Input: This study aimed to estimate the impact of a range of diabetes interventions on the population prevalence of diabetes for Australian adults between 2010 and 2025. RESEARCH DESIGN AND METHODSWe used the Australian Diabetes Projection Model to estimate the impact of a population-wide strategy, high-risk prevention, surgical diabetes treatment, and a combination strategy on the future population prevalence of diabetes and to estimate the number of diabetes cases that could be potentially prevented in the year 2025. RESULTSWe estimate that a population-wide strategy would reduce the number of diabetes cases by 60, 000-85, 000 in 2025 from an estimated 2 million cases under the status quo scenario.


Input: A high-risk prevention strategy would result in 106, 000 to 150, 000 fewer cases of diabetes in 2025, and surgically induced weight loss would result in 3, 000-6, 000 fewer cases.


Input: No single intervention, or combination of interventions, reversed the increasing trend in diabetes prevalence over the next 15 years. CONCLUSIONSTo reverse upward trends in diabetes prevalence in future years, it is essential that current approaches to diabetes prevention and treatment are optimized and implemented and that alternative approaches to reduce the prevalence of diabetes at a population level are developed.


Input: Charge transfer and Penning ionization of dopants in or on helium nanodroplets exposed to EUV radiation.

helium


Input: Helium nanodroplets are widely used as a cold, weakly interacting matrix for spectroscopy of embedded species.

Helium


Input: In this work we excite or ionize doped He droplets using synchrotron radiation and study the effect onto the dopant atoms depending on their location inside the droplets (rare gases) or outside at the droplet surface (alkali metals).

He

alkali metals


Input: Using photoelectron-photoion coincidence imaging spectroscopy at variable photon energies (20-25eV), we compare the rates of charge-transfer to Penning ionization of the dopants in the two cases.


Input: The surprising finding is that alkali metals, in contrast to the rare gases, are efficiently Penning ionized upon excitation of the (n = 2)-bands of the host droplets.

alkali metals


Input: This indicates rapid migration of the excitation to the droplet surface, followed by relaxation, and eventually energy transfer to the alkali dopants.


Input: Structural revision of methyl tortuoate D, a bis-cembranoid from Hainan Sarcophyton tortuosum and its absolute stereochemistry.

methyl tortuoate D

bis-cembranoid


Input: Methyl tortuoate D (1), together with five other known related bis-cembranoids, was isolated from Hainan soft coral Sarcophyton tortuosum.

Methyl tortuoate D

bis-cembranoids


Input: The structure of methyl tortuoate D (1a), firstly isolated and reported by Li et al. from the title organism, was corrected as 1 by an extensive analysis of its one-dimensional and two-dimensional nuclear magnetic resonance data and by comparison with those reported in the literature.

methyl tortuoate D


Input: In addition, lobophytone K (1b), recently isolated from Hainan soft coral Lobophytum pauciflorum by Lin et al., was proved to be the same compound as 1 and 1a.

lobophytone K


Input: The absolute configuration of 1 was determined by comparing its electronic circular dichroism curve with that of co-occurring ximaolide A (2).

ximaolide A


Input: Non-Contact AFM Imaging in Water Using Electrically-Driven Cantilever Vibration.


Input: An atomic force microscopy (AFM) imaging mode is presented that can simultaneously record surface topography and local electrical properties in aqueous solutions without mechanical contact between the AFM tip and the sample.


Input: The interaction between the electrically biased tip and the grounded sample in aqueous medium causes the AFM cantilever to vibrate.


Input: This operation mode is based on the previously-developed SPFM technique, though using water as the medium instead of air introduces some important practical and theoretical differences, and also greatly extends the applicability of this technique.


Input: There are two vibration modes, one at the frequency of the applied voltage (omega) and one at twice this frequency (2 omega).


Input: The surface topography can be imaged using feedback control of the 2 <F077> vibration amplitude, which is very sensitive to the tip-sample separation distance in the range of 1 ~ 10 nm.


Input: The amplitude and phase of the 1 <F077> vibration can be recorded simultaneously during imaging to obtain information on local surface charge or potential differences.


Input: Similar techniques exist for imaging in air or vacuum, but the addition of a polarizable medium such as water adds significant theoretical and practical complexities.


Input: This paper addresses those complexities, and demonstrates the effectiveness of the technique for surface imaging and analysis in aqueous environments.


Input: Involvement of p-CREB and phase II detoxifying enzyme system in neuroprotection mediated by the flavonoid calycopterin isolated from Dracocephalum kotschyi.

calycopterin


Input: PURPOSE: There is an increasing amount of experimental evidence that oxidative stress has a central role in the neuropathology of neurodegenerative diseases.


Input: It has been suggested that the loss of cell function results from the increased oxidative damage to proteins and DNA.


Input: Herein, we investigated the effect of a natural neuroprotective flavonoid, calycopterin, on H2O2-induced disruption of phase II detoxifying enzyme system and cAMP response element binding protein (CREB) phosphorylation.

calycopterin

cAMP


Input: METHODS: PC12 cells were treated with 25, 50 and 100 mu M of calycopterin for 3h, followed by adding H2O2 (150 mu M) for 24h.

calycopterin


Input: The extent of apoptosis was assessed by comet assay.


Input: The level of phosphorylated CREB, nuclear factor erythroid 2-related factor 2 (Nrf2), glutamylcysteine synthetase (gamma-GCS) and heme oxygenase 1 (HO-1) were measured by western blot method.

glutamylcysteine


Input: The concentration of glutathione (GSH) was determined in whole cell lysate using dithionitrobenzoic acid method.

glutathione

GSH


Input: Superoxide dismutase (SOD) activity was measured by colorimetric assay.


Input: RESULT: Morphological analysis of protection induced by calycopterin, determined by comet assay, showed that calycopterin reduced DNA in tail.

calycopterin

calycopterin


Input: We found that H2O2 decreased mitochondrial membrane potential (MMP), while, calycopterin prevented this decrease in MMP in presence of H2O2.

calycopterin


Input: In H2O2-treated cells, calycopterin also suppressed cytochrome C release to cytosol that is necessary for maintaining mitochondrial homeostasis in survived cells.

calycopterin


Input: Moreover, calycopterin, in presence of H2O2 inhibited the decrease caused by oxidative stress in stress-sensing transcription factors, CREB and Nrf2, which play an important role in antioxidant capacity of the cell.

calycopterin


Input: There was also an increase in gamma-GCS and HO-1 levels in calycopterin pretreated cells.

calycopterin


Input: In the presence of H2O2, calycopterin inhibited decrease in GSH level and SOD activity.

calycopterin

GSH


Input: CONCLUSION: We provided documentation of neuroprotective effect of a natural flavone, calycopterin, against H2O2-induced oxidative stress in differentiated PC12 cells by modulating the level of CREB phosphorylation and Nrf2 pathway.

calycopterin


Input: Monitoring Conformational Changes in Peroxisome Proliferator-Activated Receptor alpha by a Genetically Encoded Photo-Amino Acid, Cross-Linking, and Mass Spectrometry.

Amino Acid


Input: Chemical cross-linking combined with an enzymatic digestion and mass spectrometric analysis of the reaction products has evolved into an alternative strategy to structurally resolve protein complexes.


Input: We investigated conformational changes in peroxisome proliferator-activated receptor alpha (PPAR alpha) upon ligand binding.


Input: Using E. coli cells with a special tRNA/aminoacyl-tRNA synthetase pair, two PPAR alpha variants were prepared, in which Leu-258 or Phe-273 were site-specifically replaced by the genetically encoded photo-reactive amino acid para-benzoylphenylalanine (Bpa).

Leu

Phe

amino acid para-benzoylphenylalanine

Bpa


Input: PPAR alpha variants were subjected to UV-induced cross-linking, both in the absence and presence of ligands.


Input: After the photo-cross-linking reaction, reaction mixtures were enzymatically digested and peptides were analyzed by mass spectrometry.


Input: The inter-residue distances disclosed by the photo-chemical cross-links served to monitor conformational changes in PPAR alpha upon agonist and antagonist binding.


Input: The data obtained with our strategy underline the potential of genetically encoded internal photo-cross-linkers in combination with mass spectrometry as an alternative method to monitor in-solution 3D-protein structures.


Input: Differential Induction of Cytochrome P450 Isoforms and Peroxisomal Proliferation by Cyfluthrin in Male Wistar Rats.

Cyfluthrin


Input: Cyfluthrin effects on in vivo drug metabolizing enzymes were evaluated using the oxidative substrate antipyrine.

Cyfluthrin

antipyrine


Input: Antipyrine pharmacokinetics in plasma and urinary excretion of its major metabolites with and without cyfluthrin oral treatment (20mg/kg/day for 6 days) were investigated in rats.

Antipyrine

cyfluthrin


Input: Cyfluthrin increased the apparent intrinsic clearance and decreased the antipyrine half-life at beta phase.

Cyfluthrin

antipyrine


Input: Cyfluthrin also increased the clearance of the antipyrine metabolites, norantipyrine, 4-hydroxyantipyrine and 3-hydroxymethylantipyrine and the formation rate constants for each of the three metabolites measured in urine.

Cyfluthrin

antipyrine

norantipyrine


Input: These results suggest that cyfluthrin affects hepatic cytochrome P450 (CYP) system.

cyfluthrin


Input: In order to confirm, a second experiment was carried out.


Input: We evaluated the effects of repeated exposure to cyfluthrin on hepatic and renal CYP2E, CYP1A and CYP4A subfamilies and peroxisomal proliferation in rats following oral administration (10 and 20mg/kg/day for 6 days).

cyfluthrin


Input: At the highest dose, cyfluthrin increased renal and hepatic O-deethylation of ethoxyresorufin and O-demethylation of methoxyresorufin, metabolism mediated by the CYP1A subfamily.

cyfluthrin

O

ethoxyresorufin

O

methoxyresorufin


Input: Liver and kidney were susceptible to cyfluthrin-dependent induction of 12-and 11-hydroxylation of lauric acid, suggesting CYP4A subfamily induction.

cyfluthrin

lauric acid


Input: Also cyfluthrin increased the beta-oxidation of palmitoyl-coenzyme A and carnitine acetyltransferase activity, supporting cyfluthrin as a peroxisome proliferator.

cyfluthrin

palmitoyl

carnitine

cyfluthrin


Input: In conclusion, the demonstration that cyfluthrin induced hepatic CYP1A, CYP4A subfamilies and peroxisomal proliferation raises the possibility of cyfluthrin could produce changes in oxidative stress.

cyfluthrin

cyfluthrin


Input: Indoxyl 3-sulfate stimulates Th17 differentiation enhancing phosphorylation of c-Src and STAT3 to worsen experimental autoimmune encephalomyelitis.

Indoxyl 3-sulfate


Input: Although AhR activation regulates CD4T cell differentiation, how it works has yet to be elucidated.


Input: In the present study, using in vitro Th17 differentiation model, we examined effects of AhR activation by indoxyl 3-sulfate (I3S), a uremic toxin, on Th17 differentiation and investigated underlying mechanisms.

indoxyl 3-sulfate


Input: I3S increased expression of ROR gamma t, the master transcription factor for Th17 differentiation, and stimulated Th17 differentiation, in a comparative manner as 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD), a prototypical AhR ligand.

2, 3, 7, 8-tetrachlorodibenzo-p-dioxin

TCDD


Input: Activation of STAT3, which is phosphorylated by the IL-6 signaling pathways and thus is necessary for Th17 differentiation, was strongly stimulated by I3S and TCDD.

