bluuebunny/crossref_metadata_2025_split huggingface dataset:
Polygenic risk score for ulcerative colitis predicts immune checkpoint inhibitor-mediated colitis
Authors: Middha Pooja , Thummalapalli Rohit , Betti Michael J. , Yao Lydia , Quandt Zoe , Balaratnam Karmugi , Bejan Cosmin A. , Cardenas Eduardo , Falcon Christina J. , Faleck David M. ,   Princess Margaret Lung Group, Gubens Matthew A. , Huntsman Scott , Johnson Douglas B. , Kachuri Linda , Khan Khaleeq , Li Min , Lovly Christine M. , Murray Megan H. , Patel Devalben , Werking Kristin , Xu Yaomin , Zhan Luna Jia , Balko Justin M. , Liu Geoffrey , Aldrich Melinda C. , Schoenfeld Adam J. , Ziv Elad 
Published: May 2023

AbstractImmune checkpoint inhibitors (ICIs) are a remarkable advancement in cancer therapeutics; however, a substantial proportion of patients develop severe immune-related adverse events (irAEs). Understanding and predicting irAEs is a key to advancing precision immuno-oncology. Immune checkpoint inhibitor-mediated colitis (IMC) is a significant complication from ICI and can have life-threatening consequences. Based on clinical presentation, IMC mimics inflammatory bowel disease, however the link is poorly understood. We hypothesized that genetic susceptibility to Crohn’s disease (CD) and ulcerative colitis (UC) may predispose to IMC. We developed and validated polygenic risk scores for CD (PRSCD) and UC (PRSUC) in cancer-free individuals and assessed the role of each of these PRSs on IMC in a cohort of 1,316 patients with non-small cell lung cancer who received ICIs. Prevalence of all-grade IMC in our cohort was 4% (55 cases), and for severe IMC, 2.5% (32 cases). The PRSUCpredicted the development of all-grade IMC (HR=1.34 per standard deviation [SD], 95% CI=1.02-1.76,P=0.04) and severe IMC (HR=1.62 per SD, 95% CI=1.12-2.35,P=0.01). PRSCDwas not associated with IMC or severe IMC. The association between PRSUCand IMC (all-grade and severe) was consistent in an independent pan-cancer cohort of patients treated with ICIs. Furthermore, PRSUCpredicted severe IMC among patients treated with combination ICIs (OR = 2.20 per SD, 95% CI = 1.07-4.53,P=0.03). This is the first study to demonstrate the potential clinical utility of a PRS for ulcerative colitis in identifying patients receiving ICI at high risk of developing IMC, where risk reduction and close monitoring strategies could help improve overall patient outcomes.
Routine respiratory metagenomics service for intensive care unit patients
Authors: Charalampous Themoula , Alcolea-Medina Adela , Snell Luke B. , Alder Christopher , Tan Mark , Williams Tom G.S. , Al-Yaakoubi Noor , Humayun Gul , Meadows Christopher I.S. , Wyncoll Duncan L.A. , Richard Paul , Hemsley Carolyn J. , Jeyaratnam Dakshika , Newsholme William , Goldenberg Simon , Patel Amita , Tucker Fearghal , Nebbia Gaia , Wilks Mark , Chand Meera , Cliff Penelope R. , Batra Rahul , O’Grady Justin , Barrett Nicholas A. , Edgeworth Jonathan D. 
Published: May 2023

