bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted next-generation sequencing of Candidate Regions Identified by GWAS Revealed SNPs Associated with IBD in GSDs
Authors: Peiravan Atiyeh , Salavati Mazdak , Psifidi Androniki , Sharman Mellora , Kent Andrew , Watson Penny , Allenspach Karin , Werling Dirk 
Published: April 2021

AbstractCanine Inflammatory bowel disease (IBD) is a chronic multifactorial disease, resulting from complex interactions between the intestinal immune system, microbiota and environmental factors in genetically predisposed dogs. Previously, we identified several single nucleotide polymorphisms (SNP) and regions on chromosomes (Chr) 7, 9, 11 and 13 associated with IBD in German shepherd dogs (GSD) using GWAS and FST association analyses. Here, building on our previous results, we performed a targeted next-generation sequencing (NGS) of a two Mb region on Chr 9 and 11 that included 14 of the newly identified candidate genes, in order to identify potential functional SNPs that could explain these association signals. Furthermore, correlations between genotype and treatment response were estimated. Results revealed several SNPs in the genes for canineEEF1A1,MDH2,IL3,IL4,IL13andPDLIM, which, based on the known function of their corresponding proteins, further our insight into the pathogenesis of IBD in dogs. In addition, several pathways involved in innate and adaptive immunity and inflammatory responses (i.e. T helper cell differentiation, Th1 and Th2 activation pathway, communication between innate and adaptive immune cells and differential regulation of cytokine production in intestinal epithelial cells by IL-17A and IL-17F), were constructed involving the gene products in the candidate regions for IBD susceptibility. Interestingly, some of the identified SNPs were present in only one outcome group, suggesting that different genetic factors are involved in the pathogenesis of IBD in different treatment response groups. This also highlights potential genetic markers to predict the response in dogs treated for IBD.
Wasl is crucial to maintain microglial core activities during glioblastoma initiation stages
Authors: Mazzolini Julie , Clerc Sigrid Le , Morisse Gregoire , Coulonges Cédric , Zagury Jean-François , Sieger Dirk 
Published: April 2021

SummaryMicroglia actively promote the growth of high-grade gliomas. Within the glioma microenvironment an activated (amoeboid) microglial morphology has been observed, however the underlying causes and the related impact on microglia functions and their tumour promoting activities is unclear. Using the advantages of the larval zebrafish model, we demonstrate that pre-neoplastic glioma cells have an immediate impact on microglial morphology and functions. Overexpression of human HRasV12 in proliferating domains of the larval brain induces an amoeboid morphology of microglia, increases microglial numbers and decreases their motility and phagocytic activity. RNA sequencing analysis revealed lower expression levels of the actin nucleation promoting factorwaslain microglia. Importantly, a microglia specific rescue ofwaslaexpression restores microglial morphology and functions. This results in increased phagocytosis of pre-neoplastic cells and slows down tumour progression. In conclusion, we identified a mechanism that de-activates core microglial functions within the emerging glioma microenvironment.
Reference genome-independent taxonomic profiling of microbiomes with mOTUs3
Authors: Ruscheweyh Hans-Joachim , Milanese Alessio , Paoli Lucas , Karcher Nicolai , Clayssen Quentin , Metzger Marisa Isabell , Wirbel Jakob , Bork Peer , Mende Daniel R. , Zeller Georg , Sunagawa Shinichi 
Published: April 2021

AbstractBackgroundTaxonomic profiling is a fundamental task in microbiome research that aims to detect and quantify the relative abundance of microorganisms in biological samples. Available methods using shotgun metagenomic data generally depend on the availability of sequenced and taxonomically annotated reference genomes. However, the majority of microorganisms have not been cultured yet and lack such reference genomes. Thus, a substantial fraction of microbial community members remains unaccounted for during taxonomic profiling of metagenomes, particularly in samples from underexplored environments. To address this issue, we have developed the mOTU profiler, a tool that enables reference genome-independent species-level profiling of metagenomes. As such, it supports the identification and quantification of both “known” and “unknown” species based on a set of select marker genes.ResultsHere, we present mOTUs3, a command line tool that enables the profiling of metagenomes for >33,000 species-level operational taxonomic units. To achieve this, we leveraged the reconstruction and analysis of >600,000 draft genomes, most of which are metagenome assembled genomes (MAGs), from diverse microbiomes, including soil, freshwater systems, and the gastrointestinal tract of ruminants and other animals, which we found to be greatly underrepresented by reference genomes. Overall, two-thirds of all species-level taxa lacked a reference genome. The cumulative relative abundance of these newly included taxa was low in well-studied microbiomes, such as the human body sites (6-11%). By contrast, they accounted for substantial proportions (ocean, freshwater, soil: 43-63%) or even the vast majority (pig, fish, cattle: 60-80%) of the relative abundance across diverse non-human-associated microbiomes. Using community-developed benchmarks and datasets, we found mOTUs3 to be more accurate than other methods and to be more congruent with 16S rRNA gene-based methods for taxonomic profiling. Furthermore, we demonstrate that mOTUs3 greatly increases the resolution of well-known microbial groups into species-level taxa and helps identify new differentially abundant taxa in comparative metagenomic studies.ConclusionsWe developed mOTUs3 to enable accurate species-level profiling of metagenomes. Compared to other methods, it provides a more comprehensive view of prokaryotic community diversity, in particular for currently underexplored microbiomes. To facilitate comparative analyses by the research community, it is released with >11,000 precomputed profiles for publicly available metagenomes and is freely available at:https://github.com/motu-tool/mOTUs.
The effective population size modulates the strength of GC biased gene conversion in two passerines
Authors: Barton Henry J , Zeng Kai 
Published: April 2021

