bluuebunny/crossref_metadata_2025_split huggingface dataset:
Social hierarchy regulates ocular dominance plasticity in adult male mice
Authors: Balog Jenny , Hintz Franziska , Isstas Marcel , Teichert Manuel , Winter Christine , Lehmann Konrad 
Published: March 2019

ABSTRACTWe here show that social rank, as assessed by competition for a running wheel, influences ocular dominance plasticity in adult male mice. Dominant animals showed a clear ocular dominance shift after four days of MD, whereas their submissive cage mates did not. NMDA receptor activation, reduced GABA inhibition, and serotonin transmission were necessary for this plasticity, but not sufficient to explain the difference between dominant and submissive animals. In contrast, prefrontal dopamine concentration was higher in dominant than submissive mice, and systemic manipulation of dopamine transmission bidirectionally changed ocular dominance plasticity. Thus, we could show that a social hierarchical relationship influences ocular dominance plasticity in the visual cortex via higher-order cortices, most likely the medial prefrontal cortex. Further studies will be needed to elucidate the precise mechanisms by which this regulation takes place.
Pax6 and KDM5C co-occupy a subset of developmentally critical genes including Notch signaling regulators in neural progenitors
Authors: Gaudenzi Giulia , Dethlefsen Olga , Walfridsson Julian , Hermanson Ola 
Published: March 2019

ABSTRACTPax6 is a key transcription factor in neural development. While generally viewed as a transcriptional activator, mechanisms underlying Pax6 function as a repressor is less well understood. Here we show that Pax6 acts as a direct repressor of transcription associated with a decrease in H3K4me3 levels. Genome wide analysis of the co-occupancy of the H3K4 demethylase KDM5C and Pax6 with H3K4me3-negative regions revealed 177 peaks on 131 genes. Specific analysis of these Pax6/KDM5C/H3K4me3-peaks unveiled a number of genes associated with Notch signaling, including Dll1, Dll4, and Hes1. RNA knockdown of PAX6/KDM5C in human neural progenitors resulted in increased DLL4 gene expression, decreased DLL1 expression, and no significant effect on HES1 mRNA levels, differences that could be due to gene-specific variations in the chromatin landscape. Our findings suggest that PAX6 and KDM5C co-regulate a subset of genes implicated in brain development, including members of the Notch signaling family.
Higher order analysis of gene correlations by tensor decomposition
Authors: Yahyanejad Farzane 
Published: March 2019

AbstractThis study advances our understanding of inter- and intra-pathways higher order signaling in the cellular system and it leads to new discovery of multiple intracellular structures in signal transduction pathways in yeast Saccharomyces. We present a new tensor decomposition algorithm in reconstructing the pathways based on higher correlations among genes that compose a cellular system. The higher order gene correlation (HOGC) analysis has the power to elucidate gene’s higher interaction dependencies which has been barely understood. Recent studies i.e. [24] have experimentally revealed that multiple signaling proteins, yet sometimes infinite, may assemble to meaningful structure to transmit a receptor activation information. In this paper we reveal 3-order genomic correlations among significant component of the cellular system. This is the first time such a systematic and computational model provided for analysis of higher order correlations among genes. We use new fast algorithm to formulate a genes × genes × genes × decorrelated rank-1 sub-tensors (complexes) which can be associated with functionally independent pathways. Then we model higher order tensor decomposition which is constructed by K tensors of genes × genes × genes. Each new tensor is constructed by an orthogonal projection of data signal onto a designated basis signal to keep common sub-tensors in both signals. Our model for decomposing tensor order-4 approximates series of tensors as linear components of deccorelated rank-1 sub-tensors over tensor of order-3 and rank-3 triplings among sub-tensors. The linear components represent intra-pathway in cell signaling and triplings implicate inter-pathways higher order signaling. Through structural studies of inter- and intra-higher order signaling pathways, we uncover different scenario that involves triple formation of signaling proteins into higher order signaling machines for transmission of receptor activation information to cellular responses.
Metabolic reprogramming from glycolysis to amino acid utilization in cardiac HIF1α deficient mice
Authors: Menendez-Montes Ivan , Escobar Beatriz , Palacios Beatriz , Gomez Manuel J. , Bonzon Elena , Ferrarini Alessia , Alonso Ana Vanessa , Jimenez-Borreguero Luis Jesus , Vázquez Jesus , Martin-Puig Silvia 
Published: March 2019