AbstractBackgroundRespiratory metagenomics (RMg) needs evaluation in a pilot service setting to determine utility and inform implementation into clinical practice.MethodsFeasibility, performance and clinical impacts on antimicrobial prescribing and infection control were recorded during a pilot RMg service for patients with suspected lower respiratory tract infection (LRTI) on two general and one specialist respiratory intensive care units (ICU) at Guy’s & St Thomas NHS foundation Trust, London.ResultsRMg was performed on 128 samples from 87 patients during the first 15-weeks providing same-day results for 110 samples (86%) with median turnaround time of 6.7hrs (IQR 6.1-7.5 hrs). RMg was 92% sensitive and 82% specific for clinically-relevant pathogens compared with routine testing. 48% of RMg results informed antimicrobial prescribing changes (22% escalation; 26% de-escalation) with escalation based on speciation in 20/24 cases and detection of acquired-resistance genes in 4/24 cases. Fastidious or unexpected organisms were reported in 21 samples including anaerobes (n=12),Mycobacterium tuberculosis, Tropheryma whipplei, cytomegalovirus andLegionella pneumophilaST1326, which was subsequently isolated from the bed-side water outlet. Application to consecutive severe community-acquired LRTI cases identifiedStaphylococcus aureus(two withSCCmecand three withlukF/S virulence determinants),Streptococcus pyogenes(emm1-M1uk clone),S. dysgalactiaesubspecies equisimilis (STG62647A) andAspergillus fumigatuswith multiple treatments and public-health impacts.ConclusionsRMg provides frequent diverse benefits for treatment, infection control and public health. The combination of rapid comprehensive results, alongside revealing and characterising a hidden burden of infections makes the case for expediting routine service implementation.
Single-cell RNA sequencing data reveals rewiring of transcriptional relationships in Alzheimer’s Disease associated with risk variants
Authors: Bouland Gerard A. , Marinus Kevin I. , van Kesteren Ronald E. , Smit August B. , Mahfouz Ahmed , Reinders Marcel J.T. 
Published: May 2023

ABSTRACTUnderstanding how genetic risk variants contribute to Alzheimer’s Disease etiology remains a challenge. Single-cell RNA sequencing (scRNAseq) allows for the investigation of cell type specific effects of genomic risk loci on gene expression. Using seven scRNAseq datasets totalling >1.3 million cells, we investigated differential correlation of genes between healthy individuals and individuals diagnosed with Alzheimer’s Disease. Using the number of differential correlations of a gene to estimate its involvement and potential impact, we present a prioritization scheme for identifying probable causal genes near genomic risk loci. Besides prioritizing genes, our approach pin-points specific cell types and provides insight into the rewiring of gene-gene relationships associated with Alzheimer’s.
Inferring Skin-Brain-Skin Connections from Infodemiology Data using Dynamic Bayesian Networks
Authors: Scutari Marco , Kerob Delphine , Salah Samir 
Published: May 2023

ABSTRACTBackgroundThe relationship between skin diseases and mental illnesses has been extensively studied using cross-sectional epidemiological data. Typically, such data can only measure association (rather than causation) and include only a subset of the diseases we may be interested in.ObjectiveIn this paper, we complement the evidence from such analyses by learning an overarching causal network model over twelve health conditions from the Google Search Trends Symptoms public data set.MethodsWe learned the causal network model using a dynamic Bayesian network, which can represent both cyclic and acyclic causal relationships, is easy to interpret and accounts for the spatio-temporal trends in the data in a probabilistically rigorous way.ResultsThe causal network confirms a large number of cyclic relationships between the selected health conditions and the interplay between skin and mental diseases. For acne, we observe a cyclic relationship with anxiety and attention deficit hyperactivity disorder (ADHD) and an indirect relationship with depression through sleep disorders. For dermatitis, we observe directed links to anxiety, depression and sleep disorders and a cyclic relationship with ADHD. We also observe a link between dermatitis and ADHD and a cyclic relationship between acne and ADHD. Furthermore, the network includes several direct connections between sleep disorders and other health conditions, highlighting the impact of the former on the overall health and well-being of the patient. The averageR2for a condition given the values of all conditions in the previous week is 0.67: in particular, 0.42 for acne, 0.85 for asthma, 0.58 for ADHD, 0.87 for burn, 0.76 for erectile dysfunction, 0.88 for scars, 0.57 for alcohol disorders, 0.57 for anxiety, 0.53 for depression, 0.74 for dermatitis, 0.60 for sleep disorders and 0.66 for obesity.ConclusionsMapping disease interplay, indirect relationships, and the key role of mediators, such as sleep disorders, will allow healthcare professionals to address disease management holistically and more effectively. Even if we consider all skin and mental diseases jointly, each disease subnetwork is unique, allowing for more targeted interventions.
An amplicon-based nanopore sequencing workflow for rapid tracking of avian influenza outbreaks, France, 2020-2022
Authors: Croville Guillaume , Walch Mathilda , Lèbre Laetitia , Silva Sonia , Filaire Fabien , Guérin Jean-Luc 
Published: May 2023

