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+"**Purpose:** Dendritic cells (DCs) are a heterogeneous cell population which critically regulates the adaptive immune response. Depending on their activation status, DCs can also promote peripheral immune tolerance, thus limiting the activation of the immune system and tissue damage. Cell based therapy approaches using DCs have been approved by the FDA and clinical trials using DC immunotherapy are being performed against a variety of cancer types. However, the role of DC therapy for wound healing has not yet been investigated.\n\n**Methods:** Hematopoetic stem cells (HSCs) were isolated from the bone marrow of green fluorescent protein (GFP) expressing mice and differentiated into DCs over a 7 day in vitro culture period. Tolerogenic DCs (TDCs) were induced by stimulation of cultures with 1,25-dihydroxyvitamin D3 (1\u03b1,25(OH)~2~D3), lipopolysaccharide or dexamethasone and the angiogenic potential of the cells was evaluated by endothelial cell (EC) tube formation assays in transwell as well as direct co-cultures. The protein levels of 52 cytokines were measured in the conditioned media of DC cultures using Luminex multiplex assays. The ability of TDCs to accelerate wound healing was evaluated by treating splinted excisional wounds in C57BL6/J mice weekly with pullulan-collagen hydrogels seeded with 1\u03b1,25(OH)~2~D3-stimulated TDCs, unstimulated DCs or blank hydrogels.\n\n**Results:**"
+"Background\n==========\n\nAssisted reproductive techniques (ART) are methods used to achieve pregnancy in case of female and/or male infertility. ART are known to be associated with a higher risk of multiple pregnancies \\[[@B1],[@B2]\\], mostly due to superovulation or transfer of two or more eggs or embryos. An overall higher risk of congenital malformations in fetuses conceived following ART has been reported in several studies \\[[@B3]-[@B10]\\] using different study populations and designs and methods of analysis and at times inconsistent results, particularly for specific anomalies \\[[@B6]\\].\n\nFew studies have assessed specifically the risk of congenital heart defects (CHD) associated with ART \\[[@B6],[@B11]-[@B15]\\]. These studies have found an increased risk of 30-50% (Odds ratios \\~1.3-1.5) of the overall risk of CHD, which varied across categories of CHD and methods of ART \\[[@B12]-[@B15]\\]. In particular, a recent study assessing the risk for four individual CHD, (Transposition of Great Arteries, Hypoplastic Left Heart, Coarctation of Aorta and Tetralogy of Fallot (TOF)) \\[[@B15]\\] found a specifically higher risk of TOF associated with ART. In contrast, the authors found no statistically significant associations with the other three defects examined and the effect sizes (odds ratios) were close to the null value (i.e., close to one).\n\nEven"
+"Introduction {#Sec1}\n============\n\nDNA damage (such as double strand breaks (DSBs)) elicits cellular signalling pathways, collectively known as the DNA damage response (reviewed in ref. [@CR1]). Among these, checkpoint mechanisms control cell cycle progression as well as transcriptional and post-translational regulation of DNA repair and replication. Furthermore, local signalling events are critical in directing DNA repair pathway choice. Budding yeast Rad9 was the first checkpoint protein to be discovered^[@CR2]^. Since then, it has become evident that Rad9, as well as its orthologs such as fission yeast Crb2^[@CR3],\\ [@CR4]^ and human 53BP1 (reviewed in ref. [@CR5]), play a crucial role in the DNA damage response, having at least two functions: signal transduction in the DNA damage checkpoint (reviewed in ref. [@CR1]) and control of DNA end resection, a local process that critically determines DSB repair pathway choice (reviewed in ref. [@CR6]).\n\nAs checkpoint signalling mediator, Rad9 links the signal transduction from the apical kinase Mec1 to the effector kinase Rad53^[@CR7]--[@CR12]^. As such, it is essential for activation of Rad53 and therefore for the activation of a global checkpoint response upon DNA damage. Moreover, Rad9 is also an inhibitor of DNA end resection^[@CR13]--[@CR16]^. Since DNA end resection generates the DNA substrate for"
+"The Editors' Network is a task force of the European Society of Cardiology (ESC), representing the 44 National Society Cardiovascular Journals that are published across 37 countries ([@R1]). Among the operational goals enshrined in its mission statement is a commitment to improve the diffusion of scientific knowledge through distribution of common academic material and joint education initiatives ([@R2]). Heart already has a strong education section and its content, approved by the European Board for Accreditation in Cardiology (EBAC), is available for free access via the Heart and ESC websites. However, a recent joint publication of the Editors' Network called for educational initiatives to be extended throughout the national cardiology journals of Europe ([@R3]), and it is in response to that call that a series of Almanac 2011 papers are appearing more or less simultaneously in many of the Network Journals. Almanac--a late Middle English word derived via medieval Latin from Greek *almenikhiaka*--is defined as an annual calendar containing important dates and statistical information. It provides an approximate description of the new series of papers presenting selected recent research that has driven clinical advances in six major topic areas. The content is educative and clinically relevant and its presentation across the"
+"Introduction\n============\n\nThe rapid evolution of the Covid-19 pandemic has fundamentally challenged our health care delivery system, as the need for social distancing to curb disease spread is critical to public and health-care provider safety.[@r1]\n\nIn most health care organizations, a majority of ambulatory clinic appointments have been in-person visits, with person-to-person connection and physical examination as central elements of the diagnostic and therapeutic relationship.\n\nTelephone and video visits are convenient for patients because they don't require taking time off work, finding childcare/eldercare, or driving to a clinic appointment.[@r2] Health care systems can use telemedicine to increase overall access, scale provider services by allowing care to happen from many locations, prevent exposure, and direct patients to appropriate levels of care.[@r3] With technological advances, video visits have become much more convenient for patients and providers. However, until just recently academic medical centers (AMCs) have been slow to adopt video visits. There has been no clear consensus on the quality of clinical care delivered via such visits and patients have not demanded them.[@r4]\n\nIn March 2020, the number of SARS-CoV-2 infected patients began to escalate, making it crucial to find methods to provide high-quality medical care without exposing the clinic staff or"
+"Introduction {#Sec1}\n============\n\nApical periodontitis is an inflammatory disease in the periapical area which results from infection of the dental pulp in the root canal system. Root canal treatment aims to remove bacteria from the root canal system, and dentists achieve this through mechanical removal of infected dentin and chemical removal of remnant bacteria in the root canal. This treatment is based on scientific evidence that germ-free mice do not develop apical periodontitis, and bacterial infection of the pulp chamber or root canal can cause apical periodontitis^[@CR1]^. The success rate of initial root canal treatment is found to be lower than that of pulpectomy, which is the treatment for inflamed dental pulps without bacterial infections^[@CR2]^. It is difficult to eliminate bacteria from root canal systems, not only because of their complex anatomical structure, but also because bacteria are embedded in biofilms. Biofilms are formed not only in the root canal system but also on the outer root surface around the apical foramen^[@CR3]--[@CR5]^, where they are known as extraradicular biofilms. Extraradicular biofilms lower the success rate of root canal treatment, making apical periodontitis refractory^[@CR6]^.\n\nThe rate of bacteria removal by root canal treatment is not known. Root canal treatment is thought"
+"1. Introduction {#sec1-materials-11-01692}\n===============\n\nQuartz is the main mineral responsible for triggering the alkali--silica reaction (ASR) in concrete structures \\[[@B1-materials-11-01692],[@B2-materials-11-01692],[@B3-materials-11-01692]\\]. This mineral has a tetrahedral coordination of silicon (Si) by oxygen (O) stable, but due to tectonic stresses its crystalline structure undergoes displacements and deflections \\[[@B1-materials-11-01692]\\]. The displacement of the crystalline structure of quartz leads to changing the distances of its atoms, thus creating \"fragile zones\" which, due to the increase in internal tensions, tends to subdivide and form new grains \\[[@B4-materials-11-01692]\\]. Its crystal lattice becomes slightly bent and this can be observed under a petrographic microscope. By virtue of the undulatory extinction, this characteristic indicates the greater reactivity of quartz in alkali hydroxides of concrete. Wenk et al. \\[[@B5-materials-11-01692]\\] and Tiecher et al. \\[[@B6-materials-11-01692]\\] observed the formation of displacement walls in quartz grains by using transmission electron microscopy (TEM), thereby verifying that the displacements of the crystalline reticulum occur in small areas, where walls that divide the crystal into subgrains are formed, and that these have little or no displacement.\n\nTherefore, the same grain could have zones that are more and less reactive, and which are directly related to the thermodynamic stability of the tensioned quartz to the alkaline"
+"Introduction\n============\n\nThe glaucomas are a group of eye diseases that primarily affect the optic nerve and retinal ganglion cells and are a common cause of vision loss and blindness. Current estimates suggest that over 60 million people have glaucoma worldwide \\[[@r1]\\]. Glaucoma is defined by progressive cupping of the optic disc and a corresponding loss of visual field. Several risk factors for glaucoma have been identified including age, race, family history, intraocular pressure (IOP), and corneal thickness. The most common form of glaucoma in the United States is primary open angle glaucoma (POAG) \\[[@r2]\\]. A subset of POAG that occurs with a maximum IOP below an arbitrarily threshold of 21\u00a0mmHg is often termed normal tension glaucoma (NTG).\n\nGenetic variants have also been shown to have a significant role in the pathogenesis of POAG. Studies of rare families have mapped the position of 14 POAG genes to small regions of the genome \\[[@r3]-[@r6]\\] and glaucoma-causing genes have been discovered in two of these loci, myocilin (*MYOC*) \\[[@r7]\\] and optineurin (*OPTN*) \\[[@r8]\\]. Mutations in *MYOC* are associated with POAG that is characterized by high IOP and strong family history and are responsible for approximately 4% of POAG cases worldwide. Mutations"
+"1. Introduction {#sec1}\n===============\n\nHepatocellular carcinoma (HCC) is the fifth most frequent malignancy and the second leading fatal disease worldwide \\[[@B1]\\]. There are several canonical strategies for hepatocellular carcinoma treatment, including surgical resection, local ablation, liver transplantation, radiotherapy, chemotherapy, and molecular targeted therapy \\[[@B2]--[@B4]\\]. However, these treatments cause serious side effects sometimes; they are not applicable to all of the patients and demonstrate to be of limited efficacy \\[[@B5], [@B6]\\]. Therefore, identification of novel antitumor agents from natural products with better effectiveness is an alternative choice for management of hepatocellular carcinoma.\n\nIn recent years, many Chinese herbs have been gradually discovered to be potential sources of antitumor drugs for its role in killing tumor cells less intensively and more naturally \\[[@B7], [@B8]\\].*Trametes robiniophila* Murr. (Huaier) has been applied in traditional Chinese medicine for approximately 1600 years \\[[@B9]\\]; however, its antitumor properties are found and used as a complementary therapy only in recent decades. The main effective ingredient of this officinal fungi has been identified as proteoglycan which contains 41.53% polysaccharides, 12.93% amino acids, and 8.72% water \\[[@B10]\\]. A number of studies have demonstrated that Huaier extract inhibited proliferation and induced apoptosis in pulmonary cancer, breast cancer, melanoma, and colorectal cancer"
+"INTRODUCTION {#sec1}\n============\n\nBy international standards, the Australian annual incidence of tuberculosis is low (\\~5--6 cases per 100 000 population) \\[[@ref1]\\]. Therefore, when it presents atypically, clinical suspicion is often low, and the diagnosis can easily be missed. We present a case of a 54-year-old female with an incidental hepatic lesion resected for concerns of malignancy; however, it was found to be local hepatic tuberculosis.\n\nCASE REPORT {#sec2}\n===========\n\nA 54-year-old female, of Philippines descent, presented to our department following the incidental discovery of a 23 \u00d7 20\u00a0mm ill-defined mass within segment II/III of the liver during ultrasound workup for mildly deranged liver function tests. She had no symptoms from the lesion, and she reported no significant past medical history. A pre- and post-contrast multiphase helical computed tomography identified a 26 \u00d7 25\u00a0mm ill-defined region of hypodensity, with a small focus of central calcification, within segments II and III of the liver ([Fig. 1](#f1){ref-type=\"fig\"}). The lesion was causing biliary obstruction indicated by dilatation of the intrahepatic biliary ducts within the entire left lobe of the liver and appeared to be in continuity with the left hepatic duct. Magnetic resonance imaging of the liver identified an irregular enhancing mass"
+"Introduction {#Sec1}\n============\n\nEndometrial carcinoma is the most common malignant tumor of the female genital tract in the Western countries. A dualistic model of endometrial carcinogenesis has been proposed since the 1980s, based on light microscopic appearance, clinical behavior, and epidemiology \\[[@CR1]\\]. Type I cancers, those with endometrioid histology, comprise approximately 80% of all endometrial carcinomas. In contrast, type II endometrial cancers have nonendometrioid histology (usually serous or clear cell) with aggressive clinical course. Hormonal risk factors have not been identified. Common genetic changes in type I cancers include microsatellite instability or specific mutation of PTEN, K-ras, and \u03b2-catenin genes, while most type II cancers contain mutations of p53 \\[[@CR2]\\].\n\nMammalian mitochondrial transcription factor A (mtTFA) proteins have a molecular weight of \u223c25\u00a0kDa and consist of an amino-terminal high mobility group (HMG) domain, a basic linker region, a second HMG domain, and a basic carboxyterminal tail \\[[@CR3]\\]. It was recently demonstrated that mtTFA, which was firstly identified as a mitochondrial transcription factor, is involved in not only the transcription of mitochondrial DNA (mtDNA) but also the replication of mtDNA, recognition of mtDNA damage, stabilization of mtDNA, and indirectly, in repair of mtDNA \\[[@CR4]\\].\n\nSeveral studies showed that expression of"
+"Introduction {#s1}\n============\n\nCilia are microtubule-based projections from the cell body (general references <http://www.ifcbiol.org/Primaryciliumweb/index.html>). Cilia grow from the mature mother centriole of the mother-daughter pair of centrioles in the cell\\'s centrosome [@pone.0027058-Rieder1]. Solitary or sensory cilia are present in most cells of the body and their functions are only now beginning to be defined. Their existence has been known from morphological studies since the sixties [@pone.0027058-Satir1]; however, because very little has been known about their functions, not much attention has been paid to this particular organelle until recently.\n\nSeveral observations have illustrated the importance of the solitary cilium: 1) Smell, taste, and vision occurs via modified cilia: olfactory or gustatory sensory cilia and outer segments of rod cell, respectively (see e.g. Figure 15-43 of [@pone.0027058-Alberts1]. 2) Some receptors are specifically located on neurocilia [@pone.0027058-Handel1]. 3) mutations that occur in proteins resulting in mislocation of normal ciliary proteins or malfunction of solitary cilia itself in the renal epithelium produces a polycystic kidney disease phenotype, which is characterized by the transformation of an absorptive epithelium into a secretory one with formation of cysts [@pone.0027058-Calvet1], [@pone.0027058-Lin1], [@pone.0027058-Luo1], [@pone.0027058-Nauli1]. 5) Defects in solitary cilia present during development result in inversion of the normal left-right"
+"The views expressed in this Perspective do not necessarily reflect the views of the journal or of ASM.\n\nINTRODUCTION {#h0.0}\n============\n\nZoonotic influenza viruses circulating in poultry and swine pose an ever present threat to human health. In particular, the rapid geographical expansion of highly pathogenic avian influenza (HPAI) A(H5N1) throughout Asia and then into Europe, the Middle East, and Africa during the 2000s galvanized the global community in an attempt to control this rapidly growing threat. Despite successful control efforts in some countries, the virus remains endemic in poultry in at least six countries and continues to cause human illness and deaths as well as countless outbreaks in birds. During the past decade, 668 cases and 393 deaths were detected and reported to the World Health Organization (WHO) ([@B1]). During the 17\u00a0years since human infections with HPAI A(H5N1) were first identified in Hong Kong, Special Administrative Region, People's Republic of China, in 1997, these viruses have evolved substantially through mutation and reassortment, resulting in multiple divergent genotypes and clades ([@B2]).\n\nOngoing H5N1 circulation has appropriately resulted in a focus on sequencing viral genomes to understand the evolution of these viruses and the significance of observed genetic changes. Expanded"
+"INTRODUCTION\n============\n\nLung cancer is the leading cause of cancer-related mortality worldwide.^[@R1]^ Surgical resection constitutes the primary therapeutic option for the management of early-stage non-small cell lung cancer (NSCLC).^[@R2]^ According to the 7th edition of the American Joint Committee on Cancer (AJCC), the present pathologic stage II (pIIA) disease has been divided into 6 subgroups, which include T1aN1M0, T1bN1M0, T2aN1M0,T2bN0M0, T2bN1M0, and T3N0M0.^[@R1]^ In the 7th edition, previous stage IB subgroup T2bN0 was downgraded to stage IIA and pevious stage IIB subgroup T2aN1 was upgraded to stage IIA. Stage migration indeed happened in the new classification. A review of the literature reveals that Wang et al^[@R3]^ found different 5-year overall survival (OS) between pIIA and pIIB (59.7% vs. 47.2%).^[@R3]^ This means that pIIA and pIIB were different groups of patients and should be discussed separately. The special characteristic of stage II is N1 lymph node (LN) involvement. During the past 2 decades, many studies have evaluated the validity of the N descriptors and have suggested refinements that would allow more accurate prognostic stratification.^[@R4],[@R5]^ These findings have generated considerable interest in identifying N1 LN involvement in order to accurately predict survival.^[@R6]^ Patients who are N1-positive suffer a considerable risk of recurrence;"
+"INTRODUCTION\n============\n\nPhaeochromocytoma is a neuroendocrine tumor with a prevalence ranging from 0.05% to 0.1% ([@B1], [@B2]). Phaeochromocytomas are located in the adrenal cortex in 85% of cases ([@B2]). The main clinical manifestation of phaeochromocytomas is arterial hypertension, which is the result of uncontrolled production of catecholamines by the tumor. It is estimated that 0.1% to 0.6% of all patients with hypertension have an underlying phaeochromocytoma ([@B2], [@B3]). Moreover, catecholamine-producing neoplasms can lead to hypertensive emergencies with life-threatening consequences; thus, this tumor has major clinical importance ([@B2], [@B4]).\n\nCurative treatment for phaeochromocytoma requires surgical removal of the tumor, which can be challenging because of the high likelihood of hemodynamic instability during the procedure and substantial blood pressure fluctuations during the recovery period ([@B5]). Fortunately, the development of preoperative strategies for strict blood pressure control has led to an important reduction in mortality rates. Forty years ago, the perioperative mortality ranged from 30% to 45% ([@B5]), whereas in recent series, perioperative mortality decreased to 0% to 2.9% ([@B1], [@B3]). Surgery-related complications have also declined, but they are still frequent, occurring in one of every five patients who undergo surgery ([@B4]).\n\nPhaeochromocytomas are frequently associated with familial syndromes; in these instances, the"
+"Introduction\n============\n\nGynecomastia is a common benign condition of the male breast, most frequently observed in newborns, adolescents and the elderly, and it may be associated with discomfort and mental stress ([@b1-etm-0-0-6224]). The pathogenesis of this condition is multifactorial and in most cases idiopathic ([@b2-etm-0-0-6224]). Prevalence rates are 60--90% in newborns, 50--60% in adolescents and 70% in males aged 50--69 years ([@b1-etm-0-0-6224]).\n\nDisease progression has several stages. Asymptomatic males with long-standing breast enlargement do not usually require treatment other than therapy. In males who suffer from pain or embarrassment, treatment is guided by the cause of gynecomastia and patient expectations ([@b3-etm-0-0-6224]). It is ideal for medicinal treatments to be applied during the proliferation phase of gynecomastia ([@b4-etm-0-0-6224]). However, if gynecomastia has been present for \\>1 year, it would not be expected to regress substantially, either spontaneously or with medicinal therapy, due to the presence of fibrosis ([@b5-etm-0-0-6224]). Under these circumstances, surgical excision to remove tissue is the only effective method.\n\nSurgical management of gynecomastia includes four general approaches: Excision of breast tissue, liposuction and skin resection, alone or in combination. Liposuction may be used to treat pseudo gynecomastia, as fat deposition is a major concern in such cases ([@b6-etm-0-0-6224]). Liposuction"
+"Introduction {#s1}\n============\n\nThe healthcare systems in Eastern European countries in general, and Romania in particular, have been significantly affected by the political changes in the 1990s, de-centralisation, transition to market-orientated economies, as well as various political and economic crises [@pone.0097833-Bara1], [@pone.0097833-Holt1], [@pone.0097833-Krcmery1], [@pone.0097833-Lakey1].\n\nWith the public attention being focused mainly on HIV and tuberculosis, there are only few data available on other issues such as, *e.g.,* antibiotic resistance in various pathogens such as *Staphylococcus aureus*. Since its first description roughly 50 years ago, methicillin-resistant *S. aureus* (MRSA) has globally become a public health threat. While there is an abundance of epidemiological and typing data from Western Europe, the United States and Australia, relatively few data are available for other parts of the world. Unfortunately, this is also true for Eastern Europe including Romania. It is known that the MRSA rates are extremely high, ranging from approximately 30% up to 70% in recent Romanian studies [@pone.0097833-Dorneanu1], [@pone.0097833-Szekely1], [@pone.0097833-Dorobat1], [@pone.0097833-Ionescu1], [@pone.0097833-Kock1], [@pone.0097833-Nastase1], [@pone.0097833-Nica1], [@pone.0097833-Vremera1], thus reaching the highest prevalence levels reported anywhere in the world. According to the ECDC antimicrobial resistance surveillance (formerly EARSS), the MRSA rate among invasive infections was \"equal to or above 25%\" in 2008 and slightly above"
+"^\u00a7^ CINVESTAV Unidad Irapuato, Irapuato, Mexico.\n\nIntroduction {#sec1}\n============\n\nThe environmental mold *Aspergillus fumigatus* has become the most important airborne fungal pathogen of humans and is the second most frequent cause of systemic fungal infections.([@ref1]) In immunocompetent individuals, *A. fumigatus* can cause allergic reactions and noninvasive infections such as aspergilloma. However, in immunocompromised patients, this filamentous fungus is the main causative agent for life-threatening systemic infections named invasive aspergillosis (IA). Due to the improvements in transplant medicine and the therapy of hematological malignancies, the number of patients and thus the quantity of cases of IA has increased significantly in the last decades. Specific diagnostics are still limited, as are the possibilities of therapeutic intervention, leading to a high mortality rate of 30 up to 90% for IA.^[@ref2],[@ref3]^ Infection is most commonly initiated by inhalation of airborne fungal spores (conidia), which germinate in the lung alveoli and the formed hyphae start to grow invasively into the lung tissue. Accumulating evidence suggests that *A. fumigatus* experiences hypoxia while growing in the lung.^[@ref4]\u2212[@ref6]^ The oxygen partial pressure within the alveoli averages at 7.9 kPa (19.7 kPa in the atmosphere). In the surrounding tissue, it drops down to 2\u22124 kPa and in inflamed, necrotic"
+"Introduction {#Sec1}\n============\n\nThe ever-increasing energy demand in today's industrial world led to the widespread use of non-renewable fossil fuels such as petroleum. The transition from a society with waste generating, linear production routes to one cyclic valorization path in conjunction with renewable resource management is one of the most demanding technological goals for establishing sustainable bioeconomy \\[[@CR1], [@CR2]\\]. This scenario particularly applied renewable energy supply routes that demand a switch from finite fossilto sustainable platform solutions. Moreover, dwindling of fossil resources, escalating environmental pollution, surging CO~2~ and greenhouse gas emissions, in addition to climate change have collectively driven the search for alternative energy sources \\[[@CR3]\\]. Accordingly, technological innovations that enable a more sustainable lifestyle are coveted \\[[@CR4]\\].\n\nBiofuels have garnered great interest in recent years as alternatives for fossil fuel. In fact, plant-derived biofuel offers a partial solution to the ever-increasing energy demand, due to their renewability. However, this first-generation of biofuels, generated from edible crops, impacts agricultural activity and jeopardizes food security \\[[@CR1]\\] To meet the current annual global-demand of biodiesel, more than double of the currently arable land would be required to grow crops that are explicitly grown for fuel production \\[[@CR5]\\]. Consequently, alternative sources for biofuel"
+"Introduction {#Sec1}\n============\n\nMantle cell lymphoma (MCL) is a mature B-cell non-Hodgkin's lymphoma (NHL) accounting for 5--7% of all NHLs^[@CR1]^. Although MCL is uncommon (0.64/100,000 person-years), there has been a 130.9% rise in its incidence in recent years^[@CR2]^. Higher incidence rates have been seen in Caucasians (153.0%), Asians (96.4%), and the elderly (429.2%). Patients with MCL treated with standard therapies have a limited duration of remission, and also show frequent relapses, resulting in a short median overall survival (OS) of 4--5 years^[@CR3]^.\n\nClassical MCL expresses the hallmark t(11:14)(q13;q32) chromosomal translocation^[@CR4]^. However, the pathogenesis of MCL is complex and the alterations in the genes involved in DNA damage response (ataxia telangiectasia mutated \\[*ATM*\\], checkpoint kinase 2 \\[*CHK2*\\], and *TP53*) and cell survival signalling pathways (Bruton's tyrosine kinase \\[BTK\\], mammalian target of rapamycin \\[mTOR\\], nuclear factor-\u03baB \\[NF-\u03baB\\], tumour necrosis factor \\[TNF\\], and NOTCH) also play crucial roles^[@CR5]^. Moreover, MCL patients exhibit diverse responses to therapies and clinical courses^[@CR6],[@CR7]^, which has not been completely incorporated by current risk stratification tools. Therefore, it is essential to investigate the genetic landscape of this heterogeneous disease to gain insight into the molecular pathogenesis and to predict the prognosis of MCL patients.\n\nTargeted panel sequencing (TPS) and"
+"Introduction\n============\n\nMany investigations into the effect of ocean acidification (OA) on coral reefs have been conducted ([@B2]), and results indicate that that marine organisms which inhabit the carbonate structures of coral reefs are important and sensitive to OA ([@B40]). [@B1] and [@B47] found that changes to pH in the seawater surrounding natural coral reefs in the southern Great Barrier Reef can significantly affect calcification rates, suggesting that OA may already be altering the growth of coral reefs. By decreasing the ocean pH, OA can affect the calcifying rates of calcifying creatures such as coralline algae with carbonate skeletons ([@B29]; [@B1]). However, seagrasses can increase the pH of the ambient environment via high photosynthesis rates ([@B38]; [@B29]). Moreover, [@B39] found that seagrass in coral reef ecosystems can reduce disease levels twofold in comparison with the corals located adjacent to seagrass meadows and corals at paired sites without seagrass.\n\nSeagrass is highly productive and of great ecological importance in the marine environment. For instance, it can provide food, nursery and breeding habitats for other marine organisms inhabiting the ecosystem and nutrients for coral reefs. Nonetheless, available nitrogen is usually the main factor limiting the primary productivity of seagrass because coral reef"
+"Background {#Sec1}\n==========\n\nAlthough children differ from adults in many aspects of pharmacotherapy, children are often excluded from clinical trials, and knowledge about the efficacy and safety of drugs used in this population is scarce. This lack of knowledge often results in frequent unlicensed/off-label drug use in children. In 2004, the EMA (European Medicines Agency) published a report on the evidence of harm associated with the use of unlicensed and off-label drug use in children \\[[@CR1]\\]. However, few studies have evaluated general drug use in children based on two literature reviews \\[[@CR2], [@CR3]\\]. Some of the population-based studies provide trends of outpatient drug use \\[[@CR4], [@CR5]\\]. A few studies focus on hospitalized children \\[[@CR6]\\]. Several other studies have concentrated on a limited number of drugs, such as antibiotics and psychotropic drugs \\[[@CR7], [@CR8]\\]. However, there are no clinical tools or methods that could quantitatively measure drug safety under different pediatric conditions that can be used to balance priorities between common drugs with wide-reaching effects (such as asthma medications) and rarer drugs with smaller target populations or more serious consequences (such as cardiovascular drugs).\n\nUnder the Best Pharmaceuticals for Children Act in the US, the National Institute of Child Health and"
+"Background {#Sec1}\n==========\n\nA robust clinical training experience is essential in producing physicians capable of delivering high quality health care. Effective clinical teachers have been described in previous studies as clinically knowledgeable, compassionate, having strong integrity and possessing solid teaching skills. Additionally, effective teachers actively involve their students in patient care and provide constructive feedback and guidance \\[[@CR1]\\].\n\nReview studies have found that over 32 different instruments have been developed to assess clinical teachers \\[[@CR2]\\]. A small number of these instruments assesses only student performance \\[[@CR3]\\]. Some of those instruments are not validated, while some studies argue that instruments must be validated against the specific context they are being applied to \\[[@CR4]\\].\n\nSuch questionnaires are essential for the continuous development of medical students' education and for the ongoing improvement of clinical teaching skills. Because students at different stages of their educational careers may be looking for different attributes in a clinical teacher \\[[@CR5], [@CR6]\\], these instruments should be administered to a wide variety of samples at different points in the learning process. This will support the criterion validity of the instrument. It has been suggested that for an instrument to be used by specific groups or in different cultural and"
+"Introduction {#s1}\n============\n\nInfluenza is a highly contagious disease caused by viruses that belong to the family *Orthomyxoviridae* [@pone.0061158-Eccles1], [@pone.0061158-Wright1]. Influenza viruses are classified into 16 HA and 9 NA subtypes on the basis of two surface proteins on the virus particle, hemagglutinin (HA) and neuraminidase (NA) [@pone.0061158-Webster1], [@pone.0061158-Fouchier1], and almost all possible subtypes have been isolated from avian species [@pone.0061158-Olsen1], [@pone.0061158-Munster1]. HA is a glycoprotein responsible for virus binding to sialic acid on the host cell surface, and mediates the fusion of the viral and cellular membranes after endocytosis [@pone.0061158-Wiley1], [@pone.0061158-Martin1]. HA is translated as a precursor HA~0~, which is assembled into viral particles [@pone.0061158-Kido1]. Because the cleavage of HA~0~ into HA~1~ and HA~2~ is required for the fusion of viral and cellular membranes, the expression patterns of host proteases determine the viral organ tropism [@pone.0061158-Horimoto1], [@pone.0061158-Steinhauer1]. The HA~0~ of low pathogenic influenza viruses is cleaved by extracellular serine proteases, which exist in a limited number of cells or tissue types. However, the HA~0~ cleavage site (CS) of the highly pathogenic avian influenza (HPAI) viruses contains a multi-basic sequence, which is cleaved by ubiquitous intercellular endoproteases including PC6 and furin [@pone.0061158-Horimoto1], [@pone.0061158-Steinhauer1], [@pone.0061158-Kawaoka1]. Thus, HPAI viruses are able to"
+"INTRODUCTION {#sec0010}\n============\n\nHigh risk (high grade, cTa, cT1, and cTis), non-muscle invasive bladder cancer (NMIBC) is principally managed with transurethral resections (TUR) and adjuvant intravesical bacillus Calmette-Guerin (BCG) therapy. However, disease recurs or progresses in approximately 40%--50% of patients \\[[@r1]\\]. Available management options for patients with recurrent or progressive high grade NMIBC include radical cystectomy (RC), additional intravesical therapy typically with chemotherapy, and clinical trial entry \\[[@r2]\\]. Some advocate RC in lieu of additional intravesical therapy as BCG failure portends poor oncologic outcomes when treated with bladder preservation and long-term survival in patients undergoing cystectomy with cTa/T1/Tis disease ranges from 80%--88% \\[[@r3]\\]. Furthermore, cystectomy may be more cost-effective than intravesical therapy when used as first line treatment in certain high risk settings of NMIBC \\[[@r5]\\].\n\nMitomycin C (MMC) is predominantly utilized as treatment for patients with intermediate and high risk NMIBC as well as for patients who recur or progress despite intravesical BCG therapy \\[[@r6]\\]. There have been no randomized controlled trials (RCTs) evaluating the clinical or economic benefit of mitomycin C intravesical therapy over radical cystectomy in high risk NMIBC populations largely due to the expected challenges in patient accrual, real ethical concerns, expected costs of such a"
+"Introduction\n============\n\nDuring the Devonian, approximately 415 to 360 million years ago, the Sarcopterygii (lobe-finned fishes) constituted one of two major radiations of bony fishes. Today, only three groups of Sarcopterygii still exist: the coelacanths, the lungfishes, and the limbed vertebrates (Tetrapoda). All recent phylogenetic data indicate that lungfishes are the sister group of tetrapods, and that coelacanths are, in turn, the sister group of these taxa (Brinkmann et al., [@B1]; Takezaki et al., [@B28]). There are only two known living coelacanth species: the Comoran coelacanth, *Latimeria chalumnae*, and the Indonesian coelacanth, *L. menadoensis*. Both species are 1--2\u2009m in length and weigh 65--100\u2009kg. Both inhabit marine rocky slopes with caves at depths of 100--700\u2009m. *L. chalumnae* was discovered in 1938, and over 100 specimens have been preserved in museums internationally. Their current population, however, is estimated to be less than 400 individuals (Hissmann et al., [@B11]). *L. menadoensis* was discovered only in 1997, and there are no estimates of their population size.\n\nAlthough the anatomy of *L. menadoensis* has not been described, the general anatomy of *L. chalumnae* is known in detail (Millot and Anthony, [@B13], [@B14]; Millot et al., [@B15]), and there are several descriptions of"
+"INTRODUCTION\n============\n\nIn multi-cellular organisms, the control of gene expression is key not only for development, but also for adult cellular homeostasis, and deregulation of gene expression correlates with aging ([@b1-bmb-52-086]--[@b4-bmb-52-086]). Aging is the main risk factor for many chronic diseases, such as neurodegeneration, cardiovascular disease, type II diabetes, osteoporosis, and cancer. Several conserved and interconnected pathways are deregulated during aging, delineating \"hallmarks\" or \"pillars\" of aging ([@b5-bmb-52-086], [@b6-bmb-52-086]). However, how these hallmarks are achieved throughout the life of an organism is still poorly understood.\n\nIn the laboratory, several models are used to study aging: (i) chronological aging (*i.e*. the time that passed in the organism's life), which most closely corresponds to the most intuitive definition of aging, (ii) replicative aging (*i.e*. the number of times a cell can divide; most used to study aging in yeast) ([@b7-bmb-52-086]), (iii) cellular senescence, which corresponds to the replicative limit of cells before they enter irreversible cell cycle arrest, also dubbed the 'Hayflick limit' ([@b8-bmb-52-086]), and (iv) progeria or premature aging syndromes (*i.e*. Hutchinson-Gilford or Werner Syndrome) ([@b9-bmb-52-086]). Although aging is a common feature of many taxa, the rate of aging differs between species, and accumulating evidence suggests that the process can be"
+"1. Introduction and Discussion {#sec1}\n==============================\n\nThe risk of cardiovascular-related morbidity and mortality is known to increase in patients with schizophrenia. Patients with schizophrenia have an increased risk of sudden death and are 2--4 times more likely to die prematurely compared to the general population \\[[@B1]\\]. The second generation antipsychotics (SGAs) are associated with cardiovascular side effects that can have serious consequences to patients \\[[@B1]--[@B3]\\] ([Table 1](#tab1){ref-type=\"table\"}). Atypical antipsychotic drugs are a chemically diverse group of drugs, and the type and the degree of associated cardiovascular effects may therefore vary. Risk factors for cardiovascular adverse effects associated with the use of atypical antipsychotic drugs include advanced age, autonomic dysfunction, preexisting cardiovascular disease, female gender (for risk of QTc interval prolongation and torsade de pointes), electrolyte imbalances (particularly hypokalemia and hypomagnesemia), elevated serum antipsychotic drug concentrations, genetic characteristics, and the psychiatric illness itself.\n\nAntipsychotics have been used for more than five decades for the treatment of psychosis, which can result from a number of disorders including bipolar disorders, delirium, delusional disorders, psychotic depression, paranoia, schizophrenia, Tourette\\'s syndrome, and substance-induced psychosis and various neurologic conditions such as dementias, Huntington\\'s disease, multiple sclerosis, and parkinsonism. The first generation antipsychotic medications (FGAs), also commonly"
+"Note: Supplemental materials and tables appear at [www.ajtmh.org](http://www.ajtmh.org).\n\nINTRODUCTION {#s1}\n============\n\nNeglected tropical disease programs typically use the mean incidence or prevalence over a geographical region to assess whether an intervention is required and whether control targets have been achieved. Thresholds allow programs to easily classify populations into those that have met the criterion. Those populations above the threshold may represent high, sustained transmission areas of endemic disease or the inevitable laggards in what will be a successful elimination program. A different criterion could be achievement of subcritical transmission, where the replacement number for infectious cases (*R*) is less than unity. If subcritical, infection would be expected to eventually be eliminated even without additional programmatic efforts. Identification of the prevalence threshold for subcriticality is a goal for programs, as this implies they are moving toward elimination. Although assessment could be performed with longitudinal surveys, subcriticality can also be assessed in cross-sectional surveys.^[@b1]--[@b3]^\n\nMathematical models have suggested that a geometric distribution might be expected when an infectious disease is subcritical.^[@b4]--[@b6]^ Cross-sectional surveys of diseases such as trachoma and leprosy are consistent with a geometric distribution across some areas that were expected to be headed toward elimination. Onchocerciasis is different from these"
+"Objectives:\n===========\n\nTriamcinolone acetonide extended-release (TA-ER) is approved in the US to treat pain associated with knee osteoarthritis (OA). Intra-articular corticosteroids (IACS) are often used to manage recurrence of pain and symptoms during the prolonged course of OA. Effectiveness of IACS in advanced knee OA is unknown, and lack of effective nonoperative treatments may accelerate consideration of total knee arthroplasty (TKA). This post hoc subgroup analysis of a Phase 3b, single-arm, open-label study (NCT03046446) evaluated the efficacy of initial and repeat administration TA ER in knee OA with a range of radiographic severity classified by Kellgren-Lawrence (KL) grade.\n\nMethods:\n========\n\nPatients aged \u226540 years with symptomatic knee OA for \u22656 months, KL Grade 2-4, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) -A (pain) total sum score \u22656, and index knee pain for \\>15 days during the prior month received the 1st injection of TA-ER on Day 1. Patients received the 2nd injection at the first visit (Week 12, 16, 20, or 24) at which repeat dose criteria were met (ie, patient benefited from and tolerated the 1st injection without safety concerns and was clinically indicated to receive the 2nd injection). Patients who received 2 injections were evaluated every 4"
+"Introduction\n============\n\nIntercostal (IC) muscles are diverse and widely spread throughout the rib cage. These muscles are morphologically and functionally skeletal muscles, and it helps in upward and outward movement of the ribs which results in increase in antero-posterior diameter of the thoracic cavity (De Troyer et al., 2005\\[[@R5]\\]). The IC muscles help both in inspiration and forced expiration. Even though these muscles engage in respiration, their activities are fewer during active contraction among normal healthy adults (Hirai et al., 1996\\[[@R10]\\]). Neglect of skeletal muscle from a low level of physical activity is also a factor that may have detraining effect on muscle mass. This will have an impact on the oxidative capacity of the skeletal muscles and it will reduce the proportion of muscle fibers from type I to type II (Gosker et al., 2000\\[[@R9]\\]). Hence, it can be hypothesized intercostal muscles which aids in the mechanical aspects of breathing may undergo atrophy when there is a poor physical activity. Therefore, this could have an impact on chest wall mobility and expansion in turn to ventilation on normal healthy adults.\n\nVarious research studies demonstrated that IC stretching improved expired tidal volume, decreased the level of dyspnea level and increased"
+"Introduction {#Sec1}\n============\n\nAtherosclerosis is one of the leading causes of mortality in developed countries, and with increasing incidents in the developing countries^[@CR1]^. It is a complex disease affected by the interaction of genetic and environmental risk factors^[@CR2]--[@CR4]^. In the past decade, research efforts in the biomedical field have focused on the implications of gut microbiome on human diseases. There is evidence that symptomatic atherosclerosis is associated with an altered gut microbial community in human and mice^[@CR5]--[@CR7]^. It has been demonstrated that cecal microbial transplantation from a susceptible strain to wild-type mice enhanced choline diet-dependent atheroslceorosis and TMAO (trimethylamine-*N*-oxide) levels in wild-type mice^[@CR8]^. Examination of human oral and atherosclerotic plaque microbiota in patients with clinical atherosclerosis suggests that microbes from the oral cavity and perhaps the gut may be a reservoir for bacteria found in atherosclerotic plaques^[@CR9]^. Our previous study has also shown that genetic selection for susceptibility/resistance to diet-induced atherosclerosis has affected the Japanese quail's cecal environment to accommodate distinctly different cecal microbiota^[@CR10]^. Most published studies have compared the fecal or cecal micriobial communities between atherosclerosis and healthy subjects, but there has been sparse information on the comparison of cecal and small intestinal microbiota in the same subject.\n\nMapping"
+"Neural tube defects (NTDs), major congenital anomalies of the central nervous system, result from failure of the neural tube to close between the 3^rd^ and 4^th^ week of gestation and include spina bifida, anencephaly, and encephalocele.^[@r01]^ Because previous epidemiological studies demonstrated that low folic acid intake conclusively increases the risk of NTDs, intake of folic acid is recommended worldwide for women during their reproductive years.^[@r02]^\n\nNatural folate contained in foods has rather low and variable bioavailability compared with pure folic acid, and supplementation of folic acid is recommended to increase plasma folate levels.^[@r02]^ Accordingly, the Centers for Disease Control in the United States recommended intake of folic acid supplements in 1992 to all potentially pregnant women because the critical period for NTDs occurs before pregnancy is recognized by many women. Following this global trend, the Japanese Government in 2000 recommended intake of folic acid supplements during the period from 1 month before pregnancy to 3 months of pregnancy for potentially pregnant women.^[@r03]^ The guideline recommends intake of 400 \u00b5g of folic acid supplement per day, in addition to dietary intake of folic acids. Despite the unequivocal benefits of folic acid supplementation, use of the supplement, in particular during the recommended"
+"Introduction {#s1}\n============\n\nEvolutionary processes and genetic attributes of invasive populations may underpin their success in becoming established in a new range [@pone.0077083-Lee1]--[@pone.0077083-Dlugosch1]. Life-history traits associated with reproductive strategy are potentially good candidates for rapid evolutionary shifts during invasions [@pone.0077083-Phillips1], because reproductive strategy affects population dynamics and genetic parameters that can, in turn, have feedback effects on evolutionary processes [@pone.0077083-Lambrinos1]--[@pone.0077083-Burton1]. Indeed, when species shift their range, they encounter a suite of new selective pressures that may affect their reproductive strategy. For instance, the lower population density at an expanding front would be expected to select for higher fecundity, lower age at first reproduction, or even a switch from outcrossing to selfing, all of which increase the individual\\'s rate of reproduction [@pone.0077083-Barrett1], [@pone.0077083-Bufford1], [@pone.0077083-MacArthur1]. Rapid evolution towards higher levels of reproduction following invasions may also result from a relaxation of selection for defence against enemies in the invaded range [@pone.0077083-Blossey1], [@pone.0077083-Crawley1]. In accordance with these expectations, a number of studies have shown that invasive populations can display increased reproductive efforts, have higher levels of reproductive investment, shorter generation times or higher selfing rates than native populations [@pone.0077083-Barrett1], [@pone.0077083-Blossey1], [@pone.0077083-Buckley1]--[@pone.0077083-Amundsen1]. Reproductive strategy can also influence the adaptive potential of invasive populations. The"
+"1. Introduction {#sec1}\n===============\n\nGlioblastoma (GBM) is the most aggressive diffuse glioma of astrocytic lineage and is considered a grade IV glioma based on the WHO classification \\[[@B1]\\]. As the most common malignant primary brain tumor, GBM accounts for about 54% of all gliomas and 16% of all primary brain tumors \\[[@B2]\\]. Despite progress in the current standard treatment strategy, including maximal safe resection, followed by radiotherapy with concomitant and adjuvant Temozolomide (TMZ), the median survival was only 14.6 months \\[[@B3]\\]. The high intertumoral and intratumoral heterogeneity make the survival of patients with glioblastoma vary greatly \\[[@B4], [@B5]\\]. Traditional clinicopathological factors, including histological grade, age, and Karnofsky performance status, have failed to predict the outcome precisely \\[[@B6]\\]. Advanced sequencing and microarray technologies have paved the way for understanding the interpatient response variability for treatment at the gene expression and regulation level. Gene expression-based molecular signatures have been discovered and used for identifying new glioblastoma subtypes and gained better prognostic significance \\[[@B6], [@B7]\\].\n\nIt is evident that only less than 2% of the genome encodes proteins and at least 75% is actively transcribed into noncoding RNAs \\[[@B8]\\]. Although some of the noncoding transcripts are small, most of them surpass 200 nucleotides"
+"Background\n==========\n\nMore than 350 million of about 2 billion people in the world exposed to the hepatitis B virus (HBV) are chronically infected and at serious risk of developing liver failure, cirrhosis, and hepatocellular carcinoma (HCC) \\[[@B1]-[@B3]\\]. About 75% of them reside in the Asia-Pacific region \\[[@B4]\\], particularly in Asian endemic areas such as China. Each year, \\~600,000 HBV-related deaths occur worldwide \\[[@B5]\\]. Approved therapies for chronic hepatitis B include interferon (IFN)-alfa and nucleos(t)ide analogues, but rarely eliminate the virus \\[[@B6]\\]. HBV persists by establishing HBV covalently closed circular DNA (ccc DNA) in hepatocytes, which nuclear transcription template continues to initiate new HBV replication cycle even after serologic clearance. Long-term treatment in most cases bears the risk of adverse side-effects and mutant drug-resistant HBV strains. Therefore, combinational strategies for treating HBV from different angles are urgently needed. In infected hepatocytes, HBV produces four major classes of messenger RNAs (mRNAs). A 3.5 kb pregenomic RNA is reverse-transcribed into new HBV genomes and serves as mRNA for translating the viral core and polymerase proteins. A minimally longer RNA encodes the secretory hepatitis B e antigen (HBeAg). RNAs (2.4 and 2.1 kb) serve as mRNA for viral envelope proteins L, M, and"
+"*Dear Editor,*\n\nWe have read with interest the comments to our article [@bib0001] written by Festa et al \"Screening for active COVID-19 infection prior to biologic therapy in IBD patients: let\\'s not increase our uncertainty without reducing our concerns [@bib0002]\" recently published on Digestive and Liver Disease. The authors criticized our suggestion to expand the screening commonly recommended prior to the beginning of biologic therapy in Inflammatory Bowel Disease (IBD) patients, to include SARS-CoV-2 RT-PCR and, when available, antibody testing.\n\nAlthough available data do not support an increased risk of contracting COVID-19 infection in IBD patients, a recent report from Italy showed a case fatality rate of 8% and an hospitalization rate of 28% among 79 IBD patients with confirmed COVID-19 followed-up at 24 IBD referral units [@bib0003]. The British Society of Gastroenterology and the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD) recommendation that IBD patients do not have to stop their current medications in order to prevent infection or adverse outcome with COVID-19 [@bib0004],[@bib0005] has recently been incorporated in the expert commentary commissioned by the American Gastroenterology Association institute [@bib0006]. Considerations on specific drugs were also provided, although robust evidence on the impact of different immunosuppressive"
+"Introduction {#sec1}\n============\n\nWhole-grain foods contribute good sources of nutrients to the diet, such as fiber, B vitamins, iron, magnesium, and zinc, that are beneficial for health ([@bib1]). Higher consumption of whole-grain foods by children, adolescents, and adults is associated with improved consumption of nutrients, dietary components, and overall diet quality ([@bib2]). Individuals who consume whole-grain foods may have healthier body weight and decreased risk for developing cardiovascular disease, diabetes, and certain cancers ([@bib5]).\n\nThe 2015--2020 US Dietary Guidelines for Americans states that \"a healthy eating pattern includes .\u00a0.\u00a0. grains, at least half of which are whole grains\" (e.g., 3 oz equivalents of whole grains out\n\nof 6 oz of total grains) ([@bib2]). Although consumer interest in whole-grain foods has increased ([@bib8], [@bib9]), consumption recommendations are not being met by most Americans. Only 2.9% of children and adolescents and 7.7% of adults consume the recommended amount of whole grains each day in the United States ([@bib10]). In low-income populations, whole-grain consumption is \\<1 oz per day ([@bib11]). Similarly, whole-grain consumption is also below recommended amounts in both the general and low-income populations in the United Kingdom ([@bib12]), with recommendations for whole grains stated as \"choose wholegrain or fibre"
+"The authors wish to make the following corrections to their paper \\[[@B1-toxins-08-00352]\\].\n\nIn the caption of Figure 3, \"and TcdB~1-1851~ (0.5 nM) respectively\" should be replaced with \"respectively, and treated for 4 h with TcdB~1-1851~ (0.5 nM)\".\n\nIn the first paragraph of Section 4.9, \"CT26 cells were incubated with 10 pM TcdB~fl~ for 3 h in the presence or absence of 250 \u03bcM TcdB~\u03941756--1780~, or 500 \u03bcM TcdB~CROP~\" should be replaced with \"CT26 cells were incubated with 100 pM TcdB~fl~ for 2 h in the presence or absence of 250 nM TcdB~\u03941756--1780~, or 500 nM TcdB~CROP~\". Also, \"for 4 h with or without 250 \u00b5M TcdB~\u03941756--1780~\" should be replaced with \"for 4 h with or without 250 nM TcdB~\u03941756--1780~\".\n\nThe changes do not affect the scientific results. The manuscript will be updated and the original will remain online on the article webpage. We apologize for any inconvenience caused to our readers."
+"1. Introduction\n===============\n\nPericarditis is a common pericardial disease. Cholesterol pericarditis (CP) is a special type of pericarditis. It is characterized by chronic pericardial effusion with high cholesterol concentration and with or without the formation of crystals in pericardial effusion.^\\[[@R1],[@R2]\\]^ We described a 74-year-old male with massive pericardial effusion in this case report.\n\n2. Case presentation\n====================\n\nA 74-year-old male was hospitalized with massive pericardial effusion showed by transthoracic echocardiography in annual physical examination 2 days ago. He presented with no symptoms (no chest pain, no dizziness, no fatigue or shortness of breath). He had a history of rheumatoid polyarthritis treated by methotrexate, celecoxib, and prednisone for 8 years and hypertension medicated by amlodipine besylate for 5 years. On admission, physical examination showed muffled heart sound, without jugular vein distension, bilateral lower limb edema, cardiac pathologic murmur, or pulmonary rales. His vital signs were normal (temperature 36.8\u00b0C, blood pressure 131/78 mm Hg, heart rate 62 beats per minute). Transthoracic echocardiography revealed a large pericardial effusion (Fig. [1](#F1){ref-type=\"fig\"}). Computed tomography (CT) demonstrated interlobar effusion, pericardial effusion, and a little of pleural effusion (Fig. [2](#F2){ref-type=\"fig\"}).\n\n![A large pericardial effusion was revealed by transthoracic echocardiography.](medi-95-e5305-g001){#F1}\n\n![CT demonstrated interlobar effusion, pericardial effusion and a"
+"1. Introduction {#sec1}\n===============\n\nOptical coherence tomography (OCT) is a noninvasive technique for high-resolution, cross-sectional tomographic imaging of retinal tissue using backscattered light. OCT imaging is very similar to ultrasound B-Scan imaging but uses infrared-light instead of ultrasound waves. Two-dimensional, cross-sectional images are obtained from multiple axial scans (A-Scans) at different transverse locations \\[[@B1]\\].\n\nUntil recently, third-generation time-domain OCT (TD-OCT) using Stratus OCT (Carl Zeiss Meditec AG, Jena, Germany) has been widely used to acquire images at a rate of 400 axial scans per second with an axial resolution of 10\u2009*\u03bc*m \\[[@B2]\\]. The recently introduced fourth-generation spectral-domain OCT (SD-OCT) has improved depth resolution by a factor of three (axial resolution up to 3.8\u2009*\u03bc*m) and allows a significantly higher acquisition speed (40\\'000 axial scans per second) resulting in improved image quality and minimized motion artefacts \\[[@B3]\\]. Furthermore, software improvements allow reconstruction of a three-dimensional image of the retina.\n\nHeidelberg Spectralis OCT (Heidelberg Engineering, Heidelberg, Germany) uses an integrated eye tracking system (IETS) to compensate for eye movement artefact during data acquisition. IETS also allows an automatic re-centration, which can be used for more reliable follow-up scans. Heidelberg noise reduction technology helps producing significantly improved images by adjusting data and"
+"Sasaki M, Miyahisa I, Itono S, et\u00a0al. Discovery and characterization of a small\u2010molecule enteropeptidase inhibitor, SCO\u2010792. Pharmacol Res Perspect. 2019;e00517 10.1002/prp2.517\n\nYus uke Mo rito h and Mas ano ri Watanabe are co ntributo rs from SCOHIA P\n\nBCAA\n\n:   branched\u2010chain amino acids\n\nFRET\n\n:   Fluorescence resonance energy transfer\n\nHTS\n\n:   High\u2010throughput screening\n\n1. INTRODUCTION {#prp2517-sec-0001}\n===============\n\nProteins are pivotal macronutrients for various cellular activities, as well as whole\u2010body metabolism. Amino acids show many functions within the body. For example, amino acids serve as the only source of nitrogen in mammals.[1](#prp2517-bib-0001){ref-type=\"ref\"} Amino acid\u2010derived nitrogen is a critical element in the synthesis of the precursors (purine and/or pyrimidine) of major energy molecules, such as adenosine triphosphate, adenosine diphosphate, and/or nucleic acids.[1](#prp2517-bib-0001){ref-type=\"ref\"} In addition, nitrogen is incorporated into compounds that can regulate major biochemical signaling pathways, such as nitric oxide.[1](#prp2517-bib-0001){ref-type=\"ref\"} Furthermore, amino acid deamination in the body\\'s proteins generates a carbon skeleton rich in oxygen and hydrogen suitable for subsequent biochemical transformation.[1](#prp2517-bib-0001){ref-type=\"ref\"} This carbon skeleton can be used by the liver to generate glucose through gluconeogenesis and other macromolecules, such as lipids.[1](#prp2517-bib-0001){ref-type=\"ref\"} The carbon skeleton derived from amino acids is also relevant in producing intermediaries fueling the Kreb\\'s cycle that are"
+"Case report {#ajum00223-sec-0001}\n===========\n\nA 31\u2010year old female, G2P0, presented to the fetal medicine unit at 38 weeks gestation with a history of reduced fetal movements. Ultrasound confirmed fetal death. The amniotic fluid volume was norma; biometry was suggestive of undetected fetal growth restriction, and no fetal anomalies were identified. Targeted placental ultrasonography revealed numerous hypo\u2010echogenic lesions scattered throughout most of the substance of the placenta ([Figures 1](#ajum00223-fig-0001){ref-type=\"fig\"} & [2](#ajum00223-fig-0002){ref-type=\"fig\"}). The standard protocol for investigating a perinatal death[^1^](#ajum00223-bib-0001){ref-type=\"ref\"} was followed. Amniotic fluid was collected and sent for microarray analysis, which ruled out an underlying chromosomal abnormality. The parents consented to a full post mortem and placental examination.\n\n![Numerous hypeoechic lesions in the placenta.](AJUM-18-157-g001){#ajum00223-fig-0001}\n\n![Numerous hypeoechic lesions in the placenta.](AJUM-18-157-g002){#ajum00223-fig-0002}\n\nThe post mortem examination revealed a growth restricted but otherwise normally appearing female infant. There was evidence of chronic hypoxia and congestive cardiac failure. No developmental malformations were identified.\n\nThe placental disc was noted to be smaller than expected for the gestational age, but otherwise, externally, appeared essentially normal. Multiple, firm, cream to dark\u2010red well\u2010circumscribed lesions, measuring between 3 to 35 mm in diameter, were identified when the placenta was sliced ([Figures 3](#ajum00223-fig-0003){ref-type=\"fig\"} & [4](#ajum00223-fig-0004){ref-type=\"fig\"}). These lesions involved 60--70% of the"
+"All relevant data are within the paper.\n\nIntroduction {#sec001}\n============\n\nThe interferon (IFN)-\u03b2 induction pathway and type I IFN (IFN-I) signaling are two related pathways culminating in the induction of critical antiviral and immuno-stimulatory genes \\[[@pone.0152031.ref001]\\]. The IFN-\u03b2 induction pathway activates IFN regulatory factor (IRF) 3 and 7, which can bind specific IRF genomic DNA elements called IRF-E and stimulate the transcription of several genes \\[[@pone.0152031.ref002]\\]. Type I IFNs, including IFN-\u03b2, bind IFN-I receptor and trigger the IFN-I signaling cascade, activating STAT1, STAT2 and IRF-9. These three transcription factors form the so-called IFN-stimulated gene factor 3 (ISGF3) complex. ISGF3 binds DNA elements named IFN stimulated response elements or ISRE \\[[@pone.0152031.ref003]\\], triggering transcription of IFN-stimulated genes (ISGs) and the subsequent activation of cellular pathways associated with IFN stimulation.\n\nIRF-E elements present a consensus sequence: `WWNNRAAANNGAAA`) \\[[@pone.0152031.ref004]\\], where W can be A/T, R can be G/A and N any nucleotide. The ISRE consensus sequence is `GAAANNGAAACT` \\[[@pone.0152031.ref005]\\]. The similarity of both consensus sequences supports the fact that many genes can be activated by both signaling pathways, such as *Mx2* \\[[@pone.0152031.ref006]\\] or *ISG15* \\[[@pone.0152031.ref007]\\]. Schmidt et al. \\[[@pone.0152031.ref007]\\] completed a thorough manipulation of ISG15 IRF-E and ISRE elements and found a sequence with"
+"In the Original Investigation titled \"Estimates of Overall Survival in Patients With Cancer Receiving Different Treatment Regimens: Emulating Hypothetical Target Trials in the Surveillance, Epidemiology, and End Results (SEER)--Medicare Linked Database,\"^[@zcx200015r1]^ published March 5, 2020, the authors were in violation of the SEER-Medicare data use agreement and had to remove data from 1 sentence in the Results and remove or replace data in the Supplement. The second sentence of the fifth paragraph of the Results should read as follows: \"Compared with 569 individuals in the existing randomized clinical trial,^15^ 940 individuals included in the present analysis were older (median \\[range\\] age, 74 \\[66-93\\] years vs 64 \\[36-92\\] years), more likely to be male (547 \\[58%\\] vs 298 \\[52%\\]), and less likely to have undergone prior chemotherapy (53 \\[6%\\] vs 45 \\[8%\\]).\" This article has been corrected.^[@zcx200015r1]^"
+"Background {#Sec1}\n==========\n\nCaseous lymphadenitis (CLA) is a chronic, debilitating infection caused by the Gram-positive bacterium *Corynebacterium pseudotuberculosis*. CLA affects mainly small ruminants, such as sheep and goats, and is the leading cause of economic loss associated with the reduction of wool, meat and milk production, and also results in carcass and skin condemnation in the majority of sheep and goat production areas \\[[@CR1]\\]. CLA infection is typically initiated by inoculation via oral, respiratory, and membrane wounds \\[[@CR2]\\]. Once inside, the bacteria are phagocytosed by macrophages, which are then drained to local lymph nodes. Once internalized, the bacteria evade the cellular immune response mechanisms, being able to survive and rapidly multiply within the macrophage phagosome. Bacterium proliferation results in the death of the host cell and the subsequent release of bacteria into the extracellular environment, which can then spread through the lymphatic system to regional lymph nodes and internal organs \\[[@CR3]\\]. Clinical signs of the disease include the formation of caseous abscesses either in superficial or internal lymph nodes. While antibiotic therapy is not usually helpful, management of the disease combines the identification and removal of infected animals along with vaccination of healthy animals \\[[@CR2]\\].\n\nIn recent years, novel mechanisms"
+"Introduction {#sec1-0300060519859134}\n============\n\nCoronary artery disease (CAD) is a clinical syndrome that is characterized by impedance or blockage of one or more coronary arteries. CAD may be associated with a high risk of angina, ischemic fraction, arrhythmia, heart failure, or sudden death, although some patients remain asymptomatic. The American Heart Association 2016 heart disease and stroke statistics update reported that 15.5 million people \u226520 years of age in the United States have coronary artery disease, and this prevalence increases with age.^[@bibr1-0300060519859134]^\n\nIschemic heart disease is divided into obstructive coronary artery disease (OCAD), which develops from the erosion or rupture of atherosclerotic plaques, and non-obstructive CAD (NOCAD), resulting from impaired vasodilation of arterioles and leading to an inadequate increase in blood flow from rest to stress. OCAD is defined as epicardial coronary stenosis \u226550% by quantitative coronary angiography (CAG), with non-obstructive lesions that are additionally grouped as normal coronary vessels (0% lumen stenosis in all vessels) and mild coronary stenosis (1%--49% lumen stenosis in at least 1 vessel).^[@bibr2-0300060519859134]^ NOCAD is a common finding on diagnostic CAG, with rates of up to 50% to 60% in patients with stable angina and about 30% in certain populations with acute coronary syndrome. Symptomatic patients"
+"INTRODUCTION {#s1}\n============\n\nThe lens of the eye is a key optical element that, together with the cornea, refracts light to the retina. Unlike the cornea, the lens has the capacity to alter ocular focus so as to enable clarity of vision for objects over a range of distances. This functional capacity, termed accommodation, which decreases progressively with age leading to a loss of ability to focus on near objects, is achieved by the lens changing its shape under forces mediated by the contraction and relaxation of the ciliary muscle. Accommodative capacity is effectively lost by the sixth decade of life for, though the rates can vary in individuals based on a number of internal and external factors \\[[@R1], [@R2]\\], by the end of the sixth decade when atrophy of the ciliary muscle occurs \\[[@R1]\\] lenses have no ability to accommodate. Refractive power for distant objects is not affected or altered with age. The growth of the lens continues throughout life by accrual of layers of fibre cells over existing tissue without concomitant cellular loss creating a lamellar structure with the oldest cells in the central layers and the most recently synthesised cells on the lens surface. This renders the"
+"1. Introduction {#s0005}\n===============\n\nCardiac multislice computed tomography (MSCT) is a noninvasive imaging modality that is widely used in the clinical field for screening patients with suspected cardiovascular disease [@bb0005]. MSCT findings provide information not only on coronary atherosclerotic burden but also on precise cardiac structure [@bb0010], [@bb0015]. Calcium score (CS) determined by using MSCT enables quantitative evaluation of the degree of calcification, as total volume of calcium deposition is considered to reflect atherosclerotic change in each coronary artery, aortic valve, or aorta [@bb0020], [@bb0025]. Several previous clinical studies have demonstrated the diagnostic utility of aortic valve calcium score (AVCS) for grading of aortic stenosis (AS) initially diagnosed by using echocardiography [@bb0030], [@bb0035]. Recent interesting data proved that AVCS assessment showed new insights regarding calcified AS based on discordant markers of severity between aortic valve area (AVA) and mean pressure gradient (mPG) when combined with standard Doppler echocardiography [@bb0040]. The above findings support that AVCS determined by using MSCT is useful for screening patients in daily practice, though AVCS assessment is not routinely recommended in the clinical field. Diagnostic MSCT could be more useful for detecting the severity of AS in addition to the existence of coronary artery disease (CAD)."
+"We have read the commentary by Tariot et al. \\[[@B1]\\] with interest and are delighted that our paper has provoked additional discussion.\n\nWith regard to the presentation of the multiple metagraphs, our method of labeling did not include the term 'favors'. In figure 5 for example, the labels along the x-axis are either 'control' or 'experimental', unlike the new figure provided by Tariot et al., where the word 'favors' precedes each term. This word was omitted from the graphs in order to avoid indicating that there was any favorable response towards a particular group. The graph instead indicates that the control group showed higher Clinician\\'s Interview-Based Impression of Change Plus Caregiver Input (CIBIC-Plus) values, and this was correctly interpreted in our discussion \\[[@B2]\\] as a nonsignificant trend to favor combination therapy. A revised graph now contains a clarification in the legend (fig. [4](#F4){ref-type=\"fig\"}). The confidence interval plots and labels were set to be consistent throughout the paper for better appreciation of the results between the various assessments used.\n\nThe observation regarding the standard deviation value is valid and a correction has been made. The corrected p value however still does not reach statistical significance (\\<0.05) after this adjustment. Lastly, we"
+"Dear editor {#S0001}\n===========\n\nWe thank Wang and Miao[@CIT0001] for their interest in our recent publication[@CIT0002] and the appreciation of our work.\n\nWe agree with them on the need of using repeated-measures analysis to evaluate pain intensity at different timepoints.\n\nWe acknowledge that, for the sake of brevity, our manuscript did not properly clarify the statistical methods used for the analysis and we take this opportunity to better explain them.\n\nWe performed a repeated measure analysis of variance (ANOVA) to compare pain intensity on different time points. The analysis resulted statistically significant (*p*\\<0.01). Afterwards, we performed multiple comparisons using the error deriving from the ANOVA for repeated measures, which turned out statistically significant (*p*\\<0.01).\n\nIn addition, we used the paired *t*-test to compare pain intensity on day 0 (baseline) and day 3, as indicated in the recent publication (median NRS 6 to 0, *p*\\<0.01).[@CIT0002]\n\nDisclosure {#S0002}\n==========\n\nThe authors report no conflicts of interest in this communication."
+"Introduction {#s1}\n============\n\nRNA silencing pathways are critical regulators of gene expression in organisms ranging from yeast to humans. RNA silencing is initiated by the action of RNase III enzymes, which target RNAs with dsRNA character to generate small RNA duplexes [@pone.0055458-Kim1]. Following biogenesis, small RNA sorting directs the selection of one strand of the duplex to be retained and stabilized by an Argonaute family member in RISC [@pone.0055458-Czech1]. The RNA silencing pathways of *Drosophila melanogaster* have been extensively characterized and allow for detailed dissection of the mechanisms governing RNAi-mediated gene silencing. The siRNA silencing pathway is responsible for controlling the expression of both endogenous and exogenous targets in somatic cells. siRNA biogenesis is carried out by Dicer-2 (Dcr-2), which generates predominantly 21 nucleotide (nt) products from several types of precursors [@pone.0055458-Kim2]. Endogenous siRNAs (esiRNAs) are generated from long hairpins, retrotransposons or convergent transcription units and regulate endogenous gene expression, while exogenous siRNAs (exo-siRNAs) are processed from long dsRNAs, a process commonly manipulated in molecular biology to achieve targeted gene silencing [@pone.0055458-Kim1]. In addition, virus-derived siRNAs (vsiRNAs) are cleaved from viral RNAs produced during infection [@pone.0055458-Ding1]. The miRNA pathway generates mature miRNAs from stem-loop structures within pri-miRNA transcripts through a"
+"Introduction {#s1}\n============\n\nHeat Shock Proteins (HSPs) facilitate protein folding and guard the proteome from the dangers of misfolding and aggregation [@pone.0073217-Schmitt1]. They are expressed as responses to adverse environmental or chemical stresses, such as heat or cold shock, hypoxia, salinity, heavy metals and pathophysiological situations and play important role in cell survival [@pone.0073217-Hofmann1], [@pone.0073217-Verghese1].\n\nHsp90s account for 1--2% of all cellular proteins in most cells under non-stress conditions. Their function is dependent on the interaction with many co-chaperones [@pone.0073217-Jackson1]. They either prevent aggregation of newly synthesized or misfolded proteins, assisting in their proper folding, or direct them for proteasomal degradation [@pone.0073217-Zuehlke1], [@pone.0073217-Pearl1]. Their client proteins are involved in signal transduction, transcription and apoptosis [@pone.0073217-Hartson1]--[@pone.0073217-Brown1]. In recent years, many studies have focused on the role of this family in cancer [@pone.0073217-Whitesell1], [@pone.0073217-Trepel1].\n\nHSP90s are essential for viability under all conditions in eukaryotes; in contrast, deletion of the bacterial HtpG (High temperature protein G) is not lethal [@pone.0073217-Bardwell1], [@pone.0073217-Versteeg1]. Hsp90s are found in all organisms, except Archaea [@pone.0073217-Laksanalamai1], and are highly conserved, thus providing an excellent model for evolutionary studies.\n\nResults from previous analyses in eukaryotes indicate that members of the Hsp90 gene family have undergone major duplication events, which led"
+"Macroautophagy (hereafter referred to as autophagy) is an intracellular turnover pathway that is used to remove long-lived and aggregated proteins, organelles, and parasites from the cell[@b1]. With this pathway, damaged or senescent cytoplasmic contents are sequestered in double-membrane vesicles called autophagosomes. Biogenesis and maturation of autophagosomes begins with the phagophore, an autophagosome precursor[@b2], whose membrane lipids can be derived from multiple sources, including the endoplasmic reticulum (ER)[@b3], clathrin-coated vesicles from the plasma membrane[@b4], the outer membrane of mitochondria[@b5], and the trans-Golgi network[@b6]. The autophagosome then fuses with early or late endosomes or with lysosomes for degradation of sequestered contents.\n\nAutophagy plays a critical role in neuronal survival[@b7]. For example, blocking autophagy in neurons in the mouse central nervous system leads to protein aggregation and neurodegeneration[@b8][@b9]. Autophagosomes have been observed in many neurodegenerative disorders[@b10]. Small molecules that stimulate autophagy ameliorate pathogenic changes in a number of neurodegenerative disorders[@b1][@b11][@b12]. Despite the mounting evidence demonstrating the importance of autophagy in neurons, the molecular players that regulate neuronal autophagy are not fully understood.\n\nIn a search for novel regulators of autophagy in neurons, we investigated whether sphingosine kinase 1 (SK1), which regulates autophagy in cancer cells[@b13], is necessary for autophagy in neurons. There are"
+"Introduction\n============\n\nMitochondria are dynamic organelles responsible for the generation of ATP via oxidative phosphorylation, which is essential for cell viability. To maintain mitochondrial homeostasis, mitochondria change their shapes by mitochondrial dynamics (fusion and fission; [@B28]; [@B58]). Mitochondrial fission (fragmentation) is necessary for the biogenesis of mitochondria and their quality control by mitophagic elimination ([@B62]). Mitochondrial fusion (elongation) is also involved in mitochondrial quality control by repartition of lipids, proteins and mitochondrial DNA ([@B40]; [@B43]). Therefore, the aberrant mitochondrial dynamics result in the impaired bioenergetics, excessive generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential, dysfunction of endogenous respiration and the release of pro-apoptotic factors from mitochondria, which trigger cell death ([@B39]; [@B30]; [@B60]; [@B12]; [@B42]; [@B6]; [@B62]).\n\nThe molecular machinery of mitochondrial fission and fusion involves various proteins, which share reciprocal relationships. Briefly, dynamin-related protein 1 (DRP1) drives mitochondrial division, while mitofusin 1/2 (MFN1/2) and optic atrophy 1 (OPA1) mediate mitochondrial elongation ([@B61]). Recently, it has been reported that glutamate-mediated excitatory transmission affects mitochondrial dynamics through various signaling pathways regulating DRP1 activity under pathophysiological condition ([@B5]; [@B14]; [@B18]; [@B41]). However, the effects of glutamate on mitochondrial dynamics are distinct from each glutamate receptor subtypes. *N*-methyl-[D]{.smallcaps}-aspartate receptor (NMDAR)"
+"Introduction {#sec1}\n============\n\nLike most large-scale biological experiments, the vast majority of proteomics studies tend to produce long lists of candidate proteins. Whether these consist of lists of interactors of a protein, differentially expressed proteins, or simply proteome characterization of a sample, such data sets are difficult to analyze and interpret. No clear unifying theory consistently explains the presence of all proteins or biological processes in a given data set.^[@ref1]^ The picture becomes even more intricate when large-scale protein quantification is performed. Protein abundance measurements performed using label-free or label-based methods contain a certain amount of noise, which contributes to the complexity of proteomics data sets.^[@ref2]^ In addition, reproducibility of both protein identification and quantification across biological replicates still remains an important challenge.^[@ref3]^ While it is expected that future increases in mass spectrometry peptide detection sensitivity will help solve reproducibility issues, it will cause data sets to be even larger and therefore more convoluted.\n\nComputational approaches are required to extract biologically meaningful information from these complex data sets. Such tools are crucial in order to get a clear understanding of the biological mechanisms taking place in a given sample and are critical to guide further studies on subsets of proteins"
+"The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n\nIntroduction\n============\n\nIn 2019, there were an estimated 73,820 cases and 14,770 deaths from cancers of the kidney and renal pelvis \\[[@REF1]\\]. Of these cancers, renal cell carcinoma (RCC) is the most common. RCC typically presents in the sixth to eighth decade of life. One study cites a median age of 64 years with just 4.4% of patients presenting in the age range of 20 to 40 years \\[[@REF2]\\]. It is established that firefighters are at increased risk for a number of types of cancer including cancers of the kidney \\[[@REF3]-[@REF5]\\]. This link is highlighted by occupational exposure to toxic substances \\[[@REF3]\\]. Other documented risk factors include genetic predisposition/hereditary disorders, obesity, smoking, and various nephrotoxic industrial chemicals"
+"Introduction {#S1}\n============\n\nThe Brugada syndrome (BrS) is a rare inherited arrhythmia disease, first described in 1992, increasing the risk of ventricular fibrillation in apparently healthy young adults ([@B1]). It is suspected to be involved in 4--12% of cases of sudden cardiac death (SCD) in the general population and in at least 20% of SCD in patients with a structurally normal heart ([@B1]--[@B3]).\n\nClinical diagnosis is based on a specific electrocardiographic (ECG) pattern defined in three consecutive consensus conferences ([@B4]--[@B6]). This ECG pattern, previously known as \"type 1\" ECG pattern, is defined as a ST segment elevation with a coved-type morphology \u22650.2\u2009mV in one lead among the right precordial leads V1 and V2, positioned in the second, third, or fourth intercostal space occurring either spontaneously or after provocative drug test with intravenous administration of Class I antiarrhythmic drugs ([@B6]) (Figure [1](#F1){ref-type=\"fig\"}). The ECG pattern may be transient in affected patients ([@B7]). To address this issue, unmasking drugs, such as ajmaline, flecainide, and procainamide, can be used to reveal this pattern ([@B8]), ajmaline showing higher sensitivity than flecainide and procainamide ([@B4], [@B9], [@B10]).\n\n![**Ajmaline testing reveals the Brugada ECG pattern**. ECG pattern is recorded at 1\u2009mm/10\u2009mV and 25"
+"Introduction {#S0001}\n============\n\nThe development of chemotherapy has significantly improved the survival of cancer patients, especially for those who were diagnosed at advanced stages.[@CIT0001] Endometrial adenocarcinoma (EA) is the most common type of endometrial cancer, which is the major type of common gynaecological cancer in developed countries.[@CIT0002] EA is characterized by its extreme aggressive nature and low early diagnosis rate.[@CIT0003] A considerable portion of EA patients are initially diagnosed with the existence of tumor invasion, which are not candidates for radical tumor resection.[@CIT0004] Although chemotherapy is helpful for EA patients, chemo-resistance will inevitably develop, leading to poor treatment outcomes.[@CIT0005]\n\nIt has been reported that chemotherapy modulates the expression of endogenous genes in the body of cancer patients, and the altered expression of certain genes may induce the sensitivity of cancer cells to chemical drugs.[@CIT0006],[@CIT0007] Recent studies also showed that long non-coding RNAs (lncRNAs, longer than 200 nt) were critical regulators of cancer cell behaviors[@CIT0008] and also participate in the development of chemo-resistance during chemotherapy.[@CIT0009] Therefore, regulation of lncRNA expression may assist the use of chemical drugs in cancer treatment. PMS1 Homolog 2, Mismatch Repair System Component Pseudogene 2 (PMS2L2) is a novel lncRNA that has protective effects on chondrocytes during"
+"Background {#Sec1}\n==========\n\nSecondary small bowel volvulus is a rare condition reported to be caused by adhesions after laparotomy or tumors. As a complication after harvesting of free jejunum flap, secondary small bowel volvulus is especially rare \\[[@CR1]\\]. There are no clear guidelines for indication of laparoscopic surgery. We experienced a case of secondary small bowel volvulus, which was successfully treated laparoscopically. Herein, we present this case, particularly based on literature discussion, and investigate the indications and points to consider during laparoscopic treatment.\n\nCase presentation {#Sec2}\n=================\n\nA 69-year-old man developed a sudden epigastric pain. He was presented at this hospital as an emergency outpatient. Six years earlier, he underwent laryngoesophagopharyngectomy, bilateral lymph node dissection for hypopharyngeal cancer, and esophageal reconstruction with a free jejunum flap. On physical examination, the abdomen was flat and soft with tenderness in the epigastric region, but no sign of peritoneal irritation. Blood biochemistry findings revealed elevated values: creatinine, 1.16\u00a0mg/dl; lactate dehydrogenase, 364\u00a0U/l; and creatine phosphokinase, 622\u00a0U/l.\n\nAbdominal contrast computed tomography (CT) revealed twisted mesentery with the small intestine around the point of torsion (whirl sign) and the superior mesenteric artery as the axis. Contrast enhancement was weakened in the same area"
+"**What's Known**\n\nChemotherapy with cyclophosphamide (CTX) damages ovaries.Transplantation of bone marrow stromal cells (BMSCs), as a type of mesenchymal stem cells, repairs damaged ovaries following chemotherapy.Granulocyte colony-stimulating factor (G-CSF), as a growth factor, has beneficial effects on damaged ovaries.\n\n**What's New**\n\nG-CSF may have the potential to regenerate ovaries damaged by chemotherapy with CTX.Coadministration of BMSCs and the G-CSF may be more effective than either of them alone on ovaries damaged by chemotherapy \u2022with CTX.\n\nIntroduction {#sec1-1}\n============\n\nOvarian dysfunction is common in premenopausal women receiving chemotherapy, and approximately 30% of women aged less than 35 years and 50% of women aged between 35 and 40 years tend to experience menstrual function cessation after chemotherapy, leading to premature ovarian failure (POF) or menopause.^[@ref1]^ POF is described as secondary infertility with elevated gonadotropin levels before age 40, with an estimated incidence rate of 1%.^[@ref2]^ The use of chemotherapy increases the cure rate in young cancer patients, but some side effects such as ovarian failure and infertility may occur. POF due to chemotherapy causes cytotoxic effects, which will damage granulosa cells (GCs) and will, thus, possibly lead to folliculogenesis disruption.^[@ref3]^ Cyclophosphamide (CTX) is one of the most commonly used chemotherapy drugs, and"
+"To the Editor, {#s1}\n==============\n\nRed blood cell (RBC) transfusion is a risk factor for mortality and morbidity in coronary artery bypass graft (CABG) surgery, and transfusion-related adverse effects may be catastrophic in these patients \\[[@ref1],[@ref2],[@ref3],[@ref4]\\]. Unfortunately, there are no recommendations for these patients regarding how to proceed in the case of incompatible crossmatch tests against donors' blood. To our knowledge, there is no report about the role of therapeutic plasma exchange (TPE) in resolving incompatible crossmatches.\n\nA 73-year-old man was admitted to our hospital because of chest pain. He had no previous medical history of coronary artery disease or any other diseases, including hemolytic disease and recent infection. In addition, he used no medication and had not received blood transfusions. After coronary angiography, a CABG was planned for the patient. Because of critical coronary artery lesions, he had to undergo the operation as soon as possible. His laboratory tests revealed mild normocytic anemia with hemoglobin of 12.8 g/dL, mean corpuscular volume of 82.2 fL, white blood cell count of 9200/\u00b5L, and platelet count of 281,000/\u00b5L. His biochemical results were normal for renal and liver function tests. The patient's blood group was B Rh D positive based on forward and"
+"Introduction {#s1}\n============\n\nOlfactory receptors (ORs) are seven transmembrane domain G protein-coupled receptors (GPCRs) that govern the sense of smell in the olfactory epithelium, and comprise the largest gene family in the genome (\\~1000 OR genes in mice \\[[@B1]\\] and \\~300 \\[[@B2]\\] in humans). Although this family was first identified over 20 years ago \\[[@B3]\\], the majority of ORs remain orphan receptors, with no known ligand. This is due, in large part, to the fact that OR deorphanization is typically attempted using *in vitro* ligand screening assays in heterologous cell systems which require surface expression of the OR as a prerequisite for the assay (i.e. HEK293T cells or *Xenopus* oocytes) \\[[@B4]--[@B7]\\]. Unfortunately, many ORs do not traffic to the cell surface in heterologous cell systems; rather, they are retained in the ER and degraded \\[[@B8]--[@B10]\\], making ligand assignment impossible. To combat this problem, studies have utilized the co-expression of various accessory proteins and/or the addition of N-terminal tags \\[[@B11]--[@B14]\\]. For example, the addition of the first 20 amino acids of rhodopsin onto the N-terminus of ORs (Rho tag) enhances OR surface expression for a number of ORs \\[[@B15]\\]. Similarly, receptor transporting protein (RTP), originally identified as a potential chaperone for"
+"Introduction {#Sec1}\n============\n\nHumans are exposed in a variety of ways to organosiloxane compounds, also called silicones, which are present in many daily used products, such as deodorants, skin and hair care products, drugs and water repellants. Exposures occur from inhalation, ingestion, dermal absorption and surgical implantation. Although silicones were originally believed to be chemically and biologically inert, accumulating evidence indicates that they might have toxic side-effects^[@CR1]--[@CR5]^. The implantation of silicone gel-filled breast implants results in a continuous exposure to silicones, because these compounds are known to leak from the implants. The safety of these implants has been debated for a long time^[@CR2],[@CR4],[@CR6]^. Especially during the last ten years it has become more generally accepted that the exposure to silicones in some individuals may have adverse health effects^[@CR7],[@CR8]^.\n\nThe most common silicone in gel-filled implants is polydimethylsiloxane and its production not only yields polymers, but also cyclic oligomers^[@CR9],[@CR10]^ The cyclic oligomers consist mainly of tetramers and pentamers, which are known as D4 and D5, respectively. Silicone gels that are used in implants are composed of slightly crosslinked chains of polydimethylsiloxanes, so that they form a three-dimensional network. Due to the inherent incompleteness of crosslinking the gels contain 1--2% of methylsiloxanes"
+"###### Summary box\n\n-   Establishment of a trauma registry is the first step to understanding the regional epidemiology of injury and establishing an effective trauma system.\n\n-   Road traffic crashes result in 30%--86% of all trauma admissions in low-income and middle-income countries.\n\n-   Almost half of all motor vehicle collision victims were the main providers for their family.\n\n-   Data from the Sri Lankan Trauma Registry demonstrated that only 52% of patients arrived at the hospital within 2\u2009hours after injury, with very few of these patients receiving any prehospital care.\n\n-   Work overload of medical officers led to a significant amount of missing data, and the slow tablet speed and poor internet connectivity within the wards led to a 30\u2009min data entry time for a single patient.\n\n-   From the data obtained in this study, plans have been developed to conduct trauma first aid workshops and training programmes for school children and sports clubs, as well as public and media awareness programmes, of the importance of injury prevention in Sri Lanka.\n\nIntroduction {#s1}\n============\n\nEvery year more than 50\u2009million people sustain road traffic injuries requiring medical care[@R1] and 1.25\u2009million die from their injuries.[@R2] Those who survive"
+"Introduction\n============\n\nCardiovascular disease (CVD) is one of the main causes of morbidity and mortality worldwide.[@B1] According to 2013 death statistics in Korea, CVD was the second leading cause of death.[@B2] Previous studies have declared that dyslipidemia is an important risk factor for CVD by contributing to the initiation and progression of atherosclerosis; therefore, its management is important for reducing the burden of CVD.[@B3]\n\nMeanwhile, the prevalence of dyslipidemia is steadily rising in Korea, and statistics published by the Korean Society of Lipidology and Atherosclerosis (KSLA) revealed that in 2013 57.6% of men and 38.3% of women, accounting for a total of 47.8% of people over 30 years of age (more than 16 million), had dyslipidemia. When the low-density lipoprotein cholesterol (LDLC) cutoff value was set to 100 mg/dL for diabetic patients, 9 out of every 10 diabetic adults had dyslipidemia. For patients with hypertension, 2 out of every 3 hypertensive adults were diagnosed with dyslipidemia.[@B4]\n\nThe use of lipid-lowering medications such as statin and fibrate are important for the treatment of dyslipidemia, especially in high-risk patients. However, lifestyle interventions are also important for managing dyslipidemia and are considered initially after diagnosis, since dietary factors can influence lipid levels and"
+"1. Background\n=============\n\nThe currently favoured explanation for the origin of Mendel\\'s dominant and recessive traits is untenable \\[[@B1]\\]. The primary error in this current attempted explanation is the assumption that there is a direct, proportional, relationship in a diploid cell between a series of allegedly dominant and recessive alleles written as (*AA*+ 2*Aa*+ *aa*) and the dominant, hybrid and recessive traits written as (*AA*+ 2*Aa*+ *aa*). This assumption (Figure [2](#F2){ref-type=\"fig\"}, in reference \\[[@B1]\\]) incorporates four fundamental faults:\n\n![Accounting for Mendel\\'s observation of a 3(dominant):1(recessive) trait ratio in his F2 populations of plants. Mendel\\'s notations for a dominant trait, a hybrid and a recessive trait were (*A*), (*Aa*) and (*a*) respectively. For reasons given in the preceding paper \\[1\\], a hybrid trait is represented in Figure 2 by (*H*). The molecular components of all traits are synthesised by a metabolic pathway. When the activity of any one enzyme in a metabolic pathway is changed in discrete steps, the flux to a trait component responds in non-linear (non-additive) fashion \\[3\\]. If the flux response is quasi-hyperbolic, as shown here, the hybrid trait (*H*) will be indistinguishable from the trait (*A*) expressed in the wild-type cell or organism, even when the enzyme"
+"Efforts to understand the genetic basis of complex traits and diseases have almost exclusively focused on the role of single nucleotide variants ([@bib44]). However, vast genomic variation exists beyond the single nucleotide level, in the form of short tandem repeats, long repetitive regions, and transposable elements ([@bib44]). This variation remains poorly characterized, not just in humans but even in the most tractable model organisms. The copy number of repetitive DNA elements changes frequently through expansion and contraction, and as a consequence linkage of specific repeat numbers to surrounding single nucleotide variation is markedly reduced ([@bib72]; [@bib48], [@bib47]; [@bib45]). Hence, the power to use nearby common single nucleotide variants to tag repetitive DNA genotypes in genome-wide association studies is limited ([@bib45]; [@bib11]).\n\nRecently, long-read technology, such as PacBio and Oxford Nanopore, has made accessible some forms of repetitive DNA, including complex tandem repeats and short tandem repeats ([@bib64]; [@bib76]), although both technologies are plagued by high error rates ([@bib49]; [@bib32]; [@bib61]). Short tandem repeats (units of 2-10 bases) can also be genotyped with repeat-spanning sequence reads through a capture-based method ([@bib6]; [@bib45]) or sophisticated computational tools ([@bib73]; [@bib3]; [@bib54]; [@bib35]). Copy number variation of short tandem repeats can have significant impact"
+"We thank Yudkin and Montori ([@B1]) for their letter in response to our editorial ([@B2]).\n\nAs outlined in the editorial, we feel a great deal of attention---perhaps too much---has been paid over the recent past to the fact that the ranges of impaired glucose tolerance, impaired fasting glucose, and A1C define different groups of people as being at risk, and that the individuals with dysglycemic levels at the lower ends of the glycemic ranges are at lower risk for progressing to diabetes than the individuals at the higher ends. We would agree that all of that has been well established. In fact, American Diabetes Association (ADA) guidelines expressly acknowledge these points, but we do not see the value in repeatedly and exhaustively making these observations. We can continue to argue over what the exact diagnostic cut points for each test should be, but the bottom line is that these are categories suggesting increased risk for developing diabetes, and it is inevitable that when you have physiological ranges of a continuous variable, the risks will be lower at the lower ends of the ranges than at the higher ends.\n\nADA's Standards of Care position statement ([@B3]) specifically acknowledges this differential risk"
+"Introduction\n============\n\nHereford is a major breed of beef cattle in the United States. Over time, the Hereford breed has been subjected to a variety of different selection goals. A sub-population known as Line 1 (*L1*) was established in 1934 by joining two paternal half-sib bulls with 50 unrelated Hereford females. Thereafter, L1 has been selected primarily for growth to 1\u2009year of age and continuously maintained as a closed population (MacNeil, [@B23]). Recent separation of populations can produce dramatic genomic consequences, such as different multi-locus heterozygosity in different genomic regions (Oleksyk et al., [@B34]). In addition, strong recent bottlenecks, such as that which occurred at the founding of L1, may cause marked founder effects (Nei et al., [@B32]).\n\nEstimates of linkage disequilibrium (LD) may identify non-random associations of linked loci and may indicate population divergence (de Roos et al., [@B7]). Additional measures, such as extended haplotype homozygosity (EHH) may also reveal locus-specific genetic variants associated with line divergence (Tang et al., [@B41]). Recent studies of populations' genomic architecture have frequently targeted regions of low heterozygosity. However, a few have identified regions of increased heterozygosity or that showed a heterozygote advantage on survival traits (Hedrick et al., [@B15]; Arkush et"
+"The Japanese encephalitis (JE) virus of genus *Flavivirus* (*Flaviviridae*) has a positive sense RNA genome and presents an enzootic cycle involving mosquitoes[@ref1] and amplifying vertebrate hosts. It causes viral encephalitis which is primarily a disease of children. According to the World Health Organization (WHO), annually, there are about 68,000 global cases of JE, of whom 20-30 per cent are fatal, 30-50 per cent of survivors have significant neurological sequelae and three billion people are at the risk of infection in endemic countries including WHO South-East Asia and Western Pacific Regions[@ref2]. The causative agent, JE virus (JEV) is vector borne with *Culex* mosquitoes as its main vectors and water birds such as egrets and herons as reservoirs[@ref3][@ref4]. Pigs serve as amplifying hosts in human epidemics[@ref5], and the virus causes reproductive disorder in pigs. Pathological and pathogenesis studies have been conducted on JEV infection in rabbit, guinea pig, monkey, hamster, rat and mouse models using different routes of infection, including intravenous (*i.v.*), intraperitoneal (*i.p.*), subcutaneous (*s.c.*), intracerebral (*i.c.*), intradermal and intranasal (*i.n.*) routes, but neuronal invasion has been confirmed in some of these models[@ref6]. However, footpad inoculation closely mimics the conditions of human infection by natural route[@ref7][@ref8]. Rabbits and guinea pigs develop"
+"INTRODUCTION\n============\n\nPrimary biliary cirrhosis (PBC) is an agnogenic, chronic cholestatic autoimmune liver disease characterized by a high specificity of antimitochondrial antibody and small bile-duct destruction. PBC leads to portal area inflammation, intrahepatic cholestasis, and fibrosis and can progress to cirrhosis and eventually liver failure.^[@R1]^\n\nUrsodeoxycholic acid (UDCA) has been considered the standard therapy for improving the biochemical indexes of PBC patients. Although previous meta-analyses^[@R2],[@R3]^ have suggested that UDCA has a beneficial effect in significantly decreasing liver biochemistry, UDCA has no effect on liver disease related mortality despite the observed reduction in the incidence of liver transplantations. A proportion of patients treated with UDCA in the early stages still have a risk of progression to cirrhosis and end-stage liver disease. Many studies have revealed that the use of glucocorticoids to suppress inflammation is considered an attractive approach among PBC patients.^[@R4]--[@R6]^ Glucocorticoids also appeared to be more effective among nonresponders to UDCA.^[@R7],[@R8]^ In clinical practice, we have found that some patients who do not respond to UDCA still have disease progression, even if additional glucocorticoids are added later. Thus, the prognosis of PBC patients might be improved if we combine UDCA and glucocorticoids earlier and take measures to prevent their side"
+"Background\n==========\n\nArsenic contamination has assumed an alarming proportion in some 9 districts of West Bengal, India, so much so that it has been earmarked as \\\"the biggest arsenic calamity in the world\\\" \\[[@B1],[@B2]\\]. In view of rapid spread of various diseases arising out of arsenic contamination (e.g. arsenical dermatosis, melanosis, keratosis, oedema, gangrin etc.) in different areas of West Bengal and also in adjoining areas of Bangladesh \\[[@B1]-[@B4]\\], some effort has been made to provide arsenic-free drinking water (purified through chemical plants) to people living in the arsenic-contaminated zones, but this has proved to be grossly inadequate so far. From the vastness of the problem and new reports of arsenic contamination still emerging from other parts of South East Asia \\[[@B5]-[@B7]\\], Slovakia \\[[@B8]\\], Mexico \\[[@B9]\\] etc., a disastrous situation seems to loom large unless a tremendous all-out effort is urgently made to bring the situation under control. The problem became more complex because of the poor health and hygiene conditions and the relatively low affordability of the greater majority of population living in these zones. and for the lack of awareness of the possible consequences of arsenic intoxication in most of them. Mainly with such a background, our initial"
+"Introduction {#Sec1}\n============\n\nRiparian ecosystems are coming under increasing stress from changing climate, increasing demands on water, and loss of flood-induced disturbance^[@CR1]^. In addition, given the strong influence of beaver on fluvial and riparian function, and their decline across much of their native Northern Hemisphere habitat^[@CR2]^, these ecosystem engineers have become an important area of focus in riparian science. Attention has centered on the effects of intact dams^[@CR3],[@CR4]^ and direct impacts of herbivory^[@CR5],[@CR6]^. Nonetheless, there has been limited investigation of the effects of beaver activity on stream reaches and riparian vegetation beyond their iconic dams and ponds, or on the continuing impacts of breached and abandoned dams. For example, beaver are notorious herbivores, generating a steady supply of beaver-chewed wood^[@CR7]^ that is often transported downstream. Although seed dispersal may be the dominant and critical form of reproduction for riparian plants, sprouting from stem fragments can also play an important role in riparian plant reproduction, particularly for species that are adapted to floodplain disturbance^[@CR8]^. In prior research along beaver-occupied streams in southwestern Montana and the Rocky Mountain region, we observed that willow cuttings produced by beaver herbivory and dam building are commonly transported downstream and accumulate along channel margins. Thus, we"
+"1. Introduction\n===============\n\nPancreatic cancer (PC) is the seventh most common cause of cancer mortality worldwide,^\\[[@R1]\\]^ with a 5-year survival rate of 5%.^\\[[@R2],[@R3]\\]^ Infiltrating pancreatic ductal adenocarcinoma (PDA) is the most prevalent tumor type, making up 90% of all PC cases. According to the 2014 World Cancer Report, PC mortality is higher on the European continent (31.6%) than the rest of the world.^\\[[@R4]\\]^ Around 70% to 80% of patients present unresectable lesions at the time of diagnosis.^\\[[@R3]\\]^ The global incidence of PC based on the 2012 GLOBOCAN is 4.2 out of every 100,000 individuals.^\\[[@R5]\\]^ The estimated rate in lower in Mexico, with an incidence of 3.4 per 10,000 inhabitants, which is thought to be underestimated due to limited or incomplete data availability.^\\[[@R6]--[@R8]\\]^\n\nHistorically, early diagnosis of PC has been difficult due to technical issues related to the physiopathology of the disease. Genetic alterations have been reported for intraductal adenocarcinoma (IDA), which is characterized by mutations in several genes, including *K-Ras*, *Cdkn2a*, Tp53, *Tgfbr2*, *Epc1*, *Arid2*, and *Map2k4*, among others.^\\[[@R9]--[@R12]\\]^ Cystadenomas, intraductal papillary mucinous, and mucinous cystic neoplasms are also characterized by gene mutations in *\u03b2-catenin*, *Gnas*, *Rnf43*, and *Tp53*.^\\[[@R13]\\]^ In addition, inherited mutations such as those occurring in the *BRCA2*,"
+"Facts {#Sec1}\n=====\n\nThe chimeric-antigen receptor T-cell adoptive immunotherapy (CAR-T) is a potent instrument for treating several hematological malignancies, not only those expressing the CD19 receptor.There is a pressing need to make this therapy available to a wider spectrum of patients.However, although the safety levels of CAR-T therapy are generally acceptable, several fatal outcomes due to severe cytotoxicity have been reported in clinical trials of CAR-T therapies.Therefore, better understanding of the spectrum of toxicities, their etiology and pathogenesis as well as the knowledge of toxicity-promoting factors may help develop and validate the predictive scales and define better prophylactic strategies for high-risk patients.\n\nOpen questions {#Sec2}\n==============\n\nIt is known that some of the factors that worsen the toxicity of CAR-T therapy (higher CAR T-cell dose, intensive lymphodepletion) also positively affect its efficacy. How can one achieve the proper balance between these?\n\nWhat kind of predictive model one should use for the toxicity risk assessment and which group of patients should be given the treatment for prophylaxis of such toxicity?\n\nWould universal allogenic CAR T-cells be as safe and effective as the autologous CAR T-cells?\n\nIntroduction {#Sec3}\n============\n\nAdoptive immunotherapy is a rapidly evolving field in modern cancer biology and its"
+"Introduction {#S0001}\n============\n\nOvarian cancer is a common female malignant tumor with concealed symptoms which make it difficult to be discovered. Moreover, drug resistance to chemotherapy and delayed operation often cause unsatisfactory therapeutic effect.[@CIT0001]--[@CIT0003] There are estimated 295,414 new ovarian cancer cases and 184,799 ovarian cancer deaths worldwide in 2018.[@CIT0004] Therefore, many strategies should be developed to treat ovarian cancer.\n\nImmunotherapy can recognize and kill cancer cells effectively by motivating and enhancing immune function of the body. Effective immune response is of importance to suppress the immune escape of tumors. T cells are main effector cells of immune response. They are mainly activated by T cells receptor (TCR) and synergistic signals.[@CIT0005]--[@CIT0007] TCR is a heterodimer mainly formed by \u03b1\u03b2 or \u03b3\u03b4 polypeptide chains through disulfide linkage. Thereinto, \u03b1\u03b2 accounts for a high proportion. Gene fragments of \u03b1 and \u03b2 chains of TCR are easily rearranged to form highly variable region which is known as complementarity-determining region 3 (CDR3). Luo et al sequenced CDR3 gene, identified the high affinity part of TCR molecular sequence and provided basis for T cell immunotherapy for ovarian cancer.[@CIT0008]\n\nInterferon-\u03b3 (IFN-\u03b3) is a cytokine that is critical for innate and adaptive immunity. The immunostimulatory and immunomodulatory"
+"As professional antigen presenting cells, Dendritic cells (DCs), undergo a well-defined activation process that render them competent to activate adaptive immune responses and also to control tolerance. As a result, DCs are considered key regulators of the immune system. DC activation via pathogen recognition or by tissue injury occurs by virtue of expression of pattern recognition receptors, which has been extensively documented in previous years. However, there is a growing body of evidence demonstrating that DC activation and function can be also finely adjusted by perturbations in cellular mechanisms that are normally associated with homeostasis, and that include processes such as cell polarity, changes in the secretory demand, endoplasmic reticulum (ER) stress, epigenetics, autophagy, and metabolism among others. Moreover, evidence is now emerging that environmental cues such as nutrient availability, antibody complexes, and sodium levels are also important regulators of DC biology. In this Research Topic, we have brought together a collection of 10 primary research and review papers from experts in their respective fields to home in novel and emerging regulators of DC function that go beyond canonical pattern recognition.\n\nSeveral cellular \"household\" processes that normally function to maintain intracellular homeostasis can also serve as regulators of DC function"
+"World Heart Day will be observed September 29, 2014. The focus of World Heart Day this year is creating heart-healthy environments in which persons are able to make heart-healthy choices wherever they live, learn, work, and play. Heart disease and stroke are the world's leading causes of death, claiming an estimated 17.3 million lives in 2008, and representing 30% of all deaths worldwide ([@b1-843]). A heart-healthy environment can help persons make healthy choices to reduce their risk for heart disease. World Heart Day 2014 encourages persons to reduce their risk for cardiovascular disease by promoting smoke-free environments, environments that encourage physical activity, access to healthy food choices, and a heart-healthy planet for all.\n\nCDC is working to help create heart-healthy environments in multiple ways, including community-based approaches, such as the Sodium Reduction in Communities Program (SRCP), and community-clinical linkages, such as the Million Hearts Initiative. SRCP aims to increase access to and accessibility of lower-sodium food options while building the evidence base on population approaches to reduce sodium consumption at the community level. Million Hearts aims to prevent 1 million heart attacks and strokes by 2017 by bringing together communities, health systems, nonprofit organizations, federal agencies, and private-sector partners from"
+"See related commentary by Ikeda and Kudva, <http://stemcellres.com/content/4/6/159>\n\nIntroduction\n============\n\nThe success of islet transplantation over the last decade suggests that diabetes can be cured by a replenishment of deficient beta cells \\[[@B1],[@B2]\\]. However, according to the transplantation protocol of Edmonton, the transplanted islets into each patient should be isolated from two to three pancreatic donors, exceeding ten thousand islet equivalent (IEQ)/kg \\[[@B3]\\]. As a result, a widespread use of islet transplantation is severely limited by the shortage of donor organs. Stem cells have the capacity of self-renewal and the potential of differentiating into various cell types, making them an ideal candidate to address this issue.\n\nAlthough the possibility of generating insulin-producing cells routinely from both human embryo stem cells (ESC) and human induced pluripotent stem (iPS) cells is quite encouraging, significant challenges still remain \\[[@B4]\\]. Lumelsky \\[[@B5]\\] and Assady \\[[@B6]\\] found that islet-like cells could be generated *in vitro* by differentiation of ESC under conditions resembling those of physiological development for pancreatic beta cell development. However, insulin secretion by these cells was low and lacked a full response to glucose. Clinically, applying ESC-derived cells in treatment presents more challenges including the risk of cancer formation, functional deficiency of such"
+"Introduction {#Sec1}\n============\n\nThromboangiitis obliterans (TAO), or Buerger's disease, is an inflammatory, thrombotic-occlusive, medium- and small-sized vasculitis that usually occurs in young males with a history of tobacco use \\[[@CR1]\\]. The pathophysiology of the disease is not well understood. However, recently, the possible role of infectious pathogens as the trigger of TAO has been suggested \\[[@CR1]\\]. For instance, the antibody for the main oral pathogen responsible for gingivitis, *Porphyromonas gingivalis* (*P. gingivalis*), has been detected in the sera of TAO patients, and this pathogen has also been isolated from vascular lesions using polymerase chain reaction (PCR) \\[[@CR2], [@CR3]\\]. However, since smoking might be responsible for gingivitis and related immunologic responses in TAO patients \\[[@CR4]\\], this hypothesis has neither been confirmed nor disproved.\n\nIn addition to oral bacteria pathogens, since the 1980s, the possibility of Rickettsia infection has also been suggested as a trigger for TAO \\[[@CR5], [@CR6]\\]. In recent studies, Rickettsia infection was detected using PCR in 3 of 25 biopsies from a below-knee amputated limb in a TAO patient \\[[@CR7]\\]. Following the study, the antibodies for the Rocky Mountain spotted fever (RMSF) group were detected in the sera of TAO patients using micro-immunofluorescence (MIF) \\[[@CR8]\\].\n\nAccording to our recent"
+"Optically transparent and mechanically flexible electronics have generated significant interest in the past decade due to their ability to meet the increasing technological demands for next-generation electronics[@b1][@b2][@b3][@b4][@b5]. Emerging flexible glass substrates with a thickness as small as 50\u2005\u03bcm exhibit high transparency, superior surface quality, thermal stability, chemical compatibility, and mechanical flexibility that enable displays, photovoltaics, lighting, and touchscreens that are fabricated by roll-to-roll methods[@b6][@b7][@b8][@b9][@b10][@b11][@b12]. Transparent films with high diffuse light scattering have potential applications in solar cells, OLED light systems, backlight units of liquid crystal displays (LCD), signage, etc. In general, there are two types of methods (surface relief and particle coating) widely used to make transparent films with high light scattering properties[@b13][@b14][@b15][@b16][@b17]. Light diffuse scattering films based on surface relief have a microstructural surface with a tunable shape and a high optical transmittance and are normally fabricated from plastic films or plates, but this involves complicated and time-consuming fabrication processes and expensive equipment[@b18][@b19]. Particle diffuse scattering is the primary method to produce diffusive films with both high transparency and high haze due to its relatively simple processing procedure; however, non-uniform distribution of particles in the coating layer is still an obstacle that will affect luminance uniformity of the"
+"Introduction {#sec1-1}\n============\n\nThere has been considerable controversy regarding what constitutes the best treatment for lumbar burst fractures. Goals of thoracolumbar fracture are restoring vertebral column stability and obtaining spinal canal decompression to achieve early mobility of patient \\[[@ref1]-[@ref5]\\]. Burst fractures of the lumbar spine have unique biomechanical and neurological features as compared with burst fractures in other regions of the spine \\[[@ref6]\\]. Management of thoracolumbar burst fracture is diverse and depends upon various components. Fracture morphology, neurological status and the predilection of surgeon all play important role in determining whether the anterior, posterior or combined approach is to be taken \\[[@ref7]\\]. The fracture of the fifth lumbar vertebra with dislocation in our patient was completely different from the types of L5 fracture that had been published up to now. There have been very few reports in the literature regarding burst fracture of the fifth lumbar vertebra and various pattern of affecting it. Our patient had combination of a complete burst fracture of the fifth lumbar vertebra with dislocation and complete disruption of the posterior ligamantous and bony complex between L5 and sacrum.\n\nCase Report {#sec1-2}\n===========\n\nA case of young male patients aged 25 years old presented with history"
+"Introduction {#s0005}\n============\n\nInflammation is a natural protective mechanism that resolves infections and injuries of the target tissue.[@bib1] Failure to effectively resolve the inflammation and return the affected tissue to homeostasis leads to maladaptation and precipitation of pathophysiologic consequences that often result in the development of chronic maladies, including cardiovascular diseases and diabetic complications.[@bib2], [@bib3] It has been well established that injury-elicited inflammation in the vasculature often causes excessive proliferation of vascular smooth muscle cells within vessel walls and the subsequent expansion of the intima, leading to the eventual blockage of the vessel.[@bib4], [@bib5], [@bib6] These remodeling processes are intensified especially in patients with diabetes. Although effective in combating neointima hyperplasia, current anti-inflammatory and antimitotic drugs often display significant side effects and toxicity that deem systemic applications unfeasible, and their local delivery is achieved via drug-eluting stents.[@bib7], [@bib8] Therapeutic reagents that can be administered systemically stand the benefit of providing alternative avenues for treating acute vascular injuries as well as circumventing overall chronic inflammation in the vasculature.[@bib9]\n\nRAGE is a pattern recognition receptor that recognizes multiple endogenous ligands and triggers innate and adaptive immune responses.[@bib10], [@bib11], [@bib12], [@bib13], [@bib14] Signaling via RAGE has been associated with vascular inflammation and implicated"
+"1. Introduction {#sec1-ijms-21-03818}\n===============\n\nPost-translational modifications (PTMs) regulate many proteins functions thanks to the addition of a functional chemical group. Phosphorylation is the most important PTMs in eukaryotic cells as it plays a critical role in regulating many eukaryotic cellular processes, including metabolism, cell cycle progression, cellular proliferation, survival, migration and differentiation \\[[@B1-ijms-21-03818]\\]. Phosphorylation is synergistically balanced by the action of protein kinases (PK) and protein phosphatases (PP), which are crucial signaling mediators that act coordinately to drive signal responses \\[[@B2-ijms-21-03818],[@B3-ijms-21-03818]\\]. In human cells, 518 PKs catalyze about 100,000 phosphorylation events \\[[@B4-ijms-21-03818],[@B5-ijms-21-03818]\\] and more than 200,000 phosphorylation sites are currently registered in PhosphoSitePlus databases \\[[@B6-ijms-21-03818]\\]. On the other hand, about 160 PPs specifically regulate the phosphorylation status of target substrates \\[[@B7-ijms-21-03818]\\]. Any impairment of PKs and/or PPs activation, as well as any deviation from their balance, represents one of the most common causes of several human diseases. In human cells, phosphorylation mainly occurs at serine and threonine residues (Ser/Thr) and at a lower level at tyrosine (Tyr) residues. However, Tyr phosphorylation represents a prerequisite in cellular signaling mechanisms triggered by tyrosine kinase receptors (TKR) \\[[@B8-ijms-21-03818],[@B9-ijms-21-03818]\\]. Despite a significant number of phosphorylation sites in PKs and PPs has been identified, their"
+"Background\n==========\n\nPolydactyly of the hands or feet is a common birth deformity that occurs in many forms, ranging from varying degrees of mere splitting to completely duplicated thumb. Preaxial polydactyly is the most common of congenital hand anomalies. It can occur in isolation or as part of a syndrome. Isolated polydactyly is often autosomal dominant, while syndromic polydactyly is commonly autosomal recessive \\[[@B1],[@B2]\\]. Polydactyly is classified into preaxial, central, and postaxial types. Preaxial polydactyly, the most common type, refers to the duplication of the first digital ray \\[[@B3]\\].\n\nSeveral classfications were proposed, among which Wassel\\'s classification \\[[@B4]\\] (table [1](#T1){ref-type=\"table\"}) is being widely used in clinical fields. Interestingly sometimes clinically recognized types do not correspond with the findings recorded at surgery. Reason behind it is the presence of cartilaginous epiphysis which does not show bifurcation level between two duplicated components in immature hand. So the classifications become inappropriate to some extent. It has been understood that radiological classification alone has little value in detection of clinical types as well as in preoperative assessment.\n\n###### \n\nClassification: Types I to VII based on level of duplications\n\n  \\- I: bifid distal phalanx\n  -----------------------------------------------------------------------\n  \\- II: duplicated distal phalanx\n  \\- III: bifid proximal phalanx"
+"1. Introduction {#sec1-sensors-20-01832}\n===============\n\nOrthoimages have increasingly become a popular visualization product and planning instrument for integrating the rich information content of images with the geometric properties of maps (ground projection) and can be easily combined with additional information from geographic information systems (GIS) to create an orthoimage map \\[[@B1-sensors-20-01832]\\]. However, with the development of technology, the orthoimage spatial resolution becomes higher, and the coverage area of an individual orthoimage is typically very small Thus, image mosaicking is a necessary process of constructing multiple images into a large-scale and single seamless composite image. This process has been applied in a wide variety of applications such as environmental monitoring, agricultural monitoring, and disaster management \\[[@B2-sensors-20-01832],[@B3-sensors-20-01832]\\]. Orthoimages are typically orthorectified by the Digital Terrain Model (DTM) of the same geographical area. The quality of DTM directly affects the accuracy of orthorectification. Objects not contained in the DTM cannot be orthorectified correctly. Those objects would appear at different locations in the overlapping area and cause visual discontinuities in image mosaicking. An ideal seamline should avoid such objects \\[[@B1-sensors-20-01832],[@B4-sensors-20-01832],[@B5-sensors-20-01832],[@B6-sensors-20-01832],[@B7-sensors-20-01832],[@B8-sensors-20-01832]\\]. A seamline is the line along which overlapping areas will be mosaicked. Each pixel in the final mosaicking result is represented entirely by only one"
+"1.. INTRODUCTION {#sec1}\n================\n\nCurrently, the healthcare system faces various challenges ranging from excessive costs that could be avoided and information management issues to unnecessary Electronic Health Record (EHR) duplications and omission or unavailability of critical data ( [@ref1] ). Such difficulties lie in the fact that providers are not able to exchange information and in most cases, they are still using obsolete formats. According to the IEEE ( [@ref2] ) definition, interoperability is the \"ability of a system or a product to work with other systems or products without special effort on the part of the customer\" made possible by the implementation of standards. The Semantic Health study ( [@ref3] ) classifies the semantic interoperability of systems into those with local interoperability (within, e.g., hospitals or hospital networks) and those with regional, national and cross-border interoperability. Rector et al. ( [@ref4] ) state that EHRs are \"information models\" and that \"ontology\" is the conceptualization of healthcare information (clinical, demographics, etc.). CrowdHEALTH project aims at processing datasets with structured and unstructured information coming from different Use Cases ( [@ref5] - [@ref9] ). Thus, there is a need to identify or map the entities and attributes from a proprietary source to"
+"Background\n==========\n\nThe vertebral column is the defining character of vertebrates providing the organism with a unique ability of movement, form and function. Obviously, abnormalities to this organ can lead to severe and often painful pathological conditions. Spinal disorders are a major cause of disability for humans and an important health problem for intensively farmed animals. A number of animal models have been used to further explore the pathology and revealed that vertebral deformities present a complex but comparable cross species etiology \\[[@B1],[@B2]\\]. Morphological changes like altered bone formation and cell density, thinning of osteoblasts along with increased cell proliferation and cell death are changes found in spinal deformities and intervertebral disc degeneration (IDD) in mammals \\[[@B3],[@B4]\\]. Discs from patients with spinal deformities further have ectopic calcification of the vertebral endplates and sometimes in the disc itself \\[[@B5]\\]. Cells of the mammalian disc are derived directly from the phylogenetically conserved notochord \\[[@B6]\\]. Whereas only remnants of the notochord exists in the nucleus pulposus (NP) in humans by the age of 4, the notochord persist throughout all life stages in teleosts. Spinal disorders in teleosts like sea bass, sea bream, rainbow trout, halibut and salmon \\[[@B7]-[@B12]\\] have mostly been descriptive and"
+"All relevant data are within the paper.\n\nIntroduction {#sec001}\n============\n\nRespiratory syncytial virus (RSV) is a human pathogen of the *Pneumovirus* genus within the *Paramyxoviridae* family. Worldwide, the virus causes over 30 million lower respiratory tract illnesses per year in children and is a leading cause of infant pneumonia mortality \\[[@ppat.1005622.ref001], [@ppat.1005622.ref002]\\]. Despite a substantial clinical burden of disease, there are no available vaccines or RSV-specific therapeutics. A challenge to RSV vaccine and therapy strategies remains elucidation of the unclear relationship between RSV infection and pathogenesis.\n\nRSV is an enveloped, non-segmented, negative-strand RNA virus whose genome is approximately 15.2 kb in length and encodes 10 genes which are translated into 11 proteins. RSV attachment is mediated through host glycosaminoglycans (GAGs), cellular protein nucleolin, association with cholesterol-rich microdomains, and CX3CR1 \\[[@ppat.1005622.ref003]--[@ppat.1005622.ref009]\\]. Mechanisms surrounding RSV entry remain unclear and other host receptors, co-receptors, and co-factors contributing to infection are likely to be identified. Two envelope proteins mediate RSV infection, the attachment glycoprotein (G) and the fusion (F) protein. Prior to infection, RSV F exists in a metastable pre-fusion conformation \\[[@ppat.1005622.ref010], [@ppat.1005622.ref011]\\]. RSV F undergoes a series of conformational changes yielding a thermodynamically stable six-helix post-fusion bundle, which drives viral and host membrane"
+"Figure [8](#F8){ref-type=\"fig\"} was printed partially cropped, due to a typesetting error. This error does not change the scientific conclusions of the article in any way. The publisher apologizes for this error and the correct version of Figure [8](#F8){ref-type=\"fig\"} appears below.\n\n![**Spatially multi-peaked receptive fields. (A)** Receptive field map of a single neuron with a large number of sub-regions. The analysis was based on 98,376 spikes recorded in 22 min, with a high quality isolation (*L*-ratio\\~0). The receptive field was to the left and above the fovea, and spanned a total range of \\~15\u00b0. The general direction preference was down and to the left \\[purple; see color wheel inset in **(D)**\\]. **(B)** Statistical analysis of the RF map in **(A)**. The grayscale in this map reflects the significance of direction tuning (the log of the *p*-value of the Rayleigh test). Locations outside the estimated RF (see Materials and Methods) are shown in black. **(C)** Response of the same neuron as in **(A,B)** to a single dot moving in the preferred direction within a1 \u00d7 1\u00b0 patch (using the Grid RF stimulus; see Materials and Methods). Here the grayscale represents the average firing rate of the neuron. Unmapped parts of the visual"
+"Introduction {#s1}\n============\n\nBees navigate in a range of several kilometers around their hive and communicate about locations using the waggle dance to transmit information about the flight vector towards a feeding place or a nest site [@pone.0091364-vonFrisch1], [@pone.0091364-Seeley1]. Navigation and communication require multiple cognitive faculties. Among these are, for example, recognition of the sun compass, visual distance estimation, learning of multisensory cues inside and outside the hive and translating as well as reading the codes of the waggle dance, all processes that require integration of different navigational information. Several forms of memory have been found to guide navigation (recent reviews: [@pone.0091364-Gruter1], [@pone.0091364-Menzel1], [@pone.0091364-Menzel2], [@pone.0091364-Galizia1]). In particular, route flights between hive and feeder lead to a memory of the flight vector that are bound to the sun compass and can be communicated in the waggle dance. A more flexible memory about spatial relations of landmarks is formed during the exploratory orientations flights of bees leaving the hive for the first time. This latter form of memory allows bees to steer to learned locations e.g. the hive, a different feeding site, and a dance communicated site along novel short cutting routes. It has been concluded that that these multiple spatial representations"
+"The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#s1}\n============\n\nHoneybees are heterothermic insects which change from the ectothermic to the endothermic state for foraging. They have to keep their body temperature high throughout the entire foraging cycle to stay ready for immediate flight, and to promote fast exploitation of resources [@pone.0105432-Heinrich1]--[@pone.0105432-Stabentheiner1]. Endothermy in insects of this small size, however, means enormous efforts to compensate for the high heat loss because of the large surface to volume ratio [@pone.0105432-Bishop1]. This calls for energetic optimisation.\n\nDuring a foraging trip the challenge is especially high because not only the ambient temperature but also solar radiation may vary in a broad range within a day and during a foraging season [@pone.0105432-Kovac1], [@pone.0105432-Germ1], [@pone.0105432-Stabentheiner2]. In order to assess the energetic demand of foraging bees under variable ambient temperatures there have been measurements of metabolism in the shade, both at artificial flowers [@pone.0105432-Balderrama1]--[@pone.0105432-Blatt1], and during flight [@pone.0105432-Harrison1]--[@pone.0105432-WoodsJr1]. On many flowers, however, or at water sources honeybees are often not airborne for long periods of time [@pone.0105432-Kovac1], [@pone.0105432-Kovac2], [@pone.0105432-Schmaranzer2], [@pone.0105432-Kovac3]. Since they need not to stay airborne"
+"Introduction\n============\n\nThe novel coronavirus, 2019-nCoV, emerged in Wuhan, China in December 2019 and has rapidly spread across the world ([@ref-12]; [@ref-35]). In February 2020, the World Health Organization (WHO) renamed this epidemic disease coronavirus disease (COVID-19) as it is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The number of COVID-19 cases has rapidly increased worldwide ([@ref-30]; [@ref-8]). As of 29 February 2020, there were 85,403 confirmed COVID-19 cases and 2,924 fatalities across 49 countries ([@ref-30]; [@ref-10]). Although the emerging threat of COVID-19 has drawn global attention, the optimal strategies to reduce the spread of disease remain largely undetermined ([@ref-7]).\n\nSeveral studies have investigated the virology, transmission, risk factors and protection associated with COVID-19 ([@ref-4]; [@ref-13]; [@ref-14]; [@ref-28]; [@ref-31]; [@ref-33]). COVID-19 spreads by human-to-human transmission, primarily through respiratory droplets and direct contact with groups of infected family members, friends, colleagues, or medical health workers. However, even asymptomatic patients can be a source of infection. COVID-19 has dramatically higher rates of transmission compared to SARS and Middle East respiratory syndrome, but an observed lower fatality rate. The median age of COVID-19 patients ranged from 47 to 56 years old; approximately 65% of patients were male and 35% were female."
+"Key Points {#FPar1}\n==========\n\nThe multiple-dose pharmacokinetics of FE\u00a0999049 have been described, accounting for endogenous follicle-stimulating hormone (FSH) levels.Exposure to FE\u00a0999049 was influenced by body weight, which may be a potential factor for individualised dosing recommendations.Endogenous FSH levels were influenced by progesterone and inhibin\u00a0B levels. This time-varying contribution of endogenous FSH may be important to consider when characterising the pharmacokinetics of recombinant FSH products.\n\nIntroduction {#Sec1}\n============\n\nFollicle-stimulating hormone (FSH) is a gonadotropin that is synthesised and secreted by the anterior pituitary gland. The major function of FSH is to regulate the reproductive processes by stimulating the gonads. In females, FSH stimulates follicular development in the ovaries and production of inhibin\u00a0B, progesterone, and oestrogens by the ovarian follicular granulosa cells. Luteinising hormone (LH), another gonadotropin from the anterior pituitary, stimulates the theca cells of the follicles to deliver androgens to the granulosa cells for conversion to oestrogens. It is also responsible for ovulation of the dominant follicle that has reached a fully mature, pre-ovulatory stage. The ovarian hormones promote further follicular development as well as exerting negative and positive feedback loops to the hypothalamus and pituitary affecting the gonadotropin production and secretion. In addition, gonadotropin secretion"
+"1. Introduction {#sec1-sensors-16-01198}\n===============\n\nCracking is a major sign of structural aging and damage, which shortens the integrity and service life of structures. While the width of cracks for most ordinary reinforced concrete (RC) structures in civil engineering are over 0.2--0.4 mm, the service life of the structure can be severely shortened due to the erosion of inner steel rebar under harsh environments. Moreover, structures may be damaged if the cracks reach 1--2 mm. Therefore, crack monitoring is essential to guarantee the safety of structures. Currently, many approaches have been developed for crack monitoring, such as ultrasonic methods \\[[@B1-sensors-16-01198]\\], acoustic emission \\[[@B2-sensors-16-01198]\\], infrared thermography \\[[@B3-sensors-16-01198]\\], impact-echo \\[[@B4-sensors-16-01198]\\], large area electronics \\[[@B5-sensors-16-01198]\\], etc. All of the techniques mentioned above show good performance of crack detecting, however, they struggled to be applied in practical engineering due to the installation difficulties and vulnerability in the long-term harsh environment. Recently, the optical fiber sensing technology, such as the Bragg grating, the Michelson white light interferometer, and Brillouin scattering have been widely investigated for crack detecting \\[[@B6-sensors-16-01198],[@B7-sensors-16-01198],[@B8-sensors-16-01198]\\]. However, all of the fibers in the above approaches are silica fibers which are brittle (their elongation rates are only about 1%) \\[[@B9-sensors-16-01198]\\], which make it easy to"
+"Background {#Sec1}\n==========\n\nBreast cancer is the commonest malignancy in women and a major cause of cancer-related mortality \\[[@CR1]\\]. While mastectomy is the primary treatment modality for these patients, it can have a profoundly negative impact on their lives, impairing personal, sexual and social relationships. Fifty percent of women post-mastectomy suffer from negative self-image with negative changes in their sexuality \\[[@CR2], [@CR3]\\]. The demand for reconstructive procedures has risen, not only as a consequence of advancing cancer treatment but also because of the demonstrated functional, psychological and social benefits for patients, overcoming the psychological trauma associated with mastectomy \\[[@CR4]--[@CR9]\\]. The rates of post-mastectomy breast reconstruction doubled from 13 to 26% between 1998 and 2007 \\[[@CR10]\\].\n\nA number of reconstructive techniques exist for breast reconstruction. The two most frequently employed techniques include the autologous deep inferior epigastric perforator (DIEP) flap and implant-based reconstruction \\[[@CR11]\\]. The choice of treatment is determined by combination of patient factors (individual preference, age, body image) and surgeon factors (team experience, availability of resources) \\[[@CR8], [@CR9]\\]. Despite this, many plastic surgery units worldwide regard autologous flap reconstruction as the superior technique as it follows the paradigm of replacing 'like with like' \\[[@CR10]\\]. Indeed, there is growing evidence"
+"Background {#Sec1}\n==========\n\nPreterm birth is the leading cause for neonatal morbidity and mortality in developed countries \\[[@CR1]\\]. Survivors of preterm birth are at risk of developing neonatal morbidities such as infections, necrotizing enterocolitis, bronchopulmonary dysplasia, and brain injury \\[[@CR2], [@CR3]\\].\n\nPerinatal brain injury causes typical neurodevelopment deficits such as motor impairments, mental and developmental retardation, learning disabilities, and psychiatric disorders later in life \\[[@CR4]--[@CR6]\\]*.* The pathogenesis of perinatal brain injury is complex, but is thought to involve both inflammation and ischemia leading to the formation of free radicals and subsequent death of neurons and pre-oligodendrocytes \\[[@CR7]\\]. Additionally, the innate immune response plays a key role in the pathogenesis of perinatal brain injury. The main mediators of the innate immune response to brain injury are microglial cells, the brain's resident macrophages. Once activated upon injury, microglial cells release a large number of inflammatory factors designed to limit infectious processes. However, this immune defense mechanism causes additional brain injury and contributes substantially to the subsequent neurodevelopment deficits \\[[@CR8]\\]. Hence, multiple studies have shown that therapies targeting microglia-mediated inflammation confer neuroprotection in several types of brain injuries \\[[@CR9]--[@CR12]\\], suggesting that microglia may be a novel therapeutic target for perinatal brain injury \\[[@CR13]\\]*.*"
+"Introduction {#s1}\n============\n\nIdiopathic type 2 macular telangiectasia (mactel), also referred to as juxtafoveolar retinal capillary telangiectasia, was first classified in detail in 1982 by Gass and Oyakawa^[@i2164-2591-6-6-7-b01]^ with further elaboration on classification made in 1993 by Gass and Blodi.^[@i2164-2591-6-6-7-b02]^ This is a bilateral disease characterized by progressive changes in the macular capillary network that follow a slowly progressive course, which begins temporal to the foveal center, in association with neurosensory atrophy and loss of luteal pigment, resulting in encroachment of paracentral scotoma into the foveal center.^[@i2164-2591-6-6-7-b03]^ Visual acuity remains stable for many years in the early stages of the disease and, therefore, is not a suitable clinical endpoint in neuroprotective treatment trials.^[@i2164-2591-6-6-7-b03]^ Microperimetry now has been adopted as a promising functional endpoint for monitoring visual decline in this disease.\n\nMicroperimetry is a modified visual field test that allows assessment of retinal differential light sensitivity at selected and known retinal loci and fixation characteristics without the need for stable and foveal fixation.^[@i2164-2591-6-6-7-b04]^ This technique currently is used as an outcome measure in five type 2 mactel clinical trials registered with the United States National Institutes of Health clinical trial registry (clinicaltrials.gov--NCT 00685854; NCT 01327911; NCT 00685503; NCT 00504400; NCT 01949324).^[@i2164-2591-6-6-7-b05]^"
+"Introduction\n============\n\nAndrogen deprivation therapy (ADT, surgical or chemical castration) has been the primary treatment for prostate cancer (PCa) used to suppress the transcriptional activity of androgen receptor (AR) since the 1940s; however, a proportion of patients relapse within a median of 2-3 years with disease that is usually more aggressive and is currently defined as castration-resistant PCa (CRPC) ([@b1-ijmm-40-05-1426]--[@b3-ijmm-40-05-1426]). It was well known that AR is actively involved in the development, progression and metastasis of PCa ([@b4-ijmm-40-05-1426]). Over the past several years, studies from many groups have proposed that AR is aberrantly re-activated in CRPC ([@b4-ijmm-40-05-1426]--[@b6-ijmm-40-05-1426]). There are multiple mechanisms through which AR is aberrantly re-activated to support cell growth in CRPC in the androgen-depleted condition, including AR amplification (the hypersensitive pathway), AR mutation and co-regulator alterations (the promiscuous pathway), ligand-independent AR activation (the outlaw pathway) ([@b4-ijmm-40-05-1426]).\n\nIn general, androgen is a driver which elicits PCa initiation and progression ([@b7-ijmm-40-05-1426]). However, it is contradictory that androgen plays a role as a suppressor in LNCaP cell growth by inducing cell cycle arrest at the G1 phase following treatment with high-dose dihydrotestosterone (DHT), accompanied by p27 overexpression and the loss of the phosphorylated retinoblastoma protein ([@b8-ijmm-40-05-1426],[@b9-ijmm-40-05-1426]). Intermittent androgen deprivation therapy (IADT)"
+"Diabetic macular edema (DME), a severe form of diabetic retinopathy (DR), is the leading cause of vision loss in working age adults in developed countries.^[@R1]^ The disease has multifactorial and interconnected pathophysiological mechanisms with poor glycemic control considered of major importance. Hyperglycemia, endothelial dysfunction, retinal hypoxia and oxidative stress, local inflammatory activity with upregulation of cytokines and growth factors, microaneurysms, breakdown of the blood--retinal barrier, and retinal neurodegeneration have been shown to be involved in the development and progression of DR.^[@R2],[@R3]^ However, the molecular basis of multiple cellular mechanisms affecting the neurovascular unit remains to be elucidated.\n\nAlthough advances in understanding the etiopathogenesis of DME have already translated into new effective therapeutic interventions, such as intravitreal treatment with antiangiogenic drugs, further options for optimizing outcomes are continually pursued. Dietary supplementation with omega-3 long-chain polyunsaturated fatty acids (\u03c9-3 PUFAs) has emerged as one of these alternatives based on the significant role of docosahexaenoic acid (DHA), the dominant fatty acid of retinal phospholipids, in maintaining retinal integrity.^[@R4]--[@R6]^ The pleiotropic effects of DHA including antiinflammatory, antioxidant, antiproliferative, and antiangiogenic properties may play an important role in modulating the production of proinflammatory cytokines and proangiogenic factors, the effect of oxidative stress damage of retinal"
+"Background {#Sec1}\n==========\n\nUveitis is one of the major causes of blindness worldwide \\[[@CR1]\\]. Certain uveitis patients may complicate with cataract \\[[@CR1], [@CR2]\\]. Cataract in patients with uveitis results from both the process of primary disease and the persistent treatment with corticosteroids \\[[@CR2]--[@CR4]\\]. Among all the surgical approaches, phacoemulsification is the most effective method, because of a smaller incision of the cornea and a less stimulation of the vitreous \\[[@CR5]\\]. The ultrasound energy applied in phacoemulsification generate the heat, which may cause postoperative anterior chamber inflammation, corneal edema, incision burns, corneal endothelial cells loss, and even decompensation of corneal endothelium \\[[@CR3], [@CR4]\\]. Besides, the postoperative inflammatory reaction of cataracts caused by uveitis is usually more severe than that in senile cataracts because of the adhesive iris or intraocular environment prone to inflammation.\n\nHypothermia has been proved to be a protective factor to improve the body's tolerance to ischemia and hypoxia in numbers of studies \\[[@CR6]--[@CR9]\\]. Since hypothermia could decrease the tissue metabolism to reduce hypoxic-ischemic injury, therapeutic hypothermia is applied in many diseases. In the ocular field, it has been reported in some experiments that local hypothermia can protect the retina from acute ischemic injury and reduce postoperative inflammation in"
+"The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#s1}\n============\n\nIt is well known that the cryopreservation process negatively affects the viability and fertility of reproductive cells. There are several factors caused by cryopreservation protocols that alter sperm integrity, such as a change in the temperature of the diluents [@pone.0112382-Watson1]; osmotic and toxic stresses induced by cryoprotectants [@pone.0112382-Watson1], [@pone.0112382-Watson2]; formation/reshaping of intracellular ice during freezing and thawing [@pone.0112382-Pea1]; and dissolution of ice in the extracellular environment [@pone.0112382-Watson2]. All of these factors induce sperm volumetric changes, plasma membrane alterations, flagellum morphological defects, as well as decrease mitochondrial membrane potential, sperm motility, viability, and fertility [@pone.0112382-Watson2], [@pone.0112382-Parks1]--[@pone.0112382-Cremades1]. As a generalisation, some 40--50% of the sperm population does not survive cryopreservation even with optimised protocols [@pone.0112382-Watson2]. Thus, many of the frozen-thawed spermatozoa show a shorter life span and have difficulties in reaching the oocytes and penetrating their vestments after conventional artificial insemination [@pone.0112382-Cremades1]. Variations between individuals in sperm freezability have been reported in numerous animal species. Within this context, semen donors have routinely been categorized as \"good freezers\" (GF) or \"bad freezers\" (BF). When"
+"Nationally, schools of medicine strive to improve patient outcomes through teaching, research, and practice. Yet substantial segments of the United States population still face significant barriers to health care access and quality ([@CIT0001]--[@CIT0003]). Evidence suggests that lack of faculty diversity in schools of health education is a factor in perpetuating these disparities ([@CIT0004]). Faculty of color are more likely to provide health care in underserved regions than majority faculty. In academic medicine, they serve as important role models and mentors for minority students and trainees and promote academic excellence that improves student outcomes in cultural competence, humanism, and professionalism ([@CIT0001]). However, the Association of American Medical Colleges points out that arguing for faculty diversity\\'s dividends is insufficient ([@CIT0001]). Diversity must be seen as a driver of excellence in medical education, essential to and congruent with other calls for education reform such as those outlined by the recent Carnegie report on educating physicians ([@CIT0005]).\n\nThe terms 'faculty of color' and 'underrepresented minority faculty' (URM) refer to two overlapping but distinct groups. The former includes Asians who are minorities in the US population but not in medicine. The latter are people of African American, Native American, and Latino descent. The medical education"
+"Introduction {#Sec1}\n============\n\nWe had previously studied the development of bioartificial livers composed of a radial flow bioreactor (RFB) and human hepatocellular carcinoma-derived cell lines, FLC-4, FLC-5, or FLC-7 \\[[@CR1]--[@CR4]\\]. One of the major features of these cell lines is that they can be cultured in serum-free medium, meaning that studies can be performed without considering the amino acids present in serum. Our previous study showed that selection of serum-free medium is an important factor for effective use of bioartificial livers containing these cell lines \\[[@CR4]\\]. In the study that used RFB and FLC-7 cells, ASF104N medium was shown to be more suitable for cell growth than the IS-RPMI medium (based on RPMI-1640). However, ASF104N was less suitable for producing fibrinogen, which is specifically produced in hepatocytes, than IS-RPMI. When comparing both media types, we had focused on the effects of two amino acids, ornithine and arginine, using media that had complementary compositions of ornithine and arginine (ASF104N:\u2009+\u2009ornithine/\u2009\u2212\u2009arginine; RPMI-1640:\u2009\u2212\u2009ornithine/\u2009+\u2009arginine). Similar results were observed with respect to albumin production in another experiment. Albumin production by FLC-4 cells was improved by replacing the ASF104N (+\u2009ornithine/\u2009\u2212\u2009arginine) medium in the RFB with E-RDF"
+"Background\n==========\n\nEpitheliomesenchymal transition (EMT) is a process where epithelial cells attain fibroblastic properties. It has been postulated that in this way carcinoma cells are better able to invade to the surrounding structures and metastasize \\[[@B1],[@B2]\\]. EMT is characterised by a downregulation of adhesion molecules, such as E-cadherin, and upregulation of genes typically found in myofibroblastic or fibroblastic cells such as \u03b1-smooth muscle actin or vimentin \\[[@B1],[@B2]\\]. EMT is regulated by several transcription factors, such as snai1, slug, zeb1, twist, CarB-box-binding factor, Mesenchyme Forkhead 1 and Kruppel-like factor \\[[@B2]\\]. The expression of these transcription factors is modified and regulated by complex signaling networks present in the tumor microenvironment such as transforming growth factor \u03b2, notch or Wnt pathways \\[[@B3]\\]. There appears to be a hierarchy in the expression of these transcriptional factors, with snai1 being expressed at the onset of EMT whereas snai2, zeb1 and twist are induced later to maintain the migratory phenotype \\[[@B3]\\].\n\nZeb1 (Zinc-finger E-box-binding homeobox 1) is a transcriptional factor which contains two Kruppel-type zinc finger domains by which it becomes attached to target DNA sequences \\[[@B4],[@B5]\\]. It induces EMT and has been shown to downregulate E-cadherin in epithelial cells \\[[@B5]\\]. Zeb1 also downregulates the polarity"
+"Introduction {#Sec1}\n============\n\nIn recent years, the increased incidence of human male infertility has been of a great concern. This is possibly related to the widespread usage of endocrine disrupting substances, including pesticides, food additives, plasticizers and industrial chemicals. Cadmium, a heavy metal, may also function as an endocrine disruptor, by interfering with the endocrine cell functions or their development. Human may expose to this metal by multiple dynamics. Cadmium has been used as the stabilizer in the manufacture of polyvinyl chloride polymer, preservative pigments, phosphate fertilizers, nuclear neutron filters, and batteries. Smoking is also a major source of cadmium intake. Each cigarette contains 5\u2009mg of cadmium, which could lead to significantly higher levels of blood cadmium, with smokers of 4--5 times higher than that of non-smokers^[@CR1]^. Different from other environmental contaminants, cadmium has an especially long elimination half-life of 20--40 years, leading to a significant accumulation in the human body. This makes the metal particularly dangerous and challenging.\n\nStudies have showed that the mammalian testis is a sensitive target of cadmium toxicity^[@CR1]--[@CR3]^. Exposure to cadmium induced germ cell loss and decreased sperm production^[@CR4]^, which may account for the increased incidence of male infertility. However, it seems that the"
+"INTRODUCTION {#omy034s1}\n============\n\nCellular and humoral immunity towards distinct onconeural antigens is the hallmark of PNDs \\[[@omy034C1]\\]. Stable formation of IgG antibodies to particular onconeural antigens occurs in the majority of cases, whereas persistent coexistence of antibodies specific for multiple onconeural antigens is a relatively rare phenomenon of certain malignant tumors like SCLC \\[[@omy034C2], [@omy034C3]\\]. However, onconeural antigen spreading, i.e. the dynamic appearance and disappearance of distinct onconeural antibodies during the course of PNDs in individual patients has not yet been described.\n\nCASE REPORT {#omy034s2}\n===========\n\nA 70-year-old Caucasian male with a long history of smoking and surgically treated urothelium carcinoma 2 years ago, presented 08/2013 with radicular neuralgia and hypesthesia of the legs, disturbed fine motor skills of the hands and extinction of knee and ankle jerks on both sides, accompanied by abnormal posture and ataxic gait. Nerve conduction studies revealed severe demyelinating and axonal polyneuropathy fulfilling the Inflammatory Neuropathy Cause and Treatment (INCAT) criteria for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Initial MRI of the brain and entire spinal cord showed moderate contrast enhancement in fibers of the cauda equine an radices only (not shown). Cerebral (as part of a whole-body) FDG-PET/CT was normal (Fig. [1](#omy034F1){ref-type=\"fig\"}A). Cerebrospinal fluid (CSF)"
+"Introduction {#Sec1}\n============\n\nWeaning from mechanical ventilation (MV) is a challenging decision, it means complete transition from mechanical breathing support to patient's own respiratory drive support. This transition is very critical and needs accurate, intense, confident decision based on trusted validated clinical, radiological and laboratory parameters to avoid the risk of weaning failure \\[[@CR1]\\].\n\nThe patient's failure to accomplish this or to withstand 48\u00a0h of spontaneous breathing is defined as a weaning failure. Weaning failure is a disappointing event that, in relation to the comorbidities and other reported complications, impacts all ICU staff and patient families and costs patient exposure to reintubation risk \\[[@CR2]\\].\n\nThe readiness of the patient for weaning depends globally on the respiratory muscles' power that faces the burden of breathing. Unbalance between the power and the burden leads to weaning failure, including any factor that impairs the respiratory muscle function as ICU acquired neuromuscular dysfunction which is either due to prolonged mechanical ventilation, prolonged sedation or any other potential cause \\[[@CR3]\\].\n\nAlthough the validated respiratory parameters which are assessed during weaning process are appropriate for weaning, however, the proficiency of these parameters to detect the power of the respiratory muscles to carry on the burden"
+"Introduction\n============\n\nAs of 2005, the world is confronted by 338 generic infectious diseases, scattered in a complex fashion across over 220 countries and regions. Each new day confronts health care workers with unexpected outbreaks, epidemics and heretofore unknown pathogens. Over 2,000 named bacteria, viruses, fungi and parasites are known to cause human disease; and are confronted by 328 anti-infective agents and vaccines. Experts working in Health Geographics share an obvious and immediate need for comprehensive and timely data on the status of infection around the globe. A recent outline of GIDEON addressed uses for the Infectious Diseases clinician \\[[@B1]\\]. This review will focus on the Global Health aspect of the program.\n\nIn 1990, we initiated a project to design computer systems to follow all diseases, outbreaks, pathogens and drugs. The initial DOS-based program was written in Paradox for floppy disks, later evolving through a compact disk-based program in Windows. A commercial web-based program was eventually released under the name, GIDEON (Global Infectious Diseases and Epidemiology ON-line, Gideon Informatics, Inc, Los Angeles, California) at <http://www.GideonOnline.com>. The current version is available on CD (updated every three months) or web subscription (updated every week).\n\nThe program consists of four modules: Diagnosis, Epidemiology,"
+"Introduction {#s1}\n============\n\nEarly vigour or seedling vigour (i.e. the amount of leaf area produced early in the season) has been considered an important trait for rainfed (water-limited) wheat especially in Mediterranean climate regions such as southern Australia. In these regions, rainfall is winter dominant ([@CIT0031]; [@CIT0037]; [@CIT0032]) and coincides with early wheat growth (planted in mid-autumn to early winter). Wheat yield is often limited by insufficient rainfall around anthesis with a terminal drought during grain-filling ([@CIT0035]). More efficient use of soil moisture at early wheat growing stages (before canopy closure) is considered crucial for higher grain yields. Greater early vigour leads to faster leaf area development, reduces soil water loss via soil evaporation, increases competition with weeds ([@CIT0021]), and improves nutrient uptake ([@CIT0020]; [@CIT0039]). Consequently, it has been shown that genotypes with higher early vigour produced higher biomass and grain yield ([@CIT0048]; [@CIT0041]; [@CIT0031]; [@CIT0003]). However, greater early growth and water use may also reduce available soil water later in the season to worsen terminal drought, leading to reduced yields. Whether early vigour leads to increased or decreased yield will depend on local climate conditions. Despite the promise of benefits through greater vigour (e.g. [@CIT0003]), there is a lack"
+"INTRODUCTION {#sec1-1}\n============\n\nThe installation and preparation of a permanent vascular pathway for hemodialysis is an important challenge for surgeons. This challenge is mainly due to the increased number of dialysis patients, such as the elderly and diabetic patients, especially those who are considered and candidates for kidney transplantation, as well as patients requiring long-term dialysis.\\[[@ref1][@ref2]\\]\n\nThe guidelines to improve the outcomes of kidney disease have offered and provided standards for optimal access and maintenance of the route for dialysis.\\[[@ref3]\\] The autologous arteriovenous fistula turns as a selective vascular access in patients requiring long-term dialysis. The use of this type of access results in a long-term patency and also a few potential complications.\\[[@ref4][@ref5]\\] However, these benefits may be accompanied by a high failure rate (up to about 30%).\\[[@ref6][@ref7]\\]\n\nThe arterial/venous grafts are more favorable, compared to the autologous arteriovenous fistulas, because they have more short-term outcomes and fewer deficits; moreover, they can be used immediately for hemodialysis if needed.\\[[@ref8]\\] However, this tool is also associated with low patency, leading to increased morbidity and high hospital costs.\\[[@ref9]\\]\n\nThe application of autogenous arteriovenous fistulas has been increasingly considered today as a temporary access using tunneled catheters. However, the employment of this method"
+"Introduction {#Sec1}\n============\n\nIn 1973, Jones and Smith launched the term fetal alcohol syndrome (FAS) to describe a characteristic pattern of altered fetal growth and morphogenesis due to maternal alcohol consumption during pregnancy (Jones and Smith [@CR11]). Nowadays, the effects of prenatal alcohol exposure are collectively referred to as fetal alcohol spectrum disorder (FASD). The following anomalies are generally considered key elements of FASD: 1) prenatal and/or postnatal growth retardation, 2) dysmorphic facial features, mainly affecting the premaxillary region (smooth philtrum, thin vermillion border of the upper lip, short palpebral fissures), 3) alcohol-related birth defects, such as cardiac, skeletal, renal and ocular malformations, and 4) alcohol-related neurodevelopmental disorders, which include structural central nervous system (CNS) abnormalities (microcephaly, partial or complete corpus callosum agenesis, cerebellar hypoplasia, and leptomeningeal heterotopias) as well as behavioral, cognitive, and motor disabilities (Van Balkom et al. [@CR24]; Chudley et al. [@CR4]). FAS epitomizes the most severe form of FASD. The degree to which offspring is affected by maternal alcohol ingestion depends on the timing and level of exposure, with more serious disruptions in fetus exposed to high concentrations of alcohol during the first weeks of pregnancy (Chudley et al. [@CR4]; Guizzetti and Costa [@CR10]; Kot-Leibovich and"
+"Introduction {#s1}\n============\n\nThe accumulation of toxic heavy metals in industrial wastewater effluents has become a great challenge in less developed countries such as Nigeria, as these effluents are indiscriminately discharged into water bodies or on land (Weber et al., [@B56]). Wastewater effluents generated in some chemical process industries contain cadmium, lead, copper, zinc, nickel, and chromium (Argun and Dursun, [@B5]), which if contained above a given concentration are hazardous and has the propensity of leading to fatal health challenges. In addition, these elements, unlike most pollutants are not ecologically degradable rather they undergo a universal ecological cycle in which soil and water are the main pathways (Nwokonkwo, [@B45]). High levels of heavy metals in soils could result in uptake by local and agronomic plants and leaching to ground and surface waters.\n\nSewage sludge application causes related problems like rise in injurious level of the heavy metal concentration in edible crops (Nwajei, [@B44]). Cadmium (II) can enter the food chain via plant uptake (Nwajei, [@B44]). Natural waters are contaminated by lead through several activities in industries, which include battery, paint, metal plating, smelting, textiles, and plastics, amongst others (Opeolu et al., [@B47]). All foods contain varying amounts of lead and"
+"Peter Hotez and colleagues recently published a *PLOS Neglected Tropical Diseases* Viewpoint \\[[@pntd.0003504.ref001]\\] on the implications of the Global Burden of Disease 2010 study (GBD 2010) for the field of neglected tropical diseases (NTDs). The article highlighted the recent improvements in the GBD's [D]{.ul}isability-[A]{.ul}djusted [L]{.ul}ife-[Y]{.ul}ear (DALY) ranking system, but there remains much work to be done in reversing the DALY-mediated underestimation of NTDs' importance to the global health burden.\n\nWith regard to the inputs used for the GBD 2010's DALY calculations for schistosomiasis, I see a problem: the core team in charge of the GBD 2010 (the Institute for Health Metrics and Evaluation \\[IHME\\]) continues to systematically underestimate the burden of *Schistosoma* infection--related disability \\[[@pntd.0003504.ref002]\\]. This underestimation is based on a flawed perception of *Schistosoma* infection and its related disease manifestations---IHME continues to adhere to the concept of \"asymptomatic\" schistosomiasis, while it is my considered opinion that no such health state exists.\n\nThe unfortunate use of the term \"asymptomatic\" implies that most *Schistosoma*-infected patients are not experiencing ongoing morbidity or disability. This is not the case because, by its nature, schistosomiasis is always a chronic inflammatory disease either of the intestine, genitourinary tract, or other organs. Eggs must cause inflammation"
+"Introduction\n============\n\nChildbearing is an important, valuable issue in marital relationships, especially in traditional societies because it stabilizes the family and increases marital satisfaction ([@B1]). After attempts at pregnancy over an extended period of time, the inability to have a child may cause marital problems ([@B2]). Most infertile couples report loss of self-esteem, sexual stress, depression, anxiety, guilt, frustration, emotional distress, tension in their marital status, and reduced life satisfaction ([@B3]). Most commonly reported forms of infertility related mood disorders are anxiety and depression. These disorders are influenced by a number of factors such as gender, cause of infertility, uncertain treatment duration, financial stress, and pressure from others ([@B4]). Several studies have reported the psychosocial impacts of an infertility diagnosis on men and women ([@B1]). Infertile couples showed higher rates of psychological symptoms when they had female factor and unexplained causes for infertility. Women have been shown to experience more stress and depression, along with less marital satisfaction compared to their partners. This finding is most probably due to increased involvement in therapeutic procedures, which affects women more ([@B5]). Men diagnosed with male factor infertility have more negative emotional responses than other infertile men. They have expressed feelings of stigma"
+"Introduction {#s1}\n============\n\nImmunotherapy, represented by immune checkpoint inhibitors (ICI),\u00a0including anti-PD-1 antibodies, anti-PD-L1 antibodies, anti CTLA-4 antibodies or their combinations, is transforming the treatment of cancer. Compared to conventional therapies, ICI can induce significantly improved clinical responses in patients with various types of late-stage metastatic cancers. However, the majority of unselected patients will not respond to ICI. Most tumor types show response rates below 40% to PD-1 inhibition, and the response rates of each tumor type are reported to be correlated with the\u00a0tumor mutational burden (TMB) of that\u00a0tumor type ([@bib48]). Multiple factors are reported to affect ICI effectiveness, including: PD-L1 expression ([@bib14]; [@bib36]), TMB ([@bib31]; [@bib37]), DNA mismatch repair deficiency ([@bib18]), the degree of cytotoxic T cell infiltration ([@bib40]), mutational signature ([@bib26]; [@bib43]), antigen presentation defects ([@bib7]; [@bib50]), interferon signaling ([@bib1]), tumor aneuploidy ([@bib10]) and T-cell signatures ([@bib17]). These biomarkers have various rates of accuracy and utility,\u00a0and\u00a0the identification of\u00a0a robust ICI-response biomarker is still a critical challenge in the field ([@bib28]).\n\nICI help a\u00a0patient's immune system to recognize and attack cancer cells. The immunogenicity of cancer cells is the fundamental determinant of ICI response. Theoretically, tumors of very low or no immunogenicity will"
+"Background\n==========\n\nThe vertebrate retina consists of seven cell types organized into distinct laminar structures. In mice, retinal neurogenesis begins at embryonic (E) day 11.0 and terminates around postnatal (P) day 11. The six neuronal cell types and one glial cell type that make up the retina all derive from common retinal progenitor cells (RPCs) \\[[@B1]\\]. RPCs give rise to retinal cells in a conserved chronological sequence: ganglion cells and horizontal cells are born first, followed by cone photoreceptors and amacrine cells during the middle stage of retinogenesis. Rod photoreceptors, bipolar cells and M\u00fcller glial cells are the last cell types to be generated, mainly during postnatal stages \\[[@B2]\\].\n\nThe retina has been serving as an excellent model for the studies of cell differentiation and interaction during neural development, attributing to its limited cell types generated in a temporal-spatially defined process. Among molecules and pathways involved in retinal development, the Notch signaling has been demonstrated as an essential regulator of retinogenesis \\[[@B3],[@B4]\\]. In mice, the canonical Notch pathway includes five ligands (Delta-like \\[Dll\\] 1, 3, 4, Jagged1, 2), four receptors (Notch1-4), and the transcription factor recombination signal-binding protein J\u03ba (RBP-J) (also termed CBF1 in mammals), which regulates the expression of"
+"Background\n==========\n\nCommonly, the musculoskeletal physical exam is focused on measures of range of motion (ROM) and muscular strength of the affected segment that could not provide enough information about overall segment functional level of activity \\[[@B1]\\]. Thus, shoulder evaluation could be improved by including techniques those assess functional movements and biomechanical impairment present in professional or daily life activities \\[[@B1]\\]. Functional tests could be considered a valuable complementary low-cost clinical tool to provide quantitative data about the functional ability and performance of a body segment \\[[@B2],[@B3]\\]. Some tests also can be used to record the progress of a rehabilitation protocol by measuring, for example, performance and ability of a patient during physical task \\[[@B4]-[@B7]\\].\n\nThe *Closed Kinetic Chain Upper Extremity Stability Test* (CKCUES Test) is a performance test that provides quantitative data (score) for a upper extremity task in closed kinetic chain (CKC) with no needs of high technology to be realized in sportive or clinical settings. The test consists in counting how much times, during 15\u00a0seconds, the subject assuming a push-up position is able to touch his/her supporting hand with the swinging hand. The test is considered easy for clinicians to apply and also easy for clients"
+"Published: July 15, 2020\n\nIntroduction {#sec1}\n============\n\nAs of June 22, 2020, 9.0 million people have been infected with severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), with \\>469,939 deaths and 40,000 deaths in the United Kingdom attributed to coronavirus disease 2019 (COVID-19).[@bib1] Current clinical testing for acute SARS-CoV-2 infection and infection risk relies on nucleic acid detection using reverse transcription polymerase chain reaction (RT-PCR) on nose and throat swabs.[@bib2]^,^[@bib3] Antibodies to SARS-CoV-2 are detectable in only 50% by days 5--7[@bib4] and are therefore not suitable as a test for early infection, although they are useful in the second phase of illness, when virus detection wanes in upper respiratory tract samples.[@bib3]^,^[@bib5] Antigen tests for COVID-19 diagnosis have performed poorly to date, and therefore nucleic acid detection remains the test of choice. Nucleic acid testing usually requires central laboratory testing with concomitant delays, and turnaround times are usually in excess of 24 h, and often days.[@bib6] Due to the diverse presentations of COVID-19,[@bib7] lack of a timely diagnosis can have serious consequences, including deadly nosocomial outbreaks.[@bib8]\n\nScreening hospital admissions rapidly is therefore critical to manage patient flow and limit the potential for nosocomial transmission.[@bib9]^,^[@bib10] In the absence of a reliable point of care (POC)"
+"1. Introduction {#sec1-sensors-16-01444}\n===============\n\nThe abundant resources in oceans motivate the increasing exploration activities towards the underwater environment. In addition, underwater acoustic sensor networks (UASNs) are increasingly attracting interest due to their wide applications such as environment monitoring, resource investigation, oceanography data collection, pollution monitoring and tactical surveillance \\[[@B1-sensors-16-01444],[@B2-sensors-16-01444],[@B3-sensors-16-01444],[@B4-sensors-16-01444],[@B5-sensors-16-01444]\\]. All of these applications highly require reliable data transport techniques. However, underwater channels have unique features that are quite different from terrestrial wireless radio channels, so it is impossible to use terrestrial sensor network techniques in UASNs immediately.\n\nElectromagnetic waves, optical waves and acoustic waves are the three main propagation media in UASNs. However, radio frequency (RF) waves suffer from high propagation loss and optical waves are affected by scattering and absorption in water. Thus, acoustic waves are preferred for long-range underwater communication, and this new kind of transmission medium brings some new features and challenges for the underwater reliable data transfer protocol design.\n\nUnderwater acoustic channels are affected by many factors such as path loss, noise, multi-path and Doppler spread. All of these factors cause high error probability and packet loss in acoustic channels. Moreover, the available bandwidth of underwater acoustic channels is limited and depends on both transmission range"
+"INTRODUCTION\n============\n\nIn eukaryotic cells, cotranslational integration of membrane proteins into the endoplasmic reticulum (ER) membrane is mediated by a protein-conducting channel formed by the Sec61 complex called the translocon ([@B17]; [@B35]). Findings from electrophysiological ([@B40]) and site-specific fluorescent labeling ([@B6]) studies indicate that the translocon forms an aqueous pore. In addition, studies using site-specific cross-linking techniques demonstrated that Sec61\u03b1, a central component of the Sec61 complex, is transiently cross-linked not only with polypeptide chains translocating across the membrane but also with transmembrane (TM) segments of membrane proteins or signal sequences ([@B32], [@B31]; [@B26]; [@B7]; [@B12]). Evidence suggests that the translocon provides an environment not only for the translocation of secretory proteins, lumenal soluble proteins, and lumenal domains of membrane proteins across the ER membrane, but also for the lateral delivery of hydrophobic sequences into the lipid phase. The Sec61 complex is formed by a heterotrimer that consists of three components: Sec61\u03b1, Sec61\u03b2, and Sec61\u03b3. Based on studies of crystal structures of archaeal ([@B42]) and bacterial ([@B41]) SecY complexes, which are homologues of the eukaryotic Sec61 complex, one SecY molecule forms an hourglass-like shape across the membrane with a slight opening that faces toward the lipid environment, suggesting that a"
+"Introduction\n============\n\nObesity has become a nationwide epidemic in the United States. The prevalence of obesity among adults (\\> 20 years) has consistently increased from 2001 to 2014 \\[[@b1-ophrp-10-137]\\]. Obesity is linked to increased risk for non-communicable diseases including cancer, difficulty with physical movement, heart disease, mental illness, osteoarthritis, sleep apnea, stroke, and Type 2 diabetes \\[[@b2-ophrp-10-137]--[@b5-ophrp-10-137]\\]. Obesity and overweight together are the second leading cause of preventable death (approximately 300,000 deaths per year) in the United States, right after cigarette smoking \\[[@b6-ophrp-10-137],[@b7-ophrp-10-137]\\].\n\nPrevious studies have reported that obesity rates vary greatly between socio-demographic groups in the United States. Specifically, a larger ratio of individuals are overweight or obese among lower income groups, lower-educated groups, Non-White or Hispanics than among other socio-demographic groups \\[[@b8-ophrp-10-137]--[@b10-ophrp-10-137]\\]. Women have lower obesity rates than men for self-reported height and weight \\[[@b8-ophrp-10-137],[@b11-ophrp-10-137]--[@b13-ophrp-10-137]\\]. However, other studies have shown that even though the mean body mass index (BMI) is lower for women than men, women are gaining weight quicker than men \\[[@b14-ophrp-10-137]\\]. There may no longer be a difference between men and women based on measured height and weight \\[[@b9-ophrp-10-137]\\]. According to the National Health and Nutrition Examination Survey 2015--2016, the prevalence of obesity was 35.7% among"
+"Visual kinetic analyses extract kinetic information from the naked-eye comparison of original or modified progress reaction profiles. These analyses are becoming a popular tool in chemistry and related disciplines, even replacing traditional kinetic analyses focused on the measurement of initial rates. This increasing popularity is due to the combination of recent advances in both reaction monitoring technology and the development of new kinetic analyses. This minireview is focused on the most recent analyses developed in the last fifteen years. Also, it highlights the main differences between the most traditional kinetic analyses and answers the most frequently asked questions by new users of visual kinetic analyses.\n\nIn the past, visual analyses of the slope and interception of linearized plots (Lineweaver--Burk,[@cit1] Eadie--Hofstee[@cit2],[@cit3] and Hanes--Woolf[@cit4] plots) have been used to quickly identify different types of inhibition and concentration dependences of substrates. However, the simplest comparison of two reaction curves is to visually discern whether they are identical, that is if they overlay. These visual analyses transform the axes to achieve the overlay of the progress reaction profiles. The transformations required to achieve this overlay provide information about the relationship between the different progress reaction profiles.\n\nThe strategy of overlaying reaction profiles was first"
+"INTRODUCTION\n============\n\nThe 5-year survival rate among osteosarcoma patients has not significantly improved in the past 10 years. Osteosarcoma cell proliferation and metastasis are the key factors contributing to the poor outcomes in osteosarcoma patients \\[[@r1], [@r2]\\]. Consequently, there is an urgent need for a better understanding of the mechanisms underlying those processes at the genetic level.\n\nMiRNAs are believed to regulate gene expression at the post-transcriptional level by degrading or repressing target mRNAs. Moreover, many miRNAs are now known to be closely involved in the development and progression of cancer \\[[@r3]--[@r5]\\]. Overexpression of miR-627, for example, enhances the ability of irinotecan to inhibit cancer growth and induce apoptosis \\[[@r6]\\].\n\nPleiotrophin (PTN) is a heparin-binding growth factor that is overexpressed in several human cancers, including osteosarcoma, where it is thought to be involved in various biological functions, including cell growth, differentiation and metastasis \\[[@r7], [@r8]\\]. In a prognostic analysis, high PTN expression was associated with poor overall and disease-free survival in osteosarcoma \\[[@r9]\\]. In the present study, we demonstrated that miR-627-3p inhibits the proliferation and metastasis in osteosarcoma cells by targeting PTN.\n\nRESULTS\n=======\n\nIdentification of miRNAs differentially expressed in osteosarcoma\n-----------------------------------------------------------------\n\nCompared with adjacent tissues, 18 miRNAs were abnormally"
+"1. Introduction {#sec1}\n===============\n\nWith the discovery of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019 ([@bib76]) and very recently with the subsequent pandemic of COVID-19 ([@bib35]), society and economies worldwide are experiencing an unprecedented exogenous shock ([@bib23]). Although the occurrence of a pandemic caused by a new virus is unsurprising for virologists, the infection control measures such as social distancing ([@bib28]) taken to slow the spread of COVID-19 exert tremendous pressure on large parts of a nation's economy. Most actors central to shaping the economy would admit to the current pandemic being a metaphorical black swan event, that is, a surprising, unpredictable event of great significance and severe consequences that dramatically changes the political and economic environment ([@bib74]). While such events could be interpreted as opportunities, the unprecedented lockdown of large parts of society arising from the COVID-19 crisis marks the current situation out as an acute crisis. SARS-CoV-2 triggered a twofold crisis: The COVID-19 pandemic has placed an unprecedented burden on many health systems worldwide, and the infection control measures have caused an economic crisis by bringing a vast amount of economic activity to an abrupt halt. Moreover, while many other past crises have hit"
+"**Specifications Table**TableSubject area*Biology*More specific subject area*Microbiology, Genomics*Type of data*Table, text file, figure*How data was acquired*Shotgun whole-genome DNA sequences using Ion PGM*Data format*Raw and assembled*Experimental factors*Genomic DNA extracted from Colletotrichum sansevieriae Sa-1--2*Experimental features*de novo assembly, gene prediction, phylogenetic analysis*Data source location*Kagoshima, Japan*Data accessibility*Deposited data is available at the National Center for BiotechnologyInformation (NCBI) under the accession number NJHP00000000* (<https://www.ncbi.nlm.nih.gov/nuccore/NJHP00000000>).\n\n**Value of the data**\u2022The first draft genome sequence of *Colletotrichum sansevieriae*, a causal agent of anthracnose on sansevieria, is now available.\u2022Plant cell wall-degrading enzymes and effector proteins related to pathogenicity were predicted.\u2022The fungus belongs to a novel major clade in the genus *Colletotrichum*.\u2022These data will be useful for further research into the biology, evolution, and pathogenicity of anthracnose pathogens.\n\n1. Data {#s0005}\n=======\n\n*Colletotrichum sansevieriae* is an anthracnose pathogen identified as a new species in 2006 [@bib1]. The fungus causes water-soaked lesions and leaf blight on sansevieria, which is one of the most important plants in subtropical regions in Japan as a potted ornamental and for cut leaves [@bib1], [@bib2]. The fungus shows pathogenicity only on *Sansevieria* spp., thereby having high host specificity. We are interested in learning which factors determine their host specificity. In this work, we performed draft genome analysis"
+"The DNA damage response (DDR) is a cellular defense mechanism that integrates genotoxic event detection to the activation of checkpoint pathways to arrest cells in different phases of the cell cycle to facilitate DNA repair or induce apoptosis and eliminate damaged cells.^[@bib1]^ The product of the *TP53* gene plays an important role in DDR, where it works as a tumor suppressor mainly involved in the transcriptional regulation of a large number of growth-arrest- and apoptosis-related genes,^[@bib2]^ and inactivation of the p53 pathway is a pivotal aspect of tumor formation in the majority of human cancers.^[@bib3]^ Many factors influence the ability of p53 to determine cell fate decision. Indeed, upon genotoxic damage, p53 is rapidly subjected to a series of posttranslational modifications thought to regulate its stability and biological functions.^[@bib4]^ In addition, there is a complex interplay between p53 modifications and its interaction with specific transcriptional co-factors that cooperate with p53 to induce transcriptional activation of specific targets involved in determining cellular fate.^[@bib5]^\n\nChe-1/AATF/Traube (Che-1) is a RNA polymerase II-binding protein involved in the regulation of gene transcription and cell proliferation.^[@bib6],\\ [@bib7],\\ [@bib8]^ It has been shown that this protein exhibits strong antiapoptotic activity,^[@bib9],\\ [@bib10],\\ [@bib11]^ and it is rapidly degraded"
+"Introduction {#s1}\n============\n\nVision plays a crucial role in the sensorimotor control of actions. To grasp an object, the brain may analyze visual input to estimate grasp-relevant object features. For example, an object\\'s shape and size, center of mass, and apparent surface friction are relevant to identify grasp points on the surface of the object (Blake, [@B1]; Voudouris et al., [@B53]). These points may then guide grasp movements, especially during \"precision grips,\" such as with the thumb in opposition to the index finger of the same hand (Napier, [@B37]).\n\nGrasp movements originate from visuomotor control mechanisms that are computed by a cortical network in the inferior frontal and intraparietal cortex (Castiello, [@B3]; Castiello and Begliomini, [@B4]; Grafton, [@B20]; Davare et al., [@B11]). The hub of this dorsolateral network is the anterior intraparietal sulcus (aIPS; Culham et al., [@B8]; Frey et al., [@B15]) which has been shown to implement the initial steps of the visual analysis for grasps (Rizzolatti and Luppino, [@B43]; Tunik et al., [@B51], [@B52]; Culham and Valyear, [@B9]; Castiello and Begliomini, [@B4]; Grafton, [@B20]; Le et al., [@B31]) as well as perform ensuing transformations for visuomotor control (Castiello, [@B3]; Davare et al., [@B10], [@B12]; Cavina-Pratesi et al., [@B5];"
+"INTRODUCTION\n============\n\nDiphyllobothriasis is a fishborne tapeworm infection caused by the genus *Diphyllobothrium*. These tapeworms are creamy white in color, and can grow as long as 2-15 m in the human small intestine \\[[@b1-kjp-53-1-109],[@b2-kjp-53-1-109]\\]. Generally, the incubation period of *Diphyllobothrium* plerocercoids until they develop into an adult tapeworm is 2-6 weeks \\[[@b3-kjp-53-1-109]\\]. It can cause gastrointestinal symptoms such as abdominal pain and diarrhea, but typically does not cause severe problems. Humans can be infected with diphyllobothriid species through consumption of raw or poorly cooked fish containing larval plerocercoids.\n\nTo date, at least 13 of about 50 species of genus *Diphyllobothrium* have been reported as human pathogens, and among them, *D. latum* had been reported to be the main pathogen in Korea \\[[@b1-kjp-53-1-109],[@b4-kjp-53-1-109]\\]. In 1919, human *D. latum* infection was first reported in Korea based on recovery of eggs in the stool passages of 2 residents in Jinju by Kojima and Ko \\[[@b5-kjp-53-1-109]\\]. In 1971, *D. latum* infection was first documented on the basis of morphological identification of the expelled proglottids \\[[@b6-kjp-53-1-109]\\]. The first Korean child case of *D. latum* infection was reported in 1980 by Jeong et al. \\[[@b7-kjp-53-1-109]\\]. Since then, 6 pediatric cases of *D. latum* infection have reported"
+"INTRODUCTION\n============\n\nHuman noroviruses are the major cause of non-bacterial epidemic gastroenteritis worldwide ([@B16]). The study of human norovirus has been hampered by the lack of a cell culture system. Murine norovirus (MNV) was first isolated and characterized as a sporadic and lethal pathogen in immunocompromised knockout mice ([@B7]). MNV is the only norovirus that replicates in cell culture and in a small animal model, though several studies have reported norovirus infection in humans, cattle, swine, dogs, and mice ([@B20]; [@B16]). Thus, MNV is expected to be a surrogate for evaluating the resistance of human norovirus to disinfectants and can be used in animal model studies of human norovirus infection.\n\nNatural MNV infection is prevalent in animal facilities around the world ([@B6]; [@B17]; [@B18]). These infections might influence not only the results of a mouse model for studying the biology and pathogenesis of noroviruses, but also those of other biological studies ([@B10]; [@B2]). Until recently, no MNV infection had been reported in laboratory mice in Japan. However, the first reports of MNV detected in conventional mouse colonies in Japan were published in 2009 ([@B4]; [@B9]). Recent serological analysis of MNV found that MNV infection is also prevalent in conventional animal"
+"Background {#sec1_1}\n==========\n\nEsophageal cancer, EC, is one of the most common malignancy worldwide and mainly divided into two subtypes: squamous cell carcinoma (sqCCa) versus adenocarcinoma \\[[@B3]\\]. Even though EC currently has a stable incidence in first world countries, it still boasts one of the most common cancer related deaths world-wide, with only a 4% survival rate for those with metastasis \\[[@B5], [@B6]\\]. In the United States, in particular, EC-adenocarcinoma have overtaken sqCCa in terms of incidence and prevalence, and deserves to be further studied \\[[@B4]\\].\n\nIt is also commonly understood that EC with metastasis presents a higher morbidity and mortality in general than localized neoplasm, and, in light of this, comes the importance of further understanding its metastatic pathways, especially, metastasis to unexpected areas. In response to this, a recent extensive systematic review was completed in 2017 which evaluated EC metastasis to different sites that were not part of the typical expected sites such as the liver, lung, bone and adrenal glands. The paper was written in order to further contribute to the understanding of this field due to the increasing frequency of reported cases \\[[@B2]\\]. The systematic review, analyzed in-depth a total of 147 articles (after narrowing from"
+"1. Introduction {#sec1}\n===============\n\nOne of the major public health issues across the whole world is teenage pregnancy which is defined as pregnancy in girls aged 13--19 years \\[[@B1], [@B2]\\]. According to WHO, seven countries mainly constitute for half of all adolescent births, namely, Bangladesh, Brazil, the Democratic Republic of the Congo, Ethiopia, India, Nigeria, and the United States of America \\[[@B1], [@B3], [@B4]\\].\n\nDeterminants of teenage pregnancy in a study employed in developing countries included the following reasons as attributing factors for teenage pregnancy; lack of knowledge on sexuality education, ineffective utilization of modern contraceptives, cultural obedience, socioeconomic dependence of females on males, and peer influence \\[[@B5]--[@B7]\\].\n\nTeenage pregnancy is greatly associated with adverse pregnancy outcomes like obstructed labor, pre-eclampsia, anemia, operative deliveries, puerperal endometritis, postpartum hemorrhage, low birth weight, preterm delivery, and perinatal death \\[[@B8]--[@B15]\\].\n\nStudies conducted in North India and Turkey outlined that babies of adolescent mothers were 1.65 and 4.94 times more likely to be born prematurely and face intrauterine fetal death (IUFD), respectively \\[[@B16], [@B17]\\].\n\nStudies conducted in Taiwan, USA, and Korea showed that teenagers were 1.58, 1.36, and 1.16 times more likely to have preterm delivery than the adults, respectively \\[[@B18]--[@B20]\\]. A study in"
+"1. Introduction {#sec1}\n===============\n\nSchizophrenia is a chronic mental disorder which involves disturbances of thought, perception, affect, and social behavior \\[[@B1]\\]. It is ranked among the top ten causes of disability worldwide with mortality rates two times as high as in the general population \\[[@B2]--[@B4]\\]. Although accidents and suicide account for just a portion of this high mortality rate, more than two-thirds of the rate is caused by different forms of comorbid physical diseases such as cardiovascular and metabolic syndrome \\[[@B3]\\]. The emergence of these physical diseases has been linked to poor lifestyle (smoking, sedentary lifestyle, and poor diet) and cardiovascular risk factors \\[[@B5]\\].\n\nMetabolic syndrome (MetS) is a group of disorders which includes central obesity, dyslipidemia, hypertension, abnormal glucose homeostasis, proinflammatory state, and prothrombotic state \\[[@B6], [@B7]\\]. The prevalence of MetS seems to be common and rising in the general population possibly due to high intake of calories and a lifestyle of inactivity, irrespective of definition criteria \\[[@B8], [@B9]\\]. It is, however, worth considering that some population groups and, for that matter, particular patient groups even have an increased propensity of developing MetS. Several studies have convincingly indicated that schizophrenic patients are twice at risk of developing MetS compared"
+"INTRODUCCI\u00d3N {#sec1-1}\n============\n\nLos adenomas hipofisarios son de los tumores m\u00e1s frecuentes del sistema nervioso central, siendo la p\u00e9rdida visual el s\u00edntoma m\u00e1s com\u00fan, alcanzado una incidencia de hasta el 70%.\\[[@ref1][@ref16]\\] La indicaci\u00f3n e importancia de la descompresi\u00f3n de la v\u00eda \u00f3ptica mediante la ex\u00e9resis quir\u00fargica de estas lesiones radica en evitar la progresi\u00f3n de los da\u00f1os estructurales de la v\u00eda visual y permitir la restituci\u00f3n de los da\u00f1os funcionales, siendo el grado de recuperaci\u00f3n postoperatorio dif\u00edcil de determinar y variable entre los pacientes.\\[[@ref14]\\] La evaluaci\u00f3n oftalmol\u00f3gica preoperatoria resulta, por lo tanto, relevante siendo la campimetr\u00eda computarizada el estudio de elecci\u00f3n para la determinaci\u00f3n de la funci\u00f3n visual. Sin embargo, esta resulta una medici\u00f3n subjetiva que requiere la colaboraci\u00f3n, atenci\u00f3n y compresi\u00f3n por parte del paciente para que arroje resultados v\u00e1lidos. A partir de la introducci\u00f3n de nuevas tecnolog\u00edas en los \u00faltimos a\u00f1os, se han incrementado los esfuerzos para mejorar la evaluaci\u00f3n de los pacientes y poder determinar aquellos que tendr\u00e1n m\u00e1s posibilidades de recuperaci\u00f3n o incluso normalizaci\u00f3n del d\u00e9ficit visual. Los potenciales evocados visuales multifocales y la tomograf\u00eda de coherencia \u00f3ptica (TCO) de la capa de fibras nerviosas de la retina surgen como herramientas diagn\u00f3sticas que proveen informaci\u00f3n valiosa"
+"1. Introduction {#sec1-ijms-20-00785}\n===============\n\nThe aim of this paper is to build and explore a mathematical aggregate model of the progression of atherosclerotic plaque---a dynamic structure undergoing a continual cycle of erosion and repair. Atherosclerosis is treated as a chronic inflammatory disease of the arterial wall, which amounts to deposition of atheromatous plaque on the innermost layer of the walls of large and medium-sized arteries. To capture the basic features of the mentioned phenomena we propose a mathematical model in non-linear non-stationary differential equations, with therapy representing a control variable. We will show how our model can help the clinician to understand the disease development, and\u00a0to\u00a0prognosticate the patient's survival.\n\nThere exist mathematical models of the formation of atherosclerotic plaque, see \\[[@B1-ijms-20-00785],[@B2-ijms-20-00785],[@B3-ijms-20-00785]\\]. They\u00a0focus mainly on the changes of the local blood flow dynamics in arteries with atherosclerotic lesions. Other\u00a0researchers, e.g., \\[[@B4-ijms-20-00785]\\], have created one- and two-dimensional mathematical models to describe selected processes such as recruitment of monocytes into sub-endothelial space. Yet another team of researchers, see \\[[@B5-ijms-20-00785]\\], created a mathematical model focusing on the low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) in blood. They showed, by simulations, how the cholesterol profile determines whether plaque will"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec001}\n============\n\nHuman experience is strongly influenced by how much external stimuli are perceived as self-related. When stimuli are viewed as self-referential, associated neural activity can index a conscious reflection on oneself, which is referred to as self-referential processing (SRP) \\[[@pone.0149554.ref001]\\]. Previous studies have shown a specific pattern of neural activity during various expressions of SRP. For example, recognition of one's own face elicits activity in brain regions that is distinct from activity evoked by other-faces, and these regions include the medial prefrontal cortex (MPFC), anterior cingulate cortex (ACC), posterior cingulate cortex (PCC), precuneus, and anterior insular cortex \\[[@pone.0149554.ref002],[@pone.0149554.ref003]\\]. Based on these results, the existence of a self-specific network has been proposed \\[[@pone.0149554.ref004]\\]. A previous study has shown that a functional response within this network is more pronounced during processing of negative stimuli than positive ones \\[[@pone.0149554.ref005]\\].\n\nThere is an emerging consensus that the MPFC is strongly linked to self-related information processing \\[[@pone.0149554.ref006],[@pone.0149554.ref007]\\]. In terms of self-relatedness a functional dissociation between the dorsal and ventral portions of the MPFC is proposed, though this distinction remains controversial \\[[@pone.0149554.ref008]--[@pone.0149554.ref011]\\]. Indeed there is evidence that the role of the MPFC"
+"INTRODUCTION\n============\n\nHeilman et al. \\[[@B1]\\] showed that the right hemisphere damaged patients (RHD) without aphasia had more decreased comprehension on emotional speech as compared to the left hemisphere damaged patients (LHD), thus, he described it as \\\"auditory affective agnosia\\\".\n\nTo perform a successful conversation, the transfer of emotion is important. Most of speaker\\'s emotional delivery is done through tone of speech i.e., prosody (melodic and rhythmic components of speech), and prosody is known to be mainly related with acoustic parameters, such as pitch, stress, and duration (including pauses and prolongations) \\[[@B2]\\]. The meaning could change when you say the same sentence depending on the tone of speech, thus prosody makes up non-verbal aspects of language that are necessary for recognizing and conveying emotions during communication. Ross \\[[@B3]\\] said that right hemisphere (RH) is primarily responsible for processing of affective languages and defined \\\"aprosodia\\\" corresponding to aphasia for all kind of affective prosodic deficits after damage on right Broca\\'s homologue.\n\nIt has been revealed that RH is mainly related with prosody recognitions. Right lateralized response to prosody was evidenced from dichotic listening \\[[@B4]\\], event-related brain potentials \\[[@B5]\\], and imaging modalities \\[[@B6]-[@B8]\\].\n\nDespite the established knowledge on role of the RH"
+"Introduction\n============\n\nHepatocellular carcinoma (HCC) is one of the most common tumors worldwide, and its incidence is unlikely to be reduced in the near future, despite the developments in surgical treatment. In China and Southeast Asia, the incidence of HCC is high, with HCC occurring most frequently following the development of chronic liver disease resulting from infection with hepatitis virus ([@b1-etm-07-02-0311]). Therefore, it is important to elucidate the molecular mechanism of HCC carcinogenesis and to develop specific measures for the prevention of HCC.\n\nFragile histidine triad (FHIT) protein belongs to the family of the evolutionary conserved histidine triad (HIT) proteins, which consists of at least three subfamilies: FHIT, histidine triad nucleotide binding protein 1 (HINT1) and galactose-1-phosphate uridylyltransferase (GALT) ([@b2-etm-07-02-0311]). Our previous study showed that HINT1 functions as a tumor-suppressor gene in human hepatoma cell lines ([@b3-etm-07-02-0311]). FHIT is located at human chromosome 3p14.2, and encodes a transcript of 1.1 kb ([@b4-etm-07-02-0311]). It encompasses the FRA3B fragile site and a genomic locus that is frequently involved in cytogenetic abnormalities, genomic rearrangement and allelic loss in tumors ([@b5-etm-07-02-0311]). The aberrant methylation of normally unmethylated CpG islands, located in the 5\u2032 promoter region of genes, is associated with the transcriptional inactivation of"
+"Background {#Sec1}\n==========\n\nDiabetic macular edema (DME) is an important cause of visual impairment in patients with diabetes mellitus (DM), which affects greatly the quality of individual's life \\[[@CR1]--[@CR3]\\]. Since the prevalence of diabetes worldwide is increasing, DME has become a global health issue \\[[@CR4], [@CR5]\\]. Laser photocoagulation has once been the standard treatment protocol for DME during the past three decades \\[[@CR6]\\]. Nowadays, treatment of DME shifts to anti-vascular endothelial growth factor (anti-VEGF) therapy \\[[@CR7]\\]. Recent randomized multicenter clinical trials have showed the benefits of anti-VEGF therapy on reducing DME and improving patient's vision \\[[@CR8]--[@CR11]\\].\n\nUp to now, most of the studies recommend three loading doses of anti-VEGF injections followed by an as needed/pro re nata (PRN) regimen. However, three loading injections would be a great economic and psychological burden for patients with DME, especially for those who in developing countries. Meanwhile, a proportion of patients actually do not need three loading injections and yet maintain good vision over long period. Therefore, \"1 + PRN\" regimen, namely one anti-VEGF injection at the very first month, followed by an as needed retreatment protocol might be a treatment option for DME. However, this concept of \"1\u2009+\u2009PRN\" regimen has not"
+"Introduction {#Sec1}\n============\n\nHealth-related quality of life (HRQOL) is a multidimensional concept that can be described as the degree of influence of a medical condition or treatment to the usual or expected physical, emotional and social well-being. Factors that play a role in a quality of life (QoL) vary according to personal preferences. For many, however, having enough visual ability to do those things that they want to do is a high priority. Quality of vision is an integral part of HRQOL and the impact of ophthalmic diseases on QoL has been documented in a series of studies \\[[@CR1]--[@CR3]\\]. Patients often do not perceive the same benefit as recorded by objective measures such as visual acuity, visual field testing because the objective measurements do not evaluate the patient's perceptions of their own disease. Numerous instruments that evaluate patients' subjective perceptions regarding QoL have been developed so far. Although generic instruments can effectively assess HRQOL for persons with nonocular conditions, they usually cannot fully capture HRQOL in those with visual impairment \\[[@CR4]--[@CR7]\\]. Measuring the vision specific QoL gives us a wider view of the effect of the disease or the effect of the treatment on a patient's life.\n\nMany specific questionnaires"
+"Introduction\n============\n\nVertebrate oocytes are arrested in prophase of meiosis I in an interphase-like stage of the cell cycle with an intact germinal vesicle (nucleus; [@bib34]). Before such oocytes become fertilization competent, they undergo a cellular differentiation pathway known as oocyte maturation, during which they complete meiosis I and arrest at metaphase of meiosis II. We refer to these mature oocytes as eggs. Oocyte maturation encompasses remodeling of Ca^2+^ signaling pathways to endow the egg with the capacity to activate at fertilization and undergo the egg to embryo transition ([@bib30]). The fertilization-specific Ca^2+^ signal provides a digital cipher that encodes critical cellular events at fertilization in a sequential fashion, including the block to polyspermy and completion of meiosis. As part of Ca^2+^ signaling remodeling, the primary Ca^2+^ influx pathway, store-operated Ca^2+^ entry (SOCE), inactivates ([@bib31]; [@bib32]). SOCE inhibition could contribute to shaping the dynamics of the fertilization-specific Ca^2+^ transient and may represent a safety mechanism to prevent premature egg activation ([@bib32]; [@bib62]). SOCE also inactivates during mitosis of mammalian cells ([@bib47]; [@bib60]).\n\nSOCE is activated by the level of Ca^2+^ in intracellular stores, primarily the ER. Lowering free ER Ca^2+^ below a certain threshold activates Ca^2+^ influx at the cell"
+"Introduction {#mzx149s7}\n============\n\nThere has been a growing body of research that focus on recognizing and responding to clinically deteriorating patients in general ward settings in the past decade \\[[@mzx149C1]--[@mzx149C4]\\]. Much of this interest was prompted by studies that demonstrated patient deterioration not being recognized and responded to in a timely manner \\[[@mzx149C5]--[@mzx149C10]\\]. This lapse in patient care has led to an increase risk and incidences of serious adverse events such as unplanned admissions to intensive care units, in-hospital cardiopulmonary arrests, and unexpected deaths \\[[@mzx149C11], [@mzx149C12]\\]. Improving timely recognition and prompt interventions is therefore pivotal to the provision of safe and quality care to a deteriorating patient before his condition becomes life-threatening \\[[@mzx149C13]\\].\n\nInternational concerns over delays or failure to recognize and escalate care for clinically deteriorating ward patients have led to the widespread implementation of a hospital-wide patient safety initiative known as the rapid response system (RRS) in acute hospitals \\[[@mzx149C14], [@mzx149C15]\\]. The RRS is designed with afferent and efferent components, and mechanisms for quality control, audit and administration \\[[@mzx149C16]\\]. The afferent arm involves monitoring and identifying deteriorating patients using a set of activation criteria, commonly known as the Early Warning Scoring System (EWSS), which is based on abnormal"
+"INTRODUCTION {#sec1-1}\n============\n\nOver the last few years use of short message services (SMS) and smartphone-based communication applications in health care has shown its wide application and potential to improve access to health care; enhance efficiency of service delivery; improve diagnosis, facilitate timely treatment and support public health programmes.\\[[@ref1][@ref2][@ref3][@ref4]\\] This effective means of communication is providing timely and accurate results to the correct recipient, safeguarding their privacy and confidentiality and avoids misunderstanding and misinterpretation of the results. There are various uses of mobile phone message services and smartphone-based communication applications such as: Appointment remainders;\\[[@ref5]\\] to monitor chronic medical conditions;\\[[@ref6][@ref7][@ref8][@ref9]\\] to improve treatment compliance;\\[[@ref10][@ref11]\\] to provide psychological support;\\[[@ref12][@ref13]\\] managing communicable diseases via contact tracing and partner notification for sexually transmitted illnesses\\[[@ref14][@ref15]\\] and to promote health promotion programs like smoking cessation.\\[[@ref16][@ref17]\\]\n\nTata Memorial Hospital uses many modes of health related e-communications such as web based electronic medical records (EMR) where patients and families can access their medical records, blood investigations, scans and all patient-related information using an individual patient login key and password. This information can be accessed at home or any other remote setting using a computer or smartphone. The other modes of e-communications used are e-mail, short message service (SMS),"
+"1. Introduction {#sec1-toxins-09-00277}\n===============\n\nThe genus *Bordetella* comprises nine species. Among them, *B. pertussis*, *B. parapertussis* and *B. bronchiseptica* are so closely related, despite differences in host range, that they are often considered as subspecies of the same species and are called \"classical species\" \\[[@B1-toxins-09-00277]\\]. *B. pertussis* is the agent of whooping cough, a severe respiratory disease in humans which can be dramatic for newborns and elderly subjects. *B. parapertussis* is the agent of respiratory disease in sheep and in humans; however, the clinical symptoms induced in humans last less than those induced by *B. pertussis* although clinically similar \\[[@B2-toxins-09-00277],[@B3-toxins-09-00277]\\]. *B. bronchiseptica* is a respiratory pathogen for several mammal species and sometimes for immuno-suppressed patients \\[[@B1-toxins-09-00277]\\]. *B. pertussis* and *B. parapertussis* appear to have independently emerged from a *B. bronchiseptica* ancestor through rearrangement and loss of genetic material \\[[@B4-toxins-09-00277],[@B5-toxins-09-00277]\\]. Those three species are closely related and produce similar as well as specific virulence factors. The three species produce (i) similar adhesins such as filamentous hemagglutinin (FHA) and pertactin (PRN), but different fimbrial proteins (FIM); (ii) similar toxins such as adenylate cyclase-hemolysin (AC-Hly) toxin, tracheal cytotoxin and dermonecrotic toxin, but *B. pertussis* is the only species producing pertussis toxin (PT); (iii)"
+"Introduction\n============\n\nAt 08:02 Beijing Time (00:02UTC) on April 20, 2013, an earthquake with a magnitude of 7.0 on the Richter scale struck the Ya'an County, Sichuan Province, China, the same region devastated by the Wenchuan earthquake on May 12, 2008. The Ya'an earthquake resulted in 196 people dead, 24 missing, at least 11,826 injured with more than 968 seriously injured. A large number of houses and buildings were destroyed, and the estimated direct economic loss was over 85 billion RMB. About 1.5 years before the Ya'an earthquake, a cohort of senior high school students was surveyed to assess long-term psychological sequelae of the Wenchuan earthquake. The occurrence of the Ya'an earthquake thus provided a unique opportunity to examine effects of repeated exposure to disasters on adolescents' mental status.\n\nMajor disasters such as earthquake could cause myriad mental health problems ([@B20]), especially post-traumatic stress disorder (PTSD) and depression ([@B11]; [@B37]). Retrospective and pre- and post-design studies have suggested that predisaster stressors, predisaster psychopathology, and the severity of disaster exposure are important risk factors for post-disaster mental health problems ([@B29]; [@B25]; [@B33]; [@B10]; [@B5]; [@B4]). In addition, predisaster psychopathology may play an important mediating role between predisaster stressors and post-disaster psychological"
+"Bernhardsen GP, Stensrud T, Nystad W, Dalene KE, Kolle E, Ekelund U. Early life risk factors for childhood obesity---Does physical activity modify the associations? The MoBa cohort study. Scand J Med Sci Sports. 2019;29:1636--1646. 10.1111/sms.13504 31220367\n\n**Funding information**\n\nThe sub\u2010cohort is supported by The Research Council of Norway\u2010 Human Biobanks and Health Data (BIOBANK) (project number 221097). The Norwegian Mother and Child Cohort Study are supported by the Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, NIH/NIEHS (contract no N01\u2010ES\u201075558), NIH/NINDS (grant no.1 UO1 NS 047537\u2010 01 and grant no.2 UO1 NS 047537\u201006A1). The research is also supported by The Research Council of Norway (249932/F20).\n\n1. INTRODUCTION {#sms13504-sec-0005}\n===============\n\nChildhood obesity is related to several short\u2010term health consequences[1](#sms13504-bib-0001){ref-type=\"ref\"} and is a strong predictor of adult obesity with the accompanying risks of cardiovascular diseases and mortality.[2](#sms13504-bib-0002){ref-type=\"ref\"}, [3](#sms13504-bib-0003){ref-type=\"ref\"} The development of obesity may start before birth, with intrauterine and early life exposures having long\u2010term effects on biology, leading to an increased fat mass and risk of obesity later in life.[4](#sms13504-bib-0004){ref-type=\"ref\"}, [5](#sms13504-bib-0005){ref-type=\"ref\"} Previous research has established high maternal pre\u2010pregnancy body mass index (BMI), high birth weight, and rapid infant weight gain as risk factors for childhood obesity.[1](#sms13504-bib-0001){ref-type=\"ref\"},"
+"Introduction {#s1}\n============\n\n\"Obesity\" is commonly regarded as a disease. The term is derived from the Latin *obesus \"having eaten until fat\"* (from *ob- \"away, completely\" + esus* past participle of *edere \"eat\"*). As this word origin suggests, \"obesity\" is widely considered as a controllable condition, and its cause is often attributed to a lack of willpower or discipline (Sikorski et al., [@B113]). Recent clinical data, however, clearly contradict the prejudice of weak will, since children and adults with high body mass index (BMI) display a stronger cognitive control over eating behavior than all others (Timko and Perone, [@B120]; de Lauzon-Guillain et al., [@B22]; Snoek et al., [@B116]; Gallant et al., [@B31]). Moreover, with upcoming new epidemiological data the question arises whether a high BMI is unhealthy at all (Flegal et al., [@B29]).\n\nThe nephrologists were the first who reported that patients on dialysis treatment had better survival chances when they had a higher BMI (Kopple et al., [@B57]). This phenomenon---often referred to as the \"**obesity paradox**\", has also been observed in other diseases like myocardial infarction, stroke, pulmonary disease, sepsis, and type 2 diabetes mellitus (Buettner et al., [@B10]; Hallin et al., [@B39]; Vemmos et al., [@B122]; Carnethon et"
+"Introduction {#S1}\n============\n\nFibroblast growth factor 23 (FGF23) is a circulating phosphaturic hormone that is elevated in patients with chronic kidney disease (CKD) and is strongly associated with mortality and cardiovascular disease.^[@R1]--[@R6]^ To exert its primary physiologic functions, FGF23 binds to FGF receptor (FGFR)-klotho complexes in the kidney to stimulate urinary phosphate excretion and inhibit renal production of 1,25-dihydroxyvitamin D.^[@R7],\\ [@R8]^ In addition to these classic, klotho-dependent effects, FGF23 also induces left ventricular hypertrophy via FGFR-dependent, but klotho-independent, effects on cardiac myocytes.^[@R9]^ This finding raises the possibility that elevated FGF23 levels in CKD may also contribute to other forms of subclinical cardiovascular injury, which could further explain its strong association with cardiovascular events and mortality.\n\nArterial calcification is a common pattern of vascular injury in CKD that begins early in the course of disease and is associated with greater risk of cardiovascular events and mortality.^[@R10]--[@R14]^ Elevated serum phosphate is an independent risk factor for calcification.^[@R15]^ High phosphate conditions enhance uptake of phosphate by cultured vascular smooth muscle cells (VSMC) through the type III Na-phosphate cotransporter, PiT-1. This induces osteogenic transformation and subsequent calcification.^[@R16]--[@R18]^ Similarly, vascular deficiency of klotho may also promote calcification by increasing PiT-1-dependent phosphate uptake by VSMCs, a"
+"![](501999_1_En_6_Figa_HTML){#MO1}\n\nIntroduction {#Sec1}\n============\n\nTo apply model checking to a concurrent system, one must formulate properties that the system is expected to satisfy. A property may be expressed by specifying acceptable sequences of states, or by specifying acceptable sequences of actions---the events that cause the state to change. Each approach has advantages and disadvantages, and in any particular context one may be more appropriate than the other.\n\nIn the state-based context, there is a rich theory involving automata, logic, and reduction for model checking. Some of the core ideas in this theory can be summarized as follows. First, the behavior of the concurrent system is represented by a state-transition system *T*. One identifies a set $\\documentclass[12pt]{minimal}\n                \\usepackage{amsmath}\n                \\usepackage{wasysym} \n                \\usepackage{amsfonts} \n                \\usepackage{amssymb} \n                \\usepackage{amsbsy}\n                \\usepackage{mathrsfs}\n                \\usepackage{upgreek}\n                \\setlength{\\oddsidemargin}{-69pt}\n                \\begin{document}$$\\textsf {AP}$$\\end{document}$ of atomic propositions, and each state of *T* is labeled by the set of propositions which hold at that state. An execution passes through an infinite sequence of states, which defines a *trace*, i.e., a sequence of subsets of $\\documentclass[12pt]{minimal}\n                \\usepackage{amsmath}\n                \\usepackage{wasysym} \n                \\usepackage{amsfonts} \n                \\usepackage{amssymb} \n                \\usepackage{amsbsy}\n                \\usepackage{mathrsfs}\n                \\usepackage{upgreek}\n                \\setlength{\\oddsidemargin}{-69pt}\n                \\begin{document}$$\\textsf {AP}$$\\end{document}$. A *property* is a set of traces, and *T* satisfies the property if every trace of *T* is in *P*.\n\nProperties may be specified"
+"Glaucoma is the second most common cause of irreversible blindness, impairing 80 million people worldwide.[@bib1] Elevated intraocular pressure (IOP) is the most common indicator for diagnosis and progression of glaucoma, with reduction of IOP the only proven glaucoma intervention.[@bib2]^--^[@bib4] IOP is controlled by the balance between production and outflow of aqueous humor. In the conventional outflow pathway, the aqueous humor travels through the trabecular meshwork and juxtacanalicular connective tissue (JCT), into Schlemm\\'s canal (SC), through collector channels (CCs) passing through the sclera, and finally emptying into the episcleral veins.[@bib5]^,^[@bib6] The increased IOP characteristic of primary open-angle glaucoma is caused by increased resistance to aqueous humor outflow.[@bib7]^,^[@bib8] Most investigations of outflow resistance have focused on the JCT and inner wall of SC, which are widely regarded as the principal sites of outflow resistance.[@bib9] However, flow resistance is also generated in SC and CCs, particularly in the former as IOP is increased.[@bib8]^,^[@bib9]\n\nIn primate, humans, and mice, SC is essentially a flat tube traveling circumferentially around the limbus of the eye, whose opening thickness, the distance from the inner wall to outer wall, decreases as IOP increases.[@bib9] Greater lengths of SC are collapsed in glaucomatous eyes than healthy eyes, even when perfused"
+"Case report\n===========\n\nA 54-year-old man was referred to our clinic to undergo elective surgery for an aortic root dilation measuring 54 mm in diameter ([Fig. 1A](#f1-kjtcvs-52-376){ref-type=\"fig\"}). Routine echocardiography had been performed as a screening examination due to newly diagnosed sleep apnea/hypopnea syndrome 6 months previously and revealed aortic root dilation with a concomitant mild aortic regurgitation. The diagnosis was confirmed by means of a subsequent aortic computed tomography (CT) scan. The otherwise asymptomatic patient revealed a positive familial history of 2 female second-degree cousins. Both cousins had been previously diagnosed with Loeys-Dietz syndrome (LDS) with a heterozygous missense mutation, c.759G\\>A, p.(Met253Ile), in exon 4 of the transforming growth factor beta receptor type I (*TGFBR1*) gene. Unfortunately, the first cousin was diagnosed only postmortem after passing away from a ruptured aortic root aneurysm at the age of 30, just hours after giving birth to triplets. The other cousin (sister of the deceased) underwent genetic counseling, which revealed exactly the same mutation as well as clinical signs of arachnodactyly, dolichocephaly, scoliosis, and hypermobility, thus establishing the diagnosis of LDS. Furthermore, the triplets of the deceased sister were subsequently screened and 2 of them were detected to have the same missense mutation"
+"Actinomycetes are free living, saprophytic, filamentous bacteria, and a major source for the production of antibiotics ([@B1]). They are found in soil, fresh water and marine water environments ([@B2]). Actinomycetes provided many important bioactive compounds of high commercial value and screened for new bioactive substances ([@B3]). These bacteria are an important group of microorganisms due to their ability to produce a wide array of secondary metabolites, such as antibiotics, antitumor agents, immunosuppressive agents, cosmetics, vitamins, nutritional materials, herbicides, pesticides, anti-parasitic agents and enzymes ([@B1], [@B4], [@B5]). Around 23000 bioactive secondary metabolites produced by microorganisms have been reported. Over 10000 of these compounds are produced by actinomycetes, representing 45% of all bioactive microbial metabolites discovered. Among actinomycetes, around 7600 compounds are produced by *Streptomyces* species ([@B6]). As the frequency of novel bioactive compounds obtained from terrestrial actinomycetes decreased, it had been emphasized that actinomycetes from marine sediments might be valuable for the isolation of novel strains which could potentially yield a broad spectrum of secondary metabolites ([@B7]-[@B9]). However, it has been resolved whether actinomycetes forms part of the marine microbial community of sediment samples originated from terrestrial environments and was simply carried out to sea in the form of resistant spore"
+"Alzheimer's disease (AD), described for the first time by Alois Alzheimer in 1906, is characterized by progressive loss of cognitive functions ultimately leading to death[@b1]. Pathologically, the disease is characterized by the presence of extraneuronal amyloid plaques consisting of aggregates of amyloid-beta (A\u03b2) peptide, and neurofibrillary tangles (NFTs) which are intracellular aggregates of abnormally hyperphosphorylated tau protein[@b2]. A\u03b2 peptide is generated upon sequential cleavage of the amyloid precursor protein (APP), by beta- and gamma-secretases, and it is believed that an imbalance between A\u03b2 production and clearance results in its accumulation in the brain.\n\nClearance of A\u03b2 from the brain occurs via active transport at the blood-brain-barrier (BBB) and blood cerebrospinal fluid (CSF) barrier (BCSFB), in addition to the peptidolytic removal of the peptide by several enzymes. The receptors for A\u03b2 at the BBB bind A\u03b2 directly, or bind to one of its carrier proteins, and transport it across the endothelial cell. The low-density lipoprotein receptor-related protein 1 (LRP1) and the receptor for advanced glycation end products (RAGE) are involved in receptor-mediated flux of A\u03b2 across the BBB[@b3]. Both LRP1 and RAGE are multi-ligand cell surface receptors that, in addition to A\u03b2, mediate the clearance of a large number of proteins."
