Vangflindt7978

A recently proposed model for the incorporation of xenobiotics of forensic interest into the human skeleton suggests nerve agent metabolites may incorporate into bone at relatively elevated concentrations based on their unique chemical properties. To test the hypothesis that nerve agent metabolites interact with bone, methods for the extraction, isolation and semi-quantitative detection of nerve agent metabolites (MPA, EMPA, IMPA, iBuMPA, CMPA and PMPA, corresponding to the nerve agents VX, Russian VX, sarin, cyclosarin and soman, respectively) from osseous tissue were developed using liquid chromatography-mass spectrometry with both quadrupole time-of-flight and triple quadrupole (QqQ) instruments. The optimized methods were validated on the QqQ instrument. Despite high ion suppression, the achieved limits of detection (5-20 pg/g for four analytes; 350 pg/g for the fifth analyte) were lower than many of those published for the same analytes in other biomatrices, including serum and urine. These methods were reserved. For permissions, please email journals.permissions@oup.com.BACKGROUND Inflammation drives vascular dysfunction in HIV, but in low-income settings causes of inflammation are multiple, and include infectious and environmental factors. We hypothesised that patients with advanced immunosuppression could be stratified into inflammatory phenotypes that predicted changes in vascular dysfunction on ART. METHODS We recruited Malawian adults with CD4 less then 100 cells/ul two weeks after starting ART in the REALITY trial (NCT01825031). Carotid femoral pulse wave velocity (cfPWV) measured arterial stiffness 2, 12, 24 and 42 weeks post-ART initiation. Plasma inflammation markers were measured by electrochemiluminescence at weeks 2 and 42. Hierarchical clustering on principal components identified inflammatory clusters. RESULTS 211 HIV-positive participants grouped into three clusters of inflammatory marker profiles representing 51 (24%) (cluster-1), 153 (73%) (cluster-2) and 7 (3%) (cluster-3) individuals. Cluster-1 showed markedly higher CD4 and CD8 T-cell expression of HLADR and PD1 vs cluster-2 and cluster-3 (all p less then 0.0001). Although small, individuals in cluster-3 had significantly higher levels of cytokines reflecting inflammation (IL6, IFNɣ, IP10, IL1RA, IL10), chemotaxis (IL8), systemic and vascular inflammation (CRP, ICAM1, VCAM1) and SAA (all p less then 0.001). In mixed-effects models, cfPWV changes over time were similar for cluster-2 vs cluster-1 (relative-fold-change 0.99 (95% CI 0.86-1.14, p=0.91, but greater in cluster-3 vs cluster-1 (relative-fold-change 1.45 (95% CI 1.01-2.09, p=0.045). Staurosporine clinical trial CONCLUSIONS Two inflammatory clusters were identified one defined by high T-cell PD1 expression and another by a hyper-inflamed profile and increases in cfPWV on ART. Further clinical characterisation of these inflammatory phenotypes could help target vascular dysfunction interventions to those at highest risk. © The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America.Drosophila melanogaster is a well-established model organism that is widely used in genetic studies. This species enjoys the availability of a wide range of research tools, well-annotated reference databases and highly similar gene circuitry to other insects. To facilitate molecular mechanism studies in Drosophila, we present the Predicted Drosophila Interactome Resource (PDIR), a database of high-quality predicted functional gene interactions. These interactions were inferred from evidence in 10 public databases providing information for functional gene interactions from diverse perspectives. The current version of PDIR includes 102 835 putative functional associations with balanced sensitivity and specificity, which are expected to cover 22.56% of all Drosophila protein interactions. This set of functional interactions is a good reference for hypothesis formulation in molecular mechanism studies. At the same time, these interactions also serve as a high-quality reference interactome for gene set linkage analysis (GSLA), which is a web tool for the interpretation of the potential functional impacts of a set of changed genes observed in transcriptomics analyses. In a case study, we show that the PDIR/GSLA system was able to produce a more comprehensive and concise interpretation of the collective functional impact of multiple simultaneously changed genes compared with the widely used gene set annotation tools, including PANTHER and David. PDIR and its associated GSLA service can be accessed at http//drosophila.biomedtzc.cn. © The Author(s) 2020. Published by Oxford University Press.OBJECTIVE Anhedonia, traditionally defined as a diminished capacity for pleasure, is a core symptom of schizophrenia (SZ). However, modern empirical evidence indicates that hedonic capacity may be intact in SZ and anhedonia may be better conceptualized as an abnormality in the temporal dynamics of emotion. METHOD To test this theory, the current study used ecological momentary assessment (EMA) to examine whether abnormalities in one aspect of the temporal dynamics of emotion, sustained reward responsiveness, were associated with anhedonia. Two experiments were conducted in outpatients diagnosed with SZ (n = 28; n = 102) and healthy controls (n = 28; n = 71) who completed EMA reports of emotional experience at multiple time points in the day over the course of several days. Markov chain analyses were applied to the EMA data to evaluate stochastic dynamic changes in emotional states to determine processes underlying failures in sustained reward responsiveness. RESULTS In both studies, Markov models indicated that SZ had deficits in the ability to sustain positive emotion over time, which resulted from failures in augmentation (ie, the ability to maintain or increase the intensity of positive emotion from time t to t+1) and diminution (ie, when emotions at time t+1 are opposite in valence from emotions at time t, resulting in a decrease in the intensity of positive emotion over time). Furthermore, in both studies, augmentation deficits were associated with anhedonia. CONCLUSIONS These computational findings clarify how abnormalities in the temporal dynamics of emotion contribute to anhedonia. © The Author(s) 2020. