid 2-deoxy-D-ribofuranose 2-deoxy-D-ribofuranose 1-phosphate(2-) 2-deoxy-D-ribonate 2-deoxy-D-ribonic acid 2-deoxy-D-ribose + 2-deoxy-D-ribose 5-phosphate(2-) 2-ethyl-2-hexenal + 2-ethylhydracrylate 2-ethylhydracrylic acid 2-formamido-N(1)-(5-O-phosphonato-D-ribosyl)acetamidine + 2-formylglutarate(2-) + 2-hexylfuran 2-hydroxy-17beta-estradiol + 2-hydroxy-3-(3-oxoprop-1-enyl)but-2-enedioate 2-hydroxy-3-carboxylato-6-oxo-7-methylocta-2,4-dienoate 2-hydroxy-3-methylbutyrate 2-hydroxy-3-methylbutyric acid + 2-hydroxy-3-oxoadipate(2-) 2-hydroxy-6-oxonona-2,4,7-trienedioate + 2-hydroxyacrylic acid 2-hydroxyadipate(2-) 2-hydroxybutyrate + 2-hydroxybutyric acid + 2-hydroxychromene-2,8-dicarboxylate 2-hydroxyestrone + 2-hydroxyglutaramic acid 2-hydroxyglutarate(2-) + 2-hydroxyhepta-2,4-dienedioate 2-hydroxyhexadecanoate + 2-hydroxyhexadecanoic acid + 2-hydroxymethylglutarate + 2-hydroxyoctadecanoate + 2-hydroxyoctadecanoic acid + 2-hydroxyphytanoyl-CoA(4-) 2-isopropyl-5-methyl-1-heptanol 2-isopropylaminoethylamine 2-isopropylmalate(2-) + 2-isopropylmaleate(2-) 2-linoleoyl-sn-glycero-3-phosphoethanolamine 2-methoxy-17beta-estradiol + 2-methoxyestrone + 2-methyl-1,3-thiazolidine-2-carboxamide 2-methyl-1-pentene 2-methyl-3-ketovaleric acid 2-methyl-3-oxopropanoate + 2-methyl-3-oxosuccinate(2-) 2-methyl-3-sulfanylbutan-1-ol 2-methyl-5-propionylfuran 2-methylacetoacetyl-CoA(4-) 2-methylbutan-2-amine 2-methylbutanoyl-CoA(4-) + 2-methylbutyric acid + 2-methylbutyrylcarnitine + 2-methylcitrate(3-) + 2-methylcrotonoyl-CoA(4-) 2-methylene-3-methylsuccinate(2-) 2-methylerythritol 2-methylglutarate(2-) 2-methylhexenoyl-CoA 2-methylideneglutarate(2-) 2-methyltridecane 2-O-caffeoylglucarate(2-) 2-O-sinapoyl-D-glucarate(2-) 2-octene + 2-oxo-2H-pyran-4,6-dicarboxylate 2-oxoadipate(2-) 2-oxobutanoate 2-oxoglutaramate + 2-oxoglutarate(2-) 2-oxohept-4-ene-1,7-dioate 2-oxopentanoic acid 2-phenylethanaminium 2-phenylethylamine + 2-phospho-D-glyceric acid 2-phosphonato-D-glycerate(3-) 2-phosphonatoglycolate(3-) 2-stearoyl-sn-glycero-3-phosphocholine 2-succinatobenzoate 2-tetradecanoyl-sn-glycero-3-phosphocholine 2-trans,6-trans,10-trans-geranylgeranyl diphosphate(3-) 2-trans,6-trans-farnesyl diphosphate(3-) 20(S),25-dihydroxyvitamin D3 20-HETE + 20-hydroxy-20-oxoleukotriene B4(2-) 20-hydroxy-20-oxoleukotriene B4-20-(beta-D-glucuronide)(2-) 20-hydroxy-leukotriene B4 20-hydroxy-leukotriene B4(1-) 20-hydroxy-leukotriene E4(1-) 20-hydroxycholesterol 20beta-dihydroprednisolone 23(S),25-dihydroxy-24-oxovitamin D3 24,25-dihydrolanosterol + 25-hydroxycholesterol 26-hydroxycholesterol + 2beta-hydroxytestosterone 3',5'-cyclic AMP + 3',5'-cyclic AMP(1-) 3',5'-cyclic CMP 3',5'-cyclic dTMP 3',5'-cyclic GMP + 3',5'-cyclic GMP(1-) + 3'-AMP 3'-AMP(2-) 3'-dephospho-CoA 3'-dephospho-CoA(2-) 3'-phosphonato-5'-adenylyl sulfate(4-) 3'-UMP(2-) 3,13,19-trimethyltricosanoic acid 3,17-dioxoandrost-4-en-19-al 3,3',5'-triiodothyronine + 3,3',5,5'-tetraiodothyroacetic acid 3,3',5-triiodo-L-thyronine + 3,3',5-triiodo-L-thyronine sulfate 3,3',5-triiodo-L-thyronine zwitterion + 3,3'-diiodo-L-thyronine + 3,4-dihydroxybutyric acid 3,4-dihydroxymandelaldehyde + 3,4-dihydroxymandelate + 3,4-dihydroxymandelic acid 3,4-dihydroxyphenylacetaldehyde 3,4-dihydroxyphthalate(2-) 3,5-diiodo-L-tyrosinate(1-) 3,5-diiodo-L-tyrosine + 3,5-dimethyloctane 3,5-dioxooctanedioic acid 3,7,11-trimethyldodecan-1-ol 3,7-dimethyl-3-octanol 3,8-dimethylundecane 3-(1H-indol-3-yl)propanoate 3-(1H-indol-3-yl)propanoic acid 3-(2-methylpropyl)cyclohexene 3-(4-deoxy-beta-D-gluc-4-enosyluronic acid)-N-acetyl-D-glucosamine 3-(4-hydroxyphenyl)lactate + 3-(4-hydroxyphenyl)lactic acid + 3-(4-hydroxyphenyl)pyruvate 3-(acetamidomethylene)-2-(hydroxymethyl)succinate(2-) 3-(imidazol-5-yl)lactic acid + 3-(indol-3-yl)lactate 3-(indol-3-yl)lactic acid 3-(methylthio)propionate 3-(omega-methylthio)alkylmalate(2-) + 3-[(1-carboxylatovinyl)oxy]benzoate(2-) 3-aminopiperidine-2-one 3-carboxy-1-hydroxypropylthiamine diphosphate 3-carboxy-4-methyl-5-propyl-2-furanpropanoate 3-carboxy-4-methyl-5-propyl-2-furanpropionate(2-) 3-chloro-L-tyrosine 3-cyano-L-alanine + 3-decaprenyl-4,5-dihydroxybenzoic acid + 3-decaprenyl-4-hydroxy-5-methoxybenzoic acid 3-dehydro-4-methylzymosterol + 3-dehydro-L-gulonate 3-dehydrocarnitine + 3-dehydrocarnitinium 3-dehydrosphinganinium(1+) + 3-demethylubiquinone-10 3-deoxy-D-arabino-hexonic acid 3-deoxychenodeoxycholic acid 3-disulfanyl-L-alanine + 3-ethylmalate(2-) 3-ethylpentane 3-fucosyllactose + 3-furoic acid + 3-hydroxy-2-methylpropanoyl-CoA(4-) 3-hydroxy-3-methylglutarate(1-) 3-hydroxy-3-methylglutarate(2-) 3-hydroxy-3-methylglutaric acid + 3-hydroxy-3-methylhexanoic acid + 3-hydroxy-L-glutamate(2-) 3-hydroxy-N(6),N(6),N(6)-trimethyl-L-lysine 3-hydroxyanthranilate 3-hydroxyanthranilic acid 3-hydroxybutyrate + 3-hydroxybutyric acid + 3-hydroxydicarboxylate(2-) + 3-hydroxydocosanoyl-CoA + 3-hydroxyglutarate(2-) 3-hydroxyicosanoyl-CoA + 3-hydroxyisobutyrate + 3-hydroxyisovalerate 3-hydroxyisovaleric acid + 3-hydroxyisovalerylcarnitine 3-hydroxykynurenamine 3-hydroxykynurenine + 3-hydroxymandelic acid 3-hydroxyoctadecanoyl-CoA + 3-hydroxyphenylpyruvic acid 3-hydroxypropanoyl-CoA(4-) 3-hydroxypropionate 3-hydroxypropionic acid + 3-hydroxypyruvate 3-hydroxypyruvic acid 3-hydroxysebacate(2-) 3-hydroxytetracosanoyl-CoA 3-hydroxytetradecanoic acid + 3-iodo-L-tyrosine + 3-isopropylmalate(2-) + 3-keto-beta-D-galactose 3-mercaptopentanol 3-mercaptopyruvate 3-mercaptopyruvic acid 3-methoxy-3-methylhexane 3-methyl-2-oxobutanoate 3-methyl-2-oxobutanoic acid 3-methyl-2-oxovalerate + 3-methyl-2-oxovaleric acid + 3-methyl-3-sulfanylhexan-1-ol 3-methyladenine 3-methyladipate(2-) 3-methylbenzylsuccinate(2-) 3-methylbut-2-enoyl-CoA(4-) 3-methyleneheptane 3-methylguanine + 3-methylhexane 3-methylhistidine 3-methylhistidine zwitterion 3-methylmalate(2-) 3-methylmalic acid + 3-methylpentane 3-methylpyrrolo[1,2-a]pyrazine 3-O-beta-D-galactopyranosyl-sn-glycerol 3-O-methyldopa 3-O-methyldopa zwitterion 3-oxoadipate(2-) 3-oxoadipic acid + 3-oxochola-4,6-dien-24-oic acid 3-oxodecanoyl-CoA 3-oxodocosanoyl-CoA 3-oxodotriacontanoyl-CoA 3-oxohexacosanoyl-CoA 3-oxohexanoyl-CoA 3-oxoicosanoyl-CoA 3-oxolauroyl-CoA 3-oxooctadecanoyl-CoA 3-oxooctanoyl-CoA 3-oxopalmitoyl-CoA(4-) 3-oxopristanoyl-CoA(4-) 3-oxopropanoate 3-oxotetracosanoyl-CoA 3-oxotetradecanoyl-CoA 3-penten-1-yne + 3-phenyllactic acid + 3-phenylpropionate + 3-phenylpropionic acid + 3-phosphonato-D-glycerate(3-) 3-phosphonato-D-glyceroyl phosphate(4-) 3-phosphonatooxypyruvate(3-) 3-propylmalate(2-) 3-sulfino-L-alanine + 3-sulfino-L-alanine(1-) + 3-sulfinylpyruvic acid 3-sulfonatopyruvate(2-) 3-ureidoisobutyric acid 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestan-26-oyl-CoA + 3alpha,7alpha,12alpha-trihydroxy-24-oxo-5beta-cholestan-26-oyl-CoA(4-) 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-en-26-oyl-CoA + 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-al + 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestan-26-oic acid + 3alpha,7alpha,12alpha-trihydroxy-5beta-cholestane-5-carboxylic acid 3alpha,7alpha,12beta-trihydroxy-5beta-cholanate 3alpha,7alpha,12beta-trihydroxy-5beta-cholanic acid 3alpha,7alpha,24-trihydroxy-5beta-cholestan-26-oyl-CoA 3alpha,7alpha-dihydroxy-24-oxo-5beta-cholestan-26-oyl-CoA 3alpha,7alpha-dihydroxy-5beta-cholest-24-enoyl-CoA 3alpha,7alpha-dihydroxy-5beta-cholestan-26-al 3alpha,7alpha-dihydroxy-5beta-cholestan-26-oic acid + 3alpha,7alpha-dihydroxy-5beta-cholestan-26-oyl-CoA + 3alpha-hydroxy-5beta-androstan-17-one + 3alpha-hydroxy-5beta-androstan-17-one 3-glucosiduronic acid 3alpha-hydroxy-5beta-pregnan-20-one 3beta,12alpha-dihydroxy-5beta-cholan-24-oic acid 3beta,7alpha,12alpha-trihydroxy-5beta-cholan-24-oic acid 3beta,7alpha-dihydroxy-5beta-cholan-24-oic acid 3beta-hydroxy-4beta-methyl-5alpha-cholest-8-ene-4alpha-carboxylate 3beta-hydroxy-4beta-methyl-5alpha-cholest-8-ene-4alpha-carboxylic acid 3beta-hydroxy-5alpha-cholest-8-ene-4alpha-carboxylate 3beta-hydroxy-5alpha-cholest-8-ene-4alpha-carboxylic acid 3beta-hydroxy-5beta-pregnan-20-one + 3beta-hydroxylanost-8-en-32-al 4,4'-disulfanyldibutanoate 4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol 4,5,9,10-dehydroisolongifolene 4,5-dihydroxyphthalate(2-) 4,6,8-trimethyl-1-nonene 4,6-dimethyldodecane 4,6-dimethylundecane 4,6-dioxoheptanoic acid 4,8,12-trimethyltridecanoyl-CoA(4-) 4-(2-aminophenyl)-2,4-dioxobutanoate 4-(4-deoxy-alpha-D-gluc-4-enosyluronic acid)-D-galacturonate(2-) 4-(4-deoxy-beta-D-gluc-4-enosyluronate)-D-galacturonate(2-) 4-(trimethylammonio)butanoate 4-(trimethylammonio)butanoic acid + 4-acetamidobutanal 4-acetamidobutanoate 4-amino-4-deoxychorismate(2-) 4-ammoniobutanal 4-carboxy-2-hydroxy-cis,cis-muconate 6-semialdehyde(2-) 4-carboxy-2-hydroxymuconate semialdehyde hemiacetal(2-) 4-coumaroyl-CoA(4-) + 4-ethylphenyl sulfate 4-ethylphenyl sulfate(1-) 4-fumarylacetoacetate(2-) 4-hexen-3-one + 4-hydroxy-2-oxoglutarate(2-) + 4-hydroxy-2-oxoheptanedioate + 4-hydroxy-L-glutamate(2-) + 4-hydroxy-L-prolinate 4-hydroxy-L-proline zwitterion 4-hydroxynon-2-enal + 4-hydroxyphenylacetate 4-hydroxyphenylacetic acid + 4-hydroxyphenylpyruvic acid + 4-hydroxyproline + 4-maleylacetoacetate 4-methoxy-17beta-estradiol + 4-methoxyestrone + 4-methoxytyramine 4-methyl-2-oxopentanoate 4-methyl-2-oxopentanoic acid 4-methylcatechol + 4-methylpentanal 4-methylthio-2-oxobutanoate + 4-methylundecane 4-nitro-6-oxohepta-2,4-dienedioate 4-nitrophenyl hydrogen sulfate 4-O-methyl-L-dopa 4-oxobutanoate 4-pyridoxate 4-trimethylammoniobutanal 4a-hydroxytetrahydrobiopterin + 4alpha-formyl-4beta-methyl-5alpha-8-cholesten-3beta-ol 4alpha-formyl-5alpha-cholest-8-en-3beta-ol 4alpha-hydroxymethyl-4beta-methyl-5alpha-8-cholesten-3beta-ol 4alpha-hydroxymethyl-4beta-methylzymosterol 4alpha-hydroxymethyl-5alpha-cholest-8-en-3beta-ol 4alpha-methyl-5alpha-cholest-8-en-3-one 4alpha-methyl-5alpha-cholest-8-en-3beta-ol 4alpha-methylzymosterol + 4beta-hydroxycholesterol 4beta-methylzymosterol-4-carbaldehyde 5'-acetylphosphoadenosine 5'-adenylyl sulfate(2-) 5'-deoxyadenosine 5'-S-methyl-5'-thioadenosine 5'-xanthylate(2-) 5(S),6(S)-epoxy-18(S)-hydroxy-(7E,9E,11Z,14Z,16E)-icosapentaenoic acid 5(S)-HETE 5(S)-HPETE(1-) 5,10-(methanylylidene)tetrahydromethanopterin(2-) 5,10-dihydrophenazine-1,6-dicarboxylate 5,10-methylenetetrahydrofolate(2-) + 5,10-methylenetetrahydromethanopterin(3-) 5,6,6'-trihydroxy-5'-methoxy[biphenyl]-3,3'-dicarboxylate 5,6,7,8-tetrahydrobiopterin + 5,6,7,8-tetrahydrofolate(2-) + 5,6,7,8-tetrahydromethanopterin(3-) 5,6-dihydrothymine 5,6-dihydrouracil 5,6-dihydroxyindole-2-carboxylate + 5,6-dimethylbenzimidazole 5,6-trans-vitamin D3 5-(2-carboxylatoethyl)-4-oxo-4,5-dihydro-1H-imidazol-5-ide 5-(2-hydroxyethyl)-4-methylthiazole 5-(3-carboxylato-3-oxoprop-1-en-1-yl)-4,6-dihydroxypyridine-2-carboxylate 5-(hydroxymethyl)cytosine + 5-(methylsulfanyl)-2,3-dioxopentyl phosphate(2-) 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) + 5-amino-1-(5-phosphonato-D-ribosyl)imidazol-3-ium 5-amino-1-(5-phosphonato-D-ribosyl)imidazole-4-carboxylate 5-amino-2-oxopentanoic acid 5-aminolevulinic acid + 5-aminopentanoic acid + 5-dehydro-4-deoxy-D-glucarate(2-) 5-diphospho-1D-myo-inositol pentakisphosphate 5-dodecenoate 5-dodecenoic acid + 5-formamido-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-) 5-formimidoyltetrahydrofolate(2-) 5-formyl-2-hydroxyhepta-2,4-dienedioate 5-formyltetrahydrofolate(2-) 5-formyluracil 5-guanidino-2-oxopentanoic acid 5-hydroperoxy-15-HETE + 5-hydroxy-L-tryptophan 5-hydroxy-N-formylkynurenine + 5-hydroxybenzimidazole 5-hydroxyindole 5-hydroxyisouric acid + 5-hydroxykynurenine + 5-hydroxymethyluracil + 5-hydroxytryptophan + 5-methoxytryptamine + 5-methyl-2-furaldehyde 5-methyl-5,6,7,8-tetrahydromethanopterin(3-) 5-methylcytosine + 5-methyldec-1-ene 5-methyltetrahydrofolate(2-) + 5-methyltetrahydrofolic acid + 5-O-phosphonato-alpha-D-ribofuranosyl diphosphate(5-) 5-O-phosphono-alpha-D-ribofuranosyl diphosphate 5-oxo-delta-bilirubin(2-) 5-oxo-ETE 5-oxoprolinate + 5-oxoproline + 5-PAHSA 5-PAHSA(1-) 5-phospho-beta-D-ribosylaminium(1-) 5alpha-androstane + 5alpha-androstane-3alpha,17beta-diol + 5alpha-androstane-3beta,17beta-diol + 5alpha-cholest-7-en-3beta-ol + 5alpha-cholest-8-en-3beta-ol 5alpha-cholesta-7,24-dien-3beta-ol 5alpha-dihydrotestosterone 17-O-[beta-D-glucuronosyl-(1->2)-glucuronide](2-) 5alpha-pregnane-3,20-dione 5beta-cholestan-3-one 5beta-cholestane-3alpha,7alpha,12alpha,26-tetrol + 5beta-cholestane-3alpha,7alpha,12alpha-triol 5beta-cholestane-3alpha,7alpha,26-triol 5beta-cholestane-3alpha,7alpha-diol 5beta-dihydrotestosterone 5beta-pregnane-3,20-dione 6,7-dihydrobiopterin + 6-(2-amino-2-carboxyethyl)-4-hydroxybenzothiazole 6-(alpha-D-glucosaminyl)-1-phosphatidyl-1D-myo-inositol + 6-(N-acetyl-alpha-D-glucosaminyl)-1-phosphatidyl-1D-myo-inositol(1-) + 6-amino-2-oxohexanoic acid + 6-hydroxymethyladenine 6-lactoyl-5,6,7,8-tetrahydropterin + 6-methyladenine 6-O-phosphonato-D-glucono-1,5-lactone(2-) 6-oxoprostaglandin F1alpha 6beta-hydroxycortisol 6beta-hydroxycortisone 6beta-hydroxytestosterone + 7,8-dihydroneopterin + 7,8-dihydroneopterin 3'-triphosphate(4-) 7,9-dihydro-1H-purine-2,6,8(3H)-trione + 7-(2-amino-2-carboxyethyl)-5-hydroxy-2H-1,4-benzothiazine-3-carboxylic acid 7-(2-amino-2-carboxyethyl)-5-hydroxy-3,4-dihydro-2H-1,4-benzothiazin-3-one 7-dehydrodesmosterol 7-methylguanine + 7-oxo-5alpha-cholestan-3beta-ol 7-oxolithocholic acid + 7-PAHSA 7-PAHSA(1-) 7alpha,12alpha-dihydroxy-3-oxo-5beta-cholan-24-oic acid + 7alpha,12alpha-dihydroxy-5beta-cholestan-3-one 7alpha,12alpha-dihydroxycholest-4-en-3-one 7alpha,25-dihydroxy-4-cholesten-3-one 7alpha,25-dihydroxycholesterol 7alpha,26-dihydroxycholesterol + 7alpha-hydroxy-3-oxo-4-cholestenoic acid 7alpha-hydroxy-3-oxo-5beta-cholan-24-oic acid 7alpha-hydroxy-5beta-cholestan-3-one 7alpha-hydroxycholest-4-en-3-one 7beta-hydroxyepiandrosterone 8-aminooctanoic acid 8-epi-prostaglandin E2 8-hydroxyadenine 8-nitroguanosine 3',5'-cyclic monophosphate 8-oxoadenine 8-PAHSA 8-PAHSA(1-) 9(S)-HPODE 9,10-epoxyoctadecanoic acid + 9-HODE + 9-PAHSA 9-PAHSA(1-) [des-Phe(8), des-Arg(9)]-bradykinin [Pyr1]apelin-12(2+) [Pyr1]apelin-13(2+) Ac-Asp-Glu acetaldehyde + acetate + acetoacetate acetoacetyl-CoA(4-) acetone + acetyl dihydrogen phosphate acetyl-CoA(4-) acetylcholine + acetylenedicarboxylate(2-) acrylate + acryloyl-CoA(4-) acyl-carrier protein + acylglycerone phosphate + adenine + adenosine + adenosine 3',5'-bismonophosphate(4-) adenosine 5'-monophosphate(2-) + ADP + ADP alpha-D-glucoside(2-) ADP(3-) + ADP-alpha-D-mannose ADP-D-ribose 2'-phosphate(4-) ADP-D-ribose(2-) + adrenaline + aflatoxin B1 + aflatoxin B1 exo-8,9-epoxide agmatinium(2+) AICA ribonucleotide aldehydo-D-xylose + aldehydo-L-iduronate aldehydo-N-acetyl-D-glucosamine aldehydo-N-acetyl-D-mannosamine aldosterone + all-cis-5,8,11,14,17-icosapentaenoate + all-cis-docosa-4,7,10,13,16,19-hexaenoic acid + all-cis-docosa-7,10,13,16-tetraenoic acid + all-cis-icosa-8,11,14-trienoic acid + all-cis-icosa-8,11,14-trienoyl-CoA all-trans-4-hydroxyretinoic acid + all-trans-dodecaprenyl diphosphate all-trans-dodecaprenyl diphosphate(3-) all-trans-retinal + all-trans-retinoate + all-trans-retinoic acid + all-trans-retinol + allantoate allantoin + allocholic acid + allyl octadecyl oxalate | https://rgd.mcw.edu/rgdweb/ontology/view.html?acc_id=CHEBI%3A57991 |
Publications - Global Disability Innovation Hub
The GDI Hub brings together academic excellence, innovative practice and co-creation; harnessing the power of technology for good.
Type
Conference Paper
Themes
Assistive & Accessible Technology
Culture and Participation
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi,Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, Joyce Olenja
We present the findings of a case study of mobile technology use by People with Visual Impairment (VIPs) in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
CHI '20: Proceedings of the 2020 CHI Conference; 2020
Abstract
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Living in an informal settlement with a visual impairment can be very challenging resulting in social exclusion. Mobile phones have been shown to be hugely beneficial to people with sight loss in formal and high-income settings. However, little is known about whether these results hold true for people with visual impairment (VIPs) in informal settlements. We present the findings of a case study of mobile technology use by VIPs in Kibera, an informal settlement in Nairobi. We used contextual interviews, ethnographic observations and a co-design workshop to explore how VIPs use mobile phones in their daily lives, and how this use influences the social infrastructure of VIPs. Our findings suggest that mobile technology supports and shapes the creation of social infrastructure. However, this is only made possible through the existing support networks of the VIPs, which are mediated through four types of interaction: direct, supported, dependent and restricted.
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Giulia Barbareschi, Catherine Holloway, Katherine Arnold, Grace Magomere, Wycliffe Ambeyi Wetende, Gabriel Ngare, and Joyce Olenja. 2020. The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya. In Proceedings of the 2020 CHI Conference on Human Factors in Computing Systems (CHI '20). Association for Computing Machinery, New York, NY, USA, 1–15.https://doi.org/10.1145/331383...
The Social Network: How People with Visual Impairment use Mobile Phones in Kibera, Kenya
Editorial
Themes
Culture and Participation
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ikenna D Ebueny, Emma M Smith,Catherine Holloway, Rune Jensen, Lucía D'Arino, Malcolm MacLachlan
Social empathy is ‘the ability to more deeply understand people by perceiving or experiencing their life situations and as a result gain insight into structural inequalities and disparities’. Social empathy comprises three elements: individual empathy, contextual understanding and social responsibility. COVID-19 has created a population-wide experience of exclusion that is only usually experienced by subgroups of the general population. Notably, persons with disability, in their everyday lives, commonly experience many of the phenomena that have only recently been experienced by members of the general population. COVID-19 has conferred new experiential knowledgeon all of us. We have a rare opportunity to understand and better the lives of persons with disabilities for whom some aspects of the COVID- 19 experience are enduring. This allows us greater understanding of the importance of implementing in full a social and human rights model of disability, as outlined in the UNCRPD.
BMJ Global Health; 2020
Abstract
COVID-19 as social disability: the opportunity of social empathy for empowerment
COVID-19 has conferred new experiential knowledge on society and a rare opportunity to better understand the social model of disability and to improve the lives of persons with disabilities.
The COVID-19 experience may offer contextual knowledge of the prepandemic lives of persons with disabilities and foster greater social awareness, responsibility and opportunities for change towards a more inclusive society.
Information, family and social relationships, health protection and healthcare, education, transport and employment should be accessible for all groups of the population. The means must be developed and deployed to ensure equity – the deployment of resources so that people with different types of needs have the same opportunities for living good lives in inclusive communities.
We have learnt from COVID-19 that inclusive healthcare and universal access should be the new normal, that its provision as a social good is both unifying and empowering for society as a whole.
COVID-19 as social disability: the opportunity of social empathy for empowerment
Ebuenyi ID, Smith EM, Holloway C , et alCOVID-19 as social disability: the opportunity of social empathy for empowerment BMJ Global Health2020;5:e003039.
COVID-19 as social disability: the opportunity of social empathy for empowerment
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Social Justice
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi,Catherine Holloway&Victoria Austin
While the inadequacies of our existing assistive technology systems, policies, and services have been highlighted by the acute and rapidly changing nature of the COVID-19 pandemic, these failures are also present and important during non-crisis times. Each of these actions, taken together, will not only address needs for more robust and resilient systems for future crises, but also the day-to-day needs of all assistive technology users. We have a responsibility as a global community, and within our respective countries, to address these inadequacies now to ensure an inclusive future.
Disability & Society; 2020
Abstract
Developing inclusive and resilient systems: COVID-19 and assistive technology
Assistive technology is a critical component of maintaining health, wellbeing, and the realization of rights for persons with disabilities. Assistive technologies, and their associated services, are also paramount to ensuring individuals with functional limitations have access to important health and social service information, particularly during a pandemic where they may be at higher risk than the general population. Social isolation and physical distancing have further marginalized many within this population. We have an opportunity to learn from the COVID-19response to develop more inclusive and resilient systems that will serve people with disabilities more effectively in the future. In this Current Issues piece, we present a starting point for discussion, based on our experiences working to promote access to assistive technologies through inclusive and sustainable systems and policies.
Developing inclusive and resilient systems: COVID-19 and assistive technology
Emma M. Smith, Malcolm MacLachlan, Ikenna D. Ebuenyi, Catherine Holloway & Victoria Austin (2021) Developing inclusive and resilient systems: COVID-19 and assistive technology, Disability & Society, 36:1, 151-154, DOI:10.1080/09687599.2020.1829558
Developing inclusive and resilient systems: COVID-19 and assistive technology
Type
Conference Paper
Disability design and innovation in computing research in low resource settings
Dafne Zuleima Morgado-Ramirez,Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney,Catherine Holloway
80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes.
ASSETS '20: Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility; 2020
Abstract
Disability design and innovation in computing research in low resource settings
80% of people with disabilities worldwide live in low resourced settings, rural areas, informal settlements and in multidimensional poverty. ICT4D leverages technological innovations to deliver programs for international development. But very few do so with a focus on and involving people with disabilities in low resource settings. Also, most studies largely focus on publishing the results of the research with a focus on the positive stories and not the learnings and recommendations regarding research processes. In short, researchers rarely examine what was challenging in the process of collaboration. We present reflections from the field across four studies. Our contributions are: (1) an overview of past work in computing with a focus on disability in low resource settings and (2) learnings and recommendations from four collaborative projects in Uganda, Jordan and Kenya over the last two years, that are relevant for future HCI studies in low resource settings with communities with disabilities. We do this through a lens of Disability Interaction and ICT4D.
Disability design and innovation in computing research in low resource settings
Dafne Zuleima Morgado-Ramirez, Giulia Barbareschi, Maggie Kate Donovan-Hall, Mohammad Sobuh, Nida' Elayyan, Brenda T Nakandi, Robert Tamale Ssekitoleko, joyce Olenja, Grace Nyachomba Magomere, Sibylle Daymond, Jake Honeywill, Ian Harris, Nancy Mbugua, Laurence Kenney, and Catherine Holloway. 2020. Disability design and innovation in computing research in low resource settings. In Proceedings of the 22nd International ACM SIGACCESS Conference on Computers and Accessibility (ASSETS '20). Association for Computing Machinery, New York, NY, USA, Article 11, 1–7.https://doi.org/10.1145/337362...
Type
Editorial
Research Group
Social Justice
Assistive Technology (AT), for What?
Vicki Austin, Catherine Holloway
This year (2022) has seen the publication of the World’s first Global Report on Assistive Technology (GReAT) [1]. This completes almost a decade of work to ensure assistive technology (AT) access is a core development issue. The lack of access to assistive products (APs), such as wheelchairs, hearing aids, and eyeglasses, as well as less well-referenced products such as incontinence pads, mobile phone applications, or walking sticks, affects as many as 2.5 billion people globally. Furthermore, the provision of APs would reap a 1:9 return on investment [2]. This could result in a family in need netting (or living without) over GBP 100,000 in their lifetime [2] or more, if we count dynamic overspills in the economy such as employment of assistive technology services and manufacturing of devices [3].
Societies; 2021
Abstract
Assistive Technology (AT), for What?
Amartya Sen’s seminal Tanner lecture: Equality of What?began a contestation on social justice and human wellbeing that saw a new human development paradigm emerge—the capability approach (CA)—which has been influential ever since. Following interviews with leading global assistive technology (AT) stakeholders, and users, this paper takes inspiration from Sen’s core question and posits, AT for what?arguing that AT should be understood as a mechanism to achieve the things that AT users’ value. Significantly, our research found no commonly agreed operational global framework for (disability) justice within which leading AT stakeholders were operating. Instead, actors were loosely aligned through funding priorities and the CRPD. We suggest that this raises the possibility for (welcome and needed) incoming actors to diverge from efficiently designed collective action, due to perverse incentives enabled by unanchored interventions. The Global Report on Assistive Technology (GReAT) helps, greatly! However, we find there are still vital gaps in coordination; as technology advances, and AT proliferates, no longer can the device-plus-service approach suffice. Rather, those of us interested in human flourishing might explore locating AT access within an operational global framework for disability justice, which recognizes AT as a mechanism to achieve broader aims, linked to people’s capabilities to choose what they can do and be.
Cite
Assistive Technology (AT), for What?
Austin, V.; Holloway, C. Assistive Technology (AT), for What? Societies2022, 12, 169.https://doi.org/10.3390/soc120...
Assistive Technology (AT), for What?
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
The Digital and Assistive Technologies for Ageing initiative: learning from the GATE initiative
Chapal Khasnabis,Catherine Holloway, Malcolm MacLachlan
We are now in an era of assistive care and assistive living—whereby many people, of all ages, in good health, and those who are more frail, or with cognitive or functional impairments, are using a broad range of technologies to assist and enhance their daily living. Assistive living 1is becoming an important part of population health and rehabilitation, which can help to maximise an individual's abilities, regardless of age or functional capacity. This encouraging shift in ethos has been strengthened by the response to the COVID-19 pandemic, in which a plethora of digital and remote technologies have been used.
The Lancet; 2020
The Digital and Assistive Technologies for Ageing initiative: learning from the GATE initiative
Type
Editorial
Themes
Assistive & Accessible Technology
Culture and Participation
Research Group
Social Justice
Critical Junctures in Assistive Technology and Disability Inclusion
Dr Maria Kett,Catherine Holloway,Vicki Austin,Dr Maria Kett
It is clear from the events of the last 18 months that while technology has a huge potential for transforming the way we live and work, the entire ecosystem—from manufacturing to the supply chain—is vulnerable to the vagaries of that ecosystem, as well as having the potential to exacerbate new and existing inequalities [1]. Nowhere has this been more apparent than in the lives of people with disabilities, who make up around 15% of the world’s population and already face barriers to accessing education, employment, healthcare and other services [2]. Some of these barriers are a result of unequal access and opportunities. However, there is a growing movement to better understand how assistive technology systems and services can be designed to enable more robust and equitable access for all. As part of this growing movement, the Paralympic Games in Tokyo this autumn saw the launch of a new global campaign to transform the lives of the world’s 1.2 bn persons with disabilities: the ‘WeThe15’ campaign reached more than 4.5 billion people through its marketing and stands ready to be the biggest of its kind in history. Next year, the World Health Organization (WHO) and the United Nations Children’s Fund (UNICEF), AT scale and GDI Hub will publish the first World Report on Access to Assistive Technology, which will include research from the £20 million, UK Aid funded, GDI Hub-led, programme, AT2030. Ahead of that, in this Special Issue, we focus on how some events and situations—as diverse as the coronavirus pandemic and the Paralympics—can act as ‘critical junctures’ that can enable a rethink of the status quo to facilitate and promote change.
Sustainability; 2021
Kett, M.; Holloway, C.; Austin, V. Critical Junctures in Assistive Technology and Disability Inclusion. Sustainability2021, 13, 12744.https://doi.org/10.3390/su1322...
Type
Editorial
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Introduction to the companion papers to the global report on assistive technology
Johan Borg, Wei Zhang, Emma M. Smith,Cathy Holloway
GReAT, but do we care?
If accessible, assistive technology would be life changing for a billion people across the world today – and two billion people in 2050 (WHO,2018). It would make the difference between independence and dependence, inclusion and exclusion, life and death. It holds the potential to improve and transform health, education, livelihood and social participation; fundamental human rights everyone is entitled to. And if we are lucky to grow old, the chances are that we all would use assistive technology by then. But do we care?
Assistive Technology, The Official Journal of RESNA; 2021
Johan Borg, Wei Zhang, Emma M. Smith & Cathy Holloway (2021) Introduction to the companion papers to the global report on assistive technology, Assistive Technology, 33:sup1, 1-2, DOI:10.1080/10400435.2021.2003658
Type
Conference Paper
Themes
Assistive & Accessible Technology
Value beyond function: analyzing the perception of wheelchair innovations in Kenya
Barbareschi, G; Daymond, S; Honeywill, J; Singh, A; Noble, D; Mbugua, N; Harris, I;Austin, V;Holloway, C
The World Health Organization (WHO) defines Assistive Technology (AT) as “an umbrella term covering the systems and services related to the delivery of assistive products and services” [6]. This definition highlights how AT encompasses not only the physical and digital products used by millions of persons with disabilities (PWDs) worldwide, but also the systems and services that accompany the provision of these devices [78].
ASSETS '20: The 22nd International ACM SIGACCESS Conference on Computers and Accessibility.; 2020
Abstract
Value beyond function: analyzing the perception of wheelchair innovations in Kenya
Innovations in the field of assistive technology are usually evaluated based on practical considerations related to their ability to perform certain functions. However, social and emotional aspects play a huge role in how people with disabilities interact with assistive products and services. Over a five months period, we tested an innovative wheelchair service provision model that leverages 3D printing and Computer Aided Design to provide bespoke wheelchairs in Kenya. The study involved eight expert wheelchair users and five healthcare professionals who routinely provide wheelchair services in their community. Results from the study show that both users and providers attributed great value to both the novel service delivery model and the wheelchairs produced as part of the study. The reasons for their appreciation went far beyond the practical considerations and were rooted in the fact that the service delivery model and the wheelchairs promoted core values of agency, empowerment and self-expression.
Value beyond function: analyzing the perception of wheelchair innovations in Kenya
Type
Conference Paper
Themes
Assistive & Accessible Technology
Culture and Participation
Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh
Nusrat Jahan,Giulia Barbareschi, Clara Aranda Jan, Charles Musungu Mutuku, Naemur Rahman,Victoria Austin,Catherine Holloway
Worldwide it is estimated that there are over a billion people who live with some form of disability[1]. Approximately 80% of people with disabilities live in low-and-middle income countries (LMICs). The combination of an inaccessible environment compounded by socio-economic factors such as poverty and stigma, makes it more likely for people with disabilities to be marginalised and excluded from society[1]. Assistive Technologies (ATs) are known to bridge the accessibility gaps and allow for greater social inclusion. However, there is a lack of adequate access to ATs in LMICs, combined with often poorly designed services, which only magnifies these challenges, thus limiting the opportunities for persons with disabilities to live an independent life[2]. Despite the importance of AT, access to AT globally is inadequate with only 10 percent of those in need having access to the ATs that they need[2].
2020 IEEE Global Humanitarian Technology Conference
Abstract
Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh
Globally, mobile technology plays a significant role connecting and supporting people with disabilities. However, there has been limited research focused on understanding the impact of mobile technology in the lives of persons with disabilities in low or middle- income countries. This paper presents the findings of a participatory photovoice study looking at the role that mobile phones play in the daily lives of 16 persons with disabilities in Kenya and Bangladesh. Participants used a combination of pictures and voice recordings to capture their own stories and illustrate the impact that mobile phone use has on their lives. Through thematic analysis, we categorized the benefits of mobile phones captured by participants as 1) Improved social connection; 2) Increased independence and 3) Access to opportunities. While mobile phones are ubiquitously used for communication, for persons with disabilities they become essential assistive technologies that bridge barriers to opportunities which are not accessible otherwise. Our paper adds evidence to the need for mobile phones for persons with disabilities to enable communication and connectivity in support of development.
Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh
N. Jahan et al., "Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh," 2020 IEEE Global Humanitarian Technology Conference (GHTC), Seattle, WA, USA, 2020, pp. 1-8, doi: 10.1109/GHTC46280.2020.9342934.
Inclusion and Independence: The impact of Mobile Technology on the Lives of Persons with Disabilities in Kenya and Bangladesh
Type
Conference Paper
Themes
Assistive & Accessible Technology
Research Group
Local Productions
A Preliminary Study to Understand How Mainstream Accessibility and Digital Assistive Technologies Reaches People in Lower- and Middle-Income Countries
Tigmanshu Bhatnagar, George Torrens, Ben Oldfrey, Priya MorjariaFelipe Ramos Barajas, Katherine PerryandCatherine Holloway
Access to information on digital platforms not only facilitates education, employment, entertainment, social interaction but also facilitates critical governmental services, ecommerce, healthcare services and entrepreneurship [1]. Article 9 of United Nations Convention on the Rights of Persons with Disabilities (UNCRPD) enforces its signatories to commit to provide full accessibility to every citizen of the nation [2]. This has helped to spearhead accessibility directives such as the European Accessibility Act [3] that aims to improve the functioning of markets for accessible products and services. Such directives contribute to ensure that mainstream digital technologies (smartphones, computers etc.) are accessible for everyone and without being socially remarkable, they are able to assist in daily living. Additionally, there is evidence that improving access in mainstream technologies improves product experience and usability for everyone [4]. However, mainstream access has not been fully realized, leading to inferior opportunities for people with disabilities, a disparity which is more prominent in lower and middle-income countries [5].
RESNA Annual Conference; 2021
A Preliminary Study to Understand How Mainstream Accessibility and Digital Assistive Technologies Reaches People in Lower- and Middle-Income Countries
Type
Toolkit
Innovate Now Toolkit
As an entrepreneur, learning how to solve problems by creating and experimenting with different strategies is a core pillar of the entrepreneurial mindset you need to succeed. However, there’s rarely a single correct way to solve problems as an entrepreneur, so you need to learn how to create and compare different solutions.
The open entrepreneurship toolkit is a set of learning materials that can help you and your team do just that. Covering the domains of user, product, market and business development, the set of cards have been designed to be used by two or more group members to actively experiment with different solutions.
Innovate Now
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
Troy Bodkin
Doctoral Thesis. This work is one of four multidisciplinary research studies conducted by members of this research cluster, focusing on the area of Computer Aided Design (CAD) for improving the interface with Additive Manufacture (AM) to solve some of the challenges presented with improving prosthetic socket design, with an aim to improve and streamline the process to enable the involvement of clinicians and patients in the design process.
Loughborough University
Abstract
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
For many years, the biggest issue that causes discomfort and hygiene issues for patients with lower limb amputations have been the interface between body and prosthetic, the socket. Often made of an inflexible, solid polymer that does not allow the residual limb to breathe or perspire and with no consideration for the changes in size and shape of the human body caused by changes in temperature or environment, inflammation, irritation and discomfort often cause reduced usage or outright rejection of the prosthetic by the patient in their day to day lives. To address these issues and move towards a future of improved quality of life for patients who suffer amputations, Loughborough University formed the Next Generation Prosthetics research cluster. This work is one of four multidisciplinary research studies conducted by members of this research cluster, focusing on the area of Computer Aided Design (CAD) for improving the interface with Additive Manufacture (AM) to solve some of the challenges presented with improving prosthetic socket design, with an aim to improve and streamline the process to enable the involvement of clinicians and patients in the design process. The research presented in this thesis is based on three primary studies. The first study involved the conception of a CAD criteria, deciding what features are needed to represent the various properties the future socket outlined by the research cluster needs. These criteria were then used for testing three CAD systems, one each from the Parametric, Non Uniform Rational Basis Spline (NURBS) and Polygon archetypes respectively. The result of these tests led to the creation of a hybrid control workflow, used as the basis for finding improvements. The second study explored emerging CAD solutions, various new systems or plug-ins that had opportunities to improve the control model. These solutions were tested individually in areas where they could improve the workflow, and the successful solutions were added to the hybrid workflow to improve and reduce the workflow further. The final study involved taking the knowledge gained from the literature and the first two studies in order to theorise how an ideal CAD system for producing future prosthetic sockets would work, with considerations for user interface issues as well as background CAD applications. The third study was then used to inform the final deliverable of this research, a software design specification that defines how the system would work. This specification was written as a challenge to the CAD community, hoping to inform and aid future advancements in CAD software. As a final stage of research validation, a number of members of the CAD community were contacted and interviewed about their feelings of the work produced and their feedback was taken in order to inform future research in this area.
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
Bodkin, Troy L. (2017): Specifying a hybrid, multiple material CAD system for next-generation prosthetic design. Loughborough University. Thesis.https://hdl.handle.net/2134/25...;
Specifying a Hybrid, Multiple Material CAD System for Next Generation Prosthetic Design
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Giulia Barbareschi
Doctoral Thesis. This thesis makes two contributions to facilitate wheelchair users’ engagement in the participatory design process for ATs, while being mindful of the burden of participation. The first contribution is a framework that provides a modular structure guiding the participatory design process from initial problem identification and analysis to facilitating collaborations between wheelchair users and designers. The framework identifies four factors determining the need and adoption process for ATs: (i) People focuses on the target population, (ii) Person includes personal characteristics, (iii) Activity refers to the challenges associated with the task, and (iv) Context encompasses the effect of the environment in which the activity takes place. The second contribution constitutes a rich picture of personal and external elements influencing real world wheelchair transfers that emerged from four studies carried out to investigate the effect of the framework factors on the design process for ATs.
UCL (University College London)
Abstract
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Transferring independently to and from their wheelchair is an essential routine task for many wheelchair users but it can be physically demanding and can lead to falls and upper limb injuries that reduce the person’s independence. New assistive technologies (ATs) that facilitate the performance of wheelchair transfers have the potential to allow wheelchair users to gain further independence. To ensure that users’ needs are addressed by ATs, the active involvement of wheelchair users in the process of design and development is critical. However, participation can be burdensome for many wheelchair users as design processes where users are directly involved often require prolonged engagement. This thesis makes two contributions to facilitate wheelchair users’ engagement in the participatory design process for ATs, while being mindful of the burden of participation. The first contribution is a framework that provides a modular structure guiding the participatory design process from initial problem identification and analysis to facilitating collaborations between wheelchair users and designers. The framework identifies four factors determining the need and adoption process for ATs: (i) People focuses on the target population, (ii) Person includes personal characteristics, (iii) Activity refers to the challenges associated with the task, and (iv) Context encompasses the effect of the environment in which the activity takes place. The second contribution constitutes a rich picture of personal and external elements influencing real world wheelchair transfers that emerged from four studies carried out to investigate the effect of the framework factors on the design process for ATs. A related outcome based on these contributions is a framing document to share knowledge between wheelchair users and designers to provide focus and promote an equal collaboration among participants.
YouTransfer, YouDesign: A Participatory Approach to Design Assistive Technology for Wheelchair Transfers
Barbareschi, Giulia. “YouTransfer, YouDesign : a Participatory Approach to Design Assistive Technology for Wheelchair Transfers / Giulia Barbareschi.” Thesis (Ph.D.)--University College London, 2018., 2018. Print.
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Understanding wrist splint user needs and personalisation through codesign
Charlotte Pyatt
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy at Loughborough University.
Loughborough University
Abstract
Understanding wrist splint user needs and personalisation through codesign
Wrist splints are a common treatment for rheumatoid arthritis, however their effectiveness is compromised by patients not wearing splints as often as prescribed. Previous research has identified a number of reasons for non-compliance, but typically lacks insights that could lead to improved splint design.
This thesis investigates the motivators for patients to wear and not wear their wrist splints and, the impact of personalisation of splint appearance on patient wear. The work is based on the premise that digital design and manufacturing processes, such as Computer-Aided Design (CAD) and 3D Printing, can produce bespoke splints on demand.
The research begins with a literature review across the core areas of: splinting, additive manufacture, product appearance and personalisation. This literature review identifies gaps in knowledge from which research questions are established for the work.
The research employs a qualitative, generative design research approach and, follows a codesign framework employing telling, making and enacting tools. The thesis is made up of three studies. The first study is a sensitisation study and uses design probes to prepare the participants for the research and begin exploring the problem space. The second is a comprehensive study into participants splint wear behaviour and uses context mapping and scenario picture card tools to investigate the motivators for participants to wear and not wear wrist splints, along with positive and negative outcomes or wearing/not wearing splints. The final study uses a personalisation toolkit to elicit patient needs for a future wrist splint design and investigate self-reported expectations regarding compliance of patients who used the toolkit.
The research finds that patient compliance is affected by practical and aesthetic limitations of current splints. It identifies 4 motivating factors to wear a splint and 10 motivating factors to not wear a splint. Additionally, it identifies 6 positive outcomes of wearing splints, 6 negative outcomes of wearing splints, 3 positive outcomes of not wearing splints and 3 negative outcomes of not wearing splints. Requirements for an improved splint design are established and form the basis of the design for a prototype personalisation toolkit. Testing of this toolkit reveals that patients are keen to own more than one splint and personalise splints to match the scenario in which it is to be worn. Patients reported that they expected to be more compliant with a personalised splint when compared to their current splint.
Understanding wrist splint user needs and personalisation through codesign
Pyatt, Charlotte (2018): Understanding wrist splint user needs and personalisation through codesign. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
Type
PhD
Themes
Assistive & Accessible Technology
Shared Control for Wheelchair Interfaces
Dr Chinemelu Ejiamatu Muoma Ezeh
Doctoral Thesis. Independent mobility is fundamental to the quality of life of people with impairment. Most people with severe mobility impairments, whether congenital, e.g., from cerebral palsy, or acquired, e.g., from spinal cord injury, are prescribed a wheelchair. A small yet significant number of people are unable to use a typical powered wheelchair controlled with a joystick. Instead, some of these people require alternative interfaces such as a head- array or Sip/Puff switch to drive their powered wheelchairs. However, these alternative interfaces do not work for everyone and often cause frustration, fatigue and collisions. This thesis develops a novel technique to help improve the usability of some of these alternative interfaces, in particular, the head-array and Sip/Puff switch.
UCL (University College London)
Abstract
Shared Control for Wheelchair Interfaces
Independent mobility is fundamental to the quality of life of people with impairment. Most people with severe mobility impairments, whether congenital, e.g., from cerebral palsy, or acquired, e.g., from spinal cord injury, are prescribed a wheelchair. A small yet significant number of people are unable to use a typical powered wheelchair controlled with a joystick. Instead, some of these people require alternative interfaces such as a head- array or Sip/Puff switch to drive their powered wheelchairs. However, these alternative interfaces do not work for everyone and often cause frustration, fatigue and collisions. This thesis develops a novel technique to help improve the usability of some of these alternative interfaces, in particular, the head-array and Sip/Puff switch. Control is shared between a powered wheelchair user, using an alternative interface and a pow- ered wheelchair fitted with sensors. This shared control then produces a resulting motion that is close to what the user desires to do but a motion that is also safe. A path planning algorithm on the wheelchair is implemented using techniques in mo- bile robotics. Afterwards, the output of the path planning algorithm and the user’s com- mand are both modelled as random variables. These random variables are then blended in a joint probability distribution where the final velocity to the wheelchair is the one that maximises the joint probability distribution. The performance of the probabilistic approach to blending the user’s inputs with the output of a path planner, is benchmarked against the most common form of shared control called linear blending. The benchmarking consists of several experiments with end users both in a simulated world and in the real-world. The thesis concludes that probabilistic shared control provides safer motion compared with the traditional shared control for difficult tasks and hard-to-use interfaces.
Ezeh, Chinemelu Ejiamatu Muoma. Shared Control for Wheelchair Interfaces. UCL (University College London), 2018. Print.
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Materials For Facial Prostheses In Resource Limited Countries
Sophia Esther Liiba Tetteh
A Doctoral Thesis. Submitted in partial fulfilment of the requirements for the award of the degree of Doctor of Philosophy of Loughborough University
Loughborough University
Cite Share Read Abstract Visit publisher
Abstract
Materials For Facial Prostheses In Resource Limited Countries
Facial prostheses are artificial devices that replace a missing body part in the facial and neck regions of the body. Defects or deformities in these regions can lead to functional deficiencies; social and psychological effects in addition to cosmetic defects. Restoration or rehabilitation in resource limited countries is usually provided by charities and organisations volunteering assistance overseas, with some training of local staff in the fabrication of these prostheses. Furthermore, these countries typically lack technical knowhow and trained personnel. In industrialised nations maxillofacial prosthetics has developed into a sophisticated medical speciality requiring highly skilled staff and expensive facilities. In resource limited countries surgical procedures may be an option for rehabilitation of these deformities/defects however, they tend to be unavailable or unaffordable and donated prostheses are not suitable. Hence, this research explores, from first principles, the appropriate and affordable local provision of maxillofacial prostheses in resource constrained regions. The investigation provides knowledge on identifying requirements for resource limited areas, resulting in the creation of a guideline constituting priorities, requirements and specifications. It further explores the viability of potentially cheaper, locally available candidate materials via weathering and antimicrobial methods in ascertaining material longevity.
Materials For Facial Prostheses In Resource Limited Countries
Tetteh, Sophia (2019): Materials for facial prostheses in resource-limited countries. Loughborough University. Thesis.https://doi.org/10.26174/thesi...;
Materials For Facial Prostheses In Resource Limited Countries
Type
PhD
Themes
Assistive & Accessible Technology
Research Group
Disability Interactions
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Rhys James Williams
Thesis: Firstly, the research provides a methodological contribution showing how to conduct mixed-methods research to obtain rich insights into complex prosthesis phenomena. Secondly, the research highlights the need to appreciate psychological and contextual factors when researching prosthesis wearer thermal comfort. The research contributions are also converted into an implication for prosthesis design. The concept of 'regaining control' to psychologically mitigate thermal discomfort could be incorporated into technologies by using 'on-demand' thermal discomfort relief, rather than 'always-on' solutions, as have been created in the past.
UCL, ProQuest Dissertations Publishing
Abstract
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Cite
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Williams, Rhys James. “Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers.” ProQuest Dissertations Publishing, 2020. Print.
Exploring Thermal Discomfort Amongst Lower-Limb Prosthesis Wearers
Join the GDI Hub Expert Bench
| https://www.disabilityinnovation.com/publications?page=3&type=toolkit+editorial+working-paper+phd+conference-paper |
Supporting Notes For The European IP Address Space Request Form — RIPE Network Coordination Centre
ripe-220: Supporting Notes For The European IP Address Space Request Form
Changes to
Supporting Notes For The European IP Address Space Request Form
ripe-220: Supporting Notes For The European IP Address Space Request Form ripe-048: RIPE Internet Network Numbers Template
This
RIPE Document Internet Network Numbers Template insert: <br /> insert: <br /> D.Karrenberg insert: <br /> insert: <br /> Aug 1992 insert: <br /> insert: <br /> insert: <br /> insert: <br /> To whom it may concern, insert: <br /> insert: <br /> The RIPE Network Coordination Centre now handles all requests for IP insert: <br /> network numbers from European organisations. Our aim is to provide a insert: <br /> rapid and efficient service to all European organisations. As this is insert: <br /> a recent initiative, procedures for handling network number requests are insert: <br /> in the process of being established. Therefore we apologise in advance insert: <br /> for any duplication of effort that may be required by you due to new insert: <br /> forms and templates. As the European NIC, we require different insert: <br /> information to that required by the US and for it to be presented in a insert: <br /> format which is both easy for you to complete and for us to process. insert: <br /> Before your application can be processed any further, you will need to insert: <br /> complete the enclosed templates and return them to the appropriate insert: <br /> organisation responsible for issuing IP network numbers. In most cases insert: <br /> this will be your IP service provider or the RIPE NCC. Before insert: <br /> completion of the template, please be sure to read the following text insert: <br /> and examples carefully which will guide you. insert: <br /> insert: <br /> A new classless IP addressing scheme called CIDR has recently been insert: <br /> adopted to cope with routing table growth and address space exhaustion insert: <br /> problems in the Internet. Under this scheme it is beneficial for insert: <br /> everyone to get their network numbers allocated via their respective insert: <br /> IP service providers. Your IP service provider is the organisation insert: <br /> providing external connectivity to your network. If you are planning insert: <br /> to connect your network to other networks outside your organisation in insert: <br /> the foreseeable future we strongly urge you to get numbers allocated insert: <br /> from your current or prospective IP service provider. Alternatively, if insert: <br /> this is not likely, then you will be allocated a number from a different insert: <br /> part of the address space by the RIPE NCC. Please pay careful attention insert: <br /> to this matter. insert: <br /> insert: <br /> Class A and B network numbers are a scarce resource and some insert: <br /> justification in terms of expected network size and structure will be insert: <br /> needed before such a number can be allocated. 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A one page document detailing the information needed by insert: <br /> the NCC to evaluate requests for class B numbersis available from the insert: <br /> NCC if it is not enclosed with this letter; this document also includes insert: <br /> a list of recommended reading about CIDR and address allocationin ASCII and PDF insert: <br /> general. insert: <br /> insert: <br /> Appended to this letter is a blank template for IP number registration, insert: <br /> which we would be extremely grateful if you complete and return to the insert: <br /> appropriate organisation responsible for issuing IP network numbers. In insert: <br /> most cases this will be your IP service provider. It may of course also insert: <br /> be the RIPE NCC. insert: <br /> insert: <br /> If you have any further queries please do not hesitate to contact the insert: <br /> NCC. Please note that all queries should, if possible, be made through insert: <br /> e-mail and sent to < hostmaster@ripe.net >. 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Supporting Notes For The European IP Address Space Request Form RIPE Internet Network Numbers Template
Authors:
Paula Caslav
Mirjam Keuhne
Carol Orange
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Atmosphere | Free Full-Text | The Spatiotemporal Dynamics and Socioeconomic Factors of SO2 Emissions in China: A Dynamic Spatial Econometric Design
With the great strides of China’s economic development, air pollution has become the norm that is a cause of broad adverse influence in society. The spatiotemporal patterns of sulfur dioxide (SO2) emissions are a prerequisite and an inherent characteristic for SO2 emissions to peak in China. By exploratory spatial data analysis (ESDA) and econometric approaches, this study explores the spatiotemporal characteristics of SO2 emissions and reveals how the socioeconomic determinants influence the emissions in China’s 30 provinces from 1995 to 2015. The study first identifies the overall space- and time-trend of regional SO2 emissions and then visualizes the spatiotemporal nexus between SO2 emissions and socioeconomic determinants through the ESDA method. The determinants’ impacts on the space–time variation of emissions are also confirmed and quantified through the dynamic spatial panel data model that controls for both spatial and temporal dependence, thus enabling the analysis to distinguish between the determinants’ long- and short-term spatial effects and leading to richer and novel empirical findings. The study emphasizes close spatiotemporal relationships between SO2 emissions and the socioeconomic determinants. China’s SO2 emissions variation is the multifaceted result of urbanization, foreign direct investment, industrial structure change, technological progress, and population in the short run, and it is highlighted that, in the long run, the emissions are profoundly affected by industrial structure and technology.
