bluuebunny/crossref_metadata_2025_split huggingface dataset:
meTCRs - Learning a metric for T-cell receptors
Authors: Drost Felix , Schiefelbein Lennard , Schubert Benjamin 
Published: October 2022

AbstractT cell receptors (TCRs) bind to pathogen- or self-derived epitopes to elicit a T cell response as part of the adaptive immune system. Determining the specificity of TCRs provides context for immunological studies and can be used to identify candidates for novel immunotherapies. To avoid costly experiments, large-scale TCR-epitope databases are queried for similar sequences via various distance functions. Here, we developed the deep-learning based distancemeTCRs. Contrary to most previous approaches, the method avoids computational expansive pairwise string operations by comparing TCRs in a numeric embedding. In contrast to models which are trained specificity-agnostic, we directly utilize epitope information by applying deep metric learning to guide the training. Summarizing, we presentmeTCRsas a scalable alternative to embed TCR repertoires for clustering, visualisation, and querying against the ever-increasing amount TCR-epitope pairs in publicly available databases.
A common neural code for representing imagined and inferred tastes
Authors: Avery Jason A. , Carrington Madeline , Martin Alex 
Published: October 2022

SUMMARYInferences about the taste of foods are a key aspect of our everyday experience of food choice. Despite this, gustatory mental imagery is a relatively under-studied aspect of our mental lives. In the present study, we examined subjects during high-field fMRI as they actively imagined basic tastes and subsequently viewed pictures of foods dominant in those specific taste qualities. Imagined tastes elicited activity in the bilateral dorsal mid-insula, one of the primary cortical regions responsive to the experience of taste. In addition, within this region we reliably decoded imagined tastes according to their dominant quality - sweet, sour, or salty – thus indicating that, like actual taste, imagined taste activates distinct quality-specific neural patterns. Using a cross-task decoding analysis, we found that the neural patterns for imagined tastes and food pictures in the mid-insula were reliably similar and quality-specific, suggesting a common code for representing taste quality regardless of whether explicitly imagined or automatically inferred when viewing food. These findings have important implications for our understanding of the mechanisms of mental imagery and the multimodal nature of presumably primary sensory brain regions like the dorsal mid-insula.
Complete sequencing of a cynomolgus macaque major histocompatibility complex haplotype
Authors: Karl Julie A. , Prall Trent M. , Bussan Hailey E. , Varghese Joshua M. , Pal Aparna , Wiseman Roger W. , O’Connor David H. 
Published: October 2022

AbstractMacaques provide the most widely used nonhuman primate models for studying immunology and pathogenesis of human diseases. While the macaque major histocompatibility complex (MHC) region shares most features with the human leukocyte antigen (HLA) region, macaques have an expanded repertoire of MHC class I genes. Although a chimera of two rhesus macaque MHC haplotypes was first published in 2004, the structural diversity of MHC genomic organization in macaques remains poorly understood due to a lack of adequate genomic reference sequences. We used ultra-long Oxford Nanopore and high-accuracy PacBio HiFi sequences to fully assemble the ∼5.2 Mb M3 haplotype of an MHC-homozygous, Mauritian-origin cynomolgus macaque (Macaca fascicularis). The MHC homozygosity allowed us to assemble a single MHC haplotype unambiguously and avoid chimeric assemblies that hampered previous efforts to characterize this exceptionally complex genomic region in macaques. The high quality of this new assembly is exemplified by the identification of an extended cluster of sixMafa-AGgenes that contains a recent duplication with a remarkably similar ∼48.5 kb block of sequence. The MHC class II region of this M3 haplotype is similar to the previously sequenced rhesus macaque haplotype and HLA class II haplotypes. The MHC class I region, in contrast, contains 13MHC-Bgenes, fourMHC-Agenes, and threeMHC-Egenes (versus 19MHC-B, twoMHC-A, and oneMHC-Ein the previously sequenced haplotype). These results provide an unambiguously assembled single contiguous cynomolgus macaque MHC haplotype with fully curated gene annotations that will inform infectious disease and transplantation research.
Granulin Loss of Function in Human Mature Brain Organoids Implicates Astrocytes in TDP-43 Pathology
Authors: de Majo Martina , Koontz Mark , Marsan Elise , Salinas Nir , Ramsey Arren , Kuo Yien-Ming , Seo Kyounghee , Li Huinan , Dräger Nina M , Leng Kun , Gonzales Santiago L , Kurnellas Michael , Miyaoka Yuichiro , Klim Joseph R , Kampmann Martin , Ward Michael E , Huang Eric J , Ullian Erik M 
Published: October 2022

