bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sociodemographic and health-related differences in undiagnosed hypertension in the Health Survey for England 2015-2019
Authors: Campbell Emma , Macey Ellie , Shine Chris , Nafilyan Vahé , Clark Nathan Cadogan , Pawelek Piotr , Ward Isobel , Hughes Andrew , Raleigh Veena , Banerjee Amitava , Finning Katie 
Published: July 2023

AbstractBackgroundHypertension is a leading cause of morbidity and mortality worldwide, yet a substantial proportion of cases are undiagnosed. Understanding the scale of undiagnosed hypertension and identifying groups most at risk is important to inform approaches to detection.MethodsWe used data from the 2015 to 2019 Health Survey for England, an annual, cross-sectional, nationally representative survey. Undiagnosed hypertension was defined by a measured blood pressure of 140/90mmHg or above but no history of diagnosis. Age-adjusted prevalence of undiagnosed hypertension was estimated across sociodemographic and health-related characteristics. To assess the independent association between undiagnosed hypertension and each characteristic, we fitted a logistic regression model adjusted for sociodemographic factors.FindingsAn estimated 30.7% (29.0-32.4%) of men and 27.6% (26.1-29.1%) of women with hypertension were undiagnosed. Younger age, lower Body Mass Index, and better self-reported general health were associated with an increased likelihood of hypertension being undiagnosed for men and women. Living in rural areas and in regions outside of London and the East of England were also associated with an increased likelihood of hypertension being undiagnosed for men, as were being married or in a civil partnership and having higher educational qualifications for women.InterpretationHypertension is commonly undiagnosed, and some of the groups less at risk of hypertension are most likely to be undiagnosed. Given the high lifetime risk of hypertension and its strong links with morbidity and mortality, our findings suggest a need for greater awareness of the potential for undiagnosed hypertension, including among those typically considered ‘low risk’.
Glioblastoma Mesenchymal Transition and Invasion are Dependent on a NF-κB/BRD2 Chromatin Complex
Authors: Vadla Raghavendra , Miki Shunichiro , Taylor Brett , Kawauchi Daisuke , Jones Brandon M , Nathwani Nidhi , Pham Philip , Tsang Jonathan , Nathanson David A. , Furnari Frank B. 
Published: July 2023

AbstractGlioblastoma (GBM) represents the most aggressive subtype of glioma, noted for its profound invasiveness and molecular heterogeneity. The mesenchymal (MES) transcriptomic subtype is frequently associated with therapy resistance, rapid recurrence, and increased tumor-associated macrophages. Notably, activation of the NF-κB pathway and alterations in thePTENgene are both associated with this malignant transition. Although PTEN aberrations have been shown to be associated with enhanced NF-κB signaling, the relationships between PTEN, NF-κB and MES transition are poorly understood in GBM. Here, we show that PTEN regulates the chromatin binding of bromodomain and extraterminal (BET) family proteins, BRD2 and BRD4, mediated by p65/RelA localization to the chromatin. By utilizing patient-derived glioblastoma stem cells and CRISPR gene editing of theRELAgene, we demonstrate a crucial role for RelA lysine 310 acetylation in recruiting BET proteins to chromatin for MES gene expression and GBM cell invasion uponPTENloss. Remarkably, we found that BRD2 is dependent on chromatin associated acetylated RelA for its recruitment to MES gene promoters and their expression. Furthermore, loss of BRD2 results in the loss of MES signature, accompanied by an enrichment of proneural signature and enhanced therapy responsiveness. Finally, we demonstrate that disrupting the NF-κB/BRD2 interaction with a brain penetrant BET-BD2 inhibitor reduces mesenchymal gene expression, GBM invasion, and therapy resistance in GBM models. This study uncovers the role of hitherto unexplored PTEN-NF-κB-BRD2 pathway in promoting MES transition and suggests inhibiting this complex with BET-BD2 specific inhibitors as a therapeutic approach to target the MES phenotype in GBM.
Longitudinal hair cortisol in bipolar disorder and a mechanism based on HPA dynamics
Authors: Milo Tomer , Maimon Lior , Cohen Ben , Haran Dafna , Segman Dror , Danon Tamar , Bren Anat , Mayo Avi , Cohen Rappaport Gadi , McInnis Melvin , Alon Uri 
Published: July 2023