The Spatiotemporal Dynamics and Socioeconomic Factors of SO 2 Emissions in China: A Dynamic Spatial Econometric Design
by Zhimin Zhou
Lingnan (University) College, Sun Yat-Sen University, Guangzhou 510275, China
Atmosphere 2019 , 10 (9), 534; https://doi.org/10.3390/atmos10090534
Received: 16 August 2019 / Revised: 5 September 2019 / Accepted: 8 September 2019 / Published: 10 September 2019
Abstract
With the great strides of China’s economic development, air pollution has become the norm that is a cause of broad adverse influence in society. The spatiotemporal patterns of sulfur dioxide (SO
2
) emissions are a prerequisite and an inherent characteristic for SO
2
emissions to peak in China. By exploratory spatial data analysis (ESDA) and econometric approaches, this study explores the spatiotemporal characteristics of SO
2
emissions and reveals how the socioeconomic determinants influence the emissions in China’s 30 provinces from 1995 to 2015. The study first identifies the overall space- and time-trend of regional SO
2
emissions and then visualizes the spatiotemporal nexus between SO
2
emissions and socioeconomic determinants through the ESDA method. The determinants’ impacts on the space–time variation of emissions are also confirmed and quantified through the dynamic spatial panel data model that controls for both spatial and temporal dependence, thus enabling the analysis to distinguish between the determinants’ long- and short-term spatial effects and leading to richer and novel empirical findings. The study emphasizes close spatiotemporal relationships between SO
2
emissions and the socioeconomic determinants. China’s SO
2
emissions variation is the multifaceted result of urbanization, foreign direct investment, industrial structure change, technological progress, and population in the short run, and it is highlighted that, in the long run, the emissions are profoundly affected by industrial structure and technology.
;
spatiotemporal characteristics
;
socioeconomic determinants
;
dynamics spatial panel data model
1. Introduction
China has been the largest developing country in the world. Since the late 1980s, it has constantly expanded its economic scale and maintained at least a 9% annual economic growth rate over three decades [ 1 , 2 ]. In the meantime, considerable energy resource consumption has become a substantial cost of such rapid development, and leads to a large amount of sulfur dioxide (SO 2 ) emissions. China has inevitably appeared as a big SO 2 emitter as well as the largest energy consumer in the world [ 3 ]. Despite being the second-largest economy, China has yet fulfilled its historical task, that is, urbanization as well as industrialization [ 4 ]. Therefore, China confronts the challenge of curbing atmospheric pollution emissions when maintaining rapid economic growth [ 5 ]. During the 12th Five-Year Plan (2011–2015), the central government’s goal of SO 2 abatement was an 8% decrease in 2015 compared with the emission level of 2010 [ 6 ].
In the atmosphere, SO 2 can directly exacerbate heart disease, result in respiratory diseases in humans, and cause acid rain after reaction with other elements [ 7 ]. Except for public health, SO 2 also exerts ecological and economic effects. Owing to the rapid urbanization and industrialization process, many cities in China are affected by serious fog and haze pollution [ 8 ]. Sulfate stems from ambient SO 2 and accounts for 20–35% of the atmosphere PM2.5, which leads to smog [ 9 , 10 ] and threatens the eco-system and economic sustainability [ 11 ]. In 2008, the SO 2 pollution-related agricultural losses roughly reached $ 1.43 billion, which accounts for approximately 0.66% of the added agricultural output value in China [ 12 ]. China’s SO 2 emission level has already exceeded the levels of the United States and summed OECD (Organization for Economic Cooperation and Development) countries [ 13 ]. It is anticipated that in China, SO 2 emissions would continually increase and reach 24–31 million tons by 2020 [ 14 ]. Apparently, there is no time to delay for the SO 2 mitigation under the circumstance of sustainable development.
For many years, China has been the largest country of foreign capital inflow among developing countries. The constantly injected foreign direct investment (FDI) prompts the advancements of technology and management among domestic enterprises, economic development, and international business/export trade [ 15 ]. Hence, environmental economics scholars start to focus on the influence of FDI on pollution emissions and environmental quality in China (e.g., Wang and Jin [ 16 ], Bao et al. [ 17 ], and Dean et al. [ 18 ]). Additionally, the Chinese government began to upgrade and promote the optimization of the industrial structure since 2015 for the sake of emission-reduction and energy-saving. The cross-industry transmission of production materials could influence the pollution emissions [ 19 , 20 ], and China’s gradually updated industrial structure is expected to be beneficial for environment in practice [ 21 ]. Furthermore, over decades, the local governments have been expanding urban and suburb areas’ infrastructure construction, attempting to sprawl the cities [ 22 , 23 , 24 ], and China is transforming from an agricultural country to a modernized one [ 25 ]. Currently, more than half of the Chinese population already lives in urban areas [ 26 ]. Meanwhile, rapid urbanization and related economic activities may promote soaring resource consumptions and air pollution emissions. In sum, the relationships of SO 2 emissions to FDI, industrial adjustment, and urbanization are worthy of exploration, because a better understanding of such relationships provides a scientific basis to coordinate the economic development and reduction of SO 2 emissions.
Some recent studies focused on carbon and other kinds of pollution emissions issues [ 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ], whereas the studies that applied rigorous quantitative methods on the socioeconomic determinants of SO 2 emissions are still scarce. Several scholars tried to unfold the spatial pattern of China’s SO 2 emission in their studies. Zhao et al. [ 35 ] examined the spatial variation and driving factors of China’s industrial sulfur emissions and intensity from 2001 to 2014, and they found significant spatial clustering patterns that drastically varied over space and time. Zhou et al. [ 36 ] studied the nexus of SO 2 emissions to economic development through the spatial panel data model and concluded an inversely N -shaped environmental Kuznets curve. Yang et al. [ 37 ] examined the SO 2 geographical distributions through China’s 113 main cities and found the cities that were heavily polluted located in the north, while cities of low pollution level mainly agglomerated in the south. Zhao et al. [ 38 ] found that fossil fuel consumption is the major contributor of China’s SO 2 discharge. Li et al. [ 39 ] studied the spatial distribution of SO 2 at China’s prefecture-level. According to their results, the cities of lower SO 2 concentrations clustered in the Pearl River Delta and Yangtze River Delta regions, because there were less iron and steel manufactures, non-ferrous industries, and thermal power plants in the regions. On the other hand, the cities with higher concentrations mainly located in the Loess Plateau as well as the north plain. Giacomini and Granger [ 40 ] advocated the necessity of controlling for spatial effects (e.g., spatial autocorrelation, spillover (cross-boundary) impacts) when examining the socioeconomic activities’ influence on environmental quality. Anselin [ 41 ] also argued that it is necessary to adopt the spatial measurement approaches in the environmental/resources economics research on the regional level.
These initial explorations have preliminary investigated the spatial distributions and socio-economic influential factors of SO
2
emissions in China, yet scant researches to date have identified the emissions’ space–time characteristic. In addition, socioeconomic factors’ space–time effects on air pollution emissions have not been paid enough attention, and the effects need thorough examination through a proper empirical framework/approach. To this end, this paper makes efforts to complement prior researches by investigating SO
2
emissions’ spatiotemporal dynamics and the determinant variables across Chinese provincial-level units through exploratory spatial data analysis (ESDA), and the dynamic spatial econometric approach that organically condenses space-units’ spatial and temporal dependence into the empirical specification. The analysis and findings would help policymakers to promulgate effective policies to reinforce the SO
2
abatement and air pollution control.
The present study’s major contribution is two-fold. First, the study identifies the evolvement of SO
2
emissions’ spatial distribution and association patterns over time in China using GIS techniques and spatial statistics. Second, this study quantifies the socioeconomic–SO
2
spatiotemporal nexus through the recently improved dynamic spatial panel data model [
42
] that simultaneously integrates the spatial externalities and temporal effects. In this way, the variables’ long- and short-term impacts on the space–time dynamics of air pollution emissions are distinguished for the first time. Broadly speaking, a better realization of SO
2
emissions’ relation to socio-economic activities is helpful for figuring out the potential factors of increasing sulfur emissions witnessed among Chinese provinces, how the factors affect the emissions, and for further development of targeted policies for emission reduction.
The remainder of the paper is organized as follows. Section 2 describes the variable details, data source, and methods employed within the study. Section 3 illustrates and explains the results derived by the methods presented in Section 2 , and then Section 4 further discusses the results and illustrates the related theory as well as the mechanism. Section 5 sets out the conclusions and policy implications drawn from the results and findings.
2. Data and Methodology
2.1. Variables Selection and Data Resources
The following analysis adopted Chinese provincial panel data spanning from 1995 to 2015 (Taiwan is excluded owing to data unavailability) within the present study. The provincial data with relatively longer intertemporal enabled the empirical analysis to capture more spatial heterogeneity and temporal variations.
According to the subject, the following extended stochastic impacts by regression on population, affluence, and technology (STIRPAT) model serves as the theoretical benchmark for the regression analysis:
ln S O 2 = α + b 1 u r b + b 2 f d i + b 3 s t r u + b 4 ln P O P + b 5 ln E I + b 6 ln G D P + b 7 ( ln G D P ) 2 + ε ,
(1)
where
stru
,
urb
, and
fdi
refer to industrial structure, urbanization level, and foreign capital inflow, respectively. ln
GDP
(gross domestic product (GDP) in logarithm) together with its’ quadratic term (to capture the nonlinear environmental effects of GDP [
43
]) reflects the economic growth influence, while ln
POP
and ln
EI
refer to the impacts of population and technology on the environment, respectively. The dependent variable ln
SO
2
represents the SO
2
emissions (in logarithm) in this paper.
ε
is the error term. Because the studies that discuss the effects of economic development and population on SO
2
emissions are saturated, this paper focused on the effects of industrial structure, technology, urbanization, and FDI.
The definitions of industrial structure ( stru ), foreign capital inflow ( fdi ), urbanization level ( urb ), economic growth ( GDP ), population ( POP ), and technological progress/energy efficiency ( EI ) [ 44 ] are listed in Table 1 . The author multiplied the stru , urb , and fdi by 100, and took the logarithm of the rest of the indicators in the regression analysis ( Section 4 ). In this case, the coefficients b 1 – b 5 in Equation (1) can be interpreted as the ecological elasticity [ 45 ]. It is worth noting that all the variables are with their actual/raw values (not in logarithm) in the ESDA section ( Section 3 ).
Table 1. Definitions and descriptive statistics of the variables.
The SO 2 emissions and standard coal consumptions (kg of coal equivalent) were collected from the China Energy Statistical Yearbook. The secondary industry, tertiary output, as well as FDI can be accessed from China City Statistical Yearbook in the EPS data bank. The per capita GDP, the urban, and total population were obtained from the China Statistical Yearbook. Table 1 lists definitions and descriptive statistics of all variables.
2.2. ESDA
ESDA is regarded as the preliminary exploration before suggesting determinants to influence the spatial phenomena, and prior to testifying more confirmatory empirical analysis—the spatial regression model [ 46 ]. ESDA includes the techniques and steps of spatial data investigation—detecting and visualizing distributions and patterns in terms of geography, as well as identifying spatial heterogeneity forms, for example, regional/provincial regimes.
2.2.1. Global Spatial Autocorrelation
The most popular statistics measuring global spatial autocorrelation are Global Moran’s
I
statistics [
47
] developed by Moran [
48
]. Global Moran’s
I
statistics give a formal indication of whether the distribution pattern of a spatial index is clustered, random, or dispersed. The formula of the statistics is seen as
I = ∑ i = 1 N ∑ i ≠ j N w i j ( x i − x ¯ ) ( x j − x ¯ ) / ( ∑ i x i − x ¯ ) 2 ∑ i = 1 N ∑ i ≠ j N w i j
, −1 ≤
I
≤ 1,
N
= 30, where
x ¯ = 1 N ∑ i = 1 N x i
;
x
is the index of interest (SO
2
emissions in this research); and
w ij
is the element on the
i
-th row and
j
-th column of the spatial weight matrix
W
. The significance of Moran’s
I
statistics is identified by z-statistics, with the comparison of Moran’s
I
and its expectation as follows:
Z = [ I − E ( I ) ] / V a r ( I )
, where
E ( I ) = − ( N − 1 ) − 1
,
V a r ( I ) = N 2 w 1 + N w 2 + 3 w 0 2 w 0 2 ( N 2 − 1 ) − E 2 ( I )
,
w 0 = ∑ i = 1 N ∑ j = 1 N w i j
,
w 1 = 1 2 ∑ i = 1 N ∑ j = 1 N ( w i j + w j i ) 2
, and
w 2 = ∑ i = 1 N ∑ j = 1 N ( w i + w j ) 2
. When
I
≤ 0 significantly, the areas with the index of high values tend to locate near the ones with the index of low values (HL clustering); when 0 ≤
I
significantly, the spatial units with the index of high values cluster together and vice versa (HH/LL clustering pattern). This study applies Global Moran’s
I
statistics to explore the spatial association of overall SO
2
emissions’ in China.
2.2.2. Local Spatial Agglomeration
The identification of local hot and cold spots that indicate clustering heterogeneity in one or more provinces of the study area should be a basic consideration in the spatial pattern analysis [ 49 ]. A hot spot denotes the area of high value that is surrounded by other areas of high values (high–high), and the cold spot denotes the low–low type of spatial association. Getis and Ord [ 50 ] developed the “Getis-Ord Gi*” statistics to detect and measure the local spatial clustering patterns: G i * = ∑ i ≠ j w i j x i / ∑ i ≠ j x i , where x i > 0 , ∀ i ; w i j is the unstandardized spatial weight matrix with values between 0 and 1.
Ye and Wu [
51
] developed a spatiotemporal stability mapping of hot spots by overlaying hot spots over time-points, and this work extends Anselin’s local indicators of spatial association (LISA) significance map to spatiotemporal context. The present study follows Ye and Wu’s design [
51
], whereas it applies the “Getis-Ord Gi*” statistics instead of using LISA to identify the local spatial associations in the ESDA. This is because (a) the present study mainly focuses on the hot and cold spots, but not on the outlier type; (b) Global Moran’s
I
statistics suggest that high–high/low–low, but not high–low/low–high, is the main spatial clustering pattern (
Table 2
). Generally, the research enhances the spatiotemporal stability mapping to overlay statistically significant local spatial agglomeration (hot and cold spots) over years.
Table 2. Spatial autocorrelation of annual SO 2 emissions.
2.3. Dynamic Spatial Panel Data Model
The spatial Durbin model (SDM), spatial lag model (SLM), and spatial error model (SEM) are commonly used to fit the spatial data in the empirical analysis. The SLM presets a fixed ratio of direct effects/spillover effects of all independent variables (indices of determinants, hereafter the same) [
52
,
53
] (e.g., in Equation (1),
effects of u r b on local S O 2 effects of u r b on adjacent S O 2 = effects of f d i on local S O 2 effects of f d i on adjacent S O 2 = effects of s t r u on local S O 2 effects of s t r u e f f e c t s on adjacent S O 2 …
). Normally, such an assumption is over restricted and rather impractical in empirical studies. The SEM suggests the independent variables do not exert any spillover effects, which is not true according to the prior research [
36
] and econometric results in
Section 3.3
. Besides, it is unable to convert the SEM into a dynamics spatial framework to capture the potential spatiotemporal characteristics. Hence, following quantitative analysis adopts the dynamic SDM to examine and verify the socioeconomic determinants’ (
urb
,
fdi
,
stru
, and so on) space–time effects on sulfur emissions:
y t = γ 0 y t − 1 + λ 0 W y t + ρ 0 W y t − 1 + X 1 t β 0 + W X 2 t β 1 + c + α t l N + ε t ,
(2)
where
y t
is an
N
× 1 column, the observations of the dependent variable (the indicator to be explained, hereafter the same).
N
refers to the number of samples (provinces).
β
0
and
β
1
are
k
1
× 1 and
k
2
× 1 dimensional vectors of parameters.
X 1 t
and
X 2 t
are
N
×
k
1
and
N
×
k
2
dimensional matrixes of independent variables,
X 1 t
is the matrix of all the independent variables, while the
X 2 t
is the matrix of the variables of spillover effects.
k
1
and
k
2
equal the number of independent variables of
X 1 t
and
X 2 t
. The subscripts
t
and
t
− 1 indicate the
t
and
t
− 1 years, respectively.
β 0
and
β 1
are
k
× 1 dimension coefficient vectors.
W
is the
N
×
N
dimension spatial weight matrix, which defines the spatial arrangement of the spatial units (provinces). Considering that all the spatial units of analysis are polygons and the simplicity of the provinces’ bordering situation, the spatial weight matrix for ESDA and dynamic SDM is 0–1 specified: if the
i
-th and
j
-th (
i
and
j
represents 30 provinces of China, so 1 ≤
I
≤ 30 and 1 ≤
j
≤30) units share the same boundary, then the element on the
i
-th row and
j
-th column of
W
is 1, elsewhere 0.
W
is normalized when estimating the coefficients of dynamic SDM.
γ
0
,
λ
0
, and
ρ
0
are the parameters of
y t − 1
,
Wy t
, and
Wy t − 1
, reflecting the time lag, spatial lag, and spatiotemporal effects of the dependent variable, respectively.
ε t
is the
N
× 1 dimension vector of the error term with equal variance.
c
= (
c
1
…
c N
)
T
refers to the individual effects that control for the heterogeneity of each province, which does not change over time. As the provincial data are not randomly sampled from a bigger population and the sample is relatively small (
N
= 30), fixed individual effects are more suitable for the econometric model specification in this study [
52
,
54
].
α t
is the time fixed effects and
l N
is an
N
× 1 dimensional unit vector.
Equation (2) is the general specification of dynamic SDM. Specifically, if
γ
0
= 0 and
ρ
0
= 0, Equations (3) and (4) can be deduced from Equation (2), respectively:
y t = λ 0 W y t + ρ 0 W y t − 1 + X 1 t β 0 + W X 2 t β 1 + c + α t l N + ε t ,
(3)
y t = γ 0 y t − 1 + λ 0 W y t + X 1 t β 0 + W X 2 t β 1 + c + α t l N + ε t .
(4)
The coefficients of SDM cannot reflect the independent variables’ impacts on the dependent variable [
52
,
55
], because it incorporates the dependent variable’s spatial lag term on the right-hand side. The independent variables’ direct and spillover effects need further calculation. For instance, one can derive Equation (5) by rewriting Equation (2):
y t = ( I − λ 0 W ) − 1 ( γ 0 I + ρ 0 W ) y t − 1 + ( I − λ 0 W ) − 1 ( X 1 t β 0 + W X 2 t β 1 ) + ( I − λ 0 W ) − 1 ε t .
(5)
The partial derivatives matrix of expectation of
y t
to the
k
th independent variable of
X
from unit 1 to unit
N
at time
t
is seen as follows:
[ ∂ E y ∂ x 1 k ⋯ ∂ E y ∂ x N k ] t = ( ∂ E y 1 ∂ x 1 k … ∂ E y 1 ∂ x N k ⋮ ⋱ ⋮ ∂ E y N ∂ x N k ⋯ ∂ E y N ∂ x N k ) t = ( I − λ 0 W ) − 1 [ β 0 k I + β 1 k W ] ,
(6)
where
( I − λ 0 W ) − 1 = I + λ 0 W + λ 0 2 W 2 + λ 0 3 W 3 + ⋯
. The expectation of the diagonal elements in Equation (6) is defined to be the short-term direct effects, while the expectation of the off-diagonal elements is defined as the short-term spillover (or indirect) effects [
52
]. The long-term direct and spillover effects can similarly be defined by Equation (7):
[ ∂ E y ∂ x 1 k ⋯ ∂ E y ∂ x N k ] = [ ( 1 − γ 0 ) I − ( λ 0 + ρ 0 ) W ] − 1 [ β 0 k I + β 1 k W ] .
(7)
The theoretical foundation of the following econometric analysis is the extended STIRPAT model (Equation (1)). Owing to the incorporation of the quadratic term of ln
GDP
, the coefficients of ln
GDP
and its quadratic term are meaningless in terms of economics. Therefore, ln
GDP
and its quadratic term are only included in
X
, not in
WX
, then
y t = (ln SO 2 1 t , ln SO 2 2 t …ln SO 2 Nt ) T , X 1 t = ( u r b 1 t f d i 1 t s t r u 1 t ln P O P 1 t ln E I 1 t ln G D P 1 t ( ln G D P 1 t ) 2 u r b 2 t f d i 2 t s t r u 2 t ln P O P 2 t ln E I 2 t ln G D P 2 t ( ln G D P 2 t ) 2 ⋯ ⋯ ⋯ ⋯ ⋯ ⋯ ⋯ u r b N t f d i N t s t r u N t ln P O P N t ln E I N t ln G D P N t ( ln G D P N t ) 2 ) , and X 2 t = ( u r b 1 t f d i 1 t s t r u 1 t ln P O P 1 t ln E I 1 t u r b 2 t f d i 2 t s t r u 2 t ln P O P 2 t ln E I 2 t ⋯ ⋯ ⋯ ⋯ ⋯ u r b N t f d i N t s t r u N t ln P O P N t ln E I 1 t ) in Equations (2)–(7).
The basic strategy for dynamic spatial model analysis ( Section 3.3 ) consists of three steps: the dynamic SDMs based on Equations (2)–(4) would be estimated at first. Then, the best model specification that can better fit the empirical data will be determined, and the independent variables’ direct and spillover effects in the short and long run will be calculated according to the selected SDM, after which the relevant elaboration will be made.
Global Moran’s
I
statistics, correlation coefficients of annual SO
2
emissions, and dynamic SDM estimation are obtained from STATA 15, while the data visualization/mapping are conducted via ArcGIS 10.2.
3. Findings and Interpretation
3.1. Spatiotemporal Characteristics of SO 2 Emissions
In order to illustrate the geographical distribution of China’s regional sulfur emissions intuitively, natural breaks (Jenks) in ArcGIS are employed to divide the 31 provinces into five categories according to their emissions’ level.
Figure 1
illustrates that the spatial distribution of provincial SO
2
emissions (1995, 2005, and 2015) is likely to be subject to a certain pattern: (1) a lot of emissions activities cluster in a few provinces; (2) provinces of higher emission level tend to agglomerate together, and so do the provinces with lower emission level; and (3) the western areas tend to be less emission-intensified compared with the northern regions, resulting in a more concentrated and unbalanced spatial pattern of sulfur emissions.
Figure 1. SO 2 emissions in ( a ) 1995, ( b ) 2005, and ( c ) 2015 (Tons).
On the basis of the spatial distributing pattern of SO 2 emissions shown by Figure 1 , the emissions concentration area can be divided into two parts, namely a north (mainly at/around the Beijing–Tianjin–Hebei region) and a western emission zone. Sulfur emitting activities in the north emission zone are rather more intensive, exhibiting a robust spatiotemporal evolving characteristic over time.
Table 2 illustrates the sulfur emissions’ trend of global spatial autocorrelation during 1995–2015. Most Moran’s I statistics are significant at the 10% level, suggesting the spatial clustering phenomenon of SO 2 emissions is not just intuitive, but substantial, and the HH or LL should be the main clustering pattern.
Table 3 lists the SO 2 emissions’ time-series correlation. It is clear that the current provincial SO 2 emission level highly depends on the levels of prior years. Such time-series dependence only slightly decreases with the increase of the time interval. The space–time evolvement of SO 2 emissions and its determinants are worthy of scrutinizing, which will be carried out in the remaining analysis. After observing the SO 2 emissions’ geographical evolvement and time–series dependence, the following analysis attempts to unfold the socioeconomic determinants behind the emissions dynamics.
Table 3. Correlation coefficients of annual SO 2 emissions.
3.2. Space–Time Nexus between SO 2 Emissions and Its Socioeconomic Determinants
Local spatial patterns’ details can be masked by a bare discussion on global spatial autocorrelation. Besides, economic activities are temporal in essence [ 56 , 57 ], which would significantly affect energy consumption and pollution emissions. In order to cope with the issues, the author adopts the mapping technique of space–time stability, to overlap significant spatial agglomerations (hot and cold spots) on different time points (1995, 2005, and 2015). In this way, the spatiotemporal nexus between SO 2 emissions and their socioeconomic factors can be visualized.
Figure 2
demonstrates five classes of sulfur’s space–time stability. A province is identified as “1, 0, 0”, if it was a significant hot/cold spot in 1995, but not in the latter two years. A province is labeled “0, 1, 0” if it was a significant spot in 2005, but not in 1995 and 2015. Hence, the “0, 1, 1” pattern suggests that a province unit remained a significant spot in latter two years, but not in 1995, and “1, 1, 1” suggests a province was a significant spot in all three years. Finally, if a province had never been a significant spot in any year, it is labeled “0, 0, 0”. Following this manner,
Figure 3
,
Figure 4
and
Figure 5
demonstrate different categories of space–time stability of
fdi
,
stru,
and
urb
, respectively.
Figure 2. Spatiotemporal significant spots of SO 2 emissions.
Figure 3. Spatiotemporal significant spots of foreign direct investment (FDI).
Figure 4. Spatiotemporal significant spots of industrial structure (stru).
Figure 5. Spatiotemporal significant spots of urbanization level (urb) .
Six provincial units were the SO
2
emissions significant hot/cold spots of different four classes, mainly locating at/round the Beijing–Tianjin–Hebei region, which is also the area with more serious air pollution (e.g., smog) in China. Regarding the FDI index, eleven provinces are reported in four categories of significant spots that are mostly located in the north and the eastern coastal economic belt. Significant spots of industrial adjustment index (
stru
) are identified in three provinces/municipalities (Beijing, Tianjin, and Hainan) with three categories, while significant urbanization spots are identified in the western areas and Beijing, Tianjin, and Shanghai.
The spatiotemporal essences of these four different variables show few similarities, and it is hard to notice any connection between SO 2 emissions and the socioeconomic factors in terms of their spatial distribution and temporal evolvement through separate figures ( Figure 2 , Figure 3 , Figure 4 and Figure 5 ). Thus, Figure 6 overlays significant hot and cold spots of four variables on a single map to demonstrate the comprehensive emissions–determinates nexus in the space–time context. It is noteworthy that the SO 2 emissions’ significant spots overlap its three determinant variables and the north and north central regions have more provinces with hot/cold spots over the period. Moreover, Figure 6 also suggests that FDI might have a stronger connection with the spatiotemporal distribution of SO 2 emissions in specific areas than urbanization and industrial structure, as SO 2 and FDI share more coupled provincial units. Specifically, Xinjiang and its neighbors (Xizang, Qinghai, and Gansu) are all characterized by the low level of emissions, FDI, and urbanization; as such, Xinjiang should form a low–low spatial agglomeration and be a significant cold spot of these three variables. The emission–FDI significant spots can also be found at Shandong and Jiangsu provinces. Beijing is the capital city of China, which has relatively high levels of urbanization and industrial structure development, but is surrounded by Hebei, the emission-intensive and heavily polluted neighbor. Thus, Beijing is identified as the SO 2 , urb , and stru significant spots.
Figure 6. Comprehensive spatiotemporal significant spots.
The preliminary analysis above indicates that urbanization, FDI, and industrial structure all should have an evidently close connection with sulfur emissions in space–time extent. However, the ESDA technique has limited capability of revealing the causal relationship between the dependent and independent variables, plus it is unable to quantify the determinants’ impacts. Moreover, the data generating process (DGP) is usually unknown in empirical studies. The application of sophisticated statistical inferences and rigorous models can help us to fit the data and better describe the DGP. Therefore, the next subsection further examines the spatiotemporal nexus based on the dynamic SDM introduced in
Section 2.3
.
3.3. Econometric Results and Interpretation
In the spatial econometric analysis, the negligence of the spatial autocorrelation can lead to biased estimates [ 52 ]; in addition, the independent variables’ impacts on dependent variable could be overestimated without the incorporation of the dynamic effects/series dependence [ 58 ]. Consequently, it is necessary to control for both time-series dependence and spatial autocorrelation of the dependent variable (ln SO 2 ) within the quantitative empirical framework (dynamic SDM).
Table 4 depicts the coefficients estimated through maximum likelihood estimation [ 59 ] of Equations (2)–(4). ln SO 2 t − 1 , W ln SO 2 t − 1 , and W ln SO 2 t capture the time lag, spatial lag, and space–time lag effects, respectively. Estimations of both γ 0 and ρ 0 are significant in all three models, suggesting the incorporation of time lag and space–time lag effects is necessary for the empirical framework. Therefore, Equation (2) is superior to Equation (3) and Equation (4), and the following analysis is based on Equation (2). In Equation (2), the λ 0 estimation is positive and significant, which means that even with the inclusion of determinants’ spatial lag terms, the model should still control for emissions’ spatial association as well. This validates the Moran’s I statistics results of Table 2 . The determinants’ parameters in Table 4 cannot be interpreted as the average response of SO 2 emissions to its determinants, because the dynamic SDM includes W ln SO 2 t on the right-hand side, and, intrinsically, the partial derivatives of ln SO 2 t on the independent variables do not equal to their parameters. Instead, the socioeconomic determinants’ direct and spillover effects need further calculation by plugging the parameters (in Table 4 , Equation (2)) into Equations (6) and (7); the results are listed in Table 5 .
Table 4. Coefficients estimates of the dynamic spatial Durbin models.
Table 5. Short- and long-term effects on SO 2 emissions.
Table 5
shows that in China, urbanization, FDI, and industrial structure all have statistically significant influences on SO
2
emissions. The formal definition of spillover effects here is the impacts that a specific spatial unit exerts on its adjacent units [
55
]. In the short run, a 10% increase of FDI level will, ceteris paribus, averagely result in a 0.11% increase of emissions in the adjacent provinces, but would not have any significant influences on the emission level of the local province. In the long run, FDI does not have either direct or spillover effects on SO
2
emissions. Urbanization evidently has negative impacts on the local and neighbor sulfur emission levels in the short run, which means the urbanization development can temporarily reduce the SO
2
emissions. By contrast, the urbanization rate has no long-term influence on emissions. The industrial adjustment index is negatively related to the local and neighbors SO
2
emissions in the short run, while the index is only negatively related to the local emissions in the long run. Besides, population- and energy-related technological advancement (indicated by energy intensity, which is negatively correlated to the technological progress level [
21
]) also have significant long- and short-term influences on SO
2
emissions. A 10% growth of population would, ceteris paribus, averagely lead to a 2.75% and 5.41% temporal increase of emissions in the local and all adjacent provinces, respectively, and eventually, it would lead to a 20.15% increase of local emissions, but no significant change of neighbor emissions. As for the technological progress, its long- and short-term impacts only work on local emissions, but not on emissions of adjacent provinces. All else being equal, a 10% increase of technological progress level will averagely lead to 0.99% and 8.78% decreases of local emissions in the short and long run, respectively.
The dynamic SDM analysis above provides confirmative verification for the findings of ESDA in Section 3.2 . China’s SO 2 emissions are significantly dependent on FDI, urbanization, and industrial structure in the spatiotemporal context. Moreover, the sulfur emissions’ series dependence could be explained by industrial structure, the population, as well as energy intensity, and these three determinants have profound and eventual impacts on SO 2 emissions in China.
4. Discussion
As environmental sustainability and economic development (including urbanization, industrial structure transformation, and international trade) are both critical issues for China’s sustainable development. The focus on emission reduction motivates the discovery of the spatiotemporal characteristics of SO
2
emissions. Such explorations could help to develop a scientific foundation for the targeted decomposition of regional emissions, for a better understanding of the mechanisms of cross-region compensation, as well as for region-specific sustainable development. The ESDA results reveal that despite the distinct SO
2
emission levels in different years, overall, the clustering pattern had been stable. Similar to the findings in Zhao et al. [
35
], the emission-intensive provinces mainly agglomerate at/near the Beijing–Tianjin–Hebei region (
Figure 1
and
Figure 6
), which is in correspondence with the serious pollution of fog and haze in this region. Such a high-pollution and emissions phenomenon around the Beijing–Tianjin–Hebei region is closely related to the high proportion of the polluting heavy industry and the relative hysteresis of the tertiary industry development, especially in Hebei province [
39
]. Shandong and Jiangsu provinces form emission–FDI significant spots owing to their high level of foreign trade openness and emissions. Other than that, the capital city Beijing and municipality Tianjin have high urbanization levels and advanced industrial composition; meanwhile, they are surrounded by many pollution and emission enterprises from near areas. Thus, these two cities are identified as
urb
– and
stru
–emission significant spots.
China’s provincial SO 2 emissions are found to have significant autocorrelation ( Table 2 ), which is in line with similar previous studies [ 35 , 36 ]. Atmospheric pollutants, especially the emission type, are usually characterized by spatial dependence/diffusions, because adjacent provinces may be the mimics of each other’s socio-economic and environmental policies. Thus, the emissions’ level could be affected by neighbors’ emissions and economic activities including foreign investment promotion, the layout of industrial structure, urban infrastructure, and technological development [ 5 ]. China’s central government assigns the annual national achievements of pollution reduction and economic growth at the provincial and prefectural levels. The evaluation of such achievements is carried out among provinces and cities. The competition in economic growth and environmental production inevitably arise between provinces/cities for local governors’ political performance. If a specific local government adopts a strict pollution discharge standard, its neighboring provinces are likely to imitate and implement a similar standard on their own emissions reduction. On the contrary, if the local government takes the development as the primary task and set out a series of loose regulations on pollution emissions, the adjacent provinces are likely to adopt similar loose regulations in order to compete in terms of economic growth. Therefore, such “demonstration effects” should be responsible for the autocorrelation of SO 2 emissions found in Section 3 [ 60 ].
The dynamic spatial econometric results not only verified, but also quantified the spatiotemporal nexus of the socioeconomic factors to SO
2
emissions. The pollution haven hypothesis (PHH) can explain the adverse (positive value) effects of FDI on emissions. The PHH suggests that developed countries’ multinational enterprises, particularly the energy- and pollution-intensive ones, are likely to relocate their business and industries to developing countries owing to the incentives of profits and relatively loose environmental law in these developing countries. Therefore, PHH vividly denotes the less developed countries as a “pollution haven”, if they have lower environmental standards than the necessary level of efficient foreign capital and investment inflow. In this way, such a low barrier of international trade would be environment-deteriorating in China—the provinces with relatively loosen environmental regulations and higher openness of international trade may have been attracting less environment-friendly foreign companies, resulting in considerable pollution emissions [
61
]. Interestingly, FDI only exerts (short-term) spatial spillover effects on SO
2
emissions, but no direct effects. China’s FDI mainly agglomerates at the developed southeast coast economic belt (
Figure 6
), where stricter regulation, highly advanced-technology, and experienced management exist [
35
]. Therefore, these areas are able to minimize the FDI’s environmental adverse impact, so that the FDI does not evidently affect the local emissions.
Urbanization’s beneficial effects for the SO 2 abatement can be reflected by the modernization theory [ 62 , 63 ]. The urbanization process inevitably consumes more energies and thus generates more pollutants owing to the demand for building materials for constructing new and upgrading old public infrastructures [ 22 ]. However, improvements in urbanization level and urban density could also result in an upgrade on the efficiency of public infrastructure’s utilization, such as public transport, which decreases energy consumption and pollution emissions [ 24 , 64 ]. Urbanization also means more advanced and modernized ways of energy consumption. The replacement of inefficient solid fuels by advanced energy utilization enables urban industries and residents to lower the energy consumption and pollution emission levels [ 65 , 66 ]. Moreover, urbanization can promote environmental quality via economies of scale in environmental protection and services of sanitation [ 67 ].
The upgrade and optimization (transfer of secondary to tertiary industry) of industrial structure can lead to a reduction of SO 2 emissions in local and neighbor provinces of China, because the pollution intensities are distinct in different industries. The secondary industry is the segment of the economy that processes the raw materials (from primary industry) into products and commodities for its consumers, and the secondary industry is also known as the manufacturing industry. The tertiary industry is the economic sector that provides services to the consumers, consisting of a range of businesses, such as entertaining institutions, schools, finance companies, research and development (R&D) departments, and catering services. It is also known as the tertiary/service industry. Given the industries’ production patterns, the secondary industry is more materiel- and energy-consuming, and thus more pollution-intensive. As for the tertiary industry, it is knowledge- and service-intensive, and thus less polluting. Specifically, in China, industrial sectors (mainly in the secondary industry), including the construction sector, are the major source of emissions, accounting for 84% of the total energy-related emissions in 2014 [ 68 ]. The industrial sectors’ SO 2 emissions make up over 80% of China’s total sulfur emission [ 69 ]. On the other hand, the tertiary industry is composed of less-polluting services and light manufacturing sectors. The industrial composition’s effects are long-lasting because the structure varies with economic development all along. At the initial stage, because of the pursuit of industrialization, production resources and capital in primary industry (agricultural sectors) transfer to secondary industry, particularly the heavy industry, which boosts pollution emissions. When it comes to the middle and late stage, the demand of higher efficiency and lower emission causes a shift from the emission-intensive secondary industry towards the knowledge-intensive tertiary industry, so the process reduces the emissions’ amount [ 20 , 70 ]. During 2004–2014, the secondary industry ratio had been decreasing in developed Chinese provinces, and had first increased and then decreased in the developing provinces. China’s recently implemented industrial upgrading reform ought to be responsible for such changes [ 36 ].
Technological progress is found to be effective on SO 2 abatement in China, which is in line with findings of Zhou et al. [ 36 ], Dinda et al. [ 71 ], and Ge et al. [ 26 ]. According to the facts in China, the reason for the environmental-beneficial effects of technological advancement (a decline of energy intensity) is three-fold: exhaust-gas emission reduction’s upgrade, for example, the end-of-pipe abatement technology; the promotion of energy industrialization; and surging investment in new energy industries [ 6 , 72 ]. REN21 Global Status Report [ 73 ] reveals that China has been developing large amounts of new energies that are more sustainable and cleaner, such as hydropower, solar power, biofuels, and wind power. Highly advanced technology tend to be the primary cause that leads to environmental quality improvement in the long term [ 74 ]; this can also be seen from the absolute value of ln EI in Table 5 . Theoretically, highly advanced technology is usually characterized by efficient utilization of energy and materials during continuous economic growth, which saves more natural resource and reduces the burden on environmental protection of economic activities. The incidentally allowed renewable energies to emerge during technological advancement to enable a country to recycle and reuse the production materials more efficiently, so that they can reserve more natural resources and reduce the emissions [ 36 ]. A comparable empirical study also found technological progress to be a major contributor to SO 2 abatement in Germany and Netherlands [ 75 ].
Different from FDI, technological progress only has direct effects that only influence local SO
2
emissions, as geographic boundaries can hinder technology’s spatial-spillovers [
76
,
77
]. Without a doubt, public sectors’ R&D activities can transmit through the Internet and multimedia, although the information networks cannot utterly replace the physical communications (e.g., seminars, researcher exchange, field trips, science facilities, and paper documentation). Moreover, monopoly profits are incentives for companies to establish a technological barrier that is effective for removing other competing firms [
77
], so the technology is found to be non-effective on neighboring provinces’ emissions.
As mentioned above, previous work (Zhou et al. [ 36 ], Zhao et al. [ 35 ], Zhao et al. [ 38 ], Dinda et al. [ 71 ], Ge et al. [ 26 ], and Rui et al. [ 39 ]) also detected significant effects of technology and industrial composition on pollution emissions. However, they ignore these factors’ short-term effects because the application of the traditional static panel model is unable to account for both spatial and series dependence (the DGP’s inherent spatial and temporal characteristics) in the empirical framework, which could lead to biased results [ 78 ].
In general, the interprovincial cooperation, imitation, and competition should account for the emissions’ autocorrelation and socioeconomic activities’ spillover effects. Considering China’s continuous industrial structure upgrade and high-speed developing technology, the fundamental driving factors of SO 2 emissions’ reduction can be categorized into two types: economic structural and technological progress—a similar opinion can be found in Dinda [ 19 ].
5. Conclusions
China’s rapid economic growth is accompanied by soaring energy consumption and pollution emissions; as a result, the country has become one of the largest SO
2
emitters in the world. At such a juncture, a clear and precise understanding of the spatiotemporal patterns of China’s SO
2
emissions is essential and crucial. Relevant knowledge can constitute a practical framework for policymakers at different administrative levels to achieve the SO
2
abatement task and design a mechanism of abatement’s cross-region compensation in China.
The empirical results offer new findings and novel insights into the spatiotemporal dimensions of China’s SO
2
emissions and the socioeconomic factors spanning from 1995 to 2015. The main conclusions are summarized as follows.
The ESDA reveals that SO
2
emissions and their socioeconomic factors went through a stable and evident spatial clustering pattern during the study period. Spatial externalities of emissions exist across different provincial areas, namely the variation of provincial SO
2
emissions influence not only the local provinces, but also the adjacent provinces’ emissions. Several kinds of significant spots are recognized through the mapping technique, suggesting that significant spots of emissions generally overlay well with the influencing factors’ significant spots, and this result reflects the fact that there is a close space–time nexus of SO
2
emissions to these factors (FDI, industrial composition, and urbanization).
The econometric empirical analysis is theoretically based on the extended STIRPAT model (Equation (1)) and embeds a dynamics spatial Durbin model to quantify the spatiotemporal nexus in a confirmatory way. Spatial externality plays an important role because the factors’ spillovers significantly contribute to the space- and time-dynamics of China’s SO
2
emissions. An increase in population or FDI increases the SO
2
emissions. By contrast, the urbanization progress, industrial structure upgrade, and technological advancement can all improve the efficiency of SO
2
abatement. The urbanization progress only reduces local and adjacent provinces’ SO
2
emissions in the short run, whereas the technological advancement and optimization of industrial composition exert both short- and long-term reducing effects. In other words, the technological advancement and industrial structure update have long-lasting and profound influences on China’s SO
2
emissions. Their differences lie in the short-term influence, owing to “demonstration effects”, the industrial composition affects not only local emissions, but also the emissions of neighboring provinces, while the technological progress only influences local emissions owing to geographical barriers.
The study also provides a reference value. China’s policymakers should advocate the optimization of industrial structure and improvement of energy-related technology, which can practically constitute a more thorough and effective way of SO
2
abatement. On the other hand, the decision-maker is also urged to curb and then give up the traditional energy- and emission-intensive industries and resource-consuming developing way, and to exchange the immediate interests (e.g., foreign capital inflow with low environmental standards) for securing the long-term sustainable purpose.
As merely 30 Chinese provincial units and 21 years’ time points are analyzed in this paper, owing to the data availability, further studies are expected to adopt less aggregate spatial elements (i.e., prefecture-level, even county-level data) and longer time points to capture more spatial and temporal characteristics. In addition, the issues not covered by this paper, such as the inequality/convergence of SO
2
and other pollution emissions, should be addressed from both regional and industry perspectives.
Funding
This research was funded by Lingnan (University) College Fund (0219000088).
Acknowledgments
I would like to thank the anonymous referees for their review, comments, and valuable suggestions.
Conflicts of Interest
The author declares no conflict of interest.
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Figure 1. SO 2 emissions in ( a ) 1995, ( b ) 2005, and ( c ) 2015 (Tons).
Figure 2. Spatiotemporal significant spots of SO 2 emissions.
Figure 3. Spatiotemporal significant spots of foreign direct investment (FDI).
Figure 4. Spatiotemporal significant spots of industrial structure (stru).
Figure 5. Spatiotemporal significant spots of urbanization level (urb) .
Figure 6. Comprehensive spatiotemporal significant spots.
Table 1. Definitions and descriptive statistics of the variables.
Variables Definition Mean Std. Dev. Min Max ln SO 2 SO 2 emissions (tons) in logarithm 13.10 0.936 9.735 14.51 urb Proportion of population living in urban area (%) 46.40 16.04 20.39 89.60 fdi Ratio of FDI to GDP (%) 2.986 3.181 0.001 21.19 stru The ratio of the tertiary industry to the secondary industry (%) 95.36 42.40 403.79 49.70 ln POP population size (10 thousand) in logarithm 8.127 0.770 6.176 9.292 ln EI energy intensity (tons of coal equivalent/billion Yuan) in logarithm 9.715 0.511 8.706 11.27 ln GDP real per capita GDP (100 Yuan, in 1995 constant price) in logarithm 4.867 0.855 2.905 7.170
Note: Yuan is the unit of Renminbi (RMB), the official currency in China. SO 2 , sulfur dioxide; FDI, foreign direct investment; GDP, gross domestic product.
Table 2. Spatial autocorrelation of annual SO 2 emissions.
Year 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 Moran’s I 0.200 0.201 0.249 0.225 0.229 0.170 0.158 0.154 0.131 0.146 0.148 z-statistics 2.266 2.274 2.658 2.428 2.428 1.842 1.731 1.700 1.478 1.607 1.630 p -value 0.023 0.023 0.008 0.015 0.015 0.065 0.084 0.089 0.139 0.108 0.103 Year 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Moran’s I 0.148 0.165 0.166 0.148 0.116 0.230 0.222 0.226 0.208 0.210 z-statistics 1.629 1.775 1.789 1.626 1.335 2.380 2.309 2.339 2.184 2.206 p -value 0.103 0.076 0.074 0.104 0.182 0.017 0.021 0.019 0.029 0.027
Table 3. Correlation coefficients of annual SO 2 emissions.
Year 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 1995 1.00 - - - - - - - - - - - - - - - - - - - - 1996 1.00 1.00 - - - - - - - - - - - - - - - - - - - 1997 0.99 0.99 1.00 - - - - - - - - - - - - - - - - - - 1998 0.96 0.97 0.97 1.00 - - - - - - - - - - - - - - - - - 1999 0.95 0.95 0.94 0.96 1.00 - - - - - - - - - - - - - - - - 2000 0.89 0.90 0.91 0.94 0.93 1.00 - - - - - - - - - - - - - - - 2001 0.88 0.90 0.91 0.95 0.94 1.00 1.00 - - - - - - - - - - - - - - 2002 0.89 0.91 0.92 0.95 0.94 0.99 1.00 1.00 - - - - - - - - - - - - - 2003 0.87 0.88 0.91 0.93 0.92 0.96 0.96 0.98 1.00 - - - - - - - - - - - - 2004 0.85 0.87 0.90 0.92 0.92 0.95 0.96 0.97 0.99 1.00 - - - - - - - - - - - 2005 0.86 0.87 0.90 0.91 0.91 0.92 0.94 0.95 0.98 0.99 1.00 - - - - - - - - - - 2006 0.85 0.86 0.89 0.89 0.89 0.92 0.93 0.94 0.97 0.98 1.00 1.000 - - - - - - - - - 2007 0.83 0.84 0.88 0.88 0.89 0.91 0.92 0.94 0.97 0.99 1.00 1.00 1.00 - - - - - - - - 2008 0.83 0.84 0.88 0.88 0.88 0.89 0.91 0.92 0.96 0.98 0.99 1.00 1.00 1.00 - - - - - - - 2009 0.82 0.83 0.87 0.87 0.88 0.89 0.91 0.93 0.96 0.97 0.99 1.00 1.00 1.00 1.00 - - - - - - 2010 0.81 0.82 0.86 0.86 0.86 0.88 0.90 0.91 0.96 0.97 0.99 0.99 0.99 0.99 1.00 1.00 - - - - - 2011 0.82 0.83 0.87 0.87 0.86 0.83 0.86 0.88 0.91 0.92 0.95 0.95 0.95 0.96 0.96 0.95 1.00 - - - - 2012 0.81 0.82 0.86 0.85 0.84 0.81 0.83 0.86 0.90 0.91 0.94 0.94 0.95 0.95 0.95 0.94 1.00 1.00 - - - 2013 0.78 0.79 0.83 0.83 0.82 0.80 0.82 0.84 0.89 0.90 0.93 0.94 0.94 0.94 0.95 0.94 1.00 1.00 1.00 - - 2014 0.80 0.80 0.84 0.83 0.82 0.80 0.82 0.84 0.88 0.89 0.92 0.93 0.93 0.94 0.94 0.93 0.99 1.00 1.00 1.00 - 2015 0.80 0.80 0.84 0.83 0.82 0.79 0.81 0.84 0.88 0.89 0.92 0.93 0.93 0.94 0.94 0.93 0.99 1.00 1.00 1.00 1.00
Table 4. Coefficients estimates of the dynamic spatial Durbin models.
Note: z-statistics in parentheses, *** p < 0.01, ** p < 0.05, * p < 0.1. ln SO 2 is the dependent variable.
Table 5. Short- and long-term effects on SO 2 emissions.
ln SO 2 Direct Effects (Short-Term) Spillover Effects (Short-Term) Total Effects (Short-Term) Direct Effects (Long-Term) Spillover Effects (Long-Term) Total Effects (Long-Term) urb −0.004 ** −0.011 ** −0.015 *** −0.032 −0.065 −0.097 (−2.15) (−2.34) (−3.07) (−1.57) (−0.26) (−0.38) fdi 0.004 0.011 * 0.014 ** 0.024 0.068 0.092 (1.28) (1.88) (2.35) (0.94) (0.52) (0.69) stru −0.001 *** −0.002 ** −0.003 *** −0.008 *** −0.009 −0.017 (−3.17) (−2.04) (−2.78) (−2.72) (−0.24) (−0.45) ln POP 0.275 ** 0.541 ** 0.817 *** 2.015 * 3.066 5.081 (2.10) (2.46) (3.31) (1.67) (0.23) (0.38) ln EI 0.099 ** −0.124 −0.025 0.878 ** −0.967 −0.089 (2.24) (−0.94) (−0.18) (2.08) (−0.32) (−0.03)
Note: z-statistics in parentheses, *** p < 0.01, ** p < 0.05, * p < 0.1. The direct and spillover effects of ln GDP and (ln GDP ) 2 are meaningless in terms of economics, so they are not reported in the table. Total effects = direct effects + spillover effects.
| https://www.mdpi.com/2073-4433/10/9/534/xml |
Spliceosome GENE MUTATIONS ARE Also PRESENT In the Diverse Mutational Spectrum of CHRONIC Myelomonocytic LEUKEMIA | Blood | American Society of Hematology
Abstract. Abstract 1402Chronic myelomonocytic leukemia (CMML) is characterized by monocytic proliferation, cytomorphologic dysplasia and frequent progression to
Spliceosome GENE MUTATIONS ARE Also PRESENT In the Diverse Mutational Spectrum of CHRONIC Myelomonocytic LEUKEMIA
Hideki Makishima, MD, PhD
,
Hideki Makishima, MD, PhD
1 Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA,
Anna M Jankowska, PhD
,
Anna M Jankowska, PhD *
1 Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA,
Valeria Visconte, PhD
,
Valeria Visconte, PhD *
1 Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA,
Ramon V. Tiu, MD
,
Ramon V. Tiu, MD
2 Department of Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA,
Kathryn M Guinta
,
Kathryn M Guinta *
3 Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA,
Hadrian Szpurka, PhD
,
Hadrian Szpurka, PhD
1 Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA,
Yuka Sugimoto, MD, PhD
,
Yuka Sugimoto, MD, PhD
1 Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA,
Christine L. O'Keefe, PhD
,
Christine L. O'Keefe, PhD
3 Translational Hematology and Oncology Research, Cleveland Clinic, Cleveland, OH, USA,
Alan F. List, MD
,
Alan F. List, MD
Mikkael A Sekeres, MD
,
Mikkael A Sekeres, MD
5 Hematologic Oncology and Blood Disorders, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA,
Michael A McDevitt, MD, PhD
,
Michael A McDevitt, MD, PhD
6 Department of Oncology, Division of Hematological Malignancy, Johns Hopkins University School of Medicine, Baltimore, MD, USA
Jaroslaw P. Maciejewski, MD, PhD
Jaroslaw P. Maciejewski, MD, PhD
Hideki Makishima ,Anna M Jankowska ,Valeria Visconte ,Ramon V. Tiu ,Kathryn M Guinta ,Hadrian Szpurka ,Yuka Sugimoto ,Christine L. O'Keefe ,Alan F. List ,Mikkael A Sekeres ,Michael A McDevitt ,Jaroslaw P. Maciejewski; Spliceosome GENE MUTATIONS ARE Also PRESENT In the Diverse Mutational Spectrum of CHRONIC Myelomonocytic LEUKEMIA. Blood2011; 118 (21): 1402. doi:https://doi.org/10.1182/blood.V118.21.1402.1402
Ris (Zotero)
Abstract
Abstract 1402
Chronic myelomonocytic leukemia (CMML) is characterized by monocytic proliferation, cytomorphologic dysplasia and frequent progression to acute myelogeneous leukemia (AML). The molecular basis of CMML is poorly defined, although somatic mutations in a number of genes have recently been identified in a proportion of patients (epigenetic regulatory genes, spliceosomal genes, apoptosis genes, growth signal transducers and others). We performed a comprehensive analysis of molecular lesions, including somatic mutations detected by sequencing and chromosomal abnormalities investigated by metaphase and SNP-array karyotyping. We have selected a cohort of 72 patients (36 CMML1, 16 CMML2 and 20 sAML evolved from CMML).
Our mutational screen performed in stages (as new mutations were discovered by our and other groups) and currently reveals mutations in UTXin 8%, DNMT3Ain 9%, CBLin 14%, IDH1/2in 4%, KRASin 2.7%, NRASin 4.1%, JAK2in 1%, TET2in 48%, ASXL1in 43%, EZH2in 5.5%, RUNX137%. Based on the discovery of various spliceosomal mutations in myeloid malignancies, novel mutations were also found in CMML, in U2AF1in 12%, SF3B1in 14%, SFRS19in 6 % of cases tested.
Chromosomal defects were detected in 60% of patients. In particular, a high frequency of somatic uniparental disomy (sUPD) were identified 71% of patients with abnormal cytogenetics, including UPD1p (N=3), UPD7q (N=8), UPD4q (N=6), UPD2p (N=2), UPD17q (N=2), UPD11q (N=5), UPDX (N=1), UPD21q (N=2). Some of the detected mutations were homozygous through their association with sUPD as for example for 3 EZH2, 1 UTX, 6 TET2, 2 DNMT3A, 5 CBL, 1 NRAS, 1 U2AF1mutations. Furthermore, UPD17p implies that a P53mutation is also present in this case as previously LOH17p was shown to be invariably associated with P53mutations. Similarly, 2 cases of UPD17q imply that homozygous mutation of SRSF2, which is one of the Serine/arginine-rich splicing factor, may be present in this location and the mutation analysis is ongoing.
In over 90% of >1 mutation was found but many patients harbored multiple mutations with frequent combinations of TET2/CBLor TET2/ASXL1as well as RUNX1and U2AF1serving as examples. There was an accumulation of mutations from sAML, CMML2 and CMML1 suggesting stepwise accumulation of lesions. In serial studies, some of the mutations were present at the inception (e.g., TET2, ASXL1and DNMT3A) in some cases originally heterozygous mutations were also while other can occur in the course of disease (e.g. CBL). RASand DNMT3Amutations were associated with a higher blasts count.
In sum, combined analysis of molecular lesions in CMML reveals that similar phenotype may be a result of diverse mutations associated with seemingly unrelated pathways and that clinical phenotype may be a result of a combination of mutations which accumulate as the disease progresses. Survival analyses will require large cohorts to account for various confounding factors including the presence of multiple chromosomal abnormalities and mutations in one patient, however currently EZH2, DNMT3and CBLmutations appear to convey less favorable prognosis.
Topics:
,
mutation
,
spliceosomes
,
arginine
,
cancer
,
chromosomal disorder
,
dysplasia
,
karyotype determination procedure
,
leukemia
,
mutation analysis
| https://ashpublications.org/blood/article-split/118/21/1402/78549/Spliceosome-GENE-MUTATIONS-ARE-Also-PRESENT-In-the |
UNPO: Inner Mongolia: Korean Air Sponsors Annual Forestation Project
Inner Mongolia: Korean Air Sponsors Annual Forestation Project
The article below was published by China Daily :
More than 65 employees from the South Korean flagship carrier Korean Air headed for the Kubuqi desert in China's Inner Mongolia autonomous region in October [2012] to carry out large-scale forestation.
Korean Air announced that it will plant 80,000 trees annually on 240,000 square meters of land in the Kubuqi desert during the next five years.
This year is the sixth consecutive year Korean Air is planting trees in the desert and signals the beginning of a second round of a program aimed at improving the environment of the area to curb further desertification.
"Korean Air has always attached great importance to development of the charitable programs for ecology issues. This is the duty of a corporate citizen to fulfill a social responsibility," said Chi Chang-hoon, president of Korean Air, who came to Inner Mongolia for this year's tree-planting.
The company also invited 55 students studying to be flight attendants from Inner Mongolia Normal University, as it has done in past years.
The Green Ecology Park program, which started in 2007, targets the Kubuqi desert, China's seventh-largest. The desert covers about more than 1 million hectares and is 400 kilometers in length. Being the closest desert to Beijing, it is regarded as the source of much of the city's spring dust invasions.
Due to excessive deforestation and rapid industrialization, soil erosion in the desert has long been a serious problem. It is estimated that the desert is expanding annually at a scale of five times the size of South Korea's capital, Seoul.
The desert affects the environment of neighbouring countries.
Chosun Ilbo, one of South Korea's major daily newspapers, once reported that the Kubuqi desert, which is more than 30 times the size of Seoul, was sending sandstorms to the Korean Peninsula every year. It said that many Korean companies were taking measures to tackle the problem.
From 2007 to 2011, Korean Air planted 1 million trees on a total of 3.18 million sq m of land to help prevent sandstorms and desertification in Northeast Asia.
"Korean Air will continue to carry out various forms of public environmental protection activities in order to repay the support and love of its Chinese passengers," said Chi.
The program is an important component of the South Korea-China Friendship Green Great Wall project, which is co-funded by the All-China Youth Federation and South Korea-China Future Forest, a non-governmental organization focused on forestation. The project aims to build up a 28 kilometers long forestation area measuring between three and eight kilometers wide.
The Kubuqi desert is not Korean Air's only target as it promotes eco-development. In November 2009, Korean Air gave out 5,000 eco-friendly bags to Beijing citizens to promote a greener lifestyle.
In July and October 2010, Korean Air sent its environment ambassadors dressed as Teddy Bears to Beijing Capital International Airport and Guangzhou Baiyun International Airport, distributing cards with environmental protection information on them to promote the concept of a low-carbon lifestyle.
From 2004, Korean Air has created 50,000 sq m of forest every year on the outskirts of Ulan Bator, capital of Mongolia. It has also planted trees in Los Angeles, in the United States, annually since 2009.
