bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preventing strokes and other vascular events
Authors: Harwood Rowan H. , Huwez Farhad Umer , Guyler Paul , Alam Sajid , Gaynor Catherine 
Published: March 2023

Abstract
This chapter describes how to prevent strokes and other vascular events. It explains how preventive measures should be tailored to the patient. Stroke survivors are at high risk of another stroke or other vascular events such as heart attacks. Important risk factors include blood pressure, cholesterol, smoking, blood sugar, atrial fibrillation and carotid stenosis. The chapter explores ways to reduce risk through lifestyle, general vascular prevention and stroke-specific interventions.
The SAMI–Fornax Dwarfs Survey – III. Evolution of [α/Fe] in dwarfs, from Galaxy Clusters to the Local Group
Authors: Romero-Gómez J , Peletier Reynier F , Aguerri J A L , Mieske Steffen , Scott Nicholas , Bland-Hawthorn Joss , Bryant Julia J , Croom Scott M , Eftekhari F Sara , Falcón-Barroso Jesús , Hilker Michael , van de Ven Glenn , Venhola Aku 
Published: March 2023

ABSTRACT
Using very deep, high spectral resolution data from the SAMI Integral Field Spectrograph, we study the stellar population properties of a sample of dwarf galaxies in the Fornax Cluster, down to a stellar mass of 107 M⊙, which has never been done outside the Local Group. We use full spectral fitting to obtain stellar population parameters. Adding massive galaxies from the ATLAS3D project, which we re-analysed, and the satellite galaxies of the Milky Way, we obtained a galaxy sample that covers the stellar mass range 104–1012 M⊙. Using this large range, we find that the mass–metallicity relation is not linear. We also find that the [α/Fe]-stellar mass relation of the full sample shows a U-shape, with a minimum in [α/Fe] for masses between 109 and 1010 M⊙. The relation between [α/Fe] and stellar mass can be understood in the following way: when the faintest galaxies enter the cluster environment, a rapid burst of star formation is induced, after which the gas content is blown away by various quenching mechanisms. This fast star formation causes high [α/Fe] values, like in the Galactic halo. More massive galaxies will manage to keep their gas longer and form several bursts of star formation, with lower [α/Fe] as a result. For massive galaxies, stellar populations are regulated by internal processes, leading to [α/Fe] increasing with mass. We confirm this model by showing that [α/Fe] correlates with clustercentric distance in three nearby clusters and also in the halo of the Milky Way.
Membranihabitans maritimus sp. nov., a marine bacterium isolated from deep seawater
Authors: Guo Li-Li , Yi Li-Dong , Wang Ming-Lei , Qian Yu-Rong , Xu Xue-Wei , Fu Ge-Yi 
Published: March 2023

A Gram-stain-negative, non-motile, rod-shaped bacterial strain, designated C281T, was isolated from seawater sampled at the Marshallese seamount chain. Results of 16S rRNA gene analysis revealed that strain C281T was most closely related to Membranihabitans marinus CZ-AZ5T with 92.7 % sequence similarity. Phylogenetic analysis indicated that the new isolate represented a novel species by forming a distinctive lineage within the family

Saprospiraceae

. The DNA G+C content of strain C281T was 38.4 mol%. The genome sizes of strain C281T and the reference strain

M. marinus

CZ-AZ5T were 5 962 917 and 5 395 999 bp, respectively. The average nucleotide identity and in silico DNA–DNA hybridization values between strains C281T and

M. marinus

CZ-AZ5T were found to be low (69.3 and 17.6 %, respectively). Different functional genes were found in the genome of strain C281T, such as CZC CBA, polysaccharide utilization loci and linear azol(in)e-containing peptide cluster coding genes. The NaCl range for growth was 0.5–15.0 %. Positive results were obtained for hydrolysis of Tween 60 and urease. MK-7 was the sole respiratory quinone. The major fatty acids were C16 : 1
ω6c and/or C16 : 1
ω7c, iso-C15 : 0 and iso-C15 : 1 F. The major polar lipids of strain C281T were phosphatidylethanolamine, phosphatidylglycerol, two unidentified lipids and five unidentified glycolipids. On the basis of its taxonomic characteristics, the isolate represents a novel species of the genus Membranihabitans, for which the name Membranihabitans maritimus sp. nov. (type strain C281T=KCTC 92171T=MCCC M27001T) is proposed.
Genetic and environmental contributions to ancestry differences in gene expression in the human brain
Authors: Benjamin Kynon J.M. , Chen Qiang , Eagles Nicholas J. , Huuki-Myers Louise A. , Collado-Torres Leonardo , Stolz Joshua M. , Pertea Geo , Shin Joo Heon , Paquola Apuã C.M. , Hyde Thomas M. , Kleinman Joel E. , Jaffe Andrew E. , Han Shizhong , Weinberger Daniel R. 
Published: March 2023

