bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional program of memory B cell activation, broadly binding anti-influenza antibodies, and bystander activation after vaccination revealed by single-cell transcriptomics
Authors: Horns Felix , Dekker Cornelia L. , Quake Stephen R. 
Published: July 2019

AbstractAntibody memory protects humans from many diseases. Protective antibody memory responses require activation of transcriptional programs, cell proliferation, and production of antigen-specific antibodies, but how these aspects of the response are coordinated is poorly understood. We profiled the molecular and cellular features of the antibody response to influenza vaccination by integrating single-cell transcriptomics, longitudinal antibody repertoire sequencing, and antibody binding measurements. Single-cell transcriptional profiling revealed a program of memory B cell activation characterized by CD11c and T-bet expression associated with clonal expansion and differentiation toward effector function. Vaccination elicited an antibody clone which rapidly acquired broad high-affinity hemagglutinin binding during affinity maturation. Unexpectedly, many antibody clones elicited by vaccination do not bind vaccine, demonstrating non-specific activation of bystander antibodies by influenza vaccination. These results offer insight into how molecular recognition, transcriptional programs, and clonal proliferation are coordinated in the human B cell repertoire during memory recall.
A negative feedback loop between Insulin-like Growth Factor signaling and the lncRNA SNHG7 tightly regulates transcript levels and proliferation
Authors: Boone David N. , Warburton Andrew , Som Sreeroopa , Lee Adrian V. 
Published: July 2019

ABSTRACTEvidence suggests Insulin-like growth factor 1 (IGF1) signaling is involved in the initiation and progression of a subset of breast cancers by inducing cell proliferation and survival(1, 2). Although the signaling cascade following IGF1 receptor activation is well-studied(3, 4), the key elements of the transcriptional response governing IGF1’s actions are not well understood. Recent studies reveal that the majority of the genome is transcribed and that there are more long non-coding RNAs (lncRNAs) than protein coding genes(5), several of which are dysegulated in human cancer(6, 7). However, studies on the regulation and mechanism of action of these lncRNAs are in their infancy. Here we show that IGF1 alters the expression levels of a subset of lncRNAs. SNHG7, a member of the small nucleolar host gene family, is a highly-expressed lncRNA that is consistently and significantly down-regulated by IGF1 signaling by a post-transcriptional mechanism through the MAPK pathway. SNHG7 regulates proliferation of breast cancer cell lines in a dose-dependent manner, and silencing SNHG7 expression causes cell cycle arrest in G0/G1. Intriguingly, SNHG7 alters the expression of many IGF1 signaling intermediates and IGF1-regulated genes suggesting a feedback mechanism to tightly regulate the IGF1 response. Finally, we show with TCGA data that SNHG7 is overexpressed in tumors of a subset of breast cancer patients and that these patients have lower disease-free survival than patients without elevated SNHG7 expression. We propose that SNHG7 is a lncRNA oncogene that is controlled by growth factor signaling in a feedback mechanism to prevent hyperproliferation, and that this regulation can be lost in the development or progression of breast cancer.SIGNIFICANCE STATEMENTIGF1 signaling drives proliferation and survival and is important for the initiation and development of a subset of breast cancers. IGF1 is known to control the expression of thousands of protein coding genes, but it is unknown if it alters the expression of other gene types, such as long noncoding RNAs. Here we demonstrate that IGF regulates lncRNAs including the mostly unstudied SNHG7. We further show that SNHG7 is necessary for proliferation and modulates IGF1 signaling through a novel feedback mechanism that is required for fine-tuning of the transcriptional response to growth factor signaling and proliferation of breast cancer cells. SNHG7 is highly expressed in a subset of breast cancer patients with poor prognosis giving further credence that it is a novel oncogene.
Intricate genetic programs controlling dormancy inMycobacterium tuberculosis
Authors: Abidi Abrar A. , Peterson Eliza J. R. , Arrieta-Ortiz Mario L. , Aguilar Boris , Yurkovich James T. , Kaur Amardeep , Pan Min , Srinivas Vivek , Shmulevich Ilya , Baliga Nitin S. 
Published: July 2019