Korean Air now owns 148 aircraft and is one of the 20 biggest airlines in the world. Like many other Korean companies, it is making an effort to promote forestation and eco-friendly lifestyles in countries challenged by desertification, a move that benefits both those countries and their neighbors.
| https://unpo.org/article/15092 |
Ultimobranchial Tumor of the Thyroid and Pheochromocytoma in the bull
Download Citation | Ultimobranchial Tumor of the Thyroid and Pheochromocytoma in the bull | An ultimobranchial tumor of the thyroid and a phcochromocytoma occurred in a bull. The thyroid tumor contained amyloid. The occurrence of... | Find, read and cite all the research you need on ResearchGate
Ultimobranchial Tumor of the Thyroid and Pheochromocytoma in the bull
February 1970
Pathologia Veterinaria7(2):126-34
DOI: 10.1177/030098587000700204
PubMed
Authors:
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Bruce N. Wilkie
Bruce N. Wilkie
<here is a image f2f62089ad6ff61c-d19572ff1996375a>
Lennart Krook
Lennart Krook
Abstract
An ultimobranchial tumor of the thyroid and a phcochromocytoma occurred in a bull. The thyroid tumor contained amyloid. The occurrence of ultimobranchial tumor of the thyroid and phcochromocytoma was established in a large series of bovine necropsies and the co-existance of these tumors in the bull was highly significant; neither occurred in the cow.
... x 30.400 (LJltrastructure of a tumor cell secreting norepinephrine. Secretoric granules have an eccentrically situated electron-dense core surrounded by a wide submeOlbranous space) Mikroskobik olarak, tümörün ince vasküler st rom ayla sınırlandınlmış küçük lobüler yapısı (I, 3, 4, 5, 7), tümör hücrelerinin normal pheochromocyte'lere benzerliği, mitotik figürlerin pek görülmeyişi (5,
9)
, geniş trabeküllerin şekillenmesi (9), konjesyonlu damarların bolIuğu (I, 3,4,5,7,8), geniş kanarnaların ve yer yer nekrozların varlığı (I, 3,9) pheochromocytoma'nın bilinen özelIikieri olarak gözlenmiştir. ...
... x 30.400 (LJltrastructure of a tumor cell secreting norepinephrine. Secretoric granules have an eccentrically situated electron-dense core surrounded by a wide submeOlbranous space) Mikroskobik olarak, tümörün ince vasküler st rom ayla sınırlandınlmış küçük lobüler yapısı (I, 3, 4, 5, 7), tümör hücrelerinin normal pheochromocyte'lere benzerliği, mitotik figürlerin pek görülmeyişi (5, 9), geniş trabeküllerin şekillenmesi (9), konjesyonlu damarların bolIuğu (I, 3,4,5,7,8), geniş kanarnaların ve yer yer nekrozların varlığı (I, 3,
9)
pheochromocytoma'nın bilinen özelIikieri olarak gözlenmiştir. ...
... Tümörün vena cava caudalis'e regional invazyonu (I, 4,
9)
ve uzak metastazları (I, 4, ıi) bildirilmiştir. Sunulan bu olgudaki tümörün vena cava caudalis'e invazyonu, ayrıca, vena duvarında oluşturduğu yıkımlanma sonucu iç kanamaya ve ölüme de yol açmıştır. ...
BİR KÖPEKTE REGİONAL VASKÜLER İNVAZYONLU PHEOCHROMOCYTOMA
Article
Full-text available
Jan 1990
ANKARA UNIV VET FAK
Ümit H.
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Ayhan Atasever
<here is a image b616f92c2f0b0064-917034bc8b4f16dc> Rifki Haziroglu
<here is a image ff075d40817786ce-c15ad32f26c765bd> Vedat Baran
... Similar syndrome occurs frequently in populations of aged bulls developing thyroid C cell tumors and pheochromocytoma
[18]
, occasionally accompanied by pituitary adenoma [1]. The thyroid tumors in bulls are also designated as ultimobranchial tumors, since the tumors are suggested to be derived from remnants and cell cords of the ultimobranchial body that can differentiate into both C cells and follicular cells [5,10]. ...
... Based on the criteria reported elsewhere [1-4, 6, 10], observed tumors were diagnosed as thyroid C cell carcinoma with metastases to the cervical lymph nodes and lung, adrenal pheochromocytoma and pituitary chromophobe adenoma in the pars distalis, respectively. The concurrence of the neoplastic and hyperplastic lesions within the thyroid gland and adrenal medulla appears to indicate the developmental process from hyperplasia to tumors, as described previously [4,
18,
20]. ...
... The amyloid often localized within thyroid C cell tumors is suggested to be produced by the tumor cell [17,
18]
and to be chemically different from AA amyloid associated with chronic inflammatory processes [5,14]. In the present bull with purulent periarthritis of the legs, amyloid deposits, positive for AA amyloid antigen, were observed in several organs and small vascular walls throughout the body including the remaining normal thyroid tissues, but not within the thyroid tumor. ...
An Aged Bull with Concurrent Thyroid C Cell Carcinoma, Adrenal Pheochromocytoma and Pituitary Chromophobe Adenoma
Article
Full-text available
Mar 2009
Yukio M Seimiya
Maki TAKAHASHI
Takehiro FURUKAWA
<here is a image a0a5872a9db98b61-b1028231d3b87057> Makoto Haritani
A Japanese Black bull aged 20 years died following progressive loss of the body weight. Pathological examination disclosed multiple endocrine tumors including thyroid C cell carcinoma with metastases to the cervical lymph nodes and lung, adrenal pheochromocytoma and pituitary chromophobe adenoma in the pars distalis. The serum calcium content was as mildly low as 8.0 mg/dl at the terminal stage. The bull had daily ingested the ration containing 1.9 times the recommended calcium amount for 8 years and 120,000 units of vitamin D(3) for 5 years prior to death. The long-term dietary intake of moderately excessive calcium with vitamin D(3) might be related to the pathogenesis of the thyroid C cell carcinoma.
... The neoplasms are circumscribed, soft, tan to red or dark brown, bulge from the cut surface, and can be hemorrhagic or cystic. Microscopically, the neoplastic cells are of three types: plump to columnar with ovoid nuclei that resemble hyperplastic medullary cells, fusiform with small elongated hyperplastic nuclei, and highly pleomorphic with many bizarre nuclei [3,11,[16]
[17]
[18]. Pheochromocytomas can consist of any combination of these types [ 181, and the cells are basophilic to acidophilic [3, 161. ...
... Mitoses are rare, but tumor emboli can be found in thin-walled vessels in some instances [3,13,161. The cells are arranged in cords, lobules, packets, and sheets with abundant capillaries and vascular spaces [13,[16]
[17]
[18]. Some tumors have hemorrhagic and necrotic areas [ 13, 161. ...
Pheochromocytomas and Ultimobranchial (C-cell) Neoplasms in the Bull: Evidence of Autosomal Dominant Inheritance in the Guernsey Breed
Article
Full-text available
Aug 1983
<here is a image b8069e7d185a44bc-edc3539acb76c74e> D. Phillip Sponenberg
K McEntee
Pheochromocytomas and ultimobranchial (C-cell) neoplasms were diagnosed at a high frequency in a family of Guernsey bulls. The incidence supported the hypothesis of autosomal dominant inheritance of the neoplasms. These two neoplasms also occur in man as multiple endocrine adenomatosis type 2, which has autosomal dominant inheritance.
... In animals, medullary thyroid carcinoma (parafollicular cell tumor, ultimobranchial body tumor) has been described in rats [2,18), bulls [3,
25)
and dogs [15,19,26,27). Metastases reported in dogs have been limited to the local lymph nodes [19). ...
... Amyloid fibrils were not seen with electron microscopy, probably because of limited distribution. While amyloid is common and diagnostic in medullary thyroid carcinoma of man [8,13] and bulls
[25]
, it rarely is found in tumors of rats [2]. Amyloid has been noted in only one report of thyroid medullary carcinoma of the dog (two cases) [19]. ...
Metastatic Canine Medullary Thyroid Carcinoma: A Case Report
Jun 1980
G G Long
<here is a image f989c645424db5e9-21ad5efa5745c5a6> Roger Clemmons
H Heath
A medullary carcinoma of the thyroid in a dog first became evident because of a distant metastasis. The histologic characteristics of the tumor differ from those previously reported in dogs in that this tumor was highly malignant; anaplasia and mitotic figures were common. The diagnosis was substantiated by radioimmunoassay for calcitonin. Serotonin and 5-hydroxytryptophan also were elevated in the neoplastic tissue. The relation of the biochemical alterations to the clinical course was not clear.
... 19 Pheochromocytomas have been described in large animals as single lesions or as part of a multiple endocrine-like syndrome. 23,
24
Other endocrine tissues affected by hyperplasia or neoplasia in multiple endocrine-like syndrome include the thyroid gland, parathyroidal C cells, and the pituitary pars intermedia. Concomitant adrenal hyperplasia and bilateral pheochromocytomas have been described, 19 and 14/32 and 2/32 of horses diagnosed with PPID reportedly had diffuse adrenocortical hyperplasia and pheochromocytoma, respectively, in a retrospective study. ...
Catecholamine Metabolism in a Shetland Pony with Suspected Pheochromocytoma and Pituitary Pars Intermedia Dysfunction
Nov 2016
J VET INTERN MED
<here is a image 0914725783005f7e-4c78ee50b8226cf3> Nathalie Fouché
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Vince Gerber
<here is a image b67bb50aca9caa71-c6ed4e6ce0bbbf82> Daniela Schweizer
<here is a image ebd56bd8fd1911b5-0a5f1f138194b066> Cristobal Navas de Solis
... No cardiovascular finding was observed in the present case at necropsy and histopathological examination, probably because of the tumour bigness. Pheochromocytomas often occur in conjunction with ultimobranchial tumours of thyroid in bulls [1,2,
9]
. There was no other tumour diagnosed in this sheep including thyroid. ...
A pheochromocytoma case in a 6 year old sheep
Nov 2012
REV MED VET-TOULOUSE
<here is a image 7fa871ff13693a90-eae574dcacdc6e9a> Ahmet Aydogan
<here is a image 39277f127cf244b8-35017d629298a643> Ozlem Ozmen
Pheochromocytomas, rare in all species except rats, dogs and cattle, are neuroendocrine
tumours of adrenal chromaffin cells. This case reports the occurrence
of a tan-coloured mass in medulla of the left adrenal gland in a 6
- year - old female sheep dead from pneumonia. Histopathologically, the tumour
was composed by pleomorphic cells with marked nuclei and abundant
eosinophil cytoplasm. Immunohistochemistry evidenced expression of neuron
specific enolase (NSE) and S100 protein in neoplastic cells associated with
a strong Ki-67 activity. This tumour was diagnosed as pheochromocytoma.
This is the first report of a pheochromocytoma in a sheep.
... It may arise spontaneously or it may be transmitted as an autosomal dominant form in which case it may be accompanied by the simultaneous carcinogenic transformation of other endocrine organs (multiple endocrine adenomatosis syndromes) (Weichert 1970). This neoplasm has also been reported to arise spontaneously in the rat (Boorman et al. 1972), dog (Leav et al. 1976) and bull
(Wilkie and Krook 1970;
Capen and Black 1974). The tumor produces and secretes calcitonin and is derived from the calcitonin-producing intrathyroidal parafollicular ("C") cells (Bordi et al. 1972;Gonzalez-Licea et al. 1968;Magalhaes 1972;Meyer and Abdel-Bare 1968) or from their precursors which arise from the neural crest (Le-Douarin et al. 1974). ...
Thyroid medullary carcinoma of the Djungarian hamsterPhodopus sungorus
Dec 1987
Virchows Arch B Cell Pathol
Eladio A. Nunez
Robert F. Payette
<here is a image 639367e3f6d59ceb-7730a09c42f533b6> Fred Quimby
We have carried out an electron microscopic and immunocytochemical study of thyroid medullary carcinoma arising spontaneously
in the Djungarian hamster,Phodopus sungorus. At the ultrastructural level the cytoplasm of tumor cells contained numerous round to slightly elongated, dense-cored secretory
granules. The number of secretory granules differed from cell to cell in the tumor, being scanty in some cells but more or
less abundant in most. Electron microscopic-immunocytochemistry demonstrated that all dense-cored secretory granules in all
tumor cells exhibited calcitonin immunoreactivity. In approximately 10% of the tumor cells, unusual star-shaped secretory
vesicles were also found in the cytoplasm. These vesicles contained a small, but well-defined, lucent core surrounded by a
region of finely granular material of greater electron density. The outer contour of these unusual vesicles was stellate rather
than smooth. They appeared to originate not from the Golgi complex, but from the rough endoplasmic reticulum. These atypical
stellate vesicles did not show any calcitonin immunoreactivity. Furthermore, in a small number of tumor cells (∼1%) a third
type of membrane enclosed structure was found. These were conspicuous rods 1–5 μm in length with tapering ends and a crystalline
substructure. The presence of both normal and atypical secretory granules in some tumor cells suggests that carcinogenic transformation
may interfere with the normal synthesis and assembly of secretory products by the cell.
... The simultaneous occurrence of thyroid neoplasms with other primary tumors of endocrine glands has been recognized in animals and man; in one retrospective study of 144 thyroid neoplasms in dogs, 45 had other primary tumors [93]. Other studies show the association of thyroid (medullary) carcinoma in bulls with pheochromocytoma , and thyroid carcinoma in dogs with chemodectoma [93,100,
101]
. In dogs, the risk for thyroid cancer rises sharply with age; no sex predilection has been reported, but boxer, beagle, and golden retriever breeds are reported to have increased risk [93]. ...
Neoplasms in domestic animals: A review of experimental and spontaneous carcinogenesis
Nov 1980
Yale J Biol Med
B R Madewell
Clues to environmental and host factors in human oncogenesis are derived from clinical or epidemiologic studies; additional evidence is provided by animal experimentation. Induced tumors in animals are useful because of their reproducibility and predictability, allowing detailed study of specific carcinogens or carcinogenic influences. Spontaneously or naturally occurring tumors in domestic animals are of particular interest for comparative studies - these tumors occur in heterogenous outbred populations of animal closely sharing man's environment; their cause is generally unknown; many tumors occur in numbers suitable for detailed investigations; and tumors generally occur in aged animals, thus facilitating study of chronic processes associated with carcinogenesis in nature.
... In domestic animals, MEN is best described in the bull and is characterized by the coexistence of C-cell thyroid neoplasms, pheochromocytoma that often is bilateral, and pituitary adenoma. 1,
11
Parathyroid abnormalities were not described in these reports. 12 Similarly, as observed in our horse, a diffuse or nodular hyperplasia of secretory cells in the adrenal medulla appears to precede the development of pheochromocytoma in bulls with MEN. 12 A familial pattern of occurrence of pheochromocytoma and C-cell tumor was reported in the Guernsey breed. ...
Simultaneous Occurrence of Multiple Neoplasms and Hyperplasias in the Adrenal and Thyroid Gland of the Horse Resembling Multiple Endocrine Neoplasia Syndrome: Case Report and Retrospective Identification of Additional Cases
Dec 1999
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Hilde E V De Cock
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Nigel James Maclachlan
Neoplastic and hyperplastic disorders that affect multiple endocrine tissues in a single individual are well described in humans but less so in domestic animals. Multiple endocrine neoplasia (MEN) in humans is a genetically determined syndrome characterized by the appearance of benign or malignant proliferations within two or more endocrine glands. The primary endocrine tumors that are characteristic of MEN arise from cells that share the capacity for amine precursor uptake and decarboxylation. Here we describe the case of a 22-year-old Thoroughbred mare that died during an unattended parturition and subsequently was presented for necropsy at the University of California, Davis, Veterinary Medical Teaching Hospital. A C-cell (medullary) thyroid adenoma, pheochromocytoma, and multicentric bilateral nodular hyperplasia of the adrenal medulla were present, findings that are remarkably similar to those of human MEN syndrome. Mortality during pregnancy in women with undiagnosed pheochromocytoma is high (approximately 50%), typically because of hypertension and/or hemorrhage associated with catecholamine release from the tumor. Similarly, the mare in this report died of hemorrhage subsequent to parturition. A retrospective evaluation of endocrine tumors in horses that underwent necropsy at the Veterinary Medical Teaching Hospital from 1987 to 1997 was undertaken to identify additional possible cases of MEN in horses. Data from this retrospective evaluation suggest that coexistence of hyperplasias and neoplasias of the thyroid and adrenal glands, similar to MEN syndrome of humans, also occurs with some frequency in the horse.
... Occasional pheochromocytomas are encountered in other laboratory, domestic and wild animals. Concurrence of pheochromocytoma with other tumors is sometimes suggestive of MEN2 in bovines
(Wilkie and Krook, 1970)
and horses (De Cock and MacLachlan, 1999) or of mixed MEN syndromes in rats (Fritz et al., 2002;Lee et al., 1982), ferrets (Fox et al., 2000) and dogs (Barthez et al., 1997). Pheochromocytomas have been shown to be inducible by hormones and other non-genotoxic agents in many studies of rats and occasional studies of guinea pigs (Lupulescou, 1961), suggesting possible mechanisms by which environmental influences could affect the frequency of the tumors in genetically predisposed individuals. ...
Animal models of pheochromocytoma
Aug 2004
HISTOL HISTOPATHOL
<here is a image d3fc2e34b08d4b0f-13c7b1758d978a91> Arthur Tischler
James F Powers
J Alroy
Pheochromocytomas are neuroendocrine tumors of adrenal chromaffin cells. They are rare in all species except rats but occur with increased frequency in several human familial tumor syndromes. Concurrence of pheochromocytoma with other tumors sometimes parallels these human syndromes in rats, bovines, horses and dogs but a shared genetic basis for human and spontaneously occurring animal pheochromocytomas has thus far not been established. Pheochromocytomas are inducible in rats by a variety of non-genotoxic substances that may act indirectly by stimulating chromaffin cell proliferation. They are not known to be similarly inducible in other species but arise with increased frequency in transgenic and knockout mice that to varying degrees recapitulate human tumor syndromes. Preliminary evidence suggests that homologous somatic genetic changes might contribute to pheochromocytoma development in humans and some mouse models. The nerve growth factor-responsive PC12 cell line, established from a rat pheochromocytoma, has for almost 30 years served as a research tool for many aspects of neurobiology involving normal and neoplastic conditions. Recently developed pheochromocytoma cell lines from neurofibromatosis knockout mice supplement the PC12 line and have generated additional applications. Advantages of the mouse lines include expression of substantial levels of the epinephrine-synthesizing enzyme, phenylethanolamine N-methyltransferase and expression of high levels of the receptor tyrosine kinase, Ret, which is characteristic of sporadic and familial human pheochromocytomas but not of PC12 cells. Disadvantages include an apparently less stable phenotype. It is difficult to establish pheochromocytoma cell lines from any species, although the tumor cells persist in culture for many months. Understanding of factors that permit pheochromocytoma cells to proliferate might itself provide important insights for tumor biology.
Multiple endocrine neoplasia in a sheep: insulinoma, adrenocortical carcinoma with myxoid differentiation, and thyroid C-cell carcinoma
An ~10-y-old male sheep had anorexia and progressive weight loss for ~1 mo. The sheep was emaciated, and 20 d later, became recumbent and lethargic, and was hypoglycemic (0.33 mmol/L; RI: 2.6-4.4 mmol/L). The sheep was euthanized because of poor prognosis, and submitted for autopsy. We found no gross lesions in the pancreas; however, histologically, focal proliferations of round-to-polygonal cells were separated by connective tissue into small nests. These proliferating cells, which had abundant eosinophilic-to-amphophilic cytoplasm and hyperchromatic nuclei, were immunopositive for insulin and negative for glucagon and somatostatin; the lesion was diagnosed as an insulinoma. Insulinoma has not been reported previously in sheep, to our knowledge. In addition, autopsy and histologic examination revealed the presence of an adrenocortical carcinoma with myxoid differentiation and a thyroid C-cell carcinoma. Our case indicates that multiple endocrine neoplasms can occur in sheep, as in other animal species.
A Case of a Holstein Cow with Four Different Tumors4種の異なる腫瘍を併発した牛の1例
In a Holstein cow, we found a case with different tumors in the thyroid, adrenal gland, colon and thoracic wall. Based on histopathological, immunohistochemical and molecular biological findings, the thyroid gland was diagnosed as having C-cell carcinoma, the adrenal gland as having pheochromocytoma, the colon as having a gastrointestinal stromal tumor and the thoracic wall as having B-cell lymphoma. Infiltration of the B cell lymphoma was found in the tumor tissue of the C-cell carcinoma. This case was the first report of four different tumors in a cattle.
The Endocrine System
Primary dysfunction of the endocrine organs is as common in laboratory animals as it is in most species of animals. This chapter will highlight the most important diseases of the endocrine system and will mention only a few of the experimentally induced diseases. Since inbreeding of rodents has led to a variety of strains that are predisposed to or have endocrine dysfunction, they will be described in detail or referenced for further reading. In order to avoid duplication, the reader is referred to Chapters 7 and 4, this volume, for detailed discussion of the gonads and the endocrine pancreas, respectively.
Diseases of the Endocrine System
<here is a image c23381d9ef35c21a-51c9656bdb82cd5e> Undine Christmann
Histologic and Immunohistochemical Classification of 41 Bovine Adrenal Gland Neoplasms
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Anette Blak Grossi
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Páll S Leifsson
Tumors of the adrenal glands are among the most frequent tumors in cattle; however, few studies have been conducted to describe their characteristics. The aim of this study was to classify 41 bovine adrenal neoplasms from 40 animals based on macroscopic and histologic examination, including electron microscopy and immunohistochemistry for melan A, synaptophysin, chromogranin A, vimentin, pan-cytokeratin, 2',3'-cyclic nucleotide-3'-phosphohydrolase (CNPase), and Ki-67. The tumors were classified as 23 adrenocortical adenomas, 12 adrenocortical carcinomas, 2 schwannomas, 2 pheochromocytomas (1 malignant), and 1 ganglioneuroma. Five histologic features were characteristic of metastasizing adrenocortical tumors: invasion of the capsule, vascular invasion, diffuse growth pattern, spindle-cell morphology, and nuclear pleomorphism. Adrenocortical tumors with at least 3 of these features were classified as malignant. Immunohistochemically, adrenocortical tumors expressed melan A (16/19), vimentin (14/26), cytokeratin (11/26), and chromogranin A (9/27), whereas pheochromocytomas expressed chromogranin A (2/2), synaptophysin (2/2), and vimentin (1/2). Both schwannomas expressed CNPase. An immunohistochemistry panel consisting of antibodies against melan A, synaptophysin, and CNPase was considered most useful to classify bovine adrenal tumors. However, the distinction between benign and malignant adrenocortical tumors was based on histologic features as in human medicine.
Adrenal Cortex Carcinomas with Distant Metastases in Beef Cattle at Slaughter
J F Edwards
K.E. Ralston
Ten cases of adrenal cortex carcinomas with distant metastases were collected as subclinical lesions at slaughter of approximately 14,000 adult cattle. The primary lesion in the adrenal gland and the distant metastases, to either the lung or liver, were characterized by light microscopy and immunohistochemistry. Carcinomas were usually detected by noting metastases in the lungs as polypoid, soft, red or red and yellow masses. All adrenal tumours were unilateral and none were seen in bulls. In six of 10 carcinomas there was gross evidence of invasion of the vena cava via the adrenal vein. Normal bovine adrenal cortex labelled positively with S100, calretinin, α inhibin and melan-A; however, adenomas and seven of 10 carcinomas were labelled best by melan-A and α inhibin. Three carcinomas, grossly identical to the other seven, had numerous calcific granules and a slightly different microscopical appearance. In addition to melan-A and α-inhibin, these variant carcinomas labelled with S100. This variant may be derived from a different layer of the adrenal cortex. Because of the similarity of the bovine and human adrenal cortices, cultures of spontaneously arising bovine adrenal tumours may be a useful resource for study of human neoplasia.
Pathogenesis of C-cell neoplasia in thyroid gland. C-cell proliferation in a case of chronic hypercalcaemia
APMIS
<here is a image c15712a17367cc5e-d574c76b757d90d0> Otto Ljungberg
Hypertrophy and focal nodular hyperplasia with tumour-like proliferation of the C-cells was observed in thyroid tissue removed from a 64-year-old male with non-toxic adenomatous goitre and primary hyperparathyroidism. The patient was found to have an enlarged parathyroid gland consisting exclusively of waterclear cells. It appeared likely that chronic hypercalcaemia had been responsible for the C-cell proliferation. Morphological similarities between the thyroid change of the present case and the early stages of some forms of medullary thyroid carcinoma suggest that this neoplasm could arise from hyperplastic foci of C-cells. It is emphasized that chronic hypercalcaemia may be one aetiological factor in human C-cell neoplasia, including some types of medullary carcinoma. This implies that medullary carcinoma might have been secondarily induced by the parathyroid adenoma in some of those patients in whom both of these manifestations have been encountered.
Tumors in Domestic Animals, Fourth Edition
C C Capen
Introduction Tumors and Nonneoplastic Cysts of the Pituitary Gland Tumors of the Adrenal Gland Tumors, Hyperplasia, and Cysts of Thyroid Follicular Cells Tumors of Thyroid C (Parafollicular) Cells (Ultimobranchial Derivatives): Adenoma, Carcinoma Tumors and Nonneoplastic Cysts of the Parathyroid Gland Cancer-Associated Hypercalcemia Tumors of the Pancreatic Islet Cells Tumors of the Chemoreceptor Organs
Intermediate thyroid carcinoma in humans and ultimobranchial tumors in bulls: A comparative morphological and immunohistochemical study
The intermediate type of thyroid carcinoma in humans has been defined as having characteristics of both follicular and parafollicular
cell carcinoma. The ultimobranchial (UB) body in mammals is believed to harbor stem cells capable of developing both follicular
and parafollicular cells. Hyperplastic and neoplastic lesions of the UB remnants and of the parafollicular cell system frequently
occur in bulls. Such lesions, found in 64 individuals (6%) derived from an autopsy material of 1,101 bulls, have been compared
structurally and immunohistochemically with 18 human cases of thyroid carcinoma of the intermediate type, in order to define
their possible biological relationship. UB changes in bulls formed a continuum ranging from hyperplastic nodules to gross
tumors. They contained all epithelial components present in the normal UB remnants in cattle: UB cysts and tubules and solid
nests of small basophilic immature cells, which were immunocytochemically indifferent, as wellas mature follicular and neuroendocrine cells. The indifferent cell component dominated in most bull tumors; a minority were
mainly formed by mature follicular or parafollicular cells. Human tumors resembled the bull UB tumors structurally and immunohistochemically,
although generally the degree of maturation was higher in human tumors. A few were mainly formed by indifferent immature cells
and contained typical UB cysts and tubules. One bull tumor and one human tumor contained amyloid. UB changes in bulls were
invariably associated with a marked hyperplasia of the parafollicular cell system, in some cases even with tumor development.
A similar hyperplasia, but without neoplastic change, was found in 4 of 11 human cases in which nontumorous thyroid parenchyma
was available for examination.The findings suggest that intermediate thyroid carcinoma rather than medullary carcinoma is
the human equivalent to the bull UB tumors. It is concluded that although both the medullary and the intermediate type of
carcinoma appear to be histogenetically related to the UB body, the former shows evidence of a pure parafollicular cell differentiation,
whereas the latter develops both follicular and parafollicular, as well as intermediate, cell forms and sometimes also immature
structures of the type seen in UB remnants of the adult human thyroid gland.
Cytophysiology of Thyroid Parafollicular Cells
INT REV CYTOL
Eladio A. Nunez
<here is a image 45c0b0bd2457b202-7eed2ca5192d362a> Michael D Gershon
This chapter discusses the cytophysiology of thyroid parafollicular cells. The thyroid gland of the mammal is a bilobed structure located at the base of the neck on either side of the trachea. The most important function of the thyroid gland is the synthesis, storage, and secretion into the blood of two iodinated amino-acid hormones, L-thyroxine and 3,5,3'-triiodo-L-thyronine. Thyroid hormones are required for normal growth and development and for normal metabolic activity. Thyroid hormones act by accelerating general and specific metabolic processes of the body, leading to an increase in oxygen consumption and heat production. The mammalian thyroid gland is also responsible for the elaboration, storage, and secretion of a second type of hormone, calcitonin, which lowers the calcium concentration of blood.
Epithelial Thyroid Tumors in Cows
J. Vítovec
From 1964 to 1973, 370 tumors were collected from cows of unknown age. Ten (2.7%) of these were primary thyroid tumors. Three were malignant. The benign tumors were solitary encapsulated adenomas in the parenchyma with more or less defined trabeculae, tubular, and microfollicular pattern. One of the malignant tumors was a cystic papillary adenocarcinoma, and two were small cell carcinomas consisting of small, sometimes binuclear, pleomorphic cells.
C cell hyperplasia and carcinoma developing in sheep with experimentally-induced lymphosarcoma
Nov 1991
J COMP PATHOL
<here is a image a3ac66a0aff583f8-80ef32b6c06beece> Hidechika Okada
Y Fujimoto
K Ohshima
Kiyoshi MATSUKAWA
Two cases of C cell hyperplasia and one case of C cell carcinoma of the thyroid glands were bilaterally recognized in 11 sheep with experimentally-induced lymphosarcoma. The serum calcium concentration in the C cell carcinoma case was slightly increased above the normal concentration of around 9 mg per dl. Bilateral C cell hyperplasia also developed in the thyroid lobes of the C cell carcinoma case. Immunohistochemically, hyperplastic C cells and tumour cells were positive for calcitonin, calcitonin gene-related peptide, chromogranin A and neurone-specific enolase. No amyloid deposition nor multiple endocrine neoplasia was demonstrated in any of the cases. Ultrastructurally, many secretory granules were observed in the cytoplasm of neoplastic cells constituting the C cell carcinoma and in the hyperplastic C cells.
Pathology of animal amyloidoses
Feb 1989
PHARMACOL THERAPEUT
Wolgang Zschiesche
Willi Jakob
Hyperplastic and Neoplastic Changes in Ultimobranchial Remnants and in Parafollicular (C) Cells in Bulls: A Histologic and Immunohistochemical Study
Apr 1985
<here is a image c15712a17367cc5e-d574c76b757d90d0> Otto Ljungberg
P O Nilsson
Thyroid glands from 64 bulls with hyperplastic and/or neoplastic changes in ultimobranchial remnants and in the parafollicular (C) cell system were studied structurally and with immunohistochemical methods. Antibodies against thyroglobulin, calcitonin, somatostatin, and neurotensin were used to detect these substances. Two different types of changes were observed.
One change was hyperplasia and neoplasia of the ultimobranchial remnants that affected all their epithelial constituents. These included ultimobranchial follicles, cysts and tubules, as well as solid nests formed by basophilic immature cells which were functionally undifferentiated and unreactive with all the antisera used. Differentiated follicular cells that formed thyroid follicles and cribriform structures with immunohistochemical evidence of thyroglobulin production were also found. In addition, differentiated light and cytoplasm-rich cells were scattered in the walls of the thyroid follicles, ultimobranchial follicles, cysts and tubules as well as in the solid component. They were argyrophilic and reacted with antibodies against calcitonin and somatostatin.
The other change was a diffuse or multifocal hyperplasia of the parafollicular (C) cells that was present in other parts of the thyroid parenchyma—sometimes with gradual development of sclerotic tumors that had been exclusively formed by these cells. They corresponded to light cytoplasm-rich cells seen in the ultimobranchial lesions that were argyrophilic and harbored material reactive with antibodies against calcitonin and/or somatostatin.
The changes observed in the parafollicular cell system resembled lesions seen in human thyroid glands with the familial variant of medullary carcinoma as well as those reported in thyroid glands of patients with longstanding hypercalcemia. Bull ultimobranchial tumors closely resembled a recently defined, intermediate type of human differentiated thyroidal carcinoma that has traits of both medullary and follicular carcinoma.
Medullary Thyroid Carcinoma in Two Cows
Feb 1986
A Bundza
<here is a image 4c1b251af10edc78-2bb731b83ddfca58> Ronald H Stead
Ultimobranchial Follicles and Cysts in the Rat Thyroid During Postnatal Development
Jun 1973
Beitr Pathol
K Christov
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Reinhard Bollmann
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Carmela Thomas
In dieser Arbeit wird die postnatale Entwicklung der Ultimobranchialkörper in der Schilddrüse von Kontroll- und mit Methylthiouracil behandelten Wistarratten beschrieben. In der Schilddrüse neugeborener Ratten treten Follikel auf, die von einem zweireihigen Epithel ausgekleidet werden und ein PAS-positives Material einschließen. Sie werden als Vorstufen der Ultimobranchialfollikel und -zysten erwachsener Ratten gedeutet. Diese kommen bei allen Kontrolltieren zwischen dem 30. und 365. Lebenstag vor, bestehen aber nur noch aus Plattenepithel und schließen in ihrer Lichtung vereinzelte abgeschilferte Epithelien ein. Die eigenen Untersuchungen zeigen, daß nach MTU-Behandlung die Follikel zahlenmäßig abnehmen, während bei neugeborenen behandelten Tieren keine Abweichungen vorkommen.
Pheochromocytoma
Jul 1974
CURR PROB SURG
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Charles W Van Way III
H. William Scott
David L. Page
Robert K. Rhamy
The major unsolved problem in the management of pheochromocytoma is detection of the disease. Relatively few patients are screened for pheochromocytoma. In order to detect the tumor in the population, urinary screening tests for catecholamines and their metabolites should be obtained on all hypertensive patients. Those with paroxysmal hypertension or with hypertension 'difficult' to control are highly suspect. Hypertension in pregnant women and in children should always arouse suspicion. Patients with primary complaints of sweating episodes, tachycardia, episodic headache or 'nervous attacks', new diabetics and new patients with hyperthyroidism, and relatives of patients with pheochromocytoma or medullary carcinoma of the thyroid should be tested. These general criteria are by design not very selective. It is probable that 1/10 of the patients seen by the average internist should be screened for pheochromocytoma. In the patient with pheochromocytoma diagnosed by urinary screening tests, many additional investigative and diagnostic studies may be used. Selection among these is sometimes difficult. It should be kept firmly in mind that the patient has a life threatening disease, that he will be best served by removal of the tumor as expeditiously and safely as possible and that only studies that will further this goal are in his best interests.
Ultimobranchial thyroid neoplasms in bulls.A syndrome resembling medullary thyroid carcinoma in man
Nov 1973
H E Black
Charles C. Capen
David M. Young
A syndrome of ultimobranchial thyroid neoplasms which shares many similarities with medullary thyroid carcinoma in man occurs frequently in populations of adult bulls. The results of this investigation demonstrated that ultimobranchial neoplasms were composed of poorly differentiated parafollicular (C—) cells with extensive aggregations of microfilaments, clusters of ribosomes, and prominent Golgi apparatuses. Secretion granules often were interspersed between microfilaments. Other more columnar neoplastic cells assumed a ductal pattern. The prominent stroma contained amyloid fibrils and collagen fibers. By comparison, cells comprising medullary thyroid carcinoma were more differentiated parafollicular cells with well developed cytoplasmic organelles and numerous membrane-limited secretion granules. Calcitonin activity was demonstrated by biologic assay in both ultimobranchial adenomas (466 ± 84 MRC mU/g) and carcinomas (409 ± 93 MRC mU/g) but serum calcium and phosphorus levels were within normal limits. Plasma calcitonin-like activity was increased significantly 1 hour after calcium infusion but rapidly returned to baseline values. Parathyroid glands from bulls with ultimobranchial neoplasms had ultrastructural evidence of atrophy and secretory inactivity. Numerous lipofuscin, granules and cytosegresomes but few secretory granules were present in chief cells. Aggregations of amyloid fibrils surrounded chief cells and capillaries. Multiple endocrine tumors (pheochromocytomas and pituitary acidophil adenomas) and vertebral osteosclerosis with ankylosing spondylosis frequently were detected in bulls coincidentally with ultimobranchial thyroid neoplasms.
Calcitonin in Metabolic Disorders
Feb 1972
Adv Metab Disord
A Haymovits
John F. Rosen
This chapter discusses calcitonin in metabolic disorders. The balance between mineral deposition and mineral solubilization at the vast interphase between bone and extracellular fluid is quantitatively the predominant factor in the regulation of calcium levels in extracellular fluid and blood. The first submammalian species of calcitonin to be isolated and structurally defined was salmon calcitonin, which was extracted from ultimobranchial tissues and was resolved into three different hormones after purification. The pure human and the porcine hormones are adequate antigens and induce high titers of neutralizing antibodies, especially when given with impurities or conjugated to other proteins. Chemical modification of porcine calcitonin does not impair its immunogenicity despite total or nearly total loss of biological activity. Immunological evaluation of fragments of porcine and human calcitonin molecules suggests that major antigenic determinants are associated with the portion of the peptide extending from residues. The C-terminal amide group, although not essential for full biological activity, is important in immunogenicity.
Differentiated thyroid carcinoma, intermediate type: A new tumor entity with features of follicular and parafollicular cell carcinoma
Apr 1984
Hum Pathol
<here is a image c15712a17367cc5e-d574c76b757d90d0> Otto Ljungberg
Lennart Bondeson
Anne-Greth Bondeson
A group of differentiated thyroid carcinomas with morphologic and immunohistochemical traits of both follicular and medullary carcinoma is described. This group consists of tumors characterized by a solid and/or cribriform histologic pattern with a more or less pronounced admixture of follicular structures, immunohistochemical evidence for the production of thyroglobulin and one or more of the three neurohormonal peptides neurotensin, somatostatin, and calcitonin, and absence of amyloid. These tumors were selected from thyroid carcinomas that had been diagnosed, according to current histopathologic criteria, as differentiated follicular carcinomas. A series of pure follicular carcinomas, devoid of solid or cribriform structures, was found to contain thyroglobulin immunoreactive tumor cells only, whereas a series of classic medullary carcinoma with amyloid stroma revealed specific staining for all three neurohormonal peptides but not for thyroglobulin. The results suggest that differentiated thyroid carcinoma can be regarded as a continuous spectrum of tumor types, with pure follicular carcinomas and classic medullary carcinoma representing the two extremes and the tumors with biphasic features representing a broad intermediate group. The authors suggest that this group be designated "differentiated thyroid carcinoma, intermediate type."
Veterinary oncology: A survey
Feb 1984
E. Cotchin
Revue bibliographique prenant en compte successivement les differents appareils de l'organisme et visant a resumer brievement les caracteristiques les plus interessantes des tumeurs de chaque appareil chez les mammiferes domestiques. L'extrapolation de l'information d'une espece a une autre devrait toujours etre faite avec precaution
Ultrastructural and Biochemical Evaluation of Adrenal Medullary Hyperplasia and Pheochromocytoma in Aged Bulls
J T Yarrington
C C Capen
Pheochromocytomas and adrenal medullary hyperplasia were investigated ultrastructurally and by assaying catecholamines in tissue and urine. Three of seven bulls had concomitant thyroid C-cell neoplasms and normal parathyroid glands. Pheochromocytomas were either bilateral or unilateral, and were composed of large chromaffin cells predominantly in the storage phase of the secretory cycle. Two pheochromocytomas were composed of cells with ultrastructural characteristics of the epinephrine-secreting type and contained round secretory granules of low electron density. The norepinephrine-secreting type of chromaffin cell predominated in one pheochromocytoma and had storage granules with an electron-dense, eccentric core and a wide submembranous space. Two pheochromocytomas were composed of a mixture of epinephrine- and norepinephrine-secreting cells. Adrenal medullary hyperplasia in four bulls consisted of multinodular or diffuse areas of hyperchromatic chromaffin cells that were non-encapsulated, and compressed adjacent cortical tissue. Tissue and urinary concentrations of norepinephrine were increased in bulls with adrenal medullary hyperplasia or pheochromocytoma, but urinary vanillylmandelic acid and unconjugated epinephrine levels were not different from those of control bulls with a normal adrenal medulla.
'Aging bull'
MED HYPOTHESES
<here is a image f65c97be5b53f20c-7e30c6df70c7c3a6> Glenn William Geelhoed
An old bull, it is said by those who know, can have his troubles. Included among these are vertebral osteosclerosis and ankylosing spondylosis; this stiffening up limits, rather than accentuates, the value and reproductive potential of a stud bull past his prime. Associated with these abnormalities, however-and not seen in age-matched cows of comparable breeds-are fascinating endocrine neoplasms suggestive of a pattern that could be productive as a model of human hereditary endocrine abnormalities. Adjacent to the thyroid gland in other vertebrates are ultimobranchial bodies that are incorporated into the lateral thyroid lobes in primates as the parafollicular "C cells' of the thyroid. These are the cells in man that give rise to medullary thyroid cancer and are associated with calcitonin secretion, useful as a tumor marker. In aging bulls of whatever breed, nearly half exhibit abnormality of these ultimobranchial bodies: 20% show hyperplasia, and 30% have frank neoplasia. These ultimobranchial tumors appear in bulls passing 6 1/2 years in age, and are absent in young bulls and all cows of any age. Calcitonin can be demonstrated in the ultimobranchial tumors from bulls, and secretion is stimulated by calcium infusion, though serum calcium remains normal. The ultimobranchial tumors themselves can range from hyperplasia through adenoma to metastasizing carcinoma-in fact, representing one of the commoner cattle cancers. Parathyroid glands taken from bulls with these ultimobranchial tumors initially show evidence of inhibited secretory activity and morphologic atrophy, but later go on to develop hyperplasia and, eventually, autonomy. Cattle forage on calcium-rich diets. Bulls appear to respond to this calcium excess from the positive balance, but breeding cows have the unique calcium deficits of the high net loss of calcium through lactation and the large requirements of calcifying a fetal skeleton. Chronic stimulation of the APUD-derived ultimobranchial bodies by high calcium intake, not counterbalanced by calcium losses in the bulls, may account for the development over time of the ultimobranchial neoplasms. Further, a number of the bulls who have the ultimobranchial tumors are found to have multiple endocrine tumors in other glands-bilateral pheochromocytomas and pituitary acidophil adenomas.
Hereditary Caprine Phaeochromocytoma
B G de Gritz
This report describes a hereditary caprine phaeochromocytoma in three generations. Besides conventional haematoxylin and eosin staining, potassium dichromate native staining method and transmission electron microscopy were performed.
Immunohistochemistry of Ultimobranchial Thyroid Carcinomas in Seven Slaughtered Cows and One Bull
Eight thyroid gland epithelial tumors were found in 7 cows and 1 bull in a retrospective study of thyroid gland lesions in slaughtered cattle. All tumors were classified as ultimobranchial thyroid carcinomas based on morphology and immunohistochemistry. All tumors consisted of solid sheets and nests of polygonal to oval epithelial cells, with more sparsely dispersed colloid-filled follicles. Connective tissue separating nests of epithelial cells varied from delicate fibrovascular stroma to dense collagenous stroma. Fusiform epithelial cells with rare neural fibers and ganglion cells were present in 1 tumor. Cells within solid areas of these tumors were immunoreactive for calcitonin, calcitonin gene-related peptide, neuron-specific enolase, and synaptophysin. Colloid and follicle cells were immunoreactive for thyroglobulin. Few follicle cells also were reactive for calcitonin gene-related peptide. Neoplastic cells invaded the fibrous capsules in all 8 cattle. These tumors represented proliferation of a mixed population of undifferentiated cells, C cells, and thyroid follicular epithelial cells, presumably derived from the thyroid ultimobranchial bodies. These ultimobranchial carcinomas in slaughtered cattle are comparable to ultimobranchial tumors described in dairy bulls and the intermediate type of thyroid gland carcinomas (mixed thyroid medullary carcinomas) described in human beings.
Non-functional C-cell Adenoma in Aged Horses
J COMP PATHOL
Hideaki UEKI
<here is a image 1937ee36a50dd27a-fa33d150fae83bfe> Toshifumi Oyamada
Thyroid tumours occur in older horses, and most such tumours have been considered to be of follicular epithelial origin. However, their immunohistochemical characterization has not been investigated. The purpose of this study was to confirm a suspicion that most of these tumours are in fact parafollicular cell (C cell)-derived adenomas, and to evaluate their pathogenesis and functional state. Thyroid glands from 38 horses aged 10-29 years were evaluated, all tissue samples being examined histologically, immunohistochemically and ultrastructurally. Nodular tumour masses were found in the thyroids of 12 of 38 horses older than 10 years (31.6%), and in nine of 12 horses older than 20 years (75.0%), regardless of sex or breed. Nodular lesions were composed of solid proliferations of polygonal cells with eosinophilic granular cytoplasm. Immunohistochemically, tumour cells were positive for calcitonin and neuron specific enolase, but negative for thyroglobulin. Ultrastructurally, few if any secretion granules were found in tumour cells. On the basis of these results it was concluded that the nodular lesions were C-cell adenomas, not follicular adenomas. It was suspected that the C-cell adenomas were non-functional and unlikely to lead to calcitonin hypersecretion-related diseases.
Pheochromocytoma in the Horse and Measurement of Norepinephrine Levels in Horses
Ten cases of pheochromocytoma in horses were obtained from the literature and a computer search of medical records. The clinical, laboratory and pathological features of pheochromocytoma in horses were reviewed. Pheochromocytoma is a catecholamine secreting tumor which tends to occur in older horses without breed or sex predisposition. It is usually unilateral adrenal medullary in location and benign. Malignancy was present in one horse. The most common clinical signs were sweating, tachycardia, tachypnea, muscle tremor and anxiety; however the tumor may be asymptomatic. Clinical signs were nonspecific and could be confused with other diseases, especially abdominal pain. Hyperglycemia is a consistent finding. Venous norepinephrine levels were measured in normal horses. Norepinephrine measurements may prove to be a diagnostic aid in horses with pheochromocytoma.
Medullary thyroid carcinoma and phaeochromocytoma: A familial chromaffinomatosis
Dietary Calcium, Ultimobranchial Tumors and Osteopetrosis in the Bull
Like the former edition (see 20: 1354), this book is aimed at beginners and at research workers in biology. Many new techniques are included. Other changes include the gathering together all factorial methods in a single chapter, alterations and simplifications in notation and terminology, inclusion of some non-parametric tests, reduction in the amount of calculations in the early parts of chapters, increased emphasis on estimates rather than tests of significance, and a new chapter on design and analysis of samplings by William G. Cochran. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Thioflavin-T for Amyloid Detection
Tumours of the endocrine glands in cattle, sheep and pigs found in a British abattoir survey
A histological survey has been made of all neoplasms, except those of the brain and pituitary, found in slaughtered cattle, sheep and pigs during one year in 100 abattoirs throughout Great Britain. The specimens collected comprised 302 tumours from cattle, 107 from sheep and 139 from pigs: of these, 35 bovine, 3 ovine and 3 porcine tumours originated in endocrine glands (other than the ovary). The majority were tumours of the adrenal cortex, which were encountered in all three species. Phaeochromocytomas also occurred in each species. Less common tumours of the thyroid gland and pancreatic islets were included in the series. In this paper, the incidence of such tumours is indicated and the histological appearances are described. The findings are considered in relation to the characteristics of the corresponding neoplasms in man.
Common Cytochemical Properties of Cells Producing Polypeptide Hormones, with Particular Reference to Calcitonin and the Thyroid C Cells
| https://www.researchgate.net/publication/17649188_Ultimobranchial_Tumor_of_the_Thyroid_and_Pheochromocytoma_in_the_bull |
Multilingual evaluation of voice disability index using pitch rate - Advances in Science, Technology and Engineering Systems Journal
Multilingual evaluation of voice disability index using pitch rate
Volume 2, Issue 3, Page No 765-772, 2017
Author’s Name:Shuji Shinohara 1, a), Yasuhiro Omiya 2, Mitsuteru Nakamura 1, Naoki Hagiwara 2, Masakazu Higuchi 1, Shunji Mitsuyoshi 1, Shinichi Tokuno 1
View Affiliations
1Verbal Analysis of Pathophysiology Graduate School of Medicine, The University of Tokyo, 113-0033, Japan
2Research and Product Development, PST Inc., 231-0023, Japan
a)Author to whom correspondence should be addressed. E-mail:shinokan99@m.u-tokyo.ac.jp
Adv. Sci. Technol. Eng. Syst. J. 2(3), 765-772 (2017);DOI:10.25046/aj020397
Keywords:Pitch detection ratio, Voice disability, Read speech , Jitter, Shimmer, Harmonic to noise ratio, Multilingual evaluation
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Abstract
We propose the use of the pitch rate of free-form speech recorded by smartphones as an index of voice disability. This research compares the effectiveness of pitch rate, jitter, shimmer, and harmonic-to-noise ratio (HNR) as indices of voice disability in English, German, and Japanese. Normally, the evaluation of these indices is performed using long-vowel sounds; however, this study included the recitation of a set passage, which is more similar to free-form speech. The results showed that for English, the jitter, shimmer, and HNR were very effective indices for long-vowel sounds, but the shimmer and HNR for read speech were considerably worse. Although the effectiveness of jitter as an index was maintained for read speech, the pitch rate was better in distinguishing between healthy individuals and patients with illnesses affecting their voice. The read speech results in German, Japanese, and English were similar, and the pitch rate showed the greatest efficiency for identification. Nevertheless, compared to English, the identification efficiency for the other two languages was lower.
Received:05 April 2017,Accepted:24 May 2017,PublishedOnline:16 June 2017
Full Text
1. Introduction
This paper is an extension of the work originally presented in IEEE Engineering in Medicine and Biology Society(EMBS) 2016 [1], with the main addition being the evaluation of German and Japanese samples, in addition to the previously evaluated English data.
In recent years, the widespread use of smartphones has created interest in pathological analysis that utilizes voice data [2-4]. Voice analysis by smartphones has the advantages of being non-invasive and requiring no specialized equipment; therefore, it can be performed easily and even remotely.
It is known that changes in voice characteristics due to various illnesses can be observed. For example, patients with Parkinson’s disease often also suffer from dysarthria and stuttering. Additionally, patients with illnesses affecting the vocal cords or larynx may have hoarse voices.
Research in the relationship between mental illness and voice has been conducted by analyzing the speaking rate [12-14], as well as the switching pause and percent pause [13, 15] of depression patients.To date, jitter, shimmer, and the harmonic-to-noise ratio (HNR) have been proposed as indices to describe the degree of voice disability [5–8]. Previous research on the use of these indices in the analysis of illness has shown that patients with depression pronounce vowels with higher shimmer and jitter values. Additionally, it has been shown that the frequencies of the first and second formants of depression patient speech are lower than those of healthy individuals [9]. In other research, the Lyapunov exponents and Kolmogrov entropy of the voices of depression patients were measured using chaos analysis methods [10]. Additionally, Zhou et al. have proposed new feature values derived from the Teager energy operator for the classification of voices under stress [11].
The objective of this study is to identify and evaluate characteristics that can be used to discriminate between voices of healthy individuals and those of disorder patients based on voice recordings of free-form speech.
For this purpose, we focused on pitch degradation as an index representing sonic perturbations in patients’ voices. As a measure of this feature, we devised the concept of the pitch rate to express the ease of pitch detection in voices.
2. Materials and Methods
2.1. Voice acquisition
For the voice evaluations, we used the Disordered Voice Database and Program, Model 4337, from KayPENTAX, a division of Pentax Medical Inc. This database contains recordings of the voices of approximately 700 persons (healthy individuals and patients), with two types of sounds from each individual: the long-vowel sound “ah” (lasting approximately 3 s for healthy individuals and approximately 1 s for patients) and a read speech from the “Rainbow passage” (approximately the first 12 s).
The voice recordings of read speech from 715 individuals contain samples from 53 healthy individuals and 662 patients. The voice recordings of long vowels from 711 persons include samples from 53 healthy individuals and 658 patients. The various disorders in the patients are (duplication observed): hyperfunction (288), paralysis (77), Anterior-Posterior squeezing (182), gastric reflux (54), vocal fold edema (46), and ventricular compression (109). The format used for recording had a sampling frequency of either 25 kHz or 50 kHz with 16-bit quantization.
Conventionally, long-vowel sounds are used in the evaluation of jitter, shimmer, and HNR.
Among the data of 658 patients, no jitter, shimmer, or HNR could be detected in 13 patients regarding the long-vowel sound “ah”. Therefore, we used the data of 698 persons, including 53 healthy individuals and 645 patients.
The long-vowel sound “ah” does not change fundamentally between languages. In contrast, reciting a passage involves language differences based on the actual words used and pronunciation. In our research, we used the read speech of passages in Japanese and German, in addition to English, to investigate the language dependence of the proposed indices. Details regarding German and Japanese speech are provided below.
German speech was evaluated using the “Saarbruecken Voice Database” (http://stimmdb.coli.uni-saarland.de/) from the Institute of Phonetics of Saarland University. This voice database is available for free download, and it includes samples from over 2000 people. In our research, we used the samples of healthy individuals and patients with dysphonia saying “Guten morgen, wie geht esIhnen?” (“Good morning, how are you?”) from this database. The number of voice files used was 632 from healthy individuals and 101 from patients with dysphonia. These samples had a sampling frequency of 50 kHz with 16-bit quantization.
Japanese speech was evaluated using voice samples from “Assessment of Motor Speech for Dysarthria” [16]. This CD contains voice samples from patients with dysarthria caused by various illnesses and from healthy individuals. All samples included recordings of readings from Aesop’s fable “The North Wind and the Sun”; however, the samples from dysarthria patients also contained free-form speech. For this reason, the patient files were classified into a read-speech group and a free-form speech group. For consistency, only the read-speech samples of “The North Wind and the Sun” were used in the comparisons between patients and healthy individuals. Meanwhile, the free-form speech samples were compared to the read-speech samples of the same patients and evaluated to determine the presence of any differences between them. In this collection of samples, speech samples of the same patient were categorized and saved under multiple illnesses, so the duplicate voice files were erased. As a result, the total number of voice files from healthy individuals and patients was 6 and 35, respectively. These voice files had a sampling rate of 44.1 kHz with 16-bit quantization.
2.2. Evaluation method
Using the aforementioned data, we calculated the pitch rate, jitter, shimmer, and HNR, and compared the results of healthy individuals and patients. To evaluate the performance of each index in discriminating between patients and healthy individuals, we used the area under the curve (AUC) in the receiver-operating characteristic (ROC) plot, the sensitivity, and the specificity.
2.3. Evaluation index
We used the Praat software version 5.4.10 (http://www.fon.hum.uva.nl/praat/) to analyze the jitter, shimmer, and HNR. While shimmer measures the fluctuations in voice loudness, jitter measures the fluctuations in voice pitch and is affected by the tension and hardness of the vocal cords. The HNR is a measure of stability of the harmonic structure and indicates voice disorders, in particular, the degree of hoarseness. In this study, we used ppq5 for jitter, apq5 for shimmer, and harmonicity for HNR. In addition to these evaluation indices, we have introduced the pitch rate, which was devised by us, as an index for voice disability.
2.4. Pitch rate
Conventionally, jitter, shimmer, and HNR have been used as the measure representing the disturbance of the periodicity of speech waves. However, these cannot be measured with respect to the portion of the data in which the fundamental frequency cannot be detected. Furthermore, we focused on the ease of detection of the pitch rather than its value. The pitch detection ratio (pitch rate) is defined as the percentage of frames in which the fundamental frequency can be detected.
In normal voice recordings, there are silent intervals between utterances. In these intervals, the pitch cannot be detected. This means that the pitch rate is affected by the length of such intervals.
Figure 1. The pitch detection process. Details are listed in the text. (a) Voice signal, (b) frequency spectrum, (c) autocorrelation of the frequency spectrum, (d) plot of peak number and frequency shift exhibiting linear regression
Therefore, to calculate the pitch rate, the data of these intervals must be excluded from the voice data. For this purpose, we used the Sensibility Technology software, version 3.0 (AGI Inc., Tokyo, Japan) [17-19].
After the speech interval data were extracted, the data were separated into frames of length L. However, each frame was offset from the previous frame by L/4 (i.e., 3/4 of each frame overlapped with the previous frame). We set L to equal 46.44 ms, which corresponds to 512 data points at a sampling rate of 11025 Hz.
The pitch was calculated for each frame using the methods described below [20, 21]. First, the voice signal waveform (Figure 1a) was processed by a fast Fourier transform (Figure 1b). Next, the Fourier spectrum autocorrelation was calculated, and the corresponding peaks were determined. Each peak was assigned a sequential number, and the change in frequency, ∆Frequency (i.e., F1, F1, F3…) was determined (Figure 1c). Lastly, the peak number was plotted on the X axis, the change in frequency was plotted on the Y axis, and a linear regression of the form U= a C+ bwas determined (Figure 1d) .If the linear regression had a coefficient of determination R larger than the threshold q 1, and the absolute value of the y-intercept bwas smaller than the threshold q 2, then the pitch was considered as detected. Furthermore, if the pitch was detected, the slope of the linear regression arepresented the pitch value.
The pitch rate of every speech interval was determined by dividing the total number of frames by the number of frames in which the pitch was detected (which were subsequently analyzed). The frames that were analyzed were selected by the following methods. First, the value of the average power of the entire speech interval was determined. Next, the average power of each frame was calculated; if it was at least q 3% higher than the average power in the entire speech interval, the frame was selected for analysis. In the research presented in IEEE EMBS 2016, we established a threshold for the absolute power was to select frames for analysis: if the average power of a frame exceeded this threshold, that frame was selected for analysis. However, in this study, we defined a relative value for this threshold. It must be noted that because of this change, the number of values provided in the Results section is different from that stated in IEEE EMBS 2016.
After the pitch rate was calculated for each speech interval, the average pitch rate of all speech intervals included in the voice files was determined; this average value was considered as the pitch rate for the corresponding voice files.
While jitter and shimmer are measures representing small disturbances of the periodicity within the range in which pitch can be detected, the pitch rate can be described as a measure representing a large disturbance of periodicity, such that the pitch cannot be detected.
If the intensity or the pitch varies continuously, the jitter and shimmer are affected. On the other hand, even if the intensity or the pitch fluctuates, the pitch rate is not affected, as long as the fluctuations are sufficiently small to detect the pitch. That is, the pitch rate is robust against fluctuations. Even if the amplitude, period, or the harmonic structure is greatly disturbed, the pitch rate diminishes. That is, the pitch rate can be described as a compositive index that included jitter, shimmer, and HNR. Therefore, it can be considered to be a rough indicator in comparison with conventional indicators.
