bluuebunny/crossref_metadata_2025_split huggingface dataset:
Failure to detect mutations inU2AF1due to changes in the GRCh38 reference sequence
Authors: Miller Christopher A. , Walker Jason R. , Jensen Travis L. , Hooper William F. , Fulton Robert S. , Painter Jeffrey S. , Sekeres Mikkael A. , Ley Timothy J. , Spencer David H , Goll Johannes B. , Walter Matthew J. 
Published: May 2021

AbstractThe U2AF1 gene is a core part of mRNA splicing machinery and frequently contains somatic mutations that contribute to oncogenesis in MDS, AML, and other cancers. A change introduced in the GRCh38 version of the human reference build prevents mutations in this gene from being detected by many variant calling pipelines. We describe the problem in detail and show that a modified GRCh38 reference build with unchanged coordinates can be used to ameliorate the issue. This reference is available athttps://zenodo.org/record/4684553(doi:10.5281/zenodo.4684553)
Chord: Identifying Doublets in Single-Cell RNA Sequencing Data by an Ensemble Machine Learning Algorithm
Authors: Xiong Ke-Xu , Zhou Han-Lin , Yin Jian-Hua , Kristiansen Karsten , Yang Huan-Ming , Li Gui-Bo 
Published: May 2021

SummaryHigh-throughput single-cell RNA sequencing (scRNA-seq) is a popular method, but it is accompanied by doublet rate problems that disturb the downstream analysis. Several computational approaches have been developed to detect doublets. However, most of these methods have good performance in some datasets but lack stability in others; thus, it is difficult to regard a single method as the gold standard for each scenario, and it is a difficult and time-consuming task for researcher to choose the most appropriate software. To address these issues, we propose Chord which implements a machine learning algorithm that integrates multiple doublet detection methods. Chord had a higher accuracy and stability than the individual approaches on different datasets containing real and synthetic data. Moreover, Chord was designed with a modular architecture port, which has high flexibility and adaptability to the incorporation of any new tools. Chord is a general solution to the doublet detection problem.
Striatin 3 and MAP4K4 cooperate towards oncogenic growth and tissue invasion in medulloblastoma
Authors: Migliavacca Jessica , Züllig Buket , Capdeville Charles , Grotzer Michael , Baumgartner Martin 
Published: May 2021

AbstractMAP4K4 has been correlated with increased cell motility and reduced proliferation in mammalian cells. Consequences and regulation of this dichotomous functionality of MAP4K4 in tumor cells remained elusive. We find that MAP4K4 interacts with the STRN3 protein in medulloblastoma and that STRN3 and MAP4K4 exert opposing functions in Hippo tumor suppressor signaling and clonal growth. However, depletion of either STRN3 or MAP4K4 reduces migration and tissue invasion, and concomitant loss of both proteins halts tumor cell growth in the cerebellar tissue. Mechanistically, STRN3 couples MAP4K4 to the protein phosphatase 2A, which inactivates growth repressing activities of MAP4K4. In parallel, STRN3 enables growth factor-induced PKCθ activation and the direct phosphorylation of VASPS157by MAP4K4, which are necessary for efficient migration and tissue invasion. Thus, STRN3 controls MAP4K4 functionality in growth factor-activated tumor cells, and the cooperation of the two proteins promotes invasiveness through nPKCs and VASP and increases proliferation via inactivation of Hippo signaling. Targeting of the STRN3-MAP4K4 cooperation could reactivate Hippo signaling and repress invasiveness in growth factor-driven tumors.Graphical abstract
TMEM106B modifies TDP-43 pathology in human ALS brain and cell-based models of TDP-43 proteinopathy
Authors: Mao Fei , Robinson John , Unger Travis , Posavi Marijan , Amado Defne , Elman Lauren , Grossman Murray , Wolk David , Lee Edward , Van Deerlin Vivianna M. , Porta Sílvia , Lee Virginia , Trojanowski John , Chen-Plotkin Alice S. 
Published: May 2021

