bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brain-Specific Deletion of GIT1 Impairs Cognition and Alters Phosphorylation of Synaptic Protein Networks Implicated in Schizophrenia Susceptibility
Authors: Fass Daniel M. , Lewis Michael C. , Ahmad Rushdy , Szucs Matthew J. , Zhang Qiangge , Fleishman Morgan , Wang Dongqing , Kim Myung Jong , Biag Jonathan , Carr Steven A. , Scolnick Edward M. , Premont Richard T. , Haggarty Stephen J. 
Published: March 2018

AbstractDespite tremendous effort, the molecular and cellular basis of cognitive deficits in schizophrenia remain poorly understood. Recent progress in elucidating the genetic architecture of schizophrenia has highlighted the association of multiple loci and rare variants that may impact susceptibility. One key example, given their potential etiopathogenic and therapeutic relevance, is a set of genes that encode proteins that regulate excitatory glutamatergic synapses in brain. A critical next step is to delineate specifically how such genetic variation impacts synaptic plasticity and to determine if and how the encoded proteins interact biochemically with one another to control cognitive function in a convergent manner. Towards this goal, here we study the roles of GPCR-kinase interacting protein 1 (GIT1), a synaptic scaffolding and signaling protein with damaging coding variants found in schizophrenia patients, as well as copy number variants found in patients with neurodevelopmental disorders. We generated conditional neural-selective GIT1 knockout mice and find that these mice have deficits in fear conditioning learning and spatial memory. Using global quantitative phospho-proteomics, we revealed that GIT1 deletion in brain perturbs specific networks of GIT1-interacting synaptic proteins. Importantly, several schizophrenia and neurodevelopmental disorder risk genes are present within these networks. We propose that GIT1 regulates the phosphorylation of a network of synaptic proteins and other critical regulators of neuroplasticity, and that perturbation of these networks may contribute to cognitive deficits observed in schizophrenia and neurodevelopmental disorders.
Complete guide RNA design for CRISPR-mediated regulation of human long noncoding RNA transcription
Authors: Saberi Amir , Zhu Renjun , Kwon Chulan 
Published: March 2018

AbstractTranscription inhibition and activation of long noncoding RNAs (lncRNAs) mediated by clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 technology provides potential advantages in high-throughput functional genomics studies over RNA interference or overexpression platforms. In this work, we identify over 90,000 lncRNA transcription start sites (TSSs) based on the MiTranscriptome human genome annotation and design single guide RNA (sgRNA) libraries with strong predicted activities and low off-target effects for CRISPR-mediated inhibition and activation (CRISPRi/a) of their transcription. A large fraction of these TSSs correspond to putative genes that are not annotated in common reference genome annotations and have never been functionally studied. Our CRISPRi/a libraries, or their context-dependent subsets, are potentially useful in genome-scale functional studies of human lncRNAs.
Condition-adaptive fused graphical lasso (CFGL): an adaptive procedure for inferring condition-specific gene co-expression network
Authors: Lyu Yafei , Xue Lingzhou , Zhang Feipeng , Koch Hillary , Saba Laura , Kechris Katerina , Li Qunhua 
Published: March 2018