TCDD


Input: Phosphorylation of c-Src, which was shown to be activated by AhR ligands, was also increased by I3S and TCDD, and blocking of c-Src activity by 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3, 4-d] pyrimidine (PP2) inhibited phosphorylation of both c-Src and STAT3, raising a possibility that stimulatory activities of I3S and TCDD on Th17 differentiation could be exerted via increased phosphorylation of c-Src, which in turn stimulates STAT3 activation.

TCDD

4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3, 4-d] pyrimidine

TCDD


Input: Finally, we found that I3S worsened experimental autoimmune encephalomyelitis (EAE), which is primarily mediated by Th17 cells, enhancing the frequency of IL-17-producing cells in draining lymph nodes.


Input: Canna indica L. attenuates high-glucose-and lipopolysaccharide-induced inflammatory mediators in monocyte/macrophage.

glucose


Input: ETHNOPHARMACOLOGICAL RELEVANCE: Canna indica L.


Input: (CI) has been widely used as a folklore medicine in tropical and subtropical areas with beneficial effects in numerous diseases, including infection, rheumatism, hepatitis, and it has also been identified as an antioxidant.


Input: MATERIALS AND METHODS: The present study aimed to investigate the effect of CI ethanolic extract (CIE) on productions of nitric oxide (NO), prostaglandin E2 (PGE2), and interleukin-1 beta (IL-1 beta) in lipopolysaccharide (LPS)-induced RAW264. 7 macrophages.

nitric oxide

NO

prostaglandin E2


Input: In addition, the effects of CIE in high glucose (HG)-induced U937 monocytes on mRNA expressions of IL-8 and monocyte chemoattractant protein-1 (MCP-1), and regulation of mitogen-activated protein kinase (MAPK) pathways were also identified.

glucose


Input: RESULTS: CIE was found to inhibit the production of inflammatory mediators including NO, IL-1 beta, and PGE2 from LPS-induced RAW 264. 7 macrophages.

NO


Input: The increases in HG-induced mRNA expressions of IL-8 and MCP-1 were also significantly inhibited by CIE.


Input: Stimulation of HG in U937 monocytes resulted in activation of p38 MAPK, ERK1/2, and JNK.


Input: However, CIE treatment significantly decreased phosphorylation of p38 MAPK, ERK1/2, and JNK.


Input: CONCLUSION: The present study demonstrated that CIE suppressed the LPS-induced inflammatory mediator production and also inhibited HG-induced inflammatory mediator expression by the regulation of MAPK pathway.


Input: Nedd4 is a specific E3 ubiquitin ligase for the NMDA receptor subunit GluN2D.

NMDA


Input: NMDA receptors are a family of glutamate-gated ion channels that regulate various CNS functions such as synaptic plasticity and learning.

NMDA

glutamate


Input: However hypo-or hyper-activation of NMDA receptors is critically involved in many neurological and psychiatric conditions such as pain, stroke, epilepsy, neurodegeneration, schizophrenia, and depression.

NMDA


Input: Thus, it is important to identify mechanisms (such as by targeted ubiquitination) that regulate the levels of individual subtypes of NMDA receptors.

NMDA


Input: In this study, we used a series of tagged, carboxy terminal constructs of GluN2D to identify associating proteins from rat brain.

carboxy


Input: Of seven different GluN2D C-terminal fragments used as bait, only the construct containing amino acids 983-1097 associated with an E3 ligase, Nedd4.

C

amino acids


Input: A direct interaction between GluN2D and Nedd4 was confirmed both in vivo and in vitro.


Input: This association is mediated by an interaction between GluN2D' s C-terminal PPXY motif and the 2nd and 3rd WW domains of Nedd4.

C


Input: Of the four GluN2 subunits, Nedd4 directly interacted with GluN2D and also weakly with GluN2A.


Input: Nedd4 coexpression with GluN2D enhances GluN2D ubiquitination and reduces GluN1/GluN2D NMDA receptor responses.

NMDA


Input: These results identify Nedd4 as a novel binding partner for GluN2D and suggest a mechanism for the regulation of NMDA receptors that contains GluN2D subunit through ubiquitination-dependent downregulation.

NMDA


Input: This article is part of a Special Issue entitled' GluR-dep synaptic plasticity'.


Input: Cell-penetrating cationic siRNA and lipophilic derivatives efficient at nanomolar concentrations in the presence of serum and albumin.


Input: Despite its considerable interest in human therapy, in vivo siRNA delivery is still suffering from hurdles of vectorization.


Input: We have shown recently efficient gene silencing by non-vectorized cationic siRNA.


Input: Here, we describe the synthesis and in vitro evaluation of new amphiphilic cationic siRNA.


Input: C12-, (C12) 2-and cholesteryl-sperminex-siRNA were capable of luciferase knockdown at nanomolar concentrations without vectorization (i. e. one to two orders of magnitude more potent than commercially available cholesteryl siRNA).

(C12) 2

cholesteryl-sperminex

cholesteryl


Input: Moreover, incubation in the presence of serum did not impair their efficiency.


Input: Finally, amphiphilic cationic siRNA was pre-loaded on albumin.


Input: In A549Luc cells in the presence of serum, these siRNA conjugates were highly effective and had low toxicity.


Input: A dihydrochalcone and several homoisoflavonoids from Polygonatum odoratum are activators of adenosine monophosphate-activated protein kinase.

dihydrochalcone

homoisoflavonoids

adenosine monophosphate


Input: Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a major cellular energy sensor and master regulator of metabolic homeostasis; thus, AMPK plays a central role in studies on diabetes and related metabolic diseases.

Adenosine monophosphate

AMP


Input: From the rhizomes of Polygonatum odoratum (Mill.) Druce, six homoisoflavonoids (1-6) and one dihydrochalcone (7) were isolated, and the structures of polygonatones A-D (4-7) were elucidated by various spectroscopic analyses.

homoisoflavonoids

dihydrochalcone

polygonatones A-D


Input: Compounds 1-7 were evaluated for their effect on AMPK activation.


Input: The amount of active phosphorylated AMPK and acetyl-CoA carboxylase in rat liver epithelial IAR-20 cells increased when the cells were incubated with the aforementioned compounds.

acetyl-CoA


Input: Specifically, (3R)-5, 7-dihydroxyl-6-methyl-8-methoxyl-3-(4'-hydroxylbenzyl)-chroman-4-one (1), (3R)-5, 7-dihydroxyl-6, 8-dimethyl-3-(4'-hydroxylbenzyl)-chroman-4-one (2), (3R)-5, 7-dihydroxyl-6-methyl-3-(4'-hydroxylbenzyl)-chroman-4-one (3), and polygonatone D (7) exhibited significant activation effects.

(3R)-5, 7-dihydroxyl-6-methyl-8-methoxyl-3-(4'-hydroxylbenzyl)-chroman-4-one

(3R)-5, 7-dihydroxyl-6, 8-dimethyl-3-(4'-hydroxylbenzyl)-chroman-4-one

(3R)-5, 7-dihydroxyl-6-methyl-3-(4'-hydroxylbenzyl)-chroman-4-one

polygonatone D


Input: Synthesis and structure-activity relationships of a novel and selective bone morphogenetic protein receptor (BMP) inhibitor derived from the pyrazolo [1. 5-a] pyrimidine scaffold of Dorsomorphin: The discovery of ML347 as an ALK2 versus ALK3 selective MLPCN probe.

pyrazolo [1. 5-a] pyrimidine


Input: A structure-activity relationship of the 3-and 6-positions of the pyrazolo [1, 5-a] pyrimidine scaffold of the known BMP inhibitors dorsomorphin, 1, LDN-193189, 2, and DMH1, 3, led to the identification of a potent and selective compound for ALK2 versus ALK3.

pyrazolo [1, 5-a] pyrimidine

dorsomorphin


Input: The potency contributions of several 3-position substituents were evaluated with subtle structural changes leading to significant changes in potency.


Input: From these studies, a novel 5-quinoline molecule was identified and designated an MLPCN probe molecule, ML347, which shows > 300-fold selectivity for ALK2 and presents the community with a selective molecular probe for further biological evaluation.


Input: Synthesis and in vitro evaluation of a PDT active BODIPY-NLS conjugate.


Input: Two new photosensitizers based on the BODIPY scaffold have been synthesized, of which one bears an NLS peptide, which is linked to the BODIPY' s core using the copper catalysed azide-alkyne click reaction.

BODIPY

copper

azide

alkyne


Input: The phototoxicities of these BODIPY based photosensitizers have been determined, as well as their dark toxicities.

BODIPY


Input: Although the conjugation of a single NLS peptide to the BODIPY did not lead to any observable nuclear localization, the photosensitizer did exhibit a superior photoxicity.

BODIPY


Input: Cellular co-localization experiments revealed a localization of both dyes in the lysosomes, as well as a partial localization within the ER (for the peptide-bearing BODIPY).

BODIPY


Input: Valeriana officinalis attenuates the rotenone-induced toxicity in Drosophila melanogaster.

rotenone


Input: In this study, we investigated the potential protective effects of Valeriana officinalis (V. officinalis) against the toxicity induced by rotenone in Drosophila melanogaster (D. melanogaster).

rotenone


Input: Adult wild-type flies were concomitantly exposed to rotenone (500 mu M) and V. officinalis aqueous extract (10mg/mL) in the food during 7 days.

rotenone


Input: Rotenone-fed flies had a worse performance in the negative geotaxis assay (i. e. climbing capability) and open-field test (i. e. mobility time) as well as a higher incidence of mortality when compared to control group.

Rotenone


Input: V. officinalis treatment offered protection against these detrimental effects of rotenone.

rotenone


Input: In contrast, the decreased number of crossings observed in the flies exposed to rotenone was not modified by V. officinalis.

rotenone


Input: Rotenone toxicity was also associated with a marked decrease on the total-thiol content in the homogenates and cell viability of flies, which were reduced by V. officinalis treatment.

Rotenone

thiol


Input: Indeed, rotenone exposure caused a significant increase in the mRNA expression of antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) and also in the tyrosine hydroxylase gene (TH).

rotenone

superoxide

tyrosine


Input: The expression of SOD and CAT mRNAs were normalized by V. officinalis treatment.


Input: Our results suggest that V. officinalis extract was effective in reducing the toxicity induced by rotenone in D. melonogaster as well as confirm the utility of this model to investigate potential therapeutic strategies on movement disorders, including Parkinson disease (PD).

rotenone


Input: Direct methods for detection of protein S-nitrosylation.

S


Input: S-nitrosylation of protein cysteine residues is known to be an important mechanism for nitric oxide signaling.

S

cysteine

nitric oxide


Input: However, the detection of protein S-nitrosylation is still challenging due to technical limitations of current methods.

S


Input: This chapter provides a brief review on recent developments of methods, which directly target S-nitroso moieties for detection.

S

nitroso


Input: We also describe in detail the protocol of an organophosphine-based biotin labeling of protein S-nitroso moieties.

organophosphine

biotin

S

nitroso


Input: Mechanism of BDE209-induced impaired glucose homeostasis based on gene microarray analysis of adult rat liver.

glucose


Input: Several persistent organic pollutants are reported to be potentially associated with the risk of human diabetes that has become rapidly epidemic in China currently.


Input: 2, 2', 3, 3', 4, 4', 5, 5', 6, 6'-decabromodiphenyl ether (BDE209) is commercially most important both in the production and in the use of polybrominated diphenyl ethers (PBDEs).

2, 2', 3, 3', 4, 4', 5, 5', 6, 6'-decabromodiphenyl ether

polybrominated diphenyl ethers

PBDEs


Input: It might bioaccumulate in wildlife and human and is the only PBDEs mixture still used today.