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.All rights reserved. For permissions, please email journals.permissions@oup.com.Glucosinolate-myrosinase system is a well-known defense system and has been shown to induce stomatal closure in Brassicales. Isothiocyanates (ITC) are highly reactive hydrolysates of glucosinolates and an ITC, allyl isothiocyanate (AITC), induces stomatal closure accompanied by elevation of free cytosolic Ca2+ concentration ([Ca2+]cyt) in Arabidopsis. It remains unknown whether AITC inhibits light-induced stomatal opening. This study investigated the role of Ca2+ in AITC-induced stomatal closure and inhibition of light-induced stomatal opening. AITC induced stomatal closure and inhibited light-induced stomatal opening in a dose-dependent manner. A Ca2+ channel inhibitor, La3+, a Ca2+chelator, EGTA, and an inhibitor for Ca2+ release from internal stores, nicotinamide, inhibited AITC-induced [Ca2+]cyt elevation and stomatal closure, but did not affect inhibition of light-induced stomatal opening. AITC activated nonselective Ca2+-permeable cation channels and inhibited inward-rectifying K+ channels (K+in channels) in a Ca2+-independent manner. AITC also inhibited stomatal opening induced by fusicoccin, a plasma membrane H+-ATPase activator, but had no significant effect on fusicoccin-induced phosphorylation of the penultimate threonine of H+-ATPase. Taken together, these results suggest that AITC induces Ca2+ influx and Ca2+ release to elevate [Ca2+]cyt, which is essential for AITC-induced stomatal closure but not for inhibition of K+in channels and light-induced stomatal opening. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Experimental Biology.Linker histones H1 are principal chromatin components, whose contribution to the epigenetic regulation of chromatin structure and function is not fully understood. In metazoa, specific linker histones are expressed in the germline, with female-specific H1s being normally retained in the early-embryo. Embryonic H1s are present while the zygotic genome is transcriptionally silent and they are replaced by somatic variants upon activation, suggesting a contribution to transcriptional silencing. Here we directly address this question by ectopically expressing dBigH1 in Drosophila S2 cells, which lack dBigH1. We show that dBigH1 binds across chromatin, replaces somatic dH1 and reduces nucleosome repeat length (NRL). Concomitantly, dBigH1 expression down-regulates gene expression by impairing RNApol II binding and histone acetylation. These effects depend on the acidic N-terminal ED-domain of dBigH1 since a truncated form lacking this domain binds across chromatin and replaces dH1 like full-length dBigH1, but it does not affect NRL either transcription. In vitro reconstitution experiments using Drosophila preblastodermic embryo extracts corroborate these results. Altogether these results suggest that the negatively charged N-terminal tail of dBigH1 alters the functional state of active chromatin compromising transcription. © The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.Awns are bristle-like structures formed at the tip of the lemma on the florets of some cereal grasses. Wild-type wheat is awned, but awnletted and awnless variants have been selected and nowadays all forms are cultivated. In this study, we dissected the genetic control underlying variation of this characteristic feature by association mapping in a large panel of 1110 winter wheat cultivars of worldwide origin. We identified the B1 (Tipped 1) locus on chromosome 5A as the major determinant of awnlessness globally. Using a combination of fine-mapping and expression analysis, we identified a putative C2H2 zinc finger protein with an EAR domain, characteristic of transcriptional repressors, as likely candidate for Tipped 1. This gene was found to be up-regulated in awnless B1 compared to awned b1 plants, indicating that mis-expression of this transcriptional regulator may contribute to the reduction of awn length in B1 plants. Taken together, our study provides an entry point towards a better molecular understanding of the evolution of morphological features in cereals through selection and breeding. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Experimental Biology.Cells maintain a fine-tuned, dynamic concentration balance in the pool of deoxyribonucleoside 5'-triphosphates (dNTPs). This balance is essential for physiological processes including cell cycle control or antiviral defense. Its perturbation results in increased mutation frequencies, replication arrest and may promote cancer development. An easily accessible and relatively high-throughput method would greatly accelerate the exploration of the diversified consequences of dNTP imbalances. The dNTP incorporation based, fluorescent TaqMan-like assay published by Wilson et al. has the aforementioned advantages over mass spectrometry, radioactive or chromatography based dNTP quantification methods. Nevertheless, the assay failed to produce reliable data in several biological samples. Therefore, we applied enzyme kinetics analysis on the fluorescent dNTP incorporation curves and found that the Taq polymerase exhibits a dNTP independent exonuclease activity that decouples signal generation from dNTP incorporation. Furthermore, we found that both polymerization and exonuclease activities are unpredictably inhibited by the sample matrix.