AbstractUnderstanding the determinants of genomic base composition is fundamental to understanding genome evolution. GC biased gene conversion (gBGC) is a key driving force behind genomic GC content, through the preferential incorporation of GC alleles over AT alleles during recombination, driving them towards fixation. The majority of work on gBGC has focussed on its role in coding regions, largely to address how it confounds estimates of selection. Non-coding regions have received less attention, particularly in regard to the interaction of gBGC and the effective population size (Ne) within and between species. To address this, we investigate how the strength of gBGC (B= 4Neb, wherebis the conversion bias) varies within the non-coding genome of two wild passerines. We use a dataset of published high coverage genomes (10 great tits and 10 zebra finches) to estimateB, nucleotide diversity, changes inNe, and crossover rates from linkage maps, in 1Mb homologous windows in each species. We demonstrate remarkable conservation of bothBand crossover rate between species. We show that the mean strength of gBGC in the zebra finch is more than double that in the great tit, consistent with its twofold greater effective population size.Balso correlates with both crossover rate and nucleotide diversity in each species. Finally, we estimate equilibrium GC content from both divergence and polymorphism data, which indicates thatBhas been increasing in both species, and provide support for population expansion explaining a large proportion of this increase in the zebra finch.Significance statementUnderstanding the forces that change the nucleotide base composition of genomes is central to understanding their evolution. One such force is GC biased gene conversion, a process that during recombination converts some heterozygous base positions to homozygous. This process is more likely to convert adenine and thymine bases to guanine and cytosine bases than the other way around, hence is GC biased. This increases the frequency of GC alleles in a way similar to positive selection. This process has largely been studied within protein coding regions, and not often compared between species. We measure its strength in the non-coding areas of the genomes of two bird species, showing it to be stronger in the species with the larger population size.
Epitranscriptome changes triggered by ammonium nutrition regulate the proteome response of maritime pine roots
Authors: Ortigosa Francisco , Lobato-Fernández César , Pérez-Claros Juan Antonio , Cantón Francisco R. , Ávila Concepción , Cánovas Francisco M. , Cañas Rafael A. 
Published: April 2021

ABSTRACTEpitranscriptomic modifications constitute a gene expression checkpoint in all living organisms. As nitrogen is an essential element for plant growth and development, a reasonable hypothesis is that changes in the epitranscriptome may regulate nitrogen acquisition and metabolism. In this study, epitranscriptomic modifications caused by ammonium nutrition were monitored in maritime pine roots through direct RNA sequencing using Oxford Nanopore Technology. Transcriptomic responses mainly affected transcripts involved in nitrogen and carbon metabolism, defense, hormone synthesis/signaling, and translation. Global detection of epitranscriptomic marks was performed to evaluate this posttranscriptional mechanism in untreated and ammonium-treated seedlings. Increased m6A deposition in the 3’-UTR was observed in response to ammonium, which seems to be correlated with poly(A) lengths and changes in the relative abundance of the corresponding proteins. The results showed that m6A deposition and its dynamics seem to be important regulators of translation under ammonium nutrition. These findings suggest that protein translation is finely regulated through epitranscriptomic marks likely by changes in mRNA poly(A) length, transcript abundance and ribosome protein composition. An integration of multiomics data suggests that the epitranscriptome modulates responses to developmental and environmental changes, including ammonium nutrition, through buffering, filtering, and focusing the final products of gene expression.
Commensal rodent habitat expansion enhances arthropod disease vectors on a tropical volcanic island
Authors: Wu De-Lun , Shih Han-Chun , Wang Jen-Kai , Teng Hwa-Jen , Kuo Chi-Chien 
Published: April 2021

