bluuebunny/crossref_metadata_2025_split huggingface dataset:
tRNA epitranscriptomic alterations associated with opioid-induced reward-seeking and long-term opioid withdrawal
Authors: Blaze J. , Browne C. J. , Futamura R. , Zachariou V. , Nestler E. J. , Akbarian S. 
Published: September 2023

AbstractDNA cytosine methylation has been documented as a potential epigenetic mechanism of transcriptional regulation underling opioid use disorder. However, methylation of RNA cytosine residues, which would drive another level of biological influence as an epitranscriptomic mechanism of gene and protein regulation has not been studied. Here, we probed whether chronic morphine exposure could alter tRNA cytosine methylation (m5C) and resulting expression levels in the medial prefrontal cortex (mPFC), a brain region crucial for reward processing and executive function that exhibits opioid-induced molecular restructuring. We identified dynamic changes in glycine tRNA (tRNAGlyGCC) cytosine methylation, corresponding to altered expression levels of this tRNA at multiple timepoints following 15 days of daily morphine. Strikingly, a robust increase in methylation, coupled with decreased expression, was present after 30 days of withdrawal, suggesting that repeated opioid administration produces changes to the tRNA regulome long after discontinuation. Furthermore, forebrain-wide knockout of neuronalNsun2, a tRNA methyltransferase, was associated with disruption of reward-seeking in the conditioned place preference paradigm, and this effect was recapitulated by regional mPFCNsun2knockout. Taken together, these studies provide a foundational link between the regulation of tRNA cytosine methylation and OUD and highlight the tRNA machinery as a potential therapeutic target in addiction.
The assembly of neutrophil inflammasomes during COVID-19 is mediated by type I interferons
Authors: Cabrera Luz E. , Jokiranta Suvi T. , Mäki Sanna , Miettinen Simo , Kant Ravi , Kareinen Lauri , Sironen Tarja , Pietilä Jukka-Pekka , Kantele Anu , Kekäläinen Eliisa , Lindgren Hanna , Mattila Pirkko , Kipar Anja , Vapalahti Olli , Strandin Tomas 
Published: September 2023

AbstractThe severity of COVID-19 is linked to excessive inflammation. Neutrophils represent a critical arm of the innate immune response and are major mediators of inflammation, but their role in COVID-19 pathophysiology remains poorly understood. We conducted transcriptomic profiling of neutrophils obtained from patients with mild and severe COVID-19, as well as from SARS-CoV-2 infected mice, in comparison to non-infected healthy controls. In addition, we investigated the inflammasome formation potential in neutrophils from patients and mice upon SARS-CoV-2 infection. Transcriptomic analysis of polymorphonuclear cells (PMNs), consisting mainly of mature neutrophils, revealed a striking type I interferon (IFN-I) gene signature in severe COVID-19 patients, contrasting with mild COVID-19 and healthy controls. Notably, low-density granulocytes (LDGs) from severe COVID-19 patients exhibited an immature neutrophil phenotype and lacked this IFN-I signature. Moreover, PMNs from severe COVID-19 patients showed heightened nigericin-induced caspase1 activation, but reduced responsiveness to exogenous inflammasome priming. Furthermore, IFN-I emerged as a priming stimulus for neutrophil inflammasomes, which was confirmed in a COVID-19 mouse model. These findings underscore the crucial role of neutrophil inflammasomes in driving inflammation during severe COVID-19. Altogether, these findings open promising avenues for targeted therapeutic interventions to mitigate the pathological processes associated with the disease.
Effect of the 2022 COVID-19 booster vaccination campaign in 50 year olds in England: regression discontinuity analysis in OpenSAFELY
Authors: Schaffer Andrea L , Hulme William J , Horne Elsie , Parker Edward P K , Walker Venexia , Stables Catherine , Mehrkar Amir , Bacon Seb CJ , Bates Chris , Goldacre Ben , Walker Alex J ,   The OpenSAFELY Collaborative, Hernán Miguel A , Sterne Jonathan A C 
Published: September 2023

