bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iron-sulfur clusters are involved in post-translational arginylation
Authors: Van Verna , Brown Janae B. , Rosenbach Hannah , Mohamed Ijaz , Ejimogu Nna-Emeka , Bui Toan S. , Szalai Veronika A. , Chacón Kelly N. , Span Ingrid , Smith Aaron T. 
Published: April 2021

AbstractEukaryotic arginylation is an essential post-translational modification that both modulates protein stability and regulates protein half-life through the N-degron pathway. Arginylation is catalyzed by a family of enzymes known as the arginyl-tRNA transferases (ATE1s), which are conserved across the eukaryotic domain. Despite its conservation and importance, little is known regarding the structure, mechanism, and regulation of ATE1s. In this work, we have discovered that ATE1s bind a previously unknown iron-sulfur cluster that is conserved across evolution. We have extensively characterized the nature of this iron-sulfur cluster, and we show that the presence of the iron-sulfur cluster is linked to alterations in arginylation efficacy. Finally, we demonstrate that the ATE1 iron-sulfur cluster is oxygen sensitive, which could be a molecular mechanism of the N-degron pathway to sense oxidative stress. Thus, our data provide the framework of a cluster-based paradigm of ATE1 regulatory control.
Interpretable, scalable, and transferrable functional projection of large-scale transcriptome data using constrained matrix decomposition
Authors: Panchy Nicholas , Watanabe Kazuhide , Hong Tian 
Published: April 2021

AbstractLarge-scale transcriptome data, such as single-cell RNA-sequencing data, have provided unprecedented resources for studying biological processes at the systems level. Numerous dimensionality reduction methods have been developed to visualize and analyze these transcriptome data. In addition, several existing methods allow inference of functional variations among samples using gene sets with known biological functions. However, it remains challenging to analyze transcriptomes with reduced dimensions that are interpretable in terms of dimensions’ directionalities, transferrable to new data, and directly expose the contribution of individual genes. In this study, we used gene set non-negative principal component analysis (gsPCA) and non-negative matrix factorization (gsNMF) to analyze large-scale transcriptome datasets. We found that these methods provide low-dimensional information about the progression of biological processes in a quantitative manner, and their performances are comparable to existing functional variation analysis methods in terms of distinguishing multiple cell states and samples from multiple conditions. Remarkably, upon training with a subset of data, these methods allow predictions of locations in the functional space using data from experimental conditions that are not exposed to the models. Specifically, our models predicted the extent of progression and reversion for cells in the epithelial-mesenchymal transition (EMT) continuum. These methods revealed conserved EMT program among multiple types of single cells and tumor samples. Finally, we demonstrate this approach is broadly applicable to data and gene sets beyond EMT and provide several recommendations on the choice between the two linear methods and the optimal algorithmic parameters. Our methods show that simple constrained matrix decomposition can produce to low-dimensional information in functionally interpretable and transferrable space, and can be widely useful for analyzing large-scale transcriptome data.
In vitroreconstitution of Sgk3 activation by phosphatidylinositol-3-phosphate
Authors: Pokorny Daniel , Truebestein Linda , Fleming Kaelin D. , Burke John E. , Leonard Thomas A. 
Published: April 2021

SummarySerum- and glucocorticoid-regulated kinase 3 (Sgk3) is activated by the phospholipid phosphatidylinositol-3-phosphate (PI3P) downstream of growth factor signaling and by Vps34-mediated PI3P production on endosomes. Upregulation of Sgk3 activity has recently been linked to a number of human cancers. Here, we show that Sgk3 is regulated by a combination of phosphorylation and allosteric activation by PI3P. We demonstrate that PI3P binding induces large conformational changes in Sgk3 associated with its activation, and that the PI3P binding pocket of the PX domain of Sgk3 is sequestered in its inactive conformation. Finally, we reconstituted Sgk3 activation via Vps34-mediated PI3P synthesis on phosphatidylinositol liposomesin vitro. In addition to defining the mechanism of Sgk3 activation by PI3P, our findings open up potential therapeutic avenues in allosteric inhibitor development to target Sgk3 in cancer.
eIF2α integrates proteotoxic signals both from ER and cytoplasm: Hsp70-Bag3 module regulates HRI-dependent phosphorylation of eIF2α
Authors: Patel Shivani , Kumar Santosh , Hesin Arkadi , Yaglom Julia , Sherman Michael Y. 
Published: April 2021

