bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic effect estimates in case-control studies when a continuous variable is omitted from the model
Authors: Sheng Ying , Huang Chiung-Yu , Lobach Siarhei , Zablotska Lydia , Lobach Iryna ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: September 2019

ABSTRACTLarge-scale genome-wide analyses scans provide massive volumes of genetic variants on large number of cases and controls that can be used to estimate the genetic effects. Yet, the sets of non-genetic variables available in publicly available databases are often brief. It is known that omitting a continuous variable from a logistic regression model can result in biased estimates of odds ratios (OR) (e.g., Gail et al (1984), Neuhaus et al (1993), Hauck et al (1991), Zeger et al (1988)). We are interested to assess what information is needed to recover the bias in the OR estimate of genotype due to omitting a continuous variable in settings when the actual values of the omitted variable are not available. We derive two estimating procedures that can recover the degree of bias based on a conditional density of the omitted variable or knowing the distribution of the omitted variable. Importantly, our derivations show that omitting a continuous variable can result in either under- or over-estimation of the genetic effects. We performed extensive simulation studies to examine bias, variability, false positive rate, and power in the model that omits a continuous variable. We show the application to two genome-wide studies of Alzheimer’s disease.Data Availability StatementThe data that support the findings of this study are openly available in the Database of Genotypes and Phenotypes at [https://www.ncbi.nlm.nih.gov/projects/gap/cgibin/study.cgi?study_id=phs000372.v1.p1], reference number [phs000372.v1.p1] and at the Alzheimer’s Disease Neuroimaging Initiative http://adni.loni.usc.edu/.
Comprehensive epigenome characterization reveals diverse transcriptional regulation across human vascular endothelial cells
Authors: Nakato Ryuichiro , Wada Youichiro , Nakaki Ryo , Nagae Genta , Katou Yuki , Tsutsumi Shuichi , Nakajima Natsu , Fukuhara Hiroshi , Iguchi Atsushi , Kohro Takahide , Kanki Yasuharu , Saito Yutaka , Kobayashi Mika , Izumi-Taguchi Akashi , Osato Naoki , Tatsuno Kenji , Kamio Asuka , Hayashi-Takanaka Yoko , Wada Hiromi , Ohta Shinzo , Aikawa Masanori , Nakajima Hiroyuki , Nakamura Masaki , McGee Rebecca C. , Heppner Kyle W. , Kawakatsu Tatsuo , Genno Michiru , Yanase Hiroshi , Kume Haruki , Senbonmatsu Takaaki , Homma Yukio , Nishimura Shigeyuki , Mitsuyama Toutai , Aburatani Hiroyuki , Kimura Hiroshi , Shirahige Katsuhiko 
Published: September 2019

ABSTRACTBackgroundEndothelial cells (ECs) make up the innermost layer throughout the entire vasculature. Their phenotypes and physiological functions are initially regulated by developmental signals and extracellular stimuli. The underlying molecular mechanisms responsible for the diverse phenotypes of ECs from different organs are not well understood.ResultsTo characterize the transcriptomic and epigenomic landscape in the vascular system, we cataloged gene expression and active histone marks in nine types of human ECs (generating 148 genome-wide datasets) and carried out a comprehensive analysis with chromatin interaction data. We identified 3,765 EC-specific enhancers, some of which were associated with disease-associated genetic variations. We also identified various candidate marker genes for each EC type. Notably, reflecting the developmental origins of ECs and their roles in angiogenesis, vasculogenesis and wound healing.ConclusionsWhile the importance of several HOX genes for early vascular development and adult angiogenesis in pathological conditions has been reported, a systematic analysis of the regulation and roles of HOX genes in mature tissue cells has been lacking. These datasets provide a valuable resource for understanding the vascular system and associated diseases.
Genome Tree of Life:Deep Burstof Organism Diversity
Authors: Choi JaeJin , Kim Sung-Hou 
Published: September 2019