AbstractDuring the recent avian influenza epizootics that occurred in France in 2020/21 and 2021/22, the virus was so contagiousness that it was impossible to control its spread between farms. The preventive slaughter of millions of birds consequently was the only solution available. In an effort to better understand the spread of avian influenza viruses (AIVs) in a rapid and innovative manner, we established an amplicon-based MinION sequencing workflow for the rapid genetic typing of circulating AIV strains.An amplicon-based MinION sequencing workflow based on a set of PCR primers targeting primarily the hemagglutinin gene but also the entire influenza virus genome was developed. Thirty field samples from H5 HPAIV outbreaks in France, including environmental samples, were sequenced using the MinION MK1C. A real-time alignment of the sequences with MinKNOW software allowed the sequencing run to be stopped as soon as enough data were generated. The consensus sequences were then generated and a phylogenetic analysis was conducted to establish links between the outbreaks.The whole sequence of the hemagglutinin gene was obtained for the 30 clinical samples of H5Nx HPAIV belonging to clade 2.3.4.4b. The consensus sequences comparison and the phylogenetic analysis demonstrated links between some outbreaks.While several studies have shown the advantages of MinION for avian influenza virus sequencing, this workflow has been applied exclusively to clinical field samples, without any amplification step on cell cultures or embryonated eggs. As this type of testing pipeline requires only a short amount of time to link outbreaks or demonstrate a new introduction, it could be applied to the real-time management of viral epizootics.
A Resource of Gene Expression Data from a Multiethnic Population Cohort of Induced Pluripotent Cell–Derived Cardiomyocytes
Authors: Lv Wenjian , Babu Apoorva , Morley Michael P. , Musunuru Kirin , Guerraty Marie 
Published: May 2023

ABSTRACTInduced pluripotent stem cells (iPSCs), upon differentiation into somatic cell types, offer the ability to model the genetic states of tissues in the individuals from whom the iPSCs were derived.1A prior study used a multiethnic cohort of healthy individuals to derive iPSCs and iPSC-hepatocytes and perform gene expression and expression quantitative trait locus (eQTL) analyses, identifying causal genes and variants linked to blood lipid levels.2We sought to use this cohort of iPSC lines to generate a similar resource with iPSC-cardiomyocytes (iPSC-CMs) and make the results available to the community.
TREM2 limits necrotic core formation during atherogenesis by controlling macrophage survival and efferocytosis
Authors: Piollet Marie , Porsch Florentina , Rizzo Giuseppe , Kapser Frederieke , Schulz Dirk J.J. , Kiss Máté G. , Schlepckow Kai , Morenas-Rodriguez Estrella , Sen Mustafa Orkun , Gropper Julius , Roesch Melanie , Göderle Laura , Hladik Anastasiya , Knapp Sylvia , Colonna Marco , Martini Rudolf , Haass Christian , Zernecke Alma , Binder Christoph J. , Cochain Clément 
Published: May 2023

AbstractAtherosclerosis is a chronic disease of the vascular wall driven by lipid accumulation and inflammation in the intimal layer of arteries [1], [2], and its main complications, myocardial infarction and stroke, are the leading cause of mortality worldwide [3]. Recent studies have identified Triggering receptor expressed on myeloid cells 2 (TREM2), a lipid-sensing receptor regulating several key myeloid cell functions [4], as a highly expressed marker of macrophage foam cells in experimental and human atherosclerosis [5]. However, the function of TREM2 in the development of atherosclerosis is unknown. Here, we show that hematopoietic or global TREM2 deficiency increases necrotic core formation in early experimental atherosclerosis. We further demonstrate that TREM2 is essential for the efferocytosis capacities of macrophages, and to the survival of lipid-laden macrophages, altogether indicating a crucial role of TREM2 in maintaining the balance between foam cell death and their clearance in atherosclerotic lesions, thereby controlling plaque necrosis.
Putrescine acetyltransferase (PAT/SAT1) dependent GABA synthesis in astrocytes
Authors: Lim Jiwoon , Bhalla Mridula , Park Mingu Gordon , Koh Wuhyun , Lee C. Justin 
Published: May 2023