PBDEs


Input: In the present study, male adult rats treated with BDE209 (0, 0. 05, 1, and 20 mg/kg) for 8 weeks were used to explore the effects of BDE209 on glucose homeostasis and possible mechanisms; 0. 05 mg/kg of BDE209 induced dose-related hyperglycemia.

glucose


Input: Then, we performed the full-genome gene expression microarrays, gene ontology analysis, and pathway analysis in this group and control.


Input: BDE209 induced 1, 257 liver gene transcript changes, and 18 canonical pathways were significantly enriched.


Input: Four of them were involved in immune diseases, including autoimmune thyroid disease, graft-versus-host disease, allograft rejection, and type I diabetes mellitus (T1MD), which was confirmed by the decrease in serum insulin.


Input: Subsequently, gene act network and gene co-expression network found that some MHC molecules and TNF-alpha were involved in T1DM pathway, which was then confirmed by the increase in serum TNF-alpha.


Input: Additionally, reduced glutathione and superoxide dismutase in plasma indicated that oxidative damage might partly contribute to BDE209-induced hyperglycemia.

reduced glutathione

superoxide


Input: The results of this study provide some new experimental evidence that the exposure to high levels of BDE209 may contribute to the onset of diabetes in human populations.


Input: Further work needs to be done to confirm this link.


Input: The Development and Validation of a Decision-Analytic Model Representing the Full Disease Course of Acute Myeloid Leukemia.


Input: BACKGROUND: The treatment of acute myeloid leukemia (AML) is moving towards personalized medicine.


Input: However, due to the low incidence of AML, it is not always feasible to evaluate the cost-effectiveness of personalized medicine using clinical trials.


Input: Decision analytic models provide an alternative data source.


Input: OBJECTIVE: The aim of this study was to develop and validate a decision analytic model that represents the full disease course of AML.


Input: METHODS: We used a micro simulation with discrete event components to incorporate both patient and disease heterogeneity.


Input: Input parameters were calculated from patient-level data.


Input: Two hematologists critically evaluated the model to ensure face validity.


Input: Internal and external validity was tested by comparing complete remission (CR) rates and survival outcomes of the model with original data, other clinical trials and a population-based study.


Input: RESULTS: No significant differences in patient and treatment characteristics, CR rate, 5-year overall and disease-free survival were found between the simulated and original data.


Input: External validation showed no significant differences in survival between simulated data and other clinical trials.


Input: However, differences existed between the simulated data and a population-based study.


Input: CONCLUSIONS: The model developed in this study is proved to be valid for analysis of an AML population participating in a clinical trial.


Input: The generalizability of the model to a broader patient population has not been proven yet.


Input: Further research is needed to identify differences between the clinical trial population and other AML patients and to incorporate these differences in the model.


Input: The design and realization of a large-area flexible nanofiber-based mat for pollutant degradation: an application in photocatalysis.


Input: This work demonstrates a novel multifunctional nanofibrous mat for photocatalytic applications based on TiO2 nanocables functionalized by Ag nanoparticles and coated with a thin (~ 2 nm) graphitic shell.

Ag

graphitic


Input: In this mat, which was realized by an electrospinning technique, each component serves a unique function: the carbon coating acts as both an adsorption material for capturing pollutants and as a charge-transfer material, the Ag nanoparticles act as a visible-light sensitizing agent and also as a charge-transfer material, finally the TiO2 nanocable mat acts as a UV sensitive photocatalytic matrix and as the flexible substrate for the other functional components.

carbon

Ag


Input: This multicomponent nanocable mat exhibits excellent photocatalytic activity under simulated solar irradiation for the degradation of model pollutants including RhB and phenol.

RhB

phenol


Input: The significant photocatalytic properties are attributed to the synergetic effect of the three functional components and the unique charge transport " freeway " property of the nanofibrous mat.


Input: In addition, the porous carbon coating infiltrated into the nanocable matrix endows the mat with excellent flexibility and enables robust, large-area (10 x 10 cm) fabrication, representing a significant advantage over previous brittle ceramic nanofibrous mat photocatalyst substrates.

carbon


Input: This study provides new insight into the design and preparation of an advanced, yet commercially practical and scaleable photocatalytic composite membrane material.


Input: The as-prepared photocatalytic mat might also be of interest in solar cell, catalysis, separation technology, biomedical engineering, and nanotechnology.


Input: Toxic Shock Syndrome: Characterization of Human Immune Responses to TSST-1 and Evidence for Sensitivity Thresholds.


Input: Noninvasive vaginal infections by S. aureus strains producing the superantigen TSST-1 can cause menstrual toxic shock syndrome (mTSS).


Input: With the objective of exploring the basis for differential susceptibility to mTSS the relative responsiveness to TSST-1 of healthy women has been investigated.


Input: Peripheral blood mononuclear cells from healthy donors were incubated with purified TSST-1, or with the T cell mitogen phytohaemmaglutinin (PHA), and proliferation measured.


Input: The concentrations of TSST-1 and PHA required to elicit a response equivalent to 15% of the maximal achievable response (EC15) was determined.


Input: Although with PHA EC15 values were comparable between donors, subjects could be classified as being of high, medium or low sensitivity based on responsiveness to TSST-1.


Input: Sensitivity to TSST-1-induced proliferation was associated with increased production of the cytokines interleukin (IL)-2 and interferon gamma (IFN-gamma).


Input: When the entire T lymphocyte population was considered, there were no differences between sensitivity groups with respect to the frequency of cells known to be responsive to TSST-1 (those bearing CD3 (+) V beta 2 (+)).


Input: However, there was an association between sensitivity to TSST-1 and certain HLA-class II haplotypes.


Input: Thus, the frequency of DR7DQ2, DR14DQ5, DR4DQ8, and DR8DQ4 haplotypes were greater among those with high sensitivity; a finding confirmed by analysis of responses to immortalized homozygous B cell lines. Collectively, the results reveal that factors other than neutralising antibody and the frequency of V beta 2 (+) T lymphocytes determine immunological responsiveness to TSST-1.


Input: Differential responsiveness of lymphocytes to TSST-1 may form the basis of inter-individual variations in susceptibility to mTSS.


Input: Distinct role of PYK2 in mediating thromboxane generation downstream of both G12/13 and integrin alpha iib beta in platelets.

thromboxane


Input: Proline-rich tyrosine kinase 2 (Pyk2) is activated by various agonists in platelets.

Proline

tyrosine


Input: We evaluated the signaling mechanism and the functional role of Pyk2 in platelets by using pharmacological inhibitors and Pyk2-deficient platelets.


Input: We found that platelet aggregation and secretion in response to 2-MeSADP and AYPGKF were diminished in the presence of Pyk2 inhibitors or in Pyk2-deficient platelets, suggesting that Pyk2 plays a positive regulatory role in platelet functional responses.


Input: It has been shown that ADP-, but not thrombin-, induced thromboxane (TxA2) generation depends on integrin signaling.

ADP

thromboxane


Input: Unlike ADP, thrombin activates G12/13 pathways, and G12/13 pathways can substitute for integrin signaling for TxA2 generation.

ADP


Input: We found that Pyk2 was activated downstream of both G12/13 and integrin-mediated pathways, and both 2-MeSADP-and AYPGKF-induced TxA2 generation was significantly diminished in Pyk2-deficient platelets.


Input: In addition, TxA2 generation induced by co-stimulation of Gi and Gz pathways, which is dependent on integrin signaling, was inhibited by blocking Pyk2.


Input: Furthermore, inhibition of 2-MeSADP-induced TxA2 generation by fibrinogen receptor antagonist was not rescued by co-stimulation of G12/13 pathways in the presence of Pyk2 inhibitor.


Input: We conclude that Pyk2 is a common signaling effector downstream of both G12/13 and integrin alpha IIb beta 3 signaling which contributes to thromboxane generation.

thromboxane


Input: Bioanalysis of antibody-drug conjugates: American Association of Pharmaceutical Scientists Antibody-Drug Conjugate Working Group position paper.


Input: Antibody-drug conjugates (ADCs) typically consist of a cytotoxic drug covalently bound to an antibody by a linker.


Input: These conjugates have the potential to substantially improve efficacy and reduce toxicity compared with cytotoxic small-molecule drugs.


Input: Since ADCs are generally complex heterogeneous mixtures of multiple species, these novel therapeutic products present unique bioanalytical challenges.


Input: The growing number of ADCs being developed across the industry suggests the need for alignment of the bioanalytical methods or approaches used to assess the multiple species and facilitate consistent interpretation of the bioanalytical data.


Input: With limited clinical data, the current strategies that can be used to provide insight into the relationship between the multiple species and the observed clinical safety and efficacy are still evolving.


Input: Considerations of the bioanalytical strategies for ADCs based on the current industry practices that take into account the complexity and heterogeneity of ADCs are discussed.


Input: Immunogenicity assays for antibody-drug conjugates: case study with ado-trastuzumab emtansine.


Input: Background: Antibody-drug conjugates (ADCs) such as Kadcyla (TM) (ado-trastuzumab emtansine [T-DM1]) present covalently bound cytotoxic drugs, which may influence their immunogenicity potential compared with antibody therapies.


Input: Therefore, ADCs require assay strategies that allow measurement of responses to all the molecular components.


Input: Results: The immunogenicity strategy for T-DM1 used a risk-based, tiered approach that included screening and titration to detect antitherapeutic antibodies; confirmation of positive responses; and characterization to assess whether the immune response is primarily to the antibody or to the linker-drug and/or new epitopes in trastuzumab resulting from conjugation.


Input: Conclusion: The tiered immunogenicity assay strategy for T-DM1 allowed detection of antitherapeutic antibodies to all components of the ADC in multiple nonclinical and clinical studies.


Input: Characterization strategies implemented in clinical studies provided additional insights into the specificity of the immune response.


Input: Immunogenicity testing strategy and bioanalytical assays for antibody-drug conjugates.


Input: Background: Immunogenicity testing is an important component of clinical development for large-molecule biotherapeutics.


Input: New complex types of large molecules, such as antibody-drug conjugates (ADCs), require careful evaluation of the testing strategy and bioanalytical assays used to monitor the development of antitherapeutic antibodies.


Input: Results: An electrochemiluminescence-based immunoassay for the detection and epitope characterization of anti-ADC antibodies was validated.


Input: Using this assay format, antibodies directed against the monoclonal antibody and linker-drug components of the ADC were successfully detected in a multiple-dose rat toxicity study.


Input: Conclusion: Immunogenicity assays incorporating epitope determination may provide additional information about the characteristics of induced antitherapeutic antibodies, including the magnitude and timing of the various types of antibody responses.


Input: A novel approach to capillary plasma microsampling for quantitative bioanalysis.


Input: Background: A novel device and procedure for the collection and isolation of microvolumes of plasma have been developed and two pilot rodent PK studies have been completed.


Input: Results: This method involves collection of blood into a plastic-wrapped, EDTA-coated capillary tube, containing a small amount of a thixotropic gel and a porous plug.

EDTA


Input: Following blood collection, the capillary is placed into a secondary labeled container suitable for centrifugation and plasma is generated.


Input: During centrifugation, the thixotropic gel isolates the plasma from the red blood cells and creates a physical barrier between the two matrices.


Input: The plasma is then dispensed from the capillary tube into a separate container for storage or processing.


Input: Conclusion: A simple and robust novel approach for the collection of small plasma volumes from rodent TK studies has been demonstrated.


Input: Solution pH and Oligoamine Molecular Weight Dependence of the Transition from Monolayer to Multilayer Adsorption at the Air-Water Interface from Sodium Dodecyl Sulfate/Oligoamine Mixtures.