AbstractMycobacterium tuberculosis(MTB), responsible for the deadliest infectious disease worldwide, displays the remarkable ability to transition in and out of dormancy, a hallmark of the pathogen’s capacity to evade the immune system and opportunistically exploit immunocompromised individuals. Uncovering the gene regulatory programs that underlie the dramatic phenotypic shifts in MTB during disease latency and reactivation has posed an extraordinary challenge. We developed a novel experimental system to precisely control dissolved oxygen levels in MTB cultures in order to capture the chain of transcriptional events that unfold as MTB transitions into and out of hypoxia-induced dormancy. Using a comprehensive genome-wide transcription factor binding location map and insights from network topology analysis, we identified regulatory circuits that deterministically drive sequential transitions across six transcriptionally and functionally distinct states encompassing more than three-fifths of the MTB genome. The architecture of the genetic programs explains the transcriptional dynamics underlying synchronous entry of cells into a dormant state that is primed to infect the host upon encountering favorable conditions.One Sentence SummaryHigh-resolution transcriptional time-course reveals six-state genetic program that enables MTB to enter and exit hypoxia-induced dormancy.
Injection molded open microfluidic well plate inserts for user-friendly coculture and microscopy
Authors: Day John H. , Nicholson Tristan M. , Su Xiaojing , van Neel Tammi L. , Clinton Ivor , Kothandapani Anbarasi , Lee Jinwoo , Greenberg Max H. , Amory John K. , Walsh Thomas J. , Muller Charles H. , Franco Omar E. , Jefcoate Colin R. , Crawford Susan E. , Jorgensen Joan S. , Theberge Ashleigh B. 
Published: July 2019

AbstractOpen microfluidic cell culture systems are powerful tools for interrogating biological mechanisms. We have previously presented a microscale cell culture system, based on spontaneous capillary flow of biocompatible hydrogels, that is integrated into a standard cell culture well plate, with flexible cell compartment geometries and easy pipet access. Here, we present two new injection molded open microfluidic devices that also easily insert into standard cell culture well plates and standard culture workflows, allowing seamless adoption by biomedical researchers. These platforms allow culture and study of soluble factor communication among multiple cell types, and the microscale dimensions are well-suited for rare primary cells. Unique advances include optimized evaporation control within the well, manufacture with reproducible and cost-effective rapid injection molding, and compatibility with sample preparation workflows for high resolution microscopy (following well-established coverslip mounting procedures). In this work, we present several use cases that highlight the usability and widespread utility of our platform including culture of limited primary testis cells from surgical patients, microscopy readouts including immunocytochemistry and single molecule fluorescence in situ hybridization (smFISH), and coculture to study interactions between adipocytes and prostate cancer cells.
The Autoimmune Susceptibility Gene, PTPN2, Restricts Expansion of a Novel Mouse Adherent-Invasive E. coli
Authors: Shawki Ali , Alvarez Rocio , Spalinger Marianne R. , Ruegger Paul M. , Sayoc Anica , Santos Alina N. , Chatterjee Pritha , Mitchell Jonathan , Macbeth John , Tremblay Michel L. , Hsiao Ansel , Borneman James , McCole Declan F. 
Published: July 2019

AbstractInflammatory bowel diseases (IBD) involve genetic and environmental factors that play major roles in disease pathogenesis. Loss-of-function single-nucleotide polymorphisms (SNPs) in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene increase the risk of IBD and are associated with altered microbiome population dynamics in IBD. Moreover, expansion of intestinal pathobionts, such as adherent-invasive E. coli (AIEC), is strongly implicated in the pathogenesis of IBD as AIEC increases pro-inflammatory cytokine production and alters tight junction protein regulation suggesting a potential mechanism of pathogen-induced barrier dysfunction and inflammation. The aim of this study was to identify if PTPN2 deficiency disturbs the composition of the intestinal microbiome to promote expansion of specific bacteria with pathogenic properties. In mice constitutively lacking Ptpn2 we identified increased abundance of a novel adherent-invasive E. coli (AIEC) that showed similar adherence and invasion of intestinal epithelial cells, but greater survival in macrophages to the IBD associated AIEC, LF82. Furthermore, we confirmed this novel mouse AIEC (mAIEC) caused disease when administered to germ-free and mice lacking segmented-filamentous bacteria (SFB). Moreover, mAIEC infection increased severity of and prevented recovery from dextran-sodium sulfate (DSS)-induced colitis. mAIEC genome sequence analysis showed >90% similarity to LF82. Interestingly, mAIEC contained distinct attachment genes not found in LF82 thereby also demonstrating the novelty of this AIEC. We show here for the first time that an IBD susceptibility gene, PTPN2, plays a key role in modulating the gut microbiome to protect against a novel pathobiont. This study generates new insights into gene-environment-microbiome interactions in IBD.
Large-scale ciliary reversal mediates capture of individual algal prey by Müller’s larva
Authors: von Dassow George , Ellison Christina I. 
Published: July 2019