AbstractRationaleHypoxia is an important environmental cue implicated in several physiopathological processes, including heart development. Several mouse models of activation or inhibition of hypoxia have been previously described. While gain of function models have been extensively characterized and indicate that HIF1 signaling needs to be tightly regulated to ensure a proper cardiac development, there is lack of consensus in the field about the functional outcomes of HIF1α loss.ObjectiveIn this study, we aim to assess the consequences of cardiac deletion of HIF1α during heart development and identify the cardiac adaptations to HIF1 loss.Methods and ResultsHere, we used a conditional deletion model ofHif1ain NKX2.5+cardiac progenitors. By a combination of histology, electron microscopy, massive gene expression studies, proteomics, metabolomics and cardiac imaging, we found that HIF1α is dispensable for cardiac development.Hif1aloss results in glycolytic inhibition in the embryonic heart without affecting normal cardiac growth. However, together with a premature increase in mitochondrial number by E12.5, we found global upregulation of amino acid transport and catabolic processes. Interestingly, this amino acid catabolism activation is transient and does not preclude the normal cardiac metabolic switch towards fatty acid oxidation (FAO) after E14.5. Moreover,Hif1aloss is accompanied by an increase in ATF4, described as an important regulator of several amino acid transporters.ConclusionsOur data indicate that HIF1α is not required for normal cardiac development and suggest that additional mechanisms can compensateHif1aloss. Moreover, our results reveal the metabolic flexibility of the embryonic heart at early stages of development, showing the capacity of the myocardium to adapt its energy source to satisfy the energetic and building blocks demands to achieve normal cardiac growth and function. This metabolic reprograming might be relevant in the setting of adult cardiac failure.
Pan-filovirus one-step reverse transcription-polymerase chain reaction screening assay
Authors: Kopp Katharina , Smith Ina , Klein Reuben , Todd Shawn , Marsh Glenn A. , Ward Alister C. 
Published: March 2019

ABSTRACTFive species within the genera Ebolavirus and Marburgvirus of the family Filoviridae are known to cause severe hemorrhagic fever with high mortality rates in humans and non-human primates. Recent large outbreaks of Ebola virus disease in West Africa (2014 - 2016) and the Democratic Republic of the Congo (2018 - ongoing) have demonstrated the epidemic potential with devastating public health consequences. Several known and novel filovirus species have been found in bats in recent years. However, the role of each virus species in the disease ecology of human disease is still unclear. In particular, the transmission mechanism from potential animal hosts to humans is not known. Therefore, a simple, flexible, cost-effective screening tool for detecting the presence of any (putative) member of the filovirus family in animal samples is needed. In this study, a one-step conventional pan-filovirus RT-PCR assay was developed. The designed universal consensus primers of this screening test target two highly conserved regions of the nucleoprotein (NP) of all currently known filoviruses. The assay was capable of specific amplification of viral RNA of all six primate-pathogenic (human and non-human) filovirus species and resulted in 317 bp long RT-PCR products. This amplicon length renders the assay suitable for flexible application as conventional reverse transcription polymerase chain reaction (RT-PCR) as well as for future use as rapid real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR).
Primo: integration of multiple GWAS and omics QTL summary statistics for elucidation of molecular mechanisms of trait-associated SNPs and detection of pleiotropy in complex traits
Authors: Gleason Kevin J , Yang Fan , Pierce Brandon L , He Xin , Chen Lin S 
Published: March 2019

