bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-cell RNA sequencing reveals the distinctive roles of CD4+and CD8+T cells in autoimmune uveitis
Authors: Kang Hao , Sun Hongjian , Yang Yang , Shu Minglei , Wei Yunbo , Zhang Yu , Yu Di , Tao Yong 
Published: December 2022

AbstractUveitis is a common cause of blindness and classified as infectious or non-infectious types. Non-infectious uveitis is often secondary to systemic autoimmune diseases, with Behçet’s disease (BD) and Vogt-Koyanagi-Harada disease (VKHD) as the two most common causes. Uveitis in BD and VKHD often show similar clinical manifestations, but the underlying immunopathogenesis remains unclear. We collected immune cell infiltrates in aqueous humour of BD and VKHD uveitis patients and analysed them by single-cell RNA paired with T cell receptor (TCR) sequencing. T cells were found as the dominant immune cell infiltration. Intriguingly, a majority of CD4+in T cell infiltrates was only observed in VKHD but not in BD. In agreement with this discrepancy between VKHD and BD, T cell clonality analysis and Clonotype Neighbour Graph Analysis (CoNGA) also revealed a selective expansion of pro-inflammatory CD4+T cell clones in VKHD. In contrast, BD showed a selective expansion of pro-inflammatory CD8+T cell clones. Our study reveals distinct immunopathogenesis of uveitis driven by CD4+T cells in VKHD and by CD8+T cells in BD, and therefore suggests differential approaches for their diagnosis and therapy.
What do people think of intuitive eating? A qualitative exploration with rural Australians
Authors: Van Dyke Nina , Murphy Michael , Drinkwater Eric J 
Published: December 2022

AbstractEvidence supports that intuitive eating is associated with many indicators of positive physical and mental health, with more recent longitudinal studies establishing causality. Most research, however, comprises either survey data or clinical trials. This study attempts to fill this evidentiary gap by using a qualitative methodology to explore people’s understandings and reactions to intuitive eating, including perceived barriers and enablers to implementation.Three focus group discussions were conducted in a non-metropolitan region of Victoria, Australia, with a total of 23 participants. Focus group transcripts were thematically analysed using a grounded theory approach within a constructionist perspective.Findings indicate that the concept of intuitive eating was either unknown or misunderstood. Once intuitive eating was explained, most responses to implementing intuitive eating were negative. Participants felt that having complete choice around what they ate was unlikely to equate to a healthy or balanced diet, at least in the short term. They also argued that because everyday life was not intuitive in its structures, it would be difficult to eat intuitively. Despite these difficulties, participants appreciated that if they were able to overcome the various barriers and achieve a state of intuitive eating, they anticipated a range of long-term benefits to health and weight management. For intuitive eating to become a viable public health approach, this research suggests that people would need assistance overcoming their existing habits and food preferences, and developing insight into their bodies’ needs, desires, and cravings. The structural barriers, however, would likely continue to be substantial. Most significantly, however, are the barriers imposed by the food environment. Intuitive eating requires choice of foods, yet ample evidence demonstrates that true choice is often not available and that healthful and less healthful foods are not evenly presented.
Asthma hospitalisations and heat exposure in England: A case-crossover study during 2002-2019
Authors: Konstantinoudis Garyfallos , Minelli Cosetta , Yu Lam Holly Ching , Fuertes Elaine , Ballester Joan , Davies Bethan , Vicedo-Cabrera Ana Maria , Gasparrini Antonio , Blangiardo Marta 
Published: December 2022

AbstractBackgroundPrevious studies have found an association between warm temperature and asthma hospitalisation. They have reported different sex- and age-related vulnerabilities, nevertheless little is known about how this effect has changed over time and how it varies in space. This study aims to evaluate the association between asthma hospitalisation and warm temperature and investigate vulnerabilities by age, sex, time, and space.MethodsWe retrieved individual-level data on summer asthma hospitalisation at high temporal (daily) and spatial (postcodes) resolution during 2002-2019 in England from the NHS Digital. Daily mean temperature at 1km x 1km resolution was retrieved from the UK Met Office. We focused on lags 0-3 days. We employed a case-cross over study design and fitted Bayesian hierarchal Poisson models accounting for possible confounders (rainfall, relative humidity, wind speed, national holidays, and recurrent hospitalisations).ResultsAfter accounting for confounding, we found a 0.85% (95% Credible Interval: 0.64% to 1.07%) increase in the asthma hospitalisation risk for every 1°C increase in the ambient summer temperature. The effect was highest for males aged 15-65 (2.44%, 1.99% to 2.90%). During 2002-2007 we observed a 2.23% (1.86% to 2.60%) increase in hospitalisation risk per 1°C increase in temperature, whereas inconclusive evidence for the periods 2008-2013 and 2014-2019. Populations in Yorkshire and the Humber and East Midlands were the most vulnerable.ConclusionThis study provides evidence of an association between warm temperature and hospital admission for asthma, which was attenuated over time suggesting adaptive mechanisms to heat exposure or differences in lifestyle, comorbid conditions, and occupation over time.
Mental Health, Substance Use, and the Importance of Religion during the COVID-19 Pandemic
Authors: Park Ji-Yeun , Galbadage Thushara , Lee Hyuna , Wang David C. , Peterson Brent M. 
Published: December 2022

