bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age and Sex Differences in the Genetics of Cardiomyopathy
Authors: Akinrinade Oyediran ,   Genomics England Research Consortium, Lougheed Jane , Mondal Tapas , Smythe John , Altamirano-Diaz Luis , Oechslin Erwin , Mital Seema 
Published: April 2021

AbstractAimsCardiomyopathy is a clinically and genetically heterogeneous disorder with age and sex-related differences in severity and outcomes. The aim of our study was to identify age and sex-related differences in the genetic architecture of cardiomyopathy.Methods and ResultsWe analyzed whole genome sequence data from 471 pediatric and 926 adult cardiomyopathy patients from our Heart Centre Biobank and from the Genomics England cohort. Overall yield of rare deleterious coding variants was higher in pediatric compared to adult onset cardiomyopathy, but not different by sex.MYH7, TNNT2, MYL3, andVCLvariants were more frequent in pediatric patients;TTNandOBSCNvariants were more frequent in adult patients, withMYH7(Odds ratio 3.6; CI 2.1-6.3) andOBSCN(Odds ratio 5.5, CI 2.0-21.4) remaining significant after adjusting for multiple testing. Variants in early-onset cardiomyopathy clustered in highly constrained coding regions compared to those in adult patients (p=3.9×10−3). There were also differences between pediatric and adult patients in variant location withinMYH7andTTNgenes. When analyzed by sex, variants in female compared to male patients were in more highly constrained coding regions (p=0.002).ConclusionOur findings highlight under-appreciated genetic differences in early versus late onset cardiomyopathy. Variants in childhood cardiomyopathy and in female patients were in highly constrained coding regions of the genome suggesting greater deleterious effects and strong purifying selection in the general population. Knowledge of the affected gene, variant location within the gene, and variant constraint scores may be useful in predicting early versus late onset cardiomyopathy.
Rapid neural encoding of the contrast between native and nonnative speech in the alpha band
Authors: Tavano Alessandro , Nagels Arne , Gagl Benjamin , Muralikrishnan R. 
Published: April 2021

AbstractMore than half of the world’s population is multilingual, yet it is not known how the human brain encodes the perception of native vs. nonnative speech. To find out, we asked German native speakers to detect the onset of native and nonnative (English and Turkish) vowels in a roving standard stimulation. Using EEG, we show that nonnativeness is robustly registered by an increase in phase coherence in the alpha band (8-12 Hz), beginning as early as ∼100 ms after stimulus onset and lasting more than 200 ms. The alpha band effect is speech-specific, successfully predicts the response speed advantage of nonnative speech, and grants ∼90% decoding accuracy in distinguishing native vs. nonnative speech irrespective of language familiarity. We propose alpha phase coherence as a candidate neural channel for the online resolution of the native-nonnative contrast in the adult brain.Significance StatementWe show that the human brain takes only ∼ 100 ms to distinguish native vs. nonnative speech. This difference is neurally encoded in the alpha band in a reliable and specific way, supporting a processing model in which the mixture of top-down and bottom-up information represented in the speech signal is concurrently partitioned into different frequency channels.
Stable motifs delay species loss in simulated food webs
Authors: Cirtwill Alyssa R. , Wootton Kate 
Published: April 2021

AbstractSome three-species motifs (unique patterns of interactions between three species) are both more stable when modeled in isolation and over-represented in empirical food webs. This suggests that these motifs may reduce extinction risk for species participating in them, ultimately stabilizing the food web as a whole. We test whether a species’ time to extinction following a perturbation is related to its participation in stable and unstable motifs and assess how motif roles co-vary with a species’ degree or trophic level. We found that species’ motif roles are related to their times to extinction following a disturbance. Specifically, participating in many omnivory motifs (whether in absolute terms, as a proportion of the species’ role, or relative to other species in the network) was associated with more rapid extinction, even though omnivory has previously been identified as a stable motif. Participating in the other three stable motifs (three-species chain, apparent competition, and direct competition) was associated with longer times to extinction. While motif roles were associated with extinction risk, they also varied strongly with degree and trophic level. This means that these simpler measures of a species’ role may be sufficient to roughly predict which species are most vulnerable to disturbance, but the additional information encapsulated in a motif role can further refine predictions of vulnerability. Moreover, where researchers area prioriinterested in motif roles, our results confirm that these roles can be interpreted with respect to extinction risk.
Identification of decondensed large-scale chromatin regions by TSA-seq and their localization to a subset of chromatin domain boundaries
Authors: Gholamalamdari Omid , Zhang Liguo , Chen Yu , Belmont Andrew 
Published: April 2021

