bluuebunny/crossref_metadata_2025_split huggingface dataset:
Recombinant human soluble thrombomodulin is associated with attenuation of sepsis-induced renal impairment by inhibition of extracellular histone release
Authors: Akatsuka Masayuki , Masuda Yoshiki , Tatsumi Hiroomi , Yamakage Michiaki 
Published: September 2019

AbstractMultiple organ dysfunction induced by sepsis often involves kidney injury. Extracellular histones released in response to damage-associated molecular patterns are known to facilitate sepsis-induced organ dysfunction. Recombinant human soluble thrombomodulin (rhTM) and its lectin-like domain (D1) exert anti-inflammatory effects and neutralize damage-associated molecular patterns. However, the effects of rhTM and D1 on extracellular histone H3 levels and kidney injury remain poorly understood. Our purpose was to investigate the association between extracellular histone H3 levels and kidney injury, and to clarify the effects of rhTM and D1 on extracellular histone H3 levels, kidney injury, and survival in sepsis-induced rats. Rats in whom sepsis was induced via cecal ligation and puncture were used in this study. Histone H3 levels, histopathology of the kidneys, and the survival rate of rats at 24 h after cecal ligation and puncture were investigated. Histone H3 levels increased over time following cecal ligation and puncture. Histopathological analyses indicated that the distribution of degeneration foci among tubular epithelial cells of the kidney and levels of histone H3 increased simultaneously. Administration of rhTM and D1 significantly reduced histone H3 levels compared with that in the vehicle-treated group and improved kidney injury. The survival rates of rats in rhTM- and D1-treated groups were significantly higher than that in the vehicle-treated group. The results of this study indicated that rhTM and its D1 similarly reduce elevated histone H3 levels, thereby reducing acute kidney injury. Our findings also proposed that rhTM and D1 show potential as new treatment strategies for sepsis combined with acute kidney injury.
The Effects of Sex and Strain onPneumocystis murinaFungal Burdens in Mice
Authors: Tisdale Nikeya L. , Ashbaugh Alan , Hendrix Keeley , Collins Margaret S. , Porollo Alexey P. , Cushion Melanie T. 
Published: September 2019

AbstractMany preclinical studies of infectious diseases have neglected experimental designs that evaluate potential differences related to sex with a concomitant over-reliance on male model systems. Hence, the NIH implemented a monitoring system for sex inclusion in preclinical studies.MethodsPer this mandate, we examined the lung burdens ofPneumocystis murinainfection in 3 mouse strains in both male and female animals at early, mid and late time points.ResultsFemales in each strain had higher infection burdens compared to males at the later time points.ConclusionFemales should be included in experimental models studying Pneumocystis.
Discovery of a celecoxib binding site on PTGES with a cleavable chelation-assisted biotin probe
Authors: Miyamoto David K. , Flaxman Hope A. , Wu Hung-Yi , Gao Jinxu , Woo Christina M. 
Published: September 2019

AbstractThe coxibs are a subset of non-steroidal anti-inflammatory drugs (NSAIDs) that primarily target cyclooxygenase-2 (COX-2) to inhibit prostaglandin signaling and reduce inflammation. However, mechanisms to inhibit other members of the prostaglandin signaling pathway may improve selectivity and reduce off-target toxicity. Here, we report a novel binding site for celecoxib on prostaglandin E synthase (PTGES), an enzyme downstream of COX-2 in the prostaglandin signaling pathway, using a cleavable chelation-assisted biotin probe 6. Evaluation of the multi-functional probe 6 revealed significantly improved tagging efficiencies attributable to the embedded picolyl functional group. Application of the probe 6 within the small molecule interactome mapping by photo-affinity labeling (SIM-PAL) platform using photo-celecoxib as a reporter for celecoxib identified PTGES and other membrane proteins in the top eight enriched proteins from A549 cells. Carbonic anhydrase 12, a known protein target of celecoxib, was also enriched. Four binding sites to photo-celecoxib were additionally mapped by the probe 6, including a binding site with PTGES. The binding interaction with PTGES was validated by competitive displacement with celecoxib and known PTGES inhibitor licofelone. The binding site of photo-celecoxib on PTGES enabled the development of a structural model of the interaction and will inform the design of new selective inhibitors of the prostaglandin signaling pathway.
Presynaptic developmental plasticity allows robust sparse wiring of theDrosophilamushroom body
Authors: Elkahlah Najia A. , Rogow Jackson A. , Ahmed Maria , Clowney E. Josephine 
Published: September 2019