AbstractCOVID-19 has impacted all areas of life, with lasting effects on physical, mental, and societal health. Specifically, COVID and related losses have exacerbated prolonged grief responses and mental disorders including depression and anxiety. These mental health concerns are associated with increased detrimental coping strategies including substance use. In this study, we analyzed secondary data from the National Survey on Drug Use and Health (NSDUH) collected during the COVID-19 pandemic. Our results showed a positive association between serious psychological distress and marijuana use, while frequent religious service attendance acted as a moderator in this relationship. Individuals involved in communal religious activity were less likely to use marijuana. This study highlights the impact of religion and faith in bringing hope and purpose during periods of loss, coping with stress, grief, mental health challenges, and substance use.
Circadian regulation of human immunodeficiency virus type 1 replication
Authors: Borrmann Helene , Ulkar Görkem , Kliszczak Anna E. , Ismed Dini , Schilling Mirjam , Magri Andrea , Harris James M. , Balfe Peter , Vasuvedan Sridhar , Borrow Persephone , Zhuang Xiaodong , McKeating Jane A. 
Published: December 2022

ABSTRACTHuman immunodeficiency virus 1 (HIV-1) is a life-threatening pathogen that still lacks curative therapies or vaccines. Circadian rhythms are endogenous daily oscillations that coordinate an organism’s response to its environment and invading pathogens. Recent reports of diurnal variation in peripheral viral load in HIV-1 infected subjects highlights the need for mechanistic studies. Here, we demonstrate rhythmic HIV-1 replication in circadian-synchronised model systems and show the circadian transcription factors, BMAL1 and REV-ERB, bind conserved motifs in the HIV-1 promoter. REV-ERB competes with ROR for binding to the same regulatory motif, and we uncover a role for ROR inhibitors to perturb rhythmic HIV-1 replication and host gene expression. We demonstrate that many HIV-1 host factors are circadian regulated and likely to define rhythmic viral replication. In summary, this study increases our understanding of the mechanisms underlying the circadian regulation of HIV that can inform HIV therapy and management.
Isoforms of the TAL1 transcription factor have different roles in hematopoiesis and cell growth
Authors: Sharma Aveksha , Mistriel-Zerbib Shani , Najar Rauf Ahmad , Engal Eden , Bentata Mercedes , Taqatqa Nadeen , Dahan Sara , Cohen Klil , Jaffe-Herman Shiri , Geminder Ophir , Baker Mai , Nevo Yuval , Plaschkes Inbar , Kay Gillian , Drier Yotam , Berger Michael , Salton Maayan 
Published: December 2022

