bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interdependence of EGFR with PTPs on juxtaposed membranes generates a growth factor sensing and responding network
Authors: Stanoev Angel , Mhamane Amit , Schuermann Klaus C. , Grecco Hernán E. , Stallaert Wayne , Baumdick Martin , Brüggemann Yannick , Joshi Maitreyi S. , Roda-Navarro Pedro , Fengler Sven , Stockert Rabea , Roßmannek Lisaweta , Luig Jutta , Koseska Aneta , Bastiaens Philippe I. H. 
Published: April 2018

SummaryThe proto-oncogenic epidermal growth factor receptor (EGFR) is a tyrosine kinase whose sensitivity to growth factors (GFs) and signal duration determines cellular behavior. We resolve how EGFR’s response to epidermal growth factor (EGF) originates from dynamically established recursive interactions with spatially organized protein tyrosine phosphatases (PTPs). Opposed genetic PTP perturbations enabled identification of receptor-like PTPRG/J at the plasma membrane (PM) and endoplasmic reticulum (ER) associated PTPN2 as the major EGFR dephosphorylating activities. Imaging spatial-temporal PTP reactivity then revealed that vesicular trafficking establishes a spatially-distributed negative feedback with PTPN2 that determines signal duration, whereas single cell dose-response analysis uncovered a ROS-mediated toggle switch between autocatalytically activated monomeric EGFR and the tumor suppressor PTPRG that governs EGFR’s sensitivity to EGF. Vesicular recycling of monomeric EGFR unifies the interactions with these PTPs on juxtaposed membranes, dynamically generating a network architecture that can sense and respond to time varying growth factor signals.
Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit
Authors: Nadjsombati Marija S. , McGinty John W. , Lyons-Cohen Miranda R. , Pollack Joshua L. , Gowda G.A. Nagana , Erle David J. , Locksley Richard M. , Raftery Daniel , von Moltke Jakob 
Published: April 2018

SummaryInitiation of immune responses requires innate immune sensing, but immune detection of the helminths, protists, and allergens that stimulate type 2 immunity remains poorly understood. In the small intestine, type 2 immune responses are regulated by a tuft cell-ILC2 signaling circuit. Tuft cells express components of a canonical taste transduction pathway, including the membrane channel TRPM5, but the ligands and receptors that activate tuft cells in the small intestine are unknown. Here we identify succinate as the first ligand that activates intestinal tuft cells to initiate type 2 immune responses. Using mRNA-Seq on tuft cells from different tissues, we show that all tuft cells express the intracellular taste transduction pathway, but expression of upstream receptors is tissue-specific. In the small intestine, tuft cells express the succinate receptor SUCNR1. Remarkably, providing succinate in drinking water is sufficient to induce a multifaceted type 2 immune response in the murine small intestine, involving all known components of the tuft-ILC2 circuit. The helminthNippostrongylus brasiliensissecretes succinate as a metabolite, and sensing of both succinate andN. brasiliensisrequires tuft cells and TRPM5, suggesting a novel paradigm in which type 2 immunity monitors microbial metabolism. Manipulation of succinate sensing may have therapeutic benefit in numerous intestinal diseases.
Cargo-Loading of Misfolded Proteins into Extracellular Vesicles: The CSPα-EV Export Pathway
Authors: Pink Desmond , Donnelier Julien , Lewis John , Braun Janice E.A. 
Published: April 2018

AbstractExtracellular vesicles (EVs) are secreted vesicles of diverse size and cargo that are implicated in the cell-to-cell transmission of disease-causing-proteins in several neurodegenerative diseases. Mutant huntingtin, the disease-causing entity in Huntington’s disease, has an expanded polyglutamine track at the N terminus that causes the protein to misfold and form toxic intracellular aggregates. In Huntington’s disease, mutant huntingtin aggregates are transferred between cells by an unknown route. We have previously identified a cellular pathway that is responsible for the export of mutant huntingtin via extracellular vesicles, given the heterogeneity of EVs, here we examine the specific EVs involved. In this work we expressed a form of polyglutamine expanded huntingtin (GFP-tagged 72Qhuntingtinexon1) in cells to assess the EVs involved in cellular export. We demonstrate that the molecular chaperone, cysteine string protein (CSPα; DnaJC5), mediates export of disease-causing-polyglutamine-expanded huntingtin cargo via two distinct vesicle populations of 180-240nm and 15-30μm. In doing so, our data links the molecular chaperone, CSPα, and the packaging of pathogenic misfolded huntingtin into two separate extracellular vesicles pathways.
Optimizing the identification of causal variants across varying genetic architectures in crops
Authors: Miao Chenyong , Yang Jinliang , Schnable James C. 
Published: April 2018