AbstractWe documented capture of microalgal prey by several species of wild-caught Müller’s larvae of polyclad flatworm. To our knowledge, this is the first direct observation of feeding mechanism in this classical larval type. High-speed video recordings show that virtually all captures are mediated by large-scale transient ciliary reversal over one or more portions of the main ciliary band corresponding to individual lobes or tentacles. Local ciliary beat reversals alter near-field flow to suck parcels of food-containing water mouthward. Many capture episodes entail sufficient coordinated flow disruption that these compact-bodied larvae tumble dramatically. Similar behaviors were recorded in at least four distinct species, one of which corresponds to the ascidian-eating polyclad Pseudoceros.
Enzyme annotation in UniProtKB using Rhea
Authors: Morgat Anne , Lombardot Thierry , Coudert Elisabeth , Axelsen Kristian , Neto Teresa Batista , Gehant Sebastien , Bansal Parit , Bolleman Jerven , Gasteiger Elisabeth , Castro Edouard de , Baratin Delphine , Pozzato Monica , Xenarios Ioannis , Poux Sylvain , Redaschi Nicole , Bridge Alan ,   The UniProt Consortium
Published: July 2019

AbstractMotivationTo provide high quality computationally tractable enzyme annotation in UniProtKB using Rhea, a comprehensive expert-curated knowledgebase of biochemical reactions which describes reaction participants using the ontology ChEBI (Chemical Entities of Biological Interest).ResultsWe replaced existing textual descriptions of biochemical reactions in UniProtKB with their equivalents from Rhea, which is now the standard for annotation of enzymatic reactions in UniProtKB. We developed improved search and query facilities for the UniProt website, REST API, and SPARQL endpoint that leverage the chemical structure data, nomenclature, and classification that Rhea and ChEBI provide.Availability and ImplementationUniProtKB at https://www.uniprot.org/; UniProt REST API at https://www.uniprot.org/help/api; UniProt SPARQL endpoint at https://sparql.uniprot.org/sparql; Rhea at https://www.rhea-db.org/.Contactanne.morgat@sib.swiss
The BioLuminescent-OptoGenetic in vivo Response to Coelenterazine is Proportional, Sensitive and Specific in Neocortex
Authors: Gomez-Ramirez Manuel , More Alexander I. , Friedman Nina G. , Hochgeschwender Ute , Moore Christopher I. 
Published: July 2019