ABSTRACTT-cell acute lymphoblastic leukemia (T-ALL) protein 1 (TAL1) is a central transcription factor in hematopoiesis. The timing and level of TAL1 expression orchestrate the differentiation to specialized blood cells and its overexpression is a common cause of T-ALL. Here we studied the two protein isoforms of TAL1, short and long, that are generated by the use of alternative promoters as well as by alternative splicing. We analyzed the expression of each isoform by deleting an enhancer or insulator, or by opening chromatin at the enhancer location. Our results show that each enhancer promotes expression from a specific TAL1 promoter. Expression from a specific promoter gives rise to a unique 5’ UTR with differential regulation of translation. Moreover, our study suggests that the enhancers regulate TAL1 exon 3 alternative splicing by inducing changes in the chromatin at the splice site, which we demonstrate is mediated by KMT2B. Furthermore, our results indicate that TAL1-short binds more strongly to TAL1 E-protein partners and functions as a stronger transcription factor than TAL1-long. Specifically TAL1-short has a unique transcription signature promoting apoptosis. Finally, when we expressed both isoforms in mice bone-marrow, we found that while overexpression of both isoforms prevents lymphoid differentiation, expression of TAL-short alone leads to hematopoietic stem cell exhaustion. Furthermore, we found that TAL1-short promoted erythropoiesis and reduced cell survival in the CML cell line K562. While TAL1 and its partners are considered promising therapeutic targets in the treatment of T-ALL, our results show that TAL1-short could act as a tumor suppressor and suggest that altering TAL1 isoform’s ratio could be a preferred therapeutic approach.
Targeting of MMP-13 prevents aortic aneurysm formation in Marfan mice
Authors: Zimmermann Laura-Marie A. , Furlan Ariane G. , Mehrkens Dennis , Geißen Simon , Zuk Alexandra V. , Pryymachuk Galyna , Pykarek Nadine , Beers Tim van , Sonntag-Bensch Dagmar , Marzi Julia , Schenke-Layland Katja , Brinckmann Jürgen , Zigrino Paola , Grandoch Maria , Baldus Stephan , Sengle Gerhard 
Published: December 2022

AbstractFibrillin-1 assembles into microfibrils that not only define the structural integrity and biomechanics of the aorta but also target and sequester growth factors within the extracellular microenvironment of aortic resident cells. To better understand how dominant negative effects on fibrillin microfibril stability manifest in growth factor driven aortic disease, we analyzed early events of aortic aneurysm formation within the first two weeks of postnatal life in the dominant negativeFbn1GT8 Marfan mouse model. Echocardiography analysis of homozygous GT8Fbn1mice showed significant aortic root enlargement within the second week of postnatal life which correlated with the onset of fibrillin-1 fiber degradation, aberrantly increased BMP activity and upregulated transcript levels of the collagenase MMP-13. We also found the aortic collagen network structurally disturbed where the mutant GT8-fibrillin-1 was detected. Genetic ablation or pharmacological inhibition of MMP-13 inFbn1GT8 Marfan mice prevents aortic root dilatation implicating the relevance of this mechanism in aortic aneurysm formation in Marfan syndrome.
Origin and Evolution of Pseudomurein Biosynthetic Gene Clusters
Authors: Lupo Valérian , Roomans Célyne , Royen Edmée , Ongena Loïc , Jacquemin Olivier , Kerff Frédéric , Baurain Denis 
Published: December 2022

AbstractThe peptidoglycan (PG; or murein) is a mesh-like structure, which is made of glycan polymers connected by short peptides and surrounds the cell membrane of nearly all bacterial species. In contrast, there is no PG counterpart that would be universally found in Archaea, but rather various polymers that are specific to some lineages. Methanopyrales and Methanobacteriales are two orders of Euryarchaeota that harbor pseudomurein (PM) in their cell-wall, a structural analogue of the bacterial PG. Owing to the differences between PG and PM biosynthesis, some have argued that the origin of both polymers is not connected. However, recents studies have revealed that the genomes of PM-containing Archaea encode homologues of the bacterial genes involved in PG biosynthesis, even though neither their specific functions nor the relationships within the corresponding inter-domain phylogenies have been investigated so far. In this work, we devised a bioinformatic pipeline to identify all potential proteins for PM biosynthesis in Archaea without relying on a candidate gene approach. After anin silicocharacterization of their functional domains, the taxonomic distribution and evolutionary relationships of the collected proteins were studied in detail in Archaea and Bacteria through HMM similarity searches and phylogenetic inference of the Mur domain-containing family, the ATP-grasp superfamily and the MraY-like family. Our results notably show that the extant archaeal muramyl ligases are ultimately of bacterial origin, but likely diversified through a mixture of horizontal gene transfer and gene duplication. Moreover, structural modeling of these enzymes allowed us to propose a tentative function for each of them in pentapeptide elongation. While our work clarifies the genetic determinants behind PM biosynthesis in Archaea, it also raises the question of the architecture of the cell wall in the last universal common ancestor.
Mincle-GSDMD-mediated release of IL-1β containing small extracellular vesicles contributes to ethanol-induced liver injury
Authors: Zhang Quanri , Liu Weiwei , Bulek Katarzyna , Wang Han , McMullen Megan R. , Wu Xiaoqin , Welch Nicole , Zhang Renliang , Dasarathy Jaividhya , Dasarathy Srinivasan , Nagy Laura E. , Li Xiaoxia 
Published: December 2022