AbstractIn order to represent complex stimuli, principle neurons of associative learning regions receive combinatorial sensory inputs. Density of combinatorial innervation is theorized to determine the number of distinct stimuli that can be represented and distinguished from one another, with sparse innervation thought to optimize the complexity of representations in networks of limited size. How the convergence of combinatorial inputs to principle neurons of associative brain regions is established during development is unknown. Here, we explore the developmental patterning of sparse olfactory inputs to Kenyon cells of theDrosophila melanogastermushroom body. By manipulating the ratio between pre- and post-synaptic cells, we find that postsynaptic Kenyon cells set convergence ratio: Kenyon cells produce fixed distributions of dendritic claws while presynaptic processes are plastic. Moreover, we show that sparse odor responses are preserved in mushroom bodies with reduced cellular repertoires, suggesting that developmental specification of convergence ratio allows functional robustness.
DrosophilaNeuroblast Selection Gated by Notch, Snail, SoxB and EMT Gene Interplay
Authors: Arefin Badrul , Parvin Farjana , Bahrampour Shahrzad , Stadler Caroline Bivik , Thor Stefan 
Published: September 2019

SUMMARYIn the developingDrosophilacentral nervous system neural progenitor (neuroblast; NB) selection is gated by lateral inhibition, controlled by Notch signalling and proneural genes. However, proneural mutants only display partial NB reduction, indicating the existence of additional genes with proneural activity. In addition, recent studies reveal involvement of key epithelial-mesenchymal transition (EMT) genes in NB selection, but the regulatory interplay between Notch signalling and the EMT machinery is unclear. We find that the SoxB geneSoxNeuroand the Snail geneworniouare integrated with the Notch pathway, and constitute the missing proneural genes. Notch signalling, the proneural,SoxNeuro, andworniougenes regulate key EMT genes to orchestrate the NB specification process. Hence, we uncover an expanded lateral inhibition network for NB specification, and demonstrate its link to key players in the EMT machinery. Because of the evolutionary conservation of the genes involved, the Notch-SoxB-Snail-EMT network may control neural progenitor selection in many other systems.
Automated Spatially Targeted Optical Micro Proteomics (autoSTOMP) to determine protein complexity of subcellular structures
Authors: Yin Bocheng , Mendez Roberto , Zhao Xiaoyu , Rahkit Rishi , Hsu Ku-Lung , Ewald Sarah E 
Published: September 2019

ABSTRACTSpatially Targeted Optical Micro Proteomics (STOMP) is a method to study region-specific protein complexity of a biological specimen. STOMP uses a confocal microscope to both visualize structures of interest and to tag the proteins within those structures by a photo-driven crosslinking reaction so that they can be affinity purified and identified by mass spectrometry1. STOMP has the potential to perform discovery proteomics on sub-cellular structures in a wide range of primary cells types and biopsy-scale tissue samples. However, two significant limitations have prevented the broad adoption of this technique by the scientific community. First, STOMP is performed across two software platforms written in different languages, which requires user operation at each field of view. Up to 48 hours of microscope time is necessary to tag sufficient protein (∼1 μg) for mass spectrometry making STOMP prohibitively time and labor-consuming for many researchers. Second, the original STOMP protocol uses a custom photo-crosslinker that limits the accessibility of the technique for some user. To liberate the user, we developed a protocol that automates communication between Zeiss Zen Black imaging software and FIJI image processing software using a customizable code in SikuliX. To fully automate STOMP (autoSTOMP), this protocol includes a tool to make tile array, autofocus and capture images of fields of view across the sample; as well as a method to modify the file that guides photo-tagging so that subsets of the structures of interest can be targeted. To make this protocol broadly accessible, we implemented a commercially available biotin-benzophenone crosslinker as well as a procedure to block endogenous biotin and purify tagged proteins using magnetic streptavidin beads. Here we demonstrate that autoSTOMP can efficiently label, purify and identify proteins that belong to structures measuring 1-2 μm in diameter using human foreskin fibroblasts or mouse bone marrow-derived dendritic cells infected with the protozoan parasiteToxoplasma gondii(Tg). The autoSTOMP platform can easily be adapted to address a range of research questions using Zeiss Zen Black microscopy systems and LC-MS protocols that are standard in many institutional research cores.
P2X1 selective antagonists block HIV-1 infection through inhibition of envelope conformation-dependent fusion
Authors: Soare Alexandra Y. , Malik Hagerah S. , Durham Natasha D. , Freeman Tracey L. , Alvarez Raymond , Patel Foramben , Satija Namita , Upadhyay Chitra , Hioe Catarina E. , Chen Benjamin K. , Swartz Talia H. 
Published: September 2019