Figure 2 ROC curves used for discriminating between healthy individuals and patients using the jitter, shimmer, and HNR in the data of the long-vowel sound “ah”.
The purpose of this study is to distinguish patients based on free-form speech rather than long-vowel sounds. Because more uncertainties are included in free-form speech compared with long vowels, we consider that a rough indicator is more adequate for free-form speech.
3. Results
3.1. Ability to discriminate based on long-vowel sound
The mean values for healthy individuals and patient in the data of the long-vowel sound “ah”
Index Healthy Individuals (n=53) Patients (n=645) P-value Jitter (ppq5) 0.0016±0.00066 0.0061±0.0078 1.23∙10 −39 Shimmer (apq5) 0.012±0.0062 0.039±0.0293 7.04∙10 −55 HNR (harmonicity) 23.94±2.86 15.18±6.19 4.76∙10 −34
Table 1 shows the mean values for healthy individuals and patients in the data of the long vowel sound “ah”.
With respect to jitter, the mean values for healthy individuals and patients were 0.0016 (Number of Subjects (n) = 53, Standard Deviation (SD) = 0.00066) and 0.0061(n = 645, SD= 0.0078), respectively. Based on the t-test, significant differences were observed between the two groups (t(695) = −14.05, p = 1.23∙10 −39).
Regarding shimmer, the mean values for healthy individuals and patients were 0.012 (n = 53, SD = 0.0062) and 0.039 (n = 645, SD = 0.0293), respectively. Based on the t-test, significant differences were observed between the two groups (t(329) = −19.01, p = 7.04∙10 −55).
With respect to the HNR, the mean values for healthy individuals and patients were 23.94 (n = 53, SD = 2.86) and 15.18 (n = 645, SD = 6.19), respectively. Based on the t-test, significant
Figure 3 ROC curves used for discriminating between healthy individuals and patients using the pitch rate, jitter, shimmer, and HNR in the “Rainbow passage” read speech data.
differences were observed between the two groups (t(97) = 18.77, p = 4.76∙10 −34).
Figure 2 shows the ROC curves, which demonstrate the discrimination between healthy individuals and patients using these indices. The horizontal axis represents 1-specificity (false positive rate) and the vertical axis represents sensitivity (true positive rate).
Table 2 shows the AUC for the ROC curve, sensitivity, and specificity for these indices. The best discriminability was achieved by the shimmer in terms of AUC and sensitivity and by the HNR regarding specificity. For all the indices, the AUC was approximately 0.9, showing a strong discriminability between healthy individuals and patients.
The discriminability of the indices (for the long-vowel sound “ah”)
Index AUC Sensitivity Specificity Jitter (ppq5) 0.900 0.802 0.887 Shimmer (apq5) 0.911 0.811 0.868 HNR (harmonicity) 0.897 0.778 0.925
3.2. Ability to discriminate based on read speech in English
The mean values for healthy individuals and patients in the data of read speech of “rainbow passage”
Index Healthy Individuals (n=53) Patients (n=662) P-value Pitch rate 0.903±0.047 0.643±0.25 8.98∙10 −39 Jitter (ppq5) 0.0084±0.0016 0.014±0.0076 2.84∙10 −39 Shimmer (apq5) 0.042±0.010 0.057±0.026 4.55∙10 −14 HNR (harmonicity) 13.12±2.18 11.41±3.48 1.91∙10 −6
Regarding the total speech time, the average values of healthy individuals and patients were 10089.23 ms (n = 53, SD = 734.33), and 9270.70 ms (n = 662, SD = 1394.42), respectively. As a result of the t-test, there was a significant difference between them (t(86) = 7.15, p = 2.71∙10 −10).
Table 3 shows the mean values for healthy individuals and patients in the data of read speech of “Rainbow Passage”.
With respect to pitch rate, the mean values for healthy individuals and patients were 0.903 (n = 53, SD = 0.047) and 0.643 (n = 662, SD = 0.25), respectively. Based on the t-test, significant differences were observed between the two groups (t(394) = 22.285, p = 8.98∙10 −39).
With respect to jitter, the mean values for healthy individuals and patients were 0.0084 (n = 53, SD = 0.0016) and 0.014 (n = 662, SD = 0.0076), respectively. Based on the t-test, significant differences were observed between the two groups (t(321) = −15.09, p = 2.84∙10 −39).
With respect to shimmer, the mean values for healthy individuals and patients were 0.042 (n = 53, SD = 0.010) and 0.057 (n = 662, SD = 0.026), respectively. Based on the t-test, significant differences were observed between the two groups (t(117) = −8.58, p = 4.55∙10 −14).
Regarding the HNR, the mean values for healthy individuals and patients were 13.12 (n = 53, SD=2.18) and 11.41(n=662, SD=3.48), respectively. Based on the t-test, significant differences were observed between the two groups (t(75) = 5.166, p = 1.91∙10 −6).
Figure 4 ROC curves used for discriminating between healthy individuals and patients using the pitch rate, jitter, shimmer, and HNR in data containing read speech of “Guten Morgen, wie geht es Ihnen?”(German).
Discriminability of the indices (for read speech of “rainbow passage”)
Index AUC Sensitivity Specificity Pitch rate 0.902 0.962 0.713 Jitter (ppq5) 0.827 0.588 0.943 Shimmer (apq5) 0.706 0.761 0.566 HNR (harmonicity) 0.655 0.636 0.660
Figure 3 shows the ROC curves, which demonstrate the discrimination between healthy individuals and patients using these indices.
Table 4 shows the AUC for the ROC curve, sensitivity, and specificity for these indices. The pitch rate had the best values for the AUC and sensitivity. However, the jitter had the best value for specificity. Compared to Table 1, the AUC for the shimmer and HNR was considerably reduced.
3.3. Ability to discriminate based on read speech in German
Regarding the total speech time, the average values of healthy individuals and patients were 1561.81 ms (n = 632, SD = 331.24) and 1920.62 ms (n = 101, SD = 488.37), respectively. As a result of the t-test, there was a significant difference between them (t (115) = −7.13, p = 9.67 ∙10 −11).
The mean values for healthy individuals and patients in the data of read speech of “Guten Morgen, wie geht es Ihnen?”
Index Healthy Individuals (n=632) Patients (n=101) P-value Pitch rate 0.826±0.094 0.701±0.180 6.55∙10 −10 Jitter (ppq5) 0.0101±0.0028 0.0122±0.0056 0.00039 Shimmer (apq5) 0.036±0.012 0.045±0.019 4.48∙10 −5 HNR (harmonicity) 14.89±2.29 14.47±3.27 0.22
Table 5 shows the mean values for healthy individuals and patients in the data of read speech of “Guten Morgen, wie geht es Ihnen?”.
With respect to the pitch rate, the mean values for healthy individuals and patients were 0.826 (n = 632, SD = 0.094) and 0.701 (n = 101, SD = 0.180), respectively. Based on the t-test, significant differences were observed between the two groups
Figure 4 ROC curves used for discriminating between healthy individuals and patients using the pitch rate, jitter, shimmer, and HNR in data containing read speech of “Guten Morgen, wie geht es Ihnen?”(German).
(t(109) = 6.78, p = 6.55∙10 −10).
With respect to jitter, the mean values for healthy individuals and patients were 0.0101 (n = 632, SD = 0.0028) and 0.0122 (n = 101, SD = 0.0056), respectively. Based on the t-test, significant differences were observed between the two groups (t(632) =−3.66, p = 0.00039).
Regarding shimmer, the mean values for healthy individuals and patients were 0.036 (n = 632, SD = 0.012) and 0.045 (n = 101, SD = 0.019), respectively. Based on the t-test, significant differences were observed between the two groups (t(112) = −4.25, p = 4.48∙10 −5).
With respect to the HNR, the mean values for healthy individuals and patients were 14.89 (n = 632, SD = 2.29) and 14.47 (n = 101, SD = 3.27), respectively. Based on the t-test, no significant differences were observed between the two groups (t(116) = 1.230, p = 0.22).
As shown above, in all indexes other than the HNR, there were significant differences between healthy individuals and patients.
Figure 4 shows the ROC curves, which demonstrate the discrimination between healthy individuals and patients using these indices.
Discriminability of the indices (for read speech of “‘Guten Morgen, wie geht es Ihnen?'”)
Index AUC Sensitivity Specificity Pitch rate 0.725 0.672 0.703 Jitter (ppq5) 0.598 0.734 0.475 Shimmer (apq5) 0.628 0.736 0.475 HNR (harmonicity) 0.519 0.927 0.218
Table 6 shows the AUC for the ROC curve, sensitivity, and specificity for these indices. For the AUC and specificity, the pitch rate was the most suitable. In terms of sensitivity, the HNR showed the best value. However, the value of the AUC tended to be lower than in the case of English.
3.4. Ability to discriminate based on read speech in Japanese
Regarding the total speech time, the average values of healthy individuals and patients were 26144.17 ms (n = 6, SD = 2995.73) and 18676.11 ms (n = 35, SD = 5145.64), respectively. As a result of the t-test, there was a significant difference between them (t(39) = 3.43, p = 0.0014).
The mean values for healthy individuals and patients in the data of read speech of ” Kitakaze to Taiyo “
Index Healthy Individuals (n=6) Patients (n=35) P-value Pitch rate 0.831±0.051 0.668±0.232 0.00078 Jitter (ppq5) 0.011±0.0026 0.013±0.0084 0.12 Shimmer (apq5) 0.040±0.014 0.0625±0.035 0.013 HNR (harmonicity) 13.64±2.46 11.85±3.59 0.25
Regarding pitch rate, the mean values for healthy individuals and patients were 0.831 (n = 6, SD = 0.051) and 0.668 (n = 35, SD = 0.232), respectively. Based on the t-test, significant differences were observed between the two groups (t(36) = 3.67, p = 0.00078).Table 7 shows the mean values for healthy individuals and patients in the data of read speech of “Guten Morgen, wie geht es Ihnen?”.
With respect to the jitter, the mean values for healthy individuals and patients were 0.011 (n = 6, SD = 0.0026) and 0.013 (n = 35, SD = 0.0084), respectively. Based on the t-test, no significant differences were observed between the two groups (t(26) = −1.61, p = 0.12).
Regarding shimmer, the mean values for healthy individuals and patients were 0.040 (n = 6, SD = 0.014) and 0.062 (n = 35, SD = 0.035), respectively. Based on the t-test, no significant differences were observed between the two groups (t(19) = −2.76, p = 0.013).
With respect to the HNR, the mean values for healthy individuals and patients were 13.64 (n = 6, SD = 2.46) and 11.85 (n = 35, SD = 3.59), respectively. Based on the t-test, no significant differences were observed between the two groups (t(39) = 1.17, p = 0.25).
As shown above, there was a significant difference between healthy individuals and patients only in the pitch rate.
Figure 5 shows the ROC curves, which display the discrimination between healthy individuals and patients using these indices.
Discriminability of the indices (for read speech of “Kitakaze to Taiyo”)
Index AUC Sensitivity Specificity Pitch rate 0.752 0.833 0.686 Jitter (ppq5) 0.562 1 0.343 Shimmer (apq5) 0.733 1 0.486 HNR (harmonicity) 0.624 1 0.314
Figure 5 ROC curves used for discriminating between healthy individuals and patients using the pitch rate, jitter, shimmer, and HNR in the data containing read speech of “Kitakaze to taiyo” (Japanese).
Table 8 shows the AUC for the ROC curve, sensitivity, and specificity for these indices. For the AUC and specificity, the pitch rate was the most suitable. The sensitivity was 1 for all indices other than the pitch detection rate. As with German, the value of the AUC tended to be lower than in English.
Patient speech in Japanese included both read speech and free-form speech; these were separated manually. The differences between free-form speech and the recitation of a passage were investigated using these voice samples.
With respect to jitter, the mean values for reading and free-form speech were 0.013 (n = 35, SD = 0.007) and 0.013 (n = 35, SD = 0.008), respectively. Based on the t-test, no significant differences were observed between the two groups (t(68) = −0.304, p = 0.762). The correlation coefficient between them was 0.88.
With respect to shimmer, the mean values for reading and free-form speech were 0.059 (n = 35, SD = 0.030) and 0.067 (n = 35, SD = 0.034), respectively. Based on the t-test, no significant differences were observed between the two groups (t(68) = −0.95, p = 0.348). The correlation coefficient was 0.88.
With respect to the HNR, the mean values for reading and free-form speech were 12.30 (n = 35, SD = 3.23) and 11.65 (n = 35, SD = 3.56), respectively. Based on the t-test, no significant differences were observed between the two groups (t(68) = −0.806, p = 0.423). The correlation coefficient was 0.85.
With respect to pitch rate the mean values for reading and free-form speech were 0.668 (n = 35, SD = 0.232) and 0.582 (n = 35, SD = 0.277), respectively. Based on the t-test, no significant differences were observed between the two groups (t(68) = 1.41, p = 0.162). The correlation coefficient was 0.79.
4. Discussion and Conclusion
In this article, we propose a method for predicting whether a voice sample belongs to a healthy individual or a patient based on the pitch rate of a speech interval in English, German, and Japanese speech. Similar studies conducting comparative analyses of healthy individuals and patients have been performed using the same samples [22, 23]. However, those studies utilized voice samples of the long-vowel sound “ah.” Instead, our research focused on the detection of illness via a smartphone using free-form speech in the form of reciting a set passage.
As shown in Table 2, in the case of the long-vowel sound, the jitter, shimmer, and HNR all resulted in an AUC of approximately 0.9, showing that these indices have good discriminability. However, as shown in Table 4, in the case of read speech, the discriminability diminished. In particular, for the shimmer and HNR, the AUC decreased considerably, to approximately 0.7 or lower.
In contrast, in the case of read speech, the pitch rate resulted in an AUC exceeding 0.9, demonstrating better discriminability between healthy individuals and patients than the conventional indices. However, in the case of the long-vowel sound, the pitch rate for both healthy individuals and patients was approximately 1.0, making it unsuitable for discrimination between healthy individuals and patients.
As stated above, the AUC of the pitch rate for the English passage was 0.902, which was a favorable outcome. In German and Japanese, the pitch rate showed the highest identification efficiency, as was the case in English. However, the AUC values were 0.725 and 0.752 for German and Japanese, respectively, which is more than 0.15 lower that the AUC value for English. In English, the average pitch rate values for healthy individuals and for patients were 0.903 and 0.643, respectively. The corresponding values in German were 0.826 and 0.701 and in Japanese 0.831 and 0.668, respectively. These results demonstrate that the healthy individual pitch rates in German and Japanese are lower than the healthy individual pitch rates in English and the patient pitch rates in German and Japanese are higher than the patient pitch rates in English. Differences in patient pitch rates may be due to differences in the severity of illnesses among the patients in the databases.
However, the question of why healthy individuals reciting in English have a higher pitch rate than in the other two languages remains. This could be owing to the characteristics of the languages, and the differences in the contents of the recited passages could also be a factor. Furthermore, the different sampling frequency used for each database and differences in the noise from the recording environment could be factors contributing to the pitch rate discrepancy.
Regarding the difference in the speech contents, in German, for example, the passage used was a greeting used in daily life, which is close to free-form speech. The influence of these differences was examined in Japanese patient speech through a comparison of free-form speech and read speech. The results showed that all indices—jitter, shimmer, HNR, and pitch rate—had a strong correlation of about 0.75 to 0.85 between free-form speech and read speech. In addition, there was a significant difference between free-form speech and read speech only in the pitch detection rate. The average value of the pitch detection rate was 0.582 in the case of free-form speech and 0.668 in case of read speech, and the free-form speech tends to be lower. Perhaps the German pitch detection rate is lower than that of English because the content of the speech is close to free conversation.
Additionally, the average total speech time for the German passage used was 1561.81 ms for healthy individuals, which is extremely short compared to the English passage (10089.23 ms) and the Japanese passage (26144.17 ms). However, because the average pitch rate value was calculated for each utterance, the difference in the total length of the voice samples is not expected to have an effect on the results.
The thresholds q 1, q 2, and q 3 ,used for the pitch rate calculation algorithm described in section 2.4 had the same value for every language. In a separate pilot study, it was determined that if the thresholds are set at an appropriate value for each separate language, the AUC for German and Japanese exceeds 0.8. Therefore, these thresholds may need to be tuned separately for each language. These points will be further evaluated in future studies.
Although we have demonstrated that for read speech, the pitch rate has high discriminability, it must be noted that read speech and everyday conversation in telephone calls are not equivalent. In the read speech data used here, both the healthy individuals and the patients read the same sentences. However, in everyday conversation, the content is diverse. For example, the percentage of consonants varies in each case and the pitch rate decreases when there are more consonants. It has been reported [24] that compared with read speech, spontaneous speech can better classify patients with major depressive disorders. We believe that further studies are required on the effects of the speech content on the pitch rate or the differences between read speech and spontaneous speech.
Although long vowels can be recorded by using a smartphone, it is necessary that day-to-day recording is performed regularly. It has been reported [25] that the frequency of voice recording in such conditions gradually decreases compared with telephone calls.
In this study, we used the algorithm proposed in [20, 21]. The pitch rate itself is naturally affected by the performance of the algorithm. However, if the algorithms are used to process the same pitch, although there may be variations in the absolute pitch rate values, we believe that the relative magnitude relationship between healthy individuals and patients will not change. This means that it is likely that differences in the algorithm do not adversely affect the discriminability between healthy individuals and patients. This is also a topic for future study.
In this study, each analysis was performed for well-recorded speech signals using a PC processor. However, when analyzing real speech recorded in real conditions using smartphones, the analysis might be influenced by the audio transducer or processor of the smartphone. These points are under verification.
The voice database used in the study contained data from patients with diverse disorders. It can therefore be argued that although we have suggested an index to broadly discriminate between healthy individuals and patients, this index cannot be applied to diagnose a specific disorder. In the future, we aim to develop algorithms for diagnosing specific disorders.
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgment
This research is (partially) supported by the Center of Innovation Program from the Japan Science and Technology Agency, JST. This work was supported by JSPS KAKENHI Grant Numbers JP16K01408 and JP15H03002.
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Endometrial Luteal Phase Characteristics and Luteal Phase Support in Controlled Ovarian Stimulation Protocols With GnRH Antagonists:Focusing on MicroRNA - Tabular View - ClinicalTrials.gov
Endometrial Luteal Phase Characteristics and Luteal Phase Support in Controlled Ovarian Stimulation Protocols With GnRH Antagonists:Focusing on MicroRNA
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government.
Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01510054 Recruitment Status :
Withdrawn First Posted : January 13, 2012 Last Update Posted : April 3, 2015
Sponsor:
Johns Hopkins University
Information provided by (Responsible Party):
Yulian Zhao, Johns Hopkins University
Study Details
Tabular View
Tracking Information
First Submitted Date December 22, 2011
First Posted Date January 13, 2012
Last Update Posted Date April 3, 2015
Study Start Date July 2002
Actual Primary Completion Date November 2014 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures (submitted: January 10, 2012) microRNA expression in human endometrium after IVF [ Time Frame: Up to 4 years are estimated for the study to be completed including all measures. ]
Original Primary Outcome Measures Same as current
Change History Complete list of historical versions of study NCT01510054 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title Endometrial Luteal Phase Characteristics and Luteal Phase Support in Controlled Ovarian Stimulation Protocols With GnRH Antagonists:Focusing on MicroRNA
Official Title Endometrial Luteal Phase Characteristics and Luteal Phase Support in Controlled Ovarian Stimulation Protocols With Gonadotropin Releasing Hormone (GnRH) Antagonists: Focusing on MicroRNA Identification and Expression
Brief Summary
MiRNAs are single-stranded small non-coding RNAs that act on specific mRNAs to regulate the gene expression. Studies have suggested that miRNAs influence cellular activities in the uterus, including cell differentiation and embryo implantation.In assisted reproductive cycles, controlled ovarian stimulation (COS) results in supraphysiological steroid levels and is associated with very low luteinizing hormone concentration during the luteal phase, the peri-implantation and implantation period. Luteal phase support, administration of medication aimed at supporting the implantation process, has been a routine practice in in vitro fertilization (IVF) clinics. Luteal phase support with steroid hormone has been found to improve pregnancy rates when human menopausal gonadotropins were used in conjunction with GnRH agonists for ovarian stimulation and IVF. Reports on effect of steroid supplementation in GnRH antagonist protocols are limited.The proposed project is an extension of our previous study on Endometrial Luteal Phase Characteristics and Luteal Phase Support in Controlled Ovarian Hyperstimulation Protocols with Gonadotropin Releasing Hormone Antagonists. The significance of this study is based on the importance of luteal phase endometrial after COS for the process of implantation. The availability of oocycte donors in assisted reproduction technology programs offers a unique opportunity to study the impact of different stimulation protocols on the quality of the luteal phase. In addition, the oocyte donor model may allow us to evaluate the impact of different luteal support protocols directly on the endometrial preparation by histological as well as biochemical markers.Study design: Study subjects underwent ovarian stimulation according to a gonadotropin/GnRH antagonist protocol. All donors had a baseline measurement of serum follicle stimulating hormone (FSH) and estradiol levels on the second day of their menstrual cycles. Provided serum FSH levels were less than 10mIU/ml and E2 levels were less than 60pg/ml, ovarian stimulation was initiated with recombinant FSH. The daily dose was adjusted according to follicular development by serial transvaginal ultrasound and serum E2 response. A daily evening dose of ganirelix acetate was initiated on the 6th day of stimulation and continued through the day of human chorionic gonadotropin administration. When at least three follicles reached a mean diameter of 18mm, ovulation was triggered with a single dose of Human chorionic gonadotropin (hCG). Sonographically guided transvaginal oocyte retrieval was performed 34-36 hours after the hCG administration.Thirty endometrial biopsies from oocyte donors on their COS cycles will be used for the study. Study subjects have been randomized into 4 groups. Grp 1: day of retrieval, did not receive any luteal-phase support, which serves as base line; grp2: 3, 5 and 10 days after retrieval with no luteal phase support, which serves as control; grp3: 3, 5 and 10 days after retrieval, luteal phase support with progesterone in the form of vaginal suppositories starting from the day after retrieval; grp4: daily oral dose of 2 mg 17β-estradiol in addition to the micronized progesterone. Immediately after the endometrial biopsy all specimens were stored in liquid nitrogen tanks at -196°C.Total RNA will be isolated and microarray will be performed using an Illumina miRNA expression panel. Array results will be compiled and analyzed focusing on the following aspects: the target genes of prominent miRNAs, miRNA profile in relation to target gene pathways; miRNA expression profile in relation to endometrial dating and status; effect of luteal phase support on miRNA expression after ovarian stimulation. Minimum of 3 miRNA arrays will be run for each sample for the purpose of statistical analysis. A total of 30 arrays will be needed for all samples from all groups.In this study, the investigators pose three questions: 1) How many and what types of miRNAs are in the endometrium during ovarian stimulation? This is to identify miRNAs and associated target genes that are relevant for endometrium receptivity; 2) Do levels of miRNA expression change during the luteal phase, or during the window of implantation? This is to examine the dynamics of miRNAs that are associated with remodeling process of endometrium; and 3) Do luteal phase support alter miRNA expression in the luteal phase? This is to investigate the steroid effect on miRNA regulation. The investigators hypothesize that many critical genes related to implantation are regulated by miRNAs. This research effort will potentially advance our knowledge of endometrial characteristics after COS and the impact of sex steroid supplementation. Overall the study should help better understand the genetic control of implantation. Completion of this study may also provide measurable scientific evidence and useful information for the management of IVF cycles.
Detailed Description Not Provided
Study Type Observational
Study Design Not Provided
Target Follow-Up Duration Not Provided
Biospecimen Retention: Samples With DNA Description: endometril tissue
Sampling Method Probability Sample
Study Population 30 emdometrial biopsy from oocyte donors
Condition Controlled Ovarian Stimulation
Intervention Not Provided
Study Groups/Cohorts steroid support Endometrial biopsies from subjects of with or without luteal phase steroid support will be compared for miRNA expression
Publications * Not Provided
* Includes publications given by the data provider as well as publications
identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status Withdrawn
Actual Enrollment (submitted: April 2, 2015) 0
Original Estimated Enrollment (submitted: January 10, 2012) 30
Actual Study Completion Date November 2014
Actual Primary Completion Date November 2014 (Final data collection date for primary outcome measure)
Eligibility Criteria
Inclusion Criteria: 21 to 31 years of age female who underwent a standard screening protocol for oocyte donation, in accordance with the recommendations of the American Society for Reproductive Medicine.Exclusion Criteria: Women with a body mass index exceeding 28 kg/m2,history of: pelvic inflammatory disease, sexually transmitted diseases, reproductive tract pathology, or other systemic diseases or conditions
Sex/Gender Sexes Eligible for Study: Female
Ages 21 Years to 31 Years (Adult)
Accepts Healthy Volunteers Yes
Contacts Contact information is only displayed when the study is recruiting subjects
Listed Location Countries United States
Removed Location Countries
Administrative Information
NCT Number NCT01510054
Other Study ID Numbers IISP 38749
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement Not Provided
Current Responsible Party Yulian Zhao, Johns Hopkins University
Original Responsible Party Same as current
Current Study Sponsor Johns Hopkins University
Original Study Sponsor Same as current
Collaborators Not Provided
Investigators Principal Investigator: Yulian Zhao, Ph.D Johns Hopkins University
PRS Account Johns Hopkins University
Verification Date April 2015
For Researchers
| https://clinicaltrials.gov/ct2/show/record/NCT01510054 |
Crocodile vs. Climate | U.S. Fish & Wildlife Service
Key Largo, Florida -- If Florida is the poster child for
Crocodile vs. Climate
Image Details
Not even the American crocodile escapes rising temperatures, seas
USFWS pegs September as "Learning From Nature" month and the croc teaches valuable lessons as the world warms
Key Largo, Florida-- If Florida is the poster child for climate change climate change Climate change includes both global warming driven by human-induced emissions of greenhouse gases and the resulting large-scale shifts in weather patterns. Though there have been previous periods of climatic change, since the mid-20th century humans have had an unprecedented impact on Earth's climate system and caused change on a global scale. Learn more about climate changerun amok then the Keys – the fragile, low-lying string of tropical islands that curves out into the Atlantic Ocean and the Gulf of Mexico – are the even more troubled siblings struggling against rising seas and saltwater intrusion.
Nowhere along the 150-mile-long archipelago does the elevation rise above 18 feet. Average height: 3.2 feet above sea level. It doesn’t take a rocket scientist to discern what harm a projected three-to-eight-foot rise in the Atlantic Ocean by 2100 will do to the Keys.
Or the crocodiles.
Even the armored and menacing-looking American crocodile, who lives only in south Florida, can’t escape the ravages of a warming world. The federally threatened species, kin to the darker-skinned and more plentiful American alligator, suffers from rising temperatures and rising seas.
Yet, paradoxically, there are more crocodiles in Florida today than at any time in the last half century. Protections offered by the Endangered Species Act surely help boost their numbers. A robust artificial-nest building program also ensures the survival of more baby crocs. And, like many animals and plants, migration northward toward fresher water and more stable habitats has become a life-saving necessity.
Still, the climate threat is only expected to worsen with a particular harsh prognosis for the mangrove habitats crocodiles call home. And, with south Florida building out virtually every square foot of coastal property, crocodiles may struggle to find room to nest.
American crocodiles get a bad rap. Shy and secretive by nature, crocs go out of their way to avoid conflict with humans belying Tarzanesque depictions of large, toothy reptiles chomping on unsuspecting explorers. They inhabit the coastal mangrove forests of Cuba, Jamaica, Mexico and Ecuador. South Florida is their northernmost reach. They can live past 50. Males can grow beyond eight feet. Crocs are distinguished from their more ubiquitous cousin, the alligator, by their olive-green skin, slender snouts, and the visibility of the fourth tooth on their lower jaw when their mouths are shut. They were listed as endangered by the U.S. Fish and Wildlife Service in 1975.
Back then, a few hundred crocs inhabited the brackish ponds, coves and creeks of Florida’s mangrove swamps. The coastal crocodilians were hunted to near extinction to satisfy the demand for purses, wallets, shoes, and belts. Florida’s unrelenting sprawl wiped out most of the reptiles’ habitat. Starting in the 1960s, developers began buying up waterfront properties in North Key Largo with hopes of building massive resorts and bedroom communities. They gouged out canals and stacked the spoils into neat rows to serve as marinas. Recessions, bankruptcies, illegal permits, and a heightened awareness of the need to conserve land for a variety of threatened and endangered species doomed some of the developments.
Out of the developers’ broken dreams, in 1980, rose the Crocodile Lake National Wildlife Refuge. Much of the refuge that hugs U.S. 1 atop the Keys housed antiaircraft missiles intended to shoot down Soviet bombers approaching Florida from Cuba. In addition to the mangroves and salt marshes, the refuge is renowned for its hardwood hammocks which provide much-needed habitat for a slew of threatened and endangered species, including the Key Largo wood rat, the Schaus’ swallowtail butterfly, and the Florida semaphore cactus. Today, the 6,700–acre refuge is off-limits to the public, though a butterfly garden is open daily and more intrepid visitors can volunteer to track invasive pythons.
The crocodile, though, is the refuge’s rock star. And its habitat is under siege. The state of Florida’s Climate Adaptation Explorer reports that the crocodile’s habitat “is expected to become significantly inundated” with at least a third of its home turf disappearing by 2100.
“I’ve been here nine years and I can definitely tell you that the water’s coming up quick,” says Jeremy Dixon, the refuge manager standing amidst a field of artificial crocodile nests. “On the water’s edge, where the saltwater is moving in, we’re transitioning from upland species to wetland species. At some point buttonwoods can’t withstand saltwater inundation so it’s transformed into mangroves. Change is happening so fast. We’re seeing huge impacts.”
Jeremy Dixon, who manages Crocodile Lake National Wildlife Refuge, stands alongside a field of artificial crocodile mounds.
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Image Details
The Atlantic Ocean off Florida has risen almost a foot over the last century and will likely rise at least another foot by 2050. Key Largo sits, on average, seven feet above sea level and could lose hundreds, if not thousands of acres of coastal habitat.
“Florida is among the most vulnerable states to climate change impacts, primarily due to a combination of increasing ocean temperatures, sea level rise, extreme weather events, low elevation, and heavy coastal human development,” reads the National Fish, Wildlife, and Plants Climate Adaptation Strategy published last year by the National Oceanic and Atmospheric Administration.
A warming world melts glaciers and causes seas to rise. Hotter temperatures also warm the oceans. And, since water expands as it heats up, the seas rise even higher.
A 2020 study in the Journal of Thermal Biology tracked the relationship between sea surface temperatures and the time when crocodiles hatch in south Florida. Scientists with the Service, the United States Geological Survey, and other partners found that, over the last four decades, temperatures have increased, on average, 0.05 degrees centigrade per year. Consequently, at one test site in the nearby Everglades National Park, crocodile babies hatch 1.5 days earlier every two years. The scientists didn’t explore potential ramifications of the earlier hatchings. Other studies, though, show that higher temperatures produce more male than female crocodiles.
Anthropogenic irony
Yet the very factors that harm the American crocodile’s survival – man and his modern ways – afford previously unheard-of opportunities for the reptile’s survival. Fifty years ago, the remaining crocs nested in Key Largo and the northeastern corner of Florida Bay in the Everglades National Park. Running out of space, and freshwater, the crocs adapted by moving north and west. Today, they’re found as far north as Key Biscayne, below Miami, and Marco Island on the Gulf. They inhabit public beaches, marinas, golf courses, even an airport.
The “Croc Docs” are on their tails. The University of Florida scientists have tracked the reptiles’ whereabouts – and notched their successes – for 50 years. They tallied 93 nests in the 1970s – and a total of 3,013 nests by 2020. More importantly, the nesting success rate rose from 61 percent to almost 90 percent.
A handful of baby crocodiles at Turkey Point Nuclear Power Plant. | Image Details
And here’s where it gets interesting. While the Endangered Species Act and the creation of croc-friendly habitats like Crocodile Lake refuge deserve much credit for the animal’s survival, so too do man-made canals and man-made maternity wards. Consider the Turkey Point nuclear power plant in Homestead. The company that owns the nuke plant, Florida Power and Light, maintains the artificial, flood-proof berms that crocodiles prefer for nesting. And the 40 cooling ponds afford the fresh water the hatchlings need. Only two nests were counted at Turkey Point in the 1970s; 540 have been tallied since, according to the University of Florida.
Or consider the Cape Sable area of Everglades National Park. Freshwater marshes and lakes once covered the southwestern corner of Florida until settlers in the early 1900s drained the land for farms. Two of the major canals, though, were plugged in the 1980s and the crocodiles began nesting on the levees. There were no nests in Cape Sable during the 1970s and, in the 2020s, there were 1,180.
And then there’s Crocodile Lake refuge. Dixon, the refuge manager, tours a stripped-bare field alongside a red mangrove forest. Canals, intended for a marina that was never built, stretch a half-mile into Barnes Sound. Twenty man-made mounds of packed sand, five feet long and two feet high, sit close enough to the water, yet far enough upland to avoid most of the damage wrought by rising seas.
“The really cool thing is we have nesting sites right next to great hatchling habitat,” Dixon says. “Crocodiles will use what’s available. You put sand out there and they’ll be happy.”
The reptiles nest between March and May. Dixon and crew counted eight active nests this year and tagged 48 hatchlings. Over the last 15 years, the Service, along with state, federal and nonprofit partners, built 40 maternity wards for expectant croc moms on the refuge. Crocodile Lake has totaled 258 nests over the years.
In 2007, the American crocodile in Florida was down-listed from endangered to threatened. An estimated 2,700 crocs live in the Keys and the Everglades.
“What we’re doing is working,” Dixon says.
Numbers leveling
But for how long? In this century’s first decade, 59 nests were counted at Crocodile Lake, according to the UF study published in the June 2022 edition of Frontiers in Ecology and Evolution. In the last decade, the number of nests dropped to 55. The drop-off is similar at Turkey Point: 202 to 192 nests. (Nest numbers continued to rise at Cape Sable.)
In all, five of the 12 sites studied by UF showed lower nesting levels the last two decades.
“We have no explanation, or even a good speculation, for why the increase in nesting leveled off during 2010 to 2020,” the UF scientists write before offering a few possible explanations.
Nests fail primarily due to flooding or drought, extreme weather events that are hallmarks of climate change. 2015, for example, was a very bad year for nests with higher-than-usual temperatures causing water temperatures – and salinity levels – to rise. As the seas rise, more low-lying nests flood.
Dixon, the refuge manager, displays the skull and spine of a baby crocodile that didn't survive at Crocodile Lake National Wildlife Refuge.
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Image Details
Rising seas, temperatures, and salinity levels appear to push the crocodiles further and further north. Steven Bertone, an environmental specialist with the Florida Department of Environmental Protection, says crocs from Cape Sable appear to be moving up Florida’s west coast nearing Goodland and Marco Island. There they find mangrove forests and freshwater marshes a good distance from the saltier estuaries found along the coast.
If they keep migrating, though, they’ll hit the subdivisions and highways – stuff made by man – that is endemic to south Florida, yet bad for crocodiles. It remains to be seen whether other anthropogenic stuff, like canals and levees, offer enough of a benefit to keep the reptiles from going extinct as the climate warms.
“The adaptive capacity that American crocodiles exhibited in Florida gave the species advantages to face changes in climate and landscape over the last 50 years,” the UF scientists write. “However, it does not imply that the adaptive capacity of the species to face these changes ... cannot reach a limit if changes continue.”
Story Tags
Adaptation
Animal migration
Biodiversity
Biologists (USFWS)
Climate change
Coasts
Ecosystem recovery
Endangered and/or Threatened species
Erosion
Habitat conservation
Hunting
Partnerships
Reptiles
Salt marshes
Water conservation
Recreational Activities
Wildlife watching
Photography
Birding
Written By
Climate Change
Facilities
Crocodile Lake National Wildlife Refuge
Turning the tide on sea level rise
| https://www.fws.gov/story/crocodile-vs-climate?page=734 |
prEN IEC 62752:2022 - In-cable control and protection device for mode 2 charging of electric road
prEN IEC 62752:2022 - In-cable control and protection device for mode 2 charging of electric road vehicles (IC-CPD)
Abstract
German
French
Slovenian
In-cable control and protection device for mode 2 charging of electric road vehicles (IC-CPD)
CD assessment requested on 2020-02-05.
Ladeleitungsintegrierte Steuer- und Schutzeinrichtung für die Ladebetriebsart 2 von Elektro-Straßenfahrzeugen (IC-CPD)
Appareil de contrôle et de protection intégré au câble pour la charge en mode 2 des véhicules électriques (IC-CPD)
Integrirana zaščita kabla in zaščitna naprava tipa 2 za napajanje električnih cestnih vozil (IC-CPD)
General Information
Status
Not Published
Publication Date
03-Dec-2023
ICS
29.120.50 - Fuses and other overcurrent protection devices
Technical Committee
CLC/TC 23E - Circuit breakers and similar devices for household and similar applications
Drafting Committee
IEC/SC 23E - IEC_SC_23E
Current Stage
4060 - Enquiry results established and sent to TC, SR, BTTF - Enquiry
Start Date
23-Jun-2023
Directive
2014/30/EU - Directive 2014/30/EU of the European Parliament and of the Council of 26 February 2014 on the harmonisation of the laws of the Member States relating to electromagnetic compatibility (recast)
2014/35/EU - Directive 2014/35/EU of the European Parliament and of the Council of 26 February 2014 on the harmonisation of the laws of the Member States relating to the making available on the market of electrical equipment designed for use within certain voltage limits
Mandate
M/511 - Mandate to CEN, CENELEC and ETSI relating to harmonised standards in the field of the Low Voltage Directive
M/552 - [C(2016) 7641 final] Standardisation request as regards harmonised standards in support of Directive 2014/30/EU of the European Parliament and of the Council of 26 February 2014 on the harmonisation of the laws of the Member States relating to electromagnetic compatibility
Ref Project
oSIST prEN IEC 62752:2022 - In-cable control and protection device for mode 2 charging of electric road vehicles (IC-CPD)
Relations
Revises
EN 62752:2016/AC:2019-03 - In-cable control and protection device for mode 2 charging of electric road vehicles (IC-CPDs)
Effective Date
14-Jan-2020
Revises
EN 62752:2016 - In-cable control and protection device for mode 2 charging of electric road vehicles (IC-CPD)
Effective Date
07-Jan-2020
Revises
EN 62752:2016/A1:2020 - In-cable control and protection device for mode 2 charging of electric road vehicles (IC-CPD)
Effective Date
08-Jun-2021
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Standards Content (Sample)
prEN IEC 62752:2022
SLOVENSKI STANDARD
oSIST prEN IEC 62752:2022
01-julij-2022
Integrirana zaščita kabla in zaščitna naprava tipa 2 za napajanje električnih cestnihvozil (IC-CPD)
In-cable control and protection device for mode 2 charging of electric road vehicles (IC-CPD)
Ladeleitungsintegrierte Steuer- und Schutzeinrichtung für die Ladebetriebsart 2 vonElektro-Straßenfahrzeugen (IC-CPD)
Appareil de contrôle et de protection intégré au câble pour la charge en mode 2 desvéhicules électriques (IC-CPD)
Ta slovenski standard je istoveten z: prEN IEC 62752:2022
ICS:
29.120.50 Varovalke in druga Fuses and other overcurrent
nadtokovna zaščita protection devices
43.120 Električna cestna vozila Electric road vehicles
oSIST prEN IEC 62752:2022 en,fr,de
2003-01.Slovenski inštitut za standardizacijo. Razmnoževanje celote ali delov tega standarda ni dovoljeno.---------------------- Page: 1 ----------------------
oSIST prEN IEC 62752:2022
---------------------- Page: 2 ----------------------
oSIST prEN IEC 62752:2022
23E/1246/CDV
COMMITTEE DRAFT FOR VOTE (CDV)
PROJECT NUMBER:
IEC 62752 ED2
DATE OF CIRCULATION: CLOSING DATE FOR VOTING:
2022-05-13 2022-08-05
SUPERSEDES DOCUMENTS:
23E/1233/CD, 23E/1245/CC
IEC SC 23E : CIRCUIT-BREAKERS AND SIMILAR EQUIPMENT FOR HOUSEHOLD USE
SECRETARIAT: SECRETARY:
Italy Mr Giovanni Cassinelli
OF INTEREST TO THE FOLLOWING COMMITTEES: PROPOSED HORIZONTAL STANDARD:
SC 23B,SC 23H,TC 64,TC 69
Other TC/SCs are requested to indicate their interest, if
any, in this CDV to the secretary.
FUNCTIONS CONCERNED:
EMC ENVIRONMENT QUALITY ASSURANCE SAFETY
SUBMITTED FOR CENELEC PARALLEL VOTING NOT SUBMITTED FOR CENELEC PARALLEL VOTINGAttention IEC-CENELEC parallel voting
The attention of IEC National Committees, members of
CENELEC, is drawn to the fact that this Committee Draft
for Vote (CDV) is submitted for parallel voting.
The CENELEC members are invited to vote through the
CENELEC online voting system.
This document is still under study and subject to change. It should not be used for reference purposes.
Recipients of this document are invited to submit, with their comments, notification of any relevant patent rights ofwhich they are aware and to provide supporting documentation.
TITLE:
In-cable control and protection device for mode 2 charging of electric road vehicles (IC-CPD)PROPOSED STABILITY DATE: 2026
NOTE FROM TC/SC OFFICERS:
Copyright © 2022 International Electrotechnical Commission, IEC. All rights reserved. It is permitted to
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1 CONTENTS
2 CONTENTS ............................................................................................................................ 2
3 FOREWORD ......................................................................................................................... 10
4 INTRODUCTION ................................................................................................................... 12
5 1 Scope ............................................................................................................................ 13
6 2 Normative references .................................................................................................... 14
7 3 Terms and definitions .................................................................................................... 16
8 3.1 Terms and definitions relating to plugs and socket-outlets .................................... 17
9 3.2 Terms and definitions relating to terminals ............................................................ 18
10 3.3 Terms and definitions relating to residual current functions ................................... 1911 3.3.1 Terms and definitions relating to currents flowing from live parts to
12 earth .............................................................................................................. 19
13 3.3.2 Terms and definitions relating to the energization of the residual current
14 function ......................................................................................................... 2015 3.3.3 Terms and definitions relating to the operation and to the functions of
16 the IC-CPD .................................................................................................... 2017 3.3.4 Terms and definitions relating to values and ranges of energizing
18 quantities ....................................................................................................... 2219 3.3.5 Terms and definitions relating to values and ranges of influencing
20 quantities ....................................................................................................... 24
21 3.3.6 Terms and definitions relating to conditions of operation ................................ 2422 3.3.7 Terms and definitions relating to control functions between electric
23 vehicle and IC-CPD ....................................................................................... 25
24 3.4 Terms and definitions relating to tests ................................................................... 25
25 3.5 Terms and definitions relating to construction ....................................................... 26
26 4 Classification ................................................................................................................. 26
27 4.1 According to the supply ......................................................................................... 26
28 4.1.1 General ......................................................................................................... 2629 4.1.2 IC-CPD supplied from one phase and neutral and from two phases
30 (LNSE/LLSE or LNE/LLE) .............................................................................. 26
31 4.1.3 IC-CPD supplied from three phases and neutral (LLLNSE or LLLNE) ............. 26
32 4.2 According to the construction ................................................................................ 26
33 4.2.1 General ......................................................................................................... 2634 4.2.2 IC-CPD including the function box separated from the plug and
35 connector ...................................................................................................... 26
36 4.2.3 Modular IC-CPD ............................................................................................ 26
37 4.3 According to the method of connecting the cable(s) .............................................. 27
38 4.3.1 General ......................................................................................................... 27
39 4.3.2 Non-rewirable IC-CPDs ................................................................................. 27
40 4.3.3 IC-CPDs wired by the manufacturer ............................................................... 27
41 4.3.4 Pluggable IC-CPD ......................................................................................... 27
42 4.4 Classification according to the protective conductor path ...................................... 27
43 4.4.1 General ......................................................................................................... 27
44 4.4.2 IC-CPDs with switched protective conductor .................................................. 27
45 4.4.3 IC-CPDs with non-switched protective conductor ........................................... 27
46 4.5 Classification according to behaviour in case of open protective conductor ........... 27
47 4.5.1 General ......................................................................................................... 2748 4.5.2 IC-CPD with verification of the availability of the upstream protective
49 conductor ...................................................................................................... 27---------------------- Page: 4 ----------------------
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50 4.5.3 IC-CPD without verification of the availability of the upstream protective
51 conductor ...................................................................................................... 28
52 4.6 Classification according to the usage .................................................................... 28
53 4.6.1 IC-CPD for portable use ................................................................................ 28
54 4.6.2 IC-CPD for wall mounting .............................................................................. 28
55 4.6.3 IC-CPD for portable use and for wall mounting .............................................. 28
56 5 Characteristics of IC-CPDs ............................................................................................ 28
57 5.1 Summary of characteristics ................................................................................... 28
58 5.2 Rated quantities and other characteristics ............................................................. 29
59 5.2.1 Rated voltages .............................................................................................. 29
60 5.2.2 Rated current (I ) .......................................................................................... 29
61 5.2.3 Rated residual operating current (I ) ........................................................... 29
62 5.2.4 Rated residual non-operating current (I ) .................................................. 29no
63 5.2.5 Rated frequency ............................................................................................ 29
64 5.2.6 Rated making and breaking capacity (I ) ...................................................... 29
65 5.2.7 Rated residual making and breaking capacity (I ) ....................................... 2966 5.2.8 Operating characteristics in case of residual currents comprising a DC
67 component ..................................................................................................... 30
68 5.2.9 Insulation coordination including creepage distances and clearances ............ 30
69 5.2.10 Coordination with short-circuit protection devices (SCPDs) ............................ 30
70 5.3 Standard and preferred values .............................................................................. 30
71 5.3.1 Preferred values of rated operational voltage (U ) ......................................... 30
72 5.3.2 Preferred values of rated current (I ) ............................................................. 30
73 5.3.3 Standard values of rated residual operating current (I ) .............................. 31
74 5.3.4 Standard value of rated residual non-operating current (I ) ....................... 31no
75 5.3.5 Standard minimum value of the non-operating overcurrent through the
76 IC-CPD .......................................................................................................... 31
77 5.3.6 Preferred values of rated frequency ............................................................... 31
78 5.3.7 Minimum value of the rated making and breaking capacity (I ) ..................... 3179 5.3.8 Minimum value of the rated residual making and breaking capacity
80 (I ) ............................................................................................................. 31
81 5.3.9 Standard value of the rated conditional short-circuit current (I ) ................... 3182 5.3.10 Standard value of the rated conditional residual short-circuit current
83 (I ) .............................................................................................................. 32
84 5.3.11 Limit values of break time .............................................................................. 32
85 6 Marking and other product information ........................................................................... 32
86 6.1 Data to be marked on the IC-CPD ......................................................................... 32
87 6.2 Information to be provided to the end-user ............................................................ 34
88 7 Standard conditions for operation in service and for installation ..................................... 35
89 7.1 Standard conditions .............................................................................................. 35
90 7.2 Conditions for installations .................................................................................... 35
91 8 Requirements for construction and operation ................................................................. 35
92 8.1 Mechanical design ................................................................................................ 35
93 8.2 Pluggable electrical connections of pluggable IC-CPDs according to 4.3.4 ............ 36
94 8.2.1 General ......................................................................................................... 3695 8.2.2 Degree of protection of pluggable electrical connection against solid
96 foreign objects and water for pluggable IC-CPD ............................................. 37---------------------- Page: 5 ----------------------
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97 8.2.3 Breaking capacity of pluggable electrical connection for pluggable IC-
98 CPD .............................................................................................................. 37
99 8.3 Construction ......................................................................................................... 37
100 8.3.1 General ......................................................................................................... 37
101 8.3.2 Terminations of IC-CPDs ............................................................................... 38
102 8.3.3 Enclosure of IC-CPDs according to 4.3.3 ....................................................... 38
103 8.3.4 Terminal screws or nuts of IC-CPDs according to 4.3.3 ................................. 39
104 8.3.5 Strain on the conductors of IC-CPDs according to 4.3.3 ................................ 39
105 8.3.6 Additional requirements for IC-CPDs according to 4.3.3................................. 39
106 8.3.7 Insulating parts which keep the live parts in position ...................................... 39
107 8.3.8 Screws for IC-CPD according to 4.3.3 ............................................................ 40
108 8.3.9 Means for suspension from a wall or other mounting surfaces ....................... 40
109 8.3.10 Plug as an integral part of direct plug-in equipment ....................................... 40
110 8.3.11 Flexible cables and cords and their connection .............................................. 40
111 8.4 Electrical performance .......................................................................................... 41
112 8.4.1 Protective conductor path .............................................................................. 41
113 8.4.2 Contact mechanism ....................................................................................... 41
114 8.4.3 Clearances and creepage distances (see Annex C) ....................................... 42
115 8.5 Protection against electric shock ........................................................................... 45
116 8.5.1 General ......................................................................................................... 45
117 8.5.2 Requirements relating to plugs, whether incorporated or not in integral
118 items ............................................................................................................. 45
119 8.5.3 Degree of protection of the function box ........................................................ 45
120 8.5.4 Requirements relating to vehicle connectors .................................................. 46
121 8.6 Dielectric properties .............................................................................................. 46
122 8.7 Temperature rise .................................................................................................. 46
123 8.8 Operating characteristics ...................................................................................... 47
124 8.8.1 General ......................................................................................................... 47
125 8.8.2 Safe connection operating characteristics ...................................................... 47126 8.8.3 Operating characteristics with AC residual currents and residual
127 currents having a DC component ................................................................... 47
128 8.8.4 Operating characteristics with smooth DC residual current ............................ 47
129 8.8.5 Behaviour of the IC-CPD after a residual current operation ............................ 47130 8.8.6 Residual pulsating direct currents which may result from rectifying
131 circuits supplied from two phases .................................................................. 47132 8.8.7 Residual pulsating direct currents which may result from rectifying
133 circuits supplied from three phases ................................................................ 48
134 8.9 Mechanical and electrical endurance .................................................................... 48
135 8.10 Performance at short-circuit currents .................................................................... 48
136 8.11 Resistance to mechanical shock and impact ......................................................... 48
137 8.12 Resistance to heat ................................................................................................ 48
138 8.13 Resistance to abnormal heat and to fire ................................................................ 49
139 8.14 Performance of the test function ........................................................................... 49
140 8.15 Behaviour in case of loss of the supply voltage ..................................................... 49
141 8.16 Resistance of IC-CPDs against unwanted tripping due to surge currents to
142 earth resulting from impulse voltages .................................................................... 50
143 8.17 Control pilot function controller ............................................................................. 50
144 8.18 Reliability .............................................................................................................. 50
145 8.19 Resistance to tracking ........................................................................................... 50
146 8.20 Electromagnetic compatibility (EMC) ..................................................................... 50---------------------- Page: 6 ----------------------
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147 8.21 Behaviour of the IC-CPD at low ambient air temperature....................................... 50148 8.22 Operation with supply failure and hazardous live protective conductor
149 conditions ............................................................................................................. 50
150 8.23 Verification of a standing current in the protective conductor in normal
151 service .................................................................................................................. 50
152 8.24 Behaviour at specific environmental conditions ..................................................... 51
153 8.25 Resistance to vibration and shock ......................................................................... 51
154 9 Tests ............................................................................................................................. 51
155 9.1 General ................................................................................................................. 51
156 9.1.1 Opening and closing of contacts .................................................................... 51
157 9.1.2 Type tests ...................................................................................................... 51
158 9.1.3 Test sequences ............................................................................................. 52
159 9.1.4 Routine tests ................................................................................................. 53
160 9.2 Test conditions ..................................................................................................... 53
161 9.3 Test of indelibility of marking ................................................................................ 53
162 9.4 Verification of protection against electric shock ..................................................... 54
163 9.5 Test of dielectric properties ................................................................................... 54
164 9.5.1 Resistance to humidity ................................................................................... 54
165 9.5.2 Insulation resistance of the main circuit ......................................................... 55
166 9.5.3 Dielectric strength of the main circuit ............................................................. 56
167 9.5.4 Secondary circuit of detection transformers ................................................... 56168 9.5.5 Verification of impulse withstand voltages (across clearances and
169 across solid insulation) and of leakage current across open contacts ............. 56
170 9.6 Temperature-rise test ............................................................................................ 59
171 9.6.1 Test conditions .............................................................................................. 59
172 9.6.2 Test procedure .............................................................................................. 59
173 9.6.3 Measurement of the temperature rise of different parts .................................. 60
174 9.6.4 Temperature rise of a part ............................................................................. 60
175 9.7 Verification of the operating characteristic ............................................................ 60
176 9.7.1 Test circuit ..................................................................................................... 60
177 9.7.2 Residual sinusoidal alternating currents tests ................................................ 60
178 9.7.3 Verification of the correct operation with residual currents having a DC
179 component ..................................................................................................... 63
180 9.7.4 Verification of behaviour in case of composite residual current ...................... 64181 9.7.5 Verification of the correct operation in case of smooth DC residual
182 current ........................................................................................................... 65
183 9.7.6 Miswiring and supply failure tests .................................................................. 66
184 9.7.7 Verification of protective conductor contact behaviour ................................... 70
185 9.7.8 Verification that the protective conductor is connected to the electric
186 vehicle ........................................................................................................... 70
187 9.7.9 Verification of standing current in the protective conductor connection in
188 normal service ............................................................................................... 70
189 9.7.10 Verification of the correct operation in case of residual direct currents
190 which may result from rectifying circuits supplied from two phases ................ 71
191 9.7.11 Verification of the correct operation in case of residual direct currents
192 which may result from rectifying circuits supplied from three phases .............. 71
193 9.8 Verification of mechanical and electrical endurance .............................................. 72
194 9.8.1 Endurance of plug and vehicle connector part ............................................... 72
195 9.8.2 Endurance of the residual current function of the IC-CPD .............................. 72
196 9.9 Verification of the behaviour of the IC-CPD under overcurrent conditions .............. 73
197 9.9.1 List of the overcurrent tests ........................................................................... 73---------------------- Page: 7 ----------------------
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198 9.9.2 Short-circuit tests .......................................................................................... 74
199 9.9.3 Verification of the making and breaking capacity of the plug of the IC-
200 CPD .............................................................................................................. 79
201 9.10 Verification of resistance to mechanical shock and impact .................................... 79
202 9.10.1 General ......................................................................................................... 79
203 9.10.2 Drop test ....................................................................................................... 80
204 9.10.3 Test for screwed glands of IC-CPDs .............................................................. 80
205 9.10.4 Mechanical strength test on IC-CPDs provided with cords ............................. 80
206 9.10.5 Mechanical impact test and shock test ........................................................... 81
207 9.11 Test of resistance to heat ...................................................................................... 81
208 9.11.1 General ......................................................................................................... 81
209 9.11.2 Temperature test in heating cabinet ............................................................... 81
210 9.11.3 Ball pressure test for insulating material necessary to retain in position
211 current-carrying parts .................................................................................... 81212 9.11.4 Ball pressure test for insulating material not necessary to retain in
213 position current-carrying parts ....................................................................... 82
214 9.12 Resistance of insulating material to abnormal heat and to fire ............................... 82
215 9.13 Verification of the self-test .................................................................................... 83
216 9.13.1 Test conditions .............................................................................................. 83
217 9.13.2 Verification of the self-test with IC-CPD in normal operation .......................... 83
218 9.13.3 Verification of the self-test with simulated welded contacts of IC-CPD ........... 84
219 9.14 Verification of the behaviour of IC-CPDs in case of loss of the supply voltage ....... 84
220 9.14.1 Verification of correct operation at the minimum operating voltage (U ) ......... 84221 9.14.2 Verification of the automatic opening in case of loss of the supply
222 voltage .......................................................................................................... 85
223 9.14.3 Verification of the reclosing function .............................................................. 85224 9.15 Verification of the limiting values of the non-operating current under
225 overcurrent conditions ........................................................................................... 85
226 9.16 Verification of resistance against unwanted tripping due to surge currents to
227 earth resulting from impulse voltages .................................................................... 85
228 9.17 Verification of reliability ......................................................................................... 86
229 9.17.1 Climatic test................................................................................................... 86
230 9.17.2 Test at a temperature of 45 °C ....................................................................... 87
231 9.18 Resistance to ageing ............................................................................................ 88
232 9.19 Resistance to tracking ........................................................................................... 89
233 9.20 Test on pins provided with insulating sleeves ........................................................ 89
234 9.21 Verification of the effects of strain on the conductors ............................................ 89
235 9.22 Checking of the torque exerted by IC-CPDs on fixed socket-outlets ...................... 89
236 9.23 Tests of the cord anchorage.................................................................................. 90
237 9.24 Flexing test of non-rewirable IC-CPDs .................................................................. 90
238 9.25 Verification of the electromagnetic compatibility (EMC) ......................................... 92
239 9.25.1 Emission ...............................................................................................
Questions, Comments and Discussion
Ask us and Technical Secretary will try to provide an answer. You can facilitate discussion about the standard in here.