AbstractBackgroundAssociation studies use statistical links between genetic markers and variation in a phenotype’s value across many individuals to identify genes controlling variation in the target phenotype. However, this approach, particularly conducted on a genome-wide scale (GWAS), has limited power to identify the genes responsible for variation in traits controlled by complex genetic architectures.ResultsHere we employ simulation studies utilizing real-world genotype datasets from association populations in four species with distinct minor allele frequency distributions, population structures, and patterns linkage disequilibrium to evaluate the impact of variation in both heritability and trait complexity on both conventional mixed linear model based GWAS and two new approaches specifically developed for complex traits. Mixed linear model based GWAS rapidly losses power for more complex traits. FarmCPU, a method based on multi-locus mixed linear models, provides the greatest statistical power for moderately complex traits. A Bayesian approach adopted from genomic prediction provides the greatest statistical power to identify causal genetic loci for extremely complex traits.ConclusionsUsing estimates of the complexity of the genetic architecture of target traits can guide the selection of appropriate statistical methods and improve the overall accuracy and power of GWAS.
U1 snRNP regulates chromatin retention of noncoding RNAs
Authors: Yin Yafei , Yuyang Lu J. , Zhang Xuechun , Shao Wen , Xu Yanhui , Li Pan , Hong Yantao , Zhang Qiangfeng Cliff , Shen Xiaohua 
Published: April 2018

AbstractThousands of noncoding transcripts exist in mammalian genomes, and they preferentially localize to chromatin. Here, to identify cis-regulatory elements that control RNA-chromatin association, we developed a high-throughput method named RNA element for subcellular localization by sequencing (REL-seq). Coupling REL-seq with random mutagenesis (mutREL-seq), we discovered a key 7-nt U1 recognition motif in chromatin-enriched RNA elements. Reporter assays indicated a direct role for U1 snRNP recognition in regulating RNA-chromatin localization. Globally, U1 motifs and U1 binding are strongly enriched in long noncoding RNA (lncRNA) transcripts. Inhibition of U1 snRNA, and of U2 to a lesser degree, led to global reduction in chromatin association of hundreds of lncRNAs. For promoter- and enhancer-associated noncoding RNAs, U1 binds to their genomic neighborhoods, and their chromatin association depends on both U1 and U2 snRNAs. These findings reveal that U1 snRNP, perhaps together with the splicing machinery, acts widely to promote the chromatin association of noncoding transcripts.
The MarR Family Regulator BmrR is involved in Bile Tolerance ofBifidobacterium longumBBMN68 via Controlling the Expression of an ABC-Transporter
Authors: Xu Qi , Zhai Zhengyuan , An Haoran , Yang Yang , Yin Jia , Wang Guohong , Ren Fazheng , Hao Yanling 
Published: April 2018