SummaryLoss of function (LoF) of Tar-binding protein 43 (TDP-43) and mislocalization, together with TDP-43-positive and hyperphosphorylated inclusions, are found in postmortem tissue of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients, including those carrying LoF variants in the progranulin gene (GRN). Modelling TDP-43 pathology has been challengingin vivoandin vitro. We present a 3D-induced pluripotent stem cell (iPSC)-derived paradigm - mature brain organoids (mbOrg) - composed of cortical-like-astrocytes (iA) and neurons (iN). When devoid ofGRN, mbOrgs spontaneously recapitulate TDP-43 mislocalization, hyperphosphorylation and LoF phenotypes. Mixing-and-matching genotypes in mbOrgs showed thatGRN−/−iA are drivers for TDP-43 pathology. Finally, we rescued TDP-43 LoF by adding exogenous progranulin, demonstrating a link between TDP-43 LoF and progranulin expression. In conclusion, we present an iPSC-derived platform that shows striking features of human TDP-43 proteinopathy and provides a tool for mechanistic modelling of TDP-43 pathology and patient-tailored therapeutic screening for FTD and ALS.HighlightsGRN−/−iPSC-derived 3D paradigm (mbOrg) composed of mature cortical-like astrocytes and neurons recapitulates features of TDP-43 proteinopathyGRN−/−cortical-like astrocytes are necessary and sufficient for the development of the TDP-43 loss of function phenotype in mbOrg.A TDP-43 phenotype can be rescued in neurons by treating neuron and astrocyte co-cultures with progranulin full length protein.eTOC blurbIn this article, de Majo and colleagues present a novel 3D iPSC-derived model to study neurodegenerative disorders such as ALS and FTD. When devoid ofGRNexpression, these cultures present features of ALS and FTD associated pathology hardly ever observedin vitro. These phenotypes are shown to be primarily driven by diseased astrocytes and can be rescued by progranulin supplementation.
hgtseq: a standard pipeline to study horizontal gene transfer
Authors: Carpanzano Simone , Santorsola Mariangela ,   nf-core community, Lescai Francesco 
Published: October 2022

AbstractHorizontal gene transfer (HGT) is well described in prokaryotes, it plays a crucial role in evolution, and has functional consequences in insects and plants: less is known about HGT in Humans. Studies have reported bacterial integrations in cancer patients, and microbial sequences have been detected in data from well-known Human sequencing projects. Few of the existing tools to investigate HGT are highly automated. Thanks to the adoption of Nextflow for life sciences work-flows, and the standards and best practices curated by communities such as nf-core, fully automated, portable, and scalable pipelines can now be developed. Here we present nf-core/hgtseq, to facilitate the analysis of HGT from sequencing data in different organisms. We showcase its performance by analysing six exome datasets from five mammals. Hgtseq can be run seamlessly in any computing environment and accepts data generated by existing exome and whole-genome sequencing projects: this will enable researchers to expand their analyses into this area. Fundamental questions are still open, about the mechanisms and the extent or the role of horizontal gene transfer: by releasing hgtseq we provide a standardised tool which will enable a systematic investigation of this phenomenon, thus paving the way for a better understanding of HGT.
Development and application of genetic ancestry reconstruction methods to study diversity of patient-derived models in the NCI PDXNet Consortium
Authors: Sanderson Brian J. , Lott Paul , Chiu Katherine , Quino Juanita Elizabeth , Vang April Pangia , Lloyd Michael W. , Srivastava Anuj ,   PDXNet Consortium, Chuang Jeffrey H. , Carvajal-Carmona Luis G. 
Published: October 2022