AbstractBipolar disorder (BD) is a dynamic disease in which mania, depression and mixed states vary on a timescale of months to years. BD patients characteristically exhibit elevated levels of the hormone cortisol. Persistently elevated cortisol can also cause mood episodes in a substantial fraction of the general population. Although BD is a dynamic disease that is related to cortisol, longitudinal cortisol dynamics in BD have rarely been studied. Here we use hair to measure past cortisol where each cm of hair corresponds to a month of growth. Cortisol was measured in 12 cm hair samples from people with BD (n=26) and controls (n=59), corresponding to one year of cortisol data. We found that hair cortisol exhibited a frequency spectrum with enhanced year-scale fluctuations whose amplitude was about 4-fold higher on average in BD compared to controls. Cortisol in the proximal 2 cm hair segment correlated with mood scales that report on mood in the past two months. In line with the notion that cortisol correlates with mood, we find that the mean frequency spectrum of depression (n=266) and mania (n=273) scores from a large longitudinal study of BD is similar to the hair cortisol spectrum from the present cohort. Taken together, these results suggest a mechanism for BD as the intersection of two neuropsychological traits: cortisol-induced mood episodes (CIM) and high emotional reactivity (ER). High ER causes fluctuations in which cortisol is elevated for months, as shown by a mathematical model of the hypothalamic-pituitary-adrenal (HPA) axis that regulates cortisol. In individuals with CIM, the magnitude of these persistent cortisol fluctuations can be high enough to trigger mood episodes. Thus, this study combines longitudinal cortisol measurements and mathematical modeling to provide a potential mechanistic link between the timescales of cortisol and moods in BD.
Identification and distribution of novel candidate T6SS effectors encoded inSalmonellaPathogenicity island 6
Authors: Blondel Carlos J. , Amaya Fernando A. , Bustamante Paloma , Santiviago Carlos A. , Pezoa David 
Published: July 2023

ABSTRACTThe type VI secretion system (T6SS) is a contact-dependent contractile multiprotein apparatus widely distributed in Gram-negative bacteria. These systems can deliver different effector proteins into target bacterial and/or eukaryotic cells, contributing to the environmental fitness and virulence of many bacterial pathogens.Salmonellaharbors five different T6SSs encoded in different genomic islands. The T6SS encoded inSalmonellaPathogenicity Island 6 (SPI-6) contributes toSalmonellacompetition with the host microbiota and its interaction with infected host cells. Despite its relevance, information regarding the total number of effector proteins encoded within SPI-6 and its distribution among differentSalmonella entericaserotypes is limited. In this work, we performed bioinformatic and comparative genomics analyses of the SPI-6 T6SS gene cluster to expand our knowledge regarding the T6SS effector repertoire and the global distribution of these effectors inSalmonella. The analysis of a curated dataset of 60Salmonella entericagenomes from the Secret6 database revealed the presence of 23 novel putative T6SS effector/immunity protein (E/I) modules. These effectors were concentrated in the variable regions 1 to 3 (VR1-3) of the SPI-6 T6SS gene cluster. VR1-2 were enriched in candidate effectors with predicted peptidoglycan hydrolase activity, while VR3 was enriched in candidate effectors of the Rhs family with C-terminal extensions with predicted DNase, RNase, deaminase, or ADP-ribosyltransferase activity. A global analysis of known and candidate effector proteins inSalmonella entericagenomes from the NCBI database revealed that T6SS effector proteins are differentially distributed amongSalmonellaserotypes. While some effectors are present in over 200 serotypes, others are found in less than a dozen. A hierarchical clustering analysis identifiedSalmonellaserotypes with distinct profiles of T6SS effectors and candidate effectors, highlighting the diversity of T6SS effector repertoires inSalmonella enterica. The existence of different repertoires of effector proteins suggests that different effector protein combinations may have a differential impact on the environmental fitness and pathogenic potential of these strains.
Emergence of putative energy parasites withinClostridiarevealed by genome analysis of a novel endosymbiotic clade
Authors: Takahashi Kazuki , Kuwahara Hirokazu , Horikawa Yutaro , Izawa Kazuki , Kato Daiki , Inagaki Tatsuya , Yuki Masahiro , Ohkuma Moriya , Hongoh Yuichi 
Published: July 2023

