bluuebunny/crossref_metadata_2025_split huggingface dataset:
Legionellarelative abundance in shower hose biofilms is associated with specific microbiome members
Authors: Cavallaro Alessio , Rhoads William J. , Sylvestre Émile , Marti Thierry , Walser Jean-Claude , Hammes Frederik 
Published: May 2023

AbstractLegionellaare natural inhabitants of building plumbing biofilms, where interactions with other microorganisms influence their survival, proliferation, and death. Here, we investigated the associations ofLegionellawith prokaryotic and eukaryotic microbiomes in biofilm samples extracted from 85 shower hoses of a multiunit residential building.Legionellaspp. relative abundance in the biofilms ranged between 0 - 7.8%, of which only 0 - 0.46% wasL. pneumophila. Our data suggest that some microbiome members were associated with high (e.g.,Chthonomonas,Vrihiamoeba) or low (e.g.,Aquabacterium,Vannella)Legionellarelative abundance. The correlations of the differentLegionellavariants (30 Zero-Radius OTUs detected) showed distinct patterns, suggesting separate ecological niches occupied by differentLegionellaspecies. This study provides insights into the ecology ofLegionellawith respect to: 1) the colonization of a high number of real shower hoses biofilm samples; 2) the ecological meaning of associations betweenLegionellaand co-occurring prokaryotic/eukaryotic organisms; 3) critical points and future directions of microbial-interaction-based-ecological-investigations.
TLR priming licenses NAIP inflammasome activation by immunoevasive ligands
Authors: Grayczyk James P. , Egan Marisa S. , Liu Luying , Aunins Emily , Wynosky-Dolfi Meghan A. , Canna Scott , Minn Andy J. , Shin Sunny , Brodsky Igor E. 
Published: May 2023

AbstractNLR family, apoptosis inhibitory proteins (NAIPs) detect bacterial flagellin and structurally related components of bacterial type III secretion systems (T3SS), and recruit NLR family, CARD domain containing protein 4 (NLRC4) and caspase-1 into an inflammasome complex that induces pyroptosis. NAIP/NLRC4 inflammasome assembly is initiated by the binding of a single NAIP to its cognate ligand, but a subset of bacterial flagellins or T3SS structural proteins are thought to evade NAIP/NLRC4 inflammasome sensing by not binding to their cognate NAIPs. Unlike other inflammasome components such as NLRP3, AIM2, or some NAIPs, NLRC4 is constitutively present in resting macrophages, and not thought to be regulated by inflammatory signals. Here, we demonstrate that Toll-like receptor (TLR) stimulation upregulates NLRC4 transcription and protein expression in murine macrophages, which licenses NAIP detection of evasive ligands. TLR-induced NLRC4 upregulation and NAIP detection of evasive ligands required p38 MAPK signaling. In contrast, TLR priming in human macrophages did not upregulate NLRC4 expression, and human macrophages remained unable to detect NAIP-evasive ligands even following priming. Critically, ectopic expression of either murine or human NLRC4 was sufficient to induce pyroptosis in response to immunoevasive NAIP ligands, indicating that increased levels of NLRC4 enable the NAIP/NLRC4 inflammasome to detect these normally evasive ligands. Altogether, our data reveal that TLR priming tunes the threshold for NAIP/NLRC4 inflammasome activation and enables inflammasome responses against immunoevasive or suboptimal NAIP ligands.Significance StatementCytosolic receptors in the neuronal apoptosis inhibitor protein (NAIP) family detect bacterial flagellin and components of the type III secretion system (T3SS). NAIP binding to its cognate ligand engages the adaptor molecule NLRC4 to form NAIP/NLRC4 inflammasomes culminating in inflammatory cell death. However, some bacterial pathogens evade NAIP/NLRC4 inflammasome detection, thus bypassing a crucial barrier of the immune system. Here, we find that, in murine macrophages, TLR-dependent p38 MAPK signaling increases NLRC4 expression, thereby lowering the threshold for NAIP/NLRC4 inflammasome activation in response to immunoevasive NAIP ligands. Human macrophages were unable to undergo priming-induced upregulation of NLRC4 and could not detect immunoevasive NAIP ligands. These findings provide a new insight into species-specific regulation of the NAIP/NLRC4 inflammasome.
Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior
Authors: Al-Kachak Amni , Fulton Sasha L. , Di Salvo Giuseppina , Chan Jennifer C , Farrelly Lorna A. , Lepack Ashley E. , Bastle Ryan M. , Kong Lingchun , Cathomas Flurin , Newman Emily L. , Menard Caroline , Ramakrishnan Aarthi , Safovich Polina , Lyu Yang , Covington Herbert E. , Shen Li , Gleason Kelly , Tamminga Carol A. , Russo Scott J. , Maze Ian 
Published: May 2023

