bluuebunny/crossref_metadata_2025_split huggingface dataset:
Corynebacterium diphtheriaecauses keratinocyte-intrinsic ribotoxic stress and NLRP1 inflammasome activation in a model of cutaneous diphtheria
Authors: ROBINSON Kim S. , TOH Gee Ann , FIRDAUS Muhammad Jasrie , THAM Khek Chian , ROZARIO Pritisha , LIM Chrissie , TOH Ying Xiu , LAU Zhi Heng , BINDER Sophie Charlotte , MAYER Jacob , BONNARD Carine , SCHMIDT Florian I. , COMMON John E. A. , ZHONG Franklin L. 
Published: January 2023

ABSTRACTNLRP1 is an innate immune sensor protein that activates inflammasome-driven pyroptotic cell death. Recent work demonstrates that human NLRP1 has evolved to sense viral infections. Whether and how human NLRP1 responds to other infectious agents is unclear. Here, and in a companion manuscript, we report that human NLRP1, as an integral component of the ribotoxic stress response (RSR), is activated by bacterial exotoxins that target human ribosome elongation factors EEF1 and EEF2, including Diphtheria Toxin (DT) fromCorynebacterium diphtheriae, exotoxin A fromPseudomonas aeruginosaand sidI fromLegionella pneumophila. In human keratinocytes, DT activates RSR kinases ZAKα, p38 and JNKs, upregulates a set of signature RSR transcripts and triggers rapid NLRP1-dependent pyroptosis. Mechanistically, these processes require 1) DtxR-mediated de-repression of DT production in the bacteria, as well as 2) diphthamide synthesis and 3) ZAKα/p38-driven NLRP1 phosphorylation in the host. In 3D human skin cultures,Corynebacterium diphtheriae infection disrupts barrier function and induces IL-1 driven inflammation. Pharmacologic inhibition of p38 and ZAKα suppresses keratinocyte pyroptosis and rescues barrier integrity ofCorynebacterium diphtheriae-treated organotypic skin. In summary, these findings implicate RSR and the NLRP1 inflammasome in antibacterial innate immunity and might explain certain aspects of diphtheria pathogenesis.KEY POINTSEEF1/EEF2-targeting bacterial exotoxins activate the human NLRP1 inflammasome.DT+ve toxigenicCorynebacterium diphtheriaeinduces ZAKα-driven RSR and NLRP1-driven pyroptosis in human keratinocytes.Identification of transcripts that are induced by multiple RSR agents across multiple cell types.p38 and ZAKα inhibition rescues epidermal integrity by limiting pyroptosis in 3D skin mode of cutaneous diphtheria.
A controller-peripheral architecture and costly energy principle for learning
Authors: Luo Xiaoliang , Mok Robert M. , Roads Brett D. , Love Bradley C. 
Published: January 2023

AbstractComplex behavior is supported by the coordination of multiple brain regions. How do brain regions coordinate absent a homunculus? We propose coordination is achieved by a controller-peripheral architecture in which peripherals (e.g., the ventral visual stream) aim to supply needed inputs to their controllers (e.g., the hippocampus and prefrontal cortex) while expending minimal resources. We developed a formal model within this framework to address how multiple brain regions coordinate to support rapid learning from a few example images. The model captured how higher-level activity in the controller shaped lower-level visual representations, affecting their precision and sparsity in a manner that paralleled brain measures. In particular, the peripheral encoded visual information to the extent needed to support the smooth operation of the controller. Alternative models optimized by gradient descent irrespective of architectural constraints could not account for human behavior or brain responses, and, typical of standard deep learning approaches, were unstable trial-by-trial learners. While previous work offered accounts of specific faculties, such as perception, attention, and learning, the controller-peripheral approach is a step toward addressing next generation questions concerning how multiple faculties coordinate.
Discovering dynamic plant enzyme complexes in yeast for novel alkaloid pathway identification from a medicinal plant kratom
Authors: Wu Yinan , Liu Chang , Gong Franklin L. , Li Sijin 
Published: January 2023