+"Introduction\n============\n\nEnteral nutrition has surpassed parenteral nutrition in terms of safety and physiological benefits \\[[@B1],[@B2]\\]. For a patient who has problems swallowing but has an intact intestinal tract, enteral nutrition is primarily recommended \\[[@B1]\\]. Semi-solid enteral nutrition has the advantage of lowering the risk of diarrhea and esophageal reflux \\[[@B3]\\]. Here we report a case in which malnutrition, diarrhea and a pressure ulcer were improved by high viscosity semi-solid nutrition via a large-bore nasogastric tube.\n\nCase presentation\n=================\n\nA 67-year-old man (mongoloid race, Japanese) was admitted to our hospital because of a 3-day history of fever. Acid-fast bacilli was found to be smear-positive in his sputum, and a chest radiograph and computed tomography examinations showed parenchymal opacities with scattered fine nodules in his right apical region. He was diagnosed with pulmonary tuberculosis, so he was started on anti-tuberculosis therapy with isoniazid, rifampicin, ethambutol, and pyrazinamide on the first day that he was hospitalized. He had developed a cerebral hemorrhage 18 months before this hospitalization, and he had right hemiplegia, dysphagia, and aphasia as sequelae. He had been receiving 600 kcal/day of liquid nutrition via a nasogastric tube for 6 months before the current hospitalization.\n\nOn admission to our hospital,"
+"Background {#Sec1}\n==========\n\nInvestigating the barriers faced by women in academic medicine is a century-old endeavor \\[[@CR1]\\], but gender disparity persists. Women remain underrepresented in academic medical centers \\[[@CR2]\\], particularly in senior and leadership positions, despite enrollment in medical schools hovering at 50% since the 1980s \\[[@CR3]\\]. Since 2008, the Association of American Medical Colleges (AAMC) has been administering the Women in Medicine and Science (WIMS) survey to track the progress of women in medicine through the academic life cycle \\[[@CR3]\\]. The findings are noteworthy: the number of female full professors in United States academic medical centers increased from 14% to 22% between 2009 and 2014, a gain that nonetheless falls short based on the gender balance of medical school graduates over the past four decades. Furthermore, the percentage of newly tenured women over the same period stagnated at 30% \\[[@CR3]\\]. Women comprised only 15% of department chairs and 16% of deans \\[[@CR3]\\]. A recent cross-sectional analysis showed that only seven out of 50 National Institutes of Health (NIH)-funded institutions had more than 20% female department leaders \\[[@CR4]\\]. There are fewer women than men serving as lead authors of publications in top medical journals \\[[@CR5]\\], presenting at medical grand rounds"
+"Understanding how nervous systems integrate sensory information to generate behavioral outputs is key to our efforts to analyze how nervous systems function. This is a daunting challenge, given the immense complexity of most nervous systems. Even within the nervous systems of insects like *Drosophila*, there is a daunting complexity, with over 100,000 neurons and 100s of cell types that can make analysis very difficult. Despite this challenge it is possible to build an understanding of how a system works if it can be broken into simple modules that can be placed into a functional hierarchy. The power of this type of approach is evident in the vertebrate spinal cord, where the complex sensory motor circuitry that controls locomotion is generated from distinct pools of progenitor cells. These progenitors form discrete and identifiable populations of interneurons, each with defined roles in the locomotor circuits (Grillner and Jessell, [2009](#cne23988-bib-0012){ref-type=\"ref\"}). Furthermore, this functional organization has a deep evolutionary significance, with progenitor domains and transcription factors that define different interneuron classes being conserved between fish and mammals (Lupo et al., [2006](#cne23988-bib-0022){ref-type=\"ref\"}) despite their very different modes of locomotion.\n\nThese organizational principles are similar to the insect ventral nervous system (VNS), which, like the spinal"
+"Introduction {#Sec1}\n============\n\nCardiovascular (CV) diseases are the leading cause of death and morbidity in developed countries^[@CR1]^. The underlying cause of the most serious CV events is atherosclerosis, which is defined as a chromic inflammatory disease characterized by the build-up of subendothelial cholesterol deposits and the formation of leukocyte-rich plaques in the intimal layer of arteries. The fibrous cap is an atheroprotective layer of vascular smooth muscle cells (VSMCs) that covers the atherosclerotic plaque^[@CR2]^ and induces acute thrombo-occlusive events, such as myocardial infarction and stroke^[@CR3]^. Immune cells and inflammation play a key role in promoting the disruption of the fibrous cap^[@CR2]^. Full comprehension of the mechanisms of atherosclerosis is linked to revealing the role of the paracrine mediators released by the heterogenous cell populations involved in the development, progression, and complications of atherosclerosis.\n\nCardiotrophin-1 (CT-1) is a member of the interleukin (IL)-6 family of cytokines, and was initially cloned based on its ability to induce hypertrophy in neonatal cardiomyocytes^[@CR4]^. CT-1 is highly expressed in the cells of the cardiovascular system -- cardiomyocytes, cardiac fibroblasts, vascular endothelial cells, vascular smooth muscle cells (VSMCs), macrophages^[@CR5]--[@CR8]^, as well as in other organs^[@CR9],[@CR10]^. Factors like mechanical stretching, hypoxia, angiotensin II, aldosterone, growth factors, insulin,"
+"Introduction {#s1}\n============\n\nAn integrated strategy of surgery, antibiotics, facial cleanliness, and environmental improvement -- the SAFE strategy in short -- is recommended to eliminate blinding trachoma in endemic countries by the year 2020 [@pntd.0002223-World1]. The F and E components aim to reduce the transmission of *Chlamydia trachomatis* via flies, fingers, and fomites within the community [@pntd.0002223-Emerson1]. Face washing is promoted specifically to keep faces free of infectious ocular and nasal discharge, and make them less attractive to eye-seeking flies. The construction and use of latrines are promoted as a form of fly control to reduce fly-to-eye contact [@pntd.0002223-Emerson1], [@pntd.0002223-Emerson2]. Improved accessibility to clean water is also promoted, but whether or not water is used for hygiene is more important than absolute access to clean water in trachoma prevention. Where water is not readily accessible, household use of a limited supply of water may not be prioritized for bathing [@pntd.0002223-Bailey1]--[@pntd.0002223-West1]. These aims of the F and E components go beyond trachoma control and align with other major initiatives, such as the WASH program of UNICEF and Millennium Development Goal (MDG) 7c which, by 2015, aim to provide access to clean water and sanitation to all children and to reduce by"
+"INTRODUCTION\n============\n\nThe continuing emergence of drug resistant variants of the human immunodeficiency virus (HIV) calls for new tools to combat this epidemic ([@B1]). Current clinical treatment of HIV targets essential enzymatic activities associated with the reverse transcription of the viral genome and the protease activity required for maturation of protein components of the virus. The most effective control of the disease has been achieved with combination therapy targeting these pathways simultaneously. The inclusion of additional targets in a combination drug regimen is highly desirable for potent and long-term disease management.\n\nThe ribonuclease H (RNase H) activity associated with HIV-reverse transcriptase (HIV-RT) degrades the viral RNA genome in RNA/DNA hybrids ([@B2]), and has been identified as a potential target for antiretroviral therapy as it is required for virus infectivity ([@B3]); yet there are no antiRNase H agents in clinical use. Few inhibitors of HIV-1 RNase H were identified until the transition of testing methods from gel-based techniques to fluorescent assays amenable to high-throughput screening (HTS) ([@B4; @B5; @B6; @B7; @B8]). The most widely used assay was developed by Parniak and co-workers ([@B6]) and utilizes a two label, molecular beacon strategy ([@B9]) in which the RNA strand is labeled with a"
+"Introduction {#S1}\n============\n\nThe cell nucleus is a complex organelle, in which genetic material (DNA) is compacted up to several thousand fold and organized into chromosomes in a form that allows the genome to be replicated, repaired and transcribed in a cell-type specific manner ([@R66]; [@R67]). In three-dimensional space, the interphase nucleus represents a highly compartmentalized organelle that consists of the nuclear membrane, individual chromosomes occupying the distinct territories, as well as a number of nuclear bodies (nucleoli, Cajal bodies, promyelocytic leukaemia (PML) bodies, nuclear speckles, Polycomb bodies, etc.) located in the inter-chromosomal compartments ([@R70]; [@R83]) (**[Fig. 1 A](#F1){ref-type=\"fig\"}**). In contrast to the cytoplasmic organelles, distinct nuclear compartments are not separated by the membranes and are formed by the dynamically-changing protein-protein and/or nucleic acid-protein complexes ([@R39]).\n\nIn the mammalian epidermis, progenitor cells of the basal layer proliferate and differentiate, forming multi-layered epithelium, as well as give rise to a variety of skin appendages (hair follicles, nails, glands, etc.) ([@R14]; [@R58]; [@R79]). Keratinocyte differentiation in the epidermis and skin appendages is driven by coordinated changes in the expression of the lineage-specific genes including those that constitute several genomic loci (Keratin type I and II loci, Epidermal Differentiation Complex (EDC), keratin-associated protein"
+"Introduction\n============\n\nChildhood cardiovascular (CV) risk factors, such as obesity, dyslipidemia, low physical fitness, and high blood pressure (BP), precede arteriosclerotic changes^[@bib1]--[@bib6])^ and lead to increases in CV event risks and mortality rate in early adulthood^[@bib7],\\ [@bib8])^. In Japan, the rate of overweight/obesity among children at present is higher than that in the 1980s^[@bib9])^, and further increases in the percentage of individuals with CV risk factors are expected. Primary prevention in early life is thus all the more important.\n\nInadequate sleep is associated with both CV risk factors^[@bib10],\\ [@bib11])^ and CV events in adults^[@bib12])^. Several studies have reported that children and adolescents with sleep problems, including short sleep duration, had more CV risk factors, such as overweight/obesity and high BP, than children without sleep problems^[@bib10],\\ [@bib13]--[@bib15])^. Given that arteriosclerosis progression is aggravated by these CV risk factors, we postulate that arteriosclerotic changes may occur in short sleepers, even in children and/or adolescents.\n\nBrachial--ankle pulse wave velocity (PWV) is an indicator of systemic arterial stiffness and is shown to be related to CV events and mortality^[@bib16])^. Although relationships between PWV and CV risk factors in children have been reported^[@bib5],\\ [@bib17],\\ [@bib18])^, little is known about the influences of an individual\\'s daily"
+"Background\n==========\n\nIntravenously injectable contrast agents (CA) consisting of gas-filled microbubbles (MBs) with a mean diameter of 2--5\u00a0\u03bcm can be used for improved image quality during ultrasound examinations, which results in diagnostic benefits. An ideal ultrasound CA must be biocompatible, stable during image acquisition, and circulate without causing obstructions or negative physiological effects. In addition, it should have the ability to increase backscattering efficiency when exposed to an acoustic field. In 1968, the first contrast-enhanced echocardiography examination was described \\[[@B1]\\]. At that time, fragile free-air MBs with a short lifetime of a few seconds were used. Since then, more stable CAs have been developed by encapsulating a low-solubility gas within a stabilizing shell \\[[@B2]\\]. In parallel, the development of specific ultrasound contrast pulse sequences, which use the nonlinear response generated by the MBs when exposed to acoustic pressure, has further improved the possibility of successfully using these CAs during ultrasound examinations \\[[@B3],[@B4]\\].\n\nAlthough commercially available ultrasound CAs are relatively stable and used in various diagnostic procedures, there is still a need for improvement and extended applicability. One such example is targeted imaging, which would enable the visualization of specific areas, e.g., inflammatory tissue. Local deposition of drugs might also"
+"THE CLINICAL PROBLEM\n====================\n\nThe prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) is dramatically increasing \\[[@b1]\\], and at the same time, the Medicare cost of ESRD has risen from \\$12.2 in 2000 to \\$20.8 billion in 2007 \\[[@b2]\\]. ESRD is incurable, requiring renal replacement therapy, that is, dialysis or preferably renal transplantation. However, the shortage of available organs for transplantation continues to severely limit this option \\[[@b3]\\].\n\nHow can organ shortage be combated? In general, supply of organs can be increased, or their demand can be decreased.\n\nWhen considering cell replacement in diseased kidneys via cell transfer, one should carefully dissect the timing of such a therapy, as end-stage kidneys are already small and fibrotic and would therefore not allow for the incorporation of cells or for their paracrine effects. Thus, late CKD stages warrant whole kidney replacement, independent of the native kidneys, leading to a need for increased organ supply. Accordingly, we have previously demonstrated that stage-specific human and porcine embryonic kidney tissue can remarkably grow, differentiate, and undergo vascularization, achieving successful organogenesis of urine-producing miniature kidneys in immuno-deficient animals \\[[@b4]--[@b6]\\]. The \"growing kidneys\" concept is suggested to be applicable to ESRD as whole kidney"
+"INTRODUCTION {#sec1-1}\n============\n\nMelanoma of prostatic origin is very rare. It presents a difficult diagnostic, management challenge and a very poor prognosis. We report a case of primary malignant melanoma of the prostate found incidentally following transurethral resection of the prostate.\n\nCASE REPORT {#sec1-2}\n===========\n\nA 75-year-old White man was referred to the urology department for management of urinary tract obstruction. He reported an 18-month history of recurrent urinary tract infection. On examination, the patient was emaciated with stable vital signs. Digital examination and serum prostate specific antigen revealed no evidence of malignancy; urinary tract obstruction was managed with transurethral resection of the prostate. Urethroscopy had revealed a black discoloration of the prostate. Histology of the surgical specimen demonstrated melanoma cells distributed in the stroma, independent of the acinar glands with intact urethral epithelium \\[[Figure 1](#F0001){ref-type=\"fig\"}\\]. No other focus of malignant melanoma was found after physical examination of body skin surface, mucosa, tomography of brain, abdomen and pelvic cavity, and endoscopy of gastrointestinal tract.\n\n![Proliferation of big tumoral cells with very atypical cores. The tumoral cells express HMB45](UA-2-76-g001){#F0001}\n\nRadical prostatectomy with chemotherapy was suggested. However, the patient refused further surgical and systemic treatment. He was discharged and died at home"
+"In the past decade, cancer has been reported as the second major cause of death in the United States.^[@ref1]^ Although there are several types of cancer, a common cause for any type of cancer is the abnormal growth of cells.^[@ref2]\u2212[@ref4]^ Further, very often, cancer cells form a tumor. A tumor larger than a millimeter will starve itself for oxygen and energy, unless new blood vessels are built to provide supplies. During such circumstances, a process known as angiogenesis is found to be involved in building new blood vessels for many types of cancer.^[@ref5]^ Angiogenesis is a complex process and is defined as the growth of new blood vessels from existing vessels.^[@ref6],[@ref7]^ Mediators of angiogenesis such as vascular endothelial growth factor (VEGF) stimulate endothelial cells to secrete proteases and plasminogen activators. Cells will then migrate, proliferate, and eventually differentiate to form a new lumen vessel.^[@ref8]^ Several pathological conditions involve or mimic the angiogenic process. Cancer switches on angiogenesis by breaking the balance between productions of angiogenic stimulus and inhibiting factors.^[@ref9],[@ref10]^ Vascular endothelial growth factor receptor (VEGFR) refers to a family of endothelial cell membrane receptors that bind with the VEGFs secreted by tumors. VEGF--VEGFR binding process is the key point of"
+"Introduction\n============\n\nTree species have varying leaf life spans, nitrogen concentrations, respiration rates, carboxylation rates, and other traits that are collectively described species\\' ecophysiological traits (Kitao et\u00a0al. [@b12]; Walters and Reich [@b25]; Miller et\u00a0al. [@b16]; Niinemets [@b18]; Hitsuma et\u00a0al. [@b10]). Ecophysiological traits are considered to influence where species can appear, which species can coexist, and how species respond to light conditions such as shading and full sun (Yoshimura [@b29]; Wyka et\u00a0al. [@b27]). Studies on species distribution and coexistence often demonstrate that some environment factors can induce the plastic response of important ecophysiological traits (Miller et\u00a0al. [@b16]; Niinemets [@b18]; Hitsuma et\u00a0al. [@b10]). Vegetation is likely to experience heterogeneous patch habitats throughout the gap-phase dynamics. According to a theory of gap-phase dynamics proposed by Whitmore ([@b26]), cycle progress is initiated by a natural disturbance. Four distinct patches may be recognized: a gap patch (G), building patch (B), mature patch (M), and degeneration patch (D) (Whitmore [@b26]). The forest community is composed of different patches, and the heterogeneous light conditions in the different patches can lead to changes in patch development and dynamics (Whitmore [@b26]).\n\nSpecies-specific responses to heterogeneous environments reflect a number of adjustment mechanisms that"
+"Introduction {#sec1-1}\n============\n\nEarly onset bipolar disorder, usually becomes chronic, does not have specified periods and reveals a high level of the mixed mania.\\[[@ref1]\\] Early onset bipolar disorder can affect the development and function of the individual\\'s psychosocial characteristics and increase the risk of suicide and substance abuse, as well as academic and social behavior problems. The average onset of symptoms to diagnosis and therapy lasts 10 years which arises the need for early diagnosis and prompt treatment of symptoms.\\[[@ref2]\\] Bipolar disorder type one with early onset has a slow response to treatment, sustaining mood swings, high relapse rate, high suicide risk, and severe social and psychological destruction.\\[[@ref3]\\]\n\nSymptoms of mania include uncontrolled and risky behaviors in early onset bipolar disorder differ from adults' symptoms.\\[[@ref2]\\]\n\nWhen mania has been recognized based on the Diagnostic and Statistical Manual of Mental Disorders (DSM), there must be decrease of executive function which has a separate definition in youth patients. The performance of children and adolescents is specified according to chronological age and intellectual ability mentioned in the definition of psychosocial development. Due to the lack of insight associated with the symptoms of mania in children and adolescents, much of information should be obtained"
+"Introduction {#s1}\n============\n\nAlzheimer's disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in the elderly. The well-known neuropathological hallmarks of AD are extracellular senile plaques, which are aggregates of toxic amyloid \u03b2 (A\u03b2) peptides, such as A\u03b240 and A\u03b242. A\u03b2s, A\u03b240 and A\u03b242, are peptides generated from the amyloid precursor protein (APP) through sequential proteolytic cleavages by \u03b2-secretase (BACE1) and \u03b3-secretase complexes [@pone.0094576-Thinakaran1], [@pone.0094576-Kaneko1]. APP, a type I transmembrane glycoprotein with a short intracellular carboxyl terminus, is folded and *N*-glycosylated in the endoplasmic reticulum (ER). The \"*Swedish*\" *APP* double mutation results in A\u03b2 overproduction, causing early onset familial AD [@pone.0094576-Mullan1]. Aggregated A\u03b2 peptides form characteristic senile plaques in the brain tissues of AD patients, whereas intracellular neurofibrillary tangles (NFTs) are composed of paired helical filaments of hyperphosphorylated microtubule-associated protein tau [@pone.0094576-Selkoe1] in affected cortical and subcortical neurons. A number of *tau* mutants, such as P301L, V337M, and R406W, accelerate the aggregation of tau into filaments [@pone.0094576-Nacharaju1]. Tau pathology is a later event in AD progression, probably triggered by A\u03b2-dependent hyperphosphorylation of tau [@pone.0094576-Jin1]. Toxic A\u03b2 peptides and hyperphosphorylated tau both interfere with numerous neuronal functions, such as ER function and intracellular trafficking of proteins [@pone.0094576-Hoozemans1]."
+"Introduction {#S1}\n============\n\nA major push in neurology and neurological research related to late-onset Alzheimer's disease (LOAD) in the last 5\u2009years has been to better define the preclinical pathological stages that herald the development of clinically overt disease ([@B1]). As it relates to this paper, when we use the term AD, we mean LOAD, the most common clinical form of the disease and featuring a combination of genetic and epigenetic etiologies. In this context, we define preclinical LOAD as the separate stages of pathobiologic development that immediately precede prodromal amnestic mild cognitive impairment (aMCI) and manifest LOAD. We define, therefore, aMCI and LOAD to comprise the clinical stages of AD. Since treatments initiated during the preclinical stages may be more effective due to a more receptive brain substrate, the discovery and validation of biomarkers that define such a preclinical period has gained significant momentum ([@B1]). Our current investigative efforts focus on defining a more accurate and predictive set of plasma-based metabolomic biomarkers compared to those from our previous study ([@B2]). While the majority of LOAD biomarker studies to date have been carried out via case--control comparisons, our investigations arise from data developed from a 5-year longitudinal observation study. Longitudinal"
+"Published: April 21, 2020\n\nIntroduction {#sec1}\n============\n\nA series of recent discoveries has uncovered how cells of the innate immune system such as monocytes and macrophages undergo functional reprogramming to mount a de facto immune memory of an infectious or inflammatory injury by a process called trained immunity, which facilitates augmented responses to subsequent pathogenic encounters ([@bib30]). In the context of infections or vaccination, trained immunity provides beneficial heterologous effects by the enhanced cytokine response to stimulation with non-related pathogens. Prototypical stimuli of trained immunity include the fungal cell wall component \u03b2-glucan ([@bib35]) and the bacillus Calmette-Gu\u00e9rin (BCG) vaccine ([@bib26]). Recent attention has also turned to endogenous drivers of inflammation as inducers of trained immunity ([@bib5], [@bib41]). These stimuli shape innate immunological memories by reprogramming metabolic and transcriptional profiles ([@bib3], [@bib8]).\n\nPosttranslational methylation of proteins conveys information to cellular pathways, including those that regulate gene expression. *In\u00a0vitro* experiments with pan-methyltransferase inhibitors revealed the pivotal importance of this chemical modification for trained macrophages ([@bib8], [@bib35]). Changes in histone lysine methyl modifications (H3 histones monomethylated \\[H3K4me1\\] or trimethylated \\[H3K4me3\\] at lysine 4) underlie \u03b2-glucan-induced trained immunity ([@bib32]). Signaling factors derived from local tissue environments play key roles in determining macrophage fate,"
+"Introduction\n============\n\nEsophageal squamous cell carcinoma (ESCC), the major histological form of esophageal cancer in East Asian countries, is a highly aggressive malignancy with a poor prognosis ([@B01]). Because of its high frequency of lymph node metastases and recurrence, multimodality treatments including surgery, chemotherapy, and radiotherapy are often required to counter this disease. Despite such treatment combinations, the prognosis of patients with ESCC is still unsatisfactory ([@B02]). Assessment of prognosis based on clinicopathologic features remains inadequate even when using the staging systems of tumor node metastasis (TNM) classification because of the considerable variability and heterogeneity within the same stage ([@B03]). Therefore, it is important to evaluate and establish novel prognostic markers for ESCC to enable its diagnosis at an early stage when radical resection is possible.\n\nThe tumor metastatic cascade consists of multiple successive steps, including adhesion of tumor cells at primary site, invasion of intravascular space, dissemination to distant sites, adhesion of tumor cells to the vascular endothelium of distant tissues, extravasation and invasion of surrounding tissues, and finally formation of secondary tumor colonies ([@B04],[@B05]). To facilitate cell motility, invading cells need to change the cell-cell adhesion properties, rearrange the extracellular matrix (ECM) environment, suppress anoikis and reorganize their"
+"The story {#Sec1}\n=========\n\nCopying/pasting, note-forwarding, and templating are common practices in the electronic medical record (EMR) even though early observations indicated a\u00a0widespread belief that such behaviours would be rare \\[[@CR1]\\]. Recent surveys indicate much broader acceptance and existence of copying/pasting, and other purportedly efficiency-producing behaviours than initially was predicted \\[[@CR2]\\]. Medical educators and clinicians have raised concerns about the impact on notes, which may be rendered bloated or meaningless \\[[@CR3], [@CR4]\\], as well as the impact on the patient-physician relationship, the physician-learner relationship, and the ability of learners to interact with patients \\[[@CR3], [@CR5], [@CR6]\\]. Learners (and providers) engaging in copying/pasting and other EMR-based efficiency measures may have less in-depth knowledge about their patients \\[[@CR7]\\]. Whether there is any causation in this correlation is not well studied, but studies in other fields suggest that technological multitasking may overwhelm individuals' ability to attend to detail \\[[@CR8]\\].\n\nEducational impact of the EMR, particularly that of interpersonal and communication skills, has been discussed by previous authors \\[[@CR9], [@CR10]\\]. Of concern to us is the possibility that critically important aspects of learning (including direct patient care, professionalism and accountability) and patient care are suffering as metrics and efficiency measures are increasingly prioritized"
+"Introduction {#s1}\n============\n\nCardiovascular diseases remain the number one killer in Western society. Coronary artery disease which is associated with myocardial ischemia accounts for 1 in 6 of deaths in the United States [@pone.0056089-Roger1]. Reperfusion approach is the most effective means of rescuing the ischemic myocardium, however, reperfusion itself can cause injury to the myocardium and initiate myocardial apoptosis [@pone.0056089-Yellon1]. To date, the mechanism involved in the reperfusion-induced myocardial injury and apoptosis is still not fully understood, thus, lack of effective strategy to prevent the reperfusion-induced injury.\n\nReperfusion of ischemic myocardium can activate apoptotic pathways leading to the death of cardiomyocytes that were viable just before reperfusion [@pone.0056089-Logue1]. Apoptosis is a tightly regulated energy-dependent process. Common biochemical features of apoptosis include internucleosomal DNA fragmentation. Fragmentation of DNA to 180 to 200 base pairs by DNAses produces a ladder pattern after electrophoresis. The DNAse responsible for DNA cleavage resides in the cytoplasm in inactive form in normal cells. Upon pro-apoptotic stimulus, DNAse becomes activated by action of caspases. Specifically, caspase-3 has been found to play a key role in regulating apoptosis where its activation lead to cell death and its inhibition lead to cell survival [@pone.0056089-Saraste1].\n\nc-Jun N-terminal kinase (JNK) is"
+"INTRODUCTION\n============\n\nObesity and overweight are defined as the accumulation of abnormal or excessive fat that can be detrimental to health. A simple way to measure obesity is body mass index (BMI), this is the weight of a person in pounds divided by the square of height in meters. A person with a BMI of 30 or above is considered obese and a BMI of 25 or above is overweight. Overweight and obesity are risk factors for many chronic diseases including diabetes, cardiovascular disease and cancer are included. Once considered problems in high-income countries, obesity and overweight are increasing in low- and middle-income countries, especially in urban areas[@B27].\n\nThis disease is of multifactorial origin. The causes of obesity are manifold and include genetic, behavioral, nervous, endocrine and metabolic factors, as well as the type or lifestyle the individual adopts. Among the factors causing obesity, 30% can be attributed to genetic factors, 40% non-hereditary and 30% to the purely social, that is, the relationship between genetic and environmental factors is 30% and 70% respectively[@B16].\n\nAs one of the main clinical treatments and as one of the most effective solutions, there is bariatric surgery. It promotes a significant reduction in excess body"
+"1. Introduction {#sec1-molecules-25-02356}\n===============\n\nAlzheimer's disease (AD) is one of the greatest concerns confronting the medical community, and is the fourth leading cause of neurodegenerative disease-related death. Furthermore, AD has been predicted to affect 100 million patients within 30 years \\[[@B1-molecules-25-02356]\\]. AD accounts for 70% of all reported cases of dementia, being characterized by cholinergic functional decline, \u03b2-amyloid oligomer formation, and the dysregulations of other cellular processes \\[[@B2-molecules-25-02356]\\]. Over past years, many efforts have been made to identify the key biochemical events responsible for AD. However, AD is a multifactorial disease and, thus, its management requires the simultaneous modulations of multiple targets \\[[@B3-molecules-25-02356]\\]. Based on greater understanding of the disease, recent research efforts have increasingly focused on multitarget-drugs that simultaneously bias different biological targets \\[[@B4-molecules-25-02356]\\].\n\nThis novel approach is viewed optimistically, and hybridizations of the pharmacophore subunits of bioactive molecules have already resulted in the identification of multifunctional drugs \\[[@B5-molecules-25-02356]\\] and, as a result, synthetic drugs, like donepezil, rivastigmine, and tacrine, have been used as structural models for molecular hybridization experiments ([Figure 1](#molecules-25-02356-f001){ref-type=\"fig\"}) \\[[@B6-molecules-25-02356]\\]. Tacrine was the first cholinesterase (ChE) inhibitor that was approved by the FDA for the treatment of AD. However, the use of tacrine is limited by"
+"For many years, anterior cruciate ligament (ACL) injury has been the primary focus when considering impaired knee stability.[@bib1] However, numerous articles have reported an anterolateral capsular injury (Segond fracture) associated with ACL tears.[@bib2], [@bib3], [@bib4], [@bib5], [@bib6] Despite this well-known association, little has been published on the anatomy of this region, and the importance of the anterolateral structures to rotational stability has been downplayed. Historically, some authors believed that anterolateral rotational instability caused by an ACL tear could be treated by extra-articular surgery rather than ACL reconstruction. Numerous techniques were developed that focused exclusively on extra-articular reconstruction to control the instability.[@bib7], [@bib8], [@bib9], [@bib10], [@bib11], [@bib12]\n\nThe current standard of care is to reconstruct the ACL with autograft tissue and disregard any anterolateral injuries. However, the recent \"rediscovery\" and description of the anterolateral ligament (ALL) by Claes et\u00a0al.[@bib13] in 2013 brought new attention to treatment of the anterolateral corner of the knee.[@bib7] In an effort to decrease failure rates in patients with ligamentous laxity, prior failed ACL surgery, or grade 3 pivot-shift findings, numerous surgeons have described combining ACL reconstruction with extra-articular surgery. They have reported improved knee stability and patient-reported outcomes (PROs).[@bib14], [@bib15], [@bib16], [@bib17], [@bib18], [@bib19], [@bib20],"
+"Introduction {#Sec1}\n============\n\nGlioneuronal tumor (GNT) is one type of biphasic central nervous system (CNS) tumor which exhibits both glial and neuronal immunohistological characteristics^[@CR1]^. In the WHO classification of CNS tumors, they are given a specific category under the heading of neuronal and mixed neuronal-glial tumors which consists of diverse morphological neuroepithelial tumors with neuronal and/or glial differentiation^[@CR2],[@CR3]^. Most of the tumors under the neuronal and mixed neuronal-glial tumors are benign and usually shows good prognosis although some exceptions exist^[@CR4]^. Controversies still exist, however, concerning the spectrum of glial tumors with neuronal differentiation, and their sub-classification is still under active investigation based on genetic and epigenetic backgrounds identified^[@CR5],[@CR6]^. Among those few studies on genetic events in the GNT category to date, *NTRK1* or *BRAF* gene fusions are found in the subset of GNTs^[@CR5]^. Recent study identified the signature *PRKCA* gene fusions and *FGFR1* gene mutation in papillary glioneuronal tumors (PGNT)^[@CR6]--[@CR9]^. However, there are still blanks in genetic events that need to be investigated in GNTs.\n\nThere has been evidence identifying mesenchymal--epithelial transition factor (*MET*) related gene fusions as an oncogenic driver in glioma progression by upregulating mitogen-activated protein kinase (MAPK) signaling pathways^[@CR10]--[@CR13]^. Among them, CAP-GLY-domain-containing linker protein 2 (*CLIP2*) with"
+"Introduction\n============\n\nPhaeohyphomycosis is a heterogeneous group of infections due to dematiaceous fungi with several clinical presentations, from superficial to deep infections ([@B4]; [@B11]). Subcutaneous phaeohyphomycosis cases are rare and clinical manifestations may vary ([@B16]). One study found that the incidence rate of phaeohyphomycosis in a tertiary care center hospital varies from 1.0 to 3.1 cases per 100,000 patient-days ([@B3]). They affect predominantly the skin and can disseminate in immunocompromised patients, especially transplant patients.\n\nThere are more than 100 species of dematiaceous fungi associated with phaeohyphomycosis (*Alternaria* spp., *Curvularia* spp., and *Exophiala* spp...). There is no known correlation between etiologic agents and the clinical presentation of phaeohyphomycosis ([@B10]).\n\n*Pyrenochaeta romeroi* has been recently described as a causative agent of phaeohyphomycotic cyst in few cases while it was already known as an agent of mycetoma ([@B15]; [@B8]; [@B1]; [@B9]). This saprophytic fungus is widely distributed in the environment and found in soil, wood and plants in tropical area. It was first described by [@B4].\n\nThe diagnosis of subcutaneous phaeohyphomycosis is difficult because of the lesions' clinical polymorphism. It is usually established with histological examination and culture.\n\nWe present a case of subcutaneous phaeohyphomycosis due to *P. romeroi* mimicking a synovial cyst"
+"Introduction {#s1}\n============\n\nBlooms of toxin-producing cyanobacteria (harmful algal blooms, HABs) continue to be a threat to water resources in the U.S. and across the globe (Carmichael and Boyer, [@B7]). Research surrounding these bloom events with respect to cyanobacteria has generally focused on freshwater planktonic species and a suite of well-characterized toxins, including the anatoxins, saxitoxins and microcystins (Bl\u00e1ha et al., [@B5]). However, species of cyanobacteria in the marine realm have been a prolific source of exquisitely potent cytotoxic metabolites (Luesch et al., [@B15]; Taori et al., [@B24]; Pereira et al., [@B18]). Members of the bloom-forming genus *Trichodesmium* are an understudied group of marine cyanobacteria with respect to toxin production and environmental impact. With respect to new natural products, the cyclic peptide trichamide was characterized from a cultured strain of *Trichodesmium erythraeum*, although no significant cytotoxicity was observed against HCT-116 cells and CEM-TART cells when tested at 10 and 50 \u03bcg/mL, respectively (Sudek et al., [@B23]). The lipoamides, credneramides A and B were isolated and characterized from a field-collected benthic cyanobacterium identified as a new species of *Trichodesmium* (Malloy et al., [@B16]). These metabolites inhibited spontaneous calcium oscillations in murine cerebrocortical neurons (Malloy et al., [@B16]). Several known cyanotoxins, such"
+"Background {#Sec1}\n==========\n\nCHARGE (MIM\\# 214800) is the acronym of an autosomal dominant genetic condition, characterized by ocular [C]{.ul}oloboma, congenital [H]{.ul}eart defects, choanal [A]{.ul}tresia, [R]{.ul}etardation (of growth and/or of development), [G]{.ul}enital anomalies and [E]{.ul}ar anomalies (abnormal pinnae and/or hearing loss, abnormal semicircular canals) \\[[@CR1]\\]. *CHD7* gene has been causally linked to this disorders. The embryologic expression of the gene involves many tissues, including the eye, inner ear, and olfactory bulb cells. In addition it is widely expressed in undifferentiated neuroepithelium and in neural crest mesenchyme, and, at the end of the first trimester, in dorsal root ganglia, cranial nerves and ganglia, and auditory, pituitary and nasal tissues, as well as in neural retina \\[[@CR2]\\]. Typical CHARGE patients are mutated in *CHD7* gene in over 90 % of the cases \\[[@CR3]\\], 65 %--70 % for all typical and milder phenotypes combined \\[[@CR4]--[@CR7]\\]. The *CHD7* gene codes for one member of a family of proteins thought to play a role in the organization of chromatin, belonging to the chromodomain helicase DNA binding domain family of ATP-dependent chromatin remodeling enzymes \\[[@CR8]\\]. Members of this family share a unique combination of functional domains consisting of two N-terminal chromodomains, followed by a SWI2/SNF2-like ATPase/helicase domain"
+"Background\n==========\n\nHeart failure (HF) is the most common hospital discharge diagnosis in elderly patients \\[[@B1]\\]. Between the age of 70 and 80 years the incidence of HF is 10 to 20%. HF is associated with high mortality and morbidity, readmission rates and costs \\[[@B1]\\]. The readmission rates vary between 25% and 50% within 6 months after the first hospitalisation for HF, with a higher readmission rate within the first month after discharge\\[[@B2],[@B3]\\]. The costs related to HF contribute to 1-2% of all healthcare expenditures and are mainly the result of hospital stay \\[[@B4]-[@B6]\\]. Because of an increasing shortage of resources, HF is a major public health problem and therefore, a more effective and efficient organisation of care for HF patients needs to be reconsidered. A first step in organising treatment and care for patients with chronic HF more efficiently, was the implementation of specialised outpatient HF clinics. In the recent European Society of Cardiology (ESC) guidelines, HF management programmes are strongly recommended for all patients with HF \\[[@B1]\\] and HF clinics are considered as \\'usual care\\' in several European countries \\[[@B7]\\]. A widely used way to implement HF management is the use of specific disease management (DM) programs.\n\nDM"
+"Introduction {#Sec1}\n============\n\nDuring the last few decades, the theory of convex analysis has turned into one of the most interesting and useful fields to study a wide class of problems arising in pure and applied sciences. Innovative techniques and calculations have yielded different directions for the study of convex analysis. In recent years, various inequalities for convex functions and their variant forms have been developed using novel techniques; see \\[[@CR1]--[@CR7]\\].\n\nThe theory of convex functions is closely related to theory of inequalities. It is well known that a function is convex, if and only if it satisfies an integral inequality, which is known as the Hermite-Hadamard inequality; see \\[[@CR8], [@CR9]\\]. Such types of integral inequalities are useful in finding the upper and lower bounds. For recent developments and applications, see \\[[@CR10]--[@CR14]\\].\n\nThe convex sets and convex functions have been extended and generalized in different directions using innovative ideas to study different problems in a general and unified frame work; see \\[[@CR15]--[@CR21]\\]. One of the most recent significant generalizations of convex functions is the *\u03c6*-convex function, introduced by Gordji *et al.* \\[[@CR22]\\]. These functions are non-convex functions. For recent developments, see \\[[@CR16], [@CR22]--[@CR26]\\] and the references therein.\n\nThe main purpose"
+"Background {#Sec1}\n==========\n\nIt is estimated that 5.9\u00a0% of global deaths and 5.1\u00a0% of the global burden of disease are attributable to alcohol consumption \\[[@CR1]\\]. In England, although young adults are less likely than other age groups to report drinking any alcohol at all, they are the age group most likely to report very excessive alcohol consumption (over 8 units) on at least one day in the previous week \\[[@CR2]\\]. Among females, those in the 16--24 age group have the highest prevalence of hazardous and harmful drinking and of alcohol dependence \\[[@CR3]\\], whilst among young adult males there was a 57\u00a0% increase in alcohol-related hospital admissions from 2002 to 2010 \\[[@CR4]\\].\n\nYoung adults are frequently the target of alcohol marketing \\[[@CR5]\\]. One policy option to reduce harmful alcohol consumption in this age group is to restrict the marketing of alcoholic products. However, despite consistent evidence that exposure to alcohol advertising has a dose--response association with earlier initiation of alcohol use and increased consumption in young people \\[[@CR6], [@CR7]\\], there is a lack of high quality evidence to support the implementation of alcohol marketing bans or restrictions to reduce alcohol consumption \\[[@CR8]\\]. This is one reason that such"
+"Background {#Sec1}\n==========\n\nLung cancer is one of the most lethal malignant tumors. According to statistics from the American Cancer Society, lung cancer had the second highest incidence and the highest mortality rate in the United States in 2017 \\[[@CR1], [@CR2]\\]. Lung cancer is divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), with NSCLC accounting for about 80% of all cases \\[[@CR3]\\]. Surgery, radiotherapy, chemotherapy and immunotherapy are the main methods for treating lung cancer, though the outcome of those methods is quite different \\[[@CR4]\\]. Infiltration and distant metastasis in situ often occur to patients with lung cancer, and the 5-year survival rate of patients is still low \\[[@CR5]--[@CR7]\\]. Moreover, although tyrosine kinase inhibitor (TKI) was well developed in recent years, the problem of high recurrence rate still exists \\[[@CR8]\\].\n\nThe activation of tyrosine kinase receptor-associated signaling system plays an important role in the development and progression of lung cancer. Ras/Raf/mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) regulates a variety of cellular processes including proliferation and apoptosis \\[[@CR9], [@CR10]\\]. Recent studies have found that Ras/Raf/MEK/ERK pathway also plays a critical role in regulating cellular senescence \\[[@CR11]--[@CR13]\\].\n\nCellular senescence is a state of cell cycle arrest"
+"1. Introduction {#sec1}\n===============\n\nSkeletal muscle injury can be caused by a variety of conditions such as direct trauma, disuse, ischemia, exercise, toxins, and genetic diseases. To face these challenges, skeletal muscle has developed a remarkable regenerative capacity, which relies on muscle stem cells, named satellite cells. Skeletal muscle regeneration is a tightly regulated process during which quiescent satellite cells are activated and become proliferating myoblasts, which will differentiate and fuse to form multinucleated myotubes (newly formed muscle fiber) \\[[@B1]\\]. The coordination of the myogenesis process (formation of new muscle tissue) involves the cooperation of numerous other cellular and molecular components \\[[@B2]\\]. Particularly, the onset, development, and the resolution of the inflammatory response play an instrumental role in the regulation of myogenesis.\n\nMonocytes and macrophages are predominant myeloid cells that chronologically accumulate in skeletal muscle at the onset of injury-induced inflammation \\[[@B3]\\]. There are numerous evidences indicating that macrophages are key regulators of different biological processes involved during skeletal muscle regeneration, such as myogenesis, fibrosis, inflammation, and revascularization \\[[@B3]--[@B9]\\]. On the other hand, in chronic degenerative conditions, the excessive and disorganized influx of macrophages stimulates muscle necrosis, fibrosis, and defective muscle repair. Therefore, the spatiotemporal regulation of inflammation is vital"
+"INTRODUCTION {#sec1-1}\n============\n\nSubdural empyema (SDE) and epidural abscess (EDA) comprise between 6 and 20% of intracranial infections.\\[[@ref1][@ref7][@ref10]\\] In the precomputed tomography (CT) era, these infections carried a 50% mortality rate, now reduced to 10--28% in the modern era with improved imaging techniques.\\[[@ref1][@ref11]\\] They are often the consequence of direct spread from sinusitis, but sometimes result from previous cranial procedures.\\[[@ref1][@ref2]\\] Patients typically present with fever, headache, and focal neurological deficit. We report a case of EDA presenting as depression with suicidal ideation.\n\nCASE REPORT {#sec1-2}\n===========\n\nThe patient is a 57-year-old man with past medical history significant for epilepsy and left hemiplegia secondary to right-sided traumatic brain injury (TBI) 28 years prior to presentation. He presented with a 3-week history of depression, anxiety, and active suicidal ideation resulting in psychiatric admission to an outside hospital. He had three prior craniotomies for right subdural hematoma (SDH), one at the time of his TBI, one 8 years prior to presentation, and one 5 years prior to presentation. On follow-up imaging 3 years after his last craniotomy, he underwent head CT showing a small subacute SDH, which was managed nonoperatively \\[[Figure 1](#F1){ref-type=\"fig\"}\\]. He has no significant prior psychiatric history. His home medications include"
+"See related research article by Sharma et al at, <http://breast-cancer-research.com/content/7/5/R634>\n\nIn their recent report \\[[@B1]\\], Sharma and coworkers explore the early detection of breast cancer. They analyzed a gene expression data set (1368 genes in 62 normal and 40 tumour samples, including sample duplication in different batches) using the nearest shrunken centroid method. They identified a panel of 37 genes that permitted early detection, with the classification accuracy being about 82%. This is a typical problem with sample classification based on gene expression profiling. The objective is to achieve high prediction accuracy with as few genes as possible, and so feature selection plays an important role; examination of a large number of genes will increase the dimensionality, computational complexity, and clinical cost. According to our previous study of data sets from patients with colon cancer, leukaemia and breast cancer \\[[@B2]\\], we estimated that five or six genes -- rather than 37 -would be sufficient for the early detection of beast cancer \\[[@B1]\\]. So how many genes are indeed needed? In order to address this question, we evaluated the data presented by Sharma and coworkers using the Tclass system \\[[@B2]\\].\n\nIn the Tclass system, Fisher\\'s linear discriminant analysis and a step-wise"
+"Introduction {#s1}\n============\n\n> If you come to any more conclusions about polymorphism, I should be very glad to hear the result: it is delightful to have many points fermenting in one\\'s brain, and your letters and conclusions always give one plenty of this same fermentation.\n>\n> \\- Charles Darwin, letter to Joseph Hooker, 1846 [@pone.0093622-Darwin1]\n\nPolymorphism has fascinated evolutionary biologists since the time of Darwin [@pone.0093622-Darwin2], [@pone.0093622-Darwin3]. Polymorphism is defined as that there exist more than one distinct phenotype of a species occupying the same habitat at the same time [@pone.0093622-Ford1], [@pone.0093622-Smith1]. Polymorphism does not include continuous variations, but only discrete variations or in the case of continuous traits, such as body size and color, strongly bimodal or multimodal phenotype variation distributions. The existence of more than one distinct phenotype of a species demands an explanation, because the theory of natural selection predicts that the fittest phenotype should drive the other, lesser fit phenotypes to extinction. In general, polymorphism is maintained if the \"fitness curves\" of the polymorphic phenotypes intersect, where the crossover-point is an evolutionarily stable state, realizing a polymorphic evolutionarily stable strategy (ESS) [@pone.0093622-Smith2], [@pone.0093622-Smith3]. Common features of the evolution and the maintenance of behavioral polymorphism"
+"1. Introduction\n===============\n\nRetroviruses are enveloped RNA viruses that copy their genome into DNA, then insert it into their host cell's chromosomes as an essential part of their replication cycle. Classical retroviruses, like HIV or HTLV, propagate through extracellular particles that infect fresh cells in the host and ensure transmission to other individuals of the host species. When this cycle involves somatic cells, the replication cycle involves no alteration of the genetic structure of the host species, but if germline cells are infected but remain competent, the viral genetic information can be passed to successive generations and may eventually become a feature of all members of the host species. Such genetic sequences are called endogenous retroviruses and the dynamic process of their acquisition is called viral endogenization (see [Box 1](#viruses-06-04914-box001){ref-type=\"boxed-text\"}). *In silico* analysis of eukaryote genomes has revealed that such endogenous retroviruses are widespread \\[[@B1-viruses-06-04914]\\].\n\n###### Endogenization: However could a viral sequence get into my genes?\n\nFor a viral sequence to become an endogenous element of the host's genome, the germinal cells themselves must suffer viral infection. The pathway from fusion of germinal cells to the birth of viable and reproductively competent offspring is exceedingly complex and finely balanced. Major"
+"1. Introduction {#sec1}\n===============\n\nFor topical application of active agents various novel carrier systems were explored till date in the form of microparticles, nanoparticles, liposomes and cochleates, and so forth. Food and Drug Administration (FDA) has approved wide range of products like Retin-A, Carac cream, MicroPeel Plus, and oil control lotion due to improved efficacy and safety compared to the conventional topical drug delivery systems. Typically, such products form a highly concentrated layer of active ingredients on the skin which results in skin irritation and toxicity \\[[@B1]--[@B4]\\].\n\nAt present, the need of an exclusive delivery system has been required for the topically active sunscreen agents. Microsponge is sponge-like porous polymeric system in the range of 10--25\u2009*\u03bc*m with extended release of drug. It offers increased payload of drug and stability with reduced irritation, mutagenicity, allergenicity, and side effects for the topical applications. Due to these undue advantages, in the current era of topical products, microsponge has got wide acceptance. Microsponge for topical route has been reported for the controlled release of benzyl peroxide, mupirocin, retinoid, and 5-fluorouracil which reported minimal penetration through dermis, less drug accumulation, and irritation without sacrificing the efficacy of drug \\[[@B5]--[@B7]\\].\n\nThe ultraviolet (UV) rays responsible"
+"INTRODUCTION\n============\n\nThe knowledge about the main problems of public health enables actions with practical and real effects in health services. In this context, epidemiologic profile in Brazil has been changing since the 1950. Currently, non-communicable chronic diseases (NCCD) had assumed a prominent role among main causes of morbimortality,^(^ [@B1] ^,^ [@B2] ^)^ among which metabolic diseases are highlighted in relation to improvements in life conditions of humans and development of new technologies applied to health.^(^ [@B3] ^)^\n\nOf these diseases, the *diabetes mellitus* (DM) deserves emphasis on studies that involve actions and health services needed for population's integral health assistance because of this disease impact on individuals socioeconomic status and health.^(^ [@B4] ^)^\n\nComplications of DM can be acute. We highlight, among them, hypoglycemia, ketoacidosis and hyperosmolar coma. They can also be chronic such as nephropathy, diabetic neuropathy and retinopathy.^(^ [@B5] ^)^ Therefore, the cost per patient increases with time, especially because of the presence of later complications.^(^ [@B6] ^)^\n\nConsidering this scenario, the impact of visual loss in individual's life is devastating, periodic visits to the ophthalmologist are fundamental for diagnosis and early treatment of eye diseases.^(^ [@B7] ^,^ [@B8] ^)^\n\nPublic policies such as the statement 957/2008"
+"Glucocorticoids (GCs) are potent anti-inflammatory agents that are commonly used to treat a broad range of inflammatory and autoimmune conditions. They are prescribed long-term to \u223c0.75% of the general population, most frequently to patients with inflammatory rheumatologic disease ([@B1]). Despite the advent of disease-modifying antirheumatologic drugs and biologic therapies, long-term GC prescription rates are still increasing ([@B1]). Long-term prescription of GCs is most prevalent in the elderly, at prednisolone-equivalent doses of \\<10 mg daily ([@B1],[@B2]).\n\nThe acute effects of high-dose GCs on carbohydrate metabolism have been extensively investigated. High-dose GCs cause peripheral tissue insulin resistance ([@B3]), because they reduce both oxidative and nonoxidative glucose disposal ([@B4]). The effects of high-dose GCs on endogenous glucose production (EGP) and hepatic insulin sensitivity are less clear, but a number of studies report a deleterious effect ([@B3],[@B5],[@B6]). High-dose GCs also acutely reduce insulin secretion ([@B7],[@B8]), which will contribute to their hyperglycemic effect.\n\nThere are fewer data regarding the metabolic consequences of typical long-term (lower) GC doses, which are generally considered to be modest ([@B9]--[@B11]). Furthermore, which components of carbohydrate metabolism are perturbed by low-dose GCs is not clear. We recently reported that older patients with inflammatory rheumatologic disease using long-term low-dose prednisolone had a"
+"*Sir,*\n\nAggrecan is a chondroitin sulphated proteoglycan encoded by the *ACAN* gene with essential structural functions in the extracellular matrix of cartilages \\[[@CR1]\\]. Heterozygous *ACAN* mutations have been associated with a broad spectrum of non-lethal skeletal dysplasias, called Aggrecanopathies, including spondyloepimetaphyseal dysplasia, Kimberly type spondyloepiphyseal dysplasia, autosomal dominant short stature, early onset osteoarthritis and recurrent osteochondritis dissecans (OCD) \\[[@CR2]--[@CR5]\\].\n\nHere, we present a child with severe inflammatory elbow involvement mimicking septic arthritis who carried a new missense variant of the *ACAN* gene.\n\nA 14-year-old boy developed swelling and pain at the right elbow after a physical effort. Symptoms were not associated to other systemic inflammatory signs and worsened during the following days, leading to a severe joint limitation. Laboratory tests and X-ray of the right elbow were normal. Non steroidal anti-inflammatory drugs (NSAIDs) were administered for a month without any improvement.\n\nThe patient was admitted to our Institute after 2 months of symptoms onset. On physical examination, acute arthritis of the right elbow was present: it appeared painful and warm, without local erythema. Laboratory tests showed slight elevation of the acute phase reactants (C reactive protein 1.7\u2009mg/dl, erythrocyte sedimentation rate 26\u2009mm/h). Ultrasound revealed a distension of coronoid and"
+"1. Introduction {#sec1-nutrients-12-02270}\n===============\n\nThe substitution of animal proteins with plant proteins has become increasingly important in human nutrition for ecological and health reasons. Ecologists recommend limiting the intake of proteins from animal sources to reduce greenhouse gas emissions and the use of biological resources \\[[@B1-nutrients-12-02270]\\]. Nutritionists and clinicians emphasize the beneficial effects of dietary plant proteins versus animal proteins on lipid and glucose metabolism and for the prevention of obesity and hypertension \\[[@B2-nutrients-12-02270],[@B3-nutrients-12-02270],[@B4-nutrients-12-02270],[@B5-nutrients-12-02270],[@B6-nutrients-12-02270],[@B7-nutrients-12-02270]\\].\n\nAmong protein crops, soy and other legumes, such as lupin, are characterized by a favorable profile of indispensable amino acids and are thus an important component of the human diet. Another promising plant source of protein is rapeseed. Rapeseed is primarily used for the production of edible rapeseed oil. Protein-rich by-products from oil production, such as rapeseed cake or meal, are predominantly used as animal feed. Analyses have revealed that the amino acid composition of rapeseed proteins is comparable to that of other legume proteins \\[[@B8-nutrients-12-02270]\\]. This indicates that rapeseed protein, in principle, meets the requirements for being an indispensable amino acid source for human consumption \\[[@B9-nutrients-12-02270]\\]. Fleddermann et al. were the first to demonstrate that the intake of rapeseed protein resulted in a postprandial amino"
+"Background\n==========\n\nInfluenza is currently considered as one of the most severe threats to human health and animal welfare. The highly pathogenic avian influenza (HPAIV) H5N1 viruses have been isolated from avian species in more than 50 countries. As of January 2008, 349 human H5N1 infections have been reported to the World Health Organization (WHO) \\[[@B1]\\]. Of these 349 cases, 216 patients have died (62%) and there has been no decline in mortality rate. Because the virus has evolving antigenicity for which humans may not have a pre-existing immunity, the conditions for a possible pandemic exist.\n\nThe entry of influenza virus into susceptible cells is mediated by the viral hemagglutinin (HA) membrane glycoprotein which binds sialic acids of cell-surface glycoproteins and glycolipids. The binding preference of a given HA for different receptors correlates to some extent with the species specificity for infection. Human isolates preferentially bind to receptors with \u03b12,6 linkages to galactose (SA\u03b12,6Gal), whereas avian isolates prefer \u03b12,3 linkages (SA\u03b12,3Gal) \\[[@B2]-[@B6]\\]. A change in receptor preference is, however not necessary since the lower respiratory tract also expresses \u03b1 2.3 receptors \\[[@B7]\\]. It has also been reported that influenza virus can infect host cells via a sialic acid-independent pathway, either"
+"Introduction {#sec1}\n============\n\nThe requirement of continuously growing energy demand can be compensated by means of utilizing solar energy. After continuous efforts, one of the major breakthroughs has been to harness solar photons to split water. The process commonly known as photoelectrochemical (PEC) water splitting is a compelling approach of harvesting solar energy into chemical energy stored as hydrogen in an environmentally friendly manner. For the advancement of such systems, semiconductor nanostructures have gained wide attention to develop cleaner energy conversion systems.^[@ref1]^ It has been investigated that a material must confirm to a number of firm requirements for efficient photoassisted water splitting, which include (i) light absorption in visible region, (ii) efficient charge carrier separation and transportation, (iii) fast charge-transfer kinetics at the interface between liquid and solid, (iv) appropriate positions of the conduction and valence band (VB) energy levels with respect to required reaction potentials, and (v) respectable stability in aqueous solutions.^[@ref1]^ Although such systems have been heavily investigated, a suitable candidate still does not exist, which can satisfy all of these conditions.^[@ref2],[@ref3]^ Recent advances in nanoscience and electrochemistry have made significant strides toward developing a material capable of efficiently converting photons from sunlight into chemical fuels.^[@ref4],[@ref5]^ In this"
+"Research in contextEvidence before this studyThe compendium of transcriptome datasets either from laboratory or clinical isolates showed divergent functional responses associated with variation in strain genotype, host pre-existing immunity and *in vitro* culture conditions. The functional importance of transcriptome variation during infection is unclear due to the underlying complexity in a natural human malaria infection, but is central to our understanding of parasite adaptation in the human hosts. Thus, the the establishment of controlled human malaria infection (CHMI) trials provide a unique experimental model to study parasite adaptation upon transmission and infection.Added value of this studyHere, we identified a unique transcriptional signature of a single strain malaria infection in a non-immune background. Transcriptional changes between sporozoite route of infection (intradermal *versus* intravenous), sporozoite dose (high *versus* low) and before-after mosquito passage (CHMI-derived strain *versus* pre-mosquito strain) reveal intriguing functional gene clusters associated with host immune evasion and parasite transmission. We applied and showed significant association of the variable transcriptome component from this study into the transcriptome component of parasites obtained from acute human infections from Africa, Bangladesh, Mekong, Myanmar and Cambodia.Implications of all the available evidenceParasites derived from CHMI studies can yield novel insights into the adaptation process in different"
+"Introduction {#Sec1}\n============\n\nThe exposome was originally conceived as the sum of all exposures encountered by an individual during their lifetime \\[[@CR1]\\]. Despite more than 10\u00a0years of dedicated research, the exposome is not well-characterized for individuals or populations, owing (in part) to a lack of suitable monitoring tools. Traditional exposure monitoring has relied on targeted analytical methods, developed and validated for specific high-interest compounds. These methods have generally proven impractical for exposome studies, where a goal is to characterize previously unknown compounds that may be of eventual interest. Time and resource limitations simply prohibit the development of enough targeted methods to cover the expanse of the exposome.\n\nAdvancements in analytical and computational technologies have enabled a shift from targeted monitoring methods to non-targeted analysis (NTA) methods. High-resolution mass spectrometers (HRMS), utilizing Orbitrap and quadrupole time-of-flight (Q-TOF) mass analyzers, now provide the combination of resolution, sensitivity, and speed needed to support NTA studies. Whereas targeted methods only monitor specific compounds during data acquisition, HRMS instruments generate data with sufficient quality that compound selection/identification can be performed at later stages of analysis, without reliance on pre-conceived chemical target lists. The confidence in eventual chemical identifications depends, in part, on the experimental"
+"INTRODUCTION {#s0}\n============\n\nLeishmaniasis is the general name for a group of diseases caused by different species of the parasitic protozoan *Leishmania* that produce distinct clinical outcomes, ranging from localized, self-limiting cutaneous lesions, to more chronic forms of cutaneous and mucocutaneous disease, to visceral disease, which is fatal if untreated. According to the WHO there are around 1.3 million new cases of leishmaniasis around the world, with 20,000 to 30,000 deaths each year (<http://www.who.int/mediacentre/factsheets/fs375/en/>).\n\n*Leishmania* parasites have a dimorphic life cycle, shifting between the alimentary tract of their sand fly vector as extracellular, flagellated promastigotes and the phagolysosomal vacuoles of their mammalian host mononuclear phagocytes as intracellular amastigotes. The ability of the parasite to adapt to these vastly different environments has been the focus of a number of studies comparing the transcriptomes, proteomes, and metabolomes of amastigotes and promastigotes during their transformation *in vitro* ([@B1][@B2][@B6]). More recent studies have addressed the differential gene expression levels associated with the maturation of promastigotes to the mammalian-infective, metacyclic stage, again using *in vitro* conditions ([@B7]). Finally, two recent studies have demonstrated differential gene expression between *L.\u00a0infantum* promastigtoes in the anterior midgut of a natural vector, *Phlebotomus perniciosus*, versus those in stationary-phase culture"
+"1. Introduction {#sec0001}\n===============\n\nModeling and simulation are eminently appropriate tools for optimizing malaria control strategies [@bib0001], helping elucidate their probable mechanisms of action, and optimizing intervention timing and coordination. To compare different methods of suppressing infection in a community with endemic disease, we extend an established Ross/Macdonald model variant for mosquito-born parasite transmission to simply incorporate time-dependent control interventions. In particular, we focus on mass drug administration (MDA) and indoor residual spraying (IRS), two strongly effective interventions which address, respectively, the human and the mosquito reservoirs of parasitemia. These interventions have direct and complementary effects on the transmission dynamics.\n\nThere is context and precedence for this investigation from a long history of both MDA and IRS campaigns, sometimes used in combination. In the post-WWII era, DDT and Chloroquine prompted large scale campaigns with the ensuing Global Malaria Eradication Programme of 1955--1969 [@bib0002], [@bib0003]. Subsequent eradication efforts both succeeded and failed [@bib0004], [@bib0005] and a legacy of this era is acquired resistance [@bib0006]. Both Chloroquine and DDT lost efficacy with successive sprayings and the regularly high chemical pressure stemming from frequent treatment with a single pharmaceutical. Later, from 1969 to 1976, the Garki project investigated and recorded many aspects of"
+"Introduction {#sec1}\n============\n\nThe activity of guanidinium-rich oligomers and polymers in biomembranes has attracted much scientific attention because of their biological importance and their complex behavior. In biology, these oligomers are usually arginine-rich peptides or proteins, such as heptaarginine **R7** or polyarginine **R72** (Figure [1](#fig1){ref-type=\"fig\"}). Prominent examples of arginine-rich proteins and their intriguing biomembrane activities include cell-penetrating peptides (CPPs),^[@ref1]--[@ref4]^ such as HIV-TAT and many synthetic mimics,([@ref1]) the voltage sensors of potassium channels,^[@ref2]--[@ref5]^ and synthetic multifunctional pores.([@ref6]) The unique properties of arginine-rich oligo/polymers have made it difficult to understand their behavior on the molecular level, and as a result, these phenomena have sometimes been referred to informally as \"arginine magic\". Today, there is increasing evidence that the counterions of arginine-rich peptides and proteins account for much of this arginine magic.^[@ref2]--[@ref5]^ The functional relevance of counterions originates in the weak acidity of the guanidinium group of the arginine side chain. Reduction of the p*K*~a~ to minimize charge repulsion by release of a proton, as in the more acidic ammonium-containing oligomers of lysine, is thus not possible for arginine-rich oligomers. As a result, tight binding of counterions remains as the only solution to compensate for the excess of positive charge.\n\n![Structure of polyguanidino-oxanorbornenes"
+"1. Introduction {#s1}\n===============\n\nHost--pathogen interactions are crucial aspects to the immune response. Innate immunity comprises generalized defense to invading microorganisms and involves cellular functions, including chemotaxis and phagocytosis, that can be traced at least 1 billion years (Cosson and Soldati, [@B6]; Jin et al., [@B9]; Bozzaro and Eichinger, [@B4]), where ancient professional phagocytes utilized the pathways in a search for and an uptake of new nutrient sources. Thus, similar molecular processes, including receptor signaling and directed cytoskeletal mobilization, are essential for both destruction of pathogenic bacteria by macrophage and neutrophils, and for nutrient capture by *Dictyostelium discoideum* (Cosson and Soldati, [@B6]; Jin et al., [@B9]; Bozzaro and Eichinger, [@B4]). Significantly, the ease in genetic manipulation of *Dictyostelium* (Basu et al., [@B2]) has made it an ideal model for mechanistic studies of these processes.\n\n*Dictyostelium* can rapidly sense multiple chemoattractants in very broad and dynamic concentration gradients (Jin, [@B8]; Artemenko et al., [@B1]; Nichols et al., [@B18]). We established a new quantitative system for high-throughput chemoattractant gradient perception at very low concentration (\\<1 nM) sensitivity and then extended conditions for use of live bacteria as the source for secreted chemoattractants (Meena and Kimmel, [@B17]). This further permitted analyses to understand"
+"Background {#Sec1}\n==========\n\nStroke is an important cause of mortality and morbidity, accompanied with heavy economic and social burden worldwide. Although great advances have been made on the therapy of stroke, mortality and disability remain high. In addition, the absolute number of people affected by stroke worldwide increases significantly over years \\[[@CR1]\\]. Therefore, prevention of stroke has been a major public health priority. Preventive strategies targeting high-risk individuals including diet and lifestyle changes have been proposed. Recently, mounting evidence showed that increase in the consumption of fruits is associated with reduced risk of stroke \\[[@CR2], [@CR3]\\]. However, the potential mechanism of dietary factors on stroke is not fully understood.\n\nAmong many dietary components, curcumin is a safe, natural polyphenol compound isolated from the plant *Curcuma longa*, which is a widely cultivated plant in the tropical regions of Asia. Curcumin is well recognized as a dietary spice for a long time and exerts a wide spectrum of biological functions including anti-cancer \\[[@CR4]\\], cardioprotection \\[[@CR5]\\], anti-inflammatory \\[[@CR6]\\], antioxidant \\[[@CR7]--[@CR9]\\] and neuroprotection \\[[@CR10]--[@CR12]\\]. Notably, beneficial effects of curcumin on stroke have been suggested. Curcumin could decrease risk factors of stroke, such as lowering total cholesterol, boosting high density lipoprotein cholesterol level \\[[@CR13]\\] and"
+"Introduction {#Sec1}\n============\n\nThe relevance of long non-coding RNA (lncRNA) is growing following the discovery of significant roles for members of this abundant family of human transcripts. Although these RNAs may hold some coding capacity for micro peptides^[@CR1]^, their broad functionality is suggested to be derived from their ability to adopt elaborate structures^[@CR2]^. The lack of conservation of primary sequences has contributed to the challenge of determining the biological significance of newly discovered lncRNA transcripts. An explanation for the lack of sequence conservation may be the evolutionary conservation of important secondary structural modules^[@CR3]--[@CR5]^.\n\nDecades have passed since the observation of RNA triplex formation^[@CR6]^, but the spotlight has returned to this feature following the most recent mechanistic characterization of lncRNAs^[@CR7]--[@CR9]^. Sequence specific interaction between lncRNA and short stretches of genomic DNA leads to the formation of RNA: DNA: DNA triplexes^[@CR7]--[@CR9]^. This occurs through the recognition of short homopolypurine/homopolypyrimidine sequences of the duplex DNA by the single-stranded RNA that inserts into the major groove in a parallel or antiparallel orientation^[@CR10],\\ [@CR11]^. The triplex is stabilised by the formation of Hoogsteen hydrogen bonding between the RNA and the target duplex DNA^[@CR12]^. Bioinformatics approaches have suggested that multiple triplex target sequences are distributed across"
+"Introduction {#s1}\n============\n\n*Staphylococcus aureus* is one of the most prevalent and clinically significant pathogens worldwide, causing a variety of illnesses ranging from benign, superficial skin eruptions to life-threatening infections with bacteraemia, endocarditis, pneumonia and toxic shock syndrome [@pone.0027328-Lowy1]. Since methicillin-resistant *S. aureus* (MRSA) was first identified in 1961, it has become the most common cause of nosocomial and community infections worldwide [@pone.0027328-Deresinski1]. The recent emergence of highly virulent community-associated MRSA (CA-MRSA) isolates which cause disease in individuals with no apparent risk factors for hospital acquisition of MRSA has raised widespread concern over how CA-MRSA is transmitted in the community setting [@pone.0027328-Taiwo1], [@pone.0027328-Cohen1].\n\n*S. aureus* is a member of commensal microflora and readily colonizes the anterior nares in humans. Many infections caused by *S. aureus* occur in persons with prior nasal carriage [@pone.0027328-Wertheim1], and this carriage is an important risk factor for nosocomial *S. aureus* infection in patients undergoing surgery, hemodialysis, implantation of intravascular devices, and among HIV-infected patients [@pone.0027328-Kluytmans1]. One study revealed that nasal carriage of *S. aureus* is an important source of *S. aureus* bacteremia [@pone.0027328-vonEiff1], and eliminating nasal carriage of *S. aureus* may prevent systemic *S. aureus* infection [@pone.0027328-vonEiff1]. Determination of the prevalence of *S. aureus* nasal"
+"Background\n==========\n\nThe goal of genomic selection (GS) \\[[@B1]\\] is to capture all quantitative trait loci (QTL) influencing a trait by tracing all chromosome segments defined by adjacent markers. With use of highly dense markers, GS is supposed to be able to overcome the problem of traditional maker assisted selection (MAS) that only a limited proportion of the total genetic variance is captured by the markers of QTL. GS has become feasible very recently with the high throughput genotyping technology and the availability of highly dense markers covering whole genome. Genomic breeding value estimation is the key step in GS. A number of approaches have been proposed for estimating genomic breeding values \\[[@B1]-[@B9]\\], among which BLUP methods and Bayesian methods are most commonly used. Here, we applied two BLUP methods (GBLUP \\[[@B3]\\], TABLUP \\[[@B4]\\]) and three Bayesian methods (BayesA, BayesB \\[[@B1]\\], BayesC\u03c0 \\[[@B5]\\]) to the common dataset provided by the 15^th^QTL-MAS Workshop to evaluate and compare their predictive performances.\n\nMethods\n=======\n\nDataset\n-------\n\nThe common dataset consisted of an outbred population, which had been simulated using the LDSO software \\[[@B10]\\], with 1000 generations of 1000 individuals, followed by 30 generations of 150 individuals. 9990 SNP markers were distributed on 5"
+"Background {#Sec1}\n==========\n\nThe phylloplane alone represents the largest biological surface on Earth, outnumbering the cells of the plants themselves \\[[@CR1], [@CR2]\\]. The microorganisms that live in this region multiply and occupy newly formed niches while the leaves are expanding \\[[@CR2], [@CR3]\\]. They are influenced by sunlight and the plants metabolism that have nutrients, including carbohydrates, organic acids and amino acids \\[[@CR4], [@CR5]\\]. Furthermore, the cuticle reduces water evaporation as well as leaching the metabolites in the leaves, resulting in a favorable environment \\[[@CR6]--[@CR8]\\]. These surfaces are an open environment that receive migrants transferred by various mechanisms including rain, animals and deposition of aerial particles, which contributes to a large microbial diversity \\[[@CR2], [@CR9]\\].\n\nThe phylloplane microorganisms can be shared randomly among its neighbors, but their survival and presence is generally regulated by the plant \\[[@CR10]\\]. Furthermore, a theory proposes a possible transfer of microorganisms through generations \\[[@CR11]\\]. However, this whole microbiome can be affected by environmental factors, including radiation \\[[@CR12]\\] and pollution \\[[@CR13]\\], as well as biotic factors such as leaf age and the presence of other microorganisms \\[[@CR14]\\].\n\nThe microbiome present in the phylloplane includes a diversity of bacteria, fungi, yeasts, algae and other microorganisms that have commensal,"
+"Background {#Sec1}\n==========\n\nIn the global scale, lung cancer is one of all common carcinoma, which always keeps the leading position, and is the first cancer in the morbidity and mortality of carcinoma. According to the GLOBOCAN 2008 data, there are 23\u00a0% of total cancer-related mortalities and 17\u00a0% of newly diagnosed cancer cases for primary lung cancer \\[[@CR1]\\]. Over the past 30\u00a0years in China, the mortality rate of lung cancer has increased by 465\u00a0% \\[[@CR2]\\], it is responsible for more deaths than prostate, colon, and breast tumors combined \\[[@CR3]\\]. Although there are great advances recently in the cancer treatments, the prognosis of patients with lung cancer is poor even after curative surgery and chemotherapy, the rate of 5-year survival is less than 15\u00a0% \\[[@CR4]\\]. The main reasons for the low survival rate of the patients could involve the lack of sensitive and specific biomarkers for prognosis of lung cancer. Therefore, it is necessary to identify the biomarkers for the prognosis of lung cancer that lead to enhancing more effective individual therapies, reduce the mortality, and increase 5-year survival rate.\n\nClassically, lung cancer is pathologically classified into non-small cell lung cancer (NSCLC) and small cell lung"
+"1. Introduction {#sec1-materials-12-00255}\n===============\n\nWith the demand of electromagnetic shielding devices, conductive coatings, and antistatic materials, the conductive polymer materials have attracted more attention recently \\[[@B1-materials-12-00255],[@B2-materials-12-00255],[@B3-materials-12-00255]\\]. The electrical and thermal conductivities of polymers can be achieved by adding two or more carbon nano-fillers with different geometries in the matrix. Among three geometrically different types of carbon nano-fillers, i.e., particles, tubes, and platelets, the carbon nanotube and graphene are the most popular candidates as fillers used to enhance the electrical and thermal conductivities of the polymer materials. Compared with the carbon fillers with other geometrical characteristics, the one-dimensional shape of CNTs makes them potential fillers in the polymer materials to enhance the electrical and thermal conductivities because of their high aspect ratios. Recently, the application of graphene as the nano-fillers to reinforce the properties of polymer materials has rapidly increased because graphene has larger aspect ratio than CNTs, which makes it easy for electrical and thermal conduction \\[[@B4-materials-12-00255],[@B5-materials-12-00255],[@B6-materials-12-00255]\\]. However, the problem of agglomeration caused by the metallic bonds and Van der Waals interactions between the graphene sheets increases the difficulty of dispersion in the polymer matrix \\[[@B7-materials-12-00255],[@B8-materials-12-00255]\\]. To overcome the shortcoming of agglomeration, some studies proposed that adding CNTs in the"
+"Introduction {#s1}\n============\n\nRegulation of gene expression and protein levels is the result of a series of complex intra-cellular mechanisms which involve interactions with various macromolecules.\n\nThe first major step occurs in the nucleus and includes the transcription of the DNA to messenger RNA (mRNA) by RNA polymerase (RNAP), whilst the second major step is the translation of mRNA to protein by the ribosome in the cytoplasm [@pone.0102308-Alberts1]--[@pone.0102308-Dana1]. Additional regulatory steps include the degradation of the mRNA and protein molecules during the transcription and translation steps [@pone.0102308-Alberts1].\n\nThe current study is related to the interaction between two of the gene expression stages: the translation of mRNA molecules to proteins and the degradation of mRNA molecules. In both stages intra-cellular macromolecules interact with mRNA molecules: in the case of translation, mRNA molecules are scanned by ribosomes, the elongation step includes the translation of the mRNA nucleotides (nts) triplets to amino acids [@pone.0102308-Alberts1], [@pone.0102308-Kapp1], [@pone.0102308-Sonenberg1]; the degradation step includes the digestion of the mRNA molecules by intracellular enzymes [@pone.0102308-Alberts1], [@pone.0102308-Shalem1].\n\nTranscript degradation regulation is not fully understood [@pone.0102308-Schoenberg1]--[@pone.0102308-Sharova1] and not much is known regarding the enzymes that degrade mRNAs and how they are regulated [@pone.0102308-Schoenberg1], [@pone.0102308-Ross1], [@pone.0102308-Newbury1]. mRNA decay can be divided"
+"Introduction\n============\n\n\u03b1-Actinin is an actin-binding cytoskeletal protein present in a variety of cells \\[[@B1]\\] and in focal adhesion sites where cells adhere to the substrate \\[[@B2]\\]. There is biochemical \\[[@B3]\\] and histologic \\[[@B4]\\] evidence that focal adhesion complexes, containing \u03b1-actinin and other footpad material, are left behind as a result of normal movement of cells \\[[@B2]\\], perhaps at increased rates when neutrophils and monocytes move into inflammatory tissue. We have shown that \u03b1-actinin is abundant in the bone marrow stroma matrix, presumably at focal adhesion sites \\[[@B5]\\]. We have also reported that a 31 kDa amino-terminal \u03b1-actinin fragment, which we have named mactinin, is generated by the degradation of extracellular \u03b1-actinin by monocyte-secreted urokinase \\[[@B6]\\]. Furthermore, we have demonstrated that mactinin is present in inflammation caused by *Pneumocystis carinii*pneumonia, by examining bronchoalveolar lavage fluid from mice with infection \\[[@B6]\\]. It was not present in mice not challenged with *P. carinii*, suggesting that inflammaton is necessary for mactinin formation. We have also reported that mactinin promotes monocyte/macrophage maturation \\[[@B7]\\]. For example, \u03b1-actinin fragments significantly increase lysozyme secretion and tartate-resistant acid phosphatase staining in peripheral blood monocytes. In contrast, intact \u03b1-actinin has no maturation-promoting activity. We proposed that mactinin is present"
+"Systemic lupus erythematosus (SLE) is a common autoimmune disease characterized by abnormal T- and B-cell activation, cytokines disorders, and considerable production of autoantibodies ([@CIT0001]). Despite central mechanisms of tolerance, some T cells recognizing self-antigens are released into the periphery. One of the mechanisms employed to eliminate or control these potentially damaging cells is regulatory T cells (Tregs). A number of immune Tregs have been described ([@CIT0002]). CD4^+^ Tregs play an important role in the maintenance of peripheral tolerance and are characterized by the expression of the CD25 surface marker and the transcription factor forkhead box protein 3 (FOXP3), making up to 5--10% of the normal CD4^+^ T-cell population. Abrogation of CD4 Tregs development and/or peripheral function may cause autoimmune diseases ([@CIT0003]).\n\nCD8^+^CD25^+^FOXP3^+^ T cells with regulatory function in maintaining self-tolerance have been identified and can be generated by continuous antigen stimulation. Human CD8^+^ Tregs are implicated in autoimmune disorders: multiple sclerosis and inflammatory bowel disease ([@CIT0002], [@CIT0004]). Suppressive CD8 Tregs appear after T-cell receptor stimulation, suppressing cellular proliferation of CD4^+^ na\u00efve and effector T cells via cell--cell contact lysis or soluble factors like interleukin (IL) 10 and transforming growth factor beta (TGF-\u03b2). CD8 Tregs have suppressive ability typically associated with"
+"Regulatory T (T~reg~) cells are central players in establishing homeostasis of the immune system by suppressing activation, proliferation and effector functions of various immune cells^[@R1]^. They develop in the thymus from CD4^+^ single-positive (CD4SP) cells or differentiate from na\u00efve CD4^+^ T cells^[@R2]^. The cytokine TGF-\u03b2 drives differentiation of T~reg~ cells by up-regulating expression of Foxp3 transcription factor that is necessary for suppressive activity and serves as a marker of T~reg~ cells^[@R3]--[@R5]^. Deregulation of T~reg~ cell development and function leads to autoimmune diseases and immunopathology^[@R1],[@R6]--[@R8]^. Because of their important roles in numerous diseases including allergy^[@R9]^, autoimmunity^[@R1],[@R6]--[@R8]^, microbial infections^[@R10]^ and cancer^[@R11]^, T~reg~ cells have become a focus for development of various therapies aiming to treat autoimmune disorders and graft-versus-host disease^[@R12],[@R13]^. Thus, a thorough understanding of the regulatory processes that govern T~reg~ cell differentiation is necessary.\n\nCell specification is under control of cell-specific enhancers. Foxp3 is the signature transcription factor that defines T~reg~ cells, which is regulated by three distal enhancer elements including conserved noncoding-sequence (CNS) 1, CNS2 and CNS3 at different stages of T~reg~ cell development^[@R14]^. The genome-wide enhancer landscape in T~reg~ cells has been recently described^[@R15]^. Foxp3 does not establish T~reg~-specific enhancer landscape but instead exploits previously established already existing enhancers^[@R16]^."
+"Introduction\n============\n\nRheumatoid arthritis is a chronic inflammatory disorder, characterized by cellular infiltration of and proliferation in the synovium, leading to the progressive destruction of the joints. Dendritic cells, monocytes, T cells, B cells, and neutrophils infiltrate the synovium and interact with each other to induce chronic synovitis \\[[@B1],[@B2]\\].\n\nDendritic cells are efficient antigen-presenting cells, and develop innate and adaptive immune responses through interactions with T cells \\[[@B3]\\]. Dendritic cells determine the fate of T cell differentiation through the cytokines they produce; IL-12 induces Th1 cells, the combination of IL-6, IL-23, and TGF-\u03b2 induces Th17 cells, and TGF-\u03b2 induces regulatory T cells (Treg) \\[[@B3],[@B4]\\]. Recently, Th17 cells have been shown to play a major role in both human and mouse arthritis \\[[@B5]-[@B7]\\]. Moreover, CD4^+^T cells activated by dendritic cells express RANKL and facilitate osteoclast development, leading to bone erosion in joints with rheumatoid arthritis \\[[@B8]\\]. It is hypothesized that dendritic cells are activated by unknown stimuli in peripheral tissues, and migrate into the lymph nodes, where they induce T cells to proliferate. Activated T cells, as well as dendritic cells, migrate into the joints and induce inflammatory processes, including the production of cytokines such as TNF-\u03b1, IL-1, and IL-6, resulting"
+"Introduction\n============\n\nEndogenous fungal endophthalmitis, especially caused by *Candida*, is usually seen in patients under intravenous hyperalimentation (IVH) or with indwelling lines. Apart from catheter-related factors, supposed risk factors include abdominal operations, major cardiopulmonary vascular surgery, diabetes mellitus, other compromising conditions, immunocompromised status, and neutropenia.[@b1-imcrj-10-189],[@b2-imcrj-10-189] These significant conditions continue to be of concern to medical personnel, including ophthalmologists. Some patients continue to experience poor visual prognoses despite the prescription of systemic anti-fungal drugs.[@b3-imcrj-10-189] However, early detection and treatment generally allow the progression of the distinctive cholioretinitis to be controlled.\n\nUsually, fungal endophthalmitis is identified via systemic examination (a blood culture positive for a fungus \\[i.e., fungemia\\] in those with prolonged fever). A recent report indicates that the frequency of fungal endophthalmitis among patients with fungemia is relatively low; it was speculated that anti-fungal treatments had already been administered prior to ophthalmic examination.[@b4-imcrj-10-189]\n\nIn the early stage of the disease, a chorioretinal lesion is evident upon fundus examination. Next, a small circle of yellowish-white spots (an exudate) appear on the retina. If the anterior chamber becomes inflamed, this may trigger the development of anterior synechiae, iris rubeosis, and (secondary) glaucoma.\n\nHere, we report a case of *Candida* fungemia in a 92-year-old"
+"INTRODUCTION {#s1}\n============\n\nBreast-conserving surgery with adjuvant radiotherapy has been shown in several large randomized controlled trials to yield survival rates equivalent to those of mastectomy in the treatment of early-stage breast cancer \\[[@RRT019C1]\\]. For patients with left breast cancer, the supine tangential fields anatomically include partial volumes of the underlying lung, heart and left anterior descending coronary artery (LAD). Clinical experiences in the last two decades have indicated the advantages of prone position in achieving better dose distributions and in sparing normal tissue in large-breasted western women \\[[@RRT019C2], [@RRT019C3]\\]. Prone breast irradiation has provided consistently lower lung doses, with varied effects on cardiac dose \\[[@RRT019C4]--6\\]. The criteria for selecting patients who would benefit most from prone radiotherapy are still under investigation.\n\nThe standard technique for treating breast cancer patients is conventional wedged tangential fields. Intensity-modulated radiotherapy (IMRT)---including simplified IMRT \\[[@RRT019C7]\\], forward IMRT (fIMRT) \\[[@RRT019C8]\\], and inverse IMRT \\[[@RRT019C9], [@RRT019C10]\\]---has been applied to whole-breast irradiation to achieve better dose homogeneity and to reduce acute toxicities compared with conventional wedged tangential fields. However, the IMRT procedure does not consistently prevent doses to normal tissues. Although most IMRT studies have demonstrated a potential reduction of high-dose area in cardiac and lung toxicity,"
+"Introduction {#Sec1}\n============\n\nWorldwide, there are currently 425 million people estimated to suffer from type 1 and 2 diabetes, which results in a yearly healthcare expenditure of 727 billion USD. By 2045, the number of sufferers is predicted to increase to 693 million, which will further increase the economic burden of the disease \\[[@CR1]\\]. One of the most common and debilitating complications associated with diabetes is the development of diabetic eye disease associated with diabetic retinopathy (DR), diabetic macular edema and glaucoma \\[[@CR1]\\]. Over 90% of patients with type 1 diabetes and around 60% of patients with type 2 diabetes will suffer from a level of DR ranging from blurred vision to complete vision loss \\[[@CR2]\\]. Given the increasing incidence of diabetes, there is thus a significant need to understand the mechanisms which regulate DR, with the aim of developing effective therapeutic agents for the complication.\n\nEndothelial cell injury is a hallmark of the microvascular complications observed due to chronic hyperglycaemia in diabetes. Indeed, small improvements in glycosylated-haemoglobin directly correlate with a significantly reduced risk of developing DR \\[[@CR3]\\]. Hyperglycaemia increases metabolic disruption, inflammation and hypoxia in patients with diabetes, associated with the pathophysiology of DR \\[[@CR2]\\]. DR, characterised by"
+"Background {#Sec1}\n==========\n\nMedical knowledge bases (KBs) play an important role in healthcare research. Existing KBs vary from coding systems such as ICD10 \\[[@CR1]\\], terminology systems such as UMLS \\[[@CR2]\\], clinical ontology systems such as SNOMED CT \\[[@CR3]\\] to medical databases such as DrugBank \\[[@CR4]\\]. The major objectives for these KBs are to provide knowledge to medical workers and to promote standardization and interoperability for biomedical information systems and services. Besides, there exist many different types of biomedical KBs. For example, SIDER \\[[@CR5]\\], and AMDD \\[[@CR6]\\] contain drug-related information. Diseasome \\[[@CR7]\\], ParkDB \\[[@CR8]\\], and ChemProt \\[[@CR9]\\] describe disease and disease-related gene information. These KBs are necessary in automatically processing and analyzing electronic medical records (EMRs) and then form the basis of the upper information applications such as clinical decision support systems.\n\nCurrently there are many general-purpose KBs built by automatic approaches. The DBpedia project \\[[@CR10]\\] extracted structured information from Wikipedia and published them on the Web. YAGO \\[[@CR11]\\] was derived from Wikipedia, WordNet, and GeoNames. NELL \\[[@CR12]\\], SOFIE \\[[@CR13]\\], and PROSPERA \\[[@CR14]\\] extracted data from the Web. The input data for NELL consisted of an initial ontology as well as a small number of instances. SOFIE extracted ontological facts from"
+"INTRODUCTION {#s1}\n============\n\nThe definition and nature of driver genes have been discussed intensely in the last decade. Here, for the sake of simplicity, we highlight a manageable number of cancer driver genes as therapeutic targets based on the 138 driver genes identified by B. Vogelstein and his group and treat these genes as common feature points of multiple cancer genome mutational landscapes, a kind of focus that is critical for targeted drug development \\[[@R1]--[@R5]\\].\n\nSince the majority of targeted therapies address only one oncogene, resistance develops eventually even if one of the actual drivers was targeted. The rapid development of drug resistance is due to the fact that more than a single driver may exist in a given tumor \\[[@R6]--[@R8]\\]. In addition, all tumor types are heterogeneous and certain cancer cell subpopulations or subclones tend to persist \\[[@R9]--[@R11]\\]. After the initial shock caused by the inhibition of a single key driver other non-targeted drivers come to the forefront. They are activated via feedback loops and/or with increased expression at the protein level and sometimes newly acquired mutations within the already mutated genes or in others \\[[@R12]--[@R15]\\]. All tumors with multiple driver mutations in their genome have the potency to"
+"1. Introduction {#sec1}\n===============\n\nPrior to the availability of commercial intact parathyroid hormone (PTH) assays, serum total alkaline phosphatase (TAP) measurements were used as one of the surrogate markers of high bone turnover that was utilized in the management of chronic kidney disease mineral and bone disorder (CKD-MBD) \\[[@B1]\\]. Subsequently, in 2003 the Kidney Disease Outcome Quality Initiative (KDOQI) guidelines on CKD-MBD made no recommendations regarding the use of alkaline phosphatase and this has made it a less preferred marker to PTH. However, in 2009 the Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommended measurement of TAP every 12 months in CKD 4-5D \\[[@B2]\\] and more recently evidence continued to emerge on the importance of higher levels of alkaline phosphatase in the pathogenesis of vascular calcification via hydrolysis of pyrophosphate which is a potent inhibitor of vascular calcification \\[[@B3]--[@B5]\\]. This was further supported by a study that showed elevated levels of alkaline phosphatase, independent of PTH, calcium, or phosphorus as predictor of coronary artery calcification in haemodialysis patients \\[[@B6]\\]. Interestingly, in a recent secondary analysis of the handling erythropoietin resistance with oxypentifylline (HERO) trial, high levels of alkaline phosphatase were also associated with erythropoietin stimulating agent hyporesponsiveness \\[[@B7]\\]. These findings"
+"Cardiac biomarkers have evolved as essential tools in cardiology over the last 50 years, that is, for primary and secondary prevention, the diagnosis and management of acute myocardial infarction (AMI), and the diagnosis and risk stratification of heart failure (HF). We are beginning an era when it may be possible for biomarkers to direct treatment to optimize patient management. This is already the case with cardiac troponin (cTn) but should be the goal with all biomarkers. This special issue is a compilation of timely reviews and original articles on this topic.\n\nMore than 60 years ago in 1954 Karmen et al. \\[[@B1]\\] first reported that release of aspartate aminotransferase (AST), formerly glutamate oxaloacetate transaminase (GOT), from necrotic cardiac myocytes could be detected in the serum and could aid in the diagnosis of AMI. This initiated the era of enzymology in cardiology. In 1955 lactate dehydrogenase (LDH) was first published as a marker of AMI \\[[@B2]\\], and a direct enzymatic assay for *\u03b1*-hydroxybutyrate dehydrogenase activity was later developed to increase cardiac specificity \\[[@B3]\\]. Subsequently an effective enzymatic assay for the quantification of creatine kinase (CK) activity was developed by Rosalki \\[[@B4]\\] and established this enzyme as the standard marker for the"
+"1. Introduction {#sec1-nutrients-12-00978}\n===============\n\nSkeletal muscle atrophy and loss of strength is frequently observed and correlated with poor outcomes in patients with cancer \\[[@B1-nutrients-12-00978]\\]. We previously reported that low volume of skeletal muscle at diagnosis is associated with worse survival in patients with hematological malignancies \\[[@B2-nutrients-12-00978],[@B3-nutrients-12-00978]\\]. Recently, metabolomics analysis has been used to understand how amino acid profiles are affected by glucose metabolism \\[[@B4-nutrients-12-00978]\\], aging \\[[@B5-nutrients-12-00978]\\], and cancer \\[[@B6-nutrients-12-00978]\\]. Toyoshima et al. \\[[@B7-nutrients-12-00978]\\] have reported an association between plasma amino acid profiles and age-related sarcopenia, and demonstrated that sarcopenia was correlated with lower tryptophan (Trp) and histidine (His) and higher glutamine (Gln) and proline (Pro) concentrations. Furthermore, plasma Trp and His concentrations are often reduced in patients with particular types of cancer \\[[@B8-nutrients-12-00978]\\]. These findings suggest that Trp may be a key essential amino acid associated with cancer-related sarcopenia; hence, analysis of serum Trp levels may help improve our understanding of the mechanisms underlying sarcopenia in patients with cancer.\n\nTrp is involved in two important metabolic pathways, namely, kynurenine and serotonin synthesis pathways \\[[@B9-nutrients-12-00978]\\]. Most of Trp degradation occurs through the kynurenine pathway. Indoleamine 2,3-dioxygenase (IDO) is involved in the first and rate-limiting step of Trp metabolism, which produces kynurenine"
+"INTRODUCTION\n============\n\nThe prognosis of high-risk neuroblastoma after conventional chemotherapy is generally poor ([@B1]-[@B3]). Therefore, a strategy using high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) has been explored to improve the prognosis of patients with high-risk neuroblastoma ([@B2]-[@B5]). This strategy is based on the hypothesis that dose escalation might improve the survival of children with high-risk neuroblastoma. The results of randomized trials comparing HDCT/ASCR with chemotherapy alone showed a better event-free survival (EFS) in the HDCT/ASCR arm than in the continuous chemotherapy arm ([@B3], [@B6]). However, the overall EFS was unsatisfactory.\n\nIn this context, a few studies have examined the efficacy of double or triple tandem HDCT/ASCR procedures to further improve the outcome of high-risk neuroblastoma patients ([@B7]-[@B9]). George et al. ([@B7]) and Sung et al. ([@B8]) carried out a single arm trial of tandem HDCT/ASCR as consolidation therapy and reported improved long-term survival with acceptable toxicity. Kletzel et al. ([@B9]) also conducted a single arm trial of triple tandem HDCT/ASCR and reported improved survival. These studies demonstrated that further dose escalation might result in additional improvements in the EFS of high-risk neuroblastoma patients. However, there is no study that has compared the efficacy of single and tandem HDCT/ASCR"
+"Introduction {#s1}\n============\n\nDendritic cells (DCs) are known to be professional antigen-presenting cells (APC), as these cells are capable of presenting processed peptides from various antigens, initiating and modulating the adaptive immune response by activating both T and B lymphocytes ([@B1], [@B2]). Therefore, they are considered to be of great importance for the induction of an adequate adaptive immune responses ([@B1], [@B3]). DCs were first reported in 1973 by Steinman et al., where their morphological characteristics were defined, although it was not until 1998 that their function, as well as the proteins expressed on their surface, were characterized ([@B1], [@B4]). Since then, the knowledge acquired about DCs has increased over time.\n\nDuring an infection, several molecules might be recognized and used to initially activate the innate immune system. These can be classified as pathogen-associated molecular or damage-associated patterns (PAMPs and DAMPs, respectively) ([@B5], [@B6]). These molecules will be recognized by pattern recognition receptors (PRRs) -expressed in most innate cells-, among which Toll-like receptors (TLRs), RIG-I-like receptors (RLRs), and NOD-like receptors (NLRs) are included. The interaction between PAMPs and PRRs promotes the release of cytokines, chemokines, and other chemical mediators that induce the inflammation of the infected tissue ([@B7]--[@B9]). TLRs are"
+"Introduction {#s1}\n============\n\nBovine tuberculosis (bTB) is an insidious, progressive disease of livestock that has cost the United States livestock industry millions of dollars in losses prior to and since the establishment of a national eradication campaign in 1917 [@pone.0050147-Essey1]. Despite this large-scale eradication effort, bTB is a reemerging infectious disease in the U.S. It is endemic in select areas of Michigan and recent outbreaks have occurred in Minnesota, California, and New Mexico.\n\n*Mycobacterium bovis*, the causative agent of bovine tuberculosis, creates significant problems for agriculture at both the state and national levels. From a management and animal health perspective, it is essential that infected animals are reliably detected and removed to prevent the spread of the disease. Current diagnostic tests are primarily based on immune responses to crude protein extracts from *M. bovis* (PPDb) injected intradermally. Three days after injection of PPDb, excessive swelling at the injection site indicates that the animal may be infected with *M. bovis*.\n\nThe sensitivity (*Se*) and specificity (*Sp*) of the single intradermal test (SIT) depends on a cut-off value, and there is an inverse relationship between test *Se* and *Sp* values [@pone.0050147-delaRuaDomenech1]. For example, the SIT test *Se* could be as high as"
+"1. Introduction {#sec1}\n===============\n\nCats and dogs are often considered more than household pets; they are esteemed family members. Over the years, not only their population has grown immensely but also the interest in animal health and well-being has grown immensely (Grze\u015bkowiak et al.) \\[[@B1]\\]. Recent efforts have focused on the development of functional foods for pets, such as probiotics, which are live microorganisms that confer health benefits to the host when ingested in adequate quantities (Hill et al.) \\[[@B2]\\]. The composition of animal gut microbiota may be negatively impacted by antibiotics, gastrointestinal infections, changes in diet, and weaning (Vezquez-Mendonza et al.) \\[[@B3]\\]. Probiotics have been widely used for the prevention and treatment of disorders and diseases, ranging from allergies to acute gastroenteritis. They have shown a great potential for the control of overweight, urogenital tract infection, and parasitic gastritis, but further research is needed to confirm these applications (Grze\u015bkowiak et al.) \\[[@B1]\\].\n\nThe microorganisms most used as probiotics are those belonging to the group of Gram-positive bacteria, that present the outermost portion of the cell wall composed of peptidoglycans and lipoteichoic acid and are more porous (*Lactobacillus*, *Streptococcus*, *Lactococcus*, *Pediococcus*, *Enterococcus*, *Bifidobacterium*, *Bacillus*, and *Clostridium*) (de Melo et al.)"
+"Introduction {#Sec1}\n============\n\nThe subduction of the oceanic lithosphere into Earth's convecting mantle is typically associated with narrow sub-planar regions of earthquakes called Wadati--Benioff zones. These earthquakes can be as deep as 650--700 km^[@CR1]^, providing strong evidence that subducting slabs penetrate into the mantle transition zone (MTZ). Since the early 1990s, independent constraints on slab extent and morphology have been provided by seismic tomography, which has imaged high seismic wavespeed anomalies associated with regions of subduction^[@CR2]--[@CR4]^. Tomographic studies have demonstrated that contiguous slabs can extend well beyond the limits of deep seismicity. Some of these slabs penetrate aseismically into the lower mantle, while others stagnate in the MTZ^[@CR3],[@CR5]--[@CR8]^. Slabs exhibit a wide range of morphologies, from near-planar (e.g., Japan--Kamchatka) to folded and contorted (e.g., Tonga--Fiji--Kermadec) and from contiguous to torn or thinned^[@CR9]--[@CR12]^. These variations in slab morphology must be a function of the history and distribution of forces acting on the slab, and the material properties of the slab itself. In this study, we seek to constrain the shape of the Izu--Bonin slab using high-resolution tomographic images, and use the morphology to make inferences about the physical characteristics and geodynamics of the region.\n\nThe Izu--Bonin subduction zone (Fig.\u00a0[1](#Fig1){ref-type=\"fig\"}) is"
+"INTRODUCTION\n============\n\nThe increase in life expectancy has raised the number of older individuals living in the community with disabilities and with a higher risk of dependence, who need frequent human help or care beyond the kind habitually required by a healthy adult[@B1]. As a result, the aging population is increasing the attention to the challenges and demands for long-term care[@B2], especially in low- and middle-income countries, where most older individuals will live[@B2].\n\nLong-term care are the activities undertaken by informal (family, friend, or neighbors) or formal (health and social professionals or paraprofessionals) caregivers to ensure that people with or at risk of an ongoing loss of intrinsic capacity can maintain a level of functional ability and quality of life[@B2] ^,^ [@B3]. Accordingly, unmet need for personal assistance for activities of daily life is related to increased risk of mortality[@B4] and morbidity (e.g. falls, weight loss)[@B5], hospitalization and re-hospitalization^6--8^, and psychological distress[@B9].\n\nUnmet need for basic activities of daily life (BADL) was found to range from 14% in the United States[@B8], to 61% in China[@B4]. Regarding instrumental activities of daily life (IADL) unmet need ranged from 18% in the United States[@B5], to 40%, among women in Montreal[@B9]. Moreover, the main"
+"Introduction {#Sec1}\n============\n\nFisher information is proposed to detect the precision of the parameter in estimation theory^[@CR1]^. Extending the estimation theory from the classical regime to the quantum regime, quantum Fisher information plays a paramount role in quantum information theory^[@CR2]--[@CR4]^ and quantum metrology^[@CR5],[@CR6]^. Quantum Fisher information has been widely studied theoretically and experimentally^[@CR7]--[@CR18]^. Quantum Fisher information has become a highly studied subject because it measures the phase sensitivity of the systems^[@CR19]--[@CR23]^. Moreover, quantum Fisher information in non-inertial frames has been investigated for different systems, such as the performance of quantum Fisher information under the Unruh-Hawking effect in the context of relativistic quantum information theory^[@CR24]^, the dynamic of the teleported quantum Fisher information^[@CR25]^, and the Unruh acceleration effect on the precision of parameter estimation for a general two-qubit system^[@CR26]^. The existence of the maximal quantum information matrix in multi-parameter quantum estimation^[@CR27]^ and entanglement detection have been discussed extensively^[@CR28],[@CR29]^. The dynamics of quantum Fisher information in the two-level system coupled to a single bosonic reservoir^[@CR30],[@CR31]^ and multiple bosonic reservoirs^[@CR32],[@CR33]^ has been discussed. Quantum Fisher information is used as a predictor of decoherence in the preparation of spin-cat states for quantum metrology^[@CR34]^. Also, quantum Fisher information of a single qubit has quantified^[@CR35],[@CR36]^. The"
+"Notch in the fly nervous system: selection of a neural progenitor and specification of neuronal subtype identity\n================================================================================================================\n\nThe Notch pathway is a crucial signalling pathway involved in development and disease that functions through the binding of transmembrane ligands (the DSL proteins, for Delta-Serrate-Lag2) to transmembrane receptors (the Notch molecules) on adjacent cells. Such binding triggers the proteolysis of Notch and the release of its intracellular domain (the so-called Notch-intra fragment), which is translocated into the nucleus. Canonical Notch signalling involves the binding of Notch-intra to DNA-binding cofactors belonging to the CSL family (for CBF1 in human, Suppressor of Hairless in *Drosophila*and Lag-1 in *Caenorhabditis elegans*) \\[[@B1],[@B2]\\]. Notch-intra/CSL complexes subsequently activate transcription of target genes through the recruitment of the histone-acetyl transferases CBP/p300 \\[[@B3],[@B4]\\] and PCAF \\[[@B5]\\].\n\nNotch activity has been extensively studied in the *Drosophila*nervous system, where it regulates cell fate choice in several different contexts. First, the Notch pathway is required to select single cells to become neural precursors from a cluster of equipotent progenitors that express basic helix-loop-helix (bHLH) transcription factors called proneural genes (Figure [1A](#F1){ref-type=\"fig\"}). Expression of proneural genes endows cells with a neural potential as these genes are both necessary and sufficient for the formation"
+"1. Introduction {#sec1-polymers-12-00573}\n===============\n\nAn open wound is a type of injury that happens when the skin is punctured, torn, or cut. It specifically refers to the epidermis of the skin damaged by a sharp injury in pathology \\[[@B1-polymers-12-00573]\\]. The main factors that promote wound healing include mechanical protection of the localized wound, prevention of infection, absorption of wound exudates, and maintenance of the microenvironment \\[[@B2-polymers-12-00573]\\]. Modern wound dressings are technical products that create an ideal healing environment for wounds \\[[@B3-polymers-12-00573]\\]. Given these requirements, the ideal wound dressing should be designed with certain specialties, including excellent biocompatibility, good mechanical properties as barriers, the ability to create a native extracellular matrix to stimulate cell migration, ability to remove excessive exudates, and sustained drug release properties to prevent bacterial infections and promote tissue structure proliferation and recombination \\[[@B4-polymers-12-00573],[@B5-polymers-12-00573]\\]. No particular dressing has all of these characteristics, which is why the dressing is selected only after strict assessment. Therefore, composite films composed of biocompatible polymer and multifunctional drugs as wound dressings have attracted great attention in the field of wound healing \\[[@B6-polymers-12-00573]\\].\n\nRecently, electrospinning membranes and scaffolds have aroused great interest because of their biomedical applications in wound dressing, such as drug delivery,"
+"Introduction {#s1}\n============\n\nThe development and progression of hepatocellular carcinoma (HCC) is significantly correlated to the accumulation of genomic alterations [@pone.0028404-Coleman1]. Therefore, it is important to have a clear landscape of the genomic aberrations that occur during the multistep process of hepatocarcinogenesis. Previous studies have used high-resolution molecular karyotyping analyses to provide a comprehensive catalog of structural aberrations of the whole chromosomes in HCC [@pone.0028404-Wong1]. However, this method is highly specialized and time-consuming. As a consequence, only a very limited number of HCC cases have been evaluated in these studies. Moreover, the modest resolution of the karyotyping analysis made it difficult to fully define the overall genomic profiles of HCC in a more accurate manner. Comparative genomic hybridization (CGH) has been developed in recent years to monitor the DNA copy number changes at a global level [@pone.0028404-Kallioniemi1]. However, traditional CGH techniques still have the limitation of modest resolution (approximately 2 Mb for amplifications and 10--20 Mb for deletions) and thus could not detect changes in smaller chromosomal regions [@pone.0028404-Hermsen1]. In comparison, array-based CGH (array CGH) is a newly developed technology that allows for high-throughput and high-resolution (at 1 Mb) screening of genome-wide DNA copy number changes (either amplifications or deletions)"
+"***Cite this article as:*** Sabzghabaei F, Salajeghe M, Soltani Arabshahi SK. Evaluating ambulatory care training in Firoozgar hospital based on Iranian national standards of undergraduate medical education. Med J Islam Repub Iran. 2017 (17 Dec);31:99. https://doi.org/10.14196/mjiri.31.99\n\n\u2191 What is \"already known\" in this topic: {#box1}\n========================================\n\nEvaluating the quality of education is one of concerns in Iranian medical education, specifically in ambulatory section. That highlights the urgency of paying extra attention to the effectiveness of the higher education system.\n\n\u2192 What this article adds: {#box2}\n=========================\n\nThe national standards of ambulatory training in undergraduate medical education are highly useful in evaluating ambulatory training. There is an appropriate approach towards applying the national standards of ambulatory training in undergraduate medical education in Firoozgar Hospital.\n\nIntroduction {#s1}\n============\n\nIranian medical universities need to improve the quality of their medical education and constantly evaluate its status because of their important role in promoting medical education and providing health care and sanitation services.\n\nClinical training mainly concerns training and learning about the patients and their problems, which is the backbone of medical education. Since most of the patients seek ambulatory care services in ambulatory care centers and only a few of them go to"
+"Background\n==========\n\nAromatic amino acids and aromatic compounds are the essential components for the plant as well as for microorganism survival and hence their biosynthesis via shikimate pathway is crucial for their continued existence. EPSPS (5-enolpyruvylshikimate-3-phosphate synthase, EC 2.5.1.1.9), is considered as the sixth crucial enzyme of the shikimate pathway, catalyzes the formation of 5-enolpyruvylshikimate-3-phosphate (EPSP) from shikimate-3-phosphate (S3P) and phophoenolpyruvate (PEP) in the chloroplast \\[[@B1]\\] where EPSPS, a product of this pathway, acts as a precursor for the biosynthesis of aromatic amino acid in plants and microorganism \\[[@B2],[@B3]\\]. Two types of EPSPS from different organisms have been classified \\[[@B4],[@B5]\\]: type I EPSPS synthases, which are mainly found in all types of plants and bacteria and are naturally sensitive to herbicide named glyphosate (GLP; N-Posphonomethyl- glycine), and type II EPSPS synthases, that have been isolated from naturally occurring specific forms of microbes and are tolerant to glyphosate. The two types of EPSPS were found to share less than 30% homology with respect to their amino acid sequences. The identification of EPSPS as primary target of the broad spectrum non-selective herbicide glyphosate has generated immense interest in characterization of the enzyme \\[[@B6]\\]. Glyphosate can starve the plants of aromatic amino acids"
+"Introduction\n============\n\nQuestions of cost containment resolve into two distinct sorts of question. One sort is normative: For example, what are the right level and growth rate of health care costs? This question in welfare economics is appropriately discussed in terms of the value of the beneficial outcomes that health services produce in relation to the value of what is necessarily forgone. The other sort is positive: For example, given the available technology, what resources are necessary in order to produce any given level of outcome? These questions can be tackled at either the microeconomic or the aggregate level. In microeconomic analysis, the focus is on cost effectiveness, cost utility, and cost-benefit analysis ([@b9-hcfr-89-supp-021]). The aim is to make cross-program comparisons of marginal costs and benefits in order to determine both the optimal mix of programs and the payoff to increased spending (or the marginal lost benefits of reduced spending). A dense jungle must be hacked through here, and, although the methodology that ought to be used seems clear, its empirical implementation is underdeveloped. (A pioneering study is [@b36-hcfr-89-supp-021].) In aggregate analysis, the emphasis is on total spending, its share in gross domestic product (GDP) and its principal components, the"
+"INTRODUCTION {#s0005}\n============\n\nCancers of the liver and intrahepatic bile ducts are expected to contribute to an estimated 21,600 United States deaths in 2019 \\[[@bb0005]\\]. Intrahepatic cholangiocarcinoma (ICC) is currently the second most common primary liver malignancy, and the incidence of ICC appears to be increasing \\[[@bb0010]\\]. ICC is, in general, associated with poor survival. Surgical resection is the therapeutic modality that offers the greatest potential to prolong survival and the only therapeutic modality that carries the potential to cure patients presenting with early-stage ICC. ICC is often, however, diagnosed at late stages when patients have distant metastatic disease. Surgical resection in these cases offers no potential to meaningfully impact survival and is used rarely to provide palliation.\n\nSurgical resection in patients with evidence of regional nodal involvement (N1) but no evidence of distant metastatic disease at diagnosis remains somewhat controversial. Consensus guidelines regarding optimal surgical management of patients with clinical evidence of regional lymph node involvement are not definitive. There are no prospective randomized trials comparing resection to systemic therapy alone in patients presenting with clinical evidence of node-positive resectable ICC. Results from various institutional and registry studies have primarily examined predictors of poor outcome including nodal status as"
+"Introduction {#Sec1}\n============\n\nThe inability of mature cardiomyocytes (CMs) to proliferate leads to a permanent loss of functional cells after injury \\[[@CR1]\\]. Previous studies in animal models of myocardial infarction have demonstrated that the function of a damaged heart may be improved by transplantation of sufficient numbers of functional CMs \\[[@CR2]\\]. Over the last years, pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have emerged as an attractive candidate stem cell source for obtaining CMs \\[[@CR3], [@CR4]\\]. The inherent capacity to grow indefinitely and to differentiate into all mature cells of the human body make PSCs the only cell source that can provide ex-vivo an unlimited number of functional and potentially autologous CMs for transplantation. The clinical translation of human ESC-derivatives has been greatly hampered by the risk of immune rejection due to their allogenicity and by ethical concerns \\[[@CR5]\\]. iPSCs can circumvent these drawbacks, allowing for ethically \"acceptable\" and safe patient-specific therapies \\[[@CR6], [@CR7]\\]. Moreover, iPSCs constitute a promising tool to establish disease-specific models of human inherited cardiac disorders and platforms for drug discovery and toxicity testing \\[[@CR7], [@CR8]\\].\n\nIn the last 5\u00a0years, several methodologies have been described for the differentiation"
+"Introduction {#s1}\n============\n\nAtherosclerotic disease is the primary cause of myocardial infarction, stroke, and peripheral vascular disease, which remains as the leading cause of death worldwide [@pone.0066607-Jaffer1]. Identification of atherosclerosis at the subclinical stages would essentially facilitate earlier selection of more effective treatments which may lead to a better prognosis. Currently, indexes including the intima-media thickness (IMT), flow mediated vasodilatation (FMD) (markers of endothelial dysfunction), arterial stiffness, and ankle-brachial index (ABI) are most commonly used in routine clinical practice to evaluate subclinical atherosclerosis [@pone.0066607-Kotliar1]. Nevertheless, more convenient and reliable markers, such as serum biomarkers, for subclinical atherosclerosis are yet to be identified.\n\nDiabetes is one of the most important risk factors for atherosclerosis [@pone.0066607-Beckman1]. In fact, 70% of the morbidity associated with type 2 diabetes is related to atherosclerosis. In light of this, a better understanding on the missing link between type 2 diabetes and atherosclerosis would help to design more effective strategies for early intervention of this disease.\n\nType 2 diabetes is commonly accompanied by the abnormal production of adipokines [@pone.0066607-Rabe1]. Notably, a number of adipokines have been implicated in vascular and atherothrombotic complications. The circulating levels of several pro-inflammatory adipokines are elevated in pro-atherothrombotic and atherothrombotic states [@pone.0066607-Berg1]."