AbstractTo provide a comprehensive mechanistic interpretation of how known trait-associated SNPs affect complex traits, we propose a method – Primo – for integrative analysis of GWAS summary statistics with multiple sets of omics QTL summary statistics from different cellular conditions or studies. Primo examines SNPs’ association patterns to complex and omics traits. In gene regions harboring known susceptibility loci, Primo performs conditional association analysis to account for linkage disequilibrium. Primo allows for unknown study heterogeneity and sample correlations. We show two applications using Primo to examine the molecular mechanisms of known susceptibility loci and to detect and interpret pleiotropic effects.
Embryonic geometry underlies phenotypic variation in decanalized conditions
Authors: Huang A. , Saunders T. E. 
Published: March 2019

AbstractDuring development, many mutations cause increased variation in phenotypic outcomes, a phenomenon termed decanalization. Such variations can often be attributed to genetic and environmental perturbations. However, phenotypic discordance remains even in isogenic model organisms raised in homogeneous environments. To understand the mechanisms underlying phenotypic variation, we used as a model the highly precise anterior-posterior (AP) patterning of the earlyDrosophilaembryo. We decanalized the system by depleting the maternalbcdproduct and found that in contrast to the highly scaled patterning in the wild-type, the segmentation gene boundaries shift away from the scaled positions according to the total embryonic length. Embryonic geometry is hence a key factor predetermining patterning outcomes in such decanalized conditions. Embryonic geometry was also found to predict individual patterning outcomes underbcdoverexpression, another decanalizing condition. Further analysis of the gene regulatory network acting downstream of the morphogen identified vulnerable points in the networks due to limitations in the available physical space.
Human intestinal enteroids with inducible neurogenin-3 expression as a novel model of gut hormone secretion
Authors: Chang-Graham Alexandra L. , Danhof Heather A. , Engevik Melinda A. , Tomaro-Duchesneau Catherine , Karandikar Umesh C. , Estes Mary K. , Versalovic James , Britton Robert A. , Hyser Joseph M. 
Published: March 2019

AbstractBackgroundEnteroendocrine cells (EECs) are specialized epithelial cells that produce molecules vital for intestinal homeostasis, but due to their limited numbers, in-depth functional studies have remained challenging. Human intestinal enteroids (HIEs) that are derived from intestinal crypt stem cells are a biologically relevantin vitromodel of the intestinal epithelium. HIEs contain all intestinal epithelial cell types; however, like the intestine, HIEs spontaneously produce few EECs, which limits their study.MethodsTo increase the number of EECs in HIEs, we used lentivirus transduction to stably engineer jejunal HIEs with doxycycline-inducible expression of neurogenin-3 (NGN3), a transcription factor that drives EEC differentiation (tetNGN3-HIEs). We examined the impact ofNGN3induction on EECs by quantifying the increase in the enterochromaffin cells and other EEC subtypes. We functionally assessed secretion of serotonin and EEC hormones in response to norepinephrine and rotavirus infection.ResultsTreating tetNGN3-HIEs with doxycycline induced a dose-dependent increase of chromogranin A (ChgA)-positive and serotonin-positive cells, demonstrating increased enterochromaffin cell differentiation. Despite increased ChgA-positive cells, other differentiated cell types of the epithelium remained largely unchanged by gene expression and immunostaining. RNA sequencing of doxycycline-induced tetNGN3- HIEs identified increased expression of key hormones and enzymes associated with several other EEC subtypes. Doxycycline-induced tetNGN3-HIEs secreted serotonin, monocyte chemoattractant protein-1, glucose-dependent insulinotropic peptide, peptide YY, and ghrelin in response to norepinephrine and rotavirus infection, further supporting the presence of multiple EEC types.ConclusionsWe have combined HIEs and inducible-NGN3expression to establish a flexiblein vitromodel system for functional studies of EECs in enteroids and advance the molecular and physiological investigation of EECs.SynopsisEnteroendocrine cells have low abundance but exert widespread effects on gastrointestinal physiology. We engineered human intestinal enteroids with inducible expression of neurogenin-3, resulting in increased enteroendocrine cells and facilitating investigations of host responses to the dynamic intestinal environment.
Evolutionary dynamics in structured populations under strong population genetic forces
Authors: Feder Alison F. , Pennings Pleuni S. , Hermisson Joachim , Petrov Dmitri A. 
Published: March 2019

