bluuebunny/crossref_metadata_2025_split huggingface dataset:
MapToCleave: high-throughput profiling of microRNA biogenesis in living cells
Authors: Kang Wenjing , Fromm Bastian , Houben Anna J. S. , Høye Eirik , Bezdan Daniela , Arnan Carme , Thrane Kim , Asp Michaela , Johnson Rory B. , Biryukova Inna , Friedländer Marc R. 
Published: August 2021

SummaryPrevious large-scale studies have uncovered many features that determine the processing of microRNA (miRNA) precursors, however, they have been conducted in vitro. Here we introduce MapToCleave, a new method to simultaneously profile processing of thousands of distinct RNA structures in living cells. Our new in cell method captures essentially all the biogenesis features that have been discovered through near two decades of in vitro studies - providing support for both approaches. We find that miRNA precursors with a stable lower basal stem are more efficiently processed and also have higher expression in vivo in tissues from twenty animal species. We systematically compare the importance of known and novel sequence and structural features and test biogenesis of miRNA precursors from ten animal and plant species in human cells. Lastly, we provide evidence that the GHG motif better predicts processing when defined as a structure rather than sequence motif, consistent with recent cryo-EM studies. In summary, we apply a new screening assay in living cells to reveal the importance of lower basal stem stability for miRNA processing and in vivo expression.
Ancestral contributions to contemporary European complex traits
Authors: Marnetto Davide , Pankratov Vasili , Mondal Mayukh , Montinaro Francesco , Pärna Katri , Vallini Leonardo , Molinaro Ludovica , Saag Lehti , Loog Liisa , Montagnese Sara , Costa Rodolfo , Metspalu Mait , Eriksson Anders , Pagani Luca 
Published: August 2021

AbstractThe contemporary European genetic makeup formed in the last 8000 years as the combination of three main genetic components: the local Western Hunter-Gatherers, the incoming Neolithic Farmers from Anatolia and the Bronze Age component from the Pontic Steppes. When meeting into the post-Neolithic European environment, the genetic variants accumulated during their three distinct evolutionary histories mixed and came into contact with new environmental challenges.Here we investigate how this genetic legacy reflects on the complex trait landscape of contemporary European populations, using the Estonian Biobank as a case study.For the first time we directly connect the phenotypic information available from biobank samples with the genetic similarity to these ancestral groups, both at a genome-wide level and focusing on genomic regions associated with each of the 27 complex traits we investigated. We also found SNPs connected to pigmentation, cholesterol, sleep, diastolic blood pressure, and body mass index (BMI) to show signals of selection following the post Neolithic admixture events. We recapitulate existing knowledge about pigmentation traits, corroborate the connection between Steppe ancestry and height and highlight novel associations. Among others, we report the contribution of Hunter Gatherer ancestry towards high BMI and low blood cholesterol levels.Our results show that the ancient components that form the contemporary European genome were differentiated enough to contribute ancestry-specific signatures to the phenotypic variability displayed by contemporary individuals in at least 11 out of 27 of the complex traits investigated here.
A distinct core regulatory module enforces oncogene expression in KMT2A-rearranged leukemia
Authors: Harada Taku , Heshmati Yaser , Kalfon Jérémie , Ferrucio Juliana Xavier , Perez Monika , Ewers Jazmin , Kossenkov Andrew , Ellegast Jana M. , Yi Joanna S. , Bowker Allyson , Zhu Qian , Eagle Kenneth , Dempster Joshua M. , Kugener Guillaume , Wickramasinghe Jayamanna , Herbert Zachary T. , Li Charles H. , Koren Jošt Vrabič , Weinstock David M. , Paralkar Vikram R. , Nabet Behnam , Lin Charles Y. , Dharia Neekesh V. , Stegmaier Kimberly , Orkin Stuart H. , Pimkin Maxim 
Published: August 2021

SummaryA small set of lineage-restricted transcription factors (TFs), termed core regulatory circuitry (CRC), control cell identity and malignant transformation. Here, we integrated gene dependency, chromatin architecture and TF perturbation datasets to characterize 31 core TFs in acute myeloid leukemia (AML). Contrary to a widely accepted model, we detected a modular CRC structure with hierarchically organized, partially redundant and only sparsely interconnected modules of core TFs controlling distinct genetic programs. Rapid TF degradation followed by measurement of genome-wide transcription rates revealed that core TFs directly regulate dramatically fewer genes than previously assumed. Leukemias carrying KMT2A (MLL) rearrangements depend on the IRF8/MEF2 axis to directly enforce expression of the key oncogenes MYC, HOXA9 and BCL2. Our datasets provide an evolving model of CRC organization in human cells, and a resource for further inquiries into and therapeutic targeting of aberrant transcriptional circuits in cancer.
Selection bias in mutation accumulation
Authors: Wahl Lindi M. , Agashe Deepa 
Published: August 2021

