bluuebunny/crossref_metadata_2025_split huggingface dataset:
A new SARS-CoV-2 lineage that shares mutations with known Variants of Concern is rejected by automated sequence repository quality control
Authors: Thornlow Bryan , Hinrichs Angie S. , Jain Miten , Dhillon Namrita , La Scott , Kapp Joshua D. , Anigbogu Ikenna , Cassatt-Johnstone Molly , McBroome Jakob , Haeussler Maximilian , Turakhia Yatish , Chang Terren , Olsen Hugh E , Sanford Jeremy , Stone Michael , Vaske Olena , Bjork Isabel , Akeson Mark , Shapiro Beth , Haussler David , Kilpatrick A. Marm , Corbett-Detig Russell 
Published: April 2021

AbstractWe report a SARS-CoV-2 lineage that shares N501Y, P681H, and other mutations with known variants of concern, such as B.1.1.7. This lineage, which we refer to as B.1.x (COG-UK sometimes references similar samples as B.1.324.1), is present in at least 20 states across the USA and in at least six countries. However, a large deletion causes the sequence to be automatically rejected from repositories, suggesting that the frequency of this new lineage is underestimated using public data. Recent dynamics based on 339 samples obtained in Santa Cruz County, CA, USA suggest that B.1.x may be increasing in frequency at a rate similar to that of B.1.1.7 in Southern California. At present the functional differences between this variant B.1.x and other circulating SARS-CoV-2 variants are unknown, and further studies on secondary attack rates, viral loads, immune evasion and/or disease severity are needed to determine if it poses a public health concern. Nonetheless, given what is known from well-studied circulating variants of concern, it seems unlikely that the lineage could pose larger concerns for human health than many already globally distributed lineages. Our work highlights a need for rapid turnaround time from sequence generation to submission and improved sequence quality control that removes submission bias. We identify promising paths toward this goal.
Comprehensive multi-omics integration identifies differentially active enhancers during human brain development with clinical relevance
Authors: Yousefi Soheil , Deng Ruizhi , Lanko Kristina , Salsench Eva Medico , Nikoncuk Anita , van der Linde Herma C. , Perenthaler Elena , van Ham Tjakko , Mulugeta Eskeatnaf , Barakat Tahsin Stefan 
Published: April 2021

AbstractBackgroundNon-coding regulatory elements (NCREs), such as enhancers, play a crucial role in gene regulation and genetic aberrations in NCREs can lead to human disease, including brain disorders. The human brain is complex and can be affected by numerous disorders; many of these are caused by genetic changes, but a multitude remain currently unexplained. Understanding NCREs acting during brain development has the potential to shed light on previously unrecognised genetic causes of human brain disease. Despite immense community-wide efforts to understand the role of the non-coding genome and NCREs, annotating functional NCREs remains challenging.ResultsHere we performed an integrative computational analysis of virtually all currently available epigenome data sets related to human fetal brain. Our in-depth analysis unravels 39,709 differentially active enhancers (DAEs) that show dynamic epigenomic rearrangement during early stages of human brain development, indicating likely biological function. Many of these DAEs are linked to clinically relevant genes, and functional validation of selected DAEs in cell models and zebrafish confirms their role in gene regulation. Compared to enhancers without dynamic epigenomic rearrangement, these regions are subjected to higher sequence constraints in humans, have distinct sequence characteristics and are bound by a distinct transcription factor landscape. DAEs are enriched for GWAS loci for brain related traits and for genetic variation found in individuals with neurodevelopmental disorders, including autism.ConclusionOur compendium of high-confidence enhancers will assist in deciphering the mechanism behind developmental genetics of the human brain and will be relevant to uncover missing heritability in human genetic brain disorders.
DeepTrio: Variant Calling in Families Using Deep Learning
Authors: Kolesnikov Alexey , Goel Sidharth , Nattestad Maria , Yun Taedong , Baid Gunjan , Yang Howard , McLean Cory Y , Chang Pi-Chuan , Carroll Andrew 
Published: April 2021

