bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromatin sensing by the auxiliary domains of KDM5C regulates its demethylase activity and is disrupted by X-linked intellectual disability mutations
Authors: Ugur Fatima S. , Kelly Mark J. S. , Fujimori Danica Galonić 
Published: January 2022

ABSTRACTThe H3K4me3 chromatin modification, a hallmark of promoters of actively transcribed genes, is dynamically removed by the KDM5 family of histone demethylases. The KDM5 demethylases have a number of accessory domains, two of which, ARID and PHD1, lie between the segments of the catalytic domain. KDM5C, which has a unique role in neural development, harbors a number of mutations adjacent to its accessory domains that cause X-linked intellectual disability (XLID). The roles of these accessory domains remain unknown, limiting an understanding of how XLID mutations affect KDM5C activity. Throughin vitrobinding and kinetic studies using nucleosomes, we find that while the ARID domain is required for efficient nucleosome demethylation, the PHD1 domain alone has an inhibitory role in KDM5C catalysis. In addition, the unstructured linker region between the ARID and PHD1 domains interacts with PHD1 and is necessary for nucleosome binding. Our data suggests a model in which the PHD1 domain inhibits DNA recognition by KDM5C. This inhibitory effect is relieved by the H3 tail, enabling recognition of flanking DNA on the nucleosome. Importantly, we find that XLID mutations adjacent to the ARID and PHD1 domains break this regulation by enhancing DNA binding, resulting in the loss of specificity of substrate chromatin recognition and rendering demethylase activity lower in the presence of flanking DNA. Our findings suggest a model by which specific XLID mutations could alter chromatin recognition and enable euchromatin-specific dysregulation of demethylation by KDM5C.
Chlorpyrifos degradation by combined solar photo-Fenton and bacterial metabolism and simultaneous toxicity analysis in zebrafish (Danio rerio)
Authors: Nayak Tanmaya , Ghosh Arpan , Das Sourav , Adhya Tapan Kumar , Patel Paritosh , Mohanty Swabhiman , Umar Mahwish , Das Biswadeep , Tripathy Suraj K. , Raina Vishakha 
Published: January 2022

AbstractChlorpyrifos (CP) is a widely used insecticide that has been used extensively, contributing towards a negative impact on public health concerns and associated ecosystems. Bioremediation is one of the key biological methods used for reducing these environmental toxicants. The present study examined the effectiveness of a combined process including solar photo-Fenton process followed by bacterial degradation using Ochrobactrum sp. CPD-03 for effective CP degradation in wastewater. Results showed that solar photo-Fenton treatment had CP degradation efficiency of ~42% in 4 h with a final degradation efficiency of ~92% in 96 h upon combined bacterial degradation. Simultaneous survivability of zebrafish (Danio rerio) was also studied during CP degradation. Compared to control, adult zebrafishes showed increased survivability following the addition of CPD-03 in water resulting a reduced CP concentration. CP toxicity in wastewater had caused acetylcholinesterase inhibition in zebrafish; however, this inhibition is due to absence of CP degrading bacteria. Therefore, a combined approach would influence for regulating CP degradation in wastewater along with simultaneous survival of Danio rerio.
Syndecan Regulates Cellular Morphogenesis in Cooperation with the Netrin Guidance Pathway and Rho-family GTPases
Authors: Dima Raphaël , Tahé Marianne Bah , Chabi Yann A. , Rivollet Lise , Arena Anthony F. , Socovich Alexandra M. , Shaye Daniel , Bénard Claire Y. 
Published: January 2022

ABSTRACTThe establishment of complex cell shapes is essential for specific cellular functions, and thus critical in animal development and physiology. Heparan sulfate proteoglycans (HSPGs) are conserved glycoproteins that regulate interactions between extracellular signals and their receptors, to orchestrate morphogenetic events and elicit cellular responses. Although HSPG-regulated pathways have been implicated in regulating the guidance of neuronal migrations, whether HSPGs regulate earlier aspects of cellular development that dictate cell shape remains unknown. HSPGs consist of a protein core (e.g., Syndecan, Perlecan, Glypican, etc.) with attached heparan sulfate (HS) glycosaminoglycan chains, which are synthesized by glycosyltransferases of the exostosin family. Using mutations in the two C. elegans HS glycosyltransferases genes, rib-1 and rib-2, we reveal that HSPGs control the number of cellular projections in the epithelial excretory canal cell, which can form more than its normal four canals in these mutants. We identify SDN-1/Syndecan as the key HSPG that regulates the number of excretory canal cell projections in a cell-autonomous manner. We also find that Syndecan and guidance receptors for Netrin function in the same pathway to restrict the number of cellular projections. Furthermore, we show that the formation of extra projections in the absence of Syndecan requires the conserved Rho-family GTPases CED-10/Rac and MIG-2/RhoG. Our findings not only contribute to understanding the roles of conserved HSPGs in cellular morphogenetic events, but also reveal the existence of an HSPG-regulated system operating to guarantee that a precise number of cellular projections is established during cell development. Given the evolutionary conservation of developmental mechanisms and the molecules implicated, this work provides information relevant to understanding the cellular and molecular bases of the development of precise cellular morphologies in varied cell types across animals.
Multiple UBX proteins reduce the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase
Authors: Fujisawa Ryo , Labib Karim P.M. 
Published: January 2022