AbstractDiscovering natural product biosynthetic pathways from medicinal plants is challenging and laborious, largely due to the complexity of the transcriptomics-driven pathway prediction process. Here we developed a novel approach that captures the protein-level connections between enzymes for pathway discovery with improved accuracy. We proved that heterologous protein-protein interaction screening in yeast enabled the efficient discovery of both dynamic plant enzyme complexes and the pathways they organize. This approach discovered complexes and pathways in the monoterpene indole alkaloid metabolism of a medicinal plant, kratom with high success rate. Screening using a strictosidine β-D-glucosidase (MsSGD1) against 19 medium-chain dehydrogenase/reductases (MsMDRs) identified five MsSGD1-MsMDR complexes. Three out of the five interacting MsMDRs were then proven functional, while the remaining 14 non-interacting candidates did not show obvious activities. The work discovered three branched pathways by combining transcriptomics, metabolomics, and heterologous PPI screening and demonstrated a new plant pathway discovery strategy.
Sequencing ofN6-methyl-deoxyadenosine at single-base resolution across the mammalian genome
Authors: Feng Xinran , Cui Xiaolong , Zhang Li-Sheng , Ye Chang , Wang Pingluan , Zhong Yuhao , Zheng Zhong , He Chuan 
Published: January 2023

SummaryWhile DNAN6-methyl-deoxyadenosine (6mA) is abundant in bacteria and protists, its presence and function in mammalian genomes have been less clear. We present Direct-Read 6mA sequencing (DR-6mA-seq), an antibody-independent method to measure 6mA at base-resolution with high sensitivity. DR-6mA-seq employs a unique mutation-based strategy to reveal 6mA sites as misincorporation signatures without any chemical or enzymatic modulation of 6mA. We validated DR-6mA-seq through successful mapping of the well-characterized G(6mA)TC motif in theE. coliDNA and identified 6mA sites in the mammalian mitochondrial DNA. As expected, when applying DR-6mA-seq to mammalian systems, we found that genomic DNA (gDNA) 6mA abundance is in general low in most mammalian tissues and cells; however, we did observe distinct gDNA 6mA sites in mouse testis and glioblastoma cells. DR-6mA-seq provides an enabling tool to detect 6mA at single-base resolution with high sensitivity for a comprehensive understanding of DNA 6mA in eukaryotes.
MultiCOVID: a multi modal Deep Learning approach for COVID-19 diagnosis
Authors: Hardy-Werbin Max , Maiques José Maria , Busto Marcos , Cirera Isabel , Aguirre Alfons , Garcia-Gisbert Nieves , Zuccarino Flavio , Carbullanca Santiago , Del Carpio Luis Alexander , Ramal Didac , Gayete Ángel , Martínez-Roldan Jordi , Marquez-Colome Albert , Bellosillo Beatriz , Gibert Joan 
Published: January 2023

AbstractThe rapid spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to a global overextension of healthcare. Both Chest X-rays (CXR) and blood test have been demonstrated to have predictive value on Coronavirus Disease 2019 (COVID-19) diagnosis on different prevalence scenarios. With the objective of improving and accelerating the diagnosis of COVID-19, a multi modal prediction algorithm (MultiCOVID) based on CXR and blood test was developed, to discriminate between COVID-19, Heart Failure (HF) and Non-Covid Pneumonia (NCP) and healthy (Control) patients. This retrospective single-center study includes CXR and blood test obtained between January 2017 and May 2020. Multi modal prediction models were generated using opensource DL algorithms. Performance of the MultiCOVID algorithm was compared with interpretations from five experienced thoracic radiologists on 300 random test images using the McNemar-Bowker test. A total of 8578 samples from 6123 patients (mean age 66 +/- 18 years of standard deviation, 3523 men) were evaluated across datasets. For the entire test set, the overall accuracy of MultiCOVID was 84%, with a mean AUC of 0.92 (0.89-0.94). For 300 random test images, overall accuracy of MultiCOVID was significantly higher (69.6%) compared with individual radiologists (range, 43.7%- 58.7%) and the consensus of all five radiologists (59.3%, P<.001). Overall, we have developed a multimodal deep learning algorithm, MultiCOVID, that discriminates among COVID-19, heart failure, non-covid pneumonia and healthy patients using both CXR and blood test with a significantly better performance than experienced thoracic radiologists.
Most clinical trials involving American children that violated FDAAA legal reporting requirements had not published outcomes in the scientific literature
Authors: Bruckner Till , Yerunkar Samruddhi , Basegmez Okan , Borana Ronak , Chavarría Belén , Velarde Mayra , DeVito Nicholas J. 
Published: January 2023