AbstractRelease from predators and competitors on volcanic islands can lead to increased body size and population density, as well as expanded habitat usage of introduced animals relative to their mainland counterparts. Such alterations might help the spread of diseases on islands when these exotic animals also carry pathogenic agents, but is rarely investigated. The commensal Asian house rat (Rattus tanezumi) is confined to human residential surroundings in Taiwan mainland but can be observed in the primary forests of the nearby Orchid Island, a tropical volcanic island. Orchid Island is also a hotspot of scrub typhus, a lethal febrile disease transmitted by larval trombiculid mites (chiggers) infective of the rickettsiaOrientia tsutsugamushi(OT). We predicted an increase in chigger abundance when rodents, the primary host of chiggers, invade forests from human settlements as soils are largely devoid of in the latter habitat but is necessary for the survival of nymphal and adult mites. A trimonthly rodent survey in ten sites of three habitats (human resident, grassland, and forest) found onlyR. tanezumiand showed moreR. tanezumiand chiggers in forest than in human residential sites. There was a positive association between rodent and chigger abundance, as well between rodent body weight and load of chiggers. Lastly, >95% of chiggers wereLeptotrombidium delienseand their OT infection rates were similar among the habitats. Our study demonstrated potentially elevated risks of scrub typhus when the commensal rat is allowed to invade natural habitats on islands. In addition, while the success of invasive species can be ascribed to their parasites being left behind, island invaders might instead attain more parasites when the parasite requires only a single host (e.g. trombiculid mite), is a host generalist (L. deliense), and is transferred from unsuitable to suitable habitats (human settlement on mainland to forest on island).
Locating Macromolecular Assemblies in Cells by 2D Template Matching withcisTEM
Authors: Lucas Bronwyn A. , Himes Benjamin A. , Xue Liang , Grant Timothy , Mahamid Julia , Grigorieff Nikolaus 
Published: April 2021

AbstractOver the last decade, single-particle electron cryo-microscopy has become one of the main techniques contributing to the growing library of high-resolution structures of macromolecules and their assemblies. For a full understanding of molecular mechanisms, however, it is important to place them into the broader context of a cell. Traditionally, this context can be visualized in 3D by electron cryo-tomography, and more recently, has also been studied by template matching of 2D images of cells and viruses. A current limitation of the latter approach is the high computational cost that limits the throughput and widespread adoption of this method. We describe here a GPU-accelerated implementation of 2D template matching in the image processing softwarecisTEM that allows for easy scaling and improves the accessibility of this approach. We apply 2D template matching to identify ribosomes in images of frozen-hydratedMycoplasma pneumoniaecells and demonstrate that it can function as a versatile tool forin situvisual proteomics andin situstructure determination. We compare the results with 3D template matching of tomograms acquired on identical sample locations. We identify strengths and weaknesses of both techniques which offer complementary information about target localization and identity.
Molecular features of exceptional response to neoadjuvant anti-androgen therapy in high-risk localized prostate cancer
Authors: Tewari Alok K. , Cheung Alexander T.M. , Crowdis Jett , Conway Jake R. , Camp Sabrina Y. , Wankowicz Stephanie A. , Livitz Dimitri G. , Park Jihye , Lis Rosina T. , Boosma-Moody Alice , He Meng Xiao , AlDubayan Saud H. , Zhang Zhenwei , McKay Rana R. , Leshchiner Ignaty , Brown Myles , Balk Steve , Getz Gad , Taplin Mary-Ellen , Van Allen Eliezer M. 
Published: April 2021

ABSTRACTHigh-risk localized prostate cancer (HRLPC) is associated with a substantial risk of recurrence and prostate cancer-specific mortality1. Recent clinical trials have shown that intensifying anti-androgen therapies administered prior to prostatectomy can induce pathologic complete responses (pCR) or minimal residual disease (MRD) (<5 mm), together termed exceptional response, although the molecular determinants of these clinical outcomes are largely unknown. Here, we performed whole exome (WES) and whole transcriptome sequencing (RNA-seq) on pre-treatment multi-regional tumor biopsies from exceptional responders (ER: pCR and MRD patients) and non-responders (NR: pathologic T3 or lymph node positive disease) treated with intensive anti-androgen therapies prior to prostatectomy. SPOP mutation and SPOPL copy number loss were exclusively observed in ER, while TP53 mutation and PTEN copy number loss were exclusively observed in NR. These alterations were clonal in all tumor phylogenies per patient. Additionally, transcriptional programs involving androgen signaling and TGFβ signaling were enriched in ER and NR, respectively. The presence of these alterations in routine biopsies from patients with HRLPC may inform the prospective identification of responders to neoadjuvant anti-androgen therapies to improve clinical outcomes and stratify other patients to alternative biologically informed treatment strategies.
A push-pull system of repressors matches levels of glucose transporters to extracellular glucose in budding yeast
Authors: Montaño-Gutierrez Luis Fernando , Sturrock Marc , Farquhar Iseabail , Correia Kevin , Shahrezaei Vahid , Swain Peter S. 
Published: April 2021