AbstractAncestral differences in genomic variation are determining factors in gene regulation; however, most gene expression studies have been limited to European ancestry samples or adjusted for ancestry to identify ancestry-independent associations. We instead examined the impact of genetic ancestry on gene expression and DNA methylation (DNAm) in admixed African/Black American neurotypical individuals to untangle effects of genetic and environmental factors. Ancestry-associated differentially expressed genes (DEGs), transcripts, and gene networks, while notably not implicating neurons, are enriched for genes related to immune response and vascular tissue and explain up to 26% of heritability for ischemic stroke, 27% of heritability for Parkinson’s disease, and 30% of heritability for Alzhemier’s disease. Ancestry-associated DEGs also show general enrichment for heritability of diverse immune-related traits but depletion for psychiatric-related traits. The cell-type enrichments and direction of effects vary by brain region. These DEGs are less evolutionarily constrained and are largely explained by genetic variations; roughly 15% are predicted by DNAm variation implicating environmental exposures. We also compared Black and White Americans, confirming most of these ancestry-associated DEGs. Our results highlight how environment and genetic background affect genetic ancestry differences in gene expression in the human brain and affect risk for brain illness.SummaryWe examine the impact of genetic ancestry on gene expression and DNA methylation of admixed African/Black Americans, highlighting how genetic and environmental background affect risk for brain illness.
Percutaneous Coronary Intervention vs Coronary Artery Bypass Graft In- hospital Outcomes in Diabetes
Authors: Luo Qianyun , Li Renxi 
Published: March 2023

AbstractBackgroundDespite extensive research on coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI) outcome differences, current literature lacks representation of short-term in-hospital outcomes in patients with existing medical conditions. This study aimed to compare perioperative outcomes of these two revascularization procedures in diabetes mellitus (DM) patients.MethodsThe National Inpatient Sample (NIS) was used to extract patients who received CABG or PCI surgery between the last quarter of 2015 to 2020 based on ICD10-PCS. Patients of age<40 were excluded for congenital heart defects. Preoperative differences were noted and adjusted using multivariable logistic regression. Adjusted odds ratios (aOR) with 95% confidence intervals (CI) were estimated between PCI and CAGB groups.ResultsA total number of 90,662 CABG and 173,725 PCI cases of patients with DM were identified in NIS. Compared to CABG, patients who underwent PCI had increased mortality (2.75% vs 2.00%, aOR 1.266, p<0.0001), myocardial infarction (1.5% vs 1.17%, aOR 1.223, p<0.0001), and were less likely to experience respiratory events (0.38% vs 6.33%, aOR 0.055, p<0.0001), stroke (0.03% vs 0.06%, aOR 0.385, p<0.0001), acute kidney injury (20.37% vs 25.37%, aOR 0.727, p<0.0001), sepsis (0.01% vs 0.05%, aOR 0.172, p<0.0001), shock (0.11% vs 0.74%, aOR 0.139, p<0.0001).ConclusionsThe NIS database collects enormous records from nationwide providers, offering great statistical power. PCI was associated with a markedly higher in-hospital mortality rate but a lower morbidity rate in patients with DM as compared to CABG. Therefore, physicians should weigh both mortality and morbidity when considering surgical treatment to DM patients.
IL-21/23 axis modulates inflammatory cytokines and RANKL expression in RA CD4+T cells via p-Akt signaling
Authors: Bhattacharya Gargee , Sengupta Soumya , Jha Rohila , Shaw Shubham K , Jogdand Gajendra M , Barik Prakash K , Padhan Prasanta , Parida Jyoti R , Devadas Satish 
Published: March 2023