AbstractNon-publication, incomplete publication and excessively slow publication of clinical trial outcomes contribute to research waste and can harm patients. In this cohort study, we used publicClinicalTrials.govregistry records to identify 81 paediatric clinical trials in the United States that appear to have violated the FDA Amendments Act 2007 (FDAAA) reporting requirements. We then searched the literature for the outcomes of these 81 trials and contacted trial sponsors about the status of results.We found that only 22/81 trials (27.2%) had made their results public in a full-length peer-reviewed publication, and that only 8/81 (9.9%) trials had done so within one year of their primary completion date. Our findings highlight the need for US Food and Drug Administration and the National Institutes of Health to systematically monitor FDAAA compliance and enforce reporting requirements.
Traditional male circumcision and the risk for HIV transmission among men: a systematic review
Authors: Asa Gregorius Abanit , Fauk Nelsensius Klau , Ward Paul Russell 
Published: January 2023

AbstractIntroductionAlthough traditional male circumcision (TMC) is still practiced in a number of countries, and its healing process may have a high risk of HIV and other STIs transmission, there have been no published systematic reviews on TMC, HIV risk, and impacts on circumcised men and their families. The aim of this study is to synthesise evidence of how TMC practices contribute to HIV transmission among males and the impacts of HIV on themselves and their families.MethodsThe systematic search started with an initial search following the PICO (Population, Intervention, Comparison and Outcomes) framework. A systematic review was conducted to find literature using databases including PubMed, CINHAL, SCOPUS, ProQuest, Cochrane, and Medline. The search was limited to the English language, and with no year limit in order to capture as many articles as possible about circumcision, traditional male circumcision, HIV, and impact on men and their families. Critical appraisal tools developed by the Joanna Briggs Institute (JBI) for study design were used to assess the methodological quality of included studies.ResultA total of 18 studies were included: 11 were qualitative studies, 5 were quantitative studies, and 2 were mixed-method studies. All the studies included were conducted in areas where traditional male circumcision was performed (17 in Africa and 1 in Papua New Guinea). The findings of the review were categorized into themes namely TMC as a cultural practice, consequences of not being traditionally circumcised on men and their families, and TMC-related risk of HIV transmission. The review showed that TMC and HIV risk could bring significant and negative challenges for men and their families.ConclusionThe findings indicated the need for targeted health intervention programs and efforts to address psychological and social challenges in communities practicing TMC.Prospero Number RegistrationCRD42022357788.
Apoptosis recognition receptors regulate skin tissue repair in mice
Authors: Justynski Olivia , Bridges Kate , Krause Will , Forni Maria Fernanda , Phan Quan , Sandoval-Schaefer Teresa , Driskell Ryan , Miller-Jensen Kathryn , Horsley Valerie 
Published: January 2023

AbstractApoptosis and clearance of apoptotic cells via efferocytosis are evolutionarily conserved processes that drive tissue repair. However, the mechanisms by which recognition and clearance of apoptotic cells regulate repair are not fully understood. Here, we use single-cell RNA sequencing to provide a map of the cellular dynamics during early inflammation in mouse skin wounds. We find that apoptotic pathways and efferocytosis receptors are elevated in fibroblasts and immune cells, including resident Lyve1+macrophages, during inflammation. Interestingly, human diabetic foot wounds upregulate mRNAs for apoptotic genes and display increased and altered efferocytosis signaling via the receptor Axl. During early inflammation in mouse wounds, we detect upregulation of Axl in dendritic cells and fibroblasts via TLR3-independent mechanisms. Inhibition studiesin vivoin mice reveal that Axl signaling is required for wound repair but is dispensable for efferocytosis. By contrast, inhibition of another efferocytosis receptor, Timd4, in mouse wounds decreases efferocytosis and abrogates wound repair. These data highlight the distinct mechanisms by which apoptotic cell detection coordinates tissue repair and provides potential therapeutic targets for chronic wounds in diabetic patients.
Higher Angiotensin I Converting Enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer’s disease
Authors: Louise Reveret , Manon Leclerc , Vincent Emond , Andréanne Loiselle , Philippe Bourassa , Cyntia Tremblay , Bennett David A , Sébastien Hébert , Frédéric Calon 
Published: January 2023