AbstractLarge-scale chromatin compaction is nonuniform across the human genome and correlates with gene expression and genome organization. Current methodologies for assessing large-scale chromatin compaction are indirect and largely based on assays that probe lower levels of chromatin organization, primarily at the level of the nucleosome and/or the local compaction of nearby nucleosomes. These assays assume a one-to-one correlation between local nucleosomal compaction and large-scale compaction of chromosomes that may not exist. Here we describe a method to identify interphase chromosome regions with relatively high levels of large-scale chromatin decondensation using TSA-seq, which produces a signal proportional to microscopic-scale distances relative to a defined nuclear compartment. TSA-seq scores that change rapidly as a function of genomic distance, detected by their higher slope values, identify decondensed large-scale chromatin domains (DLCDs), as then validated by 3D DNA-FISH. DLCDs map near a subset of chromatin domain boundaries, defined by Hi-C, which separate active and repressed chromatin domains and correspond to compartment, subcompartment, and some TAD boundaries. Most DLCDs can also be detected by high slopes of their Hi-C compartment score. In addition to local enrichment in cohesin (RAD21, SMC3) and CTCF, DLCDs show the highest local enrichment to super-enhancers, but are also locally enriched in transcription factors, histone-modifying complexes, chromatin mark readers, and chromatin remodeling complexes. The localization of these DLCDs to a subset of Hi-C chromatin domain boundaries that separate active versus inactive chromatin regions, as measured by two orthogonal genomic methods, suggests a distinct role for DLCDs in genome organization.
ALT Neuroblastoma Chemoresistance due to ATM Activation by Telomere Dysfunction is Reversible with the ATM Inhibitor AZD0156
Authors: Koneru Balakrishna , Farooqi Ahsan , Nguyen Thinhh H. , Chen Wan Hsi , Hindle Ashly , Eslinger Cody , Makena Monish Ram , Burrow Trevor A. , Wilson Joanne , Smith Aaron , Reddy Venkatesh Pilla , Cadogan Elaine , Durant Stephen T. , Reynolds C. Patrick 
Published: April 2021

AbstractCancers overcome replicative immortality by activating either telomerase or an alternative lengthening of telomeres (ALT) mechanism. ALT occurs in ∼ 25% of high-risk neuroblastomas and relapse or progression in ALT neuroblastoma patients during or after front-line therapy is frequent and almost uniformly fatal. Temozolomide + irinotecan is commonly used as salvage therapy for neuroblastoma. Patient-derived cell-lines and xenografts established from relapsed ALT neuroblastoma patients demonstratedde novoresistance to temozolomide + irinotecan (as SN-38in vitro, P<0.05)andin vivo(mouse event-free survival (EFS)P<0.0001) relative to telomerase-positive neuroblastomas. We observed that ALT neuroblastoma cells manifest constitutive ATM kinase activation due to spontaneous telomere dysfunction while telomerase- positive tumors lacked constitutive ATM activation or spontaneous telomere DNA damage. We demonstrated that induction of telomere dysfunction resulted in ATM activation that in turn conferred resistance to temozolomide + SN-38 (4.2 fold-change in IC50,P<0.001). ATM kinase shRNA knock-down or inhibition using a clinical-stage small molecule inhibitor (AZD0156) reversed resistance to temozolomide + irinotecan in ALT neuroblastoma cell-linesin vitro(P<0.001) and in 4 ALT xenograftsin vivo(EFSP<0.0001). AZD0156 showed modest to no enhancement of temozolomide + irinotecan activity in telomerase-positive neuroblastoma cell lines and xenografts. ATR inhibition using AZD6738 did not enhance temozolomide + SN-38 activity in ALT neuroblastoma cell lines. Thus, resistance to chemotherapy in ALT neuroblastoma occurs via ATM kinase activation and was reversed with the ATM inhibitor AZD0156. Combining AZD0156 with temozolomide + irinotecan warrants clinical testing in neuroblastoma.One Statement SummaryATM activation at telomeres confers resistance to DNA damaging chemotherapy in ALT neuroblastoma that was reversed with ATM knockdown or inhibition.
Antibodies to the SARS-CoV-2 receptor-binding domain that maximize breadth and resistance to viral escape
Authors: Starr Tyler N. , Czudnochowski Nadine , Zatta Fabrizia , Park Young-Jun , Liu Zhuoming , Addetia Amin , Pinto Dora , Beltramello Martina , Hernandez Patrick , Greaney Allison J. , Marzi Roberta , Glass William G. , Zhang Ivy , Dingens Adam S. , Bowen John E. , Wojcechowskyj Jason A. , De Marco Anna , Rosen Laura E. , Zhou Jiayi , Montiel-Ruiz Martin , Kaiser Hannah , Tucker Heather , Housley Michael P. , di Iulio Julia , Lombardo Gloria , Agostini Maria , Sprugasci Nicole , Culap Katja , Jaconi Stefano , Meury Marcel , Dellota Exequiel , Cameroni Elisabetta , Croll Tristan I. , Nix Jay C. , Havenar-Daughton Colin , Telenti Amalio , Lempp Florian A. , Pizzuto Matteo S. , Chodera John D. , Hebner Christy M. , Whelan Sean P.J. , Virgin Herbert W. , Veesler David , Corti Davide , Bloom Jesse D. , Snell Gyorgy 
Published: April 2021