AbstractBackground & AimsMacrophage inducible C-type lectin (Mincle) is expressed on Kupffer cells and senses ethanol-induced danger signals released from dying hepatocytes and promotes IL-1β production. However, it remains unclear what and how ethanol-induced Mincle ligands activate downstream signaling events to mediate IL-1β release and contribute to alcohol-associated liver disease (ALD). In this study, we investigated the association of circulating β-glucosylceramide (β-GluCer), an endogenous Mincle ligand, with severity of ALD and examined the mechanism by which β-GluCer engages Mincle on Kupffer cells to release IL-1β in the absence of cell death and exacerbates ALD.Approach and ResultsConcentrations of β-GluCer were increased in serum of patients with severe AH and correlated with disease severity. Challenge of Kupffer cells with LPS and β-GluCer induced formation of aMincleandGsdmd-dependent secretory complex containing chaperoned full-length GSDMD (Hsp90-CDC37-NEDD4) with polyubiquitinated pro-IL-1β and components of the Casp8-NLRP3 inflammasome loaded as cargo in small extracellular vesicles (sEV). Gao-binge ethanol exposure to wild-type, but notMincle-/-andGsdmd-/-, mice increased release of IL-1β containing sEVs from liver explant cultures. Myeloid-specific deletion ofGsdmdsimilarly decreased the formation of sEVs by liver explant cultures and protected mice from ethanol-induced liver injury. sEVs collected from ethanol-fed wild-type, but notGsdmd-/-, mice promoted injury of cultured hepatocytes and, when injected into wild-type mice, aggravated Gao-binge ethanol-induced liver injury.Conclusionβ-GluCer functions as a DAMP activating Mincle-dependent GSDMD-mediated formation and release of IL-1β-containing sEVs, which in turn exacerbate hepatocyte cell death and contribute to the pathogenesis of ALD.
Integration of mass-spectrometry-based global metabolomics and proteomics analysis to characterise different senescence induced molecular sub-phenotypes
Authors: Berardi Domenica , Farrell Gillian , Alsuntan Abdullah , McCulloch Ashley , Rattray Zahra , Rattray Nicholas JW 
Published: December 2022

ABSTRACTCellular senescence is a key driver of ageing and its related disease. Thus, targeting and eliminating senescent cells is a major focus in biogerontology to predict and ameliorate age-related malady. Many studies have focused on targeting senescence through the identification of its molecular biomarkers. However, these are not specific for senescence and have different expression patterns across various senescence phenotypes. Here we report a combination of molecular studies (ß-galactosidase expression, DNA damage and replication immunodetection) with a mass spectrometry analysis integrating intra and extracellular global metabolomics to reveal small molecules differentially expressed across multiple senescence phenotypes (replicative senescence, x-ray, and chemical-induced senescence).Altered key intracellular metabolic changes were identified, depending on the stress stimuli, which were consistent with the presence of pro-inflammatory metabolites in the cellular secretome.Our work shows the advantage of combining molecular and metabolomics studies for the detailed analysis of cellular senescence and that senescence phenotype changes upon induction method.
RNA- and DNA-binding proteins generally exhibit direct transfer of polynucleotides: Implications for target site search
Authors: Hemphill Wayne O. , Voong Calvin K. , Fenske Regan , Goodrich James A. , Cech Thomas R. 
Published: December 2022

AbstractWe previously demonstrated that the PRC2 chromatin-modifying enzyme exhibits the ability to directly transfer between RNA and DNA without a free-enzyme intermediate state. Simulations suggested that such a direct transfer mechanism may be generally necessary for RNA to recruit proteins to chromatin, but the prevalence of direct transfer capability is unknown. Herein, we used fluorescence polarization assays and observed direct transfer for several well-characterized nucleic acid-binding proteins: three-prime repair exonuclease 1 (TREX1), heterogeneous nuclear ribonucleoprotein U, Fem-3-binding factor 2, and MS2 bacteriophage coat protein. For TREX1, the direct transfer mechanism was additionally interrogated by single molecule assays, and the data suggest that direct transfer occurs through an unstable ternary intermediate with partially associated ligands. Generally, direct transfer could allow many DNA- and RNA-binding proteins to conduct a one-dimensional search for their target sites. Furthermore, presumably long-lived protein-polynucleotide complexes might instead be readily replaced by other protein-polynucleotide complexesin vivo.SignificanceClassically, the lifetime of a protein-ligand complex is presumed to be an intrinsic property, unaffected by competitor molecules in free solution. By contrast, a few oligomeric nucleic acid binding proteins have been observed to exchange competing ligands in their binding sites, and consequently their lifetimes decrease with competitor concentration. Our findings indicate that this “direct transfer” is a more general property of nucleic acid binding proteins. This suggests that many DNA- and RNA-binding proteins can reduce the dimensionality of their search for their target sites by intramolecular direct transfer to nucleosome DNA, instead of relying entirely on three-dimensional diffusion, and it suggests that their mean complex lifetimesin vivocan be regulated by the concentration of free ligand molecules.
Changes in brain metabolite levels across childhood
Authors: Perdue Meaghan V. , DeMayo Marilena M. , Bell Tiffany K. , Boudes Elodie , Bagshawe Mercedes , Harris Ashley D. , Lebel Catherine 
Published: December 2022