AbstractBackgroundSARS-CoV-2 vaccines are highly effective in preventing severe COVID-19 but require boosting to maintain protection. Changes to circulating variants and prevalent natural immunity may impact on real-world effectiveness of boosters in different time periods and in different populations.MethodsWith NHS England approval, we used linked routine clinical data from >24 million patients to evaluate the effectiveness of the 2022 combined COVID-19 autumn booster and influenza vaccine campaign in non-clinically vulnerable 50-year-olds in England using a regression discontinuity design. Our primary outcome was a composite of 6-week COVID-19 emergency attendance, COVID-19 unplanned hospitalisation, or death. The secondary outcomes were: respiratory hospitalisations or death; any unplanned hospitalisation; and any death.ResultsOur study included 1,917,375 people aged 45-54 years with no evidence of being in a high-risk group prioritised for vaccination. By 26 November 2022, booster vaccine coverage was 11.1% at age 49.75 years increasing to 39.7% at age 50.25 years. The estimated effect of the campaign on the risk of the primary outcome in 50-year-olds during weeks 7-12 after the campaign start was -0.4 per 100,000 (95% CI -7.8, 7.1). For the secondary outcomes the estimated effects were: -0.6 per 100,000 (95%CI -13.5, 12.3) for respiratory outcomes; 5.0 per 100,000 (95%CI -40.7, 50.8) for unplanned hospitalisations; and 3.0 per 100,000 (95%CI -2.7, 8.6) for any death. The results were similar when using different follow-up start dates, different bandwidths, or when estimating the effect of vaccination (rather than the campaign).ConclusionThis study found little evidence that the autumn 2022 vaccination campaign in England was associated with a reduction in severe COVID-19-related outcomes among non-clinically vulnerable 50-year-olds. Possible explanations include the low risk of severe outcomes due to substantial pre-existing vaccine- and infection-induced immunity. Modest booster coverage reduced the precision with which we could estimate effectiveness. The booster campaign may have had effects beyond those estimated, including reducing virus transmission and incidence of mild or moderate COVID-19.
Application of the Concept ‘Avoidable Mortality’ in Assessing the Socioeconomic Status related Inequalities in Health: A Scoping Review
Authors: Marouzi Anousheh , Plante Charles , Neudorf Cory 
Published: September 2023

AbstractIntroductionAvoidable mortality is widely used by public health researchers to measure population health, and many related methodologies have been proposed for doing so. This scoping review presents a comprehensive view of global peer-reviewed and grey literature exploring the association between socioeconomic status (SES) and avoidable mortality.MethodsWe searched Ovid Medline, Scopus, and Web of Science to find articles that investigated SES inequalities in avoidable mortality. We limited our review to articles in English published between 2000 and 2020. For grey literature, we searched leading global and Canadian health information websites. We extracted data on different study characteristics, avoidable mortality definition, SES indicator, method of analysis of the association between avoidable mortality and SES, and main findings of the studies.ResultsWe identified 34 articles to review, including 29 scientific papers and 5 grey literature documents. The findings of the selected articles consistently indicate a negative association between SES and avoidable mortality rates. Studies have not all used the same definitions of avoidable mortality or SES nor operationalized them in the same way.ConclusionOur review highlights the absence of a globally standard definition in avoidable mortality health equity research. Additional work to establish a standardized definition is crucial for supporting global comparability.
Universal digital high resolution melt analysis for the diagnosis of bacteremia
Authors: Aralar April , Goshia Tyler , Ramchandar Nanda , Lawrence Shelley M. , Karmakar Aparajita , Sharma Ankit , Sinha Mridu , Pride David T. , Kuo Peiting , Lecrone Khrissa , Chiu Megan , Mestan Karen , Sajti Eniko , Vanderpool Michelle , Lazar Sarah , Crabtree Melanie , Tesfai Yordanos , Fraley Stephanie I. 
Published: September 2023