AbstractMutation accumulation (MA) experiments, in which de novo mutations are sampled and subsequently characterized, are an essential tool in understanding the processes underlying evolution. In microbial populations, MA protocols typically involve a period of population growth between severe bottlenecks, such that a single individual can form a visible colony. While it has long been appreciated that the action of positive selection during this growth phase cannot be eliminated, it is typically assumed to be negligible. Here, we quantify the effect of both positive and negative selection in MA studies, demonstrating that selective effects can substantially bias the distribution of fitness effects (DFE) and mutation rates estimated from typical MA protocols in microbes. We then present a simple correction for this bias which applies to both beneficial and deleterious mutations, and can be used to correct the observed DFE in multiple environments. Finally, we use simulated MA experiments to illustrate the extent to which the MA-inferred DFE differs from the underlying true DFE, and demonstrate that the proposed correction accurately reconstructs the true DFE over a wide range of scenarios. These results highlight that positive selection during microbial MA experiments is in fact not negligible, but can be corrected to gain a more accurate understanding of fundamental evolutionary parameters.
Three-axis classification of mouse lung mesenchymal cells reveals two populations of myofibroblasts
Authors: del Pilar Odemaris Narvaez , Chen Jichao 
Published: August 2021

ABSTRACTThe mesenchyme consists of heterogeneous cell populations that support neighboring structures and are integral to intercellular signaling. Despite such importance, mesenchymal cell types are poorly defined morphologically and molecularly, lagging behind their counterparts in the epithelial, endothelial, and immune lineages. Leveraging single-cell RNA-seq, three-dimensional imaging, and lineage tracing, we classify the mouse lung mesenchyme into three proximal-distal axes that are associated with the endothelium, epithelium, and interstitium, respectively. From proximal to distal, (1) the vascular axis includes vascular smooth muscle cells and pericytes that transition as arterioles and venules ramify into capillaries; (2) the epithelial axis includes airway smooth muscle cells and two populations of myofibroblasts: ductal myofibroblasts, surrounding alveolar ducts and marked by CDH4, HHIP, and Lgr6, which persist post-alveologenesis, and alveolar myofibroblasts, surrounding alveoli and marked by high expression of PDGFRA, which undergo developmental apoptosis; (3) the interstitial axis, residing between the epithelial and vascular trees and sharing a newly-identified marker MEOX2, includes fibroblasts in the bronchovascular bundle and the alveolar interstitium that are marked by IL33/DNER/PI16 and Wnt2, respectively. Single-cell imaging reveals distinct morphology of each mesenchymal cell population. This classification provides a conceptual and experimental framework applicable to other organs.
Llamanade: an open-source computational pipeline for robust nanobody humanization
Authors: Sang Zhe , Xiang Yufei , Bahar Ivet , Shi Yi 
Published: August 2021