AbstractCo-expression network analysis provides useful information for studying gene regulation in biological processes. Examining condition-specific patterns of co-expression can provide insights into the underlying cellular processes activated in a particular condition. One challenge in this type of analysis is that the sample sizes in each condition are usually small, making the statistical inference of co-expression patterns highly underpowered. A joint network construction that borrows information from related structures across conditions has the potential to improve the power of the analysis.One possible approach to constructing the co-expression network is to use the Gaussian graphical model. Though several methods are available for joint estimation of multiple graphical models, they do not fully account for the heterogeneity between samples and between co-expression patterns introduced by condition specificity. Here we develop the condition-adaptive fused graphical lasso (CFGL), a data-driven approach to incorporate condition specificity in the estimation of co-expression networks. We show that this method improves the accuracy with which networks are learned. The application of this method on a rat multi-tissue dataset and The Cancer Genome Atlas (TCGA) breast cancer dataset provides interesting biological insights. In both analyses, we identify numerous modules enriched for Gene Ontology functions and observe that the modules that are upregulated in a particular condition are often involved in condition-specific activities. Interestingly, we observe that the genes strongly associated with survival time in the TCGA dataset are less likely to be network hubs, suggesting that genes associated with cancer progression are likely to govern specific functions, rather than regulating a large number of biological processes. Additionally, we observed that the tumor-specific hub genes tend to have few shared edges with normal tissue, revealing tumor-specific regulatory mechanism.Author summaryGene co-expression networks provide insights into the mechanism of cellular activity and gene regulation. Condition-specific mechanisms may be identified by constructing and comparing co-expression networks of multiple conditions. We propose a novel statistical method to jointly construct co-expression networks for gene expression profiles from multiple conditions. By using a data-driven approach to capture condition-specific co-expression patterns, this method is effective in identifying both co-expression patterns that are specific to a condition and that are common across conditions. The application of this method on real datasets reveals interesting biological insights.
Changes in the genetic requirements for microbial interactions with increasing community complexity
Authors: Morin Manon , Pierce Emily C. , Dutton Rachel 
Published: March 2018

ABSTRACTMicrobial community structure and function rely on complex interactions whose underlying molecular mechanisms are poorly understood. To investigate these interactions in a simple microbiome, we introduced E. coli into an experimental community based on a cheese rind and identified the differences in E. coli’s genetic requirements for growth in interactive and non-interactive contexts using Random Barcode Transposon Sequencing (RB-TnSeq) and RNASeq. E. coli’s genetic requirements varied among pairwise growth conditions and between pairwise and community conditions. Our analysis points to mechanisms by which growth conditions change as a result of increasing community complexity and suggests that growth within a community relies on a combination of pairwise and higher order interactions. Our work provides a framework for using the model organism E. coli as a probe to investigate microbial interactions regardless of the genetic tractability of members of the studied ecosystem.
Female ornamentation and the fecundity trade-off in a sex-role reversed pipefish
Authors: Mobley Kenyon B. , Morrongiello John R. , Warr Matthew , Bray Diane , Wong Bob B. M. 
Published: March 2018

AbstractFemale ornaments are a rare occurrence in nature. One explanation for this is that female ornaments are costly to produce and maintain and, therefore, females must trade-off resources related to reproduction to promote ornament expression. Here, we investigate the potential trade-off between female ornamentation and fecundity in the sex-role reversed, wide-bodied pipefish, Stigmatopora nigra. We measured two components of the female ornament, body width and stripe thickness, and tested the relationship between these ornaments and female fecundity and the mean egg size. Both body width and stripe thickness were strongly and positively related to female body size. After controlling for the influence of body size, we found no evidence of a cost of belly width or stripe thickness on female fecundity. Rather, females that have larger ornaments have higher fecundity and thus a greater relative fitness advantage. However, larger females suffered a slight decrease in egg size, consistent with a potential trade-off between egg size and body size, although no relationship between egg size and ornaments was observed. Our results suggest that larger S. nigra females accurately advertise their reproductive value to males, and underscore the importance of investigating the potential mechanisms that promote and maintain honesty of female ornaments.
A translaminar genetic logic for the circuit identity of intracortically-projecting neurons
Authors: Klingler Esther , De la Rossa Andres , Fièvre Sabine , Jabaudon Denis 
Published: March 2018

