bluuebunny/crossref_metadata_2025_split huggingface dataset:
Shared genetic contribution to type 1 and type 2 diabetes risk
Authors: Aylward Anthony , Chiou Joshua , Okino Mei-Lin , Kadakia Nikita , Gaulton Kyle J 
Published: May 2018

AbstractThe role of shared genetic risk in the etiology of type 1 diabetes (T1D) and type 2 diabetes (T2D) and the mechanisms of these effects is unknown. In this study, we generated T1D association data of 15k samples imputed into the HRC reference panel which we compared to T2D association data of 159k samples imputed into 1000 Genomes. The effects of genetic variants on T1D and T2D risk at known loci and genome-wide were positively correlated, which we replicated using data from the UK Biobank and clinically-defined diabetes in the WTCCC. Increased risk of T1D and T2D was correlated with higher fasting insulin and fasting glucose level and decreased birth weight, among T1D- and T2D-specifc correlations, and T1D and T2D associated variants were enriched in regulatory elements for pancreatic, insulin resistance (adipose, CD19+ B cell), and developmental (CD184+ endoderm) cell types. We fine-mapped causal variants at known T1D and T2D loci and found evidence for co-localization at five signals, four of which had same direction of effect, including CENPW and GLIS3. Shared risk variants at GLIS3 and other signals were associated with measures of islet function, while CENPW was associated with early growth, and we identified shared risk variants at GLIS3 in islet accessible chromatin with allelic effects on islet regulatory activity. Our findings support shared genetic risk involving variants affecting islet function as well as insulin resistance, growth and development in the etiology of T1D and T2D.
Combining landscape genomics and ecological modelling to investigate local adaptation of indigenous Ugandan cattle to East Coast fever
Authors: Vajana Elia , Barbato Mario , Colli Licia , Milanesi Marco , Rochat Estelle , Fabrizi Enrico , Mukasa Christopher , Del Corvo Marcello , Masembe Charles , Muwanika Vincent , Kabi Fredrick , Sonstegard Tad Stewart , Jay Huson Heather , Negrini Riccardo , Joost Stéphane , Ajmone-Marsan Paolo ,   on behalf of The NextGen Consortium^
Published: May 2018

AbstractEast Coast fever (ECF) is a fatal sickness affecting cattle populations of eastern, central, and southern Africa. The disease is transmitted by the tickRhipicephalus appendiculatus, and caused by the protozoanTheileria parva parva, which invades host lymphocytes and promotes their clonal expansion. Importantly, indigenous cattle show tolerance to infection in ECF-endemically stable areas. Here, the putative genetic bases underlying ECF-tolerance were investigated using molecular data and epidemiological information from 823 indigenous cattle from Uganda. Vector distribution and host infection risk were estimated over the study area and subsequently tested as triggers of local adaptation by means of landscape genomics analysis. We identified 41 and seven candidate adaptive loci for tick resistance and infection tolerance, respectively. Among the genes associated with the candidate adaptive loci arePRKG1andSLA2.PRKG1was already described as associated with tick resistance in indigenous South African cattle, due to its role into inflammatory response.SLA2 is part of the regulatory pathways involved into lymphocytes’ proliferation. Additionally, local ancestry analysis suggested the zebuine origin of the genomic region candidate for tick resistance.Author summaryThe tick-borne parasiteTheileria parva parvainfects cattle populations of eastern, central and southern Africa, by causing a highly fatal pathology called “East Coast fever”. The disease is especially severe for the exotic breeds imported to Africa, as well as outside the endemic areas of East Africa. In these regions, indigenous cattle populations can survive to infection, and this tolerance might result from unique adaptations evolved to fight the disease. We investigated this hypothesis by using a method named “landscape genomics”, with which we compared the genetic characteristics of indigenous Ugandan cattle coming from areas at different infection risk, and located genomic sites potentially attributable to tolerance. In particular, the method pinpointed two genes, one (PRKG1) involved into inflammatory response and potentially affecting East Coast fever vector attachment, the other (SLA2) involved into lymphocytes proliferation, a process activated byT. parva parvainfection. Our findings can orientate future research on the genetic basis of East Coast fever-tolerance, and derive from a general method that can be applied to investigate adaptation in analogous host-vector-parasite systems. Characterization of the genetic factors underlying East Coast-fever-tolerance represents an essential step towards enhancing sustainability and productivity of local agroecosystems.
HiCAGE : an R package for large-scale annotation and visualization of 3C-based genomic data
Authors: Workman Michael J. , Silva Tiago C. , Coetzee Simon G. , Hazelett Dennis J. 
Published: May 2018