AbstractThe major heat shock protein Hsp70 has been implicated in many stages of cancer development. These effects are mediated by a scaffold protein Bag3 that binds to Hsp70 and links it to components of multiple cancer-related signaling pathways. Accordingly, the Hsp70-Bag3 complex has been targeted by small molecules, which showed strong anti-cancer effects. Here, our initial question was how JG-98, an allosteric inhibitor of Hsp70 that blocks its interaction with Bag3, causes cell death. Breast epithelial cells MCF10A transformed with a single oncogene Her2 showed higher sensitivity to JG-98 then parental MCF10A cells. RNA expression analysis showed that this enhanced sensitivity correlated with higher induction of the UPR genes. Indeed, depletion of the pro-apoptotic UPR responsive transcription factor CHOP significantly protected cells from JG-98. Surprisingly, only the eIF2α-associated branch of the UPR was activated by JG-98, suggesting that the response was not related to the ER proteotoxicity. Indeed, it was dependent on activation of a distinct cytoplasmic eIF2α kinase HRI. HRI-dependent phosphorylation of eIF2α was also activated by the cytoplasmic proteotoxicity via Hsp70-Bag3 complex, which directly associates with HRI. Dissociation of Hsp70-Bag3 complex led to Bag3-dependent degradation of HRI via autophagy. Therefore, eIF2α integrates proteotoxicity signals from both ER and cytoplasm, and the cytoplasmic response mediates cytotoxicity of the Hsp70-Bag3 inhibitors.
Intergenic ORFs as elementary structural modules ofde novogene birth and protein evolution
Authors: Papadopoulos Chris , Callebaut Isabelle , Gelly Jean-Christophe , Hatin Isabelle , Namy Olivier , Renard Maxime , Lespinet Olivier , Lopes Anne 
Published: April 2021

AbstractThe noncoding genome plays an important role inde novogene birth and in the emergence of genetic novelty. Nevertheless, how noncoding sequences’ properties could promote the birth of novel genes and shape the evolution and the structural diversity of proteins remains unclear. Therefore, by combining different bioinformatic approaches, we characterized the fold potential diversity of the amino acid sequences encoded by all intergenic ORFs (Open Reading Frames) ofS. cerevisiaewith the aim of (i) exploring whether the large structural diversity observed in proteomes is already present in noncoding sequences, and (ii) estimating the potential of the noncoding genome to produce novel protein bricks that can either give rise to novel genes or be integrated into pre-existing proteins, thus participating in protein structure diversity and evolution. We showed that amino acid sequences encoded by most yeast intergenic ORFs contain the elementary building blocks of protein structures. Moreover, they encompass the large structural diversity of canonical proteins with strikingly the majority predicted as foldable. Then, we investigated the early stages ofde novogene birth by identifying intergenic ORFs with a strong translation signal in ribosome profiling experiments and by reconstructing the ancestral sequences of 70 yeastde novogenes. This enabled us to highlight sequence and structural factors determiningde novogene emergence. Finally, we showed a strong correlation between the fold potential ofde novoproteins and the one of their ancestral amino acid sequences, reflecting the relationship between the noncoding genome and the protein structure universe.
FAN1 nuclease activity affects CAG expansion and age at onset of Huntington’s disease
Authors: McAllister Branduff , Donaldson Jasmine , Binda Caroline S. , Powell Sophie , Chughtai Uroosa , Edwards Gareth , Stone Joseph , Lobanov Sergey , Elliston Linda , Schuhmacher Laura-Nadine , Rees Elliott , Menzies Georgina , Ciosi Marc , Maxwell Alastair , Chao Michael J. , Hong Eun Pyo , Lucente Diane , Wheeler Vanessa , Lee Jong-Min , MacDonald Marcy E. , Long Jeffrey D. , Aylward Elizabeth H. , Landwehrmeyer G. Bernhard , Rosser Anne E. ,   REGISTRY Investigators of the European Huntington’s disease network, Paulsen Jane S. ,   PREDICT-HD Investigators of the Huntington Study Group, Williams Nigel M. , Gusella James F. , Monckton Darren G. , Allen Nicholas D. , Holmans Peter , Jones Lesley , Massey Thomas H. 
Published: April 2021