AbstractPersonalized medicine holds great promise for improving cancer outcomes, yet there is a large inequity in the demographics of patients from whom genomic data and models, including patient derived xenografts (PDX), are developed and for whom treatments are optimized. In this study we develop a genetic ancestry pipeline for the Cancer Genomics Cloud, which we use to assess the diversity of models currently available in the National Cancer Institute (NCI) supported PDX Development and Trial Centers Research Network (PDXNet). We show that there is an over-representation of models derived from patients of European ancestry, which is consistent with other cancer model resources. We discuss these findings in the context of disparities in cancer incidence and outcomes among demographic groups in the US. For example, for the top cancer health disparities affecting African Americans and Latinos, there is a significant lack of ethnic/race appropriate models needed to advance pre-clinical research and personalized clinical treatment. For stomach and liver tumors, which represent disparities in these two minority populations, there are only three available models derived from patients from such backgrounds. Fortunately, ongoing NCI-funded efforts in minority focused PDXNet centers are actively addressing these gaps. We further discuss these results in the context of power analyses to highlight the immediate need for the development of models from minority populations to address cancer health equity in personalized medicine.
EUGENe: A Python toolkit for predictive analyses of regulatory sequences
Authors: Klie Adam , Stites Hayden , Jores Tobias , Solvason Joe J , Farley Emma K , Carter Hannah 
Published: October 2022

AbstractDeep learning (DL) has become a popular tool to study cis-regulatory element function. Yet efforts to design software for DL analyses in genomics that are Findable, Accessible, Interoperable and Reusable (FAIR) have fallen short of fully meeting these criteria. Here we present EUGENe (Elucidating theUtility ofGenomicElements withNeural Nets), a FAIR toolkit for the analysis of labeled sets of nucleotide sequences with DL. EUGENe consists of a set of modules that empower users to execute the key functionality of a DL workflow: 1) extracting, transforming and loading sequence data from many common file formats, 2) instantiating, initializing and training diverse model architectures, and 3) evaluating and interpreting model behavior. We designed EUGENe to be simple; users can develop workflows on new or existing datasets with two customizable Python objects, annotated sequence data (SeqData) and PyTorch models (BaseModel). The modularity and simplicity of EUGENe also make it highly extensible and we illustrate these principles through application of the toolkit to three predictive modeling tasks. First, we train and compare a set of built-in models along with a custom architecture for the accurate prediction of activities of plant promoters from STARR-seq data. Next, we apply EUGENe to an RNA binding prediction task and showcase how seminal model architectures can be retrained in EUGENe or imported from Kipoi. Finally, we train models to classify transcription factor binding by wrapping functionality from Janngu, which can efficiently extract sequences in BED file format from the human genome. We emphasize that the code used in each use case is simple, readable, and well documented (https://eugene-tools.readthedocs.io/en/latest/index.html). We believe that EUGENe represents a springboard toward a collaborative ecosystem for DL applications in genomics research. EUGENe is available for download on GitHub (https://github.com/cartercompbio/EUGENe) along with several introductory tutorials and for installation on PyPi (https://pypi.org/project/eugene-tools/).
The Impact of Model Misspecification on Phylogenetic Network Inference
Authors: Cao Zhen , Li Meng , Ogilvie Huw A , Nakhleh Luay 
Published: October 2022

1AbstractThe development of statistical methods to infer species phylogenies with reticulations (species networks) has led to many discoveries of gene flow between distinct species. These methods typically assume only incomplete lineage sorting and introgression. Given that phylogenetic networks can be arbitrarily complex, these methods might compensate for model misspecification by increasing the number of dimensions beyond the true value. Herein, we explore the effect of potential model misspecification, including the negligence of gene tree estimation error (GTEE) and assumption of a single substitution rate for all genomic loci, on the accuracy of phylogenetic network inference using both simulated and biological data. In particular, we assess the accuracy of estimated phylogenetic networks as well as test statistics for determining whether a network is the correct evolutionary history, as opposed to the simpler model that is a tree.We found that while GTEE negatively impacts the performance of test statistics to determine the “tree-ness” of the evolutionary history of a data set, running those tests on triplets of taxa and correcting for multiple testing significantly ameliorates the problem. We also found that accounting for substitution rate heterogeneity improves the reliability of full Bayesian inference methods of phylogenetic networks, whereas summary statistic methods are robust to GTEE and rate heterogeneity, though currently require manual inspection to determine the network complexity.
OzFAD: Ozone-enabled fatty acid discovery reveals unexpected diversity in the human lipidome
Authors: Menzel Jan Philipp , Young Reuben S.E. , Benfield Aurélie H. , Scott Julia , Butler Lisa M. , Henriques Sónia Troeira , Poad Berwyck L.J. , Blanksby Stephen J. 
Published: October 2022