AbstractChromatin interactions measured by the 3C-based family of next generation technologies are becoming increasingly important for measuring the physical basis for regulatory interactions between different classes of functional domains in the genome. Software is needed to streamline analyses of these data and integrate them with custom genome annotations, RNA-seq, and gene ontologies. We introduce a new R package compatible with Bioconductor—Hi-C Annotation and Graphics Ensemble (HiCAGE)—to perform these tasks with minimum effort. In addition, the package contains a shiny/R web app interface to provide ready access to its functions.Availability and ImplementationThe software is implemented in R and is freely available under GPLv3. HiCAGE runs in R (version 3.4) and is freely available through github (https://github.com/mworkman13/HiCAGE) or on the web (https://junkdnalab.shinyapps.io/hicage).
Estrogen Signaling in Arcuate Kiss1 Neurons Suppresses a Sex-Dependent Circuit That Promotes Dense Strong Bones in Female Mice
Authors: Herber Candice B. , Krause William C. , Wang Liping , Bayrer James R. , Li Alfred , Schmitz Matthew , Fields Aaron , Ford Breanna , Reid Michelle S. , Nomura Daniel K. , Nissenson Robert A. , Correa Stephanie M. , Ingraham Holly A. 
Published: May 2018

AbstractCentral estrogen signaling coordinates energy expenditure, reproduction, and in concert with peripheral estrogen impacts skeletal homeostasis in female rodents. Here, we ablate estrogen receptor alpha (ERα) in the medial basal hypothalamus and find a robust bone phenotype only in female mice that results in exceptionally strong trabecular and cortical bones, whose density surpasses other reported mouse models. Stereotaxic guided deletion of ERα in the arcuate nucleus increases bone mass in both intact and estrogen-depleted females, confirming the central role of estrogen signaling in this sex-dependent bone phenotype. Loss of ERα activity in kisspeptin (Kiss1)-expressing cells is sufficient to recapitulate the bone phenotype, identifying Kiss1 neurons as a critical node in this powerful neuroskeletal circuit. We propose that this newly identified female brain-to-bone pathway exists as a homeostatic regulator to divert calcium and energy stores from bone building when energetic demands are high. Our work reveals a previously unknown target for the treatment of age-related bone disease.
Genome Sequence of Indian Peacock Reveals the Peculiar Case of a Glittering Bird
Authors: Jaiswal Shubham K. , Gupta Ankit , Saxena Rituja , Vishnu Prasoodanan P. K. , Sharma Ashok K. , Mittal Parul , Roy Ankita , Shafer Aaron B.A. , Vijay Nagarjun , Sharma Vineet K. 
Published: May 2018

ABSTRACTThe unique ornamental features and extreme sexual traits of Peacock have always intrigued the scientists. However, the genomic evidence to explain its phenotype are yet unknown. Thus, we report the first genome sequence and comparative analysis of peacock with the available high-quality genomes of chicken, turkey, duck, flycatcher and zebra finch. The candidate genes involved in early developmental pathways including TGF-β, BMP, and Wnt signaling pathway, which are also involved in feather patterning, bone morphogenesis, and skeletal muscle development, showed signs of adaptive evolution and provided useful clues on the phenotype of peacock. The innate and adaptive immune components such as complement system and T-cell response also showed signs of adaptive evolution in peacock suggesting their possible role in building a robust immune system which is consistent with the between species predictions of Hamilton-Zuk hypothesis. This study provides novel genomic and evolutionary insights into the molecular understanding towards the phenotypic evolution of Indian peacock.
Spatial variation in exploited metapopulations obscures risk of collapse
Authors: Okamoto Daniel K , Hessing-Lewis Margot , Samhouri Jameal F , Shelton Andrew O , Stier Adrian , Levin Philip S , Salomon Anne K 
Published: May 2018