AbstractAn ideal anti-SARS-CoV-2 antibody would resist viral escape1–3, have activity against diverse SARS-related coronaviruses4–7, and be highly protective through viral neutralization8–11 and effector functions12,13. Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD), including S3094, the parental antibody of the late-stage clinical antibody VIR-7831. We observe a tradeoff between SARS-CoV-2 in vitro neutralization potency and breadth of binding across SARS-related coronaviruses. Nevertheless, we identify several neutralizing antibodies with exceptional breadth and resistance to escape, including a new antibody (S2H97) that binds with high affinity to all SARS-related coronavirus clades via a unique RBD epitope centered on residue E516. S2H97 and other escape-resistant antibodies have high binding affinity and target functionally constrained RBD residues. We find that antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency, but we identify one potent RBM antibody (S2E12) with breadth across sarbecoviruses closely related to SARS-CoV-2 and with a high barrier to viral escape. These data highlight functional diversity among antibodies targeting the RBD and identify epitopes and features to prioritize for antibody and vaccine development against the current and potential future pandemics.
Caspase-dependent cleavage of DDX21 suppresses host innate immunity
Authors: Wu Wei , Qu Yang , Yu Shengqing , Wang Sa , Yin Yuncong , Liu Qinfang , Meng Chunchun , Liao Ying , Rehman Zaib Ur , Tan Lei , Song Cuiping , Qiu Xusheng , Liu Weiwei , Ding Chan , Sun Yingjie 
Published: April 2021

AbstractDEAD (Glu-Asp-Ala-Glu)-box RNA helicases have been proven to contribute to antiviral innate immunity. DDX21 RNA helicase was identified as a nuclear protein involved in ribosomal RNA processing and RNA unwinding. DDX21 was also proved to be the scaffold protein in the complex of DDX1-DDX21-DHX36 which senses double strand RNA and initiates downstream innate immunity. Here, we identified that DDX21 undergoes caspase-dependent cleavage after virus infection and treatment with RNA/DNA ligands, especially for RNA virus and ligands. Caspase-3/6 cleave DDX21 at D126and promotes its translocation from the nucleus to the cytoplasm in response to virus infection. The cytoplasmic cleaved DDX21 negatively regulates the IFN-β signaling pathway by suppressing the formation of DDX1-DDX21-DHX36 complex. Thus, our data identify DDX21 as a regulator of immune balance and most importantly uncover a potential role of DDX21 cleavage in the innate immunity response towards virus.ImportanceInnate immunity serves as the first barrier against virus infection. DEAD (Glu-Asp-Ala-Glu)-box RNA helicases, originally considered to be involved RNA processing and RNA unwinding, have been shown to play an important role in anti-viral innate immunity. The precise regulation of innate immunity is critical for the host because the aberrant production of cytokines leads to unexpected pathological consequences. Here, we identified DDX21 was cleaved at D126by virus infection and treatment with RNA/DNA ligands via the caspase-3/6-dependent pathway. The cytoplasmic cleaved DDX21 negatively regulates the IFN-β signaling pathway by suppressing the formation of DDX1-DDX21-DHX36 complex. In sum, our data identify DDX21 as a regulator of immune balance and most importantly uncover a potential role of DDX21 cleavage in the innate immunity response towards virus.
Tracking of Anopheles stephensi in Ethiopia using mitochondrial DNA reveals pattern of spread
Authors: Carter Tamar E. , Yared Solomon , Getachew Dejene , Spear Joseph , Choi Sae Hee , Samake Jeanne N. , Mumba Peter , Dengela Dereje , Yohannes Gedeon , Chibsa Sheleme , Murphy Matthew , Dissanayake Gunawardena , Flately Cecilia , Lopez Karen , Janies Daniel , Zohdy Sarah , Irish Seth R. , Balkew Meshesha 
Published: April 2021

