bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic pleiotropy between mood disorders, metabolic, and endocrine traits in a multigenerational pedigree
Authors: Kember Rachel L. , Hou Liping , Ji Xiao , Andersen Lars H. , Ghorai Arpita , Estrella Lisa N. , Almasy Laura , McMahon Francis J. , Brown Christopher , Bućan Maja 
Published: September 2017

AbstractBipolar disorder (BD) is a mental disorder characterized by alternating periods of depression and mania. Individuals with BD have higher levels of early mortality than the general population, and a substantial proportion of this may be due to increased risk for comorbid diseases. Recent evidence suggests that pleiotropy, either in the form of a single risk-allele or the combination of multiple loci genome-wide, may underlie medical comorbidity between traits and diseases. To identify the molecular events that underlie BD and related medical comorbidities, we generated imputed whole genome sequence (WGS) data using a population specific reference panel, for an extended multigenerational Old Order Amish pedigree (400 family members) segregating BD and related disorders. First, we investigated all putative disease-causing variants at known Mendelian disease loci present in this pedigree. Second, we performed genomic profiling using polygenic risk scores to establish each individual's risk for several complex diseases. To explore the contribution of disease genes to BD we performed gene-based and variant-based association tests for BD, and found that Mendelian disease genes are enriched in the top results from both tests (OR=20.3, p=1×10−3; OR=2.2, p=1×10−2). We next identified a set of Mendelian variants that co-occur in individuals with BD more frequently than their unaffected family members, including the R3527Q mutation inAPOBassociated with hypercholesterolemia. Using polygenic risk scores, we demonstrated that BD individuals from this pedigree were enriched for the same common risk-alleles for BD as in the general population (β=0.416, p=6×10−4). Furthermore, in the extended Amish family we find evidence for a common genetic etiology between BD and clinical autoimmune thyroid disease (p=1×10−4), diabetes (p=1×10−3), and lipid traits such as triglyceride levels (p=3×10−4). We identify genomic regions that contribute to the differences between BD individuals and unaffected family members by calculating local genetic risk for independent LD blocks. Our findings provide evidence for the extensive genetic pleiotropy that can drive epidemiological findings of comorbidities between diseases and other complex traits. Identifying such patterns may enable the subtyping of complex diseases and facilitate our understanding of the genetic mechanisms underlying phenotypic heterogeneity.
Improving the Generation and Selection of Virtual Populations in Quantitative Systems Pharmacology Models
Authors: Rieger Theodore R. , Allen Richard J. , Bystricky Lukas , Chen Yuzhou , Colopy Glen Wright , Cui Yifan , Gonzalez Angelica , Liu Yifei , White R. D. , Everett R. A. , Banks H. T. , Musante Cynthia J. 
Published: September 2017

AbstractQuantitative systems pharmacology (QSP) models aim to describe mechanistically the pathophysiology of disease and predict the effects of therapies on that disease. For most drug development applications, it is important to predict not only the mean response to an intervention but also the distribution of responses, due to inter-patient variability. Given the necessary complexity of QSP models, and the sparsity of relevant human data, the parameters of QSP models are often not well determined. One approach to overcome these limitations is to develop alternative virtual patients (VPs) and virtual populations (Vpops), which allow for the exploration of parametric uncertainty and reproduce inter-patient variability in response to perturbation. Here we evaluated approaches to improve the efficiency of generating Vpops. We aimed to generate Vpops without sacrificing diversity of the VPs’ pathophysiologies and phenotypes. To do this, we built upon a previously published approach (Allen, Rieger et al. 2016) by (a) incorporating alternative optimization algorithms (genetic algorithm and Metropolis-Hastings) or alternatively (b) augmenting the optimized objective function. Each method improved the baseline algorithm by requiring significantly fewer plausible patients (precursors to VPs) to create a reasonable Vpop. #ddct #qsp
A novel dimeric active site and regulation mechanism revealed by the crystal structure of iPLA2β
Authors: Malley Konstantin R. , Koroleva Olga , Miller Ian , Sanishvili Ruslan , Jenkins Christopher M. , Gross Richard W. , Korolev Sergey 
Published: September 2017