ABSTRACTBioLuminescent (BL) light production can modulate neural activity and behavior through coexpressed OptoGenetic (OG) elements, an approach termed ‘BL-OG’. Yet, the relationship between BL-OG effects and bioluminescent photon emission has not been characterized in vivo. Further, the degree to which BL-OG effects strictly depend on optogenetic mechanisms driven by bioluminescent photons is unknown. Crucial to every neuromodulation method is whether the activator shows a dynamic concentration range driving robust, selective, and non-toxic effects. We systematically tested the effects of four key components of the BL-OG mechanism (luciferin, oxidized luciferin, luciferin vehicle, and bioluminescence), and compared these against effects induced by the Luminopsin-3 (LMO3) BL-OG molecule, a fusion of slow burn Gaussia luciferase (sbGLuc) and Volvox ChannelRhodopsin-1 (VChR1). We performed combined bioluminescence imaging and electrophysiological recordings while injecting specific doses of Coelenterazine (substrate for sbGluc), Coelenteramide (CTM, the oxidized product of CTZ), or CTZ vehicle. CTZ robustly drove activity in mice expressing LMO3, with photon production proportional to firing rate. In contrast, low and moderate doses of CTZ, CTM, or vehicle did not modulate activity in mice that did not express LMO3. We also failed to find bioluminescence effects on neural activity in mice expressing an optogenetically non-sensitive LMO3 variant. We observed weak responses to the highest dose of CTZ in control mice, but these effects were significantly smaller than those observed in the LMO3 group. These results show that in neocortex in vivo, there is a large CTZ range wherein BL-OG effects are specific to its active chemogenetic mechanism.
Test Gene-Environment Interactions for Multiple Traits in Sequencing Association Studies
Authors: Zhang Jianjun , Sha Qiuying , Hao Han , Zhang Shuanglin , Gao Xiaoyi Raymond , Wang Xuexia 
Published: July 2019

AbstractThe risk of many complex diseases is determined by a complex interplay of genetic and environmental factors. Data on multiple traits is often collected for many complex diseases in order to obtain a better understanding of the diseases. Examination of gene-environment interactions (GxEs) for multiple traits can yield valuable insights about the etiology of the disease and increase power in detecting disease associated genes. Most existing methods focus on testing gene-environment interaction (GxE) for a single trait. In this study, we develop novel approaches to test GxEs for multiple traits in sequencing association studies. We first perform transformation of multiple traits by using either principle component analysis or standardization analysis. Then, we detect the effect of GxE for each transferred phenotypic trait using novel proposed tests: testing the effect of an optimallyweighted combination of GxE (TOW-GE) and/or variable weight TOW-GE (VW-TOW-GE). Finally, we employ the Fisher’s combination test to combine the p-values of TOW-GE and/or VW-TOW-GE. Extensive simulation studies based on the Genetic Analysis Workshop 17 data show that the type I error rates of the proposed methods are well controlled. Compared to the existing interaction sequence kernel association test (ISKAT), TOW-GE is more powerful when there are only rare risk and protective variants; VW-TOW-GE is more powerful when there are both rare and common risk and protective variants. Both TOW-GE and VW-TOW-GE are robust to directions of effects of causal GxEs. Application to the COPDGene Study demonstrates that our proposed methods are very powerful.
Universal activation mechanism of class A GPCRs
Authors: Zhou Qingtong , Yang Dehua , Wu Meng , Guo Yu , Guo Wangjing , Zhong Li , Cai Xiaoqing , Dai Antao , Shakhnovich Eugene , Liu Zhi-Jie , Stevens Raymond C. , Madan Babu M. , Wang Ming-Wei , Zhao Suwen 
Published: July 2019

AbstractClass A G protein-coupled receptors (GPCRs) influence virtually every aspect of human physiology. GPCR activation is an allosteric process that links agonist binding to G protein recruitment, with the hallmark outward movement of transmembrane helix 6 (TM6). However, what leads to TM6 movement and the key residue-level changes of this trigger remain less well understood. Here, by analyzing over 230 high-resolution structures of class A GPCRs, we discovered a modular, universal GPCR activation pathway that unites previous findings into a common activation mechanism, directly linking the bottom of ligand-binding pocket with G protein-coupling region. We suggest that the modular nature of the universal GPCR activation pathway allowed for the decoupling of the evolution of the ligand binding site, G protein binding region and the residues important for receptor activation. Such an architecture might have facilitated GPCRs to emerge as a highly successful family of proteins for signal transduction in nature.
Effects of repetitive Iodine Thyroid Blocking on the Development of the Foetal Brain and Thyroid in rats: a Systems Biology approach
Authors: Cohen David P.A. , Benadjaoud Mohamed Amine , Lestaevel Phillipe , Lebsir Dalila , Benderitter Marc , Souidi Maâmar 
Published: July 2019