AbstractAn organism Tree of Life (organism ToL) is a conceptual and metaphorical tree to capture a simplified narrative of the evolutionary course and kinship among the extant organisms of today. Such tree cannot be experimentally validated but may be reconstructed based on characteristics associated with the extant organisms. Since the whole genome sequence of an organism is, at present, the most comprehensivedescriptorof the organism, agenome Tolcan be an empirically derivable surrogate for the organism ToL. However, a genome ToL has been impossible to construct because of the practical reasons that experimentally determining the whole genome sequences of a large number of diverse organisms was technically impossible. Thus, for several decades,gene ToLs, based onselected genes, have been commonly used as a surrogate for the organisms ToL. This situation changed dramatically during the last several decades due to rapid advances in DNA sequencing technology. Here we describe the main features of a genome ToL that are different from those of the broadly accepted gene ToLs: (a) the first two organism groups to emerge are the founders of prokarya and eukarya, (b) they diversify into six large groups and all thefoundersof the groups haveemergedin a“Deep Burst”at the very beginning period of the emergence of Life on Earth and (c) other differences are notable in the order of emergence of smaller groups.Significance StatementTree of Lifeis a conceptual and metaphorical tree that captures a simplified narrative of theevolutionary courseandkinshipamong all living organisms of today. Since the whole genome sequence information of an organism is, at present, the most comprehensive description of the organism, we reconstructed aGenome Tree of Lifeusing the proteome information from the whole genomes of over 4000 different living organisms on Earth. It suggests that (a) the first two primitive organism groups to emerge are the founders of prokarya and eukarya, (b) they diversify into six large groups, and (c) all thefoundersof the groups haveemergedin a“Deep Burst”at the very beginning period of the emergence of Life on Earth.
Colour preferences of Spotted Wing Drosophila, Drosophila suzukii, under field conditions in various crops
Authors: Fahrentrapp Johannes , Roosjen Peter , Green David R. , Gregory Billy , Panassiti Bernd 
Published: September 2019

The authors have withdrawn this manuscript because of conflicting authorship views of an unnamed person claiming authorship. Therefore, the authors do not wish this work to be cited as reference for the project.However, the original results of the withdrawn preprint remain valid. If you have any questions, please contact the corresponding author (Johannes.fahrentrapp@zhaw.ch).
The Chikungunya virus nsP3 macro domain inhibits activation of the NF-κB pathway
Authors: Roberts Grace C. , Stonehouse Nicola J. , Harris Mark 
Published: September 2019

AbstractThe role of the chikungunya virus (CHIKV) non-structural protein 3 (nsP3) in the virus lifecycle is poorly understood. The protein comprises 3 domains. The N-terminus is a macro domain, biochemically characterised to bind both RNA and ADP-ribose, and to possess ADP-ribosyl hydrolase activity – an enzymatic activity that removes ADP-ribose from mono-ADP-ribosylated proteins. As ADP-ribosylation is important in the signalling pathway leading to activation of the transcription factor NF-κB, we sought to determine if the macro domain might perturb NF-κB signalling. We first show that CHIKV infection did not induce NF-κB activation, and could not block exogenous activation of the pathway via TNFα, although TNFα treatment did reduce virus titres. Ectopic expression of nsP3 was able to block TNFα-mediated NF-κB activation and this was dependent on the macro domain, as mutations previously shown to disrupt either ADP-ribose binding or hydrolase activity lost the ability to inhibit NF-κB activation. Lastly, we determined the phenotype of the macro domain mutants in the context of virus infection in a range of cell types. Our data are consistent with cell- and species-dependent roles of the macro domain, however, these phenotypes do not correlate with the ability to inhibit NF-κB activation suggesting that the macro domain plays multiple independent roles in the virus lifecycle.
OmicsOne: Associate Omics Data with Phenotypes in One-Click
Authors: Hu Yingwei , Ao Minghui , Zhang Hui 
Published: September 2019