AbstractPurinergic receptors detect extracellular ATP and promote inflammatory processes. Emerging literature has demonstrated that inhibition of these proinflammatory receptors can block HIV-1 productive infection. The specificity of receptor type and mechanism of interaction has not yet been determined. Here we characterize the inhibitory activity of P2X1 receptor antagonists, NF279 and NF449 in cell lines, primary cells, and in a variety of envelope clades. NF279 and NF449 blocked productive infection at the level of viral membrane fusion with a range of inhibitory activities against different HIV-1 envelopes. A mutant virus carrying a truncation deletion of the C-terminal tail of HIV-1 envelope (Env) glycoprotein 41 (gp41) showed reduced sensitivity to P2X1 antagonists, indicating that the sensitivity of inhibition by these molecules is modulated by Env conformation. By contrast, a P2X7 antagonist, A438079, had limited effect on productive infection and fusion. Inhibition with NF449 interfered with the ability of the V1V2 targeted broadly neutralizing antibody PG9 to block productive infection, suggesting that these drugs may antagonize HIV-1 Env at gp120 V1V2 to block viral membrane fusion. Our observations indicate that P2X1 antagonism can inhibit HIV-1 replication at the level of viral membrane fusion through interaction with Env. Future studies will probe the nature of these compounds in inhibiting HIV-1 fusion and in development of a different class of small molecules to block HIV-1 entry.IMPORTANCEWhile effective treatment can lower the severe morbidity and mortality associated with HIV-1 infection, patients infected with HIV-1 suffer from significantly higher rates of non-communicable comorbidities associated with chronic inflammation. Emerging literature suggests a key role for P2X1 receptors in mediating this chronic inflammation but the mechanism is still unknown. Here, we demonstrate that HIV-1 infection is reduced by P2X1 receptor antagonism. This inhibition is mediated by interference with HIV-1 Env and can impact a variety of viral clades. These observations highlight the importance of P2X1 antagonists as potential novel therapeutics that could serve to block a variety of different viral clades with additional benefits for their anti-inflammatory properties.
DRD2 TaqI A polymorphism in Eastern Uttar Pradesh population
Authors: Chaudhary Amrita , Yadav Upendra , Kumar Pradeep , Rai Vandana 
Published: September 2019

AbstractDopamine receptor D2 (DRD2) encoded by DRD2 gene, is located on chromosome 11q22-23. Dopamine plays the central role in motivation, cognition, and reward seeking behaviour. Its dysfunction is implicated in numerous neurological and psychiatric disorders including drug abuse, schizophrenia, ADHD etc. The TaqI A polymorphism is localized 9.8 kb downstream from DRD2 gene in exon 8 of protein kinase gene (ANKK1). It is a SNP demonstrated to cause Glutamate to Lysine substitution at 713 amino acid residue in putative binding domain of ANKK1. Due to the central role of dopamine in reward seeking behavior, DRD2 TaqI A loci is a suitable candidate for investigation of molecular basis of addiction. The aim of the present study is to evaluate the frequency of DRD2 TaqI A polymorphism in Eastern Uttar Pradesh population. 3ml blood samples were collected from 50 individuals randomly selected from Eastern UP. Written informed consent along with profile detail was taken from each subject prior to blood sample collection. DRD2 TaqI A polymorphism analysis was done by PCR-RFLP method. Genomic DNA was extracted from each collected blood samples and amplified using DRD2 Taq1 region specific primers. PCR amplification produced 310bp long amplicon which was digested with Taq I enzyme for polymorphism analysis. In case of A2 allele, Taq1 enzyme cleaved 310bp long fragment into two fragments of 180bp and 130bp. In case of A1 allele, a C to T substitution demolished the restriction site of Taq1, so amplicon of A1 allele remained uncut. In total 50 sample analyzed in present study, A2/A2, A2/A1 and A1/A1 genotype were found in 12, 32 and 06 samples respectively. The genotypic frequencies of mutant homozygous (A1/A1) is 0.12, heterozygous (A2/A1) is 0.64 and normal homozygous (A2/A2) is 0.24. The allelic frequency of A1 is 0.44 and of A2 is 0.56. In conclusion, the results of present study suggests that in TaqI A polymorphism of DRD2 gene, the frequency of allele A2 is higher than that of A1 allele in population of Eastern Uttar Pradesh.
Bacteriological Monitoring and Evaluation of Cleaning-disinfection of Computer-related Equipment in an Obstetric and Gynecology Hospital
Authors: Li Meiling , Lu Tingyan , Zhang Hongwei , Chen Shufang , Mao Xueying , Shen Li , Lu Yan , Leng Shufang 
Published: September 2019