+"On page 929, Ashton et al. report that an intracellular parasite regulates its own growth and exploits the inflammatory environment within its host to continue its survival and mediate long-term damage.\n\nFigure 1*T. cruzi* (blue dots) thrives in cells lacking (bottom) TXA~2~ receptors.\n\n*Trypanosoma cruzi*, the bug that causes Chagas\\' disease, initiates a short-lived acute infection in humans. A third of those infected, however, develop chronic cardiac disease that sets in after a long asymptomatic period. The mechanism by which the parasite facilitates this long-term pathology is still unclear.\n\nAshton et al. now show that the parasite infects vascular endothelial cells and secretes a bioactive lipid called thromboxane (TXA~2~). When produced by human cells, TXA~2~ has pro-inflammatory effects and can cause cardiac injury by triggering platelet aggregation, clotting, and vasoconstriction.\n\nThe parasitic TXA~2~ also promotes cardiac injury, the team finds, yet it somehow mediates an anti-inflammatory immune response in the host. Mice that lack cell surface receptors for TXA~2~ had increased inflammatory damage.\n\nThese mice also had a higher parasite load than wild-type mice, suggesting that the parasite suppresses its own replication by a negative feedback through the TXA~2~ receptor. The group is now dissecting TXA~2~ receptor signaling within infected"
+"Introduction {#sec1}\n============\n\nSarcoidosis is a multisystemic disease of unknown etiology characterized by the formation of noncaseating granulomas in several organs. The skin is the second most commonly involved organ with cutaneous involvement occurring in 25% to 30% of patients.[@bib1] Two types of cutaneous lesions are recognized in sarcoidosis: specific cutaneous sarcoidal lesions and nonspecific reactive lesions.[@bib1] Specific lesions manifest as noncaseating granulomas on skin biopsies; non-specific lesions are reactive to systemic sarcoidosis but do not have granulomas on biopsy.[@bib1] Sarcoidosis of the scalp most commonly manifests as alopecia, which may be scarring or nonscarring, and is primarily seen in women of African descent.[@bib1]^,^[@bib2] Sarcoidal scalp morphologies include erythema and indurated plaques and nodules, which may have scale, and all of which demonstrate noncaseating granulomas on biopsy. We present an unusual case of sarcoidosis imitating acne keloidalis nuchae (AKN).\n\nCase report {#sec2}\n===========\n\nA 47-year-old woman presented with a 2-month history of papules on the occipital scalp without an identifiable precipitating cause. Medical history was significant for a 17-year history of pulmonary sarcoidosis treated with oral corticosteroids and reportedly well controlled. However, review of systems found chronic dyspnea, loss of appetite, malaise, and a 20-pound weight loss in the previous"
+"Background {#Sec1}\n==========\n\nIn image guided radiotherapy, the ability to improve tumor control and reduce toxicity \\[[@CR1]\\], e.g. through dose escalation and hypo-fractionation \\[[@CR2]\\], and through advanced techniques \\[[@CR3], [@CR4]\\], relies on an accurate target concept \\[[@CR5]\\] and precise positioning to achieve the desired dose distribution \\[[@CR6], [@CR7]\\].\n\nThree-dimensional ultrasound (3D-US) is an attractive imaging modality in external beam radiotherapy \\[[@CR8], [@CR9]\\], both during planning (e.g. to improve soft tissue contrast for better target and organ at risk delineation) and during treatment (for non-invasive dose-free patient positioning control, and monitoring of inter- and intra-fraction organ movements). The accuracy of the technique depends not only on the achievable image quality in clinical routine \\[[@CR10]\\], but also on technical limitations of achievable precision during calibration \\[[@CR11]\\].\n\nIn ultrasound imaging, speed-of-sound effects \\[[@CR12], [@CR13]\\] and refractive effects have been known to distort the reconstructed geometry, and iterative approaches have been developed to reverse the curvature of ultrasound waves as described by Snell's law \\[[@CR14], [@CR15]\\]. Recently, such corrections have been applied to regions of the body known to harbor strong gradients in refraction index, like the cranium \\[[@CR16]\\] and the breast \\[[@CR17]\\].\n\nCalibration phantoms, however, are typically made of homogenous tissue equivalents, and"
+"Paris, M. T., Lafleur, B., Dubin, J. A., and Mourtzakis, M. (2017) Development of a bedside viable ultrasound protocol to quantify appendicular lean tissue mass. Journal of Cachexia, Sarcopenia and Muscle, 8: 713--726. doi: [10.1002/jcsm.12213](10.1002/jcsm.12213).\n\nIntroduction {#jcsm12213-sec-0005}\n============\n\nQuantifying lean tissue or muscle mass in ageing and clinical populations is of increasing importance due to emerging associations between low muscle mass and poor physical function, as well as increased rates of morbidity and mortality.[1](#jcsm12213-bib-0001){ref-type=\"ref\"}, [2](#jcsm12213-bib-0002){ref-type=\"ref\"}, [3](#jcsm12213-bib-0003){ref-type=\"ref\"}, [4](#jcsm12213-bib-0004){ref-type=\"ref\"}, [5](#jcsm12213-bib-0005){ref-type=\"ref\"} Lean tissue or muscle mass can be assessed by using several accurate and precise modalities such as dual\u2010energy X\u2010ray absorptiometry (DXA), computed tomography (CT), and magnetic resonance imaging (MRI).[6](#jcsm12213-bib-0006){ref-type=\"ref\"} DXA is often used in research settings because it provides a cost\u2010effective and accurate assessment of lean tissue, with minimal exposure to radiation. These advantages have led to DXA being commonly utilized for the assessment of low lean tissue mass in ageing populations[7](#jcsm12213-bib-0007){ref-type=\"ref\"}; however, it is rarely applied for lean tissue assessment purposes in clinical centres due to the limited accessibility of these scanners for body composition analysis in these settings. In certain clinical populations, CT and MRI scans, which have been performed as part of routine care, can be utilized for muscle"
+"Background {#section1-1073274817729043}\n==========\n\nIn 1907, Halsted published his results for radical mastectomy in the treatment of breast cancer.^[@bibr1-1073274817729043]^ Depending on the type of cancer, his cure rate results ranged between 25% and 75%. The surgery itself was morbid but remained the standard for many years to come. Since the advent of the radical mastectomy, an effort has been made to treat breast cancer effectively not only oncologically but also aesthetically. The radical mastectomy gave way to the modified radical mastectomy that followed with the simple mastectomy. Today, if a surgeon can maintain the breast form, the standard has become the partial mastectomy operation when operating for breast cancer. Large volume displacement oncoplastic surgery allows the surgeon the ability to resect large volumes of breast tissue and achieve the advantages in large volume resection which include fewer positive margins,^[@bibr2-1073274817729043],[@bibr3-1073274817729043]^ while maintaining and possibly improving the aesthetics of the breast form using mastopexy and breast reduction designs. Patients who would have been previously thought to be mastectomy candidates can now have breast-sparing procedures with improved aesthetics.\n\nThe oncoplastic surgical team typically consists of a breast surgeon and a plastic surgeon who work together in designing mastectomy skin incision patterns to best access"
+"\"Make in India\"---A Challenge Accepted! {#sec1-1}\n=======================================\n\nCorneal transplantation as we enjoy it today owes its success in large measure to the efficiency of the Eye Banking network across the world and to the high standards of technical, ethical, and legal processes that are maintained. According to the Global Survey, India has the largest number of Eye Banks in the world\\[[@ref1]\\] and, thus, has an opportunity to lead the way in this important sector of eye care. Scarcity of donor corneas, a large burden of corneal blindness, and inaccessibility to surgical centers are some of the challenges that beg to be addressed. Nonetheless, it is commendable that a new corneal storage medium has been developed indigenously, with facilities at par with the best in the world, tested and validated scientifically and offered, in keeping with the philosophy of its parent organization, at a fraction of the cost of comparable media used internationally. We salute the Aurolab and the Aravind Eye Care system for their priceless contributions.\n\nHypothermic storage at 2 \u00b0C--8 \u00b0C remains the most popular method of corneal preservation worldwide.\\[[@ref2]\\] The earliest hypothermic storage solution, the McCarey-Kaufman (MK) medium has been succeeded by other solutions, claiming better and longer"
+"1. Introduction {#sec1-nanomaterials-09-01216}\n===============\n\nUltrafast fiber lasers have wide applications in a wide variety of areas, such as information transmission, frequency metrology, scientific research and so on. Over the past few decades, ultrashort pulses fiber lasers have received much attention due to their potential applications in industrial manufacturing, environmental monitoring, toxic gas detection, biomedical, defense, optical sensing and optical imaging. Currently, several passively mode-locked techniques have been employed for generating pulsed laser operations. In 2016, Ivanenko et al. reported a mode-locked long fiber master oscillator based on a nonlinear amplifying loop mirror (NALM) with intra-cavity power management, and achieved a record-high pulse energy exceeding 12 \u03bcJ \\[[@B1-nanomaterials-09-01216]\\]. In addition, various types of saturable absorbers (SAs), including semiconductor saturable absorber mirrors (SESAMs) \\[[@B2-nanomaterials-09-01216],[@B3-nanomaterials-09-01216]\\], single-wall carbon nanotubes (SWCNTs) \\[[@B4-nanomaterials-09-01216],[@B5-nanomaterials-09-01216],[@B6-nanomaterials-09-01216]\\], and graphene \\[[@B7-nanomaterials-09-01216],[@B8-nanomaterials-09-01216],[@B9-nanomaterials-09-01216]\\], have been considered the most promising approach to obtain mode-locked pulses. As known, SESAM has been widely employed in a majority of commercial mode-locked fiber lasers to achieve ultrashort pulses. However, SESAM shows some drawbacks, such as a narrow absorption bandwidth, low damage threshold, complex fabrication and packaging and high cost, which have restricted its further advanced development. In addition, SWCNTs have also been widely used as SAs due to"
+"Introduction {#s1}\n============\n\nCD8^+^ T cells are not directly infected during HIV-1 infection, but nonetheless exhibit profound functional deficits, alongside a highly skewed maturation profile, and accumulation of a population of highly activated CD8^+^ T cells [@pone.0077412-Migueles1]--[@pone.0077412-dEttorre1]. Individuals who spontaneously contain virus replication in the absence of anti-retroviral treatment (ART), display low T cell activation levels [@pone.0077412-Emu1]--[@pone.0077412-Bello1] and exhibit maintenance of CD8^+^ T cell effector functions, including proliferative capacity, the ability to produce multiple cytokines (polyfunctionality), and elevated cytotoxic activity [@pone.0077412-Horton1]--[@pone.0077412-Betts1]. An expanding body of evidence points towards the quality of CD8^+^ T cell effector functions, including the ability to produce IFN-\u03b3, express cytotoxic molecules such as perforin, granzymes and surface CD107\u03b1, as a key factor limiting viral replication [@pone.0077412-Hersperger1]--[@pone.0077412-Makedonas1]. Defects in these CD8^+^ T cell functions in HIV-1 disease contribute to the development of immunodeficiency.\n\nHIV-1 disease is characterized by elevated, persistent immune inflammation, which drives a suite of changes to the immune system and solid tissues of the body [@pone.0077412-Hunt1]. Elevated expression of the ecto-NADase, CD38 and the class II human leukocyte antigen HLA-DR on the surface of circulating CD8^+^ T cells are commonly used as 'activation' markers tracking HIV-1-driven immune inflammation levels. High CD8^+^ T cell activation"
+"1 INTRODUCTION\n==============\n\nMost cellular processes require a large number of proteins to assemble into functional complexes to perform their activity. Therefore, describing functional protein complexes taking part in given processes is critical to the underlying molecular mechanism understanding. Experimental protocols such as Affinity Purification followed by Mass-Spectrometry (AP-MS) have been devised to *pull down* a protein of interest (*bait*) together with all the interacting proteins within the same protein complex (*preys*). However, these sets of *preys* may contain both false positives, proteins detected despite not actually interacting with the *bait*, and omit false negatives ([@btu517-B4]), proteins interacting in the cellular context studied but not detected. Effective control experiments and usage of contaminants repositories can remove some false positives. However, false negative interacting partners identification, thereby the definition of the entire protein complex, remains challenging. Protein--Protein Interaction (PPI) data represents abundant information that can be used for this purpose.\n\nProtein complexes extraction from PPI networks is a very active area of research and many methodologies have been developed to tackle this problem. These computational methods generally model protein complexes as dense subnetworks within the complete set of PPIs and thus try to solve a graph clustering problem or to identify"
+"Introduction\n============\n\nCystic fibrosis (CF) is a severe, autosomal recessive, multi-system condition, predominantly affecting the respiratory and digestive systems. CF is caused by mutations, of which there are more than 1900, in the cystic fibrosis transmembrane conductance regulator (*CFTR*) gene. The prevalence of CF is 1 in 2500 to 1 in 3500 live births, and for people with Northern European ancestry, the carrier frequency is 1 in 25.[@b1] Advances in multi-disciplinary care have improved long-term outcomes for people with CF. In the UK, median survival is now 43\u2009years.[@b2],[@b3]\n\nPrenatal diagnosis of CF currently requires an invasive test to obtain fetal genetic material and so carries a small risk of miscarriage[@b4] but is an option that is valued by carrier couples as it allows them to either plan and prepare for the birth of an affected child or make decisions about termination of pregnancy.[@b5] Non-invasive prenatal diagnosis (NIPD) based on analysis of cell-free fetal DNA (cffDNA) in maternal plasma has been reported to exclude the paternal mutation in couples carrying different CF mutations.[@b6]--[@b8] However, these reports described analyses developed for individual families, a labour-intensive approach for implementation into routine clinical practice. Here, we describe the development of a next-generation sequencing"
+"Introduction {#s1}\n============\n\nMost adults need, on average, about 8 h of sleep per night, and sleeping \\<6 h nightly is associated with decreased daytime functioning, poorer general health, increased risk of cardiovascular and metabolic diseases and an increased likelihood of accidents ([@B1]--[@B5]). However, many people do not get enough sleep daily because of conflicting obligations, personal choices, health conditions, and other factors. Both acute and chronic sleep restriction are especially common among college-aged students \\[e.g. ([@B6])\\].\n\nAttention is a fundamental mechanism underlying cognitive abilities that is affected by sleep debt. Experimentally shortened sleep impairs attention in children ([@B7], [@B8]), and impaired attention related to reduced sleep in members of the military causes performance deficits in reaction times and accuracy, as measured by the Attention Network Test (ANT), and in continuous visual tracking ([@B9]). Thus, the impacts of sleep loss on attention, and the consequences for cognitive performance, are far-reaching and may be applicable to a wide range of both clinical and otherwise healthy populations.\n\nThe model of attention proposed by ([@B10]) includes three functional systems that depend on separate, but interacting neural networks: vigilance/alerting; orienting/selection; and executive control (or regulation of attentional resources). The relative independence of these systems"
+"Background {#Sec1}\n==========\n\nIn the United States, 30% of outpatient antibiotic prescribing is estimated to be unnecessary, resulting in almost 47 million unnecessary antibiotic prescriptions each year \\[[@CR1], [@CR2]\\]. Excessive antibiotic prescribing drives the spread of antibiotic resistance, which contributes to increased morbidity, mortality, and economic costs associated with infections \\[[@CR3]--[@CR5]\\]. In response, the 2015\u2009U.S. National Action Plan for Combatting Antibiotic-Resistant Bacteria set a goal of reducing inappropriate antibiotic prescribing in outpatient settings by 50% by 2020 \\[[@CR6]\\].\n\nA major source of unnecessary outpatient antibiotic prescriptions is acute bronchitis cases \\[[@CR7]--[@CR10]\\]. Acute bronchitis is a common self-limited respiratory illness, characterized predominantly by cough, typically lasting less than 3 weeks \\[[@CR7], [@CR11]\\]. In the US in 2011, cough was the most common illness-related reason for ambulatory care visits, accounting for 2.6 million outpatient visits \\[[@CR12]\\]. A study in the UK estimated that 44/1000 adults are affected by acute bronchitis each year \\[[@CR13]\\]. Antibiotics are not effective for treating acute bronchitis, which is usually of viral etiology \\[[@CR11]\\], and long-standing professional guidelines recommend against antibiotics for uncomplicated cases \\[[@CR14], [@CR15]\\]. Nevertheless, US adults are prescribed antibiotics for acute bronchitis approximately 60--70% of the time \\[[@CR7]--[@CR9], [@CR16]\\]. Further, relative to other upper"
+"Background {#Sec1}\n==========\n\nAbnormal Wnt/Wingless signaling pathway activation has been reported in many cancers and is supposed to promote proliferation, invasion, and metastasis \\[[@CR1], [@CR2]\\]. Wnt/\u03b2-catenin signaling is active during embryogenesis facilitating new organism formation. Normally, it is down-regulated in differentiated cells, however, the deregulated Wnt signaling is correlated with almost all stages of oncogenesis, from malignant transformation to metastatic dissemination and resistance to treatment \\[[@CR3], [@CR4]\\], it also induces radioresistance in several human cancers including head and neck, breast, nasopharyngeal, esophageal, glioblastoma, and colorectal cancers \\[[@CR5]\\]. Abnormalities of Wnt components such as: mutation in \u03b2-catenin or APC gene, overexpression of Wnt ligands, loss of inhibition of regulatory could induce the activity and stimulates expression of downstream genes, such as: cyclin D1 and c-myc, matrix metalloproteinase-7 (MMP-7), connexin 42, CD44, claudin-1 and so on \\[[@CR6]--[@CR9]\\]. The overexpression of its downstream targets is correlated with the alteration of cell cycle progression, proliferation, invasiveness, Epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and contribute to tumorigenesis \\[[@CR6]--[@CR9]\\].\n\nDisabled-2 (Dab2) is a member of the Mammalian/Drosophila disabled gene family, which can stabilizes Axin and serves as an inhibitor of the Wnt pathway \\[[@CR10]--[@CR14]\\]. Lung cancer is now the leading cause of malignant tumor related"
+"Introduction {#s1}\n============\n\nPhoto molecular switches can reversibly exhibit different properties due to their structural changes upon a light stimulus, making them new favorites in recent decades in fields that require switching effects, such as information science and chemical sensing (Sun et al., [@B25]; Yuan et al., [@B30]; Chiang and Chu, [@B8]; Kim et al., [@B14]; Bian et al., [@B2]). Generally, photo switches possess a conjugated structure and precise spatiotemporal control such as chiral helicene, azobenzene, diarylethene, spiropyran, binaphthyl compounds (Beharry and Woolley, [@B1]; Sun et al., [@B25]; Yuan et al., [@B30]; Chiang and Chu, [@B8]; Kim et al., [@B14]; Bian et al., [@B2]; Lubbe et al., [@B18]; Chen et al., [@B6]; Lerch et al., [@B15]). Among these molecules, azobenzene\\'s have been intensively investigated on account of their flexible property (Chen et al., [@B7], [@B6]; Schmidt et al., [@B24]; Beharry and Woolley, [@B1]; Li et al., [@B16]; Yuan et al., [@B30]; Deka et al., [@B9]; Bian et al., [@B2],[@B3]; Lin et al., [@B17]; Lubbe et al., [@B18]; Lerch et al., [@B15]). Upon UV light stimulation, azobenzene can isomerizes from the trans-form to the cis-form (Henzl et al., [@B11]). Upon visible light or slight heat, cis-form of azobenzene is reversely recovered"
+"This study uses de-identified data that are publicly available at no cost at the following locations: Health and Retirement Study (HRS) <http://hrsonline.isr.umich.edu/> and RAND HRS Data Files <https://www.rand.org/labor/aging/dataprod/hrs-data.html>. Additional information was derived from Centers for Medicare and Medicaid Services (CMS) data that contain protected health information and, therefore, require a data use agreement for access. Researchers interested in accessing the HRS-CMS linked data can go to the following website and apply for a data use agreement: <http://hrsonline.isr.umich.edu/index.php?p=medicare>.\n\nIntroduction {#sec005}\n============\n\nThough obesity is a well-known risk factor for cardiovascular disease (CVD) \\[[@pone.0188636.ref001]\\], a more recent and debated literature suggests that obesity may be associated with improved survival once CVD is established \\[[@pone.0188636.ref002]--[@pone.0188636.ref006]\\], a finding that is termed an \"obesity paradox\". For example, among persons with chronic heart failure, a meta-analysis estimates that obesity is associated with a 33% lower risk of mortality relative to the normal weight category \\[[@pone.0188636.ref006]\\]. Risk reductions of 30--40% have also been reported among persons with various types of ischemic heart disease \\[[@pone.0188636.ref003]--[@pone.0188636.ref005]\\].\n\nThere are various physiologic pathways by which obesity could confer a protective effect. Obese patients have more catabolic reserve, and catabolic stress occurs in states such as heart failure and acute myocardial infarction"
+"INTRODUCTION\n============\n\nObesity triggers a variety of metabolic derangements ([@B1]-[@B6]) that include type 2 diabetes, hypertension, dyslipidemia, and cardiovascular disease ([@B7]). In addition, obesity causes chronic inflammation ([@B8]), which, in turn, results in insulin resistance ([@B9]) and mitochondrial dysfunction ([@B10]).\n\nKetone bodies (acetone, acetoacetate, and b-hydroxybutyrate) increase appreciably in the blood of people on very low calorie diet (VLCD) ([@B11], [@B12]). Acetone is a water-soluble volatile product of metabolism that can be detected upon exhalation and which is excreted in the urine. After a few days of VLCD, fat becomes the main source of energy, and VLCD regimens are consequently ketogenic ([@B13]). One study conducted during a Muslim fasting period observed that fasting in excess of 10 hr was associated with development of ketosis in normal controls after 3-6 days and presence of \u03b2-hydroxy butyric and diacetic acids in the urine, whereas obese individuals did not show ketosis even after 20 days of a ketogenic diet ([@B14]). According to this study, obese people did not readily develop ketosis and ketonuria, however, it was clear that the level of ketone bodies in the blood depended on the balance between their rate of production by the liver and their rate of utilization"
+"1. Introduction {#sec1-materials-12-00449}\n===============\n\nTo improve oil and gas recovery, CO~2~ injection is used in the exploitation of oil, natural gas, coalbed methane and shale gas \\[[@B1-materials-12-00449]\\]. However, CO~2~ injection is accompanied by CO~2~ corrosion \\[[@B2-materials-12-00449]\\]. Corrosion will decrease the mining yield, resulting in oil wells failure, shutting down and even cause safety accidents, which will have a serious impact on the development of the oilfield and the economic benefits of the market \\[[@B3-materials-12-00449],[@B4-materials-12-00449],[@B5-materials-12-00449],[@B6-materials-12-00449]\\]. The most common and effective way to control corrosion is to use chemical additives that reduce corrosion at very small dosages \\[[@B7-materials-12-00449],[@B8-materials-12-00449]\\]. In recent years, various corrosion inhibitors have been successfully applied to the industry, and the corrosion has been controlled obviously and effectively \\[[@B9-materials-12-00449],[@B10-materials-12-00449]\\].\n\nSo far, phosphorus and nitrogen-containing compounds have been widely used as corrosion inhibitors, including organic phosphorus, nitrogen-containing compounds and phosphorus-containing organic water-soluble polymers \\[[@B11-materials-12-00449]\\]. Phosphorus-containing corrosion inhibitors have excellent corrosion inhibition properties. However, they have some fatal defects; for example, phosphorus compounds are difficult to degrade in water and usually lead to eutrophication. The widespread use of this chemical may cause oxygen deficiency in the water, which leads to the death of aquatic organisms \\[[@B12-materials-12-00449]\\]. Therefore, in the last few years,"
+"INTRODUCTION {#SEC1}\n============\n\nIn all domains of life, the biological function of RNAs is often associated with the presence of posttranscriptional chemical modifications. These modifications influence the stability, the folding pathways, the structure and the function of RNAs by e.g. modulating hydrogen bonding capabilities, stacking and hydrophobic interactions between nucleotides or the local charge distribution ([@B1]). Ribosomal RNAs (rRNAs) and transfer RNAs (tRNAs) contain particularly large numbers of modified nucleotides. Most modifications of nucleotides in rRNA are chemically simple. The most frequent nucleotide modifications in rRNAs are methylations of ribose 2\u2032-hydroxyl groups and the isomerization of uridines to pseudouridines. Other chemically simple modifications in rRNA are methylations or acetylations of exocyclic or endocyclic nitrogen atoms in the nucleobases. The chemically most complex modification found for rRNA nucleotides so far is an *N*1-methyl-*N*3-(3-amino-3-carboxypropyl) pseudouridine (m^1^acp^3^\u03a8) present at a single conserved position in the small ribosomal subunit RNA of eukaryotes ([@B2]). In archaea such as *Haloferax volcanii* an *N*3-(3-amino-3-carboxypropyl)-uridine (acp^3^U) nucleotide is found in an equivalent position ([@B3]).\n\nIn tRNAs, the frequency of posttranscriptional modifications and also their chemical variety and complexity is much higher than in rRNAs. The chemical structures of tRNA modifications, their enzymatic synthesis and their biological impact were"
+"Background {#Sec1}\n==========\n\nWith the population rapidly aging, the global burden of chronic diseases is also increasing dramatically \\[[@CR1], [@CR2]\\]. Approximately three quarters of older adults in Canada reported having at least one chronic health condition \\[[@CR3]\\]. Older adults with multiple chronic conditions typically have more complex needs, and often seek care across different healthcare settings \\[[@CR4]\\]. A care transition is defined as the movement of a patient between different healthcare settings, and/or between health care providers \\[[@CR5]\\]. In addition, these older adults may have multiple care transitions between health settings (e.g., acute care to convalescence to home) \\[[@CR6]\\]. However, these older adults rarely have cohesive treatment plans due to the lack of coordination amongst different health care providers \\[[@CR7]\\]. Poor care transitions often lead to fragmentation in care, decreased quality of care, and an increase in adverse events \\[[@CR8]--[@CR11]\\]. An Ontario study examined the experiences of older adults and their caregivers with navigating through the Canadian health care system, and found that 66% of participants reported difficulties \\[[@CR12]\\]. Research has attributed these long-standing difficulties to the inadequate engagement of patients and families in the transitional care \\[[@CR13]--[@CR15]\\].\n\nEngaging with patients and/or their family members is fundamental to a person-centered"
+"Introduction {#Sec1}\n============\n\nMesenteric panniculitis (MP) \\[[@CR1]\\] describes inflammation of mesenteric fat and is manifest on CT scanning as a circumscribed region of increased mesenteric density, often exhibiting a mass-like effect, containing several lymph nodes, and engulfing mesenteric vessels \\[[@CR2], [@CR3]\\]. MP is known by a variety of alternative terms including 'mesenteric lipodystrophy' \\[[@CR4]\\], 'liposclerotic mesenteritis' \\[[@CR5]\\] and 'misty mesentery' \\[[@CR6], [@CR7]\\]. The latter term includes entities such as 'sclerosing mesenteritis' \\[[@CR8]\\] and 'retractile mesenteritis' \\[[@CR9]\\]. Such varied terminology reflects confusion regarding the precise definition of MP.\n\nAn association between MP and development of subsequent malignancy has been raised \\[[@CR10], [@CR11]\\], suggesting MP is an important finding. Alternatively, others state there is no association between MP and malignancy \\[[@CR12]\\]. Lack of consensus regarding the clinical significance of MP thus presents radiologists with a diagnostic dilemma because MP is encountered frequently as an apparently incidental finding on cross-sectional imaging, usually abdominopelvic CT. Furthermore, referring clinicians will usually be unfamiliar with MP and will therefore look to the reporting radiologist for management guidance. To attempt to clarify the significance of MP in the face of apparently contradictory evidence we performed a systematic review of available medical literature, focusing on the cross-sectional imaging"
+"Introduction\n============\n\nThe understanding of the biology behind lipid-metabolism has increased exponentially in the past two decades, enabled by the vast interrogation of the human genome. To date, genome-wide association studies have identified over 170 candidate single-nucleotide variants (SNVs), with many residing in common regions of the genome ([@B26]; [@B9]). However, two major limitations exist in the current exploration for causal loci associated with lipid metabolism: (1) Identification of SNVs in non-coding regions or SNVs in large regions that span several candidate genes; and (2) missing detection of candidate genes altogether, particularly if population-specific ([@B3]). Exome-wide association studies naturally expand on findings from genome-wide association studies through their exploration of the functional region of the genome ([@B20]).\n\nExome-wide association studies have been extensively used to dissect the genetic architecture of complex diseases and quantitative traits ([@B14]). Exonic variants, particularly loss-of-function variants, tend to show the most dramatic effect sizes, yielding the greatest power for detection. Recent evidence on lipid traits provides support that rare variants can be ancestry-specific ([@B18]). Therefore, examining exonic variants across diverse ancestry groups likely augments the identification of novel loci.\n\nThe Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) cohort, recruited from families of European"
+"Introduction {#Sec1}\n============\n\nAmong the over 450 subcortical structures of the human brain is the subthalamic nucleus (STN), which is involved in many functions, ranging from speeded decision-making to emotional regulation (Frank [@CR34]; Herculano-Houzel [@CR46]; Alkemade [@CR2]; P\u00e9ron et al. [@CR80]; Aron et al. [@CR13]; Forstmann et al. [@CR33]), the STN is of particular interest as a target for deep brain stimulation (DBS) to alleviate symptoms in a variety of movement disorders including Parkinson's disease (PD) (Temel et al. [@CR100]).\n\nThe internal structure of the human STN is a topic of ongoing discussion and consistency between empirical studies is limited (Keuken et al. [@CR54]; Alkemade et al. [@CR9]). A prominent model of the internal structure of the STN in the scientific literature is the tripartite model, which divides the STN in a limbic medial tip, a ventromedial cognitive area, and a dorsolateral motor area (Temel et al. [@CR100]). The level of anatomical separation between the subdivisions of the STN is unknown, and findings vary based on the applied research technique (Alkemade and Forstmann [@CR3]; Lambert et al. [@CR59]). The principle of functional segregation offers a theoretical framework for defining subdivisions in the STN at the cellular level. According to this"
+"Mitotic spindle formation, the transport of macromolecules between the cytoplasm and the nucleus, and nuclear envelope formation are critical functions of a eukaryotic cell. These seemingly disparate functions are all regulated by a concentration gradient of the small GTPase Ran in its GTP bound state (RanGTP) around the chromosomes^[@R1]--[@R3]^. This RanGTP gradient signal is generated when the Ran guanine-exchange factor (RanGEF) also known as RCC1 (regulator of chromosome condensation), binds to the nucleosome repeating unit of chromatin, recruits Ran to chromatin and activates Ran's nucleotide exchange activity.\n\nThe binding of RCC1 to the nucleosome is central to the formation of this spatial signal within the nucleus. Structurally, RCC1 is a \u03b2-propeller protein with an N-terminal tail extension^[@R4]^. Previous studies have shown that the RCC1 \u03b2-propeller domain binds the histone H2A/H2B dimer component of the histone octamer and that this interaction does not require the N-terminal tail implicated in DNA-binding^[@R5]^. An unusual post-translational modification, N-terminal \u03b1-methylation, of human RCC1 appears to further regulate RCC1's association with chromatin^[@R6],[@R7]^. Despite these important findings, we currently lack a structural description of how RCC1 interacts with the nucleosome.\n\nThe inadequate understanding of how RCC1 binds the nucleosome reflects a more fundamental deficit of structural information"
+"Physical inactivity is associated with increased risk of several adverse health outcomes including heart disease, type 2 diabetes, colon cancer, breast cancer, and mortality ([@r9]; [@r28]; [@r29]; [@r51]). Active commuting, such as walking or biking to work on a daily basis, has been shown to decrease risk of all-cause mortality and cardiovascular disease ([@r1]; [@r22]; [@r57]). Various attributes of the built environment (e.g., population density, street connectivity, land use mix) have been associated with rates of physical activity at the neighborhood level ([@r14]; [@r18]; [@r42]; [@r44]). Furthermore, the type of transportation mode used (public transit vs. car) affects personal energy expenditure ([@r36]). Thus, an important research question is whether urban planning can reduce physical inactivity and improve health.\n\nExposure to outdoor urban air pollution is associated with various adverse health outcomes including heart disease, respiratory disease, lung cancer, asthma, and mortality ([@r4]; [@r19]; [@r41]; [@r39]). Chronic exposures vary at similar magnitudes within-cities as between-cities ([@r26]; [@r35]), suggesting that neighborhood location, urban design, and proximity to roads can affect exposures ([@r24]; [@r33]).\n\nRecently, the World Health Organization (WHO) cited physical inactivity (4th) and exposure to outdoor urban air pollution (14th) among the top 15 risk factors for the Global Burden of"
+"Permanent prostate seed implantation is a minimally invasive approach to implant low activity radioactive sources to the prostate gland with the guidance of transperineal ultrasound technique. Historically, radium was used therapeutically within a decade of its discovery for intracavitary prostate brachytherapy.\\[[@CIT1]\\] Naturally occurring radioisotopes are not ideal sources for permanent seed implantation. One of the first man-made radioisotopes was Gold - 198 (^198^Au)\\[[@CIT2]\\] used for prostate permanent seed implantation. In the modern era of prostate implant brachytherapy, two radioisotopes - iodine-125 (^125^I) and palladium-103 (^103^Pd) have extensively been used for the purpose.\\[[@CIT3]\\]\n\nRecently, a new cesium -131 (^131^Cs) radioactive seed has been introduced (Iso Ray, Richmond, WA) in the clinical practice for permanent seed implants of early prostate cancer.\\[[@CIT4]\\] ^131^Cs is a 4.5 mm \u00d7 0.8 mm seed, titanium - encased ceramic with gold wire. Since being introduced in 2004, about 3000 prostate implants using ^131^Cs seeds have been performed.\\[[@CIT5]\\]\n\nThe introduction of ^131^Cs seed, for prostate permanent implants, is not without controversy and some researchers oppose its use stating that there is not enough data on dosimetric and clinical use of this source. However, our experience at UPMC, Pittsburgh, in prostate permanent seed implants using ^131^Cs source is encouraging.\\[[@CIT6]\\]"
+"Introduction {#s1}\n============\n\nNeuromyelitis optica (NMO) is a rare, aggressive, often fatal, inflammatory demyelinating disease that predominantly affects the optic nerves and spinal cord [@pone.0015050-Jarius1], [@pone.0015050-Lucchinetti1], [@pone.0015050-Graber1]. For many years, NMO was considered a subtype of multiple sclerosis (MS). However, it is now recognized that a majority of NMO patients develop autoantibodies (NMO-IgG) against aquaporin 4 (AQP4) [@pone.0015050-Lennon1]. AQP4 is the predominant water channel in the central nervous system and is localized in astrocyte foot processes, but can also be found in other organs, including kidneys, heart and lungs. Therefore, restricted inflammation of NMO cannot be solely explained by the pattern of expression of AQP4. AQP4-specific antibodies in NMO patients are IgG1 [@pone.0015050-Lennon2], an antibody subclass that requires help from antigen (Ag)-specific CD4^+^ T cells [@pone.0015050-Kishimoto1], [@pone.0015050-Isakson1]. Although little is known regarding recognition of AQP4 by T cells, AQP4-specific T cells may drive the humoral AQP4-specific immune response.\n\nWhile AQP4 is the most characterized candidate autoantigen in NMO, it is not known whether an immune response that selectively targets AQP4 initiates the pathologic changes associated with NMO. Development of animal models for NMO should permit direct assessment of immune responses in vivo. A \\\"Devic-like\\\" disease, characterized by spontaneous optic neuritis"
+"INTRODUCTION {#SEC1}\n============\n\nCell division not only requires the accurate replication of DNA but also efficient propagation of chromatin and associated 'epigenetic' modification states. In eukaryotic organisms, this epigenetic information is encoded both in the DNA and the histone proteins of chromatin through complex patterns of posttranslational modifications. The basic building block of chromatin, the nucleosome, consists of an octamer of histone proteins wrapped with \u223c147 bp of genomic DNA ([@B1],[@B2]). The histone core consists of two H3--H4 dimers that assemble into a (H3--H4)~2~ tetramer which organizes the central 70--80 bp of the DNA, flanked by two H2A--H2B dimers which organize the peripheral 30--40 bp on either side of the tetramer. The passage of the replication fork requires the temporary removal and subsequent reassembly of the parental nucleosomal histones along with a full complement of newly synthesized histones ([@B3]).\n\nTo enable propagation of chromatin, cells have evolved efficient nucleosome assembly machineries. These include components of the replication machinery, nucleosome remodelers, and a diverse class of proteins known as histone chaperones ([@B4]). The histone chaperones mediate the stepwise processes of disassembly and reassembly of nucleosomes ([@B3]). Histone chaperones are typically highly acidic proteins that bind dimers of H2A--H2B, H3--H4 or assemble"
+"Introduction {#Sec1}\n============\n\nInfantile cortical hyperostosis (ICH, OMIM 114000) was first reported by Roske \\[[@CR26]\\] and subsequently studied by De Toni who recognized the congenital and regressive aspects of this disorder \\[[@CR13], [@CR14]\\]. Caffey and Silverman \\[[@CR9]\\] and Caffey \\[[@CR8]\\] formally defined ICH, which is a neonatal and infantile familial disease, spontaneously healing in the first years of life. The disease is characterized by regressive subperiosteal hyperosteogenesis mainly affecting the long bones, mandible, clavicles, and ribs, which are remarkably swollen and deformed on X-ray. The presence of fever, inflammatory signs, and pain led clinicians to suspect different disorders, in particular those caused by infectious agents \\[[@CR2], [@CR22], [@CR25], [@CR30]\\]. Familial clustering has been reported by several authors who also outlined the autosomal dominant pattern of inheritance and a possible reduced penetrance \\[[@CR1], [@CR4], [@CR6], [@CR10], [@CR15], [@CR17], [@CR19], [@CR20], [@CR23], [@CR24], [@CR27], [@CR31]\\].\n\nA genome-wide analysis in three unrelated ICH families allowed Gensure et al. \\[[@CR18]\\] to map the disease locus on chromosome 17q21. All affected individuals were found to be heterozygous for a missense mutation (3040C\u2192T) in the *COL1A1* that altered residue 836 (R836C). Suphapeetiporn et al. \\[[@CR29]\\] and Cho et al. \\[[@CR11]\\] corroborated these results by confirming the"
+"Introduction {#S1}\n============\n\nAdipose tissue development is not well understood. One view is that adipose tissue is a single organ that develops from a single lineage^[@R1],\\ [@R2],\\ [@R3],\\ [@R4]^. However, lipodystrophies often manifest as lipid distribution disorders in which regionalized depot atrophy coexists with preservation and often expansion of other depots^[@R5]^. The basis for this regionalization is not understood. Adipose tissues exist in multiple discrete white (WAT) and brown (BAT) depots. WAT is typically generalized as being subcutaneous or visceral^[@R2],\\ [@R6]^. Visceral WAT is considered unfavorable because its accumulation (e.g. in obesity) correlates with metabolic disease, while subcutaneous WAT is considered more metabolically favorable because its accumulation can be protective, although this generalization is likely oversimplified because metabolic properties vary between visceral depots and even between adipocytes within the same depot^[@R2],\\ [@R6]^. Why this metabolic heterogeneity exists within and between depots is also not understood. One possible explanation is that adipocytes arise from diverse lineages and that this influences fat distribution and function. However, the ability to determine this is precluded by the fact that the developmental origin of adipocytes is largely unknown^[@R7]^.\n\nWe recently provided both genetic and lineage-tracing evidence that brown adipocytes and a subset of white adipocytes"
+"1. Introduction {#sec1}\n===============\n\n*Caryocar brasiliense*Camb., known as \"pequi,\" is a tree that belongs to the Caryocaraceae family and is widely distributed in the Cerrado region of Brazil \\[[@B1], [@B2]\\]. Pequi fruit are rich in A and E vitamins \\[[@B3]\\] and are popularly used to flavor cuisine. Oil extracted from the fruits is used in the cosmetic industry for the production of soaps and skin creams and is a useful tool in the production of fuel and lubricants \\[[@B4], [@B5]\\]. In folk medicine, pequi fruit is used against colds and flu. The seed fat is used for the treatment of respiratory tract diseases, such as asthma and bronchitis, whereas a decoction of the leaves and flowers is used to boost energy, as an aphrodisiac, and for the treatment of liver disease. The bark and fruit are used as febrifuges and diuretics \\[[@B3]\\].\n\nStudies exploring the biological effects of *C. brasiliense* have shown that the hydroethanolic extract of pequi leaves presents leishmanicidal, antibacterial, and antioxidant effects \\[[@B6]\\]. In addition, the aqueous extract of pequi fruit pulp has revealed anticlastogenic potential, antigenotoxic activity, and antioxidant properties \\[[@B7], [@B8]\\].\n\nThe chemical characterization of polar components of pequi ethanolic extracts revealed the presence of"
+"Objective\n=========\n\nTo assess the ability of the SOFA score (Sequential Organ Failure Assessment) to discriminate outcome in neurological patients admitted to intensive care unit (ICU).\n\nSetting\n=======\n\nA 24-bed general ICU in a 260-bed public hospital.\n\nMethods\n=======\n\nWe prospectively followed (from May to September 2001) neurological patients admitted to our ICU measuring daily SOFA score throughout the first 7-day ICU stay and recording the 28-day mortality. We compared median scores between survivors and non-survivors (Mann-Whitney U-test) and calculated risk relative of death. Admission APACHE II score was calculated for each patient.\n\nResults\n=======\n\nWe studied 45 patients (29 M/16 F). The mean age was 47.8 \u00b1 13.2 years and mean APACHE II was 14.2 \u00b1 5.1. The mean LOS was 12.8 \u00b1 8.3 days. The 28-day ICU mortality was 31% (*n* = 14).The best cut-off value of SOFA score was 7. Clinical diagnosis at admission were: intracerebral haematoma (*n* = 14), extradural haematoma (*n* = 9), subarachnoid hemorrhage (*n* = 7), brain swelling (*n* = 5), subdural haematoma (*n* = 4), gun shot injury (*n* = 3), diffuse axonal lesion (*n* = 2), meningitis (*n* = 1).\n\nConclusions\n===========\n\nSOFA score can be used to discriminate outcome in"
+"Introduction\n============\n\nIn patients with chronic renal failure (CRF), secondary hyperparathyroidism (sHPT) is a common problem. With a decrease in calcium receptors in patients with CRF, the serum level of the intact parathyroid hormone (iPTH) increases, and this is positively correlated with the volume of the parathyroid glands \\[[@b1-usg-16022],[@b2-usg-16022]\\]. If the volume of one or more parathyroid glands is more than 0.5 cm^3^ or medical treatment such as active vitamin D or calcimimetics fails, the clinician considers parathyroidectomy \\[[@b3-usg-16022]\\]. Therefore, clinicians want to know a more exact volume of the enlarged parathyroid glands. In addition, the parathyroid volume could be used as the index of response for medical treatment. Thus far, neck ultrasonography (US) has been performed in patients with CRF for an imaging diagnosis of sHPT and the localization of the parathyroid glands prior to parathyroidectomy.\n\nRecently, a three-dimensional (3D) volume measurement technique using US has emerged, and the virtual organ computer-aided analysis (VOCAL, General Electric Medical Systems, Milwaukee, WI, USA) technology, one of the 3D ultrasonographic semi-automated volume measurement tools to provide accurate and reliable volume calculations, is now commercially available. In the VOCAL technique, after acquiring the 3D volume dataset on US scanning using a 3D probe,"
+"Introduction {#S0001}\n============\n\nPharmacy is the health profession that is committed to ensuring safe and effective use of medication and it links the health sciences with the basic sciences.[@CIT0001] Pharmacy is among the respected professions worldwide, and it has experienced tremendous developments over the years.[@CIT0002]\n\nNowadays pharmacists' scope of practice widened from previous dispensing and suppling of medications to a variety of health services straddling prevention, addressing patient needs and expectations. All transition of focus is related to change of health care system, aging populations, health care workforce supply issues, emerging chronic diseases and changing expectations have re-engineered pharmacy in many developed nations.[@CIT0003],[@CIT0004]\n\nFor advancing pharmacy knowledge in a specific field or area of interest, postgraduate education (PGE) opportunities are the major options for pharmacy students and graduates. Often PGE is needed as a prerequisite for certain employment opportunities as well as to diversify pharmacists' skills and knowledge within the health care environment.[@CIT0005] Postgraduate education in Ethiopia is popular and it enhances job prospects. Also, there is Higher Education Relevance and Quality Agency (HERQA) which ensures whether higher education curriculum supports the countries' development needs. Postgraduate Master's programs under the school of pharmacy in Ethiopia include Clinical Pharmacy, Pharmacology, Pharmacognosy,"
+"Background {#Sec1}\n==========\n\nMelanoma is a cancer derived from neuroectoderm that is often fatal once it has metastasised \\[[@CR1], [@CR2]\\]. Current treatment approaches include the molecular targeting of oncogenic gene products and immune-based therapies, both of which induce significant responses in many patients with advanced disease \\[[@CR3], [@CR4]\\]. Despite this, many patients develop therapy resistance or do not respond to treatment \\[[@CR5]--[@CR7]\\]. Since alterations in cellular metabolism may contribute to the malignant phenotype, targeting the metabolic circuitry of melanoma cells may offer a promising additional therapeutic strategy \\[[@CR8], [@CR9]\\].\n\nThe reprogramming of cellular metabolism is one of the hallmarks of cancer \\[[@CR10]\\]. Whereas normal cells direct glucose to mitochondrial oxidative phosphorylation to generate ATP when oxygen is abundant, cancer cells generally exhibit greater glucose uptake and lactate secretion, regardless of oxygen availability. This phenomenon is termed \"aerobic glycolysis\" or the \"Warburg effect\" \\[[@CR10]--[@CR12]\\]. This can benefit cancer cells by facilitating increased proliferation, enhanced invasion and resistance to apoptosis, which in turn promote tumor progression and metastasis \\[[@CR13]\\]. These observations have raised the possibility that targeting metabolic pathways that the cancer cell depends upon may be a useful therapeutic strategy. Metabolic profiling of melanoma cells has revealed their dependence upon the"
+"Globally, physical activity (PA) has been recognized as one of the important lifestyle behaviors that brings major health benefits to, and affects the healthy growth of, school-aged children and adolescents.[@bib0001], [@bib0002], [@bib0003] Yet, epidemiologic data[@bib0004] indicate that most children and adolescents do not engage in sufficient activities to meet the 60-min daily moderate-to-vigorous PA (MVPA) recommended in the World Health Organization\\'s guidelines.[@bib0005] Research also shows that children who have low levels of PA are more likely to have a high risk of being overweight or obese,[@bib0006] a health state that, if not appropriately modified, will carry into adulthood,[@bib0007], [@bib0008] along with the increased likelihood of developing additional health problems, including an increased risk for heart disease, caused by adult obesity.[@bib0009]\n\nIn China, 3 decades of unprecedented, rapid economic development have resulted in high rates of urbanization and accelerated advances in technology, which in turn have led to major changes in the health behaviors[@bib0010], [@bib0011] of its population of more than 1.3 billion people.[@bib0012] The resulting social-economic transformation has caused Chinese society to gradually move toward adopting an unhealthy lifestyle characterized by physical inactivity and poor dietary habits.[@bib0011], [@bib0013] Among China\\'s school-aged population of approximately 170 million children and adolescents,[@bib0014] who"
+"This article is part of the Thematic Series \\\"Functional materials for environmental sensors and energy systems\\\".\n\nIntroduction\n============\n\nGraphene, being a thin (semi)conducting material, is a promising gas sensing system. Highly sensitive response, down to single molecule resolution, has been demonstrated with graphene-based devices under laboratory conditions \\[[@R1]--[@R3]\\]. However, in order to develop gas sensing applications working under real conditions, much effort has been dedicated to modification of graphene for improving its gas sensing characteristics. In particular, increasing the selectivity of graphene-based gas sensors is crucial for their future implementation. Recently, the improvement of gas sensing characteristics has been demonstrated with resistive type gas sensors based on single-layer graphene modified by a deposited layer of precious metal \\[[@R4]\\] or metal oxide nanoparticles \\[[@R5]\\]. Also, introduction of suitable defects was shown to have a positive effect on gas adsorption and sensor properties of graphene \\[[@R6]\\].\n\nTransition metal oxides constitute an important class of catalysts and photosensitizers. Apart from the very first and last 3d elements, scandium and zinc, the rest of the metals possess several oxidation states. The presence of several stable oxidation states serves as a basis of catalytic activity in redox reactions and is most noticeable for vanadium, chromium,"
+"1. Introduction {#s1}\n===============\n\nBenchmarking is a notoriously difficult task. Benchmarks are often created by the creators of the tools being benchmarked, resulting in biased comparisons favoring their tool. Benchmarking can be an inefficient process, as the tool being benchmarked may need changes to collect certain performance metrics. Even once that effort is undertaken, benchmarks are often run a few times and then forgotten, quickly becoming obsolete. However, benchmarks can spur progress as tool developers have an objective metric to maximize or minimize.\n\nPrior work benchmarking neural simulators and neuromorphic hardware has focused on low-level neural performance. For example, Sharp and Furber ([@B18]) showed that SpiNNaker can simulate a recurrent network of leaky integrate-and-fire neurons with similar firing rates and inter-spike intervals as the NEST neural simulator, but around six times faster. Stromatias et al. ([@B22]) showed that SpiNNaker\\'s power consumption varies between 15 and 37 Watts (0.5--0.8 Watts per chip) depending on the number of neurons being simulated. Goodman and Brette ([@B14]) showed that Brian simulated a randomly connected network of 4000 leaky integrate-and-fire neurons twice as fast as an equivalent Matlab implementation, but around three times slower than a C implementation. In all of these cases, none of"
+"Introduction {#btpr2459-sec-0001}\n============\n\nThe industry in recent years has become increasingly interested in the use of spectroscopy technologies such as Raman, near\u2010infrared (NIR), and 2D\u2010fluorescence (2D\u2010F) for the measuring, monitoring, and control of bioprocesses. This is, in part, a result of the American Food and Drug Administration\\'s (FDA) guidance on process analytical technology (PAT), which encourages the use of innovative tools and technologies to increase understanding and control of manufacturing processes.[1](#btpr2459-bib-0001){ref-type=\"ref\"} Since the publication of this work, there has been an increasing move to develop biopharmaceutical processes using a Quality by Design (QbD) approach. The ICH Q8 guideline defines QbD as \"a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.\"[2](#btpr2459-bib-0002){ref-type=\"ref\"} Spectroscopy technologies offer a nondestructive, rapid, and robust method for generating multianalyte data.[3](#btpr2459-bib-0003){ref-type=\"ref\"} These technologies are used routinely to monitor chemical pharmaceutical production processes, but their application to mammalian cell culture for production of biologics is much more challenging. This is primarily due to the complex matrix background[4](#btpr2459-bib-0004){ref-type=\"ref\"} and low concentrations of the metabolites of interest. Despite these challenges, there is a growing body of literature demonstrating their ability to measure multiple"
+"This study is funded by the US Centers for Disease Control and Prevention Preventive Health and Health Services Block Grant, award number 2B01OT009042\u201015, and by the US Department of Agriculture Nutrition Education and Obesity Grant Program, award numbers G\u20101415\u201017\u20100847 and G\u20101617\u20100452, and the Centers for Disease Control and Prevention Health Promotion and Disease Prevention Research Center supported by Cooperative Agreement Number 1U48DP005030. We are grateful to the data collection team, study participants, and partners involved in this research.\n\nChildhood obesity rates among US children aged 2 to 19\u2009years have tripled during the past few decades from about 5% in the 1980s to 17% from 2011 to 2014.[1](#josh12747-bib-0001){ref-type=\"ref\"} Substantial racial and economic disparities in childhood obesity rates remain of great public health concern. For instance, African American (19.5%) and Hispanic (21.9%) children are disproportionately affected by obesity, compared to their white counterparts (14.7%).[2](#josh12747-bib-0002){ref-type=\"ref\"} Furthermore, childhood obesity increases risk for preventable chronic diseases such as hypertension and type 2 diabetes that manifest both in the short\u2010term as well as over the life course.[3](#josh12747-bib-0003){ref-type=\"ref\"}\n\nOne strategy to shift childhood obesity trends is to implement interventions designed to establish healthy dietary behaviors during childhood.[4](#josh12747-bib-0004){ref-type=\"ref\"}, [5](#josh12747-bib-0005){ref-type=\"ref\"}, [6](#josh12747-bib-0006){ref-type=\"ref\"} A key behavioral target for these types"
+"Introduction {#s1}\n============\n\nOverweight/obese status is the fifth leading risk factor for global deaths and is a major global public health problem. Obesity is a medical condition in which excess body fat is accumulated. Adipose tissue is regarded as an endocrine organ that secretes a number of adipocytokines (e.g., adiponectin and tumor necrosis factor-\u03b1), which play important roles in the development of obesity, insulin resistance, and their associated complications [@pone.0095270-VanGaal1].\n\nAdiponectin is a protein secreted by adipose tissue that was independently discovered by different researchers in the 1990s and named \"adipocyte complement-related protein of 30 kDA\" (ACRP30) [@pone.0095270-Scherer1], \"gelatin-binding protein 28\" (GBP28) [@pone.0095270-Nakano1], \"AdipoQ\" [@pone.0095270-Hu1], and \"adipose most abundant gene transcript 1\" (APM1) [@pone.0095270-Maeda1]. This protein is encoded by the adiponectin (*ADIPOQ,* also known as *APM1*) gene, which is comprised of three exons and two introns (17 kb). The *ADIPOQ* gene is located on chromosome 3q27, which has been demonstrated to be a susceptibility locus for obesity by several genome-wide scan studies [@pone.0095270-Imperatore1]--[@pone.0095270-Ling1]. Researchers have reported that adiponectin in plasma can regulate fatty acid oxidation and glucose levels through the phosphorylation and activation of AMP-activated protein kinase (AMPK) [@pone.0095270-Tomas1]. Moreover, adiponectin levels are significantly decreased in patients with obesity, type"
+"1. Introduction\n===============\n\nMethotrexate (MTX) is an anchor drug in the management of rheumatoid arthritis (RA). Lymphoproliferative disorder (LPD) occasionally develops in patients treated using MTX, and is termed MTX-associated LPD (MTX-LPD). The predominant primary site of MTX-LPD is the lymph nodes, followed by extra-nodal sites such as the gastrointestinal tract, skin, and lungs.[@R1] The pathophysiology of MTX-LPD is not well understood. The hyperimmune state of RA itself or the immunosuppressive state induced by MTX administration is thought to play a role in the development of LPD.\n\nThe increased risk of LPD in RA patients has been well established. The incidence rate of LPD is 2-times higher in Western RA patients and 6-times higher in Japanese RA patients than that in the general population.[@R2][@R3] However, LPD in the central nervous system (CNS) is rare because it accounts for less than 1% of LPD.[@R4] We present the rare case of an RA patient who developed lymphoma in the CNS and stomach during MTX therapy.\n\n2. Case report\n==============\n\nThe patient was a 75-year-old Japanese man with a 9-year history of seropositive RA. The disease activity of RA was controlled well by MTX at 14\u200amg/week and bucillamine at 100\u200amg/day. He"
+"Background {#Sec1}\n==========\n\nHepatocellular carcinoma (HCC) is the sixth most common cancer and the third leading cause of cancer death, with 782,000 newly-diagnosed cases and 746,000 deaths in the year of 2012 worldwide \\[[@CR1]\\]. Moreover, the increasing incidence of HCC makes a serious challenge to the public health. Despite current advances in the early diagnosis and treatment of HCC, the five-year survival rate of HCC remains unsatisfying. Chronic viral hepatitis, alcohol abuse, obesity and metabolic syndrome are generally considered as risk factors for HCC \\[[@CR2], [@CR3]\\]. During the pathogenesis of HCC, the expression of thousands of genes has been aberrantly changed, including the activation of oncogenes and inactivation of tumor suppressor genes \\[[@CR4]\\]. Therefore, identification of novel molecular markers whose aberrant expression are involved in the initiation or progression of HCC may be helpful for the diagnosis and treatment of this disease.\n\nHuman spindle and kinetochore associated complex subunit 1 (SKA1) is a microtubule-binding protein of the outer kinetochore that is essential for stabilizing kinetochore-spindle microtubule attachment and proper chromosome segregation during mitosis \\[[@CR5]\\]. Depletion of SKA1 can lead to severe defects in chromosome segregation, whereas overexpression of SKA1 results to the nucleation of interphase microtubules \\[[@CR6], [@CR7]\\]. Recent data"
+"INTRODUCTION {#s1}\n============\n\nAcute lymphoblastic leukemia (ALL) is a life-threatening neoplasm characterized by uncontrolled growth and leukemic expansion of immature lymphoblastic progenitor cells \\[[@R1]-[@R4]\\]. The prognosis and outcome in ALL depend on age, molecular defects and response to therapy \\[[@R1]-[@R6]\\]. In about 30% of all adult patients, leukemic cells display the Philadelphia chromosome (Ph) and the related fusion gene, *BCR/ABL1* \\[[@R1]-[@R6]\\]. In the \u00b4pre-imatinib-era\u00b4, these patients had an extremely poor prognosis compared to patients with Ph^\u2212^ ALL \\[[@R5],[@R6]\\]. Since then the prognosis of patients with BCR/ABL1^+^ ALL has improved, which is largely attributable to the effects of novel BCR/ABL1-targeting drugs \\[[@R7]-[@R12]\\]. In fact, the BCR/ABL1 tyrosine kinase inhibitor (TKI) imatinib is effective in most patients with newly diagnosed Ph^+^ ALL, and sometimes even in patients with chemotherapy-resistant or relapsed Ph^+^ ALL, especially when applied in combination with conventional chemotherapy \\[[@R7]-[@R13]\\]. Second- and third generation BCR/ABL1 blockers are also effective in patients with Ph^+^ ALL \\[[@R14]\\].\n\nHowever, not all patients with Ph^+^ ALL respond to standard treatment and TKI. Therefore, depending on age, risk factors, and availability of a donor, stem cell transplantation (SCT) is recommended for patients with drug-resistant and high risk ALL \\[[@R15]-[@R18]\\]. In these patients, the overall treatment"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec001}\n============\n\nPancreatic cancer remains a fatal condition. The 5-year survival rate of patients afflicted by the disease of less than 5 percent has not changed over the last three decades \\[[@pone.0149833.ref001]\\]. One of the main reasons for this lack of progress is the inability to provide patients with more effective treatment options \\[[@pone.0149833.ref002], [@pone.0149833.ref003]\\]. For example, erlotinib, in combination with gemcitabine, received regulatory approval as the first molecular therapy in advanced pancreas cancer based on both a progression-free and overall survival difference of slightly more than two weeks between the gemcitabine plus erlotinib group and patients having received gemcitabine only \\[[@pone.0149833.ref004]\\]. While there has been recently regulatory approval of the chemotherapy triplet (FOLFIRINOX) and the combination of gemcitabine and nab-paclitaxel (Abraxane^\u00ae^) improving outcome from 6.8 and 6.7 months in the gemcitabine-only control arm to 11.1 and 8.5 months, respectively, there have been no breakthroughs in the molecular therapy arena for patients with pancreatic cancer so far \\[[@pone.0149833.ref002], [@pone.0149833.ref005], [@pone.0149833.ref006]\\].\n\nOne of the strategies to accelerate progress has been the deployment of improved deep sequencing technologies to interrogate pancreatic cancer genomes for novel somatic variants in genes,"
+"INTRODUCTION {#s1}\n============\n\nSeveral flaviviruses, such as the yellow fever virus (YFV), Japanese encephalitis virus (JEV), dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), and tick-borne encephalitis virus, are important human pathogens. Flaviviruses are spread worldwide, though some species show a pronounced restriction to defined regions of endemicity, such as YFV to sub-Saharan Africa and tropical Latin America and JEV to Southeast Asia and the Asia-Pacific. Certain flaviviruses, such as DENV, WNV, and, most recently, ZIKV, are (re-)emerging in new areas ([@B1][@B2][@B3]). Some evidence suggests the first autochthonous transmission of JEV in Africa ([@B4]).\n\nYellow fever (YF) is an acute viral hemorrhagic disease which is currently endemic to \u223c50 countries with \u223c1 billion people living at risk of infection. Despite the availability of a highly efficient vaccine (YFV-17D; e.g., Stamaril), an estimated \u223c0.2 million YFV infections with 29,000 to 60,000 deaths occur annually ([@B5]). Recent YFV outbreaks in Angola (2015-2016), the Democratic Republic of the Congo (2016), Brazil (2017), and Nigeria (2018) and a shortage of the YF vaccine supply raised serious concerns about the preparedness for future outbreaks ([@B6], [@B7]). Since the Aedes aegypti mosquito, the main YFV vector, is omnipresent in (sub)tropical Asia, YFV spillover to"
+"Introduction\n============\n\nCervical cancer is the most common gynecological carcinoma in women worldwide [@B1]. In particular, locally advanced cervical cancer (LACC) accounts for a large proportion of patients in China, most likely because cervical cytologic screening methods have not been widely used in Chinese practice. The current standard treatment for patients with LACC is concurrent chemoradiotherapy (CCRT) globally. For LACC patients without para-aortic lymph node metastases, the standard radiation therapy treatment field is the pelvis. The para-aortic lymph node region is excluded from the treatment field, despite the fact that it plays an important role in cervical cancer metastasis and is one of the most common sites of tumor relapse [@B2], [@B3]. To reduce the incidence of para-aortic lymph nodes failure (PALNF) and improve the survival of cervical cancer patients without para-aortic lymph node, para-aortic lymph nodes region is included in the target volume of radiation therapy in some institutes. This is prophylactic extended-field irradiation in patients with cervical cancer.\n\nIt is controversial whether prophylactic extended-field irradiation is beneficial for patients with LACC who were treated with CCRT [@B4]-[@B10]. In our previous study, extended-field irradiation decreased para-aortic lymph node failure (PALNF) and distant failure rates in patients with cervical cancer."
+"Introduction {#Sec1}\n============\n\nAntibodies against RSV proteins play an important role in preventing disease with RSV by various mechanisms including virus neutralization, antibody-dependent cellular cytotoxicity (ADCC), and complement-mediated neutralization. The RSV attachment (G) and fusion (F) proteins are the major targets of RSV-specific neutralizing antibodies but antibodies against other virus proteins are also induced by infection and can contribute to serological diagnosis of infection. EIA detects both neutralizing and non- neutralizing antibodies and use of RSV lysate antigen in EIA provides a way to detect antibodies against multiple RSV proteins. Use of F or G gene-expressed antigens, e.g., in a HEp-2 cell line, can be used to determine protein-specific antibody response. The 30-amino acid synthetic peptides are from a region of the G protein that is immune active and antibodies to this region can prevent some aspects of RSV disease.\n\nMaterials {#Sec2}\n=========\n\nProduction of RSV Virus and HEp-2 Lysate Antigens {#Sec3}\n-------------------------------------------------\n\nClass II biosafety laminar flow cabinet.175 cm^2^ Vented cell culture flasks.HEp-2 cells.RSV virus stock.37 \u00b0C Incubator with 5\u2009% CO~2~.SF-MEM: Serum-free minimum essential medium (MEM).5\u2009% Fetal bovine serum-minimum essential medium (FBS-MEM): MEM, 5\u2009% v/v FBS, 1\u00d7 penicillin/streptomycin, 1\u00d7 glutamine.\u221280 \u00b0C Freezer.15 mL Conical tubes.50 mL"
+"Introduction {#Sec1}\n============\n\nThe detection of uranium trace concentrations is of great importance due to its extensive use in nuclear power plants. According to estimations by the International Atomic Energy Agency (IAEA), the total generated nuclear power will rise in coming decades^[@CR1]^,pp. 21. Simultaneously, nuclear power plant dismantling will require fast on-site monitoring of uranium in nearby water and soils. A variety of spectroscopic techniques such as atomic absorption spectroscopy (AAS), inductively coupled plasma optical emission spectroscopy (ICP-OES), mass spectroscopy (ICP-MS)^[@CR2]^, and X-ray fluorescence spectroscopy (XFR)^[@CR3]^ can be used to detect uranium content in water samples at lab-scale. However, all these classic techniques are not portable and thus, involve large sample campaigns, making fast on-site monitoring difficult. In addition they are complicated and of high cost.\n\nTo address fast and simple on-site analysis, we have recently proposed a portable electrochemical sensor for trace uranium detection in water^[@CR4]^. These sensors are made of track-etched poly(vinylidene fluoride) (PVDF) membranes functionalised with poly(bis\\[2-(methacryloyloxy)ethyl\\] phosphate) (PB2MP) enabling efficient uranyl preconcentration thanks to their nanoporous structure. The limit of detection (LOD) was estimated to be 17 ppb (3*\u03c3*/slope) with a quantification limit (LOQ) of 51 ppb. In aqueous solutions, the most thermodynamically stable form of"
+"1. Introduction {#se0010}\n===============\n\nJupiter\\'s moon, Europa, and Saturn\\'s moon, Enceladus, are two of only a few moons in the solar system that bear the possibility of extraterrestrial life (e.g., [@br0090], [@br0270]). Europa has a deep (\u223c100 km) ocean that underlies an icy shell, more than several kilometers deep (e.g., [@br0070], [@br0060], [@br0280], [@br0170], [@br0160], [@br0250], [@br0390], [@br0320], [@br0420]), where chemical interactions at the rocky bottom of the ocean may enable the existence of a habitable environment (e.g., [@br0090], [@br0100], [@br0130], [@br0200]). The Voyager and Galileo (and to a lesser extent, the Cassini-Huygens and New Horizons) spacecrafts/missions discovered many interesting features of Europa including chaos terrains ([@br0330], [@br0410]) and craters ([@br0190], [@br0230], [@br0120], [@br0340]). More recently, based on the Hubble telescope observations, scientists raised the possibility of water vapor plumes at Europa\\'s south pole ([@br0310], [@br0350]). Europa is one of the youngest, largest, and brightest moons in the solar system ([@br0290]). A basic property of Europa is its surface temperature; surface temperature is needed to calculate the properties of its icy shell and ocean dynamics. Thus, an accurate estimation of Europa\\'s surface temperature is required.\n\nThe annual mean surface temperature of Europa was previously estimated by [@br0260]. These authors took"
+"1. Introduction\n===============\n\nTuberculous pleural effusion (TPE) is one of the most common forms of extrapulmonary tuberculosis.^\\[[@R1]\\]^ On a global scale, tuberculosis (TB) remains one of the most frequent causes of pleural effusion.^\\[[@R2]\\]^ TPE occurs in approximately 5% of patients with *Mycobacterium tuberculosis* infection.^\\[[@R3]\\]^ In the same way, pleural effusion can also be caused by some parasitic infections, such as paragonimiasis, infections by amoeba, and *Echinococcus granulosus*. With increasing travel and migration, the rates of parasitic pleural diseases are also increasing.^\\[[@R4]\\]^ Parasitic pleural effusion (PPE) and TPE present with similar clinical manifestations, but the prognosis and therapy for each are quite different. Therefore, rapid differentiation of the 2 types is important. However, the differential diagnosis of PPE and TPE remains a challenge.\n\nThe gold standard for diagnosing TPE includes the Ziehl Neelsen (ZN) acid-fast bacilli stain and a laboratory culture of *Mycobacterium tuberculosis*. However, *Mycobacterium tuberculosis* is rarely observed on direct examination by acid fast bacilli (AFB) staining in pleural fluid. Less than 30% of cultured pleural fluid samples are positive for *Mycobacterium*.^\\[[@R2]\\]^ Furthermore, laboratory culture of *Mycobacterium tuberculosis* requires 8 weeks to yield a positive result.^\\[[@R5]\\]^ The other method considered for diagnosing TPE is a pleural biopsy, which is"
+"List\u2009of\u2009editors {#Sec58587}\n===============\n\nEdited by Mizaton Hazizul Hasan, Kalavathy Ramasamy, Lim Siong Meng, Aisyah Hasyila Jahidin, Gurmeet Kaur Surindar Singh, Kamran Ashraf, Nor Hayati Abu Samah, Neoh Chin Fen and Fazlin Mohd Fauzi\n\nSponsorship {#Sec1581}\n===========\n\nPublication charges for this supplement were funded by the conference.\n\nNumbering\u2009format {#Sec1587}\n================\n\nI - Introduction\n\nKN -- Keynote Lecture\n\nPL -- Plenary Lecture\n\nIL -- Invited Lecture\n\nOPT -- Oral Presenter Pharmaceutics\n\nOPP -- Oral Presenter Pharmacology\n\nOPL-- Oral Presenter Life Sciences\n\nOPC -- Oral Presenter Chemistry\n\nPPT -- Poster Presenter Pharmaceutics\n\nPPP -- Poster Presenter Pharmacology\n\nPPL-- Poster Presenter Life Sciences\n\nPPC -- Poster Presenter Chemistry\n\nPPR -- Poster Presenter Pharmacy Practice\n\nINTRODUCTION {#Sec1}\n============\n\nAsian Conference on Pharmaceutical Sciences (Asia Pharm) is an international conference dedicated to promoting advances in pharmaceutical sciences. Asia Pharm was first held in Vietnam, from July 10-12 2016, with the theme of \"*Advances in Pharmaceutical and Biosciences*\". Asia Pharm I was co-organised by Ton Duc Thang University, Vietnam and Seoul National University, South Korea. Following the success of Asia Pharm I, Asia Pharm II was hosted from July 20-22 2017 at Seoul National University with the theme of *\"Education and Science in Pharmacy*\"."
+"All relevant data are within the paper.\n\nIntroduction {#sec001}\n============\n\nTea (*Camellia sinensis* (L.) O. Kuntze) is an important commercial crop that is grown mostly in the tropical and subtropical countries of Asia, Africa and to some extent Latin America \\[[@pone.0177816.ref001]\\]. In recent years, tremendous attention has been focused on tea plant due to its pleasant flavor and bioactive substances. Tea leaves are a valuable source of secondary metabolic products, including flavonoids, alkaloids, polysaccharides and theanine \\[[@pone.0177816.ref002]\\]. Among these secondary metabolites, flavonoids (which comprise polyphenols, flavones, flavanonols and anthocyanins) are considered to contribute numerous pharmacological beneficial effects on human health \\[[@pone.0177816.ref003]--[@pone.0177816.ref004]\\]. The health benefits of tea are thought to account for tea's protective role against cardiovascular disease \\[[@pone.0177816.ref003]\\], atherosclerosis \\[[@pone.0177816.ref004]\\], oxidant activity \\[[@pone.0177816.ref005]\\], and cancer \\[[@pone.0177816.ref006]\\].\n\nThe color of tea leaves has been diversified through long-time natural hybridization and artificial selection. Study on purple leaves of tea plant will positively promote the diversification of tea products and the fully utilization of different tea germplasm resources. Furthermore, tea products made from purple tea leaves are highly preferred by consumers. Compared with conventional tea, the anthocyanin-rich purple tea has multiple benefic functions including strong antioxidant activity \\[[@pone.0177816.ref007]\\], inhibition of colorectal carcinoma cell"
+"All relevant data are within the paper and its Supporting Information files.\n\n1 Introduction {#sec001}\n==============\n\nOne of the most important properties that is common to complex systems is the presence of critical thresholds in its dynamics \\[[@pone.0181953.ref001]\\] at which the system shifts abruptly (relative to its own long-range time scales) from one state to another. These abrupt changes in the state of a system occur near bifurcation points. At a bifurcation, the state of the system becomes unstable and the system jumps to an alternative (usually radically different) stable state. Stable states are related to a minimum in the potential energy and are separated by a potential barrier associated with unstable states. The point at which the bifurcation begins is called a critical point (CP). At this point the potential barrier flattens almost to the point of disappearing, giving place to a phenomenon known as critical slowing down (CSD) \\[[@pone.0181953.ref001]\\], the fact that the recovery time of a system after a perturbation increases when the system approaches a bifurcation in the dynamics. There are several examples of this across many fields: in medicine, asthma attacks or epileptic seizures; in global finances, in the vicinity of market crashes; in Earth"
+"1. Introduction {#sec1-ijms-20-01390}\n===============\n\nInflammatory bowel disease (IBD) is a group of long-lasting idiopathic disorders characterized by a chronic inflammatory process involving the gastrointestinal (GI) tract. Both immunological dysregulation and environmental factors are key players in the pathogenesis of the disease. The main types of IBD are represented by ulcerative colitis (UC), affecting the large intestine (colon), and Crohn's disease (CD), which can affect any section of the GI tract, while atypical forms are recognized as collagenous colitis and indeterminate colitis \\[[@B1-ijms-20-01390]\\]. The signs and symptoms comprise abdominal pain, diarrhea, rectal bleeding, weight loss, fever, and fatigue, while stricture formation, abscesses, and fistulas are common complications \\[[@B2-ijms-20-01390]\\]. Extra-intestinal manifestations, such as osteoarticular and skin involvement, can accompany the course of IBD, and are often the first evidence of the disease \\[[@B3-ijms-20-01390]\\]. Furthermore, IBD patients are at an increased risk for colorectal cancer, mainly depending on the duration and extent of the disease \\[[@B4-ijms-20-01390]\\]. Epidemiological data estimate that more than one million people in the United States and two million people in Europe suffer from IBD \\[[@B5-ijms-20-01390]\\]. Aminosalicylates, corticosteroids, antibiotics, immunomodulators, and biological drugs represent the large variety of medical therapy currently available for the management of IBD. Nevertheless, limited efficacy"
+"1. INTRODUCTION {#sec1-1}\n===============\n\nChickenpox is highly contagious, usually mild childhood disease caused by varicella-zoster. Rash usually begins with several red spots (macula) which are soon filled with liquid creating small vesicles. Vesicles appear in groups, first on body and afterwards are spread on extremities, face and scalp in two to four day. Varicella is contagious disease characterized by itching (pruritus) and skin rash (vesicles filled with liquid) which is later converted to crusts. In prodromal period, usually day before rash appears patient may have mild fever and exhaustion (1). More severe secondary infection can indicate hospital treatment. Chickenpox is spread by airborne infections or direct contact with liquid form vesicle. Person having this disease can infect others during period of 2 days before rash develop and up to 6 days after first vesicles appears, or even until vesicles are turned into crusts. Incubation period range from 10-21 days. Most of children are infected with virus until 10 years of age. Patients after disease usually acquire lifelong immunity. Diagnosis is confirmed based on specific clinical course and positive epidemiological data (2, 3) . Therapy is supportive with antipyretics and analgesics, topical and antimicrobial in case of infection (4). Newborns are"
+"**To the Editor:** Hantavirus pulmonary syndrome (HPS) is characterized by fever, gastrointestinal symptoms, respiratory distress, elevated hematocrit, hypoalbuminemia, and thrombocytopenia. Most cases in North America are acquired from rodent vectors and are caused by the Sin Nombre virus. Person-to-person transmission has been reported for Andes virus ([@R1]*,*[@R2]) but not for Sin Nombre virus ([@R3]). We describe a patient with fatal hantavirus pulmonary syndrome.\n\nThe patient was a previously healthy 15-year-old Canadian girl. In the spring of 2006, she had traveled to the Santa Cruz-San Jose de Chiquitas corridor of Bolivia with her parents and siblings for a 4-week visit ([Figure](#F1){ref-type=\"fig\"}), where they stayed with family and friends on their farms. The family noted rodent droppings outside but no rodents were seen. The patient had no known exposure to rodents or rodent droppings after her return to Canada.\n\n![Map of Bolivia with an inset map of North America showing the location of British Columbia (BC) and its relation to Bolivia.](07-0708-F){#F1}\n\nOn day 26 after her return from Bolivia, the patient sought treatment at a community hospital at 6:30 [am]{.smallcaps} for malaise and mild fever. During the night before seeking treatment, she had mild confusion. Her initial blood pressure was 99/50, heart"
+"Introduction\n============\n\nPlant species or cultivars differ in growth responses to submergence stress. Escape or quiescence can be a strategy for plant survival from submergence stress ([@B3]). Escape type plants show rapid shoot elongation to potentially grow above the water and re-stablish air contact. In contrast, quiescence type plants conserve energy by minimizing shoot elongation under the water, allowing plants to generate new tissues after de-submergence ([@B29]; [@B13]). The severity and duration of stress, plant species and cultivars, and variation of environmental conditions all influence submergence tolerance, as well as the capability of plant regrowth following de-submergence.\n\nNumerous physiological and molecular alterations are involved in genotypic variations in response to submergence stress and recovery ([@B46]; [@B56]; [@B44]; [@B9]). Carbohydrate consumption and conservation play an important role in stress tolerance, and depletion of carbohydrates under submergence stress largely influenced plant growth and survival ([@B36]; [@B34]; [@B25]). In C3 cool-season temperate grasses, fructan is a major component of non-structural carbohydrate reserve ([@B10]). Decreases in fructan and total water soluble carbohydrate (WSC) content were found in perennial ryegrass exposed to submergence stress, but the tolerant accession had relatively higher levels of fructan and WSC than the intolerant one ([@B56]). WSC and fructan contents"
+"> The practice of evidence-based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that we individual clinicians acquire through clinical experience and clinical practice.\n>\n> ---David Sackett, et al,\n>\n> BMJ\n>\n> , January 1996\n\n![](gahmj.2013.071.g001){#d35e110}\n\nWhen Dr Tom Sult, author of *Just Be Well*, says, \"Neither information nor knowledge is adequate; one must have wisdom to make impactful lasting change,\" he\\'s in good company. David Sackett, OC FRSC, one of the leaders of evidence-based medicine, says much the same. *Just Be Well* is not only informative; once you start to read it, you will have a hard time putting it down. Dr Sult\\'s distinctive style allows his skill as a writer and storyteller, brilliance as a physician, and compassion as a human being to shine through.\n\nIn *Just Be Well*, Dr Sult tells a compelling narrative story of his exploration of the foundations of health and illness. He begins by asking the reader a question: \"When was the last time you were completely and truly well? I don\\'t mean the last time you \\'felt okay\\' for a day"
+"INTRODUCTION {#s1}\n============\n\nMicroRNAs (miRNAs) are important regulators of cell signaling pathways crucial for the growth of human cancer cells \\[[@R1]\\]. Cancer-associated miRNAs are located downstream of major oncogenes and tumor suppressor genes that act as transcription factors \\[[@R2]\\]. Alterations in miRNAs can result in cancer genesis and progression. For example, levels of some miRNAs are decreased in human cancers \\[[@R3]\\]. Therefore, understanding the regulatory function of miRNAs during tumor progression will contribute to the development of targeted molecular therapies.\n\nA member of the miRNA-200 family, miRNA-200c (miR-200c), recently was found to have tumor-suppressive properties by inhibiting the epithelial-mesenchymal transition (EMT) process in several cancers. In primary glioblastoma multiforme (GBM) tissues, miR-200c and E-cadherin were found to be downregulated when epidermal growth factor receptor (EGFR) was highly amplified \\[[@R4]\\]. *EGFR* wild-type non-small cell lung cancer (NSCLC) cell lines regained sensitivity to EGFR tyrosine kinase inhibitors when EMT was inhibited by miR-200c overexpression \\[[@R5]\\]. miR-200c also interacts with various cellular signaling molecules and regulates many important signaling pathways, such as STAT3, PI3K/Akt \\[[@R6]\\], and ERK \\[[@R7]\\]. Clinically, analysis of patient data using The Cancer Genome Atlas (TCGA) datasets showed that decreased miR-200 family expression was associated with poor overall survival in"
+"The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n\nIntroduction\n============\n\nDiabetes mellitus (DM) is a syndrome of chronic hyperglycemia due to relative insulin deficiency, insulin resistance, or both \\[[@REF1]\\]. In 2019, the International Diabetes Federation estimated the number of people with diabetes worldwide to be nearly 463 million. Also, the number of diabetes mellitus patients is increasing worldwide and is expected to reach 578 million by 2030\u00a0\\[[@REF2]\\].\u00a0\n\nVitamin D is a group of steroid hormones that are mainly formed in the skin under the effect of the sun\\'s ultraviolet B rays and then modified in the liver and kidneys to convert it to the active form (1,25-dihy\u00addroxyvitamin D3). It is also present in food as vitamin D3 (animal source) and vitamin D2 (plant source)"
+"Introduction\n============\n\nPatients with cholangiocarcinoma (CAA) have extremely poor prognosis with an average 5-year survival rate of 5%--10%.[@b1-cmo-2009-121] Among the clinicopathologic factors influencing the survival after surgical treatment, curative surgery, lymph node metastases, tumor size and cancer-free margin are the most predictive factors.[@b2-cmo-2009-121]--[@b8-cmo-2009-121] Recently, in a large series of CCA, multivariate analysis showed that EGFR expression was a risk factor for recurrence of intrahepatic CCA[@b9-cmo-2009-121] with a five-year survival rate at around 20% and in hilar bile duct cancer, after curative resection, 40% of the patients had disease recurrence.[@b8-cmo-2009-121] In these patients with high risk factors, adjuvant therapy may play a role in prolonging survival. The aim of this pilot study was to assess the efficacy and safety of adjuvant chemotherapy (GEMOX) in high-risk patients with intrahepatic and hilar CAA after curative surgery.\n\nPatients and Methods\n====================\n\nPatients and treatment\n----------------------\n\nPatients were eligible for entry into this pilot study if they fulfilled the following criteria: age \u226518 years, Karnofsky Performance Status (KPS) \u2265 80%, histologically confirmed diagnosis of CCA tumor tissue available for immunohistochemical EGFR detection and curative surgery. Laboratory acceptance parameters included an absolute neutrophil count of \u22651,500 cells/\u03bcL, a platelet count of \u2265100,000 cells/\u03bcL, a serum creatinine"
+"INTRODUCTION {#s1}\n============\n\nOvarian cancer is the most lethal gynecological malignancy in the United States \\[[@R1]\\]. Over the past three decades, advances in cytotoxic chemotherapy have allowed a subset of patients to survive for 3--5 years \\[[@R1]\\]. While initial treatment with taxane-platinum combination chemotherapy and debulking surgery allows eighty percent of patients to achieve clinical remission, the vast majority of these patients recur with a median time to recurrence of 12--24 months \\[[@R2], [@R3]\\]. The remaining twenty percent of patients fail initial treatment, with progression of disease either during or within the first six months following chemotherapy. Relapsed ovarian cancer is universally incurable and current standard of care is cytotoxic chemotherapy with symptomatic management \\[[@R4]\\]. Data from large genetic analyses, including The Cancer Genome Atlas, has demonstrated that epithelial ovarian cancer is a genetically heterogeneous disease, and has failed to identify targetable driver gene mutations for the majority of patients \\[[@R5]\\]. Thus, an alternative strategy must be employed to define signaling pathways which may be targeted to either enhance chemotherapeutic response by synthetic lethality, or render otherwise chemo-resistant cells susceptible to currently used drugs such as platinum or taxanes.\n\nOvarian cancer is marked by a high degree of cellular heterogeneity"
+"Introduction {#Sec1}\n============\n\nConvergence analysis has been one of the central and very active applications of variational analysis and mathematical optimization. Examples of recent contributions to the theory of the field that have initiated efficient programs of analysis are \\[[@CR1], [@CR2], [@CR7], [@CR38]\\]. It is the common recipe emphasized in these and many other works that there are two key ingredients required in order to derive convergence of a numerical method (1) regularity of individual functions or sets such as *convexity* and *averaging property*, and (2) regularity of collections of functions or sets at their critical points such as *transversality*, *Kurdyka-\u0141ojasiewicz property* and *metric subregularity*. As a result, the question about convergence of a solving method can often be reduced to checking whether certain regularity properties of the problem data are satisfied. There have been a considerable number of papers studying these two ingredients of convergence analysis in order to establish sharper convergence criteria in various circumstances, especially those applicable to algorithms for solving nonconvex problems \\[[@CR5], [@CR12], [@CR13], [@CR19], [@CR26], [@CR27], [@CR31]--[@CR33], [@CR38], [@CR42], [@CR45]\\].\n\nThis paper suggests an algorithm called $\\documentclass[12pt]{minimal}\n                \\usepackage{amsmath}\n                \\usepackage{wasysym} \n                \\usepackage{amsfonts} \n                \\usepackage{amssymb} \n                \\usepackage{amsbsy}\n                \\usepackage{mathrsfs}\n                \\usepackage{upgreek}\n                \\setlength{\\oddsidemargin}{-69pt}\n                \\begin{document}$$T_{\\lambda }$$\\end{document}$, which covers both the backward-backward and the"
+"1. Introduction {#sec1-nanomaterials-09-00090}\n===============\n\nAdditive manufacturing (AM), also known as 3D printing, is playing an increasingly significant role in various industries, including automotive, aerospace, and biomedical areas. AM is based on an additive principle of depositing material layer by layer, offering the beneficial ability to make complexly shaped objects from 3D model data by joining materials. AM technologies open opportunities to make components on-demand for customization, to fabricate structures with complex geometries, to save on material costs, and to compress supply chains by reducing the time to market.\n\nHowever, AM components are limited to passive structural support material without built-in functionality \\[[@B1-nanomaterials-09-00090]\\]. Thus, there have been intense efforts to achieve a fully functional 3D structural electronic device by integrating the conductive structures and components (sensors, antennas, or circuits) into AM parts \\[[@B2-nanomaterials-09-00090]\\]. Among various AM techniques, fused deposition modeling (FDM) shows a high compatibility with electronic components. Espalin et al. reported that a miniature satellite named Cubesat that integrated FDM-produced structures with embedded electronics was successfully launched into space in 2013 \\[[@B3-nanomaterials-09-00090]\\]. There have been intense studies on integrating electronics into FDM parts \\[[@B4-nanomaterials-09-00090]\\].\n\nTo integrate electronic functions with AM components, the key procedure is to introduce the conductive channel"
+"1. Introduction {#sec1-ijms-20-03455}\n===============\n\nBuckwheat is a nutritional and economically cope adapted to harsh environments, which belongs to the genera *Fagopyrum*. It has been widely distributed around the world and already praised as a potential functional food for tea, cookies, noodles and so on. Meanwhile, buckwheat contains high-quality proteins with a high content of essential amino acids; retrograded starch; multiple mineral elements; and abundant secondary metabolic products such as flavonoids, phenolic derivatives, and fagopyrin, which are recognized as the major bioactive components for heath improvement and disease treatment \\[[@B1-ijms-20-03455],[@B2-ijms-20-03455]\\]. At the same time, the protein in buckwheat is gluten-free, and it will process buckwheat and its products as an alternative nutritious food to substitute the gluten grains without causing allergens and digestive issues \\[[@B3-ijms-20-03455],[@B4-ijms-20-03455]\\]. Subsequently, buckwheat contains rare bioactive components such as rutin, quercetin, vitexin, anthocyanidins, and myo-inositol, which play an important role in anti-oxidation metabolism of the human body as scavengers of active oxygen and possess healing effects on some chronic diseases like diabetes \\[[@B5-ijms-20-03455]\\], fatty liver \\[[@B6-ijms-20-03455]\\], and even cancer \\[[@B7-ijms-20-03455]\\]. Additionally, it is should be noticed that buckwheat is the only pseudocereal rich in natural rutin, which process buckwheat became a beneficial source of dietary rutin \\[[@B2-ijms-20-03455]\\]."
+"INTRODUCTION\n============\n\nOral health is a state of being free from mouth and facial pain, oral sores and infections, periodontal (gum) disease, tooth decay, tooth loss, and other diseases and disorders that limit an individual\\'s capacity in biting, chewing, smiling, speaking, and psychosocial wellbeing.^[@R1]^ Dental care is an important aspect of oral health which deals with the maintenance of healthy teeth and it is an important aspect of general oral health. The mouth is the major gateway to the body hence, oral health is essential to the general health and quality of life.^[@R2]^\n\nThe practice of regular dental care, otherwise known as oral hygiene, helps in keeping the mouth and teeth clean in order to prevent dental diseases.^[@R3]^ Basic dental care involves brushing and flossing of the teeth regularly, seeing a dentist for regular checkups and cleanings. In a broader perspective, oral hygiene is the practice of keeping the mouth and teeth clean to prevent dental problems, most commonly, dental cavities, gingivitis, periodontal (gum) diseases and bad breath.^[@R1],[@R4]^\n\nOral care practices such as brushing with fluoride toothpaste, dental flossing, regular dental checkup including cleaning the teeth professionally at least twice a year, are recommended measures for maintaining good oral health.^[@R5]^"
+"1. Introduction {#sec1}\n===============\n\nAging is a major risk factor for Parkinson\\'s disease (PD), meaning that the number of patients living with PD is steadily increasing as people live longer \\[[@B1]\\]. In addition, individuals with PD experience not only motor symptoms but also various nonmotor symptoms, such as cognitive dysfunction, psychiatric symptoms, sleep disturbance, urinary problems, sexual dysfunction, and dysautonomia, all of which affect their quality of life (QOL). These symptoms can fluctuate throughout the day and from day-to-day, thus requiring frequent reassessment. At an advanced disease stage, patients may require device-aided therapy, such as a levodopa-carbidopa intestinal gel or deep brain stimulation, due to motor complications such as the \"wearing off\" phenomenon and dyskinesia.\n\nDue to the fluctuating symptoms and multiple therapeutic choices, it is preferable for patients with PD to consult a neurologist specializing in PD treatment. In fact, reports suggest that, in patients with PD, care under a neurologist might be associated with a better prognosis \\[[@B2]\\]. However, access to PD specialists may be limited for some individuals as a result of declining mobility with the disease progression, as well as uneven distribution of these specialists between urban and rural areas and the limited number of neurologists"
+"Main {#Sec1}\n====\n\nDendritic cells (DCs) are located throughout the body to capture and internalize invading pathogens, and subsequently process and present antigen on MHC class I and class II molecules to CD8^+^ and CD4^+^ T cells, respectively^[@CR1]^. Antigen presentation by DCs is in itself not sufficient to induce effective T cell responses against pathogens. CD4^+^ T cells need to differentiate into distinct [T helper (T~H~) cell](#Glos1){ref-type=\"list\"} subsets depending on the type of infection; T~H~1 cells secrete interferon-\u03b3 (IFN\u03b3), which activates macrophages to fight intracellular microorganisms, T~H~2 cells secrete interleukin-4 (IL-4), IL-5 and IL-13 to induce humoral immune responses against helminths, and IL-17-secreting T~H~17 cells mobilize phagocytes to clear extracellular fungi and bacteria^[@CR1]^. Furthermore, [regulatory T cells](#Glos2){ref-type=\"list\"} are needed to control the activity of effector T~H~ cells. Thus, DCs need to translate information about the invading pathogen into a cytokine gene expression profile that directs the correct T~H~ cell differentiation pathway.\n\nPathogen recognition is central to the induction of T cell differentiation. Although the variety of pathogens is immense, groups of pathogens share similar structures known as [pathogen-associated molecular patterns](#Glos3){ref-type=\"list\"} (PAMPs), which enable their recognition^[@CR2]^. DCs express numerous pattern recognition receptors (PRRs) that interact with PAMPs to induce cytokine expression."
+"1. Introduction {#sec1}\n===============\n\nRestricting a child\\'s movements in order to provide health care, although poorly quantified, seems quite common and is often implicit in pediatric health care [@bib1]. Indeed, children often undergo procedures for diagnostic or therapeutic purposes, which can be painful, stressful, and potentially traumatic \\[[@bib2], [@bib3], [@bib4], [@bib5], [@bib6], [@bib7]\\]. Health professionals are sometimes required to hold them more or less firmly \\[[@bib4], [@bib5]\\] to be able to carry out these procedures [@bib8], especially in the youngest patients. It is worth pointing out that some health professionals consider that restraint is acceptable if applied in the child\\'s best interests \\[[@bib9], [@bib10]\\]. Hull et\u00a0al. refer to the Department of Health [@bib11] to define restraint as: '*the positive application of force with the intention of overpowering the child*.' [@bib12]. According to Kirwan [@bib13] who refers to the NCN\\'s recommendations [@bib14]: *\"Restraint is described as a force that is reasonably or unreasonably applied by one person against another\\'s resistance\".*\n\nHowever, some authors suggested that frequent restraint by nurses could be compared to a form of abuse [@bib9]. Restraint is also a practice that worries and stresses out the parents \\[[@bib7], [@bib15], [@bib16]\\]. Furthermore, it has been shown that restraint"
+"Introduction {#sec1-1}\n============\n\nGoat cheese has been commonly produced in many countries. Many use probiotic lactic acid bacteria (LAB) of *Lactobacillus* spp. and *Bifidobacterium* spp., which have been proven capable of improving health. Previously, we isolated and identified two indigenous LAB (*Lactobacillus plantarum* TW14 and *Lactobacillus rhamnosus* TW2) from the milk of local Indonesia goat breeds \\[[@ref1]\\], which were proven resistant to low pH and bile salt 0.3% and capable of colonizing in the intestinal epithelium, possessing antimicrobial property \\[[@ref2]\\]. Both types of LAB are used as a starter to produce cheese which is expected to generate specific characteristics in goat cheese different from any existing goat cheese. *L. plantarum* TW14 and *L. rhamnosus* TW2 are used in this work to manufacture cheese from goat milk. The use of mixed probiotic bacteria improves the viability of probiotic in cheese when compared to a single strain, \\[[@ref3]\\], which were similar to the observation on whey cheese \\[[@ref4]\\].\n\nCheese is potential for delivering probiotic LAB to the gut; however, storage temperature and duration during distribution and display might affect the survivability of the probiotics and cheese characteristics. Previous study \\[[@ref5]\\] was only limited on storage under room and cold temperature of the"
+"Introduction\n============\n\nType 2 diabetes mellitus (T2DM) is a chronic progressive disease that often requires combination of antidiabetic drugs with different mechanisms of action to achieve glycaemic targets [@b1]--[@b3]. The broadly used combination of metformin and a sulphonylurea (SU) fails to maintain glycaemic control over time [@b4] and the addition of a third antihyperglycaemic agent is required.\n\nWhen choosing options for the third agent, physicians should consider improvement of glycaemic control without additional risks such as hypoglycaemia and weight gain [@b5]. While insulin is recommended as a preferred next step by many international and local guidelines in patients failing on dual therapy [@b1]--[@b3], parenteral administration, increased risk of hypoglycaemia and weight gain may limit the use of insulin. Negative attitudes towards initiation of insulin and a preference for oral therapies by many patients should also be taken into account. Hence, a third oral agent that provides sustained glycaemic control and delays the time to permanent use of insulin could benefit patients who are reluctant to start injectable therapy [@b1],[@b6].\n\nVildagliptin, a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4), improves glycaemic control by increasing the availability of endogenous incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) [@b7],[@b8]. Complementing"
+"1. Introduction {#sec1}\n===============\n\nLumbar disc herniation (LDH) is a state of displaced intervertebral disc material, including the nucleus pulposus or annulus fibrosis, which can cause low-back pain and/or radicular pain, paresthesia, or weakness in the lower limbs \\[[@B1], [@B2]\\]. Current therapies include nonsurgical and surgical methods. The nonsurgical treatments include conservative management and invasive treatments \\[[@B3], [@B4]\\]. For the conservative management, nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, muscle relaxants, and steroidal drugs are commonly used among others. Nonpharmacological strategies such as acupuncture, physical therapy, and exercise are also recommended. If the conservative therapy fails to relieve the symptoms, more invasive treatments such as epidural steroid injection can be applied. When these more invasive procedures fail to control the LDH symptoms, subsequent surgeries are considered.\n\nBefore considering surgery, it is important to discuss other therapeutic options in patients who received nonsurgical treatments with no success. Epidural injections are effective in pain relief for a short time but may require additional injections because of recurring symptoms \\[[@B5], [@B6]\\]. There have been attempts to find effective and safe treatments before surgical procedures for symptomatic LDH \\[[@B7]--[@B9]\\].\n\nAs a valuable option in LDH, acupotomy has the characteristics of both acupuncture and surgical procedures \\[[@B10],"
+"1. Introduction {#sec1}\n===============\n\nCardiovascular diseases (CVD) constitute the major risk of morbidity and mortality in chronic kidney disease (CKD) patients \\[[@B1], [@B2]\\]. Uremic patients have both traditional cardiovascular (CV) risk factors (i.e., old age, hypertension, diabetes, smoking, dyslipidemia, heart failure, and physical inactivity) and nontraditional CV risk factors, including malnutrition, anemia, hyperhomocysteinemia, neuropathy, hyperparathyroidism, and chronic inflammation \\[[@B3]--[@B5]\\]. Patients with end-stage renal disease (ESRD) undergoing renal replacement therapy (RRT), either hemodialysis (HD) or peritoneal dialysis (PD), may face a partial loss of some low-molecular-weight plasma factors (i.e., vitamins A, C, and E) \\[[@B6], [@B7]\\] that normally contrast inflammation by neutralizing reactive oxygen species (ROS) \\[[@B8]\\]. Indeed, the latter are increased during the two therapies \\[[@B9]\\]. The imbalance in antioxidant and pro-oxidant factors generates an oxidative stress (OS) that increases the inflammatory state already present in these patients.\n\nIn recent years, OS has been postulated to be an important risk factor for CVD \\[[@B10]\\]. OS results from an imbalance between prooxidant and antioxidant defence and mechanisms with increased levels of prooxidants leading to tissue damage \\[[@B10]\\]. Antioxidants can be divided into intracellular and extracellular antioxidants. Intracellular enzymatic antioxidants are superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-GPx), which convert"
+"Introduction {#s1}\n============\n\nIntravenous medication administration is complex, and data suggest that errors are common. For example, a systematic review of nine studies across various stages of intravenous medication preparation and administration reported errors in 73% of intravenous doses.[@R1] However, published error rates vary widely, from 18% to 173% of intravenous doses in studies using structured observation of medication administration.[@R2]\n\nAmidst concerns over safety, technologies such as 'smart pumps' have been advocated. These incorporate dose error reduction software to check programmed infusion rates against preset limits within a customisable drug library. However, dose limits can be over-ridden, and evidence regarding their impact is mixed.[@R3] While unintended infusion overdoses represent a major safety concern, there are many factors that affect infusion administration, and smart pumps are just one possible solution.\n\nA recent multisite US study using structured observation reported a high prevalence of intravenous infusion administration errors and procedural failures, even with the use of smart pumps, yet few potentially harmful errors.[@R4] Building on this and an earlier US study,[@R5] we therefore wanted to conduct a similar study in the UK with a larger sample size[@R6] to confirm or refute these findings in a different context in which smart pumps are"
+"Introduction\n============\n\nLarge-scale cooling water systems are widely used to remove heat from industrial equipment using a heat exchanger in chemical manufacturing facilities, power plants and petroleum refineries ([@B42]). Natural water from a river, lake or sea can be used ([@B36]). In some cooling water systems, the treated refinery wastewater was used ([@B27]). These water systems contain diverse species of microorganisms, organic matters and inorganic salts that enable microbial growth, leading to microbiologically influenced corrosion (MIC) and biofouling ([@B41]; [@B28]). Cooling tower systems typically have a water temperature between 25\u00b0C and 35\u00b0C that is ideal for microbes to grow ([@B29]). Microbes attach to the surfaces to form biofilms by secreting extra polymeric substances (EPS) ([@B12]). These biofilms can cause MIC and biofouling ([@B7]; [@B21]; [@B37]; [@B43]).\n\nMicrobiologically influenced corrosion is a major problem in various industrial sectors, such as water utilities, oil and gas, and power generation ([@B35]; [@B44]; [@B18]). MIC in recirculating cooling water systems causes deterioration of metallic surfaces and reduces the lifetime of the systems ([@B15]). Biofouling on the other hand reduces the heat exchanging efficiency and hinders pipe flows ([@B40]). Thus, these problematic biofilms reduce the reliability and increase the operating cost of the systems ([@B33])."
+"Scientific Reports 6: Article number: 23138;10.1038/srep23138 Published online: 03182016; Updated: 05092016\n\nThe Acknowledgements section in this Article is incomplete.\n\n\"We thank Richard Randall for providing A549 cells stably expressing MxA or shMxA, Georg Kochs for providing the NP-specific antibody and Geoffrey Chase, Georg Kochs and Peter Staeheli for critically reading of the manuscript.\"\n\nshould read:\n\n\"We thank Richard Randall for providing A549 cells stably expressing MxA or shMxA, Georg Kochs for providing the NP-specific antibody and Geoffrey Chase, Georg Kochs and Peter Staeheli for critically reading of the manuscript. This was work was supported by the Deutsche Forschungsgemeinschaft (SCHW 632/15 and SFB 1160, project 13) to MS.\""
+"1. Introduction {#sec1}\n===============\n\nChronic atrophic gastritis (CAG) is often associated with intestinal metaplasia and atypical hyperplasia, which are characterized by local or extensive chronic inflammation of gastric mucosa, atrophy and reduction of the intrinsic glands, thinning of the mucosal layer and thickening of the mucosal myometrium. CAG is defined as precancerous lesions when accompanied by moderate or severe atypical hyperplasia (ATP) or intestinal metaplasia (IM), according to the 1978 WHO Expert Meeting of Gastroenterology. We must take CAG seriously because gastric cancer (GC) is the fifth most commonly diagnosed malignancy and the third leading cause of cancer-related deaths worldwide \\[[@B1]\\].\n\nStudies have shown that precancerous lesions are a nonspecific process, characterized by long-term cell degradation and proliferation. Even when some oncogenes are activated, cell metabolism may be deficient, especially nucleic acid metabolism and DNA repair, but these are reversible processes \\[[@B2], [@B3]\\]. Precancerous cells can develop to carcinoma *in situ* without interventional therapy or revert to normal cells after treatment.\n\nModerate and severe atrophic gastritis create a significantly less acidic environment, with decreased parietal cells, G\u2009cells, and chief cells in the stomach, which are directly related to decreased hydrochloric acid, pepsinogen, and gastrin \\[[@B4], [@B5]\\]. This structural disorder"
+"Introduction {#s1}\n============\n\nThe Rosetta software suite, an object-oriented protein structure prediction tool [@pone.0021931-LeaverFay1], can effectively perform protein structure prediction and design [@pone.0021931-Das1] [@pone.0021931-Kaufmann1]. Common tasks such as design, docking, and folding produce text files containing the Cartesian coordinates of each atom of the protein. Molecular visualization tools are used later to interpret the output [@pone.0021931-ODonoghue1]. Thus, visualization is typically separated from Rosetta. Output structures could be viewed after a simulation, but not during a calculation or protocol. Real-time structural visualization would facilitate development of new methods and make Rosetta more accessible to new users.\n\nRosetta protocols are useful to a broad range of scientists, but many protocols are complex. Scientists who are not trained in computation can become frustrated with Rosetta\\'s steep learning curve. Two new interfaces to Rosetta were built to bridge this gap. PyRosetta [@pone.0021931-Chaudhury1] is a Python-based interface to Rosetta objects and protocols enabling users to easily develop custom algorithms and to explore Rosetta through the Python interpreter. RosettaScripts [@pone.0021931-Fleishman1] provides an XML-scriptable interface to Rosetta allowing users to design custom algorithms. PyRosetta and RosettaScripts have successfully lowered the barrier to learn Rosetta by providing an interactive and scriptable layer. To further improve access to Rosetta,"
+"1. Introduction {#j_med-2019-0088_s_001}\n===============\n\nPain is a very complex physiopathological entity. It can take on different aspects both from a clinical and biological/ physiological point of view, and present itself as an epiphenomenon of a pathophysiological process, until it becomes a real pathological entity in its own right. Pain is defined as chronic when it is continuous for more than three tosix months \\[[@j_med-2019-0088_ref_001]\\]. It is a condition reported in 20% of people worldwide, in 15-20% of all physician examinations \\[[@j_med-2019-0088_ref_002]\\], and should receive more attention because a proper pain therapy is a human right \\[[@j_med-2019-0088_ref_002],[@j_med-2019-0088_ref_003]\\]. The trigger for the development of chronic pain may be different in different situations. Inflammation causes inflammatory pain, while nerve injuries as the result of mechanical trauma (iatrogenic or not), metabolic or autoimmune disorders, and cancer and chemotherapy may give neuropathic pain \\[[@j_med-2019-0088_ref_004], [@j_med-2019-0088_ref_005], [@j_med-2019-0088_ref_006]\\]. The excitation of the primary neurons due to prolonged inflammation induce a pathological response that persist beyond the period of recovery of the tissue, constantly stimulating the nociceptive pathways and thus generating chronic pain with changes in ion channels, receptors and nerve synapses. The distribution of neurotransmitters and neuromediators allows peripheral and central neurons to reach the depolarization threshold"
+"Introduction {#Sec1}\n============\n\nIn mammals, endogenous odors, such as body odors, urine, feces, or blood, serve as attractants to predators and warning signals to prey species^[@CR1]^. These types of odors typically transfer information between predator-prey species pairs sharing a long evolutionary history^[@CR1]^. However, this information flow is normally confined to discrete pairs of predator-prey species but the odor from blood seems to be a more universal cue. Mammalian predators use the odor of blood to home-in on wounded prey^[@CR1]^, whereas prey species display avoidance behavior and increased vigilance towards conspecific, as well as heterospecific, blood odors^[@CR2]--[@CR7]^. This suggests the presence of an old and evolutionarily conserved chemosensory cue within blood odor.\n\nHowever, the odor of blood is a complex mixture of volatiles, and mammals very seldom respond to a single volatile compound as they do to the naturally occurring odor mixture the volatile belongs to^[@CR8]--[@CR14]^. Nonetheless, we recently demonstrated that the volatile chemical *trans*-4, 5-epoxy-(E)-2-decenal (see E2D; Fig.\u00a0[1a](#Fig1){ref-type=\"fig\"}), that is present in mammalian blood is as strong an attractant to four mammalian predator species as the full blood mixture^[@CR9]^. E2D is generated by lipid peroxidation^[@CR15]^. This physiological process is present in all mammals and it is very likely that"
+"1. Introduction {#s0005}\n===============\n\nParkinson\\'s disease (PD) is a neurodegenerative condition, affecting 1% of people aged 65 or older in industrialized countries ([@bb0060]), characterized by disabling motor and non-motor symptoms. Though dopamine-replacement medications treat motor symptoms early in PD, later in disease, these therapies are less effective, whereas other symptoms are not dopamine-responsive at all ([@bb0145]). There are no cures or disease-modifying therapies ([@bb0045]). The inadequate state of current therapy urgently requires correction. The development of sensitive and reliable biomarkers is critical to aid in the diagnosis of PD and to measure the efficacy of new treatments aiming to slow, halt, or reverse PD ([@bb0205]; [@bb0125]). *Diagnostic biomarkers* that distinguish PD patients from healthy controls will improve the appropriate enrollment of patients in clinical trials. *Progression biomarkers* that objectively track disease evolution are needed to act as endpoints for critical tests of potential treatments. Prevention or delay of disease progression can only be ascertained if these objective endpoints are available. Clinical response alone is an insufficient measure that is subjective and confounds symptom-alleviating with disease-altering impacts ([@bb0180]).\n\nMagnetic resonance imaging (MRI) offers substantial promise to provide biomarkers of PD. There have been advances in determining potential structural ([@bb0160]; [@bb0185]; [@bb0170];"
+"INTRODUCTION {#s1}\n============\n\nIn allogeneic mice, not all types of tumor cells initiate early stage tumors after inoculation, while the tumors, if initiated, are unavoidably regressed at later stage. The regression is mainly resulted from the cellular immune response to the allogeneic tumor cells. After inoculation, allogeneic tumor cells, much like the cell in transplanted allogeneic organs, are recognized by both of CD8^+^ T cells and CD4^+^ T cells. The CD8^+^ T cells recognize MHC-class I molecules on the allogeneic tumor cells and are activated to proliferate and differentiate into effector cytotoxic T lymphocytes (CTLs) at the later stage of allogeneic tumor formation. The effector CTLs move to the allogeneic tumors and kill the tumor cells \\[[@R1]\\]. CD4^+^ T cells are activated after recognizing MHC class II molecules on allogeneic cells \\[[@R2]\\] to launch adaptive immune responses, resulting in directly killing or promoting the generation of allogeneic cell specific CTLs \\[[@R3], [@R4]\\]. Recently, depletion of CD4^+^ or CD8^+^ T cells prior to allogeneic tumor inoculation was found to prevent eventual tumor regression in mice, confirming that CD4^+^ or CD8^+^ T cells mediate the allogeneic tumor regression at the later stage \\[[@R5]\\]. The tumor-reactive T cells were activated by dendritic cells"
+"Background {#Sec1}\n==========\n\nDuring the past 50 years, incisional and ventral hernia repair surgery has evolved from direct suture repair to the use of synthetic mesh to obtain a tension-free repair \\[[@CR1]--[@CR3]\\]. Finally, the tension-free concepts have been applied to laparoscopic surgery. Laparoscopic repair of incisional/ventral hernias (LIVHR) has gained increasing popularity, since many studies, included three meta-analyses, have reported encouraging results in terms of wound infection, hospital stay and post-operative pain, and recurrence rates comparable with the open approach \\[[@CR1]--[@CR8]\\].\n\nBesides patient selection (age, sex, comorbidities, obesity, hernia site and size, eventual recurrence and type of previous abdominal surgery) and patient compliance, the choice of the mesh (bio-materials, size and shape) and fixation methods (titanium tacks, absorbable tacks, fibrin glue) are considered crucial issues to achieve optimal results and reduce complication and recurrence rates \\[[@CR4],[@CR5],[@CR9]--[@CR12]\\]. Lightweight meshes are often considered the first choice for hernia repair by many authors, since the evidence that the decreased density of the non-absorbable material could reduce the \"foreign-body response,\" improve abdominal wall compliance, cause less shrinkage and enhance the integration in host tissues \\[[@CR13]--[@CR15]\\]. Titanium helicoidal tacks are still considered the \"gold standard\" for mesh fixation \\[[@CR16]--[@CR20]\\]. However, several complications caused by these"
+"Introduction {#s1}\n============\n\nEvidence that mitochondria are a key mediator of cell death through apoptotic and/or necrotic processes [@pone.0069718-Goldstein1], [@pone.0069718-Green1] as well as an organelle essential for cellular respiration is accumulating in the literature. Cytosolic free Ca^2+^ ions would induce an opening of the mitochondrial permeability transition pore (mPTP) [@pone.0069718-Hunter1], [@pone.0069718-Halestrap1] responsible for the increased permeability of mitochondrial outer membranes for different cytotoxic molecules, such as cytochrome C, apoptosis inducing factor, etc. [@pone.0069718-Baines1], [@pone.0069718-Shalbuyeva1]. Accordingly, mPTP would mediate a disruption of the mitochondrial membrane potential (\u0394\u03a8) for subsequent mitochondrial swelling to cell death. Calcium entry is shown to more easily occur into mitochondria after activation of *N*-methyl-D-aspartate (NMDA) receptor (NMDAR) channels rather than other Ca^2+^ gates, including kainate receptors and voltage-sensitive Ca^2+^ channels [@pone.0069718-Peng1], [@pone.0069718-Young1].\n\nThe inhibition of Ca^2+^ transport into mitochondria protects neurons from cell death mediated by glutamate (Glu), suggesting that Glu-induced neuronal death requires Ca^2+^ entry into mitochondria [@pone.0069718-Stout1]. In fact, mitochondrial dysfunction is a primary determinant of the fate of neurons exposed to Glu [@pone.0069718-Schinder1]. Reversible nuclear oxidative DNA damage occurs in cerebral cortical neurons in response to transient Glu receptor stimulation [@pone.0069718-Yang1]. The mechanism seems to involve the mitochondrial calcium uniporter (mCU), which has been"
+"Significance Statement {#s1}\n======================\n\nMossy cells of the dentate gyrus (DG) have been implicated in hippocampal circuits regulating pattern separation, an important function attributed to the DG. However, physiologic inputs regulating mossy cell activity are incompletely understood. Here, we show development-dependent changes in the sources of both excitatory and inhibitory inputs. Our results suggest that excitatory inputs from the DG and local inhibitory inputs are positioned to powerfully sculpt receptive fields in mature mossy cells.\n\nIntroduction {#s2}\n============\n\nMossy cells are principal excitatory neurons in the dentate gyrus (DG) of the hippocampal formation ([@B31]; [@B20]; [@B23]). Mossy cells are of significant interest, as they are an important circuit element within the DG, which has been implicated in mediating cognitive functions such as pattern separation ([@B17]; [@B21]; [@B12]). In addition, mossy cells have been proposed to play an important role in temporal lobe epilepsy, as selective loss of DG neurons accompanies this disorder, and mossy cells appear to be among the neurons most vulnerable to injury and cell death ([@B30]). Very recently, three studies functionally characterized mossy cells, focusing particularly on *in vivo* firing properties distinguishing mossy cells from granule cells, another major neuron type in the DG, during behavior ([@B6];"
+"Background\n==========\n\nGene duplications are traditionally considered to be a major evolutionary source of new protein functions. The conventional view, pioneered by Susumu Ohno, holds that a gene duplication produces two functionally redundant, paralogous genes and thereby frees one of them from selective constraints. This unconstrained paralog is then free to accumulate neutral mutations that would have been deleterious in a unique gene \\[[@B1]\\]. Although the most likely outcome of such neutral evolution is for one of the paralogs to fix a null mutation and become a pseudogene, there is also the possibility of fixation of mutations that lead to a new function \\[[@B2],[@B3],[@B4],[@B5],[@B6]\\].\n\nOne of the predictions of the conventional model of evolution of duplicated genes is the rapid loss of paralogs due to null mutations \\[[@B2],[@B3],[@B5],[@B7]\\]. However, this prediction was not supported by studies on isozyme spectra of polyploids in a number of organisms (reviewed in \\[[@B8]\\]). Furthermore, a study of 17 pairs of duplicated genes in the tetraploid frog *Xenopus laevis* has shown that both copies were subject to purifying selection \\[[@B9]\\], contrary to the notion of neutrality of one of the copies \\[[@B1]\\]. The failure of empirical research to support Ohno\\'s model has led to the"
+"Introduction {#Sec1}\n============\n\nParkinson's disease (PD), the most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons and the formation of intracellular Lewy bodies (LBs), which consist primarily of \u03b1-synuclein (hereafter referred to as synuclein) and ubiquitin^[@CR1]^. Interactions between genetic predisposition and environmental factors are likely the primary events inducing mitochondrial dysfunction and oxidative damage, resulting in oligomerization and aggregation of synuclein, but the underlying molecular mechanisms remain poorly understood. The vast majority of PD occurs sporadically, with inherited familial forms of the disease accounting for roughly 5% of all cases^[@CR2]^. The identification of PD-related genes and risk factors has implicated several pathways in PD etiology, with growing evidence suggesting a link between dysfunctional intracellular protein catabolism and PD pathogenesis. In *PARK1*-linked PD, intrinsically disordered mutant synuclein initiates the disease process. Given that highly aggregated proteins are deposited in nigral neurons in PD, dysfunctions of proteolytic systems, i.e., the ubiquitin--proteasome system and autophagy--lysosomal pathway, seem to contribute to the final neurodegenerative process.\n\nMacroautophagy (hereafter, referred to as autophagy) is a highly conserved bulk protein degradation pathway in eukaryotes. Cytoplasmic proteins and organelles are engulfed within autophagosomes, which fuse with the lysosome, where they are degraded along with"
+"Introduction {#s1}\n============\n\nThe endocrine disruption hypothesis states that hormonally active pollutant chemicals are interfering with endocrine function in the general population.\u00a0 Estrogen-mimicking compounds are perhaps the best studied of the endocrine disrupting chemicals. Exposure to these chemicals during critical periods of development, such as infancy, is of particular concern. However, while it is possible to measure an infant or child's *exposure* to a potentially estrogenic compound, there are few feasible, well validated ways of assessing *response* \\[[@B1]\\].\u00a0 For example, exposure to an estrogenic endocrine disruptor during infancy may alter the timing of pubertal onset, but such an outcome takes many years of follow up to observe. Previously, we have attempted to develop valid, reliable methods of assessing estrogen response in young infants. Our model for estrogen exposure exploits the large natural change that occurs between birth (high estrogen exposure) and later in infancy (low estrogen exposure).\u00a0 We have shown that the uterus and male breast are large at birth, consistent with the known trophic effect of maternal estrogen, and that these organs shrink as the infant gets older and estrogen exposure is lost \\[[@B2]\\]. Accordingly, reproductive organ volume may be a useful measure for evaluating whether an infant is"
+"Background\n==========\n\nFoodborne illnesses are an important public health problem worldwide \\[[@B1]\\]. The World Health Organization (WHO) has created an initiative to estimate the global burden of foodborne illnesses, and they have stated that the achievement of certain Millennium Development Goals are being directly compromised due to foodborne illness \\[[@B2],[@B3]\\]. However, governments have finite resources with which to address the health of their populations, and thus require high-quality scientific evidence to prioritize resource allocation. Accurate burden of illness estimates are useful for decision makers seeking to allocate resources to address the issues caused by foodborne pathogens \\[[@B4],[@B5]\\]. The cost-of-illness (COI) methodology is one technique used to estimate the economic burden of a disease \\[[@B6]\\]. However, there is concern in the scientific literature that COI estimates are limited in usefulness, due to variability in their execution (e.g., varying cost inventories and study methodologies), and a lack of transparency and detail when describing such methodologies. Of particular concern are the differing cost inventories being used when estimating the cost of foodborne illnesses \\[[@B7]-[@B10]\\].\n\nThe COI approach traces the flow of resources associated with adverse health outcomes through the quantification of measurable individual and societal level costs \\[[@B7],[@B11],[@B12]\\]. Costs at the individual level"
+"Background {#Sec1}\n==========\n\nPlants experience various biotic and abiotic stresses in their natural environment, such as drought and salt stress. Abscisic acid (ABA) plays an important role in plant response to drought and high salinity. ABA was first discovered in the 1960s and isolated from cotton as a promoter of leaf abscission \\[[@CR1], [@CR2]\\]. ABA also regulates diverse plant growth and developmental processes, including seed development, stomatal closure, promotion of seed dormancy and reproduction \\[[@CR3]--[@CR6]\\].\n\nProtein phosphorylation/dephosphorylation is an important mechanism for mediating intracellular responses, i.e. responses to hormonal, pathogenic, and environmental stresses \\[[@CR7]\\]. Various studies in plants have indicated that protein kinases are involved in stress signaling via phosphorylation/dephosphorylation, for example, the plant mitogen-activated protein kinase (MAPK) \\[[@CR8]\\], calcium-dependent protein kinase (CDPK) \\[[@CR9]\\], and sucrose non-fermenting1 (SNF1) kinase families. The SNF1 kinase family is known as SNF1 protein kinases in yeasts, AMP-activated protein kinases in mammals, and SNF1-related protein kinases (SnRKs) in plants \\[[@CR10]\\]. All kinases in yeasts and mammals play key roles in carbohydrate metabolism, whereas plant SnRKs may function as interfaces between stress and metabolic signaling pathways \\[[@CR11]--[@CR13]\\].\n\nThe SnRK protein kinases are classified into three subfamilies: SnRK1, SnRK2 and SnRK3 \\[[@CR12], [@CR14]\\]. *SnRK1* is the plant"
+"The emerging of SARS-CoV-2 and COVID-19 pandemia with a high mortality rate in older subjects with one or more known cardiovascular comorbidities [@b0005] has prompted the question of \"sharing bio-molecular targets\" between coronaviruses and Renin Angiotensin Aldosterone System (RAAS), a system that is involved, at multiple levels, in the control of the cardiovascular function and, also, is a favorite drug target in cardiovascular diseases [@b0010]. Indeed during treatment with Angiotensin-Converting Enzyme inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) the known up-regulation of ACE2/Ang 1-7/MasR axes might be very useful to treat arterial blood pressure, ischemic heart disease and heart failure but, at the same time, detrimental since during COVID-19 it might open the route to SARS-CoV-2 that have been proven to use the ACE2 as functional receptor to enter the human cells [@b0015]. This evidence at the bimolecular level has generated several commentary-style articles that claim it is more prudent to replace ACEi/ARBs during COVID-19 [@b0010], [@b0020], [@b0025], [@b0030]. The main scientific societies have taken a critical position towards any therapeutic change in the absence of supporting data [@b0035] and this is dictated by prudence. Nonetheless it should be said that switching can be done safely in arterial hypertension if"
+"While antiretroviral therapy for human immunodeficiency virus (HIV) infection is highly effective at preventing AIDS-related complications, treated patients are at a significant risk for a number of diseases typically associated with older age, including cardiovascular disease, osteoporosis, cancer, neurocognitive impairment, and frailty \\[[@JIV277C1]--[@JIV277C11]\\]. Among the aging HIV-infected population, it has become evident that the incidence of HIV-associated non--AIDS-defining conditions is increasing \\[[@JIV277C12]\\]. In recent years, the Working Group on HIV and Aging published a report for the National Institutes of Health Office of AIDS Research, in which it stated that the cause of this increasing incidence is unclear but proposed that it may be due to an accelerated aging process \\[[@JIV277C13]\\]. To show that HIV infection is associated with accelerated normal aging, one first needs to understand what is meant by normal aging and to find a way of measuring it. Owing to its modest accuracy, telomere length will probably have to be supplemented by additional biomarkers of aging when it comes to understanding and measuring normal aging. DNA methylation levels are particularly promising biomarkers of aging since chronological age (ie, the calendar years that have passed since birth) has a profound effect on DNA methylation levels in most human"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec007}\n============\n\nMaternal health is central to the development of any country to achieve equity, reduce poverty, and build social capital \\[[@pone.0183739.ref001]\\]. Reducing maternal mortality was one of the key indicators of the Millennium Development Goals \\[[@pone.0183739.ref002]\\]. Almost all the maternal deaths (99%) occur in developing countries and one-third of them occur in South Asia \\[[@pone.0183739.ref003]\\]. Birth preparedness and complication readiness (BPCR) is one of the key interventions to reduce the maternal mortality. BPCR is defined as a programmatic approach to improve the use and effectiveness of key maternal and newborn health services, based on the premise that preparing for birth and being ready for complications reduces all three phases of delays in receiving the services (i.e., delays in seeking care, reaching the healthcare facility, and in receiving adequate care at the point of service) \\[[@pone.0183739.ref004]\\]. Since a wide range of factors contribute to these delays, it requires people at multiple levels---women and their families, communities, providers, facilities, and policymakers---to engage in BPCR actions \\[[@pone.0183739.ref004]\\].\n\nThe World Health Organization (WHO) recommends that pregnant woman should receive focused 'antenatal care' (ANC) in which BPCR is a key component"
+"1. Introduction {#sec1}\n===============\n\nThe deep-sea (\\>1000\u2009m depth) covers about 70% of the Earth\\'s surface, representing one of the last large unexplored areas on the planet. Only within the last few decades the technology has advanced sufficiently to reach the deep-sea effectively, revealing unexpected high levels of biodiversity and extremely diverse habitats (canyons, cold seeps, hydrothermal vents, deep-water coral reefs, mud volcanoes, seamounts, and trenches) of significant conservation interest and potential high economic values. Deep-sea environments are characterized by extremely high hydrostatic pressures (1\u2009MPa every 100\u2009m), lack of light, and low temperatures (down to 1-2\u00b0C). Therefore, fish as well as any other organism living in the deep-sea had to adapt to tolerate conditions of this extreme habitat \\[[@B1]\\].\n\nFirst studies on adaptation to high pressure and low temperatures are dated back in the '70s and they report comparison of common proteins present in shallow and deep-water fishes \\[[@B2], [@B3]\\]. Key enzymes in muscle tissues that exhibit adaptive differences among species at different depths are the lactate dehydrogenase (LDH) and malate dehydrogenase (MDH) presenting differences in structural stability (reviews in \\[[@B4]--[@B6]\\]). More recent studies on evolutionary adaptation of functional genes to high pressure report unique amino acid substitutions"
+"Pluripotent stem cells, such as embryonic stem cells (ESCs) are able to differentiate into many different cell types *in vitro*[@b1]. Because the ESCs are also immortal and can maintain their pluripotency, they can be inexhaustible research tools for investigating cell differentiation processes. Previously, we had established a \"NIA Mouse ESC Bank\" of 137 ESC lines, each of which carries a transcription factor (TF) that can be induced in a doxycycline-controllable manner[@b2][@b3]. We also carried out global gene expression profiling of these ESC lines 48\u2009hours after the induction of TFs and demonstrated that these transcriptome data indicate the direction of cell differentiation[@b2][@b3]. In particular, we have validated the cell differentiation into neural lineages, skeletal muscles, hepatocytes, and blood cells[@b4].\n\nTo increase the number of manipulated TFs and the coverage of cell types, we have generated ESC lines with 48 new transgenic TFs. With a total of 185 TFs, the \"NIA Mouse ESC Bank\" covers about 10% of all TFs encoded in the mouse genome[@b5]. We have measured the global gene expression profiles of these new ESC lines 48\u2009hours after overexpressing each TF and compared the changes to tissue-specific gene expression profiles and functionally annotated gene sets.\n\nResults\n=======\n\nGeneration"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec001}\n============\n\nGinseng (*Panax ginseng* Meyer) has been widely used as a folk and conventional medicine for the prevention and/or treatment of many diseases for a long time. The fundamental compounds behind ginseng's multiple pharmacological activities are ginsenosides \\[[@pone.0146843.ref001]\\]. In Asia, ginseng is air-dried into white ginseng or steamed at 90--100\u00b0C for 2--3 h to produce red ginseng. It has been reported that red ginseng is more pharmacologically effective than white ginseng, which may result from the heat transformation and deglycosylation of ginsenosides occurring during the steaming process \\[[@pone.0146843.ref002],[@pone.0146843.ref003]\\].\n\nBlack ginseng, a new type of processed ginseng, is produced from white ginseng after nine cycles of steaming and drying. During the steaming process for black ginseng, ginsenosides transform into low polarity constituents through hydrolysis, isomerization and dehydration at C-3, C-6 or C-20 \\[[@pone.0146843.ref004]\\]. Black ginseng has been shown to display protective effects against obesity \\[[@pone.0146843.ref005]\\], breast cancer \\[[@pone.0146843.ref006]\\], cognitive impairment \\[[@pone.0146843.ref007]\\], and fetal alcohol syndrome \\[[@pone.0146843.ref008]\\] in animals and cell culture models. Moreover, recent studies have demonstrated that black ginseng exhibits more potent antioxidant and cholinesterase inhibitory activity than white or red ginseng \\[[@pone.0146843.ref009]--[@pone.0146843.ref011]\\]. Since ginseng, particularly"
+"Background {#Sec1}\n==========\n\nAccounting for 45% of all brain malignancies and 54% of all human gliomas, glioblastoma (GBM) is the most aggressive and lethal type of brain tumor \\[[@CR1],[@CR2]\\]. Despite multimodality therapies including maximal resection and adjuvant chemotherapy and radiotherapy, the overall outcome of patients with newly diagnosed GBM remains dismal. According to the most recent report of The Central Brain Tumor Registry of the United States (CBTRUS), less than 5% of GBM patients survive five years post diagnosis \\[[@CR1]\\]. Clearly more effective therapies are urgently needed and identification of valuable prognostic biomarkers and potential molecular targets is one key strategy to achieve this goal.\n\nThere are several different genetic alterations of important genes that may contribute to the pathogenesis of GBM, and these aberrations may differ from patient to patient. Therefore, treatment regimens for patients with GBM may be more effective if they are tailored toward the particular pathogenesis of patients' neoplasm. In recent years, substantial efforts have been made to explore molecular profiles to better understand the pathogenesis of GBM and biomarkers associated with patients' survival. There also have been several public resources that have provided insight into the pathogenesis of GBM through allowing researchers to correlate levels"
+"Tropomyosins (Tpms) form end-to-end polymers along actin filaments and determine the functional properties of the filament in fungi[@b1], flies[@b2] and mammals[@b3]. They belong to a highly conserved family of proteins with the greatest sequence divergence occurring at the N- and C-terminal ends due to alternative promotor use and exon splicing[@b4]. The N- and C-termini of adjacent Tpm molecules form an overlap complex that is required for Tpm to form cables along both sides of the helical actin filament[@b5]. It is not clear how the isoform-specific sequence information contained within the overlap complex contributes to differences in the way Tpms bind to and regulate actin.\n\nFunctionally distinct actin filament populations, characterised by their Tpm isoform composition, directly regulate a wide range of physiological processes in mammals[@b6]. In malignancy the Tpm profile is significantly altered, concomitant with dramatic rearrangements in actin cytoskeleton architecture[@b7]. Despite a down-regulation in high-molecular weight Tpm isoforms, actin filaments incorporating the low molecular weight isoform Tpm3.1 persist in all malignant cell types and are required for tumour cell survival in, at least, melanoma and neuroblastoma[@b8][@b9]. Studies implicating Tpm3.1-containing actin filaments in focal adhesion stability[@b10], ERK mediated proliferation[@b11] and myosin-dependent mechanical tension[@b12] may speak to the specific reliance on"
+"Occupational consciousness emerged as a construct from my doctoral work on intergenerational play within families in post-apartheid South Africa. It refers to ongoing awareness about the dynamics of hegemony and recognition that dominant practices are sustained through what people do every day, with implications for personal and collective health (Ramugondo, [@cit0046]). The emergence of the construct in this context signifies an ongoing struggle with negotiating long-standing dynamics of power that were laid down during colonialism, and maintained under black majority rule. Occupational consciousness provides a language through which people can describe how their individual and collective everyday doing can resist and challenge hegemonic practices that sustain all forms of unequal power relations. In providing a theoretical foundation to occupational consciousness as a construct in occupational science, this discussion advances the theorizing practice of the discipline in promoting understandings of human occupation.\n\nThe first three sections of the paper introduce theorizing as a distinct scholarly practice, outline the genesis of occupational consciousness as a construct and provide both theoretical and philosophical foundations to the construct. This is followed by an analysis of synergies between occupational consciousness and other related constructs. Occupational consciousness is then advanced as a critical notion that frames"
+"In contrast to charge based electronic devices, spintronic devices are supposed to include or solely use the spin degree of freedom of charge carriers[@b1][@b2]. This requires materials and methods that allow the creation and control of pure spin currents in solid-state systems. Currently there exist a few methods capable of creating pure spin currents, like spin Hall effect[@b3][@b4], spin pumping[@b5][@b6][@b7] and spin Seebeck effect[@b7][@b8][@b9]. The detection of spin currents usually exploits the inverse spin Hall effect[@b5][@b6][@b7][@b8][@b9]. However, the efficiency of these methods is low regarding the power needed to create a sizeable spin current[@b7].\n\nTopological insulators (TIs) are materials, which are insulating in the bulk but possess conducting states at the surface or, in the two-dimensional (2D) limit, at the edges[@b10][@b11]. The spin of these edge states is locked with the propagation direction along the edge, i.e. electrons with opposite spin orientation move in opposite direction[@b12][@b13][@b14][@b15]. In addition, the surface states are topologically protected which precludes backscattering and conserves the spin-momentum locking of the edge states[@b16]. These properties make TIs promising candidates for spintronic devices[@b17][@b18].\n\nRecent experimental progress has resulted in creation of ferromagnetic topological insulators. Ferromagnetism is either induced by doping with transition metal atoms[@b19][@b20][@b21][@b22][@b23][@b24] or by the proximity"
+"Introduction {#sec1}\n============\n\nSyncope is an important symptom that though most commonly benign, deserves extensive evaluation since it can also be caused at times by life threatening causes that are potentially treatable. An important cause of syncope is symptomatic bradycardia either due to sick sinus syndrome or atrioventricular block that is treated easily by pacemaker therapy. However, the most common cause of syncope in patients with normal heart is vasovagal or neurocardiogenic syncope where pacemaker therapy has a very limited role. When syncope recurs in a patient who received the pacing therapy for the same symptom, it not only becomes very difficult to explain to the patient but also poses significant diagnostic challenges.\n\nHead-up tilt test (HUTT) has been in use for evaluation of patients with suspected recurrent vasovagal syncope for many decades. However, data regarding its use in patients with pacing devices is scanty. Hence, the study by Haarmark et\u00a0al. in this issue of the journal [@bib1], reporting the results of HUTT in patients with pacemakers and recurrent syncope is a welcome addition to the literature. Though, the authors suggest that a positive HUTT even in a patient with pacemaker indicates a diagnosis of vasovagal syncope implying a"
+"GITR/TNFRSF18 is a member of the TNF-receptor superfamily preferentially expressed on regulatory T cells (Tregs) and activated T effector cells. Antibody agonists to GITR claim two distinct mechanisms to overcome the repressive tumor microenvironment and drive anti-tumor efficacy *in vivo*: receptor agonism (forward signaling) on T effector cells and Fc\u03b3R-mediated Treg depletion. We sought to better understand the contribution of these two mechanisms using pharmacodynamic readouts relating target coverage, Treg depletion and efficacy using isotypic variants of a surrogate antibody against mouse GITR, DTA-1.\n\nFirst, target coverage was determined in spleen, tumor and draining lymph node following treatment with a single dose of mouse IgG2a DTA-1. In this study, efficacy correlated with doses that covered \\>90% GITR-expressing intratumoral leukocytes and depleted \\>90% intratumoral Tregs at 24 hours post-dose. Though displaying equivalent agonistic activity *in vitro* and achieving a similar level of target coverage, the mouse IgG1 N297A variant of DTA-1 neither depleted Tregs nor displayed anti-tumor activity *in vivo*, in confirmation of recent literature. To further explore the influence of Fc engagement, additional DTA-1 isotypic variants were generated and tested *in vivo*. In this study, we confirmed that preferential engagement of Fc\u03b3 receptors was necessary for optimal activity, as the"
+"1. Introduction {#sec1}\n===============\n\nNew Zealand has an increasing aging active population with increasing rates of primary and revision joint arthroplasty surgery. In 2009, 1467 hip and knee revision arthroplasty operations were conducted nationwide, which represented 11% of all hip and knee arthroplasty operations performed during that time period. Aseptic loosening was one of the most common indications for revision, being the cause for revision in 35% and 23% of total hip and knee joints, respectively \\[[@B1]\\]. Differentiating between prosthetic joint infection (PJI) and aseptic loosening is important, as the treatment of the two groups is significantly different. Despite attempts to differentiate between the two, no single investigation has been identified as being reliable in determining the presence of infection.\n\nThe American Academy of Orthopaedic Surgeons guidelines for the diagnosis of PJI of the hip and knee recommend risk stratification on the basis of preoperative C-reactive protein and erythrocyte sedimentation rates and selective hip aspiration in patients where infection is suspected or likely \\[[@B2]\\]. On the basis of current evidence, they do not recommend intraoperative Gram stain, but they do recommend intraoperative frozen section and cultures in cases of likely infection.\n\nSome microorganisms, especially*Staphylococcus*species, are able to attach to implants"
+"The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#s1}\n============\n\nThe central dogma of molecular biology defines the transfer of information from DNA to protein through an RNA intermediate [@pone.0108475-Crick1]. The irreversible transfer of information from RNA to protein relies on ribosomal translation. Both prokaryotic and eukaryotic translation progress through initiation, elongation and termination phases. For successful initiation, the small ribosomal subunit must successfully bind to the translational start site and recruit the large ribosomal subunit to form a functional ribosome. In prokaryotes, the small ribosomal subunit targets the initiation site through the base pairing of the 16s rRNA and the Shine-Dalgarno sequence on the mRNA transcript. Originally characterized in 1974, the Shine-Dalgarno sequence is a consensus sequence (AGGAGGU) generally found immediately upstream of the translational start site [@pone.0108475-Shine1].\n\nIn eukaryotes, targeting the small ribosomal subunit to the mRNA transcript is complicated through the addition of required protein: protein interactions [@pone.0108475-Sachs1]. However, characterization of nucleotide sequences surrounding known translational start sites revealed a DNA consensus sequence (5\u2032-GCCRCC**ATG**G-3\u2032) suggesting a conserved role in translational efficiency [@pone.0108475-Kozak1]. This consensus sequence, now known as"
+"Introduction {#s1}\n============\n\nIn constitutional states such as Switzerland, the use of coercion against persons requires explicit legal legitimation (see below); moreover, within this legal framework, ethical justification is regarded to be mandatory. Medicine and healthcare workers are, therefore, obliged to consistently justify any limitation of their patient's personal freedom within reason, specifically to prevent harm to the patient or others. Some of the questions regarding the use of coercion are, e.g.: How to appropriately manage an inpatient violating the house rules and refusing long-term medication? Is involuntary hospitalization of an incompetent patient with aggressive and self-harming behavior justified? Examples such as these illustrate that the lack of insight and cooperation as well as aggressive patient behavior are central issues that indicate not only a psychiatric context. Critically ill patients in somatic care may also trigger discussion on coercive measures. Coercion may concern treatment, diagnostic measures, patient location, accommodation, and social environment. It may also affect the therapeutic alliance between patient and therapist and, thus, cause problems for the involved healthcare professional ([@B1]--[@B3]). Quantitative data on coercive measures applied in patient care are \"hard to compare, since coercive measures are rarely systematically recorded, nor calculated and analyzed or expressed in"
+"Introduction {#sec0005}\n============\n\nThe Alma-Ata Declaration, elaborated in Kazakhstan on September 12, 1978 and adopted by the World Health Organization (WHO) defines the concept of Primary Health Care as the first contact level of the individual and the community with the health system.[@bib0005] The concepts of health and disease require a reformulation of thinking and the verification of epidemiological transition leads to a change in the models for preventive action and health promotion.[@bib0010] The approach to the primary level of health care was based on the need to create prevention and rehabilitation services that would maximize the health and the well-being of the individual, accompanying globally and longitudinally all his health/disease process and not just the disease episodes.[@bib0015] Adequate primary care provision now presupposes a cross-sectoral (among different health sectors) and multidisciplinary (among different health professional groups) approach, as well as a greater diversity of care provision.[@bib0020]\n\nThe approach to primary eyecare involves a complementarity between the health sector *per se* and the community, that is, between clinical practice and the component of eyecare protection and promotion. Approach epidemiologically the ocular conditions according to their prevalence, incidence, socioeconomic implication in human life, costs of prevention *vs* treatment and availability of"
+"1. Introduction {#sec1-materials-12-02385}\n===============\n\nFunctionally graded materials (FGMs) are a class of advanced composite materials. The mechanical properties of FGMs change continuously over the thickness of structures. In general, FGM is made from a mixture of ceramic and metal. In recent years, they have gained significant attention in many engineering fields such as automotive, civil engineering, aerospace, and nuclear engineering. Hence, due to the exotic properties of FGMs, many researchers have been captivated to investigate the bending behaviors, free vibration, and dynamic and buckling behaviors of FGM beams, plates, and shells. According to the literature, the analysis of FGM plates can be investigated with some different theories such as the classical plate theory (CPT), the first-order shear deformation theory (FSDT), higher-order shear deformation theory (HSDT), the quasi-3D theory and Carrera unified formulation (CUF).\n\nIn the CPT, transverse shear deformation is neglected, so only thin plates can be regarded by this theory. Timoshenko et al. \\[[@B1-materials-12-02385]\\] used the CPT to analyze plates and shells. Liessa \\[[@B2-materials-12-02385]\\] applied the CPT for the free vibration of isotropic thin rectangular plates. Javahenri et al. \\[[@B3-materials-12-02385]\\] investigated the buckling behavior of FGM plates under compressive loading. Mohammadi et al. \\[[@B4-materials-12-02385]\\] developed analytical solutions based on"
+"ORGANELLE MOVEMENT IN PLANT CELLS\n=================================\n\nPlant cells are characterized by a powerful flow of intracellular components, generally termed as \"cytoplasmic streaming\" ([@B79]). This mechanism allows the efficient transport and the uniform redistribution of membranes and molecules in plant cells, especially in very large cells ([@B91]) such as those of the alga *Chara* that are considered the model par excellence in which to investigate this process ([@B29]). It is largely accepted that cytoplasmic streaming is based upon the interaction between actin filaments and myosins ([@B79]). The *Arabidopsis* genome contains 17 myosin members ([@B46]) and only two plant-specific subfamilies (myosin VIII and myosin XI) have been identified ([@B80]). The rice genome contains 14 myosin genes, with only two of the predicted sequences belonging to class VIII and the others to class XI ([@B36]). Both myosin XI and myosin VIII subfamilies are closely related to animal and fungal myosin V. Myosins XI are motor proteins showing high processive velocity and are therefore candidates to drive cytoplasmic streaming in plant cells. However, it remains to understand if plant myosins XI interact with specific organelles. Immunolocalization analysis have not clarified this question, since a myosin XI was found to be associated with various particles"
+"INTRODUCTION {#s1}\n============\n\nPain is inherently subjective, and pain measurement in patients with knee osteoarthritis (OA) relies primarily on self-reports[@r1]^)^. The most common approaches to self-reported pain measurement are the use of a visual analog scale (VAS), numeric pain rating scales, and the Western Ontario and McMaster Asteoarthritis Index pain scale[@r2],[@r3],[@r4]^)^. Although self-reported pain intensity is important, it is a composite of the physiological and psychological features of the patient and their health problem that is further mediated by social aspects, which can make it difficult to interpret responses[@r5], [@r6]^)^. Thus, objective pain measures are invaluable as they reflect different perspectives of the health condition. Therefore, measuring knee pain is an important component of clinical practice; its importance is evident in the frequency with which it drives healthcare utilization as well as its impact on quality of life[@r7]^)^.\n\nAn important step toward integrating pressure pain threshold (PPT) testing into routine clinical practice is the establishment of the reliability of viable instruments[@r8], [@r9]^)^. Such instruments must be commercially available, meet measurement standards under knee OA, and function under ideal conditions; furthermore, they must not be cost-prohibitive when used in a clinical setting. However, the clinimetrics of PPT testing with devices currently"
+"Microcephaly is a neurodevelopmental disorder characterized by small brain and mental retardation. A significant number of proteins implicated in microcephaly, including ASPM (abnormal spindle-like microcephaly associated) participate in organizing mitotic spindle poles[@R1]. The function of a spindle pole depends on microtubule nucleation as well as stabilization, disassembly and bundling of microtubule minus ends. Microtubule minus ends can grow and shrink in vitro[@R2], however, it is generally believed that within mitotic spindles, minus ends are either stable or slowly depolymerize, resulting in poleward microtubule flux[@R3]. The molecular mechanisms controlling microtubule minus-end behavior in the spindle are poorly understood.\n\nPrevious work indicated that ASPM (known as Asp in fly and ASPM-1 in worm) is an excellent candidate for being a mitotic microtubule minus-end regulator[@R4]--[@R13]. It is encoded by the gene that is most frequently mutated in microcephaly[@R14], but the molecular mechanism underlying ASPM activity is not understood. Katanin, a conserved microtubule-severing protein complex, which consists of the AAA ATPase containing enzymatic subunit p60 and the regulatory subunit p80[@R15]--[@R17], is also linked to microcephaly[@R18],[@R19]. Formation of the katanin p60/p80 heterodimer is mediated by the N-terminal Microtubule Interacting and Trafficking domain of p60 and a conserved C-terminal domain of p80[@R20]. Katanin localizes to spindle"
+"I[NTRODUCTION]{.smallcaps} {#sec1-1}\n==========================\n\nClinical scores have traditionally been used in thyroidology to help in the diagnosis of thyroid dysfunction. The time honored Wayne\\'s score and Billewicz score are well known to older generations of endocrinologists, for their utility in the clinical diagnose of hyperthyroidism and hypothyroidism, respectively.\n\nSadly, however, these scores do not find place in current textbooks of surgery or medicine, having been discarded as being too old fashioned. Current students of medicine therefore do not have easy access to these, and to newer scoring systems in thyroidology.\n\nNewer clinical scores and grading systems have also been developed by workers, highlighting the numerous diagnostic developments and advances in the field. Results from imaging studies such as ultrasound are also used in grading thyroid malignancy.\n\nThis compendium seeks to bring together, and comment upon, the various scoring and grading systems used in clinical endocrinology. It is hoped that this collation will be of use to endocrinologists, physicians, and all workers in the field of thyroidology.\n\nG[OITER]{.smallcaps} {#sec1-2}\n====================\n\nThe diagnosis of goiter is a clinical one arrived at by inspection and palpation. The presence of goiter does not necessarily indicate thyroid dysfunction.\n\nThe World Health Organization has classified goiter in"
+"Introduction\n============\n\nThe understanding of the evolution of beetles in the late Cenozoic has changed drastically within recent decades. This concerns especially the Pleistocene beetles preserved as unmineralized subfossil specimens. Originally, the remains from the Pleistocene peatbog or asphalt deposits were assigned to extinct species by historical authors (e.g. [@B44], [@B33], [@B54], [@B56], [@B57], [@B58], [@B59], [@B67]), supporting the idea of a high evolutionary rate induced by the climate changes during the Pleistocene. Later, more detailed studies of subfossil specimens sometimes based even on the study of their well-preserved genitalia revealed that the majority of Pleistocene subfossil beetles belong to recent species ([@B23]; for examples of taxonomic revisions see e.g., [@B18], [@B3], [@B8], [@B49], [@B20], [@B50]) and resulted in the Pleistocene evolutionary stasis paradigm ([@B16], [@B17]). Recent studies of many beetle groups based on molecular data contradict the results based on the fossil record for many beetle groups and indicate a high evolutionary rate during the Pleistocene (e.g., [@B62], [@B14], [@B34], [@B12], [@B61]). This disagreement of molecular and fossil results is interpreted as resulting from fossil data being only available for high latitude areas ([@B62], [@B1]).\n\nThe presence of recent species in Pleistocene deposits invites the question as to whether"
+"Introduction {#s1}\n============\n\nAdherent cells exert mechanical forces on the extracellular matrix (ECM) to regulate adhesions, propel their migration [@pone.0069850-Li1] and to sense the ECM stiffness by a process generally referred as mechanosensing [@pone.0069850-Engler1], [@pone.0069850-Discher1]. In our organism, cells are often embedded in three-dimensional (3D) ECMs, which they deform in all spatial directions by generating three-dimensional forces in order to migrate [@pone.0069850-Bloom1]. Even cells that form stable two-dimensional (2D) monolayers, such as vascular endothelial cells, are known to exert three-dimensional traction forces [@pone.0069850-Hur1] both in isolation and confluency [@pone.0069850-Hur2]. The ability of cells to apply three-dimensional forces on two-dimensional layers is also important for the extravasation of leukocytes during the immune response [@pone.0069850-Rabodzey1] and for cancer cell invasion [@pone.0069850-Poincloux1], [@pone.0069850-Aung1].\n\nThe past few years have witnessed the development of several 2D traction force microscopy (TFM) methods, which allow investigators to measure only the in-plane (tangential) components of the traction stresses generated by cells adhering to plane substrata [@pone.0069850-Dembo1]--[@pone.0069850-Trepat1]. More recently, 3D TFM methods have been introduced allowing for the determination of the out-of-plane (normal) component of the traction stresses [@pone.0069850-Hur1], [@pone.0069850-Maskarinec1]. However, these 3D TFM methods are based on numerical calculations performed on large volumetric grids, which can limit their"
+"Introduction {#s1}\n============\n\nGliomas are one of the most prevalent primary intracranial tumors, representing about 81% of malignant brain tumors. Although relatively rare, it usually causes significant mortality and morbidity ([@B1]). So far, gliomas remain incurable, despite many attempted treatment approaches ([@B2]). Concomitant loss of chromosomes 1p and 19q is one of the best studied molecular alterations in gliomas and is strongly associated with oligodendroglia morphology and mortality ([@B3]). In addition, high mutation rates of p53 in gliomas is reported to be responsible for the initiation of rapid glioma growth, which has led researchers to examine this alteration in association with glioma onset ([@B4]). Bevacizumab, a targeted therapeutic for gliomas, still does not improve overall survival (OS) in either recurrent gliomas or newly-diagnosed gliomas. Thus, novel, effective, targeted therapies for gliomas are in urgent need ([@B5]).\n\nInflammation is a key component of the glioma microenvironment. Neuroinflammatory cytokines such as interleukin-1 (IL-1) secreted by glioma cells are known to contribute to tumor initiation and early progression ([@B6]). The inflammatory response and cancer are highly linked by specific intrinsic pathways, whereby genetic alterations that cause cancer orchestrate the proinflammatory microenvironment, and IL-1 has been associated in this process. For example, IL-1\u03b1 is"
+"1.. Movement ecology paradigm {#s1}\n=============================\n\nThe movement of organisms has profound influence on population, community and ecosystem dynamics over contemporary and evolutionary timescales. Multiple areas of research have focused on the internal and external stimuli that lead to movement, and the consequences of this movement. For plants, unlike most animals, movement is limited to particular life-history stages, i.e. the dispersal of pollen or seed, although long-living clonal plants can grow and hence move slowly over large distances. This review applies a movement ecology framework to enhance our understanding of the causes, mechanisms and consequences of movement in highly clonal, marine angiosperms, the seagrasses.\n\nA general movement ecology paradigm was recently proposed that integrated conceptual, theoretical, methodological and empirical frameworks for studying the movement of organisms \\[[@RSPB20140878C1]\\]. This paradigm developed a common language and identified a unified research agenda on movement. It has been specifically applied to plants by addressing the obvious dichotomy between evolutionary and ecological elements that occur in plants \\[[@RSPB20140878C2]\\]. Conceptually, this model defines the movement path of an individual as a function of how (*\u03a9*---motion capacity), where (*\u03a6*---navigation capacity) and why it moves (*W*---internal state), and how these interact with external factors (*R*) \\[[@RSPB20140878C1]\\]. The plant-centric"
+"1. Introduction\n===============\n\nAn international workshop was held on April 22--23, 1995, at the Town and Country Hotel in San Diego, to discuss the scientific and standardization issues associated with instrumented indentation, also known as dynamic hardness testing or depth-sensing, ultra-low-load, or nano indentation. The workshop was sponsored jointly by the NIST Standard Reference Materials Program (SRMP) and the Institute for Mechanics and Materials (IMM) in San Diego, with additional support for student travel from Nano Instruments, Inc., Oak Ridge, TN, and Instron Corporation, Canton, MA, and was part of the program of the 1995 International Conference on Metallurgical Coatings and Thin Films (ICMCTF95). The 96 attendees represented 14 U.S. and 6 foreign companies, 18 U.S. and 7 foreign universities, and 15 national laboratories, including NIST, the National Physical Laboratory (NPL) in England and the Commonwealth Scientific and Industrial Research Organization (CSIRO) in Australia. The 2-day program consisted of 22 oral presentations, 22 poster presentations, and several open discussion sessions. This report summarizes the workshop program. More detailed proceedings of the workshop will be available as a NIST Special Publication.\n\n2. Background\n=============\n\nIndentation has been used for many years to measure the hardness of materials. The technique involves pushing"
+"Background\n==========\n\nThe variability of HIV and the appearance of escape mutants are a major obstacle for HIV/AIDS vaccine development. In previous phase I/II studies recombinant MVA-Nef and MVA-BN^\u00ae^-Polytope expressing conserved epitopes from multiple proteins of HIV-1 induced good and broad cellular immune responses and indicated an inhibitory effect on viral replication during treatment interruption (MVA-Nef). To further broaden the immune responses a new MVA-BN^\u00ae^-Multiantigen vaccine candidate expressing full length or truncated HIV-1 proteins (gag, pol, nef, tat, vpr, vpu, vif, rev) has been developed and tested for safety and immunogenicity.\n\nMethods\n=======\n\nFifteen HIV-1 infected patients on HAART therapy with CD4 counts above 350/\u03bcl received 2 \u00d7 10^8^TCID^50^MVA-BN^\u00ae^-Multiantigen at weeks 0, 4 and 12. Cellular immune responses against HIV-1 proteins were measured by IFN-gamma ELISPOT from PBMC preparations. Peptide pools consisted of overlapping peptides: three pools each for gag and pol, four pools for nef and three pools for the remaining proteins.\n\nResults\n=======\n\n13 out of 15 (87%) of the subjects generated new or increased HIV specific responses following vaccination independent of their vaccinia prevaccination status. Amongst these subjects 77% (10/13) elicited a response to at least two and 54% (7/13) to at least three HIV proteins. Gag"
+"One of the great tragedies of our times is the extent to which HIV prevention efforts are falling short. In 2004, more new HIV infections occurred than in any previous year: close to 14,000 a day, 570 per hour, almost ten per minute. The greater part of new infections occurs in young people, over half in persons between 15 and 24 years of age, and over half in women. The increasing feminization of the HIV/AIDS epidemic reflects the vulnerable position of women in many societies \\[[@pmed-0020248-b1]\\]. HIV is a virus, but inequity is at the roots of most of its spread.\n\nCondoms are highly effective at preventing sexual transmission of HIV, but only if they are available and used \\[[@pmed-0020248-b2]\\]. Even if the former is the case, women are often in a difficult position to negotiate use by their male partners \\[[@pmed-0020248-b3]\\]; this applies to female as well as male condoms.\n\nIn the absence of an effective preventive HIV vaccine \\[[@pmed-0020248-b4]\\], which is felt to be the only tool that can definitively break the epidemic, there is thus great need for alternative prevention technologies, especially those that can be \"female-controlled\", i.e., use of which does not require consent of the"
+"Abbreviations used in this paper: 4-HT, 4-hydroxytamoxifen; DCIS, ductal carcinoma in situ; EMT, epithelial--mesenchymal transition; ERK, extracellular signal--regulated kinase; FMI, final mean intensity; HPV, human papillomavirus; MEK, MAPK/ERK kinase; MLC, myosin light chain; MLCK, MLC kinase; ROCK, Rho kinase.\n\nIntroduction\n============\n\nThe architecture of mammary glandular epithelium is disrupted during the development of preinvasive mammary lesions, such as ductal carcinoma in situ (DCIS). Interestingly, the gene expression profiling of DCIS lesions indicates that gene products that are not known to regulate proliferation or survival are also involved in tumor progression ([@bib1]; [@bib17]; [@bib28]). This suggests that the current mechanistic understanding of preinvasive epithelial tumor growth as being the product of excessive proliferation and resistance to cell death is incomplete and that there are additional unidentified cellular traits acquired during the preinvasive stage of tumor growth ([@bib28]). A more precise understanding of mechanisms that promote the disruption of architecture that is observed in preinvasive tumors could assist in diagnosis and treatment of human breast cancer ([@bib3]).\n\nThe MAPK extracellular signal--regulated kinases (ERK) 1/2 are activated by receptor tyrosine kinases that promote the development of mammary tumors, and ERK1/2 are hyperactivated in breast cancer patient samples ([@bib38]; [@bib21]; [@bib25]; [@bib27]). ERK1/2 are"
+"1. Introduction {#sec1}\n===============\n\nThe human nicotinic acetylcholine receptor (AChR) composed of five subunits (2 *\u03b1*, 1 *\u03b2*, 1 *\u03b4*, and either 1 *\u03b3* or 1 *\u03b5* subunit) is well characterized as the target antigen in myasthenia gravis (MG) \\[[@B1]\\]. The *\u03b3* subunit of the fetal receptor is replaced by an *\u03b5* subunit in adult muscle; both subunits share about 53% homology at the amino acid level \\[[@B2]\\]. Pathogenic antibodies are predominantly directed against the *\u03b1* subunit of the AChR. Both antibody responses as well as B-lymphocyte activity have been investigated extensively in MG and are of great diagnostic and prognostic value.\n\nImmunoglobulin G (IgG) autoantibody production is T helper cell-dependent. Although MG is considered a prototypic paradigm for an antibody-driven autoimmune disorder, the pathogenetic importance of T-helper cells is well appreciated. Several studies have been performed comparing T-cell responses involving the *\u03b1* subunit versus the developmentally regulated *\u03b5* subunit using recombinant fragments and purified polypeptides of the human AChR \\[[@B2]--[@B8]\\]. The *\u03b5* subunit is of particular interest as its expression in the adult muscle differs from the fetal *\u03b3* subunit, a fact that may contribute to the escape of clonal deletion and the development of autoreactive T lymphocytes in"
+"Introduction {#s1}\n============\n\nThe bacterium *Burkholderia pseudomallei* is a gram-negative bacterial pathogen that is the etiologic agent of the disease melioidosis. Melioidosis is a serious and often fatal disease of humans and animals which is endemic in Southeast Asia, northern Australia, and other tropical areas of the world (Cheng and Currie, [@B4]). Infection usually follows percutaneous inoculation or inhalation of the bacterium that are present in soil and surface water. The disease may be localized or disseminated, and virtually any organ system can be affected, resulting in a wide range of symptoms that are often mistaken for other illnesses, such as tuberculosis or pneumonia (Loveleena et al., [@B19]). The overall mortality rate of melioidosis in endemic areas may reach as high as 50% (White, [@B35]).\n\nWhile community-acquired cases of melioidosis are most likely a consequence of the bacterium in soil or water entering the host through cuts or skin abrasions, the bacterium is much more infective via the inhalation route as determined in small animal models of disease (Titball et al., [@B29]). This is possibly consistent with the higher incidence of melioidosis during monsoon season, when surface waters are aerosolized by severe weather, and the higher incidence of reported cases"
+"The discovery of intrinsically disordered proteins (IDPs) has challenged the view that protein function depends on a defined three-dimensional structure, and their recently unveiled involvement in diseases marked by pathological protein aggregation has raised significant interest in their biochemical properties and cellular functions[@b1][@b2][@b3]. Many IDPs contain low complexity domains (LCDs), unstructured protein sequences composed of repetitive sequence elements that tend to phase separate into liquid droplets, very much like oil undergoes liquid demixing (also referred to as liquid--liquid demixing) in aqueous solutions[@b4][@b5][@b6][@b7]. In cells, such liquid demixing events have the potential to dynamically organize the soluble intracellular space into spatially confined compartments[@b8], but what initiates such phase separations has remained largely elusive. The formation of a liquid droplet by phase separation can be triggered by nucleation, occurring either spontaneously via random collisions of molecules or at specific pre-existing subcellular sites[@b8]. In the case of LCD-containing IDPs, certain RNA species can initiate their assembly into higher-order structures[@b9]. However, other nucleation or seeding events might exist. An exciting possibility is that nucleation may not only occur on pre-existing sites but also via the *de novo* generation of molecular seeds. Such a mechanism would provide cells with the opportunity to respond to internal"
+"INTRODUCTION\n============\n\nThe present genomic era was made possible by the automated determination of nucleotide sequences and restriction digest fingerprints from electrophoretic gel images. Systems to perform these tasks were developed soon after the introduction of large-format film scanners in the 1980s ([@b1],[@b2]) and continue to facilitate what would otherwise be a rate-limiting step in sequence determination and assembly. Now a major challenge of genomics is the discovery of single-nucleotide differences, such as naturally occurring single-nucleotide polymorphisms (SNPs) and induced point mutations ([@b3]--[@b5]). Many methods to discover such differences are in use, among which are those that compare differences in physical characteristics of DNA fragments recognizable in images produced by gel electrophoresis and other technologies. However, recognition of subtle differences between otherwise identical patterns is potentially rate-limiting for these methods.\n\nA popular strategy for SNP and mutation discovery is to observe novel fragments produced by cleavage of a mismatch between annealed DNA strands ([@b6]). Mismatch cleavage of heteroduplexed DNA allows discovery of single-base differences in pooled samples ([@b7]). This is an especially valuable feature for discovery of rare SNPs and induced mutations, which are difficult and costly to detect by sequencing ([@b5]). Software specifically designed for mapping novel fragments found"
+"Introduction {#Sec1}\n============\n\nStudies of mate choice traditionally focus on females because these are usually the sex that invests the most into reproduction and, hence, should be more selective in regard to their mating partners (Andersson [@CR4]; Trivers [@CR84]). Variability in the quality of available females and the costs of mating may, however, favor the evolution of mate choice in males as well, even in species with no sex-role reversal (Edward and Chapman [@CR26]; Kokko and Monaghan [@CR50]). In particular, male mate choice is particularly likely to evolve when multiple females are available at the same time and when the rate of encounters with females is high (Kokko and Monaghan [@CR50]), such as in many group-living primates.\n\nSeveral primate species have evolved a certain degree of male mate choice to limit the costs of reproducing and allocate limited sperm resources toward the most valuable females (Kappeler [@CR48]; Keddy-Hector [@CR49]; Setchell and Kappeler [@CR75]). Male--male competition for access to mates, including monopolization of females, is often costly for male primates because it may increase the risk of injury (Drews [@CR24]) and affect a male's feeding time, energy balance, or physiological stress levels (Alberts *et al*. [@CR1]; Bergman *et al*. [@CR12]; Georgiev"
+"Introduction {#S1}\n============\n\nDepression is a highly prevalent and recurrent illness that affects people of all ages and carries high individual, family, and social costs ([@B1]). Depression in adolescents is of particular importance -- prevalence begins to increase in this period ([@B2]) and is associated with persistent and considerable functional impairment and serious negative consequences, such as suicide, poor performance at school, difficulty with interpersonal relationships, risk-taking behavior, and physical health problems ([@B2]--[@B4]).\n\nIn developed countries, the point-prevalence of depression in adolescents is estimated to range between 4 and 8% ([@B5]). The lifetime prevalence of having had at least one depressive episode reaches 10% at 16\u2009years of age ([@B6]), and more than 20% at 18\u2009years of age ([@B7]). Even more adolescents have sub-threshold depressive symptoms. Those symptoms also have negative consequences and are a risk factor for later depression and suicidal behavior ([@B7], [@B8]). Furthermore, most adults with recurrent depression began having depressive episodes as adolescents ([@B9]).\n\nIn an epidemiological study carried out in Chile, 8.3% of adolescents between the ages of 12 and 18 were found to be suffering from major depression. The same study reported a huge gap between the adolescent population who manifest some form"
+"1. Introduction\n===============\n\nStanding balance ability is one of the most necessary physical abilities for humans regardless of age. Standing balance impairment is associated with a lower quality of life in elderly people, stroke patients, and Parkinson\\'s disease patients.^\\[[@R1]--[@R3]\\]^ Therefore, in a rehabilitation setting, it is important to implement interventions aimed at maintaining and improving this ability.\n\nSeveral studies have stressed the need for standing balance ability intervention (e.g., exercise interventions^\\[[@R4]--[@R8]\\]^) that exists above the threshold of consciousness (i.e., supraliminal). The existing methods of exercise intervention aimed at standing balance ability originally targeted highly motivated and/or well-functioning patients who were able to respond to supraliminal stimulation (including elderly people) (e.g., inclusion criteria: \"requiring no walking aid or using a single-point stick only.\"^\\[[@R8]\\]^\\] Therefore, it is possible that patients (including elderly people) who were unable to respond to supraliminal stimulation with low motivation to exercise and/or low body function will not adapt to conscious balance exercise. Conversely, subliminal stimulation is an intervention method that may stimulate such patients to participate in standing balance exercises. Subliminal stimulation promotes a desired message in an image at a speed unrecognizable by humans,^\\[[@R9]\\]^ which may affect the standing balance ability of humans unconsciously. If this"
+"Introduction {#s1}\n============\n\nThe secondary motor cortex (MOs) is located in the anterior lateral area of the brain cortex in rodents. The MOs is also termed the medial agranular cortex (AGm), medial precentral cortex (PrCm), second frontal area (Fr2), and frontal orienting field (FOF) (Van De Werd et al., [@B41]; Brecht, [@B3]; Sul et al., [@B39]; Barthas and Kwan, [@B2]). Recent studies have provided evidence for potential roles of the MOs in cognitive and executive processes, such as decision making, goal-directed actions, skill learning, and spatial memory (Sul et al., [@B40], [@B39]; Gremel and Costa, [@B12]; Cao et al., [@B4]; Siniscalchi et al., [@B38]; Yamawaki et al., [@B44]). Impairment or inactivation of the MOs results in neglect of the contralateral space in movement and motor order learning impairment (Barthas and Kwan, [@B2]).\n\nTo data, most knowledge of the MOs has been based on anatomical studies of its neural circuit structures and physiological studies of its neuronal activities. In recent decades, researchers have used virus-assisted anterograde or retrograde tracing techniques to characterize the long-range inputs and outputs of neurons in the MOs. Optogenetics and electrophysiology have also been used to investigate the neuronal activities of the MOs in brain functions. By"
+"1 Introduction\n==============\n\nAutomatic gene function annotation is an important first step to interpret genomic data. Kyoto Encyclopedia of Genes and Genomes (KEGG) is a widely used reference knowledge base, which helps investigate genomic functions by linking genes to biological knowledge such as metabolic pathways and molecular networks ([@btz859-B4]). In KEGG, the KEGG Orthology (KO) database---a manually curated large collection of protein families (i.e. KO families)---serves as a baseline reference to link genes with other KEGG resources such as metabolic maps through *K* number identifiers. Currently, KOs are assigned to 12\u00a0934\u00a0525 (48%) protein sequences in the KEGG GENES database (27\u00a0173\u00a0868 proteins). Three existing tools, BlastKOALA, GhostKOALA ([@btz859-B5]) and KAAS ([@btz859-B7]), are available to assign KOs to protein sequences. These tools use homology search software such as BLAST ([@btz859-B1]) and GHOSTX ([@btz859-B8]) to search amino acid sequences against GENES. To reduce the lengthy computational times required for multiple pairwise sequence comparisons, these tools use selected representative sequences from GENES to build their target database. In this study, we propose to employ profile hidden Markov model (pHMM) to compress the database and to define adaptive thresholds for similarity scores, which can be used for reliable KO assignments.\n\n2"
+"Our study {#s0001}\n=========\n\nIt has become increasingly clear that the manner of cell death and the resulting inflammatory responses are tightly linked processes.[@cit0001] Cell death by programmed necrosis (necroptosis) elicits potent inflammatory responses, whereas apoptosis is considered largely immunologically silent.\n\nOur recent observation that X-linked inhibitor of apoptosis protein (XIAP, also known as BIRC4) mediates nuclear factor kappa-B (NF-\u03baB) activation in the nucleotide-binding oligomerization domain containing 2 (NOD2) signaling pathway suggested a proinflammatory function of XIAP in this context.[@cit0002] In striking contrast, XIAP-deficient patients who are diagnosed with the primary immune deficiency syndrome X-linked lymphoproliferative disease-2 (XLP-2) often respond to common viral infections with systemic hyperinflammation, which points to an anti-inflammatory function of XIAP.[@cit0003] Recent data suggest that this condition is substantially underdiagnosed due to the lack of a simple diagnostic test.[@cit0004] We hypothesized that NOD2-independent inflammatory processes must be affected when XIAP is absent or non-functional.\n\nNot surprisingly, we found that loss of XIAP led to increased death of innate immune cells such as macrophages and dendritic cells when these cells were activated by tumor necrosis factor (TNF). However, this cell death turned out to be caspase-independent. In contrast, TNF-driven cell death of Xiap^\u2212/\u2212^ dendritic cells and macrophages"
+"Introduction {#s1}\n============\n\n*Helicobacter pylori* (Hp) has been implicated in the pathogenesis of most important gastroduodenal diseases, such as gastritis, peptic ulcer, gastric carcinoma and has been defined as a Class I carcinogen [@pone.0016306-Moller1]. Hp can be subclassified into 'cag' pathogenicity island positive (*cag*)^+ve^ and negative (*cag*)^-ve^ strains based on the presence or absence of *cag*PAI, a 40-kb genome fragment containing 31 genes [@pone.0016306-Tomb1]. There is enormous heterogeneity in the consequences of Hp-infections, however more severe disease manifestations have been attributed to infection by *cag* ^+ve^ isolates [@pone.0016306-Blaser1].\n\nCurrently, the most preferred Hp eradication therapy (triple-therapy) employ, one proton pump inhibitor and two antibiotics [@pone.0016306-Bytzer1]. However, such multiple therapy regimens have not been very successful in clinical practice, since the overuse or rather misuse of antibacterial agents have resulted in the emergence of antibiotic-resistant strains which is the prime cause of treatment failure apart from potential side effects [@pone.0016306-Bytzer1], [@pone.0016306-Cameron1]. Increasing complications in the conventional triple-therapy (TT) stimulate an urgent need to develop new non-antibiotic antibacterial agents against Hp-infection that are safe, highly effective and have specific cellular targets.\n\nSeveral studies have demonstrated that Hp-infection induces the secretion of matrix metalloproteinases (MMPs) from a variety of gastric cells *in vivo*"
+"Introduction {#S1}\n============\n\nIt has become increasingly accepted that most individuals have self-reactive lymphocytes circulating throughout their peripheral tissues. In the wrong context, these cells may be capable of mediating pathogenic autoimmune responses. By contrast, in healthy individuals, these cells are counterbalanced by regulatory cells, which act to stably suppress the pathogenic potential of self-reactive cells. Regulatory T (Treg) cells, a subset of CD4^+^ T cells defined by their expression of the transcription factor Foxp3, constitute a major immune-regulatory cell population in the body. The majority of Treg cells arise during T cell development in the thymus, where moderate- to high-avidity recognition of self-antigen leads to the development of Foxp3^+^ thymic Treg (tTreg). The second pathway of Treg generation is in the periphery, where mature, na\u00efve CD4^+^ T cells develop into peripheral Treg (pTreg) cells upon antigen encounter under certain conditions ([@B1]). The choice between tolerance (i.e., control of inflammation) and autoimmunity is determined to a significant extent, by the relative generation and maintenance of pathologic effector T cells (Teff) and protective Treg cells specific for self-antigens. An imbalance in this number or activity of Treg cells is thought to underlie many inflammatory and autoimmune disorders. When Treg cells are"
+"INTRODUCTION\n============\n\nDNA encodes not just the gene but also the program for expression. At the level of transcription, a given gene\\'s program consists of the promoter sequences necessary for recruiting RNA polymerase along with *cis*-regulatory sequences specific for different transcriptional activators and repressors ([@B1]). In bacteria, these regulatory proteins bind specific DNA sequences, also known as operator sites, typically proximal to the promoter. The sequence of the operator site determines which activators and repressors regulate the activity of the promoter. In order for this regulation to work, the proteins regulating a given promoter must bind specifically to the associated operator sites, otherwise aberrant regulation will occur. Understanding the molecular basis for this recognition and specificity has been the focus of innumerable studies \\[cf. ([@B2; @B3; @B4])\\]. This information can potentially be used to change the DNA-binding specificity of transcription factors, enabling the reprogramming of gene expression in cells with applications, for example, in synthetic biology and metabolic engineering ([@B5; @B6; @B7; @B8; @B9; @B10; @B11]). As a result, an active area of protein engineering has been to identify mutations that alter the DNA-binding specificity of these transcription factors ([@B12]). While a number of experimental methods exist for generating such"