ABSTRACTA single dose of potassium iodide (KI) against repeated exposure to radioactive iodine, such as the one of the Fukushima accident, might not be effective enough to protect the thyroid. Our group showed that repetitive dose of KI for eight days offers efficient protection without toxic effects in adult rats. However, the effect of repetitive KI on the developing foetus still unknown especially on brain development, but a correlation between the impaired maternal thyroid status and a decrease in intelligence quotient has been observed. In this study, gene expression analysis of the progeny of repetitive KI-administered pregnant rats performed by our group showed distinct gene expression profile from two different organs: thyroid and cortex. To understand how these differentially expressed genes are implicated in the observed behaviour change, a systems biology approach was used to construct networks using three different techniques; Bayesian statistics using ShrinkNet, sPLS-DA on the DIABLO platform using mixOmics and manual construction of a Process Descriptive network. For each organ, we were able to construct gene expression network, to select genes that are most contributing to either control or KI-treated groups, respectively, and to construct the PD network from differentially expressed (DE) gene enriched with data from publications. Furthermore, we were able to connect DE genes from both organs into one network with genes from both organ participating in the same cellular processes that affect mitophagy and neuronal outgrowth.This work may help to evaluate the doctrine for using KI in case of repetitive or prolonged exposure to radioactive particles upon nuclear accidents.
Evolutionary history and classification of Micropia retroelements in Drosophilidae species
Authors: Cordeiro Juliana , Carvalho Tuane L. , Valente Vera L. da S. , Robe Lizandra J. 
Published: July 2019

AbstractCurrent knowledge indicates TEs have been shaping the evolution of genomes and host species, contributing to the creation of new genes and promoting rearrangements frequently associated with new regulatory networks. Support for these hypothesis frequently result from studies with model species, and Drosophila detaches as a great model organism to the study of TEs. Micropia belongs to the Ty3/Gypsy group of LTR retroelements, and comprises one of the least studied Drosophila transposable elements. In this study, we assessed the evolutionary history of Micropia within Drosophilidae, while trying to assist in the classification of this TE. At first, we analyzed its presence in the genome of several species from natural populations and then, based on searches within genomic databases, we retrieved Micropia-like sequences from distinct Drosophilidae species genomes. We expanded the knowledge of Micropia distribution within Drosophila, and detected an array of divergent sequences, which allowed subdividing this retroelement in 20 subfamilies. Even so, a patchy distribution of Micropia sequences within the Drosophilidae phylogeny could be identified combined with incongruences of the species and the Micropia phylogenies. Comparing dS values between Micropia and host nuclear sequences, we found several cases of unexpected high levels of similarity between Micropia sequences found in divergent species. All these findings propose a hypothesis to the evolution of Micropia within Drosophilidae, including several VTTs and HTTs events, associated to ancestral polymorphisms and recurrent Micropia sequences diversification.
CPO Complete, a novel test for fast, accurate phenotypic detection and classification of carbapenemases
Authors: Thomson Gina K. , AbdelGhani Sameh , Thomson Kenneth S. 
Published: July 2019

AbstractRapid, accurate detection of carbapenemase-producing organisms (CPOs) and the classification of their carbapenemases are valuable tools for reducing the mortality of the CPO-associated infections, preventing the spread of CPOs, and optimizing use of new β-lactamase inhibitor combinations such as ceftazidime/avibactam and meropenem/vaborbactam. The current study evaluated the performance of CPO Complete, a novel, manual, phenotypic carbapenemase detection and classification test. The test was evaluated for sensitivity and specificity against 262 CPO isolates ofEnterobacteriaceae, Pseudomonas aeruginosaandAcinetobacter baumanniiand 67 non-CPO isolates. It was also evaluated for carbapenemase classification accuracy against 205 CPOs that produced a single carbapenemase class. The test exhibited 100% sensitivity 98.5% specificity for carbapenemase detection within 90 minutes and detected 74.1% of carbapenemases within 10 minutes. In the classification evaluation, 99.0% of carbapenemases were correctly classified. The test is technically simple and has potential for adaptation to automated instruments. With lyophilized kit storage at temperatures up to 38°C the CPO Complete test has the potential to provide rapid, accurate carbapenemase detection and classification in both limited resource and technologically advanced laboratories.