bluuebunny/crossref_metadata_2025_split huggingface dataset:
The GTEx Consortium atlas of genetic regulatory effects across human tissues
Authors: Aguet François , Barbeira Alvaro N , Bonazzola Rodrigo , Brown Andrew , Castel Stephane E , Jo Brian , Kasela Silva , Kim-Hellmuth Sarah , Liang Yanyu , Oliva Meritxell , Parsana Princy E , Flynn Elise , Fresard Laure , Gaamzon Eric R , Hamel Andrew R , He Yuan , Hormozdiari Farhad , Mohammadi Pejman , Muñoz-Aguirre Manuel , Park YoSon , Saha Ashis , Segrć Ayellet V , Strober Benjamin J , Wen Xiaoquan , Wucher Valentin , Das Sayantan , Garrido-Martín Diego , Gay Nicole R , Handsaker Robert E , Hoffman Paul J , Kashin Seva , Kwong Alan , Li Xiao , MacArthur Daniel , Rouhana John M , Stephens Matthew , Todres Ellen , Viñuela Ana , Wang Gao , Zou Yuxin ,   The GTEx Consortium, Brown Christopher D , Cox Nancy , Dermitzakis Emmanouil , Engelhardt Barbara E , Getz Gad , Guigo Roderic , Montgomery Stephen B , Stranger Barbara E , Im Hae Kyung , Battle Alexis , Ardlie Kristin G , Lappalainen Tuuli 
Published: October 2019

AbstractThe Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues, and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the v8 data, based on 17,382 RNA-sequencing samples from 54 tissues of 948 post-mortem donors. We comprehensively characterize genetic associations for gene expression and splicing incisandtrans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue-specificity of genetic effects, and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
Heroin Choice Depends on Income Level and Economy Type
Authors: Gunawan Tommy , Hachiga Yosuke , Tripoli Christopher S. , Silberberg Alan , Kearns David N. 
Published: October 2019

AbstractRationaleIn a previous study investigating choice between heroin and a non-drug alternative in animals, reductions in income (i.e., choices/day) caused the percentage of income spent on heroin to progressively decrease. In contrast, another study found that humans with opioid use disorder spent the majority of their income on heroin even though they had little income. Comparison of these two studies suggests that the seemingly conflicting results could be explained by differences in the underlying economy types of the choice alternatives.ObjectiveThe present experiment tested the hypothesis that the effect of income changes on choice between heroin and a non-drug alternative depends on economy type.MethodsRats chose between heroin and saccharin under three income levels. For the Closed group, the choice session was the only opportunity to obtain these reinforcers. For the Heroin Open group and the Saccharin Open group, choice sessions were followed by 3-h periods of unlimited access to heroin or saccharin, respectively.ResultsAs income decreased, the Closed and Heroin Open groups, but not the Saccharin Open group, spent an increasingly greater percentage of income on saccharin than on heroin. The Saccharin Open group, compared to the other groups, spent a greater percentage of income on heroin as income decreased.ConclusionsResults confirm that the effects of income and economy type can interact and this may explain the apparently discrepant results of earlier studies. More generally, findings suggest that situations where heroin choice has little consequence for consumption of non-drug alternatives may promote heroin use.
DeltaNeTS+: Elucidating the mechanism of drugs and diseases using gene expression and transcriptional regulatory networks
Authors: Noh Heeju , Hua Ziyi , Chrysinas Panagiotis , Shoemaker Jason E. , Gunawan Rudiyanto 
Published: October 2019