AbstractUnanticipated declines among exploited species have commonly occurred despite harvests that appeared sustainable prior to collapse. This is particularly true in the oceans where spatial scales of management are often mismatched with spatially complex metapopulations. We explore causes, consequences and potential solutions for spatial mismatches in harvested metapopulations in three ways. First, we generate novel theory illustrating when and how harvesting metapopulations increases spatial variability and in turn masks local scale volatility. Second, we illustrate why spatial variability in harvested metapopulations leads to negative consequences using an empirical example of a Pacific herring metapopulation. Finally, we construct a numerical management strategy evaluation model to identify and highlight potential solutions for mismatches in spatial scale and spatial variability. Our results highlight that spatial complexity can promote stability at large scales, however ignoring spatial complexity produces cryptic and negative consequences for people and animals that interact with resources at small scales. Harvesting metapopulations magnifies spatial variability, which creates discrepancies between regional and local trends while increasing risk of local population collapses. Such effects asymmetrically impact locally constrained fishers and predators, which are more exposed to risks of localized collapses. Importantly, we show that dynamically optimizing harvest can minimize local risk without sacrificing yield. Thus, multiple nested scales of management may be necessary to avoid cryptic collapses in metapopulations and the ensuing ecological, social and economic consequences.
Mobile-CRISPRi: Enabling Genetic Analysis of Diverse Bacteria
Authors: Peters Jason M. , Koo Byoung-Mo , Patino Ramiro , Heussler Gary E. , Hearne Cameron C. , Inclan Yuki F. , Hawkins John S. , Lu Candy H. S. , Harden M. Michael , Osadnik Hendrik , Peters Joseph E. , Engel Joanne N. , Dutton Rachel J. , Grossman Alan D. , Gross Carol A. , Rosenberg Oren S. 
Published: May 2018

Introductory paragraphThe vast majority of bacteria, including human pathogens and microbiome species, lack genetic tools needed to systematically associate genes with phenotypes. This is the major impediment to understanding the fundamental contributions of genes and gene networks to bacterial physiology and human health. CRISPRi, a versatile method of blocking gene expression using a catalytically inactive Cas9 protein (dCas9) and programmable single guide RNAs (sgRNAs), has emerged as a powerful genetic tool to dissect the functions of essential and non-essential genes in species ranging from bacteria to human. However, the difficulty of establishing effective CRISPRi systems in non-model bacteria is a major barrier to its widespread use to dissect bacterial gene function. Here, we establish “Mobile-CRISPRi”, a suite of CRISPRi systems that combine modularity, stable genomic integration and ease of transfer to diverse bacteria by conjugation. Focusing predominantly on human pathogens associated with antibiotic resistance, we demonstrate the efficacy of Mobile-CRISPRi in Proteobacteria and Firmicutes at the individual gene scale by examining drug-gene synergies and at the library scale by systematically phenotyping conditionally essential genes involved in amino acid biosynthesis. Mobile-CRISPRi enables genetic dissection of non-model bacteria, facilitating analyses of microbiome function, antibiotic resistances and sensitivities, and comprehensive screens for host-microbe interactions.
A role for differential gene regulation in the rapid diversification of melanic plumage coloration in the dark-eyed junco (Junco hyemalis)
Authors: Abolins-Abols Mikus , Kornobis Etienne , Ribeca Paolo , Wakamatsu Kazumasa , Peterson Mark P. , Ketterson Ellen D. , Milá Borja 
Published: May 2018

ABSTRACTColor plays a prominent role in reproductive isolation, therefore understanding the proximal basis of pigmentation can provide insight into speciation. Subspecies of the dark-eyed junco (Junco hyemalis) have evolved marked differences in plumage coloration since the Last Glacial Maximum, yet whether color differences are caused by mutations in coding regions of expressed genes or are instead the result of regulatory differences remains unknown. To address this question, we studied the pigment composition and the genetic basis of coloration in two divergent subspecies, the slate-colored and Oregon juncos. We used HPLC and light microscopy to investigate pigment composition and deposition in feathers from four body areas. We then used RNAseq to compare the relative roles of differential gene expression in developing feathers and sequence divergence in transcribed loci under common garden conditions. Junco feathers differed in eumelanin and pheomelanin content and distribution. Within subspecies, in lighter feathers melanin synthesis genes were downregulated (including PMEL, TYR, TYRP1, OCA2, MLANA), ASIP was upregulated. Feathers from different body regions also showed differential expression of HOX and Wnt genes. Feathers from the same body regions that differed in color between the two subspecies showed differential expression of ASIP and three other genes (MFSD12, KCNJ13, HAND2) associated with pigmentation in other taxa. Sequence variation in the expressed genes was not related to color differences. Our findings support the hypothesis that differential regulation of a few genes can account for marked differences in coloration, a mechanism that may underlie the rapid diversification of juncos.
Quantifying heterogeneity of stochastic gene expression
Authors: Iida Keita , Obata Nobuaki , Kimura Yoshitaka 
Published: May 2018