AbstractDistinct subtypes of intracortically-projecting neurons (ICPN) are present in all layers, allowing propagation of information within and across cortical columns. How the molecular identities of ICPN relate to their defining anatomical and functional properties is unknown. Here we show that the transcriptional identities of ICPN primarily reflect their input-output connectivities rather than their birth dates or laminar positions. Thus, conserved circuit-related transcriptional programs are at play across cortical layers, which may preserve canonical circuit features across development and evolution.
Hemolysin liberates bacterial outer membrane vesicles for cytosolic lipopolysaccharide sensing
Authors: Chen Shouwen , Yang Dahai , Wen Ying , Jiang Zhiwei , Zhang Lingzhi , Jiang Jiatiao , Chen Yaozhen , Hu Tianjian , Wang Qiyao , Zhang Yuanxing , Liu Qin 
Published: March 2018

AbstractInflammatory caspase-11/4/5 recognize cytosolic LPS from invading Gram-negative bacteria and induce pyroptosis and cytokine release, forming rapid innate antibacterial defenses. Since extracellular or vacuole-constrained bacteria are thought to rarely access the cytoplasm, how their LPS are exposed to the cytosolic sensors is a critical event for pathogen recognition. Hemolysin is a pore-forming bacterial toxin, which was generally accepted to rupture cell membrane, leading to cell lysis. Whether and how hemolysin participates in non-canonical inflammasome signaling remains uncovered. Here, we show that hemolysin-overexpressed enterobacteria triggered significantly increased caspase-4 activation in human intestinal epithelial cells (IECs). Hemolysin promoted LPS cytosolic delivery from extracellular bacteria through dynamin-dependent endocytosis. Further, we revealed that hemolysin was largely associated with bacterial outer membrane vesicles (OMVs) and induced rupture of OMV-containing vacuoles, subsequently increasing LPS exposure to the cytosolic sensor. Accordingly, overexpression of hemolysin promoted caspase-11 dependent IL-18 secretion, gut inflammation, and enterocyte pyroptosis in orally-infected mice, which was associated with restricting bacterial colonization in vivo. Together, our work reveals a concept that hemolysin promotes noncanonical inflammasome activation via liberating OMVs for cytosolic LPS sensing, which offers insights into innate immune surveillance of dysregulated hemolysin via caspase-11/4 in intestinal antibacterial defenses.SignificanceSensing of lipopolysaccharide (LPS) in the cytosol triggers non-canonical inflammasome-mediated innate responses. Recent work revealed that bacterial outer membrane vesicles (OMVs) enables LPS to access the cytosol for extracellular bacteria. However, since intracellular OMVs are generally constrained in endosomes, how OMV-derived LPS gain access to the cytosol remains unknown. Here, we reported that hemolysin largely bound with OMVs and entered cells through dynamin-dependent endocytosis. Intracellular hemolysin significantly impaired OMVs-constrained vacuole integrity and increased OMV-derived LPS exposure to the cytosolic sensor, which promoted non-canonical inflammasome activation and restricted bacterial gut infections. This work reveals the role of hemolysin in promoting non-canonical inflammasome activation and alerting host immune recognition, which provides insights into the more sophisticated biological functions of hemolysin upon infection.
Effects of adaptive harvesting on fishing down processes and resilience changes in predator-prey and tritrophic systems
Authors: Tromeur Eric , Loeuille Nicolas 
Published: March 2018

AbstractMany world fisheries display a declining mean trophic level of catches. This “fishing down the food web” is often attributed to reduced densities of high-trophic-level species. We show here that the fishing down pattern can actually emerge from the adaptive harvesting of two- and three-species food webs, where changes in fishing patterns are driven by the relative profitabilities of the harvested species. Shifting fishing patterns from a focus on higher trophic levels to a focus on lower trophic levels can yield abrupt changes in the system, strongly impacting species densities. In predator-prey systems, such regime shifts occur when the predator species is highly valuable relative to the prey, and when the top-down control on the prey is strong. Moreover, we find that when the two species are jointly harvested, high adaptation speeds can reduce the resilience of fisheries. Our results therefore suggest that flexibility in harvesting strategies will not necessarily benefit fisheries but may actually harm their sustainability.
ERBB2andKRASAlterations Mediate Response to EGFR Inhibitors in early stage Gallbladder Cancer
Authors: Iyer Prajish , Shrikhande Shailesh V , Ranjan Malika , Joshi Asim , Prasad Ratnam , Gardi Nilesh , Thorat Rahul , Salunkhe Sameer , Dharavath Bhasker , Sahoo Bikram , Chandrani Pratik , Kore Hitesh , Mohanty Bhabani , Chaudhari Vikram , Choughule Anuradha , Kawle Dhananjay , Chaudhari Pradip , Ingle Arvind , Banavali Shripad , Ramadwar Mukta R , Prabhash Kumar , Barreto Savio George , Dutt Shilpee , Dutt Amit 
Published: March 2018