ABSTRACTThe recent detection of the South Asian malaria vector Anopheles stephensi in the Horn of Africa (HOA) raises concerns about the impact of this mosquito on malaria transmission in the region. The mode and history of introduction is important for predicting the likelihood of continued introduction and future spread. Analysis of An. stephensi genetic diversity and population structure can provide insight into the history of the mosquito in the HOA. We investigated genetic diversity of An. stephensi in eastern Ethiopia where detection suggests a range expansion to this region to understand the history of this invasive population. We sequenced the cytochrome oxidase subunit I (COI) and cytochrome B gene (CytB) in 187 An. stephensi collected from 10 sites in Ethiopia in 2018. Phylogenetic analyses using a maximum-likelihood approach and minimum spanning network were conducted for Ethiopian sequences. Molecular identification of bloodmeal sources was also performed using universal vertebrate CytB sequencing. Six COI-CytB haplotypes were observed based on five segregating sites, with the highest number of haplotypes in the northeastern sites (Semera, Bati, and Gewana towns) relative to the southeastern sites (Kebridehar, Godey, and Degehabur) in eastern Ethiopia. In the phylogenetic and network analysis, we observed population differentiation based on the distribution of the haplotypes across the northeastern and central sites (Erer Gota, Dire Dawa, and Awash Sebat Kilo) compared to the southeastern sites and evidence of a South Asian origin of the HOA An. stephensi lineages. The presence of the putative South Asian haplotype of origin at sites closest to Ethiopia’s northeastern borders support route of introductions into Ethiopia from the northeast. Finally, molecular bloodmeal analysis revealed evidence of feeding on bovines, goats, dogs, and humans, as well as evidence of multiple (mixed) blood meals. In conclusion, we find support for the hypothesis for the recent expansion of An. stephensi into southeastern Ethiopia with multiple introductions. We also find evidence that supports the hypothesis that HOA An. stephensi populations originate from South Asia rather than the Arabian Peninsula. The evidence of both zoophagic and anthropophagic feeding support the potential for livestock movement to play a role in vector spread in this region.
Effective gene expression prediction from sequence by integrating long-range interactions
Authors: Avsec Žiga , Agarwal Vikram , Visentin Daniel , Ledsam Joseph R. , Grabska-Barwinska Agnieszka , Taylor Kyle R. , Assael Yannis , Jumper John , Kohli Pushmeet , Kelley David R. 
Published: April 2021

AbstractThe next phase of genome biology research requires understanding how DNA sequence encodes phenotypes, from the molecular to organismal levels. How noncoding DNA determines gene expression in different cell types is a major unsolved problem, and critical downstream applications in human genetics depend on improved solutions. Here, we report substantially improved gene expression prediction accuracy from DNA sequence through the use of a new deep learning architecture called Enformer that is able to integrate long-range interactions (up to 100 kb away) in the genome. This improvement yielded more accurate variant effect predictions on gene expression for both natural genetic variants and saturation mutagenesis measured by massively parallel reporter assays. Notably, Enformer outperformed the best team on the critical assessment of genome interpretation (CAGI5) challenge for noncoding variant interpretation with no additional training. Furthermore, Enformer learned to predict promoter-enhancer interactions directly from DNA sequence competitively with methods that take direct experimental data as input. We expect that these advances will enable more effective fine-mapping of growing human disease associations to cell-type-specific gene regulatory mechanisms and provide a framework to interpret cis-regulatory evolution. To foster these downstream applications, we have made the pre-trained Enformer model openly available, and provide pre-computed effect predictions for all common variants in the 1000 Genomes dataset.One-sentence summaryImproved noncoding variant effect prediction and candidate enhancer prioritization from a more accurate sequence to expression model driven by extended long-range interaction modelling.
ULTRASTRUCTURAL STUDY OF THE ESOPHAGUS AND STOMACH OFArapaima gigas(Schinz 1822), JUVENILE PAICHE, CREATED EXCAVATED TANK
Authors: Pinto Keila Silva , de Melo Luana Félix , de Aquino Julia Bastos , Dantas Filho Jerônimo Vieira , Miglino Maria Angelica , de Vargas Schons Sandro , Rici Rose Eli Grassi 
Published: April 2021