AbstractThe rapid advancements of high-throughput “omics” technologies have brought huge amount of data to process during and after experiments. Multi-omic analysis facilitates a deeper interrogation of a dataset, and discovery of interesting genes, proteins, lipids, glycans, or metabolites, or pathways related to the corresponding phenotypes in a study. Many individual software tools have been developed to analyze and visualize the data. However, integrating multiple omics data analysis strategies and approaches in a single data processing pipeline is still a challenge task. OmicsOne is a software developed in R, Python and Jupyter Notebook that can achieve statistical analysis, machine learning, and data visualization on multi-‘omics’ data by taking the advantages of integrating the useful tools from individual software packages. OmicsOne can simplify “omics” data analysis, and delineate molecules, or pathways associated to interested phenotypes.
CaATP prolongs strong actomyosin binding and promotes futile myosin stroke
Authors: Ge Jinghua , Gargey Akhil , Nesmelova Irina V. , Nesmelov Yuri E. 
Published: September 2019

AbstractCalcium plays an essential role in muscle contraction, regulating actomyosin interaction by binding troponin of thin filaments. There are several buffers for calcium in muscle, and those buffers play a crucial role in the formation of the transient calcium wave in sarcomere upon muscle activation. One such calcium buffer in muscle is ATP. ATP is a fuel molecule, and the important role of MgATP in muscle is to bind myosin and supply energy for the power stroke. Myosin is not a specific ATPase, and CaATP also supports myosin ATPase activity. The concentration of CaATP in sarcomeres reaches 1% of all ATP available. Since 294 myosin molecules form a thick filament, naïve estimation gives three heads per filament with CaATP bound, instead of MgATP. We found that CaATP dissociates actomyosin slower than MgATP, thus increasing the time of the strong actomyosin binding. The rate of the basal CaATPase is faster than that of MgATPase, myosin readily produces futile stroke with CaATP. When calcium is upregulated, as in malignant hyperthermia, kinetics of myosin and actomyosin interaction with CaATP suggest that myosin CaATPase activity may contribute to observed muscle rigidity and enhanced muscle thermogenesis.
Developmental Reactive Oxygen Species Target Histone Methylation to Individualize Stress resistance and Lifespan
Authors: Bazopoulou Daphne , Knoefler Daniela , Zheng Yongxin , Ulrich Kathrin , Oleson Bryndon , Xie Lihan , Kim Minwook , Kaufmann Anke , Lee Young-Tae , Dou Yali , Chen Yong , Quan Shu , Jakob Ursula 
Published: September 2019

SummaryA central aspect of aging research concerns the question as to when individuality in lifespan arises and what mechanism(s) promote and potentially manifest individual differences in longevity. We have now discovered that a transient increase in reactive oxygen species (ROS), which occurs naturally during early development in a subpopulation of synchronized Caenorhabditis elegans, sets processes into motion that increase stress resistance, improve redox homeostasis and ultimately prolong lifespan in those animals. We find that these effects are linked to the global ROS-mediated decrease in developmental histone H3K4me3 levels. Studies in HeLa cells confirmed that global H3K4me3 levels are ROS-sensitive, and that depletion of H3K4me3 levels increases stress resistance in mammalian cell cultures. In vitro studies identified the Set1-MML histone methyltransferase as the redox sensitive unit of the H3K4-trimethylating COMPASS complex. Our findings imply a novel link between early-life events, ROS-sensitive epigenetic marks, stress resistance and lifespan.
DNA breaks-mediated cost reveals RNase HI as a new target for selectively eliminating antibiotic resistance
Authors: Balbontín Roberto , Frazão Nelson , Gordo Isabel 
Published: September 2019

AbstractAntibiotic resistance often generates a fitness cost to bacteria in drug-free environments. Understanding the causes of the cost is considered the Holy Grail in the antibiotic resistance field, as it is the main determinant of the prevalence of resistances upon reducing antibiotics use. We show that DNA breaks can explain most of the variation in the cost of resistances common in pathogens. Here we demonstrate that targeting the RNase that degrades R-loops, which cause DNA breaks, exacerbates the cost of resistance. Consequently, lack of RNase HI function drives resistant clones to extinction in populations with high initial frequency of resistance, both in laboratory conditions and in a mouse model of gut colonization. Thus, RNase HI provides a target specific against resistant bacteria, which we validate using a repurposed drug. In summary, we revealed key mechanisms underlying the cost of antibiotic resistance that can be exploited to specifically eliminate resistant bacteria.
miR-206 Enforces a Slow Muscle Phenotype
Authors: Bjorkman Kristen K. , Guess Martin G. , Harrison Brooke C. , Polmear Michael M. , Peter Angela K. , Leinwand Leslie A. 
Published: September 2019