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Debra Creevy and others - Australian Press Council
Debra Creevy and others / Herald Sun
The Australian Press Council has considered complaints by a number of people about the coverage in the Herald Sun on 22 May 2012 of the speech by Craig Thomson MP to Federal Parliament on the previous day. The coverage featured a very large photograph of Mr Thomson, digitally altered to have a Pinocchio-like nose, over which was a headline reading "Teary Thomson claims he's a victim of bizarre conspiracy”. A headline lower on the page read “But reader's jury says his story is full of holes:” under which was a further headline reading “We don't believe you".Pages 4 to 7 of the newspaper comprised a series of reports and comments about the speech (each of which had a banner headline running across the top which read "We don't believe you"). Pages 4 and 5 were headed “Cops doubt Thomson phone clone claim” and quoted “law enforcement experts” to that effect. Page 5 consisted largely of a section headed “Reasons we know Craig is lying” which listed a number of his claims and reported evidence from court documents and the report of a Fair Work Australia investigator which appeared to conflict with those claims.Page 7 consisted mainly of a section with the principal heading “The Reader Verdict”, above which was a heading “We asked our own jury if they believed Craig Thomson’s claims”. The names and photographs of each of twelve people were shown, together in each case with the heading “Don’t believe” (or, in two cases, “Can’t decide”) and a few sentences were shown as quotes of their views. The page also reported, under a heading, “What you said”, that of the 12,082 readers who replied to a poll on the newspaper’s website asking “Do you believe Craig Thomson was set up and did nothing wrong?” some 89% had answered in the negative.Some complainants concentrated on the front page, but others were concerned about the overall coverage. The principal criticism was that the material unfairly pre-judged Mr Thomson and constituted “trial by media”. Some complainants thought the coverage did not provide adequate balance or was unreasonably offensive. It was also complained that the quoted comments accompanying some of the "verdicts" headed "Don’t believe" were not as unequivocal as that summary suggested.The newspaper responded that the trustworthiness of parliamentarians was of crucial importance in a democracy and therefore required very close scrutiny by the media, especially when there were such strong grounds for concern. It said the coverage should be assessed as an overall package and had been accurate, fair and balanced. It said that the coverage accurately represented its readers’ opinions, as shown by its jury and poll, as well as those of many parliamentarians and press gallery members.The newspaper said the coverage did not imply a jury verdict in a court of law, as the term jury was also used in many other, non-legal contexts. It said each juror had been shown the full speech by Mr Thomson and then chosen whether his or her views should be summarised as “Don’t believe” or “Can’t decide”. It also pointed out that the digital alteration of Mr Thomson’s photograph had been acknowledged on the front page.The Press Council considers that detailed and forthright description and analysis of the issues in this case was not only acceptable but a matter of considerable public importance. It was reasonable to include extensive reference to the views of the newspaper’s readership and other members of the public, as well as the kind of trenchant criticism of Mr Thomson’s claims which was provided in the articles on pages 4 and 5.The Council has concluded, however, that the overall impact of the front page and page 7 was highly unfair to Mr Thomson by seeking to convey too close an analogy with a courtroom conviction on criminal charges, especially at a time when the laying of such charges was being widely demanded and anticipated. Accordingly, the complaints against the newspaper’s coverage are upheld on that ground. Supplementary Note(not required for publication by the newspaper):Although many of the complaints focused especially on the altered image of Mr Thomson, the adjudication does not mean that the image in itself constituted a breach of the Council’s principles. It also does not imply any change in the Council’s principles relating to depictions of people in cartoons. Relevant Council Standard(not required for publication by the newspaper):This adjudication applies part of the Council’s General Principle 1: “Publications should take reasonable steps to ensure reports are accurate, fair and balanced.”
Latest Adjudications
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The Press Council considered a complaint about the publication of an article in the Northern District Times in print on 23 November 2016, headed “Building’s high energy surrounds are too good to ignore”, with a...
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| https://presscouncil.org.au/document/1556-debra-creevy-and-others/page/42 |
Journal of the Association of Physicians of India - JAPI
JAPI propose to publish original articles on medical and allied subjects of a good standard, and invite contributions from all over the country and from abroad.
Prevalence of Metabolic Syndrome and its Association with Coronary Artery Disease Among an Urban Elderly South Indian Population (CURES- 145)
Rajendra Pradeepa 1, Jayagopi Surendar 2, Karunakaran Indulekha 2, Sundarapandi Chella 3, Ranjit Mohan Anjana 4, Viswanathan Mohan 5
1Senior Scientist and Head, Dept. of Research Operations, 2Research Fellow, Dept of Epidemiology, 3Senior Research Officer, Dept. of Research Operations, 4Vice President, 5President and and Chief of Diabetes Research, Madras Diabetes Research Foundation, Chennai, Tamil NaduReceived: 13.05.2014; Revised: 16.10.2014; Accepted: 28.07.2015
Editorial Viewpoint
There is a rising incidence of metabolic syndrome (MS) among elderly, urban South Indian population.
MS predisposes to coronary artery disease irrespective of age, gender or family history of diabetes.
Impact of interventions like weight reduction and control of hypertension and diabetes on risk reduction needs to be studied further.
Abstract
Objective:The aim of this study was to assess the prevalence of metabolic syndrome (MS) and its association with coronary artery disease (CAD) among an elderly urban population in south India.
Results:MS was identified in 45.9% (n=102) by modified ATP-III, 37.4% (n=83) by IDF and 45.5% (n=101) by WHO criteria respectively. Only 61 subjects (27.5%) were identified by all the three criteria. Female subjects had a significantly higher prevalence of MS compared to their male counterparts (45.8 vs, 31.0%, p=0.023 respectively) according to IDF criteria. It was observed that 59.8%, 53% and 45.6% of the subjects had all five abnormalities according to modified ATP-III, IDF and WHO, respectively. Subjects with MS had significantly higher prevalence of CAD compared to those without MS using all the 3 criteria (modified ATP-III -20.6 vs.8.5%; IDF-20.5 vs.10.1%; WHO-19.8 vs.9.1% respectively). The odds ratio of developing CAD among MS subjects was 2.93, 2.39 and 2.48 compared to those without MS after adjusting for age, gender and family history of diabetes according to modified ATP-III, IDF and WHO, respectively.
Conclusion:Nearly 40% of the elderly urban south Indians have MS and it is strongly associated with CAD.
Introduction
The clustering of metabolic risk factors like central
obesity, glucose intolerance, dyslipidemia, hypertension,
hyperinsulinemia collectively defined as metabolic syndrome (MS)1 is
observed in about one-third of urban South Asians.2 The prevalence of MS
among urban Indians ranges between 25-45%.3-4 Globally, among the
elderly population, MS prevalence is high and ranges from 45-65%5,6
depending on the population studied and criteria used to define MS.
MS is considered as one of the major public health problems
and is found to have high risk for CAD.7 Among men 45 years and older
and women 55 years and older, MS confers a moderately high risk of CAD
(10-year risk of 10% 20%).8 Combined with the metabolic derangements of
MS, insulin resistance (IR) is an important factor that may potentate
the risk of premature CAD and type 2 diabetes.9 Several studies have
published information on the prevalence of MS in the general population,
However, only a few studies have reported MS and its association with
CAD among the elderly, and none to our knowledge from India. Hence the
present study was taken up to assess the prevalence of MS using three
criteria (WHO, modified ATP-III and IDF) and evaluate its association
with CAD among a representative elderly urban population in southern
India.
Methods
The Chennai Urban Rural Epidemiology Study (CURES) is a large
cross-sectional study done on a representative population of Chennai
(formerly Madras) city in southern India with a population of about 5
million people. The detailed study design of CURES is described
elsewhere10 and the sampling frame is shown on the web site
(http://www.drmohansdiabetes .com/ mdrf /CURES.pdf). Briefly, of the 155
Corporation wards in Chennai, 46 wards were randomly selected to provide
a total sample size of 26001 individuals ≥20 years of age. Phase 1 of
CURES was conducted in the ï¬eld and involved a door-to-door survey of
26001 individuals. A detailed questionnaire was administered to all
study subjects to collect information regarding demographic,
socio-economic, behavioural and health status. A fasting capillary blood
sugar, blood pressure and basic anthropometric measures were done in
all eligible individuals. Phase 2 of CURES deals with studies on the
prevalence of microvascular and macrovascular complications of diabetes
among those identified with diabetes in Phase 1. Phases 1 and 2 are not
discussed further in this article.
In Phase 3 of CURES, every tenth subject recruited in Phase 1
of CURES (n=2600) were invited to our centre for detailed
anthropometric measurements and biochemical tests [response rate was
90.4% (n=2350)]. Out of these 2350 subjects, individuals aged ≥60 years
(n=222) were included for the present study. The institutional ethical
committee approval was obtained and written informed consent was
obtained from all study subjects.
Clinical and Biochemical Studies
Anthropometric measurements including weight, height, hip and
waist measurements were obtained using standardized techniques. The
body mass index (BMI) was calculated using the following formula: weight
(kg)/height (m)2 and waist hip ratio (WHR) was calculated by dividing
waist circumference (cms) by hip circumference (cms). Blood pressure was
recorded in the sitting position in the right arm with a mercury
sphygmomanometer (Diamond Deluxe Industrial Electronics and Products,
Pune, India) and rounded off to the nearest 2 mmHg. Two readings were
taken 5 minutes apart, and the mean of the two was taken as the blood
pressure reading.
A fasting blood sample was taken for estimation of plasma
glucose and serum lipids after an overnight fast of 8 hours. All study
subjects underwent an oral glucose tolerance test (OGTT) using 75 gm
glucose load, except self-reported diabetic subjects, for whom only
fasting venous plasma glucose was measured. Fasting plasma glucose
(glucose oxidase-peroxidase method), serum cholesterol (cholesterol
oxidase peroxidase-amidopyrine method), serum triglycerides (glycerol
phosphate oxidase peroxidase amidopyrine method) and high-density
lipoprotein (HDL) cholesterol (direct method polyethylene
glycol-pretreated enzymes) were measured using the Hitachi-912
Autoanalyzer (Roche Diagnostics/Hitachi, Mannheim, Germany). Urine
samples were collected after an overnight fast. Microalbumin
concentration was measured using an immunoturbidometric assay (Hitachi
902 autoanalyser, Roche Diagnostics, Mannheim, Germany). Serum insulin
concentration was estimated using Dako kits (Dako, Glostrup, Denmark).
Definitions
Diabetes: Individuals diagnosed by a physician and on
antidiabetic medications (self-reported) and/or those who had fasting
plasma glucose (FPG) ≥ 126 mg/dl (³7 mmol/L) and/or 2 hour post load
plasma glucose (2 h PG) ≥11.1 mmol/L (≥200 mg/dl).11
Impaired Glucose Tolerance (IGT): Diagnosed if the 2 h PG was
≥7.8 mmol/L and <11.1 mmol/L (≥ 140 mg/dl and <200 mg/dl).11
Normal Glucose Tolerance (NGT): If 2hPG was <7.8 mmol/L (<140 mg/dl).11
Coronary Artery Disease (CAD): CAD was diagnosed based on a
past history of documented myocardial infarction and/or
electrocardiographic evidence of Q wave and/or ST segment changes.12
Insulin Resistance (IR): Calculated using the homeostasis
assessment (HOMA) model using the following formula: fasting insulin
(μLU/mL) x fasting glucose (mmol/L)/22.5. Subjects whose HOMA insulin
resistance values were above the 4th quartile for the non-diabetic
population (i.e.>2.58) were considered to have insulin resistance
(homeostasis assessment insulin resistance (HOMA-IR).3
Metabolic Syndrome Definitions
WHO Criteria: MS was deï¬ned as the presence of diabetes,
impaired glucose tolerance or insulin resistance plus any two or more of
the following: body mass index ≥30 kg/m2 and/or waist-to-hip ratio
>0.90 for men and >0.85 for women; high blood pressure ≥140/90 mm
Hg or antihypertensive medication; triglycerides ≥150 mg/dL; reduced HDL
cholesterol <35 mg/dL for men or <39 mg/dL for women; and Urinary
albumin excretion rate ≥20 μg/min.11
IDF Criteria: MS was deï¬ned as the presence of central
obesity deï¬ned using South Asian cut points for waist circumference (≥90
cm for men and ≥80 cm for women) plus any two of the following factors:
high blood pressure ≥130/85 mm Hg or treatment of previously diagnosed
hypertension; elevated fasting glucose ≥100 mg/dL or previously
diagnosed type 2 diabetes; triglycerides ≥150 mg/ dL or speciï¬c
treatment for this lipid abnormality; reduced HDL cholesterol <40
mg/dL for men or <50 mg/dL for women or speciï¬c treatment for this
lipid abnormality.13
Modified ATP-III Criteria : MS was deï¬ned according to the
National Cholesterol Education Program ATP III criteria for adults.14 MS
was deï¬ned as the presence of any three of the following abnormalities:
central obesity deï¬ned using South Asian cut points for waist
circumference (≥90 cm for men and ≥80 cm for women); high blood pressure
≥130/85 mm Hg, elevated fasting glucose ≥100 mg/dL, triglycerides ≥150
mg/dL, reduced HDL cholesterol <40 mg/dL for men or <50 mg/dL for
women.
Statistical analysis was done using SPSS version 20.0 (SPSS,
Inc., Chicago, IL) for Windows. Data are expressed as mean ± SD. Chi
square test for trend was used to compare proportions among groups.
Logistic regression analysis was performed to assess the association of
MS with CAD, adjusted for multiple key variables. Kappa (κ) statistics
was used for finding the agreement between the three definitions. p
values <0.05 were considered significant.
Results
The mean age of the study population (n = 222) was 66 ± 6
years and 56.8% (n = 126) of the subjects were males. Figure 1 presents
the prevalence of MS among the elderly subjects using the three
criteria. Overall, MS was identified in 102 subjects (45.9%) by modified
ATP-III criteria, in 83 subjects (37.4%) by IDF criteria and in 101
subjects (45.5%) by WHO criteria. The Venn diagram shows the overlap of
subjects with MS based on the three deï¬nitions (Figure 2). Only 61
subjects (27.5%) were identified by all the three criteria. The κ
statistics for agreement between IDF and modified ATP-III criteria was
0.77 (p <0.001), for IDF and WHO criteria it was 0.45 (p <0.001)
and between the modified ATP-III and WHO criteria it was 0.56 (p
<0.001).
Table 1 presents the clinical and biochemical characteristics
of the elderly with MS using the three criteria. Subjects having MS
according to WHO criteria were older (65.6 ± 6.0 years; p<0.05)
compared to those with MS based on IDF criteria. For every 10 year
increment in age, there was a decreasing trend in MS in the elderly
population in both modified ATP-III (p<0.001) and IDF criteria
(p<0.001) group. The prevalence of insulin resistance in the MS
subjects was 43.1%, 45.8% and 54.5% using revised ATPIII, IDF and WHO
criteria respectively.
The prevalence of metabolic risk factors as classified using
the three different criteria in the elderly population was as follows;
impaired fasting glucose (including self-reported diabetes) was observed
in 42.8% and 39.6% of individuals on the basis of IDF and modified ATP-
III criteria respectively. Abdominal obesity was present in 48.2%,
raised blood pressure was seen in 63.1%, increased triglycerides in
29.3% and decreased HDL cholesterol levels in 54.1% of the elderly
subjects, which is similar using both modified ATP-III and IDF criteria.
According to the WHO criteria, abdominal obesity was present in 70.3%,
increased triglycerides in 29.3% and decreased HDL cholesterol levels in
20.7%, raised blood pressure in 52.7% and microalbuminuria in 21.2% of
the elderly population.
Figure 3 shows the prevalence of CAD in elderly subjects with
and without MS according to different criteria. The overall prevalence
of CAD in the study subjects was 14% (n=31). Subjects with MS had
significantly higher prevalence of CAD compared to those without MS
irrespective of the criteria used for defining MS (modified ATP-III
-20.6 vs. 8.5%, p= 0.009; IDF-20.5 vs. 10.1%, p=0.030; WHO-19.8 vs.
9.1%, p=0.022 respectively).
To assess the association of CAD with MS, multiple logistic
regression analysis was done using CAD as the dependent variable (Table
2). The risk for developing CAD in subjects with MS was 2.9 times higher
(p=0.012) than those without MS based on modified ATP-III criteria, 2.4
times higher (p=0.037) than those without MS based on IDF criteria and
2.5 times higher (p=0.028) than those without MS based on WHO criteria
after adjusting for age, gender and family history of diabetes.
Discussion
The study highlights the following findings 1) A high
prevalence of MS was observed in this elderly South Indian urban
population based on the modified ATP-III, IDF and WHO criteria for MS.
2) Subjects with MS by all the three criteria were significantly
associated with CAD after adjusting for potential confounders like age,
gender and family history of diabetes.
In the past few decades, increased attention given to MS has
led to several attempts to develop a definition that is accepted
worldwide. However, there is as yet no internationally agreed deï¬nition
for MS and, hence, prevalence of MS varies substantially depending on
the criteria used. The World Health Organization (WHO) proposed a set of
diagnostic criteria,11 in 1998 followed by definitions from the
National Cholesterol Education Program's Adult Treatment Panel III
(ATP-III)17 and the International Diabetes Federation (IDF).13 These
definitions agreed that hyperglycemia, obesity, dyslipidaemia, and
hypertension are core components of MS, but they differed in the details
and criteria. In 2005, a modification (ATP-III) by the American Heart
Association and National Heart, Lung, and Blood Institute (AHA/NHLBI)
was proposed with a reduced threshold for hyperglycemia and some minor
modifications.14
A wide variation is demonstrated in the MS prevalence among
the elderly with a study from France showing 11.3 % and 12.5 % in women
and men respectively as having MS according to modified ATP-III
criteria,16 Use of the IDF criteria in a Greek population resulted in
69% of the elderly subjects having MS. Our study showed 45.9% and 37.4%
of the elderly subjects, as having MS according to the modified ATP-III
and IDF criteria respectively.17 These differences could be attributed
to population specific factors and different diagnostic criteria
applied. Moreover, our study showed an increased prevalence according to
the modified- ATP-III criteria, whereas in other populations, a higher
number of MS individuals was captured by the IDF criteria.6 Since the
ATP-III criteria adopt ethnicity specific cut points, the prevalence
rates might have been higher. Due to the variations in the prevalence of
MS and the differential diagnostic ability of the criteria observed
amongst different populations, it is necessary to obtain data for each
country.
MS has been established as a strong predictor of
cardiovascular disease and mortality in the general population and these
findings have been extended to the elderly population as well in recent
reports.18 In our study participants, the prevalence of CAD was nearly
20% in MS subjects categorized by ATP-III, IDF and WHO criteria showing a
high degree of concordance between the three criteria. This agreement
between ATP-III and IDF criteria has been recorded in other reports as
well.19 The higher rates of insulin resistance observed in our elderly
subjects (>40%) might be because of the tendency of Asian Indians
towards higher visceral (abdominal) fat deposition and the direct causal
link between abdominal fat and insulin resistance, might augment the
prevalence of insulin resistance in our subjects.20
In subjects with MS, intervention strategies for the control
of hypertension, hyperglycemia and dyslipidemia would lead to reductions
in the subsequent cardiovascular mortality.21 Moreover, approaches like
weight reduction in the elderly might increase their insulin
sensitivity. Implementation of these strategies is important in the
elderly population as they are at increased MS risk due to age
associated physiology.22
There are some limitations for our study. Due to the
cross-sectional design of the study, no cause/effect relationships can
be made. Lifestyle factors like physical inactivity and their effect on
occurrence of MS in the elderly were not assessed. However, ours is the
first estimate of the burden of the metabolic syndrome in elderly
subjects in India to report on population based study and hence the
findings are of significance.
In conclusion, we report that nearly 40% of the elderly urban
south Indians have MS using all three criteria, although they seem to
identify different individuals. In addition, MS is strongly associated
with CAD in the elderly subjects.
Competing Interests
None to declare.
Acknowledgements
VM conceived and designed the study. RP, JS, KI and SC
analysed the data and wrote the manuscript. RMA and VM helped revising
the manuscript critically for important intellectual content, read and
approved the final manuscript.
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Athyros VG, Ganotakis ES, Elisaf M, Mikhailidis DP. The
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DE, et al. Metabolic syndrome and the risk of cardiovascular disease in
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He Y, Jiang B, Wang J, Feng K, Chang Q, Fan L, et al.
Prevalence of the metabolic syndrome and its relation to cardiovascular
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Sharp PS, Mohan V, Levy JC, Mather HM, Kohner EM. Insulin
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UA563 Flight Tracker-Raleigh-durham to Houston (United Airlines Cargo UA 563)-PlaneMapper
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JFMK | Free Full-Text | FGFs Treatment on Amputated Lizard Limbs Stimulate the Regeneration of Long Bones, Opening New Avenues for Limb Regeneration in Amniotes: A Morphological Study
Previous studies indicated that Fibroblast Growth Factors (FGFs) are present during tail and early limb regeneration in lizards, but FGFs disappear in the limb that turns into a scar and does not regenerate at 25–40 days post-amputation. Based on these indications, the aim of the present study was to evaluate the influence of administered FGFs on limb regeneration in lizards by injections of FGF1–2 into amputated hind-limbs that were studied between 40 and 70 days post-amputation. Outgrowths of 2.0 to 3.5 mm were produced but they did not develop an autopodium during this period. The skin remained most un-scaled, resembling that of a tail blastema. Four hours before sacrifice, the animals were injected with 5BrdU to study cell proliferation using microscopic and immunofluorescent methods. Histological examination of the outgrowths at 40–70 days of regeneration showed the presence a rod of cartilage (femur), or partially or completely sub-divided into two parts likely corresponding to a tibia and fibula. The regenerated cartilage was in continuity with the transected long bones and was surrounded by a perichondrium and a dense connective tissue, sparse nerves while muscles were reduced or absent. Qualitative observations on 5BrdU-immunolabeling indicated that most proliferating cells were present in the apical wound epidermis, the apical-most perichondrium and in the regenerating scales at 40–60 days post-amputation, but decreased at 70 days. Few 5BrdU-labeled cells were seen in other tissues, including in the regenerated cartilages. The present study indicates that FGF1-2 treatment in lizards mainly stimulate cartilage regeneration and the formation of a thick epidermis with an Apical Epidermal Peg, the epidermal micro-region that favors regeneration. In summary, these results suggest that FGFs treatments on amputated limbs could also be attempted in others amniotes, including mammals. However FGFs are not capable to induce an autopodium, which requires further signaling factors for its formation.
FGFs Treatment on Amputated Lizard Limbs Stimulate the Regeneration of Long Bones, Opening New Avenues for Limb Regeneration in Amniotes: A Morphological Study
by Lorenzo Alibardi
Comparative Histolab and Department of Biology, University of Bologna, via Selmi 3, 40126 Bologna, Italy
J. Funct. Morphol. Kinesiol. 2017 , 2 (3), 25; https://doi.org/10.3390/jfmk2030025
Received: 29 April 2017 / Revised: 6 July 2017 / Accepted: 14 July 2017 / Published: 21 July 2017
Abstract
:
Previous studies indicated that Fibroblast Growth Factors (FGFs) are present during tail and early limb regeneration in lizards, but FGFs disappear in the limb that turns into a scar and does not regenerate at 25–40 days post-amputation. Based on these indications, the aim of the present study was to evaluate the influence of administered FGFs on limb regeneration in lizards by injections of FGF1–2 into amputated hind-limbs that were studied between 40 and 70 days post-amputation. Outgrowths of 2.0 to 3.5 mm were produced but they did not develop an autopodium during this period. The skin remained most un-scaled, resembling that of a tail blastema. Four hours before sacrifice, the animals were injected with 5BrdU to study cell proliferation using microscopic and immunofluorescent methods. Histological examination of the outgrowths at 40–70 days of regeneration showed the presence a rod of cartilage (femur), or partially or completely sub-divided into two parts likely corresponding to a tibia and fibula. The regenerated cartilage was in continuity with the transected long bones and was surrounded by a perichondrium and a dense connective tissue, sparse nerves while muscles were reduced or absent. Qualitative observations on 5BrdU-immunolabeling indicated that most proliferating cells were present in the apical wound epidermis, the apical-most perichondrium and in the regenerating scales at 40–60 days post-amputation, but decreased at 70 days. Few 5BrdU-labeled cells were seen in other tissues, including in the regenerated cartilages. The present study indicates that FGF1-2 treatment in lizards mainly stimulate cartilage regeneration and the formation of a thick epidermis with an Apical Epidermal Peg, the epidermal micro-region that favors regeneration. In summary, these results suggest that FGFs treatments on amputated limbs could also be attempted in others amniotes, including mammals. However FGFs are not capable to induce an autopodium, which requires further signaling factors for its formation.
Keywords:
lizards
;
limb regeneration
;
FGF administration
;
histology
;
Graphical Abstract
1. Introduction
The loss of limbs in amniotes, if not immediately fatal due to extensive bleeding, results in a permanent deficit since the limb cannot regenerate, a condition that in nature leads more or less rapidly to death. The only amniotes occasionally capable to regenerate a short and heterotypic appendage replacing the lost limb are lizards, making these reptiles an important research model [ 1 , 2 , 3 , 4 , 5 ]. The recovery from limb loss in lizards, however, generally results in the formation of a flat scar of 0.5–1.0 mm that rapidly becomes scaled. Rare records of tail-like limbs found in individuals collected in the wild with a length of 10–25 mm have been described in different species and lizard families [ 1 , 2 , 3 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. The time elapsed for the formation of these rare long tail-like outgrowths is generally unknown, aside for the wall lizard Podarcis muralis where 3–12 months were recoded [ 3 , 6 ]. Other experiments with Podarcis. sicula and P. muralis [ 4 ] showed a rapid, but limited growth, of 2–3 mm in rare cases within 2 months post-amputation. In the snake-eyed skink, indicatively 2–4 mm of limb outgrowths were formed at 106 and 203 days post-amputation [ 9 ].
Also, in these exceptional cases the internal anatomy of the regenerated limb outgrowth is simplified in comparison to the original limb, often lacking skeletal elements and joints (knee or elbow) or, in the best cases, containing few ossified axial elements generally organized in a single sequence, likely representing irregular zygopodial and stylopodial elements [ 1 , 2 , 3 ]. The latter studies showed in rare cases, small distal-most bones, perhaps corresponding to an autopodium with carpals or tarsals, and in one exceptional case a single row of metatarsals and small phalanges was also described. However, a regenerated joint (knee or elbow) or the autopodium with two or more digit elements in lizards has never been reported, indicating a lack of joint and finger determination signaling during lizard regeneration [ 13 , 14 ]. Around the axial skeletal bones within these limb outgrowths, few muscle and nerve fascicles variably developed were described, but often a dense connective and tendon-like fibers were prevalent [ 1 , 2 , 3 , 6 ]. These 5–25 mm long tail-like appendages represent rudimentary regenerated limbs, but even the lack of an autopodium can help these lizards to efficiently survive in the wild [ 12 ].
Microscopic studies on the process of healing and regeneration of the limb have indicated an initial regenerative phase, whereas the wound epidermis seals the limb stump within 15–25 days post-amputation, the period depending from the permanence of the exposed bones (femur or humerus) on the stump surface [ 4 , 5 , 7 , 15 ]. The detachment of the injured long bones occurs through the action of osteoclasts, and this slow process appears to retard the re-epithelialization of the stump and stimulates the formation of a dense, scarring connective tissue. Microscopic studies have indicated that the limb, differently from the amputated tail, undergoes a massive and lasting inflammation that determines the destruction of injured tissues with the infiltration of numerous granulocytes, macrophages and lymphocytes. These immune cells remain for 20–25 days and their number is reduced when fibroblasts have deposited dense masses of extracellular matrix [ 4 , 5 , 15 , 16 , 17 ]. Some nerve bundles, in correspondence of their main transected diameter, penetrate the regenerative limb outgrowth [ 6 , 9 , 18 ]. This observation suggests that a neurotrophic stimulation of the nerve was delivered during limb regeneration, and this was also suggested by experiments on nerves deviation [ 19 ], or implants of normal or regenerating spinal cord [ 20 , 21 ].
Since previous studies on the regenerating tail have indicated the presence of FGF1 and FGF2 in the regenerating nerves and spinal cord growing into the new tail, a growth factor retained among the main candidates representing the neurotrophic factor [ 22 ] in amphibians, it is possible that Fibroblast Growth Factors (FGFs) may represent a growth stimulator also in lizards. This has also been indicated by the effect of inhibitors of FGF and/or their receptors that show a delay or block the process [ 23 , 24 , 25 ]. Previous studies have also indicated that FGFs are present in the initial stages after limb amputation in lizards but later disappear as the limb turns into a scar and does not regenerate [ 26 ]. Based on the above considerations, it was decided to evaluate the influence of infused FGF solutions into amputated limbs and study their macro- and micro-scopic effect on the healing process. Therefore we have studied the macroscopic and microscopic effects of FGF1 and FGF2 delivered into regenerating limbs of lizards within 40–70 days from the beginning of regeneration, a period known to represent a temporal frame in which the untreated limb usually forms scars [ 5 , 15 , 26 ]. The experiments have indeed shown the important role of FGFs to constantly induce limb and skeletal regeneration in lizards. Due to the difficulty of the study, this is qualitative and aims to describe the possible induction of new skeletal elements in the regenerating limbs of lizards.
2. Materials and Methods
2.1. Experimental Procedures
The present study was conducted on 15 adult individuals of the wall lizard
Podarcis muralis
, maintained at variable summer temperatures, 26–33 °C during daytime. The experiments were conducted following the general Italian regulations for animal care and handling (art. 5, DL 116/92). The animals were left at 4 °C for about 20 min to induce numbness, and they were successively anesthetized with ethylic ether before the hind-limb was truncated with a sharp scalpel. All the animals showed little bleeding, and they recovered well the amputation, and were fed with insects. Two days after the operation, the stump surface was checked under the stereomicroscope, and the protruding bones were further trimmed to make and even stump surface that favors re-epithelialization. Two lizards, apparently debilitated after the capture, died after 1 week post-amputation, while the remaining 13 survived well, and were active, feeding regularly during the entire period of the study, from 40 to 70 days post-amputation.
The FGF1 (F-5267, Sigma, Saint Louis, MI, USA) were initially diluted in Ringer solution at a concentration of 0.04 μg/μL, which was taken to 0.02 μg/μL after a further dilution 1:1
v
/
v
with a Polybed-Polystyrene suspension containing 45 μm diameter microspheres (Polyscience, Niles, IL, USA, cat. 07314). The FGF2 (SRP4038, Sigma-Aldrich, Saint Louis, MO, USA) was initially diluted in Ringer at 0.04 μg/μL, and was further diluted 1:1
v/v
with the polybed-polystyrene suspension at 1:1 volume, therefore with a final concentration of 0.02 μg/μL (20 μg/mL). The mixed solution and suspension were left at least 1 h before injection, in order to have the FGF adsorbed into the microspheres in the attempt to produce a lasting FGF delivery into the tissue after the injection. Before use, the mix was gently shaken to obtain a homogenous mixture, and the injection delivered 4–5 μL of this suspension containing FGFs-adsorbed beads (indicatively 0.08–0.10 μg FGF1 or FGF2 in each injection), and was performed with the thin needle of a Hamilton syringe penetrating the stump or the blastema. In total 4 injections were done in each animal, the first at 1 week after amputation underneath the scab to ensure the delivery of the suspension, and the following injections in the softer blastema or healing wound 5 days after the first injection (12 days post-amputation), a week later the third injection (19 days post-amputation), and after a further week the 4th and last injection (26 days post-amputation). Therefore, about 0.3–0.4 μg total FGF1 or FGF2 were delivered per animal at the end of the experiment, part absorbed in the beads for a presumably slow release into the tissues and part in the surrounding Ringer solution.
Four lizards amputated at mid tibia-fibula level received FGF1 injections, while other 4 lizards with truncated limbs at the mid tibia-fibula level received FGF2 injections. Another group of 3 lizards, amputated at mid femur level, received FGF2 injections. Two lizards amputated at mid tibia-fibula level only received the vehicle (Ringer) solution, and served as controls. The animals were left to regenerate for 10–40 more days before their limbs were utilized for the histological analysis. At different and progressive intervals (4–7 days), their macroscopic recovery was documented through photography under a stereomicroscope (
Figure 1
).
2.2. Tissue Preparation and Microscopic Methods
The entire regenerating limbs with about 2 mm of the limb stump were collected and immediately fixed in 5% formaldehyde in 0.1 M Phosphate buffer for 12 h, dehydrated in ethanol, clarified in xylene, and embedded in paraffin. The embedded tissues were sectioned in the longitudinal plane with a rotatory microtome (Reichert, Munich, Germany) at 6–8 μm, collected on gelatin-coated glass slides, and dried in a hot plate. Representative sections were stained with 1% Methylene Blue and 1% Eosin, while other parallel sections were immuno-reacted for the detection of 5BrdU (cell proliferation) using the G3G4 mouse monoclonal antibody. This antibody was purchased from the University of Iowa, Developmental Studies Hybridoma Bank, Iowa City, USA.
The sections were de-paraffinized, hydrated and treated with 0.01 M citrate buffer at pH 6.5 for 5 min in microwave oven, rinsed in distilled water, than in the incubation buffer for 2 min (1% Bovine Serum Albumin, BSA Sigma, in 0.05 M Tris/HCl buffer at pH 7.6). The sections were incubated for 30 min at room temperature with Tris buffer solution containing 2.0% normal goat serum, and for 4 h at room temperature in the primary anti-serum diluted in the Tris buffer (1:70). In control sections, the primary antibody was omitted from the incubating solution. Most sections were later rinsed in the Tris buffer and incubated for 1 h at room temperature with a secondary Tetramethyl Rhodamine Isothiocyanate conjugated antibody (TRITC, red fluorescence, from Sigma, dilution 1:150). The sections were later rinsed in the Tris buffer and mounted in Fluoroshield anti-fading medium (Sigma, Saint Louis, MO, USA), and were studied under an optical microscope in bright field (for general histology), and using a fluorescent microscope (Euromex, Arnhem, The Netherlands) equipped with TRITC selective filters, in order to detect 5BrdU-labeled cells. Photographs were collected using a digital camera, and the plates of microscopic images were composed into figures using Adobe Photoshop 8.0 (San José, CA, USA).
3. Results
3.1. Macroscopic Observations
The amputated limbs completely re-epithelialized the stump in both treated ( Figure 1 A–C) and control limbs within 14–18 days post-amputation, and FGF 1 and FGF2 showed similar effect of the speed of regeneration. Regenerating limbs from the tibia-fibula amputation or from the femur amputation grew in the following days forming outgrowths ranging from 2.0 to 3.5 mm in length ( Figure 1 B–I). The outgrowths were collected at 40, 50, 60 and 70 days post-amputation in order to study their histology and the main sites of cell proliferation (qualitative observations). The outgrowths were covered with a shiny and soft epidermis, and very little scaling was seen at 40–50 days post-amputation while few but still immature scales were present at 60–70 days. However, also at 60 and 70 days post-amputation, the tips of all the outgrowths appeared smooth and shiny, often pigmented, resembling the regenerating blastema of a tail ( Figure 1 H). Initially the outgrowths were conical in shape ( Figure 1 D,E,G), but at 60–70 days they tended to flatten ( Figure 1 H).
Four cases treated with FGF2 (3 after mid tibia-fibula-amputation and 1 after mid-femur-amputation), generated 2.0 mm outgrowths that were analyzed histologically at 40 days post-amputation. One case treated with FGF1 after mid tibia-fibula amputation, formed a 2 mm long outgrowth that was studied histologically at 40 days post-amputation. From other 4 cases treated with FGF2, 3 cases after mid tibia-fibula amputation and 1 case after mid-femur amputation, 2.5 mm long outgrowths were collected at 50 days post-amputation and analyzed histologically. Another case treated with FGF2 after mid femur amputation, produced an outgrowth of 3.0 mm in length after 50 days post-amputation, that was collected and studied histologically. Another case with a regenerated outgrowth of 3 mm in length, treated with FGF1 after mid tibia-fibula amputation, was collected at 60 days post-amputation, and studied histologically. Finally, the last case, treated with FGF1 after mid tibia-fibula amputation, reached 3.5 mm at 70 days post-amputation, and was collected, fixed and studied histologically. The two control lizards at 20 and 30 days post-amputation showed scarring outgrowths (pale and scaling) of about 0.5 mm (
Figure 1
J), that formed scales at 40 days post-amputation.
3.2. Histology of Outgrowths
The histological study on the two scarring controls analyzed at 40 days post-amputation showed the presence of a dense irregular connective tissue made of elongated fibrocytes, differentiated underneath a thick wound epidermis (
Figure 2
A,B). The latter showed an external and pale region, poorly stained or unstained, possibly containing a hard type of corneous material. Within the prevalent dense fibroblasts and fibers, some nodules of cartilaginous tissue were also present, in continuity with the transected femur. The immunolabeling for 5BrdU showed few labeled cells in both the wound epidermis and the underlying connective tissue (
Figure 2
C) while no labeling was present in control sections, aside from a non-specific fluorescence of blood vessels and the external corneous layer (
Figure 2
D).
The examination of sections of regenerated limbs at 40 days of regeneration showed the formation of a cartilaginous rod at the center of the outgrowth, made of immature and small chondrocytes (
Figure 3
A,B). The cartilaginous matrix was low stained or unstained using methylene-blue, and only the larger chondrocytes present in the center of the rod and contacting the bone tissues of the tibia and fibula showed a metachromatic staining (
Figure 3
A). Most of the small and fusiform chondrocytes therefore represented immature cartilaginous cells, still devoid of metachromatic (sulfated) glycosaminoglycans. In the apical part of the cartilaginous rod a thick perichondrium containing flat chondroblasts was seen toward the apical blastema that was made of a dense connective tissue and sparse chromatophores. The wound epidermis was 6–8 cells thick and a thin corneous layer was present externally (
Figure 3
B and inset). The remaining tissues appeared as dense connective tissues in the dermis (
Figure 3
A), and in form of long fibrous, tendon-like belts surrounding the central cartilage. No muscles were seen inside these outgrowths.
At 50 days post-amputation at the mid tibia-fibula level, the analyzed outgrowths also showed a central axial cartilage in continuation with the damaged tibia and fibula, whereas only the more central and proximal chondrocytes appeared hypertrophic and metachromatic (
Figure 3
C). At the tip of the main cartilaginous rod, chondrocytes became thinner and unstained with methylene blue, indicating that they were still immature cells (
Figure 3
D). The distal tip of the cartilaginous rod was in contact with one or two cartilaginous nodules containing central metachromatic chondrocytes. The nodules were surrounded by a circular perichondrium, in continuity with that of the remaining cartilaginous rod (
Figure 3
D). A dense connective tissue surrounded the axial cartilaginous rod, delimited by a perichondrium connected to a tendon-like fibrous tissue (
Figure 3
C,D and inset). Few thin muscles were seen in contact with the original ones but the outgrowth appeared mostly devoid of muscle fibers.
At 60 days post-amputation, the cartilage appeared more mature and most of its chondrocytes were metachromatic, forming one rod with two separated distal parts (one case,
Figure 3
E,F) or two completely separated rods (another case,
Figure 4
A), indicating the separation between a cartilaginous tibia and fibula. This cartilage was in continuity with the fibula-tibia bones (
Figure 3
F). Most dense and fibrous connective tissues surrounded the axial cartilage, and at the tip of these outgrowths the wound (regenerated) epidermis was thinner than at 40–50 days, and no scale were still formed. One or two cartilaginous nodules were seen by the apex of the outgrowth, surrounded by an irregular dense connective tissues contacting the papillated apical wound epidermis (
Figure 4
A). No muscle bundles were seen in these old regenerating limbs, and sparse nerves were not clearly identified using the employed staining method.
In the longer specimen analyzed at 70 days after mid tibia-fibula amputation and treated with FGF1 (3.5 mm, see
Figure 1
H), a regenerated cartilaginous fibula and tibia were detected, and each element was surrounded by a thick perichondrium along the perimeter, in continuation with the bones of the original tibia and fibula (
Figure 4
B). Additionally, sparse regions of the cartilage and along the perichondrium of the proximal region of these cartilaginous elements appeared calcified (
Figure 4
C). The wound epidermis present at the tip of the outgrowth, in front of the two cartilaginous elements, was also papillated (
Figure 4
D). Most of the tissues located between the two cartilages and underneath the regenerated skin consisted in irregular fibrous connective tissues, among which few muscle cells were hardly detected.
In the limb outgrowth derived from mid femur amputation after 50 days, a long rod of mature and metachromatic cartilage in continuation with the femur was present, in contact with an apical, dense and irregular fibrous connective tissue (
Figure 5
A). At the tip of the outgrowth, the wound epidermis was still relatively stratified and showed epidermal papillae while a thin corneous layer was formed on the surface. One or two isolated cartilaginous nodules, possibly in continuity with the remaining cartilaginous rod, were formed near the apical region (
Figure 5
B). The proximal region and the regenerated cartilaginous femur (like those of the tibia-fibula elements), showed regions of calcification of the cartilage at 50 days (as well as at 60–70 days in the other samples), characterized by disappearing of the metachromasia, while the perichondrium was connected to tendon-like belts (
Figure 5
B). It appeared that in these regions the perichondrium became osteogenic, turning into a periosteum, but further study on this aspect is needed.
3.3. Proliferation Using 5BrdU Immunolabeling
In the mid-femur amputated limbs ( Figure 1 F,I, Figure 4 C–F and Figure 5 ) as well as in those amputated at mid tibia-fibula level ( Figure 1 A–E,G–H and Figure 6 , Figure 7 and Figure 8 ), the nuclear labeling using TRITC showed most 5BrdU-labeled cells localized in the apical front of all outgrows, while sparse labeled cells were present in more proximal and differentiated regions, close to the normal limb stump. Because of the heterogeneity of the different outgrowths, a quantification of the labeling distribution was considered not essential to be performed, and the following description only reports the qualitative description of the main distribution sites of labeled cells in different areas.
In the case of femur regeneration after FGF2 injection, sparse labeled cells were seen in the basal layer of the wound epidermis (but also labeled supra-basal cells were present), including the apical epidermal papilla located at the tip of the outgrowth at 50 days of regeneration ( Figure 5 C,D). Sparse labeled cells were also seen in the apical connective tissue located underneath the wound epidermis and close to the apical periosteum of the cartilaginous rod ( Figure 5 E). Numerous labeled and flat cells were also seen in the more distal perichondrium surrounding the cartilaginous femur, and some 5BrdU-labeled cells were also present in the perichondrium located around the apical cartilaginous nodules ( Figure 5 F). Sparse labeled chondrocytes were localized in the central and proximal regions of these cartilaginous elements at 50 days of regeneration while labeled cells were more numerous in the surrounding perichondrium ( Figure 6 A,B). A number of labeled cells were also present in the tendon-like belt close to the rod of cartilage ( Figure 3 A,C and Figure 6 B). Labeled cells were seen numerous especially in the epidermis of the regenerated scales ( Figure 6 C), and 5BrdU-labeled cells were also observed among the regenerating muscles of the proximal regions of the outgrowths, close to the older muscles of the limb stump ( Figure 3 C and Figure 6 D).
In the cases amputated at mid tibia-fibula after 40 days post-amputation following FGF1 injections, labeled cells were seen especially in the apical wound epidermis and perichondrium, formed in front of the apical part of the cartilaginous rod ( Figure 3 B and Figure 7 A,B). The apical connective tissue located underneath the wound epidermis and most of the non-apical cartilage rod forming large part of the regenerated cartilage, contained sparse 5BrdU-labeled chondrocytes ( Figure 7 C). An intense labeling in the regenerated limbs at 40 days post-amputation was also observed in the epidermis of the regenerating scales, in the dermis and among the regenerated proximal muscles ( Figure 7 C). Also the bone marrow of the tibia and fibula contained numerous labeled cells ( Figure 7 D).
A similar observation, indicating active cell proliferation, resulted from the microscopic examination of limb outgrowths at 50 days post-amputation of the tibia-fibula, and injected with FGF1 or FGF2. The observations on these cases evidenced the presence of numerous labeled cells in the apical (blastema) wound epidermis, in the underlying apical connective tissue of the outgrowth ( Figure 8 A,B), and in the regenerating scales of the outgrowths ( Figure 8 C,D). Sparse labeled cells were also seen in the connective tissues and cartilage of more proximal regions and in their perichondrium.
The case analyzed at 70 days post-amputation, the longest outgrowth produced in this series of experiments after injections of FGF1 in a limb amputated at mid tibia-fibula level ( Figure 1 H), showed a general reduction of labeled cells in all areas, and most of the proximal connective tissues, cartilage and skin contained only sparse labeled cells, indicating little cell proliferation. At the tip of the outgrowth some labeled cells were instead more frequently detected than in proximal regions, however, they appeared less numerous that at 40–60 days post-amputation, especially in the apical wound epidermis and in the apical connective tissue present underneath the wound epidermis ( Figure 9 A,B). Although a quantitative study was not done, only sparse labeled cells were present in the dermis, while they were more numerous in the epidermis of the forming scales ( Figure 9 C). Some labeled cells were sparsely distributed in the cartilaginous tissues, forming the regenerated single or double rods of tibia and fibula ( Figure 4 B and Figure 9 A,D), as well as in the dense connective tissues and in the tendon-like belts surrounding the cartilage and perichondrium of the cartilaginous elements ( Figure 4 B, and data not shown). Finally, numerous labeled cells were noted in the bone marrow of the transected tibia and femur present in the limb stump.
4. Discussion
4.1. FGFs Mainly Stimulates Limb and Bone Regeneration
It is known that the failure of regeneration in limbs of lizards determines the formation of flat scars or small outgrowths containing irregular fibrous connective tissue and sometimes even a callus of cartilaginous tissue in continuation with the transected bones that becomes calcified or possibly ossified in old regenerated outgrowths [ 1 , 2 , 4 , 5 , 6 , 7 , 9 , 15 ]. In comparison to the controls where no regeneration occurred at 40 days post-amputation, both FGF1 and FGF2 stimulated limb regeneration at the employed concentrations. It is however unknown whether a more effective (higher) concentration of FGFs could be utilized for improving or accelerate limb regeneration. Previous studies on the regeneration of amputated limb buds of chick embryos utilized a concentration of 25 μg/mL to soak gel beads [ 27 ], a higher concentration of the 20 μg/mL utilized in the present experiments. The histological and immunofluorescent study indicated the formation of an Apical Epidermal Peg (AEP) or a papillated wound epidermis in the apical front of the regenerating limbs ( Figure 3 and Figure 4 ). This result suggests that FGFs administration can stimulate the formation of epidermal areas similar to the AEP found at the tip of the regenerating tail, the epithelial micro-region essential for regeneration [ 16 , 17 ]. In those cases where limb outgrowths longer than 2.5 mm (6 cases out of 11) were originated within the 40–70 days post-amputation period, the induction of an AEP or of a papillated wound epidermis was observed. The adjacent mesenchymal blastema, located at the tip of the outgrowths, appeared in continuation with layers of perichondrial cells that surrounded one (femur-amputated or tibia-fibula-amputated) or two (fibula-tibia amputated), neo-generated cartilaginous bones.
The common observation made in the present experimentally produced outgrowths, like in those found in the wild, is the shortage or the almost complete lack of regenerated muscles [ 1 , 2 , 3 , 4 , 6 , 9 ]. FGFs have been immune-detected in the regenerating tail of lizards [ 17 , 28 , 29 ], and their inhibition depresses tail regeneration [ 23 , 24 , 25 ]. Besides, while FGF1 and FGF2 immunofluorescence remains in the wound epidermis of the tail, this immunofluorescence disappears in the limb after about 25 days of regeneration, during scarring. The frequency of spontaneous limb regeneration after amputation in the documented cases is only 20–30% in the best conditions in P. muralis and P. sicula [ 4 ] while, after injection of FGFs in the present study, all amputated limbs showed some degree of regeneration, and 6 out of 11 cases formed outgrowths longer than 2.5 mm up to 60–70 days. One of the main problems encountered in the amputated limbs of lizards is the tendency of the original skin to close down the stump, reducing the stump surface, and favoring scarring [ 5 , 6 , 7 ]. This process, also due to the shrinkage of the muscles and connective tissues after amputation, determines the flapping of the skin over the stump surface, and may be also be caused from the contraction of the dermis, a typical process occurring in wounds of amphibians [ 29 ] and mammals [ 30 ].
The constant formation of limb outgrowths after FGF treatment in our experiments suggests that these proteins, like in embryonic limb buds [ 26 , 31 ], are one of the signaling and growth molecules needed for limb (ant tail) regeneration in lizard, as this was long indicated for amphibians [ 32 ]. The present study has shown that both FGF1 and FGF2 stimulates the regeneration of the limb, in particular of the stilopodium (cartilaginous femur) and of the two zeugopodium elements, partially or completely subdivided in cartilaginous tibia and fibula. Whether more distal cartilaginous nodules may represent tarsal elements, such as the tibial and fibular, remains to be further studied, but an autopodium with two or more distal elements (metatarsal or phalangeal) was never formed using only FGFs. Also, in the longest cases found in nature, induced in 12 months or longer, and occasionally over 10 mm or one case over 20 mm, no autopodium was however regenerated [ 2 , 33 ]. The histological study of this exceptional case revealed the presence of a regenerated axial skeleton comprising the femur, one or two zeugopodial elements, and also a linear row of likely autopodial segments [ 1 , 2 , 6 ]. These skeletal elements probably calcified and ossified in the following periods as indicated from the bone elements of the regenerated limbs found in the wild [ 2 ]. These bone elements likely elongated to such length with the growth of the lizard so that it is hard to separate true regeneration from bone growth [ 33 ].
The present study was limited in time, about 70 days, and therefore we cannot say if longer outgrowths could be eventually obtained. Since in nature lizards with long tail-like limbs have been recorded, it is possible that also in our FGF-induced cases, despite the low proliferation rate, both the regenerated femur and tibia-fibula could have continuously grown further 3.5 mm, providing more time was left, in relation the growth of long bones during the lizard lifetime [ 4 , 17 ]. It was however likely that these FGF-induced outgrowths were destined to arrest their growth linked to regeneration as they did not elongated much further after 50 days of regeneration, and they initiated to form scales, an indication of cessation of growth [ 15 ]. This was later confirmed by the 5BrdU labeling that detected few proliferating cells in the apical regions of these outgrowths, mainly in the apical perichondrium and in the wound epidermis at 70 days post-amputation while very few sparse labeled cells were observed in the dense connective tissues, tendons, and within most of the cartilages. The study in general confirms the broad capability to regenerate cartilage in lizards after injury of long bones, including the epiphyses [ 4 , 33 , 34 ], and vertebrae [ 4 , 35 ], making lizards a good experimental model to analyze cartilage regeneration in amniotes [ 36 , 37 , 38 ]. Whether FGFs can stimulate the production of Shh, retained the main inductor of cartilage differentiation in the tail of lizard [ 37 ], remains to be studied.
4.2. Proliferative Activity in the Outgrowths
Although the present study reports only qualitative observations, the detection of more frequently labeled cells in the apical regions of the outgrowths, epidermis, connective tissue and cartilage, indicated that these regions maintain an active growth until 50–60 days, but the decrease of labeling at 70 days because of much Extracellular Matrix deposition. The poor development of the muscles inside the outgrowths obtained in the present experiments may be in relation to the relatively scarce number of 5BrdU-long retaining cells (putative satellite cells) found in limb muscles in comparison to tail muscles, suggesting that the myogenic lineage is little represented in the adult, fully developed limb [
17
,
39
]. This may suggests that a negligible number of myogenic cells migrate in the blastema after limb amputation while most cells derive from the numerous 5BrdU-long retaining labeled fibroblasts present in the dermis and in the inter-muscle septa, driving the blastema toward scarring. Future experiments may use specific myogenic growth factors in addition to FGFs and other signaling proteins to stimulate the regeneration of larger outgrowths in lizards, comprising larger muscle masses.
In contrast, numerous proliferating cells were seen in the cartilage and bone of the truncated limb at 40 days of regeneration. The new scales were formed from epidermal pegs, like in those of the tail, explaining the high labeling required for scale morphogenesis and epidermal stratification. Proliferating chondroblasts formed a new femur, a fused or separated tibia and fibula, although of shorter length in comparison to the original ones, indicating that the elongation and the ossification of these bones might take a much longer time than 70 days. In comparison, the occasional limbs spontaneously regenerated and previously described [
4
] missed most of any cartilaginous elements 2–3 months after amputation, and were composed of dense connective tissue with few muscles and nerves. These results indicate that FGFs administration somehow mainly stimulates epidermal, nerve and cartilage proliferation, but not muscle regeneration.
The presence of few proliferating cells still at 60 and 70 days in the perichondrium and in the apical epidermis suggests for a slow growth of the regenerated bones after this period. The long cartilaginous bones regenerated in the limb outgrowths obtained after FGFs treatment, probably elongate by the full enlargement and maturation of their initial chondroblasts into fully mature chondrocytes. The appearance of likely secondary centers formed within the regenerated cartilaginous bones at 50–70 days suggests the beginning of endochondral ossification, but further study is needed on this point. The permanence of still proliferating cells in the distal-most cartilaginous regions of the outgrowths indicate that a slow elongation of these outgrowths can take place in the following months post-amputation, probably forming similar skeletal elements as the long bones detected in the tail-like limbs found in the wild [
1
,
2
,
3
,
6
].
5. Conclusions
The present study has shown that limbs in lizards are an outstanding case of reparative process for an amniote, since a blastema can be initially induced by FGFs injections. Cartilage and later bone tissue, fibrous connective tissues and tendons, nerves and skin, can largely regenerate within the outgrowths. Muscles instead appear to have a limited regenerative capability in the limb, so that this generally remains thinner than the stump, forming a tail-like appendage. This lack of muscle regeneration is likely related to the high inflammation occurring after limb amputation. Differently from the limb, in the tail an Apical Epidermal Peg (AEP) is formed on top of a mesenchymal blastema, and the AEP likely contributes to maintain a low but persistent growth front, capable to elongate into a new and wide tail. The present study affirms that re-creating an AEP in the limb improves healing in the effort to induce limb and autopodial regeneration in amniotes, perhaps even in mammals. The present innovative study, done for the first time on amputated lizard limbs, can have important clinical relevance since these amniotes are much closer to mammals than the classical amphibian model of limb regeneration. The limitation of the lizard model for studies on muscle-skeletal development and regeneration is related to its ectothermic condition and the lower activity of the immune system, one of the main obstacles for organ regeneration in endothermic amniotes like mammals. It remains to be further evaluated whether longer periods that the 40–70 days here analyzed can produce longer regenerated limbs, although likely also a prolonged FGFs treatment at higher dosage, and a lasting delivery system, may improve limb regeneration. The present, promising results address future experimentation where the addition of other signaling proteins known to determine the formation of the autopodium (digits), can be specifically injected into the initial limb outgrowth. This would open new avenues for limb regeneration in mammals, including humans.
Acknowledgments
The study was conducted over the years through personal financial support, and no grant was received from public or private institutions. FGFs were in part purchased through an Australian Department of Education, Employment and Training Fellowship. Stephen Kaufman of the University of Illinois at Urbana, IL, USA developed the G3G4 mouse antibody, maintained by the Developmental Studies Hybridoma Bank, University of Iowa, USA.
Conflicts of Interest
The author declares no conflict of interest.
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Figure 1.
Macroscopic view showing the aspect of regenerating hind-limbs at progressive days (d) post-amputation. (
A
–
C
,
G
,
H
) FGF1-treatment. (
D
–
F
,
I
) FGF2 treatments. Bars in all figures represent 1 mm. (
A
–
E
) and (
G
–
H
) show regenerating limbs after leg (mid tibia-fibula) amputation; (
F
,
I
) are regenerating limbs after thigh (mid femur) amputation; (
A
) at 6 days post-amputation the stump surface is covered by a scab (arrows); (
B
) at 15 days regenerating case with wound epidermis and underlined mesenchyme (arrows) sealing almost completely the stump surface; (
C
), in this case at 16 days a blastema (arrow) is fully formed; (
D
–
I
), gross aspect of elongating conical blastemas in representative cases at different days post-amputation; (
H
) the longest case at 60 days post-amputation features some flattening; (
J
) control of amputated limb at 25 days post-amputation.
Figure 1. Macroscopic view showing the aspect of regenerating hind-limbs at progressive days (d) post-amputation. ( A – C , G , H ) FGF1-treatment. ( D – F , I ) FGF2 treatments. Bars in all figures represent 1 mm. ( A – E ) and ( G – H ) show regenerating limbs after leg (mid tibia-fibula) amputation; ( F , I ) are regenerating limbs after thigh (mid femur) amputation; ( A ) at 6 days post-amputation the stump surface is covered by a scab (arrows); ( B ) at 15 days regenerating case with wound epidermis and underlined mesenchyme (arrows) sealing almost completely the stump surface; ( C ), in this case at 16 days a blastema (arrow) is fully formed; ( D – I ), gross aspect of elongating conical blastemas in representative cases at different days post-amputation; ( H ) the longest case at 60 days post-amputation features some flattening; ( J ) control of amputated limb at 25 days post-amputation.
Figure 2.
Histological images of scarring controls at 40 days (
A
,
B
) with 5BrdU immunolabeling (
C
,
D
). (
A
) longitudinal section of a scarring limb that is occupied by an irregular fibrous connective tissue with some cartilaginous nodules (arrows) in the center. The wound epithelium presents un-stainable areas in the stratum corneum. Bar, 50 μm; (
B
) detail of the apical region of the scarring outgrowth showing the cells forming the fibrous connective tissue where sparse blood vessels are present under the apical wound epidermis. The arrow indicates the apical cartilage. Bar, 20 μm; (
C
) 5brdU immunolabeling showing few and sparse labeled cells in the apical connective tissue present underneath the wound epidermis. Bar, 20 μm; (
D
) control section of the apical connective tissue present beneath the wound epidermis. Bar, 10mm Legends: a, apical connective tissue (blastema); CO, control section; fc, fibrous connective tissue; v, blood vessel; w, wound epidermis. Dashes underline the epidermis.
Figure 2. Histological images of scarring controls at 40 days ( A , B ) with 5BrdU immunolabeling ( C , D ). ( A ) longitudinal section of a scarring limb that is occupied by an irregular fibrous connective tissue with some cartilaginous nodules (arrows) in the center. The wound epithelium presents un-stainable areas in the stratum corneum. Bar, 50 μm; ( B ) detail of the apical region of the scarring outgrowth showing the cells forming the fibrous connective tissue where sparse blood vessels are present under the apical wound epidermis. The arrow indicates the apical cartilage. Bar, 20 μm; ( C ) 5brdU immunolabeling showing few and sparse labeled cells in the apical connective tissue present underneath the wound epidermis. Bar, 20 μm; ( D ) control section of the apical connective tissue present beneath the wound epidermis. Bar, 10mm Legends: a, apical connective tissue (blastema); CO, control section; fc, fibrous connective tissue; v, blood vessel; w, wound epidermis. Dashes underline the epidermis.
Figure 3.