AbstractThe role of CD4+T cells specifically, Th17 has been well documented in RA pathogenesis. Here we focus on the critical role of cytokines IL-21 and IL-23 in facilitating the aberrant status of RA Th17-like cells and report their significant contribution(s) in modulating the expression of inflammatory cytokines and RANKL. Neutralizing IL-21 or IL- 23 (p19 and p40) or both, resulted in downregulation of the cytokines, TNF-α, IFN-γ and IL- 17 and RANKL expression in RA CD4+T cells. Ourex vivohuman Th17 studies also validated the above findings and we hypothesize a common pathway responsible for regulation of inflammatory cytokines and RANKL expression. Subsequent dissection of the signalling pathway found p-Akt1 as the key phosphoprotein downstream of both IL-21 and IL-23, capable of augmenting inflammatory cytokines and RANKL production. Altogether, these findings identify IL-21/23 axis in RA CD4+T cells as a key regulator dictating two critical processes i.e. exaggerated inflammation and higher osteoclastogenesis and provide critical targets in their downstream signalling for therapeutic approaches.
Splicing accuracy varies across human introns, tissues and age
Authors: García-Ruiz S , Zhang D , Gustavsson E K , Rocamora-Perez G , Grant-Peters M , Fairbrother-Browne A , Reynolds R H , Brenton J W , Gil-Martínez A L , Chen Z , Rio D C , Botia J A , Guelfi S , Collado-Torres L , Ryten M 
Published: March 2023

AbstractAlternative splicing impacts most multi-exonic human genes. Inaccuracies during this process may have an important role in ageing and disease. Here, we investigated mis-splicing using RNA-sequencing data from ~14K control samples and 42 human body sites, focusing on split reads partially mapping to known transcripts in annotation. We show that mis-splicing occurs at different rates across introns and tissues and that these splicing inaccuracies are primarily affected by the abundance of core components of the spliceosome assembly and its regulators. Using publicly available data on short-hairpin RNA-knockdowns of numerous spliceosomal components and related regulators, we found support for the importance of RNA-binding proteins in mis-splicing. We also demonstrated that age is positively correlated with mis-splicing, and it affects genes implicated in neurodegenerative diseases. This in-depth characterisation of mis-splicing can have important implications for our understanding of the role of splicing inaccuracies in human disease and the interpretation of long-read RNA-sequencing data.
TNF-NFkB-p53 axis restrictsin vivosurvival of hPSC-derived dopamine neuron
Authors: Kim Tae Wan , Koo So Yeon , Riessland Markus , Cho Hyunwoo , Chaudhry Fayzan , Kolisnyk Benjamin , Russo Marco Vincenzo , Saurat Nathalie , Mehta Sanjoy , Garippa Ralph , Betel Doron , Studer Lorenz 
Published: March 2023

AbstractOngoing, first-in-human clinical trials illustrate the feasibility and translational potential of human pluripotent stem cell (hPSC)-based cell therapies in Parkinson’s disease (PD). However, a major unresolved challenge in the field is the extensive cell death following transplantation with <10% of grafted dopamine neurons surviving. Here, we performed a pooled CRISPR/Cas9 screen to enhance survival of postmitotic dopamine neuronsin vivo. We identified p53-mediated apoptotic cell death as major contributor to dopamine neuron loss and uncovered a causal link of TNFa-NFκB signaling in limiting cell survival. As a translationally applicable strategy to purify postmitotic dopamine neurons, we performed a cell surface marker screen that enabled purification without the need for genetic reporters. Combining cell sorting with adalimumab pretreatment, a clinically approved and widely used TNFa inhibitor, enabled efficient engraftment of postmitotic dopamine neurons leading to extensive re-innervation and functional recovery in a preclinical PD mouse model. Thus, transient TNFa inhibition presents a clinically relevant strategy to enhance survival and enable engraftment of postmitotic human PSC-derived dopamine neurons in PD.HighlightsIn vivoCRISPR-Cas9 screen identifies p53 limiting survival of grafted human dopamine neurons.TNFα-NFκB pathway mediates p53-dependent human dopamine neuron deathCell surface marker screen to enrich human dopamine neurons for translational use.FDA approved TNF-alpha inhibitor rescuesin vivodopamine neuron survival within vivofunction.
Prevalence of Slam-dependent hemophores in Gram-negative bacteria
Authors: Shin Hyejin Esther , Pan Chuxi , Curran David M. , Bateman Thomas J. , Chong Derrick HY , Ng Dixon , Shah Megha , Moraes Trevor F. 
Published: March 2023