AbstractStriated muscle is a highly specialized collection of tissues with contractile properties varying according to functional needs. Although muscle fiber types are established postnatally, lifelong plasticity facilitates stimulus-dependent adaptation. Functional adaptation requires molecular adaptation, partially provided by miRNA-mediated post-transcriptional regulation. miR-206 is a muscle-specific miRNA enriched in slow muscles. We investigated whether miR-206 drives the slow muscle phenotype or is merely an outcome. We found that miR-206 expression increases in both physiologic (including female sex and endurance exercise) and pathologic conditions that promote a slow phenotype. Consistent with that observation, the slow soleus muscle of male miR-206 knockout mice displays a faster phenotype than wild-type mice. Moreover, their left ventricles have a faster myosin profile accompanied by male-specific dilation and systolic dysfunction. Thus, miR-206 appears necessary to enforce a slow skeletal and cardiac muscle phenotype and to play a key role in muscle sexual dimorphisms.
Design and analysis of the 4-anilino-quin(az)oline kinase inhibition profiles of GAK/SLK/STK10 using quantitative structure activity relationships
Authors: Asquith Christopher R. M. , Laitinen Tuomo , Bennett James M. , Wells Carrow I. , Elkins Jonathan M. , Zuercher William J. , Tizzard Graham , Poso Antti 
Published: September 2019

AbstractThe 4-anilino-quinoline and 4-anilino-quinazoline ring systems have been the focus of significant efforts in prior kinase drug discovery programs, which have led to approved medicines. Broad kinome profiles of these compounds have now been assessed with the advent of advanced screening technologies. These ring systems while, originally designed for specific targets including epidermal growth factor receptor (EGFR), actually display a number of potent collateral kinase targets, some of which have been associated with negative clinical outcomes. We have designed and synthesized a series of 4-anilino-quin(az)olines in order to better understand the structure activity relationships of three main collateral kinase targets of quin(az)oline-based kinase inhibitors: cyclin G associated kinase (GAK), STE20-like serine/threonine-protein kinase (SLK) and Serine/threonine-protein kinase 10 (STK10) through a series of quantitative structure activity relationship (QSAR) analysis and water mapping of the kinase ATP binding sites.
Transcriptome of the parasitic flatwormSchistosoma mansoniduring intra-mammalian development
Authors: Wangwiwatsin Arporn , Protasio Anna V. , Wilson Shona , Owusu Christian , Holroyd Nancy E. , Sanders Mandy J. , Keane Jacqueline , Doenhoff Mike J. , Rinaldi Gabriel , Berriman Matthew 
Published: September 2019