SummaryThe age at onset of motor symptoms in Huntington’s disease (HD) is driven byHTTCAG repeat length but modified by other genes. We used exome sequencing of 683 HD patients with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We identified damaging coding variants in candidate modifier genes from prior genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier onset HD. Nuclease activities of these variants correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion comparable to those observed with completeFAN1knock out. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.
Investigating the correlation of muscle function tests and sarcomere organization in C. elegans
Authors: Lesanpezeshki Leila , Qadota Hiroshi , Norouzi Darabad Masoud , Kashyap Karishma , Lacerda Carla M. R. , Szewczyk Nathaniel J. , Benian Guy M. , Vanapalli Siva A. 
Published: April 2021

AbstractBackgroundCaenorhabditis elegans has been widely used as a model to study muscle structure and function due to many genes having human homologs. Its body wall muscle is functionally and structurally similar to vertebrate skeletal muscle with conserved molecular pathways contributing to sarcomere structure, and muscle function. However, a systematic investigation of the relationship between muscle force and sarcomere organization is lacking. Here, we investigate the contribution of various sarcomere proteins and membrane attachment components to muscle structure and function to introduce C. elegans as a model organism to study the genetic basis of muscle strength.MethodsWe employ two recently developed assays that involve exertion of muscle forces to investigate the correlation of muscle function to sarcomere organization. We utilized a microfluidic pillar-based platform called NemaFlex that quantifies the maximum exertable force and a burrowing assay that challenges the animals to move in three dimensions under a chemical stimulus. We selected 20 mutants with known defects in various substructures of sarcomeres and compared the physiological function of muscle proteins required for force generation and transmission. We also characterized the degree of sarcomere disorganization using immunostaining approaches.ResultsWe find that mutants with genetic defects in thin filaments, thick filaments and M-lines are generally weaker, and our assays are successful in detecting the functional changes in response to each sarcomere location tested. We find that the NemaFlex and burrowing assays are functionally distinct informing on different aspects of muscle physiology. Specifically, the burrowing assay has a larger bandwidth in phenotyping muscle mutants, because it could pick ten additional mutants impaired while exerting normal muscle force in NemaFlex. This enabled us to combine their readouts to develop an integrated muscle function score that was found to correlate with the score for muscle structure disorganization.ConclusionsOur results highlight the suitability of NemaFlex and burrowing assays for evaluating muscle physiology of C. elegans. Using these approaches, we discuss the importance of the studied sarcomere proteins for muscle function and structure. The scoring methodology we have developed lays the foundation for investigating the contribution of conserved sarcomere proteins and membrane attachment components to human muscle function and strength.
Auditory attention detection with EEG channel attention
Authors: Su Enze , Cai Siqi , Li Peiwen , Xie Longhan , Li Haizhou 
Published: April 2021