Sodium Dodecyl Sulfate


Input: Neutron reflectivity and surface tension have been used to investigate the solution pH and oligoamine molecular weight dependence of the adsorption of sodium dodecyl sulfate (SDS)/oligoamine mixtures at the air-water interface.

sodium dodecyl sulfate

SDS


Input: For diethylenetriamine, triamine, or triethylenetetramine, tetramine mixed with SDS, there is monolayer adsorption at pH 7 and 10, and multilayer adsorption at pH 3.

diethylenetriamine

triamine

triethylenetetramine

tetramine

SDS


Input: For the slightly higher molecular weight tetraethylenepentamine, pentamine, and pentaethylenehexamine, hexamine, the adsorption is in the form of a monolayer at pH 3 and multilayers at pH 7 and 10.

tetraethylenepentamine

pentamine

pentaethylenehexamine

hexamine


Input: Hence, there is a pH driven transition from monolayer to multilayer adsorption, which shifts from low pH to higher pH as the oligoamine molecular weight increases from tetramine to pentamine.

tetramine

pentamine


Input: This results from the relative balance between the electrostatic attraction between the SDS and amine nitrogen group which decreases as the charge density decreases with increasing pH, the ion-dipole interaction between the amine nitrogen and SDS sulfate group which is dominant at higher pH, and the hydrophobic interalkyl chain interaction between bound SDS molecules which changes with oligoamine molecular weight.

SDS

amine nitrogen

amine nitrogen

SDS sulfate

SDS


Input: Barnacle Cement as Surface Anchor for' Clicking' of Antifouling and Antimicrobial Polymer Brushes on Stainless Steel.


Input: Barnacle cement (BC) was utilized' beneficially' as a surface anchor on stainless steel (SS) for coupling of functional polymer brushes via' click' reactions in both " grafting-to " and " grafting-from " processes.


Input: Ethylene sulfide (ES), propargyl carbonylimidazole (PPC) and azidoethyl carbonylimidazole (AEC) reacted with amine and/or hydroxyl groups in BC to introduce the corresponding thiol, alkyne and azide groups on SS surfaces (SS-thiol, SS-alkyne and SS-azide, respectively).

Ethylene sulfide

propargyl carbonylimidazole

PPC

azidoethyl carbonylimidazole

AEC

amine

hydroxyl

thiol

alkyne

azide

thiol

alkyne

azide


Input: Antifouling zwitterionic SS-PMPC surface was prepared by thiol-ene photopolymerization of 2-methacryloyloxyethyl phosphorylcholine (MPC) from the SS-thiol surface.

thiol

2-methacryloyloxyethyl phosphorylcholine

MPC

thiol


Input: Protein-resistant SS-PPEGMA and protein-adsorbing SS-PPFS surfaces were prepared by coupling of the respective azide-functionalized poly (poly (ethylene glycol) methyl ether methacrylate) (azido-PPEGMA) and poly (2, 3, 4, 5, 6-pentafluorostyrene) (azido-PPFS) polymer brushes in azide-alkyne' click' reaction.

PPEGMA

PPFS

azide

poly (poly (ethylene glycol) methyl ether methacrylate)

azido-PPEGMA

poly (2, 3, 4, 5, 6-pentafluorostyrene)

azido-PPFS

azide

alkyne


Input: Antifouling alkyne-functionalized poly (N-hydroxyethyl acrylamide) (alkynyl-PHEAA) and antibacterial alkyne-functionalized poly (2-(methacryloyloxy) ethyl trimethylammonium chloride) (alkynyl-PMETA) polymer brushes were clicked on the SS-azide surface.

alkyne

poly (N-hydroxyethyl acrylamide)

alkynyl-PHEAA

alkyne

poly (2-(methacryloyloxy) ethyl trimethylammonium chloride)

alkynyl-PMETA

azide


Input: Adsorption of bovine serum albumin and bacteria fouling of Gram-negative Escherichia coli (E. coli) and Gram-positive Staphylococcus epidermidis (S. epidermidis) were investigated on the polymer-functionalized SS surfaces.


Input: The versatile bio-anchor and functional polymer brush coatings are stable in abiotic aqueous environment for over a month.


Input: Revisiting the Mechanism of Neutral Hydrolysis of Esters: Water Autoionization Mechanisms with Acid or Base Initiation Pathways.

Esters


Input: The mechanism of neutral hydrolysis of ester has long been explored by theoretical studies.

ester


Input: However, reliable theoretical calculations show that the usual bifunctional catalysis mechanism reported by different authors cannot explain the experimental kinetics.


Input: An important advance was recently reported by Gunaydin and Houk, suggesting that ions are involved in the mechanism and the process initiates by water autoionization followed by protonation of the ester (WAIA mechanism).

ester


Input: However, this mechanism does not explain the hydrolysis of activated esters.

esters


Input: In this work, we have used ab initio calculations, continuum solvation models and ab initio classical trajectory to support the WAIA mechanism for normal ester.

ester


Input: In the case of activated esters, the process can also be viewed as water autoionization with formation of hydroxide ion aided by a second water moleculeacting as a general base (WAIB mechanism).

hydroxide


Input: This is the mechanism proposed by Jencks and Carriuolo fifty years ago.


Input: Our analysis point out that the usual method for exploring mechanisms, searching for saddle points, may not work for problems like the present one, since there are no saddle points on the reaction pathway.


Input: Rather, the formation of a pair of ions from a neutral species may have an asymptotic barrier.


Input: The approach used in this paper allows the calculation of the free energy profile and enable us to explain the mechanism and kinetics of the neutral hydrolysis of normal (methyl acetate) and activated (methyl trifluoroacetate) esters.

methyl acetate

methyl trifluoroacetate

esters


Input: In addition, the present study suggests that formation of a pair of ions should be always considered in reactions in aqueous solution.


Input: Nanoscale Patterning of Membrane-Bound Proteins Formed through Curvature-Induced Partitioning of Phase-Specific Receptor Lipids.


Input: This work describes a technique for forming high-density arrays and patterns of membrane-bound proteins through binding to a curvature-organized compositional pattern of metal-chelating lipids (Cu (2 +)-DOIDA or Cu (2 +)-DSIDA).

Cu (2 +)

Cu (2 +)


Input: In this bottom-up approach, the underlying support is an e-beam formed, square lattice pattern of hemispheres.


Input: This curvature pattern sorts Cu (2 +)-DOIDA to the 200 nm hemispherical lattice sites of a 600 nm X 600 nm unit cell in Ld-Lo phase separated lipid multibilayers.

Cu (2 +)


Input: Binding of histidine-tagged green fluorescent protein (His-GFP) creates a high density array of His-GFP-bound pixels localized to the square lattice sites.


Input: In comparison, the negative pixel pattern is created by sorting Cu (2 +)-DSIDA in Ld-L beta' phase separated lipid multibilayers to the flat grid between the lattice sites followed by binding to His-GFP.

Cu (2 +)


Input: Lattice defects in the His-GFP pattern lead to interesting features such as pattern circularity.


Input: We also observe defect-free arrays of His-GFP that demonstrate perfect arrays can be formed by this method suggesting the possibility of using this approach for the localization of various active molecules to form protein, DNA, or optically active molecular arrays.


Input: A Minimal Transcriptional Controlling Network of Regulatory T Cell Development.


Input: Regulatory T cells (Treg) are a subpopulation of T cells that are central to immune homeostasis and develop under the control of a complex regulatory network consisting of FoxP3 and its partner factors.


Input: A central question about this network is how does it enable T cells to robustly specify and stably maintain their states despite intrinsic and environmental fluctuations.


Input: Inspired by recent experimental advances, we propose here a minimal transcriptional controlling network and use it to illustrate the robustness and dynamic features of Treg development.


Input: Our study shows that the controlling network may exhibit distinct dynamics depending on its parameter regimes and that the maintenance of multistability requires the orchestration of both its positive and negative feedback loops.


Input: In addition, system volume contributes monotonically to the increase of the network' s robustness.


Input: We further show that the dynamics of our model varies with the alteration of FoxP3-DNA binding affinity, consistent with recent experimental findings.


Input: This minimal model thereby offers new insights into the dynamics and robustness of Treg development and may serve as a platform for future exploration towards a more quantitative and systematic understanding of the immune system.


Input: Synthesis of Hollow Ag-Au Bimetallic Nanoparticles in Polyelectrolyte Multilayers.

Ag-Au


Input: Ag nanoparticles of ~ 20 nm size and rather uniform size distribution were synthesized in polyelectrolyte multilayers (PEMs) via an ion-exchange/reduction process in two stages (seeding and growth), which were used as sacrificial templates to fabricate Ag-Au bimetallic hollow nanoparticles via galvanic replacement reaction.

Ag

Ag-Au


Input: The reaction process was monitored by UV-vis spectroscopy.


Input: The morphology and structure of the nanoparticles were characterized by transmission electron microscopy (TEM) and energy dispersive X-ray spectroscopy, which confirmed the formation of hollow Ag-Au bimetallic nanoparticles.

Ag-Au


Input: UV-vis absorbance spectroscopy and TEM results indicated that both size and optical properties of the Ag nanoparticles in the PEM can be controlled by manipulating ion content in the PEM and the number of the ion-exchange/reduction cycle, whereas that of Ag-Au bimetallic nanoparticles were dependent on size of the Ag templates and the replacement reaction kinetics.

Ag

Ag-Au

Ag


Input: The hollow Ag-Au bimetallic nanoparticles exhibited a significant red shift in the surface plasmon resonance to the near-infrared region.

Ag-Au


Input: The strategy enables facile preparation of hollow bimetallic nanoparticles in situ in polymer matrices.


Input: Vibrational Perturbations of W (CO) 6 Trapped in a Molecular Lattice Probed by Linear and Non Linear Spectroscopy.

W (CO) 6


Input: Vibrational dynamics of the T1u CO stretching mode of tungsten hexacarbonyl is explored when the molecule is embedded in a nitrogen matrix at low temperature.

CO

tungsten hexacarbonyl

nitrogen


Input: Experiments combined IR absorption spectroscopy and IR stimulated photon echoes at the femtosecond timescale.


Input: W (CO) 6 is found to be trapped in two main families of sites differing by their symmetries (called hereafter Oh and D2h).

W (CO) 6


Input: In Oh sites, the vibrational coherence is strongly temperature dependent, exhibiting a coupling with librational phonons of the nitrogen lattice.

nitrogen


Input: Perturbation in D2h sites results in the splitting of the T1u band in three components.


Input: Each component is inhomogeneously broadened, with dephasing times in the tens of picoseconds, weakly coupled to the lattice phonons.


Input: Experiments in solid krypton are performed to compare the effect of atomic and diatomic host lattices.

krypton


Input: Dephasing time in Kr does not depend on temperature and remains in the hundreds of picosecond, highlighting the molecular origin of dephasing process in N2.

Kr


Input: Additionally, non linear signals show oscillations due to quantum beats and polarization interferences between different frequency components of the induced third order polarization, giving information, in particular, on the overtone vibrational transition.


Input: Base-Specific Ionization of Deprotonated Nucleotides by Resonance Enhanced Two-Photon Detachment.

Nucleotides


Input: The intrinsic ionization energy of a base in DNA plays a critical role in determining the energies at which damage mechanisms may emerge.


Input: Here, a two-photon resonance-enhanced ionization scheme is presented that utilizes the 1 pi pi * transition, localized on the DNA base, to elucidate the base-specific ionization in a deprotonated nucleotide.

nucleotide


Input: In contrast to previous reports, the scheme is insensitive to competing ionization channels arising from the sugar-phosphate backbone.

sugar

phosphate


Input: Using this approach, we demonstrate that for all bases except guanine, the lowest electron detachment energy corresponds to detachment from the sugar-phosphate backbone and allows us to determine the lowest adiabatic ionization energy for the other three bases for the first time in an isolated nucleotide.

guanine

sugar

phosphate

nucleotide


Input: The Pyrimidyn compounds: dual-action small molecule pyrimidine-based dynamin inhibitors.