AbstractIn order to colonize the human gastrointestinal tract and exert their beneficial effects, bifidobacteria must effectively cope with the toxic bile salts in the intestine, but the molecular mechanism underlying bile tolerance is poorly understood. In this study, heterologous expression of a MarR family transcriptional regulator BmrR significantly reduced ox-bile resistance ofLactococcus lactisNZ9000, suggesting that it might play a role in bile stress response.In silicoanalysis combined with RT-PCR assay demonstrated thatbmrRwas co-transcribed withbmrAandbmrB,which encoded multidrug resistance (MDR) ABC transporters. Promoter prediction and EMSA assay revealed that BmrR could autoregulate thebmrRABoperon by binding tobmrbox (ATTGTTG-6nt-CAACAAT) in the promoter region. Moreover, heterologous expression ofbmrAandbmrBinL. lactisshowed 20.77-fold higher tolerance to 0.10% ox-bile compared to wild type strain. In addition, ox-bile could disrupt the DNA binding activity of BmrR as a ligand. Taken together, our findings indicate thatbmrRABoperon is autoregulated by transcriptional regulator BmrR and ox-bile serves as an inducer to activate the bile efflux transporter BmrAB in response to bile stress inB. longumBBMN68.ImportanceBifidobacteria are natural inhabitants of the human intestinal tract. Some bifidobacterial strains are used as probiotics in fermented dairy production because of their health-promoting effects. Following consumption, bifidobacteria finally colonize the lower intestinal tract where the concentration of bile salts remains nearly 0.05% to 2.0%. Bile salts as detergent-like antimicrobial compounds can cause disruption of the cellular membrane, protein misfolding and DNA damage. Therefore, tolerance to physiological bile stress is indeed essential for bifidobacteria to survive and exert the probiotic effects in gastrointestinal tract. InB. longumBBMN68, the MarR-type regulator BmrR was involved in bile stress response by auto-regulatingbmrRABoperon and ox-bile as an inducer could increase the expression of BmrAB transporter to enhance the bile tolerance of BBMN68.This is the first report about functional analysis ofbmrRABoperon in bile stress response, which will provide new insight into bile tolerance mechanisms inBifidobacteriumand other bacteria.
Forces on nascent polypeptides during membrane insertion and translocation via the Sec translocon
Authors: Niesen Michiel J.M. , Müller-Lucks Annika , Hedman Rickard , von Heijne Gunnar , Miller Thomas F. 
Published: April 2018

ABSTRACTDuring ribosomal translation, nascent polypeptide chains (NCs) undergo a variety of physical processes that determine their fate in the cell. Translation arrest peptide (AP) experiments are used to measure the external pulling forces that are exerted on the NC at different lengths during translation. To elucidate the molecular origins of these forces, a recently developed coarsegrained molecular dynamics (CGMD) is used to directly simulate the observed pulling-force profiles, thereby disentangling contributions from NC-translocon and NC-ribosome interactions, membrane partitioning, and electrostatic coupling to the membrane potential. This combination of experiment and theory reveals mechanistic features of Sec-facilitated membrane integration and protein translocation, including the interplay between transient interactions and conformational changes that occur during ribosomal translation to govern protein biogenesis.
Anthropogenic habitat alteration leads to rapid loss of adaptive variation and restoration potential in wild salmon populations
Authors: Thompson Tasha Q. , Bellinger Renee M. , O’Rourke Sean M. , Prince Daniel J. , Stevenson Alexander E. , Rodrigues Antonia T. , Sloat Matthew R. , Speller Camilla F. , Yang Dongya Y. , Butler Virginia L. , Banks Michael A. , Miller Michael R. 
Published: April 2018

AbstractPhenotypic variation is critical for the long-term persistence of species and populations. Anthropogenic activities have caused substantial shifts and reductions in phenotypic variation across diverse taxa, but the underlying mechanism (i.e., phenotypic plasticity and/or genetic evolution) and potential to recover previous phenotypic characteristics are unclear. Here we investigate changes in adult migration characteristics of wild salmon populations caused by dam construction and other anthropogenic habitat modifications. Strikingly, we find that dramatic allele frequency change (i.e., genetic evolution) from strong selection at a single locus explains the rapid phenotypic shift observed after recent dam construction. Furthermore, ancient DNA analysis confirms the abundance of a specific allele associated with adult migration type in historical habitat that will soon become accessible through a large restoration (i.e., dam removal) project. However, analysis of contemporary samples suggests the restoration will be challenged by loss of the allele from potential source populations. These results highlight the need to conserve and restore critical adaptive variation before the potential for recovery is lost.
Genome-wide DNA methylation patterns in Autism Spectrum Disorder and mitochondrial function
Authors: Stathopoulos Sofia , Gaujoux Renaud , O’Ryan Colleen 
Published: April 2018