AbstractAuditory attention detection (AAD) seeks to detect the attended speech from EEG signals in a multi-talker scenario, i.e. cocktail party. As the EEG channels reflect the activities of different brain areas, a task-oriented channel selection technique improves the performance of brain-computer interface applications. In this study, we propose a soft channel attention mechanism, instead of hard channel selection, that derives an EEG channel mask by optimizing the auditory attention detection task. The neural AAD system consists of a neural channel attention mechanism and a convolutional neural network (CNN) classifier. We evaluate the proposed framework on a publicly available database. We achieve 88.3% and 77.2% for 2-second and 0.1-second decision windows with 64-channel EEG; and 86.1% and 83.9% for 2-second decision windows with 32-channel and 16-channel EEG, respectively. The proposed framework outperforms other competitive models by a large margin in all test cases.
Multipotent progenitors and hematopoietic stem cells arise independently during the endothelial to hematopoietic transition in the early mouse embryo
Authors: Dignum Tessa , Varnum-Finney Barbara , Srivatsan Sanjay , Dozono Stacey , Waltner Olivia , Heck Adam , Nourigat-McKay Cynthia , Jackson Dana L. , Rafii Shahin , Trapnell Cole , Bernstein Irwin D. , Hadland Brandon 
Published: April 2021

SUMMARYDuring embryogenesis, waves of hematopoietic progenitors develop from hemogenic endothelium (HE) prior to the emergence of self-renewing hematopoietic stem cells (HSC). Although previous studies have shown that yolk sac-derived erythromyeloid progenitors and HSC emerge from distinct populations of HE, it remains unknown whether the earliest lymphoid-competent progenitors, multipotent progenitors, and HSC originate from common HE. Here we demonstrate by clonal assays and single cell transcriptomics that rare HE with functional HSC potential in the early murine embryo are distinct from more abundant HE with multilineage hematopoietic potential that fail to generate HSC. Specifically, HSC-competent HE are characterized by expression of CXCR4 surface marker and by higher expression of genes tied to arterial programs regulating HSC dormancy and self-renewal. Together, these findings suggest a revised model of developmental hematopoiesis in which the initial populations of multipotent progenitors and HSC arise independently from HE with distinct phenotypic and transcriptional properties.
Ancient DNA reveals that few GWAS loci have been strongly selected during recent human history
Authors: Simonti Corinne N. , Lachance Joseph 
Published: April 2021

AbstractGenetic data from ancient humans has provided new evidence in the study of loci thought to be under historic selection, and thus is a powerful tool for identifying instances of selection that might be missed by methods that use present-day samples alone. Using a curated set of disease-associated variants from the NHGRI-EBI GWAS Catalog, we provide an analysis to identify disease-associated variants that bear signatures of selection over time. After accounting for the fact that not every ancient individual contributed equally to modern genomes, a Bayesian inference method was used to infer allele frequency trajectories over time and determine which disease-associated loci exhibit signatures of natural selection. Of the 2,709 variants analyzed in this study, 895 show at least a weak signature of selection (|s| > 0.001), including multiple variants that are introgressed from Neanderthals. However, only nine disease-associated variants show a signature of strong selection (|s| > 0.01). Additionally, we find that many risk-associated alleles have increased in frequency during the past 10,000 years. Overall, we find that disease-associated variants from GWAS are governed by nearly neutral evolution. Exceptions to this broad pattern include GWAS loci that protect against asthma and variants in MHC genes. Ancient samples allow us an unprecedented look at how our species has changed over time, and our results represent an important early step in using this new source of data to better understand the evolution of hereditary disease risks.
Genome stability is in the eye of the beholder: recent retrotransposon activity varies significantly across avian diversity
Authors: Galbraith James D. , Kortschak R. Daniel , Suh Alexander , Adelson David L. 
Published: April 2021