+"Intercellular heterogeneity plays a role in cell differentiation as well as disease development, progression, and remission or relapse in response to treatment.^[@ref1]\u2212[@ref3]^ Studying mRNA expression at the single-cell level can provide a means to characterize variability in cellular activity and thus study disease etiology and pathology. Standard macroscale methods for quantitative assessment of gene expression are not designed to handle very small volumes and are limited by their sensitivity and accuracy when applied to single-cell analyses.^[@ref4],[@ref5]^ In response to these challenges, various microfluidic platforms have been developed to measure gene expression in single cells using digital polmerase chain reaction (dPCR). High-throughput platforms, such as the BioMark HD system (Fluidigm), have provided a way to study expression levels of multiple genes in a set of single cells simultaneously.^[@ref6]^ However, challenges persist in dealing with the technical variability in single-cell protocols, where uncertainty can be introduced from cell lysis, reverse transcription, preamplification, PCR, and other steps.^[@ref7]^ It has been found that when performing microfluidic RNA quantification, using different reagents and protocols can give varying results for each step and that some methods do not work for certain genes.^[@ref8]^ It has also been shown that when dealing with the small quantities of mRNA"
+"Introduction {#Sec1}\n============\n\nAntibody (Ab)-mediated immune responses require the coordinated activation and differentiation of antigen inexperienced (naive) B cells into Ab secreting cells (plasma cells) and B cells with immunological memory (memory B cells). The most effective Abs arise from the germinal center (GC) reaction, in which B cells undergo Ab affinity maturation, acquire specialized effector functions via isotype switching, and develop into long-lived memory and plasma cells^[@CR1]^. These processes are crucial for pathogen elimination and the development of durable immunity; yet, when aberrantly targeted against host, graft, or innocuous antigen, these same processes can drive autoimmune and autoinflammatory disease, transplant rejection, and chronic allergy. Consequently, deciphering the molecular mechanisms governing B cell activation and differentiation remains a central goal in understanding both normal and aberrant immune responses^[@CR2]^.\n\nGlycoprotein-linked carbohydrates, or glycans, are increasingly being recognized for their key regulatory functions during immune homeostasis and inflammation^[@CR3],[@CR4]^. Through post-translational addition to either asparagine (N-linked) or serine/threonine resides (O-linked), glycans can alter the biophysical properties of their protein scaffolds^[@CR3],[@CR4]^. Alternatively, in a specific manner, glycan can themselves serve as binding determinants for a vast array of endogenous glycan binding proteins (lectins) that have myriad functions in the immune system, such as regulation"
+"Background\n==========\n\nHypertension is a world-wide epidemic affecting more than 1 billion people and causing 7.1 million deaths per year \\[[@B1]\\]. The consequences of untreated hypertension include increased risk of: coronary and peripheral vascular disease, stroke, congestive heart failure, and chronic renal impairment. Early identification of treatable and/or curable forms of hypertension is therefore critical to the prevention of the associated chronic diseases.\n\nArterial blood pressure is regulated by the renin-angiotensin-aldosterone system (RAAS). Dysregulation of this system leads to the development of certain hypertensive states that are responsive to surgical, vascular, or medical intervention--most notably primary aldosteronism (PA) and renal arterial stenosis. The RAAS is regulated by renin, a proteolytic enzyme secreted by the juxtaglomerular cells of the renal glomerulus in response to \u03b2-1 adrenergic stimulation, decreased arterial blood pressure, and decreased delivery of NaCl to the macula densa. Renin cleaves the decapeptide angiotensin-I (Ang-I) from angiotensinogen, an \u03b1-2 globulin constitutively manufactured by the liver. Through the action of the angiotensin-converting-enzyme (ACE), Ang-I is converted to angiotensin-II (Ang-II), a potent vasoconstrictor. This leads to a rapid rise in blood pressure and subsequent upregulation of aldosterone production by the adrenal glands. Both Ang-II and aldosterone then feedback to decrease plasma renin"
+"Introduction\n============\n\nHistone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl groups from lysine residues of proteins. Initially studied for their ability to deacetylate histones and influence chromatin, HDACs also remove acetyl groups from non-histone substrates thus playing a broader role in cell biology.[@b1],[@b2] In recent years, HDACs have received increasing attention in the context of neurological disease not only because protein acetylation has been implicated in neuropathology in myriad ways but also because HDACs are druggable targets. In this review, we present an overview of the HDAC superfamily, describe the role of HDACs in a few emblematic neurological disorders, and then move on to discuss the potential neurological side effects of modulating HDAC functions, particularly as we learn more about the functions of HDACs in the nervous system.\n\nThe HDAC Superfamily\n====================\n\nHDACs belong to an evolutionary conserved family divided into four classes.[@b3] Classes I, II, and IV are similar in that they all require Zn^2+^ as a cofactor.[@b4] Class III, on the other hand, requires nicotinamide adenine dinucleotide (NAD^+^).[@b5]\n\nEach of these classes, with the exception of class IV, is composed of more than one member. In addition, the metazoan HDACs are also often described by"
+"Background {#Sec1}\n==========\n\nOligodendrocytes (OLs) are responsible for generating myelin, a lipid-rich structure that envelops central nervous system (CNS) axons, allowing for rapid communication between neurons. OLs generate myelin as they differentiate by extending multiple processes that contact adjacent axons, forming concentric wrappings of lipid-rich OL membrane mostly devoid of cytoplasm and stabilized by myelin structural proteins \\[[@CR1]\\]. Prior to the onset of myelination, newborn OL precursor cells (OPCs) undergo a transient period of local proliferation followed by migration \\[[@CR2]\\], their direction and extent governed by patterning molecules. Proper myelination is therefore highly dependent on the capacity of OPCs to migrate to target destinations and initiate the differentiation program. As such, researchers have endeavored to dissect the extracellular cues and the intracellular machinery governing OPC migration. This is especially relevant in neurological diseases like multiple sclerosis (MS) where the capacity for endogenous repair may be limited partly by the hampered migration of OPCs into lesions \\[[@CR3]\\].\n\nOver the years, our understanding of OL biology has vastly improved through the study of rat OLs in vitro, for which several isolation methods exist \\[[@CR4]--[@CR6]\\]. However, these strategies are often not ideal for isolating mouse OPCs for a number of reasons. First and"
+"Background\n==========\n\nThe burden of central line-associated bloodstream infection (CLAB) in critically ill patients has been widely addressed in the scientific literature worldwide. According to studies from developed \\[[@B1]\\] and developing countries \\[[@B2],[@B3]\\], including Turkey \\[[@B4]\\], the most serious clinical consequences attributable to CLAB are increased mortality rates \\[[@B1]\\], significant morbidity \\[[@B1]\\], and increased LOS \\[[@B2],[@B5],[@B6]\\]. From an economic perspective, CLABs are also responsible for significant increases in healthcare costs, as reported in both developed \\[[@B1]\\] and developing countries \\[[@B2],[@B5]\\], but there are not available published data on costs of CLAB from Turkey.\n\nThe results reported from hospitals members of the International Nosocomial Infection Control Consortium (INCC) revealed that device-associated healthcare-acquired infections (DA-HAI) rates in the intensive care units (ICUs) of limited-resources countries are 3 to 5 times higher than rates in the ICUs of high-income countries \\[[@B7]-[@B10]\\]. However, most hospitals in limited-resource countries do not implement basic infection control programs, resulting in a general unawareness of the incidence of CLAB at their healthcare facilities \\[[@B11]\\].\n\nIn addition, the socio-economic level of a country and hospital type were reported to have an impact on DA-HAI rates in the ICU settings of developing countries in two studies \\[[@B12],[@B13]\\]. As regards hospital"
+"INTRODUCTION\n============\n\nWhen a missing tooth is located at the distal free-end, there are only a few treatment options: a conventional fixed partial denture or single implantation \\[[@B1]\\].\n\nIf this type of missing tooth is treated in conventional fixed partial denture therapy, the cantilever has a leverage effect on the second premolar \\[[@B1]\\]. Many studies have suggested that an implant is a satisfactory choice for posterior single tooth restorations with a good prognosis \\[[@B2]-[@B8]\\]. Becker and Becker \\[[@B4]\\] reported the results of treatment for single molar replacements. For two years, a 95.7% success rate was shown. Levin et al. \\[[@B5]\\] reported that the overall survival rate of single molar implants was 92.6%, at an average of 36 months of follow-up. Jung et al. \\[[@B6]\\] reported that the cumulative survival rate of the second molar single implant was 93.93%.\n\nUnless the missing second molar is restored, complications may occur such as supra-eruption of the opposing tooth \\[[@B1],[@B9]\\]. Extrusion of an opposing molar may disrupt occlusion \\[[@B9]\\]. This situation may lead to periodontal problems or heightened risk of caries development \\[[@B9]\\]. Some have reported that loss of a post-canine tooth results in a loss of chewing ability \\[[@B10],[@B11]\\]. Others reported that there"
+"Background\n==========\n\nInvasive pulmonary aspergillosis is a severe and often lethal infection. It mainly occurs in patients with malignancy who experience deep and prolonged neutropenia, but there are other established risk factors (e.g. high-dose long-term corticosteroid therapy or advanced forms of AIDS) \\[[@B1]\\]. Invasive pulmonary aspergillosis has recently been described in critically ill patients without malignancy \\[[@B2]-[@B4]\\], and Aspergilluss is increasingly considered as an emerging pathogen in non-hematological patients. Among the non-hematological patients diagnosed with invasive pulmonary aspergillosis in the critical care setting were patients with Child C liver cirrhosis \\[[@B3]\\]. This condition has thus be considered as a possible risk factor for invasive pulmonary aspergillosis, all the more so that acute liver failure is known to promote fungal infection \\[[@B5]\\]. In support of this contention and to raise the awareness of clinicians managing patients with decompensated cirrhosis, we report invasive pulmonary aspergillosis in three such patients.\n\nCase presentations\n==================\n\nThe three cases were diagnosed over a 18 months period, in two different hospitals.\n\nCase 1\n------\n\nA 54-year-old man was admitted for ascites and acute renal failure revealing Child-Pugh stage C13 alcoholic cirrhosis. A liver biopsy showed severe acute alcoholic hepatitis and treatment with prednisolone 1 mg/kg a day"
+"Introduction {#S0001}\n============\n\nHip and knee arthroplasty continue to be among the most common surgical procedures performed in the United States with an expected increase in utilization as indications expand and an aging population lives longer with an increased demand for more active, pain-free lifestyles.[@CIT0001] As a result, the likelihood of patients having ipsilateral hip and knee prostheses increases, as does the risk of periprosthetic complications, specifically, interprosthetic femur fractures (IFF), defined by a fracture of the femur between an ipsilateral hip and knee prostheses. Early reports on the treatment of these fractures were presented with significant reservation. The earliest report by Dave et al described successful treatment of a single patient who sustained an interprosthetic femur shaft fracture around a stemmed total knee and total hip implant with the use of a Mennan plate, iliac crest bone grafting, and a 3-month period of restricted weight-bearing.[@CIT0002] However, subsequent reports by Kenny et al demonstrated poor outcomes in treating similar fractures, with all four patients in that series failing initial treatment, two of whom required either above knee amputation or hip disarticulation.[@CIT0003] Since these early reports advancement in treatment strategies, namely implant choice and understanding and classifying the fracture pattern have"
+"All correspondence should be made to the journal editorial office: bmcmedicineeditorial\\@biomedcentral.com\n\nProgress and challenges in individualizing cancer treatment\n===========================================================\n\nDaniel F Hayes\n\n![**Daniel F Hayes is the Stuart B Padnos Professor of Breast Cancer Research and co-Director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center.** His research interests are in clinical and translational breast cancer research regarding new drug development, clinical trials and the development of biomarkers. Dr Hayes and colleagues published the first reports concerning the development of the CA15-3 blood test, used to evaluate patients with breast cancer. He has expertise in the use of this and other tumor markers, such as HER-2, circulating tumor cells and pharmacogenomics.](1741-7015-12-37-1){#F1}\n\n![**Hugh S Markus is a Professor of Stroke Medicine and Honorary Consultant Neurologist at the University of Cambridge.** He specializes in care of patients with stroke. He runs a specialist clinic for patients with genetic causes of stroke, including cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). His research interests are in using genetic and imaging techniques to investigate the pathogenesis of stroke.](1741-7015-12-37-2){#F2}\n\n![**David Leslie is consultant physician at St Bartholomew's Hospital, Professor of Diabetes and Autoimmunity at the Blizard Institute, University of London.**"
+"Anterior temporal lobe resection (ATLR) is an effective treatment for refractory temporal lobe epilepsy (TLE).^[@R1]^ Surgical damage to Meyer loop, the most anterior part of the optic radiation, results in a visual field deficit (VFD) in between 48%^[@R2]^ and 100% of patients.^[@R3]^ This precludes driving, a key goal of surgery,^[@R4]^ in 4%--50% of patients even if seizure-free.^[@R5][@R6][@R7]^\n\nOptic radiation fibers passing from the lateral geniculate nucleus (LGN) anteriorly over the roof of the lateral ventricle before turning backwards (Meyer loop) represent the superior visual quadrant so surgery may cause a contralateral superior quadrantanopia. VFD are hard to predict as the anterior extent of Meyer loop is variable^[@R8]^ and cannot be visualized intraoperatively. Diffusion tensor imaging tractography enables in vivo delineation of the optic radiation that can be used for epilepsy surgery planning.^[@R9],[@R10]^ Preoperative imaging has been used in neuronavigation systems to guide surgery^[@R11]^ but brain shift following craniotomy renders preoperative imaging inaccurate.^[@R12]^\n\nIntraoperative MRI (iMRI) allows updated images to be acquired during surgery. Tractography can be repeated using deterministic algorithms,^[@R13]^ but these depict Meyer loop poorly.^[@R14]^ More accurate probabilistic algorithms can be performed on preoperative data but are too time-consuming to employ during surgery. While preoperative tractography can be superimposed"
+"Introduction {#S1}\n============\n\nParkinson's disease (PD) is the most common neurodegenerative movement disorder and is likely to increase due to the aging population ([@B1]). PD is principally attributed to the death of dopamine (DA) neurons in the substantia nigra, but other neurotransmitters, such as glutamate, are also affected ([@B2]). There is no cure for PD but symptomatic treatments are available ([@B3]). Restoring lost DA with its precursor, [l]{.smallcaps}-3,4-dihydroxyphenylalanine ([l]{.smallcaps}-DOPA), remains the most effective treatment ([@B4]). However, many patients (\u226540%) develop motor complications after 5--10\u2009years of treatment ([@B5]). These motor complications include motor fluctuations and abnormal involuntary movements, such as [l]{.smallcaps}-DOPA-induced dyskinesias (LID), and contribute to limit the quality of life in PD patients and can be very difficult to manage ([@B6]). Motor fluctuations such as \"wearing-off\" are also common. Wearing-off is defined as a reduced duration of benefit from an individual [l]{.smallcaps}-DOPA dose and a recurrence of parkinsonian symptoms before the next normal dose of [l]{.smallcaps}-DOPA ([@B7]).\n\nNo drug is yet available for LID, aside from some benefit with amantadine that has anti-glutamatergic properties ([@B8]). Glutamatergic transmission is increased in the basal ganglia in PD ([@B9]) and is also believed to be involved in LID ([@B10], [@B11]).\n\nThe mechanisms"
+"###### Strengths and Limitations of the study\n\n-   To our knowledge, this is the first systematic review protocol that has\u00a0attempted to evaluate the burden of tuberculin skin test and interferon-gamma release assay-confirmed latent tuberculosis infection\u00a0(LTBI) in Africa.\n\n-   This study could potentially inform policy and practice to reduce the reservoir of latently infected persons from which new tuberculosis\u00a0(TB) cases arise.\n\n-   The chosen time period is short; however, it portrays an important era in Africa as significant gains have been made in the screening and treatment of TB, which could have theoretically huge impact on the burden of LTBI on the continent.\n\nIntroduction {#s1}\n============\n\nTuberculosis\u00a0(TB) is the second leading cause of mortality from an infectious disease globally after the HIV\u00a0infection.[@R1] In 2013, WHO estimated 9\u2009million new TB cases and 1.5\u2009million TB deaths globally, of which 80% of the cases and 70% of deaths were reported in low-income and middle-income countries.[@R2] Latent tuberculosis infection (LTBI) is defined as a state in which individuals harbour live *Mycobacterium tuberculosis* without evidence of manifestation of clinical or other symptoms of active disease.[@R3] Projections from mathematical models in 2000 estimate that over 30% of the population globally"
+"INTRODUCTION {#s1}\n============\n\nCiclopirox olamine (CPX) (also called Batrafen, Loprox, Penlac and Stieprox), a synthetic hydroxypyridone derivative, is currently used for the treatment of superficial fungal infections and available in a variety of formulations, including cream, lotion, gel, nail lacquer and shampoos \\[[@R1]\\]. CPX has a broad spectrum of action against dermatophytes, yeast, filamentous fungi and bacteria. Mechanistically, CPX has been proposed to act as an iron chelator, forming complexes with trivalent metal cations, such as Fe^3+^, and inhibiting metal-dependent enzymes, such as catalase and peroxidase, which play an essential role in the intracellular degradation of toxic peroxides, though this remains to be determined \\[[@R2]\\]. Recent studies have shown that CPX induces cell death in different cancer cells, such as primary human acute myeloid leukemia cells, human breast cancer MDA-MB231 cells and human rhabdomyosarcoma Rh30 cells \\[[@R3], [@R4]\\]. However, the mechanism by which CPX induces cancer cell death is only at the beginning to be investigated. Eberhard *et al*. reported that CPX displays preclinical anticancer activity against hematologic malignancies and induces cell death through its ability to chelate intracellular iron and inhibit the iron-dependent enzyme ribonucleotide reductase \\[[@R4]\\]. We showed that CPX inhibits tumor growth in human breast cancer MDA-MB231"
+"Application of resuscitation science to improve patient care and outcomes requires effective strategies for education and implementation. Systematic reviews suggest that there are significant opportunities to improve education, enhance individual and team performance, and avoid delays in implementation of guidelines into practice. It is within this context that the International Liaison Consensus on Resuscitation (ILCOR) Education, Implementation, and Teams (EIT) Task Force was established and addressed 32 worksheet topics. Reviewers selected topics from the *2005 International Consensus on Cardiopulmonary Resuscitation* (*CPR*) and *Emergency Cardiovascular Care* (*ECC*) *Science With Treatment Recommendations* [@bib0005] and new topics identified by an expert group.\n\nOne challenge for the EIT Task Force was extrapolating outcomes from simulation studies to actual patient outcomes. During the evidence evaluation, if the PICO (*P*opulation, *I*ntervention, *C*omparator, *O*utcome) question outcomes were limited to training outcomes such as improved performance on a manikin or simulator, studies were classified to a level of evidence (LOE) according to study design (e.g., a randomised controlled trial \\[RCT\\] on a manikin would be LOE 1). Manikin or simulator studies were labeled as LOE 5 irrespective of the study design if the PICO question also included patient outcomes.\n\nThe following is a summary of key 2010 recommendations"
+"Introduction {#s1}\n============\n\nSocial anxiety disorder (SAD) is one of the most common mental disorders with a lifetime prevalence of up to 12% in Western countries (Fehm et al., [@B17]; Kessler et al., [@B28]). Hallmark characteristics are intense fear and avoidance of being evaluated or criticized resulting in extreme discomfort and self-consciousness in everyday social situations (American Psychological Association, [@B1]). Theoretical models highlight the importance of cognitive biases in the processing of ambiguous or negative cues during social interactions for the etiology and/or maintenance of social anxiety (Rapee and Heimberg, [@B42]; Clark and Mcmanus, [@B10]). More specifically, studies show that socially anxious individuals have attentional biases in the processing of negative, rejection-related cues (Bar-Haim et al., [@B6]) and interpret ambiguous social situations as more threatening and negative than healthy controls (e.g., Stopa and Clark, [@B50]; Beard and Amir, [@B7]).\n\nRelatively little attention, however, has been paid to biases in gaze perception. This is particularly surprising since individuals with SAD experience intense feelings of being looked at by other individuals and show a marked avoidance and fear of eye contact during social interactions (Schneier et al., [@B48]). Biases in the self-referential perception of gaze directions, for instance, might more easily elicit"
+"Introduction {#sec1}\n============\n\nThe multicolored Asian ladybeetle, *Harmonia axyridis* Pallas (Coleoptera: Coccinellidae), was introduced from Asia into Western Europe and other parts of the world to control aphid and coccid populations ([@bibr02]; [@bibr10]). In Belgium, *H. axyridis* was used as a biological control agent beginning in 1997 and was first observed in the wild in 2001. Since then *H. axyridis* populations have increased and gradually expanded into Belgium ([@bibr02]).\n\nThis species presents all the characteristics shared by an efficient aphid predator: large body size, high voracity, high predation efficiency ([@bibr35]), high colonization aptitude ([@bibr60]), rapid development, high fecundity, and low susceptibility to pathogens or natural enemies ([@bibr41]). *Harmonia axyridis* has become ubiquitous in many parts of the world, including America, Europe, and Africa ([@bibr37]; [@bibr12]), and has been reported in many different habitats, such as agroecosystems, gardens, and arboreal habitats ([@bibr40]).\n\nDue to its large body and efficient physical and chemical defenses, *H. axyridis* has become an intraguild predator ([@bibr50]; [@bibr58]). Intraguild predation has been observed among other ladybeetle species ([@bibr45]; [@bibr58]); other aphid natural enemies, including syrphids, chrysopids, and parasitoids ([@bibr46]; [@bibr59]; [@bibr31]); and aphid pathogenic fungus ([@bibr45]). This intraguild predation behavior is thought to have led to a"
+"Worldwide, mosquitoes are responsible for nearly 1 million deaths each year by transmitting approximately 100 different diseases[@b1]. Chief among them is malaria, which infects about 200 million and kills 200,000 people annually, mostly children under age five[@b2][@b3][@b4]. Mosquitoes are also vectors of yellow fever, which is fatal in 30,000 to 80,000 of the roughly 200,000 annual cases[@b5][@b6][@b7]; of dengue fever, whose incidence is rapidly on the rise and infects 50 to 100 million people per year, with around 20,000 deaths[@b8][@b9]; and for numerous other diseases like chikungunya[@b10][@b11], West Nile[@b12][@b13], and various other encephalitic conditions[@b14][@b15].\n\nBesides the toll on humans, mosquitoes and other similarly sized insects are major agricultural pests. Livestock can be infected by the same or closely related pathogens as infect humans, leading to heavy losses[@b1][@b16]. Dairy production is negatively impacted by nuisance insects[@b17][@b18], which may cost the US dairy industry upwards of \\$350 million per year[@b17]. Fruit infestations by pests such as the Queensland[@b19][@b20] and Mediterranean[@b21] fruit flies (Qfly and medfly, respectively), spotted wing *Drosophila*[@b22], and Asian citrus psyllid[@b23] can wreak havoc on a region's produce industry. For example, the Qfly costs Australian growers up to \\$50 million each year in produce lost both to Qfly-induced damage and"
+"1. Introduction {#sec1-sensors-17-01607}\n===============\n\nAutonomous Underwater Vehicles (AUVs) and underwater gliders have found important applications in ocean exploration, oil and gas production, environmental monitoring, underwater infrastructure monitoring, weather services, and coastal surveillance \\[[@B1-sensors-17-01607],[@B2-sensors-17-01607],[@B3-sensors-17-01607]\\]. Typically, these vehicles are programmed to visit a number of predetermined targets, perform some tasks at the target locations, and then return home. With the increased demand and commercial success of the AUVs and gliders, it is of increasing interests to employ a fleet of vehicles simultaneously and cooperatively to perform a mission. Therefore, multi-vehicle task assignment and path planning become an important research topic in recent years.\n\nDue to the size, weight, and fuel constraints, these vehicles have strong limitations in underwater missions, such as limited mission length, stringent nonholonomic motion constraints, and limited communication with each other or with the home base. A nonholonomic motion constraint requires that the vehicle motion is along a smooth curvature without reversing direction. This often requires that the vehicle paths satisfy geometric continuity to support their kinematic constraints \\[[@B4-sensors-17-01607],[@B5-sensors-17-01607]\\]. For point-to-point path planning, Dubins curves have been widely utilized to achieve $G^{1}$ continuity and shortest path length \\[[@B6-sensors-17-01607],[@B7-sensors-17-01607]\\]. Recent literatures on Dubins vehicles also consider environmental conditions such as"
+"Introduction {#s1}\n============\n\nAlthough some perceive infertility as a quality-of-life issue, it is in fact a disease with increasing public health concerns [@pone.0097324-Practice1]. Infertility is a global health issue affecting 10--15% of the 1.5 billion women of reproductive age [@pone.0097324-ZegersHochschild1]. The majority of these women have no access to infertility treatment, and even in developed economies there are great inequalities in access to diagnosis and treatment [@pone.0097324-ZegersHochschild2]. Furthermore, when access to medical treatment is fully available, the basis of the infertility does not have a clear cause in 10--15% of the cases and is thus classified as 'unexplained', implying that the precise molecular basis of the infertility is unknown. Using knowledge obtained by studying a genetically engineered mouse model, we propose a new molecular basis for unexplained female infertility involving the ZFP36L2 RNA-binding protein\\'s role in ovulation and oocyte maturation. Our results suggest that decreased ZFP36L2 expression can, conceivably, be the basis of some cases of unexplained female infertility in humans.\n\nZFP36L2 (Zinc Finger Protein 36 Like 2) is an RNA-binding protein that binds and destabilizes certain adenine/uridine rich element (ARE)-containing transcripts in cell transfection studies by promoting their deadenylation [@pone.0097324-Lai1], [@pone.0097324-Ramos1]. ZFP36L2 is also known as TIS11D (Tetradecanoyl Phorbol"
+"Background {#Sec1}\n==========\n\nGlioblastoma multiforme (GBM) is one of the most aggressive primary brain tumor. It has been demonstrated that mutations of the IDH1 gene correlate with outcome in patients with malignant glioma and are considered as independent factors for predicting longer overall survival and progression free survival in patients with GBM \\[[@CR1]\\]. In GBM, cancer cells with stem cell-like features, called cancer stem cells (CSCs), were identified \\[[@CR2], [@CR3]\\]. GBM stem-like cells (GSCs) have a high capacity to resist or to adapt to standard therapies which include surgery followed by radiotherapy and chemotherapy \\[[@CR4]--[@CR6]\\], resulting in a poor prognosis with a median survival time of about 14\u00a0months \\[[@CR7], [@CR8]\\]. Thus, the development of efficient strategies targeting these cells \u00a0is urgently needed.\n\nIt has been demonstrated that CSC distinct pools reside within different regions of the same GBM \\[[@CR9]--[@CR11]\\]. More recently, the presence of two GSC populations, one derived from the GBM area called enhanced lesion (GCSCs) and the other one from the brain area adjacent to the tumor margin (PCSCs) that greatly differ in their growth properties and tumor-initiating ability, \u00a0was identified. Indeed, GCSCs and PCSCs possess key neural stem cell features, such as multipotency, clonogenic ability and"
+"Introduction\n============\n\nSystemic inflammatory responses (SIRS) are one of the main risk factors after liver transplantation^[1](#fn1){ref-type=\"fn\"}^ , can be caused by hepatic ischemia/reperfusion (I/R) injury^[@B2]^ , and their manifestation includes neutrophil infiltration, edema, pulmonary alveoli, inner hemorrhage, and endothelial cell activationin^[@B3]^ .\n\nIn hepatic I/R injury^[@B4]\\ ,\\ [@B5]^ , matrix metalloproteinases (MMPs) often increase because of ischemia-induced oxidative stress and cytokines^[@B8]\\ ,\\ [@B9]^ , which would lead to further liver damage, like hepatic cell variation, and matrix structure remodeling^[@B6]^ ~.~ In addition, tumor necrosis factor-alpha (TNF-\u03b1) is involved in the destruction of the extracellular matrix, and may increase MMP-9 levels^[@B7]^ .\n\nSevoflurane is a volatile anesthetic with the unique clinical characteristic of rapid recovery time and relatively low risk. It is suitable for both the induction and maintenance of anesthesia^[@B8]^ , and sevoflurane preconditioning has a protective effect during liver I/R-induced pulmonary injury^[@B9]\\ -\\ [@B12]^ .\n\nIn the present study, we evaluated if there is a direct beneficial relationship between MMP-9/TNF-\u03b1 and sevofluranein I/Rinjury^[@B13]\\ ,\\ [@B14]^ . This study aimed to evaluate the protective effect of sevoflurane preconditioning on liver I/R-induced pulmonary and hepatic injury.\n\nMethods\n=======\n\nThis study was carried out in strict accordance with the recommendations in the"
+"Introduction {#section1-2058-5241.5.190032}\n============\n\nFrozen shoulder, despite being a common and debilitating complaint, is a subject of considerable uncertainty both within scientific literature and clinical practice. Even its name is a topic of serious contention in the medical profession; across papers published over the past 70 years, alternative names put forward or utilized in leading journals have included 'adhesive capsulitis',^[@bibr1-2058-5241.5.190032]^ 'fibrotic capsulitis',^[@bibr2-2058-5241.5.190032]^ 'primary idiopathic stiff shoulder',^[@bibr3-2058-5241.5.190032]^ and 'contracture of the shoulder'.^[@bibr4-2058-5241.5.190032]^ These terms have all been applied to the painful, debilitating contraction of the shoulder^[@bibr5-2058-5241.5.190032]^ which has been the subject of many attempts at definition. Most of these attempts do not deviate far from that given by Codman in 1934,^[@bibr6-2058-5241.5.190032]^ usefully provided in updated terminology by Bunker in 2009:\n\n1.  'This is a condition which comes on slowly with pain over the deltoid insertion, inability to sleep, painful incomplete elevation and external rotation, the restriction of movement being both active and passive, with a normal radiograph, the pain being very trying and yet all patients are able to continue their daily habits and routines.'^[@bibr4-2058-5241.5.190032]^\n\nThere have been very few notable improvements on Codman's definition. For example, the American Shoulder and Elbow Surgeons (ASES) in their 2011 consensus paper provided the following"
+"1. Introduction\n===============\n\nThe measurement of absorption and scattering in a turbid environment is an important problem. Such measurements are used to characterize impurities in water \\[[@b1-v114.n02.a01]\\] and to characterize aquatic particles \\[[@b2-v114.n02.a01]\\]. In these applications, a spectrometer with an integrating sphere detector (IS) is ideal since the IS can reduce the effect of scattering and enhance the effect due to molecular absorption. Description of the use of IS with a cuvette holder inside the IS was given by Nelson \\[[@b3-v114.n02.a01]\\]. A description of the IS with an internal sample is given by Labsphere \\[[@b4-v114.n02.a01]\\]. An approach that places samples outside the IS was also described \\[[@b5-v114.n02.a01]\\]. Although the IS with an internal sample seems to provide the least sensitivity to scattering, this arrangement results in an non-ideal IS \\[[@b6-v114.n02.a01]\\] and has problems with stirring and temperature control. An IS with the sample filling the complete volume of the IS have been described in the literature \\[[@b7-v114.n02.a01],[@b8-v114.n02.a01]\\]. This later technique is not practical for biological samples with requirements for small sample volume. Microalgae cultivation is an important area where absorption measurements will gain in importance. The absorption spectra of chlorophyll in plants is a rich source of information about the"
+"Introduction\n============\n\nOptical coherence tomography (OCT) is a powerful imaging tool that can be used for cross-sectional imaging of biological tissues. The relatively thin and transparent retina makes OCT an ideal method for ocular imaging. It can be used for visualization and delineation of the retinal cell layers to detect and monitor a variety of retinal diseases. Nearly 2 decades since its introduction, OCT has become an indispensable tool for research, screening, diagnosing, and monitoring diseases of the macula and optic nerve head.\n\nOCT imaging technology has been evolving rapidly. Rapid acquisition speed of spectral domain (SD) OCT provides multiple advantages including reduced motion artifacts, improved transverse sampling, and increased axial resolution. These factors enable production of more detailed images and accurate portrayal of the true retinal contour.\n\nWithin the outer retina, a hyperreflective band previously thought to represent the photoreceptor inner segment/outer segment (IS/OS) junction can be appreciated on SD-OCT. Integrity of this layer has been found to be of high clinical importance as absence or disruption of this layer has been found to be associated with various diseases affecting the photoreceptors and/or choroid.[@b1-opth-8-2507]--[@b7-opth-8-2507]\n\nAnatomical considerations\n-------------------------\n\nIn the foveal region, SD-OCT imaging of the macula has conventionally been"
+"The national ecosystem survey was conducted by the Korean Ministry of Environment, and authors do not have special access privileges to these data. The Korean National Institute of Ecology has uploaded these species data onto the ECObank website: <http://ecobank.nie.re.kr/eclgySpceInfo/eclgySpceInfo.do>. To access the plant data; 1. Click \"\ub808\uc774\uc5b4\uc120\ud0dd\", which is the third button to the left from the top right corner of the linked site; 2. Click \"\uc804\uad6d\uc790\uc5f0\ud658\uacbd\uc870\uc0ac(3\ucc28)\", the fourth item down; 3. Click the grey box to the left of the fourth item, \"\uc2dd\ubb3c\uc0c1\", then click \"ok\"; 4. Click the top-right corner button; and 5. Click the fourth button \"\uc18d\uc131\uc815\ubcf4(\uc810)\" (this is the left-most button of the 2nd row of blue buttons); then, click on one of the orange-colored squares (observation points) on the screen. To download the species' information, when the species list comes out, scroll all the way to the bottom of the list and click the blue button labelled \"\uc5d1\uc140\ucd9c\ub825\". You can download species from this location in an Excel format. This download approach can be used for site-by-site data acquisition. For more information on these data, you can contact Dr. Namsin Kim (<geotop@nie.re.kr>) at the Korean National Institute of Ecology.\n\nIntroduction {#sec001}\n============\n\nBiological diversity contributes"
+"Introduction\n============\n\nGlioblastoma multiforme (GBM) is the most aggressive malignant brain tumour ([@B39]; [@B25]). Despite of numerous new strategies for targeted treatment of glioblastoma, progress in the field remains insufficient ([@B22]; [@B40]). After the surgical resection of the tumour node, the main purpose of all consequent treatment strategies is to eliminate the remaining glioblastoma cells and prevent the disease relapse being a main cause of the patient's deaths.\n\nHowever, being concentrated to destroy the glioblastoma cells, one can overlook a danger coming from a significant impairment of the surrounding normal brain tissue during the adjuvant therapy. In fact, the most dangerous trait of glioblastoma is its' active invasion into the surrounding healthy brain tissue ([@B28]; [@B4]), and the invasiveness of GBM cells and tumour development depend on not only migration capabilities of the proliferating glioblastoma cells but also structure of the surrounding normal brain tissue ([@B36]; [@B17]). One of the key invasion-related component of normal brain tissue is extracellular matrix (ECM) which occupies near 20% of its volume and serve as a main basic element of tissue structure and physiology ([@B24]). ECM is not only a physical non-specific barrier but is actively involved in cell--cell and cell--matrix interactions and signalling"
+"Dear Sir,\n\nI read with great interest the review article by Kaushik.\\[[@ref1]\\] I congratulate the author for covering this basic topic, which is still unexplored and under-reported. I appreciate the effort of the author for suggesting a basis for classification of bleeding into major and minor groups after laparoscopic cholecystectomy. I would like to add that if we lose the patient because of the bleeding, irrespective of whether any open surgical intervention was done or not, it should be grouped under major category. Though the issue has been discussed very nicely, the author has overlooked the criteria he has followed for the classification of the bleeding into major group in Table 1. It should have been clearly mentioned in materials and methods section. There is a need for consensus on this debatable issue. The author has not included the secondary haemorrhage, which could occur 7--14 days after surgery and may be precipitated by factors such as infection, pressure necrosis or malignancy.\\[[@ref2]\\] The standard classification of any bleeding related with surgery whether open or laparoscopic are primary, reactionary and secondary. One should follow the standard norm. It is true that the secondary haemorrhage after any surgery, particularly laparoscopic surgery is extremely"
+"Introduction {#s1}\n============\n\nA brain-computer interface (BCI) is a system that interprets the thoughts of the user to produce commands that control a computer or device. Many systems adapt to the user, who in turn is continually adapting to the system. The role of this feedback-adaptation loop between the system and user is of considerable importance in BCI systems that attempt to approximate neural function ([Figure 1](#pone-0026322-g001){ref-type=\"fig\"}).\n\n![A diagrammatic representation of the presented BCI system.\\\nUsing specifically trained motor imaginations learned in single dimensional cursor tasks, subjects control the three-dimensional movement of a virtual helicopter. Raw EEG is temporally and spatially filtered to produce individualized control signal components. These components are weighted and digitized in a subject specific manner and output to influence control in the virtual world.](pone.0026322.g001){#pone-0026322-g001}\n\nUntil recent years, sophisticated thought-based control of movement in multiple dimensions was relegated to the subcategory of invasive BCI systems [@pone.0026322-Georgopoulos1], [@pone.0026322-Hochberg1], [@pone.0026322-Kennedy1], [@pone.0026322-Musallam1], [@pone.0026322-Santhanam1], [@pone.0026322-Taylor1], [@pone.0026322-Velliste1]. While these invasive BCI systems have shown great promise for controlling an external device from signals extracted from the brain of animals or human subjects, these systems present various degrees of risk associated with the implantation of a recording device in the subject\\'s brain. As"
+"Background {#Sec1}\n==========\n\nThe prevention of oral disease and the promotion of oral health have been established as high priorities by the World Health Organization \\[[@CR1]\\]. The etiologies of oral disease are generally progressive and cumulative, such that compared with younger individuals, elderly people are at greater risk of active dental caries and periodontal disease risk \\[[@CR2]--[@CR4]\\]. However, although middle-aged and elderly people are aware of the importance of oral health to their quality of life \\[[@CR5]\\], the majority of them seek dental care only when they experience toothaches \\[[@CR6]\\]. As consequence, middle-aged and elderly individuals usually suffer from multiple oral diseases, and obstacles to their use of dental care services are numerous \\[[@CR7]\\]. As the population ages and the retention rate of natural teeth increases, the demand for dental care becomes more urgent in middle-aged and elderly people than in adolescents \\[[@CR8]\\].\n\nIn the traditional sense, obtainment of dental care services is related to the ability to access oral health resources \\[[@CR9]\\]. If dental care-seeking behavior can be characterized in middle-aged and elderly people, then the reasons underlying the obstacles to timely and proper dental care might be identified. In addition to human resources such as dental care and"
+"Background\n==========\n\nAutism is a heterogeneous disorder characterized by impairments in social interaction, deficits in verbal and nonverbal communication, restricted interests and repetitive behaviors \\[[@B1]\\]. Autism comprises the severe end of a group of autism spectrum disorders (ASD) \\[[@B2]\\]. The prevalence of autism is estimated at 0.2%, with males being more likely than females to have a diagnosis of autism (ratio of approximately 4:1) \\[[@B3]\\].\n\nThere is compelling evidence from twin and family studies indicating a strong genetic component in autism. The average risk of recurrence of autism in siblings is approximately 10% \\[[@B4]\\] in families with one affected sibling, which is much higher than the prevalence in the general population, but much lower than would be expected for a single-gene disease \\[[@B2]\\]. Indeed, cases of autism have only rarely been associated with mutations in single genes or with chromosomal duplications or other abnormalities \\[[@B5]-[@B9]\\]. Furthermore, the inheritance pattern in most cases of autism is complex and not compatible with simple Mendelian inheritance \\[[@B10],[@B11]\\]. A series of common autism susceptibility genes has been identified in the literature, but taken individually, the risk associated with these genes remains modest. Although spontaneous mutations may help explain isolated cases of autism, the inheritance"
+"Introduction {#s1}\n============\n\nDespite advances in medicine, infectious diseases remain a major cause of death and inflict social and economic upheaval on millions of people worlwide. Respiratory infections alone are responsible for 4 million deaths every year, with *Streptococcus pneumoniae* the predominant causal agent [@pone.0101037-UNICEF1]. Indeed, it is the leading cause of non-invasive infections such as bacterial pneumonia, sinusitis and otitis media (all biofilm-related infections [@pone.0101037-Coates1]), and is commonly the culprit in life-threatening invasive conditions such as bacteremia/sepsis and meningitis. In developing countries, pneumococcal septicemia is a major cause of infant mortality, leading to the deaths of more than 1.2 million infants every year [@pone.0101037-Kadioglu1]. HIV infection, sickle-cell anemia, and a variety of chronic organ failure conditions, increase the risk of serious pneumococcal disease.\n\nThe alarming, global increase in multidrug resistance, particularly in pneumococcal strains resistant to \u03b2-lactams, macrolides, tetracyclines and sulfonamides, has renewed interest in the development of novel drugs and strategies for controlling the spread of antibiotic resistant bacteria [@pone.0101037-Maestro1]. Ceragenins, also known as CSAs (for [C]{.ul}ationic [S]{.ul}teroid [A]{.ul}ntibiotics), are based on a cholic acid scaffolding, and mimic antimicrobial peptides [@pone.0101037-Lai1]. Ceragenins, however, are easier to synthesize than the latter and are much more stable. Further, since they"
+"Introduction {#sec1-1}\n============\n\nHIV counseling and testing services are a key entry point in HIV prevention and treatment of people with HIV. These services provide accurate information about HIV and help the clients to undergo HIV test in a supportive and confidential environment.\\[[@ref1]\\] With the introduction of antiretroviral therapy (ART), the scope of voluntary counseling and testing centers (VCTCs) further expanded to include preparedness and adherence along with counseling for people on ART. HIV counseling and testing services were provided to 66.62 lakh persons in the year 2010.\\[[@ref2]\\] Barriers to voluntary counselling and testing (VCT) include low perceived risk for HIV infection, negative perceptions of testing services, lengthy pre- and post-test counseling, and shortages of counselors.\\[[@ref3][@ref4][@ref5]\\] To provide integrated services, earlier VCTCs and prevention of parental to child transmission were brought under one roof to cater general and ANC clients and was renamed as integrated counseling and testing centers (ICTCs).\\[[@ref6]\\] In India, the ICTC services are provided through 4486 standalone ICTCs, 4071 Facility ICTCs at 24 \u00d7 7 PHCs and 902 ICTCs under public--private partnership model. A total of 90.52 lakh clients tested for HIV in the year 2011--2012.\\[[@ref7]\\] Evaluation of counseling, testing, and referral services increase the effectiveness, efficiency,"
+"Introduction {#s1}\n============\n\nAn enduring question in object recognition is what defines expert perceptual processes and how different they are from regular, everyday object recognition. This question was amply explored in the domain of face processing, a domain of natural expertise in all human adults. Faces form a highly homogenous set of stimuli with a very similar spatial configuration of parts. Therefore, discriminating between individual faces and extracting other relevant information from them should be, in theory, a difficult perceptual task. Nonetheless, humans are extremely adept in recognizing individual faces and categorizing faces along many other subordinate dimensions such as race or gender. This remarkable ability has been attributed by some to specifically tuned neural mechanisms distinguished by behavioral [@pone.0067024-Maurer1], electrophysiological [@pone.0067024-Bentin1], and neuroimaging [@pone.0067024-Kanwisher1]--[@pone.0067024-Puce1] markers. Others considered face perception as an extreme manifestation of perceptual expertise [@pone.0067024-Carey1]--[@pone.0067024-Tarr1], which may be generalized to objects other than faces, specifically to objects that form a visually homogenous category with a prototypical part configuration [@pone.0067024-Diamond1]--[@pone.0067024-Gauthier1]. The latter view challenges face specificity suggesting that processing characteristics usually attributed to faces are a general expression of expert visual processing rather than a peculiarity of face recognition. The present study addresses this contended issue by investigating"
+"Introduction {#s1}\n============\n\nDrought stress is one of the most pressing issues inhibiting global agriculture today (Osakabe et al., [@B30]). But with the growing of world\\'s population, more food must be produced with less fresh water (Fu et al., [@B11]; Zhang, [@B51]). Rice (*Oryza sativa* L.) is the main food for more than half of the world\\'s population. Water deficit may reduce rice production seriously and threaten world food security (Serraj et al., [@B34]; Luo, [@B25]; Ahmadi et al., [@B1]). So, there is an urgent need to understand the underlying physiological and molecular mechanisms of drought resistance to sustain rice production in water-limiting areas (Nguyen et al., [@B28]; Lanceras et al., [@B21]; Rabello et al., [@B32]; Bernier et al., [@B4]; Serraj et al., [@B35]). As the main organ to uptake water in soil, root is the key contributor of plants\\' drought resistance (Kato et al., [@B18]; Henry et al., [@B16]). Therefore, recently root has become a hot area of research to improve drought resistance (Coudert et al., [@B7]).\n\nDeep roots play important role in enhancing plants drought resistance, and it is an important component of roots architecture. According to the research of Uga (Uga et al., [@B39]; Uga, [@B38]), the"
+"Introduction {#s1}\n============\n\nNeurons are the basic cells that process information within the brain. They are compartmentalized into two morphologically, molecularly and functionally distinct domains; the axonal and the somatodendritic compartments. Multiple short and highly branched dendrites function in receiving and integrating electrical synaptic inputs from thousands of neurons. In contrast, only a single axon is responsible for transmitting this integrated information in the form of an action potential, an electrical excitation wave that travels along the axonal membrane. To ensure that information is transmitted properly, the axon has a unique cytoskeletal organization and contains several specialized structures, including the axon initial segment (AIS) and presynaptic boutons (Figure [1](#F1){ref-type=\"fig\"}).\n\n![**The axonal cytoskeleton and axon-specific structures**. The axon is specialized in transmitting information to other cells. To ensure this function, the axon has a unique cytoskeletal organization **(A,B)** and has several specialized structures **(C,D)**. **(A)** The unique unipolar orientation of the microtubules (MTs) within the axon provides anterograde transports of various axonal cargoes via plus-end directed kinesins. Various mechanisms exist that regulate the activity of kinesins. **(B)** The actin cytoskeleton within the axon exists as periodically spaced rings underneath the axonal plasma membrane, organized by spectrin and adducing, and provides the"
+"Background {#s1}\n==========\n\nInterleukin-1\u03b2 (IL-1\u03b2) is a potent pro-inflammatory mediator that is produced following activation of one of the multiple inflammasome multi-protein complexes. One of the best characterized is the nucleotide-binding oligomerization domain-like receptor (NLR) family, pyrin domain-containing 3 (NLRP3), whose activation and subsequent release of IL-1\u03b2, has been demonstrated in chronic obstructive pulmonary disease, severe asthma, and respiratory infections ([@B1]). Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterized by scar tissue accumulation in the lungs leading to impaired gas exchange and restricted ventilation ([@B2]--[@B4]). The underlying causes of the disease are still unclear, although persistent epithelial injury and/or exposure to pathogens is thought to drive an exaggerated wound healing response from fibroblasts, that contributes toward the development and progression of IPF ([@B2], [@B4]). In the case of this respiratory disease, the role of IL-1\u03b2 is yet to be established although there is a report of showing increased levels in bronchoalveolar lavage ([@B5]). In addition, there are conflicting reports as to whether IL-1\u03b2 elicits pro-fibrotic or anti-fibrotic activities ([@B6], [@B7]). IL-1\u03b2 was previously shown to drive IL-6 expression in orbital and synovial fibroblasts *in vitro* ([@B8]), although nothing is known regarding its effect on lung fibroblasts.\n\nNon-coding RNAs (ncRNAs)"
+"INTRODUCTION\n============\n\nThe preventive treatment of latent tuberculosis infection (LTBI) has gradually gained a vital role in tuberculosis (TB) control worldwide since the 1950s. Currently, the global strategy in the treatment of TB is divided into two basic parts: in areas with a high incidence of TB, the main goal is to treat the active cases, but in areas with a low incidence of TB, the goal also includes prophylactic treatment for LTBI. According to the World Health Organization (WHO), approximately 2--3 billion people in the world are latently infected with *Mycobacterium tuberculosis* (Mtb), and 5%--15% of these people will suffer from reactivation of TB during their lifetime.^[@bib1]^ Therefore, the treatment of LTBI directly influences the future global prevention of TB infection. At present, the study of LTBI relies heavily on screening for high-risk populations and on treatment strategies for the disease.\n\nSCREENING FOR LATENT TUBERCULOSIS INFECTION\n===========================================\n\nCurrently, a golden standard for the diagnosis of the LTBI is lacking. Because the amount of *Mycobacterium tuberculosis* is small in LTBI patients, diagnosis of LTBI mainly depends on the immune reaction of the host rather than the bacteria itself. There are two currently available screening tests for LTBI: the tuberculin skin"
+"Introduction {#sec0001}\n============\n\nAccording to the WHO, hospital acquired infections account for 7% of all infections in developed countries and 10% in developing countries.[@bib0001] Several outbreaks within long-term care facilities and acute care facilities have been reported across Canada from COVID-19 and many were reported in acute-care facilities during the SARS epidemic.[@bib0002], [@bib0003], [@bib0004] The recent outbreak of COVID-19 has caused many countries to go to extreme measures of setting up dedicated health care facilities as a containment measure, which clearly highlights the continuous importance of managing nosocomial infections to control epidemics.[@bib0005]\n\nFrequent systematic cleaning and disinfecting practices (CDP) are key in controlling the spread of infection[@bib0006] within in-patient settings, since pathogens can persist on surfaces for several weeks if left uncleaned.[@bib0007], [@bib0008], [@bib0009] Technological advancements have resulted in new cleaning and disinfecting tools and processes to improve the effectiveness of CDP to support infection control[@bib0010] ^,^ [@bib0011] but cleaning standards and best practices are useful only if they are actually followed. Despite its importance, environmental cleaning and disinfecting remains inadequate in hospitals.[@bib0012] ^,^ [@bib0013] A 2008 study across 23 acute care hospitals across the United States showed that only 49% of 14 high risk surfaces (33% chance of contamination)"
+"Multiple factors are contributing to the expansion of allergens on a worldwide scale. Increased travel and trade have led to the introduction of certain allergenic species to other environments that had never seen them previously \\[[@B1]\\]. These include pollens from many plant species that are new to these environments. The climate changes that are occurring owing to global warming may serve as another influence that will allow new allergens to expand into different regions in the future. These changes include the increasing length of the growing seasons, changes in agricultural practices, ozone exposure, and increased atmospheric CO~2~levels. Exposure to air pollutants has been repeatedly shown to influence the immune system\\'s response to allergens \\[[@B2],[@B3]\\]. Long-distance transport of anemophilus pollens could represent a source of pollen exposure for inhabitants in areas in which the species are not present in sufficient quantities to invoke symptoms \\[[@B1],[@B4],[@B5]\\]. As allergy sufferers are exposed to increasing amounts of air pollution in the future, this could lead to increased sensitization and thus symptoms. Increased allergen exposure may have a number of detrimental effects on the exposed population related to higher rates of sensitization. Sensitization in children can lead to the classic \\\"allergic march,\\\" which includes a"
+"Background {#s1}\n==========\n\nMeasuring liver stiffness (LS) by transient elastography (TE) is a noninvasive and rapid method for diagnosing liver fibrosis in chronic liver diseases. A strong correlation between LS values and liver fibrosis stage, as assessed by liver biopsy, has been reported in chronic hepatitis C and other chronic liver diseases \\[[@R1]\\]\\[[@R2]\\]\\[[@R3]\\]\\[[@R4]\\]\\[[@R5]\\]\\[[@R6]\\]. However, LS values can be influenced by other factors, which should be taken into account when interpreting such values in assessing liver fibrosis in chronic liver diseases. Thus, irrespective of etiology, LS values are influenced by gender, body mass index, metabolic syndrome, and biochemical flares of hepatitis and cirrhosis \\[[@R7]\\]\\[[@R8]\\]\\[[@R9]\\]\\[[@R10]\\]\\[[@R11]\\]\\[[@R12]\\]\\[[@R13]\\]. Recently, extrahepatic cholestasis that is caused by benign or malignant diseases has also been reported to increase LS, regardless of fibrosis \\[[@R14]\\]\\[[@R15]\\].\n\nObjectives {#s5}\n==========\n\nThe aim of this study was to assess LS by TE in patients with extrahepatic cholestasis that was caused by choledocholithiasis before and after endoscopic sphincterotomy and stone removal.\n\nPatients and Methods {#s2}\n====================\n\nPatients {#s2sub3}\n--------\n\nTwelve patients with extrahepatic cholestasis due to choledocholithiasis, referred to the Gastroenterology and Hepatology Institute of Iasi, Romania, for therapeutic endoscopic retrograde cholangiopancreatography (ERCP) between April 2009 and October 2009, were enrolled in this prospective"
+"All relevant data are within the manuscript and its Supporting Information files.\n\nIntroduction {#sec005}\n============\n\nNext-generation sequencing (NGS) has been rapidly adopted for HLA typing in clinical laboratories to evaluate donor-recipient histocompatibility. The key advantage of NGS over Sanger sequencing for high-resolution HLA typing is that NGS can phase the large number of sequence variants within HLA genes into haplotypes with minimal cis-trans ambiguity \\[[@pone.0232050.ref001]--[@pone.0232050.ref003]\\]. In addition, most current NGS HLA typing assays cover full or near-whole target HLA genes, allowing the detection of clinically relevant variants outside of key exons (exons 2 and 3 of class I genes and exon 2 of class II genes). The high throughput of NGS enables multiplexed sequencing of DNA enriched from multiple genes and many samples in one run, which maximizes the efficiency and lowers the per sample cost.\n\nWhile sequencing of the whole genome \\[[@pone.0232050.ref004]\\], whole exome \\[[@pone.0232050.ref005], [@pone.0232050.ref006]\\], transcriptome \\[[@pone.0232050.ref007], [@pone.0232050.ref008]\\], or captured HLA genes can lead to successful HLA typing, most commercially available NGS assays amplify target HLA genes by polymerase chain reaction (PCR) followed by library preparation and sequencing \\[[@pone.0232050.ref009]--[@pone.0232050.ref012]\\]. One common approach is the \"long-amplicon, short-read\" approach. The whole, or near-whole HLA genes are enriched by PCR, and"
+"The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Sequence of amplified mitochondrial DNA from the skin lesion is available on Figshare <http://dx.doi.org/10.6084/m9.figshare.1146216>.\n\nIntroduction {#s1}\n============\n\nSkin lacerations and bites are frequently reported on stranded harbour porpoises (*Phocoena phocoena*), with a bite being defined as any rupture in the skin caused by the teeth of an animal [@pone.0108993-DeMunnynck1]. The origin of lacerations can sometimes be associated with by-catch in fishing nets, while in other cases, the cause remains unclear. Finally, definitive distinction should be made between ante-mortem injuries and post-mortem depredation by scavengers (birds, dogs, red fox, wild boar,...), such post-mortem interference being well known in forensic pathology. Recently, bite-like skin lacerations on porpoises have been suspected to be associated with the predation by grey seals (*Halichoerus grypus*) [@pone.0108993-Haelters1]. Such lesions could be differentiated into two types: either large flaps of loose or missing skin or blubber with frayed edges or punctures. In both cases, lesions were considered as being ante-mortem and were highly similar to those inflicted by large dogs [@pone.0108993-DeMunnynck1] even if excluded by Haelters *et al.*, 2012. Nevertheless, grey seal"
+"Background\n==========\n\nEffective typing of microorganisms is a prerequisite for establishing epidemiological or phylogenetic links between corresponding isolates. A plethora of different methods has been successfully applied to type and differentiate bacterial strains and clonal groups from each other \\[[@B1]\\]. A critical point to all of these methods is their applicability to answer distinct questions ranging from investigation of outbreaks to establishing rather broad phylogenetic trees of relatedness and arrangement of strains within major clonal complexes. Each method has its respective weaknesses and strengths according to the question(s) addressed and the methodology behind \\[[@B2]-[@B7]\\].\n\nRecently, a new method was introduced using small repetitive elements appearing in a variable number and distributed among the genome of a given species. Accordingly this technique based on a variable number of tandem repeats (VNTR) was named multiple-locus variable-number tandem repeat analysis (MLVA; \\[[@B8]\\]). Initially MLVA was established to differentiate high-risk pathogens such as *Bacillus anthracis*and *Francisella tularensis*\\[[@B9]-[@B11]\\] but has been extended to a numerous number of other bacterial species and scientific questions \\[[@B8],[@B12]\\] including outbreak investigations for pathogenic bacteria \\[[@B4],[@B13]\\].\n\nMLVA was applied also recently to type isolates of *Enterococcus*spp. Its discriminatory power was compared to MLST for a collection of 392 *E. faecium*\\[[@B14]\\]"
+"1. Introduction {#sec1}\n===============\n\nVisuo-motor adaptation to rightward prismatic shifts reduces signs of left spatial neglect on a wide range of measures ([@bib11; @bib2; @bib6; @bib9; @bib13]). As there are hemispheric asymmetries in spatial attention mechanisms, it may be useful to examine whether prism adaptation can produce similar improvements in neglect of the *right* hemispace following left hemisphere damage. We report improvement in a patient with mild right spatial neglect following adaptation to leftward-shifting prisms.\n\n2. Participants and methods {#sec2}\n===========================\n\n2.1. Participants {#sec2.1}\n-----------------\n\nParticipants were one patient with right spatial neglect (female, age\u00a0=\u00a075 years, left-handed) and eight right-handed, neurologically healthy age- and gender-matched control participants (Mean age\u00a0=\u00a073.4 years, Standard Error of the Mean -- SEM\u00a0=\u00a0.82).\n\nPatient DS was hospitalised with unintelligible speech, left gaze deviation, right neglect, right facial weakness and hemiplegia with brisk reflexes on the right and bilateral Babinski signs. A Computerised Tomography (CT) scan revealed a large left fronto-parietal haematoma due to haemorrhagic infarction.\n\nThree months later, at the time of the current investigation, DS was referred to us after her speech therapist noticed a tendency to leave the rightmost part of her workbooks uncompleted. At this time she"
+"Introduction {#Sec1}\n============\n\nThe invention of and advancements in the childhood vaccination has revolutionized human healthcare and facilitated to averting morbidity and mortality from many vaccine-preventable infectious diseases^[@CR1]^. Immunization not only has helped preventing life-threatening diseases but also benefitted mankind by increasing their life expectancy (life span has increased by 15 to 25\u00a0years since the commencement of vaccines) and in improving quality of life^[@CR2],[@CR3]^. However, these successes cannot mask the failures in shape of millions of deaths of the unvaccinated children annually, across the globe^[@CR4]^. Estimated 1.5 million children died of vaccine-preventable diseases in each of 2013 and 2017 respectively which construes that the world could have avoided an additional huge number of deaths a year had the universal immunization coverage achieved^[@CR5],[@CR6]^.\n\nDespite the fact that overall vaccination coverage in 2018 remained around 86%^[@CR6]^, there remained a wide disparity between different World Health Organization (WHO) regions, e.g., the Americas, Europe and Western Pacific maintained over 90% immunization coverage of DTP3 containing vaccine whilst these rates were low for most of the countries in Africa and some in Asia^[@CR7]^. Low levels of immunization coverage in the low-and middle-income countries pose a serious challenge to achieving universal vaccination coverage goals^[@CR8],[@CR9]^. For"
+"Introduction {#sec0005}\n============\n\nDengue is one of the most rapidly spreading mosquito-borne viral disease in the world \\[[@bib0005]\\]. Annually, about 50 million dengue infections occur, travelers from non-endemic countries to endemic dengue areas are at risk \\[[@bib0010]\\], most infections are asymptomatic, the hemorrhagic complication of the disease mainly affect children under 15 years of age \\[[@bib0015]\\].\n\nCase report {#sec0010}\n===========\n\nA 4-year-old boy was admitted to the pediatric intensive care unit in Jizan City Hospital in Saudi Arabia with acute viral hepatitis A after 2 weeks of illness; the patient had initially been diagnosed in Jordan during a family visit there, the family left Saudi Arabia two months before the child becoming ill, the child was a product of a term pregnancy (Twin A). He was healthy before this illness, but his vaccine history did not document hepatitis A virus immunization. In Jordan, during the visit, patient had acute illness of fever, abdominal pain and vomiting, with a deep yellow colour of the sclera. The diagnosis of hepatitis A was confirmed with IgM for anti-HAV. The patient was managed supportively with intravenous fluid and observation, after 2 weeks of illness, he partially improved and was discharged from the Jordan hospital,"
+"A traditional optical lens refracts light with designed spatially varying refractive indices to form images; such images can be magnified or demagnified according to the law of geometrical optics on both surfaces of the lens by linear refraction, e.g. plano-convex lens, plano-concave lens. These images formed by optical lenses have a limited resolution due to the well-known diffraction limit, caused by lack of detections of the near-field evanescent waves at the far field[@b1]. In order to overcome this limit, a slab-like flat lens, namely \"superlens\"[@b2][@b3], has been demonstrated with sub-diffraction-limited resolution imaging capability in the near field by exploiting the idea of negatively refracted evanescent waves in some carefully engineered meta-materials or photonic crystals[@b4][@b5]. However, images can only be formed by superlens in the near-field without any magnification. To mitigate these constrains, the concept of hyperlens was introduced later to convert the near-field evanescent waves into propagating ones providing magnification at the far field by the help of transformation optics[@b6][@b7] to enable negative refraction near some hyperbolic dispersion surfaces[@b8][@b9][@b10][@b11][@b12]. Besides optics, various forms of these sub-diffraction-limited resolution lenses have recently been realized in many other fields including microwave and acoustic[@b13][@b14][@b15]. One major drawback of these lenses is associated with high"
+"INTRODUCTION\n============\n\nSince its advent in the 1980s,^[@R1]^ advanced 3-dimensional (3D) computer technologies have transformed many health care fields and enabled many new treatment paradigms.^[@R2]^ Virtual surgical planning (VSP)^[@R3]^ and 3D modeling (3DM)^[@R4]^ are 2 tools used in craniofacial surgery due to advances in imaging resolution^[@R5]^ and rigid biomaterial production^[@R6]^ in recent decades. Some centers use these techniques routinely in complex reconstruction, such as free flap mandible reconstruction.^[@R7]--[@R11]^ The concept of patient-specific custom implants (PCI) for craniofacial reconstruction predates such advanced 3D technical developments by nearly a decade,^[@R12]^ though the fabrication of craniofacial PCIs by 3D printing (3DPCI) has occurred only recently.^[@R13]--[@R17]^ A systematic review in 2016 by Bauermeister et al.^[@R18]^ identified 226 articles on the biologic application of 3D printing. Kamali et al.^[@R19]^ suggests that 3D printing in medicine will grow into a multibillion-dollar industry within the next 10 years. Gerstle et al.^[@R20]^ suggests that \"plastic surgeons may likely find this technology indispensable ... in the near future.\" As advanced 3D technologies continue to proliferate, it becomes imperative to asses their impact on the treatment of complex craniofacial deformities and become familiar with the use of VSP, 3DM, and 3DPCI.\n\nThe use of 3DPCIs is a burgeoning area within"
+"Background {#Sec1}\n==========\n\nThe monogenean *Gyrodactylus salaris* Malmberg, 1957 has been an important pathogen of juvenile freshwater stages of Atlantic salmon, *Salmo salar* L. in Norway since the 1970s, when it is thought to have been introduced from the Baltic region \\[[@CR1]\\]. An early conclusion was that, following the introduction of this parasite, Norwegian (Eastern Atlantic) salmon stocks were especially susceptible due to a lack of co-adaptative evolutionary experience of *G. salaris*, contrary to Baltic salmon stocks \\[[@CR2]\\]. This hypothesis has been repeated, with numerous studies comparing parasite performance on different salmon stocks and other salmonids, generating one of the largest available data sets using a common garden experimental approach to examine host specificity of a metazoan parasite infecting vertebrates. Studies with other gyrodactylid-host systems have shown that parasite infra-populations grow rapidly to a peak, followed by decline and eventual elimination \\[[@CR3]--[@CR14]\\], a pattern interpreted as exponential increase before induction of immunity after a short period of recognition and activation \\[[@CR15]--[@CR19]\\]. The continuous growth of *G. salaris* on susceptible Norwegian salmon was therefore interpreted as evidence of impaired immunity \\[[@CR20]\\], despite earlier suggestions that even on these fish, parasite population growth rates could decline throughout infection \\[[@CR21]\\]. The resulting 'Atlantic"
+"1. Introduction {#sec1}\n===============\n\nEndometriosis is a benign but potentially debilitating gynecologic disorder affecting 10% to 15% of patients during their reproductive life \\[[@B1]\\]. It is a well-known cause of chronic pelvic pain, dysmenorrhea, and dyspareunia affecting quality of life (QOL) \\[[@B2]--[@B4]\\]. There are three types of endometriosis defined by the presence of endometrial glands and stroma outside the uterus: the peritoneal, the ovarian, or the deep infiltrating endometriosis (DIE); this latter type is characterized by involvement of organs and pelvic anatomic structures by endometriotic lesions.\n\nSpecific multidimensional questionnaires to evaluate QOL in patients with endometriosis have been developed---by Bodner et al. in 1997 \\[[@B2]\\], Colwell et al. in 1998 \\[[@B3]\\], and Jones et al. in 2001 \\[[@B4]\\]---but have only been validated in English. Nonspecific multidimensional QOL questionnaires such as the short form health survey SF-36 have also been developed and validated in various languages allowing comparison between countries \\[[@B5], [@B6]\\]. Despite the absence of specificity for the population of patients with endometriosis, the SF-36 questionnaire has been demonstrated to be a useful tool to select patients with colorectal endometriosis for surgery and to evaluate long-term functional results \\[[@B7]--[@B9]\\]. However, both the SF-36 and the Endometriosis Health Profile-30 (EHP-30) questionnaire"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec005}\n============\n\nLaparoscopic surgery has become increasingly prevalent in diverse major surgical procedures. Moreover, the patients indicated for laparoscopic surgery have become older and have more comorbidities, such as cardiovascular disease with a high illness severity in some patients, than before \\[[@pone.0142125.ref001]\\]. Therefore, it might be a substantial issue to monitor the cardiovascular function in those patients in order to achieve appropriate management and finally favorable outcomes. The FloTrac/Vigileo^\u2122^ system (Edwards Lifesciences, Irvine, CA, USA) could be selected for such a purpose, given its accessibility and safety. However, the performance of this system to measure the stroke volume (SV) and track changes in the SV during laparoscopic surgery has not been identified.\n\nThe arterial tone should be considered for the FloTrac/Vigileo^\u2122^ system to be adequately used in a specific condition that can alter the arterial tone, because this system does not conduct external calibration \\[[@pone.0142125.ref002]\\]. The FloTrac/Vigileo^\u2122^ system has been tried to show a reliable performance for variable arterial tones. Although the third-generation FloTrac/Vigileo^\u2122^ system was developed using a large data set, including septic and liver cirrhosis patients, it still shows an unacceptable performance in the subset"
+"Introduction\n============\n\nSolitary plasmacytomas (SPs) are rare and are characterized by a localized accumulation of neoplastic monoclonal plasma cells, without proof of systemic myelomatosis. The tumors represent \u22645% of all plasma cell neoplasms ([@b1-ol-09-01-0191]) and mostly occur in the spine, pelvis, ribs and pectoral girdle ([@b1-ol-09-01-0191]--[@b3-ol-09-01-0191]), while rarely occurring in the sternum. Radiologically, SP of the bone typically appears as an osteolytic lesion; the tumor usually destroys the cortex in several places and invades the soft tissues ([@b2-ol-09-01-0191],[@b4-ol-09-01-0191]). In rare cases, the radiological findings may take unusual forms, for example, they can manifest as bony spicules on the surface of the bone, which resemble the appearance of sunrays ([@b5-ol-09-01-0191]--[@b12-ol-09-01-0191]). The sites of bony spiculation in the lesions previously described in the literature are the mandible, orbit, vertebral body and skull vault ([@b5-ol-09-01-0191]--[@b12-ol-09-01-0191]).\n\nThe current study presents a case of a solitary plasmacytoma of the sternum with a spiculated periosteal reaction on radiological imaging. Written informed consent was obtained from the patient.\n\nCase report\n===========\n\nA 74-year-old female presented with neck and anterior chest wall pain, along with swelling in the chest area that had persisted for one month. The past medical history consisted of type II diabetes mellitus and hypertension."
+"Introduction {#s1}\n============\n\nThe term \"myopathies\" encompasses a wide spectrum of childhoodand adulthood, acquired and inherited diseases affecting skeletal muscle whose main feature is muscle weakness. Other features that may be variably associated are muscle pain, contractures, exercise intolerance, myoglobinuria, and multi system involvement i.e., heart, liver, central, and peripheral nervous system ([@B1]).\n\nThe diagnosis of myopathy has been traditionally based on the clinical, electromyography and muscle biopsy findings, which indicated the subsequent genetic investigations.\n\nCurrently, however, there is a large availability of other powerful diagnostic technologies, especially in the field of genetics, which have widely changed our approach to the diagnosis of muscle diseases. The possibility to broadly study patients\\' genomes through Next Generation Sequencing (NGS), approaches such as Whole Exome Sequencing (WES) and Whole Genome Sequencing (WGS) are already revolutionizing the entire diagnostic process, allowing us to detect several molecular changes whose role and pathogenicity need to be evaluated in the specific clinical context ([@B2]).\n\nIn the last years, magnetic resonance imaging (MRI) has become a very powerful tool to improve our capability of diagnosing muscle diseases because it can show the severity and distribution of tissue damage in different muscles of the body or within a single"
+"Introduction\n============\n\nNeuroretinitis is a disease entity in which there is an inflammatory disorder characterized by optic disc edema and macular star.[@b1-imcrj-8-255] It was originally described by Leber[@b2-imcrj-8-255] in 1916 as stellate maculopathy, but Don Gass[@b3-imcrj-8-255] in 1977 found it to be due to leakage from the optic disc. The underlying pathophysiology involves increased permeability of disc vasculature with exudation of fluid into the peripapillary retinal.[@b4-imcrj-8-255] It can be caused by infection or can be idiopathic. Common infections that cause neuroretinitis are cat scratch disease (CSD), syphilis, burkholderia, and leptospirosis.[@b4-imcrj-8-255],[@b5-imcrj-8-255] Other causes include toxoplasmosis, tuberculosis, and histoplasmosis.[@b5-imcrj-8-255],[@b6-imcrj-8-255] It is rarely caused by nematodes or diffuse unilateral subacute neuroretinitis (DUSN).[@b7-imcrj-8-255] Hence, a complete diagnostic examination in patients presenting with acute neuroretinitis should include a thorough history and general medical evaluation. Exposure history should be thoroughly explored, including details about recent travel, unpasteurized and uncooked foods consumed, sexual experience, and animal contacts. Detailed physical examination and laboratory tests tailored to the history and examination should be performed to aid in diagnosis.\n\nWe report a case of neuroretinitis, which involved two pathogens and discuss its features on presentation as well as serological importance in detecting the underlying pathogens.\n\nCase report\n===========\n\nA 22-year-old"
+"Background\n==========\n\nLesions of the \\'tail\\' of the parotid gland are difficult to assess clinically and provide a diagnostic dilemma on imaging, especially in the axial plane. Pedunculated lesions of the \\'tail\\' of parotid can be mistaken for an extra parotid lesion. Accurate localisation of these lesions on imaging is essential to assist the clinical diagnosis, to prevent inadequate/incomplete excision and complications, especially damage to facial nerve.\n\nIn this case report, we present a case of a pleomorphic adenoma arising from the \\'tail\\' of the parotid gland, which on imaging, appears to be extra parotid in location. We also review the anatomy of the parotid \\'tail\\' and relevant literature.\n\nCase report\n===========\n\nA 65 yr old female presented to the Ear Nose and Throat \\[ENT\\] clinic of our institution with a one-month history of a lump in the right neck. On examination, a mobile lump was palpable in the angle of the mandible/upper cervical region. A flexible endoscopy did not reveal any mucosal lesion in the posterior nasal space, oropharynx, hypo pharynx or in the larynx. Clinically a lymph node mass was considered as a possible diagnosis. Fine needle aspiration \\[FNA\\] and Magnetic Resonance Imaging \\[MRI\\] were then performed.\n\nMRI"
+"INTRODUCTION\n============\n\nIn dim anoxic waters of stratified lakes where oxygen-respiring organisms normally cannot survive, a tiny aerobic eukaryote nevertheless makes a living. This heterotrophic ciliate, *Histiobalantium natans*, can survive without external oxygen because it sequesters chloroplasts from ingested euglinoid flagellates (*Phacus suecicus*). The chloroplasts, kept active in the ciliate and surrounded by the mitochondria, photosynthesize and produce oxygen that allows the host to thrive in deep waters of stratified lakes, where it avoids metazoan predation and competition with other aerobic ciliates ([@B16]). This is just one example of nature's many twists that allow organisms to take a specific niche: If an essential compound is not available, make it yourself by inventing a variation on a general theme.\n\nFor a long time, photosynthesis was the only biological process known to produce oxygen. Cyanobacteria, green plants, and algae use light energy to split water$\\left( {E_{0}}^{\\prime} = + 0.82V \\right)$ via photosystem II. The electrons obtained serve NADPH and ATP generation for carbon dioxide fixation; oxygen is a mere by-product of this metabolism. This pathway evolved at least 2.7 billion years ago ([@B6]), and, after the vast pools of reduced compounds on early earth were exhausted, oxygen started to accumulate in the"
+"Introduction\n============\n\nAppendiceal adenocarcinoma is a rare malignancy, accounting for only 0.5% of all gastrointestinal malignancies ([@B1]). A mucinous type of appendiceal adenocarcinoma (MAA) is frequently accompanied by mucocele ([@B2]). The tumor itself is not aggressive; however, the disease has an unfavorable prognosis due to the absence of specific symptoms and the potential of tumor rupture, resulting in difficulty achieving an early diagnosis ([@B3]-[@B5]). Mucocele rupture leads to pseudomyxoma peritonei (PMP), which is the dissemination of malignant cells in the intraperitoneal cavity ([@B6]). Fistula formation into adjacent organs is an unusual presentation of MAA. Although some authors have reported that fistula formation might improve the patient outcome by preventing the development of PMP ([@B7], [@B8]), the prognosis of such cases remains unclear.\n\nWe herein report a case of MAA with fistula formation and review the pertinent literature to discuss the clinical features and prognostic impact of this rare manifestation.\n\nCase Report\n===========\n\nA 90-year-old man with no significant medical history was referred to our hospital for a positive fecal occult blood test (FOBT). No remarkable findings were noted in a physical examination. A laboratory analysis revealed a slightly decreased level of hemoglobin (12.7 g/dL; normal range 13.4-17.6 g/dL). Tumor markers"
+"In a recent study Soon et al. ([@B16]) predicted abstract intentions from fMRI BOLD activities in localized areas of the brain. Activities in a spherical cluster of voxels served as input to a multivariate pattern classifier (linear SVM). The accuracy for predicting the intention to add or subtract two numbers was determined for clusters centered on different voxels. A prediction accuracy of 60% averaged across participants and based on 10-fold cross-validation was achieved for patterns of voxel activities in the *medial frontopolar cortex* and *precuneus* up to 4 s *before* participants reported being consciously aware of their decision. The prediction accuracy in this study was similar to studies on predicting spontaneous left or right motor decisions (Soon et al., [@B15]; Bode et al., [@B1]). Since the task demands placed on the participants create similar methodological issues as in previous studies (Lages and Jaworska, [@B10]), it seems possible that the multivariate classifier picked up sequential information processing between trials (Bode et al., [@B2]).\n\nAlthough the average prediction accuracy of 60% returned to chance level for patterns of voxel activity in the two brain areas shortly after the onset of a new trial and remained at 50% between trials, this observation is"
+"Background {#Sec1}\n==========\n\nIn recent years, it is emphasized that consuming the organic food is associated with a healthier lifestyle. Thus, new food consumption trends indicate that people are interested in freshly produced organic foods. Among them, the consumption of fresh cut or minimally-processed fruit and vegetables have undergone a sharp increase. Such trends have been reflected in an increase in the popularity of salad bars in many countries \\[[@CR1]--[@CR3]\\]. In terms of retail, vegetables can be sold intact or minimally processed to provide a ready-to-eat product and can be contaminated at any point in the chain, starting from the farm to the plate. As they are not subjected to any treatment to eliminate pathogens, a diverse range of human enteric pathogens can contaminate them. There are a number of reports showed the correlation between foodborne illness outbreaks and the consumption of raw vegetables, annually \\[[@CR4], [@CR5]\\]. Several bacterial pathogens have been implicated in foodborne illnesses associated with the consumption of raw vegetables, such as *Salmonella* spp., thermo-tolerant *Campylobacter*, *Listeria monocytogenes*, and certain enteric viruses \\[[@CR6]\\]. These may contaminate vegetables during any stage of production. The yearly average frequency of foodborne outbreaks linked with fresh produce contamination between 2002 and"
+"Introduction\n============\n\nComplex fractures of the tibial plateau commonly occur in patients following high-energy trauma, typically accompanied by severe damage to the knee articulation and the surrounding tissues. The diagnosis and treatment of complex tibial plateau fractures remains a significant challenge in orthopedic trauma ([@b1-etm-07-01-0199],[@b2-etm-07-01-0199]). In the past, normal X-ray films were applied in the Schatzker classification of tibial plateau fractures; however, the information provided by the normal films is limited and does not satisfactorily assist clinical orthopedic physicians in the diagnosis and treatment process. In the present study, images from X-ray films, multidetector-row computed tomography (MDCT) and magnetic resonance imaging (MRI) were systematically analyzed and various indices, such as fracture location, displacement degree, degree of comminution and degree of joint surface collapse were analyzed. The ability to identify injuries to the menisci of the knee joint and cruciate and collateral ligaments, as well as insidious fractures, preoperatively to enable a precise diagnosis and the appropriate surgical treatment was evaluated. A total of 71 patients with complex fractures of the tibial plateau who were admitted to hospital from March 2004 to January 2009 were included in the study and their treatment and its effects are reported.\n\nPatients and methods\n===================="
+"Introduction {#Sec1}\n============\n\nGeographical separation and extreme climates have resulted in the long isolation of Antarctica and the subantarctic islands. The result is a unique assemblage of animals, some relying entirely on the frozen continent, with others utilising the fringes. Such geographic isolation has been proposed to explain why Antarctic fauna supposedly harbour a paucity of viruses, and is supported by the observation that captive Antarctic penguins are highly susceptible to infectious disease \\[[@CR1]\\]. It has therefore been hypothesised that Antarctic fauna have evolved in a setting of low \"pathogen pressure\", reflected in limited microbial diversity and abundance \\[[@CR1], [@CR2]\\]. As a consequence, the potential for climate driven and human mediated movement of microorganisms makes the expansion of infectious diseases to the Antarctic a matter of concern \\[[@CR1], [@CR3]--[@CR5]\\].\n\nTo date, a small number of viral species have been described in Antarctic fauna \\[[@CR6]\\]. Serological studies have revealed that Antarctic penguins are reservoirs for influenza A virus (IAV), avian avulaviruses (formerly avian paramyxoviruses), birnaviruses, herpesviruses, and flaviviruses \\[[@CR7]--[@CR13]\\]. Despite improvements in the molecular tools for virus detection, it is only in recent years that full viral genomes have been characterised \\[[@CR6]\\]. For example, adenoviruses, astroviruses, paramyxoviruses, orthomyxoviruses, polyomaviruses, and papillomavirus"
+"Introduction {#Sec1}\n============\n\nTreatment resistance to pharmacotherapy in bipolar disorder is unfortunately common across all phases of the illness (Thirthalli et al. [@CR64]). Treatment resistance to pharmacotherapy is dependent on the phase of illness and has multiple definitions and thresholds. In the context of bipolar depression, treatment resistance is commonly defined as a failure of two antidepressant trials with concurrent treatment with a mood stabilizer (Gitlin [@CR20]). Despite optimal treatment in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), 25% of the bipolar subjects failed to achieve symptom remission in 2\u00a0years of follow-up (Perlis et al. [@CR43]). Treatment resistance and acuity are common indications for electroconvulsive therapy (ECT) in bipolar patients. ECT is effective in mania, mixed, and depressed states of bipolar disorder as well as maintenance phases of treatment (Medda et al. [@CR38]). Despite the overwhelming effectiveness as a true mood stabilizer, patients and clinicians do not consider ECT earlier in the treatment algorithm because of the risk of neurocognitive impairment (Thirthalli et al. [@CR64]; MacQueen et al. [@CR33]; UK ECT Review Group [@CR65]). The risk of ECT-mediated neurocognitive impairment is related to both patient (age, medical comorbidities, cognitive reserve) and treatment related factors (electrode placement, stimulation"
+"INTRODUCTION {#sec1-1}\n============\n\nOral mucositis as a consequence of cytotoxic therapy is a major cause of morbidity and dose-limiting toxicity in cancer patients. It was reported in up to 90% of patients after somatotoxic chemotherapy.[@ref1] Moreover, the duration and severity of that complication is strikingly associated with high-dose chemoradiotherapy and hematopoietic stem-cell transplantation.[@ref2]--[@ref4] The pain in mucositis is usually intensively excruciating and may lead to weight loss from odynodysphagia. Furthermore, the breakdown of the mucosal epithelium barrier exposes cancer patients to infection and subsequent septicemia particularly in association with chemotherapy-induced neutropenia.[@ref5][@ref6] On the other hand, neutropenia and local secondary infection can also aggravate oral mucositis after chemotherapy. Moreover, severe sloughing of the oral mucosa may lead to airway compromise and may necessitate parenteral nutrition.\n\nThe efficacy of recombinant human hematopoietic growth factors in improving the neutropenic state is well documented.[@ref7]--[@ref11] Recently, a coincidental 75% decrease in oral mucositis associated with granulocyte colony-stimulating factor (G-CSF) and methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy of genitourinary cancer was first reported by Gabrilove et al.[@ref12] The mucosal protection effects of G-CSF of granulocyte-macrophage colony-stimulating factor (GM-CSF) were also observed in other chemotherapy regimens.[@ref13]--[@ref16] One report showed a lowered incidence of oral mucositis when"
+"Tuberculosis (TB) is a leading cause of death worldwide. According to a recent report by the World Health Organization (WHO), TB killed 1.5 million and caused illness in 9.6 million people in 2014. Bacille Calmette-Gu\u00e9rin (BCG) is the only licensed vaccine against TB. Although it is effective at reducing disseminated forms of TB (e.g., miliary TB and tubercular meningitis) in children[@b1][@b2], BCG has highly variable efficacy (0--80%) against adult pulmonary TB[@b3][@b4], the most contagious form of the disease. Another concern with BCG is its safety in immunocompromised individuals. Disseminated BCG disease has been observed in HIV-infected children following BCG vaccination[@b5], and the risk outweighs the benefit of TB prevention[@b5][@b6]. In 2007, the WHO revised its recommendation and declared that HIV infection is a contraindication for giving BCG[@b7]. In light of this, there is an urgent need to develop a more effective and safe TB vaccine.\n\nOne hypothesis to account for the highly variable protective efficacy of BCG observed in clinical trials concerns the heterogeneity of BCG strains[@b8]. Although colloquially referred to as BCG, there are a number of BCG substrains that have been used in different vaccination programs[@b9][@b10]. Genetic differences including deletions and duplications of genomic regions and single nucleotide"
+"**Author Information** An event is serious (based on the ICH definition) when the patient outcome is:\\* death\\* life-threatening\\* hospitalisation\\* disability\\* congenital anomaly\\* other medically important event\n\nA 39-year-old man developed severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) during treatment with mycophenolate mofetil, prednisone and tacrolimus as immunosupression therapy \\[*routes not stated; not all dosages stated*\\].\n\nThe man with a history of idiopathic dilated cardiomyopathy and chronic kidney disease, and underwent combined heart/kidney transplant in 2017, presented for COVID-19 testing. He had symptoms of fever, headache, dyspnoea, fatigue, sore throat, dry cough and myalgia. On the nest day of the testing, he was found positive for COVID-19. As the symptoms were minimal, he was quarantined at his home. On the next day, his symptoms worsened. Therefore, he was advised to return to the hospital for further evaluation. Previously, he had antibody-mediated cardiac graft rejection, which was being treated with methylprednisolone, plasmapheresis, IV immunoglobulin \\[Gamunex\\] and antithymocyte-globulin \\[rabbit anti-thymocyte globulin\\]. He had completed this treatment approximately 8\u00a0months prior to the admission. His history was significant for poorly controlled insulin-dependent diabetes mellitus, morbid obesity, hypertension and chronic diabetic foot ulcers. Upon his repeat presentation, he had headache, fatigue and dyspnoea. He was afebrile,"
+"INTRODUCTION {#s1}\n============\n\nKLF4, a member of the kr\u00fcppel-like factor (KLF) transcription factor family, is a potential tumor suppressor in several types of human malignancies \\[[@R1]--[@R4]\\]. For instance, KLF4 was significantly down-regulated in prostate cancer cell lines compared with nontumorigenic prostate cells \\[[@R5]\\]. RNA activation-mediated overexpression of KLF4 inhibited prostate cancer cell proliferation and altered the expression of several downstream cell-cycle-related genes \\[[@R5]\\]. Besides, ablation of KLF4 in gastric progenitor cells promoted transformation of the gastric mucosa and tumorigenesis in the antrum in mice \\[[@R6]\\]. Moreover, KLF4 protein expression was decreased or lost in hepatocellular carcinoma (HCC) tissues and, in particular, lymph node metastases when compared with that in normal liver \\[[@R7]\\]. Deficiency of KLF4 expression was significantly associated with poor survival, and also a prognostic marker in HCC patients \\[[@R7]\\]. Indeed, KLF4 could inhibit cell proliferation, invasion and epithelial to mesenchymal transition (EMT) through up-regulation of vitamin D receptor (VDR) and repression of \u03b2-catenin and SLUG, respectively \\[[@R7]--[@R10]\\]. However, the molecular mechanisms for the down-regulation of KLF4 in HCC tissues remain poorly understood.\n\nIt has been shown that KLF4 protein could be regulated by acetylation, phosphorylation and sumoylation \\[[@R11]--[@R14]\\]. More importantly, Lim KH et al. reports that KLF4 undergoes"
+"Massive irreparable cuff tears may represent as high as 20% to 40% of total cases of operated rotator cuff tears (RCTs) and can be a challenging clinical problem.[@bib1] Massive cuff tear is not synonymous with irreparable cuff tear, which is different from pseudo-paralytic shoulder.[@bib2] Massive tears are defined as lesions with diameters \\>5\u00a0cm or the involvement of 2 or more tendons. Irreparable tears can be also defined as stage 3 tendon retraction according to Patte, stage 3 or 4 fatty infiltration as described by Goutallier et\u00a0al., stage 3 muscle atrophy according to Thomazeau et\u00a0al., or superior escape of the humeral head with a subacromial distance \\<6\u00a0mm, Hamada stage 3 with acetabulization of the acromion, failed previous cuff repair, or inability to anatomically repair the cuff after full arthroscopic release.[@bib2], [@bib3], [@bib4], [@bib5]\n\nPseudo-paralytic shoulder was redefined by Burks et\u00a0al.[@bib2]^,^[@bib6] as the association of a normal passive range of motion (no stiffness) with no active forward flexion (FF; \\<45\u00b0) or limited active external rotation and/or internal rotation.[@bib2]\n\nMany treatment options have been proposed to manage irreparable RCT including debridement with subacromial bursectomy[@bib7] and/or tenotomy or tenodesis of the long head of the biceps,[@bib8]^,^[@bib9] partial repair of"
+"Background\n==========\n\nDietary strategies may prevent childhood allergies and reduce the burden of disease. We undertook this systematic review to evaluate the relationship between maternal diet and childhood allergies.\n\nMethods\n=======\n\nWe included studies published up to August 2011 which compared a food-based maternal dietary intervention (intake during pregnancy &/or lactation) with another intervention or no intervention, as well as studies examining associations between maternal dietary intake during pregnancy &/or lactation and allergic outcomes in their children from the index pregnancy. Primary outcomes included child eczema, asthma, hayfever and sensitization (to food or environmental allergens). Studies assessing dietary supplements were not eligible for inclusion, nor were studies where dietary intakes were expressed only in terms of nutrients. Studies exclusively investigating maternal nut and peanut consumption during pregnancy &/or lactation were excluded.\n\nResults\n=======\n\n43 studies were included in this systematic review: 11 intervention studies, 27 prospective cohort studies, four retrospective cohort studies and one case-control study. In the RCTs no significant difference was noted overall in the prevalence of eczema and asthma in the offspring of women on diets free from common food allergens during pregnancy. One study (with multiple interventions) reported a lower rate of sensitisation in the intervention"
+"Background {#Sec1}\n==========\n\nMany insects harbor symbiotic bacteria in their gut, body cavity, and/or cells \\[[@CR1]\\]. Some bacterial symbionts are indispensable for the growth, survival, and reproduction of their insect hosts through synthesizing essential nutrients \\[[@CR2], [@CR3]\\], assisting food digestion \\[[@CR4], [@CR5]\\], or providing food sources \\[[@CR6], [@CR7]\\]. Other bacterial symbionts are not essential, but nonetheless influence a variety of host biological traits, such as susceptibility to natural enemies \\[[@CR8], [@CR9]\\], tolerance to environmental stresses \\[[@CR10], [@CR11]\\], resistance to noxious chemicals \\[[@CR12], [@CR13]\\], adaptation to specific food plants \\[[@CR14], [@CR15]\\], or sex ratios and related reproductive traits \\[[@CR16], [@CR17]\\]. The most intimate host--symbiont associations often involve development of a specific symbiotic organ, called the bacteriome, consisting of specialized cells for symbiosis, called the\u00a0bacteriocytes, the cytoplasm of which harbors symbiotic bacteria \\[[@CR1], [@CR18], [@CR19]\\].\n\nBeetles, comprising the largest insect order Coleoptera, are characterized by sclerotized exoskeleton, including thick and hard forewings, known as elytra \\[[@CR20]\\]. Some beetles cause significant damage to stored cereals, beans, seeds, spices, dried fruits, and other durable commodities, and are thus regarded as stored-product pests \\[[@CR21], [@CR22]\\]. Probably relevant to their peculiar ecological niche, namely continuous living on non-fresh and monotonous food sources under low-humidity conditions,"
+"Introduction\n============\n\nBifidobacteria are ideal hosts for food-grade delivery of useful enzymes. Strong promoters can regulate high-level gene expression thereby improving the efficiency of microbial cell factories. However, most of those finely defined promoters that had been used in other hosts cannot be readily applied in bifidobacteria ([@B30]). Therefore, researchers turn to isolate promoters from bifidobacteria themselves ([@B32]). The housekeeping gene glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is widely expressed in both prokaryotic and eukaryotic cells. Therefore, its promoter P*~gap~* was cloned and showed strong capacity for driving high-level expression of several proteins ([@B15]; [@B12]; [@B20],[@B21]). Our previous study revealed that P*~gap~* works in three species of *Bifidobacterium* ([@B29]). However, proteomic studies suggest that proteins of elongation factor Tu and groEL are more abundantly expressed than GAPDH in many bacteria, including *B. longum* NCC2705 and *B. bifidum* S17 ([@B18]; [@B35]). Hence, their promoters may be stronger than P*~gap~*. *B. longum* JCM 1217 (also known as ATCC 15707) is a typical probiotic strain that protects host from enteropathogenic infection (*Escherichia coli* O157:H7) through production of acetate ([@B5]). The strain also reduced biofilm formation in pathogenic *E. coli*, reduced colitis in rats, and increased survival rate of *Clostridium difficile* infection in mice ([@B14]; [@B2]; [@B37])."
+"Introduction {#Sec1}\n============\n\nAlternative metrics (altmetrics) is a new fast-moving area in scientometrics (Galloway et al. [@CR16]). Initially, altmetrics---a collection of many web-based indicators---have been proposed as a supplement to traditional bibliometric indicators. They measure attention related to research papers on internet platforms. The core of altmetrics is gathered from social media platforms, but mentions in mainstream media or in policy documents also belong to the umbrella term altmetrics (National Information Standards Organization [@CR29]; Work et al. [@CR45]). According to Haustein ([@CR22]), sources of altmetrics can be grouped into (i) social networks, (ii) social bookmarks and online reference management, (iii) social data (e.g., data sets, software, presentations), (iv) blogs, (v) microblogs, (vi) wikis, and (vii) recommendations, ratings, and reviews.\n\nRecently, some indicators based on altmetrics have been proposed which are normalized with respect to the scientific field and publication year. These indicators were developed because studies have shown that altmetrics are---similar to bibliometric data---field- and time-dependent (see, e.g., Bornmann [@CR4]). Some fields are more relevant to the general public or a broader audience than other fields (Haustein et al. [@CR23]). The Mean Normalized Reader Score (MNRS) was introduced by Haunschild and Bornmann ([@CR19]) for normalization of data from social bookmarks"
+"Introduction {#Sec1}\n============\n\nIn Western-Turkey, Barcin Hoy\u00fck is a 8500\u00a0year old Neolithic mound (6500\u00a0cal BC) which has been (geo-) archaeologically explored over the past years (*3*. in Fig. [3](#Fig3){ref-type=\"fig\"}; Gerritsen et al. [@CR9], [@CR10]; Groenhuijzen et al. [@CR11]). It is the oldest Neolithic site in the region, making it of particular interest regarding the spread of farming from the regions of origin (southeast and central Anatolia) to northwest Anatolia (Fig.\u00a0[1](#Fig1){ref-type=\"fig\"}). The Neolithic settlers used a natural elevation to found their first dwelling place in a generally wet marshy environment, situated on the margin of a retreating lake and likely in the vicinity of a natural stream (Groenhuijzen et al. [@CR11]). A position at the junction of a river or stream and a lacustrine water body demonstrates the strategic importance of a multiple land--water gradient (land--lake and land--river).Fig.\u00a01The Neolithic mound of Barcin H\u00f6yuk, western Turkey: a seven meter high elevation of cultural layers for more than 7000\u00a0years (*photo* F. Gerritsen)\n\nThis example suggests that a gradient driven selection procedure was used by the first settlers. In such a selection procedure humans favour locations that are located on land--water divides---'landscape gradients'. On the long term these gradients"
+"Introduction {#s1}\n============\n\nOesophageal cancer is the third most common malignancy of the digestive tract and the seventh leading cause of cancer-related deaths worldwide [@pone.0029366-Howlader1]. Cancer of the esophagus exists in two main forms with different etiological and pathological characteristics: oesophageal squamous cell carcinoma (OSCC) and oesophageal adenocarcinoma (OADC). OSCC is the predominant histological subtype in developing countries [@pone.0029366-Day1] and occurs at higher frequencies in Southern and Eastern Africa, Northern China and the central Asian belt from Turkey through Iran, Iraq and Kazakhstan [@pone.0029366-Ferlay1]--[@pone.0029366-Kamangar1]. In South Africa it is one of the most common malignancies and the most common cancer among Black males, with a variable incidence rate among regions [@pone.0029366-Venters1]. The regional difference in the frequency of OSCC is probably due to genetic polymorphism and variable exposure to environmental factors, including nutritional factors that are associated with the development of this disease [@pone.0029366-Hendricks1]. Epidemiological studies have also identified smoking and alcohol consumption as major risk factors associated with OSCC [@pone.0029366-Dlamini1]--[@pone.0029366-Freedman1]. Our studies have shown that genetic polymorphisms in the alcohol metabolizing enzymes (*ADH2\\*1* and *ADH3\\*2*) and detoxification enzymes (*SULT1A1*, *CYP3A5* and *P450 2E1*) are associated with susceptibility to OSCC in the South African population [@pone.0029366-Li1]--[@pone.0029366-Li3].\n\nThe Glutathione S-transferases (GSTs)"
+"Introduction {#s1}\n============\n\nOroxylin A (C~16~H~12~O~5~, [Figure S1](#pone.0069555.s001){ref-type=\"supplementary-material\"}) is one of the main bioactive compounds purified from the root of the medicinal herb *Scutellaria* *baicalensis* Georgi that has been widely used in China, Japan, and Korea for treating inflammation and infections in the respiratory and gastrointestinal system \\[[@B1]\\]. Although many biological activities of Oroxylin A, including anti-tumor \\[[@B2],[@B3]\\], anti-bacterial \\[[@B4]\\], and cognitive enhancement \\[[@B5]\\], have been reported, the underlying molecular mechanisms are largely unknown.\n\nOroxylin A is a natural flavonoid, and flavonoids are a class of polyphenolic compounds. Studies from our group and others have showed that some flavonoids have estrogenic activity \\[[@B6]--[@B10]\\] and thus, are named phytoestrogens. Whether Oroxylin A is also a phytoestrogen remains to be determined.\n\nThe effects of estrogen and phytoestrogens are mediated through two well-characterized intracellular receptors, estrogen receptor (ER) \u03b1 and \u03b2 \\[[@B11],[@B12]\\]. ERs are members of the nuclear receptor superfamily and act as a ligand-activated transcription factors to regulate the expression of target genes. They are expressed in various immune cells, including macrophages \\[[@B13],[@B14]\\] that play a critical role in many inflammatory diseases by expressing pro-inflammatory mediators, including tumor necrosis factor (TNF)-\u03b1, Interleukin (IL)-1, interleukin (IL)-6, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase"
+"Knowledge of plant and environmental factors determining photosynthesis by submerged plants is essential for understanding aquatic plant ecophysiology and ecosystem productivity, as well as submergence tolerance of terrestrial plants. Following the pioneering studies by Arens ([@B3]) and Steemann Nielsen ([@B103]) on the use of dissolved inorganic carbon (DIC) for photosynthesis of aquatic plants, numerous studies on the regulatory role of light and DIC for underwater photosynthesis of aquatic plants have been conducted. Particularly, the use of DIC by aquatic plants has fascinated researchers and been reviewed several times (e.g., Madsen and Sand-Jensen, [@B44]; Maberly and Madsen, [@B39]; Raven and Hurd, [@B73]) because this process is important for growth and survival and the uptake mechanisms are very different from those of terrestrial, amphibious, and floating leaved plants exposed to atmospheric air (definitions of these life forms and examples of species are in Sculthorpe ([@B93])). Since the physical conditions differ markedly between water and air, we have often been approached by researchers asking for practical advice, unavailable in the literature, before engaging in work with underwater photosynthesis. Thus, this review serves to offer the background and a practical guide for measurements of carbon fixation by plants when under water.\n\nMoreover, a growing"
+"Introduction\n============\n\nLeishmaniasis is a neglected tropical diseases caused by the *Leishmania* species, and covers a disease spectrum from a self-resolving cutaneous ulcer by *L. aethropica* and *L. tropica* complex in Old World and *L. mexi*c*ana* complex in the New World to a mutilating mucocutaneous due to *L. braziliensis* complex disease or a lethal visceral systemic illness due to species of the *L. donovani* complex ([@B1]--[@B3]). Approximately, 0.2 to 0.4 million of new visceral leishmaniasis (VL) cases and 0.7 to 1.2 million of new cutaneous leishmaniasis (CL) cases occur each year worldwide ([@B4]). The annual incidence of CL in Iran is estimated at approximately 20000 new cases, whereas this value for VL is much lower, approximately 100--300 new cases in endemic area ([@B5]).\n\nThe first-choice procedure for the diagnosis of CL is the microscopic demonstration of the *Leishmania* organism in the lesion aspirate, scraping, or biopsy specimen ([@B6]). However, the accuracy of microscopic examination is associated with various criteria including ability of the laboratory technician and the quality of the used reagents ([@B7]). Moreover, low and variable sensitivity and the need for invasive sampling techniques are major problems in such conventional methods. The routine methods for diagnosis of VL are"
+"Introduction\n============\n\nThe implementation of quality programs^[@r01]^ in public and private health services, as well as its increase in those that are already in course, is growing in Brazil. The adoption of indicators as tools for control of programs is necessary in this context, but the institutions, due to their complexities and multiple subdivisions, not always present specific indicators for each one of their areas. The search for quality requires that assessment tools should exist in each subdivision of a complex of health. Except for clinical laboratories and pathology anatomy that for years have indicators in their processes, there is a shortage of them to other areas of diagnostic medicine^[@r02]^. Particularly, in the context of the ergometric tests, it was not possible to find the proposition of indicators for this area in indexed publications. Whereas examination is noninvasive, but of risk, and it requires the informed consent form for its conduction, one deducts that tools of quality control can be useful and should be implemented.\n\nIn recent years, publications of Guidelines for medical practice, by specialty societies, have been increasing. The adoption of its recommendations has been strongly encouraged by representing the synthesis of reviews and analyzes of the available"
+"INTRODUCTION\n============\n\nAlthough the abundance of messenger RNAs (mRNAs) in the cell is the net result of mRNA synthesis and degradation, expression profiling experiments usually take a snapshot of the mRNA levels in the cell and do not capture the dynamics of mRNA synthesis and breakdown. This lack of information on the dynamic component of the regulation of mRNA levels limits biological investigations in general and proper modeling of transcriptional networks in systems biology approaches in particular. When mRNA synthesis is shut down completely, the effect may be immediate for very short-lived mRNAs but only manifest after hours or days for mRNAs with long half lives. The current study fills in part of this gap and surveys mRNA degradation rates during muscle differentiation on a genome-wide scale. With the availability of these data, the genetic network orchestrating muscle differentiation can be revised and improved.\n\nFrom the results of previous genome-wide analyses of mRNA degradation rates, we know that there are large differences between the stabilities of individual mRNAs, and that mRNA stability is strongly related to the molecular function of the encoded protein ([@B1; @B2; @B3; @B4; @B5; @B6; @B7; @B8]). However, the mechanisms underlying differential stability of transcripts remain"
+"1. Introduction {#sec1}\n===============\n\nIn the treatment of critically ill and/or injured patients, it is important to detect those who are at high risk for lethal outcome. Major determinant of outcome is intensity of insult (infection, trauma) as well as immunoinflammatory response \\[[@B1], [@B2]\\]. It is difficult to find adequate biomarker of immune response in critical illness, regardless of its cause, with good predictive value regarding outcome because there is wide and complex array of immune-related mediators. Many of them were explored in this clinical setting with contradictory results. Recently, some readily available parameters, originated from routine complete blood count (CBC), have been investigated as potential biomarkers with mixed results and no consensus so far regarding its accuracy and clinical usefulness: neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and mean platelet volume-to-platelet count (MPV/PC) ratio \\[[@B3]--[@B6]\\].\n\nBearing in mind how intertwined immune and coagulation cascades are, the aim of our prospective observational study was to assess the prognostic value of NLR, MLR, PLR, and MPV/PC ratio regarding outcome in a cohort of critically ill patients with secondary sepsis and/or trauma. Outcome measure was hospital mortality. Our secondary endpoint was to assess possible differences of these biomarkers regarding different"
+"Introduction {#Sec1}\n============\n\nApart from its remarkable success to interpret cosmological observations, the $\\documentclass[12pt]{minimal}\n                \\usepackage{amsmath}\n                \\usepackage{wasysym} \n                \\usepackage{amsfonts} \n                \\usepackage{amssymb} \n                \\usepackage{amsbsy}\n                \\usepackage{mathrsfs}\n                \\usepackage{upgreek}\n                \\setlength{\\oddsidemargin}{-69pt}\n                \\begin{document}$$\\Lambda $$\\end{document}$-cold dark matter ($\\documentclass[12pt]{minimal}\n                \\usepackage{amsmath}\n                \\usepackage{wasysym} \n                \\usepackage{amsfonts} \n                \\usepackage{amssymb} \n                \\usepackage{amsbsy}\n                \\usepackage{mathrsfs}\n                \\usepackage{upgreek}\n                \\setlength{\\oddsidemargin}{-69pt}\n                \\begin{document}$$\\Lambda $$\\end{document}$CDM) model still lacks according a satisfactory explanation to the issue why the energy density of the cosmological constant is so small if compared to the vacuum energy of the Standard Model (SM) of particle physics. Furthermore, the today observed equivalence, in order of magnitude, of dark matter and dark energy escapes any general explanation a part the introduction of a very strict fine tuning.\n\nStarting from these facts, one cannot consider the cosmological constant fully responsible for the whole anti-gravity dynamics, like the incapability to find a convincing candidate for dark matter, and/or a quantum theory of gravity, many scientists started questioning whether the theory, i.e. general relativity (GR), needed to be changed, in order to explain the accelerating expansion and the large scale structure clustering without the introduction of \"ad hoc\" cosmological constant and new particles; see, for example, \\[[@CR1]--[@CR3]\\]. The most usual modifications consist in the introduction of new fields either in the matter sector (e.g. quintessence) or by modifying gravity"
+"Introduction\n============\n\nWith the advent of DNA sequencing technology to infer phylogenetic relationships, investigators began searching for genetic loci that were both phylogenetically informative and readily sequenced in most organisms. The use of nuclear ribosomal DNA (nrDNA) soon became a popular choice for phylogenetic inference ([@ref-16]; [@ref-18]; [@ref-4]; [@ref-5]; [@ref-1]). Nuclear ribosomal DNA offered several advantages over other loci: the combination of highly conserved and variable regions allowed phylogenetic inference across a broad range of evolutionary time scales; conserved regions allowed the use of \"universal\" PCR primers applicable to a wide range of taxa; the high copy number of nrDNA repeats allowed reliable amplification from lower quality DNA extractions; and the process of concerted evolution ensured that these copies were similar within individuals ([@ref-5]). The use of nrDNA, particularly the variable internal transcribed spacer (ITS) regions, became widespread, to the extent that many studies were based exclusively on ITS data ([@ref-1]).\n\nHowever, nrDNA loci have been shown to harbor limitations in their phylogenetic utility. Nuclear ribosomal DNA copies are assembled as tandem repeats at one or more loci in the genome, with each locus being known as an array. The number of repeats present within an array is labile, as"
+"###### Strengths and limitations of this study\n\n-   The surveys were population-based, which provide an updated examination of disability trends among Chinese adults in Hong Kong aged 65\u2005years and older.\n\n-   This study includes the adjustment for multiple potential cofounders, including sociodemographic characteristics, lifestyle factors, comorbidities as well as self-rated health, which are known to influence functional status.\n\n-   The surveys ended in the birth cohort 1947. Therefore, we were unable to examine the cohort differences on disability between prewar generations and postwar baby boomers, whose early-life and mid-life experiences were remarkably different from each other.\n\n-   Information on birth place or risk factors in early-life and mid-life that may affect disability at older ages was not available, limiting the ability to identify causes of the increased disability burden in late life.\n\n-   Finally, our results only apply to the community-dwelling elderly. Disability prevalence in institutions tends to be higher than that in the community.\n\nIntroduction {#s1}\n============\n\nLife expectancy at birth of Hong Kong has taken one of the world\\'s leading positions and reached 81.2\u2005years in men and 86.9\u2005years in women in 2014.[@R1] The lengthening of life, however, does not mean that Hong Kong people have"
+"Introduction\n============\n\nTransplantation of haematopoietic stem cells (HSCs) is considered to be one of successful alternatives to treat malignant and non-malignant haematopoietic disease \\[[@b1], [@b2]\\], and a new therapy for non-haematologic diseases, including autoimmune diseases, multiple organ dysfunction and allogeneic transplantation rejection \\[[@b3]--[@b7]\\]. HSCs can be recovered from bone marrow (BM), peripheral blood (PB) and umbilical cord blood (UCB). HSCs from UCB have been suggested to be the major resource for clinical applications of HSC transplantation. UCB--HSC transplantation has a number of advantages, *e.g.* to reduce the incidence of acute graft-*versus*-host disease \\[[@b8], [@b9]\\], have faster availability of banked cryopreserved UCB units \\[[@b10], [@b11]\\], and process the tolerance of one to two human leucocyte antigen (HLA) locus mismatch \\[[@b12]\\]. However, it remains largely unknown that how can donor HSCs, particularly from UCB resource, engraft successfully *in vivo* in a host with intact innate immunity.\n\nNatural killer (NK) cells play a fundamental role in the innate immune response through their ability to secrete cytokines and kill target cells without prior sensitization. The cytotoxic effect of NK cells is executed *via* natural cytotoxicity receptors (NCRs) expressed on NK cells and HLA-G expressed on target cells. NCRs is a main group of the"
+"Background\n==========\n\nThe National Kidney Foundation has recently launched a major effort to define Chronic Kidney Disease (CKD) and formulate clinical practice guidelines \\[[@B1],[@B2]\\]. It has been clearly shown that complications of CKD, such as anemia, metabolic acidosis, nutritional deficits, secondary hyperparathyroidism, and hypertension, significantly contribute to morbidity and mortality \\[[@B3]-[@B10]\\]. It has been proposed that care for patients with CKD be best delivered in dedicated CKD clinics that provide a multidisciplinary approach to patients with CKD \\[[@B11],[@B12]\\]. Typically, these clinics are staffed with nephrologists, dieticians, social workers, and educators, and the team works closely with vascular surgeons for access placement. However, little is known about the effectiveness of these clinics at academic centers. The purpose of this cross-sectional analysis is determine to what extent K/DOQI goals are achieved in a dedicated CKD clinic serving a urban, socio-economically disadvantaged minority population.\n\nMethods\n=======\n\nPatients\n--------\n\nIRB approval for this study was obtained from the Human Subjects Research Office of the University of Miami, Miami, FL (protocol number 2004--3071). All study procedures were carried out in accordance with the Declaration of Helsinki regarding research involving human subjects. Our chronic kidney disease (CKD) clinic focuses on the care of patients with an"
+"1. Introduction {#sec1}\n===============\n\nReactions between atomic nitrogen and molecule are of great interest in atmospheric chemistry and combustion processes.^[@ref1]^ The three lowest adiabatic electronic states (labeled 1^2^A\u2033/1^2^B~1~, 1^2^A\u2032/1^2^A~1~, and 2^2^A\u2032/1^2^B~2~ in the *C*~*s*~/*C*~2*v*~ symmetry, respectively) of NH~2~ have been studied quite extensively over a number of years by various experimental^[@ref2]\u2212[@ref5]^ and theoretical techniques.^[@ref6]\u2212[@ref34]^ Jungen and co-workers^[@ref6]^ obtained an accurate potential energy surface for X^2^B~1~ and A^2^A~1~ states of NH~2~ in 1980. Carter and Handy^[@ref7]^ generated three-dimensional (3D) potential energy functions of the A^2^A~1~--X^2^B~1~ bent--bent Renner--Teller system of NH~2~. Alijah and Duxbury^[@ref8],[@ref9]^ used the stretch--bender approach method to study the rovibronic energies for the ground state of NH~2~, and the Renner--Teller and spin--orbit interactions between the A^2^A~1~ and the X^2^B~1~ states of NH~2~. The global potential energy surface (GPES) for 1A\u2033 has been careful studied by Pederson and co-workers.^[@ref15]^ In this work, the authors found a saddle point energy of 2.3 kcal/mol for the perpendicular approach of the second-order configuration interaction surfaces, and got the collinear stationary point energy of 5.5 kcal/mol. Another GPES^[@ref24]^ for the ground state of NH~2~(X^2^A\u2033) has been constructed by three-dimensional cubic spline interpolation method, and the vibrational frequencies of NH~2~ and its isotopomers were calculated."
+"In the 19th century, Rudolf Virchow first proposed a potential link between inflammation and cancer based on his observations on the presence of leukocytes in tumors.[@bib1] Inflammation is a physiological mechanism evolved for wound healing and therefore is counter-intuitive to consider it to be oncogenic. Nevertheless, inflammation is a 'double-edged sword' with a pathologic edge that can promote various aspects of tumorigenesis deregulated such as cell proliferation, migration, angiogenesis, and apoptosis.[@bib1] Within the last decade, a multitude of studies demonstrating the a) abundance of inflammatory cells such as macrophages and fibroblasts in cancer biopsies, b) the role of proinflammatory molecules such as cyclooxygenase-2 (COX-2), prostaglandin E2, leukotrienes, transforming growth factor beta (TGF-\u03b2), hypoxia inducible factor-1 alpha, vascular endothelial growth factor (VEGF), nitric oxide synthase, nitric oxide, reactive oxygen species (ROS), cytokines and chemokines in the pathogenesis of several cancers, and the tumorigenic nurturing properties of the proinflammatory tumor microenvironment strongly indicates that inflammation plays a pathogenic role in several cancers.[@bib1], [@bib2], [@bib3], [@bib4], [@bib5], [@bib6], [@bib7], [@bib8] Chronic persistent inflammation is believed to play an important role in the pathogenesis of 15% of all malignancies.[@bib1], [@bib2], [@bib3], [@bib4], [@bib5] Depending on the type and stage of cancer, the physiological to"
+"Introduction {#Sec1}\n============\n\nIn the past few years the mechanical measurements of bone tissue, especially in small animal models, have increasingly gained importance^[@CR1],[@CR2]^. Mouse bone has proven to be excellent for mechanical testing^[@CR1]^. The analysis of the mechanical properties of the bone is indispensable for experimental studies on bone, especially in the field of trauma and orthopaedics^[@CR3]^. Stiffness, strength and loading capacity can only be evaluated by mechanical testing^[@CR4]^. Normally, the widely used load to failure test is performed as the final procedure and is usually reserved for a latter stage of the experiment. Therefore, it is necessary to store bone for a longer time period from harvesting to testing^[@CR3]^. Several different techniques of bone storage, such as freezing or fixation with varying methods, for example, with ethanol, formaldehyde or paraformaldehyde, have been described in current literature. All of these techniques carry certain advantages and disadvantages^[@CR5],[@CR6]^. For bone freezing, different protocols varying from \u221280\u2009\u00b0C to \u22124\u2009\u00b0C exist. In most cases, the bone is frozen to \u221220\u00b0 and rehydrated to regain normal mechanical properties for testing^[@CR7],[@CR8]^.\n\nRegarding formalin and ethanol based storage methods, negative effects are described in the literature. Formalin based methods reveal changes of the organic matrix"
+"Introduction\n============\n\nThis paper is the continuation of a series of original research papers published by the authors on the topic of nutritionally driven organic cation transporter (OCT) functional status determination (herein referred to as OCT assay\\[s\\]). This paper correlates original research previously published by the authors on the topic of transporter-driven centrally acting monoamine observations with the monoamine hypothesis.[@b1-ijgm-5-135]--[@b12-ijgm-5-135]\n\nThe centrally acting monoamines serotonin, dopamine, norepinephrine and epinephrine (herein referred to as \"monoamine\\[s\\]\") exist in one of two states. The \"endogenous state\" is present when no supplemental amino acids are being administered, and the \"competitive inhibition state\" is found when significant amounts of serotonin and/or dopamine amino acid precursors are simultaneously administered.[@b1-ijgm-5-135]--[@b7-ijgm-5-135]\n\nPrevious literature described the competitive inhibition state as \"functionally meaningless.\" The basis for this assertion was the inability to alter monoamine levels with amino acid precursors and then objectively quantify the changes.[@b7-ijgm-5-135] With the perfection of the novel OCT assay analysis by the authors, the competitive inhibition state is no longer functionally meaningless.[@b1-ijgm-5-135]--[@b12-ijgm-5-135]\n\nSince the early 1960s, the monoamine hypothesis has been a reference point for understanding the etiology of the electrical defects associated with monoamine-related disease and the mechanism of action of reuptake inhibitors. The monoamine"
+"Background\n==========\n\nT cell immune activation is a strong predictor of HIV-1 disease progression and HIV-1 transmission, and IFN-alpha production following TLR7 stimulation has been associated with elevated CD8^+^ T cell activation (Meier et al., Nat Med 2009). We therefore hypothesized that modulation of TLR7 stimulation could be used to manipulate IFN-alpha production and subsequently reduce HIV-1-associated immune activation. TLR7/9-specific antagonists developed for treatment of auto-immune diseases were used in vitro and in vivo in a humanized mouse model.\n\nMethods\n=======\n\nHumanized BLT mice were generated by transplanting irradiated NOD/SCID/\u03b3c^-/-^ mice with human fetal thymus and injected with human hematopoietic stem cells isolated from matching liver tissue. Following reconstitution, cells were harvested from the mice to examine the effects of the antagonist in vitro. Humanized mice were also infected with HIV-1 and then either treated or untreated with TLR7/9 antagonist from Idera. T cell activation markers were examined pre-infection, following infection and during treatment with the antagonist. Additionally, responsiveness of DCs to TLR7/8 stimulation ex vivo following in vivo TLR7/9 antagonist treatment was assessed by intracellular cytokine staining.\n\nResults\n=======\n\n16-20 weeks after transplant, human DC, monocyte and T cell populations were detectable in the mice. Ex vivo stimulation with"
+"Endometrial cancer is the most common gynecologic malignancy among women in developed countries. Most are diagnosed at stage I and their probability of surviving the disease is excellent. Most women at diagnosis are older, obese, and have multiple comorbidities. These factors need to be considered when treating patients with this highly curable disease. When recurrences occur at the vaginal apex, almost 50% are salvaged with radiation therapy with or without surgical excision. However, treatment of nodal or distant recurrences or of advanced disease at diagnosis is more challenging.\n\nOne of the challenges faced by those treating this disease is how to identify those women who are at risk of having occult metastatic disease at initial diagnosis and to provide effective adjuvant therapy that would prevent recurrences in this select group of patients while minimizing therapy-induced morbidity.\n\nIn this special issue on endometrial cancer, the authors tackle some of these issues. The articles accurately and succinctly summarize the current approach to the treatment of this disease and looks at the future by discussing possible novel interventions for the treatment of advanced or recurrent disease. The controversies in the surgical management of endometrial cancer are discussed, as are the minimally invasive surgical"
+"1. Background {#sec1}\n=============\n\nSince laparoscopic surgery was introduced in 1987 by Mouret and more frequently employed, it has rapidly evolved as a major innovation in the history of surgery \\[[@B1]\\], offering an important contribution to the reduction of all the typical complications related to open surgery. On the other hand, laparoscopic surgery can be associated with a specific type of incisional hernia through the trocar site causing complications such as small bowel obstruction. Trocar site hernia (TSH) is defined as an incisional hernia which occurs after minimally invasive surgery on the trocar incision site \\[[@B2]\\]; some authors also define this condition as a port site hernia.\n\nIn 2004 Tonouchi classified trocar site hernias into 3 types \\[[@B3]\\] as follows.\n\n\\(i\\) Early onset typeDehiscence of anterior and posterior fascial plane and peritoneum characterized by early onset after surgery. It usually occurs as a small bowel obstruction. An example of this type is the so-called Richter\\'s hernia.\n\n\\(ii\\) Late onset typeDehiscence of anterior and posterior fascial plane. Peritoneum constitutes the hernia sac. Hernias usually develop several months after surgery and they are not associated with small bowel obstruction. They appear as an asymptomatic swelling by the wound site.\n\n\\(iii\\) Special typeDehiscence"
+"Purpose\n=======\n\nIncreased numbers of OX40+ T cells in the tumor microenvironment of colorectal cancer (CRC) patients have been associated with improved outcome. However, the OX40+ T cell population is heterogeneous and includes, among others, CD4+Foxp3+ regulatory T cells (Treg) as well as CD4+Foxp3- effector T cells (Teff). In this study, we used a novel triple immunofluorescence assay for CD4, FoxP3 and OX40 to determine the relationship between tumor-associated CD4+ T cell subsets and patient disease stage as well as outcome in CRC.\n\nMethods\n=======\n\nWe investigated OX40 expression in tumor-associated CD4+ T cell subsets in 48 CRC patients including primary site (n = 48) and matched metastases (n = 19) with a triple immunofluorescence assay for CD4/FOXP3/OX40. Stained sections were digitally imaged and single, double and triple-positive tumor-associated cell subsets were enumerated and associations between CD4 subsets and stage and outcome as well as that of CD4 subsets between primary site and metastases were determined.\n\nResults\n=======\n\nMean counts of total OX40+cells (p = 0.005), OX40+ Treg cells (p = 0.006), and OX40+ Teff (p = 0.019) cells showed statistically significant inverse correlation with increased stage at diagnosis. Associations remained statistically significant when counts were normalized to total cells."
+"Introduction {#sec1-1}\n============\n\nThe use of laryngeal mask airway (LMA) is popular in pediatric anesthesia as it avoids the risk of laryngeal injury and edema commonly associated with endotracheal intubation.-\\[[@ref1]\\] Successful insertion of LMA requires adequate depth of anesthesia. LMA if inserted under lighter planes of anesthesia can result in coughing, gagging, body movements, breath holding, and even rejection of LMA.\\[[@ref2]\\]\n\nCertain clinical tests used to assess the neurological status in unconscious patients have also been used in anesthetic practice to assess the depth of anesthesia. Few such tests are loss of verbal contact, eyelash reflex (ER), corneal reflex, acceptance of anesthesia mask (AM), ease of manual ventilation, loss of ability to hold light object, and jaw relaxation.\\[[@ref3]--[@ref7]\\] Loss of corneal reflex and jaw relaxation are the most frequently used clinical end points in the studies conducted for evaluation of LMA insertion in anesthetized spontaneously breathing patients.\n\n\"Trapezius squeeze test\" (TST) is a clinical test used to assess the depth of sedation/consciousness by observing the response to central noxious stimulation. It is a simple test to perform in which 1--2 inches of full thickness trapezius muscle is held and squeezed for 1--2 s and response evaluated in the form of"
+"Introduction {#Sec1}\n============\n\nThe layered ZrTe~5~ crystal, with large thermopower^[@CR1]--[@CR5]^, has been studied by scientists for many years. Recently, it has attracted more attention after been predicted as a 2D topological insulator(TI) with a bulk direct band gap of 0.4\u2009eV^[@CR6]^. But experimentally, the topological nature of ZrTe~5~ is still under debate. Some studies reported ZrTe~5~ as a weak TI^[@CR7],[@CR8]^. While, several other experimental studies have suggested that ZrTe~5~ might be a Dirac semimetal^[@CR9],[@CR10]^. The discrepancy may come from the fact that ZrTe~5~ is in a topological critical state placed between a weak-TI and a strong-TI which is sensitive to the lattice constant. The lattice constant is influenced by the growth conditions and the measurement environments.\n\nIn this work, we have studied the quantum oscillations of bulk ZrTe~5~ grown by the chemical vapor transport method (CVT) using iodine as the transport agent. Quantum oscillations from the bulk states have been observed having a high mobility of 41000\u2009cm^2^V^\u22121^s^\u22121^. The Fermi surface was shown to be two-dimensional with a Berry phase of \u03c0 in the infinite field limit, which indicated that ZrTe~5~ is a topologically non-trivial material. More importantly, we have found quantized Hall resistance with a filling number of *\u03bd*"
+"Background {#Sec1}\n==========\n\nWorldwide prevalence of obesity almost doubled between 1980 and 2008 \\[[@CR1]\\] and a similar trend has been observed in Switzerland \\[[@CR2]\\]. Several socio-demographic and behavioural factors have been shown to influence weight gain. A consistent positive association between marital status \\[[@CR3]\\], occupational position \\[[@CR4]\\], low educational level, economic difficulties \\[[@CR5]\\] and weight gain has been reported. Still, the impact of SES on weight gain might differ according to gender \\[[@CR6]\\] or to the country's level of socioeconomic development -- while in high income countries a high socioeconomic status (SES) is generally related to a lower prevalence of obesity, the opposite association is found in low income countries \\[[@CR7]\\].\n\nIn Switzerland, several cross-sectional studies have shown an inverse association between obesity and socio-demographic and behavioural factors \\[[@CR8],[@CR9]\\], but whether socio-demographic and behavioural factors have an impact on weight gain has never been investigated prospectively. Indeed, one of the main objectives of the Swiss national programme on healthy eating and physical activity (PNAAP) is achieving a health weight \\[[@CR10]\\] and such data are important for adequately designing health promotion policies and to evaluate their impact in the target population.\n\nThus, we aimed to assess the socio-demographic and behavioural determinants"
+"Citation {#SECID0EVCAC}\n========\n\nGoulding TC, Khalil M, Tan SH, Dayrat B (2018) Integrative taxonomy of a new and highly-diverse genus of onchidiid slugs from the Coral Triangle (Gastropoda, Pulmonata, Onchidiidae). ZooKeys 763: 1--111. [https://doi.org/10.3897/zookeys.763.21252](10.3897/zookeys.763.21252)\n\nIntroduction {#SECID0EPDAC}\n============\n\nThe Onchidiidae is a group of shell-less, marine, air-breathing slugs that live in intertidal habitats worldwide. Most of the diversity is found in mangroves of South-East Asia, where onchidiids have diversified into several genera, such as *Onchidium* Buchannan, 1800, *Peronina* Plate, 1893, *Platevindex* Baker, 1938, and *Melayonchis* Dayrat & Goulding, 2017. The genus *Peronia* Fleming, 1822, which can easily be identified externally by branched gills on the dorsal notum, has diversified in the rocky intertidal across the Indo-West Pacific. However, for decades the diversity of onchidiid slugs has remained poorly known for a variety of reasons: mangroves have rarely been explored; preserved slugs can hardly be distinguished externally; and taxonomists have avoided the overwhelming nomenclature ([@B13]). As a result, most species could not be reliably identified even though many species are geographically widespread and common.\n\nThe Dayrat lab is currently engaged in a global revision of the Onchidiidae, based on an integrative approach involving extensive fieldwork (sampling thousands of individuals at more than"
+"Background {#Sec1}\n==========\n\nIn this study we address an important pattern recognition problem in protein structures, *viz*. the identification of structural tandem repeats. Repeats are ubiquitous in protein sequences and vary considerably from single amino acid repetitions, e.g., runs of glutamine in the protein huntingtin, to large globular domains of size 100 or more residues that fold independently \\[[@CR1]\\]. The structural classification of repetitive proteins based on the repeat lengths and the possible 3-dimensional structure of these proteins has been given by Kajava (2001) \\[[@CR2]\\]. Repeats of intermediate length of 20--50 amino acids are most commonly observed in proteins to form integrated assemblies providing multiple binding sites. This class of non-globular repeat proteins form various 3-dimensional folds, *viz.*, spirals, solenoids, closed structures, etc. \\[[@CR3]\\]. Examples of such repeats include leucine-rich repeat (LRR), Ankyrin repeat (ANK), armadillo (ARM) /HEAT repeat, tetratricopeptide repeat (TPRs), Kelch repeat, etc.\n\nEarlier approaches for the identification of repeats in protein sequences range from methods based on Fourier analysis of amino acid sequences \\[[@CR4]-[@CR7]\\], to short-string searches \\[[@CR8],[@CR9]\\], sequence-alignment based approaches \\[[@CR10]-[@CR13]\\], and HMM-profile based methods \\[[@CR14],[@CR15]\\]. The Fourier transform methods fail in the presence of insertions between the repeating units, while the performance of the alignment-based"
+"Introduction {#sec1}\n============\n\nUnder ambient conditions, almost all solid surfaces are covered in a thin film of water.^[@ref1]^ The ubiquitous nature of water--solid interfaces means that they are relevant to an almost endless list of everyday and technological phenomena, ranging from the slipperiness of ice to electrochemical reactions and from ice formation to water purification. As a result of this widespread importance and the pressing need for clean water, renewable energy, and deeper insight into environmental chemical processes, interfacial water has been the subject of much detailed investigation. Great strides have been made in rationalizing water at interfaces from various perspectives, and the \"field\" of interfacial water is now flourishing.^[@ref2]\u2212[@ref9]^\n\nOne area that has been particularly instrumental in improving understanding of interfacial water is the study of water on clean well-defined solid surfaces under ultrahigh vacuum conditions.^[@ref2],[@ref3],[@ref7],[@ref10]^ In these studies, the full arsenal of surface science techniques has been applied to interrogate interfacial water and obtain clear atomic and molecular-level insight. This has shed light on the chemistry of interfacial water and, in turn, on the balance between water--water and water--substrate bonding, precise information that is otherwise rarely available. Of the various techniques employed, the application of low-temperature scanning tunneling"
+"INTRODUCTION {#s1}\n============\n\nHepatocellular carcinoma (HCC) is one of the most common cancers worldwide \\[[@R1], [@R2]\\]. Chronic infection with hepatitis B virus (HBV) is one of the major risk factors for HCC and plays an important part in the prevalence of HCC \\[[@R3]--[@R5]\\].\n\nCytokines can mediate a variety of biological behavior of cells and have a role in the development of HBV-related HCC. It was reported that HBV can upregulate the expression of cytokines and cause liver damage directly through the cytokines signaling pathway. For instance, we previously reported that HBx induced IL-32 expression through NF-\u03baB activation \\[[@R6]\\]. HBV surface antigen (HBsAg) could efficiently induce IL-23 secretion in a mannose receptor (MR)-dependent manner \\[[@R7]\\]. HBx induced IL-23 secretion through the activation of the ERK/NF-\u03baB pathway \\[[@R8]\\]. The baseline level of IL-23 in serum and hepatic tissue was found to be higher in patients with CHB than in controls \\[[@R8], [@R9]\\]. IL-23 belongs to the IL-12 cytokine family, which shares the p40 subunit of IL-12 but is distinguished from the latter by its cytokine subunit, p19 \\[[@R10]\\]. Consistent with the structural and biological similarities of IL-12 and IL-23, IL-23 receptor is composed of the IL-12R\u03b21 subunit and the novel IL-23R subunit"
+"A 75-year-old man (body mass index 24.49\u2005kg\u00b7m^\u22122^) presents to the emergency department with fever, myalgia and dyspnoea, which he has had for the last 4\u2005days. He quit smoking 15\u2005years ago (40\u2005pack-years). His only medical history is hypertension treated with valsartan and amlodipine. He travelled recently and stayed in a motel. On admission, his temperature is 38.7\u00b0C, blood pressure 132/67\u2005mmHg, heart rate 102 beats per min and respiratory rate 24 breaths per min. Arterial blood gases (ABG) analysis shows severe hypoxaemia with arterial oxygen tension (*P*~aO~2~~) 47.1\u2005mmHg (6.3\u2005kPa), arterial carbon dioxide tension (*P*~aCO~2~~) 40.9\u2005mmHg (5.5\u2005kPa), pH 7.464, HCO~3~^\u2212^ 28.4\u2005mmol\u00b7L^\u22121^ and arterial oxygen saturation (*S*~aO~2~~) 84.2% while breathing room air. Laboratory tests show anaemia (haemoglobin 10.7\u2005g\u00b7dL^\u22121^), elevated white blood cells (11\u200a420 per \u03bcL; 92.0% neutrophils and 4.6% lymphocytes), elevated C-reactive protein (19.97\u2005mg\u00b7dL^\u22121^) and hyponatraemia with serum Na^+^ 127\u2005mmol\u00b7L^\u22121^. The rest of laboratory tests are normal. Chest radiograph showa infiltrates in both lungs. Antibiotic therapy with intravenous ampicillin/sulbactam 3\u2005g per 6\u2005h and antiviral therapy with oral oseltamivir 75\u2005mg per 12\u2005h are initiated.\n\nTask 1 {#s2}\n======\n\nBased on the patient\\'s history and laboratory tests, which"
+"**Related research article** Adler CE, Seidel CW, McKinney SA, S\u00e1nchez Alvarado AS. 2014. Selective amputation of the pharynx identifies a FoxA-dependent regeneration program in planaria. *eLife* **3**:e02238. doi: [10.7554/eLife.02238](http://dx.doi.org/10.7554/eLife.02238)\n\n**Image** A planarian with its pharynx extended\n\n![](elife02517inf001.jpg)\n\nPlanarian flatworms are well known for their amazing regenerative capacity. In a manner reminiscent of the Sorcerer's Apprentice, chopping one worm into little pieces will result in a dish full of tiny worms regenerated from the fragments in just a few days. In recent years this system has been rediscovered as an experimental model for probing how and why tissues regenerate, with the hope that this will help us to improve tissue repair in our own bodies.\n\nRegeneration in planarians depends on the presence of stem cells called neoblasts. These cells are distributed throughout the body and, when part of the worm has been amputated, they are activated to reform the tissues that have been removed ([@bib10]). It is still not entirely clear how the stem cells regenerate specific organs. Are there different types of stem cell that form different tissues? Do signals produced by nearby cells cause specific tissues to form? Or is a combination of both stem cell bias and local"
+"A diagnosis of cancer can cause great suffering to patients and families. The revealing of the diagnosis of cancer to patients is a key event in their cancer journey. The word cancer is often avoided in these consultations ([Thomsen *et al*, 1993](#bib20){ref-type=\"other\"}). Over recent years, communication and information have increasingly been considered important in helping people with cancer ([Fallowfield *et al*, 1994](#bib11){ref-type=\"other\"}; [Coulter, 1998](#bib5){ref-type=\"other\"}). Research indicates that the vast majority of cancer patients want to be informed of their illness ([Meredith *et al*, 1996](#bib16){ref-type=\"other\"}). Women with ovarian cancer need honest communication that is appropriate to their level of understanding. Communication needs will vary across patient\\'s age, stage of disease and treatment. At present, there are no minimal legal recommendations for documenting such consultations. Furthermore, complaints made by patients often focus on a perceived failure of communication rather than on clinical errors ([Department of Health, 2000](#bib7){ref-type=\"other\"}).\n\nIn its guide 'Good Clinical Practice' ([General Medical Council, 2001](#bib14){ref-type=\"other\"}), the General Medical Council (GMC) states 'a good medical record should contain sufficient information to: identify the patient; support the diagnosis; justify the treatment; document the course and results and promote continuity of care among healthcare providers', and continues, 'Doctors must keep colleagues well informed"
+"INTRODUCTION\n============\n\nSince the sixth century when Chinese oriental medicine including acupuncture and herbs was introduced in Korea, acupuncture has been the most widely used procedure in the Korean society over the centuries as alternative or complementary medicine.[@B1] Acupuncture is generally regarded as a less invasive, more natural, and less liable treatment by the general population.[@B2] The National Institutes of Health Acupuncture Consensus Development Panel already concluded that acupuncture is either effective (2 conditions) or may be useful (12 conditions) in 1998.[@B3] Acupuncture is effective in postoperative nausea, vomiting and dental pain, and also may be useful as an adjunct treatment for stroke rehabilitation, headache, menstrual cramps, tennis elbow, fibromyalgia, myofascial pain, osteoarthritis, low back pain, carpal tunnel syndrome, and asthma.\n\nHowever, most procedures have some complications and acupuncture treatment is no exception. Reported complications of acupuncture treatment were mostly mild or temporary symptoms. Minor adverse effects included bruising, tingling, tenderness on acupoints, and fainting, and more severe adverse effects included retroperitoneal abscess, tissue trauma, pneumothorax, cardiac tamponade, and peripheral nerve or spinal cord injuries.[@B4]-[@B6] The use of non-sterile needles may cause infections as well, such as human immunodeficiency virus, hepatitis, and endocarditis.[@B7] Here, we present a 69 year old"
+"INTRODUCTION\n============\n\nProlonged mitotic arrest can lead to DNA damage and p53 induction ([@B27]; [@B13]; [@B37]), followed by cell cycle arrest or apoptosis. These processes may all contribute to the therapeutic activities of a drug like Taxol (paclitaxel), but the causal relationships between them and their consequences in the tumor environment remain elusive. For example, DNA damage can result in the expression of ligands on the cell surface that in turn recruit natural killer cells to remove the damaged cells ([@B18]) and p53-driven senescence can up-regulate inflammatory cytokine production, resulting in tumor clearance via innate immune response ([@B55]). A better understanding of the causal relationships among mitotic arrest, DNA damage, and p53 could help improve therapeutic strategies that employ antimitotic drugs.\n\nThe tumor suppressor p53 is a central regulator of stress responses. When cells are stressed, for example by DNA damage, p53 becomes phosphorylated, resulting in its stabilization and induction of target genes that affect cell fate ([@B25]). These include key regulators of apoptosis (PUMA, NOXA) and cell cycle arrest (p21). p53 also induces MDM2, an E3 ligase that catalyzes p53 degradation, and together with other proteins, this circuit generates a series of uniform pulses of p53 in response to"
+"1. Circadian Rhythms {#sec1-biology-08-00018}\n====================\n\nCircadian rhythms are \\~24 h cycles of physiology and behaviour that occur in virtually all organisms from bacteria to man. These rhythms are generated by an internal biological clock and persist even in isolation from any external environmental cues. In mammals, the master circadian clock is located in the hypothalamic suprachiasmatic nuclei (SCN), and is based upon an intracellular transcriptional-translational feedback loop (TTFL), comprised of a number of core clock genes \\[[@B1-biology-08-00018]\\]. Output from the SCN in turn coordinates rhythms of physiology and behaviour, as well as synchronising peripheral clocks found in tissues and organs throughout the body \\[[@B2-biology-08-00018]\\]. As a result, the circadian system can be regarded as an integrated network of clocks, responding to neural, hormonal and behavioural signals to ensure an appropriate phase relationship with each other as well as the external world.\n\nA clock is of no use unless it can be set to local time. In mammals, the primary time cue (zeitgeber) is light detected by the eye. The retinal photoreceptors mediating this response include the rods and cones involved in vision, as well as the recently identified photosensitive retinal ganglion cells (pRGCs) expressing the blue-light sensitive pigment melanopsin \\[[@B3-biology-08-00018],[@B4-biology-08-00018],[@B5-biology-08-00018]\\]."
+"Published: April 7, 2020\n\nIntroduction {#sec1}\n============\n\nDuring development, cells need to know their location and fate in order to form an embryo. The required positional information can be conveyed by gradients of secreted signaling molecules that diffuse from a localized source to induce exposure-dependent cell responses (reviewed in [@bib36], [@bib47]). The earliest cell-fate decisions during vertebrate development are controlled by the signaling molecules Nodal and BMP, which form orthogonal overlapping activity gradients in zebrafish embryos ([Figure\u00a01](#fig1){ref-type=\"fig\"}A). Nodal induces the formation of the germ layers, which are subdivided into ventral and dorsal territories by BMP signaling (reviewed in [@bib46]). Nodal and BMP are secreted transforming growth factor \u03b2 (TGF-\u03b2) superfamily ligands ([@bib69], [@bib64]), which signal through a hetero-tetrameric complex composed of ligand-specific serine/threonine kinase receptors ([@bib65]) as well as co-receptors ([@bib55]). Nodal signaling leads to the phosphorylation of the latent cytoplasmic signaling effectors Smad2/3, whereas BMP signaling causes the phosphorylation of Smad1/5/8. These pSmads then accumulate in the nucleus, where they regulate the expression of target genes ([@bib22]).Figure\u00a01Secondary Axis Inducing Nodal and BMP Double Clones Produce a Localized Region of pSmad2 Activity Overlapping with a Broad Domain of pSmad5 Activity(A) Nodal and BMP form orthogonal overlapping gradients in"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec005}\n============\n\nAmniotic fluid (AF) is maintained in a dynamic equilibrium and its volume derived from the sum of inflow (from fetal urine and lung fluid) and outflow (fetal swallowing and intramembranous absorption) of fluid from the amniotic space.\\[[@pone.0144334.ref001]\\] Amniotic fluid volume (AFV) is an important parameter in the assessment of fetal wellbeing since it provides a number of functions vital to fetal development such as a supportive environment for growth,, protection from trauma and infection and a medium which allows fetal movement thus promoting the development of the musculoskeletal system. AF also prevents a possible compression of the umbilical cord and placenta thereby protecting the fetus from vascular and nutritional compromise.\\[[@pone.0144334.ref002]\\]\n\nTo date several methods are used to assess AFV ranging from subjective assessment (where the volume is described as average, above average, below average or scant) to semi-quantitative estimations including measurement of the deepest vertical pocket and amniotic fluid index (AFI).\\[[@pone.0144334.ref003]\\]\n\nWhile debate continues regarding the best method to estimate AFV, it has become evident that there are numerous maternal and fetal risk factors associated with a reduction of this parameter. \\[[@pone.0144334.ref004]--[@pone.0144334.ref008]\\] Indeed, an increased"
+"Chagas disease ranks highly among the main neglected tropical diseases in the Americas ([@B20]). The main vector for Chagas disease, *Triatoma infestans* (Klug, 1834) (Hemiptera: Reduviidae), has historically played a crucial role in the Southern Cone Region. Although the geographical range of *T. infestans* has been strongly reduced over the last three decades, this species still persists in the Gran Chaco eco-region of Argentina, Bolivia and Paraguay, where it represents a serious health problem ([@B20]). Chagas disease affects approximately 1.6 million people in Argentina, and *T. infestans* is present in a large fraction of the territory ([@B30]).\n\nChagas disease in the Argentine Chaco is characterised by a complex eco-epidemiological scenario with high levels of house infestations by *T. infestans* ([@B11]) and increasing professional vector control efforts over the last decade ([@B23]). Several efforts have been made to understand the processes related to *T. infestans* house infestation and re-infestation patterns as well as the transmission of *Trypanosoma cruzi* (Chagas, 1909) ([@B17]). However, the eco-epidemiology of Chagas disease remains mostly unknown in western Argentina, where the SW extreme of the Gran Chaco creates a biogeographic transition area known as the Monte Desert ([@B25]). Mendoza province is located at the heart of the"
+"Background {#Sec1}\n==========\n\nGenome-wide association studies (GWAS) have revealed unprecedented numbers of disease-associated loci \\[[@CR1], [@CR2]\\]. However, previously reported loci explain only a small proportion of heritability \\[[@CR2]--[@CR4]\\]. Previous GWAS mainly focused on common variants that was readily accessible via initial genomic technologies \\[[@CR2]\\]. Through recent advancements in high-throughput sequencing technology, more complete genome-wide assessment of variants has become possible \\[[@CR5]\\]. Recent large scale sequencing studies reported that the population frequencies of a large proportion of discovered variants were rare (Minor Allele Frequency (MAF)\u2009\\<\u20091\u00a0%) \\[[@CR6]--[@CR8]\\]. Given their abundance, rare variants have been increasingly recognized as an alternative source of missing heritability \\[[@CR5], [@CR7], [@CR9]\\]. However, large-scale, population-based genomic sequencing studies are not yet feasible, due to high cost and computation-intensive analysis \\[[@CR10], [@CR11]\\].\n\nAlternatively, imputation has been widely used for studying rare variants. Imputation has estimated untyped rare variants using thousands of sequenced samples available as a reference panel such as the 1,000 genomes project data \\[[@CR12], [@CR13]\\]. Recent imputation-based association studies have revealed numerous uncommon or rare variants associated with coronary artery disease, blood cell traits, serum creatinine, chronic kidney disease, and adult body height \\[[@CR10], [@CR12], [@CR13]\\]. However, imputing rare variants has been challenging, due"
+"Introduction {#s1}\n============\n\nIn humans, chronic inflammatory diseases represent a major medical challenge, both in terms of our understanding of their underlying mechanisms as well as their treatments. In a disease such as rheumatoid arthritis (RA), the pathological roles of pro-inflammatory cytokines such as TNF\u03b1, interleukin (IL)-1\u03b2, and IL-6 have been demonstrated. Therapeutic inhibitors of these targets, such as etanercept, a p75-TNFR immunoglobulin Fc fusion protein, infliximab, a TNF specific monoclonal antibody, and anakinra, an IL-1R antagonist, represent major treatment advances in this disease (reviewed in [@pone.0002267-Andreakos1]). Nevertheless, a therapeutic response and efficacy are not always achieved and may be of limited duration. There is thus still a major need to understand pathways which sustain chronic inflammation in these diseases with the hope that treatment can be improved.\n\nNicotinamide adenine dinucleotide (NAD) is an important coenzyme found in all cells that plays key roles as carrier of electrons in the redox reaction, but also as cofactor for NAD-consuming enzymes. Evidence suggests that TNF\u03b1 and other inflammatory stimuli affect NAD metabolism. For example, endotoxin, the potent stimulus of innate immunity, induces a dramatic increase in the expression of NAMPT, a crucial enzyme involved in the salvage pathway of NAD, recycling NAD"
+"1. Introduction {#sec1}\n===============\n\nObesity has reached pandemic proportions worldwide, significantly contributing to reduce life quality and lifespan at a global scale [@bib1]. This condition is characterized by abnormal and excessive fat accumulation and is influenced by both genetic and environmental determinants. While several genetic loci have been associated with obesity, they explain only a fraction of the total variance within populations; moreover, genes deemed obesity-predisposing interact with environmental factors to regulate, for instance, satiety and energy expenditure [@bib2]. Among the environmental determinants of obesity and its associated dysmetabolic conditions, dietary habits play a central role. Diet\u00a0also strongly influences our \"other genome\" (*i.e.*, the metagenome), modeling gut microbial community structure [@bib3] and impacting host metabolism and energy partitioning [@bib4]. Research conducted throughout the last decade has revealed a clear association between obesity and gut microbial dysbiosis, which is generally characterized by a reduction in bacterial richness and by major taxonomic and functional changes [@bib5].\n\nThe consumption of fiberless diets rich in simple sugars and saturated fat (often referred to as Western diets) generates well-known detrimental metabolic consequences, leading to insulin resistance and glucose intolerance in the early-term, which later evolves to overt obesity, type 2 diabetes, and cardiovascular complications."
+"1. Introduction {#sec1}\n===============\n\nKorea has designated notifying infectious diseases and controlled infectious diseases since 1954, and the division of disease control in the Korea National Institute of Health (KNIH) conducted epidemiological investigation on infectious diseases until the introduction of Epidemic Intelligence Service (EIS) officers in 1999. In major epidemics, joint investigation was conducted with experts in the civil sector. Control was for epidemics only and no epidemiological investigators were available except in central government, therefore, control and surveillance of infectious diseases had limitations [@bib1]. The existing control system has reached its capacity since the 1980s with massive outbreaks of water and food-borne diseases and emergence/outbreaks of various infectious diseases such as leptospirosis, legionella, *Vibrio vulnificus* septicemia, scrub typhus, hemorrhagic fever with renal syndrome, anthrax, and tularemia. Epidemiological investigations on shigellosis were not routinely conducted, with the exception of some outbreaks, which is a huge limitation in establishing disease control policy. Furthermore, there has been a re-emergence and consistent increase in\u00a0incidence of vivax malaria since 1993, after elimination in 1978, and it has not been systematically investigated [@bib2].\n\nIn the late 1990s, the Field Epidemiology Training Program (FETP) was developed to cope with emerging/re-emerging infectious diseases, and Japan, Thailand,"
+"1. Introduction {#sec1}\n===============\n\nPulmonary arterial hypertension (PAH) is a severe condition that frequently leads to right ventricular failure and death \\[[@B1], [@B2]\\]. Remodeling of small pulmonary arteries represents the main pathologic finding related to PAH. The remodeling process includes marked proliferation of pulmonary artery smooth muscle cells (PASMCs) that contribute to vascular wall hypertrophy \\[[@B1], [@B3]\\].\n\nStudies in both animal models and in human patients have shown that cigarette smoke exerts a direct effect on pulmonary vascular structure, resulting in pulmonary vascular remodeling and pulmonary hypertension \\[[@B4], [@B5]\\]. However, the molecular mechanisms underlying this process remain unclear.\n\nPlatelet-derived growth factor (PDGF) is a potent mitogen and chemoattractant for pulmonary vascular smooth muscle cells \\[[@B6]\\]. Although there are several PDGF family members (A, B, C, and D), PDGFB is a prime candidate to study, because the PDGFB isoform is a potent inducer of VSMC proliferation and only acts through the beta-subunits of the PDGF receptor (PDGFR) \\[[@B6]--[@B8]\\]. The upregulated expression of PDGF and PDGFR has been correlated with PAH in various experimental animal models \\[[@B9], [@B10]\\] and in humans \\[[@B11]\\]. However, whether PDGF is also activated in rPASMCs by cigarette smoke extract (CSE) has not been explored.\n\nProtein kinase C"
+"Bowman\u2010Smart H, Savulescu J, Gyngell C, Mand C, Delatycki MB. Sex selection and non\u2010invasive prenatal testing: A review of current practices, evidence, and ethical issues. Prenatal Diagnosis. 2020;40:398\u2010407. 10.1002/pd.5555 31499588\n\nWhat\\'s already known about this topic?\n\nSex\u2010selective termination of pregnancy is a widespread practice in many areas of the world.It is commonly motivated by a son preference and possibly also for the purpose of \"family balancing.\"Non\u2010invasive prenatal testing can determine the sex very early in the pregnancy, and there are concerns that this will further facilitate sex\u2010selective termination of pregnancy.\n\nWhat does this study add? Evidence that NIPT is facilitating sex selection remains anecdotal, and further research is required to quantify this.\n\n1. INTRODUCTION {#pd5555-sec-0001}\n===============\n\nThe introduction of non\u2010invasive prenatal testing (NIPT) has the potential to make the practice of sex\u2010selective termination of pregnancy (TOP) an even more pressing issue. NIPT can determine the sex of the fetus very accurately and very early in the pregnancy. It is increasingly accurate from 7 weeks\\' gestation.[1](#pd5555-bib-0001){ref-type=\"ref\"} This is earlier than when other techniques that can determine sex, such as ultrasound or chorionic villus sampling (CVS), are generally performed.[2](#pd5555-bib-0002){ref-type=\"ref\"}, [3](#pd5555-bib-0003){ref-type=\"ref\"}\n\nThere can be medical reasons to determine the sex of the fetus."
+"The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are included in the paper.\n\nBackground {#s1}\n==========\n\nChronic obstructive pulmonary disease (COPD) is a serious, though preventable and treatable, disease [@pone.0111078-Caballero1]--[@pone.0111078-Bridevaux1]. According to the World Health Organization (WHO), there are about 65 million people suffering from moderate to severe COPD. In 2005, more than three million people died of COPD, which equates to 5% of all deaths globally. COPD has recently become the third most common cause of death worldwide. Overall, COPD mortality in the 28 countries of the European Union (EU) is about 150,000 deaths per 260 million EU adults aged \u226540 years [@pone.0111078-Mathers1]--[@pone.0111078-World2]. The mortality rate and socioeconomic burden are also increasing in the post-communist countries of Central Europe [@pone.0111078-Poznaska1], [@pone.0111078-Maly1]. COPD is still underestimated and underdiagnosed in the global population [@pone.0111078-Decramer1]. In addition to the global treatment strategies and guidelines, there are also several sets of national diagnostic and therapeutic recommendations [@pone.0111078-Bellamy1]--[@pone.0111078-Gupta1]. The comprehensive Czech COPD guidelines are based on two elementary principles [@pone.0111078-Koblizek1]. The first is based on the current GOLD strategy, and the second represents a phenotypic approach to symptomatic COPD patients (especially for subjects coming from"
+"1. Introduction {#sec1}\n===============\n\nChronic low back pain (CLBP) that lasts for six months or longer is estimated to occur in 60--80% of the general population in their lifetime \\[[@B1]\\] and is associated with substantial healthcare costs. The sacroiliac joint (SIJ) complex is one of the major sources of chronic low back pain, accounting for around 10--33% of the total number of CLBP cases \\[[@B1]--[@B5]\\]. The SIJ complex consists of the joint capsule, various muscular and ligamentous structures overlying the joint, and neural structures that innervate the SIJ \\[[@B6]\\]. Current treatment options for SIJ complex-mediated CLBP include intra-articular and periarticular steroid injections, SIJ fusion, and radiofrequency ablation of the neural structures innervating the SIJ. Intra-articular injection of the joint using a mixture of steroids and local anesthetics is a simple procedure and provides quick pain relief, but the effect is short-lived \\[[@B7]\\]. In addition, SIJ fusion is an invasive surgical procedure that should be reserved for cases refractory to nonoperative measures \\[[@B8], [@B9]\\]. On the other hand, radiofrequency ablation (RFA) of the SIJ complex offers longer-lasting effects and has gained wide attention in the last decade \\[[@B10]\\], with increasing numbers of reports advocating for its efficacy \\[[@B7], [@B11]--[@B14]\\]. RFA is"
+"###### Strengths and limitations of this study\n\n-   This review will highlight which components of care transition interventions work and how they operate within various contexts, rather than considering intervention effectiveness as a whole entity.\n\n-   Thorough retrieval of pertinent information about the intervention components, mechanisms and study context (ie, search for associated relevant publications and direct contact with study authors if required).\n\n-   Systematic screening protocol with all steps completed in duplicate.\n\n-   Study quality will not be formally assessed.\n\n-   Only English language studies will be included.\n\nIntroduction {#s1}\n============\n\nBy the year 2030, the percentage of persons over the age of 65\u2005years is predicted to double, with an estimated 20--25% of the world\\'s population being 65\u2005years of age and older.[@R1] Over 60% of adults aged 65\u2005years and older have at least one chronic health condition, and approximately 30--50% have two or more conditions and are referred to as multimorbid or complex patients.[@R2] [@R3] These complex older adults use extensive healthcare resources and often require visits to various healthcare providers in a number of settings.[@R2] [@R4] Evidence suggests that managing the transition between these providers and/or settings is difficult within current healthcare delivery systems, and"
+"Introduction {#s1}\n============\n\nBreast cancer accounts for almost one third of cancers diagnosed among women. In the United States, there were approximately 288 thousand new cases expected for 2011 \\[[@B1]\\]. Breast cancer is also the second leading cause of cancer death among women, with nearly 40 thousand attributable deaths expected in 2011 in the US \\[[@B1]\\]. Dietary interventions are emerging as increasingly important strategies for reducing risk of developing breast cancer or recurrence \\[[@B2],[@B3]\\]. Among breast cancer survivors, for instance, the Women's Healthy Eating and Living (WHEL) study found that interventions with a diet high in fruits and vegetables, dietary fibre, and low in saturated fat reduced recurrence by 31% among women without hot flashes compared to the control group \\[[@B4]\\], and that higher vegetable intake, particularly cruciferous vegetables, may have enhanced the effect of tamoxifen, with a 44% reduction in recurrence \\[[@B5]\\]. If shown effective, these and other dietary strategies represent an important way for women to reduce their cancer risk, or for breast cancer patients to reduce recurrence and safely augment the effects of cancer treatment. Soy has emerged as a specific food that may reduce breast cancer risk \\[[@B6]\\], and is among the most commonly used complementary"
+"1. Introduction {#sec1-ijms-19-03728}\n===============\n\nThere are two important biological targets related to breast cancer: Human Epidermal Growth Factor Receptor 2 (HER-2) and Epidermal Growth Factor Receptor (EGFR) \\[[@B1-ijms-19-03728]\\]. Overexpression of ErbB (this abbreviation is derived from the name of a viral oncogene to which these receptors are homologous: erythroblastic leukemia viral oncogene) family members has implicated in many human cancers, and HER-2 expression is predictive of recurrence of human disease and prognosis. Inhibitors of the kinase domain of EGFR and HER-2 have been approved for the treatment of cancer, for example, erlotinib, lapatinib and trastuzumab \\[[@B2-ijms-19-03728]\\]. Receptors of the HER (ErbB) family are critical for the development of various organs and systems. When activated, these receptors bind to dimers, transphosphorylate and become capable of transducing intracellular signals that can affect cell growth, the inhibition of apoptosis, the migration and invasiveness, and angiogenesis, among other processes that lead to progression of malignant tumors \\[[@B3-ijms-19-03728]\\]. The simple overexpression of HER-1 (EGFR) does not transform cells, since the HER1:HER1 dimer is only capable of being transphosphorylated when one of its extracellular ligands is coupled in its active site. HER-2, for which an extracellular ligand has not yet been described, may spontaneously form dimers,"
+"Background {#Sec1}\n==========\n\nAntimicrobial peptides (AMPs) are components of the innate immune system in animals and plants, and play an important role in antagonistic relationships between microorganisms \\[[@CR1]--[@CR5]\\]. There is a great expectation in biotechnological applications of AMPs that include their use as therapeutic agents, biopreservatives in cosmetics, materials and food; and substitutes of antibiotics in animal feed and in crop protection. AMPs are of particular interest in the field of crop protection because they meet the regulatory requirements for low environmental impact of pesticides \\[[@CR3]\\]. However, the exploitation of natural AMPs presents limitations, as they are produced in low amounts in the living organisms and their extraction and purification requires complex and costly procedures. In addition, natural AMPs might show toxicity against non-target organisms \\[[@CR6]\\].\n\nThe rational design of AMPs may overcome these limitations by developing peptides with improved biological properties, like increased antimicrobial activity and stability, and reduced toxicity against non-targeted organisms \\[[@CR7]--[@CR9]\\]. In this context, a library of synthetic linear undecapeptides consisting of cecropin A (1--7)-melittin (2--9) hybrids (named CECMEL11 library), was previously obtained by combinatorial chemistry \\[[@CR8]\\]. Several peptides from this library showed potent antibacterial and/or antifungal activities with low cytotoxicity (hemolytic and phytotoxic activity) and"
+"Introduction {#sec1-1}\n============\n\nAtypical mycobacterial infections from organisms such as *Mycobacterium chelonae* have been well documented in the literature following laser-assisted *in situ* keratomileusis (LASIK).\\[[@ref1][@ref2]\\] However, it is not until recently that there have been further reports of the involvement of this pathogen in a patient with Sjogren\\'s syndrome\\[[@ref3]\\] and no other apparent risk factors and also following corneal graft surgery for a range of indications,\\[[@ref4][@ref5]\\] manifesting almost three decades posttransplant.\\[[@ref6]\\] We present a case of *M. chelonae* keratitis occurring 1 year after tectonic keratoplasty.\n\nCase Report {#sec1-2}\n===========\n\nA 71-year-old male presented to our Emergency Department with a short history of reduced vision and pain in the left eye. His only known previous ophthalmic history was of corneal foreign body removal 45 years previously although previous medical history included peripheral vascular disease, ischemic heart disease, chronic obstructive pulmonary disease, and osteoporotic vertebral fractures. Initial ophthalmic assessment revealed vision of light perception only, with an inferior descemetocoele and positive Seidel test. His right eye was unremarkable with no evident corneal pathology. Emergency tectonic keratoplasty was performed and culture of samples taken at the time of surgery revealed skin flora only. Recovery following tectonic keratoplasty was complicated by a nonhealing epithelial"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec005}\n============\n\n*Streptococcus pneumoniae*, a commonly isolated bacterial pathogen in otitis media, can also cause invasive disease such as bacteremia, bacteremic pneumonia and meningitis, and is associated with high case fatality rates. Nigeria, the most populous nation in Africa, is one of the countries with the highest pneumococcal mortality rates in the world; in 2000, there were an estimated 86,000 deaths in children under 5 years of age, the second highest of any country worldwide \\[[@pone.0152253.ref001]\\]. However, invasive pneumococcal disease (IPD) is likely being underreported, based on the high prevalence of pneumococcal carriage in Nigerian infants \\[[@pone.0152253.ref002]\\] and reports of substantial pneumococcal disease burden in other parts of sub-Saharan Africa \\[[@pone.0152253.ref003]--[@pone.0152253.ref005]\\].\n\nA major challenge in accurately determining the prevalence of IPD is the lack of resources necessary for obtaining and processing diagnostic specimens. In addition, the widespread use of non-prescription antibiotics prior to evaluation by a physician makes recovery of viable bacteria difficult in children who present for care \\[[@pone.0152253.ref006], [@pone.0152253.ref007]\\]. Dried blood spot (DBS) testing is an ideal method for diagnosing infections in resource-limited settings because of its low cost, minimal blood volumes involved, and capacity"
+"Widespread concern exists among policymakers and the public about the potential effects of alcohol advertising on alcohol consumption and problems, especially among children and adolescents. It is especially important to counter the potential effects of advertising on young people because these age groups may be more susceptible to those effects. Children are less able to discriminate between advertising and other media content and are less critical of commercial messages than are adults ([@b3-15-21]). Moreover, recent studies of children and adolescents (e.g., [@b8-15-21]; [@b16-15-21]; [@b39-15-21]) have shown that attention to and liking of alcohol advertising are related to (1) greater knowledge about alcohol slogans and beer brands, (2) more favorable beliefs about drinking, (3) increased intentions to drink as an adult, and (4) increased drinking. Similarly, it may be important to counter the potential effects of alcohol advertising on young adults, and especially college students, who frequently are at risk for heavy and problematic drinking ([@b38-15-21]).\n\nA recent national survey indicates that 67 percent of adults in the United States support banning liquor advertisements on television and 61 percent favor banning beer and wine advertisements in this medium ([@b37-15-21]). Similarly, public health advocates routinely call for the strict regulation or even"
+"Charcot-Marie-Tooth disease is a demyelinating peripheral neuropathy and is a heterogeneous inherited disorder (40 loci have been described so far) affecting peripheral nerves. Two forms, CMT1A and CMTX, account for 60 and 15% of patients, respectively, with clear familial transmission (Boerkel et al., [@B3]).\n\nCMTX is caused by mutations in the GBJ1 gene encoding the synthesis of connexin 32 (Cx32, Bergoffen et al., [@B2]), which is a myelin protein related to PNS and CNS (Scherer et al., [@B21]). Cx32 is a membrane protein located in gap junctions, which forms hexameric hemichannels called connexons. However, the mechanism by which anomalies in connexin 32 affect myelination and function of PNS remains is still unclear. Here, we share our opinion that CamKinase are involved in the pathophysiology of CMTX and likely involve genomic instability caused by mutations in Gjb1.\n\nConnexin, CamKII, and genomic stability {#s1}\n=======================================\n\nApart from its role in the synthesis of Cx32, an inappropriate expression of the gene Gjb1 has recently been associated with genomic instability during mitosis (Mones et al., [@B13], [www.mitocheck.org](http://www.mitocheck.org)) leading to the hypothesis that connexins may be linked, directly or indirectly, to genomic stability. The literature suggests that at least one signaling pathway is associated with"
+"The epidemic of severe acute respiratory syndrome (SARS), an emerging infectious respiratory disease caused by a novel coronavirus,[@bib1] started in Guangdong Province, China in November 2002 and swept over 31 countries and regions worldwide, accounting for a cumulative number of 8,098 infected cases and 774 deaths (case fatality, 9.56% as reported on January 24, 2004).[@bib2] With regards to the treatment of SARS, no specific approaches so far are available. Glucocorticosteroid administration for acute lung injury (ALI) or ARDS arising from critical SARS remains controversial, as does for ALI or ARDS arising from other etiologies. Many studies have looked into the use of corticosteroids in SARS management in terms of efficacy, duration, dose, and severe adverse events; however, further investigations are needed to characterize the treatment efficacy and safety profiles of steroids in this condition.[@bib3] Some authors[@bib4], [@bib5], [@bib6] implied that large-dose steroids were indicated during the early phase once a diagnosis was made, to prevent further deterioration, while some others[@bib7], [@bib8], [@bib9] thought that large-dose therapy was not advisable although steroids could help. Open clinical trials[@bib6], [@bib9], [@bib10], [@bib11], [@bib12], [@bib13], [@bib14] also demonstrated that pulse steroid therapy could reduce mortality without associating an increased rate of life-threatening complications. Unfortunately,"
+"Introduction {#Sec1}\n============\n\nGlaciers are sensitive climate indicators^[@CR1]^, and have been shrinking globally for the past decades with some localized exceptions (*e.g*., eastern Pamir Plateau and central Karakoram)^[@CR1]--[@CR5]^. Due to that glaciers store important water resources in the form of snow and ice (\\~75% of the world's freshwater), contributing significantly to runoff, especially in mountainous areas, changes of glaciers exert a considerable influence on mountainous watershed hydrology, and indirectly have a significant and lasting impact on local and downstream ecosystems and populations^[@CR6]--[@CR10]^. Because of environmental lapse rates and orographic lifting (and associated cloudiness)^[@CR11]^, many high-elevation catchments are energy-limited where much of the globe's important fresh water resources are conserved^[@CR12],[@CR13]^. The impacts of climate warming could vary considerably between different glaciers^[@CR14]--[@CR17]^, inducing different hydrological responses in glacierized mountainous basins.\n\nThe Tibetan Plateau and its surrounding area contain the largest number of the glaciers (with an area of \\~100, 000 km^2^) outside the Polar Regions^[@CR4]^, and 78% of them are continental^[@CR18]^, which has been regarded as the Asian Water Tower and supporting 1.4 billion people^[@CR10]^. Evidence showed that most of the glaciers (excluding the Karakorum) are retreating influenced by the climate changes on the Tibetan Plateau^[@CR4]^. Glacier changes on the Tibetan Plateau"
+"INTRODUCTION\n============\n\nCellular senescence is a cell cycle arrest program induced by various stresses that renders cells insensitive to mitogenic signals and impairs the proliferation and expansion of damaged cells ([@R1]). Activation of oncogenes such as *RAS* in somatic cells induces a senescence program termed oncogene-induced senescence (OIS) ([@R2]). OIS is a cell-intrinsic tumor suppressor mechanism that impairs tumor progression ([@R2]--[@R7]). Senescence is also characterized by the activation of the senescence-associated secretory phenotype (SASP). The SASP is a cocktail of proinflammatory cytokines, chemokines, growth factors, and matrix-remodeling proteins with diverse functions and roles ([@R8]--[@R10]). Through the SASP, senescent cells elicit multiple paracrine effects to promote the normal processes associated with inflammation, wound healing, tissue remodeling, and cell plasticity ([@R11]--[@R14]) or it can disrupt tissue homeostasis, promoting aging and other pathophysiological conditions such as fibrosis and cancer ([@R12]). The SASP reinforces the cell cycle arrest by activating p53 and the cell cycle inhibitors p21^CIP1^ and p15^INK4b^ ([@R8], [@R10], [@R15]). The SASP also promotes paracrine senescence ([@R15]) and stimulates immune surveillance that results in clearance of the senescent cells ([@R16]--[@R18]), which collectively contribute to the tumor suppressor program elicited by OIS. Therefore, the immune system can regulate senescence and determine senescent cell"
+"1. Introduction {#sec1}\n===============\n\nTranssexualism is a condition in which a person lives a significant incongruence between gender identity and physical phenotype \\[[@B1]\\]. This conflict causes general suffering called gender dysphoria and a strong desire to live and be accepted as a member of the opposite sex. Treatment for person with gender identity disorder is based on psychiatric and psychological support, hormonal therapy, and gender reassignment surgery \\[[@B1]\\]. Female-to-male reassignment surgery is a series of complex surgical procedures which may include mastectomy, hysterectomy with bilateral salpingo-oophorectomy (BSO), and penile and scrotal reconstruction. The aim of our study is to evaluate if robotic single-site hysterectomy with BSO could play a role in reassignment surgery for female-to-male transsexualism (FMT).\n\n2. Material and Methods {#sec2}\n=======================\n\nWe conducted a retrospective analysis of perioperative data from ten consecutive patients who underwent robotic-assisted single-site laparoscopic hysterectomy (RSSH) for FMT at our institution from April to December 2013. Candidates for gender reassignment were referred to us for the operation from various centers. All patients had diagnosis of gender identity disorder assessed by mental health professional according to DSM-IV-TR criteria \\[[@B2]\\] and all of them met World Professional Association for Transgender Health Standards \\[[@B3]\\] including documentation of"
+"Introduction {#Sec1}\n============\n\nThe novel trend for the management of chronic diseases is evolving and is leading towards integrative approaches that include health promotion and non-pharmacologic therapies. Active and Healthy Ageing (AHA) is being promoted through these approaches. The European Innovation Partnership on AHA (EIP on AHA) is deployed in 3 areas and 6 action plans including the scaling up and replication of successful innovative integrated care models for chronic diseases amongst older patients \\[[@CR1]\\].\n\nThe R\u00e9gion Languedoc-Roussillon is the umbrella organization for an interconnected and integrated project on AHA which covers the 3 pillars of the EIP on AHA \\[[@CR2]\\]. All subactivities are included in MACVIA-LR^\u00ae^ (MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon), one of the Reference Sites of the EIP on AHA, built around chronic diseases, ageing and disability. The MACVIA-LR^\u00ae^ framework has the vision that the prevention and management of NCDs are essential for AHA promotion and for reducing disability. The main objective of MACVIA-LR^\u00ae^ is to develop innovative solutions in order to (1) improve the care of patients affected by NCDs, (2) reduce avoidable hospitalization and (3) scale up the innovation to regions of Europe. One of the strengths of MACVIA-LR is the sound link"
+"Background\n==========\n\nFew studies, if any, of hepatitis B (HBV), hepatitis C (HCV) and HIV co-infections in pregnant women in Zambia have been undertaken. HBV, HCV and HIV share at least one common route of infection: blood to blood contact through various transmission modalities.\n\nObjective\n=========\n\nIn this study, the researcher attempted to evaluate the prevalence of HBV and HCV co-infections among HIV positive pregnant women.\n\nMethod\n======\n\nNinety-seven HIV positive pregnant women (not yet on HAART) admitted to mostly labor ward were clinically examined and had their case files reviewed. They were also on PMTCT program for HIV. HBV surface antigens and anti-HCV antibodies were checked using ELISA. Information concerning their HIV status was obtained from the case files and antenatal cards.\n\nResults\n=======\n\n\u2022 HCV antibody seroprevalence was 4.1%(4/97), while the prevalence of HBV was found to be 9.3%(9/97).86.6%(84/97) of the cases had only HIV infection\n\n\u2022 Those with HBV/HCV co-infection tended to be older (age range 26--37 years), and all were black women three quarters of whom had poor socio-economic status\n\n\u2022 38.5% of those with co-infection reported having had a sexually transmitted infection (STI)\n\n\u2022 Only 9.3% of all the cases had done their CD4 counts."