ABSTRACTFast and accurate diagnosis of bloodstream infection is necessary to inform treatment decisions for septic patients, who face hourly increases in mortality risk. Blood culture remains the gold standard test but typically requires ∼15 hours to detect the presence of a pathogen. Here, we assess the potential for universal digital high-resolution melt (U-dHRM) analysis to accomplish faster broad-based bacterial detection, load quantification, and species-level identification directly from whole blood. Analytical validation studies demonstrated strong agreement between U-dHRM load measurement and quantitative blood culture, indicating that U-dHRM detection is highly specific to intact organisms. In a pilot clinical study of 21 whole blood samples from pediatric patients undergoing simultaneous blood culture testing, U-dHRM achieved 100% concordance when compared with blood culture and 90.5% concordance when compared with clinical adjudication. Moreover, U-dHRM identified the causative pathogen to the species level in all cases where the organism was represented in the melt curve database. These results were achieved with a 1 mL sample input and sample-to-answer time of 6 hrs. Overall, this pilot study suggests that U-dHRM may be a promising method to address the challenges of quickly and accurately diagnosing a bloodstream infection.Universal digital high resolution melt analysis for the diagnosis of bacteremiaApril Aralar, Tyler Goshia, Nanda Ramchandar, Shelley M. Lawrence, Aparajita Karmakar, Ankit Sharma, Mridu Sinha, David Pride, Peiting Kuo, Khrissa Lecrone, Megan Chiu, Karen Mestan, Eniko Sajti, Michelle Vanderpool, Sarah Lazar, Melanie Crabtree, Yordanos Tesfai, Stephanie I. Fraley
An imputed ancestral reference genome for theMycobacterium tuberculosiscomplex better captures structural genomic diversity for reference-based alignment workflows
Authors: Harrison Luke B , Kapur Vivek , Behr Marcel A 
Published: September 2023

AbstractReference-based alignment of short-reads is a widely used technique in genomic analysis of theMycobacterium tuberculosiscomplex (MTBC) and the choice of reference sequence impacts the interpretation of analyses. The most widely used reference genomes include the ATCC type strain (H37Rv) and the putative MTBC ancestral sequence of Comaset al. both of which are based on a lineage 4 sequence. As such, these referents do not capture the complete structural variation now known to be present in the MTBC. To better represent the base of the MTBC, we generated an imputed ancestral genomic sequence, termed MTBC0from reference-free alignments of closed MTBC genomes. When used as a reference sequence in alignment workflows, MTBC0mapped more short sequencing reads and called more SNPs relative to the Comas et al. sequence while exhibiting minimal impact on the overall phylogeny of MTBC. The results also show that MTBC0provides greater fidelity in capturing genomic variation and allows for the inclusion of regions absent in H37Rv such as the TbD1 and RvD4496/RD7/RD713 regions in standard MTBC workflows without additional steps. The use of MTBC0as an ancestral reference sequence into a standard workflows modestly improved read mapping, SNP calling and intuitively facilitates the study of structural variation and evolution in MTBC.Data SummaryThe MTBC0sequence, is available in the online data supplement in FASTA format athttps://github.com/lukebharrison/MTBC0. Included with the MTBC0sequence in the data supplement are: the reference-free alignment of MTBC closed genomes in hierarchical alignment (HAL) format, control files for cactus, annotations for H37Rv and L8, a BED file of regions excluded from SNP calls lifted over onto MTBC0, as well as the scripts used to call SNPs and the phylogenetic trees generated in this article. All previously published sequence data is available at the NCBI nucleotide and SRA databases, accession number for sequences used in this manuscript are available in Supplementary Tables 1 and 2.Impact StatementThis article describes an imputed ancestral genomic sequence (MTBC0) at the base of the MTBC for use as a reference sequence forMycobacterium tuberculosisgenomic workflows. Widely used reference sequences are limited to the structural diversity present in H37Rv, a lineage 4 isolate. MTBC0obviates this limitation by incorporating the structural variation present at the base of theMycobacterium tuberculosiscomplex (MTBC) by encompassing a wide sample of human and animal lineages including newly discovered lineages (L8,M. orygis). Use of MTBC0enables the mapping of more reads and calling of more SNPs and allows for the investigation of structural variation not present in the current used reference sequences within this important group of animal and human pathogens.
Human Brain Dynamics Dissociate Early Perceptual and Late Motor-Related Stages of Affordance Processing
Authors: Wang Sheng , Djebbara Zakaria , de Oliveira Guilherme Sanches , Gramann Klaus 
Published: September 2023