AbstractCalcium-independent phospholipase A2β (iPLA2β) regulates several physiological processes including inflammation, calcium homeostasis and apoptosis. It is linked genetically to neurodegenerative disorders including Parkinson’s disease. Despite its known enzymatic activity, the mechanisms underlying pathologic phenotypes remain unknown. Here, we present the first crystal structure of iPLA2β that significantly revises existing mechanistic models. The catalytic domains form a tight dimer. The ankyrin repeat domains wrap around the catalytic domains in an outwardly flared orientation, poised to interact with membrane proteins. The closely integrated active sites are positioned for cooperative activation and internal transacylation. A single calmodulin binds and allosterically inhibits both catalytic domains. These unique structural features identify the molecular interactions that can regulate iPLA2β activity and its cellular localization, which can be targeted to identify novel inhibitors for therapeutic purposes. The structure provides a well-defined framework to investigate the role of neurodegenerative mutations and the function of iPLA2β in the brain.
Measuring nonapoptotic caspase activity with a transgenic reporter in mice
Authors: Nicholls P. J. , Pack Thomas F. , Urs Nikhil M. , Kumar Sunil , Zhou Yang , Ichim Gabriel , Ginzel Joshua D. , Turu Gabor , Calabrese Evan , Roberts Wendy L. , Fan Ping , Ostapchenko Valeriy G. , Lenis Monica S. Guzman , Beraldo Flavio , Hatina Jiri , Prado Vania F. , Prado Marco A. M. , Spasojevic Ivan , Snyder Joshua C. , Dzirasa Kafui , Johnson G. Allan , Caron Marc G. 
Published: September 2017

AbstractThe protease caspase-3 is a key mediator of apoptotic programmed cell death. But weak or transient caspase activity can contribute to neuronal differentiation, axonal pathfinding, and synaptic long-term depression. Despite the importance of sublethal, or nonapoptotic, caspase activity in neurodevelopment and neural plasticity, there has been no simple method for mapping and quantifying nonapoptotic caspase activity in rodent brains. We therefore generated a transgenic mouse expressing a highly sensitive and specific fluorescent reporter of caspase activity, with peak signal localized to the nucleus. As a proof of concept, we first obtained evidence that nonapoptotic caspase activity influences neurophysiology in an amygdalar circuit. Then focusing on the amygdala, we were able to quantify a sex-specific persistent elevation in caspase activity in females after restraint stress. This simplein vivocaspase activity reporter will facilitate systems-level studies of apoptotic and nonapoptotic phenomena in behavioral and pathological models.Significance StatementCaspase-3 is an enzyme that can cause cell death when highly active but can also perform important cellular functions, such as maturation and structural changes, when only weakly or transiently active. Despite the importance of this nonlethal type of caspase activity, there is no straightforward method to measure it in live rodents. We therefore developed mice that have a fluorescent reporter that is sensitive enough to detect nonlethal caspase activity. Surprisingly, we found that weak caspase activity influences the synchrony of neuronal firing across different brain regions. We also observed increased caspase activity in female mice after severe stress. This simple caspase activity reporter can subserve multiple applications in behavior and pathology research.
indCAPS: A tool for designing screening primers for CRISPR/Cas9 mutagenesis events
Authors: Hodgens Charles , Nimchuk Zachary L. , Kieber Joseph J. 
Published: September 2017

AbstractGenetic manipulation of organisms using CRISPR/Cas9 technology generally produces small insertions/deletions (indels) that can be difficult to detect. Here, we describe a technique to easily and rapidly identify such indels. Sequence-identified mutations that alter a restriction enzyme recognition site can be easily distinguished from wild-type alleles using a cleaved amplified polymorphic sequence (CAPS) technique. If a restriction site is created or altered by the mutation such that only one allele contains the restriction site, a polymerase chain reaction (PCR) followed by a restriction digest can be used to distinguish the two alleles. However, in the case of most CRISPR-induced alleles, no such restriction sites are present in the target sequences. In this case, a derived CAPS (dCAPS) approach can be used in which mismatches are purposefully introduced in the oligonucleotide primers to create a restriction site in one, but not both, of the amplified templates. Web-based tools exist to aid dCAPS primer design, but when supplied sequences that include indels, the current tools often fail to suggest appropriate primers. Here, we report the development of a Python-based, species-agnostic web tool, called indCAPS, suitable for the design of PCR primers used in dCAPS assays that is compatible with indels. This tool should have wide utility for screening editing events following CRISPR/Cas9 mutagenesis as well as for identifying specific editing events in a pool of CRISPR-mediated mutagenesis events. This tool was field-tested in a CRISPR mutagenesis experiment targeting a cytokinin receptor (AHK3) inArabidopsis thaliana. The tool suggested primers that successfully distinguished between wild-type and edited alleles of a target locus and facilitated the isolation of two novelahk3null alleles. Users can access indCAPS and design PCR primers to employ dCAPS to identify CRISPR/Cas9 alleles athttp://indcaps.kieber.cloudapps.unc.edu/.
Spatial RNA proximities reveal a bipartite nuclear transcriptome and territories of differential density and transcription elongation rates
Authors: Morf Jörg , Wingett Steven W. , Farabella Irene , Cairns Jonathan , Furlan-Magaril Mayra , Liu Xin , Craig Frank F. , Andrews Simon , Marti-Renom Marc A. , Fraser Peter 
Published: September 2017