Histological longitudinal sections of regenerating limbs at 40 days treated with FGF1 (
A
,
B
), 50 days treated with FGF2 (
C
,
D
) and 60 days with FGF1 (
E
,
F
) post-amputation; (
A
) section of a limb outgrowth derived from a tibia-fibula amputation that shows a central mass of immature and unstained cartilaginous tissue partially sub-divided into two regions that show a mature stained cartilage (metachromatic) in the more proximal areas (arrowheads), in continuity with the tibia bone. The two arrows indicate the plane of amputation. Bar, 200 μm; (
B
) close-up to the tip of the previous figure showing the small apical immature cartilage (arrowheads) in continuation with distal perichondrium cells, reaching the apical connective tissue region located underneath the apical wound epidermis. The latter shows a thin corneous layer. Bar, 50 μm. The inset shows a detail of the apical wound epidermis with the corneous layer (arrowhead). Bar, 10 μm; (
C
) other section of a conical blastema, showing the axial rod of cartilage containing mature chondrocytes (arrowhead), and surrounded by immature chondrocytes (non metachromatic to methylene blue). Bar, 200 μm; (
D
) apical region showing the thick wound epidermis and the cartilaginous nodules (arrows) containing centrally-located metachromatic chondrocytes, and surrounded by a perichondrium (arrowheads). Bar, 50 μm. The inset shows a tendon-like belt (arrowheads). Bar, 10 μm; (
E
) section showing the mature regenerated axial cartilage divided into two elements (arrows) representing the tibia and fibula. The apical blastema after 60 days of regeneration is mainly turned into a fibrous connective tissue (arrowhead). Bar, 200 μm; (
F
) detail of the proximal region of the previous section contacting the bone of the larger tibia. Bar, 100 μm. Legends: a, apical connective tissue (blastema); c, corneous layer; AE, apical wound epidermis; b, bone; ca, regenerated cartilage; df, dense fibrous connective tissue; e, new epidermis; ic, immature cartilage; mu, regenerated muscles; pc, proximal cartilage; pr, perichondrial cells; sc, scale; t, tendon-like; w, wound (regenerating) epidermis.
Figure 3. Histological longitudinal sections of regenerating limbs at 40 days treated with FGF1 ( A , B ), 50 days treated with FGF2 ( C , D ) and 60 days with FGF1 ( E , F ) post-amputation; ( A ) section of a limb outgrowth derived from a tibia-fibula amputation that shows a central mass of immature and unstained cartilaginous tissue partially sub-divided into two regions that show a mature stained cartilage (metachromatic) in the more proximal areas (arrowheads), in continuity with the tibia bone. The two arrows indicate the plane of amputation. Bar, 200 μm; ( B ) close-up to the tip of the previous figure showing the small apical immature cartilage (arrowheads) in continuation with distal perichondrium cells, reaching the apical connective tissue region located underneath the apical wound epidermis. The latter shows a thin corneous layer. Bar, 50 μm. The inset shows a detail of the apical wound epidermis with the corneous layer (arrowhead). Bar, 10 μm; ( C ) other section of a conical blastema, showing the axial rod of cartilage containing mature chondrocytes (arrowhead), and surrounded by immature chondrocytes (non metachromatic to methylene blue). Bar, 200 μm; ( D ) apical region showing the thick wound epidermis and the cartilaginous nodules (arrows) containing centrally-located metachromatic chondrocytes, and surrounded by a perichondrium (arrowheads). Bar, 50 μm. The inset shows a tendon-like belt (arrowheads). Bar, 10 μm; ( E ) section showing the mature regenerated axial cartilage divided into two elements (arrows) representing the tibia and fibula. The apical blastema after 60 days of regeneration is mainly turned into a fibrous connective tissue (arrowhead). Bar, 200 μm; ( F ) detail of the proximal region of the previous section contacting the bone of the larger tibia. Bar, 100 μm. Legends: a, apical connective tissue (blastema); c, corneous layer; AE, apical wound epidermis; b, bone; ca, regenerated cartilage; df, dense fibrous connective tissue; e, new epidermis; ic, immature cartilage; mu, regenerated muscles; pc, proximal cartilage; pr, perichondrial cells; sc, scale; t, tendon-like; w, wound (regenerating) epidermis.
Figure 4.
Longitudinal sections of regenerating limbs treated with FGF1 at 60 days (
A
–
C
) and 70 days (
D
) post-amputation. (
A
) distal region of an outgrowth containing two separated cartilaginous elements (arrows), the upper considered a regenerated tibia, and the lower a regenerated fibula. A dense fibrous connective tissue (fc) surrounds the cartilage, forming the perichondrium. In front of them a cartilaginous nodule (arrowhead) is seen. The apical wound epithelium (w) shows numerous epidermal papillae (small pegs). Bar, 200 μm; (
B
) separated regenerated cartilages of the tibia (upper arrow) and fibula (lower arrow), surrounded by a thick perichondrium (arrows) in the long outgrowth illustrated in Fig 1H, examined at 70 days post-amputation. The tibia cartilage is attached to the original tibia bone (b). Bar, 50 μm; (
C
) detail of calcified cartilage (cc) localized near the perichondrium (arrow) of the cartilaginous tibia. Bar, 20 μm; (
D
) detail of apical wound epidermis of the outgrowth of figure B, featuring the numerous epidermal papillae (arrows). Bar, 200 μm.
Figure 4. Longitudinal sections of regenerating limbs treated with FGF1 at 60 days ( A – C ) and 70 days ( D ) post-amputation. ( A ) distal region of an outgrowth containing two separated cartilaginous elements (arrows), the upper considered a regenerated tibia, and the lower a regenerated fibula. A dense fibrous connective tissue (fc) surrounds the cartilage, forming the perichondrium. In front of them a cartilaginous nodule (arrowhead) is seen. The apical wound epithelium (w) shows numerous epidermal papillae (small pegs). Bar, 200 μm; ( B ) separated regenerated cartilages of the tibia (upper arrow) and fibula (lower arrow), surrounded by a thick perichondrium (arrows) in the long outgrowth illustrated in Fig 1H, examined at 70 days post-amputation. The tibia cartilage is attached to the original tibia bone (b). Bar, 50 μm; ( C ) detail of calcified cartilage (cc) localized near the perichondrium (arrow) of the cartilaginous tibia. Bar, 20 μm; ( D ) detail of apical wound epidermis of the outgrowth of figure B, featuring the numerous epidermal papillae (arrows). Bar, 200 μm.
Figure 5.
Histological (
A
,
B
) and 5BrdU-immunofluorescent (
C
–
F
) images of a regenerating outgrowth at 50 days after mid femur transection (FGF2 treatment). (
A
) Distal part of regenerated femur cartilage surrounded by a fibrous and dense connective tissue. Bar, 100 μm; (
B
) detail of an apical cartilaginous nodule surrounded by perichondrium (arrowheads), located near the tip of the femur cartilage. Bar 20 μm; (
C
) labeled cells (red dots) are distributed in the apical region of the outgrowth (see location in the pink inset drawing featuring a limb blastema with the central cartilaginous rod, dotted, derived from the transected femur). The wound epidermis and the tip of the regenerated cartilage are indicated by dashes. Bar, 50 μm; (
D
) detail of the apex of the outgrowth with most labeled cells in the apical wound epidermis outlined by dashes. Bar, 20 μm; (
E
) detail of labeled cells within the apical region (blastema), that are present near the tip of the regenerated cartilaginous rod (dashed). Bar, 20 μm; (
F
) detail of a cartilage nodule present at the tip of the regenerated outgrowth, and surrounded by labeled cells of the perichondrium (arrows). Bar, 20 μm. Legends: a, apical region (blastema); AE, apical wound epidermis; ca, regenerated cartilaginous rod of the transected femur; dc, dense connective tissue; fc, femur cartilage. nc, nodule cartilaginous; w, wound epidermis.
Figure 6.
Immunofluorescence for 5BrdU of different regions of 50 days old outgrowths, obtained after mid femur transection and FGF2 treatment. (
A
) Distribution of labeled cells in the cartilage rod (in the inset, the indicative position is shown with an arrow pointing the regenerated cartilage rod formed within the outgrowth; the arrowhead refers to regenerating scales). The arrows indicate the perichondrium. Bar, 50 μm; (
B
) detail of the region localized between the cartilage rod and the close tendon-like belt (the inset drawing shows the indicative position with an arrow pointing near the regenerated cartilage rod; the arrowhead refers to the proximal repairing muscles). The arrows indicate the perichondrium while the dashes outline the dense tendon-like belt. Bar, 50 μm; (
C
) regenerating scales (their indicative position is shown by the arrowhead seen in the inset in (
A
). Bar, 20 μm; (
D
) detail of repairing muscles located at the base of the outgrowth (their indicative position is shown by the arrowhead in the inset in (
B
). Bar, 20 μm. Legends: ca, regenerated cartilage; dc, dense connective tissue of the dermis; e, regenerating scale epidermis; ls, limb stump; mu, regenerating muscles; o, limb outgrowth; t, tendon-like belt.
Figure 6. Immunofluorescence for 5BrdU of different regions of 50 days old outgrowths, obtained after mid femur transection and FGF2 treatment. ( A ) Distribution of labeled cells in the cartilage rod (in the inset, the indicative position is shown with an arrow pointing the regenerated cartilage rod formed within the outgrowth; the arrowhead refers to regenerating scales). The arrows indicate the perichondrium. Bar, 50 μm; ( B ) detail of the region localized between the cartilage rod and the close tendon-like belt (the inset drawing shows the indicative position with an arrow pointing near the regenerated cartilage rod; the arrowhead refers to the proximal repairing muscles). The arrows indicate the perichondrium while the dashes outline the dense tendon-like belt. Bar, 50 μm; ( C ) regenerating scales (their indicative position is shown by the arrowhead seen in the inset in ( A ). Bar, 20 μm; ( D ) detail of repairing muscles located at the base of the outgrowth (their indicative position is shown by the arrowhead in the inset in ( B ). Bar, 20 μm. Legends: ca, regenerated cartilage; dc, dense connective tissue of the dermis; e, regenerating scale epidermis; ls, limb stump; mu, regenerating muscles; o, limb outgrowth; t, tendon-like belt.
Figure 7.
Immunofluorescence for 5BrdU of different regions of 40 days old outgrowths after mid tibia-fibula transection and FGF1 treatment. (
A
Figure 2
B showing the numerous 5BrdU-labeled cells detected in the apical connective tissue and wound epidermis (outlined by dashes). Most labeled cells are present in the apical perichondrium while little labeling is seen in the immature cartilage (outlined by dashes). Bar, 50 μm; (
B
) detail of the very tip of the same outgrowth shown in (A) evidencing the numerous labeled epidermal cells (arrows). Bar 20 μm; (
C
) lateral region of the outgrowth (its indicative position is shown by an arrow in the inset drawing; the arrowhead points to the bone marrow of the tibia). Numerous labeled cells are seen in the epidermis (outlined by dashes), dermis and among repairing muscles are seen. The arrows indicate the perichondrium surrounding the central cartilaginous rod. Bar, 50 μm; (
D
) detail on labeled cells within the bone marrow (its position is indicated by an arrowhead in the inset of figure C. Bar, 20 μm. Legends: a, apical connective tissue (blastema); AE, apical wound epidermis; bm, bone marrow; ca, regenerated cartilaginous rod; d, dermis; e, epidermis; f, femur (stump); ic, immature apical cartilage; mu, regenerating muscles; o, outgrowth; pr, apical perichondrium; w, wound epidermis.
Figure 7. Immunofluorescence for 5BrdU of different regions of 40 days old outgrowths after mid tibia-fibula transection and FGF1 treatment. ( A ) Parallel section of Figure 2 B showing the numerous 5BrdU-labeled cells detected in the apical connective tissue and wound epidermis (outlined by dashes). Most labeled cells are present in the apical perichondrium while little labeling is seen in the immature cartilage (outlined by dashes). Bar, 50 μm; ( B ) detail of the very tip of the same outgrowth shown in (A) evidencing the numerous labeled epidermal cells (arrows). Bar 20 μm; ( C ) lateral region of the outgrowth (its indicative position is shown by an arrow in the inset drawing; the arrowhead points to the bone marrow of the tibia). Numerous labeled cells are seen in the epidermis (outlined by dashes), dermis and among repairing muscles are seen. The arrows indicate the perichondrium surrounding the central cartilaginous rod. Bar, 50 μm; ( D ) detail on labeled cells within the bone marrow (its position is indicated by an arrowhead in the inset of figure C. Bar, 20 μm. Legends: a, apical connective tissue (blastema); AE, apical wound epidermis; bm, bone marrow; ca, regenerated cartilaginous rod; d, dermis; e, epidermis; f, femur (stump); ic, immature apical cartilage; mu, regenerating muscles; o, outgrowth; pr, apical perichondrium; w, wound epidermis.
Figure 8.
Immunofluorescence for 5BrdU in different regions of 50 days old outgrowths (tibia-fibula transection and FGF2 treatment). (
A
) Apical region of the outgrowth, showing intense labeling in the apical epidermis (outlined by dashes), apical connective tissue, and in the cartilaginous nodules (outlined by dashes). Little labeling is observed in the cartilaginous rod, outlined by dashes in the lower part of the figure (indicative position shown in the drawing inset). Bar, 50 μm; (
B
) detail of the apical region of the outgrowth, showing the numerous labeled cells present in the wound epidermis and underlying connective tissue (dashes outline the tip of the cartilaginous rod). Bar 20 μm; (
C
) epidermal peg (outlined by dashes) containing numerous labeled cells at the beginning of scale regeneration. Bar, 20 μm; (
D
) regenerated scale with numerous labeled cells localized in the stratum basale. Bar, 20 μm. Legends: a, apical connective tissue (blastema); AE, apical wound epidermis; ca, regenerated cartilage (rod); d, dermis; h, hinge region; I, inner scale surface; nc, nodulus cartilaginous; os, outer scale surface (dorsal); p, epidermal peg (beginning of scale formation); w, wound epidermis (regenerating).
Figure 8. Immunofluorescence for 5BrdU in different regions of 50 days old outgrowths (tibia-fibula transection and FGF2 treatment). ( A ) Apical region of the outgrowth, showing intense labeling in the apical epidermis (outlined by dashes), apical connective tissue, and in the cartilaginous nodules (outlined by dashes). Little labeling is observed in the cartilaginous rod, outlined by dashes in the lower part of the figure (indicative position shown in the drawing inset). Bar, 50 μm; ( B ) detail of the apical region of the outgrowth, showing the numerous labeled cells present in the wound epidermis and underlying connective tissue (dashes outline the tip of the cartilaginous rod). Bar 20 μm; ( C ) epidermal peg (outlined by dashes) containing numerous labeled cells at the beginning of scale regeneration. Bar, 20 μm; ( D ) regenerated scale with numerous labeled cells localized in the stratum basale. Bar, 20 μm. Legends: a, apical connective tissue (blastema); AE, apical wound epidermis; ca, regenerated cartilage (rod); d, dermis; h, hinge region; I, inner scale surface; nc, nodulus cartilaginous; os, outer scale surface (dorsal); p, epidermal peg (beginning of scale formation); w, wound epidermis (regenerating).
Figure 9.
Immunofluorescence for 5BrdU of different regions of 70 days old outgrowths after tibia-fibula transection (FGF1 treatment). (
A
) Diffusely distributed labeled cells in the apical region of the outgrowth. The regenerating epidermis is outlined by dashes. Below, the tip of the regenerated cartilaginous rod is also outlined by dashes. Bar, 50 μm; (
B
) detail of the tip of the outgrowth containing sparse labeled cells, especially in the wound epidermis (outlined by dashes). The dashed line below indicates the cartilaginous rod. Bar 20 μm; (
C
) detail on regenerating scale epidermis (outlined by dashes) containing various labeled cells (their indicative position is shown by the arrow in the inset of figure D). Bar, 20 μm; (
D
) detail of the scarce labeled cells present in the cartilage rod of a the regenerated fibula (indicative position shown by the arrowhead in the inset). Bar, 20 μm. Legends: a, apical connective tissue; AE, apical wound epidermis; ca, regenerated cartilage; d, dermis; e, epidermis of the forming scale; ls, stump of the limb; o, limb outgrowth; w, wound epidermis.
Figure 9. Immunofluorescence for 5BrdU of different regions of 70 days old outgrowths after tibia-fibula transection (FGF1 treatment). ( A ) Diffusely distributed labeled cells in the apical region of the outgrowth. The regenerating epidermis is outlined by dashes. Below, the tip of the regenerated cartilaginous rod is also outlined by dashes. Bar, 50 μm; ( B ) detail of the tip of the outgrowth containing sparse labeled cells, especially in the wound epidermis (outlined by dashes). The dashed line below indicates the cartilaginous rod. Bar 20 μm; ( C ) detail on regenerating scale epidermis (outlined by dashes) containing various labeled cells (their indicative position is shown by the arrow in the inset of figure D). Bar, 20 μm; ( D ) detail of the scarce labeled cells present in the cartilage rod of a the regenerated fibula (indicative position shown by the arrowhead in the inset). Bar, 20 μm. Legends: a, apical connective tissue; AE, apical wound epidermis; ca, regenerated cartilage; d, dermis; e, epidermis of the forming scale; ls, stump of the limb; o, limb outgrowth; w, wound epidermis.
MDPI and ACS Style
Alibardi, L. FGFs Treatment on Amputated Lizard Limbs Stimulate the Regeneration of Long Bones, Opening New Avenues for Limb Regeneration in Amniotes: A Morphological Study. J. Funct. Morphol. Kinesiol. 2017, 2, 25.
https://doi.org/10.3390/jfmk2030025
Alibardi L. FGFs Treatment on Amputated Lizard Limbs Stimulate the Regeneration of Long Bones, Opening New Avenues for Limb Regeneration in Amniotes: A Morphological Study. Journal of Functional Morphology and Kinesiology. 2017; 2(3):25.
https://doi.org/10.3390/jfmk2030025
Chicago/Turabian Style
Alibardi, Lorenzo. 2017. "FGFs Treatment on Amputated Lizard Limbs Stimulate the Regeneration of Long Bones, Opening New Avenues for Limb Regeneration in Amniotes: A Morphological Study" Journal of Functional Morphology and Kinesiology2, no. 3: 25.
https://doi.org/10.3390/jfmk2030025
Alibardi, Lorenzo. 2017. "FGFs Treatment on Amputated Lizard Limbs Stimulate the Regeneration of Long Bones, Opening New Avenues for Limb Regeneration in Amniotes: A Morphological Study" Journal of Functional Morphology and Kinesiology2, no. 3: 25.
https://doi.org/10.3390/jfmk2030025
| https://www.mdpi.com/2411-5142/2/3/25/html |
Electrochemical dissolution and recovery of tin from printed circuit board in methane–sulfonic acid solution | ScienceGate
Read Electrochemical dissolution and recovery of tin from printed circuit board in methane–sulfonic acid solution
Electrochemical dissolution and recovery of tin from printed circuit board in methane–sulfonic acid solution
Hydrometallurgy ◽
10.1016/j.hydromet.2021.105726 ◽
2021 ◽
pp. 105726
Author(s):
Chaobo Tang ◽
Xinjie Deng ◽
Yongming Chen ◽
Yun Li ◽
Chaoyong Deng ◽
...
Keyword(s):
Acid Solution ◽
Sulfonic Acid ◽
Printed Circuit Board ◽
Circuit Board ◽
Electrochemical Dissolution ◽
Methane Sulfonic Acid ◽
Printed Circuit
406. An Ergonomic Hazards Survey of Printed Circuit Board Factories
10.3320/1.2765087 ◽
1999 ◽
Author(s):
C. Lu ◽
S. Wang ◽
C. Wei ◽
S. In
Keyword(s):
Printed Circuit Board ◽
Circuit Board ◽
Printed Circuit
Characteristics of Radiated Emission from a Printed Circuit Board with a Slit
IEEJ Transactions on Fundamentals and Materials ◽
10.1541/ieejfms.132.404 ◽
2012 ◽
Vol 132 (6) ◽
pp. 404-410 ◽
Cited By ~ 2
Author(s):
Kenichi Nakayama ◽
Kenichi Kagoshima ◽
Shigeki Takeda
Keyword(s):
Printed Circuit Board ◽
Circuit Board ◽
Printed Circuit ◽
Radiated Emission
Confirming the Signal Integrity in Transmission of Digital Signals on Microstrip Straight Circuits via the Eye Diagrams
JOURNAL OF ADVANCES IN PHYSICS ◽
10.24297/jap.v5i1.1972 ◽
2014 ◽
Vol 5 (1) ◽
pp. 737-741
Author(s):
Alejandro Dueñas Jiménez ◽
Francisco Jiménez Hernández
Keyword(s):
Integrated Circuits ◽
Printed Circuit Board ◽
Signal Integrity ◽
High Volume ◽
Information Storage ◽
Circuit Board ◽
Electromagnetic Simulation ◽
Electronic Systems ◽
Digital Signals ◽
Printed Circuit
Because of the high volume of processing, transmission, and information storage, electronic systems presently requires faster clock speeds tosynchronizethe integrated circuits. Presently the “speeds†on the connections of a printed circuit board (PCB) are in the order of the GHz. At these frequencies the behavior of the interconnects are more like that of a transmission line, and hence distortion, delay, and phase shift- effects caused by phenomena like cross talk, ringing and over shot are present and may be undesirable for the performance of a circuit or system.Some of these phrases were extracted from the chapter eight of book “2-D Electromagnetic Simulation of Passive Microstrip Circuits†from the corresponding author of this paper.
Root Cause Analysis of a Connector Time-Delayed Fracture
ISTFA 2015: Conference Proceedings from the 41st International Symposium for Testing and Failure Analysis ◽
10.31399/asm.cp.istfa2015p0451 ◽
2015 ◽
Author(s):
Prabjit Singh ◽
Ying Yu ◽
Robert E. Davis
Keyword(s):
Printed Circuit Board ◽
Ceramic Substrate ◽
Circuit Board ◽
Delayed Fracture ◽
Ceramic Substrates ◽
Printed Circuit ◽
Root Cause ◽
Chip Carrier ◽
Electrical Connections ◽
Grain Boundary Grooves
Abstract
A land-grid array connector, electrically connecting an array of plated contact pads on a ceramic substrate chip carrier to plated contact pads on a printed circuit board (PCB), failed in a year after assembly due to time-delayed fracture of multiple C-shaped spring connectors. The land-grid-array connectors analyzed had arrays of connectors consisting of gold on nickel plated Be-Cu C-shaped springs in compression that made electrical connections between the pads on the ceramic substrates and the PCBs. Metallography, fractography and surface analyses revealed the root cause of the C-spring connector fracture to be plating solutions trapped in deep grain boundary grooves etched into the C-spring connectors during the pre-plating cleaning operation. The stress necessary for the stress corrosion cracking mechanism was provided by the C-spring connectors, in the land-grid array, being compressed between the ceramic substrate and the printed circuit board.
Application of Lock-in Thermography on PCB for Fault Localization and Validation of Failure Mechanism Due to External Discrete Component Variation
ISTFA 2010: Conference Proceedings from the 36th International Symposium for Testing and Failure Analysis ◽
10.31399/asm.cp.istfa2010p0191 ◽
2010 ◽
Author(s):
William Ng ◽
Kevin Weaver ◽
Zachary Gemmill ◽
Herve Deslandes ◽
Rudolf Schlangen
Keyword(s):
Failure Mechanism ◽
Integrated Circuit ◽
Printed Circuit Board ◽
Hot Spot ◽
Circuit Board ◽
Discrete Component ◽
Printed Circuit ◽
Thermal Signature ◽
Lock In
Abstract
This paper demonstrates the use of a real time lock-in thermography (LIT) system to non-destructively characterize thermal events prior to the failing of an integrated circuit (IC) device. A case study using a packaged IC mounted on printed circuit board (PCB) is presented. The result validated the failing model by observing the thermal signature on the package. Subsequent analysis from the backside of the IC identified a hot spot in internal circuitry sensitive to varying value of external discrete component (inductor) on PCB.
Temperature and Humidity Dependent Reliability Analysis of RGB LED Chips
ISTFA 2006: Conference Proceedings from the 32nd International Symposium for Testing and Failure Analysis ◽
10.31399/asm.cp.istfa2006p0137 ◽
2006 ◽
Author(s):
Jun-Xian Fu ◽
Shukri Souri ◽
James S. Harris
Keyword(s):
Reliability Analysis ◽
Printed Circuit Board ◽
Light Emitting Diode ◽
Circuit Board ◽
Light Emitting ◽
Printed Circuit ◽
Root Cause ◽
Micro Cracks ◽
Temperature And Humidity
Abstract
Temperature and humidity dependent reliability analysis was performed based on a case study involving an indicator printed-circuit board with surface-mounted multiple-die red, green and blue light-emitting diode chips. Reported intermittent failures were investigated and the root cause was attributed to a non-optimized reflow process that resulted in micro-cracks and delaminations within the molding resin of the chips.
Materials Characterization of Lead Free Compositions for Minimum Temperature SMT Processes at the SLI-Second Level Interconnect Solder Joint
ISTFA 2004: Conference Proceedings from the 30th International Symposium for Testing and Failure Analysis ◽
10.31399/asm.cp.istfa2004p0261 ◽
2004 ◽
Author(s):
Norman J. Armendariz ◽
Prawin Paulraj
Keyword(s):
Solder Joint ◽
Printed Circuit Board ◽
Gold Surface ◽
Circuit Board ◽
Lead Free ◽
Processing Temperature ◽
The European Union ◽
Printed Circuit ◽
Higher Temperature ◽
Tin Silver Copper
Abstract
The European Union is banning the use of Pb in electronic products starting July 1st, 2006. Printed circuit board assemblies or “motherboards” require that planned CPU sockets and BGA chipsets use lead-free solder ball compositions at the second level interconnections (SLI) to attach to a printed circuit board (PCB) and survive various assembly and reliability test conditions for end-use deployment. Intel is pro-actively preparing for this anticipated Pb ban, by evaluating a new lead free (LF) solder alloy in the ternary Tin- Silver-Copper (Sn4.0Ag0.5Cu) system and developing higher temperature board assembly processes. This will be pursued with a focus on achieving the lowest process temperature required to avoid deleterious higher temperature effects and still achieve a metallurgically compatible solder joint. One primary factor is the elevated peak reflow temperature required for surface mount technology (SMT) LF assembly, which is approximately 250 °C compared to present eutectic tin/lead (Sn37Pb) reflow temperatures of around 220 °C. In addition, extended SMT time-above-liquidus (TAL) and subsequent cooling rates are also a concern not only for the critical BGA chipsets and CPU BGA sockets but to other components similarly attached to the same PCB substrate. PCBs used were conventional FR-4 substrates with organic solder preservative on the copper pads and mechanical daisychanged FCBGA components with direct immersion gold surface finish on their copper pads. However, a materials analysis method and approach is also required to characterize and evaluate the effect of low peak temperature LF SMT processing on the PBA SLI to identify the absolute limits or “cliffs” and determine if the minimum processing temperature and TAL could be further lowered. The SLI system is characterized using various microanalytical techniques, such as, conventional optical microscopy, scanning electron microscopy, energy dispersive spectroscopy and microhardness testing. In addition, the SLI is further characterized using macroanalytical techniques such as dye penetrant testing (DPT) with controlled tensile testing for mechanical strength in addition to disbond and crack area mapping to complete the analysis.
2003 ◽
Author(s):
O. Crépel ◽
Y. Bouttement ◽
P. Descamps ◽
C. Goupil ◽
P. Perdu ◽
...
Keyword(s):
Magnetic Field ◽
Mobile Phone ◽
Printed Circuit Board ◽
Magnetic Sensors ◽
Circuit Board ◽
Magnetic Disturbance ◽
Passive Components ◽
Printed Circuit ◽
Integrated Inductor ◽
The Magnetic Field
Abstract
We developed a system and a method to characterize the magnetic field induced by circuit board and electronic component, especially integrated inductor, with magnetic sensors. The different magnetic sensors are presented and several applications using this method are discussed. Particularly, in several semiconductor applications (e.g. Mobile phone), active dies are integrated with passive components. To minimize magnetic disturbance, arbitrary margin distances are used. We present a system to characterize precisely the magnetic emission to insure that the margin is sufficient and to reduce the size of the printed circuit board.
ISTFA 2009: Conference Proceedings from the 35th International Symposium for Testing and Failure Analysis ◽
10.31399/asm.cp.istfa2009p0293 ◽
2009 ◽
Author(s):
Bhanu Sood ◽
Diganta Das ◽
Michael H. Azarian ◽
Michael Pecht
Keyword(s):
Thick Film ◽
Printed Circuit Board ◽
Negative Resistance ◽
Circuit Board ◽
High Humidity ◽
Circuit Boards ◽
Chemical Modifications ◽
Current Leakage ◽
Printed Circuit ◽
Degradation Analysis
Abstract
Negative resistance drift in thick film chip resistors in high temperature and high humidity application conditions was investigated. This paper reports on the investigation of possible causes including formation of current leakage paths on the printed circuit board, delamination between the resistor protective coating and laser trim, and the possibility of silver migration or copper dendrite formation. Analysis was performed on a set of circuit boards exhibiting failures due to this phenomenon. Electrical tests after mechanical and chemical modifications showed that the drift was most likely caused by moisture ingress that created a conductive path across the laser trim.
10.31399/asm.cp.istfa1996p0357 ◽
1996 ◽
Author(s):
P. Singh ◽
G.T. Galyon ◽
J. Obrzut ◽
W.A. Alpaugh
Keyword(s):
Experimental Data ◽
Thermal Degradation ◽
Printed Circuit Boards ◽
Printed Circuit Board ◽
Elevated Temperatures ◽
Dielectric Breakdown ◽
Circuit Board ◽
Printed Circuit ◽
Data Matching
Abstract
A time delayed dielectric breakdown in printed circuit boards, operating at temperatures below the epoxy resin insulation thermo-electrical limits, is reported. The safe temperature-voltage operating regime was estimated and related to the glass-rubber transition (To) of printed circuit board dielectric. The TG was measured using DSC and compared with that determined from electrical conductivity of the laminate in the glassy and rubbery state. A failure model was developed and fitted to the experimental data matching a localized thermal degradation of the dielectric and time dependency. The model is based on localized heating of an insulation resistance defect that under certain voltage bias can exceed the TG, thus, initiating thermal degradation of the resin. The model agrees well with the experimental data and indicates that the failure rate and truncation time beyond which the probability of failure becomes insignificant, decreases with increasing glass-rubber transition temperature.
| https://www.sciencegate.app/document/10.1016/j.hydromet.2021.105726 |
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Illustrated History of the United States Mint
The Immigrant Woman and Her Job : Women's Bureau Bulletin, No. 74
Impact of Automation : A Collection of 20 Articles About Technological Change, From the Monthly Labor Review : Bulletin of the United States Bureau of Labor Statistics, No. 1287
The Impact of Economic Recovery Efforts on Corporate and Commercial Real Estate Lending : Hearing Before the Congressional Oversight Panel, One Hundred Eleventh Congress, First Session, May 28, 2009
Impact of Federal Pollution Control and Abatement Expenditures on Manpower Requirements : Bulletin of the United States Bureau of Labor Statistics, No. 1836
Impact of Office Automation in the Insurance Industry : Bulletin of the United States Bureau of Labor Statistics, No. 1468
Impact of Office Automation in the Internal Revenue Service: A Study of the Manpower Implications During the First Stages of the Changeover : Bulletin of the United States Bureau of Labor Statistics, No. 1364
Impact of Technological Change and Automation in the Pulp and Paper Industry : Bulletin of the United States Bureau of Labor Statistics, No. 1347
The Impact of Technology on Labor in Four Industries: Textiles/Paper and Paperboard/Steel/Motor Vehicles : Bulletin of the United States Bureau of Labor Statistics, No. 2228
The Impact of the Debt Crisis on the U.S. Economy : Hearings Before the Joint Economic Committee, Congress of the United States, Ninety-Ninth Congress, First Session, June 17, 21, and 24, 1985
Impact of the Drought on Prices and Production : Hearing Before the Subcommittee on Economic Stabilization of the Committee on Banking, Finance, and Urban Affairs, House of Representatives, One-Hundredth Congress, Second Session, July 6, 1988
The Impact of the Federal Reserve's Money Policies on the Economy : Hearings Before the Subcommittee on Domestic Monetary Policy of the Committee on Banking, Currency and Housing, House of Representatives, Ninety-Fourth Congress, Second Session, June 8, 9, 10, and 24, 1976
The Impact of the Federal Reserve System's Monetary Policies on the Nation's Economy : Staff Report of the Subcommittee on Domestic Monetary Policy of the Committee on Banking, Currency and Housing, House of Representatives, Ninety-Fourth Congress, Second Session
The Impact of the Payment of Interest on Demand Deposits : A Study of the Staff of the Board of Governors of the Federal Reserve System
Impact of the War on Employment in 181 Centers of War Activity : Bulletin of the United States Bureau of Labor Statistics, No. 826
Impact on Money and Credit Policy of Federal Debt Management : Hearing Before the Subcommittee on Domestic Monetary Policy of the Committee on Banking, Finance, and Urban Affairs, House of Representatives, Ninety-Eighth Congress, First Session, April 25, 1983
Impact on Workers and Community of a Plant Shutdown in a Depressed Area : Bulletin of the United States Bureau of Labor Statistics, No. 1264
Impaired Workers in Industry: The Comparative Performance of Impaired Workers and Their Able-Bodied Fellow Workers : Bulletin of the United States Bureau of Labor Statistics, No. 857
Implications of Automation and Other Technological Developments: A Selected Annotated Bibliography (1963) : Bulletin of the United States Bureau of Labor Statistics, No. 1319-1
Improvement of Federal Supervision of Banks
Improvement of Labor-Utilization Procedures : Bulletin of the United States Bureau of Labor Statistics, No. 807
Improving Federal Consumer Protection in Financial Services : Hearing Before the Committee on Financial Services, U.S. House of Representatives, One Hundred Tenth Congress, First Session, June 13, 2007
Improving Productivity: Labor Management Approaches : Bulletin of the United States Bureau of Labor Statistics, No. 1715
Incentive-Wage Plans and Collective Bargaining : Bulletin of the United States Bureau of Labor Statistics, No. 717
Income and Spending and Saving of City Families in Wartime : Bulletin of the United States Bureau of Labor Statistics, No. 724
Income and Wages in the South
Income From Wages and Salaries in the Postwar Period : Bulletin of the United States Bureau of Labor Statistics, No. 845
Increase in Permanent Debt Limitation : Hearing Before the Committee on Finance, United States Senate, Eighty-Fifth Congress, Second Session, on H.R. 13580, August 15, 1958
Increase the Public Debt Limit : Hearing Before the Committee on Ways and Means, House of Representatives, Eighty-Fifth Congress, Second Session, on H.R. 13580 and H.R. 13581, July 30, 1958
Indebtedness in the United States, 1929-41
The Independent Treasury of the United States and Its Relations to the Banks of the Country
Indexes of Output Per Man-Hour: Corrugated and Solid Fiber Boxes Industry, 1958-66 : Bulletin of the United States Bureau of Labor Statistics, No. 1641
Indexes of Output Per Man-Hour: Gray Iron Foundries Industry, 1954-66 : Bulletin of the United States Bureau of Labor Statistics, No. 1636
Indexes of Output Per Man-Hour: Motor Vehicles and Equipment Industry, 1957-66 : Bulletin of the United States Bureau of Labor Statistics, No. 1613
Indexes of Output Per Man-Hour, Selected Industries : Bulletin of the United States Bureau of Labor Statistics, No. 1827
Indexing With the Consumer Price Index : Problems and Alternatives
Index Numbers of Wholesale Prices in the United States and Foreign Countries : Bulletin of the United States Bureau of Labor Statistics, No. 173
Index Numbers of Wholesale Prices in the United States and Foreign Countries : Bulletin of the United States Bureau of Labor Statistics, No. 284
Index of Volumes 72-83: Monthly Labor Review, January 1951 to December 1960 : Bulletin of the United States Bureau of Labor Statistics, No. 1335
Index of Witnesses & Exhibits for the Hearings before the Reserve Bank Organization Committee
Index to Proceedings of International Association of Industrial Accident Boards and Commissions, 1914-1924 : Bulletin of the United States Bureau of Labor Statistics, No. 395
Individual Statements of Condition of National Banks
Industrial Accidents and Hygiene Series
Industrial Accident Statistics : Bulletin of the United States Bureau of Labor Statistics, No. 157
Industrial Accidents to Men and Women : Women's Bureau Bulletin, No. 81
Industrial Accidents to Women in New Jersey, Ohio, and Wisconsin : Women's Bureau Bulletin, No. 60
Industrial Advances Act
Industrial Court of the Cloak, Suit, and Skirt Industry of New York City : Bulletin of the United States Bureau of Labor Statistics, No. 144
Industrial Development Activities of the Federal Reserve Banks
Industrial Efficiency and Fatigue in British Munition Factories: Reprints of Interim Report and Memoranda of the British Health of Munition Workers Committee : Bulletin of the United States Bureau of Labor Statistics, No. 230
Industrial Experience of Trade-School Girls in Massachusetts : Bulletin of the United States Bureau of Labor Statistics, No. 215
The Industrial Experience of Women Workers at the Summer Schools, 1928 to 1930 : Women's Bureau Bulletin, No. 89
Industrial Health and Efficiency: Final Report of the British Health of Munition Workers Committee : Bulletin of the United States Bureau of Labor Statistics, No. 249
Industrial Home Work in Rhode Island: With Special Reference to the Lace Industry : Women's Bureau Bulletin, No. 131
Industrial Home Work : Women's Bureau Bulletin, No. 79
Industrial Injuries in the United States During 1942 : Bulletin of the United States Bureau of Labor Statistics, No. 758
Industrial Injuries to Women and Men, 1932 to 1934 : Women's Bureau Bulletin, No. 160
Industrial Injuries to Women in 1928 and 1929 Compared With Injuries to Men : Women's Bureau Bulletin, No. 102
Industrial Injuries to Women in 1930 and 1931 Compared With Injuries to Men : Women's Bureau Bulletin, No. 129
Industrial Injuries to Women : Women's Bureau Bulletin, No. 212
Industrial-Injury Statistics by States : Bulletin of the United States Bureau of Labor Statistics, No. 700
The Industrial Nurse and the Woman Worker : Women's Bureau Bulletin, No. 228
Industrial Opportunities and Training for Women and Girls : Women's Bureau Bulletin, No. 13
Industrial Poisoning in Making Coal-Tar Dyes and Dye Intermediates : Bulletin of the United States Bureau of Labor Statistics, No. 280
Industrial Poisons Used in the Rubber Industry : Bulletin of the United States Bureau of Labor Statistics, No. 179
Industrial Poisons Used or Produced in the Manufacture of Explosives : Bulletin of the United States Bureau of Labor Statistics, No. 219
Industrial Production, 1957-59 Base
Industrial Relations in the West Coast Lumber Industry : Bulletin of the United States Bureau of Labor Statistics, No. 349
Industrial Retraining Programs for Technological Change: A Study of the Performance of Older Workers : Bulletin of the United States Bureau of Labor Statistics, No. 1368
Industrial Survey in Selected Industries in the United States, 1919 : Bulletin of the United States Bureau of Labor Statistics, No. 265
Industrial Unemployment: A Statistical Study of Its Extent and Causes : Bulletin of the United States Bureau of Labor Statistics, No. 310
Industrial Unrest in Great Britain : Bulletin of the United States Bureau of Labor Statistics, No. 237
Industry Sector Opportunities : Women Working in Green Construction & Energy Efficiency
Industry Wage Survey: Appliance Repair
Industry Wage Survey: Auto Dealer Repair Shops
Industry Wage Survey: Banking
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Industry Wage Survey: Contract Cleaning Services
Industry Wage Survey: Contract Construction
Industry Wage Survey: Corrugated and Solid Fiber Boxes
Industry Wage Survey: Cotton and Man-Made Fiber Textiles
Industry Wage Survey: Department Stores
Industry Wage Survey: Drug Manufacturing, September 1978 : Bulletin of the United States Bureau of Labor Statistics, No. 2077
Industry Wage Survey: Eating and Drinking Places
Industry Wage Survey: Educational Institutions: Nonteaching Employees
Industry Wage Survey: Electric and Gas Utilities
Industry Wage Survey: Fabricated Structural Metal
Industry Wage Survey: Fertilizer Manufacturing
Industry Wage Survey: Fluid Milk
Industry Wage Survey: Grain Mill Products
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Industry Wage Survey: Hospitals
Industry Wage Survey: Hotels and Motels
Industry Wage Survey: Industrial Chemicals
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Industry Wage Survey: Leather Tanning and Finishing
Industry Wage Survey: Life Insurance
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Industry Wage Survey: Meat Products
Industry Wage Survey: Men's and Boys' Shirts
Industry Wage Survey: Men's and Boys' Suits and Coats
Industry Wage Survey: Men's and Women's Footwear
Industry Wage Survey: Metal Mining
Industry Wage Survey: Metalworking Machinery Manufacturing
Industry Wage Survey: Millwork
Industry Wage Survey: Miscellaneous Plastic Products
Industry Wage Survey: Motion Picture Theaters
Industry Wage Survey: Motor Vehicles and Motor Vehicle Parts
Industry Wage Survey: Nonferrous Foundries
Industry Wage Survey: Nursing and Personal Care Facilities
Industry Wage Survey: Oil and Gas Extraction
Industry Wage Survey: Paints and Varnishes
Industry Wage Survey: Paperboard Containers and Boxes
Industry Wage Survey: Petroleum Refining
Industry Wage Survey: Pressed or Blown Glass and Glassware
Industry Wage Survey: Pulp, Paper, and Paperboard Mills
Industry Wage Survey: Scheduled Airlines
Industry Wage Survey: Semiconductors
Industry Wage Survey Series
Industry Wage Survey: Shipbuilding and Repairing
Industry Wage Survey: Southern Sawmills and Planing Mills
Industry Wage Survey: Structural Clay Products
Industry Wage Survey: Synthetic Fibers
Industry Wage Survey: Temporary Help Supply
Industry Wage Survey: Textile Mills
Industry Wage Survey: Textile Mills and Textile Dyeing and Finishing Plants
Industry Wage Survey: West Coast Sawmilling and Logging
Industry Wage Survey: Women's and Misses' Coats and Suits
Industry Wage Survey: Women's and Misses' Dresses
Industry Wage Survey: Wood Household Furniture
Industry Wage Survey: Wool Textiles
Industry Wage Survey: Work Clothing
Inflation and Growth : The Economic Policy Dilemma
Inflation Control : Hearing Before the Committee on Banking and Currency, House of Representatives, Eightieth Congress, Second Session, on S.J. Res. 157, July 29, 30, August 2, 3, and 4, 1948
Information Respecting United States Bonds, Paper Currency and Coin, Production of Precious Metals, Etc. : Revised July 1, 1915
Injuries and Accident Causes in Carpentry Operations : Bulletin of the United States Bureau of Labor Statistics, No. 1118
Injuries and Accident Causes in Fertilizer Manufacturing : a Detailed Analysis of Hazards and Injury-frequency Rates in 1946 by Region, Plant-Size, and Department : Bulletin of the United States Bureau of Labor Statistics, No. 949
Injuries and Accident Causes in Plumbing Operations: A Detailed Analysis of Accidents Experienced by Plumbers During 1948 and 1949 : Bulletin of the United States Bureau of Labor Statistics, No. 1079
Injuries and Accident Causes in Textile Dyeing and Finishing : Bulletin of the United States Bureau of Labor Statistics, No. 962
Injuries and Accident Causes in the Boilershop-Products Industry : Bulletin of the United States Bureau of Labor Statistics, No. 1237
Injuries and Accident Causes in the Brewing Industry, 1944 : Bulletin of the United States Bureau of Labor Statistics, No. 884
Injuries and Accident Causes in the Foundry Industry, 1942 : Bulletin of the United States Bureau of Labor Statistics, No. 805
Injuries and Accident Causes in the Longshore Industry, 1942 : Bulletin of the United States Bureau of Labor Statistics, No. 764
Injuries and Accident Causes in the Manufacture of Clay Construction Products : Bulletin of the United States Bureau of Labor Statistics, No. 1023
Injuries and Accident Causes in the Manufacture of Paperboard Containers: A Detailed Analysis of Hazards and of Injury Rates for 1950 by Region, Plant Size, and Operating Departments : Bulletin of the United States Bureau of Labor Statistics, No. 1139
Injuries and Accident Causes in the Manufacture of Pulp and Paper: A Detailed Analysis of Hazards and of Injury Rates for 1948 by Region, Plant Size, and Operating Departments : Bulletin of the United States Bureau of Labor Statistics, No. 1036
Injuries and Accident Causes in the Pulpwood-Logging Industry, 1943 and 1944 : Bulletin of the United States Bureau of Labor Statistics, No. 924
Injuries and Accident Causes in the Slaughtering and Meat-Packing Industry, 1943 : Bulletin of the United States Bureau of Labor Statistics, No. 855
Injuries and Accident Causes in Warehousing Operations: A Detailed Analysis of Injuries, Injury Rates, and Hazards for 1950, by Type of Warehouse, Region and Occupation : Bulletin of the United States Bureau of Labor Statistics, No. 1174
Injuries in Oil and Gas Drilling and Services : Bulletin of the United States Bureau of Labor Statistics, No. 2179
Injuries in the Logging Industry : Bulletin of the United States Bureau of Labor Statistics, No. 2203
Injuries Related to Servicing Equipment : Bulletin of the United States Bureau of Labor Statistics, No. 2115
Injuries Resulting From Falls From Elevations : Bulletin of the United States Bureau of Labor Statistics, No. 2195
Injuries Resulting From Falls on Stairs : Bulletin of the United States Bureau of Labor Statistics, No. 2214
Injuries to Construction Laborers : Bulletin of the United States Bureau of Labor Statistics, No. 2252
Injuries to Warehouse Workers : Bulletin of the United States Bureau of Labor Statistics, No. 2257
Injuries to Women in Personal Service Occupation in Ohio : Women's Bureau Bulletin, No. 151
Injury Rates by Industry
Inquiry Into Consumer Instalment Lending : A Progress Report on the Mobile Consumer Loan Survey
Inquiry Into Continental Illinois Corp. and Continental Illinois National Bank : Hearings Before the Subcommittee on Financial Institutions Supervision, Regulation, and Insurance of the Committee on Banking, Finance, and Urban Affairs, House of Representatives, Ninety-Eighth Congress, Second Session, September 18, 19 and October 4, 1984
An Inquiry Into the Nature and Effects of the Paper Credit of Great Britain
Inquiry on Membership in Federal Reserve System : Joint Hearings Before the Committees on Banking and Currency, Congress of the United States, Sixty-Eighth Congress, Pursuant to Public Act No. 503, October 2, 3, 4, 5, 9, 10, 11, and 12, 1923
In Senate, March 24, 1834 : Message from the Governor
Inside the Vault
Insolvency of Systemically Significant Financial Companies : Bankruptcy vs. Conservatorship/Receivership
The Installation and Maintenance of Toilet Facilities in Places of Employment : Women's Bureau Bulletin, No. 99
Installment Buying by City Consumers in 1941 : Bulletin of the United States Bureau of Labor Statistics, No. 773
Institutional Investors and the U.S. Government Securities Market : Staff Study
Instructions to Examiners and Assistant Examiners of the Federal Deposit Insurance Corporation
Insurance of Bank Obligation in Six States During the Period 1829-1866
Intensity of Relief : July 1933 - June 1935, Series I, No. 18
The Inter-Ally Debts : An Analysis of War and Post-War Public Finance, 1914-1923
Interchange Fees and Payment Card Networks : Economics, Industry Developments, and Policy Issues
Intercity Differences in Costs of Living in March, 1935, 59 Cities, Research Monograph XII
Inter-City Differences in the Cost of Living, Series I, No. 20
Intercity Variations in Wage Levels : Bulletin of the United States Bureau of Labor Statistics, No. 793
Interim Adjustment of Consumers' Price Index: Correction of New Unit Bias in Rent Component of Consumers' Price Index and Relative Importance of Items : Bulletin of the United States Bureau of Labor Statistics, No. 1039
Intermediate Targets and Indicators for Monetary Policy : A Critical Survey
International Banking Act of 1977 : Hearings Before the Subcommittee on Financial Institutions Supervision, Regulation and Insurance of the Committee on Banking, Finance and Urban Affairs, House of Representatives, Ninety-Fifth Congress, First Session, on H.R. 7325, July 12, 13, and 19, 1977
International Banking Act of 1978
International Banking Act of 1978 : Hearing Before the Subcommittee on Financial Institutions of the Committee on Banking, Housing, and Urban Affairs, United States Senate, Ninety-Fifth Congress, Second Session, on H.R. 10899, June 21, 1978
International Banking Facility Deposit Insurance Act
International Comparison of Unit Labor Cost in the Iron and Steel Industry, 1964: United States, France, Germany, United Kingdom : Bulletin of the United States Bureau of Labor Statistics, No. 1580
International Comparisons of Unemployment : Bulletin of the United States Bureau of Labor Statistics, No. 1979
International Documents on the Status of Women : Women's Bureau Bulletin, No. 217
International Economic Trends
International Economic Update
International Labor Legislation and the Society of Nations : Bulletin of the United States Bureau of Labor Statistics, No. 254
International Lending Supervision Act of 1983
International Monetary Fund : Materials Relating to the COVID-19 Pandemic
International Monetary Fund : Press Releases Relating to the Financial Crisis of 2007-2009
International Monetary Policies
International Monetary System, the European Monetary System, and a Single European Currency in a Single European Market
International Money Laundering Abatement and Anti-Terrorist Financing Act of 2001
International Petrodollar Crisis : Hearings Before the Subcommittee on International Finance of the Committee on Banking and Currency, House of Representatives, Ninety-Third Congress, Second Session, July 9 and August 13, 1974
International Seamen's Union of America: A Study of Its History and Problems : Bulletin of the United States Bureau of Labor Statistics, No. 342
Interpretations of Banking Act of 1933 : A Series of Letters Sent to Various Banks in Answer to Requests for Information
Interpreting Early Warnings of Inflation : A Study of Statistical Indicators
Interpreting Movements in Broad Money
Interviews on the Banking and Currency Systems of Canada : By a Subcommittee of the National Monetary Commission
Interviews on the Banking and Currency Systems of Canada : By a Subcommittee of the National Monetary Commission, Box 5, Item 6
Interviews on the Banking and Currency Systems of England, Scotland, France, Germany, Switzerland, and Italy
Interviews on the Banking and Currency Systems of England, Scotland, France, Germany, Switzerland, and Italy, Box 7, Item 1
In the Balance : Perspectives on Household Balance Sheets
Introduction to Economic Science
Introduction to Flow of Funds, 1975
Introduction to Flow of Funds, 1980
Investigation of Economic Problems : Hearings Before the Committee on Finance, United States Senate, Seventy-Second Congress, Second Session, Pursuant to S. Res. 315, February 13 to 28, 1933
Investigation of the Financial Condition of the United States : Hearings Before the Committee on Finance, United States Senate, Eighty-Fifth Congress, First Session (1957-1958)
Invest in Women, Invest In America : A Comprehensive Review of Women in the U.S. Economy
Investment Company Act and Investment Advisers Act of 1940
Investments in Capital Structure of Banks and Loans to Banks and Others By the Reconstruction Finance Corporation
Iowa Women in Industry : Women's Bureau Bulletin, No. 19
Is Payment Tokenization Ready for Primetime? : Perspectives from Industry Stakeholders on the Tokenization Landscape
Issue Briefs of the United States Women's Bureau
J
January 1957 Economic Report of the President : Hearings Before the Joint Economic Committee, Congress of the United States, Eighty-fifth Congress, First Session, Pursuant to Sec. 5 (a) of Public Law 304 (79th Congress), January 28, 29, 30, 31, February 1, 4, 5, and 6, 1957
January 1963 Economic Report of the President : Hearings Before the Joint Economic Committee, Congress of the United States, Eighty-Eighth Congress, First Session, Pursuant to Sec. 5(a) of Public Law 304 (79th Congress)
Japanese Evacuation from the West Coast, 1942 : Final Report
Job Histories of Women Workers at the Summer Schools, 1931-34 and 1938 : Women's Bureau Bulletin, No. 174
Job Horizons for College Women : Women's Bureau Bulletin, No. 288 (Revised)
Job Performance and Age: a Study in Measurement : Bulletin of the United States Bureau of Labor Statistics, No. 1203
Job Redesign for Older Workers: Ten Case Studies : Bulletin of the United States Bureau of Labor Statistics, No. 1523
Jobseeking Methods Used by American Workers : Bulletin of the United States Bureau of Labor Statistics, No. 1886
Jobs for Which Apprenticeships Are Available
Jobs for Which Junior College, Technical Institute, or Other Specialized Training is Usually Required
Jobs for Which You Can Qualify If You're a High School Graduate
Jobs for Which You Can Qualify If You're Not a High School Graduate
Jobs for Which You Can Qualify If You're Not a High School Graduate
Jobs for Which You Can Train Through Apprenticeship
Jobs for Which You Probably Will Need a College Education
Jobs for Which You Probably Will Need Some College Or Specialized Training
Jobs, Production, and Living Standards
Job Tenure and Occupational Change, 1981 : Bulletin of the United States Bureau of Labor Statistics, No. 2162
Job Vacancy Statistics : Hearings Before the Subcommittee on Economic Statistics of the Joint Economic Committee, Congress of the United States, Eighty-Ninth Congress, Second Session, May 17 and 18, 1966
John W. Snyder Papers, 1918-1980
The Joint Economic Report : Report of the Joint Economic Committee, Congress of the United States, on the Economic Report of the President
Joint Industrial Control in the Book and Job Printing Industry : Bulletin of the United States Bureau of Labor Statistics, No. 481
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The Sphere of GovernmentNineteenth Century Theories: 3. Thomas Henry Huxley - Foundation for Economic Education
The Sphere of GovernmentNineteenth Century Theories: 3. Thomas Henry Huxley
Henry Hazlitt, noted economist, author, editor, reviewer and columnist, here continues a series of nineteenth century theories on the sphere of government.
His views on the proper sphere of government are principally set forth in two essays: “Administrative Nihilism” (1871), and “Government: Anarchy or Regimentation?” (1890).
In the first of these essays, he begins with an unsympathetic description of the opponents of wide-ranging state powers:
“To these opponents, the Education Act is only one of a number of pieces of legislation to which they object on principle; and they include under like condemnation the Vacci nation Act, the Contagious Diseases Act, and all other sanitary Acts; all attempts on the part of the State to prevent adulteration, or to regulate injurious trades; all legislative interference with anything that bears directly or indirectly on commerce, such as shipping, harbors, railways, roads, cab-fares, and the carriage of letters; and all attempts to promote the spread of knowledge by the establishment of teaching bodies . . . . According to their views, not a shilling of public money must be bestowed upon a public park or pleasure ground; not sixpence upon the relief of starvation, or the cure of disease. Those who hold these views support them by two lines of argument. They enforce them deductively by arguing from an assumed axiom, that the State has no right to do anything but protect its subjects from aggression. The State is simply a policeman, and its duty is neither more nor less than to prevent robbery and murder and enforce contracts . . . . On the other hand these views are supported a posteriori, by an induction from observation, which professes to show that whatever is done by a Government beyond these negative limits, is not only sure to be done badly, but to be done much worse than private enterprise would have done the same thing.”
Huxley declares that he is unconvinced by these arguments, or by that “great negative commandment—“Thou shalt not allow any man to interfere with the liberty of any other man.’” He goes on:
“If my next-door neighbor chooses to have his drain in such a state as to create a poisonous atmosphere, which I breathe at the risk of typhoid and diphtheria, he restricts my just freedom to live just as much as if he went about with a pistol, threatening my life; if he is allowed to let his children go unvaccinated, he might as well be allowed to leave strychnine lozenges about in the way of mine; and if he brings them up untaught and untrained to earn their living, he is doing his best to restrict my freedom, by the burden of taxation for the support of jails and workhouses, which I have to pay.”
Huxley dismisses offhand the argument that, “If the right of the State to step beyond the assigned limits is admitted at all, there is no stopping.” And he blandly concludes: “The Government, being nothing but the corporate reason of the community, will find out when State interference has been carried far enough.”
No Fixed Limits as to Extent of Government Action
It is not only modern libertarians who will rub their eyes today at this argument, but the great majority who write on political affairs. It is naive to identify the politicians in office with the community, or to conclude that those who gain political powers can be safely trusted to decide the proper limits of those powers. But Huxley does not hesitate to carry this assertion to its logical conclusion, and to tell us: “I do not see how any limit whatever can be laid down as to the extent to which, under some circumstances, the action of Government may be rightfully carried . . . . The question where to draw the line between those things with which the State ought, and those with which it ought not, to interfere, then, is one which must be left to be decided separately for each individual case.”
So we are back to “the merits of the case” argument that Spencer had so eloquently derided—an argument which could be finally used to justify the totalitarian state.
Huxley returned to the subject of the proper sphere of State power in two other essays, both published in 1890. The first of these was “Natural Rights and Political Rights.” I commend it to anyone who still takes Natural Law or Natural Rights doctrines seriously. Huxley regards such doctrines as the product of “the vicious method of a priori political speculation.” Their plausibility depends upon a confusion between two senses of the word “right”—right as might, the “natural right” of tigers, for example, to attack and devour men—and moralright, which is utterly different. Huxley’s essay is, incidentally, a devastating analysis of the theories of Henry George’s Progress and Poverty.
But some of Huxley’s own deductions combine truth with error. For example: “It is a necessary condition of social existence that men should renounce some of their freedom of action; and the question of how much is one that can by no possibility be determined a priori.” The first part of that sentence is almost a truism; the part after the semicolon is a contention that, as we shall see, no freedom-loving democracy today has been willing to concede.
Anarchy or Regimentation
The second 1890 essay by Huxley to which I earlier referred, “Government: Anarchy or Regimentation?” bore directly on the question of the proper province of the State.