AbstractHigh rates of migration between subpopulations result in little population differentiation in the long-term neutral equilibrium. However, in the short-term, even very abundant migration may not be enough for subpopulations to equilibrate immediately. In this study, we investigate dynamical patterns of short-term population differentiation in adapting populations via stochastic and analytical modeling through time. We characterize a regime in which selection and migration interact to create non-monotonic patterns of the population differentiation statisticFSTwhen migration is weaker than selection, but stronger than drift. We demonstrate how these patterns can be leveraged to estimate high migration rates that would lead to panmixia in the long term equilibrium using an approximate Bayesian computation approach. We apply this approach to estimate fast migration in a rapidly adapting intra-host Simian-HIV population sampled from different anatomical locations. Notably, we find differences in estimated migration rates between different compartments, all aboveNem= 1. This work demonstrates how studying demographic processes on the timescale of selective sweeps illuminates processes too fast to leave signatures on neutral timescales.
ProtCID: A data resource for structural information on protein interactions
Authors: Xu Qifang , Dunbrack Roland L. 
Published: March 2019

AbstractStructural information on the interactions of proteins with other molecules is plentiful, and for some proteins and protein families, there may be 100s of available structures. It can be very difficult for a scientist who is not trained in structural bioinformatics to access this information comprehensively. Previously, we developed the Protein Common Interface Database (ProtCID), which provided clusters of the interfaces of full-length protein chains as a means of identifying biological assemblies. Because proteins consist of domains that act as modular functional units, we have extended the analysis in ProtCID to the individual domain level. This has greatly increased the number of large protein-protein clusters in ProtCID, enabling the generation of hypotheses on the structures of biological assemblies of many systems. The analysis of domain families allows us to extend ProtCID to the interactions of domains with peptides, nucleic acids, and ligands. ProtCID provides complete annotations and coordinate sets for every cluster.
High-resolution cryo-EM structures of outbreak strain human norovirus shells reveal size variations
Authors: Jung James , Grant Timothy , Thomas Dennis R. , Diehnelt Chris W. , Grigorieff Nikolaus , Joshua-Tor Leemor 
Published: March 2019

AbstractNoroviruses are a leading cause of food-borne illnesses worldwide. Although GII.4 strains have been responsible for most norovirus outbreaks, the assembled virus shell structures have been available in detail for only a single strain (GI.1). We present high-resolution (2.6-4.1 Å) cryo-electron microscopy (cryo-EM) structures of GII.4, GII.2, GI.7 and GI.1 human norovirus outbreak strain virus-like particles (VLPs). Although norovirus VLPs have been thought to exist in a single-sized assembly, our structures reveal polymorphism between and within genogroups with small, medium and large particle sizes observed. We developed a new asymmetric reconstruction method and resolved a metal ion adjacent to the co-receptor binding site, which affected the structural stability of the shell. Our structures serve as valuable templates for facilitating vaccine formulations.
Colonization and extinction rates estimated from temporal dynamics of ecological communities: The islandrpackage
Authors: Ontiveros Vicente J. , Capitán José A. , Arthur Rohan , Casamayor Emilio O. , Alonso David 
Published: March 2019

AbstractThe temporal dynamics of ecological communities are inherently complex, as dispersal processes, interspecific biotic interactions and environmental fluctuations interact to shape species assemblages. We developed anrpackage,island—a community ecology tool to analyse temporal patterns and explore potential drivers of community dynamics.Therpackageislandis inspired by the simplicity of the Theory of Island Biogeography. Our package includes a suite of functions to easily confront models of increasing complexity to community data from the simplest stochastic model underlying Island Biogeography Theory to more elaborate models that include species responses to environmental variables and imperfect detectability, obtained at regular or irregular sampling times, using maximum‐likelihood andAIC‐based model selection.Models implemented inislandshould be regarded as simple approximations of true temporal community dynamics. In this sense, we call themeffective modelswhich we use to estimateeffective parameters. These models are simple, but dynamic, as opposed to purely statistical. We illustrate the concept of dynamiceffective modelsby using an immigration–birth–death stochastic model of population dynamics. We generated simulated community data to demonstrate the correspondence between the underlying true model parameters values and our effective parameter estimates.We present three examples showcasing the uses of our package: detectability estimation and model selection, influence of environmental covariates on community dynamics and estimation of co‐occurrence networks. Three detailed vignettes with a full set of examples accompany therPackageislandavailable onCRAN.
The immunocytochemical expression of VE‐1 (BRAF V600E‐related) antibody identifies the aggressive variants of papillary thyroid carcinoma on liquid‐based cytology
Authors: Straccia Patrizia , Brunelli Chiara , Rossi Esther D. , Lanza Paola , Martini Maurizio , Musarra Teresa , Lombardi Celestino Pio , Pontecorvi Alfredo , Fadda Guido 
Published: March 2019