ABSTRACTBackgroundMajor depressive disorder (MDD), along with related mood disorders, is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of mood disorders, stress-mediated disruptions in brain function that precipitate these illnesses remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of mood disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures.MethodsWe employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics, as well as associations between the mark and stress-induced gene expression. We additionally assessed stress-induced regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy to reduce H3K4me3Q5ser levels in DRN and examine the impact on stress-associated gene expression and behavior.ResultsWe found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to rescue stress-mediated gene expression and behavior.ConclusionsThese findings establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity in DRN.
CTCF-mediated insulation and chromatin environment modulateCar5bescape from X inactivation
Authors: Fang He , Tronco Ana R. , Bonora Giancarlo , Nguyen Truong , Thakur Jitendra , Berletch Joel B. , Filippova Galina N. , Henikoff Steven , Shendure Jay , Noble William S. , Disteche Christine M. , Deng Xinxian 
Published: May 2023

AbstractBackgroundThe number and escape levels of genes that escape X chromosome inactivation (XCI) in female somatic cells vary among tissues and cell types, potentially contributing to specific sex differences. Here we investigate the role of CTCF, a master chromatin conformation regulator, in regulating escape from XCI. CTCF binding profiles and epigenetic features were systematically examined at constitutive and facultative escape genes using mouse allelic systems to distinguish the inactive X (Xi) and active X (Xa) chromosomes.ResultsWe found that escape genes are located inside domains flanked by convergent arrays of CTCF binding sites, consistent with the formation of loops. In addition, strong and divergent CTCF binding sites often located at the boundaries between escape genes and adjacent neighbors subject to XCI would help insulate domains. Facultative escapees show clear differences in CTCF binding dependent on their XCI status in specific cell types/tissues. Concordantly, deletion but not inversion of a CTCF binding site at the boundary between the facultative escape geneCar5band its silent neighborSiah1bresulted in loss ofCar5bescape. Reduced CTCF binding and enrichment of a repressive mark overCar5bin cells with a boundary deletion indicated loss of looping and insulation. In mutant lines in which either the Xi-specific compact structure or its H3K27me3 enrichment was disrupted, escape genes showed an increase in gene expression and associated active marks, supporting the roles of the 3D Xi structure and heterochromatic marks in constraining levels of escape.ConclusionOur findings indicate that escape from XCI is modulated both by looping and insulation of chromatin via convergent arrays of CTCF binding sites and by compaction and epigenetic features of the surrounding heterochromatin.
Non-pathogenic leaf-colonising bacteria elicit pathogen-like responses in a colonisation density-dependent manner
Authors: Miebach Moritz , Faivre Léa , Schubert Daniel , Jameson Paula , Remus-Emsermann Mitja 
Published: May 2023