AbstractGABA synthesis in astrocytes mediates tonic inhibition to regulate patho-physiological processes in various brain regions. Monoamine oxidase B (MAO-B) has been known to be the most important metabolic enzyme for synthesizing GABA from the putrescine degradation pathway. MAO-B converts N1-acetylputrescine to N1-acetyl-γ-aminobutyraldehyde and hydrogen peroxide (H2O2). Putrescine acetyltransferase (PAT), also known as spermidine and spermine N1-acetyltransferase 1 (SAT1), has been thought to be a feasible candidate enzyme for converting putrescine to N1-acetylputrescine. However, it has not been rigorously investigated or determined whether PAT/SAT1 contributes to GABA synthesis in astrocytes. To investigate the contribution of PAT/SAT1 to GABA synthesis in astrocytes, we conducted sniffer patch and whole-cell patch experiments with gene silencing of PAT/SAT1 bySat1shRNA expression. Our results showed that the gene silencing of PAT/SAT1 significantly decreased the MAO-B-dependent GABA synthesis, which was induced by putrescine incubation, leading to decreased Ca2+-dependent release of GABAin vitro. Additionally, we found that, from the brain sliceex vivo, putrescine incubation induces tonic GABA inhibition in dentate gyrus granule cells, which can be inhibited by MAO-B inhibitor, selegiline. Consistent with ourin vitroresults, astrocytic gene silencing of PAT/SAT1 significantly reduced putrescine incubation-induced tonic GABA current, possibly by converting putrescine to N1-acetylputrescine, a substrate of MAO-B. Our findings emphasize a crucial role of PAT/SAT1 in MAO-B-dependent GABA synthesis in astrocytes.
Cardiopharyngeal Mesoderm specification into cardiac and skeletal muscle lineages in gastruloids
Authors: Argiro Laurent , Chevalier Céline , Choquet Caroline , Nandkishore Nitya , Ghata Adeline , Baudot Anaïs , Zaffran Stéphane , Lescroart Fabienne 
Published: May 2023

AbstractCardiopharyngeal mesoderm contributes to the formation of the heart and head muscles. However, the mechanisms governing cardiopharyngeal mesoderm specification remain unclear. Indeed, there is a lack of anin vitromodel replicating the differentiation of both heart and head muscles to study these mechanisms. Such models are required to allow live-imaging and high throughput genetic and drug screening. Here, we show that the formation of self-organizing or pseudo-embryos from mouse embryonic stem cells (mESCs), also called gastruloids, reproduces cardiopharyngeal mesoderm specification towards cardiac and skeletal muscle lineages. By conducting a comprehensive temporal analysis of cardiopharyngeal mesoderm establishment and differentiation in gastruloids and comparing it to mouse embryos, we present the first evidence for skeletal myogenesis in gastruloids. By inferring lineage trajectories from the gastruloids single-cell transcriptomic data, we further suggest that heart and head muscles formed in gastruloids derive from cardiopharyngeal mesoderm progenitors. We identify different subpopulations of cardiomyocytes and skeletal muscles, which most likely correspond to different states of myogenesis with “head-like” and “trunk-like” skeletal myoblasts. These findings unveil the potential of mESC-derived gastruloids to undergo specification into both cardiac and skeletal muscle lineages, allowing the investigation of the mechanisms of cardiopharyngeal mesoderm differentiation in development and how this could be affected in congenital diseases.
Lipase-mediated detoxification of host-derived antimicrobial fatty acids byStaphylococcus aureus
Authors: Tchoupa Arnaud Kengmo , Elsherbini Ahmed M. A. , Fu Xiaoqing , Ghaneme Oumayma , Seibert Lea , Böcker Marieke A. , Lebtig Marco , Camus Justine , Lambidis Stilianos Papadopoulos , Schittek Birgit , Kretschmer Dorothee , Lämmerhofer Michael , Peschel Andreas 
Published: May 2023

AbstractLong-chain fatty acids with antimicrobial properties are abundant on the skin and mucosal surfaces, where they are essential to restrict the proliferation of opportunistic pathogens such asStaphylococcus aureus. These antimicrobial fatty acids (AFAs) elicit bacterial adaptation strategies, which have yet to be fully elucidated. Characterizing the pervasive mechanisms used byS. aureusto resist AFAs could open new avenues to prevent pathogen colonization. Here, we identify theS. aureuslipase Lip2 as a novel resistance factor against AFAs. Lip2 detoxifies AFAs via esterification with cholesterol. This is reminiscent of the activity of the fatty acid-modifying enzyme (FAME), whose identity has remained elusive for over three decades.In vitro, Lip2-dependent AFA-detoxification was apparent during planktonic growth and biofilm formation. Our genomic analysis revealed that prophage-mediated inactivation of Lip2 was more common in blood and nose isolates than in skin strains, suggesting a particularly important role of Lip2 for skin colonization. Accordingly, in a mouse model ofS. aureusskin colonization, bacteria were protected from sapienic acid - a human-specific AFA - in a cholesterol- and lipase-dependent manner. These results suggest Lip2 is the long-sought FAME that exquisitely manipulates environmental lipids to promote bacterial growth. Our data support a model in whichS. aureusexploits and/or exacerbates lipid disorders to colonize otherwise inhospitable niches.
The ecological characteristics of the safe sites for early-stage establishment ofChamaecyparis obtusavar.formosanaseedlings in Taiwan
Authors: Wei Shuo , Tseng Yu-Pei , Zelený David 
Published: May 2023