AbstractEvery human inherits one copy of the genome from their mother and another from their father. Parental inheritance helps us understand the transmission of traits and genetic diseases, which often involve de novo variants and rare recessive alleles. Here we present DeepTrio, which learns to analyze child-mother-father trios from the joint sequence information, without explicit encoding of inheritance priors. DeepTrio learns how to weigh sequencing error, mapping error, and de novo rates and genome context directly from the sequence data. DeepTrio has higher accuracy on both Illumina and PacBio HiFi data when compared to DeepVariant. Improvements are especially pronounced at lower coverages (with 20x DeepTrio roughly equivalent to 30x DeepVariant). As DeepTrio learns directly from data, we also demonstrate extensions to exome calling solely by changing the training data. DeepTrio includes pre-trained models for Illumina WGS, Illumina exome, and PacBio HiFi.
East-African savanna dynamics: from a knowledge-based model to the possible futures of a social-ecological system
Authors: Cosme Maximilien , Hély Christelle , Pommereau Franck , Pasquariello Paolo , Tiberi Christel , Treydte Anna , Gaucherel Cédric 
Published: April 2021

AbstractSub-Saharan savanna ecosystems are undergoing transitions such as bush encroachment, desertification or agricultural expansion. Such shifts and persistence of land cover are increasingly well understood, especially bush encroachment which is of major concern in pastoral systems. Although dominant factors can explain such transformations, they often result from intertwined causes in which human activities play a significant role. Therefore, in this latter case, these issues may require integrated solutions, involving many interacting components. Ecosystem modelling has proved appropriate to support decision-makers in such complex situations. However, ecosystem models often require lots of quantitative information for estimating parameters and the precise functional form of interactions is often unknown. Alternatively, in rangeland management, States-and-Transitions Models (STMs) have been developed to organize knowledge about system transitions and to help decision-makers. However, these conceptual diagrams often lack mathematical analyzing tools, which strongly constrains their complexity. In this paper, we introduce the Ecological Discrete-Event Network (EDEN) modelling approach for representing the qualitative dynamics of an East-African savanna as a set of discrete states and transitions generated from empirical rules. These rules are derived from local knowledge, field observations and scientific literature. In contrast with STMs, EDEN generates automatically every possible states and transitions, thus enabling the prediction of novel ecosystem structures. Our results show that the savanna is potentially resilient to the disturbances considered. Moreover, the model highlights all transitions between vegetation types and socio-economic profiles under various climatic scenarios. The model also suggests that wildlife diversity may increase socio-economic resistance to seasonal drought. Tree-grass coexistence and agropastoralism have the widest ranges of conditions of existence of all vegetation types and socio-economic profiles, respectively. As this is a preliminary use of EDEN for applied purpose, analysis tools should be improved to enable finer investigation of desirable trajectories. By translating local knowledge into ecosystem dynamics, the EDEN approach seems promising to build a new bridge between managers and modellers.
Overturning the paradigm that IL6 signaling drives liver regrowth while shining light on a new therapeutic target for regenerative medicine
Authors: Dong Jinrui , Viswanathan Sivakumar , Adami Eleonora , Schafer Sebastian , Kuthubudeen Fathima F. , Widjaja Anissa A. , Cook Stuart A. 
Published: April 2021

AbstractIt is accepted that IL6 signaling in hepatocytes, mediated via glycoprotein 130 (gp130), is beneficial and that HyperIL6 promotes liver regeneration by activating STAT3. Recently, autocrine IL11 activity, which also signals via gp130 and ERK, was found to be hepatotoxic. Here we examined whether the beneficial effects of HyperIL6 could reflect unappreciated competitive inhibition of IL11 signaling. In hepatocytes, HyperIL6 inhibited N-acetyl-p-aminophenol (APAP)-induced cell death that mimicked inhibition of IL11 signaling and was unrelated to STAT3 phosphorylation. In mice, expression of HyperIL6 reduced liver damage due to IL11 dosing or APAP and promoted hepatic regeneration in a STAT3-independent manner. Following APAP, mice deleted forIl11were protected from liver failure and exhibited spontaneous regeneration. Despite robustly activating STAT3, HyperIL6 had no beneficial effect inIl11null mice. These data overturn the premise that IL6 promotes liver regeneration, show STAT3 activation to be redundant and suggest IL11 as a focus for regenerative medicine.
Ultrafast, alignment-free detection of repeat expansions in next-generation DNA and RNA sequencing data
Authors: Fearnley L.G. , Bennett M.F. , Bahlo M. 
Published: April 2021