ABSTRACTFatty acid isomers are responsible for an under-reported lipidome diversity across all kingdoms of life. Isomers of unsaturated fatty acid are often masked in contemporary analysis by incomplete separation and the absence of sufficiently diagnostic methods for structure elucidation. Here, we introduce a comprehensive workflow to discover new unsaturated fatty acids through coupling liquid chromatography and mass spectrometry with gas-phase ozonolysis of double bonds. The workflow encompasses semi-automated data analysis and enablesde novoidentification in complex media including human plasma, cancer cell lines and human sebaceous wax (i.e., vernix caseosa). The targeted analysis including ozonolysis enables structural assignment over a dynamic range of five orders of magnitude, even in instances of incomplete chromatographic separation. Thereby we expand the number of identified plasma fatty acids two-fold, including non-methylene interrupted fatty acids. Detection, without prior knowledge, allows discovery of non-canonical double bond positions. Changes in relative isomer abundances reflect underlying perturbations in lipid metabolism.
Hortaea werneckiiisolates exhibit different pathogenic potential in the invertebrate infection modelGalleria mellonella
Authors: Anthonies Stephanie , Vargas-Muñiz José M. 
Published: October 2022

AbstractHortaea werneckiiis a black yeast with a remarkable tolerance to salt. Most studies have been dedicated to understanding howH. werneckiiadapt to hypersaline environments.H. werneckiihas an unconventional cell cycle in which it alternates between fission and budding, which is modulated by cell density. Additionally,H. werneckiican cause superficial mycosis of the palm and sole of humans. Here, we determine the impact of salt concentration on the EXF-2000 strain’s cell division pattern and morphology. At low density and no salt, EXF-2000 primarily grows as pseudohyphae dividing mainly by septation. When grown in the presence of salt at a similar concentration to saltwater or hypersaline environments, we observe it grows by first by undergoing fission followed by budding at the poles. Then, we examined a collection of 16 isolates, including isolates from marine and hypersaline environments and isolates from patients. Isolates exhibit a wide diversity in colony shape and cellular morphology. The isolates grew as yeast, pseudohyphae, and true hyphae, indicating that isolates can exhibit various cell morphologies under similar environmental conditions. We used the insect larvaeGalleria mellonellato determine the pathogenic potential of our isolates. We observe that only a subset of isolates can cause death in our model, and there was no correlation betweenH. werneckiimorphology and capacity to cause disease. Taken together,H. werneckiigenomic and phenotypic diversity can serve as a model to better understand how phenotypes and pathogenic potential evolve in environmental fungi.
A ZTF-7/RPS-2 complex mediates the cold-warm response inC. elegans
Authors: Xu Ting , Liao Shimiao , Zhu Chengming , Jin Qile , Xu Demin , Fu Chuanhai , Chen Xiangyang , Feng Xuezhu , Guang Shouhong 
Published: October 2022

AbstractTemperature greatly affects numerous biological processes in all organisms. How multicellular organisms respond to and are impacted by hypothermic stress remains elusive. Here, we found that cold-warm stimuli induced depletion of the RNA exosome complex in the nucleoli but enriched it in the nucleoplasm. To further understand the function and mechanism of cold-warm stimuli, we conducted forward genetic screening and identified ZTF-7, which is required for RNA exosome depletion from nucleoli upon transient cold-warm exposure inC. elegans. ZTF-7 is a putative ortholog of human ZNF277 that may contribute to language impairments. Immunoprecipitation followed by mass spectrometry (IP-MS) found that ZTF-7 interacted with RPS-2, which is a ribosomal protein of the small subunit and participates in pre-rRNA processing. A partial depletion of RPS-2 and other proteins of the small ribosomal subunit blocked the cold-warm stimuli-induced reduction of exosome subunits from the nucleoli. These results established a novel mechanism by whichC. elegansresponds to environmental cold-warm exposure.
In vitroreplicative potential of an HIV-1/MO intergroup recombinant virus compared to HIV-1/M and HIV-1/O parental viruses
Authors: Moisan Alice , Oliveira Fabienne De , Mabillotte Manon , Alessandri-Gradt Elodie , Mourez Thomas , Plantier Jean-Christophe 
Published: October 2022