AbstractIt is already known that computer keyboards and mouses in hospitals are contaminated with different kinds of bacteria. However, the mouse pad has been neglected with regard to both research and regular cleaning and disinfection in hospitals. In our study, we monitored and evaluated the bacteriology degrees of 74 computers’ keyboards, mouses and mouse pads from six departments. The results showed that before cleaning-disinfection, the contamination rate of the mouse pad ranked second following the keyboards. Enterococcus Faecium was cultured from the mouse pads. The computer-related equipment in the wards and outpatient rooms were much more contaminated than that in the operating rooms. Acinetobacter spp. was only isolated from the doctor’s computers. After cleaning-disinfection, 4 strains of MRSA were isolated from the keyboards and the mouses, one and 3 were cultured at day 3 and day 5 after cleaning-disinfection, respectively. One strain of Pseudomonas Aeruginosa was isolated from the mouses at day 3 after cleaning-disinfection. These demonstrated that the bacterial contamination of the mouse pads must be as emphasized as that of the keyboards and mouses. Furthermore, It is better to clean and disinfect the computer-related equipment(keyboards, mouses, mouse pads) at least once a day.
Humans adapt their anticipatory eye movements to the volatility of visual motion properties
Authors: Pasturel Chloé , Montagnini Anna , Perrinet Laurent Udo 
Published: September 2019

AbstractAnimal behavior constantly adapts to changes, for example when the statistical properties of the environment change unexpectedly. For an agent that interacts with this volatile setting, it is important to react accurately and as quickly as possible. It has already been shown that when a random sequence of motion ramps of a visual target is biased to one direction (e.g. right or left), human observers adapt their eye movements to accurately anticipate the target’s expected direction. Here, we prove that this ability extends to a volatile environment where the probability bias could change at random switching times. In addition, we also recorded the explicit prediction of the next outcome as reported by observers using a rating scale. Both results were compared to the estimates of a probabilistic agent that is optimal in relation to the assumed generative model. Compared to the classical leaky integrator model, we found a better match between our probabilistic agent and the behavioral responses, both for the anticipatory eye movements and the explicit task. Furthermore, by controlling the level of preference between exploitation and exploration in the model, we were able to fit for each individual’s experimental dataset the most likely level of volatility and analyze inter-individual variability across participants. These results prove that in such an unstable environment, human observers can still represent an internal belief about the environmental contingencies, and use this representation both for sensory-motor control and for explicit judgments. This work offers an innovative approach to more generically test the diversity of human cognitive abilities in uncertain and dynamic environments.Author summaryUnderstanding how humans adapt to changing environments to make judgments or plan motor responses based on time-varying sensory information is crucial for psychology, neuroscience and artificial intelligence. Current theories for how we deal with the environment’s uncertainty, that is, in response to the introduction of some randomness change, mostly rely on the behavior at equilibrium, long after after a change. Here, we show that in the more ecological case where the context switches at random times all along the experiment, an adaptation to this volatility can be performed online. In particular, we show in two behavioral experiments that humans can adapt to such volatility at the early sensorimotor level, through their anticipatory eye movements, but also at a higher cognitive level, through explicit ratings. Our results suggest that humans (and future artificial systems) can use much richer adaptive strategies than previously assumed.
Evaluating the informativeness of deep learning annotations for human complex diseases
Authors: Dey Kushal K. , Van de Geijn Bryce , Kim Samuel Sungil , Hormozdiari Farhad , Kelley David R. , Price Alkes L. 
Published: September 2019