Pyrimidyn

pyrimidine


Input: Dynamin is required for clathrin-mediated endocytosis (CME).


Input: Its GTPase activity stimulated by phospholipid binding to its PH domain which induces helical oligomerization.


Input: We have designed a series of novel pyrimidine-based' PyrimidynTM' compounds which inhibit the lipid stimulated GTPase activity of full length dynamin I and II with similar potency.

pyrimidine


Input: The most potent analogue, Pyrimidyn 7, has an IC50 of 1. 1 mu M for dynamin I and 1. 8 mu M for dynamin II, making it among the most potent dynamin inhibitors identified to date.

Pyrimidyn


Input: We investigated the mechanism of action of the Pyrimidyn compounds in detail by examining the kinetics of Pyrimidyn 7 inhibition of dynamin.

Pyrimidyn

Pyrimidyn


Input: The compound competitively inhibits both GTP and phospholipid interactions with dynamin I.

GTP


Input: While both mechanisms of action have been previously observed separately, this is the first inhibitor series to incorporate both and thereby targets two distinct domains of dynamin.


Input: Pyrimidyn 6 and 7 reversibly inhibit CME of both transferrin and EGF in a number of non-neuronal cell lines as well as inhibiting synaptic vesicle endocytosis (SVE) in nerve terminals.

Pyrimidyn


Input: Therefore, Pyrimidyn compounds block endocytosis by directly competing with GTP and lipid binding to dynamin, limiting both the recruitment of dynamin to membranes and its activation.

Pyrimidyn

GTP


Input: This dual mode of action provides an important new tool for molecular dissection of dynamin' s role in endocytosis.


Input: Interactive effects of smoking and glutathione S-transferase polymorphisms on the development of non-alcoholic fatty liver disease.

glutathione S


Input: Glutathione S-transferases (GSTs) protect cells against exogenous and endogenous oxidative stress.

Glutathione S


Input: GST polymorphisms are associated with the development of cardiovascular disease (CVD) and diabetes mellitus (DM), especially in current-smokers.


Input: Non-alcoholic fatty liver disease (NAFLD) is a predictor of future CVD or DM, because oxidative stress contributes to their pathogenesis.


Input: This study investigated whether the combination of smoking status and GST genotypes could affect the risk for NAFLD.


Input: A cross-sectional analysis was conducted among 713 Japanese participants (458 males and 255 females) during a health screening program.


Input: The GSTM1 null, GSTT1 null, GSTP1 * A/* B or * B/* B and GSTA1 * A/* B or * B/* B genotypes were determined and deemed to be high-risk genotypes.


Input: The prevalence of NAFLD was 18. 7%.


Input: Among never-smokers, carriers of one, and those of two or more high-risk GSTM1, GSTP1 or GSTA1 genotypes were at a higher risk for NAFLD than those who were not carriers [odds ratio (95% confidence interval): 2. 6 (1. 1-5. 9) and 3. 3 (1. 3-8. 1), respectively], and the risk was further increased among current-smokers [4. 6 (1. 6-13. 0) and 5. 4 (1. 2-23. 7), respectively].


Input: This is the first report to show that the combination of current-smoking and harboring high-risk GSTM1, GSTP1 and/or GSTA1 genotypes is interactively associated with the risk of NAFLD.


Input: Melamine activates NF kappa B/COX-2/PGE2 pathway and increases NADPH oxidase-dependent ROS production in macrophages and human embryonic kidney cells.

Melamine

NADPH


Input: Melamine is a wildly used compound in manufactures of plastics and resins.

Melamine


Input: A variety of toxic effects from melamine, including nephrolithiasis, chronic kidney inflammation, and bladder carcinoma, have been mentioned.

melamine


Input: Oxidative stress is considered to be an important pathogenic mechanism of kidney disease which may develop from an increasing free radical production through inflammation.


Input: The aim of this study is to investigate melamine-induced oxidative stress and inflammation in macrophage-like cell line RAW 264. 7 and human embryonic kidney cell line HEK293.

melamine


Input: Results indicated melamine activated nuclear factor (NF)-kappa B through increasing I kappa B-alpha degradation and NF-kappa B p65/p50 DNA-binding activity.

melamine


Input: In addition, melamine significantly increased COX-2 expression and prostaglandin E2 (PGE2) production.

melamine

prostaglandin E2


Input: Moreover, melamine activated NADPH oxidase (NOX), including NOX1, 2 and 4, accompanied with an increase in reactive oxygen species (ROS) production.

melamine

NADPH

oxygen


Input: Furthermore, melamine-induced ROS production could be attenuated by apocynin, a NOX inhibitor.

melamine

apocynin


Input: In conclusion, our findings suggest melamine increased inflammation and oxidative stress via activation of NF-kappa B/COX-2 and NOX/ROS pathway, and first revealed the critical role of NOX in melamine-induced ROS production, suggesting the potential of NOX inhibitor against melamine toxicity.

melamine

melamine

melamine


Input: Genetic Polymorphism at Val (80) (rs700518) of the CYP19A1 Gene is Associated with Aromatase Inhibitor Associated Bone Loss in Women with ER (+) Breast Cancer.

Val


Input: PURPOSE: Polymorphisms in the CYP19A1 (aromatase) gene have been reported to influence disease-free survival and the incidence of musculoskeletal complaints in patients taking aromatase inhibitors (AIs) for estrogen receptor positive (ER +) breast cancer.

estrogen


Input: Bone loss and fractures are well-recognized complications from AI therapy.


Input: The objective of this study is to determine the influence of polymorphisms in the CYP19A1 gene on bone loss among patients taking aromatase inhibitors for ER + breast cancer.


Input: PATIENTS AND METHODS: The subjects consisted of 97 postmenopausal women with ER + breast cancer who were initiated on third-generation AIs.


Input: Bone mineral density (BMD) was measured by dual energy x-ray absorptiometry at baseline and at 6 and 12 months.


Input: Twenty-four hour urine N-telopeptide (NTX) was measured by Elisa and serum estradiol was measured by ultrasensitive radioimmunoassay at baseline, and at 6 months.

N

estradiol


Input: Genotyping was done by Taqman SNP allelic discrimination assay.


Input: RESULTS: Women with the AA genotype for the rs700518 (G/A at Val (80)) developed significant bone loss at the lumbar spine and the total hip at 12 months relative to patients carrying the G allele (GA/GG); both p = 0. 03.

Val


Input: There was a borderline greater increase in urinary NTX in those with the AA genotype compared to patients with the G allele, p = 0. 05; but no significant difference in changes in estradiol levels among the genotypes.

estradiol


Input: CONCLUSION: Patients with the AA genotype for the rs700518 polymorphism in the CYP19A1 gene are at risk for AI-associated bone loss and deserve close follow-up during long-term AI therapy.


Input: Epigenetic Mechanisms of Drug Addiction.


Input: Drug addiction involves potentially life-long behavioral abnormalities that are caused in vulnerable individuals by repeated exposure to a drug of abuse.


Input: The persistence of these behavioral changes suggests that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype.


Input: Work over the past decade has demonstrated a crucial role for epigenetic mechanisms in driving lasting changes in gene expression in diverse tissues, including brain.


Input: This has prompted recent research aimed at characterizing the influence of epigenetic regulatory events in mediating the lasting effects of drugs of abuse on the brain in animal models of drug addiction.


Input: This review provides a progress report of this still early work in the field.


Input: As will be seen, there is robust evidence that repeated exposure to drugs of abuse induces changes within the brain' s reward regions in three major modes of epigenetic regulation-histone modifications such as acetylation and methylation, DNA methylation, and non-coding RNAs.


Input: In several instances, it has been possible to demonstrate directly the contribution of such epigenetic changes to addiction-related behavioral abnormalities.


Input: Studies of epigenetic mechanisms of addiction are also providing an unprecedented view of the range of genes and non-genic regions that are affected by repeated drug exposure and the precise molecular basis of that regulation.


Input: Work is now needed to validate key aspects of this work in human addiction and evaluate the possibility of mining this information to develop new diagnostic tests and more effective treatments for addiction syndromes.


Input: A new perspective on muscarinic receptor antagonism in obstructive airways diseases.


Input: Acetylcholine has traditionally only been regarded as a neurotransmitter of the parasympathetic nervous system, causing bronchoconstriction and mucus secretion in asthma and COPD by muscarinic receptor activation on airway smooth muscle and mucus-producing cells.

Acetylcholine


Input: Recent studies in experimental models indicate that muscarinic receptor stimulation in the airways also induces pro-inflammatory, pro-proliferative and pro-fibrotic effects, which may involve activation of airway structural and inflammatory cells by neuronal as well as non-neuronal acetylcholine.

acetylcholine


Input: In addition, mechanical changes caused by muscarinic agonist-induced bronchoconstriction may be involved in airway remodeling.


Input: Crosstalk between muscarinic receptors and beta 2-adrenoceptors on airway smooth muscle causes a reduced bronchodilator response to beta 2-agonists, and a similar mechanism could possibly apply to the poor inhibition of inflammatory and remodeling processes by these drugs.


Input: Collectively, these findings provide novel perspectives for muscarinic receptor antagonists in asthma and COPD, since these drugs may not only acutely affect cholinergic airways obstruction, but also have important beneficial effects on beta 2-agonist responsiveness, airway inflammation and remodeling.


Input: The clinical relevance of these findings is presently under investigation and starting to emerge.


Input: Enhanced excitability in the infralimbic cortex produces anxiety-like behaviors.


Input: The medial prefrontal cortex (mPFC) has been implicated in modulating anxiety.


Input: However, it is unknown whether excitatory or inhibitory neurotransmission in the infralimbic (IL) subregion of the mPFC underlies the pathology of anxiety-related behavior.


Input: To address this issue, we infused the GABAA receptor (GABAAR) antagonist bicuculline to temporarily activate the IL cortex.

bicuculline


Input: IL cortex activation decreased the time spent in the center area in the open field test, decreased exploration of the open-arms in the elevated plus maze test, and increased the latency to bite food in the novelty-suppressed feeding test.


Input: These findings substantiate the GABAergic system' s role in anxiety-related behaviors.

GABAergic


Input: IL cortex inactivation with the AMPA receptor (AMPAR) antagonist CNQX produced opposite, anxiolytic effects.

AMPA


Input: However, infusion of the NMDA receptor (NMDAR) antagonist AP5 into the IL cortex had no significant effect.

NMDA


Input: Additionally, we did not observe motor activity deficits or appetite deficits following inhibition of GABAergic or glutamatergic neurotransmission.

GABAergic


Input: Interestingly, we found parallel and corresponding electrophysiological changes in anxious mice; compared to mice with relatively low anxiety, the relatively high anxiety mice exhibited smaller evoked inhibitory postsynaptic currents (eIPSCs) and larger AMPA-mediated evoked excitatory postsynaptic currents (eEPSCs) in pyramidal neurons in the IL cortex.

AMPA


Input: The changes of eIPSCs and eEPSCs were due to presynaptic mechanisms.


Input: Our results suggest that imbalances of neurotransmission in the IL cortex may cause a net increase in excitatory inputs onto pyramidal neurons, which may underlie the pathogenic mechanism of anxiety disorders.