SummaryA common cellular task is to match gene expression dynamically to a range of concentrations of a regulatory molecule. Studying glucose transport in budding yeast, we determine mechanistically how such matching occurs for seven hexose transporters. By combining time-lapse microscopy with mathematical modelling, we find that levels of transporters are history-dependent and are regulated by a push-pull system comprising two types of repressors. Repression by these two types varies with glucose in opposite ways, and not only matches the expression of transporters by their affinity to a range of glucose concentrations, but also the expression of some to how glucose is changing. We argue that matching is favoured by a rate-affinity trade-off and that the regulatory system allows yeast to import glucose rapidly enough to starve competitors. Matching expression to a pattern of input is fundamental, and we believe that push-pull repression is widespread.
Genome annotation with long RNA reads reveals new patterns of gene expression in an ant brain
Authors: Shields Emily J. , Sorida Masato , Sheng Lihong , Sieriebriennikov Bogdan , Ding Long , Bonasio Roberto 
Published: April 2021

AbstractFunctional genomic analyses rely on high-quality genome assemblies and annotations. Highly contiguous genome assemblies have become available for a variety of species, but accurate and complete annotation of gene models, inclusive of alternative splice isoforms and transcription start and termination sites remains difficult with traditional approaches. Here, we utilized full-length isoform sequencing (Iso-Seq), a long-read RNA sequencing technology, to obtain a comprehensive annotation of the transcriptome of the antHarpegnathos saltator. The improved genome annotations include additional splice isoforms and extended 3’ untranslated regions for more than 4,000 genes. Reanalysis of RNA-seq experiments using these annotations revealed several genes with caste-specific differential expression and tissue-or caste-specific splicing patterns that were missed in previous analyses. The extended 3’ untranslated regions afforded great improvements in the analysis of existing single-cell RNA-seq data, resulting in the recovery of the transcriptomes of 18% more cells. The deeper single-cell transcriptomes obtained with these new annotations allowed us to identify additional markers for several cell types in the ant brain, as well as genes differentially expressed across castes in specific cell types. Our results demonstrate that Iso-Seq is an efficient and effective approach to improve genome annotations and maximize the amount of information that can be obtained from existing and future genomic datasets inHarpegnathosand other organisms.
Exploring Extreme Signaling Failures in Intracellular Molecular Networks
Authors: Ozen Mustafa , Emamian Effat S. , Abdi Ali 
Published: April 2021

AbstractDeveloping novel methods for the analysis of intracellular signaling networks is essential for understanding interconnected biological processes that underlie complex human disorders. A fundamental goal of this research is to quantify the vulnerability of a signaling network to the dysfunction of one or multiple molecules, when the dysfunction is defined as an incorrect response to the input signals. In this study, we propose an efficient algorithm to identify the extreme signaling failures that can induce the most detrimental impact on the physiological function of a molecular network. The algorithm basically finds the molecules, or groups of molecules, with the maximum vulnerability, i.e., the highest probability of causing the network failure, when they are dysfunctional. We propose another algorithm that efficiently accounts for signaling feedbacks in this analysis. The algorithms are tested on two experimentally verified ERBB and T cell signaling networks. Surprisingly, results reveal that as the number of concurrently dysfunctional molecules increases, the maximum vulnerability values quickly reach to a plateau following an initial increase. This suggests the specificity of vulnerable molecule (s) involved, as a specific number of faulty molecules cause the most detrimental damage to the function of the network. Increasing a random number of simultaneously faulty molecules does not further deteriorate the function of the network. Such a group of specific molecules whose dysfunction causes the extreme signaling failures can better elucidate the molecular mechanisms underlying the pathogenesis of complex trait disorders, and can offer new insights for the development of novel therapeutics.
Chemogenetic stimulation of a retinal circuit activates brain noradrenergic neurons, prevents apoptosis and suppresses depression-like behaviors
Authors: Bowrey Hannah E , James Morgan H , Omrani Mohsen , Mohammadkhani Aida , Aston-Jones G 
Published: April 2021

AbstractA chronically dysregulated locus coeruleus (LC) system gives rise to mood disorders. In particular, prolonged LC hyperactivity often underlies stress disorders, whereas chronically reduced function often underlies symptoms of depression. Owing to its location deep in the brainstem, LC is difficult to access which limits translational approaches that involve manipulating these neurons. Here, we circumvent this problem by utilizing the retina as a chemogenetic target for commandeering a multsynaptic circuit to LC. We show that activation of this pathway can prevent depression-like behavior and associated pathology of the LC-noradrenergic (NA) system caused by light deprivation. Additionally, we show that melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) are the likely cell type responsible for initiating activity in this pathway. By capitalizing on this ocular route of designer receptor delivery, we demonstrate a novel, minimally-invasive method for manipulating this deep-brain circuit that is relevant to a wide array of neuropsychiatric disorders.