AbstractHIV-1 is characterized by high genetic diversity and genetic recombination is one of the major evolution processes. Despite their great genetic divergence, HIV-1 group M, pandemic, and group O, endemic in Cameroon, can generate HIV-1/MO intergroup recombinants. The current description of 19 HIV-1/MO recombinant forms (URF_MO) raises the question of a possible benefit of the recombination and the modalities of their emergence.Therefore, the objectives of this work were to studyin vitrothe replicative potential of HIV-1/MO recombinant forms.The replicative potential was analyzed, based on a simple recombination pattern, [Ogag/pol-Menv], harboring a breakpoint in Vpr, due to a recombination hotspot in this region. For this, a chimeric infectious molecular clone (IMC) was synthesized from HIV-1/M subtype B and HIV-1/O subgroup T and recombinant viruses were obtained by transfection and co-culture. To compare the replicative potential of recombinant viruses with HIV-1/M and HIV-1/O parental viruses, two markers were monitored in culture supernatants: Reverse Transcriptase (RT) activity and P24 antigen concentration. The results showed a superiority of the group M parental virus compared to group O for both markers. In contrast, for the HIV-1/OM recombinant virus, RT activity data did not overlap with the concentration of P24 antigen, suggesting a hybrid behavior of the recombinant, in terms of enzyme activity and P24 production.These results highlighted many hypotheses about the impact of recombination on replicative potential and demonstrated once again the significant plasticity of HIV genomes and their infinite possibility of evolution.ImportanceHIV-1/M and HIV-1/O can generate HIV-1/MO intergroup recombinants. The current description of 19 URF_MO raises the question of a possible benefit of recombination in terms of emergence. The objectives of this work were to studyin vitrothe replicative potential of HIV-1/MO recombinant viruses. For this, a chimeric infectious molecular clone (IMC) generated from HIV-1/M subtype B and HIV-1/O subgroup T and recombinant viruses were obtained by transfection and co-culture. To compare the replicative potential of recombinant viruses with HIV-1/M and HIV-1/O parental viruses, RT activity and P24 antigen concentration were monitored in culture supernatants. A superiority of the group M parental virus compared to group O was observed for both markers whereas a hybrid behavior in terms of enzyme activity and P24 production was found for the recombinant virus. These results demonstrated once again the significant plasticity of HIV genomes and their infinite possibility of evolution.
The UK BiLEVE and Mendelian randomisation: Using multivariable instrumental variables to address “damned if you, dammed if you don’t” adjustment problems
Authors: Woolf Benjamin , Gill Dipender , Sallis Hannah , Munafò Marcus R. 
Published: October 2022

AbstractObjectiveTo explore the use of multivariable instrumental variables to resolve the “dammed if you do, dammed if you don’t” adjustment problem created for Mendelian randomisation (MR) analysis using the smoking or lung function related phenotypes in the UK Biobank (UKB).Result“dammed if you do, dammed if you don’t” adjustment problems occur when both adjusting and not-adjusting for a variable will induce bias in an analysis. One instance of this occurs because the genotyping chip of UKB participants differed based on lung function/smoking status. In simulations, we show that multivariable instrumental variables analyses can attenuate potential collider bias introduced by adjusting for a proposed covariate, such as the UKB genotyping chip. We then explore the effect of adjusting for genotyping chip in a multivariable MR model exploring the effect of smoking on seven medical outcomes (lung cancer, emphysema, hypertension, stroke, heart diseases, depression, and disabilities). We additionally compare our results to a traditional univariate MR analysis using genome-wide analyses summary statistics which had and had not adjusted for genotyping chip. This analysis implies that the difference in genotyping chip has introduced only a small amount of bias.