ABSTRACTThe neurodegenerative diseases amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TAR DNA-binding protein-43 (TDP-43) inclusions (FTLD-TDP) share the neuropathological hallmark of aggregates of TDP-43. However, factors governing the severity and regional distribution of TDP-43 pathology, which may account for the divergent clinical presentations of ALS and FTLD-TDP, are not well-understood. Here, we investigated the influence of genotypes atTMEM106B, a locus associated with risk for FTLD-TDP, and hexanucleotide repeat expansions inC9orf72, a known genetic cause for both ALS and FTLD-TDP, on global TDP-43 pathology and regional distribution of TDP-43 pathology in 899 postmortem cases from a spectrum of neurodegenerative diseases. We found that, among the 110 ALS cases, minor (C)- allele homozygotes at theTMEM106Blocus sentinel SNP rs1990622 had more TDP-43 pathology globally, as well as in select brain regions.C9orf72expansions similarly associated with greater TDP-43 pathology in ALS. However, adjusting forC9orf72expansion status did not affect the relationship betweenTMEM106Bgenotype and TDP-43 pathology. In order to elucidate the direction of causality for this association, we directly manipulatedTMEM106Blevels in an inducible cell system that expresses mislocalized TDP-43 protein. We found that partial knockdown ofTMEM106B, to levels similar to what would be expected in rs1990622 C allele carriers, led to development of more TDP-43 cytoplasmic aggregates, which were more insoluble, in this system. Taken together, our results support a causal role for TMEM106B in modifying the development of TDP-43 proteinopathy.
Dynamic behavioral and molecular changes induced by chronic stress exposure in mice
Authors: Prevot Thomas D. , Chatterjee Dipashree , Knoch Jaime , Codeluppi Sierra , Misquitta Keith A. , Fee Corey J.E. , Newton Dwight , Oh Hyunjung , Sibille Etienne , Banasr Mounira 
Published: May 2021

AbstractDepression is a leading cause of disabilities around the world, and the underlying mechanisms involved in its pathophysiology are broad and complex. Exposure to chronic stress is a risk factor for developing depressive-symptoms and contributes to cellular and molecular changes precipitating the emergence of symptoms. In the brain, excitatory neurons, inhibitory interneurons and supporting astroglial cells are all sensitive to chronic stress exposure and are known to be impaired in depression.Using an animal model of chronic stress, we assessed the impact of variable durations of chronic stress on the emergence of behavioral deficits and associated molecular changes in the prefrontal cortex (PFC), brain region highly sensitive to stress and impaired in depression. Mice were exposed to up to 35 days of chronic restraint stress and were assessed weekly on behavioral tests measuring anxiety and anhedonia. PFC Protein and RNA levels of specific markers of excitatory, inhibitory synapses and astroglia were quantified using western blot and qPCR, respectively. Correlation and integrative network analyses were used to investigated the impact of chronic stress on the different compartments.Results showed that chronic stress induces anxiety-like behaviors within 7 days, while anhedonia-like behaviors were observed only after 35 days. At the molecular level, alterations of many markers were observed, in particular with longer exposure to chronic stress. Finally, correlation analyses and integrative network analyses revealed that male and female mice react differently to chronic stress exposure and that some markers seem to be more correlated to behaviors deficits in males than in females.Our study demonstrate that chronic induces a dynamic changes that can be observed at the behavioral and molecular levels, and that male and female mice, while exhibiting similar symptoms, have different underlying pathologies.
The neuronal GPCR OCTR-1 mediates temperature effects on longevity by regulating immune response genes inC. elegans
Authors: Wibisono Shawndra , Wibisono Phillip , Chen Chia-Hui , Sun Jingru , Liu Yiyong 
Published: May 2021

ABSTRACTResearchers have long known that many animals live longer in colder climates than in warmer climates. The inverse relationship between temperature and lifespan was traditionally explained using the rate of living theory, which suggests that higher temperatures increase chemical reaction rates, thus speeding up the aging process. However, recent studies have identified specific molecules, cells and signaling pathways involved in the longevity response to temperature, indicating that such a response is not simply thermodynamic but a regulated process. Here, we report thatCaenorhabditis eleganslacking OCTR-1, a neuronal G protein-couple receptor for the neurotransmitter octopamine, had extended lifespan at warm temperature but shortened lifespan at cool temperature, indicating that OCTR-1 modulates the longevity response to both warm and cool temperatures. We further found that these responses are regulated by the OCTR-1-expressing, chemosensory ASH neurons. Transcriptomic analysis and functional assays revealed that OCTR-1 mediates temperature effects on longevity by regulating a subset of immune response genes. Our study provides cellular and molecular insights into the relationship between temperature and longevity, which could be useful for developing strategies to extend human lifespan in the midst of global warming.
Integrated Genome and Transcriptome Analyses Reveal the Mechanism of Genome Instability in Ataxia with Oculomotor Apraxia 2
Authors: Kanagaraj Radhakrishnan , Mitter Richard , Kantidakis Theodoros , Edwards Matthew M. , Benitez Anaid , Chakravarty Probir , Fu Beiyuan , Becherel Olivier , Yang Fengtang , Lavin Martin F. , Koren Amnon , Stewart Aengus , West Stephen C. 
Published: May 2021