AbstractSince the sequencing of the zebra finch genome it has become clear the avian genome, while largely stable in terms of chromosome number and gene synteny, is more dynamic at an intrachromosomal level. A multitude of intrachromosomal rearrangements and significant variation in transposable element content have been noted across the avian tree. Transposable elements (TEs) are a source of genome plasticity, because their high similarity enables chromosomal rearrangements through non-allelic homologous recombination, and they have potential for exaptation as regulatory and coding sequences. Previous studies have investigated the activity of the dominant TE in birds, CR1 retrotransposons, either focusing on their expansion within single orders, or comparing passerines to non-passerines. Here we comprehensively investigate and compare the activity of CR1 expansion across orders of birds, finding levels of CR1 activity vary significantly both between and with orders. We describe high levels of TE expansion in genera which have speciated in the last 10 million years including kiwis, geese and Amazon parrots; low levels of TE expansion in songbirds across their diversification, and near inactivity of TEs in the cassowary and emu for millions of years. CR1s have remained active over long periods of time across most orders of neognaths, with activity at any one time dominated by one or two families of CR1s. Our findings of higher TE activity in species-rich clades and dominant families of TEs within lineages mirror past findings in mammals.Author SummaryTransposable elements (TEs) are mobile, self replicating DNA sequences within a species’ genome, and are ubiquitous sources of mutation. The dominant group of TEs within birds are chicken repeat 1 (CR1) retrotransposons, making up 7-10% of the typical avian genome. Because past research has examined the recent inactivity of CR1s within model birds such as the chicken and the zebra finch, this has fostered an erroneous view that all birds have low or no TE activity on recent timescales. Our analysis of numerous high quality avian genomes across multiple orders identified both similarities and significant differences in how CR1s expanded. Our results challenge the established view that TEs in birds are largely inactive and instead suggest that their variation in recent activity may contribute to lineage-specific changes in genome structure. Many of the patterns we identify in birds have previously been seen in mammals, highlighting parallels between the evolution of birds and mammals.
Using high effective risk of Adult-Senior duo in multigenerational homes to prioritize COVID-19 vaccination
Authors: Saraswat Brijesh , Ansumali Santosh , Prakash Meher K. 
Published: April 2021

AbstractUniversal vaccination on an urgent basis is a way of controlling the COVID-19 infections and deaths. Shortages of vaccine supplies and practical deployment rates on the field necessitate prioritization. The global strategy has been to prioritize those with a high personal risk due to their age or comorbidities and those who constitute the essential workforce of the society. Rather than a systematic age-based roll-down, assigning the next priority requires a local strategy based on the vaccine availability, the effectiveness of these specific vaccines, the population size as well as its age-demographics, the scenario of how the pandemic is likely to develop. The Adult (ages 20-60) – Senior (ages over 60) duo from a multigenerational home presents a high-risk demographic, with an estimated “effective age” of an adult living with a grandparent that is not vaccinated to be 40 years more. Our model suggests that strategically vaccinating the Adults from multigenerational homes in India may be effective in saving the lives of around 70,000 to 200,000 of Seniors, under the different epidemiological scenarios possible with or without strict lockdowns.
Mechanisms of biodiversity betweenCampylobactersequence types in a flock of broiler-breeder chickens
Authors: Rawson Thomas , Colles Frances M. , Terry J. Christopher D. , Bonsall Michael B. 
Published: April 2021

ABSTRACTA long-term study ofCampylobactersequence types was used to investigate the competitive framework of theCampylobactermetacommunity, and understand how multiple sequence types simultaneously co-occur in a flock of chickens. A combination of matrix and patch-occupancy models were used to estimate parameters describing the competition, transmission, and mortality of each sequence type. It was found thatCampylobactersequence types form a strong hierarchical framework within a flock of chickens, and occupied a broad spectrum of transmission-mortality trade-offs. Upon further investigation of how biodiversity is thus maintained within the flock, it was found that the demographic capabilities ofCampylobacter, such as mortality and transmission, could not explain the broad biodiversity of sequence types seen, suggesting that external factors such as host-bird health and seasonality are important elements in maintaining biodiversity ofCampylobactersequence types.