AbstractMetabolites play important roles in brain development and their levels change rapidly in the prenatal period and during infancy. Metabolite levels are thought to stabilize during childhood, but the development of neurochemistry across early-middle childhood remains understudied. We examined the developmental changes of key metabolites (total N-acetylaspartate, tNAA; total choline, tCho; total creatine, tCr; glutamate+glutamine, Glx; and myo-inositol, mI) using short echo-time magnetic resonance spectroscopy (MRS) in the anterior cingulate cortex (ACC) and the left temporo-parietal cortex (LTP) using a mixed cross-sectional/longitudinal design in children aged 2-11 years (ACC: N=101 children, 112 observations; LTP: N=95 children, 318 observations). We found age-related effects for all metabolites. tNAA increased with age in both regions, while tCho decreased with age in both regions. tCr increased with age in the LTP only, and mI decreased with age in the ACC only. Glx did not show linear age effects in either region, but a follow-up analysis in only participants with ≥3 datapoints in the LTP revealed a quadratic effect of age following an inverted U-shape. These substantial changes in neurochemistry throughout childhood likely underlie various processes of structural and functional brain development.
SARS-CoV-2 mRNA vaccine is re-adenylatedin vivo, enhancing antigen production and immune response
Authors: Krawczyk Paweł S , Gewartowska Olga , Mazur Michał , Orzeł Wiktoria , Matylla-Kulińska Katarzyna , Jeleń Sebastian , Turowski Paweł , Śpiewla Tomasz , Tarkowski Bartosz , Tudek Agnieszka , Brouze Aleksandra , Wesołowska Aleksandra , Nowis Dominika , Gołąb Jakub , Kowalska Joanna , Jemielity Jacek , Dziembowski Andrzej , Mroczek Seweryn 
Published: December 2022

AbstractThough mRNA vaccines against COVID-19 have revolutionized vaccinology and have been administered in billions of doses, we know incredibly little about how mRNA vaccines are metabolizedin vivo. Here we implemented enhanced nanopore Direct RNA sequencing (eDRS), to enable the analysis of single Moderna’s mRNA-1273 molecules, givingin vivoinformation about the sequence and poly(A) tails.We show that mRNA-1273, with all uridines replaced by N1-methylpseudouridine (mΨ), is terminated by a long poly(A) tail (~100 nucleotides) followed by an mΨCmΨAG sequence. In model cell lines, mRNA-1273 is swiftly degraded in a process initiated by the removal of mΨCmΨAG, followed by CCR4-NOT-mediated deadenylation. In contrast, intramuscularly inoculated mRNA-1273 undergoes more complex modifications. Notably, mRNA-1273 molecules are re-adenylated after mΨCmΨAG removal. Detailed analysis of immune cells involved in antigen production revealed that in macrophages, after mΨCmΨAG removal, vaccine mRNA is very efficiently re-adenylated, and poly(A) tails can reach up to 200A. In contrast, in dendritic cells, vaccine mRNA undergoes slow deadenylation-dependent decay. We further demonstrate that enhancement of mRNA stability in macrophages is mediated by TENT5 poly(A) polymerases, whose expression is induced by the vaccine itself. Lack of TENT5-mediated re-adenylation results in lower antigen production and severely compromises specific immunoglobulin production following vaccination.Together, our findings provide an unexpected principle for the high efficacy of mRNA vaccines and open new possibilities for their improvement. They also emphasize that, in addition to targeting a protein of interest, the design of mRNA therapeutics should be customized to its cellular destination.