In this essay Huxley undertook to examine in turn the answer to this question of practically all the great political philosophers of modern times, up to 1890. Specifically mentioned and dealt with were Hobbes, Locke, Morelly, Mably, Rousseau, Von Humboldt, Dunoyer, J. S. Mill, Stirner, and Auberon Herbert. And he rejected all of them alike (with the exception of Dunoyer) for building their case on abstract a priori assumptions regarding a previous “state of nature” and a subsequent “social contract.” Huxley pointed out, however, that this had led them into two opposite camps: on the one hand, that espoused by Hobbes, Morelly, Mably and Rousseau, which justified “Regimentation” (the description suggested by Huxley) and the absolute power of the State; and, on the other hand, “Individualism,” which Huxley condemned as equivalent to anarchy. He summed up:
“Thus the whole fabric of a priori political speculation which we have had under consideration is built upon the quicksand of fictitious history. So far as this method of establishing their claims is concerned, Regimentationand Individualism—enforced Socialism and Anarchy—are alike out of court.”
And what, then, is Huxley’s own conclusion? One would expect him to come back once more to the conclusion of his “Administrative Nihilism” essay of 1871, that “the question of where to draw the line between those things which the State ought, and those with which it ought not, to interfere . . . is one which must be left to be decided separately for each individual case.” Perhaps he considers this conclusion implicit, but he does not draw it explicitly. Instead, he is content to tell us that the task which he set before himself was “simply a destructive criticism of a priori political philosophy, whether regimental or individualistic”; and if he has done this successfully, he implies, he has done all that a reader is entitled to ask of one essay.
He goes on to declare: “The political problem of problems is how to deal with overpopulation, and it faces us on all sides.” But whether or not this is true, or seemed true at the time he wrote it, it is irrelevant to the problem—the proper province of government—that his essay started out to discuss. No matter what the “problem of problems” is, the question before him was whoshall have the power to decide it.
Now let us ask whether Huxley did in fact prove that there is no room for “a priori assumptions” or deductive reasoning in political philosophy.
It is quite true that Locke’s assumptions, for example, do seem to rest in part on fictitious history. Huxley’s sarcasm makes the most of this:
“To listen to Locke, one would imagine that a general meeting of men living in the state of nature having been called to consider the ‘defects’ of their condition, and somebody being voted to the tree (in the presumable absence of chairs), this earliest example of a constituent assembly resolved to form a governmental company, with strictly limited liability, for the purpose of defending liberty and property,” and so forth.
Individualism Attacked
All this is good fun, but it does not prove that Locke was wrong in assuming that “no one ought to harm another in his life, liberty, or possessions”; that it is the province of government to ensure this state of affairs, and that this was a sufficient task to give any one agency the power to carry out.
I can think of no eminent Liberal of the nineteenth century, and certainly none holding political office, who ever propounded such a view of his duties as that laid down in the clause I have italicized. Liberals deprecated the piling up of legal prohibitions and compulsions, burdensome taxation, government efforts to redistribute wealth and income, and other specific interventions in economic life, but they believed in enforcing a fundamental framework of law to protect their citizens against fraud, theft, and violence, internal or external. This in itself, if done well, is a tremendous assignment.
Today it is not done well anywhere; because—arguing from “the merits of the case”—too many other assignments are loaded onto the State, designed to save at least some of us all effort and risk. Once we assume that it is a legitimate function of the state to redistribute income, for example, we practically guarantee that the majority of politicians running for office will be charlatans and demagogues, outpromising each other concerning the largess they can provide to the nonproductive part of the population at the expense of the productive.
To return to Huxley’s argument: No doubt some of the leading political philosophers did base their theories on fictitious history, or on basic assumptions that were not justified. But Huxley seems to reject all “aprioristic” thinking in politics, which would mean that he rejected any attempt in advance to put any constitutional limits whatever on the sphere and power of the State. He apparently would have been satisfied with a constitution which read, simply: “The government may pass and enforce any law it sees fit, guided only by what it regards as the merits of the individual case; and no part of any citizen’s freedom or property shall be respected if a majority of 51 percent or more decide otherwise.”
In his thinking in the physical sciences Huxley was a professed empiricist, and suspicious of all mere deduction. Nevertheless, in his book on Hume, we find him writing with approval: “. . . [T]he form of the crest of every wave that breaks, wind-driven, on the sea-shore, and the direction of every particle of foam that flies before the gale, are the exact effects of definite causes; and, as such, must be capable of being determined, deductively, from the laws of motion and the properties of air and water.” [ 1 ]
The scientific belief in the law of universal causation is based on something more than frequent observance of it in particular cases, plus no certain knowledge of contrary cases. The concept of universal causation is built into our thinking. We can hardly conceive of an effect without a cause. In any case, its prior assumption is necessary for all rational deduction and all rational action.
Established Principles of Law to Prevent Arbitrary Abuse
Perhaps our basic political, legal or moral principles can never enjoy the same type of definitude and certainty as the laws of physics. But the discovery and adoption of such basic principles seem no less necessary as guides in our political, legal, and moral life than the laws of physics in our physical scientific reasoning. We do not leave it to an individual judge, for example, to decide the punishment for each case of fraud, theft, assault or murder—or to decide what actions he is entitled to punish at all—simply in accordance with his own judgment of the individual iniquity of each act. The law has already sought to define and categorize each type of offense and to prescribe minimum and maximum penalties. The principles and definitions of law have been worked out over the centuries, by careful reasoning and respect for precedent, precisely to limit or prevent any capricious or arbitrary exercise of police or judicial power.
The same thing has happened in the evolution of constitutional law. In the United States, neither a city, a state, nor our federal government can enact or enforce any law it sees fit, guided only by %he merits of the individual case.” The Constitution, adopted in 1787, assigned the Congress, the President, and the judiciary only enumeratedpowers. And then, two years later, to nail things down, a Bill of Rights was adopted, beginning with the First Amendment: “Congress shall make no law respecting an establishment of religion, or prohibiting the free exercise thereof; or abridging the freedom of speech, or of the press; or the right of the people peaceably to assemble . . .” And so on through nine other amendments.
Huxley should have remembered that. And he should have remembered, also, that though not all modern democratic governments have written constitutions, and England still does not, the English Constitution was even in his own day—one might say especially in his own day—a very real and unmistakable protection against government arbitrariness or tyranny. No less than our own it protected the citizen’s freedom of speech, freedom from arbitrary arrest, freedom of religion, and freedom of association.
The English Constitution exists in no single document. It is made up of Magna Carta, the Petition of Right act, the Habeas Corpus act, the Bill of Rights and the Act of Settlement. But in addition to all these, it consists of innumerable statutes, a mass of custom and convention, hundreds of judicial decisions and precedents, and even, as the Encyclopedia Britannicahas suggested, of “textbooks, lawbooks, the writings of historians and political theorists, the biographies and autobiographies of statesmen,” and so on.
If Huxley had remembered all this, he would not so disdainfully have dismissed all the proposals of the older political philosophers as “mere apriorism.” That all political power tends to be abused, and that absolute power is certain to be abused, might reasonably have been suspected in advance. But even so it is no mere a priori conclusion. It has been forced on us by bitter and endlessly repeated experience.
Exactly where the boundaries of State power should be drawn, is one of the two great problems to which this series of articles is addressed, and which we have still to try to solve. But that they must be drawn by constitutional limitation somewhere, and unmistakably, is one conclusion no longer open to debate. What we have discovered, rather, is that in not a single country today have the existing constitutional limits on government power and interference in the lives of the citizens proved sufficient to prevent untold mischief. []
1. Hume.Ch. VI, “Propositions Concerning Necessary Truths.”
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Understanding power: the indispensable Chomsky 1565847032, 1992012032, 2942982993, 9781565847033, 9780099466062, 0099466066 - EBIN.PUB
A major new collection from " arguably the most important intellectual alive" (The New York Times). Noam Chomsk...
Understanding power: the indispensable Chomsky
1565847032, 1992012032, 2942982993, 9781565847033, 9780099466062, 0099466066
A major new collection from "arguably the most important intellectual alive" (The New York Times). Noam Chomsk
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Chomsky
Noam;Mitchell
Peter R(Editor);Schoeffel
John(Editor)
Citation preview
Understanding Power
Understanding Power
The Indispensable Chomsky
Explanatory footnotes available at WWW. understandingpower.com
Edited by Peter R. Mitchell and John Schoeffel
• THE NEW PRESS
NEW YORK
© 2002 by Noam Chomsky, Peter Rounds Mitchell, and John Schoeffel All rights reserved. No part of this book may be reproduced, in any form, without written permission from the publisher. Published in the United States by The New Press, New York, 2002 Distributed by W. W. Norton & Company, Inc., New York Explanatory footnotes available at www.understandingpower.com ISBN 1-56584-703-2 CIP data available The New Press was established in 1990 as a not-for-profit alternative to the large, commercial publishing houses currently dominating the book publishing industry. The New Press operates in the public interest rather than for private gain, and is committed to publishing, in innovative ways, works of educational, cultural, and community value that are often deemed insufficiently profitable. The New Press, 450 West 41st Street, 6th floor, New York, NY 10036 www.thenewpress.com Printed in Canada 19 18 17 16 15 14 13 12 11 10
Contents
Editors' Preface A Note on the Events of September II, 200 I Chapter One
XI XIlI
Weekend Teach-In: Opening Session
1
The Achievements of Domestic Dissidence
I
The U.S. Network of Terrorist Mercenary States
4
Overthrowing Third World Governments
6
Government Secrecy
10
The Media: An Institutional Analysis __ Testing the "Propaganda Model"
12 15
- The Media and Elite Opinion
18
Chapter Two
Filters on Reporting
24
Honest Subordination
30
"Fight it Better"; the Media and the Vietnam War
31
Teach-In: Over Coffee "Containing" the Soviet Union in the Cold War
37 37
Orwell's World and Ours
41
Contemporary Poverty
45
Religious Fanaticism
50
'The Real Anti-Semitism"
51
Ronald Reagan and the Future of Democracy
53
Two New Factors in World Affairs
58
Democracy Under Capitalism
60
The Empire
64
Change and the Future
67
Chapter Three Teach-In: Evening The Military- Industrial Complex The Permanent War Economy
70 70 73 v
vi
Contents
Chapter Four
Libyan and American Terrorism
77
The U.S. and the U.N.
84
Business, Apartheid, and Racism
88
Winning the Vietnam War "Genocide": the United States and Pol Pot Heroes and Anti-Heroes
90 92 93
"Anti - Intellectualism"
95
Spectator Sports
98
Western European Activism and Canada
101
Dispelling Illusions
103
Colloquy
106
The Totalitarian Strain
106
A Lithuania Hypothetical
109
Perpetuating Brainwashing Under Freedom Journalism LeMoyne-Style: A Sample of
II I
the Cynical Aspect
115
Rethinking Watergate
117
Escaping Indoctrination
120
Understanding the Middle East Conflict The Threat of Peace
123 126
Water and the Occupied Territories
129
Imperial Ambitions and the Arab Threat
131
Prospects for the Palestinians
134
Legitimacy in History
135
Qualifications to Speak on World Affairs; A
137
Presidential Campaign Chapter Five
Ruling the World
140
Soviet Versus Western Economic Development Supporting Terror "People's Democratic Socialist Republics"
140 144 145
Contents vii
Chapter Six
The Organ Trade The Real Crime of Cuba
146 148
Panama and Popular Invasions
151
Muslims and U.S. Foreign Policy
154
Haiti: Disturbance at an Export Platform
155
Texaco and the Spanish Revolution
159
Averting Democracy in Italy
160
P.R. in Somalia
163
The Gulf War
165
Bosnia: Intervention Questions
171
Toying With India
172
The Oslo Agreement and Imperialist Revival
174
Community Activists
177
Discussion Circle
177
The Early Peace Movement and a Change in the l970s
180
The Nuclear Freeze Movement
184
Awareness and Actions
186
Leaders and Movements
188
Levels of Change
189
Non-Violence
193
Transcending Capitalism
195
The Kibbutz Experiment 196 "Anarchism" and "Libertarianism"
199
Articulating Visions
201
"Want" Creation
203
Dissidents: Ignored or Vilified
204
Teaching About Resistance Isolation
211 212
Science and Human Nature
214
Charlatans in the Sciences
217
Adam Smith: Real and Fake
221
The Computer and the Crowbar
223
viii
Contents
Chapter Seven Intellectuals and Social Change The Leninist/Capitalist Intelligentsia Marxist "Theory" and Intellectual Fakery
224 224 227
Ideological Control in the Sciences and Humanities
Chapter Eight
231
The Function of the Schools
233
Subtler Methods of Control
238
Cruder Methods of Control The Fate of an Honest Intellectual
242 244
Forging Working-Class Culture
248
The Fraud of Modern Economics
251
The Real Market
255
Automation A Revolutionary Change in Moral Values
258 260
Popular Struggle Discovering New Forms of Oppression
267 267
Freedom of Speech
268
Negative and Positive Freedoms
272
Cyberspace and Activism
276
"Free Trade" Agreements
280
Defense Department Funding and "Clean Money" 284 The Favored State and Enemy States
286
Canada's Media
288
Should Quebec Separate from Canada?
291
Deciphering "China"
282
Indonesia's Killing Fields: U.S.-Backed Genocide 294 in East Timor Mass Murderers at Harvard
298
Changes in Indonesia
299
Nuclear Proliferation and North Korea
301
The Samson Option
303
The Lot of the Palestinians
305
P.L.O. Ambitions
310
The Nation-State System
313
Contents ix Chapter Nine Movement Organizing The Movie Manufacturing Consent Media Activism Self-Destruction of the U.S. Left
Chapter Ten
31 B 318 323 326
Popular Education
331
Third-Party Politics
333
Boycotts "A Praxis"
337 339
The War on Unions
339
Inner-City Schools
342
Defending the Welfare State
344
Pension Funds and the Law
346
Conspiracy Theories
348
The Decision to Get Involved
351
"Human Nature Is Corrupt"
355
Discovering Morality
356
Abortion
358
Moral Values
359
Turning Point Bringing the Third World Home
363
Welfare; the Pea and the Mountain
367
Crime Control and "Superfluous" People Violence and Repression International Capital; the New Imperial Age The Fairy Tale Economy Building International Unions Initial Moves and the Coming Crisis Elite Planning-Slipping Out of Hand Disturbed Populations Stirring The Verge of Fascism The Future of History Index
363 370 373 377 382 383 387 390 395 398 400 403
Editors' Preface
This book brings together the work of one of the most remarkable political activists and thinkers of our time. The discussions span a wide array of topics-from the workings of the modern media, to globalization, the education system, environmental crises, the military-industrial complex, activist strategies, and beyond-and present a revolutionary perspective for evaluating the world, and for understanding power. What distinguishes Noam Chomsky's political thinking is not anyone novel insight or single overarching idea. In fact, Chomsky's political stance is rooted in concepts that have been understood for centuries. Rather, Chomsky's great contribution is his mastery of a huge wealth of factual information, and his uncanny skill at unmasking, in case after case, the workings and deceptions of powerful institutions in today's world. His method involves teaching through examples-not in the abstract-as a means of helping people to learn how to think critically for themselves. The opening chapter introduces two themes that underlie nearly every aspect of the book: the progress of activism in changing the world, and the role of the media in staving off that activism and in shaping the way we think. The book follows a roughly chronological order, and begins with four discussions that took place in 1989 and 1990-the dawn of the postCold War era. These first chapters lay a foundation for Chomsky's subsequent analysis. The remaining chapters explore more recent developments in U.S. foreign policy, international economics, the domestic social and political environment, as well as activist strategies and problems. The book and its accompanying footnotes bring Chomsky's analysis right up to the present day. The internet has enabled us to place extensive documentation in our footnotes, which appear at the book's website. These vast online notes go well beyond mere citation to sources: they include commentary on the text, excerpts from government documents, significant quotations from newspaper articles and scholarship, and other important information. Our goal was to make accessible much of the evidence supporting each of Chomsky's factual assertions. The notes also add additional depth for those interested in a given topic. The complete footnotes-which are longer than the text itself-can be easily downloaded from the book's website, www.understandingpower.com x i
xii
Editors' Preface
(they can also be accessed through www.thenewpress.com). Information about obtaining a bound printout of the notes is available on the website, or by writing us in care of the publisher. The book was put together as follows. We transcribed tapes of dozens of question-and-answer sessions, edited them for readability, then reorganized and combined them to eliminate repetition and present the analysis in a coherent progression of topics and ideas. Our aim was to compile an overview of Chomsky's political thought that combines the rigor and documentation of his scholarly books with the accessibility of the interview format. Always we remained faithful to Chomsky's own language and answers-and he reviewed the text-but it was necessary to make superficial alterations for structural and stylistic reasons. Most of the material is from seminar-style discussions with groups of activists, or from question periods after public talks, held between 1989 and 1999. Some of the answers in chapters 6, 7, 8 and 9 are taken from conversations between Chomsky and Michael Albert. Questioners are identified as "Man" or "Woman" because frequently this device reveals when the same person is pursuing a line of questioning, or whether somebody else has taken over. We have personally checked and verified the sources cited in the footnotes, except for certain foreign language materials. Most of the sources are those Chomsky relied upon when making his comments in the text, but some are not. Emily Mitchell's assistance in retrieving reams of this material in the final months of our work on this project was invaluable. We direct readers to footnote 67 of chapter 1 for discussion of one common misunderstanding regarding the footnotes: that the frequent citation to articles from the mainstream media is at odds with the "Propaganda Model" of the media, which Chomsky outlines in chapter 1. We want to thank our parents-Emily and George Mitchell and Ron and Jone Schoeffel-whose support made the book possible. -The Editors
Note on the Events of September 11, 200 1
As this book was going to print, hijacked airplanes hit the World Trade r and Pentagon, killing thousands and potentially triggering major repercussions in U.S. society and in the world. The U.S. media devoted huge rage to the attacks and their aftermath. But, overwhelmingly, the media omitted a critical, accurate discussion of the context in which they occurred. When President Bush and U.S. officials announced that "America was targeted for attack because we're the brightest beacon for freedom and opportunity in the world," the mainstream media in the U.S. mostly echoed : refrains. A lead analysis in the New York Times stated that the perpetrators had acted out of "hatred for the values cherished in the West as freedom, tolerance, prosperity, religious pluralism and universal suffrage." Glaringly missing from the U.S. media's coverage was a full and realistic account of U.S. foreign policy and its effects around the world. It was hard ;0 find anything but a passing mention of the immense slaughter of Iraqi civilians during the Gulf War, the devastation of Iraq's population by U.S.instigated sanctions throughout the past decade, the U.S's crucial role in supporting Israel's 35-year occupation of Palestinian territories, its support for brutal dictatorships throughout the Middle East that repress the local populations, and on and on. Similarly absent was any suggestion that U.S. foreign policy should in fundamental ways be changed. This book was compiled before the events of September 11,2001. But answers to many of the most important questions presented by those attacks will be found here. Why does the media provide such a limited and uncritical perspective, and such inaccurate analysis? What is the basis of U.S. foreign policy and why does it engender such widespread hatred of the U.S.? What can ordinary citizens do to change these situations? As Chomsky noted right after the attacks, "The people in the advanced countries now face a choice: we can express justified horror, or we can seek to understand what may have led to the crimes. If we refuse to do the latter, we will be contributing to the likelihood that much worse lies ahead." From our frightening, current vantage point, the discussions collected in this book seem more urgent than ever. We hope that the book will provide a starting point for understanding, and will contribute to the critical debates-and changes-that must now occur. xiii
2
Teach-In: Over Coffee Based primarily on discussions at Rowe, Massachusetts, April 15-16, 1989.
"Containing" the Soviet Union in the Cold War WOMAN: Dr. Chomsky, it seems the terms of political discourse themselves are a tool for propagandizing the population. How is language used to prevent us from understanding and to disempower us? Well, the terminology we use is heavily ideologically laden, always. Pick your term: if it's a term that has any significance whatsoever-like, not "and" or "or"-it typically has two meanings, a dictionary meaning and a meaning that's used for ideological warfare. So, "terrorism" is only what other people do. What's called "Communism" is supposed to be "the far left": in my view, it's the far right, basically indistinguishable from fascism. These guys that everybody calls "conservative," any conservative would turn over in their grave at the sight of them-they're extreme statists, they're not "conservative" in any traditional meaning of the word. "Special interests" means labor, women, blacks, the poor, the elderly, the young-in other words, the general population. There's only one sector of the population that doesn't ever get mentioned as a "special interest," and that's corporations, and business in general-because they're the "national interest." Or take "defense": I have never heard of a state that admits it's carrying out an aggressive act, they're always engaged in "defense," no matter what they're doing-maybe "preemptive defense" or something. Or look at the major theme of modern American history, "containment" as in, "the United States is containing Soviet expansionism." Unless you accept that framework of discussion when talking about international affairs in the modern period, you are just not a part of accepted discourse here: everybody has to begin by assuming that for the last half century the United States has been "containing" the Soviet Union. 37
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Understanding Power
Well, the rhetoric of "containment" begs all questions-once you've accepted the rhetoric of "containment," it really doesn't matter what you say, you've already given up everything. Because the fundamental question is, is it true? Has the United States been "containing" the Soviet Union? Well, you know, on the surface it looks a little odd. I mean, maybe you think the Soviet Union is the worst place in history, but they're conservative whatever rotten things they've done, they've been inside the Soviet Union and right around its borders, in Eastern Europe and Afghanistan and so on. They never do anything anywhere else. They don't have troops stationed anywhere else. They don't have intervention forces positioned all over the world like we do.1 So what does it mean to say we're "containing" them? We've been talking about the media and dumping on them, so why not turn to scholarship? Diplomatic history's a big field, people win big prizes, get fancy professorships. Well, if you look at diplomatic history, it too is in the framework of "containment," even the so-called dissidents. I mean, everybody has to accept the premise of "containment," or you simply will not have an opportunity to proceed in these fields. And in the footnotes of the professional literature on containment, often there are some revealing things said. For example, one of the major scholarly books on the Cold War is called Strategies of Containment, by John Lewis Gaddis-it's the foremost scholarly study by the top diplomatic historian, so it's worth taking a look at. Well, in discussing this great theme, "strategies of containment," Gaddis begins by talking about the terminology. He says at the beginning: it's true that the term "containment" begs some questions, yes it presupposes some things, but nevertheless, despite the question of whether it's factually accurate, it still is proper to adopt it as the framework for discussion. And the reason why it's proper is because it was the perception of American leaders that they were taking a defensive position against the Soviet Union-so, Gaddis concludes, since that was the perception of American leaders, and since we're studying American history, it's fair to continue in that framework.2 Well, just suppose some diplomatic historian tried that with the Nazis. Suppose somebody were to write a book about German history and say, "Well, look, Hitler and his advisors certainly perceived their position as defensive"-which is absolutely true: Germany was under "attack" by the Jews, remember. Go back and look at the Nazi literature, they had to defend themselves against this virus, this bacillus that was eating away at the core of modern civilization-and you've got to defend yourself, after all. And they were under "attack" by the Czechs, and by the Poles, and by European encirclement. That's not a joke. In fact, they had a better argument there than we do with the Soviet Union-they were encircled, and "contained," and they had this enormous Versailles debt stuck on them for no reason after World War I. Okay, so suppose somebody wrote a book saying: "Look, the Nazi leadership perceived themselves as taking a defen-
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sive stance against external and internal aggression; it's true it begs some questions, but we'll proceed that way-now we'll talk about how they defended themselves against the Jews by building Auschwitz, and how they defended themselves against the Czechs by invading Czechoslovakia, how they defended themselves against the Poles, and so on." If anybody tried to do that, you wouldn't even bother to laugh-but about the United States, that's the only thing you can say: it's not just that it's acceptable, it's that anything else is unacceptable. And when you pursue the matter further, it becomes even more interesting. So for example, in this same book Gaddis points out-again, in sort of a footnote, an aside he doesn't elaborate on-that it's a striking fact that when you look over the American diplomatic record since World War II, all of our decisions about how to contain the Soviet Union, like the arms buildups, the shifts to detente, all those things, reflected largely domestic economic considerations. Then he sort of drops the point.3 Well, what does that mean? What does Gaddis mean by that? There he's beginning to enter into the realm of truth. See, the truth of the matter, and it's very well supported by declassified documents and other evidence, is that military spending is our method of industrial management-it's our way of keeping the economy profitable for business. So just take a look at the major declassified documents on military spending, they're pretty frank about it. For example, N.S.C. 68 [National Security Council Memorandum 68] is the major Cold War document, as everybody agrees, and one of the things it says very clearly is that without military spending, there's going to be an economic decline both in the United States and world-wide-so consequently it calls for a vast increase in military spending in the U.S., in addition to breaking up the Soviet Union.4 You have to remember the context in which these decisions were being made, after all. This was right after the Marshall Plan had failed, right after the post-war aid programs had failed. There still had been no success as yet in reconstructing either the Japanese or Western European economies and American business needed them; American manufacturers needed those export markets desperately. See, the Marshall Plan was designed largely as an export-promotion operation for American business, not as the noblest effort in history and so on. But it had failed: we hadn't rebuilt the industrial powers we needed as allies and reconstructed the markets we needed for exports. And at that point, military spending was considered the one thing that could really do it, it was seen as the engine that could drive economic growth after the wartime boom ended, and prevent the U.S. from slipping back into a depression.s And it worked: military spending was a big stimulus to the U.S. economy, and it led to the rebuilding of Japanese industry, and the rebuilding of European industry-and in fact, it has continued to be our mode of industrial management right up to the present. So in that little comment Gaddis was getting near the main story: he was saying, postwar American decisions on rearmament and detente have been keyed
40
Understanding Power
to domestic economic considerations-but then he drops it, and we go back to talking about "containment" again. And if you look still closer at the scholarship on "containment," it's even more intriguing. For example, in another book Gaddis discusses the American military intervention in the Soviet Union right after the Bolshevik Revolution-when we tried to overthrow the new Bolshevik government by force-and he says that was defensive and that was containment: our invasion of the Russian land mass. And remember, I'm not talking about some right-wing historian; this is the major, most respected, liberal diplomatic historian, the dean of the field: he says the military intervention by 13 Western nations in the Soviet Union in 1918 was a "defensive" act. And why was it defensive? Well, there's a sense in which he's right. He says it was "defensive" because the Bolsheviks had declared a challenge to the existing order throughout the West, they had offered a challenge to Western capitalism and naturally we had to defend ourselves. And the only way we could defend ourselves was by sending troops to Russia, so that's a "defensive" invasion, that's" defense." 6 And if you look at that history in more detail, you'll find the point is even more revealing. So for example, right after the Bolshevik Revolution, American Secretary of State Robert Lansing warned President Wilson that the Bolsheviks are "issuing an appeal to the proletariat of all nations, to the illiterate and mentally deficient, who by their very numbers are supposed to take control of all governments." And since they're issuing an appeal to the mass of the population in other countries to take control of their own affairs, and since that mass of the population are the "mentally deficient" and the "illiterate"-you know, all these poor slobs out there who have to be kept in their place, for their own good-that's an attack on us, and therefore we have to defend ourselves.? And what Wilson actually did was to "defend ourselves" in the two obvious ways: first by invading Russia to try to prevent that challenge from being issued, and second by initiating the Red Scare at home [a 1919 campaign of U.S. government repression and propaganda against "Communists"] to crush the threat that anyone here might answer the appeal. Those were both a part of the same intervention, the same "defensive" intervention. And it's the same right up until today. Why do we have to get rid of the Sandinistas in Nicaragua? In reality it's not because anybody really thinks that they're a Communist power about to conquer the Hemisphere-it's because they were carrying out social programs that were beginning to succeed, and which would have appealed to other people in Latin America who want the same things. In 1980 the World Bank estimated that it would take Nicaragua ten years just to get back to the economic level it had in 1977, because of the vast destruction inflicted at the end of the Somoza reign [the four-decade Nicaraguan family dictatorship ousted by the Sandinista revolution in July 1979]. But nevertheless, under the Sandinista government Nicaragua was in fact beginning economic development: it was
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establishing health programs, and social programs, and things were starting to improve for the general population there.8 Well, that set off the alarm bells in New York and Washington, like it always does, and we had to stop it-because it was issuing an appeal to the "illiterate and mentally deficient" in other desperate countries, like Honduras and Guatemala, to do the same thing. That's what U.S. planners call the "domino theory," or the "threat of a good example," and pretty soon the whole U.S.-dominated system starts to fall apart.9 Orwell's World and Ours Well, all of that is within the rhetoric of "containing" Communism and we could easily go on. But there's one word. You look at any other term of political discourse, and you're going to find the same thing: the terms of political discourse are designed so as to prevent thought. One of the main ones is this notion of "defense." So look at the diplomatic record of any country you want-Nazi Germany, the Soviet Union, Libya, pick your favorite horror-story-you'll find that everything they ever did was "defensive"; I'm sure if we had records from Genghis Khan we would find that what he was doing was "defensive" too. And here in the United States you cannot challenge that-no matter how absurd it gets. Like, we can be "defending" South Vietnam. I have never seen in the media, never in thirty years that I have been looking carefully, one phrase even suggesting that we were not defending South Vietnam. Now, we weren't: we were attacking South Vietnam. We were attacking South Vietnam as clearly as any aggression in history. But try to find one phrase anywhere in any American newspaper, outside of real marginal publications, just stating that elementary fact. It's unstatable.10 It's unstatable in the scholarly literature. Gaddis again, when he talks about the battle of Dienbienphu, where the French made their last stand to keep colonial control over Indochina, he describes it as a defensive struggle. 11 McGeorge Bundy, in his book on the history of the military system, talks about how the United States toyed with the idea of using nuclear weapons in 1954 to help the French maintain their position at Dienbienphu, and he says: we were thinking about it to assist the French in their "defense" of Indochina.12 He doesn't say defense against whom, you know, because that would be too idiotic-like, was it defense against the Russians or something? No. They were defending Indochina against the Indochinese.13 But no matter how absurd it is, you cannot question that in the United States. I mean, these are extremes of ideological fanaticism-in other countries, you could at least raise these kinds of questions. Some of you are journalists: try talking about the American "attack" on South Vietnam. Your editors will think you came from Mars or something, there was no such event in history. Of course, there was in real history.
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Understanding Power
Or take the idea that the United States is supporting "democracy" all over the world. Well, there's a sense in which that's true. But what does it mean? When we support "democracy," what do we support? I mean, is "democracy" something where the population takes part in running the country? Well, obviously not. For instance, why are El Salvador and Guatemala "democratic," but Nicaragua [i.e. under the Sandinista Party] not "democratic"? Why? Is it because two of them had elections and the other one didn't? No. In fact, Nicaragua's election [in 1984] was a hundred times as good as any election in El Salvador.14 Is it because there's a lack of popular political participation in Nicaragua? No. Is it because the political opposition can't survive there? No, the political opposition is barely harassed in Nicaragua; in El Salvador and Guatemala it's just murdered.15 Is it that there can't be an independent press in Nicaragua? No, the Nicaraguan press is one of the freest presses in the world, much more so than the American press has ever been-the United States has never tolerated a newspaper even remotely like La Prensa in Nicaragua [opposition paper supported by the U.S. during the contra war], not even close: in any time of crisis here, the American government has shut down even tiny dissident newspapers, forget a major newspaper funded by the foreign power that's attacking the country and which is openly calling for the overthrow of the government.16 That degree of freedom of the press is absolutely inconceivable here. In El Salvador, there was an independent press at one time-it was wiped out by the U.S.-backed security forces, who just murdered the editor of one newspaper and blew up the premises of the other. 15 Okay, that takes care of that independent press. So you know, by what criteria are El Salvador and Guatemala "democratic" and Nicaragua not? Well, there is a criterion: in Nicaragua [under the Sandinistas], business elements are not represented in dominating the state much beyond their numbers, so it's not a "democracy." In El Salvador and Guatemala, the governments are run by the military for the benefit of the local oligarchies-the landowners, rich businessmen, and rising professionals-and those people are tied up with the United States, so therefore those countries are "democracies." It doesn't matter if they blow up the independent press, and kill off the political opposition, and slaughter tens of thousands of people, and never run anything remotely like a free election all of that is totally irrelevant. They're "democracies," because the right people are running them; if the right people aren't running them, then they're not "democracies." And on this again there is uniformity: try to find anyone in the American press, anyone, who is willing to break ranks on the idea that there are four democracies in Central America and one totalitarian state [i.e. Sandinista Nicaragua] that never had a free election-just try to find one statement rebutting that. And if the killings in El Salvador and Guatemala are ever mentioned in the American press, they'll always call it "Death Squads Out of Control," or "Extremists Out of Control." Now, the fact of the matter is that the extremists are in Washington, and what they're
Chapter Two
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controlling are the Salvadoran and Guatemalan militaries-but you'll never find that in an American newspaper. Or just take this phrase "peace process," which we hear all the time. The phrase "peace process" has a dictionary meaning, it means "process leading to peace. " But that's not the way it's used in the media. The term "peace process" is used in the media to refer to whatever the United States happens to be doing at the moment-and again, that is without exception. So it turns out that the United States is always supporting the peace process, by definition. Just try to find a phrase in the U.S. media somewhere, anywhere, saying that the United States is opposing the peace process: you can't do it. Actually, a few months ago I said this at a talk in Seattle, and someone from the audience wrote me a letter about a week or so later saying he was interested, so he'd done a little research project on it. He took the New York Times computer database from 1980 (when it begins) up to the present, and pulled out every article that had the words" peace process" in it. There were like nine hundred articles or something, and he checked through each of them to see if there was any case in which the United States was opposing the peace process. And there wasn't, it was 100 percent. Well, you know, even the most august country in history, let's say by accident sometime, might not be supporting the peace process. But in the case of the United States, that just can't happen. And this is a particularly striking illustration, because during the 1980s the United States was the main factor in blocking two major international peace processes, one in Central America and one in the Middle East.I8 But just try to find that simple, obvious fact stated anywhere in the mainstream media. You can't. And you can't because it's a logical contradiction-you don't even have to do any grubby work with the data and the documents to prove it, it's just proven by the meaning of the words themselves. It's like finding a married bachelor or something-you don't have to do any research to show there aren't any. You can't have the United States opposing the peace process, because the peace process is what the United States is doing, by definition. And if anybody is opposing the United States, then they're opposing the peace process. That's the way it works, and it's very convenient, you get nice conclusions. MAN: Can I throw in another one? When you have a country which you can't even pretend is a democracy-there's no constitution, no parliament, there's an absolute monarch-you use the word "moderate. " Yeah, "moderate" is a word that means "follows U.S. orders"-as opposed to what's called" radical," which means" doesn't follow U.S. orders." "Radical" has nothing to do with left or right; you can be an ultra-rightwinger, but you're a "radical" if you don't follow U.S. orders. MAN: I have yet to see a single reference to Morocco's King Hassan as an "absolute monarch." He has the worst human rights record in the Arab
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Understanding Power
world, torture widespread, he invaded Western Sahara, disobeyed the World Court, one of the nastiest characters anywhere-I have never seen an article that didn't refer to him as a "moderate."19 That's right, because we have U.S. airbases in Morocco, and we get plenty of minerals from there, and so on. Or just take Saudi Arabia-Saudi Arabia is even described as "moderate" now.20 In fact, even Iraq is sometimes described as "moving towards moderation": Iraq is probably the worst terror-state in the world-death camps, biological warfare, anything you like. 21
MAN: How about Suharto [Indonesian dictator]-he's called a "moderate" too. Suharto, yeah-that's the most extreme case I've ever seen, in fact, I'm glad you mention it. This is a really astonishing one, actually. For example, there was an article in the Christian Science Monitor a couple years ago about the great business opportunities in Indonesia, and it said: after the Indonesian government stopped a Communist revolt in 1965, the West was very eager to do business with Indonesia's "new moderate leader, Suharto." 22 Well, who's Indonesia's "new moderate leader, Suharto"? Suharto is the guy who, no doubt with the backing of the United States, carried out a military coup in 1965 after which the Indonesian army slaughtered about 500,000 people within four months. Nobody knows the exact numbers-I mean, they gave 500,000, pick your number; it was mostly landless peasants.23 Well, that was very much welcomed in the West, the American media just loved it. For instance, James Reston, the New York Times's liberal columnist, had a column I remember called, "A Gleam of Light in Asia "things are really looking up. U.S. News and World Report had a story called, "Hope Where There Once Was None." 24 These were the kinds of headlines that were running throughout the U.S. press-and the reason was, Suharto had wiped out the only mass-based political party in Indonesia, the Communist Party, which had about fourteen million members at the time. The Times had an editorial saying basically: it's all great stuff, but the United States is right not to become too openly involved, because it doesn't look too good to wipe out 500,000 people-but it's going the right way, let's make sure it keeps going the right way. This was right at the time of the massacre.25 Well, that's Indonesia's "new moderate leader," Suharto. This is probably the most extreme case I've ever seen: this guy is one of the biggest mass murderers since Adolf Hitler.
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Contemporary Poverty WOMAN: Noam, I want to change gears for a moment if we could. You've said that you were politically aware as a young kid in the 1930s-I'm wondering, do you have any impressions of the differences between that time and today, in terms of general outlook and attitudes? How would you compare the two periods? Well, the Thirties were an exciting time-it was deep economic depression, everybody was out of a job, but the funny thing about it was, it was hopeful. It's very different today. When you go into the slums today, it's nothing like what it was: it's desolate, there is no hope. Anybody who's my age or more will remember, there was a sense of hopefulness back then: maybe there was no food, but there were possibilities, there were things that could be done. You take a walk through East Harlem today, there was nothing like that at the depths of the Depression-this sense that there's nothing you can do, it's hopeless, your grandmother has to stay up at night to keep you from being eaten by a rat. That kind of thing didn't exist at the depths of the Depression; I don't even think it existed out in rural areas. Kids didn't come into school without food; teachers didn't have to worry that when they walked out into the hall, they might get killed by some guy high on drugs-it wasn't that bad. There's really something qualitatively different about contemporary poverty, I think. Some of you must share these experiences. I mean, I was a kid back then, so maybe my perspective was different. But I remember when I would go into the apartment of my cousins-you know, broken family, no job, twenty people living in a tiny apartment-somehow it was hopeful. It was intellectually alive, it was exciting, it was just very different from today somehow. WOMAN: Do you attribute that to the raised political consciousness of that era as compared to now? It's possible: there was a lot of union organizing back then, and the struggles were very brutal. I remember it well. Like, one of my earliest childhood memories is of taking a trolley car with my mother and seeing the police wade into a strike of women pickets outside a Philadelphia textile mill, and beating them up-that's a searing memory. And the poverty was extreme: I remember rag-pickers coming to the door begging for money, lots of things like that. So it was not pretty by any means. But it was also not hopeless. Somehow that's a tremendous difference: the slums are now hopeless, there's nothing to do except prey on one another. In fact, a lot of life is hopeless today, even for middle-class kids. I mean, for the first time in I think human history, middle-class kids now assume they are not going to live as well as their parents-that's really something
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Understanding Power
new, that's never happened before.26 My kids, for example, assume that they are probably not going to live the way that we live. Think about it, that's never happened before in history. And they're probably right, except accidentally-like, some of them may, but on average they won't. MAN: Do you have an explanation of what's happened to the cities? I don't entirely understand it, to tell you the truth.27 You could see it beginning in the late 1940s-New York City, for example, started to become a hostile place around then. I mean, as a kid when I would go to New York, I would think nothing of walking through Central Park alone at night, or walking along Riverside Drive by the river alone at night-the kinds of things you wouldn't do now without a platoon of Marines around you, you just took for granted back then; you didn't even give it a second thought. You never thought twice about taking a walk through Harlem, let's say what the heck, you know? But that all began to change after the Second World War, and it changed throughout the whole United States: cities just became hostile. I mean, New York always had the reputation of being hostile, like there were always jokes about the guy lying in the street and everybody walking over him. But you just didn't feel that you were taking your life into your hands and that people there were going to kill you, the sense you get when you walk through a lot of the city today. And also, you didn't have the same sense of super-wealth right next to grinding poverty-like today you see people sitting at a fancy restaurant drinking wine, and some homeless person lying on the street right in front of them. There wasn't quite that kind of thing either. WOMAN: Is the change maybe related to the internationalization of the economy, and the broadening of the super-rich class here? Maybe. I really don't know, to tell you the truth, and I don't want to pretend that I know. But my feeling is, it's beyond just economics. I mean, there were radical differences in wealth at that time, and people in the slums were extremely poor-it's just that they weren't desolate. WOMAN: It wasn't such a consumer culture at the time. Yeah, certainly not to the extent that it is now-like, everybody didn't have a television set where they were seeing some impossible life in front of their eyes all the time. Although you had something like it, don't forget: in those days the movies were what television is today; you'd go to the movies for a dime, and that's where you'd get your fantasy world. And the movies were all glitter, all upper-class fake glitter. But it just didn't have the same
Chapter Two
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devastating effect, I don't know why. There's something really hopeless about contemporary life that's new, I think. MAN: The bomb had a lot to do with it. Maybe-but does that really account for what happens in the slums? Look, I mean, I never see much of it. In the late 1960s, I was with a mainly white group, RESIST [a national draft-resistance movement], but we had good contacts with the Black Panthers, and with them I did get into slum areas. In general, though, I don't tend to see the slums very much. But from the few times I've walked around poor areas of Harlem and other places like that since then, I just can't recall anything remotely like it in the 1930s, even in the poorest parts of Brownsville [a low-income section of Brooklyn]. Also, older friends of mine who've been teachers in New York since the 1920s tell me they think it's totally different today as well-kids were poor in the Thirties, but they weren't rat-bitten. WOMAN: For myself, as a radical who does a lot of political work in my community, the despair is unbelievable-what we have to fight against at the lowest rung is just incredible, I can really understand just giving up. Don't you have some explanation of how we've come to this point? Well, I think if you look over American history, you can point to at least a few factors behind it. This is an immigrant society, and before the Depression virtually every wave of immigrants who came here was more or less absorbed, at least the ones who wanted to stay-a lot of them didn't, remember; in fact, the rate of return was rather high during the peak periods of immigration.28 But for the immigrants who did stay, the United States really was a land of opportunity. So, my father could come from Russia and work in a sweatshop, and manage finally to get to college, and then see his son become a professor-that stuff was real. And it was real because there was a lot of manual labor around which could absorb the waves of immigrants: people could work in sweatshops for sixteen hours a day and make enough to live on, then accumulate a little excess, and things would gradually start to get better. But in the 1930s, there was a big break in this system-the Depression ended those opportunities. And the United States has basically never gotten out of the Depression. See, the post-World War II economic boom has been a different sort of economic growth from anything that ever happened before. For one thing, it's been basically state-funded and primarily centered in high technology based industries, which are tied to the military system. And that kind of economic growth just does not allow for absorbing new waves of immigrants. It allowed for it briefly during the Second World War, when there was a labor shortage and people could come off the farms in the South and work in the war industries. But that ended. And since then, the jobs have
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Understanding Power
mostly been in high-tech or in the service sector-which is rotten, you don't go anywhere. So there just aren't the same possibilities for people to move up: if you can get into high-tech industry, you probably were there already, and if you're working at sweeping the streets or something, that's where you're going to stay. Now, maybe that situation would have been livable if there hadn't been a new wave of immigration, but there was. There was a huge wave of immigration. It happened to have been internal immigration this time, but from the point of view of the society it was like a foreign wave: it came from rapid mechanization of agriculture in the South, which drove the black population, the former slaves, off the land. Then on top of that, there's also been a major influx of Hispanic immigration. So you had these two big waves of immigration coming up to the Northern cities, and nothing for them to do: they couldn't do what my father did, because there wasn't the same kind of manual labor going on which could occupy millions more workers. So what in fact happened is these two huge waves of immigrants were just herded into concentration camps, which we happen to call "cities." And the vast majority of them are never going to get out-just because there's nothing for them to do. The economy simply is not growing; I mean, the Gross National Product goes up, but it goes up in a way which does not constitute economic growth for a poor urban population. And with the decline of the traditional manufacturing industries in recent years, it's getting worse, not better. As capital becomes more fluid and it becomes easier for corporations to move production to the Third World, why should they pay higher wages in Detroit when they can pay lower wages in Northern Mexico or the Philippines? And the result is, there's even more pressure on the poorer part of the population here. And what's in effect happened is they've been closed off into inner-city slums-where then all sorts of other pressures begin to attack them: drugs, gentrification, police repression, cutbacks in limited welfare programs, and so on. And all of these things contribute to creating a very authentic sense of hopelessness, and also to real anti-social behavior: crime. And the crime is mostly poor people preying on one another, the statistics show that very clearly because the rich are locked away behind their barricades.29 You can see it very clearly when you drive through New York now: the differences in wealth are like San Salvador. I mean, I was giving a talk there a little while ago, and as you walk around it's kind of dramatic: there are these castles, and there are guards at the gate, and a limousine drives up and the people go inside; inside I guess it's very elegant and beautiful. But it's like living in a feudal system, with a lot of wild barbarians outsideexcept if you're rich, you don't ever see them, you just move between your castle and your limousine. And if you're poor, you've got no castle to protect you. MAN: You mentioned drugs having an impact on the problem-I'm wondering whether you agree with the theory that drugs were maybe intro-
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duced to the ghettos intentionally, to try to demoralize people there and keep them from coming together to organize to change things? It's a good question-activists who work in the ghettos and slums have been charging that for years. I mean, a lot of people have pointed out that just at the time when you started to get serious organizing in the urban ghettos in the 1960s, all of a sudden there was this huge flow of drugs which absolutely devastated the inner-city communities. And the communities just couldn't defend themselves against it: the parents couldn't do it, the churches couldn't do it, you've got guys hanging around on street corners giving ten-year-olds free drugs, and in a couple of months the neighborhood's gone. And the timing, in fact, was about when serious political organizing was beginning to take place. Beyond that, I don't know: maybe it was planned, maybe it just happened.30 But I think you can make a good case that the way the criminal justice system has been set up ever since then does have a lot to do with social control. So just take a look at the different prosecution rates and sentencing rules for ghetto drugs like crack and suburban drugs like cocaine, or for drunk drivers and drug users, or just between blacks and whites in general-the statistics are clear: this is a war on the poor and minorities.31 Or ask yourself a simple question: how come marijuana is illegal but tobacco legal? It can't be because of the health impact, because that's exactly the other way around-there has never been a fatality from marijuana use among 60 million reported users in the United States, whereas tobacco kills hundreds of thousands of people every year.32 My strong suspicion, though I don't know how to prove it, is that the reason is that marijuana's a weed, you can grow it in your backyard, so there's nobody who would make any money off it if it were legal. Tobacco requires extensive capital inputs and technology, and it can be monopolized, so there are people who can make a ton of money off it. I don't really see any other difference between the two of them, frankly--except that tobacco's far more lethal and far more addictive. But it's certainly true that a lot of inner-city communities have just been devastated by drugs. And you can see why people would want them-they do give you a sense of temporary relief from an intolerable existence, whatever else they might do. Plus I'm just convinced that by now a lot of the drug stuff is around mainly because people can make money off it-so I don't really think there's mu
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MEN'S / WOMEN'S HEATED VEST
OPERATING MANUAL
intelligent thermal technology inside
v.20230208.01 Download the most updated version on the clim8 website.
INTELLIGENT THERMAL TECHNOLOGY Powered by clim8® to employ the latest in personalized thermo-regulation. BACKED BY SCIENCE Mapped heat zones to maintain an ideal temperature.
SMART APP CONTROL Learns and reacts in real time to adapt to changing conditions.
Welcome to the future of workwear with the Carhartt Heated Vest powered by clim8® intelligent thermal technology.
Your gear features the latest in personalized thermo-regulation to efficiently respond to real-time temps, activity level and changing conditions.
Please read the operating manual carefully before operating the Heated Vest. Improper use may result in product damage.
IN THIS MANUAL
clim8® Technology................................................................4 What's In The Box? ................................................................ 5 Quick Start And Go ................................................................ 6 The clim8 App ..........................................................................7 Safety Warnings And Instructions .................................8 How To Use The Heated Vest? ....................................... 9 Troubleshooting................................................................... 10 Technical Specifications.................................................. 11 The Carhartt Built To Last Committment ............ 14 Regulatory Statements ..................................................... 14
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CLIM8® TECHNOLOGY Intelligent heating system monitors temperature and reacts to changes, maintaining comfort.
Armed with technological and scientific expertise, clim8® engineers are creating the next generation of intelligent thermal wearables that are born from work, and built to:
MONITOR temperature in real time
ANALYZE environment and activity
ACTIVATE heat automatically & safely when needed
REGULATE warmth to optimal comfort
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WHAT'S IN THE BOX?
One intelligent Heated Vest Contains a clim8® module with LED indicator (Protection: IP67*), a pouch, and a connecting socket for the battery
INSIDE
One rechargeable li-ion battery 3000mAh - 7.4V
One charger A battery charger with a charge indicator LED light
*IP67 means that the module is dustproof and waterproof to a depth of less than 1 meter for 30 minutes. Batteries and chargers are not IP-rated.
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QUICK START AND GO
1 Download the clim8® app Available on Google Play or the App Store, or flash the QR code next page.
2 Pair your Heated Vest Allow Bluetooth and localization permissions.
3 Set up your personal thermal profile (indoors)* Put your Heated Vest on to calibrate it to your most comfortable temperature.
4 Select your activity and go! clim8 intelligent system will autoactivate heating according to your profile and environment to aim to keep you comfortable.
5 Feedback and personalization The artificial intelligence learns from your feedback and personalizes the thermal response of your Heated Vest.
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THE CLIM8 APP Customize your Heated Vest according to your needs and preferences: the system learns and improves for a tailor-made heating experience. You've forgotten your smartphone? Don't worry, the heating system is fully autonomous!
*Please note the clim8 mobile application and an Internet connection are essential for the initial configuration of the product. To download the application, simply search for clim8 on Google Play or the App store or scan the QR code below. Your smartphone must support Bluetooth Low Energy.
Compatible with iOS 11+ and Android 7+
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SAFETY WARNINGS AND INSTRUCTIONS
Keep these important instructions for future reference. Please read the operating instructions carefully.
Please consult your doctor before using this Heated Vest if you have problems sensing hot or cold objects (e.g., diabetics, disabled persons, Raynaud's, etc.).
This Heated Vest is not suited for children under the age of 13 or for people with the inability to sense heat on the skin (e.g. a metabolic disorder commonly associated with diabetes).
People with a heart pacemaker, metal implants or insulin pump should first consult with their doctor before using the Heated Vest.
Children should be supervised to ensure that they are not using the Heated Vest as a toy.
Not intended to be used to warm animals.
Only use the supplied charger to charge the device. It is designed for indoor use and must not be exposed to humidity.
Do not insert any metal or other objects into sockets or plugs because this can damage the Heated Vest.
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If the charging cables or any other parts of the Heated Vest are damaged, discontinue the use of the Heated Vest.
Do not modify the product or divert it from its intended use.
Damaged chargers or charging cables cannot be repaired.
Not intended for medical use in hospitals.
Avoid kinking the Heated Vest by placing another object on top of it during storage.
Never use if inner liner is wet.
It is not recommended to use the Heated Vest with an avalanche transceiver.
The Heated Vest must only be operated with the supplied battery.
Do not sleep with your Heated Vest while it is still switched on.
If the temperature sensors are damaged, contact Carhartt Inc. prior to any further use.
HOW TO USE THE HEATED VEST?
FIRST USE AND CHARGING THE BATTERIES
Important note: charge the batteries prior to first use.
1 Plug the charger into the wall and connect the cable to the batteries. When charging, the light on the charger will turn RED.
2 Once the batteries are fully charged, the charging process automatically ends and the charge indicator changes back to GREEN. Please disconnect the batteries from the charger.
3 Open the inside pocket of the Heated Vest and plug the battery to the connector.
Batteries cannot be charged when connected to the Heated Vest.
IMPORTANT INSTRUCTIONS FOR USE
Check to make sure that the batteries are properly connected with your Heated Vest (plug locked into place).
Always set your Heated Vest to your initial reference temperature to maintain a comfortable temperature.
TURN HEATED VEST ON/ OFF:
To turn your Heated Vest on/off, simply connect/disconnect the batteries.
DOUBLE TAP FUNCTION
On your Heated Vest, simply double tap the clim8® module with two fingers. The LED color will change accordingly to the active mode
ACTIVE MODE
BATTERY HEAT USAGE LEVEL
LCEODLOR*
Stand by Very low None
Off
Eco
Low
Low
Blue
Comfort (Default)
Medium
Medium
Purple
Boost
High
High
Red
*The LED indicator is on the clim8® module attached on the Heated Vest.
HEAT SETTINGS AND DURATION
You can manually adjust the heat on your phone directly within the clim8 app. The higher the target temperature is, the shorter the battery is going to last. The heating duration per charge depends on the selected/calibrated temperature, your profile, your activity, ambient temperature and weather conditions as well as charging status of the batteries.
STORAGE AND CARE
For regular use, you can store your Heated Vest without disconnecting
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the battery. The system will go to sleep mode and consume minimal battery life.
For long-term storage, disconnect the battery from the Heated Vest. To prolong battery life, we recommend charging at least every 6 months. This ensures that the maximum battery power is preserved for many years!
To avoid damage during storage, avoid damp and humid environments and do not place heavy objects on top of the Heated Vest.
DRYING AND CLEANING
Note: Please make sure to remove the battery before cleaning the Heated Vest. Batteries should never be immersed in liquid.
The drying temperature must not exceed 140°F/60°C; Do not tumble dry the Heated Vest.
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Delicate wash cool (30°C)
Do not bleach
Do not dry clean
Dry flat
Do not tumble
dry
Do not iron
Before washing your Heated Vest,
place the cap on the connector and
close all zippers. When drying, be
sure to remove the connector cap.
Make sure the Heated Vest and the connector are dry before connecting a battery.
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TROUBLESHOOTING
LED BLINKING
Orange LED, slow blinking: the Heated Vest is running out of battery. Please refer to battery charging instructions. Purple LED, fast blinking: the firmware of the Heated Vest is being updated. DO NOT disconnect the battery! Red LED, fast blinking: please try to disconnect and reconnect the battery. If the problem persists, please remove the battery and contact Carhartt Inc.
CONTACT
If you encounter any issue with the app, please contact clim8: In the mobile app, directly in the product page or in your profile By opening a ticket on our dedicated support website https://support.myclim8.com/ By sending an email to support@myclim8.com If you encounter any other issue with the Heated Vest, please contact Carhartt Inc.
TECHNICAL SPECIFICATIONS
BATTERY
MODEL NOMINAL VOLTAGE NOMINAL CAPACITY OUTPUT WATTAGE CHARGING TIME (2 BATTERIES)
LIP-805060-2S 7.4V 3000 mA 22.2 W
Around 4h30m
CAUTION! RISK OF INJURY
Never try to open the battery pack yourself. Improper handling of the lithium-ion batteries can lead to an explosion. Moreover, the electronics of the heated garment can be damaged.
This Heated Vest is not suited for being used in locations where special conditions prevail, such as the presence of a corrosive or explosive atmosphere (dust, vapor or gas).
To reduce the risk of fire or burns, do not open, do not disassemble, do not crush, do not puncture, do not dispose in fire or water the battery, do not short external contacts.
To prevent moisture and dirt from entering the connecting socket plug, the battery should always be connected to the cable when in
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use or the cap should be placed on the socket plug when not in use.
Damaged batteries must not be used and must be disposed of properly.
CHARGER
This charger has reinforced insulation with no accessible metal parts. Class 2 equipment plugs do not have a grounding prong. This charger is for indoor use only. Class 2 Battery Charger. Backfeed Protection.
MODEL
INPUT
OUTPUT VOLTAGE (VDC)
OUTPUT CURRENT (MA)
OUTPUT WATTAGE (MAX-W)
CH0161-0842000G 100-240VAC, 50/60Hz, 0,5A 8.4V
2000mA
16,8W
This charger complies with part 15 of the FCC Rules. Operation is subject to the following two conditions:
1 This device may not cause harmful interference, and
2 This device must accept any interference received, including interference that may cause undesired operation.
NOTE: This charger has been tested and found to comply with the limits for a Class B digital device,
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pursuant to part 15 of the FCC Rules. These limits are designed to provide reasonable protection against harmful interference in a residential installation. This equipment generates, uses and can radiate radio frequency energy and, if not installed and used in accordance with the instructions, may cause harmful interference to radio communications. However, there is no guarantee that interference will not occur in a particular installation. If this equipment does cause harmful interference to radio or television reception, which can be determined by turning the equipment off and on, the user is encouraged to try to correct the interference by one or more of the following measures:
Reorient or relocate the receiving antenna.
Increase the separation between the equipment and receiver.
Connect the equipment into an outlet on a circuit different from that to which the receiver is connected.
Consult the dealer or an experienced radio/TV technician for help.
The charger must only be used in the following conditions:
Ambient operation temperature: 32°F to 104°F; 0°C to 40°C.
Storage environment: Temperature: 14°F to 122°F; -10°C to 50°C. Humidity: 5-95% RH (do not have condensate).
DANGER:
TO REDUCE THE RISK OF FIRE OR ELECTRIC SHOCK, CAREFULLY FOLLOW THESE INSTRUCTIONS.
WARNING:
USE ONLY RECHARGEABLE BATTERIES, OTHER TYPES MAY EXPLODE.
To reduce the risk of fire or electric shock, do not expose charger to rain or moisture.
CAUTION:
Read all instructions and warnings prior to using this charger. Improper use of this product may result in product damage, excess heat, toxic fumes, fire or explosion. See instructions for input voltage conversion.
IMPORTANT SAFETY INSTRUCTIONS - SAVE THESE INSTRUCTIONS. Risk of injury. Risk of fire/Risk of electric shock.
Refer to this instruction manual for the size, type, and number of batteries to be charged.
Use only in dry locations.
Charge only 7.4V Li-Ion rechargeable batteries with this charger.
Children should be supervised to ensure that they do not play with the charger.
Do not use near water.
Clean only with dry cloth. Always remove the charger from the socket before cleaning.
Dispose of the charger in accordance with local regulations at a collection site for electronic waste.
This charger is not intended for use by persons under the age of 13 or those with reduced physical, sensory or mental capabilities, or lack of experience and knowledge, unless they have been given supervision or instruction concerning use of the appliance by a person responsible for their safety.
If the shape of the plug does not fit the power outlet, use an attachment plug adapter of the proper configuration for the power outlet.
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TRANSMITTER
TRANSMITTER TYPE
FREQUENCY RANGE
TYPE OF MODULATION
MAXIMUM RADIOFREQUENCY POWER TRANSMITTED
CHANNEL SPACING
OCCUPIED BANDWIDTH
TYPE OF ANTENNA
Bluetooth 2400-2483.5 MHz GFSK
<10dBm 2 MHz 1.06 MHz Internal
Bluetooth range is about 33' (10m). This range can be reduced by obstacles (e.g. trees, walls, pockets, nearby Bluetooth devices, etc.).