AbstractThe unfolding of ubiquitylated proteins by the p97 / Cdc48 ATPase and its ubiquitin receptors Ufd1-Npl4 is essential in many areas of eukaryotic cell biology. Previous studies showed that yeast Cdc48-Ufd1-Npl4 is governed by a quality control mechanism, whereby substrates must be conjugated to at least five ubiquitins. Here we show that substrate processing by mammalian p97-UFD1-NPL4 involves a complex interplay between ubiquitin chain length and additional p97 cofactors. Using disassembly of the ubiquitylated CMG helicase as a model in vitro system, we find that reconstituted p97-UFD1-NPL4 only unfolds substrates with very long ubiquitin chains. However, this high ubiquitin threshold is greatly reduced, to a level resembling yeast Cdc48-Ufd1-Npl4, by the UBXN7, FAF1 or FAF2 partners of mammalian p97-UFD1-NPL4. Stimulation by UBXN7/FAF1/FAF2 requires the UBX domain that connects each factor to p97, together with the ubiquitin-binding UBA domain of UBXN7 and a previously uncharacterised coiled-coil domain in FAF1/FAF2. Furthermore, we show that deletion of the UBXN7 and FAF1 genes impairs CMG disassembly during S-phase and mitosis and sensitises cells to reduced ubiquitin ligase activity. These findings indicate that multiple UBX proteins are important for the efficient unfolding of ubiquitylated proteins by p97-UFD1-NPL4 in mammalian cells.
Bulk and spatially resolved extracellular metabolomics of free-living nitrogen fixation
Authors: Smercina Darian N , Kim Young-Mo , Lipton Mary S , Velickovic Dusan , Hofmockel Kirsten S 
Published: January 2022

AbstractSoil microorganisms drive ecosystem function, but challenges of scale between microbe and ecosystem hinder our ability to accurately quantify and predictively model the soil microbe-ecosystem function relationship. Quantifying this relationship necessitates studies that systematically characterize multi-omics of soil microorganisms and their activity across sampling scales from spatially resolved to bulk measures, and structural complexity, from liquid pure culture to in situ. To address this need, we cultured two diazotrophic bacteria in liquid and solid media, with and without nitrogen (N) to quantify differences in extracellular metabolites associated with nitrogen fixation under increasing environmental structural complexity. We also quantified extracellular metabolites across sampling scales including bulk sampling via GC-MS analysis and spatially resolved analysis via MALDI mass spectrometry imaging. We found extracellular production of inorganic and organic N during free-living nitrogen fixation activity, highlighting a key mechanism of terrestrial N contributions from this process. Additionally, our results emphasize the need to consider the structural complexity of the environment and spatial scale when quantifying microbial activity. We found differences in metabolite profiles between culture conditions, supporting previous work indicating environmental structure influences microbial function, and across scales, underscoring the need to quantify microbial scale conditions to accurately interpret microbial function.ImportanceStudying soil microorganisms, both who is present and what they are doing, is a challenge because of vast differences in scale between microorganism and ecosystem and because of inherent complexities of the soil system (e.g., opacity, chemical complexity). This makes measuring and predicting important ecosystem processes driven by soil microorganisms, like free-living nitrogen fixation, difficult. Free-living nitrogen fixing bacteria play a key role in terrestrial nitrogen contributions and may represent a significant, yet overlooked, nitrogen source in agricultural systems like bioenergy crops. However, we still know very little about how free-living nitrogen fixation contributes nitrogen to terrestrial systems. Our work provides key insight by hierarchically increasing structural complexity (liquid vs. solid culture) and scale (spatially resolved vs. bulk) to address the impact of environmental structure and sampling scale on detection of free-living nitrogen fixation and to identify the forms of nitrogen contributed to terrestrial systems by free-living nitrogen bacteria.
The risk of SARS-CoV-2 Omicron variant emergence in low and middle-income countries (LMICs)
Authors: Bi Kaiming , Herrera-Diestra Jose Luis , Bai Yuan , Du Zhanwei , Wang Lin , Gibson Graham , Johnson-Leon Maureen , Fox Spencer J. , Meyers Lauren Ancel 
Published: January 2022