AbstractShort tandem repeat expansions are an established cause of diseases such as Huntington’s disease. Bioinformatic methods for detecting repeat expansions in short-read sequencing have revealed new repeat expansions in humans. Current bioinformatic methods to detect repeat expansions require alignment information to identify repetitive motif enrichment at genomic locations. We present superSTR, an ultrafast method that does not require alignment. We demonstrate superSTR’s ability to efficiently process both whole-genome and whole-exome sequencing data. Using superSTR we perform the first analysis of the UK Biobank to efficiently screen the exomes of 49,953 biobank participants for repeat expansions. We identify known mutations, as well as diseases not previously associated with REs. We further demonstrate the first bioinformatic screening of RNA sequencing data to detect repeat expansions in patients with spinocerebellar ataxia and Fuchs’ endothelial corneal dystrophy, and mouse models of myotonic dystrophy. superSTR is a highly computationally-efficient repeat expansion tool screening and detection tool for genomewide novel repeat expansion analysis, significantly outperforming existing methods. superSTR is available fromhttps://github.com/bahlolab/superSTR.
Global-scale CRISPR gene editor specificity profiling by ONE-seq identifies population-specific, variant off-target effects
Authors: Petri Karl , Kim Daniel Y. , Sasaki Kanae E. , Canver Matthew C. , Wang Xiao , Shah Hina , Lee Hyunho , Horng Joy E. , Clement Kendell , Iyer Sowmya , Garcia Sara P. , Guo Jimmy A. , Newby Gregory A. , Pinello Luca , Liu David R. , Aryee Martin J. , Musunuru Kiran , Keith Joung J. , Pattanayak Vikram 
Published: April 2021

AbstractDefining off-target profiles of gene-editing nucleases and CRISPR base editors remains an important challenge for use of these technologies, therapeutic or otherwise. Existing methods can identify off-target sites induced by these gene editors on an individual genome but are not designed to account for the broad diversity of genomic sequence variation that exists within populations of humans or other organisms. Here we describe OligoNucleotide Enrichment and sequencing (ONE-seq), a novelin vitromethod that leverages customizable, high-throughput DNA synthesis technology instead of purified genomic DNA (gDNA) from individual genomes to profile gene editor off-target sites. We show that ONE-seq matches or exceeds the sensitivity of existing single-genome methods for identifyingbona fideCRISPR-Cas9 off-target sites in cultured human cells andin vivoin a liver-humanized mouse model. In addition, ONE-seq outperforms existing best-in-class single-genome methods for defining off-target sites of CRISPR-Cas12a nucleases, cytosine base editors (CBEs), and adenine base editors (ABEs), unveiling previously undescribedbona fideoff-target sites for all these editors in human cells. Most importantly, we leveraged ONE-seq to generate the first experimentally-derived population-scale off-target profiles for Cas9 nucleases that define the impacts of sequence variants from >2,500 individual human genome sequences in the 1000 Genomes Project database. Notably, some of the variants we identified that lead to increased mutation frequencies at off-target sites are enriched in specific human populations. We validated that novel population-specific, variant-sensitive off-target sites nominated by ONE-seqin vitrocan show increased frequencies of mutations in human lymphoblastoid cells (LCLs) harboring these sequence variants. Collectively, our results demonstrate that ONE-seq is a highly sensitive off-target nomination method that can uniquely be used to identify population subgroup-linked differences in off-target profiles of gene editors. ONE-seq provides an important new pathway by which to assess the impacts of global human genetic sequence diversity on the specificities of gene editors, thereby enabling a broader and more all-inclusive approach for profiling off-target effects of these transformative therapeutic technologies.
Cue overlap supports pre-retrieval selection in episodic memory: ERP evidence
Authors: Moccia Arianna , Morcom Alexa M. 
Published: April 2021