+"Introduction {#S0001}\n============\n\nCytochrome P450 (CYP450) is a superfamily of enzymes involved in the metabolism of a large number of endogenous and exogenous compounds including drugs and environmental pollutants (Anzenbacher & Anzenbacherov\u00e1, [@CIT0002]). The catalytic activity of CYP450 enzymes can be affected by various factors, including genetic background, age, sex and diet (Glue & Clement, [@CIT0005]). An assessment of the CYP450 activity is important in toxicologic and pharmaceutical studies. A variety of assays were developed to assess the activity of specific CYP450 isoforms using variable probe substrates. Generally, for activity determination, a known substrate for a specific CYP enzyme is incubated with microsomes in the presence of NADPH and the concentration of the formed substrate metabolite is measured. The main limitations of such assays are a low speed of quantification and high amount of an enzyme source (Hickman *et al.*, [@CIT0004]). Thus, the development of a method to simultaneously assess several isozymes is beneficial because it can drastically reduce the time and cost of analysis. Recently, a number of methods in which a cocktail of CYP substrates was used in a single microsomal incubation were developed (Jurica *et al.*, [@CIT0006]; Alden *et al.*, [@CIT0001]; Otten *et al.*, [@CIT0008]).\n\nHepatic microsomes,"
+"Sir,\n\nLaparoscopic (transperitoneal or retroperitoneoscopic) donor nephrectomy (DN) has become the gold standard for kidney retrieval from living donors. It requires dissection on the surface and around aorta at level of origin of renal artery to obtain good length of renal vessels during left DN. In the process, many lymphatic channels in the periaortic region are severed. Usually, they seal off on their own. Rarely, they continue to leak leading to chyloretroperitoneum/chylous ascites. We encountered one such patient who had chyloretroperitoneum following retroperitoneoscopic left DN.\n\nA 48-year-old healthy male underwent uneventful left retroperitoneoscopic DN. Post-operative period was smooth and he was discharged on 3^rd^ post-operative day (POD). He presented with left flank pain, swelling, fever, nausea and vomiting on 14^th^ POD. On examination, his vital signs were normal. A tender lump was present in left flank extending from hypochondrium to left iliac fossa. His hematological and biochemical profile was normal. Ultrasound abdomen showed fluid collection with scanty loculi in left flank. Central port site was opened under local anesthesia and a 30 French drain tube was placed into the retroperitoneum. Stat output was 1.6 l of milky white fluid. Gram staining and culture was of the fluid was non-contributory. Biochemistry"
+"Introduction {#sec1}\n============\n\nThe efficient interconversion of electrical and chemical energy requires control over inner-sphere bond activation and electron-transfer reactions taking place at electrode surfaces. Unlike outer-sphere electron-transfer reactions, inner-sphere reactions require bonding between the substrate and the surface, and thus, the local environment within molecular length scales of the surface defines the reaction profile. This local environment is radically different from the environment in the bulk of the electrolyte because the polarization of the electrode surface generates a sharp electrostatic potential gradient that corresponds to an electric field in the range of 10^9^ V m^--1^.^[@ref1]\u2212[@ref4]^ At a qualitative level, these fields are known to order the solvent, orient dipolar species, and accumulate ions, all of which serve to dramatically augment the free energy landscape for inner-sphere electrocatalysis.^[@ref5]\u2212[@ref8]^ As a poignant example, it has long been recognized that Pt electrodes are \u223c100-fold less active for H~2~ evolution catalysis in alkaline than acidic media,^[@ref9]\u2212[@ref16]^ and a recent study attributed this to an increased interfacial field strength in alkaline media that serves to slow proton transfer to the surface.^[@ref9],[@ref17],[@ref18]^ Clearly, a quantitative understanding of the interfacial field environment under reaction conditions is essential for understanding reactivity trends, and for the rational design"
+"All relevant data are within the paper.\n\nIntroduction {#sec001}\n============\n\nChronic beryllium disease (CBD) develops in up to 16% of individuals exposed to beryllium (Be) and is characterized by granulomatous inflammation and the accumulation of CD4+ T cells in the lung \\[[@pone.0117276.ref001]\\]. Using the Be lymphocyte proliferation test (BeLPT) we have identified workers with beryllium sensitization (BeS), demonstrating an immune response to Be with an abnormal BeLPT, but no evidence of CBD \\[[@pone.0117276.ref002], [@pone.0117276.ref003]\\]. Studies show that Be persists within the lungs of individuals many years after exposure has ceased \\[[@pone.0117276.ref004]\\], suggesting a failure to clear Be antigen from the lungs. This retention of Be may perpetuate an ongoing Be-specific immune response in CBD and/ or progression from BeS to CBD. It has been hypothesized that alveolar macrophages may undergo apoptosis upon exposure to Be and that this may contribute to retention of Be in the lungs of those with CBD \\[[@pone.0117276.ref004], [@pone.0117276.ref005]\\].\n\nIn human peripheral blood, monocyte subpopulations with distinct functional properties have been defined by their expression of CD14 and CD16. CD14 is the receptor for complexes of lipopolysaccharide (LPS) and LPS-binding protein \\[[@pone.0117276.ref006]\\]. CD16 is the low-affinity receptor for the Fc region of IgG (Fc\u03b3 receptor type"
+"We appreciate the comments by Dr. Zhang and Dr. Xu on our article,^1^ which affirmed our research and provided valuable suggestions. The coronavirus disease 2019 (COVID-19) outbreak in late December 2019 quickly emerged into a pandemic in 2020. However, there are currently no effective drugs or vaccines for COVID-19. The COVID-19 mortality risk score model may help clinicians reduce COVID-19-related mortality by implementing better strategies for use of limited medical resources. As the commentators suggested, our model still needs further validation studies. Patients in our study were hospitalized with laboratory-confirmed diagnosed COVID-19 in Wuhan, China, which might not be representative of the non-hospitalized patients and patients of other races and ethnicities. In addition, prediction for progression risk in COVID-19 patients requires further research. Previous studies mostly focused on the study of risk factors for COVID-19 mortality, but there have been a few studies on establishing models for COVID-19 mortality.^2--5^ To apply the prediction model to the clinic more quickly and optimally, we hope that more scholars will study and validate this model in different populations and regions: fighting the epidemic together, as peers all over the world.\n\nACKNOWLEDGMENTS {#sec0001}\n===============\n\nThis work was supported by the grants from the HUST"
+"Coronal ISH data for 4345 genes obtained from the Allen Mouse Brain Atlas (<http://mouse.brain-map.org/>) at 200 \u03bcm resolution in male, 56-day-old C57BL/6J mice at 25-\u03bcm sections. Code to download and analyze data sets are supplied as Supporting Information.\n\nIntroduction {#sec001}\n============\n\nThe mammalian neocortex is classified into a series of anatomically and functionally distinct regions or cortical areas \\[[@pone.0212898.ref001],[@pone.0212898.ref002]\\]. Areas are often identified using histochemical stains and antibodies to visualize differences in protein expression across cortex. Examples include cytochrome oxidase histochemistry and antibodies against m2 muscarinic receptors \\[[@pone.0212898.ref003]\\]. Numerous differences in expression across cortical areas have been observed, including abrupt changes in expression at area borders, more graded changes between areas, gradients in expression across an area, and changes in cell-specific expression \\[[@pone.0212898.ref004]--[@pone.0212898.ref011]\\].\n\nWe reasoned that there may be genetic markers of cortical areas that have not been identified and that we might identify additional markers by screening the Allen Mouse Brain Atlas, a database containing in situ hybridization information for thousands of genes \\[[@pone.0212898.ref012]\\]. We developed numerical tools to screen the many thousands of images in the database, using a random forest algorithm to identify changes in gene expression at the boundaries of cortical areas defined in the Allen"
+"The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are are available from the GenBank database and accession numbers are provided in the Supporting Information file S2.\n\nIntroduction {#s1}\n============\n\nThe genus *Meconopsis* Vig. includes about 50--60 species that are distributed mainly in the Qinghai-Tibetan plateau (QTP) [@pone.0104823-Taylor1]--[@pone.0104823-Yoshida1] and is a symbol of the Himalayan alpine flowers. The only European species, *Meconopsis cambrica* is distributed in the humid and shady deciduous forests of Ireland and from south-west England to Northern Spain. The genus is well known as the 'Himalayan blue poppy' and has fascinated the Western world because of its attractive flowers [@pone.0104823-Taylor1]--[@pone.0104823-Yoshida2]. Species of this genus can also be found in some European gardens, since they were introduced in these regions about two centuries ago. However, the taxonomy and phylogeny of the genus of this famous garden plant species remain largely unresolved [@pone.0104823-Wu1], [@pone.0104823-Egan1], [@pone.0104823-Toshio1].\n\nThe genus *Meconopsis* was founded in 1814 on the basis of the single European species *Papaver cambrica* L. [@pone.0104823-Taylor1]. This species is different from typical *Papaver* species because of the presence of a short style and the complete absence of a sessile stigmatic disc surmounting the"
+"INTRODUCTION\n============\n\nAtopic dermatitis (AD) has been considered as a T helper (Th) cell type 2 disease characterized by predominant Th2-mediated cytokine production, including IL-4, IL-5, and IL-13, elevated serum IgE, and eosinophilia ([@B1][@B2]). Thymic stromal lymphopoietin (TSLP), IL-25, and IL-33 are mainly produced by epithelial cells, and have important functions of inducing Th2-type adaptive responses and group 2 innate lymphoid cells, which contribute to AD phenotype ([@B3][@B4]). However, Th1 cells and innate inflammatory cytokines are also involved in the pathogenesis of AD. Interferon-\u03b3 (IFN-\u03b3) and IL-12 are also expressed in chronic AD lesions. The expression of IFN-\u03b3, but not IL-4, in skin correlates with the clinical course of AD and is known to be downregulated with AD improvement ([@B5]). AD patients have elevated levels of CC chemokine receptor 4 ligands, including thymus and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC), which mediate preferential Th2 recruitment ([@B6]). Additionally, CXC chemokine receptor 3 ligands, which induce Th1 polarization, such as monokine induced by IFN-\u03b3, are also elevated in AD patients compared to normal controls ([@B6]). In addition to inflammatory microenvironment imbalance, important barrier-related proteins including filaggrin (FLG) and loricrin (LOR) are decreased in AD ([@B7]). In primary keratinocytes, tumor necrosis factor"
+"1. Introduction {#sec1}\n===============\n\nQuantitative Structure--Activity Relationship (QSAR) studies unravel structural and physicochemical requirements for biological activity in a great variety of compounds [@bib1]. The classic QSAR studies connect information of the chemical structure of the molecule, expressed by means of numbers, with the biological activity [@bib2]. However, QSAR-like procedures are not restricted to drugs and biological activity but other systems and properties, such as allergenic character of proteins, may be predicted [@bib3], [@bib4], [@bib5], [@bib6]. One special class of indices used in QSAR called Topological Indices (TIs) are based on the concept of molecular graph; which indicates the presence of vertices or nodes (atoms) and connections or edges between nodes (chemical bonds) [@bib7], [@bib8], [@bib9], [@bib10]. In the same way, the field of application of TIs is, of course, not restricted to the chemistry of low-molecular-weight compounds and extends to other branches of sciences. In general, TIs of different types of graph representations or networks such as protein structure, gene polymorphisms, metabolic networks, food webs or host--parasite networks, internet, or social networks may be used. In these networks, amino acids, nucleotides, enzymes, microorganisms, cerebral cortex regions, web pages, social groups...etc, may play the role of nodes and electrostatic interactions,"
+"Introduction {#Sec1}\n============\n\nTreated wastewater (TWW) is frequently used for irrigation in semi-arid and arid zones. In Israel, most fruit tree plantations, including citrus orchards, are irrigated with TWW of various qualities. Depending on the original water source and level of treatment, TWW might result in increased salinity, increased concentrations of organic and inorganic compounds, and increased levels of living organisms as compared to fresh water (FW)^[@CR1],[@CR2]^, as well as changes in soil structure.\n\nSoils can be highly variable in salt concentration, soil moisture, hydraulic properties, and nutrient availability^[@CR3]^, and references within^[@CR4]^. High concentrations of clay particles enhance soil compaction, reduce aeration and available soil water, and adversely affect growth^[@CR5],[@CR6]^. Root growth is often slowed by a combination of soil physical stress and water quantity or quality. Stress may vary continually, depending on the location of the root in the soil profile, prevailing soil water conditions and soil texture^[@CR7]^.\n\nTWW contains high concentrations of saline components, and organic and inorganic suspended particles compared with fresh water (FW), which can lead to a breakdown in soil structure and reduced hydraulic conductivity, increased osmotic potential, decreased aeration and reduced root growth^[@CR8]^. Reductions in root function and water uptake^[@CR4],[@CR7],[@CR9]--[@CR12]^, may be responsible for"
+"To the editors of health economics review: {#Sec1}\n==========================================\n\nThere is ample evidence on the effects of prices and taxes on heavy drinking, including binge drinking \\[[@CR1]\\]. Experiments on \"Happy Hour\" discounts in barroom settings have shown that when the price of alcohol decreases, consumption increases, and vice versa \\[[@CR2], [@CR3]\\]. A well-cited meta-analysis of 112 studies (Wagenaar et al., \\[[@CR4]\\]) identified ten studies on heavy drinking and estimated a significant elasticity of \u22120.28. Another systematic review by Elder and colleagues \\[[@CR5]\\] concluded that alcohol tax levels were inversely associated with excessive drinking. This is consistent with the conclusion from a widely-cited review by Cook and Moore \\[[@CR6]\\] that \"an increase in price results in reduced consumption\", and this applies to drinking by youth, heavy drinkers, and alcoholics who develop cirrhosis due to chronic consumption. Xuan and colleagues \\[[@CR7]\\] showed that an improved comprehensive measure of alcohol taxes including specific excise tax and value-based taxes resulted in more negative tax elasticity and price elasticity predicting binge drinking, as compared to a conventional measure that relies only on beer excise tax. Another meta-analysis by Wagenaar and colleagues \\[[@CR8]\\] showed that increased taxes and prices were associated with reduced alcohol-related disease and"
+"Introduction {#section1-1479972316687209}\n============\n\nAsthma and chronic obstructive pulmonary disease (COPD) are chronic respiratory diseases (CRDs) of the airways and the lungs.^[@bibr1-1479972316687209]^ According to the American Thoracic Society, CRDs are responsible for around 7% of deaths worldwide; they are a major burden on public health services and are a cause of diminished quality of life and loss of productivity.^[@bibr2-1479972316687209]^ In Lebanon, and despite limited data, one study was able to determine the prevalence of COPD as 9.7%.^[@bibr3-1479972316687209]^ In addition, and as estimated by the World Health Organization, by 2030, COPD will be the third leading cause of death around the world.^[@bibr4-1479972316687209]^ Since respiratory diseases affect a considerable percentage of the population worldwide and because of the increasing risk of morbidity and mortality, more efforts should be made in order to increase prevention and optimize treatment of such diseases. One way is to improve the use of inhaler devices and appropriately train and educate patients.^[@bibr5-1479972316687209],[@bibr6-1479972316687209]^\n\nPressurized metered dose inhalers (MDIs) and dry powder inhalers (DPIs) are the most commonly used inhaler devices. MDIs, developed in the mid-1950s,^[@bibr7-1479972316687209]^ deliver a fixed drug dose from a pressurized canister requiring coordination between inhalation and actuation. Around two decades later,^[@bibr8-1479972316687209]^ DPIs were introduced to the market"
+"INTRODUCTION\n============\n\nIt is a fascinating thought that the single cell zygote contains all the information required for the development of the adult organism. Understanding how this information is encoded and deciphered is a major uncompleted scientific challenge. A group of genes known as homeobox genes has emerged as important master regulators of development. These genes have been highly conserved throughout evolution. They are expressed during embryonic development in a highly co-ordinated manner and continue to be expressed in virtually all tissues and organs throughout adult life.\n\nHomeobox (*Hox)* genes were discovered following the observation of two striking mutations in the fruit fly, *Drosophila melanogaster*. In the *antennapedia* mutation the antennae are changed into legs, whereas in the bithorax mutation, the haltere (a balancing organ on the third thoracic segment) is transformed into part of a wing. These changes were described as homeotic transformations from the Greek word homeosis, signifying a change of a complete body structure into another. *Drosophila* geneticists devised the term 'homeotic selector gene' to encapsulate the concept that a master regulatory gene could control the development of each segment of the fly. Subsequently *Drosophila* was found to contain a cluster of genes consisting of the *bithorax*"
+"1. Introduction {#sec1-nutrients-12-01048}\n===============\n\nEnteral nutrition (EN) can reduce Crohn's disease (CD) activity and maintain remission in both children and adults \\[[@B1-nutrients-12-01048],[@B2-nutrients-12-01048]\\]. According to the international guidelines, nutritional support using orally administered liquid formulas should be considered for CD patients, serious cases of ulcerative colitis (UC), in combination with steroids in undernourished individuals, in cases of steroid intolerance, and in patients with stenosis of the small intestine \\[[@B1-nutrients-12-01048],[@B2-nutrients-12-01048],[@B3-nutrients-12-01048],[@B4-nutrients-12-01048]\\]. Transforming Growth Factor-\u03b2 (TGF\u03b2), a polypeptide present in both human and bovine milk, has been shown to play an important role in the development of immune tolerance and the prevention of autoimmunity, being concurrently an inhibitor of intestinal epithelial cell growth and a stimulator of intestinal epithelial cell differentiation \\[[@B5-nutrients-12-01048]\\].\n\nStudies concerning the administration of EN formulas containing TGF\u03b2 in both adults and children with active and inactive CD have been previously published, although their promising results were based on a small number of patients \\[[@B6-nutrients-12-01048],[@B7-nutrients-12-01048],[@B8-nutrients-12-01048]\\]. Colostrum is the first milk produced after birth, being rich in a number of bioactive molecules, including growth factors. It has been experimentally used in rats, and the results of its administration were encouraging \\[[@B9-nutrients-12-01048],[@B10-nutrients-12-01048]\\], although, again, there is a lack of controlled clinical studies. Finally,"
+"Introduction {#s1}\n============\n\nIn addition to cyclic AMP and inositol triphosphate (IP~3~), cyclic GMP is an omnipresent intracellular second messenger of prokaryotes and eukaryotes. It plays a critical role in the control of physiological processes of cardiac vasculature, smooth muscle relaxation, blood pressure, blood volume, cellular growth, sensory transduction, neural plasticity, learning, and memory. Unique to itself, this second messenger system is generated by the catalysis of GTP by two structurally different guanylate cyclases, soluble and the membrane form (Figure [1](#F1){ref-type=\"fig\"}). The synthetic machinery and the modes of their operation by which they generate cyclic GMP are entirely different, and so are their physiologically regulated processes. This review is focused on the mammalian membrane guanylate cyclase transduction field, a principal area of research by the authors for several decades. It begins with its historical development. Briefly narrates the efforts involved building on small projects, brick by brick, and emerged from the chasm of disbelief, through steady, continuous work. It then moves on to its present status. To make the presentation simple and chronologically continuous, the subject matters of the earlier reviews (Sharma et al., [@B145]; Pugh et al., [@B127]; Sharma, [@B137]; Duda et al., [@B44]; Sharma, [@B138]; Sharma and Duda,"
+"Introduction {#Sec1}\n============\n\nIn spite of an over thousand year old Chinese text that hints at nitrite as a remedy for angina pectoris, the substance had long been considered to exert few physiological effects, except for causing blue baby syndrome, and being potentially carcinogenic, *via* nitrosamine formation^[@CR1],[@CR2]^. Nutritional sources for nitrite in humans are cured meat products such as hot dogs and -- as nitrate is reduced to nitrite by commensal bacteria in the saliva -- nitrate-containing vegetables such as beetroots. It is also long known that nitrite is generated by biological decomposition of nitric oxide (NO)^[@CR2]--[@CR5]^.\n\nWhat has become clear in the last decade only, is that *vice versa* nitrite is an important source for NO. Thus, besides the canonical NO generation by NO synthases, NO is formed by reduction of nitrite. This is achieved by a number of proteins including haemoglobin and myoglobin. These proteins' reductase activity is allosterically regulated by ambient partial pressure of oxygen (pO~2~) and ambient pH in such a way that reductase activity increases in hypoxic and acidic environments. Thus, whereas conventional NO-donors such as nitroglycerin bear a considerable risk for critical hypotension due to generalized vasodilation, nitrite's mechanism of action provides NO and,"
+"1.. INTRODUCTION\n================\n\nAcute intermittent porphyria (AIP) is a rare autosomal dominant metabolic disease caused by a mutation in the gene for the porphobilinogen deaminase enzyme in the haem biosynthesis ([@ref1]).\n\nIt is characterized by increased urinary excretion of the porphyrin precursors: delta-aminolevulinic acid and porphobilinogen ([@ref1]). The attack of the disease is caused by many endogenous and exogenous factors such as \"porphyrogene\" drugs, pregnancy or menstruation, hyperemesis gravidarum, hormones, dietary changes, starvation, alcohol abuse, infectious diseases and surgery which all could trigger the appearance of symptoms ([@ref2]).\n\nSymptoms include attacks of abdominal pain, motor and/or sensory polyneuropathy, autonomic nervous system dysfunction, and electrolyte disbalances such as hyponatraemia, mental changes, and seizures ([@ref1]). Pregnancy represents an essential risk factor for exacerbations in patients suffering from AIP ([@ref3]).\n\nThe association of AIP with pregnancy and as a cause of spontaneous abortion is rare. We hereby present this case because of its rarity and limited gynecological and obstetrical experience of this disorder.\n\n2.. AIM\n=======\n\nThe purpose of this article is to show a case of AIP known before pregnancy in a patient who had a spontaneous abortion.\n\n3.. CASE REPORT\n===============\n\nA gynecologist examined 26-year-old patient in the 8th week of"
+"5-methylcytosine (5\u2009mC) is an epigenetic mark in the genomic DNA that plays important roles in modulating transcriptional activities, genomic imprinting and suppressing transposable elements in most eukaryotic organisms. In mammals, DNA methylation is predominantly found in the context of a symmetric CG (5\u2009mCG)[@b1][@b2], whereas in plants, DNA methylation usually occurs in all sequence contexts: symmetric CG and CHG (5\u2009mCHG) (where H\u2009=\u2009A, T, or C), and asymmetric CHH (5\u2009mCHH)[@b3]. In a symmetric sequence, 5\u2009mC can be fully methylated (fully-5\u2009mCG or fully-5\u2009mCHG) ([Fig. 1B](#f1){ref-type=\"fig\"}) or hemi-methylated (hemi-5\u2009mCG or hemi-5\u2009mCHG). The establishment and maintenance of 5\u2009mC is required for both the inheritance and transmission of epigenetic signals from the mother cell to the daughter cell. The role of the SET- and RING-associated (SRA) domain proteins in the establishment and/or maintenance of 5\u2009mC in both plants and mammals was reported previously[@b3].\n\nIn *Arabidopsis*, the SRA domain of the SU(VAR)3-9 HOMOLOG (SUVH) histone methyltransferase recognizes 5\u2009mC (mC) in different sequence contexts and methylation statuses. The methylated CG status can be hemi-5\u2009mCG (5\u2032mCG3\u2032/3\u2032GC5\u2032) or fully-5\u2009mCG (5\u2032mCG3\u2032/3\u2032GmC5\u2032). Similarly, the methylated CHG status can be hemi-5\u2009mCHG (5\u2032mCHG3\u2032/3\u2032GDC5\u2032; H is non-G whereas"
+"Background\n==========\n\nLung disorders in children are quite common\\[[@B1],[@B2]\\] and usually of an obstructive nature, generally confined to the intra-thoracic, intrapulmonary airways\\[[@B3]\\]. Reliable information on pulmonary function would aid the diagnostic process and patients\\' follow up. Studies on respiratory function tests concerning school children and adolescents have already been published \\[[@B4],[@B5]\\]; and specific criteria for acceptance of maximal expiratory flow volume (MEFV) curves have also been proposed \\[[@B5]\\]. In recent times attention to this issue in pre-school children has increased \\[[@B3],[@B6]\\]; different methods and means of measurement have been suggested, particularly spirometry \\[[@B5],[@B7],[@B8]\\], whole body plethysmography \\[[@B9]\\], interrupter techniques \\[[@B10],[@B11]\\]. With regard to spirometry, important studies assessing the feasibility and repeatability of the tests in preschool children have been conducted and have moreover demonstrated that many children are able to perform the required manoeuvres \\[[@B5],[@B7],[@B8],[@B12]-[@B15]\\]. The latest guidelines on standardization of spirometry \\[[@B16]\\] emphasized that, with appropriate coaching, children as young as 5 years of age are often able to perform acceptable spirometry.\n\nInfants and preschool children normally have large airways in relation to their lung volume \\[[@B15]\\], thus they empty their lungs more rapidly than older children and adults do. Therefore the forced expiratory volume in one second (FEV1)"
+"Resistance to antimicrobial drugs (termed antimicrobial resistance \\[AMR\\]) in *Neisseria gonorrhoeae* is recognized as a public health problem of global importance ([@R1]*,*[@R2]). The overall magnitude of AMR in *N. gonorrhoeae* is largely unknown in many regions because of substantial gaps in global AMR surveillance ([@R3]). Ceftriaxone, a third-generation extended-spectrum cephalosporin used widely for treatment, is considered to be the last fully effective option currently recommended. However, its durability is not assured; the proportion of gonococcal strains with elevated ceftriaxone MIC values is increasing steadily, and 4 documented cases of resistance to ceftriaxone have been noted, in Japan, France, Spain, and Australia ([@R4]*--*[@R6])*.* A dual therapy treatment regimen of ceftriaxone plus azithromycin is now the recommended standard of care in many countries and was implemented in an effort to stem further development of ceftriaxone resistance ([@R7]); however, failure of this dual therapy has also been reported ([@R8]).\n\nSurveillance of *N. gonorrhoeae* antimicrobial drug sensitivity is a key component of all strategies to manage the emergence of resistance; gonorrhea treatment guidelines are currently formulated under the principle that an antimicrobial drug should be rejected for clinical use in a particular population once a threshold of 5% resistant isolates is breached ([@R1]). However,"
+"Introduction {#sec1-1}\n============\n\nEpithelioid hemangioendothelioma (EHE) is a rare, well-differentiated endothelial tumour with a wide spectrum of behaviour. The term was designed to describe vascular soft tissue tumors between hemangiomas and angiosarcomas in terms of local recurrences and metastatic potential\\[[@ref1]\\]. Epithelioid hemangioendothelioma has several synonyms: low grade anaplastic angiosarcoma, cellular hemangioma, histiocytoid hemangioma and angioendothelioma. It represents 1% of all vascular neoplasms and is locally aggressive \\[[@ref2]\\]. Hemangioendotheliomas of bone are multifocal and multi centric in contrast to other soft tissue tumors. A case of epitheloid hemangioendothelioma arising in bone is presented in the study with its clinical, radiological and histopathological features\n\nCase Report {#sec1-2}\n===========\n\nWe report a case of epithelioid haemangioendothelioma of left tibia in 7 month old boy. He presented with fever and persistent cry of about 2 weeks duration. Parents noticed a swelling on left upper tibia. On examination there was a diffuse swelling at the anteromedial aspect of the left leg in the junction of upper and middle one third, measuring approximately 8x3x3 cms. Skin was shiny. No dilated veins or visible pulsations were seen on the skin over the swelling. Tenderness was present at the site of swelling. No abnormal movements or deformities, or"
+"INTRODUCTION {#cesec10}\n============\n\nRotator cuff injuries are a frequent cause of shoulder pain in individuals of all ages. This condition represents a spectrum of diseases, ranging from reversible acute tendinitis to massive lesions involving all of its components[@bib1].\n\nThese injuries are diagnosed from the clinical history and physical examination, including by means of specific semiological maneuvers and infiltration of local anesthetic into the subacromial space in cases of diagnostic doubt (specific tests)[@bib2].\n\nRadiographic examinations help to define the cause of the impact and assess anatomical factors such as the shape and inclination of the acromion, presence of acromial spurs, presence of os acromiale and osteoarthrosis of the acromioclavicular joint. They show secondary alterations from the impact syndrome, such as subchondral cysts, sclerosis and irregularities of the greater tuberosity of the humerus. Radiographs also serve to identify tendinous and peritendinous calcifications[@bib2].\n\nThe main noninvasive methods used in diagnosing rotator cuff injuries are ultrasound and magnetic resonance imaging (MRI)[@bib3], [@bib4]. Ultrasound is less expensive, but the sensitivity and specificity of its results vary because this is an \"operator-dependent\" examination[@bib4], [@bib5], [@bib6]. MRI demonstrates the contrast between bone and soft tissues and presents degenerative lesions and tendon tears, along with other structural abnormalities"
+"1. Introduction {#sec1-nanomaterials-09-00252}\n===============\n\nConcerns about the future of energy supply availability, together with efficiency issues, or global change evidence are some of the main reasons supporting the huge efforts performed in the optimization of energy production processes, and on consumption rationalization. The required improvements in this area need a great deal of innovation, and a particularly concerned sector is that of cooling and thermal management in industrial processes involving heat transfer processes.\n\nThe optimization of the heat transfer efficiency of conventional fluids is necessary to improve the heat dissipation, energy efficiency, and the device lifetimes. This target entails bringing improvement in diverse thermo-physical properties affecting working fluid flow and heat transfer including thermal conductivity, viscosity, density, and specific heat can be pointed out for their influence \\[[@B1-nanomaterials-09-00252],[@B2-nanomaterials-09-00252]\\].\n\nA revision of literature reveals that rigorous theoretical and experimental studies were recently devoted to increase the thermal conductivity of liquids by using the suspension of small particles. Nevertheless, the limited stability of the resulting suspensions is a key concern for micrometric-sized colloids. The use of dispersed nanometric size nanoparticles has been shown to largely overcome this stability issue. Due to the high surface-to-volume ratio of the nanoparticles, they remain in suspension"
+"All relevant data are within the paper and its Supporting Information files. The data about the manuscript has been uploaded by using SPSS 17.0 format in a supplemental file.\n\nBackground {#sec005}\n==========\n\nThe prevalence of antenatal depression varies from 7.4% to 50.0% worldwide, and from 5.5% to 23.1% in China \\[[@pone.0167597.ref001]--[@pone.0167597.ref007]\\]. The prevalence of depression among pregnant women is higher than that among postpartum women, and it is higher among pregnant women in middle and late pregnancy \\[[@pone.0167597.ref005], [@pone.0167597.ref008]\\]. Antenatal depression is a debilitating experience which can lead to many problems and sequelae. For example, depressed pregnant women may experience multiple conflicting roles, insufficient social support, uncertainty about future life, instability of emotion, and the discontent of body image. Moreover, there can be a risk of preterm birth and obstetric complications. And the newborns' and husbands' mental and physical health can also be threatened by their mothers' and wives' depression as well \\[[@pone.0167597.ref009]--[@pone.0167597.ref016]\\].\n\nThe predictors of antenatal depression include several socio-demographic and health behavior factors such as young or old age, low educational background, and low socio-economic status. Besides, antenatal depression is always related with threatening life events, such as housing problems, financial difficulties, and marital problems \\[[@pone.0167597.ref017]\\]. And negative"
+"Introduction\n============\n\nIn recent years, online gambling has become a more common leisure time activity. Data from 2010 British Gambling Prevalence Survey reports that 14% of the population gambled on the internet in the past year ([@B53]). According to [@B20], there are a number of situational and structural characteristics that make online gambling potentially risky for susceptible and vulnerable individuals such as problem gamblers. Such factors include accessibility, affordability, anonymity, and specific structural features of online games such as high event frequency. Some forms of online gambling may be more problematic than others. For instance, playing online poker (rather than games of pure chance such as an online bi-weekly lottery) has been linked to problematic gambling in some players (e.g., [@B23]). Problem gambling typically refers to gambling that leads to social, psychological, and/or financial difficulties that compromise areas of gamblers' lives such as their job, education, personal relationships, health, etc. ([@B21]).\n\nA number of empirical studies have observed that there are typically more problematic gamblers among those that gamble on the internet compared to those that only gamble in land-based venues. (e.g., [@B61]; [@B22]; [@B24]; [@B60]; [@B17]). However, it should also be noted that problem gambling severity is associated with"
+"Introduction {#sec1}\n============\n\nHepatitis B Virus (HBV) is a small enveloped DNA virus known to infect humans and belongs to the hepadnaviridae family. HBV infection is a major health problem worldwide owing to its high prevalence and significant morbidity and mortality. There are about 2 billion people living with HBV worldwide and about 360 million chronic carriers \\[[@cit0001]\\]. The total number of deaths attributable to HBV was 786,000 according to the Global Burden of Disease (GBD), 2010. Of these number, 132,200 (17%) were estimated to be caused by acute hepatitis B, 341,400 (43%) were caused by liver cancer and 312,400 (40%) were caused by cirrhosis \\[[@cit0002]\\]. As a result, the GBD 2010 estimates HBV to be the 15^th^ ranked caused of human death \\[[@cit0002]\\]. It is transmitted through sexual intercourse, by exchange of saliva during kissing and also from infected mothers to their babies: during childbirth, breastfeeding and through the placenta \\[[@cit0003]\\]. Unlike Human Immunodeficiency Virus (HIV), the hepatitis B virus can survive outside the body for at least seven days \\[[@cit0004]\\]. During this time, the virus can still cause infection if it enters the body of someone who is not protected by the vaccine. The burden of HBV is"
+"Introduction\n============\n\nBased on their exposure to environmental stress, plants have constructed complex signaling networks to adapt to different stress conditions.^[@bib1]^ Protein kinases (PKs) play important roles in both growth and reproduction processes.^[@bib1],[@bib2]^ As a highly conserved sub-family of PKs, the mitogen-activated protein kinases (MAPKs) consist of the following three classes: (1) MAPKs, (2) MAPK kinases (MAPKKs), and (3) MAPKK kinases (MAPKKKs), which act as a signal transmission cascade in the cellular metabolic and transcriptional response centers.^[@bib1],[@bib2]^ MAPKs are activated by MAPKKs via phosphorylation of conserved threonine and tyrosine residues in the Thr--X--Tyr (T--X--Y) motif. MAPKKs, in turn, are activated by MAPKKKs when serine and threonine residues in the S/TXXXXXS/T motif are phosphorylated.^[@bib3; @bib4; @bib5; @bib6; @bib7; @bib8; @bib9]^\n\nIn eukaryotic organisms, MAPK pathways are relatively well-characterized cascades.^[@bib10]^ In plants, genome-wide analyses of MAPK cascades (MAPKKK---MAPKK-MAPK) have been reported in several species.^[@bib11; @bib12; @bib13; @bib14; @bib15; @bib16; @bib17; @bib18]^ In *Arabidopsis*, 23 MAPKs, 10 MAPKKs, and 80 putative MAPKKKs have been identified. MAPK and MAPKK genes in plants are each divided into four distinct classes (classes A, B, C, and D), whereas MAPKKK genes are classified into the following three subfamilies: (1) MEKK, (2) Raf and (3) ZIK.\n\nPlant MAPKs"
+"Introduction\n============\n\nChronic obstructive pulmonary disease (COPD) and heart disease are often associated. Cardiorespiratory decompensation can be related to fluid overload status with increased LVEDVI, LVEDP, airway resistance and work of breathing. This often requires tracheal intubation with a difficult weaning from mechanical ventilation (MV). The basis to treat an overload status consists of diuretic administration, which has been demonstrated to be able to reduce airway edema and resistance. Loop diuretics can induce tolerance. Their use may be associated with increased morbidity due to deleterious effects, particularly on neurohormonal activation of the renin--angiotensin--aldosterone system with increase of sympathetic renal tone, sodium and water retention, progression of cardiac dysfunction and maintenance of cardiorespiratory decompensation.\n\nMethods\n=======\n\nAn alternative approach to remove sodium and water is slow continuous ultrafiltration (SCUF), which has been demonstrated to be effective in congestive heart failure (CHF) treatment. The major hindrance to an extensive early application of SCUF is the requirement of a central venous large-bore catheter and the involvement of specialized medical and paramedical staff. Recently, a new device (Aquadex Flex Flow) for mini-SCUF able to overcome the drawbacks of traditional devices has been developed. It operates with peripheral small-bore venous catheters and does not require"
+"INTRODUCTION\n============\n\nSystemic lupus erythematosus (SLE) is an autoimmune disease involving multiple systems, including the nervous, circulatory, pulmonary, renal, and immune systems.^[@r01],[@r02]^ SLE is prevalent among younger individuals, primarily those aged in their 20s to 40s, and is more frequent in women than men.^[@r03]^ SLE is often complicated with seizures, renal insufficiency, and anemia, which substantially reduce quality of life.^[@r04],[@r05]^ In order to improve management of SLE, it is necessary to clearly understand the prevalence of the disease, including the clinical and socioeconomic characteristics of SLE patients.^[@r06]--[@r08]^ However, no population-based prevalence survey of SLE in South Korea has so far been conducted.\n\nCohort studies involving primary data collection have been used to estimate SLE prevalence, but such studies tend to be costly and time-consuming.^[@r09],[@r10]^ Alternatively, population-based administrative databases, containing physician billing and insurance information, have received increased attention for their potential to provide epidemiologic information, particularly for rare conditions like SLE.^[@r11]--[@r13]^ Along with reduced costs and time requirements, administrative data also offer the advantage of simplicity in establishing and maintaining a population-based surveillance system. However, optimal methods for extracting information from these databases have yet to be determined.^[@r14],[@r15]^ Researchers have therefore called for further studies regarding the usefulness of administrative"
+"1. INTRODUCTION\n===============\n\nInfection with hepatitis B and C virus (HBV and HCV, respectively) and hepatocellular carcinoma (HCC) are responsible for heavy disease burdens in China. In 2006, the Ministry of Health of China (MOH) estimated that, among Chinese aged 1 to 59 years as of 1992, the national prevalence of HBV infection (positivity for HBsAg or any HBV marker) and HBV carriers was 57.63% and 9.75%, respectively, which corresponds to 690 million infected persons and 120 million carriers, as well as 20 million people with chronic hepatitis.^[@r01]^ This disease burden is very large, even when compared with that of tuberculosis, which was responsible for 1.4 million new cases in 2000.^[@r02]^ Chronic hepatitis B is one of the most serious infectious diseases in China. Unfortunately, we lack a clear picture of the national impact of HCV infection. The nationwide prevalence of HCV infection in 1992 was estimated to be 3.2%, which was higher than in Japan, the United States, and most countries of the European Union. HCC is the second most common malignancy in China, and its most frequent cause is chronic HBV infection.\n\nTo date, the MOH has taken several measures to address these diseases. In its National Plan"
+"INTRODUCTION {#s1}\n============\n\nCancer stem cells (CSCs) are resistant to conventional therapeutic approaches \\[[@R1]-[@R3]\\]. As a consequence, they have been directly implicated in the disease pathogenesis of tumor recurrence and distant metastasis \\[[@R4], [@R5]\\]. In addition, drug-resistant CSCs have been linked to unfavorable clinical outcomes, across different tumor types \\[[@R6]-[@R8]\\]. As only a very small percentage of cancer cells have \"stem-like\" and \"tumor-initiating\" properties, they are difficult to study and their key distinguishing features remain relatively uncharacterized, although they appears to resist both chemo-therapy and radiation.\n\nInterestingly, CSCs share many properties with normal stem cells, including immortality and resistance to stress, as well as asymmetric cell division \\[[@R9], [@R10]\\]. A particular distinguishing characteristic of CSCs is their ability to initiate tumors and to undergo anchorage-independent growth, when cultured in suspension \\[[@R11]\\]. Under these particular cell culture conditions, CSCs proliferate and form 3D-spheroid-like structures, containing CSCs and progenitor cells, which are known as \"tumor-spheres\" or \"onco-spheres\" \\[[@R12], [@R13]\\]. In striking contrast, the vast majority of non-CSCs undergo a specialized form of apoptosis in suspension cultures, called anoikis. Importantly, each 3D-spheroid originates from the clonal proliferation of a single CSC, is not to due to the self-aggregation of cancer cells. Thus, tumor-sphere"
+"Results and Discussion {#sec1}\n======================\n\nCyclic GMP is an important signaling molecule controlling a large spectrum of physiological responses in eukaryotes. In vertebrates, for example, this system functions with photoreceptors in visual perception ([Figure\u00a01](#fig1){ref-type=\"fig\"}A) \\[[@bib6; @bib7; @bib8]\\]. It is unclear what aspects of this visual perception system are present in other eukaryotes. The fungus *Allomyces reticulatus* forms swimming zoospores and has been suggested to use rhodopsin-mediated signaling to initiate phototaxis \\[[@bib4]\\]. Nevertheless, how the light signal is transmitted to direct flagellar beating is unknown. Publicly available fungal genomes, mostly from ascomycetes and basidiomycetes (Dikarya), demonstrate that these fungi encode opsins, phytochromes, and cryptochromes \\[[@bib10]\\]. However, all of these fungi lack a motile life cycle stage powered by a flagellum, and therefore phototaxis is not observed. *Blastocladiella emersonii* is a close relative of *Allomyces*, branching below the Dikarya and Glomeromycota fungi \\[[@bib11]\\]. Nearly four decades ago, it was demonstrated that the presence of cGMP along with guanylyl cyclase and cGMP phosphodiesterase activities correlated with the completion of *Blastocladiella* sporulation stage during biogenesis of flagellated zoospores \\[[@bib12; @bib13; @bib14]\\]. These reports indicate the presence of a cGMP signaling pathway, an observation supported by the identification of cDNAs encoding putative guanylyl cyclases"
+"1. Introduction {#sec1-plants-08-00447}\n===============\n\nCassava (*Manihot esculenta* Crantz) is an important food crop in many parts of Asia, Africa and South America. It is mainly used as a raw material for extracting cassava starch which contains low protein, lipid and phosphorus and is considered a great source of carbohydrate. Cassava starch is pure white and its granules are generally round or oval, with a flat surface on one side (truncated end) and is approximately 7--20 \u00b5m in size \\[[@B1-plants-08-00447]\\] depending on genetics, growth periods and seasons \\[[@B2-plants-08-00447]\\]. The amylose contents of cassava starches from a world collection of 4,050 genotypes were reported between 15.2%--26.5% and 20.7% in average \\[[@B3-plants-08-00447]\\]. As compared with other crop starches including maize, rice, wheat and potato starches, cassava starch has fewer variations in its compositions. Cassava starch paste possesses unique characteristics including bland paste with higher viscosity and clarity as well as lower retrogradation rates than starches from cereals \\[[@B1-plants-08-00447]\\]. Nevertheless, there are limitations in cassava starch applications due to its properties, i.e., their swollen, gelatinized granules cannot retain granular structure and thus collapsing instantaneously \\[[@B4-plants-08-00447]\\].\n\nRecently, various genetic cassava starches (natural mutation; non-genetic modification (non-GM) and GM containing absent and high amylose content have"
+"Introduction {#s1}\n============\n\nOver the course of an average day, aortic valve (AoV) leaflets open and close 100,000 times allowing unidirectionality blood flow from the left ventricle to the systemic circulation. The proper function of AoV is achieved by thin leaflets composed of three distinct layers of extracellular matrix (ECM), rich in fibrillar collagen, glycosaminoglycans (GAGs) and elastin. Calcific Aortic Valve Disease (CAVD) appears first as AoV sclerosis developing into AoV stenosis ([@B1],[@B2]). Macroscopically, leaflets are thickened and progressively calcified resulting into stiff leaflets with restricted movement.\n\nCAVD is one of the most common heart valve disease and its prevalence increases with aging\u00a0([@B3]). Nowadays, in western countries, 2.8% of the general population aged over 75 years is affected with moderate to severe aortic stenosis ([@B3],[@B4]). With life expectancy increasing, prevalence of heart valve disease is expecting to rise. Nevertheless, due to a lack of drug treatment ([@B5]), surgery remains the only way to treat it through surgical valve replacement or transcatheter aortic valve implantation.\n\nThe seeking of therapeutic targets relies on mechanistic understanding of CAVD. Due to its association with aging, CAVD used to be considered as a passive disease, but is now established that CAVD is an active"
+"Proprioceptive neurons of the peripheral sensory ganglia innervate muscle spindles, Golgi tendons and joints, playing an essential role in motor control by providing information about the body's position, its movement and balance[@b1]. In a recent study, two mouse Cre lines (*Pvalb*-*Cre* and *HoxB8-Cre*) were used to target a population of sensory neurons that included proprioceptive neurons and a subset of cutaneous mechanoreceptors[@b2]. In these animals, mechanical stimulation of these peripheral neurons evoked non-selective, cationic, rapidly adapting (RA) currents that were dependent on Piezo2 expression, as well as intermediately adapting (IA) currents that were independent of Piezo2. Indeed, Piezo2-deficient mice develop deficits in peripheral proprioception, reflected by their abnormal movement and limb position, supporting a significant role for Piezo2 in proprioception.\n\nIn order to clearly define the role of Piezo2 in proprioception, we have characterized the mechanically activated (MA) currents in neurons of the mesencephalic trigeminal nucleus (MTN), a unique population of purely proprioceptive neurons in the brainstem[@b3][@b4][@b5][@b6]. The homogeneous population of neurons in this nucleus represents a much cleaner system to analyze proprioception than the peripheral sensory ganglia that contain mixed populations of sensory neurons, including proprioceptors, touch receptors, nociceptors and thermoreceptors[@b7][@b8][@b9][@b10][@b11]. These functionally homogeneous trigeminal mechanosensory neurons extend axons"
+"Introduction\n============\n\nAtrial fibrillation (AF) is the most common cardiac arrhythmia, with nonvalvular AF (defined as AF in the absence of rheumatic mitral valve disease, a prosthetic heart valve, or mitral valve repair) comprising the majority of AF cases.[@b1-ijgm-7-441] In general, AF is more prevalent among men than women and occurs more frequently among people of advanced age, with the incidence of AF rising from \\<0.1%/year in patients aged ,\\<40 years to approximately 1.5%/year in women and 2%/year in men aged \\>80 years.[@b2-ijgm-7-441] The prevalence of AF is predicted to increase in the coming decades alongside an aging population in the modern world.[@b3-ijgm-7-441],[@b4-ijgm-7-441]\n\nAF is associated with a 5-fold increased risk of stroke, and one in five strokes are attributed to this arrhythmia.[@b5-ijgm-7-441] Stroke risk in AF is dependent on major risk factors, including prior stroke, transient ischemic attack, thromboembolism, and older age (\u226575 years). Vitamin K antagonists (VKAs) reduce stroke risk in patients with AF by approximately two-thirds compared with placebo and by 38% compared with antiplatelet therapy.[@b6-ijgm-7-441] Although they have since been updated, guidelines available prior to 2010 recommended long-term oral anticoagulation with VKA dose-adjusted to an international normalized ratio between two and three for patients with AF"
+"I. INTRODUCTION {#acm20196-sec-0001}\n===============\n\nComputed tomography (CT) use in the pediatric patient population has witnessed a significant increase^(^ [^1^](#acm20196-bib-0001){ref-type=\"ref\"} ^)^ as diagnostic applications have expanded in concert with tremendous advances in CT technology. A serious concern has been raised over the risk associated with the radiation exposure from these exams in both adult and pediatric patients.^(^ [^1^](#acm20196-bib-0001){ref-type=\"ref\"} ^--^ [^9^](#acm20196-bib-0009){ref-type=\"ref\"} ^)^ The risk is of particular concern in the pediatric patient due to the increased sensitivity,^(^ [^10^](#acm20196-bib-0010){ref-type=\"ref\"} ^)^ as well as the increased opportunity for expressing radiation damage in their lifetime. While patient\u2010specific organ doses have been recommended by the BEIR VII Committee^(^ [^11^](#acm20196-bib-0011){ref-type=\"ref\"} ^)^ for use in prospective radiation epidemiologic studies of the risk from radiation exposure, very little organ dose information exists for Multi Detector Computed Tomography (MDCT) examinations, especially for the pediatric patient population.\n\nThe calculation or estimation of organ dose is quite complex, given the large variation in patient geometry,^(^ [^12^](#acm20196-bib-0012){ref-type=\"ref\"} ^)^ scanner construction, and performance, as well as differences in the technique factors used to generate the images. Methods have been developed to calculate the effective dose,^(^ [^13^](#acm20196-bib-0013){ref-type=\"ref\"} ^--^ [^14^](#acm20196-bib-0014){ref-type=\"ref\"} ^)^ but these methods require knowledge of the dose to radiosensitive organs. Since direct measurement of"
+"The vascular endothelial cell (EC)-specific receptor tyrosine kinase (RTK) TIE2 plays a crucial role in angiogenesis and cardiovascular development [@R5]-[@R13]. Its ligands, the angiopoietins (Ang), induce receptor dimerization and phosphorylation[@R14], with Ang-1 acting as an agonist and Ang-2 as context-dependent antagonist or weak agonist [@R15],[@R16]. In man, heterozygous *TIE2* substitutions that induce *in vitro* ligand-independent hyperphosphorylation cause hereditary mucocutaneous venous malformations (VMCM) [@R1]-[@R4], characterized by multifocal small bluish cutaneous and mucosal lesions, composed of enlarged, tortuous venous channels. The most common is a c.2545c\\>t change (R849W), which occurs in a total of 10/17 families reported [@R1],[@R2],[@R4],[@R17]. The remaining changes (shown in [Fig. 1a](#F1){ref-type=\"fig\"}) have each been identified in a single family [@R2],[@R4]. We previously postulated a paradominant mode of inheritance to account for the heterogeneous, focal lesions of VMCM [@R18]. Here, we identified a somatic, lesion-associated *TIE2* \"2^nd^-hit\" alteration in one resected VMCM, from a patient (Sa-I.4, in [@R1]) carrying the germline R849W. A cDNA screen revealed an in-frame deletion of 129-bp, corresponding to a loss of exon 3 and part of exon 4 (amino acids 122-165 of the extracellular *Ig2* ligand-binding domain; \"Del\", [Fig. 1a, b](#F1){ref-type=\"fig\"}; [Supplementary Fig. 1a](#SD1){ref-type=\"supplementary-material\"}). Allele-specific PCR showed that the loss, which is part of"
+"Introduction\n============\n\nEarly pregnancy loss is the loss of a pregnancy before 20 gestational weeks. Although the exact mechanisms responsible for abortion are not always clear in the first trimester, fetal factors including aneuploid are the predominant etiology and account for 80% to 90% of early miscarriage. Among fetal factor in terms of the first trimester, approximately half of miscarriages are embryonic causes and half of those is due to fetal chromosomal aberrations.\n\nFetal aneuploidy seems to occur as a result of increased chromosomal nondisjunction during the long arrest period in meiosis I, before ovulation \\[[@B1][@B2][@B3][@B4]\\]. There is well-known association between fetal aneuploidy and the maternal chronologic aging. Maternal chronologic aging is correlated to decreased ovarian reserve which is predisposed to a greater risk for fetal aneuploidy \\[[@B5][@B6]\\]. Based on such an association between maternal ovarian reserve and fetal aneuploidy, multiple predictive markers in terms of ovarian reserve including follicle stimulating hormone (FSH) and antimullerian hormone (AMH) level have been studied to predict fetal aneuploidy \\[[@B7][@B8]\\].\n\nAMH, synthesized by human granulosa cells in the ovary, has exhibited significant promise as a potential marker of ovarian reserve \\[[@B2][@B9][@B10][@B11]\\]. Serum AMH levels decline with age. Several studies have shown that AMH is"
+"The recent coronavirus disease 2019 (COVID-19) pandemic raises serious concerns about potential prophylaxis and therapy in a naive population, particularly in patients with primary or secondary immunodeficiencies. The former mainly includes patients with defects in T-cell--mediated immunity and, to a lesser extent, those with antibody deficiencies and immune dysregulation. The latter includes patients undergoing therapy with immunosuppressive drugs, such as stem cell transplanted patients. In addition, patients with B-cell malignancies and autoimmune disorders treated with selected forms of targeted therapy (such as anti-CD20) may develop secondary immunodeficiency characterized by hypogammaglobulinemia. Although many drug candidates have been identified through *in\u00a0vitro* viral neutralization experiments or based on clinical observations, thus far, there are no specific therapeutic agents to treat COVID-19. The antiviral drug remdesivir has shown some effects during compassionate use in patients with COVID-19[@bib1]; however, randomized, placebo-controlled clinical trials have yet to prove its value. Another combination of antiviral drugs (lopinavir-ritonavir) did not provide any benefit for hospitalized patients with COVID-19 with severe disease in a randomized, controlled, open-label trial.[@bib2] The antimalaria drug chloroquine/hydroxychloroquine has also been reported to show positive clinical results. However, recent studies showed no beneficial effects but rather a negative influence on cardiac function, with an"
+"See related commentary by Kovalaske and Gandhi, <http://ccforum.com/content/13/4/161>\n\nIntroduction\n============\n\nHyperglycaemia occurs frequently, even in patients without pre-existing diabetes \\[[@B1]\\], and adversely affects outcome \\[[@B2]\\]. For this reason, treatment with insulin is widely used; however, insulin therapy is associated with a substantial risk of hypoglycaemia, which is associated with both short- and long-term adverse events \\[[@B3],[@B4]\\]. Although the use of parenteral nutrition affords a stable caloric load, which minimises the incidence of hypoglycaemia \\[[@B2]\\], enteral feeding is the preferred method of nutrient delivery in critically ill patients \\[[@B5]\\]. Hence, there is a need for a therapy to manage hyperglycaemia in enterally fed patients without the risk of hypoglycaemia \\[[@B6]\\].\n\nExogenous administration of the incretin hormone, glucagon-like peptide-1 (GLP-1), has been shown to normalise blood glucose concentrations both in healthy patients and those with type 2 diabetes \\[[@B7]\\]. This occurs as a result of stimulation of insulin secretion, suppression of glucagon release and slowing of gastric emptying \\[[@B7],[@B8]\\]. Because the former effects are glucose dependent, the use of GLP-1 does not appear to be associated with hypoglycaemia \\[[@B9]\\]. The effect of GLP-1 on glycaemia in enterally fed critically ill patients has hitherto not been evaluated. The primary aim of this study"
+"Introduction\n============\n\nGlucose control to prevent both hyperglycemia and hypoglycemia is important in an intensive care unit \\[[@B1]\\]. Recent meta-analysis, including results of the NICE-SUGAR study \\[[@B2]\\], showed that intensive insulin therapy (target blood-glucose control, 80 to 110 mg/dl) was not beneficial and increased the risk of severe hypoglycemia in critically ill patients \\[[@B3]-[@B5]\\]. Thus, it is currently recommended that insulin should be used when the glucose concentration exceeds 180 mg/dl, and target glucose concentration should generally be between 144 and 180 mg/dl \\[[@B6],[@B7]\\]\n\nEven though a more-modest target for blood-glucose concentration is now accepted, the importance of glucose monitoring and its accuracy has become clearer. Because the physiological activity of glucose is dependent on its plasma concentration, central laboratory blood-glucose measurement using plasma (Glu-lab) is recommended \\[[@B8],[@B9]\\]. However, arterial blood gas analyzers (ABGs) and/or glucose meters, not Glu-lab, are commonly used to measure blood-glucose concentrations in critically ill patients, because of their convenience and speed \\[[@B10]\\]. Because most of these devices were not developed to guide the administration of insulin in critically ill patients, they might not be sufficiently accurate to guide therapy aimed at maintaining blood glucose within a 30-mg/dl range \\[[@B11]\\]. Therefore, knowledge of their limitations is"
+"1. Introduction {#sec1-ijms-21-04914}\n===============\n\nMany data presented in scientific publications report that the administration of carcinogenic substances during embryo organogenesis does not cause tumors in offspring \\[[@B1-ijms-21-04914],[@B2-ijms-21-04914]\\], while it is possible to induce tumors in offspring after the end of the cell differentiation process \\[[@B3-ijms-21-04914],[@B4-ijms-21-04914],[@B5-ijms-21-04914],[@B6-ijms-21-04914]\\]. Such data seem to indicate that cancer can be considered a reversible process, which can be controlled by the factors present during organogenesis. Taking that into account, it was decided that a systematic study of the cellular differentiation process should be conducted. Many experiments were carried out in our laboratories using the Zebrafish embryo as a model to study the cell differentiation process for the following reasons: first, that it is easy to establish the exact time of zebrafish egg fertilization. This is important for standardizing all the experiments, with the goal of obtaining repeatable results over time in different research studies; second, notwithstanding their size and relative simplicity, the proteins extracted from Zebrafish might have been overall evolutionarily conserved in humans. In fact, all the different protein types taken from Zebrafish embryos after the beginning of stem cell differentiation were identified in our research using liquid chromatography mass spectrometry testing \\[[@B7-ijms-21-04914]\\]. It was demonstrated"
+"The authors confirm that all data underlying the findings are fully available without restriction. The data have been published previously and can be accessed through the following accession numbers GSE36063 (Brogaard, 2012), E-MEXP-1172 (Lee, 2007), GSE25133 (Valouev, 2011), and SRA030538.1 (Zhang, 2011), and the following URL <http://bioinfo.stats.northwestern.edu/~jzwang/Yigit2013NAR.html> (Yigit, 2013).\n\nIntroduction {#s1}\n============\n\n*In vivo*, promoters are characterized by a nucleosome free region (NFR) that is followed by a periodic phasing of well-positioned nucleosomes continuing into the gene body. In yeast, this phasing is absent *in vitro*, but can be restored by the addition of a whole cell extract (WCE) and ATP, presumably a result of ATP-dependent chromatin remodelers (CRs) [@pone.0110479-Zhang1]. The promoter NFR, however, is largely preserved *in vitro* because yeast promoters contain sequences that are inherently refractory to nucleosome formation, such as low G/C content [@pone.0110479-Tillo1] and poly-dA:dT tracts [@pone.0110479-Kaplan1].\n\nYeast promoters have a biased distribution of poly-A and poly-T elements flanking nucleosome free regions [@pone.0110479-Wu1], [@pone.0110479-Hampson1], which cannot be explained solely by the biased base content ([**Figure 1**](#pone-0110479-g001){ref-type=\"fig\"}). This asymmetric poly-A/poly-T arrangement has no known function and is incongruous with the model that poly-dA:dT tracts simply exclude nucleosomes via a rigid DNA structure [@pone.0110479-Iyer1] since the DNA should"
+"Introduction\n============\n\n*Lactobacillus* is a major genus of the lactic acid bacteria (LAB), a GRAS (Generally Recognized as Safe) and economically important bacterial group used in foods, beverages, or dietary supplements. *Lactobacillus casei* is a facultative heterofermentative species usually used as a starter culture for milk fermentation and for the maturation of cheeses in the food industry ([@B17]). Selected certain strains of *Lactobacillus casei* can be used as probiotics ([@B18]). Promising data suggest a beneficial impact on several disorders in humans and in animals ([@B25]; [@B1]).\n\n*Lactobacillus casei* BL23, as an example, is a well-characterized probiotic. Its immunomodulatory properties were demonstrated *in vitro* ([@B4]) and *in vivo* ([@B47]; [@B31]; [@B12]; [@B34]; [@B44]). Its surface-exposed components were proposed to take part in interactions with the intestinal mucosa ([@B37]; [@B45]), in inhibition of *Staphylococcus aureus* internalization ([@B7]; [@B54]), and in the metabolism of human milk oligosaccharides, which plays a key role in establishing and maintaining the infant gut microbiota ([@B5]). Excreted microvesicles also carry key protein probiotic effectors of *L. casei* BL23 ([@B49]) Consumption of *L. casei* BL23 modulates the microbiota in favor of *Lactobacillaceae*, *Porphyromonadaceae*, and *Comamonadaceae* ([@B62]).\n\nTo deliver probiotic benefits to the hosts, a stable probiotic product with a"
+"The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n\nIntroduction\n============\n\nHysterectomy is the second most common gynecologic procedure performed in the U.S for women of reproductive age \\[[@REF1]\\]. With approximately 600,000 occurring annually, it is experienced by one in three women by the age of 60 \\[[@REF1],[@REF2]\\]. Regardless of the mode of hysterectomy (vaginal, laparoscopic, robotic, or abdominal), all are associated with complications of infection, thromboembolism, genitourinary tract injury, and also a rare but serious complication of vaginal cuff dehiscence (VCD) \\[[@REF3]\\]. VCD has been defined as partial or full-thickness separation of the anterior and posterior edges of the vaginal cuff created during a hysterectomy and can occur with or without bowel evisceration \\[[@REF4]\\]. Proposed risk factors for dehiscence include vaginal atrophy, smoking, obesity, and"
+"1. Introduction {#sec1-sensors-19-00798}\n===============\n\nThe wearable device has been widely studied in recent years. In the related researches, it is essential to monitor the cardiac and physical activities in users with congestive heart issues at home. The electrocardiogram (ECG) is an important signal in monitoring the cardiac activity. A Holter ECG device is frequently applied to record long-term ECG signals and helps to find arrhythmic heartbeats within twenty-four hours \\[[@B1-sensors-19-00798]\\]. Another apparatus is called an Event Recorder that is able to record one-minute ECG signals when a user feels uncomfortable on the chest region \\[[@B2-sensors-19-00798]\\]. Currently, the commercial Holter ECG apparatus or Event Recorder only record the ECG signals, and is lacking in the real time analysis of the ECG signals. Moreover, the user has been encouraged to neither do any severe exercises nor take a shower, because these two kinds of devices do not have a high ingress protection rating.\n\nAn ECG patch is a wearable device, which not only records ECG signal, but also shows some cardiac information on the smart phone in real time \\[[@B3-sensors-19-00798]\\]. However, its function for the arrhythmic beat detection is not better than the ECG Holter analysis. The problem is that the ECG"
+"Introduction\n============\n\nEsophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors worldwide ([@b1-ijo-52-05-1443]--[@b3-ijo-52-05-1443]) and the sixth most fatal cause of cancer-related death. Squamous cell carcinoma (SCC) is the main histological type of this cancer. Northern and central China is part of the \\'Asian belt\\' which has a very high incidence of ESCC; there are \\>100 cases per 100,000 annually. The urgency of preventing and curing ESCC is obvious ([@b4-ijo-52-05-1443],[@b5-ijo-52-05-1443]).\n\nSimilar to other types of cancer, the development of ESCC is believed to be a multi-step process caused by the accumulation of activated oncogenes and inactivated tumor suppressor genes (TSGs) ([@b6-ijo-52-05-1443]). TSGs can be inactivated by both genetic and epigenetic mechanisms. Genetic deletions and point mutations disrupt TSG functions, and epigenetic mechanisms, including CpG island promoter methylation and histone modifications, frequently lead to the loss of TSG functions and are involved in tumor development and progression ([@b7-ijo-52-05-1443]). The aberrant methylation of CpG islands leads to gene silencing, resulting in TSG inactivation, which can increase the rate of tumor formation by disabling multiple normal cellular processes, such as apoptosis and cell cycle progression ([@b7-ijo-52-05-1443]). In breast cancer and renal clear cell carcinoma ([@b8-ijo-52-05-1443]), methylation of erythrocyte membrane protein band"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec001}\n============\n\nSince the onset of agriculture, cereals have played a crucial role in human nutrition. However, the needs of the growing human population, which is projected to reach 9.7 billion by 2050 \\[[@pone.0167099.ref001]\\], together with the changing climate represent a serious challenge for breeders and researchers to meet the growing demand for food. Despite the fact that barley represents only 5.2% of the total world production of cereals with 144 mil. tons harvested per year \\[[@pone.0167099.ref002]\\], this cereal ranks among major crops in many, especially European countries responsible for 59.7% of total world production. The Czech Republic has a long tradition in barley production mainly due to the brewery industry with 14.9% of sowing areas occupied by this crop and its yearly harvest representing as much as 22.4% of total cereal production \\[[@pone.0167099.ref003]\\].\n\nThe yield is constantly exposed to the risk of adverse effects due to different abiotic and biotic factors. An obligate biotrophic fungus *Blumeria graminis*, a causal agent of powdery mildew disease, is currently ranked among the Top 10 most important fungal plant pathogens \\[[@pone.0167099.ref004]\\]. *B*. *graminis* f. sp. *hordei* (*Bgh*) is responsible for"
+"Introduction {#Sec1}\n============\n\nAn increasing body of evidence suggests that redox reactions are important for the regulation of immune responses during infection, malignancies and autoimmunity^[@CR1]^. Relapsing-remitting multiple sclerosis (RRMS) is an autoimmune disease associated with dysregulation of adaptive immunity, leading to the periodic entry of immune cells into the central nervous system (CNS) and subsequent tissue damage with symptoms of neurological dysfunction. Among a number of different pathological disease mechanisms, an imbalance in the oxidative environment has also been described^[@CR2],[@CR3]^.\n\nDimethyl fumarate (DMF; Tecfidera\u00ae) is a oral disease modulating treatment (DMT) and the most prescribed drug for RRMS in the U.S. It's suggested to act by activating the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2)^[@CR4],[@CR5]^, which is a transcript of the *NFE2L2* gene. Nrf2 is essential in redox homeostasis and responses to reactive oxygen species (ROS)^[@CR1]^ but may in addition also engage additional transcription factors, including NF\u03baB^[@CR6]^. The net activity of DMF has been described to be mainly anti-oxidative^[@CR5],[@CR7],[@CR8]^. So far targeting of redox regulation has not been a generally accepted therapeutic strategy in autoimmune diseases. However, older drugs including gold salts used for rheumatoid arthritis have been shown to possess redox regulatory properties^[@CR9]--[@CR11]^. DMF has been ascribed cyto-protective"
+"Background {#Sec1}\n==========\n\nDespite the current reported declining trends, malaria has remained an important public health problem and the main cause of morbidity and mortality in Tanzania and elsewhere in sub-Saharan Africa (SSA). Globally, an estimated 3.4 billion people were at risk of malaria and there were an estimated 627, 000 malaria deaths in 2012. Of the reported deaths, 90% occurred in SSA and majority involved children less than five years of age \\[[@CR1]\\]. Apart from other strategies, malaria control still relies on early diagnosis and prompt treatment with efficacious drugs; and artemisinin-based combination therapy (ACT) is currently the cornerstone of malaria case management \\[[@CR2], [@CR3]\\]. Currently, ACT remains highly effective in almost all settings, as long as the partner drug in the combination is locally effective. However, the recently reported artemisinin resistance in four countries in South East Asia (Cambodia, Myanmar, Thailand and Vietnam) is a major concern for the global effort to control malaria. There is an urgent need to implement/continue with therapeutic efficacy testing (TET) in all countries which have deployed ACT as recommended by the World Health Organization (WHO) \\[[@CR1]\\]. It is also crucial to intensify the surveillance of artemisinin resistance and expand containment to prevent"
+"1. Introduction\n===============\n\nThe orange is one of the major citrus fruits and its production has increased since the 1980s. Orange production is predicted to approach 66.4 million tons by 2010, representing a 14% increase within 12 years \\[[@b1-ijms-08-00777]\\]. Approximately 40--60% of oranges are squeezed to juice and the remainder, containing peel, segment membranes and other by-products is considered as citrus processing waste (hereafter referred to as orange peel for simplicity) \\[[@b2-ijms-08-00777]\\]. Part of this waste is dried to be used as animal feed, but the drying process is costly due to the high moisture content of peels, and therefore a large proportion of waste has to be disposed of. This may result in many problems from both economic and environmental points of view including high transport costs, lack of disposal sites and high organic content \\[[@b3-ijms-08-00777]\\]. Citrus processing residues contain both soluble and insoluble carbohydrates. The latter are present in the cell walls of the peels, particularly in the form of pectin, cellulose and hemicellulose. These polymers can be hydrolyzed enzymatically by cellulase, \u03b2-glucosidase and pectinase to their corresponding soluble carbohydrates \\[[@b2-ijms-08-00777],[@b4-ijms-08-00777]\\].\n\nProduction of ethanol and other valuable products from fermentable sugars in peel hydrolyzate is an alternative to"
+"Introduction {#s1}\n============\n\nThe Mediterranean fish fauna is unique, characterized by a history of isolation and connectivity [@pone.0036443-Coll1] resulting from tectonic movements and changes in ocean circulation. Isolation of the Mediterranean is reflected in its rich marine flora and fauna, with an estimated total of 17,000 species [@pone.0036443-Coll1]. 619 fish species have been inventoried in the Mediterranean, among which 13% are endemic, 2% are introduced, and 67% are non-endemic natives. 85% of these fish are teleosts [@pone.0036443-Lasram1]. General geological and oceanographic processes such as those involved at the origin of the Mediterranean Sea have been shown to influence regional histories of fish diversity globally [@pone.0036443-Friedman1],[@pone.0036443-Hurley1]. Studying the Mediterranean region may therefore illustrate mechanisms contributing to diversification of teleosts and help us understand the current distribution of diversity in the region.\n\nDuring the Cretaceous (145--65 Mya), the Mediterranean was part of the Tethys Sea and was connected with the Atlantic as well as with the Indo-Pacific oceans. At this time, Africa, Europe and the Adriatic plates were coming closer together, making this ancestral Mediterranean Sea smaller and smaller, and drastically changing its shape and connectivity. By the Miocene (23--5 Mya), the Mediterranean Sea was isolated from the Indo-Pacific. Subsequently, circa 7--5"
+"Introduction {#s1}\n============\n\nImmunoglobulin D (IgD) multiple myeloma (MM) is a rare subtype of myeloma, with an incidence of less than 2% of all myelomas \\[[@R01]\\]. It carries a poorer prognosis than other myeloma isotypes. It can cause multiorgan involvement with renal failure being the key feature, occurring in 20-40% of patients at the time of diagnosis, up to 10% requiring renal replacement therapy, and 25% later during the disease \\[[@R02]\\]. Cast nephropathy is the main underlying pathophysiologic mechanism.\n\nCase Report {#s2}\n===========\n\nA 62-year-old Caucasian male with history of diet controlled hypertension, dyslipidemia and smoking came to emergency department with complains of lower abdominal pain and decreased urination starting progressively over a couple of weeks. He also had constipation along with mild nausea, fatigue with diffuse joint pain and cold intolerance for almost a month.\n\nOn physical examination, his vitals were normal. He did not have any costovertebral angle tenderness. Patient was oliguric with 300 mL of urine upon Foley catheter insertion. On laboratory investigation, hemoglobin was 8.7 g/dL; his serum creatinine was 5.99 mg/dL (GFR MDRD of 10 mL/min), and albumin/globulin (AG) ratio was 0.84. He had mild hypercalcemia (corrected Ca^2+^: 10.6 mg/dL). Of note patient's serum creatinine"
+"Introduction {#s1}\n============\n\nCulture shapes various aspects of human cognition (Nisbett et al., [@B45]; Nisbett and Masuda, [@B44]; Henrich et al., [@B27]; Heine, [@B22]). A prominent framework that integrates diverse cultural differences centers on how people relate to those with whom they interact (Markus and Kitayama, [@B41], [@B42]; Singelis, [@B51]; Oyserman et al., [@B46]; Triandis and Suh, [@B54]; Heine and Buchtel, [@B23]): members of independent (or individualistic) cultures (e.g., Western cultures) construe their selves as distinct from others whereas members of interdependent (or collectivistic) cultures (e.g., East Asian cultures) construe their selves as interconnected with close others. Yet, how culture influences the processing of social feedback from others has not been investigated---which is surprising given that the relation between self and others defines self-construal. Here, we compared how members of an independent culture (Germans) and from an interdependent culture (Chinese) process social feedback on character traits. Social feedback processing comprises several components and mechanisms pertinent for social cognition in general. Specifically, when people receive social feedback they can take it into account to different degrees. That is, they can show various amounts of social conformity to social feedback in general and they can show differential processing of desirable and undesirable"
+"Background\n==========\n\nAcute or pending colonic obstruction, on the basis of colorectal malignancy, is a condition traditionally treated with surgery with a single or a multi-stage operative procedure. Acute surgery with colonic resection and primary anastomosis with or without a diverting stoma is the most common surgical approach in relatively healthy patients. The multi-stage approach includes initial decompression of the obstruction with a temporary colostomy and a later colonic resection with reversal of the stoma if possible. This method is mainly considered in patients with deteriorated general condition, serious co-morbidity or in cases with advanced tumors. Regardless of the technique used, surgical procedures are associated with a high morbidity and mortality rate \\[[@B1]\\]. The use of self-expanding metal stents (SEMS) for decompression of colonic obstructions was first described by Spinelli et al \\[[@B2]\\] in 1992 as a palliative treatment. In 1994, Tejero et al \\[[@B3]\\] published a preliminary report on the use of SEMS as a temporary treatment as a bridge to surgery, relieving the patient of the obstruction without the need for emergency bowel surgery. This allows time for optimization of the patient\\'s physiological parameters, completion of preoperative staging and conversion of an acute surgical intervention into an elective"
+"Introduction\n============\n\nManagement issues in diabetes\n-----------------------------\n\nType 2 diabetes is characterized by defects both in insulin secretion from the beta cells and in insulin sensitivity, leading to hyperglycemia and the resulting increased risk of microvascular and macrovascular complications. To reduce the risk of these vascular complications, intensive treatment to target fasting blood glucose (FBG) concentrations, postprandial glucose (PPG) concentrations and glycosylated hemoglobin (HbA~1c~) levels is a key goal in the management of patients with type 2 diabetes.\n\nThe response of the beta cell after a meal in people with type 2 diabetes is in two phases: the first phase 0 to 10 minutes after a meal, followed by a steady and more prolonged second phase. The loss of the first phase is a key determinant of postprandial hyperglycemia and is characteristic both of impaired glucose tolerance and type 2 diabetes.[@b1-dmso-2-101] While HbA~1c~ is the accepted measure of glucose control over time, Monnier and colleagues have shown that the relative contribution of postprandial hyperglycemia to overall hyperglycemia varies with HbA~1c~ levels.[@b2-dmso-2-101] Postprandial hyperglycemia is the main contributor to overall daily hyperglycemia in people with mild or moderate hyperglycemia, whereas fasting hyperglycemia is the main contributor in people whose diabetes is"
+"Introduction\n============\n\nThe gram-negative bacterium *Helicobacter pylori* colonizes the stomach of at least half of the world\\'s population and could induce peptic ulcers, mucosa-associated lymphoid tissue lymphoma of the stomach, and gastric atrophy as well as distal gastric adenocarcinoma ([@bib21]). The presence of a pathogenicity island (PAI)[\\*](#fn1){ref-type=\"fn\"} in *H. pylori* is connected with an increased risk of developing the aforementioned diseases. Several PAI genes are homologous to genes that encode type IV secretion system proteins ([@bib8]). After *H. pylori* adherence to epithelial cells, the bacterial PAI-encoded CagA protein is translocated into the host cell ([@bib23]; [@bib1]; [@bib2]; [@bib20]; [@bib24]), where it undergoes tyrosine phosphorylation at different sites ([@bib12]). *H. pylori* infection also triggers morphological changes and motility in host cells similar to those induced by hepatocyte growth factor (HGF; [@bib23]; [@bib6]). Cell motility is a critical rate-limiting step in the invasive growth program under physiological and pathophysiological conditions. Little is known about the mechanisms that underlie the process of *H. pylori*--induced cell motility and its putative role in tumor progression.\n\nHere, we demonstrate that *H. pylori* activates the HGF/scatter factor receptor c-Met in host cells. *H. pylori* protein CagA binds c-Met and could represent an adaptor protein, which associates with"
+"Introduction {#s1}\n============\n\nSuppose that a researcher wants to study individual differences in how children respond to a training program. The predictor is a continuous measure of some individual property P. The dependent variable is improvement in ability, measured by a pre-training test and a post-training test. However, test scores are not perfect measures of ability. The same improvement in test scores from different pretest scores may therefore reflect different changes in ability. To control for this possibility the researcher may include the pretest score as a covariate in a regression analysis, thereby investigating whether property P predicts test score improvement *among children with equal pretest scores*. The topic of our paper is how this statistical adjustment may lead to incorrect conclusions because of regression artifacts arising from biased regression to the mean.\n\nIn 1999, Campbell and Kenny [@pone.0095949-Campbell1] devoted an entire book to warning about the dangers of statistical adjustments in comparisons of treatment effects between non-randomized groups. The basic problem was pointed out already thirty years earlier in a classic paper by Campbell and Erlebacher [@pone.0095949-Campbell2]. The problem has continued to attract attention, see [@pone.0095949-vanBreukelen1] for a review of the literature and a novel analysis. One reason to"
+"Introduction {#Sec1}\n============\n\nMaxillary sinus carcinoma (MSC) is a relatively rare neoplasm with a poorly defined prognosis \\[[@CR1]\\]. Maxillary sinus squamous cell carcinoma (MSSCC) is the most common pathological type in MSC, and nearly 80% of MSSCCs are diagnosed at advanced stages due to a lack of typical symptoms \\[[@CR2], [@CR3]\\]. Although the mainstay of treatment for MSSCC has been well developed recently, the 5-year overall survival (OS) rate remains unsatisfactory \\[[@CR4]\\].\n\nIt is generally accepted that surgery-based treatment remains the first-line therapeutic strategy for MSSCC \\[[@CR5]--[@CR8]\\], according to the National Comprehensive Cancer Network (NCCN) recommendation \\[[@CR8]\\]. And comprehensive treatment involving surgery was observed to have a better curative effect than surgery alone \\[[@CR9]--[@CR11]\\]. However, controversial issues still exist that whether neoadjuvant chemotherapy and/or radiotherapy benefit patient prognosis better, comparing with post-operation adjuvant chemotherapy and/or radiation. Based on these, the objective of this retrospective study was to explore the survival outcomes of MSSCC patients according to different treatments.\n\nMaterial and methods {#Sec2}\n====================\n\nPatients {#Sec3}\n--------\n\nWe performed a retrospective review of pathological databases from 2007 to 2017 at Tianjin Medical University Cancer Institute and Hospital, and 98 patients with pathologically confirmed MSSCC were enrolled. Patients were classified according to"
+"Introduction {#Sec1}\n============\n\n*Streptococcus uberis* is one of the most common causes of clinical and subclinical mastitis in dairy cattle \\[[@CR1], [@CR2]\\]. Infections may be transient or chronic, associated with low or high somatic cell count (SCC), and limited to an individual animal or part of an outbreak affecting multiple animals \\[[@CR3], [@CR4]\\]. In addition, *S. uberis* may be found in bovine faeces and in the farm environment \\[[@CR5], [@CR6]\\]. Based on whole genome analysis of the type strain O140J, *S. uberis* has been described as an opportunistic pathogen that utilises nutritional flexibility to adapt to a range of ecological niches, including the mammary gland \\[[@CR7]\\]. Others, however, have proposed numerous virulence traits that may be associated with the ability of *S. uberis* to cause mastitis. Examples include production of antiphagocytic factors that affect interaction with macrophages and neutrophils \\[[@CR1], [@CR8]\\], the ability to adhere to and invade into bovine mammary epithelial cells, potentially mediated by the *S. uberis* adhesion molecule SUAM \\[[@CR9], [@CR10]\\], and the ability to form biofilm \\[[@CR11], [@CR12]\\].\n\nMacrophages represent a major component of the cell population in the healthy lactating mammary gland and the first line of defense against pathogens \\[[@CR13]--[@CR16]\\]. Their general function is"
+"Introduction\n============\n\nThyroid nodules are not specific to a particular disease but are a common clinical manifestation of various thyroid diseases. Only 4\u223c7% of adult cases can be found by palpation of the thyroid nodules ([@B27]), but up to 50\u223c 67% can be found by conventional ultrasound examination ([@B14]). Most thyroid nodules are benign, and approximately 5% are malignant ([@B6]). The incidence of thyroid cancer has increased in recent years ([@B23]). The degree of malignancy is low and the prognosis is good for most differentiated thyroid cancers, however, some thyroid cancers are invasive ([@B7]). Therefore, early detection, early diagnosis and early treatment are key in the prevention and treatment of thyroid malignant nodules.\n\nConventional ultrasound has become the preferred imaging examination method, but two-dimensional ultrasound overlaps to some degree between benign and malignant nodules. Therefore, the diagnosis of thyroid nodules by conventional ultrasound alone has some limitations ([@B10]; [@B1]).\n\nThe development of contrast-enhanced ultrasound (CEUS) can be traced back to 1969. [@B8] found using an aortic root injection of indocyanine blue that M echocardiography can present an echo enhancement phenomenon. Researchers later discovered that the phenomenon was due to the injection of liquid-containing microbubbles and began to search for a"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec004}\n============\n\nCardiovascular (CV) disease is a leading cause of mortality both before and after kidney transplantation (KT) \\[[@pone.0160607.ref001], [@pone.0160607.ref002]\\]. The occurrence of CV disease after KT is associated with sustained or accumulated CV risk factors before and after KT \\[[@pone.0160607.ref003]\\]. Pre-transplant (old age, high body mass index (BMI), and a history of CV event \\[[@pone.0160607.ref004]--[@pone.0160607.ref006]\\]) and post-transplant (new-onset hypertension or diabetes \\[[@pone.0160607.ref005], [@pone.0160607.ref007]\\]) CV risk factors affect the development of CV events even after successful KT. The presence of diabetes or diabetic nephropathy before KT is an independent risk factor and a strong predictor for post-transplant CV events and consequent death \\[[@pone.0160607.ref008], [@pone.0160607.ref009]\\]. Pre-transplant malnutrition, inflammation, and atherosclerosis are also correlated with CV outcomes after KT \\[[@pone.0160607.ref010]\\].\n\nSpecific KT-related risk factors, such as acute rejection (AR) episodes, as well as traditional CV risk factors, reportedly increase the risk of CV events after KT \\[[@pone.0160607.ref011], [@pone.0160607.ref012]\\]. In addition, an increased BMI after KT affects CV risk factors, including high blood pressure, an abnormal glucose profile, and an abnormal lipid profile, which leads to allograft dysfunction \\[[@pone.0160607.ref013]\\].\n\nThe associations between pre- or post-transplant CV risk factors and post-transplant"
+"1. Introduction {#sec1-materials-10-00543}\n===============\n\nAs the damage tolerance concept has been widely accepted and applied in the aerospace engineering, it becomes necessary and important to calculate the fatigue crack growth. As is known, $da/dN - \\Delta K$ curve in the log-log coordinate has three characteristic regions, which are named threshold region (region I), Paris region (region II) and high $\\Delta K$ region (region III). It can be observed in extensive experimental results that the relationships between fatigue crack growth rate $\\left( {da/dN} \\right)\\ $and stress intensity factor range $\\left( {\\Delta K} \\right)$ are not linear even in the Paris region \\[[@B1-materials-10-00543],[@B2-materials-10-00543],[@B3-materials-10-00543],[@B4-materials-10-00543]\\]. Furthermore, the stress ratio effects on $da/dN - \\Delta K$ curves are diverse in different materials. For some materials, such as 2324-T39 aluminum alloy \\[[@B5-materials-10-00543]\\], 7055-T7511 aluminum alloy \\[[@B5-materials-10-00543]\\] and Ti10V2Fe3Al titanium alloy \\[[@B6-materials-10-00543]\\], the stress ratio effects are almost the same in the three regions. In other words, the $da/dN - \\Delta K$ curves with different stress ratios are approximately \"parallel\". However, for some other materials, the stress ratio effects on the $da/dN - \\Delta K$ curves are quite different in the three regions, which means it depends on $\\Delta K$, such as spheroidal graphite cast iron \\[[@B3-materials-10-00543]\\]"
+"Introduction {#s1}\n============\n\nHuman-centered bipedal robots, such as exoskeletons, powered prostheses and humanoids are demonstrating increasing levels of functionality, reliability, and safety, and are now breaching the barrier of surviving in a rapidly evolving market. In this crucial process, the lack of accepted standards to evaluate the different facets of robotic performance is hampering the efficient introduction of these new technologies into the different application domains, each of them characterized by the needs, requirements, and regulations of diverse users. A systematic benchmarking methodology to assess robotic systems on a quantitative and reproducible basis is eagerly awaited, as demonstrated by the numerous workshops and discussions on this topic in the most relevant international forums of the last 5--10 years. Benchmarks allow comparing systems to each other and against accepted references, and are therefore useful not only to end-users in search for the most suitable solution, but also to developers aiming to identify and solve the critical shortcomings of their machines. Solid benchmarks usually arise from research results, and are eventually converted into international standards after an iterative process that can last years. It can be argued that the more effort is done by the research community in identifying effective benchmarking methods,"
+"1. Introduction {#sec1-materials-13-00258}\n===============\n\nAs a promising technology, the Additive Manufacturing (AM) technology offers a new strategy for producing customized parts with desired architecture, shape, pores and porosity \\[[@B1-materials-13-00258],[@B2-materials-13-00258]\\]. Based on the AM, the Fused deposition modeling (FDM) melts a spool of thermoplastic filament and extrudes it onto a platform to create tangible 3 dimensional parts \\[[@B3-materials-13-00258]\\]. Poly (lactic acid) (PLA) is the most extensively used material in FDM, and has been regarded as a promising material for its eco-friendly, biocompatible and processability \\[[@B4-materials-13-00258]\\]. However, its relatively hydrophobic and low degradable properties have limited its use \\[[@B5-materials-13-00258]\\].\n\nNatural biomass is known as being hydrophilic, biodegradable and recyclable \\[[@B6-materials-13-00258]\\]. Driven by the increasing environmental pollution and global energy crisis, natural biomass has been used as the reinforcements on the polymer-matrix composites \\[[@B7-materials-13-00258]\\]. Some biomass has been successfully used for PLA-matrix, including seeds (e.g., cotton and milkweed), fruit nutshells (e.g., coconut shell and peanut shell), basts (e.g., flax, lamp and jute), leaves (e.g., sisal and banana) and grass/cane/reed fibers (e.g., bamboo) \\[[@B8-materials-13-00258],[@B9-materials-13-00258]\\].\n\nSome researchers have combined the study of FDM and the PLA/natural biomass composites. Tao et al. \\[[@B10-materials-13-00258]\\] prepared the PLA/5 wt% wood flour composites using the FDM and enhanced the"
+"Background {#Sec1}\n==========\n\nTreatment of metastatic malignant melanoma has dramatically advanced with the development of targeted agents and immunotherapy in the recent past. Targeting the MAPK pathway with BRAF inhibitors, MEK inhibitors, or the combination, leads to high response rates and progression free survivals of roughly 7\u00a0months for single agents \\[[@CR1]--[@CR3]\\], to about 11\u00a0months for combination regimens \\[[@CR4], [@CR5]\\]. Approved immunotherapies now include high dose interleukin-2 (HD IL-2) and the immune checkpoint inhibitors, (ipilimumab, nivolumab, pembrolizumab). Durable responses are consistently observed in a small percentage of patients with metastatic melanoma treated with HD IL-2 \\[[@CR6]--[@CR8]\\]. Higher response rates are observed with immune checkpoint inhibitors \\[[@CR9]--[@CR13]\\], especially with combination anti-CTLA and anti-PD1 agents \\[[@CR14]--[@CR16]\\], but longer follow up is required to determine the durability of these responses and more recent studies report acquired resistance to these agents \\[[@CR17]\\].\n\nPreclinical studies suggest that oncogenic BRAF (BRAF V600E) may contribute to immune escape in melanoma \\[[@CR18]\\], and that blocking its activity via MAPK inhibition leads to increased expression of melanocytic differentiation antigens (MDAs) \\[[@CR19], [@CR20]\\] with significantly enhanced recognition by antigen-specific T lymphocytes \\[[@CR20], [@CR21]\\], enhanced antigen presentation \\[[@CR22], [@CR23]\\], without diminishing T-cell function \\[[@CR24]\\], and change in the tumor-produced immune"
+"Background {#Sec1}\n==========\n\nFoot problems are highly prevalent in patients with rheumatoid arthritis (RA) \\[[@CR1]--[@CR5]\\]. Inflammation and synovitis of foot joints may lead to changes in foot structure and foot function \\[[@CR1], [@CR6]\\]. Abnormal foot function can result in high plantar foot pressures and subsequent foot pain and disability \\[[@CR7], [@CR8]\\]. This process mainly affects the forefoot \\[[@CR1], [@CR7]\\]. Previous research showed that RA patients with foot problems experience limitations in daily activities and a reduced quality of life \\[[@CR9], [@CR10]\\].\n\nTreatment of RA-related foot problems often consists of custom made foot orthoses (FOs) and a shoe advice by a podiatrist, especially in the early stage of the disease \\[[@CR11]\\]. One of the assumed working mechanisms of FOs is redistribution of plantar pressure by creating a larger weight bearing area \\[[@CR12]--[@CR14]\\]. Overall, the reported treatment effect of FOs on foot pain in RA is small (effect size 0.4) \\[[@CR15]\\], to medium (effect size 0.45) \\[[@CR16]\\]. The immediate feedback from in-shoe plantar pressure measurements seems promising in optimizing the treatment effect of FOs, as shown in treatment with therapeutic footwear (including FOs) in diabetic foot patients \\[[@CR17]\\]. Since the evaluation and subsequent adaptations of FOs in patients with RA is usually"
+"Introduction\n============\n\nViruses are the most abundant biological entities on the planet ([@ref-9]), an order of magnitude more abundant than bacteria ([@ref-23]). Most ocean viruses prey upon bacteria ([@ref-23]), and as a result, play a critical role in ecosystem dynamics. When these viruses (bacteriophage, or phage) lyse bacterial cells, carbon is converted to its dissolved form, slowing the export of carbon to the deep ocean ([@ref-79]). Marine viruses thus ultimately influence biogeochemical cycling and can affect the rate of atmospheric warming ([@ref-90]; [@ref-18]). Besides being abundant and fundamental contributors to the Earth's biogeochemical cycles, marine viruses are also extremely diverse. Although recent work examining viral protein clusters in metagenomes suggests the global virome may be smaller than previously thought, marine viruses still constitute one of the largest reservoirs of genetic diversity on the planet ([@ref-67]; [@ref-34]). Moreover, viruses can change the genetic makeup of bacteria through horizontal gene transfer ([@ref-41]; [@ref-49]; [@ref-33]) and affect bacterial community composition through lysis of specific host cells ([@ref-52]). For all of these reasons, understanding the diversity of marine viruses has been a research focus for more than 20 years, since [@ref-4] documented high viral abundance in the oceans.\n\nStudying viral diversity is challenging because"
+"Abbreviations used in this article: BBB, Basso-Beattie-Bresnahan locomotor rating scale; BDA, biotin-dextran amine; CNS, central nervous system; CSPG, chondroitin sulfate proteoglycan; CST, corticospinal tract; GFAP, glial fibrillary acidic protein; IB4, isolectin B4; MAG, myelin-associated glycoprotein; MOSP, myelin/oligodendrocyte-specific protein; NgR, Nogo receptor; OMgp, oligodendrocyte-myelin glycoprotein; PI-PLC, phosphatidylinositol-specific PLC; PLL, poly-[l]{.smallcaps}-lysine; RGM, repulsive guidance molecule; SCI, spinal cord injury; Tuj1, neuron-specific \u03b2 tubulin III protein.\n\nIntroduction\n============\n\nAxons of the central nervous system (CNS) demonstrate no functionally significant regeneration after injury, in contrast to those of the peripheral nervous system, which regenerate vigorously, leading often to complete functional recovery. This lack of regeneration generally results in partial disability or complete paralysis after a CNS injury. However, some adult CNS axons can grow through a peripheral nerve graft ([@bib7]), suggesting that the local glial environment of the adult CNS is a major cause of the lack of regeneration. So far, three major inhibitors---Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp)---expressed by oligodendrocytes and myelinated fiber tracts have been identified. Interestingly, all these inhibitors were found to bind to the Nogo receptor (NgR) in complex with p75 or TROY, members of the TNF receptor family, suggesting that they have common signaling pathways ([@bib30]).\n\nHowever,"
+"Introduction {#s1}\n============\n\nChromosomal translocations affect cellular function by changing gene copy number, creating fusion genes with aberrant function, or repositioning regulatory elements. Classic examples of recurrent genomic rearrangements in cancer are the *BCR*-*ABL* translocation (observed in \\>90% of cases of chronic myeloid leukemia) and the *MYC-IGH* fusion (observed in \u223c90% of cases of Burkitt\\'s lymphoma) [@pone.0044196-Nowell1]--[@pone.0044196-arRushdi1]. While these alterations play important roles in driving tumorigenesis [@pone.0044196-Daley1] and directing targeted therapy in cancer patients [@pone.0044196-Druker1], the factors that contribute to the formation of the thousands of translocations observed in human disease are not fully understood [@pone.0044196-Mani1].\n\nRepeated observation of specific translocations, as well as the existence of rearrangement hotspots in cancer [@pone.0044196-De1], suggests that intrinsic cellular and genomic features predispose certain regions to translocate. Since fusion of two DSBs requires spatial contact, one attractive hypothesis is that higher-order genome organization -- that is, the physical proximity of chromosomes in the nucleus *prior* to translocation -- contributes to the occurrence of specific translocations [@pone.0044196-Luksov1], [@pone.0044196-Meaburn1]. Indeed, work over the last decade has used fluorescence *in situ* hybridization (FISH) to show that the genes involved in several recurrent translocations are positioned relatively close to one another in the nuclei of normal cells"
+"On behalf of the International Union of Pure and Applied Chemistry (IUPAC), and in particular its Commission on Atomic Weights and Isotopic Abundances, I should like to inform the readers of the *Journal of Research of the National Institute of Standards and Technology* of the following, based on Refs. \\[[@b1-j13cop]\\] and \\[[@b2-j13cop]\\].\n\nTo eliminate possible confusion in the reporting of isotopic abundances on noncorresponding scales, the Commission on Atomic Weights and Isotopic Abundances of the International Union of Pure and Applied Chemistry (IUPAC) recommended at the IUPAC 37th General Assembly in August 1993 at Lisbon, Portugal, that (i) ^2^H/^1^H relative ratios of all substances be expressed relative to VSMOW (Vienna Standard Mean Ocean Water) on a scale such that ^2^H/^1^H of SLAP (Standard Light Antarctic Precipitation) is 0.572 times that of VSMOW; (ii) ^13^C/^12^C relative ratios of all substances be expressed relative to VPDB (Vienna Peedee belemnite) on a scale such that ^13^C/^12^C of NBS19-limestone (RM 8544) is 1.00195 times that of VPDB; and (iii) ^18^O/^16^O ratios of all substances be expressed relative to either VSMOW or VPDB on scales such that ^18^O/^16^O of SLAP is 0.9445 times that of VSMOW.\n\nAs a consequence, the Commission recommends that researchers should:"
+"A 78-year-old woman with a background of type 2 diabetes mellitus, hyperlipidaemia and hypertension experienced sudden onset severe chest pain while in the emergency department, after a stressful emotional event. The pain lasted for 20--30 min and the patient developed widespread T-wave inversion on 12-lead ECG. Cardiac troponin was elevated, and a bedside transthoracic echocardiogram showed moderate left ventricular systolic dysfunction (LVSD) with no significant valvular abnormalities. Hence, she was treated as an acute coronary syndrome (ACS) and her symptoms subsequently improved.\n\nA coronary angiogram performed via the left transradial approach, demonstrated unobstructed coronary arteries with no evidence of significant atherosclerotic disease ([Figure 1A & B](#jgc-17-05-303-g001){ref-type=\"fig\"}). The diagnosis of Takotsubo syndrome (TTS) was then formulated. Therefore, we proceeded to left ventriculography, which showed moderate LVSD with akinesia of mid-level LV myocardial walls and preserved systolic function of basal and apical segments ([Figure 1C & D](#jgc-17-05-303-g001){ref-type=\"fig\"}, [Supplemental Video S1](#s01){ref-type=\"supplementary-material\"}), compatible with mid-ventricular TTS. The LV end diastolic pressure was measured at 12 mmHg. She was discharged on a \u03b2-blocker and an ACE inhibitor, following an uncomplicated hospitalisation. A cardiac magnetic resonance (CMR) two months later confirmed complete LV systolic function recovery.\n\n![Invasive coronary angiography.\\\n(A): RAO caudal view showing unobstructed left"
+"INTRODUCTION\n============\n\nHuman papillomavirus (HPV) is the most common sexually transmitted virus in the human population. Although the vast majority of these HPV infections are cleared by the immune system within a year after infection, HPVs may in rare cases persist and cause cancer ([@gkt803-B1]). HPV is present in 99.7% of all cervical cancers and is tightly associated with several other anogenital cancers and head and neck cancers ([@gkt803-B2]). Nearly half of the human cancers, which are caused by viruses are attributable to HPVs, and cervical cancer is one of the main causes of death in women in the developing world ([@gkt803-B3]). A subset of the sexually transmitted HPV types has been associated with cancer and is termed high-risk HPV types. HPV type 16 is the most common high-risk type in HPV-induced cancers as well as in the human population ([@gkt803-B4],[@gkt803-B5]).\n\nThe HPV-16 DNA genome is small, but it contains at least six early genes and two late genes under control of at least two promoters ([@gkt803-B6]). The early promoter p97 is located upstream of the E6 gene, and the late differentiation-dependent promoter named p670 is located upstream of the E1 AUG ([@gkt803-B7],[@gkt803-B8]). The early region encoding E1, E2, E4,"
+"Theophylline is a bronchodilator that relieves airflow obstruction in chronic asthma and decreases its symptoms. Theophylline is well absorbed by the gastrointestinal tract, and several sustained-release preparations are available. Previously the mainstay of asthma therapy, theophylline has been largely replaced with \u03b2~2~ agonists and corticosteroids due to a narrow therapeutic window, high side-effect profile, and potential for drug interactions. Overdose may cause seizures or potentially fatal arrhythmias. Theophylline is metabolized in the liver, is a CYP1A2 and 3A4 substrate, and interacts adversely with many drugs\\[[@ref1]\\].\n\nControlled release products are designed to maintain constant therapeutic plasma concentration of the drug within the therapeutic range of the drug over prolonged period\\[[@ref2]\\]. Matrix system is one of the methods used in the development of controlled release oral formulations. Matrix is defined as a well-mixed composite of one or more drugs with a gelling agent i.e. hydrophilic polymers\\[[@ref3]\\]. In fact, matrix system has proven popular among the oral controlled drug delivery technologies because of their simplicity, ease in manufacturing, high level of reproducibility, stability of the raw materials and dosage form and ease of scale up and process validation\\[[@ref4]--[@ref6]\\]. In the current study, hydroxypropyl methyl cellulose (HPMC) is selected as a model hydrophilic polymer"
+"1. Introduction\n===============\n\nSarcoidosis is a multisystemic granulomatous disease of unknown etiology characterized by giant cell noncaseating granuloma.^\\[[@R1]\\]^ It is an inflammatory disease whose pathophysiological mechanism is immunological but still misunderstood. It is an exaggerated immune response and granulomatous reaction to unidentified antigens (environmental or transmissing agents) in a context of genetic predisposition.^\\[[@R2],[@R3]\\]^ Significant lymphopenia involving CD4 (cluster of differenciation 4), CD8, and CD19 T-cells is common in sarcoidosis patients and correlated with disease activity. Data suggests that lymphopenia relates more to disease pathology than medical treatment.^\\[[@R4]\\]^\n\nThe treatment of symptomatic sarcoidosis usually includes glucocorticoids, and cytotoxic drugs like methotrexate, azathioprine, cyclosphosphamide, mycophenolate mofetil, and biologic agents like tumor necrosis factor alpha (TNF \u03b1) antagonist can be used in severe or refractory sarcoidosis. The use of immunosupressive drugs is associated with an increased risk for infection.^\\[[@R5]\\]^\n\nIn spite of CD4 + T-lymphocytopenia and treatment-induced immune suppression, the risk of severe or opportunistic infection is not usually considered to be higher in sarcoidosis, than in general population but this is still being debated.^\\[[@R6]\\]^ Some studies have described cases of opportunistic infections even in untreated patients, in particular cryptococcosis and progressive multifocal leukoencephalopathy (PML).^\\[[@R7],[@R8]\\]^\n\nFew data are available with respect to the"
+"Background {#Sec1}\n==========\n\nThe success of total shoulder arthroplasty (TSA) depends largely on sizing and positioning of the humeral and glenoid components, which can be challenging to optimize relying solely on intra-operative assessment. While the most frequent cause of complications and revisions after TSA is failure of the glenoid component (Pomwenger et al., [@CR20]), loosening or periprosthetic fractures are sometimes also observed around the humeral stem (Quental et al., [@CR21]; Verborgt et al., [@CR32]).\n\nNagels et al. ([@CR19]) demonstrated that stem size directly influences the extents and zones of stress-shielding in the proximal humerus, which could therefore cause peripheral bone resorption (Quental et al., [@CR21]; Razfar et al., [@CR24]). Recent studies evaluated that signs of stress-shielding in the proximal humerus can be found in 40% to 60% of uncemented short stems at a follow-up of 7--8\u2009years (Raiss et al., [@CR22]; Schnetzke et al., [@CR28]). Notably, unlike the weight-bearing hip joint, muscles surrounding the shoulder joint transmit loads more proximally (Quental et al., [@CR21]), rendering the humeral metaphysis more sensitive to stimulus than the femoral metaphysis. In the last decade, implant manufacturers introduced stemless humeral heads as well as shortened humeral stems to reduce these complications and facilitate revision if"
+"Introduction {#s1}\n============\n\nThe timing of flowering is a reproductive trait that has significant impact on fitness in plants. Physiological and molecular mechanisms that control floral change in response to environmental conditions have been the target of recent intensive studies. In model plant systems, a group of genes that control the transition from vegetative to reproductive phases has been identified [@pone.0003138-Yanovsky1]--[@pone.0003138-Boss1]. Flowering phenology is coordinated with the seasonal cycle by a complex floral gene network that uses multiple pathways and deals quantitatively with environmental signals such as photoperiod and temperature.\n\nNatural populations of widespread plant species often show extensive variation in flowering time [@pone.0003138-Weber1]--[@pone.0003138-Stinchcombe1]. In contrast to recent advances in understanding the molecular basis of floral transition, very little is known about flowering time diversification within species. For example, analyses of natural flowering time variation have detected geographic clines that may result from ecological adaptation to local environments [@pone.0003138-Weber1], [@pone.0003138-Stinchcombe1]. Such cases give rise to a series of questions regarding intraspecific processes of flowering time diversification: How is flowering time variation structured? What are the phylogenetic relationships between early-, intermediate- and late-flowering populations? How does the geographic pattern of flowering time variation reflect the process of species dispersal? To date,"
+"All relevant data are within the manuscript and its supporting information files.\n\nIntroduction {#sec001}\n============\n\nEndurance exercise is a potent, low-cost intervention with broad healthspan-extending effects \\[[@pgen.1008778.ref001]\\]. Chronic endurance training simultaneously promotes healthy physiology and prevents disease, improving function in heart, skeletal muscle and brain while reducing obesity, heart disease and cognitive decline \\[[@pgen.1008778.ref002]--[@pgen.1008778.ref004]\\]. These benefits are associated with adaptive changes to gene expression and metabolism \\[[@pgen.1008778.ref002],[@pgen.1008778.ref005]--[@pgen.1008778.ref008]\\].\n\nNonetheless, these benefits are inaccessible to much of the population that are unable to perform an endurance exercise regimen because of injury, illness, advanced age, or lifestyle. Dissecting the mechanisms underlying exercise adaptations in order to identify exercise mimetics remains a prominent research goal. Until recently, studies of life-long exercise effects were limited to rodent models and retroactive comparisons of human cohorts, making controlled, longitudinal analysis and large-scale genetic studies difficult. We and others have developed endurance training programs for *Drosophila*, taking advantage of their innate instinct for negative geotaxis, allowing for controlled training of large, genetically identical cohorts \\[[@pgen.1008778.ref009],[@pgen.1008778.ref010]\\]. After our 3 week training protocol, male flies increase climbing speed, cardiac stress resistance \\[[@pgen.1008778.ref011]\\], endurance \\[[@pgen.1008778.ref012]\\], flight performance \\[[@pgen.1008778.ref005]\\], and lysosomal activity in their fat body \\[[@pgen.1008778.ref007]\\]. Trained male flies have increased"
+"INTRODUCTION\n============\n\nIn the recent decades, video games (VGs) industry has expanded to the point of becoming one of the largest multimedia economic activities in the world. Thanks to their great availability and accessibility, VGs have become immediately and extremely popular among children, adolescents and adults. They appeared for the first time in the 1962 at M.I.T., when Steve Russell created *Spacewar!*, the very first VG of the history, with essential graphics and luminous dots moving on the display^[@r1]^. Then, mainly thanks to technological evolution, games ever more immersive and rich in details have been developed, contributing to the creation of new genres and types of VGs.\n\nSuch a great success of videogaming industry, together with the fact that it became one of the most popular recreational activities practiced by children and adolescents, fostered a strong public debate about the possible effects of VGs exposure on human well-being. Recent studies showed that in western industrialized countries many children and adolescents play VGs for a very long time during the day^[@r2],[@r3]^. Several recent investigation have shown that children and adolescents live media-saturated lives: a percentage ranging from 83 to 97% has a home console for VG with which interact for several"
+"Introduction {#Sec1}\n============\n\nDacryocystorhinostomy (DCR) is the most popular operation for treating nasolacrimal duct obstruction or chronic dacryostenosis^[@CR1]^. DCR is a surgical procedure to create drainage between the lacrimal sac and the nasal cavity^[@CR2]^. DCR procedures include standard external DCR (EX-DCR), non-laser endonasal endoscopic DCR (EN-DCR), and endonasal endoscopic laser DCR (LA-DCR). Beginning in the 1970s, ophthalmologists began to favour DCR with silicone intubation over DCR without intubation^[@CR3]^. They advocated its use and reported an increased postoperative patency rate because of maintenance of the opening of the ostium^[@CR4]^. However, other studies reported a higher failure rate when using a silicone stent because of granulomatous inflammation^[@CR5]^. The role of silicone intubation during DCR surgery has been discussed several times in the recent literature, with conflicting opinions^[@CR6],\\ [@CR7]^. The aim of this study was to evaluate the success rate with and without the use of a stent during DCR and to compare the results with those of previously published studies. We hope the results of this study will give clinicians a more definitive set of guidelines and indications for tube use.\n\nMaterials and Methods {#Sec2}\n=====================\n\nThe following electronic databases were searched from January 1, 1990 to June 1, 2016: PubMed, EMBASE,"
+"Abbreviations {#nomen0010}\n=============\n\n2-HG\n\n:   2-hydroxyglutarate\n\n6PGD\n\n:   6-phosphogluconate dehydrogenase\n\n\u03b1-KG\n\n:   \u03b1-ketoglutarate\n\nAICAR\n\n:   acadesine\n\nAMPK\n\n:   Adenosine 5\\'-monophosphate activated protein kinase\n\nCRC\n\n:   colorectal cancer\n\nCTP\n\n:   citrate transporter protein\n\nECM\n\n:   extracellular matrix\n\nEGF\n\n:   epidermal growth factor\n\nFoxO1\n\n:   forkhead box O1\n\nG6PD\n\n:   glucose-6-phosphate dehydrogenase\n\nGBM\n\n:   glioblastoma\n\nGLS\n\n:   glutaminase\n\nGSH\n\n:   reduced glutathione\n\nIDH\n\n:   isocitrate dehydrogenase\n\nME\n\n:   malic enzyme\n\nMTHFD\n\n:   methylenetetrahydrofolate dehydrogenase\n\nNAC\n\n:   N-acetylcysteine\n\nNADP\n\n:   nicotinamide adenine dinucleotide phosphate\n\nNADPH\n\n:   reduced nicotinamide adenine dinucleotide phosphate\n\noxPPP\n\n:   oxidative pentose phosphate pathway\n\nPDAC\n\n:   pancreatic ductal adenocarcinoma\n\nPDX\n\n:   patient-derived xenograft\n\nROS\n\n:   reactive oxygen species\n\n1. Introduction {#sec1}\n===============\n\nCancer cells are characterized by rapid proliferation, anchorage-independent cell growth and migration \\[[@bib1], [@bib2], [@bib3]\\]. During the process of rapid proliferation and metastasis, cancer cells encounter a drastic increase in the production of reactive oxygen species (ROS) \\[[@bib4], [@bib5], [@bib6]\\]. To survive the increased ROS levels, cancer cells have evolved precise machinery for maintaining redox homeostasis, which is important for supporting tumor growth and metastasis \\[[@bib7]\\]. NADPH is one of the most important cofactors that scavenges ROS by replenishing the reduced glutathione (GSH) and thioredoxin pools \\[[@bib8]\\]. In"
+"Introduction {#s1}\n============\n\nHomologous recombination (HR) is a ubiquitous DNA metabolic process that is essential for meiotic chromosome segregation, the repair of complex DNA damage such as DNA double-stranded breaks (DSB) or interstrand crosslinks, and the recovery of stalled or broken replication forks [@pone.0082184-Hunter1], [@pone.0082184-Li1]. HR is catalyzed by a suite of genes/proteins collectively called the *RAD52* epistasis group, and the process can be conceptually divided into three stages: presynapsis, synapsis, and postsynapsis [@pone.0082184-Heyer1]. During presynapsis, the DNA substrate is processed to allow the formation of the Rad51 nucleoprotein filament on ssDNA. The Rad51 filament catalyzes the signature reactions of HR, homology search and DNA strand invasion, which define synapsis. During postsynapsis, DNA synthesis from the 3\u2032-end of the invading DNA end restores the missing genetic information and the resulting joint molecules are processed to either crossover or noncrossover products, where the continuity of the chromosome has been restored.\n\n*RAD54* has been identified in the budding yeast *Saccharomyces cerevisiae* as a core member of the *RAD52* epistasis group and together with mutants in the *RAD51* and *RAD52* genes, *rad54* mutants are the most ionizing radiation-sensitive single gene mutants in budding yeast [@pone.0082184-Heyer2]. The gene is well conserved throughout evolution in"
+"Background\n==========\n\nAs research typically involves an investment of society\\'s limited resources, there exists at least some obligation to ensure that research activity aligns with the interests, needs and values of the larger community. Applied health services research, in particular, focuses on practical translation and uptake of research findings \\[[@B1]\\]. The knowledge transfer and exchange literature highlights that regular interaction between researchers and decisions makers is one of the most effective ways to increase the likelihood that research knowledge will be used \\[[@B2]-[@B4]\\]. Such interaction also enables each group to better understand the contexts of the other and the constraints under which each operates. It is also critical that this interaction occurs over the entire research cycle, not just in the latter stages when some notion of \\'transfer\\' is to take place \\[[@B4],[@B5]\\]. Given this, it would be of great value for researchers and decision-makers to spend more time developing research directions and potential research questions collaboratively.\n\nThe field of health care priority setting and resource allocation is a good example of an applied health services research field that should produce findings aligned with the needs of the end users. However, to our knowledge there has been limited input to"
+"Introduction {#Sec1}\n============\n\nConsumption of the so-called Mediterranean diet has been associated with a decreased risk of chronic diseases, in particular cardiovascular disease (CVD), when compared to other dietary regimes \\[[@CR1], [@CR2]\\]. These effects may be attributed, in part, to the olive oil (OO) component of the diet \\[[@CR3]\\]. Research comparing refined OO to extra virgin OO (EVOO) has highlighted the biological activity of the (poly)phenol components contained within the water-soluble fraction of EVOO \\[[@CR4], [@CR5]\\]. In addition to the fruit (from which OO is derived), the leaves of the olive plant (*Olea europaea*) also contain phenolic compounds at a much higher concentration than those of the olive fruit and oil (1450\u00a0mg total phenolics/100\u00a0g fresh leaf \\[[@CR6]\\] vs. 110\u00a0mg/100\u00a0g fruit \\[[@CR7]\\] and 23\u00a0mg/100\u00a0ml EVOO \\[[@CR8]\\]). The most abundant phenolic compounds present in the leaves are verbascoside, apigenin-7-glucoside, luteolin-7-glucoside, hydroxytyrosol (HT), tyrosol and the secoiridoid oleuropein, with secoiridoids being uniquely present in plants of the *Oleaceae* family \\[[@CR9]\\].\n\nData emanating from a number of studies suggest that olive leaf extract (OLE) may influence CVD risk via its potential to induce anti-atherosclerotic, hypotensive, antioxidant, anti-inflammatory and hypocholesterolaemic effects (for review see \\[[@CR10]\\]). The majority of these"
+"Introduction {#sec1-1}\n============\n\nNeuromyelitis optica (NMO) is an autoimmune disorder of the central nervous system, which until recently was thought to be a variant of multiple sclerosis (MS). As the name suggests it targets the spinal cord and optic nerve predominantly, is most often relapsing and has a female preponderance. The discovery of a novel biomarker anti aquoporin 4 immunoglobulin G (anti AQP4-IgG) vastly improved the specificity of diagnosis.\\[[@ref1]\\] A variety of conditions were discovered with anti AQP4-IgG positive state necessitating the coining of the term NMO spectrum disorders (NMOSD).\\[[@ref2]\\] Recently greater efforts have been made to improve the diagnostic criteria of the disease that would allow the inclusion of ever increasing clinical manifestations of the disease. Brain MRI features suggestive of NMOS have been described and additional biomarkers are being identified, which may produce an \"NMO phenotype\" disorder.\n\nThis review highlights the clinical features particularly the \"extra opticospinal\" cord manifestations and the non-neurological associations of this disorder. It briefly touches on new biomarkers associated with NMOS and the clinical relevance of the same. Lastly an attempt is made to describe the NMOS-specific lesions on magnetic resonance imaging (MRI) of both spinal cord and brain.\n\nEpidemiology {#sec1-2}\n============\n\nIn India,"
+"1. Introduction {#sec1-ijms-20-03519}\n===============\n\nRice is a major staple food consumed by more than one-third of the world's population, providing up to 80% of the daily calories intake of a vast majority of the human population, especially in Asia \\[[@B1-ijms-20-03519]\\]. However, rice is considered one of the most drought-susceptible plants due to its small root system, thin cuticular wax, and swift stomata closure \\[[@B1-ijms-20-03519]\\]. In the quest to attain self-sufficiency in rice production by 2050, the development of high yielding rice variety with a high degree of tolerance and resistance to both biotic and abiotic stresses is a prerequisite \\[[@B2-ijms-20-03519]\\]. The yield potential of 10 t/ha can be obtained, however, the average harvest by local farmers is between 4--5 t/ha \\[[@B3-ijms-20-03519]\\]. This wide gap in yield is attributed to various environmental stresses. Environmental stresses are natural phenomena that affect crop productivity and sustainability in agriculture. Stresses can be due to biotic factors such as pest, insect and disease incidence or abiotic such as flooding, salinity, drought, high temperature, air pollution, mineral deficiency, adverse pH, heavy metal toxicity, among others. Among the abiotic factors, drought is one of the most devastating and it has been estimated that more than 50% of"
+"1. Introduction {#sec1}\n===============\n\nBreast cancer is a leading cause of mortality and morbidity all over the world. In 2008, close to 1.4 million cases were diagnosed with breast cancer worldwide \\[[@B1]\\]. The incidence varies among different populations with high rates seen in developed countries compared to developing countries \\[[@B2], [@B3]\\]. In general, breast cancer rates are highest in white European and lowest in east Asian populations \\[[@B1], [@B4], [@B5]\\]. The estimated incidence rate for women living in the south-east Asia region of World Health Organization\\' is 26.1 per 100000 population and this figure is 89.7 for women living in Western Europe \\[[@B1]\\]. The established risk factors of breast cancer are, mainly, early age at menarche, late age at menopause, nulliparity, number of live birth, and age at first live birth. Contrary to the large variations seen in incidence between population of Europe and Asia, the prevalence of the established risk factors is not very much different between the two populations \\[[@B5], [@B6]\\]. A higher risk of breast cancer among American and European women has been blamed for so-called \"western lifestyle\" characterized \\[[@B7], [@B8]\\] by the combination of early menarche, decreased parity, delayed childbearing, and a sedentary lifestyle. Studies of"
+"Introduction {#sec1-1}\n============\n\nIntracranial chondroma is a rare entity of primary cerebral tumors. The incidence of these tumors is estimated as 0.2%--0.3%. It was first reported by Hirschfeld in 1851.\\[[@ref1]\\] These tumors are benign slow growing and usually arise from the embryonic cartilaginous remnants with a predilection of the sphenoethmoidal region. These tumors can originate from the falx, convexity dura, the tentorium, the choroid plexus, or the brain parenchyma. Here, we present a case of chondroma of the falx cerebri with a review of the literature.\n\nCase Report {#sec1-2}\n===========\n\nA 22-year-old female patient presented to us with a history of episodic headache, vomiting, and absence seizures for 3 years operated elsewhere 1 year back and started having generalized tonic--clonic seizures following surgery which was poorly controlled on antiepileptic medications. She presented to us in an emergency following an episode of seizure in a drowsy state with left hemiparesis Grade 2 and bilateral papilledema. Her noncontrast computed tomography of the head was suggestive of large extra-axial mass lesion arising from the falx with cystic areas and foci of calcification and absence of the dural tail sign. Magnetic resonance imaging (MRI) of the brain with contrast \\[[Figure 1](#F1){ref-type=\"fig\"}\\] revealed a large"
+"Introduction {#H1-1-ZLD200029}\n============\n\nThe movie *Joker* provides an origin story for its namesake character, played by award-winning actor Joaquin Phoenix. Phoenix's character Arthur is depicted as having a mental illness; he visits Arkham State Hospital to receive medication and frequently displays symptoms that suggest some form of serious mental illness. Because of budget cuts, Arthur stops receiving his medication and consequently carries out a campaign of violence.\n\n*Joker* is the first R-rated film to earn more than \\$1 billion at the box office, with more than 100 million people viewing it worldwide. Because *Joker* continues the tradition of movies depicting individuals with mental illness as violent,^[@zld200029r1],[@zld200029r2]^ it has reignited discussion about the role of media in perpetuating prejudice toward those with a mental illness.^[@zld200029r3]^ To investigate the associations of the *Joker*with prejudice toward those with mental illness, we had a community sample attend a screening of *Joker* or *Terminator: Dark Fate* (as the control condition) and complete a measure of mental illness prejudice before and after watching their assigned movie. We hypothesized that, compared with viewing *Terminator: Dark Fate*, viewing *Joker* would be associated with higher levels of prejudice toward individuals with mental illness.\n\nMethods {#H1-2-ZLD200029}\n=======\n\nIn this survey"
+"INTRODUCTION\n============\n\nThe acetabular labrum provides a significant functional role and may be important in overall hip preservation \\[[@hnv001-B1]\\]. Labral tears often occur in the setting of bony dysmorphisms such as dysplasia and femoroacetabular impingement (FAI). Arthroscopic surgery for FAI is a less invasive option that typically addresses bony deformities and chondrolabral pathology \\[[@hnv001-B5], [@hnv001-B6]\\]. Patients undergoing labral refixation have better outcomes than those undergoing labral debridement \\[[@hnv001-B7]\\]. When the labrum is deficient and/or irreparable, labral reconstruction has been performed with early successful outcomes \\[[@hnv001-B11]\\]. Current labral repair and reconstruction techniques utilize suture anchor fixation.\n\nSuture anchors provide a common method for fixation of soft tissues to bone. In order to restore labral function including the labral fluid seal effect, the fixation device should be placed on the acetabular rim close to but not violating the articular cartilage or joint \\[[@hnv001-B16], [@hnv001-B17]\\]. Suture anchors placed too far from the articular cartilage can evert or medialize the labrum, compromising its function; anchors placed too close to the articular cartilage can cause iatrogenic cartilage injury. Complications related to suture anchors have been documented, mainly in the shoulder literature including chondrolysis, osteolysis, synovitis, articular cartilage damage and fixation failure \\[[@hnv001-B18]\\]. Consequences from anchor-induced"
+"Introduction {#S1}\n============\n\nThe rate of surgical wound infections is strongly influenced by operating room quality, which is determined by the structural features of the facility and its systems and by the management and behavior of healthcare workers \\[[@R01], [@R02]\\]. It has been suggested that the main sources of contamination, especially in clean surgical procedures, are the patient\\'s skin and airborne particles from operating room personnel \\[[@R02], [@R03]\\]. In this regard, a study conducted by the Medical Research Council showed a correlation between microbial air contamination and the incidence of surgical site infections (SSI) in prosthetic joint surgery \\[[@R04]\\]. Hipand knee-replacement operations are common procedures and are performed to improve quality of life in individuals with end-stage joint degeneration. However, SSI can give rise to very severe complications which nullify the efficacy of the procedure. Infection rates after primary total knee arthroplasty reported in the literature range from 0.39% to 2.5%; total hip infection rates are approximately 0.2%-2.2% for primary procedures \\[[@R05]\\]. In addition to the devastating consequences for the patient, such infections have an enormous economic impact on the treating hospital, since they substantially prolong hospitalization and increase costs \\[[@R06]\\]. Approximately 12,000 joint infections occur annually in the United"
+"In this manual, the World Health Organization (WHO) updates its guidance for governments in preparing for a possible terrorist attack with biological or chemical weapons. The book has something for virtually everyone who may have an interest in this topic, from government officials to clinicians, including information about the history of biological and chemical warfare, applicable international treaties, procedures for requesting WHO technical consultation, fundamentals of public health emergency response, basics of infectious disease treatment, treatment of patients with specific infectious or toxic exposures, physical properties of various agents, utility of reconnaissance satellites for detecting weapons development, management of food and water safety programs, etc.\n\nAnd it is this ubiquity and ambitiousness that underlie the manual's limitations and strengths. At times the guidance is so general that is almost an inventory of truisms (e.g., \"If it is found that the \\[emergency\\] control measures are not effective, they must be changed or modified.\"); elsewhere, the manual is a detailed resource. Its utility for different users will depend on their backgrounds and information needs. The core chapter, Public Health Preparedness and Response, may disappoint those seeking more than general principles. Yet these principles merit articulation as the foundation for prevention and response."
+"Correspondence\n==============\n\nBackground\n----------\n\nIn 2000, the United Nations Millennium Declaration committed governments and the international community to address major issues related to peace, development and human rights. Millennium Development Goals (MDGs) Countdown to 2015 is a global initiative that tracks global and national progress towards the achievement of MDGs four and five; focuses on coverage of effective interventions for maternal, newborn and child survival and reports on 75 priority countries which account for more than 95% of maternal and child mortality worldwide \\[[@B1]\\].\n\nZambia held its first ever Countdown to 2015 Conference on Maternal, Newborn and Child Health (MNCH) in 2008. The conference was meant to raise awareness, take stock of achievements and bottle necks, identify areas for improvement in programming and budgeting, strengthen monitoring, track progress and build a common vision and strategies towards the attainment of the MDGs. The event also facilitated identification of gaps in actions and knowledge that hinder progress and building consensus on defined roles and specific actions for Zambia to achieve the health-related MDGs. The Ministry of Health engaged key stakeholders and partners to participate in planning and holding of the national conference \\[[@B2]\\].\n\nZambia is among countries in the world with very"
+"Introduction\n============\n\nEpithelial cells of the gastrointestinal tract are an important barrier between the \"milieu interne\" and the luminal content of the gut. They perform the transport of nutrients, salts and water, which is essential for the maintenance of body homeostasis. Additionally, it constitutes the major route for xenobiotic entry and is also an important site of secretion of many compounds. Biological membranes prevent transmembrane diffusion of the majority of organic molecules that bear net charges. Organic cations are polar and positively charged at physiological pH making the involvement of membrane-bound transport systems on its biokinetic, necessary. Thus, intestinal transporters play a crucial role in limiting and/or promoting the bioavailability of organic cations.\n\nIt has been demonstrated that the absorption of certain nutrients and drugs and their effects may be influenced by the concomitant ingestion of certain food components. In a previous work,[@R1] the ability of procyanidins, a group of compounds common in diet, a class of polyphenolic polymers composed of flavan-3-ol units (catechin and epicatechin) found specially in red wine, apples, tea and cocoa or chocolate, to modulate (increasing or decreasing) organic cation apical uptake into Caco-2 cells (human colon epithelial cancer cell line used as a model of"
+"###### Strengths and limitations of this study\n\n-   To the best of our knowledge, this is the largest study of patients with ischaemic stroke with isolated dysphasia treated with intravenous thrombolysis (IVT).\n\n-   We identified dysphasia using relevant scores on the National Institutes of Health Stroke Scale (NIHSS), although this method may be criticised as lacking in sensitivity; when including patients in the hyperacute phase, the use of a formal dysphasia battery is practically impossible.\n\n-   The study is observational and based on a retrospective analysis of an ongoing database, with all the limitations of this type of study design.\n\n-   Another major limitation is the lack of a control group of patients with untreated dysphasia.\n\nIntroduction {#s1}\n============\n\nStroke is an important cause of morbidity, with dysphasia as one of the most devastating symptoms.[@R1] Isolated dysphasia gives only up to three points on the National Institutes of Health Stroke Scale (NIHSS)[@R2] score, albeit additional points may be given for loss of orientation, and doctors might hesitate to prescribe thrombolysis to patients with low NIHSS scores, due to potential risk of intracranial haemorrhage.[@R3] Current guidelines lack the recommendation of whether to treat stroke with low NIHSS score or not,[@R4] [@R5]"
+"Introduction\n============\n\nSurgery is the major treatment method for lung cancer, especially for non-small cell lung cancer (NSCLC). The prevalence of chronic obstructive pulmonary disease (COPD) in patients with lung cancer is 73% in men and 53% in women.[@b1] Postoperative pulmonary complications (PPC) are the main cause of mortality during the postoperative period[@b2] and pulmonary infection is the most common of these.[@b3],[@b4] Various reports have highlighted the need to improve lung function and quality of life in patients with COPD.[@b5],[@b6] However, the value of pre-operative pulmonary rehabilitation in lung cancer patients with COPD, who are candidates for lung resection, is controversial.[@b7],[@b8] Previous studies have included small sample sizes, using conventional pulmonary function tests (PFTs) for determination of COPD level, and treating with simple physical pulmonary rehabilitation without medication.[@b9] However, none of these studies have included patients with cardiopulmonary high risks who could be determined by cardiopulmonary exercise testing (CPET).[@b10][@b11] There has been no research evaluating CPET and pre-operative pulmonary rehabilitation in lung cancer. Our study was designed to evaluate CPET and pre-operative pulmonary rehabilitation, which may improve postoperative complications and fast-track recovery in high-risk patients who undergo resection for lung cancer.\n\nMaterial and method\n===================\n\nClinical data and grouping\n--------------------------"
+"###### Strengths and limitations of this study\n\n-   The large and representative sample (n=2229) of lower secondary school students who responded to the science achievement test improves the external validity of our findings.\n\n-   Estimating students' proficiencies and task difficulties using Rasch modelling, we could compare students' proficiency in science with the difficulty of identifying and appraising a health claim in a fictitious brief news report.\n\n-   All achievement test items were piloted twice to ensure a valid and reliable measure of scientific literacy, and the use of a digitalised assessment tool reduced sources of errors.\n\n-   We did a secondary analysis of test data collected in 2013, thus a shift in proficiency in subsequent student cohorts may have occurred.\n\n-   Using raters to code responses to the open-constructed 'news report' item, there is a potential of misclassifying responses owing to rater subjectivity.\n\nBackground {#s1}\n==========\n\nNews media is a leading source of health and scientific information for the public,[@R1] including adolescents and young people, who frequently encounter and share news and information through digital media.[@R3] According to Eurostat, more than two-thirds of young people access online news media regularly.[@R4] More than half also deliberately search for health information online,"
+"Background {#Sec1}\n==========\n\nThe functional independence of individuals after stroke is directly influenced by the ability to perform reaching and grasping movements successfully \\[[@CR1]\\]. However, the performance of these motor activities is commonly affected after stroke, leading to slower and segmented movements, and these, in turn, may be associated with compensatory movements of structures such as the shoulder and trunk \\[[@CR2]\\].\n\nReach and grasp movements involve the coordination of the fingers and thumb, previously positioned according to the size, shape, and function of the object that are combined with the movement of the arm toward the object and the control of the force to hold the target and keep it in the hand during its transport \\[[@CR1], [@CR3]\\].\n\nSeveral conventional and standardized clinical measures aim to evaluate reach and grasp activities in post-stroke subjects \\[[@CR4]\\]. Instruments, such as the Fugl Meyer Functional Performance Scale (FM), Box and Blocks Test (BBT), and Action Research Arm Test (ARAT), aim to quantify movement changes through observational analyses, further classified on either ordinal or nominal scales \\[[@CR2], [@CR5]\\].\n\nThe assessment of reach and grasp through clinical tests, when applied by trained professionals, allows the verification of psychometric properties and their effects on daily activities."
+"Background {#Sec1}\n==========\n\nThe epidermal growth factor receptor (EGFR) and K-Ras are among the most investigated molecular drivers in solid tumors. In particular, EGFR is addressed as an interesting target for several biologic agents, mainly monoclonal antibodies (acting at the cellular surface level) and small molecules (inhibiting the intracellular tyrosine-kinase domain activity) \\[[@CR1]\\]. EGFR overexpression often correlates with a worse prognosis is several tumors \\[[@CR2]\\] and the blockade of the EGFR-driven cascade has been proved successful in non-small cell lung cancer (NSCLC), colorectal, head and neck and breast cancer \\[[@CR1]\\]. Mutations in K-Ras, occurring at different levels along the gene sequence, have been described in multiple malignancies \\[[@CR3]\\]. Moreover, K-Ras has been the first predictive biomarker identified and routinely used in advanced colorectal cancer management: mutations in this key oncogene predict the benefit from the anti-EGFR monoclonal antibodies panitumumab and cetuximab \\[[@CR4]\\], and the role of mutations in different Ras family members (such as N-Ras) is rapidly emerging as an essential tool for patient selection in this disease \\[[@CR5]\\].\n\nNSCLC in women is a growing health concern in Western countries \\[[@CR6]\\]. Gender-related factors (modulating smoking-dependent and independent carcinogenesis) may contribute to this increased incidence \\[[@CR7]\\]. The disease is reported as"
+"1.. Introduction {#s1}\n================\n\nIschaemic heart disease (IHD) is the leading cause of death and disability worldwide. Therefore, novel therapies are required to protect the myocardium against the detrimental effects of acute ischaemia--reperfusion injury (I/R injury) in patients with IHD, so as to reduce lethal cardiac arrhythmias and cardiomyocyte death, preserve cardiac function and prevent the onset of heart failure, and improve patient survival.^[@CVU225C1]^\n\nDespite a large number of novel cardioprotective strategies (both pharmacological and non-pharmacological) being discovered in the research laboratory, their translation into the clinical setting to improve patient outcomes has been largely disappointing. The reasons for this failure are multiple and can be divided into two main categories: (i) the failure to rigorously test the novel cardioprotective therapy in the preclinical setting before embarking into the clinical arena.^[@CVU225C2],[@CVU225C3]^ This is the topic of the current European Society of Cardiology (ESC) Working Group (WG) Cellular Biology of the Heart Position Paper; and (ii) inadequate design of the clinical studies for testing the novel therapy. This subject has been extensively reviewed in our recently published ESC WG Cellular Biology of the Heart Position Papers^[@CVU225C4],[@CVU225C5]^ and elsewhere.^[@CVU225C2],[@CVU225C6]^ In brief, the major issues with the study design of previous clinical cardioprotection"
+"Conflict of interest: None.\n\nFunding source: None.\n\nDear Editor,\n\nSince December 2019, an outbreak of Coronavirus disease 2019 (COVID\u201019) that started in Wuhan, China, has been spreading across the world and was assessed as a pandemic from March 11, 2020, by the World Health Organization (WHO). Several manifestations related to COVID\u201019 have been reported, but small data about skin manifestations in these patients is available. In Mexico, COVID\u201019 alert began on February 27, and to date no associated clinical skin manifestations have been reported in our country. Here is our experience with two patients.\n\nCase 1 {#ijd14958-sec-0002}\n======\n\nA previously healthy 33\u2010year\u2010old male arrived to the Emergency Room (ER) on March 26, 2020, with an 11\u2010day history of fever, diarrhea, altered mental status with aggressiveness, and a 4\u2010day maculopapular skin rash affecting the trunk and upper and lower limbs. Three days previous to arrival, typhoid fever was diagnosed, and he was treated with ciprofloxacin and metamizole. No cough or dyspnea was reported.\n\nDue to a current measles epidemic outbreak in Mexico, the patient was considered suspicious and evaluated by the Neurology Department, diagnosing acute infectious meningoencephalitis. Laboratory findings included significant anemia (hemoglobin 12.7\u00a0mg/dl), elevated lactic dehydrogenase (4268.7\u00a0UI/l), and"
+"Introduction {#nyas12754-sec-0010}\n============\n\nWith the increasing availability of detailed patient profiles---through the use of novel techniques such as proteomics, genomics, metabolomics, and lipidomics---a paradigm shift from a one\u2010size\u2010fits\u2010all approach toward personalized health care (PHC) is underway. The use of PHC enables treatment strategies to be tailored to individual patients through identification of the optimal drug and dosage, thereby potentially improving the benefit--risk ratio of treatment decisions. This approach can improve treatment efficiency both by reducing the number of patients receiving ineffective treatment and by potentially reducing the likelihood of adverse drugs reactions (ADRs) and their associated costs. For example, the use of *KRAS* testing before initiating cetuximab treatment has been estimated to result in cost savings of over \\$600 million per year compared to no testing. In addition, using a patient\\'s thiopurine methyltransferase status to identify optimal dosage can help to minimize drug\u2010induced morbidity in patients with rheumatologic and inflammatory bowel disorders.[1](#nyas12754-bib-0001){ref-type=\"ref\"}\n\nBiomarkers are becoming increasingly important for PHC, with uses ranging from prediction of disease course to treatment monitoring. Biomarkers can also be used to further understand the pathology of the disease, to differentiate patient populations, and to identify new treatment opportunities.[2](#nyas12754-bib-0002){ref-type=\"ref\"} Ideally, a biomarker should be (1) a"
+"INTRODUCTION\n============\n\nRecent advancements of Reproductive Medicine, especially in some technical aspects, such as hormonal stimulation, *in vitro* fertilization (IVF), and the intracytoplasmic sperm injection (ICSI), made it possible to solve many causes of male and female infertility.^(^ [@B1] ^)^ For those women with absolute infertility, the traditional options of maternity are adoption or surrogate pregnancy.^(^ [@B2] ^)^\n\nHowever, in many countries, surrogate pregnancy is not accepted due to legal, ethical and religious issues.^(^ [@B3] ^)^ Thus, women submitted to hysterectomy when young due to malignant gynecological diseases or benign conditions, such as leiomyoma, endometriosis, and adenomyosis; patients with significant blood loss after a delivery resulting in hysterectomy, and finally, women with congenital anomalies of the genital tract, such as the Mayer-Rokitansky-K\u00fcster-Hauser syndrome, are condemned to not bearing children. Unquestionably, for many women this perspective affects their quality of life very negatively.^(^ [@B4] ^--^ [@B7] ^)^\n\nThe diverse issues related to surrogate pregnancy have led these women to 'dream' of the possibility of a uterine transplant that would relieve the anguish of the immense desire to conceive and bear a child.^(^ [@B8] ^)^\n\nUterine transplant mimicks a normal situation, with the primary constituent of genetic, gestational, and legal maternity. Additionally,"
+"*Motor sensation* is defined as sensation induced by body movements, including cutaneous and proprioceptive sensations induced by voluntary and involuntary movements. Motor sensation provides feedback that enables perception of the body's position and accurate movements during motor learning (Brindle, Mizelle, Lebiedowska, Miller, & Stanhope, [@CR5]; Khoshnoodi, Motiei-Langroudi, Omrani, Ghaderi-Pakdell, & Abbassian, [@CR24]). Thus, a lack of motor sensation causes inaccurate movements. For example, if tactile sensation of the tongue is diminished by treatment with lidocaine or capsaicin, the accuracy with which the subject can control a prosthetic device with the tongue is reduced (S. A. Boudreau, Hennings, Svensson, Sessle, & Arendt-Nielsen, [@CR3]). Motor sensation is also used in cognitive learning. Cutaneous and proprioceptive sensations induced by finger and arm movements can facilitate recognition of an object's shape through touch (Heller, [@CR16]; Heller & Myers, [@CR17]; Yoshioka, Craig, Beck, & Hsiao, [@CR34]). Thus, motor sensation is involved in various learning processes.\n\nInduction and emphasis of motor sensation may facilitate learning. For example, in rehabilitation, walking speed and distance improve through forced movement (Colombo, Joerg, Schreier, & Dietz, [@CR9]; Fleerkotte et al., [@CR11]; Hesse, Uhlenbrock, Werner, & Bardeleben, [@CR18]; Hidler et al., [@CR19]; Hornby et al., [@CR20]). In addition, emphasis of motor"
+"INTRODUCTION {#s0}\n============\n\nPseudomonas aeruginosa is a Gram-negative bacterium that accounts for over 10% of health care-associated infections with an identifiable cause ([@B1]). In acute infections, P.\u00a0aeruginosa utilizes a type III secretion system (T3SS) to export proteins into host cells, where they interfere with signaling and immune function and cause cytotoxicity ([@B2]). In chronic infections, P.\u00a0aeruginosa forms biofilms resilient to clearance by antibiotics and the immune response ([@B3], [@B4]). The emergence of antibiotic-resistant strains is increasing, making this pathogen a top priority for the discovery of new therapeutic targets ([@B5]).\n\nProteases are important virulence factors for many pathogens, including P.\u00a0aeruginosa ([@B6]). One intriguing family is the carboxy-terminal processing proteases (CTPs), found in all three domains of life. CTPs belong to the S41 family of serine proteases with a serine/lysine catalytic dyad ([@B7]). They are believed to target substrates close to their C terminus ([@B8], [@B9]). A well-described CTP occurs in plant chloroplasts and cyanobacteria, where it cleaves a component of the photosystem II reaction center to activate it ([@B10], [@B11]). Gram-negative bacterial CTPs are found exclusively in the periplasmic compartment and have been implicated in cleaving proteins associated with cell envelope function ([@B8], [@B12]). Some CTPs have"
+"Introduction {#section1-0748730419876781}\n============\n\nThe temporal organization of most societies is complex and requires the arrangement of many different aspects, from school/work and transport schedules to the opening times of shops and recreational facilities. This complexity is aggravated by the conflict that often arises between biological (internal) time and social (external) time. A mismatch between internal and external time leads to chronic sleep deprivation and a condition called social jetlag ([@bibr35-0748730419876781]). Minimizing social jetlag is important for health ([@bibr29-0748730419876781]; [@bibr34-0748730419876781]). In addition, populations show a wide distribution of so-called early and late chronotypes, namely, individuals who sleep at different times ([@bibr27-0748730419876781]). To accommodate sleep and other individual needs, flexible working hours have been proposed as a possible solution ([@bibr4-0748730419876781]).\n\nSo far, the vast majority of chronobiology research has focused on circadian (daily) time, but biological timing spans over different time scales, from tidal (12.4 h) to annual (365.25 days) rhythms. Describing the influence that these other biological cycles have on human behavior and physiology may be relevant for the temporal organization of society as well. For instance, school and working hours could be adjusted according to seasonal changes in biological timing.\n\nSeasonal changes derive from the Earth's moving around the Sun."
+"Background\n==========\n\nTo describe and characterize the work of independent complaint offices for users of psychiatric services and of ombudsmen in psychiatric hospitals.\n\nMethods\n=======\n\nNationwide survey addressed to all independent complaint offices and to all psychiatric hospitals in Germany.\n\nResults\n=======\n\nThe authors were able to identify N = 39 independent complaint offices. About 50% of the hospitals surveyed (N = 423) reported having a patient\\'s advocate (\\\"Patientenf\u00fcrsprecher\\\"). Both types of intercession agency rely mainly on volunteer service. While complaint offices are regularly staffed by psychiatry-experienced, their relatives and professionals, patient\\'s advocates are often retired employees of the respective hospitals. Both types of such agencies deal with a variety of complaints.\n\nConclusion\n==========\n\nImplications of the results will be discussed with regard to differences and similarities of the different institutions."
+"Background\n==========\n\nFolate antimetabolites play a central role as anticancer agents. In mammalian tissues, intracellular folates and antifolates exist as poly-\u03b3-glutamates with typical chains ranging from five to nine residues \\[[@B1]-[@B3]\\]. Polyglutamation is catalyzed by folylpoly-\u03b3-glutamate synthetase (FPGS) and results in increased intracellular concentration and cytoxicity of classical antifolates \\[[@B4]\\]. Furthermore, when polyglutamated, some antifolates (e.g., raltitrexed, lometrexol) increase their *Ki*against targeted enzymes by over 100-fold \\[[@B5],[@B6]\\]. In childhood acute lymphoblastic leukemia (ALL) a strong correlation exists between FPGS expression, intracellular methotrexate (MTX) polyglutamate accumulation and treatment outcome \\[[@B4],[@B7]\\].\n\nThe FPGS gene is controlled by at least two mechanisms: one tissue/lineage-specific and a second proliferation-dependent \\[[@B8]-[@B11]\\]. FPGS activity is distributed to both cytosolic and mitochondrial compartments of mammalian cells. In humans, these two isoforms are encoded by a single locus in chromosome region 9q (34.1--34.2) \\[[@B12]\\], and differ by the use of two alternative translational start sites within exon 1 \\[[@B13]\\]. Use of these alternative start sites translates the FPGS protein with or without the addition of a mitochondrial leader sequence. Alternative FPGS exon 1 variants (exons 1, 1A, 1B, 1C, and 2A), all spliced to exon 2, have been described \\[[@B12],[@B14]\\]. We have demonstrated no lineage-specific differences in the"
+"How long a single eruption lasts is one of the most intriguing questions concerning volcano activity. We know that volcanic eruptions can last from less than a day to thousands of years. In 1977, the lava lake at Nyiragongo drained in less than an hour. By contrast, Stromboli has had a low-level of activity since 450 BC (about 2,400 years)[@b1]. Although the median duration of historic eruptions is \\~8 weeks[@b1], this value is largely meaningless because of its considerable variance and its non-normal distribution as we demonstrate in the following.\n\nImportant factors governing a single eruption are the volume of melt accumulated in the magma reservoir and its degree of over-pressure, but also the possible contribution of new magma from depth. An eruption will normally last until the local melt has been depleted, or until the pressure level of the gas inside the magma reservoir reaches the pre-eruption pressure conditions. Nonetheless, this is a rather simplified overview. The internal plumbing system of an active volcano can be quite intricate, though recent monitoring efforts involving geodetic, seismic and geochemical measurements are helping at improving the estimations of size, depth, and activity of magma chambers under active volcanoes[@b2][@b3][@b4].\n\nIn recent decades, different"
+"Introduction {#s1}\n============\n\nMultiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system (CNS), destroying the myelin and the axon in variable degrees. The etiology of MS is still not known, a combination of several factors may be involved, including genetics, environment, and possibly a virus [@pone.0054841-Tselis1]. But, the weight of evidence would favour a significantly greater role for the environment over genetics [@pone.0054841-Taylor1]. During the development of MS, autoreactive T cells and macrophages which are stimulated in peripheral lymphoid tissues, infiltrate into the CNS and produce inflammatory molecules, leading to oligodendrocyte death and axonal damage in the CNS [@pone.0054841-Haegert1], [@pone.0054841-Sosa1]. Thus, the pathogenesis of MS may be related to activation, migration and effector function of immune cells as well as their products such as cytokines, chemokines, adhesion molecules or other inflammatory factors [@pone.0054841-Denkinger1]--[@pone.0054841-PintoMedel1]. These constitute the modern immunological basis for the development of novel clinical and preclinical immunomodulatory therapies for MS [@pone.0054841-Martin1].\n\nExperimental autoimmune encephalomyelitis (EAE), a well-established animal model of MS, is characterized by inflammation and demyelination of the CNS [@pone.0054841-Constantinescu1], which exhibits some of the symptomatology and pathology observed in MS patients. The immunopathogenesis of EAE involves the disruption of the blood"
+"Introduction {#S1}\n============\n\nWhile the tumor promoting functions of the transforming growth factor beta (TGFB) signaling pathway have been studied extensively ([@R1]), the contribution of the bone morphogenetic protein (BMP) family, and their receptor-regulated transcription factors \\[*i.e., Smad1* and *Smad5* (herein called BR-SMADs)\\], to cancer progression is less well characterized. *In vitro* studies have shown that BMPs can suppress growth of normal cells and human colon, prostate, and breast cancer cell lines when the BMP signaling components are intact ([@R2]). In addition, the BMP pathway is inactivated in 70% of colorectal cancers, and germline mutations have been found in the BMP type I receptor, *BMPRIA/ALK3*, in patients with juvenile polyposis syndrome ([@R3], [@R4]). Deletion of two of the BMP type I receptors, *Bmpr1a* and *Bmpr1b,* in granulosa cells of the ovary in mice causes granulosa cell tumor development with evidence of increased TGFB and hedgehog signaling ([@R5]). In addition, conditional deletion in granulosa cells of *Smad1* and *Smad5* \\[*Smad1/5* double conditional knockout (dKO)\\]*,* which are phosphorylated by these receptors in response to BMP signaling, leads to the formation of highly vascularized granulosa cell tumors with full penetrance and with an increased incidence of peritoneal metastases and hemorrhagic ascites with age"
+"Introduction\n============\n\nAccording to statistics, by October 2012, the number of cases of Acquired Immune Deficiency Syndrome (AIDS) and Human Immunodeficiency Virus (HIV) in Iran had reached 25041([@B1]); 22.2% transmitted sexually and 60% through intravenous drug use (IDU) ([@B2]). Evidence suggests that the most common transmission route for AIDS around the world is sexual contact, and in Iran, it is IDU ([@B3],[@B4]). Some identified factors that speed the spread of the disease in Iran include limited sex education, a high prevalence of sexually transmitted infections (STI) and a high proportion of young people in the population ([@B5]--[@B7]).\n\nStudies in Asian countries indicate increased HIV transmission through sexual contact in addition to IDU. According to a study in Central Asia, the increased prevalence of HIV in the countries in this region was due to the increased number of female sex workers and their clients ([@B8]). Similar studies in China, India, Pakistan, and Bangladesh have focused on the transmission of AIDS and factors that set the scene or increase the transmission. Even in Pakistan, which is culturally very similar to Iran, the most common transmission route is unsafe heterosexual contact ([@B9]--[@B11]). In Iran, research on knowledge, perception and sexual/reproductive behavior of adolescents"
+"Background {#Sec1}\n==========\n\nBacteria produces different kinds of antimicrobial substances including ribosomally synthesized bacteriocins and non-ribosomally synthesized antibiotics or lipopeptides as a part of their defense strategies in complex environments such as fermented foods and the human gut. Members belonging to the lactic acid bacteria (LAB) family with ability to produce bacteriocins are frequently found in these environments \\[[@CR1]\\]. LAB strains are recognized as GRAS (Generally Regarded As Safe) microorganisms and have been studied in detail for biotechnological applications together with the bacteriocins produced by these strains \\[[@CR2],[@CR3]\\]. Members of the genus *Pediococcus* are classified within the LAB family and are reported to produce bacteriocins without post-translational modifications that are classified under class II bacteriocins \\[[@CR4],[@CR5]\\]. The bacteriocins classified under class IIa are called as pediocin-like bacteriocins because the first antimicrobial peptide of this class (pediocin PA-1) was isolated from *Pediococcus* sp. \\[[@CR6]\\]. They include variable size peptides ranging from 2.7 to 4.6\u00a0kDa \\[[@CR7]--[@CR9]\\] with high sequence homology, disulfide bonds and a conserved motif YGNGVXC in their N-terminal domain \\[[@CR10]\\]. However, bacteriocins lacking the consensus motif are also classified under pediocin-like bacteriocins \\[[@CR2]\\]. Initially pediocin-like bacteriocins were reported to be produced by members of the genus *Pediococcus* \\[[@CR10]\\] but"
+"Introduction {#s1}\n============\n\nX-chromosome inactivation (XCI) has evolved in female mammals to compensate for sex-chromosome dosage differences by suppressing gene expression from one X chromosome, and to render all cells as functionally monosomic for the X chromosome, a process considered to be important for normal embryonic development (Monk and Harper, [@B22]; Penny et al., [@B36]). The current understanding of XCI during early embryogenesis largely originates from studies in mice, partially because XCI occurs during a very early developmental window when the embryo is accessible. In female mice, dosage compensation takes place within a continual cycle of XCI and reversal, also known as X-chromosome reactivation (XCR) (Lee and Bartolomei, [@B16]). Inactivation of the paternal X chromosome occurs progressively during the first days of post-fertilization cleavage until the morula stage (Okamoto and Heard, [@B27]; Kalantry et al., [@B11]; Namekawa et al., [@B26]). At the late blastocyst stage, XCR is observed within cells from the inner cell mass (ICM) that will form the embryo proper (i.e., two active X chromosomes are present in these cells), whereas cells of the trophectoderm (TE), which will form the placenta, maintain imprinted inactivation of the paternal X chromosome (Mak et al., [@B19]; Okamoto et al., [@B28]; Patrat"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec001}\n============\n\nThe West Nile Virus (WNV) is a member of the same family as the Dengue virus (DENV), Zika virus (ZIKV) and Yellow Fever virus (YFV), the *Flaviviridae* family, *Flavivirus* genus. They are arboviruses that present RNA as a genome \\[[@pone.0223017.ref001]\\]. Diseases caused by *Flavivirus* are the major causes of fatality in poverty-stricken regions across Africa, Asia and some parts of the Americas. The combined potential health risk associated with arthropod-borne viruses like DENV, WNV, and ZIKV is enormous. These arboviruses are either emerging or re-emerging in many regions \\[[@pone.0223017.ref002]\\].\n\nThree WNV strains are known to be capable of causing unforeseen and large epidemics, leading to serious public health problems. Since 2004, lineages 1 and 3 have been circulating in Europe and, since 2010, beginning in a major epidemic in Greece, lineage 2 has been circulating in several European countries. \\[[@pone.0223017.ref003], [@pone.0223017.ref004]\\]. The WNV crossed the Atlantic and reached the Western Hemisphere in 1999, when a group of patients with encephalitis was reported in the New York City metropolitan area. Within three years, the virus spread to Canada and Mexico, followed by animal cases in Central"
+"INTRODUCTION {#SEC1}\n============\n\nAs the world population is rapidly aging, the prevalence of aging-related diseases and the demand for expensive, long term health care is also rising ([@B1]--[@B4]). To offset the burden of this shift, scientific knowledge and innovation will become increasingly crucial, and anti-aging and disease prevention strategies will become national and international priorities. Aging research as a field will boom. Nevertheless, it faces several challenges, and the growth will need direction.\n\nOne of the challenges is the current lack of a freely available, comprehensive collection of aging-related biological pathways and encyclopedia of aging knowledge. Biological pathways are one of the most powerful visualization tools in biology ([@B5]). They provide an intuitive, systems view of the interactions between the multitude of individual elements in any given process. They can be interactive for user-directed exploration and amenable to computational methods, and they are indispensable in making sense of large-scale data sets, where a multitude of individual changes may reflect a small number of more biologically important (and more statistically powerful) changes at the pathway level ([@B6]). Pathway collections are a key feature of many biological data repositories in the public domain ([@B7]).\n\nAging processes are particularly suited for representation by"
+"1.. Introduction {#s1}\n================\n\nMultiple myeloma (MM) is a neoplastic plasma cell disease with high morbidity and mortality rates. MM reportedly accounts for approximately 10--15% of haematologic malignancies in the world \\[[@RSOS192152C1],[@RSOS192152C2]\\]. Almost 6--7 individuals out of every 100 000 people in the world are diagnosed with MM each year \\[[@RSOS192152C2]\\]. In 2015, 28 850 patients were diagnosed with MM, and the number of deaths due to this illness was more than 11 000 in the United States \\[[@RSOS192152C3]\\]. However, MM is still incurable and there is a great need to develop more effective therapeutic strategies.\n\nNuclear factor-kappa B (NF-\u03baB) was reported to be abnormally activated in many types of cancer cells, including MM in the 1990s \\[[@RSOS192152C4]\\], and it inhibits the apoptosis of cancer cells by upregulating anti-apoptotic genes \\[[@RSOS192152C4],[@RSOS192152C5]\\]. A series of studies have been performed to investigate the underlying mechanism of NF-\u03baB in the pathogenesis of MM, with the aim of exploring NF-\u03baB-targeted therapies \\[[@RSOS192152C6]--[@RSOS192152C11]\\]. However, to date, no appropriate NF-\u03baB-targeted treatments have been established due to their serious side effects \\[[@RSOS192152C4]\\]. The inhibitors of NF-\u03baB similarly affect the NF-\u03baB pathway in MM and normal cells leading to serious damage. This reflects the important roles of NF-\u03baB"
+"Introduction {#sec1}\n============\n\nThe detection of biologically and environmentally related heavy metal ions (Cd^2+^, Hg^2+^, Cu^2+^, etc.) is crucial due to their important roles in biological processes and hazard to the environment.^[@ref1]^ Among various heavy metals, copper is an essential trace element for living systems. The excess of unbound Cu^2+^, the natural form of free copper in biological media, is quite harmful and can even cause various neurodegenerative diseases. Meanwhile, Cu^2+^ may be a common pollutant of drinking water that affects water quality and leads to multifarious infections.^[@ref2],[@ref3]^ Until now, the approaches for Cu^2+^ ion detection reported are inductively coupled plasma atomic emission spectroscopy (ICP-AES), atomic absorption spectroscopy, inductively coupled plasma mass spectroscopy (ICP-MS), and voltammetry. However, these approaches are time consuming, expensive, and quantitative; thus, it is necessary to develop a new method for the detection of Cu^2+^ ions.\n\nFor the past few years, the development of a range of smart fluorescence materials including transition-metal complexes,^[@ref4],[@ref5]^ organic dyes,^[@ref6]^ inorganic semiconductor nanocrystals,^[@ref7],[@ref8]^ carbon dots,^[@ref9],[@ref10]^ and lanthanide-doped upconverting nanoparticles^[@ref11],[@ref12]^ have attracted particular attention. These fluorescent compounds have great demand in optoelectronics, lighting, and so forth;^[@ref13],[@ref14]^ especially, fluorescent probing or sensing is now becoming an effective detection modality. Fluorescence detection is a"
+"1. Introduction {#sec1-nutrients-08-00243}\n===============\n\nDoxorubicin (DOX), a quinone-containing antitumor drug, is widely used for the treatment of cancer, especially for treating breast and esophageal carcinomas \\[[@B1-nutrients-08-00243]\\]. However, it has been noted that long-term use of DOX tends to induce neurotoxicity and may cause neuropsychiatric diseases including depression, anxiety, and impaired cognition function \\[[@B2-nutrients-08-00243],[@B3-nutrients-08-00243],[@B4-nutrients-08-00243]\\]. Previous studies of patients undergoing chemotherapy for breast cancer have consistently shown their depressed mood and decreased interest in surroundings \\[[@B5-nutrients-08-00243]\\], which highlight the importance of further understanding on the neurotoxic effects of DOX and seeking potential therapeutic strategies.\n\nThe impairment of neurogenesis and increased neural apoptosis in the limbic brain regions, including the prefrontal cortex and hippocampus, is considered as one of the leading causes of depression. It was reported that DOX-mediated generation of free radicals in the brain tissues increases lipid peroxidation and protein oxidation, and alters the antioxidant defense system, eventually leading to neuropsychological changes \\[[@B3-nutrients-08-00243],[@B6-nutrients-08-00243]\\]. Moreover, increased generation of superoxide anions induced by DOX may elevate the level of circulating tumor necrosis factor-alpha (TNF-\u03b1) which can directly pass blood brain barrier (BBB), and activate glial cells to initiate the local production of pro-inflammatory cytokines which exacerbate the oxidative stress and neural apoptosis \\[[@B1-nutrients-08-00243],[@B7-nutrients-08-00243],[@B8-nutrients-08-00243]\\]."
+"Introduction {#section1-0969733019871685}\n============\n\nThis article seeks to explore the context of pain management at the end of life for people who use substances. These reflections are based on a wider unique project funded by (National Lottery Community Fund) examining end-of-life care for people who use substances.^[@bibr1-0969733019871685]^ This theoretical exploration stems from data generated from five strands of the project which included a rapid evidence assessment (REA),^[@bibr2-0969733019871685]^ interviews with individuals with palliative care needs who use substances.^[@bibr3-0969733019871685]^ Interviews were also conducted to explore family, carer and friends' experiences of people using substances at the end of life,^[@bibr4-0969733019871685]^ to examine practitioners' perspectives^[@bibr5-0969733019871685]^ and to gain key informant insights into the issues pertinent to this population.^[@bibr6-0969733019871685]^ We examine the dominant narrative genres that frame the stories related to pain management and substance use and how this delineates and defines the ethical landscape. We argue that the narrative positioning of 'recovery' remains unhelpful within the context of end-of-life care with implications both for health and social care professionals and people who use substances. We contextualise these data through a narrative approach^[@bibr7-0969733019871685][@bibr8-0969733019871685][@bibr9-0969733019871685][@bibr10-0969733019871685]--[@bibr11-0969733019871685]^ highlighting how constructions such as 'recovery' narratives can unhelpfully define the frames of reference for appropriate responses to people using substances at the"
+"Introduction\n============\n\nBackground\n----------\n\nMorbidity and mortality are the most commonly used outcome parameters in trauma care literature. However, most patients survive their trauma, and depending on the severity of the trauma, they will be limited in daily life, both physically and mentally. Although quality of life (QOL) is recognized as an important outcome measure, it is still a highly neglected aspect in trauma care studies, including studies with splenic injury patients. Multiple studies that did measure QOL have shown that severely injured patients suffer from psychological complaints and decreased QOL \\[[@ref1]-[@ref3]\\]. These factors have a major social and economic impact because trauma often involves young patients who frequently are unable to return to work, to reintegrate back into society, or to retrieve their previous activity level \\[[@ref4]-[@ref11]\\]. In case of splenic injury, treatment choices have to be made in which it is currently unknown what the effects for these patients will be in the short, medium, and long term. When more knowledge becomes available about QOL, it will be useful to determine the choice of treatment.\n\nIn blunt abdominal trauma, where the spleen is one of the most frequently injured organs, much is known about morbidity and mortality \\[[@ref12]\\]."