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major cause of death in the elderly. Cognitive decline due to Alzheimer’s disease (AD) is frequent in the geriatric population disproportionately affected by the COVID-19 pandemic. Interestingly, central nervous system (CNS) manifestations have been reported in SARS-CoV-2-infected patients. In this study, we investigated the levels of Angiotensin I Converting Enzyme 2 (ACE2), the main entry receptor of SARS-COV-2 in cells, inpostmortemparietal cortex samples from two independent AD cohorts, totalling 142 persons. Higher concentrations of ACE2 protein and mRNA were found in individuals with a neuropathological diagnosis of AD compared to age-matched healthy control subjects. Brain levels of soluble ACE2 were inversely associated with cognitive scores (p = 0.02), markers of pericytes (PDGFRβ, p=0.02 and ANPEP, p = 0.007) and caveolin1 (p = 0.03), but positively correlated with soluble amyloid-β peptides (Aβ) concentrations (p = 0.01) and insoluble phospho- tau (S396/404, p = 0.002). No significant differences in ACE2 were observed in the 3xTgAD mouse model of tau and Aβ neuropathology. Results from immunofluorescence and Western blots showed that ACE2 protein is mainly localized in neurons in the human brain but predominantly in microvessels in the mouse brain. The present data show that an AD diagnosis is associated with higher levels of soluble ACE2 in the human brain, which might contribute to a higher risk of CNS SARS-CoV-2 infection.
Peripheral extracellular vesicle-derived miR-150-3p exacerbates acute kidney injury following acute pancreatitis by promoting ferroptosis through FTH1 signaling
Authors: Cui Ji-tao , Wang Guo-sheng , Yan Chang-sheng , Cheng Long , Guo Xiao-yu , Huang Zi-jian , Wang Zi-xin , Tang De-sheng , Ji Liang , Wang Gang 
Published: January 2023

ABSTRACTAcute kidney injury following acute pancreatitis (AP-AKI) is one of the most fatal complications caused by acute pancreatitis (AP). Extracellular vesicles (EVs) in circulating blood are believed to be crucial to the process of AP-AKI, but the mechanisms are still unclear. In this study, we first constructed an AP-AKI rat model by retrograde sodium taurocholate through the pancreatic duct and then injected circulating blood-derived EVs into AP-AKI rats. Measurements of peripheral blood creatinine and urea nitrogen levels showed that EVs could add to kidney injury in AP-AKI rats. By analyzing the levels of renal Fe2+, cyclooxygenase 2 (COX-2), malondialdehyde (MDA), and glutathione peroxidase 4 (GPX4), we also found that extracted EVs could aggravate renal tubular ferroptosis in AP-AKI rats. Using high-throughput sequencing, we screened for high expression of EV miR-150-3P in AP-AKI patients. In vitro, we found that overexpressed miR-150-3P can influence MDA, Fe2+, lipid peroxide and GSH levels in HK-2 cells and ultimately aggravate ferroptosis. Next, through a dual-luciferase assay, we confirmed that miR-150-3p could exacerbate ferroptosis by directly targeting ferritin heavy chain 1 (FTH1). Finally, in AP-AKI rats, we again demonstrated that overexpression of miR-150-3P exacerbated renal ferroptosis through the miR-150-3P/FTH1 axis. Collectively, these findings provide new avenues to explore the mechanisms of the onset and exacerbation of AP-AKI.
m6A methylated long noncoding RNA regulates proinflammatory response emerging as novel target for IBD
Authors: Olazagoitia-Garmendia Ane , Rojas-Márquez Henar , Sebastian-delaCruz Maialen , Ochoa Anne , Mendoza-Gomez Luis Manuel , Madrigal Alain Huerta , Santin Izortze , Castellanos-Rubio Ainara 
Published: January 2023

AbstractCytokine mediated sustained inflammation increases the risk to develop different complex chronic inflammatory diseases, such as inflammatory bowel disease (IBD). Recent studies highlighted the involvement of inflammation associated gene variants in m6A methylation. Moreover, long noncoding RNAs (lncRNAs) participate in the pathogenesis of inflammatory disorders and their function can be influenced by differential methylation. Here we describe the functional implication ofLOC339803lncRNA in the development of IBD. We found that allele-specific m6A methylation affects YTHDC1 mediated protein binding affinity.LOC339803-YTHDC1 interaction dictates chromatin localization ofLOC339803ultimately inducingIL1Band contributing to the development of intestinal inflammation. Our findings were confirmed using human intestinal biopsy samples from IBD and controls.Overall, our results supportLOC339803lncRNA as an important mediator of intestinal inflammation, presenting this lncRNA as a potential novel therapeutic target for the treatment of IBD.
Physicochemical properties of the vacuolar membrane and cellular factors determine formation of vacuolar invaginations
Authors: Kimura Yoko , Tsuji Takuma , Shimizu Yosuke , Watanabe Yuki , Kimura Masafumi , Fujimoto Toyoshi , Higuchi Miyuki 
Published: January 2023