AbstractTheClostridiais a dominant bacterial class in the guts of various animals and are considered to nutritionally contribute to the animal host. Here, we discovered clostridial endosymbionts of cellulolytic protists in termite guts, which have never been reported with evidence. We obtained (near-)complete genome sequences of three endosymbioticClostridia, each associated with a different parabasalid protist species with various infection rates:Trichonympha agilis,Pseudotrichonympha grassii, andDevescovinasp. All these protists are previously known to harbor permanently-associated, mutualisticEndomicrobiaorBacteroidalesthat supplement nitrogenous compounds. The genomes of the endosymbioticClostridiawere small in size (1.0–1.3 Mbp) and exhibited signatures of an obligately-intracellular parasite, such as an extremely limited capability to synthesize amino acids, cofactors, and nucleotides and a disrupted glycolytic pathway with no known net ATP-generating system. Instead, the genomes encoded ATP/ADP translocase and, interestingly, regulatory proteins that are unique to eukaryotes in general and are possibly used to interfere with host cellular processes. These three genomes formed a clade with metagenome-assembled genomes (MAGs) derived from the guts of other animals, including human and ruminants, and the MAGs shared the characteristics of parasites. Gene flux analysis suggested that the acquisition of the ATP/ADP translocase gene in a common ancestor was probably key to the emergence of this parasitic clade. Taken together, we provide novel insights into the multilayered symbiotic system in the termite gut by adding the presence of parasitism and present an example of the emergence of putative energy parasites from a dominant gut bacterial clade.
Robust Feature Selection strategy detects a panel of microRNAs as putative diagnostic biomarkers in Breast Cancer
Authors: Costa Maria Claudia , Noviello Teresa Maria Rosaria , Ceccarelli Michele , Cerulo Luigi 
Published: July 2023

AbstractMicroRNAs represent a comprehensive class of short, single-stranded, non-coding RNA transcripts able to interfere with the translation of their targets or degrade them. Since these molecules are dysregulated in several malignancies, they represent reliable biomarkers in various contexts. In this study, the application of several Feature Selection methods uncovers a panel of 20 microRNAs, of whichhsa-mir-337, hsa-mir-378c, and hsa-mir-483are still poorly investigated in the context of Breast Cancer. This signature is capable of discriminating between healthy and tumoral samples, showing better classification performance when compared with differentially expressed microRNAs. Furthermore, a network-based centrality analysis on the gene targets of these transcripts highlightedCDC25, TPX2, KIF18B, CDCA3, TGFBR2, CAV1, TNS1, andLHFPL6as key dysregulated genes. This study providesin silicohypotheses as new insights for futurein vivoorin vitrostudies uncovering the role of these putative diagnostic biomarkers in Breast Cancer.
Diseased human pancreas and liver microphysiological system for preclinical diabetes research
Authors: Rigal Sophie , Casas Belén , Kanebratt Kajsa P. , Huldt Charlotte Wennberg , Magnusson Lisa U. , Müllers Erik , Karlsson Fredrik , Clausen Maryam , Hansson Sara F. , Löfmark Rasmus Jansson , Ämmälä Carina , Marx Uwe , Gennemark Peter , Cedersund Gunnar , Andersson Tommy B. , Vilén Liisa K. 
Published: July 2023

ABSTRACTCurrent research on metabolic disorders such as type 2 diabetes relies on animal models because multi-organ diseases cannot be well studied with the standardin vitroassays. Here, we connect models of key metabolism organs, pancreas and liver, on a microfluidic chip to enable diabetes research in a human-based preclinical system. Aided by mechanistic mathematical modelling, we developed a two-organ microphysiological system (MPS) that replicates clinically-relevant phenotypes of diabetic dysregulation both in the liver and pancreas compartments. Exposure to hyperglycemia and high cortisone created a diseased pancreas-liver MPS which displayed beta-cell dysfunction, steatosis, elevated ketone-body secretion, increased glycogen storage, and upregulated gluconeogenic machinery. In turn, normoglycemia and physiological cortisone concentration maintained glucose tolerance and stable liver and beta-cell functions. This method was evaluated for repeatability in two laboratories and was effective in multiple pancreatic islet donors. The model also provides a platform to identify new therapeutic targets as demonstrated with a liver-secreted IL-1R2 protein that induced islet proliferation.
Intratumoral immune triads are required for adoptive T cell therapy-mediated elimination of solid tumors
Authors: Espinosa-Carrasco Gabriel , Scrivo Aurora , Zumbo Paul , Dave Asim , Betel Doron , Hellmann Matthew , Burt Bryan M , Lee Hyun-Sung , Schietinger Andrea 
Published: July 2023