AbstractChamaecyparis obtusavar.formosanais an ecologically and economically important species in Taiwan, with a high affinity for fog immersion. Our study aims to identify possible stress factors that induced seedling mortality and investigate how different ecological factors influence early-stage safe site requirements of the seedlings. We focused on the effect of large-scale climatic variables, small-scale microhabitat conditions, and biotic interactions on seedling survival and establishment by applying seasonal seedling survival monitoring and establishment survey on both regional and local scale. We identified two alternative ways of seedling death, by environmental-induced mortality and by herbivory. Opposite effects of the same environmental factors on different causes of mortality showed that seedlings might need to balance the risks posed by both causes to optimize their growing conditions. On a regional scale, we observed limited effect of regional climatic variables (namely fog frequency) on seedlings’ establishment and survival but noted a similar seasonal survival pattern among regions. We hypothesize that short-duration droughts during the transition from Plum rain to typhoon season is one of the key mechanisms of environmental-induced mortality. On a local scale, we found that decayed coarse wood debris (CWD) facilitates seedling establishment by providing a “safe site”, likely due to increased colonization of small-stature bryophytes and decreased litterfall accumulation. The effect of bryophytes on seedling establishment varies depending on their thickness, with thicker ones having stronger negative effects. Aside from the bryophytes, the accumulation of litter significantly hindered seedling establishment. We argue that to safeguard the regeneration ofChamaecyparis obtusavar.formosanapopulation, preserving CWD in the forest floor as a safe site for the seedlings after tree-replacing disturbance in natural forests is essential, particularly under ongoing climate change where more frequent and prolonged drought events are predicted.HighlightsOn a local scale, decayed coarse wood debris (CWD) provides “safe site” for the establishment ofChamaecypairs obtusavar.formosanaseedlings.Regional climatic variables had limited effects on seedlings, but all regions had similar seasonal patterns of seedling mortatlity.Facilitation effect of small-stature bryophytes and litterfall avoidance might be the underlying mechanisms behind CWD safe sites.Preserving CWD for seedlings is important in the context of predicted prolong drought events under ongoing climate change.
Dietary fibre reverses adverse post-stroke outcomes in mice via short-chain fatty acids and its sensing receptors GPR41, GPR43 and GPR109A
Authors: Peh Alex , Dinakis Evany , Jama Hamdi , Anderson Dovile , Creek Darren J. , Zheng Gang , de Veer Michael , Mackay Charles R. , Zheng Tenghao , Kemp-Harper Barbara K. , Broughton Brad R.S. , Marques Francine Z. 
Published: May 2023

AbstractDietary fibre intake is associated with fewer cases of ischaemic stroke. This is likely via the microbiota-gut-brain axis, where fibre is fermented by the gut microbiota, releasing short-chain fatty acids (SCFAs). However, whether fibre or SCFAs can reverse adverse post-stroke outcomes remains unknown. Here, we demonstrated that a low fibre diet exacerbates post-stroke outcomes in mice. This was reversed by a high fibre diet or direct supplementation with SCFAs (delivered either in the water or a high SCFA-releasing diet) immediately after stroke. These modulated the gut microbiome and improved the gut epithelial barrier integrity, which was associated with fewer activated neutrophils and more neuroblast cells in the brain. We then investigated the SCFA-receptors GPR41/43/109A using a triple knockout mouse model, which exhibited poorer stroke outcomes and recovery. These results show that post-stroke interventions using dietary fibre and/or SCFA supplementation, acting via GPR41/43/109A signalling, may represent new therapeutic strategies for stroke-induced brain injury.