AbstractVacuoles change their morphology in response to stress. In yeast exposed to chronically high temperatures, vacuolar membranes get deformed and invaginations are formed. We show that phase-separation of vacuolar membrane occurred after heat stress leading to the formation of the invagination. In addition, Hfl1, a vacuolar membrane-localized Atg8-binding protein, was found to suppress the excess vacuolar invaginations after heat stress. At that time, Hfl1 formed foci at the neck of the invaginations in wild-type cells, whereas it was efficiently degraded in the vacuole in theatg8Δ mutant. Genetic analysis showed that the endosomal sorting complex required for transport (ESCRT) machinery was necessary to form the invaginations irrespective of Atg8 or Hfl1. In contrast, a combined mutation with the vacuole BAR domain protein Ivy1 led to vacuoles inhfl1Δivy1Δ andatg8Δivy1Δ mutants having constitutively invaginated structures; moreover, these mutants showed stress-sensitive phenotypes. Our findings suggest that vacuolar invaginations result from the combination of changes in the physiochemical properties of the vacuolar membrane and other cellular factors.Summary statementVacuolar invaginations occur through a combination of the changes of physiochemical properties of the vacuolar membrane and other cellular factors in yeast. Particularly, Hfl1 suppresses the excess invaginations.
Maternal prenatal distress exposure negatively associates with the stability of neonatal frontoparietal network
Authors: Tuulari Jetro J. , Rajasilta Olli , Cabral Joana , Kringelbach Morten L. , Karlsson Linnea , Karlsson Hasse 
Published: January 2023

AbstractMaternal prenatal distress (PD), frequently defined asin uteroprenatal stress exposure (PSE) to the developing fetus, influences the developing brain and numerous associations between PSE and brain structure have been described both in neonates and in older children. Previous studies addressing PSE-linked alterations in neonates’ brain activity have focused on connectivity analyses from predefined seed regions, but the effects of PSE at the level of distributed functional networks remains unclear. In this study, we investigated the impact of prenatal distress on the spatial and temporal properties of functional networks detected in functional MRI data from 20 naturally sleeping, term-born (age 25.85 ± 7.72 days, 11 males), healthy neonates. First, we performed group level independent component analysis (GICA) to evaluate an association between PD and the spatial configuration of the functional networks. Second, we search for an association with PD at the level of the stability of functional networks over time using leading eigenvector dynamics analysis (LEiDA). No statistically significant associations were detected at the spatial level for the GICA-derived networks. However, at the dynamic level, LEiDA revealed that maternal PD significantly decreased the stability of a frontoparietal network. These results imply that maternal PD may influence the stability of frontoparietal connections in neonatal brain network dynamics and adds to the cumulating evidence that frontal areas are especially sensitive to PSE.
RNA sequencing identifies lung cancer lineage and facilitates drug repositioning
Authors: Zeng Longjin , Zhang Longyao , Li Lingchen , Liao Xingyun , Yin Chenrui , Zhang Lincheng , Chen Xiewan , Sun Jianguo 
Published: January 2023

AbstractBreakthrough therapies recently improve survival in lung adenocarcinoma (LUAD), yet we still lack a paradigm to support prospective confirmation. To classify three clusters including bronchioid, neuroendocrine, and squamoid, the non-negative matrix factorization (NMF) algorithm was first performed at The Cancer Genome Atlas (TCGA), Clinical Proteomic Tumor Analysis Consortium (CPTAC), Gene Expression Omnibus (GEO) and preclinical models. In terms of prognostic value, the squamoid cluster is of poor prognostic factor. The neuroendocrine cluster is characterized by STK11 mutations and 14q13.3 amplifications. From an immunological perspective, the bronchioid cluster is considered an immune activation because of the highest immune-related genetic perturbation. Further analysis is the estimation of the relative cell abundance of the tumor microenvironment (TME), specific cell types can be reflected among three clusters. Meanwhile, the higher portion of immune cell infiltration belonged to bronchioid and squamous, not neuroendocrine cluster. Taken together, the neuroendocrine cluster show resistance to PD-L1 blockade. While pemetrexed or platinum-based therapies are suitable for bronchioid and squamoid clusters, respectively. Our emphasis was on phenotype-based action to explore compounds. Large-scale drug sensitivity databases including ConnectivityMap (CMAP), Cancer Cell Line Encyclopedia (CCLE), and Genomics of Drug Sensitivity in Cancer (GDSC) were analyzed. MEK inhibitors exhibited resistance in the bronchioid, while sensitive to the squamous cluster. Dinaciclib and alvocidib showed similar activity and sensitivity in the neuroendocrine cluster. A lineage factor named KLF5 recognized by two networks could be suppressed by verteporfin. This work adds to the knowledge of the lung cancer lineage and facilitates drug repositioning.