AbstractBackgroundKnowledge on the molecular targets of diseases and drugs is crucial for elucidating disease pathogenesis and mechanism of action of drugs, and for driving drug discovery and treatment formulation. In this regard, high-throughput gene transcriptional profiling has become a leading technology, generating whole-genome data on the transcriptional alterations caused by diseases or drug compounds. However, identifying direct gene targets, especially in the background of indirect (downstream) effects, based on differential gene expressions is difficult due to the complexity of gene regulatory network governing the gene transcriptional processes.ResultsIn this work, we developed a network analysis method, called DeltaNeTS+, for inferring direct gene targets of drugs and diseases from gene transcriptional profiles. DeltaNeTS+ relies on a gene regulatory network model to identify direct perturbations to the transcription of genes. Importantly, DeltaNeTS+ is able to combine both steady-state and time-course gene expression profiles, as well as to leverage information on the gene network structure that is increasingly becoming available for a multitude of organisms, including human. We demonstrated the power of DeltaNeTS+ in predicting gene targets using gene expression data in complex organisms, includingCaenorhabditis elegansand human cell lines (T-cell and Calu-3). More specifically, in an application to time-course gene expression profiles of influenza A H1N1 (swine flu) and H5N1 (avian flu) infection, DeltaNeTS+ shed light on the key differences of dynamic cellular perturbations caused by the two influenza strains.ConclusionDeltaNeTS+ is an enabling tool to infer gene transcriptional perturbations caused by diseases and drugs from gene transcriptional profiles. By incorporating available information on gene network structure, DeltaNeTS+ produces accurate predictions of direct gene targets from a small sample size (~10s). DeltaNeTS+ can freely downloaded fromhttp://www.github.com/cabsel/deltanetsplus.
Indian Wellderly exomes underscoreNRAProles in elderly hypertrophic cardiomyopathy
Authors: Chimata Prasanth , Ankit Sharma , Agrawal Radhika , Rao Vinay J , Koranchery Rakesh , Rajendran Ranjith , Mohanan Kurukkanparampil Sreedharan , Shenthar Jayaprakash , Bazrafshan Sholeh , Sadayappan Sakthivel , Ahamed Hisham , Dhandapany Perundurai S 
Published: October 2019

AbstractHypertrophic cardiomyopathy (HCM) is a genetic disorder that affects people of all ages, with the elderly population being inadequately studied. It is primarily caused by gene variants that encode proteins involved in the structure and function of the heart muscle. The identification of genes associated with elderly HCM requires ethnic-specific genomic sequences from Wellderly individuals. Currently, no Indian Wellderly dataset is available. To address this, we collected and sequenced the Indian Wellderly population. We built a novel Indian database of healthy aging nucleotide sequences (named i-DHANS) and is newly accessible atIndiCardiome. Utilizing this database and Indian HCM cohort, we identified nebulin-related anchoring protein (NRAP) as a gene associated with elderly HCM. NRAP is crucial for the assembly of myofibrils and transmission of force from the sarcomere to the extracellular matrix. Our functional analysis showed that the identified NRAP variant had significantly reduced interactions with its interacting partners, such as Kelch-like protein 41 (KLHL41) and α-actinin, implying a loss of function. In summary, our findings indicate thatNRAPis a new elderly cardiomyopathy gene, and our Indian Wellderly database is a valuable resource for identifying ethnic-specific genes for various diseases.
Metabolic dysregulation of the lysophospholipid/autotaxin axis in the chromosome 9p21 gene SNP rs10757274
Authors: Meckelmann Sven W. , Hawksworth Jade I. , White Daniel , Andrews Robert , Rodrigues Patricia , O’Connor Anne , Alvarez-Jarreta Jorge , Tyrrell Victoria J. , Hinz Christine , Zhou You , Williams Julie , Aldrovandi Maceler , Watkins William J , Engler Adam J , Slatter David A. , Allen Stuart M , Acharya Jay , Mitchell Jacquie , Cooper Jackie , Aoki Junken , Kano Kuniyuki , Humphries Steve E. , O’Donnell Valerie B. 
Published: October 2019