Input: Haloperidol promotes mTORC1-dependent phosphorylation of ribosomal protein S6 via dopamine-and cAMP-regulated phosphoprotein of 32 kDa and inhibition of protein phosphatase-1.

Haloperidol

dopamine

cAMP


Input: The ribosomal protein S6 (rpS6) is a component of the small 40S ribosomal subunit, involved in multiple physiological functions.


Input: Here, we examined the effects produced by haloperidol, a typical antipsychotic drug, on the phosphorylation of rpS6 at Ser240/244 in the striatum, a brain region involved in neurodegenerative and neuropsychiatric disorders.

haloperidol


Input: Administration of haloperidol increased Ser240/244 phosphorylation in a subpopulation of GABA-ergic medium spiny neurons (MSNs), which express dopamine D2 receptors (D2Rs).

haloperidol

GABA

dopamine


Input: This effect was prevented by rapamycin, an inhibitor of the mammalian target of rapamycin complex 1 (mTORC1), or by PF470867, a selective inhibitor of the p70 ribosomal S6 kinase 1 (S6K1).

rapamycin

rapamycin


Input: We also found that the effect of haloperidol on Ser240/244 phosphorylation was prevented by functional inactivation of dopamine-and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32), an endogenous inhibitor of protein phosphatase-1 (PP-1).

haloperidol

dopamine

cAMP


Input: In line with this observation, incubation of striatal slices with okadaic acid and calyculin A, two inhibitors of PP-1, increased Ser240/244 phosphorylation.

okadaic acid

calyculin A


Input: These results show that haloperidol promotes mTORC1-and S6K1-dependent phosphorylation of rpS6 at Ser240/244, in a subpopulation of striatal MSNs expressing D2Rs.

haloperidol


Input: They also indicate that this effect is exerted by suppressing dephosphorylation at Ser240/244, through PKA-dependent activation of DARPP-32 and inhibition of PP-1.


Input: Arylpiperazine-mediated activation of Akt protects SH-SY5Y neuroblastoma cells from 6-hydroxydopamine-induced apoptotic and autophagic death.

Arylpiperazine


Input: We investigated the ability of 19 recently synthesized arylpiperazine compounds to protect human SH-SY5Y neuroblastoma cells from the neurotoxin 6-hydroxydopamine (6-OHDA).

arylpiperazine


Input: The compound with the most potent neuroprotective action was N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide (6b), which reduced 6-OHDA-induced apoptotic death through stabilization of mitochondrial membrane and subsequent prevention of superoxide production, caspase activation and DNA fragmentation.

N-{3-[2-(4-phenyl-piperazin-1-yl)-ethyl]-phenyl}-picolinamide

superoxide


Input: 6-OHDA-triggered autophagic response was also reduced by 6b, which prevented inactivation of the main autophagy repressor mTOR, upregulation of pro-autophagic beclin-1, conversion of microtubule-associated protein 1 light chain 3 (LC3)-I to autophagosome-associated LC3-II, as well as intracytoplasmic acidification induced by 6-OHDA.


Input: The inhibition of autophagy using LC3 beta gene silencing or pharmacological autophagy blockers 3-methyladenine or bafilomycin A1, mimicked the cytoprotective effect of 6b.

bafilomycin A1


Input: While the treatment with 6b had no effect on the phosphorylation of proapoptotic MAP kinases ERK and JNK, it markedly increased the phosphorylation of the prosurvival kinase Akt in 6-OHDA-treated cells.


Input: Akt inhibitor DEBC or RNA interference-mediated Akt silencing reduced the ability of 6b to block 6-OHDA-triggered apoptotic and autophagic responses, thus confirming their dependency on Akt activation.


Input: The cytoprotective effect of 6b was also observed in 6-OHDA-treated neuronal PC12 cells, but not in SH-SY5Y or PC12 cells exposed to 1-methyl-4-phenylpyridinium, indicating that the observed neuroprotection was dependent on the cytotoxic stimulus.


Input: Because of the ability to prevent 6-OHDA induced apoptotic/autophagic cell death through activation of Akt, the investigated arylpiperazines could be potential candidates for treatment of neurodegenerative diseases.

arylpiperazines


Input: The fatty acid amide hydrolase inhibitor, URB597, promotes retinal ganglion cell neuroprotection in a rat model of optic nerve axotomy.

fatty acid amide

retinal


Input: The endocannabinoid, N-arachidonoylethanolamine (AEA), is degraded by the enzyme fatty acid amide hydrolase (FAAH).

N-arachidonoylethanolamine

AEA

fatty acid amide


Input: This study examined whether the FAAH inhibitor, URB597, increases retinal ganglion cell (RGC) survival following optic nerve axotomy in young and aged animals.

retinal


Input: URB597 alone, or together with either a CB1 or CB2 receptor antagonist, was administered daily for 1 or 2 weeks post-axotomy.


Input: Histological assessment of retinas indicated that URB597 increased RGC survival in young retina at 1 and 2 weeks post-axotomy.


Input: The increase in RGC survival at 2 weeks was accompanied by a reduction in phagocytic microglia.


Input: The CB1 antagonist, AM281, but not the CB2 antagonist, AM630, ablated URB597-mediated RGC neuroprotection.


Input: CB1 or CB2 antagonism increased phagocytic microglia in URB597 and vehicle-treated animals.


Input: In aged animals, URB597 increased RGC survival at 1 week, but not at 2 weeks post-axotomy and had no effect on microglia.


Input: Retinal Iba-1 positive microglia were also decreased in URB597-treated axotomized young animals and this decrease was mitigated by CB1 but not CB2 antagonism.

Retinal


Input: As seen with phagocytotic microglia, the CB2 antagonist, AM630, increased Iba-1 positive microglia in the absence of URB597 treatment.


Input: Measurement of retinal endocannabinoid levels in URB597-treated animals at 2 weeks post-axotomy revealed a significant increase in AEA levels, accompanied by a decrease by a decrease in the AEA metabolite, N-arachidonoylglycine, in young animals but not aged animals.

retinal

AEA

AEA

N-arachidonoylglycine


Input: 2-arachidonoylglycerol levels were similar across all experimental groups.


Input: These data demonstrate that URB597-mediated retinal neuroprotective effects are mediated primarily through CB1 receptors and that URB597 neuroprotective efficacy declines with age.

retinal


Input: Differential Effects of Cholinergic and Noradrenergic Neuromodulation on Spontaneous Cortical Network Dynamics.


Input: Cholinergic and noradrenergic neuromodulation play a key role in determining overall behavioral state by shaping the underlying cortical network dynamics.


Input: The effects of these systems on synaptic and intrinsic cellular targets are quite diverse and a comprehensive understanding of how these neuromodulators regulate (spontaneous) cortical network activity has remained elusive.


Input: Here, we used multielectrode electrophysiology in vitro to investigate the effect of these neuromodulators on spontaneous network dynamics in acute slices of mouse visual cortex.


Input: We found that application of Carbachol (CCh) and Norepinephrine (NE) both enhanced the spontaneous network dynamics by increasing (1) the activity levels, (2) the temporal complexity of the network activity, and (3) the spatial complexity by decorrelating the network activity over a wide range of neuromodulator concentrations (1 mu M, 10 mu M, 50 mu M, and 100 mu M).

Carbachol

CCh

Norepinephrine


Input: Interestingly, we found that cholinergic neuromodulation was limited to the presence of CCh in the bath whereas the effects of NE, in particular for higher concentrations, induced plasticity that caused outlasting effects most prominently in the deep cortical layers.

CCh


Input: Together, these results provide a comprehensive network-level understanding of the similarities and differences of cholinergic and noradrenergic modulation of spontaneous network dynamics.


Input: Assessment of subjective cognitive and emotional effects of antipsychotic drugs.


Input: Effect by defect?


Input: Antipsychotic medication represents the first-line treatment of schizophrenia.


Input: While it is undisputed that antipsychotics ameliorate positive symptoms, the exact cognitive and emotional pathways through which its effect is exerted has remained unclear.


Input: The present study investigated the subjective effects of antipsychotics across various domains of cognition and emotion in both patients with psychotic symptoms and patients with other psychiatric diagnoses.


Input: A total of 69 patients with a probable history of psychosis or psychotic symptoms and 26 patients with psychiatric diagnoses other than psychosis participated in a survey conducted over the Internet.


Input: Multiple control measures aimed to secure response validity.


Input: All patients were currently or had previously been treated with antipsychotic agents.


Input: A questionnaire comprising 49 items and measuring possible effects of antipsychotics on cognition and emotion was administered.


Input: For 30 out of 49 items a clear response pattern emerged, which was similar for patients with psychotic disorders and patients with other diagnoses.


Input: Factor analysis of these items revealed three main effects of antipsychotic medication related to doubt and self-doubt, cognitive and emotional numbing, and social withdrawal.


Input: Antipsychotic treatment appears to be connected to a number of negative subjective effects on cognition and emotion.


Input: Further studies are warranted to assess how these effects impact on the patients' subjective well-being and quality of life, as well as their association with antipsychotic efficacy on the one hand, and adherence rates on the other.


Input: The induction of doubt and the dampening of emotion may be one reason why antipsychotics work and at the same time offer an explanation why they are experienced as rather unpleasant and are eventually discontinued by many patients.


Input: Controlling the Physical form of Mannitol in Freeze-Dried Systems.

Mannitol


Input: A potential drawback with the use of mannitol as a bulking agent is its existence as mannitol hemihydrate (MHH; C6H14O6 (.) 0. 5H2O) in the lyophile.

mannitol

mannitol hemihydrate

MHH

C6H14O6 (.) 0. 5H2O


Input: Once formed during freeze-drying, MHH dehydration may require secondary drying under aggressive conditions which can be detrimental to the stability of thermolabile components.

MHH


Input: If MHH is retained in the lyophile, the water released by MHH dehydration during storage has the potential to cause product instability.

MHH

MHH


Input: We systematically identified the conditions under which anhydrous mannitol and MHH crystallized in frozen systems with the goal of preventing MHH formation during freeze-drying.

mannitol

MHH

MHH


Input: When mannitol solutions were cooled, the temperature of solute crystallization was the determinant of the physical form of mannitol.

mannitol

mannitol


Input: Based on low temperature X-ray diffractometry (using both laboratory and synchrotron sources), MHH formation was observed when solute crystallization occurred at temperatures >=-20 degrees C while anhydrous mannitol crystallized at temperatures <=-10 degrees C.

MHH

mannitol


Input: The transition temperature (anhydrate-MHH) appears to be ~-15 degrees C.

MHH


Input: The use of a freeze-dryer with controlled ice nucleation technology enabled anhydrous mannitol crystallization at ~-5 degrees C.

mannitol


Input: Thus, ice crystallization followed by annealing at temperatures <=-10 degrees C can be an effective strategy to prevent MHH formation.

MHH


Input: Investigation on the interaction of the toxicant, gentian violet, with bovine hemoglobin.

gentian violet


Input: Gentian violet (GV) is a well-known triarylmethane dye that is used in aquacultural, industrial and medicinal fields.

Gentian violet

triarylmethane


Input: But concerns in growing number have been paid to its potential health problems to human beings and its hazardous effects to environment.


Input: Herein, the toxic interaction of GV with bovine hemoglobin (BHb) was investigated by a series of spectroscopic methods and molecular modeling method.


Input: The fluorescence emission profile exhibited a remarkable quenching upon addition of GV to the buffered aqueous solution of BHb and the analysis of results revealed the dominant role of static quenching mechanism in GV-BHb interaction.


Input: The negative Delta H and positive Delta S values demonstrated that the electrostatic interactions mainly stabilized this toxicant-protein complex.