AbstractThe heterogeneity of stochastic gene expression, which refers to the temporal fluctuation of the gene product and its cell-to-cell variation, has attracted considerable interest from biologists, physicists, and mathematicians. The dynamics of protein production and degradation have been modeled as random processes with transition probabilities. However, there is a gap between theory and phenomena, particularly in terms of analytical formulation and parameter estimation. In this study, we propose a theoretical framework in which we present a basic model of a gene regulatory system, derive a steady-state solution, and provide a Bayesian approach for estimating the model parameters from single-cell experimental data. The proposed framework is demonstrated to be applicable for various scales of single-cell experiments at both the mRNA and protein levels, and it is useful for comparing kinetic parameters across species, genomes, and cell strains.
Automated Tracking of Biopolymer Growth and Network Deformation with TSOAX
Authors: Xu Ting , Langouras Christos , Koudehi Maral Adeli , Vos Bart E. , Wang Ning , Koenderink Gijsje H. , Huang Xiaolei , Vavylonis Dimitrios 
Published: May 2018

AbstractStudies of how individual semi-flexible biopolymers and their network assemblies change over time reveal dynamical and mechanical properties important to the understanding of their function in tissues and living cells. Automatic tracking of biopolymer networks from fluorescence microscopy time-lapse sequences facilitates such quantitative studies. We present an open source software tool that combines a global and local correspondence algorithm to track biopolymer networks in 2D and 3D, using stretching open active contours. We demonstrate its application in fully automated tracking of elongating and intersecting actin filaments, detection of loop formation and constriction of tilted contractile rings in live cells, and tracking of network deformation under shear deformation.
Decoupling the impact of microRNAs on translational repression versus RNA degradation in embryonic stem cells
Authors: Freimer Jacob W. , Hu TJ , Blelloch Robert 
Published: May 2018

ABSTRACTTranslation and mRNA degradation are intimately connected, yet the mechanisms that regulate them are not fully understood. Here we studied the link between translation and mRNA stability in embryonic stem cells (ESCs). Transcripts showed a wide range of stabilities, which correlated with their translation levels. The protein DHH1 links translation to mRNA stability in yeast; however loss of the mammalian homolog, DDX6, in ESCs did not disrupt the correlation across transcripts. Instead, the loss of DDX6 led to upregulated translation of microRNA targets, without concurrent changes in mRNA stability. TheDdx6knockout cells were phenotypically and molecularly similar to cells lacking all microRNAs (Dgcr8knockout ESCs). These data show that the loss of DDX6 can separate the two canonical functions of microRNAs: translational repression and transcript destabilization. Furthermore, these data uncover a central role for translational repression independent of transcript destabilization in defining the downstream consequences of microRNA loss.
CSB-dependent CDK9 degradation and RNA Polymerase II phosphorylation during Transcription Coupled Repair
Authors: Donnio Lise-Marie , Lagarou Anna , Sueur Gabrielle , Mari Pierre-Olivier , Giglia-Mari Giuseppina 
Published: May 2018

AUTHOR SUMMARYDNA lesions block cellular processes such as transcription, inducing apoptosis, tissue failures and premature ageing. To counteract the deleterious effects of DNA damage, cells are equipped with various DNA repair pathways. Transcription Coupled Repair specifically removes helix-distorting DNA adducts in a coordinated multi-step process. This process has been extensively studied, however once the repair reaction is accomplished, little is known about how transcription restarts. In this study, we show that, after UV irradiation, the CDK9/CyclinT1 kinase unit is specifically released from the HEXIM1 complex and that this released fraction is degraded in the absence of CSB. We determine that UV-irradiation induces a specific Ser2 phosphorylation of the RNA polymerase II and that this phosphorylation is CSB dependent. Surprisingly CDK9 is not responsible for this phosphorylation but instead plays a non-enzymatic role in transcription restart after DNA repair.
Site-specific PEGylation crosslinking of L-asparaginase subunits to improve its therapeutic efficiency
Authors: Ramirez-Paz Josell , Saxena Manoj , Delinois Louis J. , Joaquín-Ovalle Freisa M. , Lin Shiru , Chen Zhongfang , Rojas-Nieves Virginia A. , Griebenow Kai 
Published: May 2018