AbstractLeaves are colonised by a complex mix of microbes, termed the leaf microbiota. Even though the leaf microbiota is increasingly recognised as an integral part of plant life and health, our understanding of its interactions with the plant host is still limited. Here, mature, axenically grownArabidopsis thalianaplants were spray-inoculated with six diverse leaf-colonising bacteria. The transcriptomic changes in leaves were tracked over time and significant changes in ethylene marker (ARL2) expression were observed only two to four days after spray-inoculation. Whole transcriptome sequencing revealed that four days after inoculation, leaf transcriptional changes to colonisation by non-pathogenic and pathogenic bacteria differed in strength but not in the type of response. Inoculation of plants with different densities of the non-pathogenic bacteriumWilliamsiasp. Leaf354 showed that high bacterial titers caused disease phenotypes and led to severe transcriptional reprogramming with a strong focus on plant defence. Anin silicoepigenetic analysis of the data was congruent with the transcriptomic analysis. These findings suggest (1) that plant responses are not rapid after spray-inoculation, (2) that plant responses only differ in strength and (3) that plants respond to high titers of non-pathogenic bacteria with pathogen-like responses.Plain Language SummaryPlants are colonised by diverse bacteria affecting many aspects of plant life. Here we show that plants do not differentiate between different bacteria but measure their quantities to keep bacterial numbers in check.
Primary series and booster COVID-19 vaccine effectiveness in a cohort of healthcare workers in Albania during a BA.1 and BA.2 variant period, January – May 2022
Authors: Finci Iris , Rojas Castro Madelyn Yiseth , Hasibra Iris , Sulo Jonilda , Fico Albana , Daja Rovena , Vasili Adela , Kota Majlinda , Preza Iria , Mühlemann Barbara , Drosten Christian , Pebody Richard , Lafond Kathryn E. , Kissling Esther , Katz Mark A. , Bino Silvia 
Published: May 2023

AbstractBackgroundHealthcare workers (HCWs) have experienced high rates of COVID-19 morbidity and mortality. We estimated COVID-19 two-dose primary series and monovalent booster vaccine effectiveness (VE) against symptomatic SARS-CoV-2 Omicron (BA.1 and BA.2) infection among HCWs in three Albanian hospitals during January–May 2022.MethodsStudy participants completed weekly symptom questionnaires, underwent PCR testing when symptomatic, and provided quarterly blood samples for serology. We estimated VE using Cox regression models (1-hazard ratio), with vaccination status as the time-varying exposure and unvaccinated HCWs as the reference group, adjusting for potential confounders: age, sex, prior SARS-CoV-2 infection (detected by PCR, rapid-antigen test or serology), and household size.ResultsAt the start of the analysis period, 76% of 1,462 HCWs had received a primary series, 10% had received a booster dose, and 9% were unvaccinated; 1,307 (89%) HCWs had evidence of prior infection. Overall, 86% of primary series and 98% of booster doses received were BNT162b2. The median time interval from the second dose and the booster dose to the start of the analysis period was 289 days (IQR:210– 292) and 30 days (IQR:22–46), respectively. VE against symptomatic PCR-confirmed infection was 34% (95%CI: -36;68) for the primary series and 88% (95%CI: 38;98) for the booster.ConclusionsAmong Albanian HCWs, most of whom had been previously infected, COVID-19 booster dose offered improved VE during a period of Omicron BA.1 and BA.2 circulation. Our findings support promoting booster dose uptake among Albanian HCWs, which, as of January 2023, was only 20%.
Transcriptomics Analyses of ALS Post-mortem Motor Cortex highlight alteration and potential biomarkers in the Neuropeptide Signalling pathway
Authors: Kabiljo Renata , Marriott Heather , Hunt Guy P , Pfaff Abigail L , Al Khleifat Ahmad , Adey Brett , Jones Ashley , Troakes Claire , Quinn John P , Dobson Richard J B , Koks Sulev , Al-Chalabi Ammar , Iacoangeli Alfredo 
Published: May 2023