AbstractThe uncommonness of gallbladder cancer has contributed to the generally poor understanding of the disease, with scant reports restricted to advance-stage tumors. Here, using an integrated analysis of whole exome and phospho-proteome, we show recurrent activatingERBB2andKRASsomatic mutations are present in 6 and 3 of 44 early-stage rare gallbladder tumors, respectively.In vitroandin vivocell-based and biochemical assays reveal an essential role of ErbB pathway activation for the survival of gallbladder cells. Interestingly, the genetic and pharmacological dependencies of gallbladder cells are dependent on theKRASmutant allele status, reminiscent of the clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer. In overall, we present the first evidence that the presence ofKRAS(G12V), but notKRAS(G13D) mutation, may preclude gallbladder cancer patients to respond to anti-EGFR treatment, leading to an early adoption of an approved treatment regimen for gallbladder cancer patients.
Large-Scale Genome-Wide Meta Analysis of Polycystic Ovary Syndrome Suggests Shared Genetic Architecture for Different Diagnosis Criteria
Authors: Day Felix , Karaderi Tugce , Jones Michelle R. , Meun Cindy , He Chunyan , Drong Alex , Kraft Peter , Lin Nan , Huang Hongyan , Broer Linda , Magi Reedik , Saxena Richa , Laisk-Podar Triin , Urbanek Margrit , Hayes M. Geoffrey , Thorleifsson Gudmar , Fernandez-Tajes Juan , Mahajan Anubha , Mullin Benjamin H. , Stuckey Bronwyn G.A. , Spector Timothy D. , Wilson Scott G. , Goodarzi Mark O. , Davis Lea , Obermeyer-Pietsch Barbara , Uitterlinden André G. , Anttila Verneri , Neale Benjamin M , Jarvelin Marjo-Riitta , Fauser Bart , Kowalska Irina , Visser Jenny A. , Anderson Marianne , Ong Ken , Stener-Victorin Elisabet , Ehrmann David , Legro Richard S. , Salumets Andres , McCarthy Mark I. , Morin-Papunen Laure , Thorsteinsdottir Unnur , Stefansson Kari ,   23andMe Research Team, Styrkarsdottir Unnur , Perry John , Dunaif Andrea , Laven Joop , Franks Steve , Lindgren Cecilia M. , Welt Corrine K. 
Published: March 2018

AbstractPolycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed with different criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (nearPLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease indicate shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. Only one locus differed in its association by diagnostic criteria, otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or Rotterdam criteria across common variants at 13 loci.
De novo transcriptome assembly, annotation, and identification of low-copy number genes in the flowering plant genus Silene (Caryophyllaceae)
Authors: Bertrand Yann J K , Petri Anna , Scheen Anne-Cathrine , Töpel Mats , Oxelman Bengt 
Published: March 2018