AbstractAimsCommon chromosome 9p21 SNPs increase coronary heart disease (CHD) risk, independent of “traditional lipid risk factors”. However, lipids comprise large numbers of structurally-related molecules not measured in traditional risk measurements, and many have inflammatory bioactivities. Here we applied lipidomic and genomic approaches to three model systems, to characterize lipid metabolic changes in common Chr9p21 SNPs which confer ∼30% elevated CHD risk associated with altered expression ofANRIL, a long ncRNA.Methods and ResultsUntargeted and targeted lipidomics was applied to plasma samples from Northwick Park Heart Study II (NPHSII) homozygotes for AA or GG in rs10757274. Elevated risk GG correlated with reduced lysophosphospholipids (lysoPLs), lysophosphatidic acids (lysoPA) and autotaxin (ATX). Five other risk SNPs did not show this phenotype. Correlation and network analysis showed that lysoPL-lysoPA interconversion was uncoupled from ATX in GG, indicating metabolic dysregulation. To identify candidate genes, transcriptomic data from shRNA downregulation ofANRILin HEK293 cells was mined. Significantly-altered expression of several lysoPL/lysoPA metabolising enzymes was found (MBOAT2, PLA2G4C, LPCAT2, ACSL6, PNPLA2, PLBD1, PLPP1, PLPP2andPLPPR2). Next, vascular smooth muscle cells differentiated from iPSCs of individuals homozygous for Chr9p21 risk SNPs were examined. Here, the presence of risk alleles was associated with altered expression of several lysoPL/lysoPA enzymes. Importantly, for several, deletion of the risk locus fully or partially reversed their expression to non-risk haplotype levels:ACSL3, DGKA, PLA2G2A, LPCAT2, LPL, PLA2G3, PNPLA3, PLA2G12A LIPC, LCAT, PLA2G6, ACSL1, MBOAT2.ConclusionA Chr9p21 risk SNP associates with complex alterations in immune-bioactive phospholipids and their enzymatic metabolism. Lipid metabolites and genomic pathways associated with CHD pathogenesis in Chr9p21 andANRIL-associated disease are demonstrated.One sentence summaryInflammatory phospholipid metabolism defines a cardiovascular disease SNP
Structure of KCNH2 cyclic nucleotide-binding homology domain reveals a functionally vital salt-bridge
Authors: Ben-Bassat Ariel , Giladi Moshe , Haitin Yoni 
Published: October 2019

AbstractHuman KCNH2 (hKCNH2, Ether-à-go-go (EAG)-Related Gene, hERG) are best known for their role in cardiac action potentials repolarization and have key roles in various pathologies. As other KCNH family members, hKCNH2 contains a unique intracellular complex crucial for channel function, consisting of an N-terminal eag domain and a C-terminal cyclic nucleotide-binding homology domain (CNBHD). Previous studies demonstrated that the CNBHD is occupied by an intrinsic ligand motif (ILM), in a self-liganded conformation, providing a structural mechanism for the lack of KCNH channels regulation by cyclic nucleotides. While significant advancements in structural and functional characterizations of the CNBHD of KCNH channels have been made, a high-resolution structure of the hKCNH2 intracellular complex was missing. Here, we report the 1.5 Å resolution structure of the hKCNH2 channel CNBHD. The structure reveals the canonical fold shared by other KCNH family members, where the spatial organization of the ILM is preserved within the β-roll region. Moreover, measurements of small-angle X-ray scattering profile in solution, as well as comparison with a recent nuclear magnetic resonance (NMR) analysis of hKCNH2, revealed high agreement with the structure, indicating an overall low flexibility in solution. Importantly, we identified a novel salt-bridge (E807-R863), which was not previously resolved in the NMR and cryogenic electron microscopy (cryo-EM) structures. Strikingly, electrophysiological analysis of charge reversal mutations revealed its crucial role for hKCNH2 function. Moreover, comparison with other KCNH members revealed the structural conservation of this salt-bridge, consistent with its functional significance. Together with the available structure of the mouse KCNH1 intracellular complex, and previous electrophysiological and spectroscopic studies of KCNH family members, we propose that this salt-bridge serves as a strategically positioned linchpin to support both the spatial organization of the ILM and the maintenance of the intracellular complex interface.SummaryHuman KCNH2 are key channels governing cardiac repolarization. Here, a 1.5 Å resolution structure of their cyclic nucleotide-binding homology domain is presented. Structural analysis and electrophysiological validation reveal a novel salt-bridge, playing an important role in hKCNH2 functional regulation.
Epigenetic regulation of protein translation in KMT2A-rearranged AML
Authors: Lenard Alexandra , Xie Hongbo Michael , Riedel Simone S. , Yuan Zuo-Fei , Zhu Nan , Neff Tobias , Bernt Kathrin M. 
Published: October 2019