AbstractNanobodies (Nbs) have recently emerged as a promising class of antibody fragments for biomedical and therapeutic applications. Despite having marked physicochemical properties, Nbs are derived from camelids and may require “humanization” to improve translational potentials for clinical trials. Here we have systematically analyzed the sequence and structural properties of Nbs based on NGS (next-generation sequencing) databases and high-resolution structures. Our analysis reveals substantial framework diversities and underscores the key differences between Nbs and human Immunoglobulin G (IgG) antibodies. We identified conserved residues that may contribute to enhanced solubility, structural stability, and antigen-binding, providing insights into Nb humanization. Based on big data analysis, we developed “Llamanade’’, a user-friendly, open-source to facilitate rational humanization of Nbs. Using Nb sequence as input, Llamanade provides information on the sequence features, model structures, and optimizes solutions to humanize Nbs. The full analysis for a given Nb takes less than a minute on a local computer. To demonstrate the robustness of this tool, we applied it to successfully humanize a cohort of structurally diverse and highly potent SARS-CoV-2 neutralizing Nbs. Llamanade is freely available and will be easily accessible on a web server to support the development of a rapidly expanding repertoire of therapeutic Nbs into safe and effective trials.Author SummaryCamelid Nbs are characterized by small size, excellent pharmacological properties and high flexibility in bioengineering for therapeutic development. However, Nbs are “xeno” antibodies, which require “humanization” to improve their translational potential. Currently, there is a lack of systematic investigation of Nbs to rationally guide humanization. No dedicated software has been developed for this purpose. Here, we report the development of Llamanade, an open-source computational pipeline and the first dedicated software to facilitate rational humanization of Nbs.To subjectively evaluate Llamanade, we used it to humanize a cohort of structurally diverse and ultrapotent antiviral Nbs against SARS-CoV-2. Robust humanization by Llamanade significantly improved the humanness level of Nbs to closely resemble fully human IgGs. Importantly, these highly humanized antiviral Nbs remained excellent solubility and comparably high bioactivities to the non-humanized Nb precursors. We envision that Llamanade will help advance Nb research into therapeutic development.
Quantifying the ongoing epidemic of disability after covid-19 in the UK population aged under 35 years; secondary analysis of the Covid Infection Survey
Authors: Spiers Nicola 
Published: August 2021

AbstractWeb-based survey and anecdotal evidence suggest that many people infected with covid-19 go on to develop long covid (symptoms persisting for more than 12 weeks) despite mild initial disease. There is particular concern that this epidemic is unfolding in the younger population where vaccination rates are low. The Covid Infection Survey (CIS) has recently published estimates of the proportion of people with long covid whose daily activities are affected a little or a lot.This paper focuses on the population aged under 35 years and uses the term ‘disabling long covid’ to describe those with symptoms lasting more than 12 weeks and daily activities limited a lot. By applying the CIS estimates to confirmed infections, with age breakdown from mid-2020 population estimates, this paper reports a first estimate of the cases of disabling long covid seeded from confirmed covid-19 infections to July 31st 2021.Results suggest there will approximately 39,000 cases of disabling long covid in those aged under 35 seeded by Covid-19 infections confirmed to July 31st. There is a need for rapid action to prevent Covid-19 infection in the younger population and support those struggling with Long Covid-related disability.
Integrated miRNA/cytokine/chemokine profiling reveals immunopathological step changes associated with COVID-19 severity
Authors: Wilson Julie C. , Kealy David , James Sally R. , Newling Katherine , Jagger Chris , Filbey Kara , Mann Elizabeth R. , Konkel Joanne E. , Menon Madhvi , Knight Sean B. , Simpson Angela ,   CIRCO collaborative group, Grainger John R. , Hussell Tracy , Kaye Paul M. , Signoret Nathalie , Lagos Dimitris 
Published: August 2021

ABSTRACTCirculating microRNAs (miRNAs) are exceptional mechanism-based correlates of disease, yet their potential remains largely untapped in COVID-19. Here, we determined circulating miRNA and cytokine and chemokine (CC) profiles in 171 blood plasma samples from 58 hospitalised COVID-19 patients. Thirty-two miRNAs were differentially expressed in severe cases when compared to moderate and mild cases. These miRNAs and their predicted targets reflected key COVID-19 features including cell death and hypoxia. Compared to mild cases, moderate and severe cases were characterised by a global decrease in circulating miRNA levels. Partial least squares regression using miRNA and CC measurements allowed for discrimination of severe cases with greater accuracy (87%) than using miRNA or CC levels alone. Correlation analysis revealed severity group-specific associations between CC and miRNA levels. Importantly, the miRNAs that correlated with IL6 and CXCL10, two cardinal COVID-19-associated cytokines, were distinct between severity groups, providing a novel qualitative way to stratify patients with similar levels of proinflammatory cytokines but different disease severity. Integration of miRNA and CC levels with clinical parameters revealed severity-specific signatures associated with clinical hallmarks of COVID-19. Our study highlights the existence of severity-specific circulating CC/miRNA networks, providing insight into COVID-19 pathogenesis and a novel approach for monitoring COVID-19 progression.
Increased circulating cell-free DNA in eosinophilic granulomatosis with polyangiitis: implications for eosinophil extracellular traps and immunothrombosis
Authors: Hashimoto Teppei , Ueki Shigeharu , Kamide Yosuke , Miyabe Yui , Fukuchi Mineyo , Yokoyama Yuichi , Furukawa Tetsuya , Azuma Naoto , Oka Nobuyuki , Takeuchi Hiroki , Kanno Kyoko , Ishida-Yamamoto Akemi , Taniguchi Masami , Hashiramoto Akira , Matsui Kiyoshi 
Published: August 2021