AbstractBackgroundAmyotrophic lateral sclerosis (ALS) is a fatal heterogeneous neurodegenerative disease that typically leads to death from respiratory failure within two to five years. Despite the identification of several genetic risk factors, the biological processes involved in ALS pathogenesis remain poorly understood. The motor cortex is an ideal region to study dysregulated pathological processes in ALS as it is affected from the earliest stages of the disease. In this study, we investigated motor-cortex gene expression of cases and controls to gain new insight into the molecular footprint of ALS.MethodsWe performed a large case-control differential expression analysis of two independent post-mortem motor cortex bulk RNA-sequencing (RNAseq) datasets from the King’s College London BrainBank (N = 171) and TargetALS (N = 132). Differentially expressed genes from both datasets were subjected to gene and pathway enrichment analysis. Genes common to both datasets were also reviewed for their involvement with known mechanisms of ALS pathogenesis to identify potential candidate genes. Finally, we performed a correlation analysis of genes implicated in pathways enriched in both datasets with clinical outcomes such as the age of onset and survival.ResultsDifferential expression analysis identified 2,290 and 402 differentially expressed genes in KCL BrainBank and TargetALS cases, respectively. Enrichment analysis revealed significant synapse-related processes in the KCL BrainBank dataset, while the TargetALS dataset carried an immune system-related signature. There were 44 differentially expressed genes which were common to both datasets, which represented previously recognised mechanisms of ALS pathogenesis, such as lipid metabolism, mitochondrial energy homeostasis and neurovascular unit dysfunction. Differentially expressed genes in both datasets were significantly enriched for the neuropeptide signalling pathway. By looking at the relationship between the expression of neuropeptides and their receptors with clinical measures, we found that in both datasetsNPBWR1, TAC3andSSTR1correlated with age of onset, andGNRH1, TACR1with survival. We provide access to gene-level expression results to the broader research community through a publicly available web application (https://alsgeexplorer.er.kcl.ac.uk).ConclusionThis study identified motor-cortex specific pathways altered in ALS patients, potential molecular targets for therapeutic disease intervention and a set of neuropeptides and receptors for investigation as potential biomarkers.
Constructing cancer-specific patient similarity network with clinical significance
Authors: Zhang Rukui , Liu Zhaorui , Zhu Chaoyu , Cai Hui , Yin Kai , Zhong Fan , Liu Lei 
Published: May 2023

AbstractClinical molecular genetic testing and molecular imaging dramatically increase the quantity of clinical data. Combined with the extensive application of electronic health records, medical data ecosystem is forming, which summons big-data-based medicine model. We tried to use big data analytics to search for similar patients in a cancer cohort and to promote personalized patient management. In order to overcome the weaknesses of most data processing algorithms that rely on expert labelling and annotation, we uniformly adopted one-hot encoding for all types of clinical data, calculating Euclidean distance to measure patient similarity, and subgrouping via unsupervised learning model. Overall survival was investigated to assess the clinical validity and clinical relevance of the model. Thereafter, we built a high-dimensional network cPSN (clinical patient similarity network). When performing overall survival analysis, we found Cluster_2 had the longest survival rates while Cluster_5 had the worst prognosis among all subgroups. Because patients in the same subgroup share some clinical characteristics, clinical feature analysis found that Cluster_2 harbored more lower distal GCs than upper proximal GCs, shedding light on the debates. Overall, we constructed a cancer-specific cPSN with excellent interpretability and clinical significance, which would recapitulate patient similarity in the real-world. The constructed cPSN model is scalable, generalizable, and performs well for various data types. The constructed cPSN could be used to accurately “locate” interested patients, classify the patient into a disease subtype, support medical decision making, and predict clinical outcomes.
Evaluation of plasma biomarkers for causal association with peripheral artery disease
Authors: Sharma Pranav , Levin Michael G. , Klarin Derek , Voight Benjamin F. , Tsao Philip S. , Damrauer Scott M. 
Published: May 2023