ABSTRACTTumor-reactive CD8 T cells found in cancer patients are frequently dysfunctional, unable to halt tumor growth. Adoptive T cell transfer (ACT), the administration of large numbers ofin vitro-generated cytolytic tumor-reactive CD8 T cells, is an important cancer immune therapy being pursued. However, a limitation of ACT is that transferred CD8 T cells often rapidly lose effector function, and despite exciting results in certain malignancies, few ACT clinical trials have shown responses in solid tumors. Here, we developed preclinical cancer mouse models to investigate if and how tumor-specific CD4 T cells can be enlisted to overcome CD8 T cell dysfunction in the setting of ACT.In situconfocal microscopy of color-coded cancer cells, tumor-specific CD8 and CD4 T cells, and antigen presenting cells (APC), combined with functional studies, revealed that the spatial positioning and interactions of CD8 and CD4 T cells, but not their numbers, dictates ACT efficacy and anti-tumor responses. We uncover a new role of antigen-specific CD4 T cells in addition to the known requirement for CD4 T cells during priming/activation of naïve CD8 T cells. CD4 T cells must co-engage with CD8 T cells and APC cross-presenting CD8-and CD4-tumor antigens during the effector phase, forming a three-cell-cluster (triad), to license CD8 T cell cytotoxicity and mediate cancer cell elimination. Triad formation transcriptionally and epigenetically reprogram CD8 T cells, prevent T cell dysfunction/exhaustion, and ultimately lead to the elimination of large established tumors and confer long-term protection from recurrence. When intratumoral triad formation was disrupted, adoptively transferred CD8 T cells could not be reprogrammed, and tumors progressed despite equal numbers of tumor-infiltrating CD8 and CD4 T cells. Strikingly, the formation of CD4 T cell::CD8 T cell::APC triads in tumors of patients with lung cancers treated with immune checkpoint blockade was associated with clinical responses, but not CD4::APC dyads or overall numbers of CD8 or CD4 T cells, demonstrating the importance of triads in non-ACT settings in humans. Our work uncovers intratumoral triads as a key requirement for anti-tumor immunity and a new role for CD4 T cells in CD8 T cell cytotoxicity and cancer cell eradication.
Investigation of swine caecal microbiomes in the northern region of Thailand
Authors: Eiamsam-ang Thanaporn , Tadee Pakpoom , Buddhasiri Songphon , Chuammitri Phongsakorn , Kittiwan Nattinee , Pascoe Ben , Patchanee Prapas 
Published: July 2023

AbstractIntroductionThe northern region of Thailand serves as a crucial area for swine production, contributing to the global food supply. Previous studies have highlighted the presence of foodborne pathogens originating from swine farms in this region, posing a threat to both human and animal health.Gap statementMultiple swine pathogens have been studied at a species level, but the distribution and co-occurrence of pathogens in agricultural swine has not been well established.AimOur study employed the intestinal scraping technique to directly examine the microorganisms interacting with the swine host.MethodologyWe used shotgun metagenomic sequencing to analyse the caecal microbiomes of swine from five commercial farms in northern Thailand.ResultsSwine caecal microbiomes contained commensal bacteria such asBifidobacterium,Lactobacillus, andFaecalibacterium, which are associated with healthy physiology and feed utilisation. We also identified multiple pathogenic and opportunistic bacteria present in all samples, includingEscherichia coli,Clostridium botulinum,Staphylococcus aureus, and theCorynebacteriumgenus. From a One Health perspective, these species are important foodborne and opportunistic pathogens in both humans and agricultural animals. Antimicrobial resistance genes were also detected in all samples, specifically conferring resistance to tetracycline and aminoglycosides which have historically been used extensively in swine farming.ConclusionThe findings further support the need for improved sanitation standards in swine farms, and additional monitoring of agricultural animals and farm workers to reduce contamination and improved produce safety for human consumption.
Structural characterization of the Sel1-like repeat protein LceB fromLegionella pneumophila
Authors: Penner Tiffany V. , Lorente Cobo Neil , Patel Deepak T. , Patel Dhruvin H. , Savchenko Alexei , Brassinga Ann Karen C. , Prehna Gerd 
Published: July 2023