AbstractBackgroundEndogenous DNA derived from nuclei or mitochondria is released into the blood circulation as cell-free DNA (cfDNA) following cell damage or death. cfDNA is associated with various pathological conditions; however, its clinical significance in antineutrophil cytoplasmic antibody-associated vasculitis (AAV) remains unclear. This study aimed to evaluate the clinical significance of cfDNA in AAV.MethodsWe enrolled 35 patients with AAV, including 10 with eosinophilic granulomatosis with polyangiitis (EGPA), 13 with microscopic polyangiitis, and 12 with granulomatosis with polyangiitis. Serum cf-nuclear DNA (cf-nDNA) and cf-mitochondrial DNA (cf-mtDNA) levels were measured by quantitative polymerase chain reaction. Tissue samples from EGPA patients were examined by immunofluorescence and transmission electron microscopy. The structure, stability, and platelet adhesion of eosinophil extracellular traps (EETs) were also assessed in vitro.ResultsSerum cf-nDNA and cf-mtDNA levels were significantly higher in AAV than in healthy controls, with the highest levels in EGPA; however, serum DNase activities were comparable among all groups. cf-nDNA and cf-mtDNA decreased after treatment and were associated with disease activity only in EGPA. Blood eosinophil count and plasma D-dimer levels were significantly correlated with cf-nDNA in EGPA and cf-mtDNA. EGPA tissue samples showed lytic eosinophils and EETs in small-vessel thrombi. EETs showed greater stability against DNase than neutrophil extracellular traps and provided a scaffold for platelet adhesion in vitro.ConclusioncfDNA was increased in EGPA, associated with disease activity. The presence of DNase-resistant EETs might contribute to the occurrence of immunothrombosis in EGPA.
Clinical characteristics and outcomes of COVID-19 breakthrough infections among vaccinated patients with systemic autoimmune rheumatic diseases
Authors: Cook Claire , Patel Naomi J. , D’Silva Kristin M. , Hsu Tiffany Y-T. , DiIorio Michael , Prisco Lauren , Martin Lily , Vanni Kathleen M.M. , Zaccardelli Alessandra , Todd Derrick J. , Sparks Jeffrey A. , Wallace Zachary S. 
Published: August 2021

AbstractObjectiveTo describe the characteristics of COVID-19 vaccine breakthrough infections among systemic autoimmune rheumatic disease (SARD) patients.MethodsWe identified SARDs patients in a large healthcare system with COVID-19 vaccination ≥14 days prior to a positive SARS-CoV-2 molecular test. Details of the patient’s SARD, vaccination status, and COVID-19 infection were extracted.ResultsOf 340 confirmed COVID-19 infections among SARDs patients between December 11th, 2020 (date of first COVID-19 vaccine approval in the US) and July 30th, 2021, we identified 16 breakthrough infections. Seven (44%) received the Pfizer-BioNtech vaccine, five (31%) received the Moderna vaccine, and four (25%) received the Janssen/Johnson & Johnson vaccine. The most common SARDs included rheumatoid arthritis (6, 38%), inflammatory myopathy (3, 19%), and systemic lupus erythematosus (3, 19%). Rituximab (5, 31%), glucocorticoids (4, 25%), and mycophenolate mofetil (4, 25%) were the most frequent treatments. Among the breakthrough infections, 15 (93%) were symptomatic, six (38%) were hospitalized, one (6%) required mechanical ventilation, and two (13%) died.ConclusionsSymptomatic, including severe, breakthrough infections were observed in SARDs patients; many were on treatments associated with attenuated antibody responses to vaccination. Further studies are needed to determine the rate of breakthrough infection associated with SARD treatments and other features.Key messagesWhat is already known about this subject?Breakthrough infections following COVID-19 vaccination are expected but some patients with systemic autoimmune rheumatic diseases (SARDs) may be at higher risk because of blunted antibody responses to vaccination associated with rheumatic disease treatments and other factors that remain poorly understood.What does this study add?We identify and describe 16 COVID-19 vaccine breakthrough infections within the Mass General Brigham system between December 11th, 2020 and June 26th, 2021. The vast majority of cases were symptomatic and two were fatal.How might this impact on clinical practice or future developments?This study complements observations regarding the attenuated antibody response to COVID-19 vaccination in patients with SARDs by identifying serious clinical outcomes from breakthrough infections in patients receiving DMARDs that have been reported to have blunted vaccine responses. Our study identifies characteristics of COVID-19 breakthrough infections that may guide the prioritization of booster vaccines and other risk-mitigating strategies in patients with SARDs.
Molecular basis of UHRF1 allosteric activation for synergistic histone modification binding by PI5P
Authors: Mandal Papita , Yerkesh Zhadyra , Kharchenko Vladlena , Zandarashvili Levani , Bensaddek Dalila , Jaremko Lukasz , Black Ben E. , Fischle Wolfgang 
Published: August 2021