AbstractWe estimated the probability of undetected emergence of the SARS-CoV-2 Omicron variant in 25 low and middle-income countries (LMICs) prior to December 5, 2021. In nine countries, the risk exceeds 50%; in Turkey, Pakistan and the Philippines, it exceeds 99%. Risks are generally lower in the Americas than Europe or Asia.
HAT-field: a cheap, robust and quantitative point-of-care serological test for Covid-19
Authors: Joly Etienne , Ribes Agnès Maurel 
Published: January 2022

AbstractWe have recently described a very simple and cheap serological test called HAT to detect antibodies directed against the RBD of the SARS-Cov-2 virus. HAT is based on hemagglutination, triggered by a single reagent (IH4-RBD) comprised of the viral RBD domain fused to a nanobody specific for glycophorin, which is expressed at very high levels at the surface of human red blood cells (RBCs).One of the main initial goals of this study was to devise a test protocol that would be sensitive and reliable, yet require no specialized laboratory equipment such as adjustable pipets, so that it could be performed in the most remote corners of the world by people with minimal levels of training. Because antibody levels against the viral RBD have been found to correlate closely with sero-neutralisation titers, and thus with protection against reinfection, it has become obvious during the course of this study that making this test reliably quantitative would be a further significant advantage.Using IH4-RBD based on the original Wuhan sequence, we have found that, in PBN, a buffer which contains BSA and sodium azide, the reagent is stable for over 6 months at room temperature, and that PBN also improves HAT performance compared to using straight PBS. We also show that performing HAT at either 4°C, room temperature or 37°C has minimal influence on the results, and that quantitative evaluation of the levels of antibodies directed against the SARS-CoV-2 RBD can be achieved in a single step using titration of the IH4-RBD reagent.The HAT-field protocol described here requires only very simple disposable equipment and a few microliters of whole blood, such as can be obtained by finger prick. Because it is based on a single soluble reagent, the test can be adapted very simply and rapidly to detect antibodies against variants of the SARS-CoV-2, or conceivably against different pathogens. HAT-field appears well suited to provide quantitative assessments of the serological protection of populations as well as individuals, and given its very low cost, the stability of the IH4-RBD reagent in the adapted buffer, and the simplicity of the procedure, could be deployed pretty much anywhere, including in the poorest countries and the most remote corners of the globe.Note: This manuscript has been refereed by Review Commons, and modified thanks to the comments and suggestions from three referees. Those comments, and our replies, are provided at the end of the manuscript’s pdf, and can also be accessed by clicking on the blue tab found to the right of the MedRXiv window.
Evaluation and modelling of the performance of an automated SARS-CoV-2 antigen assay according to sample type, target population and epidemic trends
Authors: Yin Nicolas , Debuysschere Cyril , Daubie Valery , Hildebrand Marc , Martin Charlotte , Curac Sonja , Ponthieux Fanny , Payen Marie-Christine , Vandenberg Olivier , Hallin Marie 
Published: January 2022

AbstractThe Lumipulse® G SARS-CoV-2 Ag assay performance was evaluated on prospectively collected saliva and nasopharyngeal swabs (NPS) of recently ill in- and outpatients and according to the estimated viral load. Performances were calculated using RT-PCR positive NPS from patients with symptoms ≤ 7 days and RT-PCR negative NPS as gold standard. In addition, non-selected positive NPS were analyzed to assess the performances on various viral loads. This assay yielded a sensitivity of 93.1% on NPS and 71.4% on saliva for recently ill patients. For NPS with a viral load > 103 RNA copies/mL, sensitivity was 96.4%. A model established on our daily routine showed fluctuations of the performances depending on the epidemic trends but an overall good negative predictive value. Lumipulse® G SARS-CoV-2 assay yielded good performance for an automated antigen detection assay on NPS. Using it for the detection of recently ill patient or to screen high-risk patients could be an interesting alternative to the more expensive RT-PCR.
Global and National Declines in Life Expectancy: An End-of-2021 Assessment
Authors: Heuveline Patrick 
Published: January 2022