ABSTRACTMutations in theSETXgene, which encodes Senataxin, are associated with the progressive neurodegenerative diseases Ataxia with Oculomotor Apraxia 2 (AOA2) and Amyotrophic Lateral Sclerosis 4 (ALS4). To identify the causal defect in AOA2, patient-derived cells andSETXknockouts (human and mouse) were analyzed using integrated genomic and transcriptomic approaches. We observed a genome-wide increase in chromosome instability (gains and losses) within genes and at chromosome fragile sites, resulting in changes to gene expression profiles. Senataxin loss caused increased transcription stress near promoters that correlated with high GCskew and R-loop accumulation at promoter-proximal regions. Notably, the chromosomal regions with gains and losses overlapped with regions of elevated transcription stress. In the absence of Senataxin, we found that Cockayne Syndrome protein CSB was required for the recruitment of the transcription-coupled repair endonucleases (XPG and XPF) and recombination protein RAD52 to target and resolve transcription bubbles containing R-loops, leading to error prone repair and genomic instability. These results show that transcription stress is an important contributor toSETXmutation-associated chromosome fragility and AOA2.
The MAGOH paralogs - MAGOH, MAGOHB and their multiple isoforms
Authors: Rehman Ayushi , Chandra Pratap , Singh Kusum Kumari 
Published: May 2021

ABSTRACTA central processing event in eukaryotic gene expression is splicing. Concurrent with splicing, the core-EJC proteins, eIF4A3 and RBM8A-MAGOH heterodimer are deposited 24 bases upstream of newly formed exon-exon junctions. One of the core-EJC proteins, MAGOH contains a paralog MAGOHB, and this paralog pair is conserved across vertebrates. Upon analysis of the splice variants of MAGOH-paralogs, we have found the presence of alternate protein isoforms which are also evolutionarily conserved. Further, comparison of the amino acid sequence of the principal and alternate protein isoforms has revealed absence of key amino acid residues in the alternate isoforms. The conservation of principal and alternate isoforms correlates to the importance of MAGOH and MAGOHB across vertebrates.
Glycolysis/gluconeogenesis specialization in microbes is driven by biochemical constraints of flux sensing
Authors: Schink Severin Josef , Christodoulou Dimitris , Mukherjee Avik , Athaide Edward , Brunner Viktoria , Fuhrer Tobias , Bradshaw Gary Andrew , Sauer Uwe , Basan Markus 
Published: May 2021

AbstractCentral carbon metabolism is highly conserved across microbial species, but can catalyze very different pathways depending on the organism and their ecological niche. Here, we study the dynamic re-organization of central metabolism after switches between the two major opposing pathway configurations of central carbon metabolism, glycolysis and gluconeogenesis inEscherichia coli, Pseudomonas aeruginosaandPseudomonas putida. We combined growth dynamics and dynamic changes of intracellular metabolite levels with a coarse-grained model that integrates fluxes, regulation, protein synthesis and growth and uncovered fundamental limitations of the regulatory network: after nutrient shifts, metabolite concentrations collapse to their equilibrium, rendering the cell unable to sense which direction the flux is supposed to flow through the metabolic network. The cell can partially alleviate this by picking a preferred direction of regulation at the expense of increasing lag times in the opposite direction. Moreover, decreasing both lag times simultaneously comes at the cost of reduced growth rate or higher futile cycling between metabolic enzymes. These three trade-offs can explain why microorganisms specialize for either glycolytic or gluconeogenic substrates and can help elucidate the complex growth patterns exhibited by different microbial species.Graphical synopsisStandfirst textMicrobes face a series of fundamental trade-offs that limit their ability to optimize simultaneously for both glycolytic and gluconeogenic growth.Bullet pointsLag times between glycolysis and gluconeogenesis show asymmetry in many microbes: A long lag in one direction, but a short lag in the other.Long lag times are caused by an inability to sense fluxes after nutrient shifts.With existing regulation, lag time asymmetry can only be overcome by reducing either growth rate or increasing futile cycling in metabolism.
Intergenerational adaptations to stress are evolutionarily conserved, stress-specific, and have deleterious trade-offs
Authors: Burton Nicholas O. , Willis Alexandra , Fisher Kinsey , Braukmann Fabian , Price Jon , Stevens Lewis , Ryan Baugh L. , Reinke Aaron , Miska Eric A. 
Published: May 2021