AbstractAffordances, the opportunity for action offered by the environment to an agent, are vital for meaningful behavior and exist in every interaction with the environment. There is an ongoing debate in the field about whether the perception of affordances is an automated process. Some studies suggest that affordance perception is an automated process that is independent from the visual context and bodily interaction with the environment, while others argue that it is modulated by the visual and motor context in which affordances are perceived. The present paper aims to resolve this debate by examining affordance automaticity from the perspective of sensorimotor time windows. We replicated a previous study on affordance perception in which participants actively moved through doors of different width in immersive 3D virtual environments. To investigate the impact of different forms of bodily interactions with an environment, i.e., the movement context (physical vs. joystick movement), we used the identical virtual environment from Djebbara and colleagues (2019) but displayed it on a 2D screen with participants moving through different wide doors using the keys on a standard keyboard. We compared components of the event-related potential (ERP) from the continuously recorded electroencephalogram (EEG) that were previously reported to be related to affordance perception of architectural transitions (passable and impassable doors). Comparing early sensory and later motor-related ERPs, our study replicated ERPs reflecting early affordance perception but found differences in later motor-related components. These results indicate a shift from automated perception of affordances during early sensorimotor time windows to movement context dependence of affordance perception at later stages suggesting that affordance perception is a dynamic and flexible process that changes over sensorimotor stages.
Single Cell RNA-Seq Analysis of Regenerative Drug-Treated Human Pancreatic Islets Identifies A Cycling Alpha Cell Population As Key Beta Cell Progenitors
Authors: Karakose Esra , Wang Xuedi , Wang Peng , Carcamo Saul , Demircioglu Deniz , Lambertini Luca , Wood Olivia , Kang Randy , Lu Geming , Scott Donald K. , Garcia-Ocaña Adolfo , Argmann Carmen , Sebra Robert , Hasson Dan , Stewart Andrew F. 
Published: September 2023

AbstractDiabetes ultimately results from an inadequate number of functional, insulin-producing human beta cells. Although current attempts to replenish the remaining beta cell pool in people with diabetes are encouraging, scalability and cost limit access for the millions of people with diabetes. The small molecule DYRK1A inhibitor class of beta cell regenerative drugs, either alone or in combination with GLP1 receptor agonists or TGFβ superfamily inhibitors, are capable of inducing beta cell replicationin vitroand increasing beta cell massin vivo. Despite these advances, the precise mechanisms of action of DYRK1A inhibitors remain incompletely understood. To address the mechanisms more deeply, we performed single cell RNA sequencing on human pancreatic islets treated with a DYRK1A inhibitor, either alone, or in combination with a GLP1 receptor agonist or a TGFβ superfamily inhibitor. We identify a cluster of Cycling Alpha Cells as the cells most responsive to DYRK1A inhibition. Velocity and pseudotime lineage trajectory analyses suggest that Cycling Alpha Cells serve as the primary target cell type for of DYRK1A inhibitors, and may serve as precursor cells that transdifferentiate into functional human beta cells in response to the DYRK1A inhibition. In addition to providing a novel mechanism of action for DYRK1A inhibitors, our findings suggest that efforts to target regenerative drugs to human beta cells may be mis-directed: the proper target may be Cycling Alpha Cells.
The anti-SARS-CoV-2 BNT162b2 vaccine suppresses mithramycin-induced erythroid differentiation and expression of embryo-fetal globin genes in human erythroleukemia K562 cells
Authors: Zurlo Matteo , Gasparello Jessica , Verona Marco , Papi Chiara , Cosenza Lucia Carmela , Finotti Alessia , Marzaro Giovanni , Gambari Roberto 
Published: September 2023

ABSTRACTThe COVID-19 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) the ongoing coronavirus disease 2019 (COVID-19) pandemic. The SARS-CoV-2 Spike protein (S-protein) plays an important role in the early phase of SARS-CoV2 infection through efficient interaction with ACE2. The S-protein is produced by RNA-based COVID-19 vaccines, and has been hypothesized to be responsible for damaging cells of several tissues and for some important side effects of RNA-based COVID-19 vaccines. The aim of this study was to verify the effect of the BNT162b2 vaccine on erythroid differentiation of the human K562 cell line, that has been in the past intensively studied as a model system mimicking some steps of erythropoiesis. We found that the BNT162b2 vaccine suppresses mithramycin-induced erythroid differentiation of K562 cells. Reverse-transcription-PCR and Western blotting assays demonstrated that suppression of erythroid differentiation was associated with sharp inhibition of the expression of α-globin and γ-globin mRNA accumulation. Inhibition of accumulation of ζ-globin and ε-globin mRNAs was also observed. In addition, we provide in silico studies suggesting a direct interaction between SARS-CoV-2 Spike protein and Hb Portland, that is the major hemoglobin produced by K562 cells. This study thus provides information suggesting the need of great attention on possible alteration of hematopoietic parameters following SARS-CoV-2 infection and/or COVID-19 vaccination.
Loop extrusion by cohesin plays a key role in enhancer-activated gene expression during differentiation
Authors: Stolper Rosa J. , Tsang Felice H. , Georgiades Emily , Hansen Lars L.P. , Downes Damien J. , Harrold Caroline L. , Hughes Jim R. , Beagrie Robert A. , Davies Benjamin , Kassouf Mira T. , Higgs Douglas R. 
Published: September 2023