AbstractTimely, high-quality mortality data have allowed for assessments of the impact of Covid-19 on life expectancies in upper-middle- and high-income countries. Extant data, though imperfect, suggest that the bulk of the pandemic-induced mortality might have occurred elsewhere. This article reports on changes in life expectancies around the world as far as they can be estimated from the evidence available at the end of 2021.The global life expectancy appears to have declined by .92 years between 2019 and 2020 and by another .72 years between 2020 and 2021, but the decline seems to have ended during the last quarter of 2021. Uncertainty about its exact size aside, this represents the first decline in global life expectancy since 1950, the first year for which a global estimate is available from the United Nations.Annual declines in life expectancy (from a 12-month period to the next) appear to have exceeded two years at some point before the end of 2021 in at least 50 countries. Since 1950, annual declines of that magnitude had only been observed in rare occasions, such as Cambodia in the 1970s, Rwanda in the 1990s, and possibly some sub-Saharan African nations at the peak of the HIV/AIDS pandemic.
Immunosuppression impaired the immunogenicity of inactivated SARS-CoV-2 vaccine in non-dialysis kidney disease patients
Authors: Zhang Yue-Miao , Liu Xing-Zi , Lin Miao-Miao , Zan Jin-Can , Hu Yi-Tong , Wang Xiang-Qiu , Wu Wen-Qi , Zhou Tai-Cheng , Zhang Hong , Lv Ji-Cheng , Yang Li , Zhang Zi-Jie 
Published: January 2022

AbstractPatients with chronic kidney disease (CKD) are at higher risk for coronavirus disease 2019 (COVID-19)-related morbidity and mortality. However, a significant portion of CKD patients showed hesitation toward vaccination in telephone survey of our center. Yet no serial data available on humoral response in patients with CKD, especially those on immunosuppression. We conducted a pilot, prospective study to survey the safety and humoral response to inactivated SARS-CoV-2 vaccine in CKD patients receiving a 2-dose immunization of inactivated SARS-CoV-2 vaccine. We found the neutralizing antibody titers in CKD patients was significantly lower than that in healthy controls, hypertension patients, and diabetes patients. Notably, immunosuppressive medication rather than eGFR levels or disease types showed effect on the reduction of immunogenicity. Interestingly, a third dose significantly boosted neutralizing antibody in CKD patients while immunosuppressants impeded the boosting effects. In conclude, our data demonstrates that CKD patients, even for those on immunosuppression treatment, can benefit from a third vaccination boost by improving their humoral immunity.
Quality of Care for Children Under Five with Malaria Using IMCI Approach at Public Health Centre: Literature Review
Authors: Suek Orpa Diana , Pandin Moses Glorino Rumambo 
Published: January 2022

ABSTRACTIntegrated Management of Childhood Illness is one of the strategies in health care services for infants and children under five at primary health care facilities. Children with fever in high malaria endemic areas must have a blood test done to check whether the children have malaria or not. IMCI is one of the interventions recommended by WHO to screen and also ensure that children receive proper initial treatment at first-level health facilities. This article aims to discuss the quality of care for children under five with malaria using IMCI approach. This is a systematic review by searching 4 databases including Scopus, Web of Science, SAGE and Proquest. Health care services for children under five with an integrated management of childhood illness are intended to provide immediate and appropriate treatment. The guideline for treating children under five with malaria using IMCI approach is very helpful for nurses both in assessing, classifying, treating/curing and making decisions for pre-referral measures for severe cases. Several factors to support quality of care are trained officers, supervision and procurement of essential medicines, RDT and malaria microscopy. Enforcement of the right diagnosis will improve the quality of life of children and prevent death in children under five.
Characterizing features of outbreak duration for novel SARS-CoV-2 variants of concern
Authors: Washburne Alex D. , Hupert Nathaniel , Kogan Nicole , Hanage William , Santillana Mauricio 
Published: January 2022