ABSTRACTBackgroundHundreds of biomarkers for Peripheral artery disease (PAD) have been reported in the literature, however, the observational nature these studies limit robust causal inference due to the potential of reverse causality and confounding. We aimed to perform a systematic review of plasma biomarkers associated with PAD followed by Mendelian Randomization (MR) to systematically address residual confounding and better understand the causal pathophysiology of PAD. Combining a systematic review with MR facilitates cross-domain verification of observational and experimental results.MethodsWe performed a systematic literature review for terms related to PAD and/or biomarkers using Pubmed, Cochrane, and Embase, followed by manual review to extract biomarkers and their direction of effect. To evaluate evidence for causality, we employed Two-sample Mendelian randomization (MR). We developed genetic instruments for the biomarkers by mapping them to genome wide association studies (GWAS) of circulating biomolecules aggregated by the IEU Open GWAS and deCODE projects. We tested the association of the genetic instruments with PAD using summary statistics from a GWAS of 31,307 individuals with and 211,753 individuals without PAD in the VA Million Veteran Program. We employed Wald ratio or inverse-variance weighted MR; weighted median and weighted mode methods were applied as sensitivity analyses.ResultsWe identified a total of 1,993 unique papers related to PAD and biomarkers using extant genetic instruments, and MeSH terms across PubMed, Embase, and Cochrane. After filtering and manual review, 170 unique papers remained, mentioning 204 unique biomarkers. Genetic instruments based on publicly available data were developed for 175 biomarkers. After accounting for multiple testing by controlling the false discovery rate (q < 0.05), 19/175 (10.9%) biomarkers had significant associations with PAD. Of the 19 significant associations, only 13/19 (58.3%) had concordant directions of effects with published reports. These 19 biomarkers represented broad categories including plasma lipid regulation (HDL-C, LPA, Triglycerides, APOA1, EPA, APOB, APOA5, and SHBG), coagulation-inflammatory response (CD36, IL6-sRa, VWF, IL18BP, and CD163), and endothelial damage/dysfunction (HLA-G, NPPA, VCAM-1, CDH5, MMP1, and INS).ConclusionThis systematic review paired with Mendelian randomization elucidates biomarkers with genetic evidence for causality relevant to PAD, and highlights discrepancies between published reports and human genetic findings. Conventional studies have previously highlighted biomarkers that have correlation to PAD but have not emphasized the causal pathobiology of this disease. Expansion of genetic datasets to increase the power of these analyses will be crucial to further understand the causal role of plasma biomarkers and highlighting key biological pathways in PAD.
The bladder microbiome of chronic kidney disease with associations to demographics, renal function, and serum cytokines
Authors: Liu Fengping , Du Jingjie , Lin Hao , Xu Zhenyi , Sun Yifan , Yan Feng , Gu Yifeng , Wang Yang , Guo Wei , Zhai Qixiao , Hu Jialin , Tian Yu , Hu Lei , Jiang Peng , Wei Shichao , Gu Chaoqun , Sheng Jiayi , Chen Wei , Wolfe Alan J. , Feng Ninghan 
Published: May 2023

BackgroundHigh throughput 16S rRNA gene sequencing and enhanced culture methods (e.g., expanded quantitative urine culture, EQUC) have established the existence of the human bladder microbiome. We aim to test the hypothesis that the bladder environment of patients with chronic kidney disease (CKD) differs from that of unaffected controls with associated consequences for the composition of the bladder microbiome.Methods and MaterialsFemales (n=66) and males (n=66) diagnosed with CKD and age-BMI-matched healthy control (HC) females (n=22) and males (n=22) were recruited. Transurethral catheterized urine was collected for 16S rRNA gene sequencing and Expanded Quantitative Urine Culture (EQUC). Fecal samples also were sequenced. Urinary analysis, kidney function and serum cytokines were examined.ResultsBladder microbiomes of CKD females and males versus HC females and males differed (FDR<0.05); however, the difference was more obvious in females. In CKD females, sequencing revealed depletion of 5 genera, includingLactobacillus, and enrichment of 14 genera, includingEscherichia/Shigella, Bifidobacterium, and several clostridial genera (FDR<0.05), while EQUC detected increasedEscherichiaand decreasedLactobacillusCKDB(P<0.05).Escherichia-Shigellawas positively, whereasLactobacilluswas negatively, associated with CKDB-female serum creatinine (r=0.285, P=0.020; r=-0.337, P=0.006, respectively).Lactobacilluswas positively associated with eGFR (r=0.251, P=0.042). Some CKD-related serum cytokines were negatively associated with clostridial genera. In contrast, the fecal microbiomes of CKD and HC females and males did not significantly differ in bacterial diversity or composition. However, bladder and fecal microbiomes of CKD females resembled each other more than those of controls, as assessed by the Bray-Curtis Dissimilarity Index (FDR<0.05).ConclusionsCKD bladder microbiomes were dysbiotic, which was more obvious in females. This dysbiosis was associated with kidney damage severity and dysregulation of serum cytokines. The increased similarity between bladder and fecal microbiomes of CKD females suggests possible “gut-leakage.”