AbstractL-Asparaginase is an enzyme successfully being used in the treatment of acute lymphoblastic leukemia, acute myeloid leukemia, and non-Hodgkin’s lymphoma. However, some disadvantages still limit its full application potential, e.g., allergic reactions, pancreatitis, and blood clotting impairment. Therefore, much effort has been directed at improving its performance. A popular strategy is to randomly conjugate L-asparaginase with mono-methoxy polyethylene glycol, which became a commercial FDA approved formulation widely used in recent years. To improve this formulation by PEGylation, herein we performed cysteine-directed site-specific conjugation of the four L-asparaginase subunits to prevent dissociation-induced loss of activity. The conjugation sites were selected at surface-exposed positions on the protein to avoid affecting the catalytic activity. Three conjugates were obtained using different linear PEGs of 1000, 2000, and 5000 g/mol, with physical properties ranging from a semi-solid gel to a fully soluble state. The soluble-conjugate exhibited higher catalytic activity than the non-conjugated mutant, and the same activity than the native enzyme. Site-specific crosslinking of the L-asparaginase subunits produced a higher molecular weight conjugate compared to the native tetrameric enzyme. This strategy might improve L-asparaginase efficiency for leukemia treatment by reducing glomerular filtration due to the increase in hydrodynamic size thus extending half-live, while at the same time retaining full catalytic activity.
The recognition and expectations of ex-inpatients of mental health services: A web-based questionnaire survey in Japan
Authors: Shiina Akihiro , Ojio Yasutaka , Sato Aiko , Sugiyama Naoya , Iyo Masaomi , Fujii Chiyo 
Published: May 2018

AbstractConcern about mental health issues and the treatment of mentally disordered offenders attracts a lot of public attention. This study aimed to gather the experiences and opinions of people who have experienced admission to a psychiatric ward in order to understand their reaction to, and understanding of, the legislation behind the involuntary admission of psychiatric patients. A web-based questionnaire survey was conducted with a total of 379 participants, using a cross-sectional, exploratory design. The data were analyzed using a chi-square test, Fisher’s exact test, and a logistic regression analysis. According to the results, many patients were satisfied with their psychiatric admission, however, few participants said that they had been given adequate explanation for their involuntary treatment. Most participants expected qualified aids after discharge, although the prospect of a regular visit from an official was not entirely supported by the participants. Patient satisfaction was relevant to the discussion of their needs after discharge and in developing a crisis plan during admission. These findings suggests that psychiatric patients accept inpatient treatment as long as they receive an adequate explanation. More qualified care such as relapse prevention would be expected to lead to better satisfaction. In order for them to welcome regular visits from an official, patients may need more information and discussion.
Spinal astrocyte-neuron lactate shuttle contributes to the PACAP/PAC1 receptor-induced nociceptive behaviors
Authors: Kambe Yuki , Yokai Masafumi , Takasaki Ichiro , Kurihara Takashi , Miyata Atsuro 
Published: May 2018

AbstractPreviously, we showed that spinal pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1 receptor signaling triggers long-lasting pain behaviors through astroglial activation. Since astrocyte-neuron lactate shuttle (ANLS) could be essential for long-term synaptic facilitation, we aimed to elucidate a possible involvement of spinal ANLS in the development of the PACAP/PAC1 receptor-induced pain behaviors. A single intrathecal administration of PACAP induced short-term spontaneous aversive behaviors, followed by long-lasting mechanical allodynia. These pain behaviors were inhibited by DAB, an inhibitor of glycogenolysis, and this inhibition was reversed by simultaneous L-lactate application. In the cultured spinal astrocytes, the PACAP-evoked glycogenolysis and lactate secretion were inhibited by a protein kinase C (PKC) inhibitor, and the PKC inhibitor attenuated the PACAP-induced pain behaviors. Finally, an inhibitor for the monocarboxylate transporters blocked the lactate secretion from the spinal astrocytes and inhibited the PACAP-induced pain behaviors. These results suggested that PAC1 receptor-PKC-ANLS signaling is involved in the PACAP-induced pain behaviors.