AbstractPhylogenetic methods that rely on information from multiple, unlinked genes have recently been developed for resolving complex situations where evolutionary relationships do not conform to bifurcated trees and are more adequately depicted by networks. Such situations arise when successive interspecific hybridizations in combination with genome duplications have shaped species phylogenies. Several processes such as homoeolog loss and deep coalescence can potentially hamper our ability to recover the historical signal correctly. Consequently the prospect of reconstructing accurate phylogenies lies in the combination of several low-copy nuclear markers that when, used in concert, can provide homoeologs for all the ancestral genomes and help to disentangle gene tree incongruence due to deep coalescence events. Expressed sequence tag (EST) databases represent valuable resource for the identification of genes in organisms with uncharacterized genomes and for development of molecular markers. The genus Silene L. is a prime example of a plant group whose evolutionary history involves numerous events of hybridization and polyploidization. As for many groups there is currently a shortage of low-copy nuclear markers, for which phylogenetic usefulness has been demonstrated. Here, we present two EST libraries for two species of Silene that belong to large phylogenetic groups not previously investigated with next generation technologies. The assembled and annotated transcriptomes are used for identifying low copy nuclear regions, suitable for sequencing.
Identification of microRNA clusters cooperatively acting on Epithelial to Mesenchymal Transition in Triple Negative Breast Cancer
Authors: Cantini L , Bertoli G , Cava C , Dubois T , Zinovyev A , Caselle M , Castiglioni I , Barillot E , Martignetti L 
Published: March 2018

AbstractMicroRNAs play important roles in many biological processes. Their aberrant expression can have oncogenic or tumor suppressor function directly participating to carcinogenesis, malignant transformation, invasiveness and metastasis. Indeed, miRNA profiles can distinguish not only between normal and cancerous tissue but they can also successfully classify different subtypes of a particular cancer. Here, we focus on a particular class of transcripts encoding polycistronic miRNA genes that yields multiple miRNA components. We describe clustered MiRNA Master Regulator Analysis (ClustMMRA), a fully redesigned release of the MMRA computational pipeline (MiRNA Master Regulator Analysis), developed to search for clustered miRNAs potentially driving cancer molecular subtyping. Genomically clustered miRNAs are frequently co-expressed to target different components of pro-tumorigenic signalling pathways. By applying ClustMMRA to breast cancer patient data, we identified key miRNA clusters driving the phenotype of different tumor subgroups. The pipeline was applied to two independent breast cancer datasets, providing statistically concordant results between the two analysis. We validated in cell lines the miR-199/miR-214 as a novel cluster of miRNAs promoting the triple negative subtype phenotype through its control of proliferation and EMT.
Structure of the herpes-simplex virus portal-vertex
Authors: McElwee Marion , Vijayakrishnan Swetha , Rixon Frazer , Bhella David 
Published: March 2018

AbstractHerpesviruses include many important human pathogens such as herpes simplex virus, cytomegalovirus, varicella-zoster virus and the oncogenic Epstein-Barr virus and Kaposi-sarcoma associated herpesvirus. Herpes virions contains large icosahedral capsids that have a portal at a unique five-fold vertex, similar to that seen in the tailed bacteriophages. The portal is a molecular motor through which the viral genome enters the capsid during virion morphogenesis. The genome also exits the capsid through the portal-vertex when it is injected through the nuclear-pore into the nucleus of a new host cell to initiate infection. Structural investigations of the herpesvirus portal-vertex have proven challenging, owing to the small size of the tail-like portal-vertex associated tegument (PVAT), and the dense tegument layer that lays between the nucleocapsid and the viral envelope, obscuring the view of the portal-vertex. Here we show the structure of the herpes simplex virus portal-vertex at sub-nanometer resolution, solved by electron cryomicroscopy (cryoEM) and single-particle 3D reconstruction. This led to a number of new discoveries including the presence of two previously unknown portal associated structures that occupy the sites normally taken by the penton and the Ta triplex. Our data revealed that the PVAT is composed of ten copies of the C-terminal domain of pUL25, which are uniquely arranged as two tiers of star-shaped density. Our 3D reconstruction of the portal-vertex also shows that one end of the viral genome extends outside the portal in the manner described for some bacteriophage but not previously seen in any eukaryote viruses. Finally, we show that the viral genome is consistently packed in a highly-ordered left-handed spool to form concentric shells of DNA. Our data provide new insights into the structure of a molecular machine critical to the biology of an important class of human pathogens.