AbstractSpatial transcriptomics aims to understand how the ensemble of RNA molecules in tissues and cells is organized in 3D space. Here we introduce Proximity RNA-seq, which enriches for nascent transcripts, and identifies contact preferences for individual RNAs in cell nuclei. Proximity RNA-seq is based on massive-throughput RNA-barcoding of sub-nuclear particles in water-in-oil emulsion droplets, followed by sequencing. We show a bipartite organization of the nuclear transcriptome in which compartments of different RNA density correlate with transcript families, tissue specificity and extent of alternative splicing. Integration of proximity measurements at the DNA and NA level identify transcriptionally active genomic regions with increased nucleic acid density and faster RNA polymerase II elongation located close to compact chromatin.
CYK-4 functions independently of its centralspindlin partner ZEN-4 to cellularize oocytes in germline syncytia
Authors: Lee Kian-Yong , Green Rebecca A. , Gutierrez Edgar , Sebastian Gomez-Cavazos J. , Kolotuev Irina , Wang Shaohe , Desai Arshad , Groisman Alex , Oegema Karen 
Published: September 2017

ABSTRACTThroughout metazoans, germ cells undergo incomplete cytokinesis to form syncytia connected by intercellular bridges. Formation of gametes ultimately requires bridge closure. Here, we investigate the contribution of the conserved bridge component centralspindlin to oocyte production inC. elegans. Centralspindlin is composed of the Rho family GTPase-activating protein (GAP) CYK-4/MgcRacGAP and the microtubule motor ZEN-4/kinesin-6, which are both essential for cytokinesis. In contrast, we show that oocyte production by the syncytial germline requires CYK-4 but not ZEN-4. Longitudinal imaging after conditional CYK-4 inactivation revealed a role in oocyte cellularization, rather than in generation of syncytial compartments. CYK-4’s lipid-binding C1 domain and the GTPase-binding interface of its GAP domain were individually important for oocyte cellularization and for targeting CYK-4 to bridges, where it contributes to enrichment of active RhoA. These results identify a C1-GAP module in CYK-4 that recruits it to bridges in the germline and directs their closure to produce oocytes.IMPACT STATEMENTThe CYK-4 subunit of centralspindlin, a broadly conserved component of intercellular bridges across metazoa, is required for the cytokinesis-like closure of intercellular bridges that cellularizes oocytes to separate them from germline syncytia.MAJOR SUBJECT AREASCell Biology, Developmental Biology & Stem Cells
Nicotine increases apoptosis in HUVECs cultured in high glucose/high fat via Akt ubiquitination and degradation
Authors: Cao Xiaofang , Han Chunling , Wen Jinsuo , Guo Xiaokun , Zhang Kejian 
Published: September 2017

SummaryIt is well‐documented that nicotine, the main active ingredient in cigarettes, results in endothelial cell injury in numerous diseases. However, whether nicotine plays a crucial role in endothelial cell injury in diabetes and the exact molecular mechanism that mediates this process have not been fully elucidated. The current study aimed to investigate the effects of nicotine on endothelial cell injury in diabetes and the specific molecular mechanism by which it plays a role. Human umbilical vein endothelial cells (HUVECs) were incubated in HG/HF media and treated with nicotine, PYR‐41 (a selective ubiquitin E1 inhibitor), Akt‐overexpressing adenovirus, or TTC3 and MUL1 shRNA adenovirus. Cell viability was subsequently detected by the CCK8 assay, and apoptosis was examined by caspase‐3 cleavage and activity analysis. Compared to the HG/HF incubated group, nicotine incubation significantly decreased cell survival and increased apoptosis. Moreover, nicotine induced Akt degradation via UPS, and Akt overexpression blocked nicotine‐induced apoptosis in HUVECs cultured in HG/HF media. Furthermore, the TTC3 and MUL1 shRNA adenovirus dramatically decreased the Akt ubiquitination and apoptosis induced by nicotine. These results indicate that nicotine‐induced Akt ubiquitination and degradation occurs through TTC3 and MUL1 and results in a dramatic increase in apoptosis in HUVECs cultured in HG/HF media.
MicroRNAs mir‐184 and let‐7 alter Drosophila metabolism and longevity
Authors: Gendron Christi M. , Pletcher Scott D. 
Published: September 2017