ABSTRACTEnhancers and their target promoters often come into close physical proximity when activated. This proximity may be explained by a variety of mechanisms; most recently via cohesin-mediated chromatin loop extrusion. Despite this compelling hypothesis, acute depletion of cohesin does not cause widespread changes in gene expression. We have tested the role of cohesin-mediated loop extrusion on gene expression at the mouse alpha-globin locus during erythropoiesis. Acute depletion of cohesin downregulates alpha-globin expression at early but not late stages of differentiation. When single or multiple CTCF sites are placed between the alpha-globin enhancers and promoters, alpha-gene expression is downregulated. Importantly, the orientation of the CTCF site plays a critical role, suggesting that within this activated domain, cohesin predominantly but not exclusively translocates from the enhancers to the promoters. We find that loop extrusion does play an important role in establishing enhancer-promoter proximity and consequent expression of inducible genes during differentiation.
Ecophysiological and genomic approaches to cyanobacterial hardening for soil restoration
Authors: Beatriz Roncero-Ramos , Valentina Savaglia , Benoit Durieu , Isabelle Van de Vreken , Aurore Richel , Annick Wilmotte 
Published: September 2023

AbstractCyanobacteria inhabit extreme environments, including drylands, providing multiple benefits to the ecosystem. Soil degradation in warm drylands is increasing due to land-use intensification. Restoration methods adapted to the strong stress in drylands are being developed, i.e. cyanobacterial inoculation to recover biocrusts. For success, it is crucial to optimize the survival of inoculated cyanobacterial in field. One strategy is to harden them to be re-adapted to stressful conditions after laboratory culturing. Here, we analyzed the genome and ecophysiological response to osmotic, desiccation and UVR stresses of an Antarctic cyanobacterium,Stenomitos frigidusULC029, closely related to other cyanobacteria from warm and cold dryland soils. Chlorophyllaconcentrations show that preculturing ULC029 under moderate osmotic stress improved its survival during an assay of desiccation plus rehydration under UVR. Besides, its sequential exposition to these stress factors increased the production of exopolysaccharides, carotenoids and scytonemin. Desiccation, but not osmotic stress, increased the concentrations of the osmoprotectants, trehalose and sucrose. However, osmotic stress might induce the production of other osmoprotectants, for which the complete pathways were found in the ULC029 genome. In total, 140 genes known to be involved in stress resistance were annotated and could potentially help ULC029 under stress. Here, we confirm that the sequential application of moderate osmotic stress and dehydration, could improve cyanobacterial hardening for soil restoration, by inducing several resistance mechanisms. We provide a high-quality genome of ULC029 and a description of the main resistance mechanisms found (i.e. production of exopolysaccharides, osmoprotectants, chlorophyll and carotenoids; DNA repair; oxidative stress protection).
Tardigrades dramatically upregulate DNA repair pathway genes in response to ionizing radiation
Authors: Clark-Hachtel Courtney M. , Hibshman Jonathan D. , Buysscher Tristan De , Goldstein Bob 
Published: September 2023

AbstractTardigrades can survive remarkable doses of ionizing radiation, up to about 1000 times the lethal dose for humans. How they do so is incompletely understood. We found that the tardigradeHypsibius exemplarissuffers DNA damage upon gamma irradiation, but damage is repaired. We show that tardigrades have a specific and robust response to ionizing radiation: irradiation induces a rapid, dramatic upregulation of many DNA repair genes. By expressing tardigrade genes in bacteria, we validate that increased expression of some repair genes can suffice to increase radiation tolerance. We show that at least one such gene is necessary for tardigrade radiation tolerance. Tardigrades’ ability to sense ionizing radiation and massively upregulate specific DNA repair pathway genes may represent an evolved solution for maintaining DNA integrity.One-Sentence SummaryTardigrades exposed to ionizing radiation survive DNA damage by massively upregulating DNA repair pathway genes.