THE CARHARTT BUILT TO LAST COMMITTMENT
At Carhartt, we stand behind the quality, craftsmanship, and performance of every product we make. If one of our products should fail to meet your expectations, we'll work to make it right through repair, replacement, or credit.
Since all apparel has an expected service life, this guarantee does not cover damage caused by normal wear and tear, misuse, neglect, or obvious abuse of the garment. Carhartt assumes no liability for garments that have been altered. For normal wear and tear, a reasonable and transparent charge may be applied for our repair services.
For any repair or replacement service, please contact Customer Service Contact Info:
Phone: 800-833-3118
Monday through Friday, 7am to 9pm Eastern Time Zone
Saturday, 8am to 6pm Eastern Time Zone
Sunday, Closed
Email: Just_Ask_Us@Carhartt.com
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REGULATORY STATEMENTS
Li-ion 00
FCC DECLARATION OF CONFORMITY
Contains FCC ID: 2AXEQ-CORE8PLUS
Caution: Changes or modifications not expressly approved by the party responsible for compliance could void the user's authority to operate the equipment.
This device complies with part 15 of the FCC Rules. Operation is subject to the following two conditions:
1 This device may not cause harmful interference, and
2 This device must accept any interference received, including interference that may cause undesired operation.
NOTE: This equipment has been tested and found to comply with the limits for a Class B digital device, pursuant to part 15 of the FCC Rules. These limits are designed to provide reasonable protection against harmful interference in a residential installation. This equipment generates, uses and can radiate radio frequency energy and, if not installed and used in accordance with the instructions, may cause harmful interference to
radio communications. However, there is no guarantee that interference will not occur in a particular installation. If this equipment does cause harmful interference to radio or television reception, which can be determined by turning the equipment off and on, the user is encouraged to try to correct the interference by one or more of the following measures: Reorient or relocate the receiving antenna. Increase the separation between the equipment and receiver. Connect the equipment into an outlet on a circuit different from that to which the receiver is connected. Consult the dealer or an experienced radio/TV technician for help.
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The technical specifications for this Heated Vest and the contents of this operating manual are subject to change without notice. Download the most updated version on the clim8 website. Batteries, chargers and electronic systems are made in China. Importer name: Carhartt Inc. Importer address: Carhartt Inc. P.O. Box 600 Dearborn, MI 48121 USA
WARNING Carhartt Inc. and clim8 are not responsible for the consequences whether direct, indirect or accidental or any other type of damage arising or resulting from the use of its products. You are responsible for your actions and activities, and for any consequences that may result from them.
Information subject to change. clim8® is a registered trademark of clim8 SAS. https://myclim8.com/ hello@myclim8.com
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JCM | Free Full-Text | Diabetic Foot Infection Presenting Systemic Inflammatory Response Syndrome: A Unique Disorder of Systemic Reaction from Infection of the Most Distal Body
Diabetic foot infection (DFI) is a major complication of diabetic foot that lead to nontraumatic lower-extremity amputation (LEA). Such distal infection of the body having systemic inflammatory response syndrome (SIRS) is rarely reported. Consecutive patients treated for limb-threatening DFI in a major diabetic foot center in Taiwan were analyzed between the years 2014 to 2017. Clinical factors, laboratory data, perfusion, extent, depth, infection and sensation (PEDIS) wound score in 519 subjects with grade 3 DFI and 203 presenting SIRS (28.1%) were compared. Major LEA and in-hospital mortality were defined as poor prognosis. Patients presenting SIRS had poor prognosis compared with those with grade 3 DFI (14.3% versus 6.6% for major LEA and 6.4% versus 3.5% for in-hospital mortality). Age, wound size, and HbA1c were independent risk factors favoring SIRS presentation. Perfusion grade 3 (odds ratio 3.37, p = 0.044) and history of major adverse cardiac events (OR 2.41, p = 0.036) were the independent factors for poor prognosis in treating patients with DFI presenting SIRS. SIRS when presented in patients with DFI is not only limb- but life-threatening as well. Clinicians should be aware of the clinical factors that are prone to develop and those affecting the prognosis in treating patients with limb-threatening foot infections.
Diabetic Foot Infection Presenting Systemic Inflammatory Response Syndrome: A Unique Disorder of Systemic Reaction from Infection of the Most Distal Body
by
Cheng-Wei Lin 1 ,
Shih-Yuan Hung 1 ,
Chung-Huei Huang 1 ,
Jiun-Ting Yeh 2 and
Yu-Yao Huang 1,3,4,*
Division of Endocrinology and Metabolism, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
2
Department of Plastic surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan 33305, Taiwan
College of Medicine, Chang Gung University, Taoyuan 33305, Taiwan
Department of Medical Nutrition Therapy, Chang Gung Memorial Hospital, Taoyuan 33305, Taiwan
J. Clin. Med. 2019 , 8 (10), 1538; https://doi.org/10.3390/jcm8101538
Received: 14 August 2019 / Revised: 21 September 2019 / Accepted: 23 September 2019 / Published: 25 September 2019
(This article belongs to the Section Endocrinology & Metabolism )
Abstract
Diabetic foot infection (DFI) is a major complication of diabetic foot that lead to nontraumatic lower-extremity amputation (LEA). Such distal infection of the body having systemic inflammatory response syndrome (SIRS) is rarely reported. Consecutive patients treated for limb-threatening DFI in a major diabetic foot center in Taiwan were analyzed between the years 2014 to 2017. Clinical factors, laboratory data, perfusion, extent, depth, infection and sensation (PEDIS) wound score in 519 subjects with grade 3 DFI and 203 presenting SIRS (28.1%) were compared. Major LEA and in-hospital mortality were defined as poor prognosis. Patients presenting SIRS had poor prognosis compared with those with grade 3 DFI (14.3% versus 6.6% for major LEA and 6.4% versus 3.5% for in-hospital mortality). Age, wound size, and HbA1c were independent risk factors favoring SIRS presentation. Perfusion grade 3 (odds ratio 3.37,
p
= 0.044) and history of major adverse cardiac events (OR 2.41,
p
= 0.036) were the independent factors for poor prognosis in treating patients with DFI presenting SIRS. SIRS when presented in patients with DFI is not only limb- but life-threatening as well. Clinicians should be aware of the clinical factors that are prone to develop and those affecting the prognosis in treating patients with limb-threatening foot infections.
Keywords:
diabetic foot infection
;
systemic inflammatory responsive syndrome
;
lower-extremity amputation
;
prognostic factors
1. Introduction
Diabetic foot ulcers (DFU) are prone to be infected because of impaired immunity, skin and nail disorders, peripheral arterial disease, neuropathy, and foot anatomy in patients with diabetes [ 1 ]. Among the diabetic foot complications, diabetic foot infection (DFI) is the leading threatening problem for limb loss and sepsis [ 2 , 3 , 4 ], and is the most common cause of hospital admissions [ 5 , 6 ] and costly expenditure [ 7 ] in diabetic populations. Among the in-hospital DFU cases, 82% have been reported to have DFIs in Europe and 94% in Taiwan [ 8 , 9 ].
Systemic inflammatory response syndrome (SIRS) indicates the inflammation beyond the infected site that traverses throughout the entire body. It is defined when matching two or more of the four abnormal presentations for body temperature, pulse rate, respiratory rate, and leukocyte count [ 10 ]. The presentation of SIRS is defined as the most severe grade of infection of various sites [ 11 , 12 ] suggesting higher risks to shock or mortality [ 10 , 13 ]. The presentation of SIRS in DFI, however, has been less reported. Wukich et al. reported that patients presenting with SIRS had higher major lower-extremity amputations (LEAs) and longer hospital stay compared to grade three of DFI [ 14 ].
From the mechanistic view, the infection of distal foot to affect the systemic reaction might be due to differences from SIRS of other foci of the body, especially when it has been associated with peripheral arterial disease (PAD) or neuropathy [ 1 , 15 ]. This study aimed to further understand the factors that are prone to development of SIRS in patients with DFI and factors affecting its prognosis of treatment.
2. Materials and Methods
2.1. Subjects and DFI Treatments
Consecutive type 2 diabetic patients with DFI treated at the major diabetic foot center in Taiwan, the Chang Gung Memorial Hospital at Linkou (a 3,700-bed university hospital), were reviewed from 2014 to 2017. Two hundred and three patients presenting with SIRS and 519 subjects with moderate DFI according to the Infection Disease Society of American (IDSA) [ 12 ] and the International Working Group on the Diabetic Foot (IWGDF) [ 11 ] criteria were identified. The Institutional Review Board of Chang Gung Memorial Hospital approved this study (no. 201900075B0). All patients received comprehensive foot care by a multidisciplinary team [ 16 , 17 , 18 , 19 ]. The empiric antibiotics were prescribed promptly for these patients initially, and subsequently modified according to the results of cultures. Surgical interventions, endovascular treatments, or foot amputations were scheduled after the diabetic foot team reached a consensus.
2.2. DFI and Wound Scoring
The wound classification was recorded as PEDIS describing the perfusion, extent size, depth/tissue loss, infection, and sensation of the wounds [
11
]. Patients presenting with SIRS were defined by grade 4 DFI. The definition of SIRS was according to matching two or more of the four criteria including abnormal body temperature >38 °C or <36 °C; tachycardia with pulse > 90 beat per minute; abnormal respiratory rate with > 20 breaths per minute; and abnormal leukocyte count > 12000 or < 4000 /cu mm. Patients with grade 3 DFI (presenting with either erythema >2 cm around the wound or involving the structures deeper than skin and subcutaneous tissues, but no SIRS) were included for comparison.
Their perfusion status was categorized into three grades. No symptom or sign of PAD was defined as grade 1; any symptom or sign of PAD or any non-invasive assessment document but not reaching critical limb ischemia was defined as grade 2; and critical limb ischemia was defined as grade 3. The critical limb ischemia in this study was defined by presence of gangrene or ulcers with ankle pressure <70 mmHg [ 20 ], or monophasic wave form of arteries below-the-knee [ 17 ]. Adjunct angiography was performed for confirmation.
2.3. Data Collection
Demographic information was recorded from the patients’ first visit at admission. The medical records included the patient’s age, gender, diabetes duration, HbA1c level, and medical history such as hypertension, history of major adverse cardiac events (MACEs; including coronary artery disease and cerebrovascular accidents), and dialysis. Smokers were classified as currently smoking if they smoked at least one cigarette per day. Their estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease Study equation: 175 × serum creatinine (exp[−1.154]) × age (exp[0.203]) × (0.742 if female). Renal status was categorized as follows: Normal or mild chronic kidney disease (eGFR ≥ 60 mL/min); moderate to severe chronic kidney disease (eGFR < 60 mL/min); and dialysis according to the National Kidney Disease Outcomes Quality Initiative (NKDOQI) guidelines.
2.4. Prognosis Analysis: LEAs and in-Hospital Mortality
Status at discharge was stratified into four groups: Limb-preserved, minor LEA (i.e., amputation performed including digital amputation or tarsal-metatarsal amputation, as long as it did not involve the ankle area), major LEA (i.e., amputation performed above the ankle joint), or in-hospital mortality. The major LEA and in-hospital mortality were defined as poor prognosis while subjects with limb preservation and minor LEA were used for comparison.
2.5. Statistics
Age, duration of diabetes, wound extent size, and HbA1c level were used as continuous variables, and gender, smoking status, comorbidities, and PEDIS score (except extent size) were used as categorical variables. Comparisons between patients with or without SIRS were performed using the Mann–Whiney test for continuous variables and Pearson’s chi-square test for categorical variables. Each factor odds ratio to the presence of SIRS was calculated via adjusted model of logistic regression. The same statistical method was used in comparing the two groups with different treatment outcome of the total DFI patients with SIRS. The significant risk factors in the univariate analysis found above were then entered into a multivariate logistic regression model to identify independent risk factors to adverse outcome among these patients. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS for Windows, version 19.0, IBM Corp., Armonk, NY, USA) data analysis software.
3. Results
3.1. The Characteristics of Patients DFI Presenting SIRS
The comparison of clinical characteristics of subjects, feet, and treatments between patients with grade 3 DFI and those with SIRS is shown in the
Table 1
. Patients presenting with SIRS had median age of 60.3 years and diabetes duration of 12 years, which was significantly lower than those with grade 3 DFI (age 66.0 y/o and duration 15 years,
p
< 0.001, and
p
= 0.04, respectively). Male gender predominance was noted in both groups (61.6 and 61.5%, in SIRS and grade 3 DFI, respectively). The rates of associated comorbidities were high in patients of both groups. For example, the MACE history was 30.0% versus 36.0% and dialysis was 17.2 versus 19.3% for presenting SIRS versus grade 3 DFI, respectively. In the presentation of DFUs, patients with SIRS had larger wound size compared to those with grade 3 DFI (15.0 cm versus 9.0 cm,
p
< 0.001) while no differences were found in perfusion, depth, or sensation. Osteomyelitis was noted of 40.4% in SIRS and 38.9% in grade 3 DFI (
p
= 0.716). Of note, patients with SIRS had relatively shorter days before visit (
p
= 0.066), longer stay of in-hospital treatment (
p
< 0.001), and higher blood levels of HbA1c (9.6% versus 8.1%,
p
< 0.001).
Table 1. Clinical characteristics and wound classification between severe and grade 3 diabetic foot infection (DFI).
3.2. Factors Prone to Have SIRS Presentation
When putting factors with statistical significance into the multivariate logistic regression model, the forest plot analysis of factors favored in presenting SIRS in patients with DFIs was demonstrated, as shown in
Figure 1
A. Age (odds ratio 0.97, 95% confidence interval 0.96–0.99,
p
< 0.001), wound size (OR 1.00, 95% CI 1.00–1.01,
p
= 0.006), and HbA1c (OR 1.17, 95% CI 1.09–1.25,
p
< 0.001) were the independent risk factors to predict SIRS. Analysis of HbA1c level at visiting via receiver operating characteristic (ROC) curve showed that the cutoff point was 8.4% with 67.7% sensitivity and 56.2% specificity in predicting SIRS (
Figure 1
B).
Figure 1. Factors associated with systemic inflammatory response syndrome (SIRS) presenting in DFI patients. ( A ) Forest plot of odds ratios under multivariate regression analysis, adjusted with age, wound size, HbA1c, hypertension, major adverse cardiac event (MACE) history, end-stage renal disease, and peripheral arterial disease. ( B ) Receiver operating characteristic (ROC) curve of HbA1c in predicting SIRS. According to Youden index, cutoff point in HbA1c: 8.4 had 67.7% sensitivity and 56.2% specificity; AUC, area under the curve.
3.3. Prognosis and Prognostic Factors Analysis in Patients Presenting SIRS
Among the 203 patients with SIRS, 42 patients had poor prognosis. Twenty-nine patients (14.3%) had major LEA and thirteen patients (6.4%) died during treatment ( Figure 2 A). Compared to 6.6% of major LEA and 3.5% in-hospital mortality in patients with grade 3 DFI ( Figure 2 A), patients with SIRS had significantly worse prognosis ( p < 0.001). When individual components of SIRS criteria were studied, the presentation of abnormal temperature tended to have poor prognosis but did not reach statistical significance ( p = 0.101) ( Figure 2 B).
Figure 2. Treatment outcome results and associated factors for severe DFI patients with SIRS. ( A ) The prognosis of patients with grade 3 DFI and those with SIRS. Patients with SIRS had higher major lower-extremity amputation (LEA) ( p = 0.001) and relatively higher in-hospital mortality ( p = 0.08); ( B ) The presentation of individual component of SIRS did not affect the prognosis.
The prognostic factors were analyzed between 42 and 161 patients with poor and better prognosis, respectively, in patients with SIRS ( Table 2 ). The association with MACE history (52.4% versus 24.2%, respectively), retinopathy (73.8% versus 52.2%, respectively), poor peripheral circulation (grade 3 perfusion score 76.2% versus 39.1%, respectively), and with larger or deeper wounds were noted to have poor prognosis. Following multivariate logistic regression analysis, the grade 3 perfusion score (odds ratio 3.37, 95% confidence interval 1.04–10.94, p = 0.044), MACE history (OR 2.41, 95% CI 1.06–5.47, p = 0.036), and wound size (OR 1.003, 95% CI 1.00–1.01, p = 0.017) were the three independent risk factors predicting poor in-hospital prognosis in patients with SIRS ( Table 2 ). Figure 3 demonstrates the 30-day accumulated event-free rate in these patients according to the association with MACE history ( Figure 3 A) and perfusion score ( Figure 3 B).
Figure 3. Kaplan-Meier curves of event free (major LEA or in-hospital mortality) in patients with SIRS stratified by ( A ) the association with MACE history and ( B ) the perfusion wound score.
Table 2. Factors analysis for prognosis in patients with SIRS.
4. Discussion
The association with SIRS is not rare (28.1%) in patients with limb-threatening DFIs. This study further ascertains poor prognosis, both limb loss and in-hospital mortality for such patients, factors favoring SIRS presentations or poor prognosis have been reported.
This study found that age, wound size, and higher level of HbA1c at visiting were the factors favoring SIRS presentation. Subjects with SIRS were six years younger than those with grade 3 DFIs. The presentation of SIRS was association with the immune response and circulation cytokine [ 21 ] and younger subjects usually having stronger immune activity [ 22 ]. Inversely, aged patients with longer diabetes duration usually involved higher comorbidities and poor blood perfusion of foot. Both limited blood flow and less immune reaction in the wounds may regionalize the inflammatory response in elderly patients [ 23 ].
The large wound size and higher HbA1c level were also noted as factors prone to SIRS presentation. It is reasonable that more extensive tissue injury released more inflammatory mediators [ 24 ]. Though there is inconsistent association between HbA1c levels and LEAs prognosis reported by meta-analysis [ 25 , 26 , 27 ] and our observations [ 16 , 28 ], this study is the first to demonstrate higher HbA1c level has association with SIRS presentation in patients with limb-threatening DFIs. The HbA1c > 8.4% had valid predication of SIRS (sensitivity 67.7% and specificity 56.2%) among patients with DFIs. The higher quantities of cytokines, catecholamine, or cortisol secreted from inflammation stress of SIRS [ 29 , 30 ] may produce a secondary result in hyperglycemia. In addition, chronic hyperglycemia itself enhances cytokine and chemokine release, increased leukocyte marginalization, and exaggerated superoxide release [ 31 ], which might further exaggerate inflammatory responses in long-standing foot infections. The HbA1c itself has been reported as an acute phase protein that responds to inflammation conditions [ 32 ] independently of fasting blood glucose levels or obesity [ 25 ].
Since DFIs presenting SIRS has both limb- and life-threatening status, understanding the prognostic factors is important to improve treatments. This study identified perfusion grade 3, history of MACE and large wound size as independent risk factors for poor prognosis. Peripheral arterial disease itself has been reported to associate with high major LEA rate and high mortality [ 17 , 33 , 34 ]. Poor tissue oxygen tension might compromise the host local immune defenses and hinder the delivery of antibiotics to the infected tissue in patients with severe foot infections [ 23 ]. Patients with associated history of MACE might well be fragile and therefore have higher chance of PAD [ 35 , 36 ], thereby affecting the prognosis.
This study is limited by the single center and retrospective design. Nevertheless, to the best of our knowledge, this is the first large-series study to investigate severe infection of diabetic foot complications.
5. Conclusions
The presence of SIRS is a limb- and life-threatening condition for patients with DFI. Younger age, larger wound, and higher HbA1c levels at clinical visit favor the SIRS presentation. Meanwhile, association with MACE history or poor peripheral circulation foretells poor prognosis.
Author Contributions
Conceptualization, Y.-Y.H.; Methodology, C.-W.L.; Validation, Y.-Y.H. and C.-W.L.; Formal analysis, S.-Y.H.; Investigation, S.-Y.H.; Resources, J.-T.Y.; Data curation, C.-H.H.; Writing—original draft preparation, C.-W.L.; Writing—review and editing, Y.-Y.H.; Visualization, C.-H.H.; Supervision, J.-T.Y.; Project administration, Y.-Y.H.; Funding acquisition, Y.-Y.H.
Funding
This research was funded by Chang Gung Memorial Hospital, Linkou, grant number CORPG3J0021.
Acknowledgments
The authors thank the staff and participants of these studies for their important contributions.
Conflicts of Interest
The authors declare no conflict of interest.
References
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Figure 1. Factors associated with systemic inflammatory response syndrome (SIRS) presenting in DFI patients. ( A ) Forest plot of odds ratios under multivariate regression analysis, adjusted with age, wound size, HbA1c, hypertension, major adverse cardiac event (MACE) history, end-stage renal disease, and peripheral arterial disease. ( B ) Receiver operating characteristic (ROC) curve of HbA1c in predicting SIRS. According to Youden index, cutoff point in HbA1c: 8.4 had 67.7% sensitivity and 56.2% specificity; AUC, area under the curve.
Figure 2. Treatment outcome results and associated factors for severe DFI patients with SIRS. ( A ) The prognosis of patients with grade 3 DFI and those with SIRS. Patients with SIRS had higher major lower-extremity amputation (LEA) ( p = 0.001) and relatively higher in-hospital mortality ( p = 0.08); ( B ) The presentation of individual component of SIRS did not affect the prognosis.
Figure 3. Kaplan-Meier curves of event free (major LEA or in-hospital mortality) in patients with SIRS stratified by ( A ) the association with MACE history and ( B ) the perfusion wound score.
Table 1. Clinical characteristics and wound classification between severe and grade 3 diabetic foot infection (DFI).
Characteristic DFI Presenting SIRS (N = 203) Grade 3 DFI (N = 519) p Value Age (years) 60.3 [52.5; 67.9] 66.0 [56.6; 76.3] <0.001 * Male gender 125 (61.6%) 319 (61.5%) 0.978 Diabetes duration (years) 12.0 [5.0; 20.0] 15.0 [7.0; 20.0] 0.040 * Smoker 88 (43.3%) 204 (39.3%) 0.320 Hypertension 136 (67.0%) 367 (70.7%) 0.329 MACE a History 61 (30.0%) 187 (36.0%) 0.128 Retinopathy 115 (56.7%) 299 (57.6%) 0.815 Renal status 0.563 eGFR ≥60 84 (41.4%) 226 (43.5%) eGFR <60 84 (41.4%) 193 (37.2%) Dialysis 35 (17.2%) 100 (19.3%) HbA1c (%) 9.6 [7.6; 11.3] 8.1 [6.8; 10.16] <0.001 * Perfusion score 0.192 Grade 1 77 (37.9%) 187 (36.0%) Grade 2 31 (15.3%) 110 (21.2%) Grade 3 95 (46.8%) 222 (42.8%) Extent size (cm 2 ) 15.0 [6.0; 45.0] 9.0 [4.0; 25.5] <0.001 * Depth/tissue loss score 0.175 Grade 1 9 (4.4%) 43 (8.3%) Grade 2 47 (23.2%) 124 (23.9%) Grade 3 147 (72.4%) 352 (67.8%) Sensation 0.156 Grade 1 100 (49.3%) 285 (55.1%) Grade 2 103 (50.7%) 232 (44.9%) Osteomyelitis 82 (40.4%) 202 (38.9%) 0.716 Days before visit 15.5 [9.0; 44.25] 23.5 [9.0; 60.0] 0.066 Hospital stay (days) 39.0 [24.0; 57.0] 26.0 [15.0; 40.0] <0.001 *
a Major adverse cardiac event including history of ischemic heart disease or coronary artery disease, cerebral vascular accident with embolic, ischemic, or hemorrhagic stroke; *, Significance: p value < 0.05. SIRS, systemic inflammatory response syndrome; DFI, Diabetic foot infection; MACE, major adverse cardiac events; and eGFR, estimated glomerular filtration rate.
Table 2. Factors analysis for prognosis in patients with SIRS.
Characteristic Non-Amputation or Minor LEA a (n = 161) Major LEA or Death b (n = 42) p Value Odds Ratio c (95% CI) p Value Age (years) 60.0 [50.3; 67.6] 62.2 [57.8; 73.3] 0.053 MACE history 39 (24.2%) 22 (52.4%) <0.001 * 2.41* (1.06–5.47) 0.036 * Retinopathy 84 (52.2%) 31 (73.8%) 0.012 * 1.89 (0.81–4.41) 0.141 Renal status <0.001 * eGFR ≥60 70 (43.5%) 14 (33.3%) 1 eGFR <60 74 (46.0%) 10 (23.8%) 0.46 (0.17–1.24) 0.124 Dialysis 17 (10.6%) 18 (42.9%) 2.38 (0.88–6.47) 0.089 HbA1c (%) 9.7 [7.8; 11.4] 9.25 [7.23; 10.88] 0.220 Perfusion score <0.001 * Grade 1 72 (44.7%) 5 (11.9%) 1 Grade 2 26 (16.1%) 5 (11.9%) 1.40 (0.32–6.24) 0.658 Grade 3 63 (39.1%) 32 (76.2%) 3.37* (1.04–10.94) 0.044 * Extent size (cm 2 ) 11.3 [4.98; 35.0] 44.5 [20.75; 102.38] <0.001 * 1.003* (1.00–1.01) 0.017 * Depth/tissue loss 0.038 Grade 1 8 (5.0%) 1 (2.4%) 1 Grade 2 43 (26.7%) 4 (9.5%) 0.95 (0.08–11.64) 0.989 Grade 3 110 (68.3%) 37 (88.1%) 1.93 (0.20–18.58) 0.568 Sensation 0.135 Grade 1 75 (46.6%) 25 (59.5%) Grade 2 86 (53.4%) 17 (40.5%)
* Significance: p value < 0.05; a , 81 non-amputation and 80 minor-LEA; b , 29 major-LEA and 13 death; c , Association with poor treatment outcome (major LEA or death). Including continuous variables of extent size; and categorical variables of MACE history, retinopathy, renal function status, perfusion score, and depth/tissue loss.
MDPI and ACS Style
Lin, C.-W.; Hung, S.-Y.; Huang, C.-H.; Yeh, J.-T.; Huang, Y.-Y. Diabetic Foot Infection Presenting Systemic Inflammatory Response Syndrome: A Unique Disorder of Systemic Reaction from Infection of the Most Distal Body. J. Clin. Med. 2019, 8, 1538.
https://doi.org/10.3390/jcm8101538
AMA Style
Lin C-W, Hung S-Y, Huang C-H, Yeh J-T, Huang Y-Y. Diabetic Foot Infection Presenting Systemic Inflammatory Response Syndrome: A Unique Disorder of Systemic Reaction from Infection of the Most Distal Body. Journal of Clinical Medicine. 2019; 8(10):1538.
https://doi.org/10.3390/jcm8101538
Chicago/Turabian Style
Lin, Cheng-Wei, Shih-Yuan Hung, Chung-Huei Huang, Jiun-Ting Yeh, and Yu-Yao Huang. 2019. "Diabetic Foot Infection Presenting Systemic Inflammatory Response Syndrome: A Unique Disorder of Systemic Reaction from Infection of the Most Distal Body" Journal of Clinical Medicine8, no. 10: 1538.
https://doi.org/10.3390/jcm8101538
| https://www.mdpi.com/2077-0383/8/10/1538/html |
Mark Twain Project :: Literary Works :: Autobiography of Mark Twain, Volume 3 : an electronic text
Autobiographical Dictation, 6 October 1908 ❉ Textual Commentary
Source document.
<table><tbody><tr><td> TS</td><td> Typescript, six unnumbered leaves, made from Howden’s notes and revised.</td></tr></tbody></table>
TS, as revised by Clemens, is the only authoritative source for this dictation. It is the first typescript
that Mary Louise Howden made from Clemens’s dictation (see AD,6 Oct
1908, note at 267 title). (It is also the first of several typescripts for which she used a
typewriter with a small typeface equipped with a purple ribbon; she had typed the manuscripts comprising AD,16 July and 12 September 1908, on a machine with a larger typeface using a black
ribbon.) The punctuation of TS is sparse, and Clemens added to it in revising. Howden later recalled that this was
Clemens’s preference: “He put in the punctuation himself. His stenographer was never allowed to add so much
as a comma”(Howden 1925). At the top of the first page Clemens wrote
‘Get the paging from Miss Lyon, & add it.’—apparently an instruction (not followed) to
continue the numbering sequence of TS1, which had ended on14 Julywith page
2597.
Revisions, variants adopted or rejected, and textual notes.
October 6 • Oct. 6th (TS) Stormfield. • Stormfield. This is well enough.(TS-SLC) well, • well , enough ,(TS-SLC) me; • me ;(TS-SLC) me, • me ,(TS-SLC) besides, • besides ,(TS-SLC) the • ‸the ‸(TS-SLC) it, • it ,(TS-SLC) Clara’s, • Clara’s (TS) after, • after ,(TS-SLC) reasons; but • reasons ; . B but [ period mended to a semicolon] (TS-SLC) at once • without delay and ‸at once ‸(TS-SLC) expense, • expense ,(TS-SLC) all of • ‸all of ‸(TS-SLC) for it • ‸for it ‸(TS-SLC) pigeon-holes • pigeon-hole s(TS-SLC) years, • years ,(TS-SLC) Harper’s Magazine• Harper’s Magazine (TS) “Captain • “Captain (TS-SLC) Heaven.” • Heaven. ”(TS-SLC) burglar alarm • burglar -alarm (TS-SLC) is, • is . ,(TS-SLC) when I reflect • But I have ‸when I ‸reflect ed(TS-SLC) away; • away ;[ semicolon mended to a
colon] (TS-SLC) people, • people ,(TS-SLC) dog, • dog ,(TS-SLC) along, • along ,(TS-SLC) he • thenhe (TS-SLC) a • the a(TS-SLC) burglar, and • burglar . ‸, and ‸(TS-SLC) twelve, • twelve ,(TS-SLC) midnight, • midnight ,(TS-SLC) dining room • diningroom (TS) noise, • noise ,(TS-SLC) down stairs • downstairs (TS) butler; • butler ; who came(TS-SLC) burglars • ‸burglars ‸(TS-SLC) dining room • diningroom (TS) door, • door ,(TS-SLC) gate, • gate ,(TS-SLC) alarm: • alarm ; :(TS-SLC) it. • alarm him. ‸it. ‸(TS-SLC) the burglar • the ‸burglar ‸(TS-SLC) office, • office ,(TS-SLC) A little late, but worth while. • ‸A little late, but worth while. ‸(TS-SLC) Lounsbury, • Lounsbury ,(TS-SLC) neighbor; he • neighbor ; . H he [ period mended to a semicolon] (TS-SLC) telephoned • telephoned to(TS-SLC) Banks, • Banks ,(TS-SLC) away, • away ,(TS-SLC) burglars, • burglars ,(TS-SLC) butler— • butler— [ typed hyphen retraced to make a
dash] (TS-SLC) lantern, • lantern ,(TS-SLC) a plodding and weary • ‸a plodding and weary ‸(TS-SLC) miles, • miles ,(TS-SLC) side, • side ,(TS-SLC) two, • two ,(TS-SLC) together, • together ,(TS-SLC) them— • them— [ typed hyphen retraced to make a
dash] (TS-SLC) it, • it ,(TS-SLC) says, • says ,(TS-SLC) “hold • “hold (TS-SLC) hands!” • hands! ”(TS-SLC) that, • that ,(TS-SLC) “hold • “hold (TS-SLC) feet!” • feet , ‸!” ‸(TS-SLC) footprints • foot-|prints (TS-SLC) burglars, • burglars ,(TS-SLC) followed, • followed ,(TS-SLC) pistol-shots • pistol shots (TS) him; • him . ;[ period mended to a
semicolon] (TS-SLC) meantime the • ‸meantime ‸ T the (TS-SLC) floor, • floor ,(TS-SLC) thigh • side ‸thigh ‸(TS-SLC) now, • now ,(TS-SLC) hand-bag, • hand-bag ,(TS-SLC) experienced • competent ‸experienced ‸(TS-SLC) cracksmen, • cracksmen ,(TS-SLC) recognized • recognised (TS) roadside, • roadside ,(TS-SLC) men, • men ,(TS-SLC) compassion, • compassion ,(TS-SLC) crime, • crime ,(TS-SLC) the burglar • the y ‸burglar ‸(TS-SLC) inflicts • inflict ’ s(TS-SLC) us, • us ,(TS-SLC) and • and ‸so ‸(TS-SLC) unaware • unaware ‸, until morning, ‸(TS-SLC) happened— • happened— [ typed hyphen retraced to make a
dash] (TS-SLC) instance— • instance— [ typed hyphen retraced to make a
dash] (TS-SLC) morning; • morning ;(TS-SLC) No one • No -one (TS-SLC) house • house hold(TS-SLC) the incident. • it. ‸the incident. ‸(TS-SLC) think, • think ,(TS-SLC) now, • now ,(TS-SLC) Lyon, • Lyon ,(TS-SLC) ago, • ago ,(TS-SLC) sleep, • sleep ,(TS-SLC) the • ‸the ‸(TS-SLC) years, • years ,(TS-SLC) forty, • forty ,(TS-SLC) whether • if ‸whether ‸(TS-SLC) pore— • pore— [ typed hyphen retraced to make a
dash] (TS-SLC) dream, • dream ,(TS-SLC) night, • night ,(TS-SLC) burglaries, • burglaries ,(TS-SLC) women-folk • women-|folk (TS) sleep, • sleep ,(TS-SLC) any, • any ,(TS-SLC) horrors, • horrors ,(TS-SLC) said, • said ,(TS-SLC) crime— • crime— [ typed hyphen retraced to make a
dash] (TS-SLC) the • that ‸the ‸(TS-SLC) so, • so ,(TS-SLC) law, • law ,(TS-SLC) make • make<here is a image aae9653c6062eaa3-764542f19413930f> make(TS-SLC) penalty • pnalty (TS) burglary, • burglary ,(TS-SLC) remorselessly • I wouldremorselessly (TS-SLC) now, • now ,(TS-SLC) newspapers, • newspapers ,(TS-SLC) traveled • tra veled (TS-SLC) dining room • diningroom (TS) noise— • noise— [ typed hyphen retraced to make a
dash] (TS-SLC) Please close the door • Please close the door [ SLC underscored ‘PLEASE CLOSE THE DOOR’and wrote in the margin, ‘ R Plain Roman lower-case italicsno emphasis needed.’] (TS-SLC) away. • away : .(TS-SLC)
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5905 WEST WASHINGTON CHICAGO, IL 60644
773-261-7074
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Best Nursing Homes in IL
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Below is everything shred of information that we can find about MOSAIC OF MAYFIELD, THE, along with our best effort to make sense of the data. Our purpose here is to help you to make good decisions when picking a nursing home and to keep you informed once you have chosen a home. We know from personal experience that choosing a nursing home is not something you do once and then you forget about it. In fact, it gets worse. Once you select a nursing home and get through the initial steps of figuring out how to pay for it, then the real worries start. Are they taking good care of me or my loved one? This is the question that will keep you up at night: Can I really trust these people? We wish we could answer this question, we can't. What he can do is churn through the tons of data and try and help you to make sense of it. We hope it helps.
General Data Card
These are the basic data points for the facility.
Data date:October 01, 2016
Address:5905 WEST WASHINGTON, CHICAGO, IL 60644
Phone:773-261-7074
Medicare Provider Number:145885
Participating in Medicare Since:December 01, 1996
No. of Certified Beds:156
No. of Residents:120
Occupancy:76.92 % (as of
06/18/2023 )
Amount fined in recent period:$0.00
Complaints filed:37
Ratings History for MOSAIC OF MAYFIELD, THE
Review of MOSAIC OF MAYFIELD, THE Ratings and Inspection Scores
CMS regularly inspects every skilled nursing facility. (The timing is supposed to be annually, but since the beginning of the Covid pandemic, these inspections have not occured as frequently.) The results of the multi-day inspection is reduced to a series of scores which are then translated into the star ratings. The health inspection scores are an absolute value, so you can compare one facility's score directly to another. The Overall Star rating is based on the facility's performance as compared to other facilities in the same state, so you cannot easily compare one facility's Overall star rating to a facility in another state.
Ratings
<table><tbody><tr><td> Overall Rating</td><td> 1:</td></tr><tr><td> Health Inspection Rating</td><td> 2:</td></tr><tr><td> Quality Rating</td><td> 1:</td></tr><tr><td> Staffing Rating</td><td> 1:</td></tr></tbody></table>
Inspection Scores
<table><tbody><tr><td> Cycle 1 Score (as of March 11, 2016)</td><td> 64</td></tr><tr><td> Cycle 2 Score (as of January 23, 2015)</td><td> 48</td></tr><tr><td> Cycle 3 Score (as of February 27, 2014)</td><td> 56</td></tr><tr><td> Weighted All Cycles Score</td><td> 57</td></tr></tbody></table>
It has been 6 months since the most recent inspection.
What Goes Into the Nursing Home's 5-Star Rating
CMS has put a lot of effort into creating its very elaborate 5-Star Quality Rating System specifically to provide a quick way for residents and family members to easily understand how well a nursing home is performing and to make comparing nursing homes easier. The rating system allows people to easily compare facilities across numerous dimensions with the express purpose of identifying the best and best performing nursing homes. The rating system was initially developed in 2008 and the methodologies are regularly reviewed and updated.
The rating system has five separate ratings including:
Overall rating
Health Inspection rating
Staff rating
RN Staffing rating
Quality Measures rating
Nursing homes are rated from 1-star to 5-stars with 1-star being the best rating and 5-star being the best rating. For the Health Inspection Rating the nursing homes in each state are ranked based on their weighted three year inspection score. The top 10 percent of nursing homes (those with the lowest scores) are awarded a 5-star rating; the bottom 20 percent (those with the highest scores) are awarded a 1-star rating. In between 1-star and 5-star, the remaining homes are divided equally into three tranches which correspond with the stars 2 to 4. The staff ratings and quality measure ratings follow a similar process but the divisions are based on a national ranking. The division between star ratings is called the “cut-rate”. Cut-rates are redefined periodically and are published by CMS.See the latest cut rates on this table.
Calculating the Overall Star Rating is done differently. According to CMS, the reason for adopting a different system is to give the Health Inspection Rating higher weight in the Overall Rating. So, since there are FIVE ratings and FIVE stars for each rating, there must also be a FIVE step process to calculate the Overall Rating (so symetrical!) :
Begin with the Health Inspection Rating
Add one star to the Health Inspection Rating if the Staffing Rating is at least four-stars and is higher than the Health Inspection Rating. (We will call this the "Adjusted Rating".)
Subtract one star from the Health Inspection Rating if the Staffing Rating is one-star.
Add a star to the Adjusted Rating if the Quality Measure Rating is 5-stars.
Subtract one star from the Adjusted Rating if the Quality Measure Rating is 1-star.
Throughout the calculation of the Overall Rating, the rating cannot exceed 5-stars. The Overall Rating is capped at 2-stars if the Health Inspection rating is 1-star. No Overall Rating is awarded if the nursing home does not have a Health Inspection Rating (This effectively means that a nursing home is not rated until the home has been operating for more than two years.)
Changes in a nursing homes star rating can be due to the results of a new health inspection report, the processing of new complaints, the aging of older complaints, a new inspection control survey, a revisit, or the resolution of disputes that change the scope and or severity of deficiencies.
Most Recent Nursing Home Inspections
CMS is required to inspect each senior nursing facility at least annually. These inspections take several days. Additional follow-up inspections as conducted as needed or for certain purposes. Inspections stopped for more than seven months in 2020 due to the Covid pandemic. That stoppage has caused all inspections to be delayed as the inspectors continue to deal with a backlog. The table below shows the latest inspections for MOSAIC OF MAYFIELD, THE including health, fire, and inspection control inspections:
No Inspection Information is Available
Owner and Operator Information for MOSAIC OF MAYFIELD, THE
Our database of owners and operators shows all direct owners of the nursing nurse, any managers and directors, and the most adjacent indirect owners of the facility (that is, if the direct owner is company, then the owners of that company.) Lists of nursing home owners are available and you cansearch for nursing home owners and operatorson our site.
Business Entity Name:
MAYFIELD CARE CENTER, INC.
Owners:
YOSEF DAVIS DELTA TRUST DTD(DIRECT- 83%)
YOSEF DAVIS DELTA TRUST DTD(DIRECT- 83%)
Managers and Directors:
WILLIAM PFEIFFER(MANAGING EMPLOYEE)
WILLIAM PFEIFFER(MANAGING EMPLOYEE)
AHARON SHKOP(OFFICER)
AHARON SHKOP(OFFICER)
Analysis of Nursing Hours Spent Per Patient
CMS provides detailed information about how long nursing staff spends with residents. This data includes nursing subcategories of Registered Nurse, Licensed Practical Nurse, and non-nursing Certified Nursing Assistants. More hours spend per patient should can indicate a better facility or it could indicate more complicated situations.
The nursing staff of MOSAIC OF MAYFIELD, THE spends LESS time on average with its residents than the state average and
LESS time than the national average for total nursing homes spent per resident.
Type Facility State / National Avg
Registered Nurse (RN)
Hours 0.37 0.73 /
0.65
Case Mix NA 0.41 /
0.39
Adjusted 0.23 NA /
NA
Licensed Practical Nurse (LPN)
Hours 0.92 0.66 /
0.88
Case Mix NA NA /
NA
Adjusted 1.09 NA /
NA
Certified Nursing Assistants (CNA)
Hours 1.95 2.02 /
2.21
Case Mix NA NA /
NA
Adjusted 1.84 NA /
NA
Total Licensed Staff
Hours 1.29 1.38 /
1.52
Physical Therapist (PT)
Hours 0.09 0.06 /
0.07
Total Nursing Homes Spent per Resident on Average
Hours 3.24 3.40 /
3.74
Case Mix NA 3.29 /
3.16
Adjusted 2.91 NA /
NA
Quality Measures
Quality measures are based both on patient survey information and on the results of actual claims that are filed with CMS. It is not clear what period is covered in the measures.
Desc. Perc. State Avg. / Comparison
Percentage of short-stay residents who were rehospitalized after a nursing home admission (qm521) 17.7% NA
Percentage of short-stay residents who had an outpatient emergency department visit (qm522) 12.1% NA
Percentage of short-stay residents who were successfully discharged to the community (qm523) 60.3% NA
Percentage of long-stay residents whose need for help with daily activities has increased (qm401) 15.8% NA
Percentage of long-stay residents who self-report moderate to severe pain (qm402) 7.9% NA
Percentage of high risk long-stay residents with pressure ulcers (qm403) 9.9% NA
Percentage of long-stay residents who lose too much weight (qm404) 11.5% NA
Percentage of low risk long-stay residents who lose control of their bowels or bladder (qm405) 37.4% NA
Percentage of long-stay residents with a catheter inserted and left in their bladder (qm406) 6.6% NA
Percentage of long-stay residents with a urinary tract infection (qm407) 5.7% NA
Percentage of long-stay residents who have depressive symptoms (qm408) 50.5% NA
Percentage of long-stay residents who were physically restrained (qm409) 0.4% NA
Percentage of long-stay residents experiencing one or more falls with major injury (qm410) 2.2% NA
Percentage of long-stay residents assessed and appropriately given the seasonal influenza vaccine (qm411) 77.7% NA
Percentage of long-stay residents assessed and appropriately given the pneumococcal vaccine (qm415) 39.0% NA
Percentage of long-stay residents who received an antipsychotic medication (qm419) 14.8% NA
Percentage of short-stay residents who self-report moderate to severe pain (qm424) 19.7% NA
Percentage of short-stay residents with pressure ulcers that are new or worsened (qm425) 1.1% NA
Percentage of short-stay residents who were assessed and appropriately given the seasonal influenza vaccine (qm426) 47.9% NA
Percentage of short-stay residents assessed and appropriately given the pneumococcal vaccine (qm430) 4.4% NA
Percentage of short-stay residents who newly received an antipsychotic medication (qm434) 3.1% NA
Percentage of long-stay residents whose ability to move independently worsened (qm451) 26.2% NA
Percentage of long-stay residents who received an antianxiety or hypnotic medication (qm452) 6.0% NA
Percentage of short-stay residents who made improvements in function (qm471) 54.9% NA
MOSAIC OF MAYFIELD, THE Violations, Complaints and Fines
These are complaints and fines that are reported by CMS. Some of the data is not very recent, but we have decided to include it here so that you have as much information as possible.
Amount fined in recent period:$0.00, Complaints filed:37
Deficiency Deficiency Date / Date Corrected
Ensure that residents are fully informed and understand their health status, care and treatments.
(Health) 02-27-2014 /
03-25-2014
Keep the rate of medication errors (wrong drug, wrong dose, wrong time) to less than 5%.
(Health) 02-27-2014 /
03-25-2014
Store, cook, and serve food in a safe and clean way.
(Health) 02-27-2014 /
03-25-2014
Maintain drug records and properly mark/label drugs and other similar products according to accepted professional standards.
(Health) 02-27-2014 /
03-25-2014
Have a program that investigates, controls and keeps infection from spreading.
(Health) 02-27-2014 /
03-25-2014
Provide activities to meet the interests and needs of each resident.
(Health) 02-27-2014 /
03-25-2014
Ensure that residents with limited range of motion receive appropriate treatment and services to increase range of motion or prevent further decrease in range of motion.
(Health)
02-27-2014 /
03-25-2014
Ensure that residents are fully informed and understand their health status, care and treatments.
(Health) 02-27-2014 /
03-25-2014
Keep the rate of medication errors (wrong drug, wrong dose, wrong time) to less than 5%.
(Health) 02-27-2014 /
03-25-2014
Store, cook, and serve food in a safe and clean way.
(Health) 02-27-2014 /
03-25-2014
Maintain drug records and properly mark/label drugs and other similar products according to accepted professional standards.
(Health) 02-27-2014 /
03-25-2014
Have a program that investigates, controls and keeps infection from spreading.
(Health) 02-27-2014 /
03-25-2014
Provide activities to meet the interests and needs of each resident.
(Health) 02-27-2014 /
03-25-2014
Ensure that residents with limited range of motion receive appropriate treatment and services to increase range of motion or prevent further decrease in range of motion.
(Health)
02-27-2014 /
03-25-2014
Develop and implement policies for 1) screening and training employees; and the 2) prevention, identification, investigation, and reporting of any abuse, neglect, mistreatment and misappropriation of property.
(Health)
03-25-2014 /
04-04-2014
Develop and implement policies for 1) screening and training employees; and the 2) prevention, identification, investigation, and reporting of any abuse, neglect, mistreatment and misappropriation of property.
(Health)
03-25-2014 /
04-04-2014
Have a program that investigates, controls and keeps infection from spreading.
(Health) 01-23-2015 /
02-11-2015
Provide a safe, clean, comfortable and home-like environment; and allow residents to use personal belongings to the extent possible.
(Health) 01-23-2015 /
02-11-2015
Have a program that investigates, controls and keeps infection from spreading.
(Health) 01-23-2015 /
02-11-2015
Provide a safe, clean, comfortable and home-like environment; and allow residents to use personal belongings to the extent possible.
(Health) 01-23-2015 /
02-11-2015
Immediately tell the resident, the resident's doctor, and a family member of situations (injury/decline/room, etc.) that affect the resident.
(Health) 03-18-2015 /
04-06-2015
Develop and implement policies for 1) screening and training employees; and the 2) prevention, identification, investigation, and reporting of any abuse, neglect, mistreatment and misappropriation of property.
(Health)
03-18-2015 /
04-01-2015
Conduct initial and periodic assessments of each resident's functional capacity.
(Health) 03-18-2015 /
04-06-2015
Provide necessary care and services to maintain or improve the highest well being of each resident .
(Health) 03-18-2015 /
04-06-2015
Give proper treatment to residents with feeding tubes to prevent problems (such as aspiration pneumonia, diarrhea, vomiting, dehydration, metabolic abnormalities, nasal-pharyngeal ulcers) and help restore eating skills, if possible.
(Health)
03-18-2015 /
04-06-2015
Immediately tell the resident, the resident's doctor, and a family member of situations (injury/decline/room, etc.) that affect the resident.
(Health) 03-18-2015 /
04-06-2015
Develop and implement policies for 1) screening and training employees; and the 2) prevention, identification, investigation, and reporting of any abuse, neglect, mistreatment and misappropriation of property.
(Health)
03-18-2015 /
04-01-2015
Conduct initial and periodic assessments of each resident's functional capacity.
(Health) 03-18-2015 /
04-06-2015
Provide necessary care and services to maintain or improve the highest well being of each resident .
(Health) 03-18-2015 /
04-06-2015
Give proper treatment to residents with feeding tubes to prevent problems (such as aspiration pneumonia, diarrhea, vomiting, dehydration, metabolic abnormalities, nasal-pharyngeal ulcers) and help restore eating skills, if possible.
(Health)
03-18-2015 /
04-06-2015
Provide necessary care and services to maintain or improve the highest well being of each resident .
(Health) 06-01-2015 /
06-03-2015
Provide necessary care and services to maintain or improve the highest well being of each resident .
(Health) 06-01-2015 /
06-03-2015
Provide necessary care and services to maintain or improve the highest well being of each resident .
(Health) 06-03-2015 /
06-16-2015
Provide necessary care and services to maintain or improve the highest well being of each resident .
(Health) 06-03-2015 /
06-16-2015
Reasonably accommodate the needs and preferences of each resident.
(Health) 08-10-2015 /
08-24-2015
Provide necessary care and services to maintain or improve the highest well being of each resident .
(Health) 08-10-2015 /
08-24-2015
Reasonably accommodate the needs and preferences of each resident.
(Health) 08-10-2015 /
08-24-2015
Provide necessary care and services to maintain or improve the highest well being of each resident .
(Health) 08-10-2015 /
08-24-2015
Ensure services provided by the nursing facility meet professional standards of quality.
(Health) 12-23-2015 /
12-28-2015
Assist those residents who need help with eating/drinking, grooming and personal and oral hygiene.
(Health) 12-23-2015 /
12-28-2015
Ensure that a nursing home area is free from accident hazards and provide adequate supervision to prevent avoidable accidents.
(Health) 12-23-2015 /
12-28-2015
Ensure services provided by the nursing facility meet professional standards of quality.
(Health) 12-23-2015 /
12-28-2015
Assist those residents who need help with eating/drinking, grooming and personal and oral hygiene.
(Health) 12-23-2015 /
12-28-2015
Ensure that a nursing home area is free from accident hazards and provide adequate supervision to prevent avoidable accidents.
(Health) 12-23-2015 /
12-28-2015
Give residents proper treatment to prevent new bed (pressure) sores or heal existing bed sores.
(Health) 01-02-2016 /
01-05-2016
Keep the rate of medication errors (wrong drug, wrong dose, wrong time) to less than 5%.
(Health) 01-02-2016 /
01-05-2016
Give residents proper treatment to prevent new bed (pressure) sores or heal existing bed sores.
(Health) 01-02-2016 /
01-05-2016
Keep the rate of medication errors (wrong drug, wrong dose, wrong time) to less than 5%.
(Health) 01-02-2016 /
01-05-2016
Assist those residents who need help with eating/drinking, grooming and personal and oral hygiene.
(Health) 03-11-2016 /
03-21-2016
Ensure that a nursing home area is free from accident hazards and provide adequate supervision to prevent avoidable accidents.
(Health) 03-11-2016 /
03-21-2016
Have a program that investigates, controls and keeps infection from spreading.
(Health) 03-11-2016 /
03-21-2016
Assist those residents who need help with eating/drinking, grooming and personal and oral hygiene.
(Health) 03-11-2016 /
03-21-2016
Ensure that a nursing home area is free from accident hazards and provide adequate supervision to prevent avoidable accidents.
(Health) 03-11-2016 /
03-21-2016
Have a program that investigates, controls and keeps infection from spreading.
(Health) 03-11-2016 /
03-21-2016
Reasonably accommodate the needs and preferences of each resident.
(Health) 03-24-2016 /
04-06-2016
Ensure that each resident who enters the nursing home without a catheter is not given a catheter, unless medically necessary, and that incontinent patients receive proper services to prevent urinary tract infections and restore normal bladder functions.
(Health)
03-24-2016 /
04-06-2016
Reasonably accommodate the needs and preferences of each resident.
(Health) 03-24-2016 /
04-06-2016
Ensure that each resident who enters the nursing home without a catheter is not given a catheter, unless medically necessary, and that incontinent patients receive proper services to prevent urinary tract infections and restore normal bladder functions.
(Health)
03-24-2016 /
04-06-2016
Provide necessary care and services to maintain or improve the highest well being of each resident .
(Health) 04-14-2016 /
04-15-2016
Provide necessary care and services to maintain or improve the highest well being of each resident .
(Health) 04-14-2016 /
04-15-2016
Allow residents the right to participate in the planning or revision of care and treatment.
(Health) 04-29-2016 /
05-11-2016
Allow residents the right to participate in the planning or revision of care and treatment.
(Health) 04-29-2016 /
05-11-2016
Hospitals Near MOSAIC OF MAYFIELD, THE
Quite often skilled nursing facilities and hospitals work closely together to help patients recover or manage a terminal illness. Hospitals deals with acute care while nursing homes treat patients for a longer period of time. New residents at skilled nursing homes typically come from a hospital and nursing home residents may be readmitted to a hospital if their recovery does not proceed well. (Hospital readmission rates are closely monitored by CMS.) Consequently it is important that you consider which hospitals are near a nursing home which choosing one. Below is a list of hospitals near MOSAIC OF MAYFIELD, THE.
This information is based on the most recent Hospital data. Historical data is not available.
Hospital 5-Star Overall Rating
ST BERNARD HOSPITAL
326 W 64TH ST
CHICAGO, IL 60621 1
UNIVERSITY OF ILLINOIS HOSPITAL
1740 WEST TAYLOR ST SUITE 1400
CHICAGO, IL 60612 1
HOLY CROSS HOSPITAL
2701 W 68TH STREET
CHICAGO, IL 60629 1
JACKSON PARK HOSPITAL
7531 S STONY ISLAND AVE
CHICAGO, IL 60649 1
MT SINAI HOSPITAL MEDICAL CENTER
1500 S FAIRFIELD AVE
CHICAGO, IL 60608 1
SOUTH SHORE HOSPITAL
8012 SOUTH CRANDON AVENUE
CHICAGO, IL 60617 1
FRANCISCAN HEALTH HAMMOND
5454 HOHMAN AVE
HAMMOND, IN 46320 1
ROSELAND COMMUNITY HOSPITAL
45 W 111TH STREET
CHICAGO, IL 60628 1
JOHN H STROGER JR HOSPITAL
1901 W HARRISON ST
CHICAGO, IL 60612 2
SWEDISH HOSPITAL
5145 N CALIFORNIA AVE
CHICAGO, IL 60625 2
THOREK MEMORIAL HOSPITAL
850 W IRVING PARK RD
CHICAGO, IL 60613 2
ADVOCATE CHRIST HOSPITAL & MEDICAL CENTER
4440 W 95TH STREET
OAK LAWN, IL 60453 2
HUMBOLDT PARK HEALTH
1044 N FRANCISCO AVE
CHICAGO, IL 60622 2
INGALLS MEMORIAL HOSPITAL
1 INGALLS DRIVE
HARVEY, IL 60426 2
PRESENCE SAINT FRANCIS HOSPITAL
355 RIDGE AVE
EVANSTON, IL 60202 2
WEST SUBURBAN MEDICAL CENTER
3 ERIE COURT
OAK PARK, IL 60302 2
LOUIS A WEISS MEMORIAL HOSPITAL
4646 N MARINE DRIVE
CHICAGO, IL 60640 2
LOYOLA UNIVERSITY MEDICAL CENTER
2160 S 1ST AVENUE
MAYWOOD, IL 60153 2
COMMUNITY FIRST MEDICAL CENTER
5645 W ADDISON STREET
CHICAGO, IL 60634 2
INSIGHT HOSPITAL AND MEDICAL CENTER CHICAGO
2525 S MICHIGAN AVE
CHICAGO, IL 60616 2
Medical Professionals Associated with MOSAIC OF MAYFIELD, THE
These are the doctors who are affiliated with MOSAIC OF MAYFIELD, THE. The data is from the most recent period. Historical data is not available.
NDUDI ANIEMEKA( INTERNAL MEDICINE )
HEMA AZAD( INTERNAL MEDICINE - MIDWEST MEDICAL ASSOCIATES LLC )
Detailed Analysis Pages:
Depending on the nursing home, this page can get really long. So, we have also broken up the data onto separate pages to allow you to find what you want more easily. We will keep adding to these pages as we continue to analyze the nursing home database.
CMS Five Star Ratings and Quality Measures for MOSAIC OF MAYFIELD, THE
Five different rating results plus detailed inspection numbers and quality measures for MOSAIC OF MAYFIELD, THE.
Covid Infections at MOSAIC OF MAYFIELD, THE
This report is updated weekly and shows new and historical infection levels.
Nursing Hours Analysis for MOSAIC OF MAYFIELD, THE
How long a nurse spends with a resident can be an important factor in their recovery. This page shows the average nursing hours spent per resident for RNs, LPNs, CNAs, PTs and all licensed staff.
Ownership Details for MOSAIC OF MAYFIELD, THE
A list of all of the registered owners for MOSAIC OF MAYFIELD, THE. This includes direct and indirect owners and managers.
Noted Deficiencies for MOSAIC OF MAYFIELD, THE
A list of all of the deficiencies for the facility. This includes a description, type of deficiency, incident date and when the facility reports that the incident was corrected.
Comparison Ranking of Nearby Skilled Nursing Facilities
How does MOSAIC OF MAYFIELD, THE compare to other skilled nursing facilities? This list shows the competitive set within a 25 mile radius.
Best Nursing Homes in CHICAGO, IL
Homes that you should consider. A list ranking the best skilled nursing facilities in CHICAGO based on their weighted inspection score as of October 01, 2016.
Worst Nursing Homes in CHICAGO, IL
Homes that you avoid if possible. A list ranking the worst skilled nursing facilities in CHICAGO based on their weighted inspection score as of October 01, 2016.
Other Data Periods:
Data on MOSAIC OF MAYFIELD, THE is available for the following periods:
Jan 2014 Feb 2014 Mar 2014
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