AbstractDespite reports of parental exposure to stress promoting physiological adaptations in progeny in diverse organisms, there remains considerable debate over the significance and evolutionary conservation of such multigenerational effects. Here, we investigate four independent models of intergenerational adaptations to stress inC. elegans– bacterial infection, eukaryotic infection, osmotic stress and nutrient stress – across multiple species. We found that all four intergenerational physiological adaptations are conserved in at least one other species, that they are stress-specific, and that they have deleterious trade-offs in mismatched environments. By profiling the effects of parental bacterial infection and osmotic stress exposure on progeny gene expression across species we established a core set of 279 highly conserved genes that exhibited intergenerational changes in expression in response to stress in all species tested and provide evidence suggesting that presumed adaptive and deleterious intergenerational effects are molecularly related at the gene expression level. By contrast, we found that these same stresses did not elicit any similarly conserved transgenerational changes in progeny gene expression three generations after stress exposure. We conclude that intergenerational responses to stress play a substantial and evolutionarily conserved role in regulating animal physiology and that the vast majority of the effects of parental stress on progeny gene expression are reversible and not maintained transgenerationally.
Standardized nuclear markers advance metazoan taxonomy
Authors: Dietz Lars , Eberle Jonas , Mayer Christoph , Kukowka Sandra , Bohacz Claudia , Baur Hannes , Espeland Marianne , Huber Bernhard A. , Hutter Carl , Mengual Ximo , Peters Ralph S. , Vences Miguel , Wesener Thomas , Willmott Keith , Misof Bernhard , Niehuis Oliver , Ahrens Dirk 
Published: May 2021

AbstractSpecies are the fundamental units of life and their recognition is essential for science and society. DNA barcoding, the use of a single and often mitochondrial gene, has been increasingly employed as a universal approach for the identification of animal species. However, this approach faces several challenges. Here, we demonstrate with empirical data from a number of metazoan animal lineages that multiple nuclear-encoded markers, so called universal single-copy orthologs (USCOs) performs much better than the single barcode gene to discriminate closely related species. Overcoming the general shortcomings of mitochondrial DNA barcodes, USCOs also accurately assign samples to higher taxonomic levels. These loci thus provide a powerful and unifying framework for species delimitation which considerably improves the DNA-based inference of animal species.
Fibrinogen αC-subregions critically contribute blood clot fibre growth, mechanical stability and resistance to fibrinolysis
Authors: McPherson Helen R. , Duval Cédric , Baker Stephen R. , Hindle Matthew S. , Cheah Lih T. , Asquith Nathan L. , Domingues Marco M. , Ridger Victoria C. , Connell Simon D.A , Naseem Khalid M. , Philippou Helen , Ajjan Ramzi A. , Ariëns Robert A.S. 
Published: May 2021

AbstractFibrinogen is essential for blood coagulation. The C-terminus of the fibrinogen α-chain (αC-region) is composed of an αC-domain and αC-connector. Two recombinant fibrinogen variants (α390 and α220) were produced to investigate the role of subregions in modulating clot stability and resistance to lysis. The α390 variant, truncated before the αC-domain, produced clots with a denser structure and thinner fibres. In contrast, the α220 variant, truncated at the start of the αC-connector, produced clots that were porous with short stunted fibres and visible fibre ends. These clots were mechanically weak and susceptible to lysis. Our data demonstrate differential effects for the αC-subregions in fibrin polymerisation, clot mechanical strength, and fibrinolytic susceptibility. Furthermore, we demonstrate that the αC-subregions are key for promoting longitudinal fibre growth. Together, these findings highlight critical functions of the αC-subregions in relation to clot structure and stability, with future implications for development of novel therapeutics for thrombosis.
Mathematical Analysis and Topology of SARS-CoV-2, Bonding with Cells and Unbonding
Authors: Srinivasa Rao Arni S.R. , Krantz Steven G. 
Published: May 2021