AbstractDeep learning models have shown great promise in predicting genome-wide regulatory effects from DNA sequence, but their informativeness for human complex diseases and traits is not fully understood. Here, we evaluate the disease informativeness of allelic-effect annotations (absolute value of the predicted difference between reference and variant alleles) constructed using two previously trained deep learning models, DeepSEA and Basenji. We apply stratified LD score regression (S-LDSC) to 41 independent diseases and complex traits (average N=320K) to evaluate each annotation’s informativeness for disease heritability conditional on a broad set of coding, conserved, regulatory and LD-related annotations from the baseline-LD model and other sources; as a secondary metric, we also evaluate the accuracy of models that incorporate deep learning annotations in predicting disease-associated or fine-mapped SNPs. We aggregated annotations across all tissues (resp. blood cell types or brain tissues) in meta-analyses across all 41 traits (resp. 11 blood-related traits or 8 brain-related traits). These allelic-effect annotations were highly enriched for disease heritability, but produced only limited conditionally significant results – only Basenji-H3K4me3 in meta-analyses across all 41 traits and brain-specific Basenji-H3K4me3 in meta-analyses across 8 brain-related traits. We conclude that deep learning models are yet to achieve their full potential to provide considerable amount of unique information for complex disease, and that the informativeness of deep learning models for disease beyond established functional annotations cannot be inferred from metrics based on their accuracy in predicting regulatory annotations.
GelsolinanddCryABact downstream of muscle identity genes and contribute to preventing muscle splitting and branching inDrosophila
Authors: Bertin Benjamin , Renaud Yoan , Jagla Teresa , Lavergne Guillaume , Dondi Cristiana , Da Ponte Jean-Philippe , Junion Guillaume , Jagla Krzysztof 
Published: September 2019

AbstractA combinatorial code of identity transcription factors (iTFs) specifies the diversity of muscle types inDrosophila. We previously showed that two iTFs, Lms and Ap, play critical role in the identity of a subset of larval body wall muscles, the lateral transverse (LT) muscles. Intriguingly, a small portion ofapandlmsmutants displays an increased number of LT muscles, a phenotype that recalls pathological split muscle fibers in human. However, genes acting downstream of Ap and Lms to prevent these aberrant muscle feature are not known. Here, we applied a cell type specific translational profiling (TRAP) to identify gene expression signatures underlying identity of muscle subsets including the LT muscles. We found thatGelsolin(Gel) anddCryAB, both encoding actin-interacting proteins, displayed LT muscle prevailing expression positively regulated by, the LT iTFs. Loss ofdCryABfunction resulted in LTs with irregular shape and occasional branched ends also observed inapandlmsmutant contexts. In contrast, enlarged and then split LTs with a greater number of myonuclei formed inGelmutants whileGelgain of function resulted in unfused myoblasts, collectively indicating thatGelregulates LTs size and prevents splitting by limiting myoblast fusion. Thus,dCryABandGelact downstream of Lms and Ap and contribute to preventing LT muscle branching and splitting. Our findings offer first clues to still unknown mechanisms of pathological muscle splitting commonly detected in human dystrophic muscles and causing muscle weakness.
Transforming the public sector: 1998–2018
Authors: Lapsley Irvine , Miller Peter 
Published: September 2019

PurposeThe purpose of this paper is to provide an evaluation of public sector research in the 1998–2018 period.Design/methodology/approachThe paper uses the extant literature of this era to study the theorisation of, and the findings of, public sector research.FindingsThis is a vibrant field of a study in a wide range of study settings and with many interdisciplinary studies. The influence of new public management is pervasive over this period. There are numerous instances of innovations in study settings, in key findings and the approach taken by investigators.Research limitations/implicationsThis is not a comprehensive review of all literature in this period.Practical implicationsThis study also explored the relevance of academic research of this era to policymaking by governments.Originality/valueThis paper offers a distinctive critique of theorisation of public sector accounting research. It reveals the dominant theoretical reference points in use during this period and observes the increasing tendency for theoretical pluralism to investigate complex study settings.