AbstractSchistosomes are parasitic blood flukes that survive for many years within the mammalian host vasculature. How the parasites establish a chronic infection in the hostile bloodstream environment, whilst evading the host immune response is poorly understood. The parasite develops morphologically and grows as it migrates to its preferred vascular niche, avoiding or repairing damage from the host immune system. In this study, we investigated temporal changes in gene expression during the intra-mammalian development ofSchistosoma mansoni. RNA-seq data were analysed from parasites developing in the lung through to egg-laying mature adult worms, providing a comprehensive picture ofin vivointra-mammalian development. Remarkably, genes involved in signalling pathways, developmental control, and adaptation to oxidative stress were up-regulated in the lung stage. The data also suggested a potential role in immune evasion for a previously uncharacterised gene. This study not only provides a large and comprehensive data resource for the research community, but also reveals new directions for further characterising host–parasite interactions that could ultimately lead to new control strategies for this neglected tropical disease pathogen.Author SummaryThe life cycle of the parasitic flatwormSchistosoma mansoniis split between snail and mammalian (often human) hosts. An infection can last for more than 10 years, during which time the parasite physically interacts with its mammalian host as it moves through the bloodstream, travelling through the lungs and liver, to eventually establish a chronic infection in the blood vessels around the host gut. Throughout this complex journey, the parasite develops from a relatively simple larval form into a more complex, sexually reproducing adult. To understand the molecular basis of parasite interactions with the host during this complex journey we have produced genome-wide expression data from developing parasites. The parasites were collected from experimentally-infected mice over its developmental time-course from the poorly studied lung stage, to the fully mature egg-laying adult worm. The data highlight many genes involved in processes known to be associated with key stages of the infection. In addition, the gene expression data provide a unique view of interactions between the parasite and the immune system in the lung, including novel players in host-parasite interactions. A detailed understanding of these processes may provide new opportunities to design intervention strategies, particularly those focussed on the early stages of the infection that are not targeted by current chemotherapy.
Disruption to NKCC1 impairs the response of myelinating Schwann cells to neuronal activity and leads to severe peripheral nerve pathology
Authors: Kegel Linde , Marshall-Phelps Katy LH , Baraban Marion , Almeida Rafael G , Rubio-Brotons Maria , Klingseisen Anna , Benito-Kwiecinski Silvia , Early Jason J , Bin Jenea , Livesey Matthew R , Poole Richard J , Lyons David A 
Published: September 2019

AbstractMyelinating Schwann cells of the peripheral nervous system (PNS) express numerous ion channels and transporters, and have the capacity to respond to neuronal activity. However, it remains unknown how the response of Schwann cells to neuronal activity affects peripheral nerve formation, health or function in vivo. Through a genetic screen in zebrafish, we identified a mutant,ue58, with severe disruption to the morphology of myelin along peripheral nerves and associated nerve oedema. Molecular analyses indicated that this phenotype was caused by the loss of function of a previously uncharacterized gene,slc12a2b, which encodes a zebrafish paralog of the solute carrier NKCC1. NKCC1 is a co-transporter of Na+, K+, and Cl−ions and water, typically from the extracellular space into cells. Upon impairingslc12a2bfunction, constitutively, or specifically in neurons or myelinating Schwann cells, we observed disruption to myelin and nerve oedema. Strikingly, we found that treatment ofslc12a2bmutants with TTX completely prevented the emergence of these pathologies. Furthermore, TTX treatment rescued pathology in animals with cell-type specific loss ofslc12a2bfrom myelinating Schwann cells. Together our data indicate that NKCC1 regulates ion homeostasis following neuronal activity and that this is required to maintain myelinated axon and peripheral nerve integrity.
Loss of Cdc13 causes genome instability by a deficiency in replication-dependent telomere capping
Authors: Langston Rachel E , Palazzola Dominic , Bonnell Erin , Wellinger Raymund J. , Weinert Ted 
Published: September 2019

AbstractIn budding yeast, Cdc13, Stn1, and Ten1 form a telomere binding heterotrimer dubbed CST. Here we investigate the role of Cdc13/CST in maintaining genome stability, using a Chr VII disome system that can generate recombinants, loss, and enigmatic unstable chromosomes. In cells expressing a temperature sensitiveCDC13allele,cdc13F684S, unstable chromosomes frequently arise due to problems in or near a telomere. Hence, when Cdc13 is defective, passage through S phase causes Exo1-dependent ssDNA and unstable chromosomes, which then are the source for whole chromosome instability events (e.g. recombinants, chromosome truncations, dicentrics, and/or loss). Specifically, genome instability arises from a defect in Cdc13’s replication-dependent telomere capping function, not Cdc13s putative post-replication telomere capping function. Furthermore, the unstable chromosomes form without involvement of homologous recombination nor non-homologous end joining. Our data suggest that a Cdc13/CST defect in semi-conservative replication near the telomere leads to ssDNA and unstable chromosomes, which then are lost or subject to complex rearrangements. This system defines a links between replication-dependent chromosome capping and genome stability in the form of unstable chromosomes.