+"Introduction\n============\n\nThe Lives Saved Tool (*LiST*) can use baseline coverage data, programme targets and a demographic projection to model the magnitude of mortality reduction expected from planned programme activities, as described earlier in this issue[@B1]. As a validation exercise, we modelled data from a recently completed, retrospective evaluation of a child survival programme in West Africa and compared the results with estimates of mortality measured through demographic surveys as part of the evaluation. Using this large-scale, 'real life' evaluation to validate *LiST* will help current and future users understand the strengths and limitations of mortality-modelling tools.\n\nThe United Nations Children's Fund (UNICEF) implemented the Accelerated Child Survival and Development (ACSD) programme in 11 countries from 2001 to 2005, supported by the Canadian International Development Agency (CIDA). UNICEF focused efforts on several 'high-impact' countries, including Benin, Ghana, Mali and Senegal, working closely with country governments and other partners to implement ACSD with the ultimate goal of reducing under-5 mortality. Focus districts within these countries implemented three intervention packages. The 'EPI+' package included vaccinations, vitamin A supplementation and distribution of insecticide-treated nets (ITN). The 'ANC+' package targeted pregnant women and included improved access to antenatal care and skilled delivery along with"
+"Introduction {#sec1-1}\n============\n\nThe increase in the life expectancy of the population has been in part driven by reduced mortality of aged people \\[[@ref1]\\]. The number of people aged 65 or more is expected to grow from ca. 524 million in 2010 to almost 1.5 billion in 2050, with most of the increase in the developing countries. In Brazil, for example, the same demographic ageing which took more than a century in developed France occurred in two decades \\[[@ref2]\\]. In a descriptive study covering the period from 1970 to 2010 the increase in the ageing index (AI) of 268% was determined for Brazil in general, with still higher AI established for the state of Rio Grande do Sul (RS) \\[[@ref3]\\]. According to the data from the National Public Health Care System, in the RS, during 1991-2012 absolute number of seniors increased by 652,655 corresponding to the rise of the proportion of elderly people from 8.9% to 13.6% \\[[@ref4]\\].\n\nDespite the increase in longevity, the higher proportion of comorbidities distinguishes the older from the younger population \\[[@ref1]\\]. It's known that the elderly people have 2-3 times higher incidence of acute myocardial infarction (AMI) than the younger ones. They also tend to"
+"INTRODUCTION\n============\n\nNeuroendocrine tumors (NETs) are rare neoplasms that mainly occur in the gastrointestinal system. The liver is the most common site of NET metastases, but it is a rare site of primary NETs \\[[@B1][@B2]\\]. Diagnosis of primary hepatic NET (PHNET) is based on 2 prerequisites: the liver mass must be immunohistochemically compatible with NET, and the liver should be the primary site of tumor development with strict exclusion of hepatic metastases from other locations. Differentiating between PHNET and liver metastasis from gastroenteropancreatic NETs is essential for accurate diagnosis of PHNETs. We aim to heighten our understanding of PHNET by retrospectively reviewing our surgical experiences with PHNET patients.\n\nMETHODS\n=======\n\nDuring 10 years from January 1997 to December 2015, more than 15,000 patients underwent liver resection for various diseases in our institution. Of them, 35 patients were diagnosed with NET pathologically. To select PHNET study cases, we excluded 18 patients diagnosed with metastatic NET from other sites as well as 4 patients additionally diagnosed with NET from other gastroenteropancreatic sites 3 to 12 months later during postoperative follow-up up to 12 months. Ultimately, 13 patients were diagnosed with PHNET.\n\nWe reviewed the clinicopathological characteristics and prognosis in these 13 patients"
+"1.. Introduction\n================\n\nInertial measurement units (IMUs) composed by MEMS inertial sensors exhibit a number of advantages such as strong-autonomy, small-volume, light weight, low-cost and good impact resistance. Due to these excellent characteristics, MEMS IMUs have become a hot topic in the inertial navigation field in recent years \\[[@b1-sensors-14-13661]--[@b4-sensors-14-13661]\\]. One of their most innovative applications is to promote the development of space systems and the field of aircraft, such as the application of inertial sensors to spacecraft navigation systems. In order to ensure the precise guidance of spacecraft, higher accuracy and reliability are demanded of IMUs \\[[@b5-sensors-14-13661]\\]. As for the MEMS inertial sensors, their low-accuracy characteristics have greatly restricted their performance and applications in high-accuracy fields \\[[@b6-sensors-14-13661],[@b7-sensors-14-13661]\\].\n\nThe redundant configuration technique appears to be the most mainstream method for improving the accuracy and reliability of INS, in which the configuration of the system is meticulously designed and the number of sensors is reasonably increased. By assembling a set of inertial sensors with a certain designed configuration, the redundancy of each axis in the navigation framework can be efficiently improved, as well as the accuracy of the whole IMU, because the IMU can make full use of the redundant observation data"
+"Background\n==========\n\nWhite mold, caused by *Sclerotinia sclerotiorum* (Lib.) de Bary, is a devastating disease of over 400 reported dicotyledonous hosts \\[[@B1]\\]. The disease causes economically significant losses of many crop plants including pea (*Pisum sativum* L.) under the appropriate environmental conditions \\[[@B2]\\]. Currently, little is known about the genetic control of pathogenicity in the fungus and mechanisms of resistance in pea. Although hundreds of pea cultivars have been screened for white mold resistance in replicated greenhouse and laboratory tests \\[[@B3]\\], only partial resistance has been identified to date.\n\nThe identification of genes underlying *S*. *sclerotiorum* pathogenicity and resistance in pea would increase our knowledge of the pea-*S*. *sclerotiorum* interaction and facilitate the introgression of resistance into pea varieties. However, progress in these areas has been hampered by the lack of sequence information regarding the pea genome. Although other legume genomes, including the models *Medicago truncatula*, *Lotus japonicus* and economically important *Glycine max* (soybean) are available \\[[@B4]\\], *Pisum sativum* is still genome resource-poor in part due to the large genome size and large fraction of highly repetitive DNA \\[[@B5]\\].\n\nThe performance of Next-Generation sequencing (NGS) technologies continue to rise while costs continue to fall which enables researchers to conduct whole"
+"1. Introduction {#sec1-ijms-19-02243}\n===============\n\nCeliac disease (CD) is an autoimmune disease triggered by the gluten exposure among genetically predisposed people, leading to the small intestine damage and subsequent malabsorption \\[[@B1-ijms-19-02243],[@B2-ijms-19-02243]\\]. It is estimated that about 0.3--1.5% of Americans and Europeans suffer from CD \\[[@B3-ijms-19-02243]\\], with most patients being carriers of either DQ2 or DQ8 of histocompatibility complex class II human leukocyte antigen (HLA) haplotype \\[[@B1-ijms-19-02243]\\], although other non-HLA regions have been shown to be also involved \\[[@B4-ijms-19-02243]\\]. The main auto-antigen in CD is the tissue transglutaminase (tTG), whereas gut histopathology typically reveals small bowel mucosal villi atrophy \\[[@B5-ijms-19-02243]\\]. Diagnosis is centred in clinical suspicion, which is later confirmed through duodenal biopsy, laboratory testing, and, in some instances, genetic tests. Currently, the only known treatment is a lifetime gluten-free diet (GFD), which relieves patients from a number of clinical manifestations, decreases the level of serological markers and the chances of malignant and non-malignant related complications \\[[@B6-ijms-19-02243],[@B7-ijms-19-02243]\\]. While gastro-intestinal symptoms are revealed during the onset of the disease or its early stages in both adult and paediatric patients, they do not appear often as in the past \\[[@B8-ijms-19-02243]\\]. A number of adult patients manifest various extra-intestinal involvement, even in those without typical"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec001}\n============\n\nArtemisinin (AN), a sesquiterpene lactone produced mainly in *Artemisia annua* as a secondary metabolite, is a highly effective natural product against malaria and other parasitic diseases, as well as an anti-cancer agent. The World Health Organization (WHO) has recommended the Artemisinin-based Combination Therapy (ACT) for the treatment of malaria \\[[@pone.0140266.ref001],[@pone.0140266.ref002]\\]. Our group has previously reported artemisinin in 12 *Artemisia* species found in Pakistan \\[[@pone.0140266.ref003]\\] but at very low levels, i.e. 0.01--0.8% of the dry weight of the plant \\[[@pone.0140266.ref004]\\], reaching a maximum of 1.5% in some cases \\[[@pone.0140266.ref005],[@pone.0140266.ref006]\\]. There is therefore a need either to enhance the metabolite concentration in the natural plant or seek alternative sources of artemisinin.\n\nAmong different strategies used to improve secondary metabolite production, the recombinant DNA technology has made it possible to directly modify the expression of biosynthetic genes, and manipulate the pathways that lead to secondary plant compounds \\[[@pone.0140266.ref007]\\]. Various studies have shown *rol* genes to be powerful inducers of secondary metabolism in different plant families \\[[@pone.0140266.ref008]\\]. *Rol* A is a DNA-binding protein and stimulator of growth, while the tyrosine phosphatase activity of *rol B* regulates the signal transduction"
+"Introduction {#sec1-1}\n============\n\nAlzheimer\\'s disease (AD) is a progressive neurodegenerative disorder that is characterized by cognitive and memory deterioration, progressive impairment of activities of daily living, and a variety of neuropsychiatric symptoms and behavioral disturbances.\\[[@ref1]\\] By 2005, 24.2 million people worldwide had dementia,\\[[@ref2]\\] in 2010, the number became 36.0 million, and it will continue to increase to 66 million by 2030 and 115 million by 2050;\\[[@ref3]\\] approximately 70% of these cases were due to AD.\\[[@ref2]\\] It is estimated that AD has a median prevalence of 4.8% and an annual incidence of 1275 per 100,000 in populations of individuals aged \u2265 60 years worldwide.\\[[@ref4]\\] Women have a higher risk than men with a median men: women rate ratio of 0.54.\\[[@ref4]\\] The social costs associated with AD are high; it is estimated that the global costs in 2010 was \\$604 billion,\\[[@ref3]\\] with \\$172 billion in the USA alone.\\[[@ref5]\\] In the new diagnostic guidelines for AD, AD was divided into three phases: The dementia phase (AD dementia due to AD); the symptomatic, pre-dementia phase (MCI due to AD); and the asymptomatic, preclinical phase of AD.\\[[@ref6]\\] The first two phases are intended to guide diagnosis in the clinical setting, and the preclinical phase is"
+"The bacterial flagellum: function follows form {#sec0005}\n==============================================\n\nThe striking relationship of form and function in the flagellum ([Figure 1](#fig0005){ref-type=\"fig\"}) is the product of evolution over millennia [@bib0005; @bib0010], its complex architecture underpinning perfectly its action as a rotary nanomotor that spins freely, both clockwise and counterclockwise, at speeds of up to 100\u00a0000 r.p.m. (\u223c1700\u00a0Hz) [@bib0015]. This pronounced structure--function link is evident in the three contiguous substructures that comprise the flagellum: the basal body, hook, and helical filament ([Figure 1](#fig0005){ref-type=\"fig\"}). The basal body spans the bacterial cell envelope and comprises a 'drive-shaft' rod and a series of rings. Inside the cell, the basal body broadens into a bell-like structure called the cytoplasmic (C) ring or switch. This is the rotor part of the motor and is also the input point for signals that control the direction of flagellar rotation and, consequently, cell movement [@bib0020]. Studded around the basal body are the stator units of the motor. The rotor and stator components work together to harness the electrochemical energy of proton or sodium ion-motive forces, powering flagellum rotation [@bib0025]. Motor composition is dynamic, with individual stator units recruited to the basal body in response to changes in the ion-motive"
+"Contributions to the literature {#Sec1}\n===============================\n\nSelf-management is crucial to chronic disease management, but the adoption and adherence of self-management is generally poor among older patients.Our study explores how to incorporate older couples' routine interactions into the disease management regime, and to build a collaborative management model with professional medical supervision and couple's mutual support.This collaborative model provides innovative solutions for improving and maintaining older patients' self-management behaviors; and facilitates the implementation of primary prevention for their informal carers mainly spouses at risk.\n\nBackground {#Sec2}\n==========\n\nGaps in chronic disease management for older patients {#Sec3}\n-----------------------------------------------------\n\nChina is ageing rapidly. In 2000, older people aged 65+ years were 7%, while the 2050 projection is 26%, reaching 365 million \\[[@CR1]\\]. Due to this demographic shift, the number of older people living with chronic diseases is ever-increasing. The prevalence of chronic diseases among older people increased from 50% in 2003, 60% in 2008, to 72% in 2013; with a net growth of 22% over 10\u00a0years \\[[@CR2]\\]. The healthcare system has been struggling to keep pace with the escalating chronic disease burden. The 2013 National Surveillance of Chronic Diseases and Risk Factors revealed that only 38% of older adults with diabetes received"
+"Since its discovery in 1991, *Porcine circovirus type 2* (PCV2) has been one of the most present swine virus within the domestic population, reaching seroprevalence levels near to 100%[@b1][@b2]. Even though PCV2 is a small non-enveloped ssDNA virus with a circular 1766--1768\u2009bp long genome[@b3], the complexity of Porcine circovirus diseases (PCVD)[@b4] lies in every other trait, from the variety of subclinical and clinical syndromes[@b5], to the multifactorial nature of the disease onset[@b6], passing through the plethora of transmission routes which help the dissemination and the persistence of the pathogen[@b7]. Other fascinating aspects of this small virus are the remarkable genetic variability and peculiar evolutionary pathways that have showed to be particularly relevant also in relation to the changes in clinical manifestations occurring through time.\n\nAt least five Open Reading Frames (ORF) have been reported to be effectively transcribed, but the most studied and widely sequenced region is the ORF2, which encodes for the Cap protein[@b3][@b8][@b9][@b10]. This protein represents the only component of the viral capsid and has been proven to be the major target of the host immune response[@b11][@b12][@b13]. ORF2-based classification criteria[@b14][@b15] have been collectively adopted to define PCV2 genotypes because of its higher phylogenetic signal and lower tendency"
+"Introduction {#Sec1}\n============\n\nThe ability of axons to transport cargo over long distances is critical for processes ranging from axon path finding and target innervation, to neuronal survival. Those processes are regulated by the retrograde transport of neurotrophins such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF)^[@CR1]^. Mutations or alterations in the expression of genes that enable axonal transport are linked to neurodegenerative diseases, including Charcot--Marie--Tooth disease type 2, Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD)^[@CR2],[@CR3]^. Abnormal axonal traffic in cortical and hippocampal neurons is an early feature of both AD and HD, and a trigger for synaptic loss, neuronal death and the resultant loss of cognitive abilities^[@CR4]--[@CR6]^. Thus, understanding the mechanisms that control axonal transport of survival and differentiation signals could provide important insights into the physiopathology of the brain.\n\nFast axonal transport of signaling molecules is largely mediated by endosomes. Endosomes facilitate signaling through rapid retrograde transfer of proteins such as neurotrophins, activated receptor complexes, adaptors and kinases along microtubule tracks^[@CR7]--[@CR9]^. The identity of such endosomal signaling compartments has long been debated. In hippocampal neurons, multi-vesicular bodies transport endocytic cargo retrogradely in the axon^[@CR10]^. To determine the molecular identity and signaling properties"
+"Introduction\n============\n\nIn the 1960s, researchers first suggested a link between iron metabolism and the immune system \\[[@bib1]\\]. Since then, many iron-related genes have been found to play a role in immune function. For example, the proteins lactoferrin, hepcidin, and Hfe have all been found to modulate the host defense against bacterial infection \\[[@bib2; @bib3; @bib4; @bib5; @bib6]\\]. Moreover, the expression of several genes involved in iron metabolism, including hemojuvelin (*HJV*) \\[[@bib7]\\], hepcidin (*HAMP*) \\[[@bib8]\\], and ferroportin1 (*FPN1*) \\[[@bib9], [@bib10]\\], are modulated during inflammation. Interestingly, a recent case report described a patient with hemochromatosis who died from bacterial infection \\[[@bib11]\\]. These findings prompted us to investigate the putative role of hemochromatosis-related genes in bacterial infection. We therefore screened several hemochromatosis mouse models for their immune phenotype and susceptibility to bacterial infection.\n\nHJV is a bone morphogenetic protein (BMP) co-receptor that regulates the expression of hepcidin \\[[@bib12]\\]. In humans, mutations in the *HJV* gene cause juvenile hemochromatosis \\[[@bib13]\\]. In mice, deleting *Hjv* expression causes a similar iron-overload phenotype \\[[@bib7], [@bib14]\\]. HJV is also a member of the repulsive guidance molecule (RGM) family \\[[@bib15]\\]. However, the role of HJV in the immune response is currently unknown. Recent studies suggest that two other"
+"Introduction {#Sec1}\n============\n\nSomatic symptoms are abundantly reported in the general population and at different levels of health care systems \\[e.g., [@CR1]\\]. While medical diseases account for many somatic symptoms, there is a surprisingly large proportion of patients \\[over 35\u00a0%; [@CR2], [@CR3]\\] whose complaints remain \"medically unexplained.\" The last decades have witnessed a shift towards a multi-factorial explanation of medically unexplained symptoms. One of the most frequently discussed pathogenic factors is stress, as it has been found to be involved in the predisposition, precipitation, and perpetuation of numerous medically unexplained conditions, such as chronic fatigue syndrome or fibromyalgia syndrome \\[[@CR4]\\].\n\nStress is a ubiquitous and frequently discussed phenomenon in modern societies. From a scientific point of view, stress occurs whenever a situation is perceived as threatening and one's means of dealing with it are deemed insufficient \\[[@CR5]\\]. This kind of appraisal results in an emotional, behavioral and biological \"stress response.\" The situations that lead to such a response are labelled \"stressors.\" Importantly, *acute* stress is considered adaptive, whereas it is well-known that *chronic* stress may involve a wear and tear of stress-responsive bodily systems, such as the hypothalamic-pituitary-adrenal axis or the autonomic nervous system \\[[@CR6]\\]. As such, chronic stress"
+"Introduction {#Sec1}\n============\n\nThe coexistence of strong electron correlation and topological order is garnering much attention nowadays because of various peculiar electronic phenomena that are driven by their synergetic effect^[@CR1]--[@CR3]^. The strong topological insulator realised in the bulk (3D) Kondo insulator, namely the topological Kondo insulator (TKI)^[@CR1]^, is being extensively considered as a suitable field to study these effects such as non-trivial reconstruction of the topological surface states (TSS) due to electron correlation^[@CR4],[@CR5]^ and spin collective excitation, which can break the TSS without time-reversal symmetry breakdown^[@CR6]^.\n\nSamarium hexaboride (SmB~6~) is a long-known Kondo insulator, which opens the bulk bandgap at low temperature because of the Kondo effect^[@CR7]^. It is the first material proposed as a candidate for TKI, which hosts metallic TSS coexisting with strong electron correlation^[@CR1],[@CR8]^. To investigate this unconventional TSS, extensive studies that focused on its surface electronic structure were performed^[@CR9]--[@CR14]^ mainly by using angle-resolved photoelectron spectroscopy (ARPES) and spin-resolved ARPES (SARPES) on the cleaved (001) surface of SmB~6~. Although the metallic surface states dispersed across the bulk Kondo gap were discovered in TKI, as predicted^[@CR9]--[@CR13]^, a subsequent high-resolution ARPES study made a counter-claim regarding such TKI assignment by stating that some of the metallic surface states do"
+"Liver dysfunction caused mostly due to exposure to toxic chemicals, certain drugs and environmental pollutants, has been on the increase for the past few decades. In many countries hepatopathy is increasingly being managed using herbal treatment\\[[@ref1]\\]. Ginger (*Zingiber officinale* Roscoe, Zingiberaceae), a commonly used flavoring agent and cooking spice is added as a herbal supplement. It has a large variety of pharmacological activities such as antibacterial, antioxidant, and antiinflammatory effect as well as attenuation of lipid peroxidation and oxidative stress\\[[@ref2][@ref3]\\]. It has been reported to improve various gastrointestinal illnesses\\[[@ref4][@ref5]\\] and immunologic dysfunction\\[[@ref6]\\]. It also has been reported to exert antidiabetic activity, reduce liver damage\\[[@ref7]\\] and possess anticarcinogenic effect\\[[@ref8]\\]. It also has been reported to be used in hypertension and for exerting cardioprotective and antioxidant property\\[[@ref4][@ref9]\\].\n\nChicory (*Cichorium intybus*, Asteraceae) is a root vegetable whose green leafy tops are also used in salads or as a coffee supplement. Recently pharmacological actions of chicory have attracted the attention of many researchers. It was reported to induce hypocholesterolemia\\[[@ref10]\\], protect against hepatocellular damage\\[[@ref11][@ref12]\\] and inhibit lipid peroxidation\\[[@ref13][@ref14]\\]. It also has an antihyperglycaemic effect\\[[@ref15]\\], regulate appetite and carbohydrate and lipid metabolism\\[[@ref16]\\]. It was the aim of this work to explore the hepatoprotective effect of the"
+"1. Case report {#sec1}\n==============\n\nA 78-year old patient was implanted with a biventricular defibrillator (Medtronic Viva Quad CRT-D with a 6935 Sprint Quattro Secure right ventricular lead and a 4298-88 quadripolar left ventricular lead) in 2014 for dilated non-ischemic cardiomyopathy with left ventricular ejection fraction (LVEF) of 25%, left bundle-branch block (LBBB) and New York Heart Association (NYHA) class II heart failure. Initial follow-up was unremarkable, with average percentage of biventricular (BiV) pacing of \\>97%, until December 2015 when a scheduled 6-month follow-up revealed a reduction in BiV pacing to 88%, associated with an increase in heart-failure symptoms. Device parameters are shown in [Table\u00a01](#tbl1){ref-type=\"table\"}. Interrogation of the device revealed a loss of BiV pacing of 12% due to ventricular sensed events (Vs) without any sustained arrhythmia. However, the electrocardiogram showed sinus rhythm with alternating wide unpaced and narrower paced QRS complexes ([Fig.\u00a01](#fig1){ref-type=\"fig\"}). Further device interrogation revealed excellent R-wave amplitude (\\>20mV) but with T-wave oversensing (TWOS, see [Fig.\u00a02](#fig2){ref-type=\"fig\"}) on all ventricular paced beats (BV), with the sensed T-waves at a coupling interval of 320\u00a0ms (188bpm) interpreted as ventricular events falling in the slow ventricular tachycardia (VT) zone (labelled TS). The sinus atrial beats following these TS"
+"Introduction {#s1}\n============\n\nThe middle temporal area (MT or V5) within the extrastriate primate visual cortex contains a high proportion of direction-selective neurons (Dubner and Zeki, [@B8]; Born and Bradley, [@B6]). MT is regarded as the gateway to the perception of motion because it is the first area largely dedicated to motion processing in the cortical visual pathway and direct electrical stimulation of MT alters the direction of visual motion perception in monkeys (Salzman et al., [@B26]).\n\nWhen a bar or grating is moved through the receptive field (RF) of an MT neuron, it responds only to a restricted range of directions orthogonal to the grating\\'s orientation, making the cell direction selective ([Figure 1A](#F1){ref-type=\"fig\"}). If two gratings with different orientations are presented simultaneously and moved in directions orthogonal to their orientations, a plaid stimulus is created ([Figure 1B](#F1){ref-type=\"fig\"}). Humans perceive plaids as a global motion of the pattern in the direction of the motion of the intersection points of the gratings (indicated by the black arrows in [Figure 1B](#F1){ref-type=\"fig\"}).\n\n![**(A)** Direction-selective neurons respond only to motion in a restricted set of directions. **(B)** A plaid stimulus is formed by the summation of the motion of two gratings moving in different"
+"Background\n==========\n\nModern dance developed from expressionist dance, which rejected the rules of ballet. It originated in Germany in the 1920s and was defined by rules of a specific technique evolved in the USA in the years 1930--1950, employing elements of African and Native American folklore. Modern dance employs all the techniques of ballet; however, a modern dancer is not obliged to uncritically follow the classical rules of execution of these techniques.\n\nClassical style strongly emphasizes esthetics, precision, and height. In modern dance, the distance and motion through space is of utmost importance.\n\nCohan writes that the most important elements of a modern dancer's work are: \"ground work\", \"work with the center of gravity\", and \"motion in space\" \\[[@b1-medscimonit-20-1082]\\]. He mentions that the most important thing in a well performed movement is self-awareness, and that modern dance consists of \"centering, gravitation, balance, posture, gestures, rhythm, motion in space, and breathing\".\n\nAlthough ballet is a form of art, it has much in common with professional sports. Modern style choreographers often propose very dangerous dancing movements from the point of view of biomechanics of the locomotor system. These dangerous situations created by \"movement designers\" are often the result of absence of basic"
+"Primary Objective {#section1-2374289520903415}\n=================\n\n*HWC 3.3:* *Categories of Lymphoma*. Compare and contrast low-grade or indolent lymphomas and high-grade or aggressive lymphomas with respect to underlying pathophysiology that yields specific morphologic features and clinical behavior.\n\nCompetency 2: Organ System Pathology. Topic: Hematopathology: White Cell Disorder (HWC); Learning Goal 3: Classification of Leukemia and Lymphomas.\n\nSecondary Objective {#section2-2374289520903415}\n===================\n\n*Objective N1.1:* *Genetic Mechanisms of Neoplasia.* Discuss and provide examples of molecular genetic mechanisms that underlie cancers, including germline mutations (including point mutations, deletions, amplifications, and translocations) and epigenetic changes.\n\nCompetency 1: Disease Mechanism and Processes; Topic: Neoplasia (N); Learning Goal 1: Genetic Basis of Neoplasia.\n\nPatient Presentation {#section3-2374289520903415}\n====================\n\nA 64-year-old man with no prior significant history presents to his primary care provider for vomiting bright red blood intermittently in the past few weeks before presentation along with dark black stool, decreased appetite, abdominal pain, and night sweats. He reports experiencing a sharp pain in his right leg emanating from his gluteal region for which he was prescribed daily ibuprofen 2 weeks ago at an outside hospital. The pain improves somewhat with ibuprofen but not completely. On physical examination, he has a left upper quadrant abdominal tenderness and bilateral inguinal lymphadenopathy. He"
+"INTRODUCTION\n============\n\nChordoma has poor sensitivity to radiotherapy and chemotherapy, and is mainly treated by surgery. However, chordoma still has a relatively high recurrence rate and a low disease-free survival rate after resection. Therefore, many authors suggest that patients with chordomas should be treated with a multidisciplinary team to obtain the optimal outcomes. We previously reported the safety and efficacy of percutaneous intratumoral injections with chemotherapeutic agent lipiodol suspension in treating the patients with hepatocellular carcinoma ([@B1]). Based on this, we utilized the method to treat patientx with sacral chordoma using lipiodol-pingyangmycin suspension (LPS). The following case report describes the results during a 6-year follow-up period.\n\nCASE REPORT\n===========\n\nA 74-year-old man presented with a progressively worsening pain in sacrum in January, 2004. MRI showed a mass lesion in the sacrum. In May, 2004, sacral pain was intolerable and accompanied with uroclepsia. Routine laboratory tests including blood routine, liver function and renal function all showed within normal limits. MRI showed the lesion increased in size and compressed the urinary bladder. The contrast-enhanced CT showed a 5-cm mass without enhancements ([Fig. 1A](#F1){ref-type=\"fig\"}). An additional puncture biopsy was confirmed for the histologic diagnosis of chordoma. The patient refused to undergo surgical resections"
+"Review\n======\n\nWorldwide 170 million people are estimated to live with chronic HCV \\[[@B1]\\], with annual mortality rates due to HCV-related liver diseases estimated at over 350 000 \\[[@B2]\\]. Global HCV antibody prevalence among people who inject drugs (PWID) is high. A recent systematic review, for instance, identified 24 countries where HCV antibody prevalence in PWID ranged from 40--60% (such as Australia, UK, Greece), 25 countries with a range of 60-80% (USA, Canada, Germany) and 12 (Mexico, Thailand, Russia, the Netherlands) where prevalence was 80% or higher \\[[@B3]\\]. The World Health Organisation identifies PWID as a key target group for HCV prevention and treatment \\[[@B2]\\].\n\nHCV antiviral treatment with peginterferon alfa and ribavirin is the standard of care for chronic HCV, with a 50-85% cure rate depending on genotype \\[[@B4]\\]. Modelling studies indicate that scaling-up HCV treatment access to PWID, specifically current injectors, has the potential to reduce the pool of communicable disease in the population, acting as an effective preventative measure \\[[@B5],[@B6]\\]. Qualitative \\[[@B7],[@B8]\\] and quantitative research \\[[@B9]-[@B12]\\] shows that PWID are interested in assessing and commencing HCV treatment. PWID have rates of HCV treatment adherence and successful completion comparable to other populations \\[[@B13]-[@B16]\\]. Clinical guidelines in a number"
+"GENOME ANNOUNCEMENT {#s1}\n===================\n\nStreptococcus suis is a very important Gram-positive bacterium considered worldwide to be one of the most important pathogens in the swine industry. S. suis causes a wide variety of diseases in pigs, including meningitis, septicemia, and endocarditis ([@B1], [@B2]). S. suis is also an emerging zoonotic agent responsible for septicemia with or without septic shock, meningitis, and other less common infections in humans, particularly in Asian countries ([@B3]). Among the 33 known serotypes, serotype 2 (SS2) is considered to be the most prevalent and virulent in pigs and humans ([@B4], [@B5]). Two large-scale outbreaks of SS2 in China in 1998 and in 2005 have posed public health concerns worldwide ([@B6]).\n\nThe SS2 virulent strain SS2-1 was isolated from a diseased dead pig with septicemia in Jiangsu province in 1998 and has been confirmed as virulent on the basis of animal experiments ([@B7]). The complete genome sequence was determined by the Illumina HiSeq platform at Novogene (Beijing, China). Assembly was performed using SOAPdenovo. Gaps were filled by primer walking and sequencing of PCR products. The assembly of the genome was further verified by PCR. Coding sequences (CDS) were predicted using Glimmer 3.02 and GeneMarkS ([@B8]) and further"
+"Introduction\n============\n\nThe etiological agent of Giardiasis, *Giardia* *duodenalis* (syn. *G. intestinalis, G. lamblia*) is one of the most prevalent intestinal protozoan flagellate of the human. The life cycle of *Giardia* species is simple and it is included of two active trophozoite and cystic forms.\n\nThis parasite transmits via fecal-oral route through direct or indirect ingestion of infectious cysts. The incubation period varies from 9 to 15 days after ingestion of cysts. Symptoms of infection are varied from the absence of symptoms to acute watery diarrhea, nausea, epigastric pain and weight loss ([@B1],[@B2]).\n\nGiardiasis has a global distribution and it is common in both children and adults. The prevalence of *Giardia* infection is higher in developing countries. More than 200 million cases of giardiasis are annually diagnosed worldwide. Since 2004, *Giardia* has been included in the \\\"neglected diseases initiative\\\" by World Health Organization ([@B3]). The infection rate in asymptomatic children has been reported from 8% to 30% in developing countries and 1-8% in industrialized regions ([@B4]). The occurrence of giardiasis is probably higher in individuals with diarrhea.\n\nThe prevalence of human giardiasis in different regions of Iran has been reported from 1.2% to 38% ([@B5]). In immunocompromised patients, *Giardia* is"
+"Introduction\n============\n\nObstructive sleep apnea (OSA) is by far the most common form of sleep-disordered breathing, and is defined as frequent episodes of obstructed breathing during sleep. Specifically, it is characterized by sleep-related decreases (hypopneas) or pauses (apneas) in respiration. An obstructive apnea is defined as at least a 10-second interruption of oronasal airflow, corresponding to a complete obstruction of the upper airways despite continuous chest and abdominal movements, and is associated with a decrease in oxygen saturation and/or arousals from sleep. It is confirmed by polysomnography recording determining an apnea-hypopnea index (AHI) of \\>5 per hour of sleep.[@b1-ndt-7-715]\n\nThe relation between OSA and depression has been the subject of many studies.[@b2-ndt-7-715]--[@b5-ndt-7-715] Most reported increased levels of depression in individuals with OSA.[@b2-ndt-7-715],[@b3-ndt-7-715] Studies that found an increased rate of depression in patients with OSA, also found that the prevalence of depression was variable; the rate was 17.6% using the *Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition* (DSM-IV) criteria.[@b4-ndt-7-715] When the research diagnostic criteria for an affective disorder was used, the rate was around 40%,[@b5-ndt-7-715] whereas Millman et al[@b6-ndt-7-715] observed that 45% of their OSA patients had depressive symptoms on the Zung Self-Rating Depression Scale, and another study found"
+"Findings\n========\n\nIntroduction\n------------\n\nCerebrospinal fluid (CSF) bathes the central nervous system (CNS) and plays roles in a number of important functions, including hydraulic cushioning, nutrient delivery, drainage of waste, and immune surveillance \\[[@B1]\\]. Altered CSF circulation, mainly due to blockage of CSF outflow, is implicated in hydrocephalus and increased intracranial pressure (ICP) associated with ischemic or hemorrhagic cerebrovascular disease \\[[@B2]\\]. Tracer studies have shown that CSF drains via arachnoid granulations into the bloodstream and along olfactory nerves into nasal lymphatics \\[[@B3],[@B4]\\]. Studies of CSF drainage have been performed in cat, rabbit, and sheep due to their relatively large lymphatic vessels that facilitate cannulation and collection experiments \\[[@B5],[@B6]\\]. Non-invasive imaging modalities such as scintigraphy \\[[@B7]\\] and computed tomographic scanning \\[[@B8]\\] have been used to visualize lymphatic drainage of CSF in animals such as cats and rabbits, avoiding the need for surgical exposure of the lymphatic pathway for cannulation or visualization. However, the low optical resolution of such methods has precluded their use to study CSF drainage pathways in mice. Although monitoring drainage of dyes injected into the CSF by direct visualization of surgically exposed cervical lymph nodes has been described \\[[@B9]\\], the lack of non-invasive *in vivo* methods to assess"
+"I[NTRODUCTION]{.smallcaps} {#sec1-1}\n==========================\n\nHemodialysis (HD) is one of the treatments that is done to replace renal function. Usually, HD centers in all the hospitals will carry out the treatment process appropriate with the guidelines that they used. One of the guidelines famous for HD ward is KDOQI Clinical Practice Guideline Hemodialysis.\\[[@ref1]\\]\n\nHepatitis C virus (HCV) is transmitted mainly through intravenous infusions.\\[[@ref2]\\] In Asia, HCV infection has become a serious public health problem because it is difficult to identify carriers of HCV and take effective security measures in the HD center, so patients undergoing dialysis are often exposed to HCV.\\[[@ref3]\\]\n\nThe European Renal Best Practice (ERBP) workgroup considers isolation of HCV-positive patients who are undergoing HD, although the Kidney Disease Improving Global Outcomes (KDIGO) workgroup concluded that the isolation of HCV-infected patients is not recommended.\\[[@ref4]\\]\n\nAccording to the Association of Nephrologist in Indonesia (Pernefri) recommendation, isolation and using special HD machines are not necessary for HD patients who have been infected by HCV (Recommendation for controlling hepatitis B virus and HCV infection by PERNEFRI), while the Ministry of Health Malaysia recommend that HD patients who have been infected by HCV should be dialyzed in a separate room or a separate area"
+"1. Introduction {#s0005}\n===============\n\nMature teratomas account for approximately 20% of ovarian tumors ([@bb0025]). When thyroid tissue is present in greater than 50% of the tumor histology, the tumor is defined as struma ovarii ([@bb0015]). Struma ovarii are rare and occur in 2--3% of mature ovarian teratomas ([@bb0025], [@bb0020]). Malignant transformation of these tumors is even more rare and occurs in 0.5--5% of all cases ([@bb0025]). When malignant transformation occurs, the most common histologies identified are papillary and follicular carcinoma ([@bb0055]). Additionally, there is only one case report found in the literature of a poorly differentiated or insular carcinoma subtype which has been shown to be associated with a poorer prognosis ([@bb0035]). Patients typically present with a pelvic mass or abdominal pain ([@bb0015], [@bb0010]). Hyperthyroidism has been reported to be present in 5--8% of cases ([@bb0010]).\n\nWe present a second case of insular carcinoma (poorly differentiated carcinoma) with adjacent papillary thyroid carcinoma arising out of a mature cystic teratoma composed predominantly of struma ovarii.\n\n2. Case report {#s0010}\n==============\n\nThe patient is a 61\u00a0year old female who originally presented with abdominal pain and was found to have a 22\u00a0cm pelvic mass. Her medical history was complicated by morbid"
+"Introduction\n============\n\nTwenty years ago, Milton Roemer and Max Shain raised the possibility that hospital use increases along with the number of hospital beds available in an area ([@b15-hcfr-5-1-87]). This relationship, commonly referred to as \"Roemer\\'s law,\" became a major conceptual basis for health planning. If additions to bed capacity caused an increase in utilization, then market forces might not result in the optimal number of beds. Further, because excess beds would generate additional demand, their cost would be greater than the cost of maintaining empty facilities. Regulatory constraints on hospital construction could be justified by this relationship.\n\nA decade later, Martin Feldstein pointed out that Roemer had in mind something different than the usual workings of markets---where an increase in supply raises the quantity sold via the price mechanism ([@b7-hcfr-5-1-87]). Feldstein instead conceptualized the Roemer phenomenon as a shift in supply (the change in bed capacity) inducing a shift in the demand function. To test this hypothesis, he estimated a demand with both price and the number of beds *per capita* as independent variables. The elasticity of hospital days with respect to hospital beds was found to be 0.53, which was statistically significant. That is, an increase of 1"
+"Introduction {#Sec1}\n============\n\nThe newsvendor problem (NP), also known as the single-period problem (SPP) or the newsboy problem, consists in finding the order quantity which maximizes the expected profit (or minimizes the expected loss) in a single period probabilistic demand framework. This topic has attracted a great deal of attention and played a central role at the conceptual foundations of stochastic inventory theory. It was originally related to DMSU (decision making under stochastic uncertainty) or DMR (decision making under risk) where the demand is presented as a random variable with a known probability distribution. NP has been already analyzed on diverse assumptions and with various extensions (Choi [@CR11]). Additionally, this problem has been also recently discussed in the context of DMPI---decision making with partial information (Guo [@CR39], [@CR40]; Guo and Ma [@CR41]), where the decision maker (DM) is able to subjectively define possibility degrees and satisfaction levels (the probability distribution is not known completely).\n\nNevertheless, according to Benzion et\u00a0al. ([@CR7]), newsvendor theory should not assume that the DM faces a known distribution, since in real-life situations, the demand distribution is not always known. Furthermore, the authors demonstrate that knowing probabilities does not necessarily lead the subject closer (than that"
+"Introduction {#s1}\n============\n\nCellular differentiation during development involves the coordinated change in expression of many thousands of genes in appropriate spatial and temporal contexts. A principal mechanism by which this occurs is through modification of the core histones (H3, H4, H2A, and H2B) that comprise nucleosomes, which are the fundamental units of chromatin. There are at least 8 distinct types of histone modifications, of which the most critical for transcriptional repression is lysine methylation, the enzymatic transfer of one or more methyl groups from the donor *S*-Adenosylmethionine (SAM) onto the \u03b5-nitrogen of lysine [@pone.0037647-Kouzarides1], [@pone.0037647-Shilatifard1]. Genome-wide mapping studies using ChIP-Chip and ChIP-Seq have shown that di-methylation of histone H3 at lysine 9 (H3K9me2) is widely found at repressed genes during development and in embryonic stem cells [@pone.0037647-Tan1], [@pone.0037647-Wen1] while perturbation of the H3K9me2 mark results in a profound change in the repression status [@pone.0037647-Feldman1], [@pone.0037647-Kubicek1]. The relevant histone lysine methyltransferase enzyme is G9a, a member of the highly conserved SET domain family, which, as part of a complex containing GLP, is responsible for catalyzing the H3K9me2 mark [@pone.0037647-Shinkai1]--[@pone.0037647-Peters1]. Thus, mutant mice lacking G9a are seriously impaired in the H3K9me2 mark and display embryonic lethality reflecting the consequences of global perturbation"
+"Introduction {#S1}\n============\n\nLeucyl-tRNA synthetase (LeuRS) is a large, multi-domain, class Ia aminoacyl-tRNA synthetase (aaRS) whose essential function in all organisms is to synthesize Leu-tRNA^Leu^ for use in protein synthesis. Like several other synthetases, notably the other two class 1a synthetases, valyl- (ValRS) and isoleucyl- (IleRS) tRNA synthetases, LeuRS possesses an error correction mechanism to enhance the specificity of aminoacylation and thus the accuracy of protein synthesis. This post-transfer editing mechanism hydrolytically deacylates tRNA^Leu^ that has been mischarged with non-cognate amino acids similar to leucine, such as isoleucine, methionine or non-canonical norvaline^[@R1]^.\n\nLeuRS comprises a main enzyme body (Rossmann-fold catalytic domain and class 1a anticodon binding domain) and four flexibly linked additional domains, denoted zinc (ZN1), editing, leucine-specific and C-terminal ([Fig.1a](#F1){ref-type=\"fig\"}). Proof-reading requires that the 3\u2032 end of the tRNA, which is initially charged (or mischarged) in the so-called synthetic site of the enzyme, translocates to the editing site, located \\~35 \u00c5 away in an independently folded editing, or CP1, domain^[@R2]^. Previously we and others have characterized various structural and biochemical features of the editing state of LeuRS. These include determination of the crystal structure of the *Thermus thermophilus* LeuRS (LeuRSTT) tRNA^Leu^ complex with the 3\u2032 end of the tRNA"
+"Background\n==========\n\nGeographic surveillance of chronic disease is central to understanding spatial or spatial-temporal patterns that may help to identify discrepancies in disease burden among different regions or communities. As part of ongoing efforts in New York State to understand spatial patterns of cancer and to help implement cancer prevention and control programs, small area maps of cancer relative risk, expressed as standardized incidence ratios (SIRs), have been produced and shared with the public \\[[@B1]\\] for the most common anatomical cancer sites.\n\nProstate cancer, the focus of this paper, was included because it is the most common non-dermatologic malignancy diagnosed among men and the second leading cause of cancer deaths for men in the United States (US) \\[[@B2]\\]. Although mortality from this disease in the US has statistically significantly decreased at a rate of 2.6% per year from 1990 to 2000 \\[[@B3]\\], unexplained geographic discrepancies in mortality rates do exist \\[[@B4]\\]. Furthermore, several treatment options appear to be associated with excellent long-term disease-specific survival for otherwise healthy men with localized disease \\[[@B5]\\].\n\nResults for prostate cancer (all stages combined) are reproduced in Figure [1](#F1){ref-type=\"fig\"}, where ZIP code-level standardized incidence ratios (SIRs) are presented along with results from analyzing these data"
+"Brain drug delivery for the treatment of a wide variety of central nervous system (CNS) diseases is hampered by the blood-brain barrier (BBB)[@b1]. Intranasal (IN) brain drug delivery is a noninvasive approach for transporting therapeutics from the nose directly into the CNS through the unique olfactory and trigeminal neural pathways that connect the nasal mucosa with the perivascular spaces within the CNS[@b2]. A variety of therapeutic agents, including peptides, proteins, gene vectors, and stem cells have been delivered to the brain through the IN route[@b2]. This route has unique advantages: bypassing BBB, drug administration is noninvasive and comfortable, delivery to the CNS is relatively rapid, dosages are repeatable, no modification of the drugs is required, systemic exposure is minimized, and the brain drug level is two to three orders of magnitude higher using IN compared to intravenous (IV) injection[@b3][@b4]. However, the application of this noninvasive and convenient brain drug delivery technique is hampered by two main challenges: low drug delivery efficiency due to poor nasal mucus permeability and widespread drug delivery in the brain, which is unfavorable as neurological diseases do not generally affect the brain in a global manner.\n\nBrain-derived neurotrophic factor (BDNF), the most widely expressed and studied"
+"1. Introduction {#sec1-materials-12-01405}\n===============\n\nPolymers and polymer composites have been receiving increasing interest as promising materials for a large number of applications due to their low cost, simple processing, and lightweight character, and particularly for the large number of possible filler and polymer combinations enabling a vast array of applications. Beyond their reinforcement role, fillers can provide or modify specific properties of the polymer, particularly when using nanofillers that allow the degree of crystallinity \\[[@B1-materials-12-01405],[@B2-materials-12-01405]\\] and the mechanical \\[[@B3-materials-12-01405],[@B4-materials-12-01405],[@B5-materials-12-01405]\\], electrical \\[[@B5-materials-12-01405],[@B6-materials-12-01405]\\], or thermal \\[[@B7-materials-12-01405]\\] properties of the polymer to be tuned. Thus, polymer-based composite materials are on the rise as a scientific and technological field \\[[@B8-materials-12-01405]\\].\n\nThe multifunctionality of polymer-based composites can be further explored with additive manufacturing processing technologies \\[[@B9-materials-12-01405]\\]. Polymer-based multifunctional materials have typically been processed by solvent or extrusion methods, each targeting specific applications. Thus, whereas solvent-casting processing is appropriate for screen, spray, or inkjet printing, extrusion is appropriate for the development of filaments for 3D printing. Polymer extrusion is a solvent-free and scalable process that is widely used at the industrial level \\[[@B10-materials-12-01405]\\], whereas solvent-based methods result in a more homogeneous filler dispersion with fewer and smaller agglomerates \\[[@B10-materials-12-01405],[@B11-materials-12-01405]\\]. The mechanical, electrical, or thermal properties of"
+"At the beginning of the 1980s, researchers knew that actin filaments were present in all cell types and were important for force generation and cell movement. But relatively little was known about how actin monomers assembled into filaments. In fact, researchers didn't even possess information as fundamental as the rate constants of monomer association and dissociation. In 1981, however, Tom Pollard and Mark Mooseker successfully measured these rates using electron microscopy, a method not usually associated with a process as dynamic as actin polymerization ([@bib1]).\n\nAn electron micrograph shows long filaments grown at the barbed end of an actin bundle, in contrast to the shorter filaments assembled at the pointed end.Previous studies had used light-scattering spectroscopy to measure the elongation of actin filament populations in vitro. But in 1975, Tom Pollard and colleagues demonstrated that the two ends of actin filaments grew at different rates; the \"barbed\" end elongated rapidly while the \"pointed\" end grew slowly ([@bib2]). \"That meant it would be difficult to learn anything if you only had a cuvette full of actin filaments. You'd actually have to look at them directly to see what was going on at the two ends,\" explains Pollard, who now works at"
+"All relevant raw data are in the Supporting Information files.\n\nIntroduction {#sec001}\n============\n\nIn order to manage or conserve migratory birds and other wildlife, it is essential to consider the complete annual cycle by making spatial connections between key breeding, migration and wintering sites \\[[@pone.0135938.ref001]\\]. While such migratory connections are poorly known for most of the world's migratory birds, recent development of increasingly sophisticated and light weight tracking devices are moving the field forward at a rapid rate \\[[@pone.0135938.ref002]\\]. In particular, light-sensitive geologgers have been miniaturized to now be used effectively in studies of small (\\~15g) passerines but require recapture, and can have significant error especially during the equinox \\[[@pone.0135938.ref003], [@pone.0135938.ref004]\\]. Within this scenario, the use of intrinsic markers and particularly the analysis of stable isotopes in feathers has emerged as a powerful contribution to the ecologist's toolbox by providing a relatively cheap method to describe migratory patterns and population connectivity \\[[@pone.0135938.ref005]\\]. Feathers are metabolically inert following formation and their isotopic composition thus reflects isotopic values derived from foodwebs at areas of growth. Isotopic values in foodwebs, in turn, can vary spatially in a predictable fashion creating isoscapes that can be a useful means of inferring origins of birds later"
+"Background {#Sec1}\n==========\n\nMaintaining brain acidity within the physiological norm is an important component of homeostasis in the central nervous system. pH levels affect the conformation of proteins and other biological molecules, thereby regulating the efficiency and functional activity of enzymes, receptors, and ion channels \\[[@CR1]--[@CR4]\\]. Accordingly, enzymatic reactions, ion transport, and protein and DNA synthesis, as well as the physiological integrity of cells, depend on the pH levels in neural tissue \\[[@CR1], [@CR4]--[@CR6]\\]. To ensure the functional stability of neural tissue, a powerful multicomponent pH regulatory system has evolved \\[[@CR3], [@CR7]\\]. However, the capacity of this system can become overwhelmed during critical conditions caused by various pathological or even physiological factors resulting in a transient or permanent alternation in brain acidity \\[[@CR7]\\].\n\nChanges in regional pH levels in the brain have been observed in a number of neurological and neurodegenerative disorders. Thus, acidic pH shifts were observed in the basal ganglia and the whole brain in bipolar disorder \\[[@CR8], [@CR9]\\]. Hippocampal pH levels were reduced in mild cognitive impairment (MCI) \\[[@CR10]\\] and even in normal aging \\[[@CR11]--[@CR13]\\]. Interestingly, all these conditions are characterized by increased neuroinflammation \\[[@CR9], [@CR14]\\] suggesting that neuroinflammation itself could be a factor affecting neural pH"
+"Introduction {#pmbaa4cb7s1}\n============\n\nRadionuclide imaging with Metaiodobenzylguanidine (mIBG) has a fundamental role in the diagnosis, staging and evaluation of treatment response in childhood neuroblastoma and adult neuroendocrine tumours (NETs) (Gelfand [@pmbaa4cb7bib009], Shapiro *et al* [@pmbaa4cb7bib025], Brisse *et al* [@pmbaa4cb7bib005]). Scintigraphy is routinely undertaken using ^123^I-mIBG in preference to ^131^I-mIBG, because better quality images can be obtained from 159\u2009keV ^123^I gamma photons and twenty times more ^123^I activity can be administered for diagnostic scans (Shapiro *et al* [@pmbaa4cb7bib024], Matthay *et al* [@pmbaa4cb7bib018]). Iodine-123 is also advocated for treatment planning prior to ^131^I mIBG therapy (Monsieurs *et al* [@pmbaa4cb7bib021]), despite the fact that the images obtained have been shown to be less sensitive in detecting lesions than post-therapy ^131^I-mIBG scans (Yang *et al* [@pmbaa4cb7bib029]). In response an alternative positron emission tomography tracer, ^124^I, has been used in attempts to improve diagnostic image quality and quantitative accuracy for dosimetry (Huang *et al* [@pmbaa4cb7bib014], Koopmans *et al* [@pmbaa4cb7bib016]). As ^124^I-mIBG is not widely available and its clinical efficacy remains unproven, ^123^I-mIBG remains the standard.\n\nAlthough ^123^I predominantly emits gamma photons at 159\u2009keV (83% abundance), photons above 500\u2009keV (2.3% abundance) are also emitted. These high energy photons penetrate the septa of low-energy"
+"Introduction {#s1}\n============\n\nThe Internet has emerged as an important tool for modern clinical practice. It provides health professionals with access to current, best evidence and facilitates the translation of research to clinical care. According to a recent survey, nephrologists search for medical information to guide the treatment of patients at least once per month \\[[@SFS152C1]\\]. To access best evidence, physicians can no longer rely on browsing a few key journals as relevant literature is widely dispersed. In nephrology alone, relevant literature is published across over 400 journals \\[[@SFS152C2]\\].\n\nNumerous tools are available to healthcare professionals when searching for primary literature online. These include subscription-free databases such as PubMed, Google Scholar and Scirus (which are freely accessible via the Internet), and subscription-based bibliographic databases such as EMBASE, MEDLINE and ISI Web of Knowledge. Subscription-free resources enable global access to important clinical information. This is especially important in developing nations where physicians and institutions may lack the funds needed to maintain database and journal subscriptions.\n\nWhile nephrologists increasingly rely on bibliographic databases for clinical information, evaluations of database performance are limited \\[[@SFS152C3], [@SFS152C4]\\]. Evaluating the performance of a bibliographic database involves the consideration of several factors \\[[@SFS152C5]--[@SFS152C8]\\]. For example, an important"
+"Introduction {#section1-1179544117723611}\n============\n\nOver the past several decades, osteoarthritis (OA) of the knee and hip has emerged as the 11th leading cause of global disability.^[@bibr1-1179544117723611]^ Among these 2 conditions, the prevalence of knee OA exceeds that of hip OA by several fold and it is estimated that nearly 1 in every 2 people will develop symptomatic knee joint OA by the age of 85\u2009years.^[@bibr1-1179544117723611][@bibr2-1179544117723611]--[@bibr3-1179544117723611]^ In the United States alone, more than 9\u2009million adults have symptomatic OA of the knee.^[@bibr4-1179544117723611]^ In particular, it is the senior population that is disproportionately affected, with 37.4% of adults more than the age of 60\u2009years displaying radiographic evidence of this condition. Approximately, a third of these individuals (12.1%) suffer significantly from symptoms of pain and disability.^[@bibr5-1179544117723611]^\n\nDespite the high prevalence of knee OA in those more than 60\u2009years in the United States, less than 2% of this population has a knee joint replacement, and the mean duration of time from disease onset to arthroplasty is 19\u2009years.^[@bibr5-1179544117723611],[@bibr6-1179544117723611]^ Such statistics underscore the continued importance of exploring and optimizing nonoperative treatments, such as hyaluronan (HA), which may have the potential to influence the biology of OA and ultimately improve the quality of life"
+"INTRODUCTION {#S5}\n============\n\nA dramatic increase in obesity in the United States has occurred over the past twenty years.^[@R1]^ In 2009--2010, 32% (95% CI: 29%--36%) of reproductive aged US women (20--39 y) were obese (body mass index \\[BMI\\]\u226530kg/m^2^).^[@R2]^ Obesity among women of reproductive age carries its toll with the increased risks of infertility, pregnancy complications as well as adverse offspring outcomes.^[@R3];[@R4]^\n\nDietary intake plays a pivotal role in the rising obesity rates. In particular, examination of dietary patterns, rather than individual nutrients or foods, can capture interactions between separate dietary components.^[@R5]^ One dietary pattern that has been explored in studying obesity is the Mediterranean diet (MD). The traditional MD reflects food patterns found in Greece and Southern Italy in the early 1960s, and is characterized by an abundant intake of plant foods (vegetables, legumes, fruits, nuts, cereals) with olive oil as the main source of fat, a high to moderate intake of fish, a low to moderate consumption of eggs, dairy products (mainly cheese and yogurt) and poultry, a low intake of red meat, and a regular but moderate intake of alcohol (mainly wine during meals).^[@R6];[@R7]^\n\nPrevious studies examining the association between the MD and obesity have mainly assessed BMI"
+"All relevant clinical data are within the paper. Raw data on qRT-PCR and partial/basic clinical information are available from Dryad database (doi:[10.5061/dryad.7266m](http://dx.doi.org/10.5061/dryad.7266m)). [datadryad.org/review?doi=doi:10.5061/dryad.7266m](http://datadryad.org/review?doi=doi:10.5061/dryad.7266m).\n\nIntroduction {#sec001}\n============\n\nEndometrial cancer (EC) is one of the most common malignancies among women worldwide. It is estimated that EC is the second most frequent malignant tumour of the female reproductive tract, just after cervical cancer. In 2012, approximately 320 000 newly diagnosed cases were reported globally. Due to the longer expected life duration, lifestyle diseases and increase of obesity rates, EC has become a major oncological issue in developed countries \\[[@pone.0164687.ref001]\\].\n\nBokhman's dualistic model divides EC into two distinct pathogenetic categories. Clinical, pathological and molecular evidence shows that EC may be categorized into two types: type I (estrogen-dependent) and type II (estrogen-nondependent). Type I is the more common subtype, occurring in about 70--80% of EC cases. In terms of histopathology, it corresponds to endometrioid endometrial cancer (EEC) and usually consists of low grade and low stage tumours with favourable prognosis \\[[@pone.0164687.ref002]\\]. In contrast, type II tumours occur less frequently and are represented by clear-cell and serous carcinomas. This subtype of EC is composed of poorly differentiated tumours that are characterised by unfavourable prognosis \\[[@pone.0164687.ref002],[@pone.0164687.ref003]\\]. Type"
+"1. Introduction {#sec1-ijms-20-02228}\n===============\n\nMost proteins post-translational modifications are essential for proper cellular localization, substrate activity, and associations with other proteins. One evolutionarily conserved modification is ubiquitination, which can involve one or multiple defined lysine (K) residues or the N-terminal methionine residue (M1) \\[[@B1-ijms-20-02228],[@B2-ijms-20-02228],[@B3-ijms-20-02228]\\].\n\nUbiquitin, a highly conserved regulatory protein (76 amino acids), plays an essential role in modulating protein functions. Ubiquitination is a post-translational modification mediated by a multi-step process which involves three different enzymes, including E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, and E3 ubiquitin-ligating enzymes. This function leads to the proteasomal elimination of its substrate or alteration of the substrate activity, localization, and associations with other partners in its protein networks \\[[@B2-ijms-20-02228],[@B4-ijms-20-02228],[@B5-ijms-20-02228]\\].\n\nIn the ubiquitin-proteasome pathway, anaphase promoting complex/cyclosome (APC/C) and the ubiquitin conjugating enzyme, E2C (UBE2C), are involved in the initiation of ubiquitin chain formation on APC/C substrates. UBE2C principally create Lys-11 (K11)-linked polyubiquitination on these substrates and then APC/C and another E2 enzyme, UBE2S, elongates and branches the ubiquitin, making more efficient proteolytic degradation signals (i.e., on mitotic cyclins) for the proteasome receptor, S5A, regulating mitosis progression. Various cellular processes are regulated by the ubiquitin system; therefore, it is expected its dysregulation results in human diseases,"
+"Introduction {#sec1}\n============\n\nThe link between structure and function in biological molecules is well-established and raises important questions given that proteins are dynamic in the solution phase. This means that having the ability to follow the mechanisms of structural change in real time is imperative if we are to understand and modify protein behavior *in vivo*. Observing protein structural transitions is technologically challenging, however, due to the complexity of the associated macromolecular potential energy surfaces, which are multidimensional in terms of both degrees of structural freedom and the range of time scales over which transitions occur.\n\nTemperature-jump (T-jump) initiation offers a powerful approach to understanding biomolecular dynamics.^[@ref1]\u2212[@ref4]^ T-jump pump--probe methodology exploits infrared wavelength excitation of water to create a fast rise in temperature in an aqueous biomolecular system, followed by a time delayed probe of the evolving system. The probe method employed to study proteins or peptides includes fluorescence,^[@ref5]^ circular dichroism,^[@ref6]^ and infrared spectroscopy.^[@ref3]^ The latter is particularly attractive because of the sensitivity of the amide I vibrational mode of the peptide backbone link to protein secondary structure and local molecular environment.\n\nT-jump methods have been used to access time scales ranging from the nanosecond pulse duration of the excitation"
+"Background {#Sec1}\n==========\n\nThe diagnosis of atypical non-autoimmune diabetes presents several challenges. These forms of diabetes are best exemplified by maturity onset diabetes of the young (MODY). MODY is a rare group of genetically heterogenous conditions characterised by beta cell dysfunction and defects in insulin secretion. Systematic screening of European and North American paediatric populations has identified a prevalence range of 1.2 to 4.2% \\[[@CR1]--[@CR3]\\]. Population-specific differences in the prevalence of MODY have also been reported \\[[@CR4], [@CR5]\\].\n\nA wide array of phenotypic heterogeneity is observed in subjects with different mutations in the various genes implicated in the pathogenesis of monogenic diabetes, as this disease can mimic either type 1 or type 2 diabetes mellitus. Correctly making the diagnosis of MODY is essential in view of the therapeutic and prognostic implications. Furthermore, the autosomal dominant pattern of inheritance mandates genetic counselling and family follow-up. The increasing availability of whole exome or targeted capture followed by high throughput sequencing facilitates the molecular diagnosis of monogenic diabetes, particularly in cases where the clinical phenotype is atypical or complicated by clinical features that are not routinely associated with MODY. Increasingly, next generation sequencing followed by interpretation using publicly-available aggregate exome variant datasets offers"
+"1. Introduction {#sec1-sensors-19-03524}\n===============\n\nFibre Bragg gratings (FBGs) have become one of the major elements in various fibre-optic devices over the past decades \\[[@B1-sensors-19-03524]\\]. FBGs are periodic variations in the refractive index of the core of the fibre. They are inscribed by first photosensitizing the glass and then exposing the fibre core side on to laser light with a spatially modulated intensity pattern \\[[@B2-sensors-19-03524],[@B3-sensors-19-03524]\\]. The grating is designed to act as a narrow band reflector, reflecting light of a specific wavelength known as the Bragg wavelength and transmitting light at all other wavelengths. The Bragg wavelength is expressed as $$\\lambda_{B} = 2n_{eff}\\Lambda$$ where *\u03bb~B~* is the Bragg wavelength, *n~eff~* is the effective refractive index of the FBG and *\u039b* is the modulation period of the index change. The Bragg wavelength is directly dependent on both the strain and temperature as shown in Equation (2), $$\\frac{\\mathrm{\\Delta}\\lambda_{B}}{\\lambda_{B}} = \\left( {\\alpha + \\xi} \\right)\\mathrm{\\Delta}T + \\left( {1 - \\rho_{e}} \\right)\\varepsilon$$ where \u2206*T* is the temperature change experienced at the FBG sensor location, *\u03b1* is the thermal expansion, *\u03be* is the thermo-optic coefficient, *\u03b5* is the longitudinal strain on the FBG and *\u03c1~e~* is the effective photo-elastic constant of the fibre core material \\[[@B4-sensors-19-03524]\\]."
+"Introduction\n============\n\nHuman osteoarthritis (OA) is the most frequently occurring degenerative joint disease, causing chronic pain and joint disability worldwide. Although various factors cause OA, aging is the most common factor associated with the development of OA; other factors, such as mechanical stress and hereditary and environmental factors, also lead to the development of OA ([@b1-mmr-16-04-3841],[@b2-mmr-16-04-3841]). OA is primarily characterized by joint swelling due to a progressive breakdown and loss of articular cartilage, involving increased synovial inflammation, subchondral bone sclerosis and osteophyte formation, which leads to chronic pain and functional limitations in the joint ([@b3-mmr-16-04-3841],[@b4-mmr-16-04-3841]). Furthermore, the dysregulation of glucose and energy metabolism also aggravate the symptoms in patients with OA ([@b5-mmr-16-04-3841]). In particular, the progressive degradation of the articular cartilage in OA is mediated by the concerted activation of catabolic tissue proteinases, including matrix metalloproteinases (MMPs), collagenases and aggrecanases, which are upregulated by oxidative stress and other inflammatory stimuli, including pro-inflammatory cytokines and their mediators ([@b6-mmr-16-04-3841]--[@b8-mmr-16-04-3841]). Currently, pharmacological treatment for patients with OA is based on certain steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) for the alleviation of pain and inflammation. However, they cannot fully prevent progressive cartilage degradation or repair the impaired cartilage of patients with OA, and long-term"
+"1. Introduction\n===============\n\nOcular toxoplasmosis (OT) has been reported as the most common cause of infectious posterior uveitis in immunocompetent patients.^\\[[@R1]\\]^ The prevalence of OT ranges from 3.8% to 17.7% of infectious uveitis.^\\[[@R2]\\]^ Ocular toxoplasmosis usually presents as posterior uveitis with a chorioretinal lesion associated with vitritis.^\\[[@R3],[@R4]\\]^*Toxoplasma gondii* may induce a latent disease characterized by tissue cysts in various organs, thereby leading to delayed OT or recurrence from a retinochoroidal scar.^\\[[@R5]\\]^ It has been estimated that approximately 2% of individuals experiencing toxoplasmosis will develop ocular manifestations, suggesting that 1 in 400 persons across the world might have posterior uveitis due to *Toxoplasma gondii*.^\\[[@R6]\\]^\n\nOcular toxoplasmosis sometimes causes visual impairment and blindness in the affected eye, even in young adults. In one previous study, 24% of OT patients developed legal blindness.^\\[[@R1]\\]^ Because OT is primarily an infectious disease, it remains a preventable cause of blindness. In this aspect, epidemiologic studies on OT are important for further advancement in its knowledge and prevention.\n\nHowever, there are limited data on the incidence, clinical characteristics, and disease course in Korea compared to other countries. This is because Korea is a low-endemic area of *Toxoplasma gondii*. Therefore, the objective of this study was to describe"
+"Introduction {#s1}\n============\n\nEpidemiologic studies have reported that about 4--23% of people with traumatic damages manifest post-traumatic stress disorder (PTSD) symptoms including re-experiencing, avoidance, and hyperarousal for at least 1 month (American Psychiatric Association, [@B3]; Arnberg et al., [@B4]; Zhou et al., [@B58]). Biological alterations may underline PTSD symptom onset and persistence (Cl\u00e9ment et al., [@B10]; Ozer et al., [@B36]; Segman et al., [@B46]). The hypothalamic-pituitary-adrenal (HPA) axis is the main neuroendocrine arm of the stress response. It includes corticotrophin-releasing hormone (CRH) release from the paraventricular nucleus (PVN) of the hypothalamus into the hypophyseal-portal circulation, stimulating the anterior pituitary gland to release adrenocorticotropic hormone (ACTH) and ultimately glucocorticoids from the adrenal cortex. This mechanism maintains homeostasis in stressful environmental conditions (Jacobson, [@B30]). Neuroendocrinologic studies have reported three common features in patients with PTSD: (1) decreased plasma cortisol; (2) higher CRH in the cerebrospinal fluid (CSF) and plasma; and (3) increased inhibition of the hypophysis-adrenal system (HAS), which leads to reduced cortisol levels by enhancing negative feedback (Carvalho et al., [@B7]). CRH and vasopressin are the most important mediators of the HPA axis\\' effects on neuroendocrine signaling.\n\nStudies have shown that AVP expression in paraventricular neurons and V1b receptor density in"
+"Background {#Sec1}\n==========\n\nHernias are of the most common congenital defects in pigs which often leads to poor animal welfare and severe economic losses for pig producers. The most common types of hernias in pigs are umbilical and inguinal/scrotal hernia. Umbilical hernia is diagnosed by the protrusion of abdominal contents beneath the skin at the navel (umbilicus). It is generally accepted that weakened supportive muscles around the umbilical stump or navel area of the animal causes the umbilical opening not to close properly and intestines protrude through the intestinal wall to form the \"ball-like\" structure. The threat of a hernia is the potential entrapment of intestines through this opening. Physical injury, nutrition, excessive pressure, muscular weakness and heredity have been offered as causes of hernia \\[[@CR1]\\]. Umbilical hernias often appears in pigs at 9 to 14\u00a0weeks of age, with incidences reported to range from 0.4 to 1.2% \\[[@CR1], [@CR2]\\]. The prevalence of scrotal/inguinal hernias is shown to be approximately in the same range, between 0.5 and 1.5%, and with an estimated heritability of around 0.3 in different breeds \\[[@CR3], [@CR4]\\]. Several studies have explored the genomics of scrotal/inguinal hernia \\[[@CR4]--[@CR7]\\], but very few have devoted efforts to decipher the"
+"Introduction\n============\n\nThe temporal correlation between spontaneous low-frequency fluctuations in the blood oxygenation level dependent (BOLD) signal measured using functional magnetic resonance imaging (fMRI) is being increasingly used to characterize functional connectivity (FC) in the brain. Functional connectivity MRI (fcMRI) was first demonstrated by Biswal et al. ([@B3]), who observed synchronous BOLD fluctuations within the motor cortex during rest. Subsequent studies found additional resting-state networks such as the visual network (Lowe et al., [@B46]), the default mode network (Raichle et al., [@B55]), the task positive network (Fox et al., [@B25]), and a number of task-related networks (Smith et al., [@B64]). fcMRI studies are advancing our understanding of the brain's behavioral states (Fox et al., [@B26]; He et al., [@B34]) and pathology (Lowe et al., [@B47]; Greicius et al., [@B30]; Lui et al., [@B49]; Kwak et al., [@B41]), and have also proven to be useful for the assessment of cognitive performance (Hampson et al., [@B33]; Song et al., [@B66]).\n\nIn most fcMRI studies, changes in FC measures are interpreted as evidence of underlying changes in neuronal connectivity. However, as the BOLD signal reflects both vascular and neural factors, the interpretation of resting-state FC observations can be challenging. The BOLD response is"
+"Background {#Sec1}\n==========\n\nDengue virus is transmitted by the bite of *Aedes* mosquitoes, especially *Ae. aegypti,* has recently increased dramatically in prevalence and now affects more than 100 tropical and sub-tropical countries, with half of the world's population at risk \\[[@CR1], [@CR2]\\]. Although a licensed vaccine against the four dengue serotypes recently became available \\[[@CR3]\\], and already is approved in some endemic countries \\[[@CR4], [@CR5]\\], protection is incomplete and unequal across serotypes \\[[@CR6]\\]. Hence, *Aedes* control using insecticides will remain a key intervention for dengue prevention, especially given the added benefit of simultaneously targeting other *Aedes*-transmitted arboviruses including chikungunya and Zika. In Saudi Arabia, several areas are endemic regions for the dengue virus of which Jeddah and Makkah are by far the most important (Fig.\u00a0[1](#Fig1){ref-type=\"fig\"}). First reported in Jeddah in 1994, three serotypes DENG-1, DENG-2, DENG-3 \\[[@CR7]\\] have been confirmed, and 9,096 cases were diagnosed between 2013 and 2015, with a further 3,035 in Makkah. Multiple insecticides are applied to target immature vector stages in Makkah and Jeddah, but pyrethroids are the most commonly used to control adult *Ae. aegypti* by indoor and outdoor space spraying. The efficacy of pyrethroid-based adult control has been found to be impacted by"
+"Introduction {#s1}\n============\n\nMore often than not, the study of problem solving is approached from the perspective of logical and rational thinking. In an early study, Weitzenfeld \\[[@B1]\\] defined the *isomorphic structure* of a task in terms of its elements and the relationship between those elements. Weitzenfeld further claimed that the isomorphic structure defines the strategy for accomplishing the task. However, Weitzenfeld ignored the significant impact presentation style can have on problem solving even when the isomorphic structure is preserved. Weitzenfeld took two games as an example of structure preservation: Tic-Tac-Toe and Number Scrabble. In Number Scrabble, players select in turn one of the remaining numbers from a pile that contains the numbers from 1 to 9. A player who is first to collect a triad of numbers adding up to 15 wins the game. Tic-Tac-Toe and Number Scrabble are valid isomorphic tasks. Isomorphism is obvious if numbers in Number Scrabble are arranged into a magic square where each column and row adds up to 15. Although it is highly likely that the two games require the same strategy, they are fundamentally different in terms of cognitive processes applied due to differences in visual presentation. While Number Scrabble requires top-down"
+"Introduction {#sec1}\n============\n\nDNA molecules have been widely explored as useful building materials because of their intrinsic characteristics, for example, base sequence design capability, self-assembly predicted by complementary binding, and simple adaptability with various functionalized materials. Various dimensional structures made of synthetic DNA oligonucleotides have been constructed with precise control of size, shape, and pattern.^[@ref1]\u2212[@ref9]^ DNA structures can serve as effective building platforms for arrangement of various nanomaterials to be used in specific target applications such as optoelectric devices, chemical sensors, drug delivery, and biocomputing.^[@ref10]\u2212[@ref14]^ DNA can be functionalized with various materials such as proteins, drugs, metallic and semiconducting nanoparticles, carbon-based materials, fluorescence dye molecules, and metal and lanthanide ions.^[@ref15]\u2212[@ref26]^ Similarly, natural DNA such as lambda and salmon DNA (SDNA) has also been used in the fields of biology, medicine, and bionanotechnology.^[@ref27],[@ref28]^ Such DNA can be easily obtained in large quantities at a relatively low cost, and these molecules can be easily incorporated with various functionalized nanomaterials.\n\nDNA structures embedded with individual nanomaterials such as quantum dots, gold nanoparticles, cobalt ions, and doxorubicin were fabricated, and their chemical, physical, and biological properties have been reported. However, there are certain limitations to construction of multiple function-embedded DNA complexes containing various types"
+"Introduction {#sec1-1}\n============\n\nThis study was conducted to identify the effectiveness of core indicators' monitoring in a blood storage unit of a National Accreditation Board for Hospitals and Healthcare Providers (NABH) accredited tertiary care hospital. Four core indicators were observed and monitored monthly, which were:\n\nPercentage (%) of blood component usage,Percentage (%) of transfusion reactions,Percentage (%) of wastage of blood and blood components, andAverage turnaround time for issue of blood and blood components.\\[[@ref1]\\]\n\nThe information was gathered in a structured manner and then, adverse events associated with the transfusion were reported. The root causes were analyzed and specified corrective and preventive actions were taken.\n\nMaterials and Methods {#sec1-2}\n=====================\n\nA total of four parameters were observed in all the wards, intensive care units, and operation theaters of a NABH accredited tertiary care neurosciences institute for a period of 2 years that included 2011 and 2012. The study parameters included whole blood and blood component usage, transfusion reactions, wastage of blood and blood products, and the average turnaround time for issue of blood and blood components. These were documented monthly by the concerned clinical staff that included the nursing staff and doctors of clinical departments in a specific *proforma* \\[[Annexure 1](#F1){ref-type=\"fig\"}\\]."
+"Introduction\n============\n\nThe 32-kDa peripheral membrane protein stomatin is the founding member of the stomatin family, which in mammals includes stomatin-like proteins (STOMLs) 1--3 and the kidney-specific podocin (reviewed in [@b30]). These proteins are characterized by a conserved domain of \u223c120 residues, the stomatin domain, which is a member of the SPFH (Stomatin, Prohibitin, Flotillin, HflK/C) domain family found in many proteins throughout all kingdoms of life. Membrane targeting of stomatins is mediated by a 20 amino-acid amino (N)-terminal membrane insertion domain featuring a conserved proline ([@b27]). An exception is STOML-2, which lacks this hairpin anchor. The N- and carboxy (C)-terminal regions of stomatins are cytoplasmic and unique for each family member ([@b43]; [@b45]; [@b4]; [@b39]). Stomatin has been found to be phosphorylated ([@b43]), palmitoylated ([@b51]) and to associate with lipid rafts ([@b50]) where it forms higher-order oligomers ([@b49]). Furthermore, STOML-1 was shown to form hetero-oligomers with stomatin at endosomal membranes ([@b35]). Stomatin can also form hetero-oligomers with STOML-3 in sensory neurons and this interaction requires the presence of the N-terminal membrane anchoring domain ([@b31]). Stomatin is absent in the erythrocyte membrane of patients suffering from a specific form of haemolytic anaemia ([@b53]). Since the erythrocyte membrane of affected individuals"
+"Introduction {#s1}\n============\n\nSchistosomiasis is a water-based disease caused by trematodes of the genus *Schistosoma*. The five schistosome species that are known to infect humans are *Schistosoma mansoni*, *S. haematobium*, *S. intercalatum*, *S. mekongi*, and *S. japonicum*. School-aged children are at highest risk of infection and are the main target group for interventions [@pntd.0001194-WHO1].\n\nDespite successful efforts to control schistosomiasis in different parts of the world, more than 200 million individuals are still estimated to be infected and the annual global burden due to schistosomiasis might exceed 4.5 million disability-adjusted life years (DALYs) lost [@pntd.0001194-WHO1]--[@pntd.0001194-King1]. A substantial amount of this burden is concentrated in West Africa, including Cameroon. Indeed, 72 million infections are thought to occur in this part of the world [@pntd.0001194-Chitsulo1]. However, the current statistics, as presented by Chitsulo *et al.* (2000) [@pntd.0001194-Chitsulo1], Steinmann *et al.* (2006) [@pntd.0001194-Steinmann1], and Utzinger *et al.* (2009) [@pntd.0001194-Utzinger1], are largely based on population re-adjusted data originally published by Utroska and colleagues in the late 1980s [@pntd.0001194-Utroska1]. Hence, the estimates are likely to be outdated due to, among other reasons, large-scale preventive chemotherapy campaigns, improved sanitation, water resources development and management, and socio-economic development.\n\nRecently, donors have provided new funds to control the"
+"Educational Objectives {#s5}\n======================\n\nBy the end of this activity, learners will be able to: 1.Describe the unique health risks and challenges often encountered by lesbian, gay, bisexual, and transgender (LGBT) and gender-diverse patients.2.Explain how stages of physical and identity development across the life span affect LGBT and gender-diverse patients.3.Describe historical, political, institutional, and sociocultural factors that may underlie health care disparities experienced by LGBT and gender-diverse patients.4.Identify at least two community resources that provide support to LGBT and gender-diverse patients.5.Describe how homophobia, transphobia, heterosexism, and sexism affect health care inequalities, costs, and outcomes.\n\nIntroduction {#s6}\n============\n\nUndergraduate medical education in the United States has historically been lacking in lesbian, gay, bisexual, and transgender (LGBT) content. Previous studies have placed the estimate of lesbian, gay, and bisexual Americans at 3.5% and transgender Americans at 0.3% of the population, with anywhere from 8% to 11% of Americans reporting same-sex behavior or attraction.^[@ref001]^ In a survey of medical school deans published in *JAMA* in 2011, the median number of hours of LGBT education across all 4 years of undergraduate medical education was 5.^[@ref002]^ There were 14 schools with no LGBT curricula in the preclinical years, and 33% had no clinical LGBT content."
+"Background\n==========\n\nMonitoring Prostate Specific Antigen (PSA) serum level is the best way to follow Prostate Cancer (PC) patients after treatment and to detect early recurrence of the disease [@B1]. In case of biochemical relapse (PSA\\>0.2-0.4 ng/mL), Imaging should be able to detect the site of recurrence in order to establish a correct and tailored therapeutic strategy. It is crucial to distinguish between the presence of local failure and/or distant metastasis [@B2]. The Conventional Imaging (C.I.: Bone Scan; Computed Tomography or Magnetic Resonance) accuracy is limited in this field as reported by many authors [@B3], [@B4], [@B5], [@B6]. The site of distant recurrence, mainly lymph-nodes or bone lesions, is thus, rarely detected. In the clinical daily practice it results in an enormous number of negative or inconclusive investigations performed in this setting of patients. Choueiri et al [@B5] tried to identify, in 292 patients with biochemical failure, clinical parameters that were predictive of positive Imaging studies, that could be helpful in guiding clinicians in their requests. Authors found that age, imaging type Computed Tomography (CT), Magnetic Resonace (MR), Bone scan (BS), PSA and PSA doubling time (PSAdt) were significantly associated with positive imaging results. However, CT, MR and BS were"
+"Adjuvant chemotherapy is a well-established treatment modality for patients with high-risk primary breast cancer, and has a beneficial impact on survival ([Early Breast Cancer Trialists\\' Collaborative Group, 1998](#bib8){ref-type=\"other\"}). In order to obtain this benefit, maintaining scheduled chemotherapy dose intensity (DI) is an important factor: both retrospective and prospective studies suggest that as DI is decreased, treatment outcome may be compromised. [Bonadonna *et al* (1995)](#bib3){ref-type=\"other\"} reviewed the results of therapy based on the percentage of projected dose of cyclophosphamide, methotrexate and 5-fluorouracil (CMF) received in the first Milan adjuvant trial, which involved over 300 patients. Survival was worse in those patients who received less than 85% of the projected dose of treatment ([Bonadonna *et al*, 1995](#bib3){ref-type=\"other\"}). Furthermore, patients who received \\<65% of their projected dose had similar survival rates as patients who received no chemotherapy at all. This was, however, a retrospective analysis and some of these patients may have performed poorly because of confounding factors such as medically significant comorbidities, which also may have had an impact on survival.\n\nProspective studies have evaluated the impact of chemotherapy dose and DI on clinical outcome. The CALGB 8541 study evaluated three different DI levels (low, moderate and high) of cyclophosphamide, adriamycin and"
+"Introduction\n============\n\nCancer is currently the second leading cause of human mortalities worldwide and is expected to surpass heart diseases as the leading cause of human mortality in the next few years. Esophageal cancer is the seventh leading cause of human cancer-associated mortality worldwide ([@b1-ol-0-0-6614]). Esophageal squamous cell carcinoma (ESCC) is the most major histological type of esophageal cancer. In China, the annual incidence and mortality rates of esophageal carcinoma rank fifth and fourth, respectively ([@b2-ol-0-0-6614]). The majority of patients with ESCC are diagnosed at an advanced stage of the disease, despite the development of rapid advances in surgical techniques, radiotherapy and chemotherapy, and the 5-year survival rate remains poor (between 10 and 30%) ([@b3-ol-0-0-6614]). ESCC is hypothesized to develop due to risk factors including the accumulation of genetic mutations, tobacco, alcohol consumption, consuming hot food or water frequently, a low intake of fresh fruit and vegetables, obesity and poor diet, local environmental conditions and lifestyle ([@b4-ol-0-0-6614]). There are a limited number of specific biomarkers available for diagnostic use and targeted therapies against ESCC. Therefore, identifying biomarkers which may be used for early detection, prognostic stratification and novel therapeutic interventions are required to effectively treat patients with ESCC.\n\nMelanoma-associated antigens"
+"Introduction {#s1}\n============\n\nThe detailed knowledge of plant anatomical characters and their variation among closely related taxa is key to understanding their evolution and function [@pone.0088199-Carlquist1]. Variation in anatomical structure is a result of several forces such as: the adaptation of species to the prevailing conditions in their habitats [@pone.0088199-NiklasK1], phenotypic plasticity as an ability of individuals with an identical genotype to develop differently - based on specific conditions during their ontogeny [@pone.0088199-Sultan1], [@pone.0088199-Pigliucci1], and evolutionary constraints (phylogenetic inertia) in which taxa that share part of their evolutionary history possess similar 'blue-prints' [@pone.0088199-Peat1]--[@pone.0088199-milauerov1]. One of the critical features of comparative studies on plant trait variations in relation to ecological adaptations is therefore the extent of phylogenetic relatedness among taxa [@pone.0088199-Dubuisson1], which makes them partly dependent in any statistical inference. In other words, part of the explanatory power uncovered by relating the anatomical traits to ecological preferences might be alternatively explained by phylogenetic inertia affecting both the similarity of anatomical traits among closely related taxa and the similarity of ecological niches that such taxa occupy [@pone.0088199-Harvey1].\n\nUnderstanding the evolution of plant structures requires separation of evolutionary inertia from a true adaptation to the environment. This is commonly done by comparing analyses"
+"INTRODUCTION\n============\n\nAlzheimer's disease (AD) is a serious and fatal condition affecting tens of millions of individuals worldwide \\[[@R1]\\]. This form of dementia is primarily believed to be caused by the formation of insoluble polypeptides which form neurodegenerative plaques within the brain. One of the key enzymes involved in this formation is the human aspartic protease BACE-1 \\[[@R2]\\]. This knowledge together with the fact that no amyloid plaques are found in knock-out mice lacking BACE-1, while they seem to be vital and fertile, make inhibition of BACE-1 an interesting approach for targeting AD \\[[@R3],[@R4]\\].\n\nEarlier studies of aspartic proteases such as the malaria plasmepsins \\[[@R5]\\] and human renin \\[[@R6]\\] have shown that the S1 pocket of these enzymes can accommodate large P1 residues, many of which can reach into the S3 pocket. In a previous study we explored the possibility of extending deep into the BACE-1 S1 pocket by employing statine-based inhibitors with phenyloxymethyl residues in the P1 position Fig. (**[1](#F1){ref-type=\"fig\"}**) \\[[@R7]\\]. Some of these inhibitors displayed substantial activity against BACE-1 (12-40 nM), in the enzyme assay, but they were found to be inactive in a cell-based assay, likely due to poor permeability.\n\nIn the present work we have further"
+"This paper was published ASAP on July 9, 2014. Due to production error, it was published with an error in equation 1. The corrected version was reposted on July 22, 2014.\n\nIn 1992, Potts and co-workers^[@ref1]^ discovered in the cyanobacterium *Nostoc commune* a gene encoding a product resembling protozoan and mammalian myoglobins. It was remarkable that a protein commonly associated with dioxygen transport was found in cyanobacteria and intriguing that the gene was located within a nitrogen fixation operon. Subsequent investigations have provided evidence that *N. commune* \"cyanoglobin\" belongs to a distinct and well-represented lineage of the hemoglobin (Hb) superfamily,^[@ref2]^ which has been given the general name of truncated hemoglobins (TrHbs) in reference to their primary structures containing \u223c30 fewer amino acids than myoglobin (Mb). *N. commune* cyanoglobin is thought to be involved in dioxygen scavenging, presumably to protect the nitrogenase from oxidative damage.^[@ref3]^\n\nShortly after the discovery of cyanoglobin, two light-induced TrHb genes, *LI410* and *LI637*, were found in the unicellular photosynthetic eukaryotic alga *Chlamydomonas eugametos* (*moewusii*).^[@ref4]^ Crystallization and subsequent structure determination of the globin domain of the *LI637* gene product (hereafter CtrHb) provided the first glimpse of a TrHb fold.^[@ref5]^ The heme group is buried in the protein,"
+"1. Introduction {#sec1-pathogens-09-00094}\n===============\n\nInfectious pancreatic necrosis (IPN) is a well-known disease originally named acute catarrhal enteritis by M'Gonigle in 1951 \\[[@B1-pathogens-09-00094]\\], but soon after Wood et al. \\[[@B2-pathogens-09-00094]\\] changed its name to IPN, based on a histopathological study of brook trout (*Salvelinus fontinalis*) suffering an infectious disease resembling a catarrhal enteritis. The virus causing the disease, the IPN virus (IPNV), was the first fish virus isolated in vitro \\[[@B3-pathogens-09-00094]\\] and belongs to the family *Birnaviridae* and the genus *Aquabirnavirus.* Although originally isolated from brown trout and considered a disease of great impact on cultured salmonids worldwide \\[[@B4-pathogens-09-00094]\\], it has also been isolated from non-salmonid diseased fishes, as well as from a wide range of fish species from natural environments \\[[@B5-pathogens-09-00094],[@B6-pathogens-09-00094],[@B7-pathogens-09-00094]\\]. In fact, the term IPNV is strictly used for those strains affecting salmonid fish which develop specific symptoms (see below). In those cases where the virus affects non-salmonids, with different symptoms, the term IPN is substituted by IPNV-like, and in general terms the name aquabirnaviruses is employed.\n\nThe disease mainly affects very young fry; salmonids are mostly susceptible immediately after yolk sac absorption and the first feeding. The clinical symptoms of the disease, described by many researchers since the"
+"Introduction\n============\n\nPatients with acute respiratory failure demand dynamic evaluation and interventions. Lung ultrasound is a bedside technique, very promising in this setting. Previously, Lichtenstein and colleagues proposed an algorithm approach with a diagnostic accuracy of 90.5%, named Bedside Lung Ultrasound in Emergency (BLUE protocol). However, this approach has never been validated in other populations or ultrasound operators. The aim of this study was to evaluate the diagnostic accuracy of the lung ultrasound algorithm (BLUE protocol) in ICU patients admitted with acute respiratory failure.\n\nMethods\n=======\n\nA prospective study, single-center consecutive case series evaluating critically ill adult patients in acute respiratory failure, admitted to a 23-bed general ICU between October 2011 and November 2012. The ultrasound examination was performed by an ICU physician until 20 minutes after admission, without interfering with usual care, and the ultrasound operator was blinded to the medical history of the patient. Three items were assessed: artifacts (horizontal A lines or vertical B lines indicating interstitial syndrome), lung sliding, alveolar consolidation and/or pleural effusion. BLUE protocol results were compared with clinical diagnosis by the medical assistant team at the end of the ICU stay.\n\nResults\n=======\n\nForty-two patients were evaluated (42% male), mean age was 73"
+"Introduction {#section5-2050313X16670304}\n============\n\nEndovascular aneurysm repair (EVAR) has revolutionized the management of abdominal aortic aneurysms (AAA). This technique offers many short-term benefits over open surgical repair, including improved peri-operative morbidity and mortality.^[@bibr1-2050313X16670304]^ Despite these benefits, there is question surrounding the long-term durability of EVAR.^[@bibr1-2050313X16670304]^ Late endoleaks and subsequent sac expansion may result in post-EVAR rupture and death and are thus of particular concern. Type IIIb endoleaks arise from a fabric defect and is associated with high risk of aneurysm rupture.^[@bibr2-2050313X16670304]^ We report the case of a very late Type IIIb endoleak from a hole in the fabric of a bifurcated Medtronic Talent graft, 7\u2009years after implantation.\n\nCase presentation {#section6-2050313X16670304}\n=================\n\nThe patient is an 83-year-old gentleman who underwent elective EVAR for an asymptomatic 5.9\u2009cm infrarenal AAA with a Medtronic Talent bifurcated stent graft (Medtronic, Dublin, Ireland) in 2008. The operation was performed successfully and uneventfully. The main body of the graft (30\u2009mm\u2009\u00d7\u200920\u2009mm\u2009\u00d7\u2009140\u2009mm) was deployed under fluoroscopic guidance via cannulation of the right femoral artery. The contralateral graft limb (14\u2009mm\u2009\u00d7\u200918\u2009mm\u2009\u00d7\u200919\u2009mm) was deployed, along with a contralateral extension (20\u2009mm\u2009\u00d7\u200920\u2009mm\u2009\u00d7\u200979\u2009mm)."
+"1. Introduction {#sec1}\n===============\n\nResearch suggests that the number of one-time principal investigators of drug trials regulated by The U.S. Food and Drug Administration is on the rise \\[[@bib1]\\]. Attrition from clinical trials is not limited to first-time investigators, as scholars note that challenges facing the clinical research enterprise are also causing some veteran investigators to leave research \\[[@bib2]\\]. Publicly available data in the Bioresearch Monitoring Information System (BMIS) database show that annually, approximately 40% of unique investigators choose not to participate in another FDA-regulated trial \\[[@bib3]\\]. This exodus of experienced clinical investigators, as well as the time and resources required to initiate new investigators into the clinical trial process, are believed to be linked to inefficiency, instability, and increased costs associated with conducting clinical trials \\[[@bib1]\\].\n\nPrincipal investigators contend with many challenges related to trial implementation and conduct, including site infrastructure issues \\[[@bib2]\\], lack of institutional support \\[[@bib4],[@bib5]\\], competing priorities \\[[@bib4]\\], difficulties in making research financially viable for investigators \\[[@bib6]\\], and long timelines and administrative burden \\[[@bib7]\\]. In our own previous research \\[[@bib8]\\], we identified reasons why U.S.-based investigators who conducted only a single FDA-regulated drug trial (\"one-and-done\" investigators) chose not to continue with clinical research as a principal"
+"Background\n==========\n\nThe genus *Mycobacterium*includes species found in a wide range of ecological niches. *M. tuberculosis*, *M. leprae*, and *M. avium*subsp. *paratuberculosis*, are pathogenic species causing clinical disease in humans or animals. Other species as *M. smegmatis*and *M. phlei*are saprophytes. In addition, an intermediate position is occupied by species opportunistic pathogens such as *M. fortuitum*, a rapidly growing mycobacteria that is ubiquitous in soil and water. This mycobacteria is known to cause cutaneous infection, typically in association with trauma or clinical procedures \\[[@B1],[@B2]\\]. Due to its capacity to growth and to survive intracellularly, *M. fortuitum*has been previously used as a model for studying the intracellular killing of mycobacteria \\[[@B3],[@B4]\\].\n\nMost bacteria, when exposed to toxic oxygen metabolites, exhibit an adaptive response and express several genes involved in detoxification of oxygen reactive species, such as superoxide dismutases (SOD), catalases and peroxidases \\[[@B5],[@B6]\\]. This type of adaptative response has been implicated in the intracellular survival of pathogenic mycobacteria, promoting their maintenance in the host \\[[@B7]-[@B9]\\].\n\nThe major pathogen, *M. tuberculosis*, produces an iron co-factored SOD encoded by the gene *sod*A \\[[@B10]\\] and a copper and zinc SOD encoded by the gene *sod*C \\[[@B11]\\] whose involvement in protection against oxidative stress of *M."
+"Introduction {#Sec1}\n============\n\nBeing lightweight metal, beryllium finds numerous technological applications ranging from aerospace and nuclear industry to mobile phones due to its exceptional physical properties such as high strength, electrical conductivity and high melting point. It has an anisotropic hexagonal close packed crystal lattice structure, which controls the complex properties of irradiation-induced self-point defects and dissolved foreign atoms^[@CR1],[@CR2]^. Their dynamic interplay with dislocations and grain boundaries (GBs) determines the microstructure evolution under irradiation. Therefore, investigations of beryllium microstructure after irradiation allow not only qualification of material properties for its prospective nuclear fusion reactor applications^[@CR3]^, but also contribute significantly to the physical understanding of the underlying mechanisms of microstructural changes in hexagonal closed packed metals under irradiation or high temperature aging in general. In addition, such investigations provide by analogy better understanding of the microscopic processes occurring in materials with other lattice structures.\n\nIn nuclear fusion technology, beryllium is considered as a \"First Wall\" material in ITER, presently one of the largest mankind projects worldwide^[@CR3]--[@CR5]^, but also as a neutron multiplier material in different tritium-breeding blanket concepts for the future demonstration fusion power plant DEMO^[@CR6],[@CR7]^. In one of the blanket concepts, called helium-cooled pebble bed (HCPB), interchanged layers of a"
+"Introduction {#sec1}\n============\n\nValorization of biobased feedstock into chemicals^[@ref1]\u2212[@ref4]^ and fuels^[@ref5]\u2212[@ref7]^ represents one of the pillars of a more sustainable society. The last few decades have seen an explosion of synthetic methodologies to transform natural products into building blocks for the chemical industry.^[@ref1]\u2212[@ref4]^\n\nCatalytic methodologies for the conversion of biobased carboxylic acids, however, are largely limited to esterification or amidation reactions.^[@ref8]^ More recently, chemical^[@ref9]\u2212[@ref12]^ and biocatalytic^[@ref13]\u2212[@ref17]^ reduction reactions of carboxylic acids have been developed as well as some approaches for the oxidative decarboxylation into terminal alkenes.^[@ref18]\u2212[@ref21]^\n\nIn addition, redox-neutral decarboxylation of carboxylic acids into the corresponding alkanes represents an attractive method for the synthesis of alkanes for fuel and synthetic applications. Conventional methods, however, require harsh reaction conditions and high loadings of precious metal catalysts. This implies a significant environmental impact of these reactions and questions their economic feasibility. In addition, the selectivity of the reported methods mostly is poor due to the formation of Kolbe- and Hofer--Moest-byproducts.^[@ref22],[@ref23]^\n\nTo overcome some of these drawbacks, enzymes have been gaining an increasing interest for the direct formation of hydrocarbons.^[@ref24]\u2212[@ref27]^ Recently, a new fatty acid photodecarboxylase from the unicellular photosynthetic green microalga *Chlorella variabilis* NC64A (*Cv*FAP) was reported by Beisson and co-workers.^[@ref28]^*Cv*FAP mediates"
+"Defining the latent reservoir for HIV-1 {#Sec1}\n=======================================\n\nDespite effective antiretroviral therapy (ART), HIV-1 persists in all infected individuals as proviral DNA integrated within long-lived memory CD4^+^ T cells \\[[@CR1], [@CR2]\\]. Early studies of infected donors on suppressive ART demonstrated that a subset of these quiescent proviruses could be induced to replicate in tissue culture, comprising what we now consider the latent reservoir \\[[@CR3]--[@CR8]\\]. However, subsequent investigation has revealed that a complex population of both replication-competent and defective proviruses exists within every infected individual \\[[@CR9]--[@CR17]\\]. This population of persistent proviruses not only archives the cumulative viral genotypic diversity, which arose over the course of untreated infection, but also serves as the primary barrier to curing HIV-1 infection. Recent studies are changing our understanding of what defines the HIV-1 latent reservoir, how we quantify it, and how we leverage these quantitative data to predict the dynamics of viral rebound (or lack thereof) in infected individuals who interrupt suppressive ART.\n\nGiven the complexity of HIV-1 persistence, it is critical that we employ accurate and precise definitions in our discussion. ***Persistent HIV*-*1*** is an all-encompassing term that includes all forms of integrated proviral DNA that persist in infected individuals on the time-scale of"
+"Introduction\n============\n\nNeurodegenerative disorders (NDs) are a group of diseases resulting from a neuronal loss in different regions of the central nervous system (CNS). It is fully accepted that both environmental and intercellular mechanisms are involved in the pathophysiology of NDs.^[@B1],[@B2]^ Induction of oxidative stress due to increased levels of intercellular metal ions,^[@B3],[@B4],[@B5]^ mitochondrial dysfunction^[@B6],[@B7]^ disturbances in energy metabolism and autophagy signaling pathways^[@B8]-[@B10]^ as well as releasing excessive neuroinflammatory factors in the CNS^[@B11]^ are some of the main intercellular pathways involved in neuronal death. Instead, cellular and molecular dysfunctions in neurons are mostly induced by environmental risk factors such as toxic heavy metals,^[@B12]^ unregulated homeostasis of essential metal ions^[@B13]^ and lifestyle habits.^[@B14]^\n\nWe have recently suggested that changes in the normal concentration of essential metal ions such as Iron (Fe), Copper (Cu) and Zinc (Zn) rather than other factors could initiate neurodegeneration processes.^[@B15]^ Our proposal was mainly based on increasing/decreasing activity of energy metabolism pathways in neurons due to changes in nutritional habits and lifestyle during mid-life. Basically, changes in our habits have resulted in more energy uptake than its consumption, neurological hormone alterations, and changes in the concentration of essential metal ions. All these conditions, which could be reflected"
+"Introduction\n============\n\nNasal lobular capillary hemangiomas (LCHs) are rare,^[@r1]^ rapidly growing hypervascular benign lesions whose exact etiopathogenesis is unknown. The most common location is the head and neck region. It has been reported that 76.9% of cases seen in children occur in this region with the gingiva, lips, and tongue being the most common sites and the nasal cavity as a less frequent location (15--20%).^[@r2]^ LCHs bleed easily with little manipulation or digital trauma due to excessive vascularity. Nasal LCHs arise mainly from the soft tissues of the nasal cavity and are often located (80%) on the anterior portion of the nasal septum (Little's area) and less frequently on the anterior aspect of the inferior turbinate.^[@r1]-[@r4]^\n\nHere, we describe an unusual case of a child presenting with unilateral severe nasal bleeding that proved to be a lobular hemangioma lesion arising from the posterior portion of the inferior turbinate. The patient underwent complete excision using an endonasal endoscopic approach.\n\nCase report\n===========\n\nA 12-year-old girl presented to the emergency room with severe epistaxis from the right nasal cavity. The nasal bleed was controlled after insertion of an anterior nasal pack. She had a history of recurrent epistaxis over the previous two"
+"Black phosphorus (BP), an emerging layered two-dimensional (2D) semiconductor, is presently attracting immense research interest on the global level due to its high mobility and suitable band gap for potential applications in novel electronic and optoelectronic devices[@b1][@b2][@b3][@b4][@b5]. Unlike other well-studied 2D materials, such as semimetallic graphene[@b6] with zero band gap and MoS~2~[@b7] with a direct band gap of \\~1.5\u2009eV only in its monolayer form, BP has a tunable thickness-dependent direct band gap varying from \\~0.3\u2009eV (bulk) to \\>1.4\u2009eV (monolayer)[@b4][@b5]. This prominent feature benefits layered BP in optoelectronic applications such as phototransistors, *p-n* diodes and solar cells[@b2][@b8][@b9][@b10][@b11]. So far, BP has been shown to have some remarkable properties, such as high mobility[@b1][@b2], semiconductor-metal transition[@b12] as well as superconductivity[@b13] under high pressure. Additionally, as shown in [Fig. 1(a)](#f1){ref-type=\"fig\"}, owning to the puckered honeycomb lattice in each P atom layer, much work has been involved to explore the anisotropic thermal transport properties in bulk BP[@b14][@b15][@b16], indicating that BP could be also used as a novel thermoelectric material in which the anisotropic properties might be used. Similar as the anisotropic thermal conductivity, it was theoretically predicted that BP has a large direction-dependent photonic[@b17][@b18] and magneto-transport anisotropy[@b1]. Investigations on magneto-transport properties of"
+"Rotavirus vaccination has been recommended for all infants worldwide \\[[@CIT0001]\\]. As of May 2016, 81 countries, including 44 low- and middle-income countries (LMICs), have introduced rotavirus vaccines into their national immunization programs \\[[@CIT0002]\\]. Most of these countries use 1 of the 2 oral rotavirus vaccines available globally: the monovalent (\\[RV1\\] Rotarix; GlaxoSmithKline Biologicals, Rixensart, Belgium) or pentavalent (\\[RV5\\] RotaTeq; Merck & Co., Inc.; Kenilworth, NJ) rotavirus vaccine \\[[@CIT0003], [@CIT0004]\\].\n\nThe efficacy of RV1 and RV5 is low in LMICs (39%--59%) \\[[@CIT0005]\\] and could be due to a number of factors including the following: interference by maternally acquired antibodies, gut microbiota composition, interference from oral polio vaccine (OPV), and/or altered enteric immunity due to the burden of coinfections and malnutrition among infants in LMICs \\[[@CIT0008]\\]. Potential interference by maternal antibodies seems plausible because some studies have reported high correlations (0.57--0.86) between anti-rotavirus immunoglobulin (Ig) G antibody levels in mothers and infants in LMICs \\[[@CIT0009], [@CIT0010]\\] and the potential for IgG antibodies to interfere with RV1 immune response \\[[@CIT0011], [@CIT0012]\\]. Infants in LMICs are often undernourished and have repeated exposure to a variety of enteric pathogens. This may result in chronic environmental enteropathy, which can lead to altered enteric immunity \\[[@CIT0013]\\]. In"
+"Introduction {#s1}\n============\n\nAs our understanding of the role of forces in development deepens, assessing accurate stress patterns in tissues has become increasingly important ([@bib57]). Stress patterns can be revealed through three approaches: 1- Computational models, for\u00a0example with spring networks or finite elements, with relevant assumptions on tissue mechanics for animal (e.g. [@bib63]) and plant (e.g. [@bib11]) systems, 2- Strain measurements following local cuts at the subcellular (e.g. [@bib42]) or organ (e.g. [@bib21]) scale, 3- Strain measurement of deformable objects (e.g. FRET-based molecular strain sensors \\[[@bib22]\\], oil microdroplets \\[[@bib13]\\], elastomeric force sensors \\[[@bib80]\\]). Previous work on animal single cells showed that hyperosmotic media can affect membrane tension and thus the molecular effectors of cell migration, like actin filaments, RAC activity or WAVE complex, suggesting that the corresponding mutants could be rescued by a modification of the osmotic conditions of the medium ([@bib6]; [@bib34]; [@bib1]). Consistently, adding sorbitol in growth media is sufficient to rescue defects in yeast endocytic mutants ([@bib5]). Here we take inspiration from these single cell studies and apply the same logic at the multicellular scale. Using an *Arabidopsis* mutant with severe cell adhesion defects, we partially rescue these defects by modifying the water potential of the"
+"Background\n==========\n\nThe World Health Organization (WHO) estimates that there is a global shortfall of more than 2 million doctors, nurses and midwives to meet the minimum recommended density \\[[@B1]\\]. This shortage of human resources for health negatively impacts health outcomes \\[[@B2]\\] with local shortages worsened by the migration of health workers from low- and middle-income countries (LMICs) to high-income countries \\[[@B3]\\].\n\nThe WHO World Health Report of 2006 calculated that 25% of doctors and 5% of nurses trained in African countries were working in high-income countries \\[[@B1]\\]. For instance, in the United States of America, 25% of physicians trained overseas -- 64% of them in LMICs -- as well as 4% of nurses \\[[@B4]\\]. High-income countries often actively recruit overseas-trained health workers, with a study in the United Kingdom finding that 41% of overseas-trained nurses had migrated due to active recruitment \\[[@B5]\\].\n\nEven though health worker migration to high-income countries is occurring, countries such as Australia continue to face persistent shortages, particularly in rural and outer-metropolitan areas \\[[@B6]\\]; a situation compounded by trends towards health workers' decreased work-hours, increased demand due to an ageing population \\[[@B7]\\] and an ageing health workforce \\[[@B8]\\]. Health Workforce Australia, a government agency tasked"
+"Introduction\n============\n\nPeripheral artery disease (PAD) affects approximately 5--10 million people in the USA[@b1-ijwh-4-625]--[@b4-ijwh-4-625] and is a significant cause of lower extremity functional impairment, ulceration, and limb loss. Even without these clinical consequences, PAD is an independent predictor of increased cardiovascular (CV) and all-cause mortality.[@b5-ijwh-4-625]--[@b16-ijwh-4-625] In addition, the economic burden of PAD is higher than one might expect, and comparable to that of coronary artery disease and ischemic stroke.[@b17-ijwh-4-625],[@b18-ijwh-4-625]\n\nThe prevalence and clinical consequences of PAD are similar in magnitude for women and men. Despite this, PAD remains underappreciated in women, and women have been underrepresented in contemporary PAD revascularization studies.[@b19-ijwh-4-625],[@b20-ijwh-4-625] As a result, sex-specific differences in the risk factors, management, and outcomes of PAD remain unclear, creating a critical need for clinical research to evaluate sex differences in PAD. In recognition of this growing problem, the American Heart Association recently released a \"call to action\" to raise awareness of the burden of PAD in women. [@b20-ijwh-4-625] This review will seek to highlight sex differences in the risk factors, presentation, diagnosis, and management of PAD.\n\nPrevalence of PAD\n=================\n\nPAD can be symptomatic or asymptomatic, and can be diagnosed based on several different methods: the ankle brachial index (ABI), duplex"
+"All genotypes, RNAseq and DNA methylation data are available through dbGap, <https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001717.v1.p1>.\n\nIntroduction {#sec001}\n============\n\nFunctional genomic approaches using combinations of genomic, epigenomic and transcriptomic data can define regulatory landscapes and provide a basis for biomarker discovery and insights into disease etiology. Advances in sequencing technologies have resulted in a surge in the number and complexity of multi-omics datasets, providing unprecedented opportunities to map the regulatory landscape, while imposing substantial analytical challenges. Increasingly, researchers acknowledge the limited usefulness of genome-wide approaches that examine a single component of transcriptional regulation in isolation and appreciate the growing importance of \"multi-omic\" analyses. Indeed, genomic sequence variation, epigenetic and post-translational regulators are interdependent and jointly contribute to the normal functioning or dysfunction of a tissue, calling for integrative approaches to fully appreciate the interactions between these different layers of regulation.\n\nOriginally two main lines of investigation were pursued---association studies and molecular quantitative trait loci (QTL) analysis. Association studies aim to identify traits associated with genetic variants (Genome Wide Association Studies, GWAS) and more recently traits associated with changes in DNA methylation (Epigenome Wide Association Studies, EWAS). Over the past decades, thousands of common genetic variants associated with specific diseases or phenotypes have been cataloged"
+"Introduction {#sec1-1}\n============\n\nHistory of hypothermia dates back to Hippocratic era and in modern history to the 1950\\'s when elective hypothermia (28--32\u00b0C) was practiced during general anesthesia for brain and heart protection.\\[[@ref1]\\] In 1960\\'s Peter Safar, father of modern cardio-pulmonary resuscitation (CPR) started using hypothermia, in post-cardiac arrest scenarios.\\[[@ref1]\\] The initial enthusiasm in hypothermia was followed by subdued ebb in time zone of 1960--1980, due to complications arising from hypothermia, that is, patients were cooled longer and deeper which resulted in bleeding and septic complications. From 1980 to 2000 a lot of work on experimental animals showed that hypothermia leads to neuro-protection.\\[[@ref2]\\] Two randomized controlled trials (RCT) which were published in 2002 showed the benefit of hypothermia in post-cardiac arrest situations, which changed the world regarding the use of hypothermia.\\[[@ref3][@ref4]\\] Therapeutic hypothermia (TM) is now-a-days popularly known as targeted temperature management (TTM). TTM is a unique modern era therapeutic modality for salvaging neurological tissue viability in critically ill patients.\n\nDefinitions {#sec1-2}\n===========\n\nThe normal body temperature in healthy individuals (measured in the oral cavity) is 36.8\u00b0C \u00b1 0.4\u00b0C, with normal diurnal variations of 0.5\u00b0C.\\[[@ref5]\\] Rectal temperatures are usually 0.4\u00b0C higher than oral readings.\\[[@ref5]\\] The temperature of the blood measured with"
+"Dear Editor:\n\nBeh\u00e7et\\'s disease (BD), a chronic inflammatory disease, is characterized by oral apthae and genital ulcer, arthritis, cutaneous lesions, such as non-bacterial folliculitis, and erythema nodosum, as well as ocular, gastrointestinal and neurological manifestations. Although genital ulcers are histologically similar to oral aphthae, they are deeper than oral aphthous ulcers and are a major criterion for diagnosis. We present a case of scrotal squamous cell carcinoma (SCC) in a patient diagnosed with BD.\n\nA 39-year-old male patient was admitted to our clinic with recurrent oral aphthae and a deep ulcer, covering the scrotum and perineal regions. The patient had been suffering from recurrent oral aphthous lesions for almost 11 years, and he had been medicated with 1.5 mg/day of colchicine, with a diagnosis of BD. Over the preceding 2 years, the genital ulcer had gradually enlarged and deepened. During this period, the patient received topical treatment and systemic antibiotics therapy; however, he was lost to follow-up.\n\nDermatological examination revealed a large and painless ulcer, extending from the scrotum to perineal region, which was approximately 8 cm in diameter ([Fig. 1](#F1){ref-type=\"fig\"}). This ulcer had an indurated floor and also sharp and irregular edges. No growth was observed in the bacterial"
+"Introduction {#Sec1}\n============\n\n*Clostridium difficile* is one of the prominent causes of infectious nosocomial diarrhea and is responsible for \\~25% of human antibiotic-associated diarrhea^[@CR1]^. Although patients with *C. difficile* infection (CDI) may acquire the organism from the environment^[@CR2]^, potential sources of CDI in humans may include domestic and farm animals since an overlap between isolates from humans and animals has been demonstrated^[@CR3],\\ [@CR4]^. CDI causes diseases ranging from mild diarrhea to life-threatening pseudomembranous colitis. The number of incidence and the level of severity of CDI has markedly increased across the continents^[@CR5],\\ [@CR6]^. Antimicrobial treatment plays an important role in the progression of CDI. It has been postulated that the antibiotic therapy disrupts normal gut microbiota, allowing *C. difficile* colonization and growth because it is naturally resistant to many drugs used to treat other infections, thereby enabling its toxin production^[@CR7]^. The first-line therapy for CDI includes metronidazole and vancomycin, however, the resistance to these drugs has been reported, rendering the treatment ineffective^[@CR8]^. In recent years, the antimicrobial therapy for CDI tends to be more difficult due to the development of multidrug resistant (MDR) strains including the hypervirulent drug resistant strain, BI/NAP1/027^[@CR9]^. A number of highly virulent MDR strains belonging to other"
+"Introduction {#Sec1}\n============\n\nDespite the fact that the death rate of lung cancer declined 38% between 1990 and 2012 among males and 13% between 2002 and 2012 among females \\[[@CR1]\\], lung cancer remains as the most common incident cancer and is the leading cause of deaths among cancer patients around the world, including China \\[[@CR2], [@CR3]\\]. Due to the lack of clinical symptoms in early stage, most lung cancer has been diagnosed at a distant stage, with an only 17% 5-year survival rate \\[[@CR4]\\].\n\nLow dose spiral CT (computed tomography) screening is emerging as a promising strategy in improving lung cancer survival rates due to its advantage in earlier detection. Results from the National Lung Cancer Screening Test (NLST), a randomized clinical trial of more than 50,000 people, showed that screening with low-dose CT could reduce lung cancer mortality by 20% compared to the standard chest x-ray \\[[@CR5]\\]. Benefit from the widespread use of LDCT, a great increasing number of small and non-determined pulmonary nodules have been detected in its early stage**,** especially ground glass opacities (GGO). A small pulmonary nodule was defined as nonsolid (pure GGO) when the underlying parenchyma was visible and there were no solid components except"
+"Introduction {#sec1-1}\n============\n\nAs an anesthesiologist, we must be skilled in airway management to cope with sudden loss of airway patency due to airway obstruction or serious cardiopulmonary compromise. It may be in operation room or outside operation room. It may be required to ensure patency of the airway in the lateral position in certain circumstances. Some patients who require airway support need to be tracheally intubated with an endotracheal tube to maintain airway patency as soon as possible. Previous studies have shown that tracheal intubation in lateral position can be difficult.\\[[@ref1][@ref2]\\] Several studies have shown successful ventilation in lateral position with the laryngeal mask airway,\\[[@ref3]\\] ventilation and intubation in the lateral position with the intubating laryngeal mask airway\\[[@ref4]\\] with and without the aid of a lightwand,\\[[@ref5]\\] intubation with the lightwand,\\[[@ref6]\\] and fiberoptic intubation.\\[[@ref7]\\] However, newer videolaryngoscopes like C-MAC have not been formally evaluated for tracheal intubation in laterally positioned patient. We compared C-MAC video laryngoscope and macintosh laryngoscope for tracheal intubation in lateral position.\n\nThe C-MAC video laryngoscope is a new video laryngoscope using a modified Macintosh blade, which may be a useful alternative both for routine and difficult airway management and for educational purposes. The C-MAC videolaryngoscope has"
+"INTRODUCTION {#omx049s1}\n============\n\nTuberculosis (TB) of thyroid is a rare disease even in an endemic country like India \\[[@omx049C1]\\]. To establish a diagnosis of thyroid TB is challenging since it can mimic a carcinoma, suppurative abscess or a haemorrhage in a thyroid cyst. In this paper, we present the case of thyroid TB that developed while the patient was on anti-tubercular therapy (ATT). The diagnosis was made on fine needle aspiration (FNA) of thyroid gland.\n\nCASE REPORT {#omx049s2}\n===========\n\nA 46-year-old gentleman presented with complaints of painless, progressive neck swelling for 2 months and altered sensorium for 1 week. Eight months ago, he was diagnosed to have miliary TB and was started on empirical ATT in a local health care centre. Three months later, he presented with clinical features suggestive of sub-acute meningitis and was diagnosed to have tubercular meningitis based on positive cerebrospinal fluid (CSF) TB PCR. While on the ATT, he developed gradually progressive neck swelling and acute worsening of sensorium. He had no other co-morbid illness and he was not on any immunosuppressive therapy.\n\nAt presentation in the accident and emergency department, his pulse rate was 88 beats per minute, blood pressure 130/80 mm Hg and his"
+"Introduction {#s1}\n============\n\nHumans have the ability to detect fine features of textured surfaces and to discriminate between them using *direct, active finger touch* (Katz, [@B12]; Sathian et al., [@B27]; Connor et al., [@B1]; Libouton et al., [@B20]). During this exploration mode, the tactile roughness discrimination is believed to be mediated through two combined mechanisms. Firstly, a spatial code represents texture information spatially, through the distributed activation of populations of adjacent mechanoreceptors. This channel is thought to rely on slowly adapting (SA1) mechanoreceptors (Connor et al., [@B1] and Connor and Johnson, [@B2]) and the density of the mechanoreceptors naturally limits its resolution. Secondly, a temporal code represents the time-dependent variations of the finger-surface interaction due to their relative movement. Depending on the temporal frequency of the stimulation, either rapidly adapting (RA) or Pacinian (PC) systems are thought to encode these vibrations (Muniak et al., [@B24]). Textured surfaces can also be felt *indirectly*, namely by actively exploring a surface through a probe being held in the hand (indirect touch) (Klatzky and Lederman, [@B13]; Yoshioka et al., [@B35]). During this second scanning mode, roughness is necessarily encoded through vibrations transmitted through the probe to receptors in the hand.\n\nYoshioka et al. ([@B35])"
+"Introduction {#Sec1}\n============\n\n*Riemerella anatipestifer* is a Gram-negative, non-motile, extracellular bacterium that belongs to the *Flavobacteriaceae* family, and infection of ducks with this pathogen causes acute and chronic septicaemia characterized by fibrinous polyserositis, and meningitis^[@CR1],[@CR2]^. Currently, at least 21\u2009*R*. *anatipestifer* strains that vary in virulence both between and sometimes within a given serotype have been identified and are characterized by a 5--75% mortality rate, depending on the virulence of the strain^[@CR2],[@CR3]^. Although *R*. *anatipestifer* infection is a contagious disease that has resulted in significant economic losses in the duck industry^[@CR2]^, little is known about the mechanisms of protective immune responses involved in *R*. *anatipestifer* pathogenesis.\n\nSeveral attempts have been made to understand the host immune responses to *R*. *anatipestifer*. Using an immunoproteomic approach, immunoreactive proteins have been identified in duck or rabbit antisera to *R*. *anatipestifer*^[@CR4],[@CR5]^. Upregulated host immunity was observed in ducks vaccinated with inactivated *R*. *anatipestifer* plus levamisole as an adjuvant^[@CR6]^ or with recombinant *R*. *anatipestifer* outer membrane protein A plus CpG oligodeoxynucleotides as an adjuvant^[@CR7]^. Furthermore, host genes involved in the immune response were identified in duck livers following *R*. *anatipestifer* infection^[@CR8]^. Recently, comparative expression analyses of immune-related genes in ducks and chickens indicated that duck"
+"1. Introduction {#s0005}\n===============\n\nAlthough DCCT, UKPDS and our Kumamoto Study ([@bb0005]) have shown that strict glycemic control could prevent microvascular complications, the increase of diabetes is still an important issue worldwide. The increase of type 2 diabetes mellitus (T2DM) is associated with excess visceral adiposity, which is tightly linked to metabolic syndrome (MS). MS is recognized as a cluster of cardiovascular risk factors such as hyperglycemia, dyslipidemia, elevated blood pressure and chronic inflammation ([@bb0010]). Visceral fat has been demonstrated to express more pro-inflammatory cytokines than subcutaneous fat in obese states ([@bb0015]). Inflammatory markers such as C-reactive protein (CRP) ([@bb0020]) and tumor necrosis factor (TNF)-\u03b1 have been linked to MS.\n\nCurrently, there are no medications or modalities to reduce both visceral adiposity as well as chronic inflammation in MS or T2DM subjects. Recently, we ([@bb0025], [@bb0030]) and others ([@bb0035], [@bb0040]) have shown that the beneficial metabolic advantages of heat shock response (HSR) activation, which appears to mainly involve heat shock protein (HSP) 72. HSP72 induction by mild electrical stimulation (MES) with heat shock (HS) ([@bb0025], [@bb0045]), a transgenic system ([@bb0035]), heat treatment ([@bb0040], [@bb0050]) or chemical inducers ([@bb0030]) ameliorated abnormal metabolic features in animal models of T2DM, such as insulin"
+"Introduction {#S1}\n============\n\nAging organisms exhibit functional declines at many levels of biological organization. These declines ultimately conspire to kill the organism and determine its lifespan. Because lifespans vary remarkably^[@R1]^ even within isogenic populations, useful information about aging mechanisms can be obtained by identifying their statistical signature in the response of lifespan distributions to genetic, chemical and physical interventions\n\n*C. elegans* individuals live as self-fertile adults for a few weeks, producing large numbers of isogenic offspring. Early investigations revealed single point mutations in insulin/IGF-1 pathway components capable of doubling average lifespan^[@R2]-[@R5]^. These findings subsequently generalized to other organisms, including fruit flies and mice^[@R5]^, establishing *C. elegans* as a metazoan model for studying the genetics of aging. The acquisition of survival curves in *C. elegans* thus became an essential part of aging research. In routine practice, survival curves of animals cultured on solid agar in a Petri dish, fed by a bacterial lawn of *E. coli*, are acquired manually through daily observation with a low-power dissecting microscope^[@R6],\\ [@R7]^. Death is recognized by the failure of an individual to react by motion to prodding with a wire, requiring labor-intensive, repetitive, and subjective observation. This protocol provides strong incentives to keep population sizes"
+"Introduction {#sec1}\n============\n\nThe apolar membrane creates an ideal environment for making strong hydrogen bonds. Nevertheless, direct measurements of hydrogen bonds made between amino acid side chains in membrane proteins indicate that their full potential strength is rarely realized, presumably because side-chain flexibility and water penetration into membrane proteins afford many opportunities for competing hydrogen bonds.^[@ref1]\u2212[@ref10]^ However, backbone hydrogen bonds might be generally stronger than side-chain hydrogen bonds because there are fewer alternative hydrogen bonding partners. On the other hand, strong backbone hydrogen bonds would make it difficult to create the many transmembrane (TM) helix distortions and breaks^[@ref11]\u2212[@ref13]^ often required for function.^[@ref14]\u2212[@ref18]^ We previously argued that one important mechanism for generating TM helix distortions is through the formation of alternative backbone hydrogen bonds, i.e., shifts from canonical *i*+4 \u03b1-helical hydrogen bonds to *i*+3 or *i*+5 hydrogen bonds, thereby maintaining hydrogen bonding, yet allowing for conformational flexibility.^[@ref19]^ It also remains possible that that the sequences evolved to optimize hydrogen bond strengths, sometimes to create weak points in TM helices as needed to satisfy functional requirements.\n\nTo test the possibility that backbone hydrogen bond strengths might be variable we sought a direct way to measure backbone hydrogen bond free energies. While the"
+"1. Introduction {#sec1}\n===============\n\nPsoriasis is a relatively common T-cell mediated cutaneous disease in which both environmental and genetic factors contribute to its pathogenesis \\[[@B1]\\]. Despite multiple susceptibility loci for psoriasis that have been identified, the PSORS1 locus located in the MHC class I region on chromosome 6p21.3 confers the most risk for psoriasis \\[[@B1]\\]. However, the extensive ranges of polymorphism and the preservation of HLA haplotypes in most populations have made it difficult to characterize the exact gene responsible for psoriasis susceptibility located in PSORS1. Nevertheless, HLA-C\\*06 is the strongest association found in psoriasis and is the only genetic variant repeatedly observed to be associated with psoriasis in most of the populations (1). Additionally, other MHC genes have also been associated with psoriasis independently of HLA-C\\*06 \\[[@B2], [@B3]\\].\n\nPsoriatic arthritis (PsA) is a chronic inflammatory joint disease which affects a significant proportion (10--40%) of psoriatic patients \\[[@B4], [@B5]\\]. HLA-C\\*06 has also been associated with PsA susceptibility (6). MICA-A9 (corresponding to MICA\\*002) polymorphism has been further associated with arthritis susceptibility but not with psoriasis \\[[@B7]--[@B9]\\]. Additionally, HLA-B38, HLA-B39, HLA-B57, HLA-DR7, and TNF-*\u03b1* promoter polymorphisms have been associated with PsA susceptibility in the past; however, these alleles are in linkage disequilibrium"
+"Background\n==========\n\nIn genetic association studies, individuals are often recruited based on case-control ascertainment conditions of the primary phenotype \\[[@B1]\\]. For the analysis of secondary phenotypes, this recruitment-scheme can become problematic. If the secondary phenotype is correlated with the primary phenotype in a case-control study, the distribution of the secondary phenotype can be fundamentally different from the general population. For example, in a genetic association study of COPD in which all cases have COPD and control subjects have normal pulmonary function, the distribution of quantitative lung phenotypes can deviate substantially from their distribution in the general population. For samples that are ascertained in this fashion, standard statistical methods may lead to misleading results or may lack statistical power to identify true genotype phenotype associations. There are several methods to accurately estimate the odds ratio of genetic variants for binary secondary phenotypes associated with case-control status \\[[@B2]-[@B10]\\], but these methods cannot easily accommodate continuous secondary phenotypes. For the special case that the secondary phenotype is normally distributed or binary, Lin & Zeng (2009) proposed an adjusted score test that incorporates genetic associations with affection status into the test statistic \\[[@B11]\\].\n\nWe present a more general approach that does not require any"
+"Dear Editor,\n\nAirway management is a key element of resuscitation procedures. However, due to the current COVID-19 pandemic, medical personnel should complete medical procedures wearing full personal protective equipment (PPE) for aerosol-generating procedures (AGP) \\[[@bb0005]\\]. PPE-AGP should be used especially during cardiopulmonary resuscitation, including airway management \\[[@bb0010]\\]. Emergency intubation using direct laryngoscopy carries a significant risk of failure. As many authors indicate, the effectiveness of the first intubation attempt with a Macintosh laryngoscope is from 57.6% to 89.9% \\[[@bb0015],[@bb0020]\\]. The use of PPE-AGP may reduce the efficiency of medical procedures and prolong their duration \\[[@bb0025],[@bb0030]\\]. intubation methods alternative to Macintosh laryngoscope may be a suitable solution. An example of a new type of laryngoscope is Vie Scope\u00ae (Androit Surgical, Oklahoma City, USA), which is a self-contained, battery-powered, disposable scope that takes advantage of a closed circular tube with a beveled end to visualize the vocal cords ([Fig. 1](#f0005){ref-type=\"fig\"} ). The light is transmitted through the sidewall of the tube from end to end as well as within the lumen of the tube. The intubation procedure using Vie Scope\u00ae should be based on the following steps -- the intubator should: (1) insert scope and identify glottis opening between vocal cords, (2)"
+"Introduction of combination ART was instrumental to mitigate the burden of HIV pandemic in Ethiopia and other resource limited settings. Combination ART archives sustained HIV viral suppression and contributes to reductions in mortality, progression to AIDS, opportunistic infections (OIs), and hospitalization ([@R1]). Viral suppression is also associated with decreased HIV transmission to uninfected persons. In Ethiopia, improved coverage of free antiretroviral therapy (ART) program helped to enroll hundreds of thousands of ART needy people living with HIV; an overall ART coverage reached 73% ([@R2]--[@R3]).\n\nFailure of antiretroviral treatment and toxicity are feared complication of long-term ART users. Noncompliance to medical instruction and poor adherence fosters emergence of drug resistant mutant. An observational cohort study from HIV clinic in South Africa which enrolled 19,645 patients (29,935 person-years) showed that 9.9% of first line ART (4.5/100 person-years) failed at median 16 (IQR: 12--23) months following ART initiation. Five years following ART treatment, the failure rate was 16.9% and 7.8% when using a confirmatory threshold of 400 and 10,000 copies/ml, respectively. The same study reported a 10.1% overall rate of switch to second-line by five years on ART ([@R4]). The emergence of primary and secondary HIV drug resistance is on the rise due"
+"Viruses are intracellular pathogens that are subject to intense selective pressures during their ongoing battles within the host. To propagate successfully, they must exploit numerous machineries of the infected cell. Thus, studies of their replicative cycles have yielded fundamental insights into eukaryotic biology. A prime example is the human immunodeficiency virus (HIV), which is a lentivirus that causes the acquired immunodeficiency syndrome (AIDS). Unlike simpler oncoviruses that rely exclusively on host cell machinery, lentiviruses code for additional accessory and regulatory proteins that act as molecular switches at different stages of viral entry and exit from the infected cell. Studying the actions of these viral proteins has yielded understanding of diverse cellular functions such as the innate immunity against retroviruses, control of transcriptional elongation, export of macromolecules from the nucleus to the cytoplasm, and intracellular trafficking of proteins (reviewed in \\[[@pbio-0030076-b1]\\]).\n\nThe transcriptional transactivator (Tat) is a key regulatory protein of HIV. It is expressed early after the virus integrates into the cell, and stimulates the elongation of RNA polymerase II (RNAPII). This type of transcriptional control had not been previously appreciated; thus, work on Tat established a new paradigm in the field of eukaryotic biology. Moreover, these findings impacted greatly"
+"Pandemics refer to the spread of a physical disease that adversely affects an exceptionally high proportion of the world's population. Over the past half year, the COVID-19 virus has killed over half a million people around the world ([@CIT0018]). In the absence of a treatment or vaccine, governments have implemented a variety of policies and procedures to slow the spread of the disease. In the United States, these policies led to a business shutdown during Spring, 2020, during which over 40 million workers or nearly 20% of the active labor force applied for unemployment benefits due to layoff or furloughs. According to the U.S. Bureau of Labor Statistics ([@CIT0036]), approximately 1 in 5 adults aged 65 or older participated in the labor force prior to the pandemic, with nearly 75% of these individuals working at jobs where teleworking was not an option ([@CIT0012]). Given that the chance of infection, complications, and death from COVID-19 rise sharply after age 65 ([@CIT0006]), many older workers have faced or will face a difficult personal decision---lose their job or continue work and risk their health. Although the reopening of businesses in the United States is now underway, the pandemic will undoubtedly impose powerful economic,"
+"M[embers]{.smallcaps}of the Rho subfamily of small GTPases control the adhesion, morphology, and motility of mammalian cells, and also regulate signal transduction pathways that affect gene transcription in the nucleus ([@B18]; [@B35]). The three best-understood members of the family, Rho, Rac, and Cdc42, share some 50% identity at the amino acid level and like the archetypal small GTPase, Ras, act as molecular switches in intracellular signaling pathways. They cycle between active (GTP-bound) and inactive (GDP-bound) forms, and a large number of potential regulators of this cycle have been identified, such as guanine nucleotide exchange factors, guanine nucleotide dissociation inhibitors (GDIs)^1^, and GTPase activating proteins (GAPs) ([@B55]; [@B9]; [@B30]).\n\nThe biological consequences of activating Rho, Rac, and Cdc42 have been documented in some detail in Swiss 3T3 fibroblasts. Activation of Rho using extracellular stimuli such as lysophosphatidic acid, or microinjection of constitutively activated forms of recombinant Rho protein, leads to the assembly of actin stress fibers and focal adhesion complexes, whereas activation of Rac by agonists such as PDGF or insulin stimulates the formation of lamellipodia and membrane ruffles ([@B45]; [@B47]). Further analysis has revealed that the filamentous actin found in Rac-induced lamellipodia is associated with small focal complexes which, although morphologically"
+"Background\n==========\n\nHow to interpret the nature of biological processes, which, when perturbed, cause certain phenotypes, such as human disease, is a major challenge. The completion of sequencing of many model organisms has made \\'reverse genetic approaches\\' \\[[@B1]\\] efficient and comprehensive ways to identify causal genes for a given phenotype under investigation. For instance, genome-wide knockout strains are now available for *Saccharomyces cerevisiae*\\[[@B2],[@B3]\\], and diverse high throughput RNA interference knockdown experiments have been performed, or are under development, for higher organisms, including *C. elegans*\\[[@B4]\\], *D. melanogaster*\\[[@B5]\\] and mammals \\[[@B6],[@B7]\\].\n\nCompared to the direct genotype-phenotype correlation observed in the above experiments, what is less obvious is how genetic perturbation leads to the change of phenotypes in the complex of biological systems. That is, we might perceive the cell or organism as a dynamic system composed of interacting functional modules that are defined as discrete entities whose functions are separable from those of other modules \\[[@B8]\\]. For example, protein complexes and pathways are two types of functional modules. Using this concept as a basis for hypothesis, it is tempting to conclude that it is the perturbation of individual genes that leads to the perturbation of certain functional modules and that this, in"
+"1. Introduction {#sec1-ijms-21-05932}\n===============\n\nA series of coronaviruses crossed the species barrier, with the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012, and they caused major outbreaks of lethal pneumonia. Now, a new coronavirus emerged in December 2019 in Hubei province and was named the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. The disease caused by this virus, called COVID-19 has spread worldwide causing as early as August 2020 more than 18 million cases and more than 700,000 deaths \\[[@B1-ijms-21-05932]\\].\n\nSARS-CoV-2 is an enveloped virus with a positive RNA genome belonging to the beta genus of the Coronaviridae family \\[[@B2-ijms-21-05932]\\].\n\nThe clinical features of COVID-19 range from asymptomatic or mild disease to critically life-threatening ill patients conditions. The most prevalent symptoms are fever, shortness of breath, dyspnea, cough and fatigue \\[[@B3-ijms-21-05932]\\] and are commonly associated with diarrhea, headache, anosmia, lymphopenia or liver injury. An increasing number of less common manifestations are being described like acute kidney injury, vasculitis or myocarditis \\[[@B4-ijms-21-05932]\\]. The most common comorbidities in critically ill patients are age, hypertension, diabetes, obesity, cardiovascular disease and respiratory system disease \\[[@B3-ijms-21-05932]\\].\n\nViral and host interaction plays a key role"
+"Introduction {#Sec1}\n============\n\nAs sessile organism, plant growth and yield are strongly influenced by environmental stimuli such as cold and drought^[@CR1]^. To respond and adapt to these conditions, plants develop various mechanisms at both physiological and biochemical levels^[@CR2]^. It has been well established that many adaptation processes are regulated by stress-responsive gene expression^[@CR1],\\ [@CR3]^. Transcription factors (TFs), which are a diverse family of regulatory proteins with DNA-binding domains, play a central role in mediating various aspects of cellular processes by regulating gene expression through interacting with cis-elements in the promoter regions of various downstream genes^[@CR4],\\ [@CR5]^. Series studies previously have uncovered a group of TF genes, such as *AP*2/*ERF*, *MYB* and *bZIP*, which participate in various stress-induced physiological processes and regulatory networks in higher plants^[@CR6],\\ [@CR7]^.\n\n*TCP* genes encode plant-specific transcription factors, which are named after the first four functionally identified members: *TB1* (*TEOSINTE BRANCHED 1*) in *Zea mays*, *CYC* (*CYCLOIDEA*) in *Antirrhinum majus*, and *PCF1* and *PCF2* (*PROLIFERATING CELL FACTORS 1* and *2*) in *Oryza sativa* ^[@CR8]^. Typically, N-terminus of this class of transcription factors exhibits a highly conserved TCP domain, which contains a non-canonical basic-Helix-Loop-Helix (bHLH) structure involved in DNA binding, protein-protein interaction and protein nuclear localization^[@CR9],\\ [@CR10]^."
+"Introduction\n============\n\nMicroglia are considered to be specialized cells of the mononuclear phagocyte lineage and constitute the major resident immune cells in the central nervous system (CNS). Several reports indicate that microglia may be derived from two sources, the first being myeloid precursors that colonize the CNS, referred to as resident microglia \\[[@r1]-[@r3]\\]. In contrast, exogenous microglia precursors are derived from bone marrow cells (BMC) \\[[@r4]-[@r11]\\] or from circulating monocytes in the periphery \\[[@r12],[@r13]\\]. Resident microglia have been shown to play dual roles in the progression of neurodegenerative disorders. These cells can release pro-inflammatory molecules that are neurotoxic and induce neurodegeneration \\[[@r14],[@r15]\\]. However, microglia can also promote neuroprotection and neuroregeneration by entering CNS lesions and removing toxic byproducts and engulfing pathogens and cell debris to promote repair. In addition, microglia can release neurotrophic factors and anti-inflammatory molecules that induce the re-establishment of a functional neuronal environment \\[[@r15],[@r16]\\]. However, the actions of the resident microglia alone are not sufficient to reverse neurodegenerative progression, and recent research has focused on the application of exogenous microglia precursors or monocytes to promote neuroprotection in the diseased brain and retina \\[[@r10]-[@r13]\\].\n\nOn the other hand, the number of exogenous microglia precursors that can be recruited"
+"Introduction\n============\n\n*Escherichia coli* are Gram-negative bacteria belonging to the *Enterobacteriaceae* family, which are ubiquitous colonizers of the gastro-intestinal (GI) tract in humans and companion animals. The *Enterobacteriaceae*, most notably *E. coli* and *Klebsiella pneumoniae*, are among the most important agents of serious hospital acquired and community-onset bacterial infections in humans and resistance to antimicrobial agents in these bacteria has become an increasingly serious problem ([@B33]). Over the last two decades, extended-spectrum \u03b2-lactamase (ESBL)-producing *E. coli* have been isolated with increasing frequency from human and animal samples ([@B9]; [@B13]). ESBLs confer resistance to extended-spectrum cephalosporins (ESCs, e.g., ceftiofur, cefpodoxime, ceftazidime, ceftriaxone) and monobactams, and often express resistance to non-\u03b2-lactam antimicrobials leaving only limited therapeutic options ([@B36]). In addition, isolates carrying plasmid-mediated cephalosporinases (pAmpC) have a broader spectrum of resistance, including the cephamycins and are not inhibited by \u03b2-lactamase inhibitors, resulting in resistance to almost all therapeutically available \u03b2-lactam agents ([@B37]). *E. coli* is commonly identified from clinical infections in companion animals, including urinary, respiratory, skin and soft tissues, GI tract, joint and wound infections ([@B19]; [@B53]). In veterinary medicine, the \u03b2-lactam agents are arguably the most important and widely used antimicrobial class for treating bacterial infections. Recent United Kingdom data"
+"Introduction\n============\n\nSqualenoylation is a promising, novel technique that chemically modifies drug molecules, altering their systemic and cellular transport properties [@B1]-[@B6]. Squalenoylation requires a multistep organic synthesis to prepare squalene, a ubiquitous hydrocarbon and cholesterol precursor, for conjugation to a chemotherapeutic, siRNA, antibiotic, or other therapeutic moiety [@B1], [@B2], [@B7]-[@B13]. Squalenoylation offers particular promise for the delivery of gemcitabine, a front-line therapy for pancreatic ductal adenocarcinoma [@B1], [@B14]-[@B17]. Gemcitabine suffers from a short plasma half-life that can be enhanced by encapsulation. In addition, pancreatic tumors can quickly develop resistance to gemcitabine, and chemical modification of gemcitabine with squalene alters gemcitabine\\'s transport on the cellular level, bypassing one mechanism of gemcitabine resistance [@B3], [@B18], [@B19]. Further, the squalenoylation of gemcitabine, a hydrophilic molecule, creates amphipathic chemicals capable of self-assembly into squalenoylated gemcitabine (SqGem)-based nanoparticles (NPs), which are cytotoxic in a variety of human tumor cell lines [@B15], [@B20]. The ability of SqGem to form NPs extends the plasma half-life and allows for active drug targeting, controlled drug release, and co-delivery of multiple therapeutic or imaging agents [@B3], [@B4], [@B8], [@B9], [@B17]. Here, in addition to improving upon existing methods of squalenoylation and formation of squalenoylated NPs, we evaluate the *in vitro*"
+"We start a new series with this issue.\n\nThe Looking Glass will depict how others look at medical practice, its practitioners, mental health workers and philosophers. It will also reflect on happenings in the world of Medicine and Science.\n\nWe start with Medical Journals. The *CMAJ...*\n\nThe date: Feb 20, 2006. Medical publishing was rocked by the sudden dismissal of the Editor In Chief of the *CMAJ* (Canadian Medical Association Journal), John Hoey, and a Senior Deputy Editor Anne Mary Todkill. The Editor appointed in the interim, Stephen Choe and another Deputy Editor Sally Murray, also resigned in a week\\'s time, on 28 Feb to be precise. Along with them also went Jerome Kassirer, a former *CMAJ* editorial board member and a former editor of the *New England Journal of Medicine (NEJM),* appointed to frame regulations or governance plans about editorial independence.\n\nAll these are well-respected professionals in the field of biomedical publication and there has been a huge outcry, both in the medical as well as popular press, at their abrupt sacking.\n\nIf this were not enough, fifteen out of the nineteen members of the editorial board of the *CAMJ* also resigned, precipitating a grave crisis. In the meanwhile,"
+"INTRODUCTION\n============\n\nAll living organisms age and die. In ancient Greek mythology the Moirai or Three Fates, Klotho (or Clotho), Lechesis and Atropos, were the daughters of Zeus and Themis and determined the duration of life. It was believed that Klotho spins the thread of life, Lechesis determines its length and Atropos cuts it. The *klotho* gene (symbol, *kl*) is named after the Moirai who spins the thread of life \\[[@b1-jlm-05-01]\\].\n\nThe *klotho* gene was originally identified as being mutated in a mouse strain in which inherited phenotypes closely resemble human aging \\[[@b1-jlm-05-01]\\]. Mice homozygous for a hypomorphic *klotho* allele (*kl/kl*) displayed multiple aging-like phenotypes including growth retardation, vascular calcification and osteoporosis and died prematurely at around two to three months of age \\[[@b1-jlm-05-01]\\]. Conversely, overexpression of the *klotho* gene extends the life span in mice, which supports the notion that *klotho* is an aging-suppressor gene \\[[@b2-jlm-05-01]\\]. Since the discovery of Klotho, two related paralogs, *\u03b2* Klotho and *\u03b3*Klotho (or Lctl or KLPH), have been identified as Klotho family members \\[[@b3-jlm-05-01],[@b4-jlm-05-01]\\]. Klotho is also called *\u03b1*Klotho in order to distinguish it from the other two members \\[[@b5-jlm-05-01]\\]. In this review, Klotho is simply used to refer to *\u03b1*Klotho. This review"
+"Dear Editor,\n\nWe read with great interest the article by Sohrabi et al. regarding the current 2019 novel coronavirus, SARS-CoV-2 outbreak. The article presented the timeline of the initial outbreak and response, describing key aspects such as management, transmission and symptoms \\[[@bib1]\\].\n\nIn this letter, we provide a detailed update on the supply of personal protective equipment (PPE) in the United Kingdom (UK), highlighting key statistics and updated PPE guidelines on surgical procedures. We provide comparisons to World Health Organisation (WHO) guidelines and describe recent innovations aiming to reduce hospital SARS-CoV-2 spread.\n\nSARS-CoV-2 has been shown to spread in human to human contact through aerosol droplets. Therefore, healthcare staff are at an increased risk of infection, especially during aerosol generating procedures (AGPs) including intubation, a procedure essential in maintaining ventilation of SARS-CoV-2 patients and in surgical intervention. Hence the use of PPE such as plastic face visors, filtering face pieces class 3/2 (FFP3/2) or N95 masks, which filter out 99%/94% and 95% of airborne particles respectively, are imperative in healthcare environments to prevent further spread. Government statistics state that over 761 million items of PPE have been transported to frontline staff across 58,000 different healthcare settings including hospitals, care homes"
+"1.. Introduction\n================\n\nAs the highest accuracy attitude measurement device, star trackers are capable of providing arcsec level 3-axis attitude and are widely used in many spacecrafts. A star tracker can be treated as a special electronic camera connected to a microcomputer. It can take star images of a part of the sky and identify these stars in the star image. Based on the position information of these identified stars, the attitude of spacecraft can be determined \\[[@b1-sensors-14-04914]--[@b4-sensors-14-04914]\\].\n\nWith the expansion of the application fields, especially on spacecrafts with the capability of rapid and large angle attitude maneuver control, star trackers must still work normally and steadily. Under these highly dynamic conditions, a crucial problem arises: due to the large angular velocity of the spacecraft, the star-spots in the star image will move across many pixels during the exposure time and ultimately form obvious trails. This will affect star detection sensitivity and star location accuracy seriously and result in low attitude accuracy and poor stability. This case can be ameliorated by adjusting the dynamic working parameters, especially the exposure time. Increasing the exposure time means more energy is gathered at each star-spot, which enhances high star detection sensitivity, but on"
+"Introduction {#Sec1}\n============\n\nATP binding cassette (ABC) transporters are part of the ABC protein superfamily and form the largest class of primary active transport proteins, which couple ATP hydrolysis with substrate transport. The substrate spectrum of ABC transporters ranges from small soluble molecules, hydrophobic drugs and lipids to large proteins^[@CR1]^. ABC transporters include importers, exporters, channels, and regulators. Their basic architecture comprises two nucleotide-binding domains (NBDs) and two transmembrane domains (TMDs). In eukaryotes, the ABC transporters exist as full-transporters with all four domains combined in one polypeptide chain or as half-transporters composed of one TMD and one NBD. Consequently, half-transporters can either form homo- or heterodimers. Since many transporters are linked to human diseases, such as cystic fibrosis, Tangier disease, or Dubin-Johnson syndrome, elucidating the molecular mechanisms and functions of ABC transporters is of high interest^[@CR2],[@CR3]^.\n\nA representative ABC exporter is the half-transporter associated with antigen processing-like (ABCB9, TAPL), which translocates peptides into the lumen of lysosomes^[@CR4]^. Besides its broad tissue distribution with highest expression in dendritic cells, macrophages, and Sertoli cells, TAPL orthologous are also found in invertebrates like *Caenorhabditis elegans* and even in plants^[@CR5]--[@CR8]^. The core complex of TAPL (coreTAPL), composed of 2\u2009\u00d7\u20096 C-terminal transmembrane helices"
+"The novel CoronavirusDisease2019 (COVID-19) first emerged as an outbreak in the province of Hubei, China, in December 2019, with its causative virion formally known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is a betacoronavirus, like that with Middle East respiratory syndrome coronavirus(MERS-CoV) and severe acute respiratory syndrome (SARS), which is thought to have originated from an animal host with eventual spread to humans.^[@R1]^ COVID-19 became a global pandemic in a matter of months, affecting over 100 countries and totaling 824,559 infections and 40,673 deaths worldwide as of March 31, 2020.^[@R2]^\n\nCoronaviruses constitute a large family of viruses known to infect both humans and animals. Bats have been implicated as vectors in the largest variety of coronaviruses. The human coronaviruses can be subclassified into alpha and beta coronaviruses. Clinical manifestations of coronavirus infections are typically respiratory and enteric, although some present with neurologic manifestations.^[@R1]^\n\nAt the time of publication of this article, COVID-19 is thought to have an incubation period of approximately 2 weeks, with most infected individuals becoming symptomatic 5 days after exposure. Illness severity ranges from mild to critical and fatal. Approximately 80% of cases are asymptomatic or have mild symptoms, 15% have severe illness, and 5%"
+"Introduction\n============\n\nPistachio is an edible seed from the pistachio tree grown broadly in hot--dry regions of the Middle East, Mediterranean, and Americas (Garcia et\u00a0al. [@b8]). Nutritional value, palatability, easily digestion, high calorie value, vitamins, and minerals are among the characteristics that make pistachio superior to other nuts. However, factors such as harvest, transportation, and processing enhance the risk of fungal infection in pistachio (Salek Zamani [@b21]). Favorable conditions in terms of temperature, relative humidity, and water activity result in fungal growth and production of secondary metabolites such as mycotoxin. Aflatoxins are toxic substances from mycotoxin group produced by fungi including *Aspergillus flavus*, *Aspergillus parasiticus*, and *Aspergillus nomius* (Sarhang Pour et\u00a0al. [@b22]; Daraei Garmakhany et\u00a0al., [@b22]). These toxins cause dangerous diseases such as hepatic cancer in humans (Sarhang Pour et\u00a0al. [@b22]). In order to inhibit from aflatoxin production, prevention methods should be in use (Shantha and Decker [@b25]).\n\nAntimicrobial is a kind of active packaging which can enhance storage life of the food product and protect its microbial health (Seydim and Sarkis [@b23]). Today, studies on packaging of food products are concentrated on biodegradable films such as prepared films from edible proteins of animal and plant"
+"The authors confirm that all data underlying the findings are fully available without restriction. All PCA data are available from the Running Injury Clinic and University of Calgary Institutional Data Access / Ethics Committee (CHREB) by contacting the corresponding author and Dr. Stacey A. Page, chair of CHREB at <omb@ucalgary.ca>.\n\nIntroduction {#s1}\n============\n\nFemale runners have a two-fold risk of sustaining certain running-related injuries such as patellofemoral pain syndrome, iliotibial band syndrome, and tibial stress fractures as compared to their male counterparts [@pone.0105246-Taunton1]. Furthermore, it has been reported that female runners exhibit different running kinematic waveform patterns and greater discrete joint angles, which have been postulated to contribute towards greater injury risk [@pone.0105246-Ferber1]--[@pone.0105246-Maurer1]. Traditionally, male and female running patterns have been analysed using discrete time point variables, such as peak angles and angles at touchdown and toe-off, together with inferential statistics, such as the t-test and analysis of variance (ANOVA) [@pone.0105246-Ferber1]--[@pone.0105246-Chumanov1]. More recently, pattern recognition methods have been applied in this area, and have achieved good classification performance [@pone.0105246-Eskofier1], [@pone.0105246-Vardaxis1], particularly in combination with a principal component analysis (PCA) approach and a support vector machine (SVM) classifier [@pone.0105246-Nigg1]--[@pone.0105246-Eskofier2]. Nigg et al. [@pone.0105246-Nigg1], for example, reported a classification rate of 86.6%"
+"INTRODUCTION\n============\n\nIn December 2019, a cluster of acute respiratory illness occurred in Wuhan, Hubei Province, China \\[[@sfaa086-B1]\\]. The pathogen was identified as a novel enveloped ribonucleic acid (RNA) beta coronavirus that has been named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has a phylogenetic similarity to SARS-CoV \\[[@sfaa086-B4], [@sfaa086-B5]\\]. The World Health Organization (WHO) has named the disease coronavirus disease 2019 (COVID-19). COVID-19 is more contagious than SARS and often results in acute respiratory distress syndrome (ARDS), spreads by human-to-human transmission via droplets or direct contact and has an incubation period estimated at 1--14\u2009days (usually 3--7\u2009days) \\[[@sfaa086-B6]\\]. On 11 March 2020, the WHO declared COVID-19 a pandemic.\n\nThis study evaluates the impact of chest computed tomography (CT) screening of hemodialysis (HD) patients without respiratory symptoms as well as the clinical, laboratory and radiologic features and outcomes of HD patients with COVID-19.\n\nMATERIALS AND METHODS\n=====================\n\nStudy design and patients\n-------------------------\n\nWe did a retrospective review of medical records from HD patients infected with COVID-19 at Zhongnan Hospital of Wuhan University from 12 January to 7 April 2020. The diagnosis of COVID-19 pneumonia was based on the New Coronavirus Pneumonia Prevention and Control Program (4th edition) published"
+"Introduction {#s1}\n============\n\nElectronic cigarettes, or e-cigarettes, and other electronic nicotine delivery systems (ENDS), alternative nicotine delivery systems (ANDS) or vapourised nicotine products (VNPs) are devices that heat a liquid, commonly propylene glycol and/or glycerol (glycerin), to create an inhalable aerosol that can contain nicotine.\n\nThe modern e-cigarette is often credited to Hon Lik, a Chinese pharmacist who invented the product in 2003;[@R1] Lik\\'s design was patented internationally in 2007 (Electronic Atomization Cigarette: US 20070267031 A1). E-cigarettes became commercially available in Europe and the USA around 2006.[@R2] Reported use of e-cigarettes has increased dramatically in recent years although globally use remains low; countries that report prevalence of adults using e-cigarettes include 0.3% in Indonesia, 1.2% in Italy, 1.9% in Greece and 5.9% in Poland.[@R3] The value of global sales of e-cigarettes was estimated to be 3.5 billion US\\$ in 2015,[@R4] with the largest three markets being the USA, Russia and Germany (collectively representing 60% of global sales).[@R5] E-cigarette products have been marketed by manufacturers as alternative products to combustible tobacco that can be used when cigarettes are not permitted,[@R6] or instead of cigarettes.[@R7]\n\nA number of global tobacco control researchers have stated that e-cigarettes are less harmful than combusted tobacco;[@R8]"
+"###### Strengths and limitations of this study\n\n-   We used nationally representative Demographic and Health Survey (DHS) datasets from 31 Sub- Saharan African countries.\n\n-   We used four separate measures of women's autonomy.\n\n-   DHS data are cross-sectional, and so the direct relationship between women's autonomy and the utilisation of maternal healthcare services cannot be determined with certainty.\n\nIntroduction {#s1}\n============\n\nMaternal mortality, measured as maternal mortality ratio (MMR), remains a major concern despite the decline globally from 385 to 216 maternal deaths per 100\u2009000 live births between 1990 and 2015.[@R1] Sixty-six per\u00a0cent of all maternal deaths occur in sub-Saharan Africa (SSA).[@R1] This is of concern if SSA is to achieve the Sustainable Development Goal 3 target of fewer than 70 maternal deaths per 100\u2009000 live\u00a0births by 2030.[@R1] The leading causes of maternal deaths in SSA are abortion, haemorrhage, hypertension, obstructed labour and sepsis.[@R2] Increasing the utilisation of antenatal care (ANC) and skilled birth attendants (SBA) could help reduce the high number of maternal deaths in SSA.[@R3]\n\nA better understanding of the relationship between women's autonomy and the utilisation of maternal healthcare services may contribute to reducing maternal deaths in SSA. However, examining women's autonomy is"
+"Background\n==========\n\nMagnetic Resonance Imaging (MRI) has become by far the primary tool for gaining important insights into the functional and metabolic bases of heart disease. However, the observation of a moving organ, such as a beating heart, requires synchronization: since an image cannot be acquired in one heart cycle, its successive acquisitions have to be accurately combined with the cardiac phase motion. Such requirements depend on a reliable detection of the R-wave of the electrocardiogram (ECG) to guarantee that consecutive image data collections always start at the same point of the cardiac cycle. Still, a fundamental problem for monitoring a subject\\'s cardiac activity during MRI is the corruption of the ECG signal due to adverse electromagnetic effects \\[[@B1]-[@B4]\\]. The oscillating magnetic fields may induce voltage artefacts which do not reflect actual electrophysiological events. This effect is particularly pronounced in small animals MRI microscopy, where strong and rapidly-switching gradients, leading to elevated induced voltages, are needed to obtain high spatial and temporal resolution. Conversely, a small animal\\'s ECG is just few millivolts in amplitude and with the spurious signals often resembling the QRS spike, correct cardiac gating is often greatly disrupted. Recent works have proposed to improve motion gating strategies"
+"1. Introduction {#sec1-brainsci-07-00020}\n===============\n\nAge-related cognitive decline is a common problem for many elderly people, yet its cause is poorly understood. Over 99% of investigational drugs, participating in over 200 clinical trials, failed to receive approval for the treatment of Alzheimer's disease \\[[@B1-brainsci-07-00020]\\]. Even the success of a few approved drugs provides only minimal patient improvement. There is a need for new, safe, and effective therapeutics with extensive safety and efficacy data that can be developed for use in humans within the next few years.\n\nGHK (glycyl-[l]{.smallcaps}-histidyl-[l]{.smallcaps}-lysine) is a human plasma copper-binding peptide with a stunning array of actions that appear to counter aging-associated diseases and conditions. GHK was isolated in 1973 as an activity bound to human albumin that caused aged human liver tissue to synthesize proteins like younger tissue \\[[@B2-brainsci-07-00020]\\]. It has a strong affinity for copper and readily forms the complex GHK-Cu. It was first proposed that GHK-Cu functions by modulating copper intake into cells \\[[@B3-brainsci-07-00020]\\]. Since then, it has been established that the GHK peptide has stimulating and growth-promoting effects on many cells and tissues such as chondrocytes \\[[@B4-brainsci-07-00020]\\], liver cells and human fibroblasts \\[[@B5-brainsci-07-00020]\\]. It increases stemness and stimulates integrin secretion in human epidermal basal"
+"INTRODUCTION\n============\n\nNon-LTR retrotransposons (NLRs) \\[retrotransposons lacking long terminal repeats (LTRs)\\], are a class of transposable elements that are mobilized by reverse transcription of an RNA intermediate ([@b1]). Multiple copies of NLRs inhabit variable fractions of the genome of most eukaryotes. Whereas most copies are defective, some are functional and their retrotransposition can result in several types of genetic effects including mutations associated with diseases in humans and mice ([@b2]). The *Drosophila* NLR *I factor* and the mammalian NLR L1 ([@b3]) provide well-known examples of the impact of NLR mobilization.\n\nMost NLRs contain two open reading frames, ORF1 and ORF2, which are translated from a bicistronic messenger RNA that presumably also serves as a template for retrotransposition ([@b4]--[@b6]). The sequence of the ORF2 product (ORF2p) is relatively well conserved among NLRs. ORF2p is involved in reverse transcription and integration, and its endonuclease and reverse-transcriptase activities have been demonstrated *in vitro* for different elements ([@b7]--[@b12]). The sequence of the ORF1 product (ORF1p) is, in contrast, poorly conserved in evolution. ORF1p of human and mouse L1 are expressed in some carcinoma cells and can be isolated as a 40 kDa full-size protein (p40) which forms, in association with L1 RNA, high molecular"
+"Introduction\n============\n\nBackground\n----------\n\nWorldwide, road traffic incidents (RTIs) constitute the primary cause of death due to injuries, the tenth leading cause of all deaths, and the ninth leading contributor to the global burden of disease ^[@ref-1]^. Latin America and Peru are not exceptions to these statistics ^[@ref-2],\\ [@ref-3]^. Adequate management after the occurrence of a traffic incident can decrease the probability of death and disability, limit the severity caused by injury and ensure that survivors are optimally reintegrated into the community ^[@ref-4]^. In high-income countries, studies have shown that of those that die due to a RTI, 50% will die within minutes after the incident or on the way to the hospital, 15% die within the first 4 hours, and 35% die after 4 hours ^[@ref-5]^. In low- and middle-income countries (LMIC), the majority of deaths occur among victims before arriving at a health care facility (HCF), indicating that many deaths and complications could be prevented via adequate initial management and response ^[@ref-5]--\\ [@ref-8]^. The experiences of developing countries with regards to evaluating the care of RTI victims are scarce and unsystematic ^[@ref-9]^. Providing quality health care services to RTI victims is also important, ensuring that they are at"
+"The conclusion of [@b10-ehp0115-a00126] that \"Exposure to *Pfiesteria* Species in Estuarine Waters Is Not a Risk Factor for Illness\" is unsupported because *a*) a description of *Pfiesteria*-related fish kills in the Chesapeake estuaries during 1999--2002 was omitted; *b*) quantitative data on *Pfiesteria* were not collected; *c*) data on visual contrast sensitivity (VCS) were collected but not reported; *d*) a comprehensive list of other results was not presented; and *e*) data were lost due to a 30% attrition rate. These data are needed to justify or negate the conclusion.\n\nSince the first reports of environmental *Pfiesteria*-related illness ([@b12-ehp0115-a00126]) and successful treatment ([@b13-ehp0115-a00126]), all reports were associated with concurrent *Pfiesteria*-related fish kills ([@b4-ehp0115-a00126]). Numerous kills were reported in the Chesapeake and North Carolina estuaries through 1998 in association with *Pfiesteria*-like zoospore concentrations of 600--35,000 cells/mL water ([@b1-ehp0115-a00126]). [@b2-ehp0115-a00126] previously reported relationships between impairment and increased time spent in Chesapeake estuaries. Although the degree of recovery could not be determined because premorbid data were unavailable, most of the untreated participants improved within 3--6 months. However, in 1999--2002 neither Maryland nor North Carolina reported *Pfiesteria* concentrations reaching 600 cells/mL and associated fish kills ([@b9-ehp0115-a00126]; [@b11-ehp0115-a00126]). [@b10-ehp0115-a00126] used a polymerase chain reaction (PCR) method to"
+"Polycomb repressive complex 2 (PRC2) represses gene transcription by trimethylating histone H3 on lysine 27 (H3K27me3). The core PRC2 complex is comprised of embryonic ectoderm development (EED), Suppressor of Zeste12 homolog (SUZ12), retinoblastoma-associated protein 48 (RbAp48), and a catalytic subunit, either Enhancer of Zeste Homolog 1 or 2 (EZH1 or EZH2).^[@bib1],\\ [@bib2]^ EZH1 and EZH2 are mutually exclusive in the same PRC2 complex and are partially redundant at certain developmental and disease stages.^[@bib3],\\ [@bib4]^ EED is a core component of PRC2 complex that interacts with EZH1 or EZH2 through a WD40 domain. In addition, EED recognizes H3K27me3 through an aromatic cage structure to recruit PRC2 to established H3K27me3 and thereby enforce maintenance of this repressive epigenetic mark.^[@bib5],\\ [@bib6]^\n\nPRC2 has essential roles of regulating cell fate commitment, organogenesis, homeostasis and disease-related tissue remodeling.^[@bib1]^ In early developing mouse embryos, homozygous *Eed* null mutation abolished global H3K27 methylation and caused defects in primitive streak formation and fetal lethality at E9.5.^[@bib7],\\ [@bib8]^ EZH2 also controls the fate of multiple types of tissue progenitors.^[@bib9]^ Depletion of EZH2 in epidermal precursor cells promoted premature epidermal differentiation and barrier acquisition.^[@bib10],\\ [@bib11]^ EZH2 also had developmental-stage-specific roles in regulating cardiomyocyte differentiation and proliferation.^[@bib12],\\ [@bib13]^ In adult vasculature,"
+"INTRODUCTION\n============\n\nAlport syndrome is a glomerulopathy due to abnormal type 4 collagen in the glomerular basement membrane, and predisposes affected individuals to develop glomerulosclerosis. Affected individuals present with hematuria, renal failure, hearing loss, dyslipidemia, and retinal flecks. Diagnosis can be made by skin biopsy, renal biopsy, or genetic testing. Management includes angiotensin blockade therapy in the setting of overt proteinuria, and kidney transplant if/when the disease progresses to end stage renal disease \\[[@B1]\\]. In Wilson disease (WD), copper accumulates in the liver, kidneys, brain, corneas, and other organs due to mutations in ATP7B. The diagnosis of WD may involve testing for serum ceruloplasmin, urinary excretion of copper, hepatic copper concentration, neurologic or psychiatric abnormalities and screening for ATP7B mutations \\[[@B2][@B3]\\]. In patients with renal disease that causes glomerular damage and non-selective proteinuria, the urinary copper excretion may be difficult to interpret since there are losses of heavy metals associated with proteins in their urine \\[[@B4][@B5]\\]. Little is known about levels of urinary copper and zinc excretion in children with proteinuric kidney diseases. We report on the case of a child diagnosed at an early age with Alport syndrome whom later developed abnormal liver enzymes, low serum ceruloplasmin and elevated"
+"Introduction {#s1}\n============\n\nAt elite performance levels, such as in high-level sports, expertise is expressed by individuals achieving consistent performance outcomes, often in highly dynamic performance environments. According to Ericsson and Lehman [@pone.0089865-Ericsson1], an expert is defined as an individual with at least ten years or 10000 hours of deliberate practice. They argued that expertise results from repeated, motivated engagement in an activity requiring effort and concentration, both of which have little to do with talent [@pone.0089865-Ericsson1]. In cognitivist approaches, a high level of expertise results in the capacity to reproduce a movement like an automatism, with movement variability considered as a dysfunctional aspect of motor control, representing the amount of noise to be reduced for achievement of successful performance [@pone.0089865-Davids1]--[@pone.0089865-VanEmmerik1].\n\nAlternatively, in an ecological dynamics approach [@pone.0089865-Beek1], [@pone.0089865-Davids2], it has been suggested that the nature of performer-environment relationship and the coupling of perception and action is not the same for beginners and experts. This is because the expert is more capable of exploiting information about environmental and task-related constraints to functionally (re)organize the multiple degrees of freedom of the body to achieve consistent performance outcomes. Thus, the greater adaptability of the experts to a variety of interacting constraints, categorised"
+"1. Introduction {#sec1-ijms-19-03626}\n===============\n\nBenzo\\[*\u03b1*\\]pyrene (B\\[*\u03b1*\\]P) is a prototypical polycyclic aromatic hydrocarbon (PAH) that is formed by incomplete combustion of organic materials. It is found in large amounts in diet, air pollution, cigarette smoke and some occupational atmospheres \\[[@B1-ijms-19-03626]\\]. Human exposure to this widespread environmental contaminant has been correlated to various pathological situations such as cancer development, and inflammation contributing to cardiovascular and pulmonary diseases \\[[@B2-ijms-19-03626],[@B3-ijms-19-03626]\\]. Therefore, B\\[*\u03b1*\\]P has been classified as a priority toxicant by the United States Environmental Protection Agency, the World Health Organization and the European Union. Most of the B\\[*\u03b1*\\]P-related toxic effects have been linked to the activation of the aryl hydrocarbon receptor (AhR) and its subsequent binding to specific xenobiotic responsive elements within the promoter of responsive genes \\[[@B4-ijms-19-03626]\\]. For example, the activation of the AhR-related signaling pathway by B\\[*\u03b1*\\]P results in the up-regulation of xenobiotic metabolizing enzymes such as cytochromes P-450 (CYPs) 1A1, 1A2 and 1B1; this in turn bioactivates B\\[*\u03b1*\\]P into epoxide derivatives that largely account in a major way for carcinogenic effects in several organs such as lung, liver and lymphoid tissue \\[[@B5-ijms-19-03626]\\].\n\nAmong cell types targeted by B\\[*\u03b1*\\]P, lymphocytes, in particular T cells which express AhR and possess a CYP1-metabolizing system"
+"Introduction {#sec1-1}\n============\n\nPulmonary artery catheter (PAC) placement is a common procedure in anesthetic management of patients undergoing heart surgery.\\[[@ref1]\\] In our hospital, the catheter is routinely inserted after induction of anesthesia and the placement is performed by observing the pressure waves. Our impression is that experience as an anesthesiologist may be an important factor for successful placement of PAC. In fact, a previous report by Wall *et al*.\\[[@ref2]\\] showed that the level of training affected the PAC placement time. On the other hand, a recent multivariate analysis failed to show that duration of training as an anesthesia resident is a significant factor to increase the PAC placement time.\\[[@ref3]\\] We hypothesized that the successful placement of PAC would be dependent on prior experience of PAC placement than duration of training as an anesthesiologist. Our hospital is a university-affiliated small hospital specialized in heart diseases and we provide anesthesia residents with short-term training for cardiac anesthesia. In this study, we measured the time required for the catheter placement and the effect of prior experience of PAC placement on the placement time. We also observed the incidence of ventricular arrhythmias during placement of a PAC and assessed the effect of prior experience"
+"Introduction\n============\n\nDespite national osteoporosis screening guidelines recommending routine screening for women aged 65 years or older \\[[@b1]--[@b3]\\], studies have identified rates of screening in primary care settings as low as 12% \\[[@b4]\\]. Studies of the efficacy of different interventions to screen more eligible women has led to mounting evidence that health information technology (HIT) improves adherence to osteoporosis screening guidelines \\[[@b5]\\]. However, doctors have been reluctant adopters of HIT because of the expense and time required to change their office systems or because they are not convinced of the benefits of doing so \\[[@b6]\\]. As a result, the health care industry lags behind other sectors in IT investment \\[[@b7]\\]. This means that applications that may narrow gaps in care (e.g. clinical decision support systems that prompt doctors to discuss preventive services with patients) are not being fully deployed.\n\nOsteoporosis, a common condition that affects about eight million women and two million men in the USA, is characterized by low bone mass and structural deterioration of bone tissue, leading to increased bone fragility. It poses an increased risk of fracture for people older than 50 years and, if left untreated, its debilitating consequences constitute a substantial national economic burden \\[[@b1],[@b8]\\]."