AbstractIron acquisition systems are crucial for pathogen growth and survival in iron-limiting host environments. To overcome nutritional immunity, bacterial pathogens evolved to use diverse mechanisms to acquire iron. Here, we examined a heme acquisition system driven by hemophores called HphAs from several Gram-negative bacteria. Structural determination of HphAs revealed a N-terminal clamp-like domain that binds heme and a C-terminal eight-stranded β-barrel domain that shares the same architecture as the Slam-dependent Neisserial surface lipoproteins. The structure of these HphAs is strikingly similar to a novel hemophore discovered by Latham et al. (2019), named hemophilin1. The genetic organization of HphAs consist of genes encoding a Slam homolog and a TonB-dependent receptor (TBDR). We investigated the Slam-HphA system in the native organism or the reconstituted system inE. colicells and found that the efficient secretion of HphA is dependent on Slam. The TBDR also played an important role for heme uptake and conferred specificity for its cognate HphA. Furthermore, bioinformatic analysis of HphA homologs revealed that HphAs are conserved in the alpha, beta, and gammaproteobacteria Together, these results show that HphA presents a new class of hemophores in Gram-negative bacteria and further expands the role of Slams in transporting soluble proteins supporting it role as a type 11 secretion system.
Novel insight into the etiology of ischemic stroke gained by integrative transcriptome-wide association study
Authors: Jung Junghyun , Lu Zeyun , de Smith Adam , Mancuso Nicholas 
Published: March 2023

AbstractStroke, characterized by sudden neurological deficits, is the second leading cause of death worldwide. Although genome-wide association studies (GWAS) have successfully identified many genomic regions associated with ischemic stroke (IS), the genes underlying risk and their regulatory mechanisms remain elusive. Here, we integrate a large-scale GWAS (N=1,296,908) for IS together with mRNA, splicing, enhancer RNA (eRNA) and protein expression data (N=11,588) from 50 tissues. We identify 136 genes/eRNA/proteins associated with IS risk across 54 independent genomic regions and find IS risk is most enriched for eQTLs in arterial and brain-related tissues. Focusing on IS-relevant tissues, we prioritize 9 genes/proteins using probabilistic fine-mapping TWAS analyses. In addition, we discover that blood cell traits, particularly reticulocyte cells, have shared genetic contributions with IS using TWAS-based pheWAS and genetic correlation analysis. Lastly, we integrate our findings with a large-scale pharmacological database and identify a secondary bile acid, deoxycholic acid, as a potential therapeutic component. Our work highlights IS risk genes/splicing-sites/enhancer activity/proteins with their phenotypic consequences using relevant tissues as well as identify potential therapeutic candidates for IS.
Impact of Case and Control Selection on Training AI Screening of Cardiac Amyloidosis
Authors: Vrudhula Amey , Stern Lily , Cheng Paul C , Ricchiuto Piero , Daluwatte Chathuri , Witteles Ronald , Patel Jignesh , Ouyang David 
Published: March 2023

AbstractBackgroundRecent studies suggest that cardiac amyloidosis (CA) is significantly underdiagnosed. For rare diseases like CA, the optimal selection of cases and controls for artificial intelligence (AI) model training is unknown and can significantly impact model performance.ObjectivesThis study evaluates the performance of ECG waveform-based AI models for CA screening and assesses impact of different criteria for defining cases and controls.MethodsModels were trained using different criteria for defining cases and controls including amyloidosis by ICD 9/10 code, cardiac amyloidosis, patients seen in CA clinic). The models were then tested on test cohorts with identical selection criteria as well as population-prevalence cohorts.ResultsIn matched held out test datasets, different model AUCs ranged from 0.660 to 0.898. However, these same algorithms exhibited variable generalizability when tested on a population cohort, with AUCs dropping to 0.467 to 0.880. More stringent case definitions during training result in higher AUCs on the similarly constructed test cohort; however representative population controls matched for age and sex resulted in the best population screening performance.ConclusionsAUC in isolation is insufficient to evaluate the performance of a deep learning algorithm, and the evaluation in the most clinically meaningful population is key. Models designed for disease screening are best with matched population controls and performed similarly irrespective of case definitions.
InCampylobacter jejunia new type of chaperone receives hemebfrom ferrochelatase
Authors: Beas Jordi Zamarreño , Videira Marco A.M. , Karavaeva Val , Lourenço Frederico S. , Almeida Mafalda R. , Sousa Filipa , Saraiva Lígia M. 
Published: March 2023