AbstractPeople often want to recall only currently relevant events, but this selective remembering is not always possible. We contrasted two candidate mechanisms: the overlap between retrieval cues and stored memory traces, and the ease of recollection. In two preregistered experiments (Ns = 28) we used event-related potentials (ERPs) to quantify pre-retrieval selection and the goal states – retrieval orientations – thought to achieve this selection. Participants viewed object pictures or heard object names, and one of these sources was designated as targets in each memory test. We manipulated cue overlap by probing memory with visual names (Experiment 1) or line drawings (Experiment 2). Results revealed that regardless of which source was targeted, the left parietal ERP effect indexing recollection was selective when test cues overlapped more with the targeted than non-targeted information, despite consistently better memory for pictures. ERPs for unstudied items were also more positive-going when cue overlap was high, suggesting that engagement of retrieval orientations reflected availability of external cues matching the targeted source. The data support the view that selection can act prior to recollection if there is sufficient overlap between retrieval cues and targeted versus competing memory traces.
In Silico Analysis and Characterization of Differentially Expressed Genes to Distinguish Glioma Stem Cells from Normal Neural Stem Cells
Authors: Parekh Urja , Mazumder Mohit , Kaur Harpreet , Brodsky Elia 
Published: April 2021

AbstractGlioblastoma multiforme (GBM) is a heterogeneous, invasive primary brain tumor that develops chemoresistance post therapy. Theories regarding the aetiology of GBM focus on transformation of normal neural stem cells (NSCs) to a cancerous phenotype or tumorigenesis driven via glioma stem cells (GSCs). Comparative RNA-Seq analysis of GSCs and NSCs can provide a better understanding of the origin of GBM. Thus, in the current study, we performed various bioinformatics analyses on transcriptional profiles of a total 40 RNA-seq samples including 20 NSC and 20 GSC, that were obtained from the NCBI-SRA (SRP200400). First, differential gene expression (DGE) analysis using DESeq2 revealed 348 significantly differentially expressed genes between GSCs and NSCs (padj. value <0.05, log2fold change ≥ 3.0 (for GSCs) and ≤ −3.0 (for NSCs)) with 192 upregulated and 156 downregulated genes in GSCs in comparison to NSCs. Subsequently, exploratory data analysis using principal component analysis (PCA) based on key significant genes depicted the clear separation between both the groups. Further, Hierarchical clustering confirmed the distinct clusters of GSC and NSC samples. Eventually, the biological enrichment analysis of the significant genes showed their enrichment in tumorigenesis pathways such as Wnt-signalling, VEGF-signalling and TGF-β-signalling pathways. Conclusively, our study depicted significant differences in the gene expression patterns between NSCs and GSCs. Besides, we also identified novel genes and genes previously unassociated with gliomagenesis that may prove to be valuable in establishing diagnostic, prognostic biomarkers and therapeutic targets for GBM.
Bioinformatic and mechanistic analysis of the palmerolide PKS-NRPS biosynthetic pathway from the microbiome of an Antarctic ascidian
Authors: Avalon Nicole E. , Murray Alison E. , Daligault Hajnalka E. , Lo Chien-Chi , Davenport Karen W. , Dichosa Armand E.K. , Chain Patrick S.G. , Baker Bill J. 
Published: April 2021