+"The electronic version of this article is the complete one and can be found at: <http://F1000.com/Reports/Medicine/content/1/90>\n\nIntroduction and context {#s01}\n========================\n\nRenal cell carcinoma (RCC) is the sixth leading cause of cancer deaths in developed nations \\[[@bib-001]\\]. Until recently, immunotherapy with interferon-alpha (IFN-\u03b1) and interleukin-2 were the only therapies available for patients with advanced disease, with major response rates typically seen in 10-15% of patients. Most patients died of their disease within 1 to 2 years of developing metastases. Identification of the VHL (Von Hippel-Lindau) tumor-suppressor gene and the discovery that its inactivation in clear cell RCCs leads to increased expression of hypoxia-inducible factor-alpha (HIF-\u03b1) and angiogenesis related proteins, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) B chain, led to the development of new therapies that specifically target VEGF signaling pathways. Multiple effective agents are now available that prolong progression-free survival (PFS) and/or overall survival in phase III randomized studies. These agents have become the standard care for most patients.\n\nRecent advances {#s02}\n===============\n\nBevacizumab, a humanized VEGF-neutralizing antibody, was the first VEGF-targeted therapy to show activity in metastatic RCC \\[[@bib-002]\\]. Two multicentered phase III studies compared bevacizumab plus IFN-\u03b1 to IFN-\u03b1 alone as first-line"
+"All relevant data are within the paper and its supporting information files.\n\nIntroduction {#sec001}\n============\n\nThe efficacy of acupuncture-like somatic stimulation on the treatment of gastrointestinal motility disorders has been established in both clinical and research settings \\[[@pone.0168200.ref001]--[@pone.0168200.ref007]\\]. Namely, the effect of acupuncture on gastric motility is primarily known to be associated with autonomic reflexes and the gut-brain axis \\[[@pone.0168200.ref008]\\]. Stimulation at homotopic acupoints, where afferent innervation occurs in the same or adjacent segment from that in which the efferents innervate visceral organs, decreases intra-gastrointestinal pressure, with or without spinalization. Conversely, acupuncture at heterotopic acupoints, involving different segmental innervation of the spinal cord to visceral organs, induces gastrointestinal facilitation only in complete spinal rats \\[[@pone.0168200.ref009]\\]. However, little effort has been made thus far to investigate the roles of specific ligand receptors (such as adrenergic and muscarinic acetylcholine receptors) in mediating the effects of acupuncture, at heterotopic or homotopic acupoints, on motility of various sections of gut.\n\n\u03b2-adrenoceptors (\u03b2-ARs) are divided into three different subtypes (\u03b2~1--3~), all of which are widely expressed in smooth muscle organs. \u03b2-AR stimulation has been shown to consistently produce a relaxation response in a range of human gastrointestinal smooth muscle preparations. The range of muscle relaxation"
+"Background {#s1}\n==========\n\nInfluenza A infection is most commonly associated with pulmonary disease ranging from a mild upper respiratory tract infection to severe pneumonia. However, other important manifestations include myocardial infarction, Guillain-Barr\u00e9 syndrome, encephalitis, pericarditis and rarely severe rhabdomyolysis. While myalgias are a common complaint in patients with acute influenza infection, acute myositis and rhabdomyolysis are likely under-reported.[@R1] Even though rhabdomyolysis occurs more frequently in children, it is now increasingly recognised in adults. In one series, 62.5% of patients (n=18, median age 38\u00a0years) with influenza A had elevated creatine kinase\u00a0(CK) above 200\u2009U/L on admission (range 58--2156\u2009U/L).[@R2] Current influenza guidelines do not address CK\u00a0measurement. Previous studies and our case suggest CK measurement be part of the workup for the hospitalised patient with acute influenza infection.\n\nCase presentation {#s2}\n=================\n\nA man aged 29 years with a past medical history of cerebral palsy, seizures and chronic constipation that presented in late winter with 3 days of fevers, nausea, vomiting and anorexia. On physical examination, he had a temperature of 38.8\u00b0C, heart rate of 167 beats per minute, blood pressure of 75/62\u2009mm\u00a0Hg, respiratory rate of 30 breaths per minute and an oxygen saturation of 90% on"
+"Introduction {#sec1}\n============\n\nLung cancer is one of the most common malignancies and the leading cause of cancer-related death worldwide.[@bib1]^,^[@bib2] Non-small-cell lung cancer (NSCLC) accounts for about 85% of all lung cancers.[@bib3] The predicted 5-year survival rate for NSCLC is as low as 15.9%.[@bib3] The poor prognosis of NSCLC is largely ascribed to development of metastatic disease. Identification of the molecular mechanisms for cancer metastasis is of significance in developing effective therapeutic approaches for NSCLC.\n\nDHX15 is a member of the DEXD/H box helicase family that participates in ATP-dependent unwinding of RNA substrates, consequently modulating pre-mRNA splicing and translation initiation.[@bib4]^,^[@bib5] DHX15 has been shown to recognize viral RNA and activate immune response through nuclear factor \u03baB (NF-\u03baB) and mitogen-activated protein kinase (MAPK) signaling in myeloid dendritic cells.[@bib6] Memet et\u00a0al.[@bib7] reported that DHX15 is involved in ribosome biogenesis by promoting pre-rRNA cleavage.[@bib7] DHX15 has been documented to modulate gene expression by repressing CMTR1-dependent mRNA cap formation.[@bib8] Recent reports have indicated the role of DHX15 in cancer progression.[@bib9], [@bib10], [@bib11] For instance, Ito et\u00a0al.[@bib9] reported that DHX15 is downregulated in glioma, and overexpression of DHX15 suppresses glioma growth both *in\u00a0vitro* and *in\u00a0vivo*. Jing et\u00a0al.[@bib10] demonstrated that DHX15"
+"Background {#Sec1}\n==========\n\nSquamous cell carcinoma of head and neck (SCCHN) originates from the nasal cavities, paranasal sinuses, oral cavity, nasopharynx, oropharynx, hypopharynx and larynx. It ranks as the sixth aggressive malignancy in the world. Although multiple therapies including surgery, radiotherapy and chemotherapy have been applied in clinical settings for decades, the prognosis of SCCHN patients are still unsatisfactory \\[[@CR1]\\]. Lymph node metastasis is one of major causes for a poor prognosis in SCCHN patients \\[[@CR2], [@CR3]\\]. Therefore, it is urgent and imperative to clarify the mechanisms underlying metastasis, which will benefit future surveillance and target therapy for SCCHN patients.\n\nTumor microenvironment (TME) is composed by diverse cell types including cancer cells, immune cells and multiple molecules such as cytokines, chemokines and metabolites etc. \\[[@CR4], [@CR5]\\]. Communications between cancer cells and stromal cells is important in cancer malignant transformation and progression \\[[@CR6]\\]. Peripheral monocytes infiltrate into tumors, are educated by TME and polarize into classically activated type 1 (M1) macrophages or alternatively activated type 2 (M2) macrophages. Tumor-associated macrophages (TAMs) include M1 and M2 TAMs, M2 TAMs always facilitate angiogenesis, matrix breakdown and cancer cell movement, all of which are indispensable elements for cancer metastasis \\[[@CR7], [@CR8]\\]. Therefore, macrophages represent"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec001}\n============\n\nA growing public health problem, Lyme disease (LD) is the most commonly reported vector-borne disease in the U.S. and Europe \\[[@pone.0189071.ref001]\\], inflicting a significant public health burden \\[[@pone.0189071.ref002]--[@pone.0189071.ref004]\\]. The number of annual cases of LD in the U.S. has climbed to over 300,000 \\[[@pone.0189071.ref005]\\] and is expected to rise \\[[@pone.0189071.ref006], [@pone.0189071.ref007]\\]. Human infection with the etiologic agent of Lyme disease, *Borrelia burgdorferi*, results in disease of a few hallmark clinical signs and multifarious symptoms. The most common early manifestation of Lyme disease is an erythema migrans (EM) rash at the site of the tick bite. A large clinical study of disease characterization indicated that this occurs in 70--80% of cases \\[[@pone.0189071.ref008]\\]. However, variations in rash appearance \\[[@pone.0189071.ref009]\\], region \\[[@pone.0189071.ref009], [@pone.0189071.ref010]\\], and possibly even gender \\[[@pone.0189071.ref011]\\] may influence the accurate reporting of EM incidence. Following hematogenous dissemination of the spirochete, the heart, joints and nervous system may become colonized, leading to inflammation and signs/symptoms associated with this systemic infection.\n\nThe majority of LD cases that are readily diagnosed and treated lead to clinical cure. However, a proportion of patients remain ill \\[[@pone.0189071.ref012], [@pone.0189071.ref013]\\], and delayed treatment"
+"Problem\n=======\n\nThis quality improvement project was undertaken at St Thomas\\' Hospital Birth Centre (HBC) by four fourth year medical students, under the supervision of an obstetric consultant and two junior doctors. St Thomas\\' is a tertiary teaching hospital in London, UK and is the base for maternity services for the Guy\\'s and St Thomas\\' (GSTT) NHS Foundation Trust. With 22 beds on HBC, an average of 40 patients are admitted each day. The department has 90 staff members in total with 15 present on each shift. St Thomas\\' HBC patient population encompasses South-East London and annually sees approximately 6000 births.\n\nAs part of GSTT protocol, venous thromboembolism (VTE) risk assessment of women on HBC is completed on two separate computer systems. One is BadgerNet, Clevermed version 2.9.1.0, a maternity electronic record where antenatal, postnatal, and delivery details are recorded. The second system is the electronic patient record (EPR), iSOFT version 1.6. The CQUIN target is for 95% of patients to have a VTE assessment completed within 24 hours of admission. Previously women who delivered during their admission had their VTE assessment completed on BadgerNet, while those who were admitted but did not deliver were assessed on EPR. To simplify"
+"Citation: Uneke CJ, Sombie I, Uro-Chukwu HC, Mohammed YG, Johnson E. Promoting evidence informed policymaking for maternal and child health in Nigeria: lessons from a knowledge translation workshop. Health Promot Perspect. 2018;8(1):63-70. doi: [10.15171/hpp.2018.08](http://dx.doi.org/10.15171/hpp.2018.08).\n\nIntroduction {#s1}\n============\n\nCanada Institutes of Health Research (CIHR) defines knowledge translation (KT) as *\"a dynamic and iterative process that includes synthesis, dissemination, exchange and ethically sound application of knowledge to improve the health of people, provide more effective health services and products and strengthen the health care system\"*.^[@R1]^ KT has been described as a complex multidimensional phenomenon, consequently, a call has been made on the need for better comprehension of its processes including the mechanisms, methods, measurements, and factors influencing it from individual and contextual perspectives.^[@R2]^ KT is the meeting ground between research and practice-the two fundamentally different processes that KT has knit together via relationships that can be described as communicative.^[@R3]^ KT process is by no means simple because of the involvement of a wide range of interactions between those who produce knowledge (research evidence) and those in position to use knowledge for policymaking. These interactions may vary in the nature and complexity depending on level and extent of engagement of both parties and"
+"Leahy *et\u00a0al.*[^1^](#b1){ref-type=\"ref\"} recently issued a consensus statement that recommends targeting \u03b2\u2010cell function for therapy in type\u20032 diabetes. The consensus is based on recent studies showing that declining \u03b2\u2010cell function, a pathogenesis of type\u20032 diabetes, begins early in the disease's natural history, accelerates markedly after reaching a compensatory threshold, drives the progression of the disease and is potentially reversible, particularly in the early stages. They concluded that continued multidisciplinary effort to realign treatment of type\u20032 diabetes to preserve \u03b2\u2010cell function by early intervention is both necessary and important.\n\nIn a longitudinal study of obese Pima Indians by Weyer *et\u00a0al.*[^2^](#b2){ref-type=\"ref\"}, failure to augment \u03b2\u2010cell function to compensate for increased insulin demand as a result of decreased insulin sensitivity, due to weight gain for example, was found to be involved in deterioration of glucose homeostasis in type\u20032 diabetes. It is important to determine whether or not this pathogenesis is also applicable to lean type\u20032 diabetes in Asia. Sato *et\u00a0al.*[^3^](#b3){ref-type=\"ref\"} showed, by a cross\u2010sectional study using the oral glucose tolerance test, that \u03b2\u2010cells begin to deteriorate during normoglycemia with a minimal elevation of fasting plasma glucose in Japanese subjects. In our previous cross\u2010sectional study, endogenous insulin"
+"1. Introduction {#sec1-marinedrugs-15-00289}\n===============\n\nInsulin resistance is one of the hallmarks of type 2 diabetes (T2DM) and obesity. Improvement of insulin sensitivity is an indispensable step to alleviate T2DM. The first phase of T2DM is characterized by pancreatic beta-cell compensation, displaying hyperinsulinemia in response to insulin resistance. Beta-cell overworking frequently end in dysfunction and cell death. At this point, decreased blood insulin levels exacerbate the onset of T2DM due to both insulin deficiency and resistance \\[[@B1-marinedrugs-15-00289]\\].\n\nTo this day, pharmacological management of T2DM patients aims to achieve the best possible glycemic control, while avoiding hypoglycemia. However, the natural history of T2DM includes multiple dysfunctions affecting the \u03b1-cells, \u03b2-cells, liver, skeletal muscle, adipose tissue, the gastrointestinal tract, kidney and brain, what has been termed the ominous octet \\[[@B2-marinedrugs-15-00289]\\]. This complex scenario of the pathophysiology of T2DM requires a shift in the current paradigm for the treatment of the disease.\n\nA keystone in the management of diabetes is nutritional therapy along with regular physical activity. Considering that most people with T2DM are overweight or obese, weight loss is recommended to improve glycemic control \\[[@B3-marinedrugs-15-00289]\\]. In addition, regular physical activity has demonstrated significant health benefits \\[[@B4-marinedrugs-15-00289]\\]. When lifestyle interventions fail in the appropriate"
+"1. Introduction {#sec1}\n===============\n\nPhysic nut (*Jatropha curcas* L., family of Euphorbiaceae) is a common oil seed plant, its seeds contain about 30% of inedible oil, can be found in most tropical and subtropical countries of the world, and can grow up to 5\u2009m height \\[[@B1]\\]. *Jatropha curcas* is a native of Mexico and Central American region and was later introduced in many parts of the tropics and subtropics of the world \\[[@B1]\\]. It has low requirements to soil fertility and can grow under low rainfall conditions \\[[@B2]\\].\n\n*Jatropha curcas* is a multipurpose biodiesel plant adaptable to a wide range of edaphic and climatic conditions \\[[@B3]\\]. It is easily propagated by both generative (direct seeding) and vegetative (stem cuttings) techniques \\[[@B1], [@B3]--[@B5]\\], but plants propagated from stem cuttings do not develop a taproot. The plant only develops thin roots unable to grow deep in to the soil, which makes the plants more susceptible to uprooting by strong wind \\[[@B6]\\]. In agroforestry and intercropping systems, direct seeding is preferable over precultivated *J. curcas* plants, because the taproots of direct seeded plants deeply penetrate the soil layers \\[[@B7]\\], where it can assess extra nutrient resources and compete less with the roots"
+"INTRODUCTION\n============\n\nDermatomyositis as a connective tissue disease syndrome is an idiopathic inflammatory myopathy that affects cutaneous characteristics and striated muscles. The disorder is rare, with a prevalence of one to 9.63 cases per million in adults and one to 3.2 cases per million in children ([@R1]). It indicates solitarily or could be associated with other disorders of connective tissue (overlap syndrome) and also malignancy ([@R2]).\n\nThe etiology of dermatomyositis is not perfectly recognized yet however the most agreeable cause is reported due to genetics and particular genes over expression (e.g. type 1 interferon--inducible transcripts) leading to autoimmune responses that cloud be triggered by endotheliotropic viruses and underlying neoplasia. Uncommon drugs, namely the lipid-lowering agents, also have been reported to implicate dermatomyositis ([@R3]). Although the disease can onset at any age, 40 years is the most reported average age at the diagnosis, and women are affected almost three times more than men. Dermatomyositis can indicate in children too which is called juvenile dermatomyositis. It could onset at the average age of 5 to 14. These subgroups have a better prognosis than adults ([@R4], [@R5]).\n\nThe pathologic features of dermatomyositis including autoantibody production, endothelial damage, dysregulation of both complement and mannose"
+"Introduction {#Sec1}\n============\n\nSystemic Juvenile Idiopathic Arthritis (SJIA), formerly Still's Disease, is an autoinflammatory disorder known for marked systemic, predominantly innate immune activation \\[[@CR1]\\]. The adult counterpart is Adult Onset Still's Disease \\[[@CR2]\\]. About 15% of SJIA patients will also develop overt macrophage activation syndrome (MAS), an episodic hyper-inflammatory state caused by excessive activation and expansion of macrophages with hemophagocytic properties and predominantly CD8+ T lymphocytes \\[[@CR3]\\]. It is accompanied by a surge in IFN-\u03b3 and downstream chemokines \\[[@CR4]\\], as well as strikingly high serum levels of IL-18 \\[[@CR5]\\]. MAS has been associated with significant morbidity and mortality. For reasons poorly understood, and despite the availability of biological medications blocking IL-1 and IL-6 that have markedly improved overall disease control \\[[@CR6], [@CR7]\\], MAS rates have remained unchanged \\[[@CR8]--[@CR10]\\]. Additionally, children with SJIA and MAS are now increasingly diagnosed with life-threatening chronic complications, including hepatitis and lung disease (SJIA-LD) \\[[@CR11]--[@CR13]\\]. Evaluation of lung biopsies of these patients reveals severe inflammation with features of pulmonary alveolar proteinosis (PAP), endogenous lipoid pneumonia, and fibrosis \\[[@CR12], [@CR13]\\], all supporting that SJIA~\u2212~LD is chronic and likely diagnosed late when irreversible tissue damage has already occurred. Hence, there is a profound scientific gap of how to"
+"INTRODUCTION {#s1}\n============\n\nSeveral lines of evidence suggest the involvement of mitochondrial dysfunction in the aging process ([@BIO033852C15]; [@BIO033852C69]; [@BIO033852C71]). With aging, most eukaryotic organisms accumulate mitochondrial DNA (mtDNA) point mutations and/or deletions ([@BIO033852C38]; [@BIO033852C61]; [@BIO033852C105]). Evidence indicates that the mtDNA base substitution mutations in aged cells are primarily caused by DNA polymerase gamma (POLG) errors early in development that clonally expand over the lifespan ([@BIO033852C48]). But the cause of the mtDNA deletions present in aged cells is less clear. There is evidence that oxidative stress contributes to mtDNA deletion formation ([@BIO033852C106]) and that selective replication of deleted mtDNA molecules allows them to outcompete wild-type (WT) mtDNA molecules in just a few years. This may occur because mtDNA molecules with select mtDNA deletions elude feedback inhibition of the coupled processes of mtDNA transcription and replication ([@BIO033852C43]). With aging, mtDNA mutations build up to deleterious levels in individual cells in specific tissue regions, such as muscle fibers ([@BIO033852C58]), neurons in the substantia nigra region of the brain ([@BIO033852C44]), or in stem cells such as those present in the colonic crypts ([@BIO033852C57]). The mitochondrial dysfunction that occurs in stem cells of POLG exonuclease-deficient (also called mtDNA mutator) mice is likely responsible for"
+"Introduction {#s1}\n============\n\nAnemia is a condition, characterized by reduction in the red blood cell volume or decrease in the concentration of hemoglobin (Hb) in the blood [@pone.0114059-Almaz1]. Prevalence of anemia is high in the developing world. Its causes are multifactorial, ranging from micronutrient deficiencies such as iron, folate and vitamin B~12~ to infectious diseases such as malaria and worm infections [@pone.0114059-Lee1], [@pone.0114059-Osazuwa1]. According to the joint report of World Health Organization (WHO) and Center for Disease Control and prevention (CDC) in 2008, the global prevalence of anemia in school age children was 25.4% [@pone.0114059-WHO1]. The normal proliferation and differentiation of hematopoietic stem cells in the bone marrow requires several essential nutrients, such as iron, folate, and vitamin B~12~ [@pone.0114059-Manuel1]. Iron is a micronutrient that is essential for cell growth and differentiation [@pone.0114059-Stang1]. In the human body, when iron intake and absorption no longer meets the need of normal iron turnover and losses, and iron stores are exhausted then insufficient amounts of iron will be delivered to transferrin, which is the circulating transport protein of iron. This results in decreased transferrin saturation and when the depletion is sufficient to affect Hb synthesis, a state of iron deficiency anemia occurs [@pone.0114059-Hallberg1]."
+"Why is an elephant bigger than a mouse? Why, luckily, are our arms precisely the same size? While developmental genetics over the past 20 years has provided us with fascinating insights into how segments form, limbs bud, and axons find their targets, we have made little progress towards answering these obvious questions in biology. Rather than attempting to provide the answers, we will try to frame the questions in a developmental context and highlight some approaches towards answering them. Somewhat artificially, we will consider separately the mechanisms of cell, organ, and body size control.\n\nWhat Controls the Size of Eukaryotic Cells? {#s2}\n===========================================\n\nThe size of a cell depends on intrinsic and extrinsic factors. For example, cell size can vary dramatically with cell type---some neurons or glia cells are up to 1,000 times larger than epithelial cells. Cell size is also influenced by the number of genome sets (ploidy). A haploid Drosophila epithelial cell is only about half the size of a diploid cell. A polyploid salivary gland cell, on the other hand, is more than 1,000 times larger than a diploid cell. Amongst the extrinsic factors, the availability of nutrients and temperature are well known for their effect on"
+"Introduction\n============\n\nWith increasing human activities, particularly in agriculture, trade, and transport, the numbers of introductions of non-native species have increased dramatically during the second half of the 20th century (di Castri [@b11]). If introduced species are competitive and/or lack natural enemies, they may become invasive and result in major detrimental effects on native biodiversity (see reviews by Cox [@b17]; Whitney and Gabler [@b58]; Gren et\u00a0al. [@b26]; Kenis et\u00a0al. [@b35]). However, only 2--3% of introduced species become invasive after a successful colonization and naturalization in the local ecosystem (di Castri [@b11]). One reason for this low success rate may be that populations which are established from small numbers of individuals tend to lose genetic variation (Lande [@b36]; Lee [@b38]; Simberloff [@b52]). Increased effects of genetic drift and inbreeding in small populations tend to decrease heterozygosity and cause deleterious effects on individuals\\' fitness (inbreeding depression) (Lande [@b36]; Hedrick and Kalinowski [@b27]; Keller and Waller [@b34]). Inbreeding depression can, in addition, result in more pronounced losses of genetic variation over time causing a so-called 'extinction vortex' (Tanaka [@b55]).\n\nA major question in invasion biology is how newly founded and subsequently isolated populations overcome the detrimental effects of low genetic diversity,"
+"1. Introduction {#sec1}\n===============\n\nQuantitative research methods have long dominated conventional medical research: randomised clinical trials (RCTs) produce the highest levels of evidence and occupy the pinnacle of methods hierarchies (e.g., \\[[@B1]\\]). In complementary and alternative medicine (CAM) research RCTs and methods hierarchies are more contentious, not least due to perceived fundamental differences between CAM and biomedicine \\[[@B2], [@B3]\\]. Unlike new pharmaceutical therapies CAM is already being provided, practiced, and used in the community; many CAMs are best conceptualized as multifactorial complex interventions; CAMs can have diverse and unanticipated effects on people; and the underlying mechanisms of many CAMs are still being researched \\[[@B2], [@B3]\\]. These characteristics of CAM (a) make it difficult to design good clinical trials and (b) emphasise the need to understand patients\\' perspectives. CAM methodologists have thus called for greater plurality in research methods in general and more use of qualitative research methods in particular \\[[@B4]--[@B7]\\].\n\nMixed methods research uses qualitative and quantitative approaches (or \"components\") in a single study or a series of related studies. Combining qualitative and quantitative approaches permits researchers to address a wider range of research questions, to meet the diverse needs of different stakeholders, to realise the complementary strengths of both"
+"Introduction {#S1}\n============\n\nThe evolutionary emergence of lymphocytes with diversified antigen receptors allows the immune system to recognize and respond to a myriad of unknown antigens. However, despite the enormous number of B cells and T cells in the naive compartment, the frequency of B cells or T cells with any particular specificity is miniscule, necessitating efficient mechanisms to acquire and present antigens to the responding lymphocytes ([@B1]). Moreover, B and T cells of the same specificity must find one another and interact in a cognate way in order to differentiate into effector cells ([@B2]). In order to accomplish these goals, the immune system has evolved a system of secondary lymphoid organs ([@B3]).\n\nSecondary lymphoid organs, such as spleen, lymph nodes, Peyer's patches, and other mucosa-associated lymphoid tissues, recruit naive B and T cells from the blood and sample antigens from local non-lymphoid organs and mucosal surfaces, thereby allowing naive lymphocytes to efficiently peruse antigens from all the tissues of an entire organism without having to migrate through those tissues themselves ([@B4]). Moreover, secondary lymphoid organs are highly organized and contain architectural domains that facilitate sequential cellular interactions between antigen-presenting cells and lymphocytes and efficiently promote B and T cell"
+"Background\n==========\n\nThree main issues have been identified in addressing the problem of health care providers and their approach to people with disabilities: lack of disability-specific knowledge; discomfort with working with people with disabilities; and attitudes and misperceptions about disability. People with disabilities have cited negative attitudes and behaviors of health care providers as the most formidable barriers to accessing health care services\\[[@B1]-[@B5]\\].\n\nNegative attitudes held by health care providers about patients with disabilities may affect care that the patient receives. Although these attitudes and misconceptions are usually not overtly hostile, they may result in patients with disabilities not receiving appropriate treatment or not receiving indicated preventive care\\[[@B2],[@B6]-[@B8]\\]. For example, physicians might defer a pelvic exam in a patient with a disability due to the misconception that these patients are generally not sexually active. The assumption that a patient with a disability has a baseline quality of life which is low may lead the physician to defer aggressive treatment of acute problems\\[[@B3],[@B9]\\]. Adverse outcomes may be compounded and services available to patients may be limited if these subtle attitudes unduly affect the physician\\'s judgment and actions. \\[[@B5]\\]\n\nUntil recently, disability has not been appropriately addressed in medical school curricula \\[[@B2],[@B6],[@B10]-[@B14]\\]."
+"Introduction {#s1}\n============\n\nNarcolepsy is a chronic sleep disorder, characterized by excessive daytime sleepiness with frequent uncontrollable sleep attacks (Silber et al., [@B73]; Dauvilliers et al., [@B22]). Other symptoms include rapid eye movement (REM) sleep abnormalities such as sleep paralysis, hypnagogic (upon falling asleep) or hypnopompic (upon awakening) hallucinations, and nocturnal dyssomnia with fragmented sleep and frequent awakenings. Most narcolepsy patients also suffer from cataplexy, a sudden reduction or loss of muscular tone not accompanied by loss of consciousness caused by the loss of hypocretin-1 (orexin) producing neurons in the lateral hypothalamus (Lin et al., [@B57]; Thannickal et al., [@B82]; Nishino et al., [@B65]). In addition to the sleep-related changes summarized here, the loss of hypocretin-1 is also thought to be an underlying cause to the changes in cognition observed in patients with narcolepsy (Fulda and Schulz, [@B31]; Rieger et al., [@B68]; Naumann et al., [@B63]; Bayard et al., [@B6]).\n\nResults from previous functional and structural neuroimaging studies would suggest that the loss of hypocretin-1 has numerous downstream effects in terms of both resting state glucose metabolism and perfusion and reduction in cortical gray matter. Specifically, studies investigating narcolepsy with positron emission tomography (PET) and single photon emission computed tomography"
+"1. Introduction\n===============\n\nDistal radius fractures (DRFs) are the second most prevalent fracture in elderly individuals and affect more than 85,000 older Americans each year.^\\[[@R1],[@R2]\\]^ DRFs are associated with substantial increases in healthcare consumption. In the 6-month period following a DRF, the average Medicare beneficiary incurs \\$7700 more in charges relative to prefracture levels.^\\[[@R3],[@R4]\\]^ Annually, DRFs cost \\$535 million in direct medical expenses alone.^\\[[@R5],[@R6]\\]^ The fractures in different age groups need to be treated differently and properly. When displaced DRFs occur in young active patients, open reduction and internal fixation is commonly selected as the definitive treatment.^\\[[@R7],[@R8]\\]^ However, when similar fractures occur among the elderly, the most appropriate form of management is less clear due to a number of factors, such as decreased functional demands, higher perioperative risks, poorer bone quality, etc.^\\[[@R9],[@R10]\\]^\n\nBoth conservative (such as casting) and operative treatments (such as open reduction internal fixation, external fixation, intramedullary fixation, or percutaneous pinning) had been advocated as successful treatments for distal radius fractures. Casting is noninvasive but malunion or fracture collapse can ensue. Although several surgical options are available, the 2009 American Academy of Orthopedic Surgeons clinical practice guideline was unable to recommend for or against any one specific surgical"
+"Introduction {#s1}\n============\n\nTraditionally in mental health, there has been a strong emphasis on defining recovery in terms of symptom resolution. However, there is increasing recognition that defining remission solely on the basis of clinical symptoms is inadequate. Frequently, these 'remitted' patients with diagnoses of major depression [@pone.0058176-Zimmerman1], bipolar disorder [@pone.0058176-Fagiolini1] or psychosis [@pone.0058176-Oorschot1] remain functionally impaired. Zimmerman et al. [@pone.0058176-Zimmerman1] demonstrated that half of patients with major depression who were classified as remitted based on rating scale criteria did not consider themselves to be *in remission*. Critically, these individuals were significantly more impaired in their work performance and social relationships. It is likely that subsyndromal symptoms, particularly depression [@pone.0058176-Fagiolini1] and negative symptoms [@pone.0058176-Bowie1], contribute to these 'residual' functional deficits across the major psychiatric disorders. Of significance, cognitive vulnerabilities may *additionally* contribute to persisting disability given evidence that neuropsychological dysfunction predicts later socio-occupational functioning, over and above symptom levels, as observed in depression [@pone.0058176-Withall1], bipolar disorder [@pone.0058176-Martino1], and schizophrenia [@pone.0058176-Green1].\n\nWhile in chronic cohorts psychotic disorders are associated with more pronounced neuropsychological and psychosocial disability than affective disorders [@pone.0058176-Simonsen1], neuropsychological performance appears to predict functional outcome irrespective of diagnosis [@pone.0058176-Simonsen1]. Accordingly, neuropsychological deficits have been proposed as endophenotypes that cut"
+"Background {#Sec1}\n==========\n\nTetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease (CHD). In neglected untreated cases, the mortality rate is about 33% in the first year of life and about 50% in the first 3\u2009years of life \\[[@CR1]\\]. However, advances in diagnosis, surgical techniques, and postoperative treatment have led to increasing number of patients reaching adulthood with a dramatic increase in survival rate to almost 90% at 30\u2009years. TOF was originally named after the French scientist \"Arthur Louis Etienne Fallot\" who published a paper in 1988 entitled \"Contribution a 'l'anatomie pathologique de la maladie bleue\" \\[[@CR2]\\]. He described four anatomical features that were almost always present in all post-mortem specimens of the blue patients \"la maladie bleue\" in his own words. These anatomical features consist of a tetrad of (1) ventricular septal defect (VSD), (2) aortic overriding, (3) right ventricular outflow tract (RVOT) obstruction, and (4) right ventricular (RV) hypertrophy \\[[@CR3]\\].\n\nPathophysiology {#Sec2}\n---------------\n\nThe main pathophysiological features of TOF are the antero-cephalic deviation of the cono-ventricular septum and hypertrophy of the septoparietal trabeculations of the RVOT \\[[@CR3]\\]. The antero-cephalic deviation of the cono-ventricular septum results in a mal-aligned VSD in continuity of the"
+"Introduction {#Sec1}\n============\n\nThere are approximately 19 million new cases of sepsis worldwide each year. Among them, more than one quarter of patients die. In addition, there is an upward trend in sepsis incidence; sepsis and septic shock have become serious health problems \\[[@CR1],[@CR2]\\]. Heparin was first applied in the treatment of sepsis in 1966. By evaluating a novel therapeutic concept in clinical practice, Martinez *et al*. found that lower mortality among sepsis patients may be related to the use of heparin, steroids, and vasoactive drugs \\[[@CR3]\\], which inspired many researchers to evaluate heparin for sepsis treatment. Therefore, many clinical studies have been conducted since that first report. Currently, the efficacy and safety of heparin in sepsis patients remain controversial, with some authors suggesting that heparin may reduce 28-day mortality \\[[@CR4],[@CR5]\\] and others reporting no effect on 28-day mortality \\[[@CR6]-[@CR9]\\]. We conducted a meta-analysis of studies on heparin treatment for sepsis to evaluate the effect of heparin on 28-day mortality and the occurrence of bleeding events in patients with sepsis.\n\nMethods {#Sec2}\n=======\n\nSearch strategy for identification of studies {#Sec3}\n---------------------------------------------\n\nWe conducted a systematic review and several meta-analyses of the existing literature according to the methods recommended in the"
+"Introduction\n============\n\nCongenital left ventricular aneurysm (CVA) is a rare clinical entity, defined as having a wide orifice connection to the ventricular cavity.[@B1][@B2] The etiology is largely unknown but several theories exist, such as intrinsic abnormality during embryogenesis, infection and ischemia.[@B3][@B4] The advancement of echocardiography has led to early diagnosis, including prenatal, such that several cases have been diagnosed before birth and were reported.[@B1][@B3][@B5] We present one such case of a neonate prenatally diagnosed with a large CVA and left ventricular (LV) dysfunction, who was successfully treated with a modified Damus-Kaye-Stansel (DKS)/Dor procedure.\n\nCase\n====\n\nA 33-year-old woman was referred at 21 weeks\\' gestation with abnormal fetal echocardiographic findings, showing a large apical LV aneurysm (16.2\u00d77.7 mm) ([Fig. 1](#F1){ref-type=\"fig\"}). During follow-up, LV aneurysmal dilatation had progressed (41\u00d721 mm) with newly developed mitral regurgitation. At 33+6 weeks\\' gestation there was antegrade aortic flow combined with aortic regurgitation (AR). Due to progressive LV dysfunction, urgent caesarian section was performed. A female infant weighing 3.6 kg was born at 37+6 weeks\\' gestation. Apgar score was 2 and 6 at 1 and 5 minutes, respectively. Postnatal echocardiography showed similar findings of fetal echocardiography: a large LV apical aneurysm with maximum diameter of 41\u00d723 mm"
+"1. Introduction {#sec1-ijms-21-00897}\n===============\n\nHepatitis C virus (HCV) is a major infectious disease that can cause liver cirrhosis and hepatoma. It comprises a positive-sense single-stranded RNA that encodes three structural proteins (core, E1, and E2) and seven nonstructural proteins (p7, NS2, NS3, NS4A, NS4B, NS5A, and NS5B) \\[[@B1-ijms-21-00897]\\]. There are seven genotypes with many subtypes, and the most common genotypes are known as genotypes 1 and 2 \\[[@B2-ijms-21-00897]\\]. For this reason, the 1a H77, 1b BK, 2a J6, and 2a JFH-1 strains have been mainly studied to identify the exact mechanisms of the HCV life cycle \\[[@B3-ijms-21-00897]\\].\n\nHCV is a good representative example of a virus that interacts with host lipids \\[[@B4-ijms-21-00897]\\]. In contrast to other viruses that bud from the plasma membrane (e.g., HIV), its life cycle is tightly linked to host lipid metabolism. In terms of its budding process, it has been shown that HCV can interact with lipid rafts composed of saturated lipids with cholesterol \\[[@B5-ijms-21-00897]\\]. Lipid rafts are predominantly located in the plasma membrane but are also located in the endoplasmic reticulum (ER) membrane \\[[@B6-ijms-21-00897]\\]. HCV is known to bud from these in an immature form and fuse with lipid droplets (LDs) to form mature particles"
+"Background {#Sec1}\n==========\n\nAsthma affects people of all ethnicities and ages and there has been a substantial increase in the prevalence of asthma over the past few decades, with current estimates of approximately 300 million people suffering from the disease worldwide \\[[@CR1]\\]. Asthma is characterised by coughing, shortness of breath, chest tightness and wheezing, often triggered by exposure to allergens and foreign pathogens \\[[@CR1]\\]. The initial response consists primarily of airway smooth muscle constriction and airway inflammation (oedema, inflammatory cell infiltration, increased airway secretions). Whereas more chronic responses such as structural remodelling of the airway including smooth muscle and sub-mucosal gland hyperplasia and hypertrophy, extracellular matrix (ECM) deposition and angiogenesis are generally thought to occur in parallel with inflammatory responses \\[[@CR1]\\].\n\nThe airway epithelium is the interface between the respirable environment and the sub-mucosa and acts as the first defence line against inhaled noxious agents and aeroallergens \\[[@CR2]\\]. The epithelium of conducting airways is pseudo-stratified and consists of ciliated columnar epithelial cells, goblet cells, intermediate columnar epithelial cells, side population cells, serous cells, and basal cells \\[[@CR3]\\]. The epithelium of asthmatics presents several structural and functional abnormalities, including a greater proportion of resident stem cells and basal cells, goblet-cell hyperplasia"
+"The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n\nIntroduction\n============\n\nSurgical management of sellar and suprasellar lesions, including large pituitary tumors, which have cavernous and middle fossa extension may be problematic. Traditionally, transcranial surgery has been used in pituitary adenomas that are thought to be difficult to resect via the transsphenoidal approach because of retrosellar, retrochiasmatic, subfrontal, or temporal extension; however, the transsphenoidal approach is the preferred method when feasible because there is a higher likelihood of preserving normal pituitary and visual function with less morbidity \\[[@REF1]-[@REF6]\\].\n\nThe authors report a case of a patient who underwent resection of a large pituitary adenoma with tumor encasement of the internal carotid arteries bilaterally and lateral extension to the left middle fossa. An intraoperative Valsalva maneuver was"
+"Background\n==========\n\nEukaryotic genomes are pervasively transcribed \\[[@B1],[@B2]\\] with evidence for up to three-quarters of nucleotides in the human genome being expressed in at least one cell type during development \\[[@B2]\\]. Transcripts lacking an apparent open reading frame are often classified simply based on their length, the absence of protein-coding potential and their location in the genome relative to protein-coding genes \\[[@B3],[@B4]\\]. An intriguing class of noncoding transcripts are those exceeding 200 nucleotides in length and transcribed from loci that are intergenic relative to protein-coding genes (intergenic long noncoding RNAs (lncRNAs)). At least 50,000 lncRNAs are expressed from intergenic regions of the human genome, more than twice the number of protein-coding genes \\[[@B5]\\]. Compared to protein-coding transcripts, intergenic lncRNAs are generally less abundant and their expression is more spatially and temporally restricted \\[[@B4],[@B6]\\]. Genome-wide analysis of mammalian intergenic lncRNA sequence \\[[@B7],[@B8]\\] and transcription \\[[@B9],[@B10]\\] has revealed that, in general, these loci have been conserved during evolution, albeit at substantially lower levels than protein-coding genes, suggesting that at least some intergenic lncRNAs may have conserved biological roles. Biological functions attributed to the handful of well-characterized intergenic lncRNAs are diverse, ranging from transcriptional control to post-transcriptional modulation of gene expression (for recent"
+"The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n\nIntroduction\n============\n\nBesides improving the quality of life, joint replacements are considered as life-enhancing surgical procedures \\[[@REF1]\\]. About 719000 knee replacements were performed in the United States in 2010 alone \\[[@REF2]\\]. According to previous reports, 1%-2% of joint replacements eventually become infected \\[[@REF3]\\]. Prosthetic joint infection/periprosthetic joint infection involves prosthesis and adjacent tissues \\[[@REF1]\\]. While Gram-positive Staphylococcus is a common culprit, enteroinvasive Gram-negative organisms (Salmonella) can rarely infect replacement prosthesis, especially in immunocompromised individuals \\[[@REF4]-[@REF5]\\]. We report a case of a prosthetic joint infection caused by *Salmonella\u00a0enteritidis* in an immunocompetent male.\n\nCase presentation\n=================\n\nA 79-year-old male presented with pain and swollen left knee. He was febrile and unable to weight bear on the left knee"
+"Introduction {#Sec1}\n============\n\nThe trade-off between parental reproductive effort and survival may lead to negative fitness consequences for adults (Williams [@CR72]; Trivers [@CR68]; Dijkstra et al. [@CR14]; Stearns [@CR65]). The basis for this relationship is, however, still poorly understood. Survival is an attribute of fitness, which may be difficult to quantify. In contrast, reproduction is a clearly defined physiological event with a starting and an ending point, which can be evaluated by measuring parental effort and costs (Lochmiller and Deerenberg [@CR32]). Previous explanations of the trade-off focussed on physical deterioration during breeding attempts (Drent and Daan [@CR15]) or accelerated senescence of an organism (Partridge [@CR49]). Physiological explanations assume that reproduction and survival compete for limited energy and nutrients (Harshman and Zera [@CR22]). However, external factors may also interact with this trade-off. Increased predation risk of parents, protecting offspring, as well as frequent infections during the breeding season may affect the parents' survival (Magnhagen [@CR34]; Gustafsson et al. [@CR18]; Saino et al. [@CR57]).\n\nIt is worth emphasising that immunity is one of the major physiological mechanisms, which determine host survival (Lochmiller and Deerenberg [@CR32]). The immune system is a defence mechanism to control and fight any parasitic or pathogenic infection, and"
+"INTRODUCTION\n============\n\nThe adverse health effects of air pollution on respiratory and cardiovascular diseases are well known to the public. Regulation and monitoring of air pollution are performed at both the national and international levels. Particulate matter (PM) is one type of air pollutant. It is not a specific chemical entity, unlike other commonly known pollutants such as ozone, sulphur dioxide, and nitrogen dioxide. It is a physical category of dust with different components mixed together \\[[@b1-jpmph-49-4-205]\\]. The particle size determines the different categorizations: PM~10~ (less than 10 \u03bcm aerodynamic diameter) and PM~2.5~ (less than 2.5 \u03bcm aerodynamic diameter). PM~2.5~ is also known as fine PM.\n\nPM~2.5~ has been reported to play a major role in increasing the chance of mortality due to cardiovascular diseases because it can penetrate the capillary vessel of the lungs and reach the alveoli \\[[@b2-jpmph-49-4-205],[@b3-jpmph-49-4-205]\\]. Extensive research has been conducted on the association between PM~2.5~ and respiratory diseases including asthma. Asthma is a syndrome in which reversible respiratory obstruction occurs and is characterized by hypersensitiveness to allergens. When stimulated, a person experiences wheezing and dyspnea. In most cases, asthma is caused by a genetic predisposition and is triggered by environmental allergens.\n\nThe prevalence rate of"
+"Introduction {#Sec1}\n============\n\nCancer is one of the pathological scenarios where apoptosis is inactivated, resulting in accumulation of malignant cells that will not die. Ovarian cancer is the seventh most common cancer in women worldwide, which accounts for nearly 4% of all new cases of cancer in women. This lethal malignancy usually diagnosed at later stage with a 5 years survival rate of below 30%. Since most of the ovarian cancer cases are diagnosed after wide spreading of tumors within the peritoneal cavity, it is restraining the effectiveness of chemotherapy, and associated death is believed to be therapy-resistant metastasis^[@CR1],\\ [@CR2]^. The prognosis is usually poor for ovarian cancer patients, because the disease reaching an advanced stage before it is discovered^[@CR3]^. Despite overall declining death rates for cervical and uterus cancers, the annual report of ovarian cancer mortality has risen by 250% since 1930^[@CR4]^. Primary cytoreductive surgery followed by chemotherapy with anticancer agents is the standard treatment regimen for patients with ovarian cancer, which improved survivals. Nevertheless, most of the patients with advanced cancer will eventually relapse and die of their cancer^[@CR2],\\ [@CR5]^. A preliminary study showed improved efficacy of chemotherapy and normalized cancer biomarkers following a high-dose of antioxidant (containing"
+"INTRODUCTION {#s1}\n============\n\nAvailability of antiretroviral therapy (ART) has significantly improved the length and quality of life for children living with HIV in sub-Saharan Africa.[@R1],[@R2] The World Health Organization recommends that school-aged children be fully informed and younger children told partial information about their diagnosis.[@R3] Children who learn their HIV status in structured, age appropriate, and supportive ways may be more likely to adhere to treatment and less likely to become depressed.[@R4]--[@R13] Yet, child disclosure remains a challenge in sub-Saharan Africa.[@R4],[@R8],[@R9],[@R14],[@R15] Caregivers often feel unprepared to disclose to children, fearing blame, negative judgment, resentment, stigma resulting from the child telling others, or that disclosure will psychologically harm the child.[@R4],[@R7],[@R8],[@R11],[@R14],[@R16]--[@R25] Caregivers often desire health care worker (HCW) support for the disclosure process.[@R7],[@R8],[@R18],[@R26]--[@R28] However, HCWs often do not feel prepared to fulfill this role,[@R4],[@R17],[@R18],[@R27] and there are few structured interventions to help caregivers and HCWs with the disclosure process.[@R4],[@R5],[@R9],[@R18],[@R24],[@R27],[@R29]\n\nNamibia has an antenatal HIV prevalence of nearly 18%[@R30] and over 10,000 children have initiated ART.[@R31] With scale-up of access to ART, HCWs reported experiencing high levels of stress due to their own unpreparedness for talking with pediatric patients about adherence, their HIV status, and caregiver resistance to pediatric disclosure. In response, the"
+"1. Metformin: Historical re-purposing and pleiotropy {#s0005}\n====================================================\n\nIt is a lesser-known fact that metformin was originally introduced as an anti-influenza drug and that glucose-lowering was only one of its side effects [@b0005]. The many pleiotropic effects of metformin and its widespread utility in medicine today have led scientists to call it the aspirin of the 21st century [@b0010].\n\nIn the current scenario, when there is no specific agent against COVID-19, and when re-purposing of drugs is the primary weapon, we suggest that metformin be used as one of the drugs to combat the virus.\n\n2. Metformin: Mechanism of action on molecular level {#s0010}\n====================================================\n\nMetformin activates AMP-activated protein kinase (AMPK) in hepatocytes by causing its phosphorylation. This is the main mechanism by which metformin brings about favourable effects on glucose and lipid metabolism [@b0015].\n\n2.1. Metformin-AMPK-ACE2-SARS-CoV-2 {#s0015}\n-----------------------------------\n\nThe juggernaut virus, SARS-CoV-2, that has led to the deaths of over 1.7 lakh people across the world uses angiotensin-converting enzyme 2 (ACE2) as its receptor. It enters the human body through interaction between its spike proteins (S1) and the N-terminal region of ACE2 [@b0020], [@b0025]. The receptor binding domain (RBD) of the virus binds with the protease domain (PD) of"
+"G-protein coupled receptors constitute the largest protein family in the human proteome (over 800 members). Their diversity and central role in cellular signaling makes them important drug targets. Indeed, GPCRs are the targets of about 40% of all therapeutic drugs, including 25% of the top-selling ones[@b1]. Understanding molecular mechanisms of GPCR signaling is of both fundamental scientific impact and high medical potential. Biophysical studies on these receptors are particularly challenging because they are transmembrane proteins that require the appropriate hydrophobic lipid environment for proper function. Following their isolation from cellular membranes using detergents that preserve their function, reconstitution in lipid membranes is necessary to maintain their stability. Their reconstitution from a detergent-stabilized state into a well-defined artificial lipid model system of controlled lipid composition for *in vitro* studies[@b2][@b3] can be achieved by dilution or detergent removal using dialysis, gel filtration, hydrophobic absorption using Bio-beads, or complexation by cyclodextrins. Regardless of the method used, the process itself remains most often intractable (with the exception of an indirect Isothermal Titration Calorimetry approach reported by S. Keller and coworkers based on phase transition monitoring[@b4]). Herein we demonstrate that Plasmon Waveguide Resonance (PWR) spectroscopy can be used to directly follow the reconstitution of a"
+"Multilingual abstracts {#Sec14}\n======================\n\nPlease see Additional file [1](#MOESM1){ref-type=\"media\"} translations of the abstract into the five official working languages of the United Nations.\n\nBackground {#Sec15}\n==========\n\nNeglected tropical diseases (NTDs) are a heterogeneous group of mainly chronic, debilitating and often stigmatizing diseases that largely affects low-income and politically marginalized people living in rural and urban areas of tropical and subtropical countries, especially in developing regions of sub-Saharan Africa, Asia, and Latin America \\[[@CR1]--[@CR3]\\].\n\nCurrently, there are 17 NTDs prioritized by the World Health Organization (WHO) \\[[@CR1]\\]. These NTDs are endemic in 149 countries and affect an estimated 1.4 billion people. NTDs constitute a very significant burden on the already strained public health systems, social and the economies of many developing countries, therefore may trap people in a vicious cycle of poverty and disease \\[[@CR4], [@CR5]\\]. These diseases are also associated with disfigurement or other sequelae of long-term illness, negative effects on the course and outcome of pregnancy, delayed physical and intellectual development during childhood and reduced productive capacity in older age \\[[@CR2]\\].\n\nThe causative agents of NTDs (henceforth NTD pathogens) represent a wide phylogenetic sampling of parasites, protozoa, viruses and bacteria. The main parasitic NTDs include cystiercosis, dracunculiasis, echinococcosis, foodborne"
+"INTRODUCTION\n============\n\nBone is an important organ to perform exercise by support the body and has various functions such as a store for calcium and other minerals which is essential for sustaining life, and hematopoietic action creating new blood \\[[@b1-jenb-18-1-69]\\]. In addition, bone is a highly active tissue in the body, which is sensitive to external mechanical stimuli as well as internal metabolic changes. So it occurs changes in bone mineral density (BMD) and bone metabolism. These changes in bone metabolism are influenced by the environmental factor such as gene \\[[@b2-jenb-18-1-69]\\] and nutrition \\[[@b3-jenb-18-1-69]\\], and the exercise do the most important role to increase and maintain bone mass in particular \\[[@b4-jenb-18-1-69]\\]. That is, the inactivity environment such as space flight \\[[@b5-jenb-18-1-69]\\] or weightlessness \\[[@b6-jenb-18-1-69]\\] stimulates to reduce bone mass, but it is known that regular exercise is suitable to maintain or increase bone mass \\[[@b7-jenb-18-1-69]\\]. Nuti *et al*. \\[[@b8-jenb-18-1-69]\\] also prove that even the period of growth and the adolescence, elderly group has a different form of exercise, exercise is effective on enhancing BMD. However, most of the research is usually focused on \\'phenomena\\' that reveal a degree of changes in BMD as the effects of exercise, but it is"
+"In collaboration with [C&EN](http://cen.acs.org/index.html).\n\nChemist [Jas Pal Badyal](https://community.dur.ac.uk/jps.badyal/) is committed to solving big problems with very small tools: layers of functional molecules only a few nanometers thick. His ultrathin coatings have entered the marketplace on clothing, footwear, and electronics. They impart water-repellent, antibacterial abilities to around three-quarters of the world's hearing aids and more than 100 million cell phones.\n\nAfter launching three successful high-tech start-ups, the Durham University professor is now tackling social problems in developing nations. For example, he wants to develop materials that can harvest and purify water, a need for countries in the developing world.\n\n![](oc-2018-001546_0001){#gr1}\n\nHow do you make your liquid-repellent nanocoatings? {#sec2}\n===================================================\n\nWe essentially control chemical reactions that occur on solid surfaces using plasma discharges, which are clouds of ionized atoms. One way we do it is repeatedly to expose the surface to a very short pulse, usually microseconds, of plasma discharge followed by a longer off time lasting milliseconds. The substrate is in a plasma chamber surrounded by a gaseous precursor---say, a molecule with a double bond. Passing electrical current through the gas creates plasma. The plasma pulses generate free-radical sites on many types of surfaces. In the periods between the pulses, you"
+"Introduction\n============\n\nMyxopapillary ependymoma was first described as a subtype of ependymoma by Kernohan \\[[@B1]\\] in 1932. Myxopapillary ependymoma is a tumor that typically arises in the filum terminale and conus medullaris \\[[@B1],[@B2]\\]. This tumor has a significantly better prognosis than other ependymomas, because it is slow-growing, unlikely to metastasize and does not tend to infiltrate neural tissues \\[[@B3]\\]. Intracranial ependymomas represent 6%-9% of primary central nervous system neoplasms and generally present in young children, with a mean age of four-year. Spinal myxopapillary ependymomas are rarer than intracranial types. Myxopapillary ependymomas generally present within the spinal canals of adults. Spinal myxopapillary ependymomas in children \\<5 years requiring surgery are very rare.\n\nHere we describe a rare case of a 5-year-old boy who presented with cauda equina compression due to myxopapillary ependymoma, which was treated with subtotal resection and postoperative radiation therapy.\n\nCase Report\n===========\n\nA 5-year-old boy presented with a history of right popliteal pain and abnormal gait that began after March 2000, four months prior to admission. Three months before admission, the patient visited a neighborhood hospital complaining of right popliteal pain, pain in the right hip and an abnormal gait. A magnetic resonance imaging (MRI) scan of the"
+"1. Introduction {#sec1}\n===============\n\nTwenty-four percent of Canadians are obese and a further 37% are overweight using measured height and weight data from the 2007--2009 Canadian Health Measures Survey \\[[@B1]\\]. Further, over half (58%) of the Canadian women aged 40 to 59 years are considered overweight or obese \\[[@B3]\\]. Poor eating habits and physical inactivity contribute to the increasing prevalence of overweight and obese individuals \\[[@B2]\\]. The majority of middle-aged women do not regularly participate in exercise and/or fail to report healthy nutrition practices such as consuming five or more vegetables and fruits per day \\[[@B4], [@B5]\\]. Evidence also suggests a positive trend with aging and weight gain \\[[@B1]\\]. These trends mark the need to identify lifestyle interventions that address these healthy behaviours and their contribution to addressing midlife weight gain in women, to minimize the risks for obesity and related cardiometabolic complications.\n\nIn their midlife, women undergo the biologic transition into menopause. This menopause transition is divided into several stages and clinically has been categorized by international criteria developed to help assess women\\'s reproductive stage \\[[@B6]\\]. The early menopause transition stage is specifically defined by menstrual cycles varying by seven or more days from regular cycles; the next stage"
+"Introduction {#Sec1}\n============\n\nContrary to general perceptions, sedentary behaviour (SB) does not necessarily reflect a lack of physical activity (PA) (Sedentary Behaviour Research Network [@CR89]). Instead, SB is defined as any waking behaviour characterized by an energy expenditure \u22641.5 metabolic equivalent of task (MET) while in a seated or reclined posture (Sedentary Behaviour Research Network [@CR89]). Currently, time spent sitting is increasing in modern societies, presumably linked to activities related to work, leisure or commuting. Previous research has shown that higher sitting time is related to poorer health (Gardiner et al. [@CR37]; Inoue et al. [@CR54]). Recent health improvement strategies have focused on increasing PA (Kikuchi et al. [@CR59]). While PA contributes to healthy ageing and plays a key role in the prevention of non-communicable diseases and disability, including cardiovascular disease, cancer, metabolic syndrome, mental disorders, musculoskeletal diseases and even all-cause mortality (de Rezende et al. [@CR22]; Gorman et al. [@CR44]; Gennuso et al. [@CR40]), studies that controlled for PA intensity provide evidence that also (prolonged) SB is an independent determinant of health (Gennuso et al. [@CR39]; Gorman et al. [@CR44]; de Rezende et al. [@CR23]; Gianoudis et al. [@CR41]). This has led to the proposal of a novel stratagem"
+"Pneumonia continues to provide a huge global burden of disease \\[[1](#CIT0001)\\]. Although the incidence of pneumonia increases with increasing age, it is not widely appreciated that pneumonia is also the world's biggest killer of young children \\[[2](#CIT0002)\\].\n\nA wide variety of microorganisms are listed as pneumonia pathogens \\[[3](#CIT0003)\\], and identification of pneumonia etiology is useful for both patient management and surveillance purposes. However, despite increased recognition of the burden of disease and advances in effective vaccines against major pneumonia pathogens, we continue to struggle in our efforts to identify the pathogens that cause pneumonia in individual patients \\[[4](#CIT0004)\\]. Indeed, historically, we have been unable to define a causative pathogen in a significant proportion of pneumonia episodes, even with the best methods. Determining the microbial etiology of pneumonia in children has been a particular challenge \\[[5](#CIT0005)\\]. The implications of poor pneumonia diagnostics extend to the population level as well; assessment of interventions, such as vaccines, is hindered by suboptimal measures of disease impact that often rely on accurate surveillance data \\[[6](#CIT0006)\\].\n\nWhy is it so difficult to determine the microbial etiology of pneumonia? The inability to obtain good quality specimens from the lower respiratory tract is one fundamental problem with pneumonia"
+"1. Introduction {#sec1-ijerph-13-01033}\n===============\n\nDisability is a common health outcome across the world, in both developed and developing countries \\[[@B1-ijerph-13-01033]\\]. The World Health Organization (WHO) estimates that 650 million people aged 18 and over worldwide live with disabilities \\[[@B1-ijerph-13-01033]\\]. Many people with disabilities across the world do not have equal access to health care, education, and employment, do not receive the disability-related services that they require, and experience exclusion from daily life activities \\[[@B1-ijerph-13-01033]\\]. There are about 92 million people with very significant disabilities in the world, and the presence of multiple disabilities can make the management of health care and rehabilitation services more complicate than single disability can \\[[@B1-ijerph-13-01033]\\]. Although the definition of disabilities was narrower than in other countries in China, it is estimated that approximately 85 million people live with disabilities or another condition that affects their daily lives and social activities \\[[@B2-ijerph-13-01033]\\]. Zheng et al. estimated the number of disabled people was increasing from 52.7 million to 84.6 million, and the weighted prevalence of disabilities also increased from 4.9% to 6.5% accompanying aggressive economic development \\[[@B3-ijerph-13-01033]\\]. Therefore, specific social network, policy and programs are needed to improve the living and health status of those with disabilities,"
+"Introduction\n============\n\nThe oligotrophic karstic Lake Ohrid is located in the western part of the Balkan Peninsula on the Macedonian-Albanian frontier. With a limnological age of 2-5 million years it is considered to be one of the oldest lakes in Europe ([@B1]). The lake is characterized by a high degree of biodiversity and endemicity in several groups of organisms ([@B52], [@B1]). With more than 210 known endemic species it is probably the most biodiverse lake in the world, at least when one takes surface area into account ([@B1]). Due to its peculiarities, Lake Ohrid is considered to be a key site for biodiversity and speciation research ([@B1]).\n\nThe first studies on the triclad fauna of the Ohrid area date back to the 1920's with the first description of several new species of *Phagocata* Leidy, 1847 and *Dendrocoelum* \u00d6rsted, 1844 (cf. [@B54]). Further important researches carried out during the 20th century, mainly by [@B51], [@B52], [@B53]) and [@B31], contributed to a better knowledge of this very interesting planarian fauna. In his valuable monograph, [@B52] in particular pointed out the extraordinary biogeographical situation of the endemic triclads in the Ohrid region.\n\nIn this paper we report on a new species of freshwater"
+"Introduction {#Sec1}\n============\n\nSkeletal muscles are composed of cells of different developmental origins. In vertebrate limbs, muscle fibres as well as muscle stem cells (termed satellite cells in the adult) originate from the somitic mesoderm^[@CR1]--[@CR3]^, while muscle connective tissue (MCT) originates from the lateral plate mesoderm^[@CR1],\\ [@CR2]^. A mutual interdependence and cross-talk between both cell types exist during developmental and adult regenerative myogenesis. During development the myogenic progenitors migrate from the somites to the nascent limb buds, where they form initial premuscle masses that amplify and then subdivide into individual muscles with each muscle having an individual shape and size^[@CR4],\\ [@CR5]^. It is widely accepted that vertebrate myogenic cells do not contain intrinsic information that govern their place and time of differentiation^[@CR6],\\ [@CR7]^. Instead, there is long-standing evidence that limb muscle patterning is mediated by extrinsic signals from local lateral plate mesoderm derived cells^[@CR8]--[@CR10]^. This non-cell autonomous function is most likely mediated by MCT cells providing local but still undefined cues for myogenic cell proliferation, differentiation, survival and local migration^[@CR11]--[@CR13]^.\n\nMCT is often used as a collective term for different interstitial cell types, i.e. cells that can be found between the myofibres in adult muscle. Muscle interstitial cells comprise Tcf4^+^"
+"Introduction {#S0001}\n============\n\nUndergraduate and postgraduate medical education is constantly evolving from simple knowledge acquisition to medical-based education.[@CIT0001] These changes are attributed to several elements including changes in community expectations, advancement in medical sciences, shift in a health care environment, and changes in the physician role.[@CIT0002] Learning interactions and experiences are not prioritized among patients, as a result, such changes and patient safety and quality of care are highly prioritized in patient care.[@CIT0003] Competency-based medical education (CBME)[@CIT0004] is defined as \"an outcome-based approach to the design, implementation, assessment, and evaluation of medical education programs, using an organizing framework of competencies\". The knowledge and skills through such an approach should then be demonstrated through clinical practice.[@CIT0004] In Saudi Arabia, inclination toward improvement in healthcare services led to modifications in medical education strategies towards CMBE.[@CIT0005] This shift has adopted a national-based framework, namely SaudiMEDs framework ([Figure 1](#F0001){ref-type=\"fig\"}).Figure 1Saudi MEDs framework.\n\nAccording to the SaudiMEDs framework, communication and collaboration competency is a core domain of medical competencies and is defined as \"the ability to communicate effectively with patients and their relatives and to practice collaborative care by working in partnership within a multi-professional team\".[@CIT0006] Communication skill is not just a natural gift, rather"
+"1. Introduction {#sec1}\n===============\n\nA time record consisting of beat-to-beat RR intervals is referred to as the heart rate tachogram. This forms the basis for a number of metrics of heart rate variability (HRV). The simplest measures of HRV are based on variance determined over a range of time periods. More complex measures can be derived from power spectrum density (PSD) estimations. The two most commonly used PSDs are the Welch Periodogram, based on the DFT, and the AR Spectrum, based on an autoregressive process model \\[[@B1]\\]. Both approaches require the data to be sampled regularly. Resampling the raw HRV data onto a regular time axis introduces noise into the signal and the information quality is compromised \\[[@B1]\\]. Conventionally, the HRV power is reported over 3 bandwidths: \\[0.01 \u22ef 0.04\\] Hz (Very Low Frequency, VLF) \\[0.04 \u22ef 0.15\\] Hz (Low Frequency, LF), and \\[0.15 \u22ef 0.4\\] Hz (High Frequency, HF) \\[[@B1], [@B2]\\].\n\nPrior to transformation into the frequency domain, normal practice requires that the time series data are \"detrended\" or \"high-pass filtered\" at a very low frequency, say \\~0.005\u2009Hz. There is no universally formal justification for such detrending other than it minimises the effects of medium-term nonstationarity within the"
+"Numerous progresses have been achieved in the last several decades on discrete semiconductor decices, such as memories and light emitting diodes. Nowadays, both the performance and reliability of these devices have already become sufficient for use in practical applications. Future work may involve the research of devices that possess wider functionality and compatibility in a variety of data storage and processing. Notably, the demand of high-speed inter-chip and intra-chip link has dictated the developments of communication. The conventional electronic devices gradually approach their limit due to the increasing difficulties in controlling the carriers at shrinking sizes[@b1][@b2]. Among several candidates for next-generation memory cells, resistive random access memory (RRAM) based on a simple two-terminal electrical switch has the potential to serve as a replacement for conventional memory structures due to its good switching properties, low power consumption and especially, three-dimensional multilayer stacking to achieve high density memory[@b3][@b4][@b5][@b6][@b7][@b8]. The typical current-voltage (I-V) characteristics of the RRAM cells exhibit an extreme change in resistance between high resistance state (HRS) and low resistance state (LRS). One of the underlying mechanisms responsible for the RRAMs arises from the formation of conducting filament networks under the application of a positive voltage across the cell. Upon application"
+"Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States \\[[@CIT0001]\\]; untreated infection is a leading cause of cirrhosis and hepatocellular carcinoma, is the most frequent cause of liver failure requiring transplantation, and causes more deaths annually than human immunodeficiency virus (HIV) \\[[@CIT0002]\\]. About 70% of persons with untreated HCV infection remain infected for life. HCV infection may be asymptomatic and approximately half of persons are unaware of their infection \\[[@CIT0006]\\]. Within 30 years, 41% of infected persons progress to cirrhosis, leading to liver failure, hepatocellular carcinoma, and death from liver-related causes \\[[@CIT0002]\\].\n\nThe annual number of new HCV infections in the United States was highest before HCV was discovered to be the cause of \"non-A non-B hepatitis\" in 1989; incidence declined after prevention guidelines and blood donor screening were implemented in the 1990s. After years of level incidence, new HCV infections began to rise nationally in 2010, increasing \\>2-fold by 2014. Incidence of acute HCV infections has risen among males, persons aged 20--29 years, and American Indians/Alaska Natives \\[[@CIT0007]\\]. The prevalence of HCV infection can be measured by a positive test for HCV antibody. Chronic HCV infection is associated with substantial morbidity and mortality,"
+"Introduction\n============\n\nIn most mammalian cells, the Golgi apparatus is organized into a dynamic, ribbon-like structure, which is generated by laterally linked Golgi stacks consisting of several cisternae aligned in parallel (for review, see [@B50]). Over 1000 proteins, mainly discovered in proteomics studies, are known to play a role in biogenesis and maintenance of this organelle ([@B54]; [@B12]; [@B46]). Additional regulators of the Golgi apparatus were identified in large-scale RNA interference (RNAi) microscopy-based screens. This technique is based primarily on visualization and quantitative analysis of Golgi appearance in light micrographs of fluorescently tagged Golgi resident or cargo proteins. Novel regulators of trafficking-related Golgi function have been identified in screens that analyzed Drosophila tER-Golgi units ([@B21]), the morphology of the mammalian Golgi apparatus ([@B6]), the early secretory pathway ([@B9]; [@B38]; [@B30]), TGN-to-lysosome trafficking ([@B3]), or endocytic trafficking ([@B23]). In some studies, candidate protein down-regulation or up-regulation by RNAi or cDNA over-expression, respectively, was combined with brefeldin A (BFA) induced redistribution of Golgi complex to ER in order to identify regulators of retrograde Golgi-to-ER trafficking ([@B24]; [@B11]). The list of hits derived in these studies identifies several novel individual regulators, but fails to derive their functional interactions. Combinatorial knock-downs provide a solution"
+"Introduction\n============\n\nObesity is a growing challenge for anesthesiologists because of many problems including an increased incidence of intra- and postoperative atelectasis,^[@B1]^ difficulty in tracheal intubation,^[@B2]^ an increase in airway resistance that may resemble asthma,^[@B3]^ an increased capacity to metabolize anesthetics such as halothane or enflurane^[@B4],[@B5]^ (but not apparently sevoflurane),^[@B6]^ a greater surgical demand for relaxation and decrease in functional residual capacity (FRC).^[@B7],[@B8]^ The obese or overweight patient presents kinetic issues that may delay recovery, thereby, aspiration and develop acute upper airway obstruction after tracheal extubation that add to the risks of anesthesia.^[@B9]-[@B11]^ Rapid recovery is, therefore, desirable to ensure early efficient coughing and to decrease the rate of postoperative respiratory complications.\n\nOne of the elements that determine recovery from anesthesia is the clearance of anesthetic from the effect site. Several factors influence clearance. Anesthetic in tissue depots, the solubility of the anesthetic in blood (the blood/gas partition coefficient) and tissue/blood solubility coefficients^[@B12],[@B13]^ will determine the rate of decrease of anesthetic in the arterial circulation during recovery from anesthesia because solubility determines the clearance of anesthetic at the lungs.^[@B14]^ If the fat solubility of the anesthetic is very small, most of the anesthetic will be cleared by ventilation and will"
+"INTRODUCTION\n============\n\nSpeech in everyday life is noisy: there is high variability due, for example, to differences within- and across-speakers, and to differences across linguistic and environmental contexts. Native listeners can cope with such variability better than non-native listeners ([@B8]). Having phonologically abstract speech categories could help native listeners by facilitating their ability to accommodate to the diversity in the speech signal ([@B46]; [@B41]). Formation of new abstract speech categories would therefore be beneficial when a listener is trying to master a foreign language (L2). Interestingly, variability appears to help listeners to learn new, non-native categories. It has been shown for a variety of non-native contrasts (e.g., English /r/-/l/ by native speakers of Japanese, [@B39]; Mandarin lexical tones by native speakers of English, [@B51]; Japanese geminate consonants by native speakers of Dutch, [@B43]). Exposure to a wider range of exemplars appears to enhance the process of building robust and abstract categories and hence to support generalization of learning ([@B39]; [@B43]).\n\nHigh-variability training, however, is not always helpful in non-native phonological learning. Recent studies have identified several factors that modulate the benefit of high-variability training, such as the listener's aptitude ([@B42]), the type of materials ([@B33]; [@B50]), and the age of"
+"Mate choice can generate sexual selection ([@zoy089-B21]; [@zoy089-B73]), but mate choice can only proceed if choosers can detect signalers. So understanding the basic mechanisms of signal detection is crucial to understanding the tempo and mode of sexual selection. Acoustic communication is an ideal system for such studies; it is a requisite for social behavior across a diversity of taxonomic groups as it mediates interactions such as mate choice and territory defense ([@zoy089-B77]; [@zoy089-B32]; [@zoy089-B36]). Hearing threshold, the lowest sound pressure level (SPL) detectable by a receiver, is an important factor for all functions of acoustic communication because a receiver must first detect an auditory signal prior to responding. It is especially critical for mate choice because if an animal is calling or singing for mates but receivers do not hear it, we can ask rhetorically, is the sender even sending a signal?\n\nHearing threshold is also a critical variable for determining a signal's active space, the distance over which receivers can detect a signal ([@zoy089-B59]; [@zoy089-B14]; [@zoy089-B53]; [@zoy089-B10]). Active space can vary substantially depending on the amplitude at the source, receiver sensitivity, ambient noise, competing acoustic signals, and attenuation due to habitat structure ([@zoy089-B94]; [@zoy089-B23]; [@zoy089-B4]). Measuring hearing threshold relative"
+"###### Strengths and limitations of this study\n\n-   The AIDS Therapy Evaluation in the Netherlands (ATHENA) national observational HIV cohort was established in 1998, following the introduction of triple combination antiretroviral therapy\u00a0(cART) in 1996.\n\n-   The ATHENA cohort collects clinical data from 98% of all adults and children in HIV care in the Netherlands (2% *opt-out*).\n\n-   ATHENA is an open cohort, as new participants continue to be enrolled on entry into HIV care, following a positive HIV diagnosis.\n\n-   The data are extracted from medical records: the availability of the data depends on the frequency of patient visits and the completeness and detail of the medical record.\n\n-   Findings are limited to those observed during follow-up in HIV care.\n\nIntroduction {#s1}\n============\n\nThe AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort is a nationwide observational cohort that monitors HIV management of all HIV-positive people in HIV care in the Netherlands, since the introduction of highly active antiretroviral therapy (HAART\u00a0nowadays known as combination antiretroviral therapy (cART)) when the first HIV-protease inhibitor (PI) became available. As a result of the decisive action taken by the late Dutch Minister of Health, Welfare and Sport, Professor Dr Els Borst, cART including"
+"1. Introduction {#sec1}\n===============\n\nA 55-year-old man admitted with acute abdomen surgery proved to be necessary. Histological examination of the pathologic specimens revealed fibrinoid necrosis and destruction of the internal lamina in small and medium size arteries. Although the gastrointestinal tract is frequently involved, it is rare for PAN to be accompanied by severe ischemic colitis as initial presentation \\[[@B1], [@B2]\\].\n\n2. Case Report {#sec2}\n==============\n\nA 55-year-old man, with recurrent abdominal pain since 10 months treated with antispasmodic drugs, was admitted in Rabta\\'s Department of Surgery (A), because of fever, abdominal pain, and bloody stool. Abdominal examination revealed mild rebound tenderness.\n\nLaboratory tests revealed severe inflammation. Upper gastrointestinal endoscopy was normal. Colonoscopy showed \"ulcerative and bleeding mucosa in sigmoid colon.\"\n\nCT-scan revealed \"dilatation of sigmoid colon, wall thickening, and hyperattenuation. Colon was distended upstream.\"\n\nAt laparotomy, the colon appeared cyanotic. Gentle palpation of sigmoid colon caused violaceous discoloration of the bowel. Pulsations were left in the celiac, superior mesenteric, and inferior mesenteric arteries. The entire colon was resected and ileostomy was created.\n\nHistological examination of the pathologic specimens revealed \"fibrinoid necrosis and destruction of the internal lamina in small and medium-size arteries which are rich in plasma cells, lymphocytes,"
+"All relevant data are within the paper.\n\nBackground {#sec005}\n==========\n\nMalnutrition in all its forms is a global public health problem. In low- and medium-income countries (LMIC), excess weight and obesity among adults is rapidly rising. Their prevalence exceeds that of undernourishment. However, undernourishment still largely prevails among children in these regions \\[[@pone.0229675.ref001]--[@pone.0229675.ref004]\\].\n\nIn 2015, the Millennium Development Goals (MDG) report showed that the proportion of children who are underweight worldwide fell overall from 25% in 1990 to 15% in 2015 \\[[@pone.0229675.ref005],[@pone.0229675.ref006]\\]. However, this decrease was not equal across all the world's regions \\[[@pone.0229675.ref007]\\]. In sub-Saharan Africa, only minimal progress had been made. Whereas Southeast Asia, despite the biggest decrease in the proportion of underweight children since 1990, had the highest underweight prevalence in 2015 \\[[@pone.0229675.ref006],[@pone.0229675.ref007]\\].\n\nGlobally, sub-Saharan Africa had the lowest decrease in the hunger index between 1990 and 2012 \\[[@pone.0229675.ref006]\\]. However, in 2018, the Food and Agriculture Organization of the United Nations (FAO) showed that the number of undernourished people in the world had increased in the last three years, returning to the level recorded almost ten years ago. Furthermore, the downward trend in the undernourishment rate in Asia seems to be slowing considerably \\[[@pone.0229675.ref008]\\].\n\nConsiderable progress has"
+"INTRODUCTION\n============\n\nRheumatoid arthritis (RA) is a chronic inflammatory disease with enhanced cardiovascular (CV) morbidity and mortality. Patients with RA have an approximately 70% higher risk of myocardial infarction than the general population, which is comparable to the risk in diabetic patients.[@B1] Pooled analysis of CV mortality in 91,916 patients with RA demonstrated a 60% increase in CV mortality in these patients, who were compared with the general population[@B2] and these rates did not change over time.[@B3]\n\nIn addition to the traditional risk factors such as obesity, insulin resistance, and dyslipidemia, the systemic inflammation that accelerates atherogenesis can contribute to the higher risk in RA patients.[@B4][@B5][@B6] Several lines of evidence suggest that a high number of inflamed joints, elevated erythrocyte sedimentation rate, elevated C-reactive protein, and interleukin (IL)-6 confound the development of CV complications in RA,[@B7][@B8] and the recommendations of a European League Against Rheumatism (EULAR) task force emphasize adequate control of disease activity to lower the CV risk in patients with RA.[@B9]\n\nMethotrexate is the first-line disease modifying anti-rheumatic drug (DMARD), and is widely used for monotherapy and combination therapy for RA. It effectively controls immune inflammation in the joint and vascular walls, thereby improving CV and total mortality"
+"Current state of the art MR cholangiographic examination, which relies upon the T2-weighted sequences, is highly accurate in identifying biliary diseases ([@B1]-[@B3]). However, the T2-weighted MR cholangiography (MRC) has diagnostic limitations which include poor visualization of the intrahepatic biliary tree compared with the extrahepatic biliary tree ([@B4], [@B5]), variation in the degree of T2-weighting that might obscure the biliary structures ([@B6]), and limited spatial resolution.\n\nDuring the past few years, T1-weighted MRC using hepatocyte-directed contrast agents has created interest in the field of MRC because of its potential to provide functional information and to improve the visualization of the non-dilated biliary system ([@B7]-[@B13]). Initially, mangafodipir trisodium (Mn-DPDP), which is mainly being excreted into biliary system, has been used for this purpose ([@B8], [@B9], [@B11]-[@B13]). However, dynamic MR imaging of the liver cannot be performed because this agent needs to be administered slowly. Recently, contrast agents that are excreted through both the renal and biliary pathways, such as gadobenate dimeglumine (Gd-BOPTA) have become available ([@B14]-[@B17]). Using a bolus injection technique, these agents can be used for dynamic imaging as an extracellular space agent in the early phase as well as a biliary contrast agent in the delayed phase. However, because the"
+"Introduction\n============\n\nStem cells\n----------\n\nA stem cell is defined by two fundamental properties: the capacity to self-renew and the ability to differentiate into mature cells. A hierarchy of stem cell potential exists, with pluripotent embryonic stem cells (ESCs) at the apex ([Fig. 1](#f1-ijtr-6-2013-057){ref-type=\"fig\"}). ESCs are derived from the inner cell mass of the developing blastocyst and can give rise to mature cells of all three germ layers. Due to a range of moral, bioethical, and technical issues, there are numerous hurdles to the clinical application of ESCs. Consequently, the last three to four decades have witnessed an increased interest in the use of adult stem cells. These cells can be isolated postnatally from a host of different organs and tissues. They typically have a more limited differentiation potential, often restricted to mature cells of one germ layer. Of the diverse range of adult stem cells the hematopoietic stem cell (HSC) represents perhaps the best-studied multipotent cell and can give rise to all cells of the blood. Another bone marrow resident stem cell is the mesenchymal stem cell (MSC). MSCs can differentiate into cells of mesodermal origin, typically osteoblasts, chondrocytes, and adipocytes. Neural stem cells (NSCs) represent a relatively recently"
+"THIS ARTICLE focuses on how the environment influences the ability of people with aphasia to communicate successfully. Aphasia intervention has traditionally focused on the language and communication of the individual and their close communication partners. A new trend in aphasiology, informed by the World Health Organization\\'s (WHO\\'s) International Classification of Functioning, Disability and Health (ICF; [@R50]), recognizes the importance of the environment in enabling or disabling the functioning and participation of people with aphasia.\n\nThe ICF defines *Environmental Factors* as \"those factors in the physical, social, and attitudinal environment in which people live and conduct their lives\" ([@R50], p. 10). Researchers have begun to identify how environmental factors influence the ability of people with aphasia to communicate ([@R23], [@R24]; [@R36]) and importantly, which environmental factors can be modified to improve communication and participation ([@R25]; [@R28]; [@R40]; [@R43]). These research endeavors inform the understanding of the kinds of environments that create barriers to or facilitators of communication for people with aphasia. However, this research is focused on understanding how the environment impacts the *present* communication and participation of people with aphasia. The chronic nature of aphasia necessitates that researchers and clinicians also consider how people\\'s circumstances and, therefore, their communication needs"
+"Epithelial herpes simplex keratitis is the most common form of the recurrent disease, typically presents mild clinical course, mostly which heals without any sequelae. Conversely, recurrent herpetic stromal keratitis is an immunopathologic process, can lead to stromal scarring, neovascularization, stromal thinning, and/or endothelial dysfunction and resultant astigmatism leading to visual impairment.\\[[@ref1]\\] Anecdotally, various trigger factors have been implicated in the causation of herpetic reactivation, namely, immunosuppression, febrile condition, exposures to ultraviolet light, cold wind, systemic illness, surgery, menstruation, emotional stress, and minor local trauma; many patients can clearly foresee recurrent disease following a given event. Nevertheless, the HEDS epidemiological study did not show such a statistical correlation with above-stated risk factors. In published literature, the herpetic recurrence documented in the following circumstances use of topical medications such as steroids, prostaglandin analogs, intravitreal injections of anti-vascular endothelial growth factor agents, corneal-based laser procedures, laser iridectomy or trabeculoplasty, or any corneal interventions such as partial or full thickness keratoplasty particularly in those who had an active herpetic eye diseases in the past.\\[[@ref2][@ref3]\\]\n\nIn this context, we intend to present a case of unusual reactivation of herpetic necrotizing stromal keratitis 1 week after the periocular injection of botulinum toxin for the management of"
+"Background {#Sec1}\n==========\n\nPrimary pulmonary meningiomas (PPMs) are a rare and mostly benign disease and often present as a solitary pulmonary nodule \\[[@CR1], [@CR2]\\]. Because most PPMs grow in size without any specific radiological features, it is quite difficult to distinguish them from metastatic lung tumors in patients with a history of a malignancy \\[[@CR3]--[@CR7]\\]. We described a case of a PPM initially suspected as a metastasis from thyroid cancer due to a size reduction after radioactive iodine therapy.\n\nCase presentation {#Sec2}\n=================\n\nA 62-year-old asymptomatic woman presented with an enlarging pulmonary nodule. She had undergone a total thyroidectomy and neck lymph node dissection for a stage IVC (T4aN0M1) papillary thyroid carcinoma 6\u2009years prior. Computed tomography before the thyroidectomy had revealed a peripheral well-circumscribed pulmonary nodule in the left lower lobe which was suspected as a metastasis (Fig. [1](#Fig1){ref-type=\"fig\"}a). The nodule had decreased in size from 7.0 to 5.5\u2009mm after adjuvant radioactive iodine therapy (Fig. [1](#Fig1){ref-type=\"fig\"}b) and enlarged to 8.7\u2009mm over the next 5\u2009years (Fig. [1](#Fig1){ref-type=\"fig\"}c) (Each figure showed the maximum diameter of the nodule. The difference of slice levels might be caused by a discordance in respiratory conditions.). There were no other pulmonary nor mediastinal"
+"Introduction {#s1}\n============\n\nSj\u00f6gren syndrome is a chronic, systemic autoimmune disorder characterized by lymphocytic infiltration of the exocrine glands ([@B1]). The condition can occur as a primary disease or be secondary to another connective tissue disease. Sj\u00f6gren syndrome mainly involves the salivary and lacrimal glands, but can also affect other exocrine glands, organs, and systems ([@B2]), including the peripheral and central nervous systems ([@B3]). Central nervous system involvement is a rare complication of primary Sj\u00f6gren syndrome ([@B4]) that is manifested by a variety of symptoms such as migraine, seizures, dementia, psychiatric disturbances, and cognitive dysfunction ([@B5], [@B6]). Thus far, recurrent strokes as a complication of primary Sj\u00f6gren syndrome have not been reported. Here, we report an extremely rare case of recurrent strokes associated with primary Sj\u00f6gren syndrome in a female patient.\n\nBackground {#s2}\n==========\n\nThe patient was a 66-year-old woman. In September 2017, she had an episode of aphasia and right-sided hemiplegia, which was suggestive of a stroke. She therefore underwent magnetic resonance imaging (MRI) of the brain, which revealed a lacunar infarction in the right and left pons and the left insular white matter (Figures [1A,B](#F1){ref-type=\"fig\"}). She was diagnosed with cerebral infarction and treated with butylphthalide, aspirin, and atorvastatin"
+"Introduction {#S1}\n============\n\nCutting edge, innovative science and technology creates a need for industry-specific training for scientists. Translation of discoveries into healthcare solutions is rife with pervasive, global challenges and an increased need for PhD level researchers and positions. However, most PhDs have little knowledge of industry trends, strategy and structure. Many PhD graduates and post-doctoral researchers are facing a difficult career path ahead, as faculty positions are in short supply as is the funding that is necessary to remain on the tenure track \\[[@R1]\\]. Hence, many PhDs find themselves in the precarious position of preparing for alternative paths, primarily working within the life sciences industry. In addition, industry jobs are competitive, especially as cutbacks in research and development (R&D) budgets limit the number of open positions. To be successful competing for the limited available jobs, we believe that scientists would benefit from training focused on translating their knowledge of academic R&D into a knowledge base more suitable to the industry setting.\n\nThe Clinical and Translational Science Awards (CTSA) initiative of the National Institutes of Health (NIH) National Center for Advancing Translational Science (NCATS) endorses educational and training programs that cultivate leaders in the biomedical research workforce \\[[@R2],[@R3]\\]. Our institution's"
+"Introduction {#s1}\n============\n\nDeciphering the fundamental mechanisms that underlie brain function requires an explicit description of the dynamics of the neuronal and synaptic substrate. Explicit neurodynamical models can describe the complex dynamics arising from the involved neuronal networks [@pcbi.1000587-Rolls1],[@pcbi.1000587-Dayan1]. Traditionally, theoretical neuroscience follows an *ab initio* approach consisting of two main steps: 1) construction and simulation of models based on detailed descriptions of the neuronal and synaptic operations with a large number of neurons in a specified (hypothesized) network architecture, and 2) reduction of the hypothesized models such that an in-depth analytical study is feasible, and a systematic relation between structure (parameters), dynamics, and functional behavior can be solidly established. Models of neurons such as integrate-and-fire [@pcbi.1000587-Tuckwell1] are frequently used. The advantage of this type of models is that the simulation of biologically realistic networks allows the study of the neural correlates of brain function, for comparison with experimental data. On the other hand, the model is simple enough so that it is possible to obtain a reduced description based on *mean-field* techniques [@pcbi.1000587-Brunel1],[@pcbi.1000587-Brunel2]. The mean-field reduction simplifies the analysis of networks of spiking neurons, by partitioning the network into populations of neurons that share the same statistical properties. Using"
+"Published: May 18, 2017\n\nResults {#sec1}\n=======\n\nMelanopsin-Derived Spatial Receptive Fields {#sec1.1}\n-------------------------------------------\n\nMelanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) project to the dorsal lateral geniculate nucleus (dLGN) in mice and primates \\[[@bib7], [@bib8], [@bib9]\\], allowing access to the primary visual pathway. The significance of this arrangement for form vision is not clear. Melanopsin's accepted function is to encode irradiance, and it has recently been shown that melanopsin adjusts activity in the dLGN according to background (ambient) light \\[[@bib10], [@bib11]\\]. Is that the extent of its contribution to thalamocortical vision? Or alternatively, do melanopsin signals have sufficient spatiotemporal resolution also to encode spatial patterns and, if so, what contribution do they make to form vision?\n\nAddressing these questions with melanopsin knockout or rod+cone-deficient preparations is unsatisfactory. Melanopsin knockout mice have deficits in spatial contrast sensitivity \\[[@bib12]\\], but none of the published physiology indicates that melanopsin has the high contrast sensitivity required for this effect to originate with a direct contribution to encoding patterns, and the effect could plausibly be secondary to more general deficits in\u00a0visual development and/or function in this genotype \\[[@bib10], [@bib11], [@bib13], [@bib14], [@bib15], [@bib16], [@bib17]\\]. Conversely, while human patients and animal models of advanced rod+cone degeneration"
+"Introduction {#s1}\n============\n\nHSV-1 is prevalent pathogen in various clinical manifestations ranging from common cold sore, gingivostomatitis, herpetic whitlow, corneal herpetic stromal keratitis, genital ulcers, and sometimes more serious complications such as encephalitis and meningitis (Nahmias and Roizman, [@B24]; Whitley et al., [@B35]; Whitley and Roizman, [@B36]). The current model of HSV entry suggests that the virus uses multiple pathways during entry depending on cell types and entry receptors (Spear and Longnecker, [@B32]; Karasneh and Shukla, [@B20]; Salameh et al., [@B28]). HSV-1 entry generally begins with viral attachment to host cells in which HSV glycoproteins B (gB) and C (gC) on the envelope of the virus typically bind to heparan sulfate (HS) on the surface of the host cell (WuDunn and Spear, [@B37]; Herold et al., [@B16]; Shieh et al., [@B29]). This is followed by gD binding to one of its cognate receptors including an intercellular adhesion molecule: nectin \u22121 or \u22122 (Geraghty et al., [@B14]) and a member of the tumor necrosis factor receptor family: herpesvirus entry mediator (HVEM; Montgomery et al., [@B23]). The virus also uses a modified version of HS known as 3-*O* sulfated heparan sulfate (3-*O*S HS) to bind gD and induce virus cell fusion independent"
+"The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n\nIntroduction\n============\n\nThe current novel coronavirus (2019-nCoV) pandemic was first identified in Wuhan, Hubei province, the Republic of China in December 2019 \\[[@REF1]-[@REF4]\\]. It was initially described as pneumonia of unknown origin but shortly afterward, the virus was identified as belonging to the coronavirus family and named novel coronavirus (COVID-19). From China, it spread rapidly across the globe, to be declared a pandemic by the World Health Organisation (WHO) on February 11, 2020 \\[[@REF5]\\].\n\nA chest X-ray is the primary imaging modality for investigating COVID suspected patients. The use of chest computed tomography (CT) as an imaging modality for patients with suspected COVID-19 is not well-established. From our cohort of 19 patients with typical CT findings for"
+"Introductions {#s1}\n=============\n\nLiving donor liver transplantation (LDLT) has been widely accepted as an effective therapeutic modality for a variety of end-stage liver diseases \\[[@r24]\\]. The success of LDLT has increased steadily over decades due to improvements in immunosuppressive therapy and postoperative care \\[[@r20]\\]. However, for patients requiring intraoperative portal vein (PV) reconstruction, one major challenge of LDLT is the portal vein stenosis (PVS), with the incidence remaining at 0.6--4.5% in recipients of a living-donor allograft, especially in children \\[[@r11], [@r12], [@r23]\\].\n\nAs we know, survival depends on the regeneration capacity of hepatocytes. It has been well documented that approximately 70--80% of hepatic blood flow in normal people is derived from the PV, and the PV has been reported to influence the impairment, regeneration, and function of the transplanted liver \\[[@r17], [@r19]\\]. Theoretically, a minimal change in the blood supply of the PV scarcely affects the graft's regeneration until the deprivation in flow of the PV reaches a certain level. Nevertheless, the tolerated limitation of PV deprivation and the optimal moment for intervention remain unknown. Recently, lots of clinical and animal studies have been performed to investigate the relationship between PV flow and liver regeneration \\[[@r2], [@r16]\\]. However, the blood"
+"Background {#Sec1}\n==========\n\nFor more than a century, coal, petroleum and natural gas have been the primary feedstocks for the chemical industry. However, the fossil resources are diminishing whilst demand for chemicals is ever increasing. The environmental pollution associated with discarding spent chemicals and materials is also gaining focus both on political and consumer levels. To address this issue a lot of effort is going into developing novel biotechnological strategies for producing chemicals from renewable feedstocks \\[[@CR1], [@CR2]\\], such as sugar cane, starch, biomass hydrolysates, agricultural waste, etc.\n\nOne of the chemicals that have attracted particular interest is 3-hydroxypropionic acid (3HP), which can serve as a precursor for acrylic acid and its derivatives. Additionally 3HP can be polymerized alone or in compositions to obtain biodegradable polyesters. The world annual production of acrylic acid and its esters is anticipated to increase to 6 million tons by 2017 (\"Acrylic Acid: 2014 World Market Outlook and Forecast up to 2018\", January 2014). Acrylates find application in a wide range of consumer products, e.g. personal care products, adhesives, coatings and paints, and the annual total market size is exceeding USD12 billion. One particularly important application of acrylic acid is for the production of superabsorbent"
+"The use of nanomaterials in biomedicine has allowed researchers to combine multiple functionalities into a single system. Accordingly, such materials as quantum dots[@b1][@b2], gold nanoparticles[@b3][@b4][@b5], carbon nanotubes[@b6][@b7], graphene[@b8][@b9], and polymersomes[@b10] have all been investigated and have shown promise in a wide range of biomedical applications[@b11]. Simultaneous diagnostics, therapeutics, and monitoring of response to treatment are realized with such multifunctional nanomaterials and nanostructures, which also offer the potential of both reducing common chemotherapy- or radiation-associated side effects and increasing the effectiveness of therapy[@b12][@b13][@b14].\n\nNIR light, in the range of 700--900\u2005nm or 1000--1350\u2005nm, which is the main optical transparent window for biosamples, has been widely used for bioimaging to improve spatial resolution and help localize the region needed for therapy[@b15][@b16]. Nonlinear two-photon luminescence (TPL)[@b17], upconversion fluorescence[@b18][@b19] and Raman[@b20][@b21][@b22][@b23] imaging have been widely used techniques with NIR excitation. Moreover, because of its easy use and minimal absorbance by skin and tissues, NIR radiation is also an attractive external stimulus to control the toxicity of the therapy through controlled release or enhanced therapeutic efficiency, thereby allowing noninvasive penetration of deep tissues[@b24][@b25][@b26][@b27][@b28]. Conventional nanomaterial candidates featuring NIR imaging and photothermal properties are generally based on gold nanocages or nanorods[@b12][@b29][@b30][@b31][@b32]. These materials have strong"
+"Introduction {#s1}\n============\n\nThe mammalian circadian clock is a cell-autonomous system that drives oscillations in behavior and physiology in anticipation of daily environmental change. These oscillations manifest through interactions of the central pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus with local circadian clocks present in most mammalian tissues \\[[@pbio-1000052-b001]\\]. Many clock components have been identified that act to generate circadian transcriptional oscillations through a regulatory system comprised of negative feedback loops \\[[@pbio-1000052-b002],[@pbio-1000052-b003]\\]. Studies in mouse models indicate that relatively few molecular perturbations of clock components (e.g., knockout or mutant animals) lead to complete loss of oscillator function as assessed by locomotor activity or circadian gene expression in isolated tissues \\[[@pbio-1000052-b002]\\]. This suggests that the molecular clockwork constitutes a regulatory module that is phenotypically robust, i.e., resistant to and/or buffered against genetic perturbations such as gene loss, deletion, or mutation \\[[@pbio-1000052-b004]\\]. Consistent with these findings, it often takes deletion of multiple factors (often gene paralogs) to disrupt behavioral and/or cellular rhythms (summarized in [Table 1](#pbio-1000052-t001){ref-type=\"table\"}).\n\n###### \n\nEffects of Gene Knockout or Knockdown in Animal Models and U-2 OS Cells\n\n![](pbio.1000052.t001)\n\nThe majority of identified clock components function as transcriptional activators or repressors. These proteins, along with other components that"
+"The World Health Organization has developed a single international standard for the information that authors of clinical trials must disclose \\[[@B1]\\]. The informed consent form (original or subsequent versions if the trial protocol necessitates) is not among the listed items. More recent schemes to expand registration of clinical trials also do not include full disclosure of informed consent forms \\[[@B2],[@B3]\\]. We strongly feel that the exclusion of informed consent is a serious omission in our current attempt to make clinical trials more transparent; we give four specific reasons in support of this view:\n\n1\\. The patients and the public should know whether the study involves a medication that has already been shown to be effective in other similar studies. Informed consent forms are supposed to include this information to help patients make an informed decision about the possible benefit they may get from participating in the trial. Although all clinical trials should ideally be conducted with the goal of improving medical knowledge, other reasons for clinical trials, including simple promotion, are seen \\[[@B4]\\]. There is little scientific or societal gain in repeating clinical trials with medications that have already shown efficacy \\[[@B5]\\].\n\n2\\. There can be considerable variation in how"
+"Fukushima et al. recently published research on the relationship between cost sharing policies and medical spending by the elderly (Fukushima et al., [@B6]). Japan, as the nation in the most advanced stage of population aging, is indeed the best place to search for answers (Ogura et al., [@B23]). The authors provided us with a valuable contribution on the effects of such policies on the demand for medical services and costs within the subpopulation of senior citizens. The study has been conducted within a sound methodological framework and significantly expands our knowledge on the oldest among the world\\'s large nations. I would like to complement their revealing findings with few additional facts crucial for understanding these issues.\n\nOne of the baseline results of the study claims: \"lower cost sharing significantly increases medical spending.\" This actually follows the natural logic that a patient is likely to consume more care if it is effectively free at the point of usage. Three decades ago policy makers believed it should be possible for a cost sharing mechanism to contain costs and induce net savings (Keeler and Rolph, [@B15]). It appears that the final balance is highly dependent on prevailing governing practices and legislative framework within"
+"I have read the article \"Bladder Cancer Specific Nuclear Matrix Proteins-4 May Be a Potential Biomarker for Non-Muscle-Invasive Bladder Cancer Detection\" with great interest \\[[@B1]\\]. The article reports that the urine concentration of BLCA-4 protein is a strong candidate for the diagnosis of non-muscle-invasive bladder cancer \\[[@B1]\\]. However, no normalization strategy was used to determine urinary protein concentrations. In order to eliminate physiological differences such as dehydrated individuals, urinary protein concentrations should be normalized according to proteins such as creatinine \\[[@B2]\\]. If normalization is done, I would kindly ask you to share data on normalization. If normalization is not done, I would like you to share information about how physiological condition differences between individuals are excluded.\n\nConflicts of Interest\n=====================\n\nThe author declares that there is no conflict of interest regarding the publication of this paper.\n\n[^1]: Academic Editor: Frank Tacke"
+"1. Introduction {#sec1}\n===============\n\nType 2 diabetes is an increasing health problem affecting populations worldwide. Insulin resistance is the prediabetic state where insulin sensitive tissues such as muscles, adipocytes, and liver show reduced sensitivity towards insulin and a decreased glucose uptake (GU), which leads to elevated blood-glucose levels \\[[@B1]\\]. In the late 1990s, thiazolidinediones (TZDs) were introduced as new effective oral insulin sensitizing drugs for management of type 2 diabetes but due to severe side effects such as increased water retention, weight gain, heart enlargement, and hepatotoxicity most TZDs have been withdrawn from the market \\[[@B2]\\]. Thus there is a need for new insulin sensitizing drugs with fewer side effects.\n\nTZDs such as rosiglitazone (Rosi) act as full agonists of peroxisome proliferator-activated receptor gamma (PPAR*\u03b3*). Activation of PPAR*\u03b3* by agonists leads to a conformational change in the ligand-binding domain (LBD). This process alters the transcription of several target genes involved in carbohydrate and lipid metabolism \\[[@B3]\\]. Depending on the ligands they can induce different sets of genes as a result of differential recruitment of cofactors \\[[@B4], [@B5]\\]. Recruitment of some cofactors leads to increased lipid storage and decreased energy expenditure, whereas recruitment of others increases insulin-stimulated GU, glucose metabolism, and"
+"Background\n==========\n\nThe presence of psammoma bodies (PBs) in cervicovaginal smears (CVS) is a rare finding, the prevalence ranging from 0.00047% to 0.057% in large series studies \\[[@B1]-[@B6]\\]. PBs on Papanicolau smears have been described in association with a wide variety of gynaecological conditions including malignant tumors, such as malignant serous epithelial ovarian tumors \\[[@B7]\\], endometrial carcinoma with PBs \\[[@B8]\\], neuroendocrine carcinoma of the cervix \\[[@B9]\\], primary peritoneal borderline tumour \\[[@B10]\\], tubal serous carcinoma and cervical clear cell carcinoma \\[[@B2]\\]. Exceptionally, the primary site of origin remains unclear \\[[@B1],[@B4]\\]. However, they are most frequently associated with benign conditions, presumably related to the use of an intrauterine device (IUD) \\[[@B11]-[@B13]\\], to a history of oral contraception \\[[@B14]\\] or associated with a benign ovarian neoplasm \\[[@B15]\\], inflammatory lesions, such as tubo-ovarian adhesions and endosalpingiosis \\[[@B16],[@B17]\\], endometrial benign hyperplasia and endometrial polyps \\[[@B3]\\]. The most reliable predictor of a malignancy is the association of malignant cells with PBs on the smears. The purpose of our work is to determine the prevalence and significance of PBs in a sequential series of CVS in the screening population of Trento district (Italy). Furthermore, we illustrate the first case report, as far as we are aware, of"
+"Nanoscale science has been in the research labs of industry and academia for over 20 years. Consumers increasingly confront an abundance of products that contain nanoparticles or that claim to be a result of nanotechnology, including skin-care products, wrinkle- and stain-resistant fabrics, and sports items like golf clubs and baseball bats \\[[@pbio-0050283-b001]\\]. Yet as recently as late 2006, over 80% of the American public reported that they had heard nothing or next to nothing about nanotechnology \\[[@pbio-0050283-b002]\\].\n\nThe Nanoscale Informal Science Education Network (NISE Net) is an ambitious initiative funded by the National Science Foundation (NSF) to engage families, schoolchildren, and adults in nanoscale science, engineering, and technology through informal learning experiences in science centers and museums across the United States. NISE Net has designed exhibits and public programs about nanoscience and plans to disseminate these to 100 science centers and museums by the year 2010. Two years into this multi-year project, the team has reached an inflection point---a time to assess critically the status of our work, re-evaluate our original assumptions, and redouble our efforts to support the collective vision that has emerged from this period of intensive collaboration.\n\nNanoscale Science {#s2}\n=================\n\nThe prefix \"nano\" derives from the"
+"1. Introduction {#sec1-cells-09-01189}\n===============\n\nThe modern-day obesity pandemic is propagated by increased urbanization combined with unbalanced diets and sedentary lifestyle has resulted in the prevalence of noncommunicable diseases (NCDs) worldwide \\[[@B1-cells-09-01189]\\]. While, obesity definition of the body mass index (BMI) as \\> 30 may seem as an oversimplified definition, it is accurate in capturing and computing the increased risks associated with being overweight or obese and developing NCDs such as type 2 diabetes mellitus (T2DM), dyslipidemia, hypertension, cardiovascular disease (CVD), and sleep apnea \\[[@B2-cells-09-01189],[@B3-cells-09-01189]\\]. In Kuwait, more than 75% of the adult population is currently either overweight or obese \\[[@B4-cells-09-01189]\\]; whereas, the prevalence of obesity among children and adolescents under 18 years of age is escalating. NCDs that included cancers, upper respiratory tract diseases, heart disease, and diabetes were estimated to account for 73% of the total deaths in Kuwait in 2013 \\[[@B5-cells-09-01189]\\]. Regarding prevalence rates of NCDs risk factors among Kuwaiti population, 63% account for inadequate physical activity (PA), with obesity rates exceeding 44% among women \\[[@B6-cells-09-01189]\\].\n\nAdipose tissue is dichotomously characterized as subcutaneous adipose tissue (scAT) and visceral adipose tissue (VAT). The VAT is invariably implicated in the pathophysiology of metabolic disorders such as T2DM and CVD \\[[@B7-cells-09-01189]\\]."
+"The oil palm is a monocot of the family Arecaceae and of the tribe Cocoineae belonging to the genus *Elaeis*. The genus contains three species: *Elaeis guineensis* Jacquin originating from Africa, *Elaeis oleifera* (HBK) Cort\u00e8s originating from South America, and *Elaeis madagascariensis* Beccari found in Madagascar. The most widespread species, *E. guineensis*, is grown for its fleshy fruits, from which mesocarp palm oil is extracted, and its kernel, from which palm kernel oil is extracted. *E. oleifera* is richer in unsaturated fatty acids. It displays some very worthwhile characteristics for genetic improvement, notably slow vertical growth, the quality of its oil, and resistance to several fungal diseases.\n\nIn oil palm breeding programs, *E. guineensis* and *E. oleifera* palms selected in several geographic origins are inbred or crossed to make breeding populations of restricted origin, intra- or inter-specific hybrids, and backcrosses ([@iev066-B17]). Backcrosses involve crosses between a parent of purely *E. guineensis* origin and a parent arising from a hybridization between the two species of interest (*E. guineensis*\u2009\u00d7\u2009*E. oleifera*). They are used to introgress traits of interest from *E. oleifera* (Eo) into the genome of *E. guineensis* (Eg) ([@iev066-B29]). In our study, we focused on BC1 backcrosses ((Eo\u2009\u00d7"
+"INTRODUCTION {#sec1-1}\n============\n\nDepression is defined as a common mental disorder that leads to impairment in an individual\\'s ability to take care of his or her everyday responsibilities.\\[[@ref1]\\] Depression would be the leading cause of disability in industrialized countries by 2030\\[[@ref2]\\] and accounts for 4.5% of all human disabilities.\\[[@ref3]\\] Major depressive disorder (MDD) is diagnosed when symptoms last for a minimum period of 2 weeks.\\[[@ref4]\\] The circadian rhythm disruption is involved in the pathophysiology of depression.\\[[@ref5]\\] The incidence of insomnia in depression is up to 80%. Sleep--wake cycle disturbance is one of the important symptoms of MDD. The most frequently reported sleep disturbances are nocturnal and early morning awakenings.\\[[@ref6]\\] In the last 20 years, new antidepressant classes have been introduced in therapy, i.e. selective serotonin reuptake inhibitors (SSRIs) and serotonin--norepinephrine reuptake inhibitors (SNRIs). However, continuous stimulation of SSRI and SNRI receptors leads to adverse effects such as sexual dysfunction, gastrointestinal disturbances, weight gain, and somnolence. These side effects limit the use of SSRIs and SNRIs in the community.\\[[@ref5]\\]\n\nAgomelatine {*N*-\\[2-(7-methoxynaphthalen-1-yl) ethyl acetamide\\]} is an antidepressant that was approved in India by the Central Drugs Standard Control Organization (CDSCO) on 10^th^ September 2012 for the treatment of MDD in adults.\\[[@ref7]\\] It"
+"Introduction\n============\n\nRecent investigations have revealed that the state of post-ischemic brain recirculation is of major importance in recovery from sudden death, and we developed an isolated global ischemic brain model that excludes the confounding variables of bypass, donor blood, and whole body damage to investigate the strategy of controlled reperfusion. This study examines primary damage of cerebral function and tissue with uncontrolled brain reperfusion following 30 minutes of brain ischemia, and tests whether controlled brain reperfusion can attenuate the damage.\n\nMethods\n=======\n\nSixteen pigs underwent 30 minutes of global brain ischemia by clamping major neck vessels via a small suprasternal incision. Seven pigs then received uncontrolled reperfusion with normal blood, while the other nine pigs received controlled reperfusion by infusing a modified (leukodepleted, hypocalcemic, hyperosmolar, alkalotic, normoglycemic, antioxidant enriched) warm blood solution into both carotid arteries for 20 minutes. Six pigs underwent Sham operation. Brain oxygen uptake and venous conjugated dienes (CD) were measured during reperfusion. The neurologic deficit score (NDS) (0 = normal, 500 = brain death) was determined at 24 hours after ischemia, and brain water contents and cerebral infarction by 2,3,5-triphenyl tetrazolium chloride staining were assessed post mortem.\n\nResults\n=======\n\nSham pigs were neurologically normal at"
+"GENOME ANNOUNCEMENT {#h0.0}\n===================\n\nHere, the complete genome sequence of *Salmonella enterica* subsp. *enterica* serovar Typhimurium strain 33676 is presented. It was isolated in 2011 in Mexico City, Mexico, from a blood culture taken from a 15-year-old woman suffering a febrile illness with invasive severe pancolitis, which was refractory to therapy with extended-spectrum cephalosporins (M. Wiesner, J. J. Calva, V. H. Bustamante, D. P\u00e9rez-Morales, M. Fern\u00e1ndez-Mora, E. Calva, and C. Silva, unpublished data). Strain 33676 was assigned to sequence type 213 (ST213), which is the predominant genotype recovered in Mexico since 2001 ([@B1], [@B2]), and it is multidrug resistant, expresses FljB H2-phase flagella, and displays attenuated virulence on mice (Wiesner et al., unpublished data).\n\nGenomic DNA was extracted by standard protocols ([@B3]) and sheared into \\~10-kb fragments for PacBio library preparation and P5-C3 sequencing on two SMRT cells. The continuous long reads were assembled using the HGAP/Quiver-protocol in SMRT Portal version 2.3.0.140936.p4 ([@B4]), resulting in an assembly with 4 contigs. These were circularized by trimming the terminal repeats with Minimus2 ([@B5]) and subjected to two consecutive rounds of read remapping with the RS_Resequencing.1 module for sequence polishing, resulting in a final assembly with a mean coverage of \\~119\u00d7. The size"
+"Background\n==========\n\nHuman T-lymphotropic virus types 1 and 2 (HTLV-1 and --2) are prevalent at low-level among United States blood donors, but recent data on their prevalence is lacking.\n\nMethods\n=======\n\nData on all first-time blood donors in a large network of United States blood centers was examined during the period 2000-2009. Anti-HTLV-1 and -2 was measured by enzyme immunoassay (EIA) screening with type-specific confirmation by immunofluorescence or RIBA. Prevalence and odds ratios (OR) and 95% confidence intervals (CI) for associations with demographic characteristics were assessed using multivariable logistic regression.\n\nResults\n=======\n\nAmong 2,047,740 first-time donors, 104 donors were seropositive for HTLV-I (prevalence 5.1 (95% CI: 4.1 - 6.1) per 100,000) and 300 donors were seropositive for HTLV-2 infection (prevalence 14.7 (95% CI 13.0 - 16.3) per 100,000). Prevalence was lower than reported in the 1990's but stable from 2000 to 2009. HTLV-1 seropositivity was associated with female sex (OR = 1.56, 95% CI 1.05-2.32); older age; and Black (IR = 25.29, 9% CI 13.14- 48.68) and Asian (OR = 21.43, 95% CI 10.31-44.53) race/ethnicity. HTLV-2 seropositivity was associated with female sex (OR = 2.13, 95% CI 1.67-2.73); older age; and non-white race/ethnicity; residence in the Western (OR=4.12, 95% CI"
+"Introduction {#Sec1}\n============\n\nFusions are a type of somatic alteration leading to cancer associated with up to 20% of cancer morbidity^[@CR1],[@CR2]^. Translocations, copy number changes, and inversions can lead to fusions, dysregulated gene expression, and novel molecular functions. Fusions occur and have oncogenic roles in hematological, soft tissue, and solid tumors. Fusion rates differ across cancer types, and fusions may define some cancer types, such as *BCR\\--ABL1* in chronic myeloid leukemia. A balanced translocation t(9;22) leads to *BCR\\--ABL1*, producing a hybrid protein with constitutive *ABL1* kinase domain activation, signaling cell division, and avoiding apoptosis. Imatinib inhibits the *BCR\\--ABL1* protein hybrid and in 2001 became the first FDA-approved drug to specifically target a fusion protein^[@CR2]^.\n\nMultiple myeloma (MM) is the second most common blood cancer (10% of blood cancers, 1--2% of all cancers) and involves the clonal proliferation of bone marrow (BM) plasma cells, which are fully differentiated B cells. B cells produce a diverse repertoire of antibodies through genomic alterations at immunoglobulin (Ig) loci, including VDJ recombination, somatic hypermutation, and class switch recombination. Aberrant class switch recombination may result in translocations upregulating oncogenes. Ig enhancers get repurposed to drive oncogene expression, myeloma tumorigenesis, and clonal expansion^[@CR3]^.\n\nTumor initiating genomic changes"
+"Background {#Sec1}\n==========\n\nIn developing countries, a wide range of diseases (including physical and mental diseases) are associated with social factors \\[[@CR1]\\]. The WHO has further stated that social capital is one of the factors affecting health that could be a missing link in health-related studies \\[[@CR2]\\], be protective of mental health and reduce stress \\[[@CR3]\\]. Social capital is defined as the resources accessed through social networks \\[[@CR4], [@CR5]\\]. These resources include the exchange of tangible support (e.g., cash loans, labor in kind, etc.) between network members, as well as intangible resources such as emotional support or the diffusion of information. Social capital is hypothesized to promote health through several mechanisms including the following: (a) strengthening the individual's ability to cope with stress (the \"buffering hypothesis\"), (b) acting in accordance with the established norms among the individuals within a group or workforce, and (c) boosting the individuals' ability to participate in collective action to guarantee its members' benefits (\"collective efficacy\"). Social capital has been studied in a number of settings, including the family \\[[@CR6]\\], neighborhood \\[[@CR7]\\] and the workplace \\[[@CR8]--[@CR10]\\]. Considerable efforts have been applied in recent years on understanding the role of workplace social capital as a determinant of"
+"INTRODUCTION {#sec1-1}\n============\n\nGlomerular filtration rate (GFR) is defined as the volume of plasma that can be completely cleared of a particular substance by the kidneys in unit time. GFR is customarily assessed by measuring the concentrations of serum markers such as blood urea nitrogen and serum creatinine (Scr). Although widely used, these endogenous markers are not ideal and occasionally do not perform well. The other method for determining GFR is to measure the clearance of exogenous substances such as inulin, iohexol, chromium-51-ethylenediaminetetraacetic acid (EDTA), technetium-99m labeled diethylene triamine penta acetic acid (Tc-99m DTPA) or I-125 labeled iothalamate.\n\nAs the definition of classifying chronic renal disease becomes more dependent on accurate calculation of GFR, it is imperative that a reliable method to calculate GFR is obtained. GFR can be calculated from the rate of clearance of tracer activity from the plasma following a single intravenous injection of a suitable radiopharmaceutical. As long as the radiopharmaceutical is excreted exclusively by glomerular filtration and is not bound to plasma protein or to any other component of blood or other tissue, the GFR can be calculated simply by dividing the administered dose by the integral of plasma time-activity curve. Initially GFR was calculated"
+"Introduction {#s1}\n============\n\nHuman parvovirus B19 (B19V) is a member of the genus *Erythrovirus* of the family *Parvoviridae*. It is a small (20-25 nm in diameter) \\[[@B1]--[@B3]\\] non-enveloped single-stranded linear DNA virus that was discovered in 1975 by Yvonne Cossart \\[[@B2]\\]. This virus has an icosahedral symmetrical capsid consisting of two structural proteins, viral protein 1 and 2 (VP1 and VP2). The minor capsid protein, VP1, has phospholipase activity that is necessary for viral attachment and cell entry \\[[@B4],[@B5]\\]. The major capsid protein (95% of the total), VP2, can self-assemble into empty capsids, known as virus-like particles (VLPs). In addition to the capsid proteins, there are three non-structural (NS) proteins, two without known functions, but one known as the cytotoxic NS1 protein. NS1 protein, a member of superfamily 3 of viral helicases, is a pleiotropic nuclear phosphoprotein and absolutely required for viral replication. It is a multi-functional protein that has a role in control of cellular transcription, virus replication, induction of cell death, and transactivation of cellular promoters \\[[@B6]--[@B8]\\].\n\nErythroid precursors have been shown to be the demonstrated cell type to best support an B19V productive infection \\[[@B9],[@B10]\\], but other bone marrow hematopoietic lineages support B19V productive infection, although less"
+"Introduction\n============\n\nPopulations of species occupying large geographic ranges are likely to experience different selective pressures ([@ref-91]; [@ref-66]; [@ref-21]) which, together with drift ([@ref-92]), may result in phenotypic and genotypic differences between populations (e.g., [@ref-3]; [@ref-58]; [@ref-1]). Local differences in ecology, such as prey availability (e.g., [@ref-2]; [@ref-8]) or habitat structure (e.g., [@ref-72]; [@ref-79]) can lead to differential adaptation between populations ([@ref-65]), but in species with generalized diets and habitat requirements such variation would have a limited effect on differentiation (e.g., [@ref-86]). On the other hand, environmental variation in the attributes that determine the transmission and reception of signals used in social ([@ref-88]; [@ref-84]; [@ref-87]) or sexual contexts ([@ref-77]) may lead to rapid population differentiation ([@ref-54]; [@ref-78]; [@ref-62]; [@ref-10]). This is because signals used by animals in a breeding context may convey information about the species, sex, breeding status, and even the condition of the sender ([@ref-39]; [@ref-94]), all of which may be relevant to conspecifics searching for mating partners ([@ref-15]; [@ref-28]; [@ref-34]). Geographic variation in mating signals has been widely reported in studies of character displacement, where specific traits (e.g., morphological, behavioral, ecological or physiological traits) differ among sympatric and allopatric populations due to the risk of maladaptive hybridization"
+"Background\n==========\n\nRNA interference (RNAi) provides a powerful tool for silencing gene expression. Large-scale phenotypic or pathway-driven screens of siRNA libraries may help to identify novel genes that may be targets for therapy in cancer and other diseases. Two different methods have been used to construct genome-wide siRNA libraries. One is to chemically synthesize oligonucleotides based on siRNA design algorithms (for reviews, see \\[[@B1],[@B2]\\]). Typically, the oligonucleotides are synthesized in the form of double-stranded DNA molecules containing short hairpin RNA (shRNA) templates and are cloned into a Pol III-driven expression vector. Libraries constructed with this method and targeting more than 10,000 different human genes have been successfully used for screening \\[[@B3],[@B4]\\]. The other method is to convert collections of cDNAs into shRNA templates. Three groups have developed protocols to produce genome-wide shRNA libraries \\[[@B5]-[@B7]\\]. These protocols share several common features, and all \\\"measure\\\" the appropriate length of the hairpin using the type IIS restriction endonuclease MmeI, which cuts 20/18 nt from its recognition site. The common steps, with minor variations, include (1) generating random cDNA fragments; (2) ligating the cDNA fragments with a double-stranded oligonucleotide that contains an MmeI site; (3) restriction digestion with MmeI; (4) ligating a second oligonucleotide"
+"Multilingual abstracts {#Sec1}\n======================\n\nPlease see Additional\u00a0file\u00a0[1](#MOESM1){ref-type=\"media\"} for translation of the abstract into the five official working languages of the United Nations.\n\nBackground {#Sec2}\n==========\n\nMalaria morbidity and mortality have been significantly decreased in Ethiopia and worldwide in the past decade \\[[@CR1]\\]. Ethiopia's fight against malaria started many years ago and transmission of this infectious disease significantly decreased since 1959 \\[[@CR1], [@CR2]\\]. However, malaria still remains a major public health problem in Ethiopia \\[[@CR1]\\]. Ethiopia has a population of nearly 100 million, and it is estimated that \\~\u200968% of the population is at risk of the disease \\[[@CR1], [@CR3]\\]. *Plasmodium falciparum* and *P. vivax* co-exist as major parasite species in Ethiopia \\[[@CR1]\\]. This epidemiologic feature makes malaria control more complicated than in most African countries where *P. vivax* has low or nil endemicity.\n\nMalaria transmission in Ethiopia occurs mainly at altitudes \\<\u20092000\u00a0m, although endemic regions \\>\u20092000\u00a0m have been reported \\[[@CR3]--[@CR5]\\]. The levels of malaria risk and transmission intensity, however, show marked seasonal, inter-annual and spatial variability, with the exception of the southwestern international border low land area where transmission is year-around \\[[@CR6]--[@CR8]\\]. In most regions of the country, the major transmission season is"
+"Introduction {#sec1-1}\n============\n\nCerebral venous thrombosis (CVT) is a rare cause of stroke with highly variable clinical features, heterogeneous predisposing factors, and unspecific brain imaging findings. Depending on the methodology used, the annual incidence of CVT is between 0.22 and 1.32/100,000/year.\\[[@ref1][@ref2][@ref3][@ref4][@ref5]\\] The outcome of patients with CVT varies from complete recovery to permanent neurological deficits.\\[[@ref6][@ref7][@ref8]\\] There are few studies characterizing the clinical and epidemiological experience concerning CVT, and most of them are from large centers or university hospitals. We conducted a retrospective cross-sectional review of case series of CVT from relatively peripheral region of Europe, the Algarve. Our aim was to characterize the clinical manifestations, treatment, risk factors, clinical course, and to estimate the incidence of CVT in the region.\n\nMaterials and Methods {#sec1-2}\n=====================\n\nStudy area {#sec2-1}\n----------\n\nAlgarve is the southernmost region of mainland Portugal with an area of 4,995.6 km^2^. Between the two last censuses in Portugal (2001--2011) the resident population increased from 395,218 to 451,006, and the adult population (\u226515 years) increased from 335,935 to 387,865, respectively.\\[[@ref9]\\] Algarve is essentially served by a net of primary health care units and by three hospitals (Hospital de Faro, Hospital de Portim\u00e3o and Hospital de Lagos) all belonging to"
+"Background\n==========\n\nFor any material, microclimate changes are recognised as main responsible for speeding up their degradation. An indoor environment would reach an equilibrium that generally includes circadian cycles with, at different extent, smaller variation, similar frequency and a certain delay with respect to the outdoor climate (macroclimate). Many examples of how such equilibrium, as defined by Banham's \\[[@B1]\\], must be considered the ideal conservation conditions for artefacts rely on the huge Cultural Heritage Patrimony that survived for hundred and hundred centuries even if in thermohygrometric condition that surely cannot be considered ideal (buried, dived). Unfortunately such equilibrium is incompatible with the enjoying of Cultural Heritage (CH) as all is needed to expose them to public, as well the visitors themselves, create environmental perturbation; so, a compromise must be reached to ensure the longest life of artefacts, as well as of the building containing them, that, in many cases as our one, can constitute the main CH. An accurate microclimate monitoring of such buildings must be the first step in a conservation project both to individuate the spontaneous condition and to design an eventual heating/cooling system (HVAC); the last must be set taking into account the CH safety and not"
+"1. Introduction {#sec1-molecules-22-00518}\n===============\n\nHydrogen bonding (H-bonding) to organic fluorine (C-F) represents a very weak interaction \\[[@B1-molecules-22-00518],[@B2-molecules-22-00518]\\]. Given bioactive compounds typically contain stronger oxygen and/or nitrogen (O/N) based hydrogen-bond (HB) acceptor atoms, intra- or intermolecular HB formation, in solution or in the solid phase, will preferentially involve these groups over a C-F group. The same applies for polar protic solvents (including water). This has been amply demonstrated by crystal structure analysis of fluorinated compounds, where O/N-based HB donors typically form intramolecular (IM) hydrogen bonds with O/N based HB acceptors instead of with fluorine, even when the molecule in question contains many fluorine atoms \\[[@B3-molecules-22-00518],[@B4-molecules-22-00518]\\]. This effect can lead to interesting crystal packing structures, featuring different molecular conformations in the unit cell in order to maximize, say, OH\u00b7\u00b7\u00b7O, at the expense of OH\u00b7\u00b7\u00b7F interactions \\[[@B5-molecules-22-00518]\\].\n\nHowever, in the absence of competing HB acceptors, alcohol groups have shown to form intramolecular HBs with fluorine groups. First described by Biamonte and Vasella \\[[@B6-molecules-22-00518]\\], many groups have now reported such OH\u00b7\u00b7\u00b7F IMHBs through the observation of an OH-F coupling constant (^1^H-NMR) \\[[@B1-molecules-22-00518],[@B7-molecules-22-00518]\\]. The vast majority of these cases involve conformationally constrained systems, though the occurrence of OH\u00b7\u00b7\u00b7F IMHB have recently been demonstrated in acyclic"
+"Introduction {#Sec1}\n============\n\nLung cancer is the most common malignant tumor, constituting the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers, and adenocarcinoma is the predominant histologic subtype at present^[@CR1]^. Although great progress has been made in diagnosis and treatment recently, the long-term clinical prognosis and overall survival of lung adenocarcinoma (LUAD) patients remain unsatisfactory^[@CR2]^. The inadequate comprehension of LUAD-related biological mechanisms limits the improvement in therapeutic efficacies. Thus, it is urgent to further elucidate the involved mechanisms of cancer progression to improve the clinical outcome of LUAD patients.\n\nAberrant expressions of oncogene and tumor suppressor gene are frequently observed in NSCLC and account for the carcinogenesis^[@CR2],[@CR3]^. Benefiting from the advances in high throughput analysis, increasing cancer-related long non-coding RNAs (lncRNAs) have been identified^[@CR4]^. LncRNAs are defined as a class of transcripts longer than 200 nucleotides that lack any detectable open reading frame^[@CR5]^. Accumulative studies have proved that lncRNAs exert pivotal roles in the regulation of gene expression. Aberrant expression of various lncRNAs have been identified in different tumors, including colorectal cancer, gastric cancer, breast cancer, NSCLC, etc.^[@CR6]--[@CR9]^ lncRNAs could function as either oncogene or tumor suppressor gene to participate in"
+"Introduction {#s1}\n============\n\nAssessment of eligibility for antiretroviral therapy (ART) in low and middle-income countries (LMIC) is dependent on CD4 T-lymphocyte enumeration and, if unavailable, WHO clinical staging. [@pone.0088928-Kagaayi1], [@pone.0088928-Jaffar1]. Additionally, CD4 testing is frequently used to monitor patients on ART. In most clinical settings, CD4 enumeration has typically used flow cytometry which has excellent precision, accuracy, and reproducibility. However, flow cytometry requires fresh venous blood and subsequent processing is often at a central facility distant from the sample collection point. Consequently, there is a significant time lapse from sample procurement to return of results, with delays in decisions on ART eligibility and initiation. These delays are a barrier to care and can result in losses to follow-up with negative patient and programmatic outcomes [@pone.0088928-Lawn1]--[@pone.0088928-Stringer1].\n\nPoint-of-care (POC) CD4 T-lymphocyte enumeration is a promising technology that could mitigate many of the barriers and delays associated with flow cytometry and improve access to care. POC CD4 testing could allow timely return of CD4 results to providers and patients, obviating the need for repeated patient visits and rapidly linking patients into care. Several evaluations of POC CD4 technology have been reported, but results have not been entirely consistent, and study settings have been"
+"Introduction {#s1}\n============\n\nOral-facial clefts are common birth defects with an incidence of 1--2 in 1000 live births, thus comprising almost one-half of all craniofacial anomalies. They impose adverse health, social, and economic implications for the affected individuals and their families [@pone.0045441-Gorlin1]. Although the mortality and morbidity of an infant born with a cleft lip and or a cleft palate has improved greatly in the last century, it is still elevated for infants born with multiple additional anomalies. Among the consequences of being born with clefts are shorter life span and increased risk for all major causes of death when compared to individuals without clefts [@pone.0045441-Hujoel1].\n\nCleft lip with or without cleft palate (herein called cleft lip/palate) can be classified as nonsyndromic or syndromic based on the presence of other associated congenital defects. Approximately 20--50% of all cleft cases are associated with one of more than 400 syndromes [@pone.0045441-Christensen1]. Syndromic forms usually present Mendelian inheritance patterns, which allow identification of causal genes. Nonsyndromic cleft lip/palate however, is considered a genetically complex trait with no clearly recognizable inheritance pattern [@pone.0045441-Lidral1].\n\nIdentifying the key genes responsible for the genesis of cleft lip/palate is fundamental for elucidating the pathogenetic mechanisms and developing measures"
+"The food we eat has long been linked to the rate we age. Selective pressures in times of food abundance and scarcity have influenced our very genetic makeup, instilling in our genome genes believed to control the delicate balance between metabolism and aging. However, this balance has been disrupted in western societies with developments in agriculture and technologies that have promoted the intake of high-calorie diets and sedentary lifestyles. We are witnessing an alarming increase in the rate of metabolic syndrome, which consists of a collection of abnormalities including obesity, type 2 diabetes, dyslipidemia, fatty liver, and a pro-inflammatory and prothrombotic state \\[[@R1],[@R2]\\] Currently, one in four adults in the United States suffers from metabolic syndrome and worldwide estimates are over 2.1 billion \\[[@R3],[@R4]\\]. Ultimately, this epidemic threatens human life-span projections and puts great pressure on our already overburdened health care system.\n\nThe sirtuin family of proteins appears to be at the crossroads between nutritional status and longevity. Sirtuins are highly conserved NAD^+^-dependent protein deacetylases and/or ADP ribosyltransferases that target histones, transcription factors, and co-regulators to adapt gene expression in response to the cellular energy state \\[[@R5]\\]. Many members of this family, including the founder Sir2, have been shown to"
+"Introduction {#Sec1}\n============\n\nPreviously, dentin hypersensitivity (DHS) was described as \"an enigma being frequently encountered yet poorly understood\" \\[[@CR1]\\]. More recently, an internationally accepted and widely used definition in the international literature for dentin hypersensitivity is available \\[[@CR2]\\]. Dentin hypersensitivity is characterized by distinctive short, sharp pain arising from exposed cervical dentin in response to various external stimuli that are typically thermal, evaporative, tactile, electrical, osmotic, or chemical, which cannot be ascribed to any other form of dental pathology, defect, or disease (Fig.\u00a0[1](#Fig1){ref-type=\"fig\"}) \\[[@CR3]--[@CR5]\\]. The definition provides a clinical description of the condition and identifies dentin hypersensitivity as a special clinical entity \\[[@CR6]\\]. The most frequently experienced pain from dentin hypersensitivity is characterized by a rapid onset, sharp burst of pain of short duration strongly assigned to the application time and site of the used stimuli. Since several oral conditions may cause dental pain, such as untreated caries, a cracked tooth or marginal leakage around insufficient restorations, the diagnosis of dentin hypersensitivity can be very difficult \\[[@CR2], [@CR7], [@CR8]\\]. Although there are numerous publications on all topics related to dentin hypersensitivity, a relatively high number of dental professionals are confused about the diagnosis, etiology, predisposing factors, and mechanism of"
+"INTRODUCTION\n============\n\nMaxillary expansion has been used for more than 150 years[@B1] and is a widely accepted procedure performed by orthodontists to correct posterior crossbite and transverse maxillary deficiency. To promote maxillary expansion, three treatment modalities are used today: rapid maxillary expansion (RME), slow maxillary expansion (SME) and surgically-assisted rapid palatal expansion (SARPE). Also, tooth-borne, bone-borne, tooth-tissue-borne, and hybrid (combination of two types) expanders are used to provide the maxillary expansion. The tooth-tissue-borne expander, which is recommended by Haas,[@B2] is the most commonly used type.\n\nDifferent rates of the screw activation can result in RME or SME.[@B3] ^,^ [@B4] Using the jackscrew expander, RME is usually defined as two turns per day, while SME is defined as one turn every other day or at a greater interval.[@B5] RME has been extensively used, and the greatest changes have been reported on the transverse plane (skeletally and dentally).[@B4] But some limitations also have been reported, such as excessive tipping of anchorage teeth.[@B6] Also, SME produces less tissue resistance around circummaxillary structures, improving bone formation, which theoretically should eliminate or reduce some limitations of the RME.[@B7] ^-^ [@B9]\n\nIt has been established that excessive tooth movements in the facial or buccal directions can"
+"Introduction {#s1}\n============\n\nMany RNA viruses have evolutionary rates that hover near the mutational speed limit [@pcbi.1000581-Zeldovich1] permitting them to generate incredible sequence variability among circulating strains in a relatively short time [@pcbi.1000581-Gaschen1]. Bottleneck events, such as viral introduction to new populations or species of hosts, followed by diversification in the new environments, create easily discernible substructures within individual viral species. For HIV-1, this substructure consists of 3 groups (M, N and O), 9 \"pure\" subtypes (A--D, F, G, H, J and K) of group M, and sub-subtypes (e.g. A1, A2, F1 and F2), defined entirely on the basis of phylogenetic clustering and monophyly of sequences from a given subtype in relation to all other subtypes [@pcbi.1000581-Robertson1]. The geographic distribution of HIV-1 subtypes is decidedly non-random [@pcbi.1000581-Hemelaar1]; for example of HIV-1 circulating in North America is classified as subtype B, whereas the same subtype accounts for only of infections in Southern Africa. This observation immediately suggests that reliable determination of viral subtypes is highly informative for epidemiological surveillance. HIV-1 diversity is sufficiently high to permit further stratification of subtypes by the geographic region of origin, yielding further clues to epidemiological history of modern epidemics [@pcbi.1000581-Gifford1]. However, because several established subtypes"
+"The datasets generated and/or analyzed during the current study are not publicly available to preserve the confidentiality of the respondents due to the highly sensitive data collected. These are restricted by a Data Access Committee constituted by Rakai Health Sciences Program and headed by the Director for Research. All data requests are submitted to Dr Godfrey Kigozi (<gkigozi@rhsp.org>) who chairs the data access committee. Dr Kigozi shares a data request form which is filled by the person requesting for these data. The form has space where the requester documents why there is a need for these data and how they are going to be manipulated.\n\nIntroduction {#sec005}\n============\n\nReproduction is dyadic in nature. People incorporate their partner's reproductive desires into their own intentions and adjust their pregnancy-seeking/avoiding behaviors.\\[[@pone.0210935.ref001]\\] In Sub-Saharan Africa (SSA), patriarchal gender norms often lead men to be the dominant influencers in decision-making issues related to fertility and family planning,\\[[@pone.0210935.ref002]\\] despite women's central socio-biological roles in the reproduction and procreation processes.\\[[@pone.0210935.ref003]\\] Moreover, when partner desires differ, men's preferences around pregnancy intentions, planning and prevention tend to be more influential than women's preferences and desires.\\[[@pone.0210935.ref004]\\] Studies that fail to address the differentiating roles of men and women in fertility"
+"Background {#Sec1}\n==========\n\nPrimary respiratory disease in systemic lupus erythematosus (SLE) seems not uncommon, although its exact prevalence is still unknown, since it has been reported to occur in 5% to 90% of the patients \\[[@CR1]--[@CR6]\\]. This wide range in prevalence may be explained by the characteristics of the patients studied (early or established disease), whether only symptomatic patients were included or systematic screening was done, the methodology used for diagnosis (clinical manifestations and imaging or autopsy findings), and the different study designs.\n\nAll components of the respiratory system may be affected during the course of disease. The spectrum of pulmonary manifestations caused by SLE includes pleural disease, upper and lower airway dysfunction, primary pulmonary hypertension, pulmonary thromboembolism, acute reversible hypoxemia, diffuse interstitial lung disease, acute lupus pneumonitis, diffuse alveolar hemorrhage, and shrinking lung syndrome \\[[@CR1]--[@CR16]\\]. Some patients may have more than one form of pleuropulmonary involvement during the course of their disease. The severity of these respiratory complications is highly variable and ranges from subclinical to potentially life-threatening conditions.\n\nIn general terms, primary respiratory involvement in SLE is not as well known as other major organ involvement. As in many other aspects of SLE, there is still no clear"
+"Introduction\n============\n\nCOVID-19 frequently presents as mild or uncomplicated illness. About 14% develop severe disease and 5% require intensive care \\[[@B1]\\].\n\nCOVID-19 can be complicated by the severe acute respiratory infection (SARI) and often multisystem involvement is encountered \\[[@B2]\\].\n\nSARI is defined as \"an acute respiratory illness with a history of fever or measured fever of \u226538\u00b0C and cough, with onset within the past 10 days, requiring hospitalization\" \\[[@B3]\\].\n\nSARI increases morbidity and mortality associated with COVID-19.\n\nThis potentiates the need to review the clinical management of SARI in detail and determine the existing knowledge of healthcare professions currently working in various hospital settings related to COVID-19 treatment.\n\nIn a survey conducted among patients in India with SARI, a total of 104 (1.8%) of the 5,911 SARI patients tested were positive for COVID-19 and the number of patients is still on the rise \\[[@B4]\\].\n\nCOVID-19 presenting as SARI mandates the need for ICU (Intensive Care Unit) hospitalization and mechanical ventilation which increases cost of healthcare \\[[@B5],[@B6]\\].\n\nThe sudden rise of the pandemic has placed tremendous demands on both public health and healthcare systems, and also on providers of essential community services \\[[@B7]\\].\n\nThus, appropriate knowledge of SARI and its management"
+"V. Dubreuil\\'s present address is UMR 8542, Centre National de la Recherche Scientifique, Ecole Normale Sup\u00e8rieure, F-75005 Paris, France.\n\nAbbreviations used in this paper: DIC, differential interference contrast; E, embryonic day; HH, Hamburger and Hamilton; mRFP, monomeric red fluorescent protein; NE, neuroepithelial.\n\nIntroduction\n============\n\nThe midbody is a transient structure formed during the final stage of cell division ([@bib18]; [@bib47]). Its main cytoplasmic components are the constricted actomyosin-based contractile ring and microtubule bundles derived from the central spindle ([@bib42]; [@bib18]). Often in association with these two scaffolds, numerous proteins involved in cytoskeletal organization, cytokinesis, cell cycle regulation, and signaling are concentrated at the midbody ([@bib18]; [@bib58]; [@bib59]; [@bib47]). Two principal membrane structures exist at the midbody---the plasma membrane, which corresponds to that of the cleavage furrow, and cytoplasmic membrane vesicles of biosynthetic and endocytic origin, which fuse with the plasma membrane for abscission, the terminal step of cytokinesis ([@bib18]; [@bib35]; [@bib58]; [@bib22]; [@bib37]; [@bib47]). Beyond abscission, little is known about membrane traffic events involving the midbody.\n\nAs for the midbody, microtubule bundles are key cytoskeletal elements of primary cilia ([@bib50]; [@bib61]; [@bib51]). However, in contrast to the midbody, which forms during M phase, primary cilia are plasma membrane protrusions of"
+"A global public health problem in both developing and developed countries, hepatitis C virus (HCV) has infected 130 to 150 million individuals globally according to the World Health Organisation. The annual increase of HCV infection is approximately 3.5 million ([@ref1]). A significant number of those who are chronically infected will develop liver cirrhosis, hepatocellular cancer and liver failure ([@ref2]), and more than 70% of patients with HCV infection develop chronic infections leading to end-stage liver diseases or even death ([@ref3]). Only 15-45% of infected patients successfully eliminate the virus spontaneously. In Asia, more than 100 million individuals may be chronically infected with HCV ([@ref4]). Recent data suggest that the prevalence of HCV infection ranges from 0.43% to 3.2% in the Chinese population, and varies geographically and temporally in China ([@ref5]). HCV is a blood borne virus and the major modes of transmission are through inadequate sterilisation of medical equipment, unsafe injection practices, sexual contact and unscreened blood or blood product transfusion.\n\nThe Duffy blood group antigens, recently renamed atypical chemokine receptor 1 (ACKR1) ([@ref6]), are glycoproteins expressed mainly in erythrocytes, in endothelial cells throughout the body, and in cerebellar neurons ([@ref7]). The Duffy gene is situated on chromosome 1 at"
+"Introduction {#Sec1}\n============\n\nThe proportion of children under 5\u2009years of age who are stunted is an indicator for the Sustainable Development Goals 2 (SDG 2.2) \\[[@CR1]\\]. Restricted growth as a result of inadequate nutrition and infections is an important cause of morbidity and mortality in children under 5\u2009years \\[[@CR2], [@CR3]\\]. Low educational level, poor access to water and sanitation and health services, as the insufficient household income are some of the determinants of the nutritional state \\[[@CR4]\\]. There have been estimates of trends in national prevalence of stunting, underweight, and wasting by country and by region showing an important reduction in these conditions in children under 5\u2009years in the last decade \\[[@CR5]\\]. Global estimates indicate that the prevalence of stunted children under 5 declined from 40% in 1990 to 24% in 2014 \\[[@CR6], [@CR7]\\]. Economic development, improvements in health systems and progress towards universal coverage have contributed to improved health outcomes for women and children globally \\[[@CR8]\\]. However, the complex interrelation of social, economic, and political determinants of undernutrition results in substantial inequalities between population subgroups \\[[@CR9]\\]. This is especially observed in Latin American countries where health inequalities are still treated as a major concern \\[[@CR10]\\].\n\nThe"
+"Introduction {#s1}\n============\n\n*Pseudomonas aeruginosa* is a highly heterogeneous species whose members show various levels of pathogenicity towards plants and animals [@pone.0060575-He1], [@pone.0060575-Rahme1]. It is widely distributed in the environment and is a normal human commensal. *P. aeruginosa* is naturally resistant to many drugs and its capacity to form biofilms makes it very difficult to eradicate, particularly in chronically infected cystic fibrosis (CF) patients [@pone.0060575-Davies1], [@pone.0060575-Lipuma1].\n\nDue to the recent increase in multidrug resistant bacteria, phage therapy is being considered as a therapeutic alternative to antibiotics [@pone.0060575-Kutter1], [@pone.0060575-Abedon1]. It has been used since soon after the 1917 discovery of bacteriophages by Felix d\\'Herelle at the Pasteur Institute in Paris, mostly in countries of Eastern Europe. Although controlled studies were seldom available, its efficacy has been clearly demonstrated in numerous cases [@pone.0060575-Chanishvili1], [@pone.0060575-Miedzybrodzki1]. Phages have the capacity to reach bacteria trapped inside biofilms such as those that form in the lung of cystic fibrosis patients [@pone.0060575-Brussow1], [@pone.0060575-Alemayehu1]. Therapeutic cocktails such as the \"pyophage\" formulation widely used in Georgia to treat purulent skin, wound and lung infections, contain many different phages against each of their target pathogens (which are *staphylococcus*, *streptococcus*, *proteus*, *Escherichia coli* and *P. aeruginosa*, for pyophage). Each set must"
+"Introduction {#section1-0047287513478505}\n============\n\nThe tourism sustainability debate has drawn increased attention to the environmental factors of destinations. However, the role and importance of environmental resources had been embedded in tourism research long before this environmental debate began ([@bibr33-0047287513478505]; [@bibr43-0047287513478505]). Many tourism researchers have studied environmental resources' tourism potential and how they trigger tourism demand and bring value to a destination. Initially, the researchers' interests in the issue was merely academic; however, given the increasing environmental awareness in society and the fact that tourism may cause the deterioration of environmental resources and force mass tourism destinations into economic decline, researchers have become interested in this issue for policy relevance reasons. For destinations, environmental issues are now more important than ever before and are now an integral part of their sustainable development strategies. The \"new tourists,\" defined by [@bibr46-0047287513478505] more than a decade ago, are ecologically aware; they demand more environmental resource--based experiences and are becoming sensitive to the actual environmental quality of destinations, which increasingly influences their price--quality ratio judgments. For example, research on the Balearic Islands ([@bibr1-0047287513478505]) has shown that tourists have become increasingly demanding in regard to the natural surroundings and their quality. Indeed, in the late twentieth century,"
+"Background {#Sec1}\n==========\n\nAminoglycosides remain important antibiotics in current clinical practice and are widely used globally. Their antibacterial effect includes enterococcus, mycobacteria, and especially multi-drug-resistant Gram-negative bacteria \\[[@CR1]\\]. However, their clinical usefulness is limited by their ototoxicity and nephrotoxicity \\[[@CR2]\\]. Aminoglycosides cause ototoxicity in 2--25% of patients and if high-frequency hearing loss is tested, half of all patients may be affected \\[[@CR3]\\]. The exact mechanism of GM-induced ototoxicity is unclear. The main signal transduction pathway of hair cell damage is ROS production and resulting apoptosis \\[[@CR1], [@CR4]\\]. One signaling pathway activated by aminoglycosides via ROS is the c-Jun N-terminal kinase (JNK) pathway, which contributes to cell apoptosis \\[[@CR5]\\]. One of the downstream targets of JNK is the transcription factor, activating protein-1, the main component of which is c-Fos protein \\[[@CR6]\\].\n\nGentamicin (GM), which is one of the most commonly used aminoglycoside antibiotics, can induce hearing loss and balance disturbance due to the destruction of cochlear and vestibular hair cells \\[[@CR7]\\]. The exact mechanism of GM-induced ototoxicity is unclear. The main signal transduction pathway of hair cell damage involves reactive oxygen species (ROS) production and resulting apoptosis \\[[@CR1], [@CR4]\\]. Protection of hair cell damage is an important target for the prevention"
+"Introduction\n============\n\nItraconazole (ITZ, [Figure 1](#f1-dddt-9-2801){ref-type=\"fig\"}) is a triazole antifungal agent with a broad spectrum of activity, including activity against a variety of lethal species such as *Aspergillus*, *Candida albicans*, and non-*Albicans* species, and is generally well tolerated.[@b1-dddt-9-2801],[@b2-dddt-9-2801] The solubility of ITZ in deionized water is lower than 1 ng/L, whereas its lipophilicity (log*P*\\>5) and permeability across biomembranes are very high, which is typical of class II drugs according to the Biopharmaceutics Classification System.[@b3-dddt-9-2801] Because ITZ is a weak base (p*K* a =3.7), its aqueous solubility is highly pH dependent, with approximate saturation solubility of 4 \u03bcg/mL at pH 1.0. Thus, ITZ is ionizable and can be only solubilized at low pH values, for instance, in the stomach.[@b4-dddt-9-2801] The oral bioavailability and clinical efficacy of ITZ is significantly compromised mainly due to its extremely poor water solubility. The low dissolution rate is the rate-limiting step in ITZ absorption from the gastrointestinal tract. There is a demand to improve the dissolution of ITZ so as to enhance its oral bioavailability.\n\nVarious techniques have been used to improve the solubility of poorly water-soluble drugs, including using surfactants,[@b5-dddt-9-2801] inclusion complexation,[@b6-dddt-9-2801],[@b7-dddt-9-2801] and solid dispersion (SD) techniques.[@b8-dddt-9-2801] For example, the SD technique has been well"
+"1. Introduction {#sec1-jcm-07-00428}\n===============\n\nAnalytics for predicting postoperative morbidity has been limited to the classical statistic techniques, such as logistic regression analysis and the Cox proportional hazard model. However, these models require the statistical assumption of the independent and linear relationship between explanatory and outcome variables. Furthermore, limitations of overfitting and multicollinearity of the regression analysis preclude the analysis of a large number of variables. These limitations have made prediction models to select a small number of variables that are known to be clinically relevant.\n\nRecently, novel machine learning techniques have demonstrated improved predictive performance compared to classical statistical methods limited to logistic regression. For example, there have been reports of using machine learning techniques to predict postoperative clinical outcomes including specific morbidity or in-hospital mortality \\[[@B1-jcm-07-00428],[@B2-jcm-07-00428],[@B3-jcm-07-00428]\\]. Compared to the logistic regression or Cox proportional hazard model, reports using machine learning techniques have shown lower prediction error. For acute kidney injury, previous studies demonstrated that machine learning techniques have excellent performance or better performance compared to logistic regression analysis in hospitalized patients \\[[@B4-jcm-07-00428]\\] or patients undergoing major surgery \\[[@B5-jcm-07-00428]\\]. However, although previous studies used different techniques of machine learning, including neural network \\[[@B1-jcm-07-00428],[@B2-jcm-07-00428]\\], random forest \\[[@B3-jcm-07-00428]\\], support vector machine \\[[@B5-jcm-07-00428]\\],"
+"Introduction {#Sec1}\n============\n\nLymphomas are the second most common indication for autologous hematopoietic stem cell (HSC) transplantation (HSCT). The most common method for mobilizing HSCs from the peripheral blood is treatment with granulocyte-colony stimulating factor (G-CSF) alone or combined with chemotherapy \\[[@CR1], [@CR2]\\]. However, a sizable minority of patients fail to mobilize sufficiently with G-CSF-based regimens \\[[@CR3], [@CR4]\\].\n\nPlerixafor has a mode of action different from other HSC mobilizing agents and acts by binding to chemokine (C-X-C motif) receptor 4 (CXCR4), preventing the binding of its ligand stromal cell-derived factor 1 (SDF-1, now C-X-C motif chemokine 12, CXCL12) and thereby inhibiting events downstream of CXCL12 including SDF-1-mediated G-protein activation, receptor internalization, calcium flux, and chemotaxis \\[[@CR5], [@CR6]\\]. The CXCL12/CXCR4 interaction is an integral part of the mechanism of homing and retention of HSC in the bone marrow and inhibition of this interaction by plerixafor mobilizes HSCs from the bone marrow \\[[@CR7], [@CR8]\\]. Unlike cytokines used for HSC mobilization (e.g., G-CSF), plerixafor is not a growth factor and does not cause cell proliferation or expansion. Therefore, the approved use for plerixafor is in combination with G-CSF \\[[@CR9], [@CR10]\\].\n\nAs there is a theoretical risk of tumor cell mobilization with any stem"
+"INTRODUCTION\n============\n\nChronic hepatitis B, which results from hepatitis B virus (HBV) infection, is widespread in Korea. In 2009, the prevalence of hepatitis B surface antigen (HBsAg), a marker of HBV infection, was 3.2% in Korea.^[@r01]^ Chronic HBV infection can lead to the development of liver cirrhosis and/or hepatocellular carcinoma.^[@r02]^ The majority of chronic HBV infections in Korea are acquired in the perinatal period, though some HBV infections are acquired via horizontal transmission.\n\nMetabolic syndrome, also known as insulin resistance syndrome, is a constellation of metabolic disorders, including increased waist circumference, hyperglycemia, elevated blood pressure, and an abnormal lipid profile. In Korea, the prevalence of metabolic syndrome has increased markedly in recent years, from 24.9% in 1998 to 31.3% in 2007.^[@r03]^ Metabolic syndrome is associated with liver diseases, including non-alcoholic fatty liver disease, chronic hepatitis C virus (HCV) infection, and hepatocellular carcinoma. Non-alcoholic fatty liver disease is a hepatic manifestation of metabolic syndrome.^[@r04]^ In chronic hepatitis C, metabolic syndrome is a potential independent predictor of liver-related mortality.^[@r05]^ Insulin resistance reduces the response to anti-HCV treatment.^[@r06]^ Metabolic syndrome is a possible risk factor for hepatocellular carcinoma, independent of the hepatitis virus.^[@r04],[@r07]^ However, to the best of our knowledge, there are few"
+"Introduction\n============\n\nRheumatoid arthritis (RA) is an autoimmune chronic inflammatory disease of unknown aetiology that is characterized by infiltration of monocytes, T cells and polymorphonuclear cells into the synovial joints. The pathogenesis of this disease is still poorly understood, and fundamental questions regarding the precise molecular nature and biological significance of the inflammatory changes remain to be answered \\[[@B1],[@B2]\\]. A powerful way to gain insight into the molecular complexity and pathogenesis of arthritis has arisen from oligonucleotide-based microarray technology \\[[@B3]\\], because this platform provides an opportunity to analyze simultaneously the expression of a large number of genes in disease tissues.\n\nThe earliest preclinical stages of human RA are not easily accessible to investigation, but a diverse range of experimental arthritis models are considered valuable tools for delineating mechanisms of inflammation and autoimmune phenomena. An animal model that shares some of the hallmarks of human RA is the reactivation model of streptococcal cell wall (SCW)-induced arthritis in rats. In this model, a synovitis with maximal swelling at 24 hours is induced by local injection of SCW antigen directly into an ankle joint. The initial response is reactivated by systemic (intravenous) challenge with SCW, which produces a more prolonged and severe inflammation"
+"INTRODUCTION\n============\n\nAvian paramyxovirus-1 (APMV-1), the causative agent of the Newcastle Disease (NDV), is classified as a member of genus *Avulavirus* in the family *Paramyxoviridae* ([@b14], [@b15]). Newcastle disease (ND), one of the most important viral diseases in industrial aviculture ([@b3]), affects domestic poultry and wild birds and may cause acute mortality marked by hemorrhagic lesions, respiratory and apparent or unapparent enteric infections, among others. Therefore, the etiopathogenic diagnosis should be conventionally based on isolation and biological characterization of field samples ([@b29]).\n\nNDV detection and pathotyping of avian isolates are extremely important because the appearance of virulent virus has significant economic consequences related to vaccination and eradication, impairing the ability of a given geographic region to export poultry products ([@b24]).\n\nThe widespread presence of lentogenic strains in feral birds and the use of such viruses as live vaccines mean that isolation of NDV is not enough to confirm a disease diagnosis and compliance with statutory requirements that may be in place ([@b8]). Viral characterization using the pathogenicity test or nucleotide sequencing are also required, as the importance and impact of a given NDV isolate are directly related to its virulence. Once analysis of a given field disease solely may be"
+"Introduction {#s1}\n============\n\nDespite the immediate and seemingly far reaching devastation that follows intense natural disturbances, there is an extensive literature showing that such events can ultimately generate environmental conditions favourable to the survival, growth and diversification of living organisms and ecosystems, at least as measured by species diversity [@pone.0028645-Connell1]--[@pone.0028645-Holt1]. Recently, studies have shown parallel responses to disturbance between species and genetic diversity with variation between-sites (beta diversity) increasing and within-sites (alpha diversity) decreasing [@pone.0028645-Vellend1]--[@pone.0028645-Evanno1]. However, within species the impact of catastrophes which result in severe reductions in population sizes are neither predicted nor known to result in the promotion of genetic diversity. Rather, the outcome of such population bottlenecks is usually the loss of genetic variation, the severity of which depends on both the intensity and duration of the crash and the subsequent rate of recovery and immigration [@pone.0028645-Wright1]--[@pone.0028645-Vignieri1]. Furthermore, while genetic diversity has been shown to enhance species and even ecosystem resilience to catastrophic disturbances [@pone.0028645-Hughes1]--[@pone.0028645-Reusch1], the reverse i.e. catastrophes enhancing genetic diversity, is yet to be demonstrated.\n\nCircumstances allowing for testing the impact of catastrophes on any aspect of ecosystem and evolutionary dynamics are highly unusual due to the longitudinal nature of the work required combined with"
+"Introduction\n============\n\nWeed management in maize production is essential to maximize yield and to achieve a good harvest. Glyphosate is a broad-spectrum herbicide possessing several desirable characteristics, such as environmental safety, broad-spectrum mode-of-action, and low cost ([@B44]). The development of transgenic glyphosate-tolerant crop cultivars has allowed this non-selective herbicide to be used for post-emergence weed control in crops. Glyphosate is the only commercial herbicide which operates by blocking the activity of the enzyme 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) ([@B44]). Extensive research has illustrated that tolerance of high concentrations of glyphosate depends on the expression of an EPSPS with a low binding affinity for glyphosate ([@B8]). Genetic engineering of the *cp4-epsps* gene from *Agrobacterium tumefaciens* strain CP4 into maize and other crops achieved glyphosate-specific herbicide tolerance and subsequently improved the control of weeds in these transgenic crop cultivars ([@B16]).\n\nAn important step in plant breeding is selection (usually more accurately described as \"screening\"), by which superior plant phenotypes are identified for the development of improved cultivars better suited to the needs of farmers and consumers. Visual phenotypic selection can be slow and inefficient, particularly with respect to quantitative traits. Glyphosate is a relatively slow-acting herbicide, and visual assessment of herbicide injury may take"
+"1.. Introduction\n================\n\nThere have been widespread interest in and applications of \"shrinkage\" estimators in epidemiology and demographic analysis for the purposes of smoothing spatial fluctuations, stabilizing estimates, and reducing sampling and non-sampling errors \\[[@b1-ijerph-07-00380]--[@b4-ijerph-07-00380]\\]. Prior researches have also demonstrated that the coefficient shrinkage is potentially useful for selection of epidemiological models and control of multiple confounders using modern hierarchical modeling techniques \\[[@b5-ijerph-07-00380],[@b6-ijerph-07-00380]\\]. The term shrinkage refers to a statistical phenomenon that the posterior estimate of the prior mean is shifted from the sample mean towards the prior mean \\[[@b7-ijerph-07-00380]\\]. The Bayesian approach to the shrinkage estimation is to use the prior distribution and the likelihood (based on the data) to determine the posterior distribution. It has been regarded as empirical Bayes shrinkage (EBS), when there is no information for the prior, and the observed data are employed to postulate the prior distribution, assuming the sample means were drawn from the same population \\[[@b8-ijerph-07-00380]\\].\n\nThe shrinkage estimator was first proposed by Stein \\[[@b9-ijerph-07-00380]\\] in the 1950s as an alternative to the ordinary least squares (OLS) estimator *i.e.* the sample mean to produce smaller mean squared errors. In epidemiology, the EBS has been increasingly used for stabilizing disease incidence, prevalence and"
+"Introduction\n============\n\nAccording to Global Cancer Statistics 2018, there will have been approximately 18.1 million new cancer cases and 9.6 million death cases worldwide [@B1]. Researchers around the world are constantly striving to improve the medical technology for providing more sensitive method for tumor diagnosis and effective approach for tumor therapy. However, due to the complexity of tumor formation mechanism, it is far from enough to understand the nature of cancer from the genetic layer in the traditional sense [@B2]. It is recognized that the expression of oncogene depends not only on the gene itself, but also on epigenetic modification without changing gene sequence [@B2],[@B3].\n\nEpigenetics is a research hotspot in recent years, which is defined as no change in DNA sequence, but with heritable changes in gene expression [@B3]. Previously, the epigenetic researchers are mainly focused on DNA and histone modifications. It was even believed that, for example, mRNA only played the role in information transmission. However, with the rapid development of high-throughput sequencing technology, it is found that mRNA also undergo various modifications such as N6-methyladenosine (m^6^A), N1-methyladenosine (m^1^A) and pseudouridine methylation during the process of exon splicing, 5\\'-capping and 3\\'-tailing [@B4]-[@B6]. These modifications will then affect mRNA"
+"Introduction {#Sec1}\n============\n\nThe North American Multi-Model Ensemble (NMME) was established as a means of exploiting a highly useful and somewhat counter-intuitive property of seasonal forecast models. Multi-model ensemble means (MMEMs), where multiple instances of different models are combined, typically have higher forecast skill than the individual models they are composed of (e.g. Palmer et al. [@CR20]; Jin et al. [@CR13]; Kirtman et al. [@CR16]). This property has resulted in the pursuit of multi-model ensembles (MMEs) as a means of improving intraseasonal to interannual (ISI) prediction capabilities. The success of the MME methodology combined with the straightforward, but not simple, nature of its implementation led to the creation of the National (now North American) Multi-model Ensemble (Kirtman et al. [@CR16]). This initial effort consisted of an extensive hindcast dataset, as well as real-time forecasts, composed of integrations from numerous prominent North American models, including the current US operational seasonal forecast system (Coupled Forecast System version 2; CFSv2). Following the initial success of the NMME (sometimes referred to as Phase-1) a second effort, is ongoing, with updated models and an experimental design more closely in line with the needs of the operational community.\n\nThe NMME data represents one of the most"
+"1. Introduction {#sec1-microarrays-04-00407}\n===============\n\nOver the past decade there have been a large number of studies that have explored the biological impact of constitutional (inherited and *de novo*) copy number variants (CNVs) in the human genome \\[[@B1-microarrays-04-00407],[@B2-microarrays-04-00407]\\]. CNVs are structural rearrangements that increase or decrease DNA content at regions larger than 50 base pairs (bps) in size \\[[@B1-microarrays-04-00407],[@B2-microarrays-04-00407]\\], accounting for a majority of genetic variation in humans based on bp coverage. These variants are estimated to cover 5%--10% \\[[@B2-microarrays-04-00407]\\] of the human genome which is at least an order of magnitude greater than the number of bps (\\~15 Mbps; dbSNP Human Build 142) encompassed by the more commonly studied single nucleotide polymorphisms (SNPs).\n\nMolecular technologies used to profile DNA copy number, such as microarrays (SNP-based arrays and comparative genomic hybridisation) and next-generation sequencing, have led to the identification of more than 300,000 CNVs, or 21,757 unique CNV loci in the human genome \\[[@B3-microarrays-04-00407]\\] . These technologies have also revealed the extent to which constitutional CNVs partially overlap or fully encompass genes and/or regulatory sequences. Concomitant gene expression analyses have shown a strong relationship between copy number dosage and mRNA levels with hundreds of genes \\[[@B4-microarrays-04-00407],[@B5-microarrays-04-00407]\\]. This functional effect can play"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec001}\n============\n\nIn the mammalian ovary, folliculogenesis is critically regulated to provide fertilizable oocytes for the duration of a female's reproductive life. In vitro growth (IVG) of mammalian follicles could be a promising tool for use with assisted reproductive technologies (ART) to derive large quantities of fertilizable oocytes derived from immature follicles. Moreover, this system could provide a valuable research tool for further elucidation of the poorly understood molecular mechanisms of folliculogenesis. Therefore, establishing an in vitro follicle culture model that can accurately mimic the in vivo ovarian growth environment has been crucial. Until now many different approaches have been used with varying success, however, a single standard protocol has yet to be established, even in a model species such as the mouse \\[[@pone.0143114.ref001]\\]. The difficulties of in vitro follicle development originate in the unique features of the follicle. Individual follicles within the ovary feature a vascular system built up around a 3-D structure in which the oocyte is surrounded by follicular cells \\[[@pone.0143114.ref001]\\]. Growth of the oocyte is critically dependent on autocrine and paracrine bidirectional signaling between the oocyte and the surrounding follicular cells \\[[@pone.0143114.ref002]--[@pone.0143114.ref003]\\]. Due"
+"Regulation of nociception is essential for survival in all animals. Lack of nociception and pain results in frequent injury without awareness[@b1][@b2], while strong pain can be an obstacle to prompt responses such as fight or flight. It has been shown that pain is remarkably attenuated in soldiers during combat[@b3] or in athletes during competition[@b4]. In these cases, the descending pain modulatory system regulates the strength of pain by sensing multiple factors such as stress, emotion and cognitive state[@b5][@b6] in a context-dependent manner.\n\nOrexin (hypocretin)-producing neurons (orexin neurons) in the hypothalamus are major regulators of wakefulness[@b7][@b8]. Two mature peptides, orexin A and orexin B, are derived from a precursor peptide, prepro-orexin. Orexin A and B are 46% homologous, and the sequence of orexin A is fully conserved across mouse, rat and human[@b9]. This fact strongly suggests the importance of these peptides for survival. A small number of orexin neurons are exclusively localized to the lateral hypothalamic area (LHA), but send their axons throughout the brain[@b10][@b11] and even into the spinal cord[@b12]. As expected from this projection pattern, orexin neurons have multiple physiological functions not only in wakefulness but also in feeding[@b13][@b14], reward[@b15][@b16] and nociception[@b17][@b18][@b19].\n\nCentral administration of orexin peptides reduces nociceptive"
+"Introduction {#Sec1}\n============\n\nFor many years there is an urgent need in the field of regenerative medicine to develop replacements of non-functional tissues. One way is to carry out the transplantation, but the success of this strategy is\u00a0complicated by immune reactions to allogeneic or xenogeneic grafts or deficiency of donor tissue. Therefore, many laboratories try with great effort to develop resorbable tissue scaffolds that could support the patient\u00b4s cells. The scaffold material should be biocompatible, i.e., non-toxic and non-immunogenic, biodegradable, and at the same time, ecological and easy to manufacture, thus economically viable.\n\nIn orthopaedic non\u2010load bearing devices or dental implants, the preferred materials can be resorbable ceramics chemically similar to the inorganic component of the bone tissue, such as hydroxyapatite^[@CR1],[@CR2]^. However, its biocompatibility should be adjusted to match that of autografts. It improves by increasing the hydrophilicity of the hydroxyapatite surface, especially the inner surface of its pores^[@CR3]^. Load-bearing implants are preferentially made of metals due to their mechanical properties. The dominant materials became titanium\u2010based alloys that are generally well tolerated *in vivo*^[@CR4],[@CR5]^. However, these materials fail to encourage osseointegration on the cellular level actively, so the adjustment of their parameters could also be useful^[@CR6]^.\n\nIn soft tissue"
+"1. Introduction {#sec1-molecules-20-18016}\n===============\n\nNanomedicine offers fascinating opportunities for new medical treatments and diagnosis. Here, especially superparamagnetic iron oxide nanoparticles (SPION) have received scientific interest in tissue engineering, drug delivery, hyperthermia and magnetic resonance imaging techniques \\[[@B1-molecules-20-18016],[@B2-molecules-20-18016]\\]. In addition, these particles can be used as a platform for targeted delivery of drugs to the desired region, guided by an external magnetic field, referred to as \"magnetic drug targeting\" (MDT) \\[[@B3-molecules-20-18016],[@B4-molecules-20-18016],[@B5-molecules-20-18016],[@B6-molecules-20-18016]\\]. MDT has been used for the accumulation of chemotherapeutics, antibiotics or thrombolytic agents in tumors, infection sites or thrombosis \\[[@B7-molecules-20-18016],[@B8-molecules-20-18016],[@B9-molecules-20-18016]\\], where the specific accumulation of drugs in the desired region increases therapeutic efficacy and reduces adverse side effects compared to systemic application \\[[@B10-molecules-20-18016]\\]. Especially for cancer therapy, in the last few years, numerous promising SPION systems with various drug loadings have been developed for the translation from bench to bedside \\[[@B11-molecules-20-18016],[@B12-molecules-20-18016]\\]. Therapeutic success using MDT *in vivo* has already been shown in the treatment of tumor-bearing rabbits employing mitoxantrone (MTO)-loaded iron oxide nanoparticles \\[[@B13-molecules-20-18016],[@B14-molecules-20-18016]\\].\n\nAlthough this new technology can offer great therapeutic advantages, the increasing applicability of drug-loaded nanoparticles requires detailed knowledge of their therapeutic and toxicological impact. So far, numerous studies, showing the effective killing of tumor cells by"
+"1.. Introduction {#S0001}\n================\n\nPorous ceramics are used in a variety of applications where high permeability is required, such as filtration of gases and liquids or catalytic supports.\\[[@CIT0001]\\] The main processing methods are extrusion, ceramic replication of an organic template, and direct foaming of a ceramic suspension. The final properties of porous ceramics are dependent on the processing technique and the resultant microstructure.\n\nIn general, ceramics processed by the replica method exhibit accurate porosity control and the pore size is relatively large (200--3000 $\\mathit{\\mu}$m), although the hollow struts characteristic of the replica method have a deleterious effect on strength.\\[[@CIT0002]\\] In contrast, materials obtained by direct foaming have higher mechanical properties compared to the replica method but larger pore size distribution and consequently a lower permeability.\\[[@CIT0003]\\] The microstructural effects on permeability of porous ceramics have been extensively studied in different cellular structures. Innocentini et al. \\[[@CIT0003]\\] compared the effect of pore volume (50--90%) and size (100--900 $\\mathit{\\mu}$m) in materials processed by replica and gel casting. Biasetto et al. \\[[@CIT0004]\\] conducted a similar study on porous ceramics obtained by organic burn out in a porosity range of 80--90% and pore size 10--150 $\\mathit{\\mu}$m. In both cases, permeability is increased by increasing porosity"
+"Background\n==========\n\nThe introduction of primary health care implied a focus on enhancing health service provision at the grassroots. In fact, the 'health for all' concept of the 1978 Alma-Ata declaration became a prime policy bearer for the movement of bringing health services closer to the communities \\[[@B1]\\]. A grassroots and participatory focus, rather than a top-down approach, has since then gained recognition as a fundamental principle in attempts to ensure stakeholders involvement and fair priority setting in health care. The focus on ensuring broader participation in health care decision-making processes gained renewed attention and became more manifest in the early 1990s when many countries started implementing reforms as a strategy geared towards improving the performance of their health systems \\[[@B2],[@B3]\\].\n\nOne of the major components of the health sector reforms in Tanzania was decentralisation through devolution and integration of the district health care services \\[[@B4]\\]. This reform included devolving political, administrative, financial, and personnel control from the central to the lower levels. In Tanzania, sectoral reforms were implemented in three phases between 1999 and 2001 involving all sectors. Each phase comprised a third of all local authorities \\[[@B5]\\]. Within the district health care system, the Council Health Management Team"
+"The possibility of risks specific for pregnant women and their fetuses became immediate concerns at the outbreak of the COVID-19 pandemic. In contrast to the 2015 Zika virus epidemic, when unique birth defects were identified early in the course of the spread, no novel fetal or maternal risks have yet been confirmed[@R1]. However, the limited extant data regarding the maternal and fetal effects of COVID-19 infection especially for the first trimester provide little reassurance. The pandemic posed an immediate dilemma for centers actively treating infertile couple with medically assisted reproduction (MAR) and assisted reproductive technology (ART), including in vitro fertilization.\n\nOut of caution, several professional societies around the world recommended suspending therapy for infertility services initially on March 18, 2020, 1 week after the World Health Organization declared COVID-19 infection to be a pandemic[@R2]--[@R4]. All guidelines published by reproductive medicine societies at this time endorsed cessation of infertility services although some granted exemptions for exceptional circumstances, such as oocyte or sperm cryopreservation procedures in patients about to undergo chemotherapy or radiation, that would likely deplete their gamete number. Reasons cited for these extraordinary measures included preventing possible complications of ART and MAR, possible virus induced complications of pregnancy and concerns"
+"1. Introduction {#sec1}\n===============\n\nThe endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells functioning in secretory protein synthesis and processing, lipid synthesis, calcium storage/release, and detoxification of drugs. The ER ensures correct protein folding and maturation. Unfolded proteins are retained in the ER and targeted for retrotranslocation to the cytoplasm for rapid degradation. Under normal physiological conditions, there is a balance between the unfolded proteins and the ER folding machinery. Disruption of the balance results in accumulation of unfolded proteins, a condition termed ER stress \\[[@B1]--[@B5]\\]. The ER stress triggers the unfolded protein response (UPR), which attenuates protein translation, increases protein folding capacity, and promotes degradation of unfolded proteins, thus restoring ER homeostasis. However, prolonged UPR leads to an attempt to delete the cell causing injuries. Molecular chaperones such as the glucose-regulated protein 78 (GRP78/BiP) interact with three ER membrane resident stress sensors: inositol-requiring enzyme-1 (IRE1*\u03b1*), transcription factor-6 (ATF6), and PKR-like eukaryotic initiation factor 2*\u03b1* kinase (PERK), and play a vital role in maintaining the protein homeostasis inside the ER \\[[@B1]--[@B5]\\]. Many human diseases such as metabolic syndrome, neurodegenerative diseases, alcohol-induced organ disorders, and inflammatory diseases involve ER stress and impaired UPR signaling \\[[@B1]--[@B7]\\]. Increasing evidence supports ER"
+"Introduction\n============\n\nNonsynonymous single nucleotide polymorphisms (nsSNPs) lead to amino acid substitutions (AASs) and have the potential to affect the function of the protein product of a gene via the structure, biochemistry and/or splicing of the protein. Advances in high-throughput sequencing technologies have accelerated the rate at which nsSNPs are now being identified \\[The 1000 Genomes Project, [@b44]\\]. Accurate automated computational methods capable of predicting the effects of AASs and amenable to high-throughput analyses of large datasets are therefore of increasing importance for identifying and prioritizing functional nsSNPs for further studies \\[Thusberg and Vihinen, [@b47]\\].\n\nThe majority of computational prediction methods utilize evolutionary sequence conservation and/or structural annotations within homologous (orthologous and/or paralogous) proteins from a database of known sequences and/or structures \\[Ng and Henikoff, [@b29]\\]. Traditionally, the BLAST range of pairwise alignment \\[Altschul et al., [@b2]\\] and sequence profile algorithms \\[Altschul et al., [@b3]\\] have been used to search large sequence databases for homologous proteins falling within a predefined similarity threshold. However, weaknesses of these algorithms include the position-invariant scoring matrices in BLAST and the ad hoc estimation of algorithm parameters, that is, position-invariant gap penalties, in PSI-BLAST \\[Bateman and Haft, [@b7]\\]. On the other hand, hidden Markov models"
+"The availability of biomarkers to support the diagnosis or monitor the efficacy of therapies is a major unmet clinical need in neurology and neuropsychiatry[@b1]. Indeed, in spite of the large number of published studies on the association between brain disorders and molecular markers present in biological fluids, only a few clinically useful biomarkers have been successfully validated for the routine clinical practice[@b2][@b3][@b4]. The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) is one of the most promising biomarkers for brain disorders however, a definitive clinical validation is still lacking. BDNF is a secretory, dimeric growth factor present in most human tissues, including brain and blood[@b5]. BDNF is known to play a fundamental role in survival and differentiation of selected neuronal populations during development, and in the maintenance and plasticity of neuronal networks during adulthood[@b6][@b7]. Similar to other neurotrophins, BDNF is first synthesized as a precursor protein, named pro-BDNF of 32\u2009KDa, which is cleaved by different proteases to produce either the mature form of 14\u2009KDa, or the truncated form of 28\u2009KDa. Interestingly, an altered balance of the different forms has been linked with cognitive impairment and psychiatric disorders[@b8][@b9][@b10].\n\nMeta-analyses and reviews of clinical studies based on the measurement of BDNF in"
+"1. Introduction {#sec1-medicines-05-00050}\n===============\n\nHypodermic injection is an invaluable clinical tool allowing the delivery of therapeutic agents that are otherwise unsuitable for administration through oral routes. However, the waste arising from the application of needles has long been a critical concern. There have been extensive surveys cataloguing the experiences of healthcare workers and the hazards posed by the use and disposal of needles \\[[@B1-medicines-05-00050],[@B2-medicines-05-00050],[@B3-medicines-05-00050]\\]. In particular, the possibility of needlestick injury (NSI) has become an ever-present hazard within healthcare settings and is estimated to account for 80% of percutaneous injuries \\[[@B4-medicines-05-00050]\\]. It is little surprise therefore to find that most countries have imposed a variety of legislative requirements to promote the adoption of safe working practices. The US Needlestick Safety and Prevention Act (2000) and the Occupational Safety and Health Administration (OSHA) Bloodborne Pathogen (BBP) Standard (2001) are notable in that it has been estimated that the incidence of sharps injuries dropped by some 34% shortly after their introduction \\[[@B5-medicines-05-00050],[@B6-medicines-05-00050]\\]. Despite such advances, the eradication of NSI continues to be elusive and there remains considerable concern with an estimated 300,000 needlestick injuries reported annually in the US alone \\[[@B7-medicines-05-00050],[@B8-medicines-05-00050]\\]. It must be noted that the true value is liable to"
+"State-of-the-art genetic analysis is predominantly based on fluorescence imaging, which nevertheless has an optical resolution limit[@b1][@b2][@b3][@b4][@b5][@b6]. As an alternative yet powerful approach, atomic force microscopy (AFM)-based nanomechanical imaging is distinct in its high-resolution power in ambient conditions[@b7]. Direct reading of genetic information using AFM has long been a dream since its invention[@b8]. Although AFM in principle has much higher resolution than optical microscopy and even superresolution microscopy[@b9], its application in genetic analysis remains to be limited. Unlike fluorescence imaging that has a spectrum of wavelength-specific fluorophores or fluorescent nanoparticles, the lack of shape-specific labels for AFM largely restrict site-specific labelling for distinctive visualization[@b10][@b11][@b12]. Previous studies have well documented that self-assembled DNA origami nanostructures with arbitrary shapes can be reliably fabricated by folding a long viral M13 genomic DNA with \u223c200 short complementary staple strands[@b13][@b14][@b15][@b16][@b17]. By using DNA origami as the soluble substrate, Yan and colleagues[@b17] developed nanoscale chips for hybridization detection of nucleic acids. We were thus motivated to repurpose differentially shaped origami nanostructures as unique nanomechanical shape IDs for 'multi-colour\\' labelling of genomic DNA. As a proof-of-concept, we explored high-resolution genetic phasing of haplotypes using this nanomechanical imaging method.\n\nThe human genome consists of two copies of homologous chromosomes"
+"Introduction {#sec1_1}\n============\n\nMild cognitive impairment (MCI) is regarded as the transitional state between the cognitive changes in normal aging and early dementia. Initially, memory impairment was a prerequisite for the diagnosis of MCI. Meanwhile, different clinical subtypes of MCI have been proposed to extend the concept and include prodromal forms of a variety of dementias: (a) single-domain amnestic MCI (aMCI), (b) multiple-domain aMCI, (c) single-domain non-amnestic MCI, and (d) multiple-domain non-amnestic MCI \\[[@B1]\\].\n\nAlthough memory decline is the hallmark of aMCI, impairment in executive functions has also been reported in these patients \\[[@B2]\\]. Executive functions are superordinate concepts encompassing a spectrum of cognitive functions such as monitoring, controlling, planning, behavior initiation, flexibility, inhibition, and abstract thinking \\[[@B3]\\]. Impairment in tasks requiring executive control appears to be a reliable predictor of Alzheimer\\'s disease (AD) \\[[@B4]\\]. In early AD (EAD), the presence of executive dysfunction is common \\[[@B5]\\].\n\nSet shifting, inhibition abilities and abstract thinking are executive functions which are involved in processes such as proverb comprehension \\[[@B6],[@B7]\\]. Proverbs are simple sayings which express a truth, based on common sense or practical experience. Usually, proverbs are metaphoric and cannot be interpreted literally. Impairments in interpreting proverbs are assumed to be associated"
+"Supported by the Swedish Rheumatism Association, the Swedish Heart\u2010Lung Foundation, King Gustav V\\'s 80\u2010Year Fund, Vinnova, and the Sixth Framework Programme of the European Union (grant LSHM\u2010CT\u20102006\u2010037227; CVDImmune; with Dr. Frosteg\u00e5rd as coordinator).\n\nD. Thiagarajan, MSc, PhD, A. Frosteg\u00e5rd, MD, PhD, J. Steen, PhD, M. Rahman, PhD, M. Vikstr\u00f6m, MSc, S. Lundstr\u00f6m, PhD, J. Frosteg\u00e5rd, MD, PhD: Karolinska Institutet, Stockholm, Sweden; ^2^R. Fiskesund, MD, PhD: Karolinska University Hospital, Huddinge, Sweden.\n\nDr. Frosteg\u00e5rd is named inventor on patents relating to antibodies against phosphorylcholine. No other disclosures relevant to this article were reported.\n\nINTRODUCTION {#acr211127-sec-0005}\n============\n\nPhosphorylcholine (PC) is an important component in cellular membranes and in lipoproteins that is exposed and recognized by the immune system when cells undergo apoptosis or when lipoproteins, such as low\u2010density lipoprotein (LDL), undergo oxidation. PC is also exposed in some microorganisms, including nematodes and bacteria (non\u2010self). PC can be exposed on protein, lipid, or carbohydrate carriers, and antibodies against PC (anti\u2010PCs) of the immunoglobulin M (IgM) isotype are prevalent, constituting as much as 5% to 10% of the circulating IgM pool [1](#acr211127-bib-0001){ref-type=\"ref\"}. PC exposed on oxidized phospholipids in oxidized low\u2010density lipoprotein (OxLDL) contributes to activation of immune cells such as T lymphocytes and macrophages [2](#acr211127-bib-0002){ref-type=\"ref\"}."