AbstractCharacterizing the dynamics of epidemic trajectories is critical to understanding the potential impacts of emerging outbreaks and to designing appropriate mitigation strategies. As the COVID-19 pandemic evolves, however, the emergence of SARS-CoV-2 variants of concern has complicated our ability to assess in real-time the potential effects of imminent outbreaks, such as those presently caused by the Omicron variant. Here, we report that SARS-CoV-2 outbreaks across regions exhibit strain-specific times from onset to peak, specifically for Delta and Omicron variants. Our findings may facilitate real-time identification of peak medical demand and may help fine-tune ongoing and future outbreak mitigation deployment efforts.
Structures of LIG1 engaging with mutagenic mismatches inserted by polβ in base excision repair
Authors: Tang Qun , McKenna Robert , Çağlayan Melike 
Published: January 2022

ABSTRACTDNA ligase I (LIG1) catalyzes final ligation step following DNA polymerase (pol) β gap filling and an incorrect nucleotide insertion by polβ creates a nick repair intermediate with mismatched end at the downstream steps of base excision repair (BER) pathway. Yet, how LIG1 discriminates against the mutagenic 3′-mismatches at atomic resolution remains undefined. Here, we determined X-ray structures of LIG1/nick DNA complexes with G:T and A:C mismatches and uncovered the ligase strategies that favor or deter ligation of base substitution errors. Our structures revealed that LIG1 active site can accommodate G:T mismatch in a similar conformation with A:T base pairing, while it stays in the LIG1-adenylate intermediate during initial step of ligation reaction in the presence of A:C mismatch at 3′-strand. Moreover, we showed mutagenic ligation and aberrant nick sealing of the nick DNA substrates with 3′-preinserted dG:T and dA:C mismatches, respectively. Finally, we demonstrated that AP-Endonuclease 1 (APE1), as a compensatory proofreading enzyme, interacts and coordinates with LIG1 during mismatch removal and DNA ligation. Our overall findings and ligase/nick DNA structures provide the features of accurate versus mutagenic outcomes at the final BER steps where a multi-protein complex including polβ, LIG1, and APE1 can maintain accurate repair.
Identification and Age-dependent Increase of Platelet Biased Human Hematopoietic Stem Cells
Authors: Aksöz Merve , Gafencu Grigore-Aristide , Stoilova Bilyana , Buono Mario , Meng Yiran , Jakobsen Niels Asger , Metzner Marlen , Clark Sally-Ann , Beveridge Ryan , Thongjuea Supat , Vyas Paresh , Nerlov Claus 
Published: January 2022

AbstractHematopoietic stem cells (HSC) reconstitute multi-lineage human hematopoiesis after clinical bone marrow transplantation and are the cells-of-origin of hematological malignancies. Though HSC provide multi-lineage engraftment, individual murine HSCs are lineage-biased and contribute unequally to blood cell lineages. Now, by combining xenografting of molecularly barcoded adult human bone marrow (BM) HSCs and high-throughput single cell RNA sequencing we demonstrate that human individual BM HSCs are also functionally and transcriptionally lineage biased. Specifically, we identify platelet-biased and multi-lineage human HSCs. Quantitative comparison of transcriptomes from single HSCs from young, and aged, BM show that both the proportion of platelet-biased HSCs, and their level of transcriptional platelet priming, increases with age. Therefore, platelet-biased HSCs, as well as their increased prevalence and elevated transcriptional platelet priming during ageing, are conserved between human and murine hematopoiesis.One-Sentence SummaryIn vivo barcoding and single cell RNA sequencing identifies platelet-biased human bone marrow HSCs.
CtIP-dependent nascent RNA expression flanking DNA breaks guides the choice of DNA repair pathway
Authors: Gómez-Cabello Daniel , Pappas Giorgios , Aguilar-Morante Diana , Dinant Christoffel , Bartek Jiri 
Published: January 2022

AbstractThe RNA world is changing our views about sensing and resolution of DNA damage. Here, we developed single-molecule DNA/RNA analysis approaches to visualize how nascent RNA facilitates the repair of DNA double-strand breaks (DSBs). RNA polymerase II (RNAPII) is crucial for DSB resolution in human cells. DSB-flanking, RNAPII-generated nascent RNA forms RNA:DNA hybrids, guiding the upstream DNA repair steps towards favouring the error-free Homologous Recombination (HR) pathway over Non-Homologous End Joining. Specific RNAPII inhibitor, THZ1, impairs recruitment of essential HR proteins to DSBs, implicating nascent RNA in DNA end resection, initiation and execution of HR repair. We further propose that resection factor CtIP interacts with and re-activates RNAPII when paused by the RNA:DNA hybrids, collectively promoting faithful repair of chromosome breaks to maintain genomic integrity.