AbstractIntracellular heme formation and trafficking are fundamental processes in living organisms. Three biogenesis pathways are used by bacteria and archaea to produce iron protoporphyrin IX (hemeb) that diverge after the formation of the common intermediate uroporphyrinogen III (uro’gen III). In this work, we identify and provide a detailed characterization of the enzymes involved in the transformation of uro’gen III into heme. We show that in this organism operates the protoporphyrin-dependent pathway (PPD pathway), in which the last reaction is the incorporation of ferrous iron into the porphyrin ring by the ferrochelatase enzyme. In general, following this final reaction, little is known about how the formed hemebreaches the target proteins. In particular, the chaperons that are thought to be required to traffic heme for incorporation into hemeproteins to avoid the cytotoxicity associated to free heme, remain largely unidentified. We identified inC. jejunia chaperon-like protein, named CgdH2, that binds heme with a dissociation constant of 4.9 ± 1.0 µM, a binding that is impaired upon mutation of residues histidine 45 and 133. We show thatC. jejuniCgdH2 establishes protein-protein interactions with ferrochelatase, which should enable for the observed transfer of heme from ferrochelatase to CgdH2. Phylogenetic analysis revealed thatC. jejuniCgdH2 is evolutionarily distinct from the currently known chaperones. Therefore, CgdH2 is a novel chaperone and the first protein identified as an acceptor of the intracellularly formed heme, thus enlarging our understanding of bacterial heme homeostasis.
Integrated spatiotemporal transcriptomic resolution of embryonic palate osteogenesis
Authors: Piña Jeremie Oliver , Raju Resmi , Roth Daniela M. , Chattaraj Parna , Kidwai Fahad , Faucz Fabio R. , Iben James , Mitra Apratim , Campbell Kiersten , Fridell Gus , Esnault Caroline , Dale Ryan K. , D’Souza Rena N. 
Published: March 2023

ABSTRACTThe differentiation of osteoblasts and the subsequent formation of bone marks an important terminal phase in palate formation that leads to the separation of the oral and nasal cavities. While the developmental events that precede palatal osteogenesis are well explored, major gaps remain in our understanding of the molecular mechanisms that lead to the bony union of fusing palatal shelves. Herein, the timeline of osteogenic transcriptional programming is unveiled in the embryonic palate by way of integrated bulk, single-cell, and spatially resolved RNA-seq analyses. We define spatially restricted expression patterns of key marker genes, both regulatory and structural, that are differentially expressed during palatal fusion, including the identification of several novel genes (Deup1, Dynlrb2, Lrrc23) spatially restricted in expression to the palate, providing a relevant framework for future studies that identify new candidate genes for cleft palate anomalies in humans as well as the timing of mammalian embryonic palatal osteogenesis.
Induction of mitophagy reverts age-associated decline of the hematopoietic and immune systems
Authors: Girotra Mukul , Chiang Yi-Hsuan , Charmoy Melanie , Ginefra Pierpaolo , Schyrr Frederica , Franco Fabien , Ho Ping-Chih , Naveiras Olaia , Auwerx Johan , Held Werner , Vannini Nicola 
Published: March 2023

ABSTRACTAging compromises hematopoietic and immune system functions, making elderly individuals especially susceptible to hematopoietic failure, infections and tumor development and thus representing an important medical target for a broad range of diseases. During aging, hematopoietic stem cells (HSCs) lose their blood reconstitution capability and commit preferentially toward myeloid lineage (myeloid-bias). These processes are accompanied by an aberrant accumulation of mitochondria in HSCs. The administration of the mitophagy-inducer Urolithin-A re-establishes the correct mitochondrial homeostasis in HSCs and completely restores the blood reconstitution capability of “old” HSCs. Moreover, Urolithin-A supplemented food restores lymphoid compartments, boosts HSCs function and improves the immune response to viral infection in old mice. Altogether our results demonstrate that targeting mitophagy reverts aging phenotype in the hematopoietic and immune system.