AbstractPaiche (Arapaima gigas)belongs to the KingdomAnimalia, PhylumChordata, ClassActinopterygii, OrderOsteoglossiformes,FamilyArapaimidae,GenusArapaima,and its origin may date to the Jurassic period. The species has natural habitat in the Amazonian rivers, found mainly in marginal lakes, being considered an important fishing resource, with high market value and high demand for meat and leather in both Brazilian and international trade. This study aims to describe the morphology of the esophagus and stomach by light microscopy and scanning electronics microscopy. The esophagus was presented as muscular, short, tubular and fan-shaped in the cranial portion, also presenting deep longitudinal folds, and the entire mucosa is covered by mucus secretory cells with distinct morphological characteristics. Pirarurcu’s stomach has a J-shape divided into three regions: cardiac with a lighter aspect, fundus portion with few folds in the mucosa, and pyloric with deeper folds, also presenting gastroliths in fundus and pyloric portions. Both microscopy studies highlighted three glandular regions, composed by mucoid columnar epithelial cells, gastric crypts with different shapes and sizes depending on each portion, in which the different shapes of the mucosal folds in each region of the stomach were evident, and digitiform microsaliences were found in the cardiac region, and micro-orifices and desmosome in the fundus region. Also, fundus and pyloric portions produce more mucus than the cardiac. Then morphology found was consistent with the eating habits and management of distinct characteristics of the digestive tract.
Precocious hippocampal structural and functional changes in gestational protein-restricted male elderly offspring: an Alzheimer-simile disease model?
Authors: Grigoletti-Lima Gabriel Boer , Lopes Marcelo Gustavo , Franco Ana Tereza Barufi , Damico Aparecida Marcela , Boer Patrícia Aline , Gontijo José Antonio Rocha 
Published: April 2021

ABSTRACTBackgroundMaternal undernutrition has been associated with psychiatric and neurological disorders characterized by learning and memory impairment. Considering the lack of evidence for this, we aimed to analyze the effects of gestational protein restriction on learning and memory function later in life. This research associates behavioral findings with hippocampal cell numbers and protein content related to neurodegenerative brain disease.MethodsExperiments were conducted in animals subjected to a low-protein (LP, 6% casein) or regular-protein (NP, 17% casein) diet throughout their pregnancy. Behavioral tests, isolated hippocampal isotropic fractionator cell studies, immunoblotting, and survival lifetime tests were performed. The results confirmed that the birthweight of LP male pups significantly reduced relative to NP male pups and that hippocampal mass increased in 88-week-old LP compared to age-matched NP offspring. We used the Morris water maze proximity measure, which is the sum of 10 distances each second between rat position and location of a hidden platform target, as a suitable test for assessing age-related learning or memory impairment in aged offspring.ResultsThe results showed an increased proximity measure in 87-week-old LP rats (52.6 × 104± 10.3 × 104mm) as compared to NP rats (47.0 × 104± 10.6 × 103mm, p = 0.0007). In addition, LP rats exhibited anxiety-like behaviors compared to NP rats at 48 and 86 weeks of life.Additionally, the estimated neuron number was unaltered in LP rats; however, glial and other cell numbers increased in LP compared to NP rats. Here, we showed unprecedented hippocampal deposition of brain-derived neurotrophic factor, β-amyloid peptide (Aβ), and tau protein in 88-week-old LP compared to age-matched NP offspring. To date, no predicted studies showed changes in hippocampal neuron and glial cell numbers in maternal protein-restricted elderly offspring. The current data suggest that maternal protein restriction has a high impact on lifespan and brain structure, and function.Conclusionthe gestational protein restriction may accelerate hippocampal function loss, impacting learning/memory performance, and supposedly developing diseases similar to Alzheimer’s disease (AD) in elderly offspring. Thus, we propose that maternal protein restriction could be a probable, elegant, and novel method for constructing an AD-like model in adult male offspring.