Input: Synchronous fluorescence, UV-vis absorption and CD spectroscopic studies proved that the conformational change of BHb was induced by GV' s combination.


Input: Molecular modeling studies exhibited the binding mode of GV-BHb complex and the detailed information of related driving forces.


Input: During the 1H nuclear magnetic resonance spectra (1H NMR) study, the chemical shift perturbation and spin-lattice relaxation times of different protons were further used to investigate the interaction of GV with BHb and the results indicated that GV bound orientationally to BHb.


Input: Alteration of prolyl oligopeptidase and activated alpha-2-macroglobulin in multiple sclerosis subtypes and in the clinically isolated syndrome.

prolyl


Input: Prolyl oligopeptidase (PREP) has been considered as a drug target for the treatment of neurodegenerative diseases.

Prolyl


Input: In plasma, PREP has been found altered in several disorders of the central nervous system including multiple sclerosis (MS).


Input: Oxidative stress and the levels of an endogenous plasma PREP inhibitor have been proposed to decrease PREP activity in MS.


Input: In this work, we measured the circulating levels of PREP in patients suffering of relapsing remitting (RR), secondary progressive (SP), primary progressive (PP) MS, and in subjects with clinically isolated syndrome (CIS).


Input: We found a significantly lower PREP activity in plasma of RRMS as well as in PPMS patients and a trend to reduced activity in subjects diagnosed with CIS, compared to controls.


Input: No signs of oxidative inactivation of PREP, and no correlation with the endogenous PREP inhibitor, identified as activated alpha-2-macroglobulin (alpha 2M *), were observed in any of the patients studied.


Input: However, a significant decrease of alpha 2M * was recorded in MS.


Input: In cell cultures, we found that PREP specifically stimulates immune active cells possibly by modifying the levels of fibrinogen beta, thymosin beta 4, and collagen.


Input: Our results open new lines of research on the role of PREP and alpha 2M * in MS, aiming to relate them to the diagnosis and prognosis of this devastating disease.


Input: The C1 domain-targeted isophthalate derivative HMI-1b11 promotes neurite outgrowth and GAP-43 expression through PKC alpha activation in SH-SY5Y cells.

isophthalate


Input: Protein kinase C (PKC) is a family of serine/threonine phosphotransferases ubiquitously expressed and involved in multiple cellular functions, such as proliferation, apoptosis and differentiation.

serine

threonine


Input: The C1 domain of PKC represents an attractive drug target, especially for developing PKC activators.


Input: Dialkyl 5-(hydroxymethyl) isophthalates are a novel group of synthetic C1 domain ligands that exhibit antiproliferative effect in HeLa cervical carcinoma cells.

Dialkyl 5-(hydroxymethyl) isophthalates


Input: Here we selected two isophthalates, HMI-1a3 and HMI-1b11, and characterized their effects in the human neuroblastoma cell line SH-SY5Y.

isophthalates


Input: Both of the active isophthalates exhibited significant antiproliferative and differentiation-inducing effects.

isophthalates


Input: Since HMI-1b11 did not impair cell survival even at the highest concentration tested (20 mu M), and supported neurite growth and differentiation of SH-SY5Y cells, we focused on studying its downstream signaling cascades and effects on gene expression.


Input: Consistently, genome-wide gene expression microarray and gene set enrichment analysis indicated that HMI-1b11 (10 mu M) induced changes in genes mainly related to cell differentiation.


Input: In particular, further studies revealed that HMI-1b11 exposure induced up-regulation of GAP-43, a marker for neurite sprouting and neuronal differentiation.


Input: These effects were induced by a 7-minute HMI-1b11 treatment and specifically depended on PKC alpha activation, since pretreatment with the selective inhibitor G o 6976 abolished the up-regulation of GAP-43 protein observed at 12hours In parallel, we found that a 7-minute exposure to HMI-1b11 induced PKC alpha accumulation to the cytoskeleton, an effect that was again prevented by pretreatment with G o 6976.

G o 6976

G o 6976


Input: Despite similar binding affinities to PKC, the isophthalates had different effects on PKC-dependent ERK1/2 signaling: HMI-1a3-induced ERK1/2 phosphorylation was transient, while HMI-1b11 induced a rapid but prolonged ERK1/2 phosphorylation.


Input: Overall our data are in accordance with previous studies showing that activation of the PKC alpha and ERK1/2 pathways participate in regulating neuronal differentiation.


Input: Furthermore, since PKC has been classified as one of the cognitive kinases, and activation of PKC is considered a potential therapeutic strategy for the treatment of cognitive disorders, our findings suggest that HMI-1b11 represents a promising lead compound in research aimed to prevent or counteract memory impairment.


Input: Discovery of highly potent triazole antifungal derivatives by heterocycle-benzene bioisosteric replacement.

triazole

benzene


Input: On the basis of our previously discovered triazole antifungal lead compounds, heterocycle-benzene bioisosteric replacement was used to improve their pharmacokinetic profile.

triazole

benzene


Input: The designed new triazole derivatives have good antifungal activity toward a wide range of pathogenic fungi.

triazole


Input: Their binding mode with the target enzyme was clarified by molecular docking.


Input: The MIC value of the highly potent compound 8f against Candida albicans, Candida tropicalis, and Cryptococcus neoformans is 0. 016 mu g/mL, 0. 004 mu g/mL, and 0. 016 mu g/mL, respectively.


Input: Moreover, preliminary pharmacokinetic studies revealed that it showed improved oral absorption as compared to the lead compound iodiconazole and deserved for further evaluations.

iodiconazole


Input: Metabolic Regulation of Brain Response to Food Cues.


Input: Identification of energy sources depends upon the ability to form associations between food cues and nutritional value.


Input: As such, cues previously paired with calories elicit neuronal activation in the nucleus accumbens (NAcc), which reflects the reinforcing value of food [1-4].


Input: The identity of the physiological signals regulating this response remains elusive.


Input: Using fMRI, we examined brain response to noncaloric versions of flavors that had been consumed in previous days with either 0 or 112. 5 calories from undetected maltodextrin.


Input: We report a small but perceptually meaningful increase in liking for the flavor that had been paired with calories and find that change in liking was associated with changes in insular responses to this beverage.


Input: In contrast, NAcc and hypothalamic response to the calorie-paired flavor was unrelated to liking but was strongly associated with the changes in plasma glucose levels produced by ingestion of the beverage when consumed previously with calories.

glucose


Input: Importantly, because each participant ingested the same caloric dose, the change in plasma glucose depended upon individual differences in glucose metabolism.

glucose

glucose


Input: We conclude that glucose metabolism is a critical signal regulating NAcc and hypothalamic response to food cues, and that this process operates independently from the ability of calories to condition liking.

glucose


Input: Architecture of Cortical Bone Determines in Part its Remodelling and Structural Decay.


Input: Bone remodelling accelerates and becomes unbalanced after menopause; less bone is deposited than resorbed from the surface of canals traversing the cortex.


Input: The canals enlarge so the intracortical surface area enlarges.


Input: We hypothesized that cortical bone with a larger internal surface area, due to more or larger canals, is more liable to being remodelled, further enlarging the internal surface area and facilitating more remodelling and structural deterioration.


Input: For 95 monozygotic twin pairs aged 40-61 years, we measured internal cortical surface areas and structure of the distal tibia using high resolution peripheral computed tomography, and three circulating bone remodelling markers.


Input: Using principal components (PC) analyses, we identified one summary measure of intracortical and endocortical bone surface areas, cortical porosity and volumetric bone mineral density (structure PC), and one summary measure of bone remodelling markers (remodelling PC).


Input: We applied a twin regression analysis (Inference on Causation by Examination of Familial Confounding; ICE FALCON) to assess consistency with a causal component in the association between a predictor (X) and an outcome (Y) by testing if the regression coefficient for the X value of the co-twin decreases after adjusting for the X value of the twin herself.


Input: With Y = remodelling PC, the regression coefficient for structure PC in the co-twin was 0. 29 (p < 0. 001) before, and 0. 18 (p = 0. 03) after, adjusting for her own structure PC (40% lower; p = 0. 06).


Input: With Y = structure PC, the regression coefficient for remodelling PC in the co-twin was 0. 17 (p = 0. 01) before, and 0. 20 (p < 0. 001) after, adjusting for her own remodelling PC (22% higher; p = 0. 7).


Input: The structure of bone, its surface area to bone matrix volume configuration, contributes in part to its own remodelling and deterioration, but not vice versa.


Input: Streptococcus pneumoniae ClpP protease induces apoptosis via caspase-independent pathway in human neuroblastoma cells: cytoplasmic relocalization of p53.


Input: Streptococcus pneumoniae causes the most severe form of the bacterial meningitis which is the major cause of bacterial meningitis.


Input: Virulence factors produced by S. pneumoniae have been known to contribute significantly to the disease process.


Input: ClpP protease (ClpP) which is essential for virulence and survival under stress conditions in S. pneumonia was examined for the ability to induce apoptosis and the mechanism of the induction of apoptosis in human neuron-like cells, SK-N-SH neuroblastoma cells.


Input: ClpP inhibited cell growth and induced apoptosis in SK-N-SH cells.


Input: Treatment with ClpP resulted in hypodiploid DNA contents, increased Bax/Bcl-2 ratio and induction of reactive oxygen species (ROS) production.

oxygen


Input: The release of cytochrome c from mitochondria into the cytosol, which is an initiator of the activation of caspase cascades, was not observed in ClpP-treated cells.


Input: In addition, pretreatment with Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk), a broad spectrum of caspase inhibitor, could not rescue apoptotic cells from ClpP toxicity.

Z-Val-Ala-Asp-fluoromethylketone

Z-VAD-fmk


Input: Coincidently, caspase-3 and-8 activation and cleavage of PARP were not detected.


Input: Moreover, caspase independent apoptosis-inducing factor (AIF) was released from mitochondria and translocated to the nucleus in response to ClpP.


Input: We also found that ClpP treatment resulted in the increase of p53 activity and cytoplasmic p53 levels were increased by ClpP, suggesting that functional activation of p53 is intact despite increased cytoplasmic accumulation.


Input: Taken together, these data suggest that ClpP contributes to neuronal damage in meningitis and provide further insight into the mechanisms underlying action of pneumococcal virulence factors during bacterial pathogenesis.


Input: Heterologously expressed formyl peptide receptor 2 (FPR2/ALX) does not respond to lipoxin A4.

formyl

lipoxin A4


Input: Lipoxin A4 (LXA4) has been described as an anti-inflammatory mediator, which exerts its effects through the formyl peptide receptor FPR2, also known as ALX.

Lipoxin A4


Input: However, there has been a controversy whether or not cells expressing FPR2/ALX, such as neutrophils, respond to LXA4.


Input: We, therefore, systematically examined the ability of the human and murine forms of the receptor to respond to LXA4.


Input: We show that both receptor orthologues responded to the FPR2/ALX peptide agonist WKYMVM when expressed heterologously.


Input: In contrast, LXA4 from different sources neither increased [Ca (2 +)] i and extracellular-signal-regulated kinase (ERK) phosphorylation, nor did it induce a decrease in cAMP levels or a translocation of beta-arrestin.

Ca (2 +)

cAMP


Input: Also, several LXA4 analogues were found to be unable to signal through FPR2/ALX.


Input: We conclude that FPR2/ALX is not activated by LXA4 and that the molecular mechanism by which LXA4 functions still needs to be identified.


Input: Design, synthesis and antiproliferative activity studies of novel 1, 2, 3-triazole-dithiocarbamate-urea hybrids.

1, 2, 3-triazole-dithiocarbamate-urea


Input: A series of novel 1, 2, 3-triazole-dithiocarbamate-urea hybrids were designed, synthesized and their antiproliferative activities against four selected human cancer cell lines were evaluated.