BackgroundThe recently introduced monoclonal V600E antibody (clone VE1) is likely to be an alternative strategy for detecting this mutation in thyroid lesions. Although VE1 immunostaining and molecular methods used to assess papillary thyroid carcinoma in surgical specimens are in good agreement, evaluation of VE1 in cytology and cell block samples is rarely performed, and its diagnostic value in cytology has not been well established. In this study, we sought to determine if VE1 is suitable for fine needle aspiration (FNA) and cell block methods.MethodsA total of 86 patients who had BRAF V600E mutations were investigated with molecular and immunocytochemical (ICC) analysis in 45 FNA and 41 cell blocks. In total, 83 (96.5%) patients underwent surgical treatment. Assessment of BRAF V600E mutation status was performed in 72 (83.7%) cases.ResultsAmong the 72 cases analysed, 54 cases agreed (ICC+/BRAF+ or ICC−/BRAF−), seven cases were false positive (ICC+/BRAF−) and 11 cases were false negative (ICC−/BRAF+). False negative cases were not detected in the cell block method. The statistical analysis showed that sensitivity and specificity of ICC for detecting the BRAF V600E mutation were 61% and 77% in FNA samples and 100% and 73% in cell block.ConclusionThe use of antibody VE‐1 is a reliable method and a negative result of VE1 immunostaining might help to save time and money, restricting the molecular test to antibody‐positive cases only. The identification of the aggressive variants of papillary carcinoma might be enabled by the expression of the antibody in neoplastic cells with tall cell features.
Recent patterns of vagal nerve stimulator use in the United States: Is there a racial disparity?
Authors: Fox Jonah , Lekoubou Alain , Bishu Kinfe G. , Ovbiagele Bruce 
Published: March 2019

SummaryObjectivePatients with refractory epilepsy are at a high risk of complications but may not receive the same level of care across racial groups. We aimed to ascertain racial inequalities and trends in the use of a vagal nerve stimulator (VNS) among adult patients with refractory epilepsy.MethodsA total of 24 159 adults (18 years and older) with refractory epilepsy from the National Inpatient Sample between the years 2006 and 2014 were included in this analysis. We used a multivariate logistic regression analysis to evaluate independent predictors of VNS use among patients with refractory epilepsy. Covariates included gender, age, insurance type, and household income. In addition, we evaluated for trends in VNS use over the 9‐year period of data collection.ResultsA total of 1.56% of patients with refractory epilepsy had used a VNS between 2006 and 2014. Overall, there was a trend of decreased use of a VNS between 2006‐2008 (2.1%) and 2012‐2014 (0.9%). In the adjusted multivariate logistic regression analysis, blacks (odds ratio [OR] = 0.52, 95% confidence interval [CI] = 0.35‐0.77) were significantly less likely to have used a VNS relative to non‐Hispanic whites. Additional factors independently associated with a decreased likelihood of VNS use were age > 65 years (OR = 0.51, 95% CI = 0.28‐0.95) and years 2012‐2014 (OR = 0.44, 95% CI = 0.28‐0.67).SignificanceThere was a trend toward a decrease in the use of a VNS among adult patients with refractory epilepsy. Our results also suggest that black patients with refractory epilepsy were less likely to receive a VNS independently of other variables. Increased work toward effectively reducing racial disparities in access to quality epilepsy care is crucial.