AbstractAutism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterised by phenotypic heterogeneity and overlapping co-morbidities. The genetic architecture of ASD is complex, with 100’s of risk genes cumulatively contributing to the aetiology of ASD. Epigenetic mechanisms, particularly DNA methylation, have been associated with ASD. The vast majority of ASD molecular research has focused on Northern European populations, with a paucity of data from Africa. This study examines genome-wide DNA methylation patterns in a novel cohort of South African children with ASD and matched, unrelated controls. We performed a whole-genome DNA methylation screen using the Illumina 450K Human Methylation Array. We identify differentially methylated loci associated with ASD across 898 genes (p-value ≤ 0.05). Using a pathway analysis framework, we find nine enriched canonical pathways implicating 32 of the significant genes in our ASD cohort. These pathways converge on two crucial biological processes: mitochondrial metabolism and protein ubiquitination, both hallmarks of mitochondrial function. The involvement of mitochondrial function in ASD aetiology is in line with the recently reported transcriptomic dysregulation associated with the disorder. The differentially methylated genes in our cohort overlap with the gene co-expression modules identified in brain tissue from five major neurological disorders, including ASD. We find significant enrichment of three gene modules, two of which are classified as Mitochondrial and were significantly downregulated in ASD brains. Furthermore, we find significant overlap between differentially methylated and differentially expressed genes from our dataset with a RNA seq dataset from ASD brain tissue. This overlap is particularly significant across the Occipital brain region (padj= 0.0002) which has known association to ASD. Our differential methylation data recapitulate the expression differences of genes and co-expression module functions observed in ASD brain tissue which is consistent with a central role for DNA-methylation leading to mitochondrial dysfunction in the aetiology of ASD.
A Monte Carlo method forin silicomodeling and visualization of Waddington’s epigenetic landscape with intermediate details
Authors: Zhang Xiaomeng , Chong Ket Hing , Zheng Jie 
Published: April 2018

AbstractWaddington’s epigenetic landscape is a classic metaphor for describing the cellular dynamics during the development modulated by gene regulation. Quantifying Waddington’s epigenetic landscape by mathematical modeling would be useful for understanding the mechanisms of cell fate determination. A few computational methods have been proposed for quantitative modeling of landscape; however, to model and visualize the landscape of a high dimensional gene regulatory system with realistic details is still challenging. Here, we propose a Monte Carlo method for modeling the Waddington’s epigenetic landscape of a gene regulatory network (GRN). The method estimates the probability distribution of cellular states by collecting a large number of time-course simulations with random initial conditions. By projecting all the trajectories into a 2-dimensional plane of dimensionsiandj, we can approximately calculate the quasi-potentialU(xi,xj) = −lnP(xi,xj), whereP(xi,xj) is the estimated probability of an equilibrium steady state or a non-equilibrium state. A state with locally maximal probability corresponds to a locally minimal potential and such a state is called an attractor. Compared to the state-of-the-art methods, our Monte Carlo method can quantify the global potential landscape (or emergence behavior) of GRN for a high dimensional system. The same topography of landscape can be produced from deterministic or stochastic time-course simulations. The potential landscapes show that not only attractors represent stability, but the paths between attractors are also part of the stability or robustness of biological systems. We demonstrate the novelty and reliability of our method by plotting the potential landscapes of a few published models of GRN. Besides GRN-driven landscapes of cellular dynamics, the algorithm proposed can also be applied to studies of global dynamics (or emergence behavior) of other dynamical systems.
Bracketing phenotypic limits of mammalian hybridization
Authors: Savriama Yoland , Valtonen Mia , Kammonen Juhana , Rastas Pasi , Smolander Olli-Pekka , Lyyski Annina , Häkkinen Teemu J. , Corfe Ian J. , Gerber Sylvain , Salazar-Ciudad Isaac , Paulin Lars , Holm Liisa , Löytynoja Ari , Auvinen Petri , Jernvall Jukka 
Published: April 2018