SummaryMicroRNAs (miRNAs) are small RNA molecules that regulate gene expression associated with many complex biological processes. By comparing miRNA expression between long‐lived cohorts of Drosophila melanogaster that were fed a low‐nutrient diet with normal‐lived control animals fed a high‐nutrient diet, we identified miR‐184, let‐7, miR‐125, and miR‐100 as candidate miRNAs involved in modulating aging. We found that ubiquitous, adult‐specific overexpression of these individual miRNAs led to significant changes in fat metabolism and/or lifespan. Most impressively, adult‐specific overexpression of let‐7 in female nervous tissue increased median fly lifespan by ~22%. We provide evidence that this lifespan extension is not due to alterations in nutrient intake or to decreased insulin signaling.
The effect of a behavioral activation treatment for substance use on post‐treatment abstinence: a randomized controlled trial
Authors: Daughters Stacey B. , Magidson Jessica F. , Anand Deepika , Seitz‐Brown C. J. , Chen Yun , Baker Sydney 
Published: September 2017

AbstractAimsTo compare outcomes for a behavioral activation group treatment for substance use [life enhancement treatment for substance use (LETS ACT)] versus a time and group size‐matched control condition delivered in a residential treatment setting.DesignSingle‐site two‐arm parallel‐group randomized clinical trial with follow‐up assessment at 3, 6 and 12 months post‐treatment.SettingResidential substance use treatment facility in the United States.ParticipantsParticipants were 263 adults [mean age 42.7 (11.8); 29.5% female; 95.4% African American; 73.2% court mandated] whose insurance dictated 30‐day (65.9%) or 90‐day (34.1%) treatment duration.Intervention and comparatorLETS ACT (n = 142) is a treatment developed originally for depression and modified for substance use. It teaches participants to increase positively reinforcing value‐driven activities in order to counter depression and relapse. The control group [supportive counseling (SC); n = 121] received time and group size‐matched supportive counseling. Treatment was delivered in five or eight 1‐hour sessions depending on patient length of stay.MeasurementsPercentage abstinent at follow‐up, percentage of substance use days among those reporting use, depressive symptoms [Beck Depression Inventory (BDI)] and adverse consequences of drug use [Short Inventory of Problems—Alcohol and Drug (SIP‐AD)].FindingsLETS ACT had significantly higher abstinence rates at 3 months [odds ratio (OR) = 2.2, 95% confidence interval (CI) = 1.3–3.7], 6 months (OR = 2.6, 95% CI= 1.3–5.0) and 12 months (OR = 2.9, 95% CI = 1.3–6.1) post‐treatment compared with SC. LETS ACT participants reported significantly fewer adverse consequences from substance use at 12 months post‐treatment [B = 4.50, standard error (SE) = 2.17, 95% CI = 0.22–8.78]. Treatment condition had no effect on percentage substance use days among those who resumed use or on change in depressive symptoms; the latter decreased over time only in those who remained abstinent after residential treatment irrespective of condition (B = 0.43, SE = 0.11, 95% confidence interval = 0.22–0.65).ConclusionsA behavioral activation group treatment for substance use (LETS ACT) appears to increase the likelihood of abstinence and reduce adverse consequences from substance use up to 12 months post‐treatment.
Dwarf shrub and grass vegetation resistant to long‐term experimental warming while microarthropod abundance declines on the Falkland Islands
Authors: Bokhorst S. , Convey P. , Huiskes A. , Aerts R. 
Published: September 2017