1, 2, 3-triazole-dithiocarbamate-urea


Input: The results showed that a number of the hybrids exhibited potent activity in selected human cancer cell lines.


Input: Among them, compounds 27 and 34 showed broad spectrum anticancer activity with IC50 values ranging from 1. 62 to 20. 84 mu M and 0. 76 to 13. 55 mu M, respectively.


Input: Interestingly, compounds 27 and 34, being very potent against MGC-803 cells, exhibited no significant cytotoxicity against normal human embryonic kidney cells at up to 55 mu M and 70 mu M, respectively.


Input: Evidences of cell cycle arrest and apoptosis induction were obtained for the most effective compounds 27 and 34 by means of flow cytometry and microscopic techniques.


Input: Elucidation of the pharmacophore of echinocystic acid, a new lead for blocking HCV entry.

echinocystic acid


Input: To elucidate the pharmacophore of echinocystic acid (EA), an oleanane-type triterpene displaying substantial inhibitory activity on HCV entry, two microbial strains, Rhizopus chinensis CICC 3043 and Alternaria alternata AS 3. 4578, were utilized to modify the chemical structure of EA.

echinocystic acid

oleanane

triterpene


Input: Eight new metabolites with regio-and stereo-selective introduction of hydroxyl and lactone groups at various inert carbon positions were obtained.

hydroxyl

lactone

carbon


Input: The anti-HCV entry activity of the metabolites 2-13, along with their parental compound EA and other analogs 14-15, were evaluated.


Input: Most of the metabolites showed no improvement but detrimental effect on potency except compound 5 and 6, which showed similar and even a litter higher anti-HCV entry activity than that of EA.


Input: The results demonstrated that ring A, B, C and the left side of ring E of EA are highly conserved, while ring D and the right side of ring E of EA are flexible.


Input: Introduction of a hydroxyl group at C-16 enhanced the triterpene potency.

hydroxyl

triterpene


Input: Further analysis indicated that the hemolytic effect of EA disappeared upon such modifications.


Input: Ligand-based design, synthesis, and experimental evaluation of novel benzofuroxan derivatives as anti-Trypanosoma cruzi agents.

benzofuroxan


Input: A set of substituted-[N'-(benzofuroxan-5-yl) methylene] benzohydrazides (4a-t), previously designed and synthesized, was experimentally assayed against Trypanosoma cruzi, the etiological agent of Chagas' disease, one of the most neglected tropical diseases.

N'-(benzofuroxan-5-yl) methylene] benzohydrazides


Input: Exploratory data analysis, Hansch approach and VolSurf formalism were applied to aid the ligand-based design of novel anti-T. cruzi agents.


Input: The best 2D-QSAR model showed suitable statistical measures [n = 18; s = 0. 11; F = 42. 19; R (2) = 0. 90 and Q (2) = 0. 77 (SDEP = 0. 15)], and according to the optimum 3D-QSAR model [R (2) = 0. 98, Q (2) = 0. 93 (SDEP = 0. 08)], three latent variables explained 62% of the total variance from original data.


Input: Steric and hydrophobic properties were pointed out as the key for biological activity.


Input: Based upon the findings, six novel benzofuroxan derivatives (4u-z) were designed, synthesized, and in vitro assayed to perform the QSAR external prediction.

benzofuroxan


Input: Then, the predictability for the both models, 2D-QSAR (Rpred (2) = 0. 91) and 3D-QSAR (Rpred (2) = 0. 77), was experimentally validated, and compound 4u was identified as the most active anti-T. cruzi hit (IC50 = 3. 04 mu M).


Input: N-Alkylated 2, 3, 3-trimethylindolenines and 2-methylbenzothiazoles.

N-Alkylated 2, 3, 3-trimethylindolenines


Input: Potential lead compounds in the fight against Saccharomyces cerevisiae infections.


Input: The synthesis of a variety of N-alkylated 2, 3, 3-trimethylindolenines and 2-methylbenzothiazoles is reported herein.

N-alkylated 2, 3, 3-trimethylindolenines


Input: Their potential as antifungal agents is evaluated by preliminary screening against Saccharomyces cerevisiae (S. cerevisiae), Schizosaccharomyces pombe (S. pombe), and Candida albicans (C. albicans).


Input: Statistical analyses illustrate a strong relationship between chain length and growth inhibition for S. cerevisiae and S. pombe (p < 0. 0001 in every case).


Input: Of particular interest is the activity of both sets of compounds against S. cerevisiae, as this is emerging as an opportunistic pathogen, especially in immunosuppressed and immunocompromised patients.


Input: Bioassays were set up to compare the efficacy of our range of N-alkylated compounds against classic antifungal agents; Amphotericin B and Thiabendazole.

N

Amphotericin B

Thiabendazole


Input: Synthesis and biological characterization of spiro [2H-(1, 3)-benzoxazine-2, 4'-piperidine] based histone deacetylase inhibitors.

spiro [2H-(1, 3)-benzoxazine-2, 4'-piperidine]


Input: Histone Deacetylases (HDACs) have become important targets for the treatment of cancer and other diseases.


Input: In previous studies we described the development of novel spirocyclic HDAC inhibitors based on the combination of privileged structures with hydroxamic acid moieties as zinc binding group.

hydroxamic acid

zinc


Input: Herein, we report further explorations, which resulted in the discovery of a new class of spiro [2H-(1, 3)-benzoxazine-2, 4'-piperidine] derivatives.

spiro [2H-(1, 3)-benzoxazine-2, 4'-piperidine]


Input: Several compounds showed good potency of around 100 nM and less in the HDAC inhibition assays, submicromolar IC50 values when tested against tumour cell lines and a remarkable stability in human and mouse microsomes.


Input: Two representative examples exhibited a good pharmacokinetic profile with an oral bioavailability equal or higher than 35% and one of them studied in an HCT116 murine xenograft model showing a robust tumour growth inhibition.


Input: In addition, the two benzoxazines were found to have a minor affinity for the hERG potassium channel compared to their corresponding ketone analogues.

benzoxazines

potassium

ketone


Input: Synthesis and in vitro anticancer studies of novel C-2 arylidene congeners of lantadenes.

lantadenes


Input: The antitumor pentacyclic triterpenoids, Lantadene A (1) and B (2) were isolated from the leaves of weed Lantana camara L.

Lantadene A (1) and B


Input: (Verbenaceae) and were structurally transformed to bioactive intermediates 3-6.


Input: The Claisen-Schmidt reaction of 22 beta-hydroxy-3-oxoolean-12-en-28-oic acid (5) with requisite aldehydes afforded 2-arylidene-22 beta-hydroxy-3-oxoolean-12-en-28-oic acids (7-16).

22 beta-hydroxy-3-oxoolean-12-en-28-oic acid

aldehydes

2-arylidene-22 beta-hydroxy-3-oxoolean-12-en-28-oic acids


Input: The compounds were evaluated for their in-vitro anticancer activity by National Cancer Institute (NCI), USA and some of these compounds showed marked cytotoxicity in micromolar range.


Input: The mean graph midpoint (MG _ MID) value of compound 3 (MG _ MID-5. 69) was higher than standard drug cisplatin (MG _ MID-5. 66) while comparable in case of compound 12 (MG _ MID-5. 52).

cisplatin


Input: The NCI' s COMPARE molecular mechanistic analysis showed that these compounds were in significant correlations with activity patterns of mechanistic set of compounds (PCC >= 0. 60).


Input: Low molecular weight dual inhibitors of factor Xa and fibrinogen binding to GPIIb/IIIa with highly overlapped pharmacophores.


Input: Dual antithrombotic agents acting as anticoagulants and aggregation inhibitors could have substantial advantages over currently prescribed combinations of antithrombotic drugs.


Input: Herein, we report compounds with moderate inhibitory activity for factor Xa and fibrinogen GPIIb/IIIa binding (both in the micromolar range).


Input: These compounds resulted from our efforts to merge the pharmacophores of selective factor Xa inhibitor rivaroxaban with a mimic of the Arg-Gly-Asp (RGD) sequence of fibrinogen to obtain designed multiple ligands with potential antithrombotic activity.

rivaroxaban

Arg-Gly-Asp


Input: Resulting from this study, a structurally novel class of submicromolar fibrinogen GPIIb/IIIa binding inhibitor bearing 1, 2, 4-oxadiazol-5 (4H)-one moiety is also described.

1, 2, 4-oxadiazol-5 (4H)-one


Input: Synthesis and biological evaluation of N-(4-hydroxy-3-mercaptonaphthalen-1-yl) amides as inhibitors of angiogenesis and tumor growth.

N-(4-hydroxy-3-mercaptonaphthalen-1-yl) amides


Input: A series of N-(4-hydroxy-3-mercaptonaphthalen-1-yl) amides were synthesized and investigated for their in vitro antiangiogenic activity.

N-(4-hydroxy-3-mercaptonaphthalen-1-yl) amides


Input: Among these compounds, 6d, which possesses an ortho-nitro group at the benzene ring, exhibited potent inhibitory effect on the proliferation of HUVECs, A549, K562, PC-3, HCT116, MDA-MB-231 and MCF-7 cells (IC50 = 5. 34, 40. 53, 10. 81, 52. 52, 10. 19, 21. 37 and 2. 81 mu M, respectively).

ortho-nitro

benzene


Input: Meanwhile, compound 6d inhibited in vitro angiogenesis markedly in both HUVECs tube formation assay and the rat thoracic aorta rings test.


Input: Further kinase assay study showed that compound 6d had good VEGFR2, ALK, AKT1 and ABL inhibitory activities and moderate EGFR and PDGFR-beta inhibitory activities.


Input: The data supports the further investigation of this class of compounds as potential antiangiogenic and anticancer agents.


Input: Steroidal glycosides from the bulbs of Easter lily (Lilium longiflorum Thunb.) promote dermal fibroblast migration in vitro.

Steroidal glycosides


Input: ETHNOPHARMACOLOGICAL RELEVANCE: Preparations derived from bulbs of various Lilium species have been used to promote the healing of skin abrasions, sores and burns and to aid in healing wounds in Traditional Chinese and Greco-Roman Medicine.


Input: AIM OF THE STUDY: To evaluate fractionated Easter lily bulb extracts and their steroidal glycosides (1-5) for the promotion of dermal fibroblast migration in vitro, as a model for the early events in wound healing.

steroidal glycosides


Input: MATERIALS AND METHODS: An activity-guided screening approach was used by coupling sequential solvent extraction, gel permeation chromatography (GPC), and semi-preparative reverse-phase high performance liquid chromatography (RP-HPLC) with an in vitro dermal fibroblast migration assay.


Input: Cytotoxicity was evaluated with methyl thiazole tetrazolium (MTT).

methyl thiazole tetrazolium

MTT


Input: To gain insight into the mode of action of the steroidal glycosides, nitric oxide (NO) production, and expression of genes for transforming growth factor beta-1 (TGF-beta) and its receptors were evaluated.

steroidal glycosides

nitric oxide

NO


Input: RESULTS: Fractionated bulb extracts and the two isolated steroidal glycoalkaloids (1) and (2) induced NO production and TGF-beta receptor I mRNA expression in fibroblast cell culture.

steroidal glycoalkaloids

NO


Input: In a cytotoxicity assay, steroidal glycosides (1) and (3) had IC50 values of 8. 2 and 8. 7 micro M, but the natural acetylation of the C-6''' hydroxy of the terminal glucose unit in (2) resulted in a 3-fold decrease in cell cytotoxicity when compared with (1).

steroidal glycosides

hydroxy

glucose