AbstractAn increasing number of mammalian species have been shown to have a history of hybridization and introgression based on genetic analyses. Only relatively few fossils, however, preserve genetic material and morphology must be used to identify the species and determine whether morphologically intermediate fossils could represent hybrids. Because dental and cranial fossils are typically the key body parts studied in mammalian paleontology, here we bracket the potential for phenotypically extreme hybridizations by examining uniquely preserved cranio-dental material of a captive hybrid between gray and ringed seals. We analyzed how distinct these species are genetically and morphologically, how easy it is to identify the hybrids using morphology, and whether comparable hybridizations happen in the wild. We show that the genetic distance between these species is more than twice the modern human-Neanderthal distance, but still within that of morphologically similar species-pairs known to hybridize. In contrast, morphological and developmental analyses show gray and ringed seals to be highly disparate, and that the hybrid is a predictable intermediate. Genetic analyses of the parent populations reveal introgression in the wild, suggesting that gray-ringed seal hybridization is not limited to captivity. Taken together, gray and ringed seals appear to be in an adaptive radiation phase of evolution, showing large morphological differences relative to their comparatively modest genetic distance. Because morphological similarity does not always correlate with genetic distance in nature, we postulate that there is considerable potential for mammalian hybridization between phenotypically disparate taxa.
Exome sequencing in families with severe mental illness identifies novel and rare variants in genes implicated in Mendelian neuropsychiatric syndromes
Authors: Ganesh Suhas , Husayn Ahmed P , Nadella Ravi Kumar , More Ravi Prabhakar , Sheshadri Manasa , Viswanath Biju , Rao Mahendra , Jain Sanjeev ,   The ADBS consortium, Mukherjee Odity 
Published: April 2018

AbstractIntroductionSevere Mental Illnesses (SMI), such as bipolar disorder and schizophrenia, are highly heritable, and have a complex pattern of inheritance. Genome wide association studies detect a part of the heritability, which can be attributed to common genetic variation. Examination of rare variants with Next Generation Sequencing (NGS) may add to the understanding of genetic architecture of SMIs.MethodsWe analyzed 32 ill subjects (with diagnosis of Bipolar Disorder, n=26; schizophrenia, n=4; schizoaffective disorder, n=1 schizophrenia like psychosis, n=1) from 8 multiplex families; and 33 healthy individuals by whole exome sequencing. Prioritized variants were selected by a 4-step filtering process, which included deleteriousness by 5 in silico algorithms; sharing within families, absence in the controls and rarity in South Asian sample of Exome Aggregation Consortium.ResultsWe identified a total of 42 unique rare, non-synonymous deleterious variants in this study with an average of 5 variants per family. None of the variants were shared across families, indicating a ‘private’ mutational profile. Twenty (47.6%) of the variant harboring genes identified in this sample have been previously reported to contribute to the risk of neuropsychiatric syndromes. These include genes which are related to neurodevelopmental processes, or have been implicated in different monogenic syndromes with a severe neurodevelopmental phenotype.ConclusionNGS approaches in family based studies are useful to identify novel and rare variants in genes for complex disorders like SMI. The study further validates the phenotypic burden of rare variants in Mendelian disease genes, indicating pleiotropic effects in the etiology of severe mental illnesses.
ovoDco-selection: a method for enriching CRISPR/Cas9-edited alleles inDrosophila
Authors: Ewen-Campen Ben , Perrimon Norbert 
Published: April 2018

ABSTRACTScreening for successful CRISPR/Cas9 editing events remains a time consuming technical bottleneck in the field ofDrosophilagenome editing. This step can be particularly laborious for events that do not cause a visible phenotype, or those which occur at relatively low frequency. A promising strategy to enrich for desired CRISPR events is to co-select for an independent CRISPR event that produces an easily detectable phenotype. Here, we describe a simple negative co-selection strategy involving CRISPR-editing of a dominant female sterile allele,ovoD1. In this system (“ovoDco-selection”), the only functional germ cells in injected females are those that have been edited at theovoD1locus, and thus 100% of the offspring of these flies have undergone editing of at least one locus. We demonstrate thatovoDco-selection can be used to enrich for knock-out mutagenesis via nonhomologous end-joining (NHEJ), and for knock-in alleles via homology-directed repair (HDR). Altogether, our results demonstrate thatovoDco-selection reduces the amount of screening necessary to isolate desired CRISPR events inDrosophila.