AbstractDwarf shrubs are a dominant plant type across many regions of the Earth and have hence a large impact on carbon and nutrient cycling rates. Climate change impacts on dwarf shrubs have been extensively studied in the Northern Hemisphere, and there appears to be large variability in response between ecosystem types and regions. In the Southern Hemisphere, less data are available despite dwarf shrub vegetation being a dominant feature of southern South America and mountainous regions of the Southern Hemisphere. Here, we present the response of anEmpetrum rubrumdwarf shrub and aPoagrass community to 12 years of experimental climate manipulation achieved using open top chambers on the Falkland Islands, a cold temperate island group in the South Atlantic. The dwarf shrub and grass vegetation did not change significantly in cover, biomass or species richness over the 12 years period in response to climate warming scenarios of up to 1°C reflecting annual warming levels predicted in this region for the coming decades. The soil microarthropod community, however, responded with declines in abundance (37%) under warming conditions in the grass community, but no such changes were observed in the dwarf shrub community. Overall, our data indicate that dwarf shrub communities are resistant to the levels of climate warming predicted over the coming decades in the southern South America region and will, therefore, remain a dominant driver of local ecosystem properties.
The complexity of forest borders determines the understorey vegetation
Authors: Lindgren Jessica , Kimberley Adam , Cousins Sara A. O. 
Published: September 2017

AbstractQuestionsWhat are the most important drivers of plant species richness (gamma‐diversity) and species turnover (beta‐diversity) in the field layer of a forest edge? Does the tree and shrub species richness structure and complexity affect the richness of forest and grassland specialist species?LocationSoutheast Sweden.MethodsWe sampled 50 forest edges with different levels of structural complexity in agricultural landscapes. In each border we recorded trees, shrubs and herb layer species in a 50‐m transect parallel with the forest. We investigated species composition and species turnover in relation to the proportions of gaps in the border and the diversity of trees and shrubs.ResultsTotal plant species richness in the field layer was mainly explained by the proportion of gaps to areas with full canopy cover and tree diversity. Increasing number of gaps promoted higher diversity of grassland specialist species within the field layer, resulting in open forest borders with the highest overall species richness. Gaps did however have a negative impact on forest species richness. Conversely, increasing forest species richness was positively related to tree diversity, but the number of grassland specialist species was negatively affected by tree diversity.ConclusionsManaging forest borders, and therefore increasing the area of semi‐open habitats in fragmented agricultural landscapes, provides future opportunities to create a network of suitable habitats for both grassland and deciduous forest specialist species. Such measures therefore have the potential to increase functional connectivity and support dispersal of species in homogeneous forest/agricultural landscapes.
Is acetaminophen associated with a risk of Stevens–Johnson syndrome and toxic epidermal necrolysis? Analysis of the French Pharmacovigilance Database
Authors: Lebrun‐Vignes Bénédicte , Guy Claire , Jean‐Pastor Marie‐Josèphe , Gras‐Champel Valérie , Zenut Marie ,   The French Network of Regional Centres of Pharmacovigilance and the French Investigators for Adverse Skin Reactions to Drugs
Published: September 2017

AimStevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe mostly drug‐induced cutaneous reactions. Acetaminophen is an over‐the‐counter drug used worldwide to treat pain and reduce fever. In 2013, the US Food and Drug Administration informed the public that acetaminophen was associated with a rare risk of SJS/TEN. The aim of the present retrospective study was to analyse reports of acetaminophen as a possible suspect in the development of SJS/TEN from the French Pharmacovigilance Database (FPDB).MethodsCases of TEN/SJS with acetaminophen as a suspect drug registered in the FPDB, collected from January 2002 to December 2013, were analysed by an expert group. The algorithm of drug causality for epidermal necrolysis (ALDEN) was used as a reference tool for SJS/TEN to assess the causality of each suspect drug.ResultsAfter exclusion of 16 nonvalidated cases, 112 cases (47 TEN, 51 SJS, 14 SJS/TEN overlaps) involving 574 suspected drugs (5⋅1/case) were analysed. In 80 cases, the acetaminophen ALDEN score was inferior or equal to that of other drugs, associated with a higher suspicion for causality. In 32 cases, acetaminophen had the highest score but matched with a ‘very unlikely’ or ‘unlikely’ causality in 12 cases. For the 20 remaining cases with a ‘possible’ or ‘ probable’ causality, a protopathic or a confounding bias was likely in 14 cases.ConclusionsAfter analysis of the French pharmacovigilance data using the ALDEN algorithm, we found no obvious SJS/TEN risk related to the use of acetaminophen in this large national series.