+"Introduction\n============\n\nRecently, the Seoul metropolitan government conducted a survey regarding Seoul citizen's health and frequency of family meals. According to the survey results targeting 2,425 citizens, 28.4% of respondents have a meal with their family 3\\~5 times a week, and 25% of them have a meal with their family 1\\~2 times a week ([@ref1]).\n\nHaving a meal with one's family can be used as an opportunity to recognize family members as a living community as well as to express the bond among family members ([@ref2]). In addition, it was revealed that the more the chance to have a meal with one's family, the higher the probability to have a balanced diet and healthy eating habits ([@ref3]). However, in the rapidly changing modern society, the busy life of individuals causes a reduction of family meals; this result is due to an increase in the situation where each individual needs to take care of his/her meals rather than eating together with the family at home due to increased economic activity of married women in the Korean society as well as an increase in children's afterschool and private education activities ([@ref4]). Such a different daily schedule of each family member leads to"
+"Madam,\n\nI read with interest the review entitled \"WHO safe surgery checklist: Barriers to universal acceptance.\"\\[[@ref1]\\] The World Alliance for Patient Safety initiated work on the challenge of surgical safety in January 2007. The World Alliance published World Health Organization Surgical Safety Checklist (WHO SSC) and Implementation Manual in June, 2008.\\[[@ref2]\\] It is amusing to note that 10 years after its introduction in clinical practice, the issue needs to be reviewed because it is still not universally followed.\n\nThe authors have reviewed the published articles citing barriers in the implementation of WHO SSC. The authors have focused their manuscript on contemporary publications. It is indeed most disturbing to note that a major reform introduced by the world\\'s apex healthcare regulator, to ensure safe surgery, has still not been accepted by a large part of the medical world and we are still seeking to review why this prime initiative has still not been adopted.\n\nUnfortunately, large teaching institutes have failed to join the WHO SSC bandwagon due to a detached and apathetic attitude toward patient safety, despite the fact that surgical errors are more common in teaching hospitals. The hierarchical system in the teaching hospitals and disconnect between the patient and"
+"Vision Statement\n================\n\nThe goal of the **e-Health Code of Ethics** is to ensure that people worldwide can confidently and with full understanding of known risks realise the potential of the Internet in managing their own health and the health of those in their care.\n\nIntroduction\n============\n\nThe Internet is changing how people give and receive health information and health care. All people who use the Internet for health-related purposes-patients, health care professionals and administrators, researchers, those who create or sell health products or services, and other stakeholders-must join together to create a safe environment and enhance the value of the Internet for meeting health care needs.\n\nBecause health information, products, and services have the potential both to improve health and to do harm, organisations and individuals that provide health information on the Internet have obligations to be trustworthy, provide high quality content, protect users\\' privacy, and adhere to standards of best practices for online commerce and online professional services in health care.\n\nPeople who use Internet health sites and services share a responsibility to help assure the value and integrity of the health Internet by exercising judgment in using sites, products, and services, and by providing meaningful feedback about"
+"Introduction {#section1-1179554917731072}\n============\n\nPatients with classical Hodgkin lymphoma (HL) are generally classified in 1 of 3 groups: early-stage favorable, early-stage unfavorable, or advanced-stage disease. Unfortunately, there is no universal prognostic system for early-stage disease, as each cooperative group uses unique scoring systems for stratifying patients on clinical trials. Therefore, in early-stage disease, the dose of radiation and number of chemotherapy cycles are dependent on which scoring system is used. For initial treatment planning, early-stage disease is categorized by the presence of a bulky mediastinal mass (defined by modern criteria as measuring \\>10\u2009cm on computed tomography \\[CT\\]). Those with bulky masses generally benefit from more cycles of chemotherapy and the addition of consolidative radiation. However, the role of radiation in early-stage disease has become increasingly contentious due to the long-term associated toxicities. Furthermore, patients with early-stage disease who have multiple risk factors were excluded from early-stage trials and are often treated as advanced stage.\n\nPrognostication in advanced-stage patients is defined by the International Prognostic Score (IPS) ([Table 3](#table3-1179554917731072){ref-type=\"table\"}).^[@bibr1-1179554917731072]^ Patients with low-risk IPS (1-3) are treated with 6 cycles of standard ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), whereas high-risk patients are considered for initial treatment with the more intensive German-derived regimen,"
+"Introduction {#s0001}\n============\n\nWorldwide, lung cancer (LC) is one of the most commonly occurring cancers in humans, there are more than one million deaths every year (Zajdel et\u00a0al. [@CIT0020]). Non-small cell lung cancer (NSCLC) is the most common type of LC which accounts for about 75--85% (Zhu et\u00a0al. [@CIT0022]). Depends on the histological type and the stage of NSCLC, the treatment for this cancer often employs combined methods, including radiotherapy, chemotherapy and surgery (Tezuka et\u00a0al. [@CIT0017]; Harada et\u00a0al. [@CIT0005]). The current standard first-line treatment for advanced NSCLC patients is platinum-based chemotherapy, which is not considered satisfactory to patients with the median survival time of 8--10\u00a0months (Motohashi et\u00a0al. [@CIT0011]). Therefore, exploring new drugs to improve the efficiency of NSCLC treatment and reducing the toxic side effects have been urgent problems.\n\nNatural products have drawn increasing attention because many important cancer preventive and therapeutic agents have been developed from them (Wang et\u00a0al. [@CIT0018]). Eudesmin (EDN) is a lignan which has been isolated from different plant families, including Apiaceae, Rutaceae, Ochnaceae and Magnoliaceae (Raimundo et\u00a0al. [@CIT0014]). Various investigations have shown EDN possesses broad range of biological activities, such as cytotoxic, antibacterial, antifungal, inhibitory effects on"
+"Introduction\n============\n\nNoonan syndrome (NS; MIM\u266f 163950) is a relatively common and clinically variable disorder characterized by postnatal reduced growth, facial dysmorphism, and congenital heart defects (CHDs) \\[Allanson, [@b1]; Noonan, [@b37]; Tartaglia et al., [@b59]; van der Burgt, [@b63]\\]. The distinctive and most recurrent facial features consist of a broad forehead, hypertelorism, down-slanting palpebral fissures, ptosis, high arched palate, and low-set, posteriorly rotated ears. Cardiac involvement is present in up to 80--90% of affected individuals, with pulmonic stenosis (PS), septal defects, and hypertrophic cardiomyopathy (HCM) occurring most commonly \\[Burch et al., [@b6]; Marino et al., [@b31]\\]. Other associated features include multiple skeletal defects (chest and spine deformities), webbed/short neck, variable cognitive deficits, cryptorchidism, lymphatic dysplasia, bleeding diathesis, and, rarely, predisposition to certain hematologic malignancies during childhood.\n\nNS is genetically heterogeneous, and, based upon the recent discoveries of the underlying disease genes, is now regarded as a disorder caused by enhanced signal flow through the RAS-MAPK pathway \\[Tartaglia et al., [@b59]\\]. This signaling cascade is known to mediate diverse biological functions, including cell proliferation, survival, fate determination, and differentiation. It is activated in response to cytokine, hormone, and growth factor stimulation, and is a major mediator of early and late developmental"
+"1.. Introduction {#s1}\n================\n\nLand salinization is a serious problem and leads to desertification \\[[@RSOS200637C1]\\]. Saline-alkali soils have important effects on plants. Most plants cannot or hardly survive on saline-alkali soils, since low osmotic potential of soil, imbalanced organic composition and salty toxicity inhibit plant growth and reduce land productivity \\[[@RSOS200637C2]--[@RSOS200637C4]\\]. Due to poor water condition, increased water table, seawater erosion and human activities \\[[@RSOS200637C5]\\], approximately 954 million hectares worldwide and 99.13 million hectares of lands in People\\'s Republic of China have been salinized \\[[@RSOS200637C6]\\], which are still increasing every year.\n\nRegarding bioremediation of saline-alkali, most studies focused on utilization of salty soil for agricultural production. To bioremediate saline-alkali lands, hundreds of halophyte species (such as seawater-cultivated vegetables) have been domesticated to reduce soil salinity \\[[@RSOS200637C7],[@RSOS200637C8]\\] and high-tolerant cultivars of non-halophytes have been bred to adapt to saline-alkali soils \\[[@RSOS200637C9]--[@RSOS200637C11]\\]. These studies paved an effective way to resolve saline-alkali agricultural lands.\n\nWith development of economic and living standards, requirements of landscape construction in urban areas are increasing. Worldwide, there are lots of cities built on saline-alkali lands, such as Cangzhou, Yancheng, Daqing and Chifeng in People\\'s Republic of China, the State of Victoria in Australia and California in America. Obviously,"
+"INTRODUCTION\n============\n\nAnaplastic thyroid cancer (ATC) is one of the most aggressive malignancies in humans. Multidisciplinary treatments, including radiotherapy and chemotherapy, poorly control the progression of this disease, and the mean survival is less than 1 year after initial diagnosis \\[[@B1]\\]. Therefore, discovery of new and improved therapeutic strategies are critical for improving the quality of life and survival rates of patients with ATC.\n\nCurcumin is a polyphenolic natural product found in turmeric, a commonly used food coloring and flavoring agent. The active component of turmeric, curcumin, has been shown to have antiviral, antibacterial, antioxidant, anti-inflammatory, antiproliferative, and antiangiogenic activities \\[[@B2],[@B3]\\]. Studies conducted in both animals and humans have suggested that curcumin is a promising candidate for the treatment of inflammation and cancer \\[[@B4],[@B5],[@B6],[@B7]\\].\n\nDocetaxel is an anticancer microtubule-stabilizing agent that induces apoptosis by suppressing the microtubule dynamics of the mitotic apparatus \\[[@B8],[@B9]\\]. Docetaxel arrests cells in the G2/M phase, leading to increased susceptibility of cancer cells to radiotherapies and chemotherapies \\[[@B10],[@B11],[@B12]\\]. It is severely dose-limited because of its adverse side effects, including neutropenia, diarrhea, nausea, and fatigue \\[[@B13]\\]. Combination therapies to reduce its toxicity at higher doses and/or to increase its efficacy at lower doses are highly desirable, and"
+"1. Introduction {#sec1}\n===============\n\nOver the past decade, multivoxel pattern analysis (MVPA) has become widely used in functional magnetic resonance imaging (fMRI) because of its effectiveness in decoding cognitive states \\[[@B1]--[@B7]\\]. Unlike univariate statistical methods focusing on characterizing the relationship between cognitive variables and individual brain voxels, MVPA applies powerful pattern classification algorithms to multivoxel patterns of activity to decode the information that is represented in that pattern of activity \\[[@B1]\\]. In general, MVPA considers each multivoxel pattern (referred as a sample) as an *n*-dimensional vector and separates these vectors in the high-dimensional space by classification \\[[@B8]\\]. Multivoxel patterns are first divided into training and test sets, after which a classifier is trained on the training set and tested on the test set. A cross-validation procedure is required to accurately estimate the performance of the pattern classifier. This procedure is implemented by dividing the data of all samples into portions of equal size. At each cross-validation, one portion is left out, the classifier is trained on the remaining portions, and predictions are made for the portion that was left out. The mean accuracy of all cross-validations serves as the final estimate of the classifier\\'s true performance.\n\nIn MVPA-based analysis, feature"
+"Introduction {#s1}\n============\n\nAutism is diagnosed on the basis of a triad of behavioral features: impairment of reciprocal social interaction, communication and imagination, and the presence of repetitive and ritualistic behavior. Monozygotic twins are much more highly concordant for autism as compared to dizygotic twins [@pone.0006881-Bailey1], and the sibling risk rate for autism is much larger than the risk in the general population [@pone.0006881-Smalley1]. Relatives of individuals with autism exhibit higher than normal rates of autism-related impairments including language, communication and social behavior, referred to as the broader autism phenotype (BAP) [@pone.0006881-LeCouteur1], [@pone.0006881-Piven1]. These findings provide evidence that there is a heritable component to autism. A recent twin cohort study suggests that the elements of the triad of behavioral features of autism are largely independent of each other in terms of genetic background [@pone.0006881-Ronald1]--[@pone.0006881-Happe1], thus, it is important to clarify the brain substrates for fundamental cognitive functions and identify biological or behavioral markers of genes contributing specifically to each of the three behavioral features of autism.\n\nDysfunctions of prefrontal cortex have been previously reported in individuals with autism spectrum disorders (ASD). Most neuropsychological studies have shown impairments of executive function, including planning, flexibility and working memory [@pone.0006881-Happe1]. In functional magnetic"
+"Complete data is available through the University of Bristol Research Data Repository. The repository supplied DOI identifier for our data is as follows: [10.5523/bris.tbr9pt5x55oe1lfkl5q8dfjwe](http://dx.doi.org/10.5523/bris.tbr9pt5x55oe1lfkl5q8dfjwe).\n\nIntroduction {#sec001}\n============\n\nMuch attention has been devoted to differences in prevalence in carriage of pneumococcus (Sp) and carriage of specific serotypes and how these correlate with prevalence in disease \\[[@pone.0163435.ref001]\\].\n\nIn the pre-pneumococcal conjugate vaccine (PCV) era, the rank order of serotypes found in colonisation was reasonably stable across different populations with certain disease-causing serotypes like serotypes 1 and 5 rarely detected \\[[@pone.0163435.ref001],[@pone.0163435.ref002]\\]. Subsequent studies have suggested that the diversity and overall relative prevalences of pneumococcal serotypes revert to a particular population structure following the perturbation caused by universal childhood PCV implementation \\[[@pone.0163435.ref003],[@pone.0163435.ref004]\\]. Weinberger et al. \\[[@pone.0163435.ref005]\\] showed an association between increased carriage prevalence and resistance to non-opsonic neutrophil-mediated killing: the more prevalent serotypes, such as 19F and 23F being most resistant, while types rarely isolated, such as 4 and 5, were more efficiently killed. Resistant serotypes tended to be more heavily encapsulated. An association between polysaccharide structure and carriage prevalence was also identified with more common serotypes having less energy expended on capsule generation \\[[@pone.0163435.ref005]\\]. Other microbial factors, such as adhesins, toxins and proteins"
+"1. Introduction {#sec0001}\n===============\n\nCurrently, with the significant advancement of nanotechnology, a variety of nanomedicines have been developed and introduced into the field of cancer treatment, including inorganic nanocrystals [@bib0001], polymer nanoparticles [@bib0002], biomimetic nanomaterials [@bib0003], and nanohybrids [@bib0004]. Most of the common nanomedicines incorporate nanocarriers such as nanoMOFs [@bib0005], 2D nanosheets [@bib0006], and nanogels [@bib0007] as anticancer drug-delivery nanoplatforms for oncotherapy. Typically, most of the nanomedicines, especially drug delivery nanoplatforms, suffer from the bottlenecks of low efficiency, serious side effects, and limited target efficiency to tumor tissues, which usually limit clinic translation potential. To overcome these disadvantages, the stimuli-responsive nanomedicine has been developed to precisely release drugs at specific sites for noninvasive cancer therapy [@bib0008]. Prodrug based nanomedicines are one of the typical representatives of stimuli-responsive nanomedicines that controllably release drug under external stimulations.\n\nThe prodrug (drugs conjugated to the precarrier), an inactive compound that can be enzymatically degraded into the parent bioactive drug in vivo, has gained wide attention as a practical approach to reduce off-target toxicity in cancer treatment. Due to its unique structure, most prodrugs can self-assemble into nanoparticles through simple chemical modifications. The prodrug exhibits several significant advantages, including high drug loading efficiency, ameliorative drug"
+"Background\n==========\n\nTube thoracostomy is a common procedure to drain fluids and/or air from the pleural space via an ICD. The British Thoracic Society (BTS) has published a guideline \\[[@B1]\\] for ICD insertion which in many institutions has been deployed as a standard approach to tube thoracostomy in both practice and training programs. Recently there is an increasing concern regarding the training of doctors with regard to precise and methodological ICD insertion \\[[@B2],[@B3]\\]. Harris et al \\[[@B4]\\] conducted a national survey among chest physicians in the UK recording their experiences regarding complications and serious harms following ICD insertion. The study revealed 67% of NHS trusts have experienced major complications of ICD insertion.\n\nCase presentation\n=================\n\nA 51-year-old man with history of chronic obstructive pulmonary disease (COPD) and cigarette smoking presented with a shortness of breath, chronic pneumonia and empyema involving the right side of his chest. Soon after admission his condition deteriorated developing type-2 respiratory failure necessitating intubation and commencement of mechanical ventilation. Patient required positive end-expiratory pressure (PEEP) of 10 mmHg and 80% fraction of inspired oxygen (FiO2) to maintain the oxygen saturation of 91% with PCO2 (partial pressure of carbon dioxide) and PO2 (partial pressure of oxygen) of"
+"Introduction {#s1}\n============\n\nExperiences are an area of strong academic and practical interest (Kim, [@B54]; Tung and Ritchie, [@B118]; Volo, [@B125]; Kirillova et al., [@B58]). Tourists\\' seek memorable tourism experiences (MTEs) (Scott et al., [@B105]), which have the propensity to generate destination loyalty (Chen and Rahman, [@B18]; Zhang H. et al., [@B137]), increase satisfaction (Kim, [@B53]) and promote emotional engagement (Michalk\u00f3 et al., [@B80]). However, the creation of memorable experiences requires an understanding of the mental processes which occur at different stages of a tourist experience, including the antecedent and consequent conditions (Knobloch et al., [@B60]).\n\nPrevious studies of MTEs have focused on concepts such as motivation (Gnoth and Matteucci, [@B37]; Prayag et al., [@B96]; Yoo et al., [@B136]; Passafaro, [@B91]), expectations and satisfaction (Tynan and McKechnie, [@B120]; Kim, [@B53]), well-being and quality of life (Uysal et al., [@B121]), as well as emotions and memories (Chandralal and Valenzuela, [@B16]; Moyle et al., [@B86]). Psychological antecedents of MTEs include hedonism, involvement, knowledge, refreshment, meaningfulness, and novelty (Chandralal and Valenzuela, [@B17]; Kim, [@B52]). Recent studies indicate the importance of novelty in elicitation of emotions and a connection to memorability (Ma et al., [@B70]; Mitas and Bastiaansen, [@B83]). Although the importance of novelty"
+"Introduction {#s1}\n============\n\nBurkina Faso is one of the poorest countries in the world ranking 177^th^ out of 182 according to the Human Development Index (HDI) [@pntd.0000927-UNDP1]. Its economy relies predominantly on agriculture (40% of GDP), with cotton production being the most important, followed by livestock production, accounting for 12% of the GDP [@pntd.0000927-Ministre1]. The main livestock species are cattle, small ruminants, poultry and pigs. The relative importance of each species varies across the thirteen regions of the country. The country\\'s pig population is estimated at 2 million, and is more concentrated in the regions of Centre West, South West, and Boucle du Mouhoun (with 45% of the pig population) [@pntd.0000927-Ministre2]. Pigs are kept mainly in a traditional way, with most being either tethered or allowed to roam freely for some time during the year ([Figure 1](#pntd-0000927-g001){ref-type=\"fig\"}).\n\n![Pigs kept roamed laying in a puddle of water from toilet behind a concession.](pntd.0000927.g001){#pntd-0000927-g001}\n\nPorcine cysticercosis is a parasitic zoonosis caused by the larval stage of *Taenia solium*. While pigs are the intermediate host, man is the only natural definitive host. Human tapeworm carriers shed thousands of eggs daily through their feces. Pigs usually get infected by eating infected human feces or by"
+"Background {#Sec1}\n==========\n\nPrimary caregivers worldwide are facing the dilemma of maintaining their own health while addressing the physical and emotional needs of family members \\[[@CR1]\\]. Primary caregiving of children is particularly challenging in Africa, where the Acquired Immune Deficiency Syndrome and the Human Immunodeficiency Virus (HIV/AIDS) pandemic has increased the number of orphan and vulnerable children (OVC) in need of care. More than four-fifths of all OVCs (nearly 12 million) live in Africa. The prevalence of OVC varies widely across countries and across different population sub-groups---with countries and sub-regions with a higher prevalence of HIV having a higher prevalence of OVC as well \\[[@CR2]\\].\n\nRates of overweight and obesity are high and rising in Africa, particularly among women, and are a cause for concern \\[[@CR3]\\]. Equally relevant is that over- and under-nutrition often co-exists in the same household, particularly with adults being overweight and children underweight. Due to frequent population flows between urban and rural areas, lifestyle habits may be changing with uptake of unhealthier diets and sedentary lifestyles that contribute to obesity occurring even in rural sub-Saharan African settings \\[[@CR3]\\]. It has been suggested that the presence of under-nutrition and overweight and obesity among adolescent girls is due"
+"INTRODUCTION {#sec1-1}\n============\n\nRhabdomyosarcoma (RMS) is a malignant mesenchymal neoplasm that exhibits skeletal muscle cells with varying degrees of differentiation. RMS was first described by Weber in 1854,\\[[@ref1]\\] and defined as a separate entity by Arthur Purdy Stout.\\[[@ref2]\\] About 35--40% of RMS occur in the head and neck region and the oral cavity accounts for 10--12% of these.\\[[@ref3]\\] The most commonly affected areas are head and neck, genitourinary tract, retroperitoneum and to a lesser extent the extremities. In the head and neck, frequently affected sites are orbit, paranasal sinuses, soft tissues of the cheek and the neck. Oral RMS is rare and when occurring, it is more frequent in the soft palate.\\[[@ref1]\\]\n\nThis article presents an unusual case of RMS arising in the left maxillary alveolar region in an adult patient.\n\nCASE REPORT {#sec1-2}\n===========\n\nA 50-year-old female patient presented with a complaint of painful swelling in the left upper jaw that was present since 8 months. History revealed that she had undergone extraction of her mobile and painful left maxillary third molar 2 months back. Later, she noticed a small painful swelling that gradually increased to reach the present size.\n\nIntraoral examination revealed a diffuse ulceroproliferative growth on the"
+"Modern surgical treatment for breast tumours requires a preoperative diagnosis of malignancy ([Perry, 2001](#bib13){ref-type=\"other\"}). Fine-needle aspiration and core biopsy are widely used for evaluation of palpable and nonpalpable suspicious breast lesions. However, there has been serious concern about malignant tumour cell displacement promoting iatrogenic tumour spread. Tumour cell displacement rates to the needle tract of up to 30% have been reported ([Youngson *et al*, 1995](#bib22){ref-type=\"other\"}; [Diaz *et al*, 1999](#bib4){ref-type=\"other\"}). In theory, tumour seeding into lymphatic or vascular vessels would carry the same risk of axillary lymph node metastases as true lymphatic invasion. To our knowledge, no study has investigated the rate of breast cancer cell seeding to the axillary nodes for fine-eedle aspiration and large gauge needle biopsy procedures. The concept of sentinel lymphadenectomy has been demonstrated to be an accurate staging alternative for breast cancer ([Krag *et al*, 1993](#bib12){ref-type=\"other\"}, [1998](#bib11){ref-type=\"other\"}; [Giuliano *et al*, 1994](#bib8){ref-type=\"other\"}, [1997](#bib7){ref-type=\"other\"}; [Veronesi *et al*, 1997](#bib20){ref-type=\"other\"}; [Veronesi *et al*, 2003](#bib21){ref-type=\"other\"}). The sentinel node (SLN) is as per definition 'the first lymph node that receives afferent lymphatic drainage from a primary tumour'. With the thorough pathologic examination of the SLN, it is possible to detect even early tumour cell spread in a lymph node, which might not"
+"Introduction\n============\n\nInvasive candidemia is a major cause of increased mortality among ICU patients. Antifungal agents like liposomale amphotericin B and azoles could not accomplish the claim to be first choice in the treatment of invasive fungal infection (IFI) because of side effects and effectiveness. Especially, cardiothoracic surgery patients as a group of high-risk patients are in a focus for new strategies and agents. A new class of antimycotic agents, the echinocandins, with a low profile of side effects, low interactive potential and high effectiveness in the treatment of candidemia, is a powerful option in the treatment of IFI. We report our single-center experience with a modified clinical treatment approach based on clinical score of Leon and using echinocandins as first-line therapy for proven and suspected fungal infection.\n\nMethods\n=======\n\nFrom May 2011 to October 2012, 2,844 patients were treated on our cardiothoracic ICU. We evaluated 37 cardiothoracic postoperative patients with proven or suspected IFI or prophylaxis (Figure [1](#F1){ref-type=\"fig\"}). The records were evaluated for cardiothoracic procedures, microbiological and yeast date, cardiothoracic surgery score (CASUS), ICU and clinical data.\n\n![**Cologne antifungal strategy**.](cc12023-1){#F1}\n\nResults\n=======\n\nMean age was 67.4 years with 64% male patients. Most patients had combined CABG and valve procedure"
+"Background {#Sec1}\n==========\n\nBiliary atresia (BA) is a devastating fibrotic disorder of unknown etiology. It impacts the extrahepatic biliary tree of newborns, leading to progressive fibrotic biliary duct obstruction along with the development of biliary cirrhosis \\[[@CR1], [@CR2]\\]. The disease is characterized by prolonged cholestatic jaundice during the neonatal period \\[[@CR3]\\]. From 1 in 8000 to 12,000 new BA cases are projected to occur globally per year \\[[@CR4]\\]. Kasai portoenterostomy (KPE), liver transplantation or the two approaches together have proven effective in the treatment of BA \\[[@CR5]\\]. The causes and pathogenesis of the cellular inflammation and progressive fibrosis that contribute to the progression of BA are well documented \\[[@CR5]\\].\n\nEpithelial--mesenchymal transition (EMT) was recently shown to be involved in the formation of fibrogenic myofibroblasts in liver fibrosis and to be associated with occurrences of biliary atresia and primary biliary cirrhosis \\[[@CR6]\\]. Previous developmental investigations with adult organisms and cell cultures have yielded various growth and differentiation factors, such as TGF-\u03b2, and other growth factors that act through receptor tyrosine kinases. All of these can induce and regulate EMT \\[[@CR7]\\]. Although BA management has been extensively studied, the pathological mechanisms behind the related EMT processes are poorly understood.\n\nMicroRNAs (miRNAs) are"
+"INTRODUCTION\n============\n\nA rapidly expanding body of archaeological evidence suggests that ancient humans used various deliberate means to enhance the productivity and predictability of economically important species in habitats rich in biotic resources ([@R1]). Deliberate engineering of ecological niches promotes coevolutionary interactions among humans, plants, and animals that have profound ecological effects ([@R2]). These include impacts to resource availability, hydrological regimes, and, in some cases, alterations to selection pressures that facilitate genetic responses ([@R3]--[@R5]). Although these impacts are both driven by and often lead to greater sociopolitical complexity of human communities, they do not inevitably lead to domestication of target resources ([@R6]--[@R10]). Archaeological examples of nondomestic plant management include the intensification of geophyte harvesting among the Island Chumash ([@R11]) and the silviculture of nut- and fruit-bearing woody plants in the Eastern Woodlands ([@R12]) of North America. Ancient examples of aquaculture include construction of fish ([@R13]) and eel traps in Australia ([@R14]) and clam gardens on the Pacific Northwest of North America ([@R15], [@R16]). Many examples of plant management strategies from the Pacific Northwest, such as prescribed burning to increase yield and maintain open spaces ([@R17], [@R18]) and selective harvest and tending of geophytes including wapato ([@R19]--[@R21]), are limited to the"
+"1. Introduction {#sec0005}\n===============\n\nAs high-throughput hazard screening approaches such as ToxCast and Tox21 [@bib0115], [@bib0140], [@bib0150], [@bib0155], [@bib0175] continue to evolve, there is a need to develop methods to obtain high-throughput exposure estimates so that chemical hazard screening approaches and exposure estimates together can allow for the complete development of high-throughput risk models. A major challenge in estimating the risk of chemical exposures to human health is the lack of consistent information describing how chemicals are used. A limited number of chemicals that are known to have biological targets, and with uses that suggest high exposures such as pharmaceuticals and some food use pesticides, have been well characterized on both the hazard and exposure axes. For the remaining majority of marketed chemicals, there is little publicly available information [@bib0120], [@bib0135]. This information is critical since the presence of a chemical in specific products significantly influences the nature and extent of human exposures. While information on production volume of chemicals is currently available, a large, uniformly organized repository of information on how chemicals are used, product composition, and other properties (e.g. physicochemical form of the chemical within the product) currently does not exist. This paper describes an effort to characterize"
+"Introduction\n============\n\nToll-like receptors (TLRs) activate multiple inflammatory pathways and coordinate systemic defence against microbial pathogens. The improper activation of TLR pathways by endogenous or exogenous ligands may initiate tissue injury [@b1]. Unlike TLR-7, -8 and -9, TLR3 signalling is MyD88-independent and utilizes adaptor protein toll/interleukin-1 receptor (TIR) domain-containing adaptor inducing IFN-\u03b2 (TRIF) [@b2]. TRIF also recruits additional proteins necessary for downstream signalling, including receptor-interacting protein-1 (RIP-1), tumour necrosis factor receptor-associated factor 6 (TRAF6) and TRAF-family member associated NF-\u03baB-activator (TANK) binding kinase 1 (TBK1) [@b3].\n\nThe corneal epithelium serves as a barrier to protect the eye from external agents while maintaining corneal transparency [@b4]--[@b6]. Corneal epithelial disorders are associated with various ocular surface diseases involving inflammation, a process that might disrupt corneal structure and vision changes [@b7]. Corneal epithelium and inflammatory cells are involved in various pathologic conditions, including injury, repair and wound healing processes [@b8]. The formation of pro-inflammtory cytokines and chemokines, including interleukin (IL)-1\u03b2, IL-6, IL-8, Monocyte chemoattractant protein-1 (MCP-1), tumour necrosis factor (TNF)-\u03b1, aggravates inflammation and tissue injury [@b9]. Therefore, regulation of pro-inflammatory cytokines is one of the key processes to attenuate the corneal injury after infection. TLR2, TLR4 and TLR9 are expressed in the cornea and"
+"Background\n==========\n\nLeptospirosis is an infectious disease caused by bacteria of the *Leptospira* genus, which may affect diverse species of domestic and wild animals as well as humans. The transmission of this disease occurs by direct exposure to the urine or organs of infected animals, or indirectly when there is self-exposure to an environment contaminated with bacteria, such as standing water, wet soils, vegetation or fomites \\[[@B1]\\].\n\nCanine Brucellosis is an infectious, chronic zoonotic disease whose etiologic agent is *Brucella* spp. The transmission occurs among animals by sexual contact between infected males and females or by exposure to an environment contaminated with secretions and/or infected placental membranes \\[[@B2]\\].\n\nToxoplasmosis is caused by *Toxoplasma gondii,* an obligate intracellular protozoan that utilizes domestic and wild cats as definitive hosts. Infection occurs by ingestion of oocysts spread in the environment, by cysts present in tissues of intermediate hosts and by transplacental transmission through tachyzoites \\[[@B3]\\].\n\nLeptospirosis, toxoplasmosis and brucellosis are diseases with worldwide distribution. Among stray dogs, these zoonoses are facilitated by direct contact with other animals, by the habit of scavenging garbage and hunting in search of food, by drinking standing water, smelling other animals' urine, licking female genitalia and by engaging"
+"Facts:\n======\n\nCirculating tumour cells (CTCs) are detectable at all stages of disease and persist long after treatment.CTCs are detectable, even when patients are considered disease-free, using antibodies against specific cell surface markers.Circulating melanoma cells (CMCs) are thought to be responsible for metastatic progression, making it especially lethal.Certain CMCs could be useful to monitor the disease status.Melanoma does not express the classical epithelial cell surface markers, such as EpCAM, which has formed the basis of most CTC isolation strategies.Expression of melanoma cell-adhesion molecule MCAM (MUC18/MelCAM/CD146) is associated with an aggressive, invasive phenotype and its upregulation is strongly associated with disease progression.\n\nOpen Questions:\n===============\n\nHow can CMCs be isolated? Which genotype and phenotype do they express?Have all CMC phenotypes a metastatic potential? Which phenotype should be considered dangerous?As their detection in melanoma patients is useful to monitor the disease status, can CMCs have a prognostic value?Can the CMCs\\' enumeration and characterization determine and predict the overall and disease-free survival?Can MCAM (MUC18/MelCAM/CD146), as one of the most melanoma-specific cell-surface epitope, be regarded either as a useful tool to isolate CMCs or as a possible prognostic or predictive biomarker of melanoma progression?\n\nCirculating Tumour Cells\n========================\n\nIn cancer, the metastatic spreading of"
+"Introduction\n============\n\nOral cancer is the sixth leading cancer worldwide ([@B1],[@B2]). Risk factors such as alcohol and tobacco have an harmonizing effect, other than from infection with human papilloma virus is considered in oral cancer ([@B1]). Most of the oral cancer develops from oral premalignant lesions such as leukoplakia, erythroplakia, and lichen planus ([@B3]). Oral leukoplakia, submucous fibrosis and lichen planus are major known precursor lesions. The prevalence of malignant transformation of oral lichen planus is around 0.5% and for leukoplakia is around 1% ([@B3]). Early detection of oral cancer considerably increases survival rates and diminish other health effects ([@B4]). Despite of advancement in technologies, oral cancer cases are diagnosed at very late stage due to lack of awareness of the symptoms and risk factors between public as well as lack of prevention and early detection by oral physicians ([@B5]-[@B7]). Presently, diagnosis depends mostly on a thorough clinical oral examination and histopathological examination by taking a biopsy. A definite diagnosis is based on biopsy. Various technologies such Chemiluminescence, autofluorescence, Toluidine Blue, Brush biopsy, OralCDx Brush Test, ViziLite Plus with TBlue, VELscope Vx, Sapphire Plus, MicroLux(\u2122) /DL, Identafietc have been proposed, but these technologies need strong evidences to be used in"
+"Background\n==========\n\nHypercholesterolemia represents one of the important and recognized risk factor for atherosclerosis \\[[@B1]\\]. There are compelling evidences indicating the importance of type of fats than the total amount of the fats with respect to the risk of the cardiovascular diseases \\[[@B2]\\]. Cholesterol is transported within lipoproteins in the blood stream. High density lipoprotein (HDL) cholesterol levels are inversely related to the risk for atherosclerotic events \\[[@B3]\\] and are found to possess anti-atherogenic activity \\[[@B4]\\]. Among the risk factors, total cholesterol/HDL cholesterol ratio is considered to be the most predictive for atherosclerosis \\[[@B5]\\]. The protective effect of the HDL is related partly to enzymes associated with HDL \\[[@B6]-[@B8]\\] and due to its participation in reverse cholesterol transport \\[[@B9]\\].\n\nParaoxonase1 (PON1) is one of the enzymes associated with HDL \\[[@B10]\\]. PON1 was shown to protect against oxidative stress \\[[@B11],[@B12]\\], a phenomenon that can be attributed to its ability to modulate oxidized lipids in LDL and HDL \\[[@B13],[@B14]\\], in macrophages \\[[@B15],[@B16]\\] and also in atherosclerotic plaques \\[[@B17]\\]. PON is capable of hydrolyzing lipid peroxides in LDL \\[[@B18]\\]. Serum HDL-associated PON1 reduces oxidative stress in lipoproteins, in macrophages and in atherosclerotic lesion, whereas PON2 acts as an antioxidant at the cellular and"
+"Background\n==========\n\nGenome selection refers to a method for genomic value prediction using markers of the entire genome \\[[@B1],[@B2]\\]. It is effective for genetic improvement of quantitative traits that are controlled by multiple quantitative trait loci (QTL). Some traits may be controlled by only a few QTL and marker assisted selection using only the few detected QTL can be effective. However, most quantitative traits are determined by multiple QTL and their interactions. Marker assisted selection using only a few detected loci may not be efficient for these traits. Using all QTL collectively to predict the breeding values of individual plants can outperform the traditional marker assisted selection \\[[@B3],[@B4]\\]. However, there might be some trade off between the numbers of QTL included in the model and the efficiency of prediction. Cross validation can help us determine the optimal number of QTL included in the model to maximize the efficiency of genome selection.\n\nThe importance of epistasis in genetic determination may vary across different species. In agricultural crops, most quantitative traits in barley do not have a strong basis of epistatic effects \\[[@B5]\\]. However, epistasis has been shown to be important in QTL studies in rice \\[[@B6]-[@B8]\\]. Dudley and Johnson \\[[@B9]\\] found"
+"Introduction {#Sec1}\n============\n\nMeiotic prophase is a complex process that requires coordinated activities of multiple protein families (e.g., cohesins, synaptonemal complex proteins, and recombination machinery proteins) to facilitate production of haploid gametes. The recombination events that occur between homologous chromosomes are especially important for normal chromosome disjunction. For example, in model organisms meiotic mutants that reduce recombination invariably increase meiotic nondisjunction (Marcon and Moens [@CR20]; Ross-Macdonald and Roeder [@CR27]; Yang et al. [@CR30]). Similarly, analyses of humans indicate that abnormal numbers or placement of recombination events are important contributors to trisomies. Specifically, failure to recombine or crossovers located either too near to or too far from the centromere have been implicated in the origin of trisomies 13, 15, 16, 18, 21, and 22 and sex chromosome trisomies (Hassold et al. [@CR13]). Nevertheless, despite the clinical importance of aberrant recombination, we remain remarkably ignorant of factors that influence the overall number of recombination events in oocytes or spermatocytes. Recombination rates are known to vary greatly across species and within species, among individuals and between sexes. For example, in humans genome-wide rates of recombination are approximately 1.6 times higher in females than in males (Matise et al. [@CR21]) and can vary among"
+"Introduction\n============\n\nIntensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT) became a standard treatment approach in head and neck (H&N) cancer radiotherapy due to the ability of dose escalation to the tumor with reducing/limiting the doses to critical structures. In H&N cancers IMRT and VMAT published clinical results shows better outcomes in tumour control and quality of life compare to the conventional radiotherapy. The results do confirm that IMRT does decrease xerostomia compared with conventional radiotherapy \\[[@b1-roj-2016-02054]\\]. Low dose volume regions are a major worry in modulated radiotherapy because of its risk of secondary malignancies incidence, especially in the adult and pediatric patients. The prevalence of second malignancies after radiotherapy for pediatric and young adult populations is well established as one of the significant long-term sequelae of radiation treatment \\[[@b2-roj-2016-02054]\\]. In sliding window IMRT technique the multileaf collimators (MLC) deliver doses by moving from bank 'B' towards 'A' bank with variable speed and dose rate with fixed jaws. Jaw tracking techniques offers to reduce the MLC transmission during the IMRT and VMAT, during the jaw tracking treatment the secondary jaws (Y1, Y2, X1 & X2) will dynamically move as close to the MLC segments to further minimize the MLC transmission."
+"Introduction {#s1}\n============\n\nNow that Cone Beam Computed Tomography (CBCT) is a regular diagnostic tool in oral- and maxillofacial surgery, clinical interests are shifting to digital planning and eventually robotic surgery for orthognathic cases. With 3D planning software surgery can be planned digitally and then transferred to the patient. However, 3D virtual planning of orthognathic surgery still suffers from the disadvantages CBCT imaging has. For orthognathic surgery a good representation of the dental surfaces as well as the occlusion is needed for the 3D planning to properly position the jaws and to reach a stable occlusion. In CBCT imaging visualization of the dentition is still difficult. Loubelle and co-workers and Schulze and co-workers showed that the density of enamel is so high, that it gives rise to artefacts around the teeth [@pone.0059130-Loubele1], [@pone.0059130-Schulze1]. Besides that, brackets will always be present in orthognathic patients, since treatment continues into the postsurgical phase. This means that the dentition is poorly visible on CBCT scans of these patients, since scattering (from the brackets) and other artefacts occur at the occlusal level [@pone.0059130-Gateno1], [@pone.0059130-Uechi1]. Integration of digital dental casts into CBCT scans, could increase the accuracy of the orthognathic procedure.\n\nSeveral methods have been proposed"
+"Investigators from Pavia, Rho, Brescia and Milan, Italy, studied 22 patients diagnosed with GLUT1 deficiency syndrome (GLUT1DS) to document clinical or genetic differences between patients with familial *SLC2A1* gene mutations (n=11) and those with sporadic mutations (n=11). Direct gene sequencing in sporadic cases revealed 7 missense, 3 nonsense, and 1 splice site mutation. In the group with familial inheritance, all patients presented with missense mutations. Important differences were observed regarding clinical features. Overall, patients with sporadic mutations had a more severe phenotype than those with familial inheritance. They had more severe intellectual disability, earlier epilepsy onset and greater tendency to be refractory to AEDs treatment and more disabling movement disorders. In the familial group, relatives carrying *SLC2A1* mutations presented with heterogeneous clinical features of variable severity. Furthermore, two patients with genetically confirmed GLUT1DS had siblings with a similar type of epilepsy but without *SLC2A1* gene mutations.\n\nThe milder phenotype observed in the familial group, and the reported phenotypic variability among family relatives, confirms the heterogeneity of the clinical expression of *SLC2A1* mutations. This raises the question of the incidence of GLUT1DS, using a ketogenic diet in less symptomatic patients, and genetic counseling concerns. Authors also suggest that symptomatic patients negative"
+"Background {#Sec1}\n==========\n\nIntroduction {#Sec2}\n------------\n\nThe evolutionary relationships between different species or *taxa* are usually inferred through known phylogenetic analysis techniques. Some of these techniques rely on the inference of phylogenetic trees, which can be computed from DNA or Protein sequences, or from allelic profiles where the sequences of defined loci are abstracted to categorical indexes. The most popular method is MultiLocus sequence typing (MLST) \\[[@CR1]\\] that typically uses seven 450--700 bp fragments of housekeeping genes for a given species. Phylogenetic trees are also used in other contexts, such as to understand the evolutionary history of gene families, to allow phylogenetic foot-printing, to trace the origin and transmission of infectious diseases, or to study the co-evolution of hosts and parasites\u00a0\\[[@CR2], [@CR3]\\].\n\nIn traditional phylogenetic methods, the process of phylogenetic inference starts with a multiple alignment of the sequences under study that is then corrected using models of DNA or Protein evolution. Tree-building methodologies can then be applied on the resulting distance matrix. These methods rely on some distance-based analysis of sequences or profiles\u00a0\\[[@CR4]\\].\n\nDistance-based methods for phylogenetic analysis rely on a measure of genetic evolution distance, which is often defined directly or indirectly from the fraction of"
+"All sequences are available from the GenBank database (accession number(s) MH842882-MH843092 and MH893758-MH893759.\n\nIntroduction {#sec001}\n============\n\nAccurate assessment of the number of species and correct species identification are fundamental to systematic biology. Correct species identification and knowledge of endemism patterns are particularly important for biodiversity studies, endangered species lists and the prioritization of regions for conservation \\[[@pone.0205678.ref001],[@pone.0205678.ref002]\\]. Precise species recognition is especially challenging in groups exhibiting very low morphological variation but is crucial for adequate conservation strategies, particularly of geographical regions rich in endemic species under strong anthropogenic pressure, such as those in the Eastern Mediterranean \\[[@pone.0205678.ref003]\\].\n\nRenewed interest in assessing biodiversity levels has been driven by the implementation of molecular COI DNA barcoding \\[[@pone.0205678.ref004]\\] and the emergence of new analytical methods for species delimitation \\[[@pone.0205678.ref005]--[@pone.0205678.ref007]\\]. Great effort has been invested into building a global COI DNA reference library (as well as one with the less universal cytochrome b gene) which has significantly improved our knowledge of biodiversity in different regions, resulting in the recognition of so-called \"well-known areas\", which include Europe and adjacent countries \\[[@pone.0205678.ref008]\\]. However, COI barcoding has been criticized for its use of genetic distances to assess phylogenetic relationships \\[[@pone.0205678.ref009]\\] and its inability to accurately delimit species,"
+"INTRODUCTION {#s1}\n============\n\nPatients with inflammatory bowel disease (IBD) suffer from a chronic gastrointestinal condition that is marked by periods of exacerbation, with symptoms ranging from abdominal pain, diarrhea, and extra-intestinal manifestations. Comprised of ulcerative colitis (UC) and Crohn disease (CD), IBD affects about 3 million people in the United States and exerts a negative impact on the overall well-being of affected persons.^[@CIT0001],\\ [@CIT0002]^ A significant proportion of patients are diagnosed in their youth and will have to contend with a lifetime of complex medical and surgical therapies for their disease and its complications.^[@CIT0003]^ IBD patients have a higher-than-average rate of emergency room visits and hospitalizations and have considerable lost earnings from loss of productivity related to their disease.^[@CIT0004]^ The experience of IBD exerts a particularly heavy toll on the mental health and quality of life of affected individuals.^[@CIT0007]^ In a recent population-based study in the US, IBD was found to be independently associated with depressive symptoms (DS).^[@CIT0010]^ About 49% of the IBD patient population was shown to have DS compared with 23% of the non-IBD population, with almost a quarter of them having an increase in suicidal ideation. Because of the sometimes severe mental, physical, and psychosocial consequences of"
+"Identification of biomarkers of disease heterogeneity has been a challenge in multiple sclerosis (MS) research. A subgroup of patients with MS shows neuropathologic features of antibody (Ab)-mediated demyelination (pattern II according to [@R1]). Observations in animal models have identified myelin oligodendrocyte glycoprotein (MOG), a molecule exposed on the myelin surface and therefore accessible to Abs, as a prime candidate antigen of demyelinating Abs,^[@R2]^ reviewed in references [@R3][@R4][@R5].\n\nAbs against conformation-intact MOG were initially detected in children with demyelinating syndromes,^[@R6][@R7][@R9]^ more recently also in a subset of adult patients with aquaporin-4 Ab--negative neuromyelitis optica spectrum disorders (NMOSD),^[@R10][@R11][@R14]^ in adult patients with inflammatory demyelination distinct from NMOSD and MS,^[@R15]^ bilateral optic neuritis (ON),^[@R16]^ and rarely in anti-NMDA-receptor Ab--associated demyelinating syndromes.^[@R17]^ In contrast, little is known about Abs to MOG in adults with clinically definite MS according to the McDonald criteria.^[@R3],[@R4]^\n\nRecently, we reported a patient with Abs to MOG with recurrent severe myelitis as well as brainstem involvement, who showed on biopsy a typical neuropathologic pattern II MS.^[@R18]^ This led us to hypothesize that there may exist a subgroup of patients with MS with specific clinical features who have Abs to MOG.^[@R19]^ To test this, we investigated selected patients with MS who"
+"Introduction {#Sec1}\n============\n\nHyperparathyroidism (HPT), both secondary and tertiary, is a common complication with a prevalence up to 30--49% in patients with end-stage renal disease (ESRD) \\[[@CR1], [@CR2]\\]. ESRD-related HPT has been associated with severe bone disorders, cardiovascular complications, and increased mortality \\[[@CR3]--[@CR6]\\]. More than a decade ago, the treatment algorithm of HPT consisted of calcium salts, vitamin D sterols, and (sub)total parathyroidectomy (PTx). Since its introduction in 2004, the calcimimetic agent cinacalcet is being used to treat patients with HPT, when vitamin D analogs and phosphate binders are insufficient \\[[@CR7], [@CR8]\\]. The latest update of the Kidney Disease Improving Global Outcomes (KDIGO) Chronic Kidney Disease---Mineral and Bone Disorder (CKD-MBD) guideline recommends cinacalcet even as a first step option together with vitamin D and phosphate binders in patients with secondary HPT \\[[@CR8]\\]. Despite the lack of randomized studies that compare cinacalcet with surgical treatment, the advent of cinacalcet, and in parallel, an increasing perception of PTx as a high-risk procedure in this fragile ESRD population has, among other reasons, led to a shift from surgery toward predominantly medical treatment \\[[@CR2], [@CR9]\\]. Several studies have shown a reduction in the number of parathyroidectomies per year since the introduction of cinacalcet \\[[@CR10],"
+"INTRODUCTION {#s1}\n============\n\nGlobally, noncommunicable diseases (NCDs) accounted for 71% of total deaths. In India, NCDs were estimated to account for 63% of all deaths, and cancer was one of the leading causes (9%).^[@B1]^ Cancer registries are recognized as vital components of national cancer-control programs.^[@B2]^ Publications from developed and developing countries provide updated information on cancer occurrence, trends, and projections.^[@B3]-[@B7]^ In India, the systematic collection of data on cancer has been performed since 1982 by the population-based cancer registries (PBCRs) and hospital-based cancer registries (HBCRs) under the National Cancer Registry Programme (NCRP)--National Centre for Disease Informatics and Research (NCDIR) of the Indian Council of Medical Research (ICMR; ICMR-NCDIR-NCRP), Bengaluru (Appendix). NCRP commenced with the objective of generating reliable data on the magnitude and patterns of cancer. Several NCRP reports on cancer from different registries across India have been published.^[@B8]-[@B9]^\n\nCONTEXT\n-------\n\n**Key Objective**This study reports the cancer incidence, patterns, trends, projections, cancer mortality, and clinical aspects of stage at presentation and treatment for the period 2012-2016 from 28 population-based and 58 hospital-based cancer registries in India under the network of the National Cancer Registry Programme.**Knowledge Generated**There is heterogeneity in cancer incidence (age-adjusted rate per 100,000: males: Osmanabad and Beed, 39.5"
+"1. Introduction\n===============\n\nSugar sweetened beverage consumption (including the full range of soft drinks, fruit drinks, sports drinks) has increased considerably across the globe during the last decades \\[[@B1-nutrients-07-05298],[@B2-nutrients-07-05298]\\]. Malik's review \\[[@B1-nutrients-07-05298]\\] clearly showed that sugar sweetened beverage intake significantly contributes to weight gain and can lead to increased risk of type 2 diabetes and cardiovascular disease. Sugar sweetened beverages, typically containing sucrose, high-fructose corn syrup, or fruit juice concentrates, may lead to weight gain through the high added sugar content, low satiety, and potential incomplete compensation for total energy, leading to increased energy intake \\[[@B1-nutrients-07-05298]\\]. Today, it is also hypothesized that artificially sweetened beverage consumption may be related to weight gain, diabetes, and cardiovascular disease. Due to a dysregulation of appetite control, as a consequence of the mismatch between the intense taste of sweetness during consumption and the lack of energy consumed, artificially sweetened beverages may increase weight \\[[@B3-nutrients-07-05298]\\]. Furthermore, studies have demonstrated an effect of artificial sweeteners and diet beverages on incretin hormones, which would influence insulin secretion and thus blood glucose control \\[[@B3-nutrients-07-05298]\\]. Accordingly, consumption of artificially sweetened beverages has been associated with an increased risk for diabetes \\[[@B4-nutrients-07-05298]\\].\n\nSimilar to soft drinks, the consumption of energy"
+"Background {#Sec1}\n==========\n\nAs sessile organisms, plants can accommodate to changes in the environment by modulating their cellular transcription programs to allow developmental plasticity \\[[@CR1]\\], which requires plant-specific transcriptional regulatory mechanisms that defines these programs. Despite the ever-growing genome-wide gene expression data, understanding how transcriptional programs are established and regulated to define cell identity is largely lacking.\n\nThe genome regulatory potential relies not only on DNA sequence but also on epigenetic features that dictate the time, place and level of gene transcription. The chromatin structure is highly regulated and dynamic as histones can be evicted from chromatin to expose regulatory sites and allow binding of transcription factors (TFs) and other regulatory proteins to DNA \\[[@CR2]\\] or be recruited back to hinder the regulatory DNA. Thus, the cell type-specific profile of chromatin accessibility to TF binding is an essential layer of gene regulation. The regulatory circuitry that determines the cellular transcription program relies on a network of multiple TFs and their association with cell-type-selective accessible regulatory sites \\[[@CR3]\\]. Genome-wide mapping of TF binding to chromatin is commonly performed by chromatin immunoprecipitation (ChIP)-based methods, such as ChIP-chip and ChIP-seq. However, these techniques rely on prior knowledge of candidate factors and the availability"
+"Introduction\n============\n\nNetball is one of the most popular women's sports, and is played by more than 20 million people across more than 80 countries ([@B56]). Since 1963 a netball World Championship tournament has been played every 4 years. In 1990 netball first featured in the Commonwealth Games as a demonstration sport, and has since been played competitively for medals since 1998 ([@B56]). Despite substantial international popularity, netball remained an amateur sport for several decades. However, netball now has 61 countries recognized by the International Netball Federation, which includes several professional netball leagues. This recently obtained professional status of netball will no doubt generate new pressures and demands common within professional sport, one of which will be the increased demand for successful on-court match performance. To optimize match performance, it is necessary to assess performance variables in order to provide practical feedback to players and coaches, which will guide coaches decision making and subsequently the coaching process ([@B5]).\n\nPerformance analysis (PA) in sport involves analysing and evaluating the technical, tactical, physical, and cognitive aspects of performance in training and competition to better understand the components of successful performance ([@B34]; [@B5]). There is a substantial body of PA research associated with"
+"The importance of drug repositioning in the era of genomic medicine\n===================================================================\n\nThe perceived inefficiency of pharmaceutical drug development has been widely discussed \\[[@B1]-[@B5]\\]. Only 20 to 30 new chemical entities (NCEs: drugs not containing a previously approved active ingredient) are approved per year in the US \\[[@B4]\\], and each successful NCE requires an average of US\\$1.78 billion and 13.5 years from discovery to market \\[[@B5]\\]. Although estimates of drug discovery costs vary (a recent study suggested that the minimum cost of developing an NCE is US\\$204 million \\[[@B6]\\]), it is important to note that these estimates do not yet account for drug failures. Given that only 11% of drugs investigated in clinical trials are eventually approved \\[[@B3]\\], the actual cost of drug development is much higher than the published estimates.\n\nTwo approaches to improving productivity are rapidly gaining in popularity: drug repositioning to find new uses for existing drugs and personalized medicine to find tailored therapies for individual patients. The premise of repositioning is that reusing drugs that have previously passed clinical trials will minimize the risk of failure in future late-stage clinical trials due to toxicity and thus lead to faster drug approvals. Personalized medicine takes into account"
+"Introduction {#Sec1}\n============\n\nElectrochromic (EC) materials have attracted much attention owing to their potential applications in smart windows, antiglare mirrors, data storage devices, displays, sunroofs, and sunglasses. Various materials can be used as an EC layer, including inorganic metal oxides and organic conducting polymers^[@CR1]--[@CR8]^.\n\nConducting polymers provide benefits such as multiple colors, a fast switching time, and flexibility, but their disadvantages, including relatively nonuniform films, low material stability, and a limited range of colors severely limit their practical applications^[@CR9],[@CR10]^. On the other hand, tungsten trioxide (WO~3~) is a well-known metal oxide owing to its excellent EC performance. WO~3~ with different structures has been prepared by techniques such as hydrothermal process, chemical vapor deposition, thermal evaporation, and sputtering^[@CR11]--[@CR15]^. However, these approaches have drawbacks that restrict the commercial application of WO~3~ EC films, including complicated preparation, high energy consumption, expensive equipment, or the use of toxic and dangerous reagents^[@CR16]^.\n\nMolybdenum oxide is one of the important semiconducting metal oxides and can be used in various applications, including photovoltaic cells, organic light-emitting diodes, gas sensors, hydrogen evolution systems, transistors, and EC devices^[@CR17]--[@CR22]^. However, the coloration efficiency of pure molybdenum oxide used in EC devices is not high. For example, Patil *et al*. found"
+"1. Introduction {#sec1}\n===============\n\nIt is considered that the development of any autoimmune disease requires a combination of genetic predisposition, exposure to environmental risk factors, hormones, and defects in epigenetic mechanisms that regulate immune tolerance \\[[@B1]\\]. It has been described that adaptive immunity plays a central role involving autoantibody formation, the presence and activation of autoreactive T cells, defects in regulatory functions, and the induction of anergy in these cells, among other mechanisms \\[[@B2]\\]. However, during recent years there is growing evidence regarding the participation of innate immunity in autoimmune diseases in different models. Innate immunity has an important role at the beginning of the immune response and later, perpetuating certain systemic inflammatory effects by the release of soluble factors (e.g., cytokines, chemokines and lipid mediators), the presentation of autoantigens in an inflammatory context, the activation of effector T cells, and tissue damage, among others \\[[@B3]\\].\n\nIn addition, the development of autoimmunity has been associated with defects in the pathways that regulate cell death and the recognition and clearance of apoptotic cells (ACs) \\[[@B4]\\]. Defects in the induction of apoptosis contribute to the survival of autoreactive B cells that produce autoantibodies \\[[@B5]\\]. The inefficient removal of apoptotic bodies, once they"
+"Introduction\n============\n\nIn polytocous mammals, the early-life environment provided by the mother and siblings influences the development of individuals, and may have profound effects on fitness and other phenotypic traits later in life ([@bib31]; [@bib35]; [@bib26]). In early life, individual development is mainly under the control of the mother. With progress through lactation, the genes of the offspring increasingly determine development, because individuals become self-sufficient for feeding, and milk production of the mother becomes limited. Siblings from precocial mammals are capable of actively competing early in life and behaving synchronically at the udder to increase their milk intake ([@bib13]). Individuals are expected to respond to both their own state and that of their litter mates when signaling need and soliciting resource from their mother (for example, with teat massage; [@bib23]). As a consequence, individual development is increasingly affected by social interactions among litter mates. These experiences in early life may shape individual phenotypes later in life ([@bib45]), including behavior and social skills ([@bib8]; [@bib32]; [@bib41]). Though there has been a strong research focus on the interactions between mother and offspring, the consequences of the early-life environment for the development of social effects that individuals express on traits of their social"
+"Introduction\n============\n\nRelapse is the most frequent outcome of people who stop smoking; typically, several quit attempts are required to achieve sustained tobacco abstinence ([@R1]). Relapsed smokers are interested in treatment but generally do not seek it proactively ([@R2]--[@R6]). Most smoking cessation programs lack strategies to encourage relapsed smokers to make another quit attempt (\"recycle\"). Research suggests that relapsed smokers experience decreased self-efficacy and feelings of disappointment and guilt that may hinder them from proactively seeking treatment ([@R2]). They may also have limited knowledge about treatment and health coverage for repeated quit attempts ([@R4]). Effective interventions are needed to reconnect relapsed smokers with cessation support.\n\nCarlini and colleagues ([@R3],[@R4]) conducted 2 randomized controlled trials that tested the feasibility and efficacy of proactive interventions inviting unsuccessful quitters to enroll in a new quitline-supported quit attempt. In the first trial, quitline staff contacted the participants by telephone. In the second trial, they used an automated telephone system (Interactive Voice Response \\[IVR\\]). In both studies, motivational and information barriers to a new quit attempt were addressed, followed by an immediate option to connect with quitline support. Recycling rates in both trials were 8 to 12 times higher among participants in the intervention group"
+"All relevant data are within the paper and its Supporting Information files.\n\nIntroduction {#sec005}\n============\n\nPhototransduction initiates with the absorbance of photons in retinal rods, cones and ganglion cells. Most species have a binary retina, with visual stimuli largely transmitted from the rod and cone pathways, which then send signals to downstream neurons. The synaptic terminal of the rod photoreceptor plays a crucial role in the initiation of scotopic visual signals and can also signal through an alternative pathway when directly coupled to cone terminal telodendria through gap junctions \\[[@pone.0150024.ref001]--[@pone.0150024.ref003]\\]. Rod cells form ribbon synapses with the tips of horizontal cell (HC) axons and the dendrite tips of rod bipolar cells (BPCs) in a wide range of mammalian species, which invaginate into the rod spherule \\[[@pone.0150024.ref004]--[@pone.0150024.ref009]\\].\n\nWhile rod spherules are remarkably uniform compared to cone synapses \\[[@pone.0150024.ref009]\\], several prominent differences between rod spherules within individuals of several species have been reported. A small number of rods are occasionally contacted by the dendrites of cone bipolar cells, including bipolar cell types 3a, 3b and 4 in the mouse, providing a cone independent pathway through which the rod visual pathway can interact with the cone driven photopic visual pathway \\[[@pone.0150024.ref010]--[@pone.0150024.ref013]\\]. Morphological variation"
+"1. Introduction\n===============\n\nAcute lymphoblastic leukemia (ALL) is a heterogeneous group of disorders originating from B and T progenitor cells ^\\[[@R1]\\]^, and accounts for the most frequent blood malignancy of childhood.^\\[[@R2]\\]^ Although the survival rate of childhood malignancy has increased to approximately 90% compared to 10% in the 1960s with the development of medical technology,^\\[[@R3],[@R4]\\]^ relapsed ALL remains the leading cause of cancer-related mortality during childhood.^\\[[@R5],[@R6]\\]^ It has been reported that the overall survival rate of relapsed B-ALL is only 35% to 40%, even treated with stem cell transplantation or intensified chemotherapy^\\[[@R7],[@R8]\\]^, and this condition shows a lower survival in adults than in children.^\\[[@R9]\\]^ Therefore, it is important to reveal the molecular mechanisms of relapsed ALL to develop more effective therapeutic methods for improving the survival rate of patients suffering from relapsed ALL.\n\nWith the development of sequencing techniques, genome sequencing has been widely used to identify potential biomarkers and therapeutic targets based on variations in gene expression. Yang et al^\\[[@R10]\\]^ have identified that children with ALL with the CC genotype at rs116855232 of *NUDT15* have higher mercaptopurine resistance (83.5%) than those with the TT and TC genotypes. Perez-Andreu et al^\\[[@R11]\\]^ have reported that the risk allele at rs3824662 GATA3"
+"Impaired utilization of glucose due to lack of insulin secretion or its action has been reported to alter the enzymatic activities in diabetic patients as well as in experimental animals\\[[@CIT1]--[@CIT3]\\]. Diabetic animals also showed an increased break down of muscles and other tissues proteins into amino acids due to enhanced proteases activity which in turn resulted into increased urea levels in the blood\\[[@CIT4]\\]. Likewise, increased activity of serum glutamic oxaloacetate transminase (SGOT) and of serum glutamic pyruvate transminase (SGPT) in diabetes is of clinical importance\\[[@CIT2]\\] because elevated activity of SGOT is suggestive of cardiac damage and that of SGPT liver damage\\[[@CIT3]\\].\n\nAt present, the pathophysiology of diabetes mellitus is most precisely understood. Being multiple defect disease, it is not worthwhile to prescribe a drug that selectively targeted a single defect i.e. only to control blood glucose concentrations within the normal limit since such regimen may not be of much help in alleviating late clinical manifestations of diabetes mellitus. On the other hand, the multiple activities of plant based medicinal preparations offer an enormous scope for not only to control the hyperglycaemia of diabetes mellitus but also its late complications. Moreover, WHO study groups have emphasized strongly the optimal rationale uses"
+"Introduction {#s1}\n============\n\nThe regulation of microtubule dynamics is an essential requirement for all cells and in many aspects of their daily function. The ability to precisely regulate microtubule number, the assembly of networks, and the rate of microtubule assembly and disassembly underpins cellular processes including division, differentiation and migration. Male gamete development in particular relies upon the co-ordinated development and rapid remodelling of complex microtubule structures, such as the mitotic (spermatogonia) and meiotic (spermatocyte) spindle; flagella formation needed for sperm motility; and the manchette, which determines sperm head shape and contributes to tail structure. Approximately one in 20 men of reproductive age is sub-fertile or sterile, of which 60% of cases are due to intrinsic defects in spermatogenesis. This heterogeneous disorder manifests clinically as diminished sperm number, or abnormal motility or morphology, or commonly combinations thereof, in the ejaculate [@pgen.1002698-McLachlan1]. All of these clinical presentations may be underpinned by defective microtubule dynamics.\n\nMicrotubule severing is emerging as a key regulator of microtubule dynamics [@pgen.1002698-McNally1], [@pgen.1002698-Quarmby1], [@pgen.1002698-Baas1], [@pgen.1002698-Baas2], . The most well characterized microtubule severing enzyme is the katanin complex [@pgen.1002698-McNally2], the severing function of which is carried out by an ATPase enzymatic subunit, named p60, encoded by the *Katna1*"
+"The lattice structure and morphology of a crystal often affect its properties, such as catalytic activity[@b1], electrical conductivity[@b2][@b3][@b4] and photoluminescence[@b3][@b4][@b5][@b6][@b7]. Therefore, there has been considerable interest in the development of effective ways to grow crystals with controlled morphology. To obtain such crystals, careful consideration should be given to selecting (1) a proper crystallization method that effectively manipulates the local environment of the growing crystals and (2) a proper set of materials that interact with each other in a controllable, well-understood manner. In terms of the crystallization method, solution-phase crystallization has been regarded as one of the most powerful methods because the use of various solvents can effectively manipulate the local environment of solute molecules. Most examples of solution-phase crystallization occur in a single step; there is no *external* modification or manipulation of conditions once the crystallization begins. Single-step crystallization is straightforward and facile, but it lacks variety of products. Therefore, strategies have been developed for a larger variety of products, such as controlling the ratio of the capping reagent for silver nanoparticles[@b8][@b9] or introduction of additional molecules for flower-shaped BSA-Cu~3~(PO~4~)~2~\u22193H~2~O crystals[@b10]. Other examples of solution-phase crystallization take advantage of *external* manipulation; thus, growth occurs in multiple steps. Using multi-step crystallization,"
+"> This is a *PLOS Computational Biology* Methods article.\n\nIntroduction {#s2}\n============\n\nDetermining the evolutionary relatedness of two protein sequences is most successfully performed by amino acid sequence comparison [@pcbi.1003247-Soeding1]--[@pcbi.1003247-Altschul2]. However, it is well known that structure can be preserved even when sequence has diverged past the point of amino acid similarity recognition [@pcbi.1003247-Kinch1], suggesting that sequences can bestow local, subglobal, and global properties to a protein that can be preserved in the absence of strict conservation of the side chain atoms. In other words, similar properties could exist horizontally in a sequence even when recognizable vertical conservation is lost [@pcbi.1003247-Schlessinger1]. Even if such similarities are due to analogy rather than homology [@pcbi.1003247-Krishna1], approaches are needed that can augment sequence based analysis by matching patterns that may be independent of amino acid conservation at each position.\n\nComparison of three-dimensional atomic structures [@pcbi.1003247-Sadreyev1]--[@pcbi.1003247-Holm1] is one example of such pattern matching. However, protein function and evolution arise from a manifold of physical, chemical, and biological mechanisms, only partly accounted for by side chain identity or structural similarity [@pcbi.1003247-Tokuriki1]--[@pcbi.1003247-Liberles1]. It may be the case that proteins can also be meaningfully characterized by other attributes, such as the energetic contributions to stability [@pcbi.1003247-Gu1] or"
+"Background\n==========\n\nCarbon nanotubes are allotropes of carbon with a cylindrical nanostructure and categorized as single-walled (SWCNTs) and multi-walled nanotubes. By virtue of their unique properties, SWCNTs have been demonstrated as promising nanomaterials for a wide range of applications. In particular, increasing attention has been directed to their utilization in biomedicine, such as in biosensors, drug delivery, and biomarkers \\[[@B1],[@B2]\\]. However, attention has also been directed toward human health effects that exposure to these materials may produce. Thus, nanotoxicology has become an important research topic in nanoscience.\n\nIn the past decade, various groups have independently reported toxicological studies on SWCNTs, both *in vitro* and *in vivo*. These results have mainly focused on pulmonary toxicity, cytotoxic effects, inflammatory response, and genotoxicity \\[[@B3]-[@B9]\\]. However, the studies on SWCNTs leading to hepatotoxicity in animals have been limited in scope \\[[@B10],[@B11]\\], and they only assessed the effects of SWCNTs on reactive oxygen species induction and various hepatotoxicity markers (alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), LPO, and liver morphology) in the mouse model.\n\nRecent studies have shown that metabonomic methods are useful in the assessment of toxic mechanisms and prediction of toxicity \\[[@B12],[@B13]\\]. Nuclear magnetic resonance (NMR) spectroscopy is one of the"
+"Cycloviruses (CyCVs) belong to the *Circoviridae* family and have recently been found in different sample types from different hosts, including mammals and insects[@b1][@b2][@b3][@b4][@b5]. Recently, we reported a new cyclovirus species, tentatively named cyclovirus-Vietnam (CyCV-VN), in cerebrospinal fluid (CSF) of two Vietnamese patients[@b6]. The virus was subsequently detected in 4% of 642\u2005CSF samples of patients with central nervous system (CNS) infections from 7 different provinces in southern and central Vietnam, but in none of 122\u2005CSF samples from patients with noninfectious CNS conditions[@b6]. Almost simultaneously, another novel CyCV (CyCV-VS5700009) was reported in CSF and serum from patients with paraplegia in Malawi[@b7], while other CyCVs have previously been reported in stool samples of patients with acute flaccid paralysis from Tunisia, Pakistan and Nigeria[@b3]. Together, these data suggest that cycloviruses may have a wide geographic distribution, and that specific CyCV species might be associated with specific clinical phenotypes, although it should be noted that associated pathology of cycloviruses has yet to be proven.\n\nResults\n=======\n\nTo explore whether CyCV-VN is circulating beyond central and southern Vietnam, we screened a total of 615\u2005CSF specimens from patients with acute CNS infections from northern Vietnam (n = 233), Cambodia (n = 123), Nepal (n"
+"1. Introduction {#sec0005}\n===============\n\nMulti-detector computer tomography (MDCT) is the current gold-standard imaging modality for pre-procedural planning of trans-catheter aortic valve replacement (TAVR). It allows for determination of both the optimal approach as well as accurate valve size in each case \\[[@bib0005],[@bib0010]\\]. In addition, MDCT may also identify undiagnosed pathology as may be present in some cases such as aortic aneurysms \\[[@bib0005]\\].\n\nAlthough prior landmark TAVR clinical trials excluded patients with significant aortic aneurysms \\[[@bib0015],[@bib0020]\\]. in clinical practice, patients with aortic aneurysms may undergo TAVR. Ascending aortic dilatation has been reported in up to 25% of patients undergoing TAVR; however, it does not appear to affect mid-term survival \\[[@bib0025]\\].\n\nIn Rylski's study \\[[@bib0025]\\], the impact of ascending aortic dilatation on the procedural outcomes such as vascular complications has not been addressed. It has been seen that vascular complications are associated with increased mortality after TAVR \\[[@bib0030]\\]. Prior studies have demonstrated that female gender \\[[@bib0035]\\], arterial calcification \\[[@bib0035],[@bib0040]\\] and arterial puncture above the inferior epigastric artery \\[[@bib0045]\\] are associated with vascular complications. Thus, the presence of aortic aneurysms can be associated with increased rate of vascular complications.\n\nIn contrast to ascending aortic dilatation, little is known regarding the incidence of abdominal"
+"The data used in this analysis are available upon request given the data is from a third party---the Haitian Ministry of Health. Additionally, there is too much data from the GHESKIO clinics to publish an anonymized dataset. GHESKIO is the largest provider of HIV services in the Caribbean, and this dataset includes the majority of HIV-infected patients who are in care at GHESKIO. If a researcher would like to have access to the data, they would need to contact Dr. Jean William Pape, the Director of GHESKIO (<jwpape@gheskio.org>). He would then discuss with them specifically what they would want to look at and present it to the Ministry of Health for approval, and the persons requesting data would need to sign a confidentiality agreement before viewing the data.\n\nIntroduction {#sec005}\n============\n\nOver the past decade, the scale-up of HIV services, particularly access to antiretroviral therapy (ART), in resource-poor settings has been enormously successful with over 18 million adults initiating treatment \\[[@pone.0175521.ref001]\\]. While these efforts have saved millions of lives, many patients fail to realize the benefits of ART due to discontinuation of treatment, loss to follow-up (LTF), or death within the first year of treatment \\[[@pone.0175521.ref002]--[@pone.0175521.ref009]\\]. Though the Caribbean is"
+"Introduction {#S1}\n============\n\nThe National Limb Loss Information Center reported that there are approximately 1.7 million people living with limb loss in the United States ([@B1]). Most of new amputations occur due to complications from impairment of the vascular system, and amputations of this type account for 82% of limb loss discharges between 1988 and 1996 ([@B2]). Lower-limb amputations account for 97% of all dysvascular limb loss discharges. A recent study of the prevalence of limb loss in the US estimated that one out of every 190 people has had an amputation, and this number may double by the year of 2050 ([@B3]).\n\nAdvanced Lower-Limb Prosthetic Technology {#S1-1}\n-----------------------------------------\n\nPeople who have received limb-amputation face staggering emotional and financial lifestyle changes. They require one or more prosthetic devices and services, which must be maintained for the rest of their lives ([@B4]). A transfemoral amputee (above the knee) must expend up to 60% more metabolic energy to walk than a person with two whole legs ([@B5]) and consume as much as three times the affected-side hip power and torque ([@B6]). Commercially available prostheses comprise spring structures that store and release elastic energy throughout each walking stance period ([@B7]). Because of their"
+"Citation\n========\n\nScallion ML, Gibson GAP, Sharanowski BJ (2016) Revision of *Paranastatus* Masi (Eupelmidae, Eupelminae) with descriptions of four new species. ZooKeys 559: 59--79. doi: [10.3897/zookeys.559.6134](10.3897/zookeys.559.6134)\n\nIntroduction\n============\n\n*Paranastatus* Masi, 1917 (Eupelmidae, Eupelminae) is one of 33 currently recognized genera within Eupelminae ([@B5]). This genus was initially established for two species based primarily on the distinctive triangular shape of the head of females. Four species have been described to date: *Paranastatus egregius* Masi, 1917 and *Paranastatus violaceus* Masi, 1917 from Seychelles, and *Paranastatus verticalis* Eady, 1956 and *Paranastatus nigriscutellatus* Eady, 1956 from Fiji ([@B11], [@B3]). No new specimens of either *Paranastatus egregius* or *Paranastatus violaceus* have been reported since their original description and their biology remains unknown. However, [@B13] and [@B14] subsequently reared *Paranastatus nigriscutellatus* and *Paranastatus verticalis* from the eggs of the walking stick, *Graeffea crouanii* Le Guillou (Phasmatodea: Phasmatidae). Males are known only for *Paranastatus egregius*, *Paranastatus nigriscutellatus*, and *Paranastatus verticalis*. A key to these males was provided by [@B3].\n\nEupelmidae is likely a grade-level taxon ([@B4]) rather than being monophyletic ([@B8]), though Eupelminae is supported as monophyletic ([@B4]). The subfamily is characterized in part by its extreme sexual dimorphism, and species and higher level taxonomy is based"
+"**Suggested citation:** EFSA FEEDAP Panel\u00a0(EFSA Panel\u00a0on Additives and Products or Substances used in Animal Feed) , Bampidis V, Azimonti G, Bastos ML, Christensen H, Dusemund B, Kouba M, Kos Durjava M, L\u00f3pez\u2010Alonso M, L\u00f3pez Puente S, Marcon F, Mayo B, Pechov\u00e1 A, Petkova M, Ramos F, Sanz Y, Villa RE, Woutersen R, Galobart J, Holczknecht O, Manini P, Pizzo F, Call JT and Anguita M, 2019 Scientific Opinion on the safety and efficacy of APSA PHYTAFEED^\u00ae^ 20,000 GR/L (6\u2010phytase) as a feed additive for piglets (suckling and weaned) and growing minor porcine species. EFSA Journal 2019;17(11):5894, 9 pp. 10.2903/j.efsa.2019.5894\n\n**Requestor:** European Commission\n\n**Question number:** EFSA\u2010Q\u20102019\u201000192\n\n**Panel\u00a0members:** Giovanna Azimonti, Vasileios Bampidis Maria de Lourdes Bastos, Henrik Christensen, Birgit Dusemund, Maryline Kouba, Mojca Kos Durjava, Marta L\u00f3pez\u2010Alonso, Secundino L\u00f3pez Puente, Francesca Marcon, Baltasar Mayo, Alena Pechov\u00e1, Mariana Petkova, Fernando Ramos, Yolanda Sanz, Roberto Edoardo Villa and Ruud Woutersen.\n\n**Acknowledgements:** The Panel\u00a0wishes to acknowledge the contribution of Kostas Sofianidis and Elisa Pettenati to this opinion.\n\n**Note:** Relevant information or parts of this scientific output have been blackened in accordance with the confidentiality requests formulated by the applicant pending a decision thereon by the European Commission. The full output has"
+"Despite the progress in techniques for cancer prevention, detection, and treatment, as well as for increasing the public awareness in recent years, this disease is projected to become the leading cause of death worldwide. Advancements in omics, analytical procedures, and high throughput screening in the last five years have led to the realization that human diseases and especially cancer are more complex than were originally conceived. Cancer is not a static entity that can be easily monitored and manipulated. It is characterized by a dynamic and time-dependent network of constantly altered molecular and cellular interactions between players in different pathways. This network is not invariable and rigid but is constantly reshaped and altered conforming to the pliable signaling processes/responses implicated. Its complexity is apparent by the fact that the disease state is not a disruption of a single node or specific nodes in the network organism but is organism-patient dependent, thus requiring personalized perspective approaches.\n\nNumerous challenges hamper effective cancer treatment and development of effective drugs such as ineffective therapeutic drug concentration reaching the tumor site, life-threatening side-effects caused by nonspecific tissue distribution of anticancer agents, and acquired resistance of the cancer cell upon chemotherapy that triggers cross-resistance to a"
+"1. Introduction {#sec1}\n===============\n\nDuring the last centuries living conditions in western countries changed extremely and social and economical structures shifted dramatically. As a suggested consequence of the resulting improvements in hygiene, antiparasite treatments, and the reduced exposure to pathogens and childhood infections, the occurrence of chronical inflammatory diseases and allergies increased rapidly \\[[@B1], [@B2]\\]. In 1989, David Strachan was the first one to link these two developments and enunciated the \"*Hygiene Hypothesis.*\" According to this thesis, the observed increases in certain inflammatory disorders were due to the decreased early-life exposure to microorganisms and other eukaryotic infectious agents including helminths \\[[@B3]\\].\n\nWorm-like parasites that belong to unrelated phyla, namely, the plathelminthes (trematodes and cestodes) and the nematodes, were already present in early Hominidae. This long coexistence between humans and helminths must have had a fundamental impact on the constitution and regulation of the immune system \\[[@B4]--[@B6]\\].\n\nAs an advancement of the \"*Hygiene Hypothesis,*\" the \"*Old Friend Hypothesis*\" was put forward by Graham Rook. He hypothesized that numerous harmless pseudocommensals, including the helminths, were tolerated by the immune system due to their abundant presence \\[[@B6]\\]. In this way, the tolerance of helminths reduces the negative impact on the host\\'s fitness, since"
+"Bone is a dynamic tissue being continuously degraded by osteoclasts and renewed by osteoblasts, whose functions are regulated by various hormones and cytokines ([@B1][@B2][@B3]). Bone homeostasis represents a balance between these 2 opposing processes. Once this balance is disrupted, however, metabolic bone diseases such as osteoporosis and osteopetrosis occur. Recently evidence has emerged showing TSH receptor (TSHR) expression in bone and an antiosteoporotic action of TSH that was independent of thyroid hormones. Absence of the TSHR in the global Tshr^\u2212/\u2212^ mouse caused high-turnover osteoporosis ([@B4]). Activation of TSHR in osteoclasts attenuated osteoclastogenesis and prevented bone resorption. TSH displayed osteoprotective effects in rodents by preventing bone loss after ovariectomy ([@B5], [@B6]). Hyperthyroid Tshr^\u2212/\u2212^ mice completely devoid of TSH signaling displayed higher levels of bone resorption and bone loss compared with hyperthyroid wild-type mice ([@B7]). TSH has also been shown to induce osteoblastogenesis in embryonic stem cell cultures ([@B8]). And patients with hyperthyroidism displayed strong correlations between low TSH and high bone turnover, reduced bone mineral density, osteoporosis, and increase in fracture risk ([@B9]).\n\nWe and others have shown that the TSHR stimulates a number of different cell signal transduction pathways. It activates several G proteins including G\u03b1s that stimulates the cAMP-protein"
+"The Islamic Republic of Pakistan celebrated its Golden Jubilee in 1997, 50 years after the partitioning of United India from the British Raj. For Pakistan ([fig 1](#fig1){ref-type=\"fig\"}), this was also a time to evaluate the health and population status of its people. In Pakistan, during the 1940s, population growth rates begin to accelerate as health improvements lengthened life expectancy and birth rates remained high. In 1947, at the time of independence, Pakistan\\'s population was 31 million. By 1995 it had escalated to 140 million[@b1]\n\n![Map of Pakistan](umj7603-122-f1){#fig1}\n\nFamily planning programmes were started in the 1950s and 1960s by private and government institutions. Donors such as World Bank and the UN along with the government of Pakistan funded the programmes for family planning (FP). For years these institutions focused only on women as it was thought that FP was the preserve of women, therefore the audience was 100% female.\n\nIn 1947, the fertility rate was 7.5 per women and the population growth rate 4.5% per year. In the 1990s these were reduced to 5.1 and 2.9, respectively, but this reduction is negligible. Presently, 41% of the total population in Pakistan is under the age of 15 years. A large number of"
+"Background {#Sec1}\n==========\n\nTotal hip arthroplasty (THA) has become a common treatment for end-stage hip joint diseases. With improved implant designs and surgical techniques, bearing surface wear, and the resultant wear-induced osteolysis have become a major limitation to prosthetic long-term survivorship, particularly in young and active patients \\[[@CR1],[@CR2]\\].\n\nMetal-on-polyethylene (MOP) bearing surface, a bearing surface with good long-term results in elderly patients, once was taken as gold standard for THA \\[[@CR3],[@CR4]\\]. But in the past decades, it became clear that polyethylene liner wear debris generated with time was associated with the occurrence of osteolysis which leads to subsequent loosening and eventual implant failure. It has been reported that the osteolysis rate of MOP is as high as 26%, and aseptic loosening rate is 3% at 10-year follow-up \\[[@CR1]\\]. In an attempt to avoid the problems caused by polyethylene wear debris, ceramic-on-ceramic (COC) bearing surface has been developed as an alternative. COC offered several theoretical advantages, such as extreme hardness and scratch resistance, which improved lubrication that creates low coefficient of friction resulting in excellent wear resistance and low osteolysis rate \\[[@CR5],[@CR6]\\]. Hence, COC bearing surfaces are increasingly used for THA. Literature reported that none of the 144 hips with COC"
+"Objective\n=========\n\nPhysical activity is an important contributor to health and well-being. People with more education consistently report greater participation in physical activity ([@R1]). It is also well established that neighborhood walkability and safety influence participation in physical activity ([@R2],[@R3]). However, the mediating role of the neighborhood environment, in particular walkability and safety, on the association between education level and physical activity level has not been quantified. We hypothesized that perceived neighborhood walkability and safety are important mediators of the relationship between education level and physical activity level. If true, this suggests that efforts to make environments more amenable to physical activity in neighborhoods characterized by low education levels may help to reduce disparities in physical activity ([@R4],[@R5]).\n\nMethods\n=======\n\nWe analyzed aggregated data collected in 2010 and 2012 from 2 modified Behavioral Risk Factor Surveillance System (BRFSS) surveys ([@R6]) in the 39 \"Communities Putting Prevention to Work\" (CPPW) communities ([@R7]) that included questions on perceived neighborhood walkability and safety in addition to the usual BRFSS questions on education and physical activity. CPPW was a 2-year initiative that funded 50 communities to implement policy, systems, and environmental interventions to reduce obesity and tobacco consumption ([@R7]). The median response rate based"
+"Phendimetrazine (PDM) is a clinically available and widely prescribed anti-obesity medication[@b1]. Recently, 14--21 day PDM treatment was shown to decrease cocaine self-administration in preclinical cocaine addiction models[@b2][@b3], and it is currently being evaluated as a candidate pharmacotherapy in human laboratory cocaine self-administration studies (NCT02233647 and NCT0252235). Structurally, PDM is an *N*-methyl analog of the monoamine transporter substrate phenmetrazine (PM; [Fig. 1](#f1){ref-type=\"fig\"}) and is hypothesized to function as a prodrug that requires biotransformation to PM as its active metabolite to produce its effects[@b4][@b5]. From a clinical therapeutic perspective, prodrugs are advantageous for multiple reasons[@b6]. As one example, prodrug formulations may slow onset of central nervous system-active drug effects reducing abuse liability[@b7][@b8]. A recent example is the amphetamine prodrug lisdexamfetamine[@b9][@b10][@b11]. However, research regarding whether PDM functions as an inactive prodrug or has pharmacological activity on its own has produced inconsistent results.\n\nThere are two main lines of evidence supporting the hypothesis that PDM functions as an inactive prodrug. First, *in vitro* studies found that PDM possessed measurable but very low potency to block the dopamine transporter (DAT) in rat brain synaptosomes (IC~50~\u2009=\u200919\u2009\u03bcM)[@b5]. By contrast, PM was approximately 30-fold more potent to block DAT (IC~50~\u2009=\u20090.6\u2009\u03bcM) and 100-fold"
+"Introduction\n============\n\nThere is an increasing amount of data reporting on the bioeffects of magnetic particles and magnetic fields, which has led us to carry out a study to understand the way in which they influence living organisms. Magnetic particles are widely used in medicine, and have attracted attention especially due to their potential as contrast agents for magnetic resonance imaging (MRI) and as heating mediators for cancer therapy (hyperthermia).\n\nAlthough magnetic particles are extensively used in medicine, their influence on cells and living organisms remains unclear. Various methods and applications with magnetic particles are used for gene and drug delivery, including magnetofection,[@b1-ijn-10-7307],[@b2-ijn-10-7307] magnetite cationic liposomes cell labeling,[@b3-ijn-10-7307] and antibody-conjugated magnetoliposome cell labeling,[@b4-ijn-10-7307] but the effects of magnetic particles on cellular processes have not been sufficiently investigated. There is an evidence that magnetic labeling of mesenchymal stem cells (MSCs) increased their rate of proliferation approximately five times,[@b4-ijn-10-7307] but the influence of embedded magnetic particles in nanofibrous material on MSC proliferation and differentiation has not been fully examined in the past.\n\nMagnetic nanoparticles (MNPs) usually consist of magnetic elements such as iron, nickel, or cobalt, and they may vary in composition depending on the specific application. For biomedical applications, characteristics such"
+"COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was declared a pandemic on 11 March 2020 by the World Health Organization. Children are less likely to develop severe disease from COVID-19 compared to adults, although the reasons for this remain unclear \\[[@R1]\\]. Despite the fewer number of cases reported in children, there are concerns about asymptomatic or mildly symptomatic paediatric cases going undetected and unknowingly transmitting SARS-CoV-2 in the community or schools \\[[@R2],[@R3]\\]. Understanding the role of children in the transmission of SARS-CoV-2 is of global interest and is urgently required given its policy implications in relation to reopening schools and intergenerational contacts. This rapid review aims to synthesise the latest evidence in relation to the role of children in the transmission of SARS-CoV-2.\n\nMETHODS\n=======\n\nLiterature search and eligibility criteria\n------------------------------------------\n\nWe searched PubMed, medRxiv and the WHO COVID-19 database on 30 April 2020 with entry date limits from late 2019 (please see search strategies in the Appendix S1 of the [**Online Supplementary Document**](#S1){ref-type=\"supplementary-material\"}), to identify studies that investigated transmission of SARS-CoV-2 in children (0-18 years) or in schools. We reviewed titles and abstracts and subsequently full texts to identify publications based on predefined inclusion and exclusion"
+"Introduction {#Sec1}\n============\n\nIntegration into the host cell genome, which is catalyzed by the virus-encoded integrase (IN) enzyme, is a hallmark of all members of the Retroviridae family^[@CR1],[@CR2]^. In both lenti- and gamma- retroviruses, functionally active IN is a product of endo-proteolytic cleavage of the Gag-Pol polyprotein by action of the virally encoded protease. As a result of this process, in the case of HIV-1, mature IN harbors an N-terminal phenylalanine, which renders the protein susceptible to rapid degradation by the 26S proteasome following recognition by the class of E3 ubiquitin ligases known as\u00a0recognins (N-end rule ubiquitin E3 ligases), which recognize N-degron signals^[@CR3],[@CR4]^. When the first amino-acid of HIV-1 IN is mutated to methionine, IN stability increases, however the protein is still short-lived^[@CR4]--[@CR8]^, an indication that IN is targeted for degradation through the proteasomal pathway also independent from N-terminal recognition. Indeed, this conclusion is consistent with the long-standing observation that inhibition of the proteasome enhances HIV-1 infection^[@CR9],[@CR10]^.\n\nThe 160-kDa HIV-1 Gag-Pol polyprotein is packaged into virions preceding proteolytic processing, which occurs in the virions after budding. Upon target cell infection, mature IN (32 kDa) is part of the viral pre-integration complex (PIC), which provides a secluded environment where reverse"
+"Supported by the Research Program on Hepatitis (JP18fk0210043 to T.L.) and the Program on Emerging and Reemerging Infectious Diseases (17fk0108218 to T.L.) from the Japan Agency for Medical Research and Development and by a Grant\u2010in\u2010Aid for Scientific Research (C) (17K08090 to T.L.) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.\n\nAA\n\n:   amino acid\n\nALT\n\n:   alanine aminotransferase\n\nELISA\n\n:   enzyme\u2010linked immunosorbent assay\n\nG\n\n:   genotype\n\nHEV\n\n:   hepatitis E virus\n\nHEV\u2010LPs\n\n:   HEV\u2010like particles\n\nIFA\n\n:   immunofluorescence assay\n\nIgG\n\n:   immunoglobulin G\n\nIgM\n\n:   immunoglobulin M\n\nOD\n\n:   optical density\n\nORF\n\n:   open reading frame\n\nP\n\n:   passage\n\nPBS\n\n:   phosphate\u2010buffered saline\n\np.i.\n\n:   post inoculation\n\np.t.\n\n:   post transfection\n\nRBV\n\n:   ribavirin\n\nRT\u2010qPCR\n\n:   real\u2010time quantitative reverse\u2010transcription polymerase chain reaction\n\nWB\n\n:   western blot\n\nHepatitis E virus (HEV) is a causative agent of acute hepatitis E and has been classified into the Hepeviridae family, which includes two genera, *Orthohepevirus* and *Piscihepevirus.* [1](#hep41288-bib-0001){ref-type=\"ref\"}, [2](#hep41288-bib-0002){ref-type=\"ref\"} The genus *Piscihepevirus* includes only one member, the cutthroat trout virus, whereas the genus*Orthohepevirus* includes four species, *Orthohepevirus* A to D.[2](#hep41288-bib-0002){ref-type=\"ref\"} The species A includes eight genotypes of HEV (G1 to G8 HEV) and is detected in humans, monkeys, pigs, wild boars,"
+"The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Individual data is available on request, database shared with the Italian Telethon funder of the study. Please contact <eumercuri@gmail.com>.\n\nIntroduction {#s1}\n============\n\nIn the last few years the rapidly increasing number of potentially effective therapeutical approaches for patients affected by Duchenne muscular dystrophy (DMD) has highlighted the need for improving clinical trial design. A lot of attention has been devoted to natural history studies and to the identification of possible trajectories of progression of the disease [@pone.0108205-McDonald1]--[@pone.0108205-Mayhew1]. The 6 minute walk test (6MWT) is currently being used as the primary outcome measure in most of the ongoing studies as it provides a global assessment of functional mobility, endurance, and ability to walk [@pone.0108205-McDonald4]--[@pone.0108205-Mazzone2]. The North Star Ambulatory Assessment (NSAA) a motor functional scale specifically developed for DMD, is also often used as a secondary measure providing additional information on several functional aspects that reflect everyday life activities. Both measures fit the construct for DMD, have proved to be reliable, have been validated and used in multicentric longitudinal studies [@pone.0108205-Mazzone1]--[@pone.0108205-Scott1] and reflect clinically meaningful activities."
+"Introduction {#S1}\n============\n\nThe cerebral cortex contains two predominant types of neurons, pyramidal--excitatory neurons (\\~70--85%) and inhibitory interneurons (\\~15--30%) ([@B1], [@B2]). Pyramidal neurons send axons to other areas of the cortex and distant parts of the CNS, while interneurons modulate local circuits ([@B3], [@B4]). Proper neocortical function requires the appropriate balance between excitatory and inhibitory neurons. An imbalance may result after brain damage such as traumatic brain injury (TBI), stroke, hypoxia, or ischemia. An excitatory/inhibitory imbalance can lead to functional deficits and various disorders including cognitive and/or motor problems ([@B5]--[@B7]), sleep disorders ([@B6], [@B8], [@B9]), or epilepsy ([@B10]--[@B13]). Injuries to the brain can damage both neuronal types, but it may be possible to replace lost or damaged cells and restore physiological balance ([@B11], [@B12], [@B14]). For the replacement to be effective, the transplanted cells should reach and remain in the target site; once there, cells must differentiate and integrate into the endogenous circuitry to restore lost function ([@B15]--[@B17]). Several studies demonstrate that neural progenitor cells (NPCs) in the ventricular/subventricular zone (VZ/SVZ) proliferate and migrate to the site of damage ([@B18]--[@B21]). Transplantation of exogenous cells in the damaged region has also been explored. GABA-expressing interneurons, or neuronal and glial precursors transplanted"
+"Isolated posterior cruciate ligament (PCL) ruptures are less common knee injuries compared with anterior cruciate ligament (ACL) ruptures. Isolated PCL injuries account for approximately 17% of all knee ligament injuries.^[@bibr11-2325967115599539]^ In a newly published article examining the epidemiology of all knee injuries among US high school athletes, the prevalence of ACL injuries was 25.4% and that of PCL injuries was 2.4%.^[@bibr21-2325967115599539]^ Although isolated PCL injuries are not uncommon in contact sports, such as American football, rugby, and soccer, few studies have reported the treatment and follow-up of isolated PCL injuries. Thus, it is difficult to provide evidence-based advice to patients concerning their treatment options. The majority of isolated PCL injuries are benign when it comes to regaining preinjury activity level.^[@bibr19-2325967115599539]^ However, the injury can be disabling for the affected patient, and it commonly results in a long recovery period. In some cases, the athlete may never compete again at the same level.^[@bibr18-2325967115599539],[@bibr19-2325967115599539]^ Usually, a nonoperative approach is first tried; for the majority of patients, this treatment approach results in a return to the preinjury activity level.^[@bibr16-2325967115599539],[@bibr19-2325967115599539]^ Limited research is available to provide universal guidelines for the nonoperative treatment approach, but active rehabilitation, including a PCL brace, and focusing on regaining"
+"1. Introduction {#sec1}\n===============\n\nCystic fibrosis (CF) is a multi-system disease that results in chronic pulmonary suppuration and bronchiectasis. *Staphylococcus aureus* and *Pseudomonas aeruginosa* are commonly isolated from the airway secretions of patients with CF. Despite being regularly colonised with potentially pathogenic micro-organisms, CF patients have extremely low rates of lung abscess and/or systemic bacterial infection. We describe a case of lung abscess in a child with CF and review the literature.\n\n2. Case report {#sec2}\n==============\n\nA 16-year-old female with neonatally diagnosed Delta F508 homozygous CF with severe bilateral multi-lobar bronchiectasis presented to the Emergency Department with a two-week history of non-specific ill health followed by a two-day history of severe left sided pleuritic posterior chest pain, exertional dyspnoea and fever. Prior to this illness, she had been relatively stable with forced expiratory volume in 1\u00a0second (FEV~1~) of 93% predicted and methicillin-sensitive *Staphylococcal aureus* (MSSA) isolated on multiple occasions on sputum bacterial cultures. She was on lumacaftor-ivacaftor along with nebulised dornase alpha, in addition to other routine CF medications. Her extensive radiological disease was likely a result of previous severe allergic bronchopulmonary aspergillosis (ABPA).\n\nDuring the current presentation, she reported an increasingly productive cough without haemoptysis and was"
+"Introduction {#Sec1}\n============\n\nThe construction of narrow-bandwidth emitting organic lasers relies on the accuracy of technical equipment, such as deposition techniques for the construction of optical waveguides and optical techniques for writing periodic resonant structures^[@CR1]^. As an alternative approach, the concept of random lasers in which optical modes are guided and supplied with feedback within a disordered medium has been elaborated^[@CR2]--[@CR4]^. A wide range of gain materials have been developed, which are normally prepared on flat or structured substrates^[@CR5],[@CR6]^. In the past decade, however, there has been an increased interest in simple material systems that are inexpensive, easy to build, flexible, and do not require many preparation steps to be operational. Recently, paper has emerged as a promising candidate to fulfil these requirements^[@CR7]^. As a renewable resource, paper is an economically accessible, abundant and biodegradable composite that is already used in a variety of industrial applications (including, but not limited to copy paper, filters and weighting papers). Consisting of interconnected cellulose fibres often filled with mineral fillers, such as calcium carbonate, this composite material achieves better stability and smoothness as well as opaqueness compared to just cellulose fibres^[@CR8]^. In order to improve the brightness and to maintain a white impression"
+"Introduction {#Sec1}\n============\n\nType 1 diabetes (T1D) is caused by the autoimmune destruction of pancreatic \u03b2 cells. Treatment is optimized insulin injections with regular monitoring of blood glucose concentration. Although insulin therapy has improved quality of life for patients, many patients suffer from hypoglycemic episodes \\[[@CR1]\\], have suboptimal glycemic control which increases the risk of long-term diabetes complications \\[[@CR2]\\], and prevalence of coma, seizure, or death \\[[@CR1]\\]. Thus, replacement of islet \u03b2-cell mass is an attractive option for patients not only to avoid insulin injection, but also to avoid complications associated with T1D. Replacement of islet \u03b2 cells can be performed either by whole pancreas or pancreatic islet transplantation. Pancreatic islet transplantation is technically much easier for the patient, but has variable long-term success \\[[@CR1]\\]. This is largely due to the intravascular hepatic transplantation site and resultant blood-mediated inflammatory reactions \\[[@CR3]\\], low oxygen tension \\[[@CR4]\\], and immunosuppressive drugs \\[[@CR5]--[@CR8]\\]. Thus, improvements that include encapsulation, co-transplantation with accessory cells or factors with or without a biomaterial, and alternative transplantation sites have been suggested to improve islet function and survival, potentially without the need for immunosuppression. We will introduce the native islet niche, report the current status of pancreatic islet co-transplantation with"
+"INTRODUCTION {#s1}\n============\n\nA group of immunosuppressed persons who might be at higher risk for novel coronavirus (SARS-CoV-2) disease (COVID-19) is persons living with HIV (PLWH) infection. The clinical prognosis of coinfection is unknown but could be alarming given that other chronic infections have proven to be associated with adverse COVID-19 outcomes.^[@R1],[@R2]^ By contrast, PLWH who are taking antiretroviral therapy (ART) may benefit from their ART if the drugs have partially helped the person with immune reconstitution or even have downmodulated SARS-CoV-2 replication. PLWH with excellent HIV control might have milder symptoms or shorter duration of COVID-19 than coinfected persons not taking ART. A variety of COVID-19 clinical presentations have been reported, but the course in PLWH is not yet clear.^[@R3]--[@R5]^\n\nWuhan city, Hubei province, China, was taken by surprise by the COVID-19 pandemic. Free movement of the public was limited during the eventual city lockdown, disrupting the continuity of ART for PLWH in the social distancing period,^[@R6]^ as well as complicating health care information collection and reporting. Creative approaches to effectively distribute ART were developed by community advocates. HIV/CoV-coinfected persons are under tremendous psychological pressures,^[@R7]^ but we nonetheless sought them to assess their clinical courses.\n\nMETHODS {#s2}\n=======\n\nSetting"
+"Introduction {#Sec1}\n============\n\nRespiratory tract infections (RTIs) are detrimental to the health of individuals and economies. Millions of deaths due to acute lower RTIs (ARTIs) occur each year worldwide. The deaths commonly occur in premature infants, immunocompromised patients, individuals with bronchopulmonary dysplasia, and the elderly as a result of severe pneumonia. Children under 5 years of age are also vulnerable, with annual estimates of 1.9 \\[[@CR1]\\], 10.8 \\[[@CR2]\\] and \\[[@CR3]\\] million deaths. Viruses are a major cause of ARTIs \\[[@CR4]\\]. Human respiratory syncytial virus (HRSV) is the most frequent pathogen, followed by influenza viruses, human rhinovirus, enterovirus, human coronavirus, human parainfluenza viruses, and human metapneumoviruses \\[[@CR5]\\]. In addition to these, newly emerging viruses, including severe acute respiratory syndrome-related coronavirus (SARS-CoV), Middle East respiratory syndrome-related coronavirus (MERS-CoV), and influenza viruses of swine (H1N1) and avian (H5N1, H7N9) origin are a threat to public health.\n\nIn Saudi Arabia, ARTI cases involved over 5 million (15.4%) of the population in 2013 \\[[@CR6]\\]. The epidemiology, evolution, and circulation patterns of respiratory viruses in Saudi Arabia may be affected by two major factors. One is the presence of over 11.9 million foreign workers from more than 100 countries \\[[@CR7]\\]. The movements of this huge number"
+"Background\n==========\n\nBreast cancer (BC) is a genetic disease characterized by an out of control growing breast cells, resulting in cellular proliferation, invasion of surrounding tissues and other organs, with possibility of metastasis \\[[@B1]\\]. BC is the second leading cancer in the population, it is the most common cancer among women, and the second leading cause of death within them, with approximately 460.000 deaths/year worldwide \\[[@B1],[@B2]\\].\n\nIn recent years risk factors for BC have been identified, although the etiology of the disease is still not understood. Risk factors that contribute to the development of BC include age, ethnicity, reproduction, some kind of hormones, lifestyle, bone density, genetic factors \\[[@B3]\\] and family history \\[[@B4]\\]. The majority of hereditary breast cancer (HBC) susceptibility can be attributed to germline mutations of to Breast Cancer 1 and Breast Cancer 2 genes (*BRCA1* and *BRCA2*), which are responsible for 30-40% of HBC. Clinically, the basis of HBC is established at an early age, family history, bilateral BC, male BC, ovarian and/or tube cancer, and lower survival when compared to the sporadic form \\[[@B5]\\].\n\nMost of BC are sporadic (SBC), resulting from gene mutations, uncorrected, located in somatic cells, and unrelated to germline mutation. Risk factors"
+"Third-party data from ecoClimate was used for this study and are accessible at: <http://ecoclimate.org/downloads/>. Those interested would be able to access the data in the same manner as the authors. The authors had no special access privileges to this data.\n\nIntroduction {#sec001}\n============\n\nAn accurate knowledge of species geographic distributions is critical to preserve biodiversity in a changing world. Despite the increasing availability of digitized information on biodiversity data and species occurrence, our knowledge about the geographic distribution of most species is regretfully incomplete \\[[@pone.0205164.ref001]--[@pone.0205164.ref003]\\]. This shortcoming, called the Wallacean shortfall, is more evident in highly diverse tropical ecosystems \\[[@pone.0205164.ref004]--[@pone.0205164.ref006]\\], which are paradoxically the most threatened ecosystems \\[[@pone.0205164.ref007],[@pone.0205164.ref008]\\]. Moreover, the lack of data on species distribution is frequently biased toward small, inconspicuous, and not easily detectable species \\[[@pone.0205164.ref001],[@pone.0205164.ref009]\\]. Even with the wide use of methodological tools to predict species ranges, large gaps still exist for these species, particularly because the primary data used in predictive models are scarce or incomplete, precluding a clear understanding of the threats from climate change and assessments of their conservation status.\n\nOngoing climate changes have already impacted organisms' distributions around the world in recent years \\[[@pone.0205164.ref010]--[@pone.0205164.ref013]\\]. Snakes are especially sensitive to climate changes \\[[@pone.0205164.ref014]--[@pone.0205164.ref016]\\] because"
+"Published: February 25, 2016\n\nIntroduction {#sec1}\n============\n\nVoltage- and ligand-gated ion channels are signaling complexes that are often assembled from both regulatory and pore-forming subunits ([@bib8], [@bib30], [@bib54]). AMPA-type (AMPAR) ionotropic glutamate receptors (iGluRs) are composed of pore-forming GluA1--GluA4 subunits ([@bib14]) that coassemble with a variety of auxiliary proteins, including the transmembrane AMPAR receptor regulatory protein (TARP) and cornichon (CNIH) families ([@bib30], [@bib46], [@bib52]), as well as CKAMP44 ([@bib56]) and SynDIG1 ([@bib32]), among others ([@bib22]). Each pore-forming subunit possesses four principal domains, with the extracellular amino-terminal domain (ATD) controlling assembly and trafficking ([@bib17], [@bib21]) and the ligand-binding domain (LBD) providing a bilobed agonist-binding pocket ([@bib13]). Meanwhile, the three transmembrane helices and re-entrant loop form the central pore domain, which governs cation selectivity and channel block ([@bib28]) and connects to the short, intracellular carboxyl-terminal domain (CTD). Once assembled, the native AMPAR is a homo- or heteromeric tetramer ([@bib49]) with a variable stoichiometry of TARPs ([@bib23]) that may include additional CNIH subunits ([@bib24], [@bib30]). Understanding these interactions has been an area of intense study in recent years, especially as TARPs and CNIHs have been shown to directly affect the functional behavior of native AMPARs as well as synaptic plasticity mechanisms ([@bib30]). Exactly"
+"Introduction\n============\n\nWith the increasing shortage of global available resources, efficient and sustainable agricultural production represents a major challenge ([@B49]; [@B20]). Mineral nutrients must be of sufficient availability to ensure efficient crop productivity and product quality ([@B38]; [@B7]). Fe plays an important role in cellular function, and represents one of the essential micro-elements in plants and animals. Plants use Fe to ensure electron flow through the PSII-PSI complex during photosynthesis ([@B6], [@B7]; [@B3]), and Fe plays a critical role in plant development because of its activity in regulating redox status. It is an indispensable cofactor in the respiratory chain and enzymes of tricarboxylic acid cycle, nitrate metabolism, biosynthesis of gibberellins and ethylene, amongst others ([@B33]; [@B3]; [@B7]). Improvement in Fe utilization or enhancement of tolerance to Fe deficiency are important agronomic objectives.\n\nFe(III), is the most abundant type of iron in soil. However, due to the poor solubility of Fe(III) ions under aerobic conditions, especially in high pH and calcareous soils, plants usually display a shortage of Fe ([@B13]; [@B26]). In order to adapt to Fe deficiency stress, plants have evolved two strategies to take up Fe(III) from the soil, strategy I in non-graminaceous plants (including cotton, *Arabidopsis*, and pea)"
+"We appreciate the comments by Dr. Fukui and colleagues about our paper ([@bib1]), and we fully agree with some of their views. However, there are some issues that need to be clarified and discussed.\n\nWe acknowledge and agree that right ventricular (RV) function is closely linked with the afterload. In our cohort study, 40 (34.2%) patients developed acute respiratory distress syndrome (ARDS), which contributed to increase RV afterload. Furthermore, both ARDS and right ventricular longitudinal strain (RVLS) were found to be associated with mortality, consistent with the previous study ([@bib2]).\n\nIt is difficult for us to evaluate the right ventricular to pulmonary artery (RV-PA) coupling by measuring a ratio between tricuspid annular plane systolic excursion and pulmonary artery systolic pressure (PASP), as suggested by Cavalcante ([@bib3]). Noninvasive PASP measurement depends on the presence of tricuspid regurgitation (TR), and there were only 61 patients (50.8%) had interpretable TR jet signal in our study. Among them, the majority was mild or trivial TR, which may affect the accuracy of PASP assessment. As the right heart catheterization was not available in our designated treatment hospital, PASP derived from echocardiography may be less accurate to evaluate the RV-PA coupling.\n\nCOVID-19 patients with underlying cardiovascular"
+"Edited by Yu-Xin Fang\n\nIntroduction {#sec1}\n============\n\nMucosa of the nasal septum can be injured in a number of rhinologic surgeries. With the recent advances in endoscopic skull base surgery and the use of the nasoseptal flap for reconstruction, the number and extent of iatrogenic injury to the septal mucosahas increased. However, a comprehensive understanding of the process involved in the healing of the septal mucosa is lacking and the factors that influence its regeneration have yet to be clarified.\n\nThe process of wound repair has been extensively studied in tissues such as the gingiva and the skin.[@bib1] Although the healing process of the sinonasal cavity has been reported using different animal models,[@bib2], [@bib3], [@bib4], [@bib5], [@bib6] there has been no studies evaluating wound healing after injury to the nasal septal mucosa.\n\nSilastic sheet is commonly used after nasal surgery to promote mucosal healing. It is thought to accelerate the mucosal healing process by moistening and humidifying the wound.[@bib7], [@bib8] Although there have been a number of reports on clinical outcome with a silastic sheet after septoplasty, the effect of this material on septal mucosa has not been clearly documented. Moreover, there are relatively few studies describing such effects at"
+"Introduction\n============\n\nWe compared the cross-correlation between estimates of cardiac output (CO) and left ventricular stroke volume variation (SVV) amongst three commercially available, minimally invasive devices. (LiDCOplus, FloTrac and PiCCO).\n\nMethods\n=======\n\nWe simultaneously compared continuous and bolus thermodilution CO measures from a pulmonary artery catheter (PAC) with simultaneous estimates of arterial pulse contour-derived CO using the FloTrac^\u00ae^, LiDCOplus^\u00ae^and PiCCO^\u00ae^measured at one time in 20 cardiac surgery patients during the first two postoperative hours. We also compared SVV estimates among the three devices. Mean and absolute values for CO and SVV across all devices were compared by ANOVA and Bland--Altman analysis.\n\nResults\n=======\n\nMean CO values were not different across devices (5.8 \u00b1 1.6 l/min vs 5.9 \u00b1 1.7 l/min vs 5.8 \u00b1 1.6 l/min for PiCCO, LiDCO plus and FloTrac, respectively; *P*= 0.4). The mean PAC CO (5.8 \u00b1 1.6 l/min) was similar to PiCCO and FloTrac estimated CO values, but less than LiDCO CO values (*P*\\< 0.01). Biases between PAC and PiCCO, LiDCO and FloTrac values were 0.19 \u00b1 0.57 l/min, -0.35 \u00b1 0.56 l/min and -0.30 \u00b1 1.56 l/min, respectively, and precision was -1.31 to 0.92 l/min, -1.46 to 0.77 l/min and -2.6 to 2.0 l/min, respectively."
+"Published: February 23, 2017\n\nIntroduction {#sec1}\n============\n\nHuman induced pluripotent stem cells (hiPSCs) carry the whole genetic context of a patient and can be a virtually unlimited source of differentiated cell types of interest. Increasingly, hiPSCs are being applied for disease modeling and drug screening for a number of neurodegenerative disorders, including Alzheimer\\'s disease, Parkinson\\'s disease, amyotrophic lateral sclerosis, and Huntington disease (HD) ([@bib38]). Indeed, a number of valuable disease phenotypes have been uncovered using differentiated neuronal subtypes of disease relevance ([@bib16]).\n\nHowever, one of the challenges of hiPSC-based disease modeling is the variability in differentiation potential due to variations in their genetic background ([@bib18]). This may result in inappropriate interpretation of disease phenotypes in\u00a0vitro. Furthermore, the influence of genetic background on disease phenotype can be significant even for monogenic, dominant, and highly penetrant diseases such as HD. Indeed, a recent genome-wide association study identified a number of loci with\u00a0putative disease-modifying variants that appear to influence the age of neurological onset in HD ([@bib12]). Therefore, the use of control hiPSC lines that are genetically identical is crucial to increase confidence in candidate disease phenotypes and mechanisms, and to minimize the chance of missing modifiable effects that are of"
+"Introduction: a view of attachment theory {#Sec1}\n=========================================\n\nThe term attachment or attachment relationship means in order to create one with a child which is being adopted. Adopted children in most cases go through trauma, separation due to loss of a parent or parents (death/divorce/financial burden) and then are often placed for adoption which affects their attachment relationships with new parents or caregivers (Frances [@CR14]). The children in orphan homes/foster homes are described by Levy ([@CR23]) as apparently charming and affectionate. Provence and Lipton ([@CR29]) explained foster children as promiscuously friendly. The attachments theory by Bowlby ([@CR7]); Harlow and Zimmermann ([@CR16]) suggested that children are pre-programmed since birth to form attachments with others as this will help them to live on. The behaviors of the little ones (infants), which are known as 'social releaser' such as smiling and crying that rouse inherent care giving reactions from grown-ups (adults). The determining factor of attachment is not food but concern and responsiveness.\n\nAttachment theory developed by (Bowlby[@CR11]) explained early childhood development and lays tremendous importance that a human infant has a biological need for protective attachment figure for survival and absence of such a figure can cause psychological difficulties in the child's"
+"Introduction {#Sec1}\n============\n\nPremorbid psychological functioning in paediatric patients undergoing surgery has been shown to be predictive of postoperative outcomes.^[@CR1],[@CR2]^ Multiple factors, including pain, depression, anxiety, premorbid physical functioning, adherence and family functioning can significantly influence outcomes.^[@CR1]-[@CR4]^ Mitigating these factors prior to surgical intervention has improved patient outcomes postoperatively in specific paediatric medical populations.^[@CR1],[@CR2],[@CR5]^ Previous studies have demonstrated that 33% of adolescent candidates for hip preservation surgery (HPS) reported maladaptive behaviours that significantly influenced postoperative outcomes.^[@CR3]^ However, the selected, broad measures were not sensitive enough to detect specific symptoms and change over a relatively short period of time, thus potentially under-representing HPS patient struggles. The study did highlight that preoperative mental health factors play an influential role in overall surgical outcomes. In addition, common 'red flags' were identified, which, when present, significantly raised suspicion of underlying psychological factors of patients' presentations, increasing potential negative outcomes following surgical intervention.^[@CR3]^\n\nTo improve patient care and proactively identify and prepare adolescents with chronic hip pain requiring HPS, an interdisciplinary intervention was implemented. Richard et al^[@CR6]^ proposed an interdisciplinary, preoperative care model, including psychological intervention, physical therapy and nursing education to outline postoperative expectations and goals. Patient mental health, resiliency and physical activity were"
+"Airway epithelial cells form a paracellular barrier through apical junctional complexes that physically separate the host from its external environment. This barrier serves several important functions including protection from harmful microorganisms and regulation of the bi-directional flow of ions and macromolecules across the lung epithelial barrier. Interestingly, several studies have recently reported structural and functional defects in airway epithelial cells of individuals with allergic disease \\[[@R1]\\]. Although environmental factors such as allergens, viruses and pollutants have been shown to damage the epithelial barrier and increase allergen sensitization, genetic factors also likely play a role in epithelial dysfunction of susceptible individuals. In support of this concept, a study recently published by our laboratory provides insight into a novel intracellular pathway associated with epithelial barrier integrity and susceptibility to allergic disease \\[[@R2]\\].\n\nMicroarray analyses revealed a reduction in expression of a lipid transport gene, Stard7, in nasal epithelial cells isolated from individuals experiencing an acute asthmatic exacerbation compared to those with stable asthma or nonatopic controls \\[[@R3]\\]. To further explore the significance of this gene in asthma, we generated mice globally deficient in Stard7. Although the majority of mice homozygous for the disrupted allele died at embryonic day 11 (likely of cardiovascular"
+"Introduction\n============\n\nAntigen-presenting cells (APCs), most notably dendritic cells (DCs), are powerful tools to expand antigen-specific T cells both ex vivo and in vivo, but limited by the time-consuming and cost-intensive generation when scaled up, nonspecific stimulation, and biosafety concerns raised by live cells.[@b1-ijn-14-2465],[@b2-ijn-14-2465] As an alternative strategy, the cell-free artificial antigen-presenting cells (aAPCs) were proposed by co-coupling antigenic peptide-loaded major histocompatibility complexes (pMHCs, antigen signal) and anti-CD28 (costimulatory signal) onto scaffolds of biomaterials to imitate natural APCs.[@b3-ijn-14-2465] They are more amenable to rapid manufacturing in a large-scale manner with highly uniform quality and little concern of biosafety. Therefore, numerous biomimetic aAPCs have been developed and are rapidly optimized on their physical and biochemical properties, such as size, shape, charge, surface modifications, signal strength, and the composition of new signal combinations for the establishment of therapeutic cellular immunity.[@b4-ijn-14-2465]--[@b8-ijn-14-2465] Classically, most research studies focus on cell-sized and spherical aAPCs using a variety of biomaterials from liposomes[@b9-ijn-14-2465] to paramagnetic beads,[@b10-ijn-14-2465] non-degradable[@b11-ijn-14-2465],[@b12-ijn-14-2465] and biodegradable polymeric microparticles,[@b13-ijn-14-2465]--[@b15-ijn-14-2465] and achieved intriguing prospects. But nanoscale aAPCs have also been reported recently owing to their advantages over cell-sized aAPCs: superior tissue distribution and drainage properties; and reduced risk of embolism and tissue infarction, so they are more"
+"Introduction\n============\n\nCrohn's Disease (CD) is one of the major forms of inflammatory bowel disease (IBD). CD has a prevalence of 26 to 200 per 100,000 person in populations with European ancestry ([@B34]). Family studies have shown that CD has 0.25 to 0.42 heritability ([@B14]). Dysregulated immune response to environmental factors such as gut microbiome ([@B28]; [@B27]; [@B3]) has been reported in CD. Complex diseases like CD are usually affected by a large number of genetic factors and environment factors ([@B44]). Recent genome-wide association studies (GWAS) of CD have successfully identified more than two hundreds disease-associated loci at the genome-wide significance level ([@B12]; [@B33]). However, these findings could only explain a moderate proportion of the heritability ([@B49]). Recently, integrating GWAS signals with transcriptome-wide association study (TWAS) and expression quantitative trait loci (eQTL) annotation has become an effective approach to identify new susceptibility loci and has been successfully applied in several complex diseases including CD ([@B18]; [@B36]; [@B16]). Other forms of genetic variants are also implied, such as copy number variation (CNV) and rare variants, and they are expected to have large effects ([@B50]). For example, a genome-wide association study of CNVs identified *IRGM* (immunity-related GTPase family, M) and the HLA"
+"1. Introduction {#sec1-nutrients-09-00537}\n===============\n\nAllergy is one of the leading health problems in industrialized countries, affecting around 50 million people in the United States alone, and the number of atopic individuals continues to grow. The hallmark of this disorder is a strong Th2 response with upregulated levels of the interleukin-4 (IL-4), IL-5, and IL-13, which leads to enhanced immunoglobulin E (IgE) and IgG1 production, cell recruitment to the site of allergen exposure, and exaggerated immune responses leading to tissue damage.\n\nFrom an evolutionary perspective, allergies have only recently appeared as a significant health problem. Therefore, researchers have long linked their emergence with rapid lifestyle changes, which occurred in the course of hominine evolution. The \"hygiene hypothesis\" and its derivatives (the \"old friend\" and the \"biodiversity\" hypotheses) pointed to the reduced exposure to environmental microorganisms and helminths in industrialized countries nowadays \\[[@B1-nutrients-09-00537],[@B2-nutrients-09-00537],[@B3-nutrients-09-00537]\\]. The \"toxin hypothesis\" underlined the presence of plant-derived toxins in contemporary foods and skin-care products \\[[@B4-nutrients-09-00537]\\]. Dietary habits are another example of these rapid lifestyle changes and hence, different forms of \"diet hypotheses\" have emerged \\[[@B5-nutrients-09-00537],[@B6-nutrients-09-00537],[@B7-nutrients-09-00537]\\]. The introduction of animal husbandry and agriculture in the Neolithic period slowly initiated these shifts. The Industrial Revolution and development of better tools"
+"Introduction\n============\n\nPrimary immunodeficiencies are disorders in which part of the body's immune system is missing or does not function correctly. Most primary immunodeficiencies are genetic disorders and the majority are diagnosed in children under the age of one, although milder forms may not be recognized until adulthood ([@b1-etm-06-02-0616]). The diagnostic criteria for primary immunodeficiencies were established in 1999 and distinguish between 'definitive', 'probable' and 'possible' in the diagnosis of primary immunodeficiency. A 'definitive' diagnosis is made when the patient has a \\>98% chance of the same diagnosis being made in the following 20 years; this level of diagnosis is achievable with the detection of a genetic mutation or very specific circumstantial abnormalities. A 'probable' diagnosis is made when a genetic diagnosis is not applicable, although the patient has all the other characteristics of a particular disease; the chance of the same diagnosis being made 20 years later is estimated to be 85--97%. A 'possible' diagnosis is made when the patient exhibits some of the characteristics of a disease, but not all ([@b2-etm-06-02-0616]). The treatment of primary immunodeficiency depends foremost on the nature of the abnormality. This may range from immunoglobulin replacement therapy in antibody deficiencies, in the form of"
+"INTRODUCTION {#s1}\n============\n\nAdaptive immunity involves antigen-specific immune responses of T and B cells, whereas innate immunity is mediated by antigen-presenting cells, such as macrophages and dendritic cells (DCs), that initiate adaptive immune responses following pathogen recognition \\[[@RRU040C1], [@RRU040C2]\\]. The innate immune system recognizes pathogen-associated molecular patterns (PAMPs) through pattern recognition receptors (PRRs). To date, several PRRs have been identified, including Toll-like receptors (TLRs), retinoic acid-inducible gene-I-like receptors and nucleotide-binding oligomerization domain-like receptors \\[[@RRU040C3]--[@RRU040C6]\\].\n\nTLRs are well-studied PRRs that are indispensable for antibacterial and antiviral immunity, and 12 members of the TLR family have been identified in mammals \\[[@RRU040C7], [@RRU040C8]\\]. TLRs are receptive to various components of bacterial cell walls. For example, TLR2 and TLR4 recognize peptidoglycan from gram-negative bacteria and lipopolysaccharide (LPS) from gram-positive bacteria, and subsequently initiate host defense responses against bacteria. In contrast, TLR3 and TLR9 recognize genes of single-strand RNA viruses and DNA viruses such as herpes simplex virus, and initiate the production of antiviral cytokines such as type I interferon (IFN).\n\nBoth T and B cells of the adaptive immune system are highly sensitive to ionizing radiation, whereas antigen-presenting cells such as macrophages and DCs are relatively resistant to ionizing radiation-induced cell death, although radiation-induced"
+"Introduction\n============\n\nA growing body of research indicates that symptoms of attention-deficit/hyperactivity disorder (ADHD) often persist into adulthood.[@b1-ppa-8-997]--[@b4-ppa-8-997] With increasing awareness of the need to treat adult ADHD, cost-effectiveness analyses are needed to demonstrate and compare the value of new and existing treatment options. A cost--utility model is a type of cost-effectiveness analysis that requires utilities, which are values on a scale with anchors of 1 (full health) and 0 (dead) to represent the strength of preferences for various health states.[@b5-ppa-8-997]\n\nAlthough utilities have been reported for childhood ADHD, including values associated with various levels of treatment response,[@b6-ppa-8-997]--[@b9-ppa-8-997] little is known about utilities associated with adult ADHD. Two recent reviews reported no published utility values representing ADHD in adults.[@b10-ppa-8-997],[@b11-ppa-8-997] Literature searches conducted for the current study also found no published work on adult ADHD utilities, but one conference presentation was located that reported adult ADHD utilities derived from SF-36^\u00ae^ (Medical Outcomes Trust, Hanover, NH, USA) responses via the SF-6D scoring algorithm.[@b12-ppa-8-997] However, the six items from the SF-6D do not assess attention or other constructs that are specifically relevant to ADHD,[@b13-ppa-8-997] which suggests that it may have limited content validity for this particular condition. Therefore, the purpose of this study"
+"1. Introduction {#se0010}\n===============\n\nGraphene can be described as a single layer of carbon atoms that are integrated together in a repeating pattern of hexagons. It is the thinnest substance ever made. It is the basic structural element of other allotrope, including charcoal, graphite and fullerenes carbon nanotubes. One could also consider it as an indefinitely large aromatic molecule. It has exceptional strength, thermal conductivity, and electric conductivity. The potential applications of graphene is not limited to faster computer chips, it also important in designing hyper-efficient solar cells, flexible touchscreens and desalination membranes [@br0010]. It has also shown a promising future for nanoelectronics material. An important class of graphene nanomaterials with exceptional luminescence properties is graphene quantum dot.\n\nGraphene quantum dots are kind of 0D material with characteristics derived from both graphene and carbon dots [@br0020]. It is becoming an advanced multifunctional material because of its unique optical, electronic, spin and photoelectric properties induced by the quantum confinement and edge effects. Graphene quantum dots are not single-layer graphene domains, but multi-layer formations containing up to 10 layers of reduced graphene oxide ranging from $10\\ \\text{nm}$ to $60\\ \\text{nm}$ in size.\n\nManufacturing graphene-based quantum structures seems to be of great challenge"
+"Background\n==========\n\nPaliperidone extended-release (ER) is an atypical antipsychotic that delivers the active metabolite of risperidone (9-hydroxyrisperidone) using OROS^\u00ae^technology. This formulation minimizes drug plasma fluctuations relative to oral immediate-release risperidone and eliminates the need for initial dose titration \\[[@B1],[@B2]\\]. The 2 drugs also differ in that risperidone is metabolized in the liver via the cytochrome (CYP) P450 2D6 pathway, whereas this pathway is minimally involved in the metabolism of paliperidone ER. Therefore, the potential for clinically significant interactions between paliperidone ER and other drugs metabolized by the CYP P450 2D6 pathway may be minimal \\[[@B3],[@B4]\\].\n\nThe efficacy and safety of risperidone for the treatment of schizophrenia were established more than 15 years ago \\[[@B5],[@B6]\\]. More recently, multinational placebo-controlled studies have shown paliperidone ER 3-15 mg/day to be both efficacious and safe, with discontinuation rates due to adverse events (AEs) similar to placebo \\[[@B7]-[@B9]\\]. To date, and to our best knowledge, however, no studies have been specifically designed to directly compare the efficacy of paliperidone ER and oral risperidone.\n\nThe objective of the current analysis was to perform a post hoc statistical indirect comparison of paliperidone ER and risperidone using propensity score matching. Propensity scores, originally introduced by Rosenbaum and Rubin"
+"INTRODUCTION\n============\n\nThe retinal pigment epithelium (RPE) is sandwiched between the photoreceptors and choriocapillaries (see [Figure 1](#F1){ref-type=\"fig\"}A). The tight junctions (TJs) formed between the RPE cells prevent passive diffusion of molecules and serve as a blood--retina barrier. Bidirectional transepithelial transport across the RPE critically controls the homeostasis of the subretinal space (SRS) and RPE-photoreceptor adhesion. Unlike most epithelia, which have their apical side face toward the lumen, the apical surfaces of RPE cells are in close contact with the SRS and neural photoreceptors throughout development. On retinal maturation, RPE cells develop fairly long microvilli (MV) extending from their apical surfaces interdigitated into and tightly embracing the light-sensing outer segments (OS) of the photoreceptors. Mature RPE cells also have highly convoluted membranous basal infoldings that directly interact with extracellular matrix of Bruch\\'s basement membrane and the choriocapillaries. The microenvironment of the RPE is important not only for its functions but also its morphogenesis. RPE cells tend to de-differentiate during culture and display only primitive MV and no basal infoldings ([@B43]; [@B22]). Many RPE proteins are lost in culture or have reversed polarity ([@B32]; [@B66]).\n\nThe RPE has been identified as the primary site in the etiology of various retinal degenerative diseases,"
+"1. Introduction\n===============\n\nThe level of awareness towards evidence-based medicine (EBM) is growing worldwide and the acceptance of its concept is increasing. In January 2007 the British Medical Journal conducted an online poll about the 15 most important medical milestones and EBM was in seventh place, right behind germ theory and oral contraceptive pill but ahead of computer and medical imaging \\[[@R1]\\], \\[[@R2]\\]. However, fostering an EBM culture and implementing it into practice requires the skills for identifying and appraising the literature critically \\[[@R3]\\], \\[[@R4]\\], \\[[@R5]\\]. A certain knowledge of probability and statistics is mandatory as well when accessing guidelines and evidence summaries, assessing marketing and advertising material from industry, interpreting the results of a screening test, or reading research publications for staying up to date with newly developed treatments; furthermore, knowledge of biostatistics is necessary for the analysis of numerical data, for informing patients about treatment risks, and last but not least for being prepared to the Internet-literature of varying quality presented by patients \\[[@R6]\\], \\[[@R7]\\]. Actually, the question is no longer whether to teach EBM but how to teach it \\[[@R8]\\] and when. Apart from various educational methods, e.g. on the job training, problem-based or self-directed learning \\[[@R9]\\],"
+"The editors are deeply grateful to the following reviewers (members and nonmembers of the Botanical Society of America) who have generously given of their time to review manuscripts submitted to\u00a0*Applications in Plant Sciences*. The list includes those who reviewed manuscripts from December 21, 2016, to December 31, 2017. If any reviewer\\'s name has been omitted, we apologize, and ask that a note be sent to the Managing Editor so the list can be corrected.\n\nAgrawal, Anurag\n\nAllen, Julia\n\nBack, Kyoungwhan\n\nBallard, Harvey\n\nBlackmon, Heath\n\nBlazier, Chris\n\nBlischak, Paul\n\nBonnet, Pierre\n\nBrosi, Berry\n\nBruns, Tom\n\nCampbell, Lesley\n\nChambers, Alan\n\nChambers, Sally\n\nChaney, Lindsay\n\nChang, Peter\n\nCruse\u2010Sanders, Jennifer\n\nde Vere, Natasha\n\nDeyholos, Michael\n\nDrummond, Emily\n\nDrummond, Francis\n\nEdger, Patrick\n\nEllwood, Elizabeth\n\nEndresen, Dag\n\nEscribano\u2010Rocafort, Adri\u00e1n G.\n\nEstep, Matt\n\nFaivre, Amy\n\nFine, Paul\n\nFishbein, Mark\n\nFolk, Ryan\n\nForrest, Laura\n\nFrom, Margaret\n\nGardner, Dale\n\nGoodell, Karen\n\nGrote, Paul\n\nHamilton, Matthew\n\nHegeman, Adrian\n\nHeyduk, Karolina\n\nHodel, Richard\n\nHufford, Matthew\n\nJarvis, David\n\nJinga, Percy\n\nJohnson, Matthew\n\nJolles, Diana\n\nKimura, Mitsuhiro\n\nLagomarsino, Laura\n\nLandis, Jacob\n\nLatvis, Maribeth\n\nLavoie, Claude\n\nLavor, P\u00e2mela\n\nLeonard, Joan\n\nLiang, Chengzhen\n\nLu\u2010Irving, Patricia\n\nMacklin, James\n\nMacLeod, Norman\n\nMandel, Jennifer\n\nMarx, Hannah\n\nMcDonnell, Angela\n\nMei, Wenbin\n\nMerritt, Benjamin\n\nMichaels, Helen\n\nMiller, Andrew\n\nMiller,"
+"Introduction {#s1}\n============\n\nSarcomas although rare in adult patients account for up to 20% of all paediatric malignancies ([@bib10]). These are often aggressive diseases which do not respond well to conventional therapeutic interventions ([@bib2]). As such the cure rates for many of these diseases are unsatisfactory and patient prognoses remain poor. The molecular pathology of many of these cancers is associated with recurrent chromosomal rearrangements; leading to the generation of chimeric fusion proteins. Significantly, many fusion protein generating aberrations occur in a genomic background with few co-occurring genetic alterations ([@bib18]; [@bib9]; [@bib51]; [@bib15]; [@bib40]; [@bib41]). This has led to the prevailing notion that these gene fusions are often the primary driver of disease development. These chromosomal rearrangements often effect genes involved in transcriptional/chromatin regulatory mechanisms; with the resulting fusion proteins thought to drive disease development by altering the dynamics of transcriptional control. Excitingly, recent work has highlighted the therapeutic potential of targeting mechanisms of transcriptional control in cancer cells ([@bib8]). However, effective means of blocking oncogenic transcriptional mechanisms in fusion gene driven sarcomas are currently lacking.\n\nSynovial sarcoma is a fusion gene driven malignancy, which accounts for\u00a0\\~10% of soft-tissue sarcomas. Synovial sarcoma is a poorly differentiated malignancy with an"
+"CASE REPORT\n===========\n\nA 65-year-old female visited Korea University Anam Hospital complaining of chest pain, palpitation, and dyspnea. On the basis of computed tomography, she was diagnosed with Takayasu's arteritis including a large aneurysm (58 mm) on the aortic distal arch ([Fig. 1A, B](#f1-kjtcvs-48-74){ref-type=\"fig\"}). Because the patient strongly refused surgery, we performed thoracic endovascular aortic repair (TEVAR) with left subclavian artery (LSCA) to left common carotid arterial transposition ([Fig. 1C, D](#f1-kjtcvs-48-74){ref-type=\"fig\"}). The thoracic duct was ligated due to injury during the LSCA dissection. After TEVAR, the patient's symptoms improved, and she was discharged on postoperative day 10 with a normal chest X-ray ([Fig. 2A](#f2-kjtcvs-48-74){ref-type=\"fig\"}).\n\nThe patient returned to the hospital complaining of moderate dyspnea on postoperative day 19, and the follow-up chest X-ray showed a severe left pleural effusion ([Fig. 2B](#f2-kjtcvs-48-74){ref-type=\"fig\"}). After the insertion of a chest tube, postoperative chylothorax was confirmed by a pleural fluid analysis. Conservative management with a fat-free diet and *nil per os* was attempted for 2 weeks, but there was no remarkable improvement. Chest tube drainage exceeded 300 mL/day despite the conservative management. Therefore, we administered a subcutaneous injection of octreotide (0.1 mg) every 8 hours for 2 weeks; however, even these injections had no"
+"Background {#Sec1}\n==========\n\nSnakes of the genus *Bothrops* account for the majority of snakebites in Latin America \\[[@CR1]\\]. Several signs and symptoms follow *Bothrops* envenomation, which are associated with both local effects -- such as myonecrosis, hemorrhage, edema and dermonecrosis -- and systemic disorders -- characterized by coagulopathy, hemorrhage, hypertension, cardiovascular shock and acute renal failure \\[[@CR2]\\].\n\n*Bothrops* snake venoms trigger a typical local inflammatory response that involves edema and the subsequent mobilization of leukocytes. However, it is still not clear how *Bothrops* snake venoms elicit leukocyte recruitment, which is essential to restore tissue homeostasis and repair the injured sites. Studies on *B. asper* venom suggest that the activation of the complement system (CS) is one of the mechanisms underlying this event \\[[@CR3]\\].\n\n*Bothrops* venoms are a complex mixture of components including phospholipases A~2~, metalloproteases, serine proteases (SPs) and L-amino acid oxidases (LAAOs) that exert different pharmacological and biochemical activities \\[[@CR4]--[@CR6]\\]. There are evidences that the inflammatory response elicited by *Bothrops* toxins is mainly mediated by phospholipases A~2~ and metalloproteases \\[[@CR4], [@CR7]\\]. However, the possible participation of snake venom SPs and LAAOs in the course of the inflammatory response, including activation of the CS, should not be discarded \\[[@CR5]\\].\n\nHuman"
+"INTRODUCTION {#sec1}\n============\n\nTranscriptomics is the quantitative or qualitative study of RNAs on a genome-wide scale ([@B1]). It is just one of several powerful approaches to undertake comprehensive or global analyses of large sets of related features, such as genes (genomics), proteins (proteomics), DNA modifications (epigenomics), or microbial communities (microbiomics). These approaches are often used for discovery rather than hypothesis-based investigation, since they can provide an unbiased description of similarities or differences between conditions of interest. The development of technologies for these high-dimensional analyses has been accompanied by novel computational and analytic approaches to deal with the vast amounts of data and has driven the emergence of the scientific discipline of bioinformatics ([@B2]).\n\nInitially, transcriptomic studies sought to quantify the expression levels of protein-encoding genes, often with the implicit assumption that this would broadly indicate changes in protein expression levels ([@B3]). However, as technologies and the understanding of noncoding RNAs have evolved, transcriptomic approaches have allowed a much deeper understanding of the complexities of the regulation of gene expression, alternate splicing events, and functions of noncoding RNAs as well as proving invaluable for the accurate construction and annotation of complex genomes ([@B4][@B5][@B7]). Combinations of genomic, epigenomic, transcriptomic, and proteomic approaches"
+"All relevant data are within the paper.\n\nIntroduction {#sec005}\n============\n\nThe provision of safe, reliable healthcare has become a national and international priority for both the developed\\[[@pone.0138490.ref001], [@pone.0138490.ref002]\\] and the developing world\\[[@pone.0138490.ref003]\\]. It is now more than 20 years since the widespread recognition that the delivery of healthcare in complex systems which have not been carefully and rationally designed to minimise risk can and frequently does result in harm\\[[@pone.0138490.ref004]\\], with levels of risk equivalent to micro light aircraft flight\\[[@pone.0138490.ref005]\\]. Attempts have been made to improve the sustainable delivery of safe healthcare using a variety of approaches. It has been recognised that surgery is one of the most challenging areas of healthcare in which to provide safe and reliable care, with incident analysis studies consistently finding a higher level of harm than in medical specialities\\[[@pone.0138490.ref006]--[@pone.0138490.ref008]\\].\n\nThe concept of resilience demands consistent, safe delivery of output despite changing circumstances\\[[@pone.0138490.ref009], [@pone.0138490.ref010]\\]. Studies of high reliability organisations (HROs) have highlighted both the care with which processes are designed, defined and standardised, and the emphasis put on optimising human teamwork and communications. There have been attempts to translate concepts from HROs (aviation, nuclear, manufacturing and petrochemical) into the healthcare industry through improvement interventions of various"
+"The 26S proteasome is an adenosine triphosphate (ATP)-dependent multisubunit protease complex that degrades polyubiqutinated proteins in a regulated manner. This 2.5-MDa compartmentalized protease contains \u223c33 distinctive subunits in two major subcomplexes, the 20S core particle and 19S regulatory particle (RP/PA700). The 26S\\'s central regulatory hub is its hexameric ATPase complex (Rpt1-6), located at the 19S base. The ATPase ring\\'s N terminus (containing a coiled-coil domain) is intimately integrated with subunits involved in scaffolding, ubiquitin chain binding and processing. Its C-terminal side associates with the 20S proteasome via its C-terminal HbYX motif, which induces 20S gate opening to promote substrate entry. This architecture places the ATPase ring in a position where it can accept protein substrates on its N-terminal side, then, in an ATP-dependent manner, translocate them through its central pore and into the 20S for their degradation[@b1][@b2][@b3][@b4]. Archaea also have a proteasomal ATPase complex homologous to Rpt1-6 called PAN, which binds and similarly regulates the archaeal 20S proteasome.\n\nRecent 26S cryo-electron microscopy (EM) analyses revealed that large conformational changes occur in the 19S when the ATPases bind ATP\u03b3S or substrates[@b5][@b6][@b7]. These similar ATP-bound and substrate-bound conformations are thought to be degradation competent. ATP (but not adenosine diphosphate (ADP)) binding to"
+"1. Introduction {#sec1}\n===============\n\nPeroxisome proliferator-activated receptors (PPARs) are a group of ligand-activated nuclear transcription factors belonging to the type II nuclear receptor superfamily. Three PPAR subtypes, PPAR-*\u03b1*, PPAR-*\u03b2*, and PPAR-*\u03b3*, have been identified in amphibians, rodents, and humans \\[[@B1]\\]. Recent studies have shown associations between PPAR gene polymorphisms and metabolic syndrome (MS) and the development of insulin resistance (IR). Gouda et al. \\[[@B2]\\] performed a meta-analysis of 32,849 patients with type II diabetes mellitus (T2DM) and 47,456 normal controls and found that the PPAR-*\u03b3* (Pro12Ala) gene polymorphism was associated with IR and T2DM. In addition, Spars\u00f8 et al. \\[[@B3]\\] showed that the PPAR-*\u03b1* (Leu162Val) gene polymorphism was associated with obesity, T2DM, and abnormal lipid metabolism, while Andrulionyt\u00e8 et al. \\[[@B4]\\] found a link between the PPAR-*\u03b3* coactivator-*\u03b1* (PGC-1*\u03b1*) Gly482Ser gene polymorphism and conversion from impaired glucose tolerance to T2DM.\n\nChildren with primary nephrotic syndrome (PNS) suffer from metabolic abnormalities including glycolipid disorders, altered hemodynamics, and immune dysfunction, and previous studies have demonstrated that these disorders promote the progression of renal diseases and the development of end-stage renal disease (ESRD) \\[[@B5]\\]. Furthermore, the Ala allele of PPAR-*\u03b3* was shown to be associated with a reduced glomerular filtration rate (GFR) and"
+"Introduction\n============\n\nRice (*Oryza sativa*) is a model species for crop genomics. In 2002, rice became the first crop species to have its genome sequenced ([@bib20]), and it remains one of the best characterized crop genomes due to its small size, abundant genetic variation and high-quality sequence data ([@bib43]; [@bib27]). Since the sequencing and annotation of the rice genome, there have been \\>4278 publications on rice genetics, \\~3000 genes have been structurally and/or functionally annotated (Ouyang *et al.*, 2007) and 3000 rice genomes have recently been sequenced at \\~10X coverage ([@bib1]). Although these numbers represent great progress for rice biology, they have so far had little impact on rice agriculture (Bernardo, 2008).\n\nOne of the major challenges facing the agricultural community as it seeks to integrate genomic information into applied plant improvement has been that until recently genotyping was expensive and laborious ([@bib16]; [@bib49]; [@bib30]). As a result, genomic applications were constrained by the number of marker data points that could be assayed per generation in large breeding populations. Consequently, most of the characterized genes in rice are those associated with Mendelian traits, that is, traits controlled by a few genes of large effect. The majority of agronomic traits of"
+"Introduction\n============\n\nHepatitis C virus (HCV) is a major cause of chronic liver disease worldwide. The virus causes chronic infection in 80% of acutely HCV-infected patients; a subset of these individuals develop progressive liver injury leading to liver cirrhosis and/or hepatocellular carcinoma \\[[@B1],[@B2]\\]. Immune responses to HCV play important roles at various stages of the infection. There is emerging evidence that the ability of acutely HCV-infected patients to control the primary HCV infection depends on the vigorous cellular immune reaction to the virus \\[[@B3]\\]. In the chronic phase of infection, immune responses determine the rate of progression of disease, both by limiting viral replication and by contributing to immunopathology. Livers from chronically HCV-infected individuals show T cell infiltration; however, these cells are not HCV specific and are unable to eradicate the virus \\[[@B4]\\]. These liver-infiltrating lymphocytes are associated with liver damage in chronic HCV infection via mechanisms that are not well understood \\[[@B5]\\]. There are several immune evasion mechanisms, which might explain the ability of the virus to escape the immune responses and establish a persistent infection. These immune evasion strategies include: virus mutation, primary T cell response failure, impairment of antigen presentation, suppression of T cell function by HCV"
+"Introduction {#sec1}\n============\n\nTrauma is a prominent clinical issue in medicine due to high rate of morality and life-long morbidity. Blunt thoracic trauma ranked third in the most common types of trauma after head and extremities trauma.[@bib1], [@bib2] Following chest trauma, myocardial or thoracic aorta rupture lead to immediate death while pneumothorax, cardiac tamponade, airway obstruction and uncontrollable bleeding occur within 3\u00a0min to 3\u00a0h of trauma occurrence; these latter conditions are preventable.[@bib3]\n\nChest X-ray (CXR) is a frequently used method to evaluate thoracic trauma but its efficiency has been challenged in diagnosis of thoracic injuries and determination of their severity.[@bib4], [@bib5] It is unable to show symptoms of thoracic trauma in some cases, especially vascular injuries.[@bib6] A number of studies have been published, which preferred to use chest computed tomography (CT) scan rather than CXR in evaluation of traumatic thoracic injuries.[@bib7], [@bib8] Up to 42%--59% of patients were reported to have extra findings on CT scan, which were not identified on CXR.[@bib7], [@bib9] On the other hand, Barriou et\u00a0al.[@bib10] reported only 6.2% alterations in clinical management for patients who had abnormal CT findings.\n\nCT scan is an accurate, precise and fast method for diagnosis of trauma, but"
+"Large accumulations of algae, or harmful algal blooms (HABs), can release toxins and contribute to oxygen-depleted \"dead zones\" in waters, causing human health problems and disrupting food webs.[@r1] Costs associated with closed fisheries and beaches caused by marine HABs total at least \\$82 million annually[@r2]; freshwater HABs can complicate water treatment and decrease recreational revenue, accounting for millions more in costs.[@r3] Now consortia of researchers across the country are developing forecasts to help local public health officials better monitor and respond to HABs.\n\nAnthropogenic nutrient enrichment and a warming climate are contributing to increased frequencies, intensities, and distributions of freshwater cyanobacteria HABs worldwide.[@r1]^,^[@r4]^,^[@r5] When cyanobacteria covered much of Lake Erie's western basin in July 2011, levels of the cyanotoxin microcystin-LR reached 1,000 \u00b5g/L in near-record[@r6] water temperatures averaging just above 77\u00b0F.[@r7] An Ohio Department of Health representative reports nine probable cases of algal-caused illnesses in Ohio in 2011 (unpublished data); however, many cases of illness attributable to HABs, especially milder cases, are probably never reported.\n\nAlthough reports of marine HABs---which include blooms of the dinoflagellates *Karenia brevis* and *Alexandrium* spp. and the diatoms *Pseudo-nitzschia* spp.---appear to be increasing,[@r1] researchers lack the long-term data sets needed to prove incidences really are"