ABSTRACTLegionellaare freshwater Gram-negative bacteria that in their normal environment infect protozoa. However, this adaptation also allowsLegionellato infect human alveolar macrophages and cause pneumonia. Central toLegionellapathogenesis are more than 330 secreted effectors, of which there are 9 core effectors that are conserved in all pathogenic species. Despite their importance, the biochemical function of several core effectors remains unclear. To address this, we have taken a structural approach to characterize the core effector of unknown function LceB, or Lpg1356, fromLegionella pneumophila.Here we solve an X-ray crystal structure of LceB using an AlphaFold model for molecular replacement. The experimental structure shows that LceB adopts a Sel1-like repeat fold as predicted. However, the crystal structure captured multiple conformations of LceB all of which differed from the AlphaFold model. Comparison of the predicted model and the experimental models suggests that LceB is highly flexible in solution. Additionally, molecular analysis of LceB using its close structural homologues reveals sequence and structural motifs of known biochemical function. Specifically, LceB harbors a repeated KAAEQG motif that both stabilizes the Sel1-like repeat fold and is known to participate in protein-protein interactions with eukaryotic host proteins. We also observe that LceB forms several higher-order oligomers in solution. Overall, our results have revealed that LceB has conformational flexibility, self-associates, and contains a molecular surface for binding a target host-cell protein. Additionally, our data provides structural insights into the Sel1-like repeat family of proteins that remain poorly studied.
Large-scale deorphanization ofNematostella vectensisneuropeptide GPCRs supports the independent expansion of bilaterian and cnidarian peptidergic systems
Authors: Thiel Daniel , Yañez-Guerra Luis Alfonso , Kieswetter Amanda , Cole Alison G. , Temmerman Liesbet , Technau Ulrich , Jékely Gáspár 
Published: July 2023

AbstractNeuropeptides are ancient signaling molecules in animals but only few peptide receptors are known outside bilaterians. Cnidarians possess a large number of G protein-coupled receptors (GPCRs) – the most common receptors of bilaterian neuropeptides – but most of these remain orphan with no known ligands. We searched for neuropeptides in the sea anemoneNematostella vectensisand created a library of 64 peptides derived from 33 precursors. In a large-scale pharmacological screen with these peptides and 161N. vectensisGPCRs, we identified 31 receptors specifically activated by one of 14 peptides. Mapping GPCR and neuropeptide expression to single-cell sequencing data revealed how cnidarian tissues are extensively wired by multilayer peptidergic networks. Phylogenetic analysis identified no direct orthology to bilaterian peptidergic systems and supports the independent expansion of neuropeptide signaling in cnidarians from a few ancestral peptide-receptor pairs.
SH2 domain protein E (SHE) and ABL signaling regulate blood vessel size
Authors: Schumacher Jennifer A. , Wright Zoë A. , Florat Diandra Rufin , Anand Surendra K. , Dasyani Manish , Klimkaite Laurita , Bredemeier Nina O. , Gurung Suman , Koller Gretchen M. , Aguera Kalia N. , Chadwick Griffin P. , Johnson Riley D. , Davis George E. , Sumanas Saulius 
Published: July 2023

AbstractBlood vessels in different vascular beds vary in lumen diameter, which is essential for their function and fluid flow along the vascular network. Molecular mechanisms involved in the formation of a vascular lumen of appropriate size, or tubulogenesis, are still only partially understood.Src homology 2 domain containing E (She)protein was previously identified in a screen for proteins that interact with Abelson (Abl)-kinase. However, its biological role has remained unknown. Here we demonstrate that She and Abl signaling regulate vascular lumen size in zebrafish embryos and human endothelial cell culture. Zebrafishshemutants displayed increased endothelial cell number and enlarged lumen size of the dorsal aorta (DA) and defects in blood flow. Vascular endothelial specific overexpression ofsheresulted in a reduced diameter of the DA lumen, which correlated with the reduced arterial cell number and lower endothelial cell proliferation. Chemical inhibition of Abl signaling in zebrafish embryos caused a similar reduction in the DA diameter and alleviated theshemutant phenotype, suggesting that She acts as a negative regulator of Abl signaling. Enlargement of the DA lumen inshemutants correlated with an increased endothelial expression ofclaudin 5aand5b (cldn5a / cldn5b), which encode proteins enriched in tight junctions. Inhibition ofcldn5aexpression partially rescued the enlarged DA inshemutants, suggesting that She regulates DA lumen size, in part, by promotingcldn5aexpression. SHE knockdown in human endothelial umbilical vein cells resulted in a similar increase in the diameter of vascular tubes, and also increased phosphorylation of a known ABL downstream effector CRKL. These results argue that SHE functions as an evolutionarily conserved inhibitor of ABL signaling and regulates lumen size during vascular tubulogenesis.