AbstractComplex interactions exist between microbiomes and their hosts. Increasingly, defensive metabolites that have been attributed to host biosynthetic capability are now being recognized as products of host-associated microbes. These unique metabolites often have bioactivity targets in human disease and can be purposed as pharmaceuticals. Polyketides are a complex family of natural products that often serve as defensive metabolites for competitive or pro-survival purposes for the producing organism, while demonstrating bioactivity in human diseases as cholesterol lowering agents, anti-infectives, and anti-tumor agents. Marine invertebrates and microbes are a rich source of polyketides. Palmerolide A, a polyketide isolated from the Antarctic ascidianSynoicum adareanum, is a vacuolar-ATPase inhibitor with potent bioactivity against melanoma cell lines. The biosynthetic gene clusters (BGCs) responsible for production of secondary metabolites are encoded in the genomes of the producers as discrete genomic elements. A candidate palmerolide BGC was identified from aS. adareanummicrobiome-metagenome based on a high degree of congruence with a chemical structure-based retrobiosynthetic prediction. Protein family homology analysis, conserved domain searches, active site and motif identification were used to identify and propose the function of the ∼75 kbtrans-acyltransferase (AT) polyketide synthase-non-ribosomal synthase (PKS-NRPS) domains responsible for the stepwise synthesis of palmerolide A. Though PKS systems often act in a predictable co-linear sequence, this BGC includes multipletrans-acting enzymatic domains, a non-canonical condensation termination domain, a bacterial luciferase-like monooxygenase (LLM), and is found in multiple copies within the metagenome-assembled genome (MAG). Detailed inspection of the five highly similar pal BGC copies suggests the potential for biosynthesis of other members of the palmerolide chemical family. This is the first delineation of a biosynthetic gene cluster from an Antarctic microbial species, recently proposed asCandidatusSynoicohabitans palmerolidicus. These findings have relevance for fundamental knowledge of PKS combinatorial biosynthesis and could enhance drug development efforts of palmerolide A through heterologous gene expression.
A novel SNF2 ATPase complex inTrypanosoma bruceiwith a role in H2A.Z-mediated chromatin remodelling
Authors: Vellmer Tim , Hartleb Laura , Sola Albert Fradera , Kramer Susanne , Meyer-Natus Elisabeth , Butter Falk , Janzen Christian J 
Published: April 2021

AbstractA cascade of histone acetylation events with subsequent incorporation of a histone H2A variant plays an essential part in transcription regulation in various model organisms. A key player in this cascade is the chromatin remodelling complex SWR1, which replaces the canonical histone H2A with its variant H2A.Z. Transcriptional regulation of polycistronic transcription units in the unicellular parasiteTrypanosoma bruceihas been shown to be highly dependent on acetylation of H2A.Z, which is mediated by the histone-acetyltransferase HAT2. The chromatin remodelling complex which mediates H2A.Z incorporation is not known and an SWR1 orthologue in trypanosomes has not yet been reported.In this study, we identified and characterised an SWR1-like remodeller complex inT. bruceithat is responsible for Pol II-dependent transcriptional regulation. Bioinformatic analysis of potential SNF2 DEAD/Box helicases, the key component of SWR1 complexes, identified a 1211 amino acids-long protein that exhibits key structural characteristics of the SWR1 subfamily. Systematic protein-protein interaction analysis revealed the existence of a novel complex exhibiting key features of an SWR1-like chromatin remodeller. RNAi-mediated depletion of the ATPase subunit of this complex resulted in a significant reduction of H2A.Z incorporation at transcription start sites and a subsequent decrease of steady-state mRNA levels. Furthermore, depletion of SWR1 and RNA-polymerase II (Pol II) caused massive chromatin condensation. The potential function of several proteins associated with the SWR1-like complex and with HAT2, the key factor of H2A.Z incorporation, is discussed.Author summaryTrypanosoma bruceiis the causative agent of African trypanosomiasis (sleeping sickness) in humans and nagana in cattle. Its unusual genomic organisation featuring large polycistronic units requires a general mechanism of transcription initiation, because individual gene promoters are mostly absent. Despite the fact that the histone variant H2A.Z has previously been identified as a key player of transcription regulation, the complex responsible for correct H2A.Z incorporation at transcription start sites (TSS) remains elusive. In other eukaryotes, SWR1, a SNF2 ATPase-associated chromatin remodelling complex, is responsible for correct incorporation of this histone variant. This study identified a SWR1-like complex inT. brucei. Depletion of the SNF2 ATPase resulted in a reduction of H2A.Z incorporation at the TSS and decreased steady-state mRNA levels accompanied by chromatin condensation. In addition to the SWR1-like complex, we also identified a trypanosome-specific HAT2 complex that includes the histone acetyltransferases HAT2, a key player in the H2A.Z incorporation process. This complex has a trypanosome-specific composition that is different from the NuA4/TIP60 complex inSaccharomyces cerevisiae.