ABSTRACTInhibition of the histone methyl-transferase DOT1L (KMT4) has shown encouraging activity in preclinical models of KMT2A (MLL)-rearranged leukemia. The DOT1L inhibitor pinometostat (EPZ5676) was well tolerated in early phase clinical trials and showed modest clinical activity, including occasional complete responses (CRs) as single agent. These studies support the development of combinatorial therapies for KMT2A-rearranged leukemias. Here, we investigated two novel combinations: dual inhibition of the histone methyltransferases DOT1L and EZH2, and the combination of a DOT1L inhibitor with the protein synthesis inhibitor homoharringtonine (HHR).EZH2 is the catalytic histone methyltransferase in the polycomb repressive complex 2 (PRC2), and inhibition of EZH2 has reported preclinical activity in KMT2A-rearranged leukemia. We found that the H3K79 and H3K27 methyl marks are not dependent on each other, and that DOT1L and EZH2 inhibition affect largely distinct gene expression programs. In particular, the KMT2A/DOT1L target HOXA9, which is commonly de-repressed as a consequence of PRC2 loss or inhibition in other contexts, was not re-activated upon dual DOT1L/EZH2 knockout or inhibition. Despite encouraging data in murine KMT2A-MLLT3 transformed cells suggesting synergy between DOT1L and EZH2 inhibition, we found both synergistic and antagonistic effects on a panel of human KMT2A rearranged cell lines. Combinatorial inhibition of DOT1L and EZH2 is thus not a promising strategy. We identified opposing effects on ribosomal gene transcription and protein translation by DOT1L and EZH2 as a mechanism that is partially responsible for observed antagonistic effects. The effects of DOT1L inhibition on ribosomal gene expression prompted us to evaluate the combination of EPZ5676 with a protein translation inhibitor. EPZ5676 was synergistic with the protein translation inhibitor homoharringtonine (HHR), supporting further preclinical/clinical development of this combination.
Stereo In-Line Holographic Digital Microscope
Authors: Zimmerman Thomas , Antipa Nick , Elnatan Daniel , Murru Alessio , Biswas Sujoy , Pastore Vito , Bonani Mayara , Waller Laura , Fung Jennifer , Fenu Gianni , Bianco Simone 
Published: October 2019

ABSTRACTBiologists use optical microscopes to study plankton in the lab, but their size, complexity and cost makes widespread deployment of microscopes in lakes and oceans challenging. Monitoring the morphology, behavior and distribution of planktonin situis essential as they are excellent indicators of marine environment health and provide a majority of Earth’s oxygen and carbon sequestration. Direct in-line holographic microscopy (DIHM) eliminates many of these obstacles, but image reconstruction is computationally intensive and produces monochromatic images. By using one laser and one white LED, it is possible to obtain the 3D location plankton by triangulation, limiting holographic reconstruction to only the voxels occupied by the plankton, reducing computation by several orders of magnitude. The color information from the white LED assists in the classification of plankton, as phytoplankton contains green-colored chlorophyll. The reconstructed plankton images are rendered in a 3D interactive environment, viewable from a browser, providing the user the experience of observing plankton from inside a drop of water.
Identifying conservation priorities in a defaunated tropical biodiversity hotspot
Authors: Tilker Andrew , Abrams Jesse F. , Nguyen An , Hörig Lisa , Axtner Jan , Louvrier Julie , Rawson Benjamin M. , Nguyen Quang Hoa Anh , Guegan Francois , Van Nguyen Thanh , Le Minh , Sollmann Rahel , Wilting Andreas 
Published: October 2019

AimUnsustainable hunting is leading to widespread defaunation across the tropics. To mitigate against this threat with limited conservation resources, stakeholders must make decisions on where to focus anti-poaching activities. Identifying priority areas in a robust way allows decision-makers to target areas of conservation importance, therefore maximizing the impact of conservation interventions.LocationAnnamite mountains, Vietnam and Laos.MethodsWe conducted systematic landscape-scale surveys across five study sites (four protected areas, one unprotected area) using camera-trapping and leech-derived environmental DNA. We analyzed detections within a Bayesian multi-species occupancy framework to evaluate species responses to environmental and anthropogenic influences. Species responses were then used to predict occurrence to unsampled regions. We used predicted species richness maps and occurrence of endemic species to identify areas of conservation importance for targeted conservation interventions.ResultsAnalyses showed that habitat-based covariates were uninformative. Our final model therefore incorporated three anthropogenic covariates as well as elevation, which reflects both ecological and anthropogenic factors. Conservation-priority species tended to found in areas that are more remote now or have been less accessible in the past, and at higher elevations. Predicted species richness was low and broadly similar across the sites, but slightly higher in the more remote site. Occupancy of the three endemic species showed a similar trend.Main conclusionIdentifying spatial patterns of biodiversity in heavily-defaunated landscapes may require novel methodological and analytical approaches. Our results indicate to build robust prediction maps it is beneficial to sample over large spatial scales, use multiple detection methods to increase detections for rare species, include anthropogenic covariates that capture different aspects of hunting pressure, and analyze data within a Bayesian multi-species framework. Our models further suggest that more remote areas should be prioritized for anti-poaching efforts to prevent the loss of rare and endemic species.
Environmental reservoirs ofMycobacterium bovisandMycobacterium tuberculosisin the Ruaha region, Tanzania
Authors: Travis Emma R. , Hung Yujiun , Porter David , Paul Goodluck , James Robert , Roug Annette , Kato-Maeda Midori , Kazwala Rudovick , Smith Woutrina A. , Hopewell Phil , Courtenay Orin , Wellington Elizabeth M.H. 
Published: October 2019