AbstractWe consider the structure of the novel coronavirus (SARS-Cov-2) in terms of the number of spikes that are critical in bonding with the cells in the host. Bonding formation is considered for selection criteria with and without any treatments. Functional mappings from the discrete space of spikes and cells and their analysis are performed. We found that careful mathematical constructions help in understanding the treatment impacts, and the role of vaccines within a host. Smale’s famous 2-D horseshoe examples inspired us to create 3-D visualizations and understand the topological diffusion of spikes from one human organ to another organ. The pharma industry will benefit from such an analysis for designing efficient treatment and vaccine strategies.
The role of epistasis in amikacin, kanamycin, bedaquiline, and clofazimine resistance inMycobacterium tuberculosiscomplex
Authors: Vargas Roger , Freschi Luca , Spitaleri Andrea , Tahseen Sabira , Barilar Ivan , Niemann Stefan , Miotto Paolo , Cirillo Daniella Maria , Köser Claudio U. , Farhat Maha R. 
Published: May 2021

ABSTRACTAntibiotic resistance among bacterial pathogens poses a major global health threat.M. tuberculosiscomplex (MTBC) is estimated to have the highest resistance rates of any pathogen globally. Given the slow growth rate and the need for a biosafety level 3 laboratory, the only realistic avenue to scale up drug-susceptibility testing (DST) for this pathogen is to rely on genotypic techniques. This raises the fundamental question of whether a mutation is a reliable surrogate for phenotypic resistance or whether the presence of a second mutation can completely counteract its effect, resulting in major diagnostic errors (i.e. systematic false resistance results). To date, such epistatic interactions have only been reported for streptomycin that is now rarely used. By analyzing more than 31,000 MTBC genomes, we demonstrated thateisC-14T promoter mutation, which is interrogated by several genotypic DST assays endorsed by the World Health Organization, cannot confer resistance to amikacin and kanamycin if it coincides with loss-of-function (LoF) mutations in the coding region ofeis. To our knowledge, this represents the first definitive example of antibiotic reversion in MTBC. Moreover, we raise the possibility thatmmpR(Rv0678) mutations are not valid markers of resistance to bedaquiline and clofazimine if these coincide with LoF mutation in the efflux pump encoded bymmpS5(Rv0677c) andmmpL5(Rv0676c).
Molecular competition can shape enhancer activity in the Drosophila embryo
Authors: Waymack Rachel , Gad Mario , Wunderlich Zeba 
Published: May 2021

SummaryTransgenic reporters allow the measurement of regulatory DNA activityin vivoand consequently have long been useful tools in the study of enhancers. Despite the utility of transgenic reporters, few studies have investigated the potential effects these reporters have on the expression of other transgenic reporters or endogenous genes. A full understanding of the impacts transgenic reporters have on expression is required for accurate interpretation of transgenic reporter data and characterization of gene regulatory mechanisms. Here, we investigate the impact transgenic reporters have on the expression of other transgenic reporters and endogenous genes. By measuring the expression ofKruppel(Kr) enhancer reporters in liveDrosophilaembryos that contain either one or two copies of identical reporters, we find reporters have an inhibitory effect on one another’s expression. Further, expression of a nearby endogenous gene is decreased in the presence of aKrenhancer reporter. Through the use of competitor binding site arrays, we present evidence that reporters, and potentially endogenous genes, are competing for transcription factors (TFs). Increasing the number of competitor Bcd binding sites decreases the peak levels and spatial extent of Bcd-regulated enhancer reporters’ expression. To understand how small numbers of added TF binding sites could impact gene expression to the extent we observe, we develop a simple thermodynamic model of our system. Our model predicts competition of the measured magnitude specifically if TF binding is restricted to distinct nuclear subregions, underlining the importance of the non-homogenous nature of the nucleus in regulating gene expression.