AbstractChromatin marks are recognized by distinct binding modules many of which are embedded in multidomain proteins or complexes. How the different protein functionalities of complex chromatin modulators are regulated is often unclear. Using a combination of biochemical, biophysical and structural approaches we delineated the regulation of the H3unmodified and H3K9me binding activities of the multidomain UHRF1 protein. The phosphoinositide PI5P interacts with two distant flexible linker regions of UHRF1 in a mode that is dependent on the polar head group and the acyl part of the phospholipid. The associated conformational rearrangements stably position the H3unmodified and H3K9me3 histone recognition modules of UHRF1 for multivalent and synergistic binding of the H3 tail. Our work highlights a novel molecular function for PI5P outside of the context of lipid mono- or bilayers and establishes a molecular paradigm for the allosteric regulation of complex, multidomain chromatin modulators by small cellular molecules.
Preexisting mycobacterial infection modulates Candida albicans-driven pyroptosis
Authors: Bhatt Bharat , Prakhar Praveen , Lohia Gaurav Kumar , Rajmani Raju S. , Balaji Kithiganahalli Narayanaswamy 
Published: August 2021

AbstractActive tuberculosis patients are at high risk of co-infection with opportunistic fungal pathogen C. albicans. However, the molecular mechanisms that orchestrate pathogenesis of Mycobacterium tuberculosis (Mtb)-C. albicans co-infection remains elusive. In the current study, we utilise a mouse model to demonstrate that Mtb promotes macrophage environment conducive for C. albicans survival. Mtb-dependent PKCζ-WNT signalling axis induces expression of an E3 ubiquitin ligase, COP1. A secondary infection of C. albicans in such Mtb-infected macrophages causes COP1 to mediate the proteasomal degradation of IRF9, a cardinal factor that we identified to arbitrate an inflammatory programmed cell death, pyroptosis. In vivo experiments mimicking a preexisting Mtb infection demonstrate that inhibition of pyroptosis in mice results in increased C. albicans burden and aberrant lung tissue architecture, leading to increased host mortality. Together, our study reveals the crucial role of pyroptosis regulation for manifesting a successful C. albicans-Mtb co-infection.
Identification of key genes and immune infiltration modulated by CPAP in Obstructive sleep apnea by integrated bioinformatics analysis
Authors: Fan Cheng , Huang Shiyuan , Xiang Chunhua , An Tianhui , Song Yi 
Published: August 2021

AbstractPatients with obstructive sleep apnea (OSA) experience partial or complete upper airway collapses during sleep resulting in nocturnal hypoxia-normoxia cycling. And continuous positive airway pressure (CPAP) is the golden treatment for OSA. Nevertheless, the exact mechanisms of action, especially the transcriptome effect of CPAP on OSA patients, remains elusive. The goal of this study was to evaluate the longitudinal alterations in peripheral blood mononuclear cells transcriptome profiles of OSA patients in order to identify the hub gene and immune response. GSE133601 were downloaded from Gene Expression Omnibus (GEO). We identified black module via weighted gene co-expression network analysis (WGCNA), the genes in which were correlated significantly with the clinical trait of CPAP treatment. Finally, eleven hub genes (TRAV10, SNORA36A, RPL10, OBP2B, IGLV1-40, H2BC8, ESAM, DNASE1L3, CD22, ANK3, ACP3) were traced and used to construct a random forest model to predict therapeutic efficacy of CPAP in OSA with a good performance with AUC of 0.92. We further studied the immune cells infiltration in OSA patients with CIBERSORT, and monocytes were found to be related with the remission of OSA and partially correlated with the hub genes identified. In conclusion, these key genes and immune infiltration may be of great importance in the remission of OSA and related research of these genes may provide a new therapeutic target for OSA in the future.