ABSTRACTThis study was designed to investigate the prevalence of members of the Mycobacterium tuberculosis complex (MTBC) in the environment of pastoralists and villagers in the Iringa district, adjacent to the Ruaha National Park in Tanzania. Utilising specific qPCR assays, bothMycobacterium bovisandMycobacterium tuberculosiswere detected in cattle faeces, boma soil, water and household dust.M. boviswas also found in goat faeces and goat boma soil. This is the first report of faecal shedding ofM. bovisin goats and the first molecular survey of faecal shedding in cattle. The prevalence of both bacterial species varied by village, area, season and sample type. Geographical and temporal correlations across sample types were suggestive of cross species transmission. This non-invasive test has previously been rigorously validated for screening other mammals; in this study it has successfully been applied to detectM. bovisandM. tuberculosisin livestock faeces and the environment.
Analysis of diverse eukaryotes suggests the existence of an ancestral mitochondrial apparatus derived from the bacterial type II secretion system
Authors: Horváthová Lenka , Žárský Vojtěch , Pánek Tomáš , Derelle Romain , Pyrih Jan , Motyčková Alžběta , Klápšt’ová Veronika , Vinopalová Martina , Marková Lenka , Voleman Luboš , Klimeš Vladimír , Petrů Markéta , Vaitová Zuzana , Čepička Ivan , Hryzáková Klára , Harant Karel , Gray Michael W. , Chami Mohamed , Guilvout Ingrid , Francetic Olivera , Lang B. Franz , Vlček Čestmír , Tsaousis Anastasios D. , Eliáš Marek , Doležal Pavel 
Published: October 2019

AbstractThe type 2 secretion system (T2SS) is present in some Gram-negative eubacteria and used to secrete proteins across the outer membrane. Here we report that certain representative heteroloboseans, jakobids, malawimonads and hemimastigotes unexpectedly possess homologues of core T2SS components. We show that at least some of them are present in mitochondria, and their behaviour in biochemical assays is consistent with the presence of a mitochondrial T2SS-derived system (miT2SS). We additionally identified 23 protein families co-occurring with miT2SS in eukaryotes. Seven of these proteins could be directly linked to the core miT2SS by functional data and/or sequence features, whereas others may represent different parts of a broader functional pathway, possibly also involving the peroxisome. Its distribution in eukaryotes and phylogenetic evidence together indicate that the miT2SS-centred pathway is an ancestral eukaryotic trait. Our findings thus have direct implications for the functional properties of the early mitochondrion.
Distinct microbial communities in the murine gut are revealed by taxonomy-independent phylogenetic random forests
Authors: Singh Gurdeep , Brass Andrew , Cruickshank Sheena M. , Knight Christopher G. 
Published: October 2019

AbstractGut microbiome analysis using 16S rRNA frequently focuses on summary statistics (e.g. diversity) or single taxonomic scales (e.g. Operational Taxonomic units, OTUs). This approach risks misinterpreting the phylogenetic or abundance scales of community differences (e.g. over-emphasising the role of single strains). We therefore constructed a 16S phylogenetic tree from mouse stool and colonic mucus communities. Random forest models, of all 428,234 clades, tested community differences among niches (stool versus mucus), host ages (6 versus 18 weeks), genotypes (wildtype versus colitis prone-mdr1a-/-) and social groups (co-housed siblings). Models discriminated all criteriaexcepthost genotype, where no community differences were found. Host social groups differed in abundant, low-level, taxa whereas intermediate phylogenetic and abundance scales distinguished ages and niches. Thus, treating evolutionary clades of microbes equivalently without reference to OTUs or taxonomy, clearly identifies whether and how gut microbial communities are distinct and provides a novel way to define functionally important bacteria.