bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alpha-toxin elicited CX3CL1-release via ADAM10 inStaphylococcus aureuspneumonia impairs bactericidal function of human monocytes
Authors: Shambat Srikanth Mairpady , Chen Puran , Barilla Rocky M. , Huemer Markus , Snäll Johanna , Welin Amanda , Cohen Taylor S. , Takahashi Virginia , Berry Samuel B. , Gómez-Mejia Alejandro , Schweizer Tiziano A. , Cunoosamy Danen M , Cajander Sara , Lourda Magda , Özenci Volkan , Maggio Ewerton Marques , Schüpbach Reto A. , Strålin Kristoffer , Zinkernagel Annelies S. , Norrby-Teglund Anna , Svensson Mattias 
Published: September 2023

ABSTRACTStaphylococcus aureusis an important human pathogen causing severe invasive infections. Pathogenesis is attributed to a wide array of virulence factors, including several potent exotoxins such as the pore-forming alpha-toxin. In this study, we found that patients withS. aureusrespiratory tract infections had elevated CX3CL1 levels in airway fluid and plasma. Using humanized organotypic lung models, we observed that stimulation of lung epithelium with alpha-toxin induce an intensified CX3CL1 expression apically in the epithelium as well as the release of CX3CL1. Blocking alpha-toxin or ADAM10 activity in organotypic lung using an alpha-toxin-blocking antibody or a specific ADAM-10 inhibitor confirmed their role in modulating CX3CL1 cleavage and release. Analyses of CD14+human monocytes in combination with a CX3CR1 inhibitor revealed that alpha-toxin-mediated CX3CL1 release induce CX3CL1-dependent chemotaxis. In line with these data, lung tissue from patients withS. aureusrespiratory tract infection showed elevated CX3CL1 and CD14 staining as compared to tissue from patients with non-infectious lung diseases. Functional studies of monocytes showed that CX3CL1 released by lung models resulted in upregulated CD83 and downregulated CD86, as well as impaired killing of phagocytosedS. aureus. Furthermore, stimulation of monocytes with soluble CX3CL1 hampered their reactive-oxygen and nitric-oxide production. Taken together, our data show thatS. aureustriggers the release of lung epithelial CX3CL1; a process found to be dependent on the alpha-toxin’s effect on ADAM10 mediating cytotoxicity and resulting in impaired monocyte phagocytic killing. Hence, we identify an immunomodulatory effect of alpha-toxin involving the CX3CL1-ADAM10 axis extending beyond the cytolysis function.
Development of peptides for targeting cell ablation agents concurrently to the Sertoli and Leydig cell populations of the testes: an approach to non-surgical sterilization
Authors: Fraser Barbara , Wilkins Alex , Whiting Sara , Liang Mingtao , Rebourcet Diane , Nixon Brett , Aitken R. John 
Published: September 2023

AbstractThe surgical sterilization of cats and dogs has been used to prevent their unwanted breeding for decades, but this is an expensive and invasive procedure, and often impractical in wider contexts, for example the control of feral populations. A sterilization agent that could be administered in a single injection would not only eliminate the risks imposed by surgery but also be a much more cost-effective solution to this worldwide problem. In this study, we sought to develop a targeting peptide that would selectively bind to Leydig cells of the testes. Subsequently, after covalently attaching a cell ablation agent, Auristatin, to this peptide we aimed to apply this conjugated product (LH2Auristatin) to adult male micein vivo, both alone and together with a previously developed Sertoli cell targeting peptide (FSH2Menadione). The application of LH2Auristatin alone resulted in an increase in DNA damage, reduced mean testes weights and mean seminiferous tubule size, along with extensive germ cell apoptosis and a reduction in litter sizes. Together with FSH2Menadione there was also an increase in embryo resorptions. These promising results were observed in around a third of all treated animals. Given this variability we discuss how these reagents might be adjusted in order to increase target cell ablation and improve their efficacy as sterilization agents.
casmini-tool: a comprehensive database for efficient and specific guide RNA design using dCasMINI
Authors: Lopp Spencer , Borrman Tyler , Jha Nishant , Silvis Melanie , Swan Ryan , Yang Xiao , Alvarez Gabriella , Klappenbach Courtney , Liu Yanxia , Hart Daniel O. , Qi Lei S. , Daley Timothy P. , Yeo Robin W. 
Published: September 2023

AbstractThe dCasMINI protein is a hypercompact, nuclease-inactivated CRISPR-Cas system engineered for transcriptional modulation and epigenetic editing [Xu et al., 2021]. The small size of dCas-MINI (529 amino acids), less than half the size of comparable Cas9 molecules, makes it ideal for AAV-based therapies which are frequently limited by AAV’s small cargo capacity. Unlike Cas9 or Cas12a, there are no available computational tools for designing dCasMINI guides. To facilitate and accelerate the development of dCasMINI-based applications, we synthesized knowledge regarding dCasMINI guide design and built a website to assist researchers in designing optimal guides for dCasMINI-based experiments for transcriptional inhibition (CRISPRi) and activation (CRISPRa); to ensure that our tool would be useful for therapeutic guide design, in which a guide’s off-target safety profile is of paramount importance, we specifically optimized alignment parameters for high-sensitivity to comprehensively report genome-wide off-targets. To investigate dCasMINI’s full protospacer adjacent motif (PAM) profile, we engineered libraries of PAMs and exhaustively characterized dCasMINI’s ability to activate a locus with different PAMs. We also experimentally investigated the importance of each nucleotide position on the guide RNA’s ability to activate its target, and characterized a 6bp high-fidelity seed region at the 5’ end of the protospacer sequence which we identified to be intolerant to mismatches and deletions, and thus critical for true binding events. Taken together, our tool offers CRISPRi/a guide design for every protein-coding gene in the human genome along with comprehensive off-target prediction, incorporating the most up-to-date information about dCasMINI’s full PAM and protospacer design rules. The tool is freely available to use atwww.casmini-tool.com.
Evidence associating neutrophilia, lung damage, hyperlactatemia, blood acidosis, impaired oxygen transport, and mortality in critically ill COVID-19 patients
Authors: Yasseen Basma A. , Elkhodiry Aya A. , El-sayed Hajar , Zidan Mona , Kamel Azza G. , Hamdy Rehab , El-Shqnqery Hend E. , Samir Omar , Sayed Ahmed A. , Badawy Mohamed A. , Saber Aya , Hamza Marwa , El-Messiery Riem M. , Ansary Mohamed El , Abdel-Rahman Engy A. , Ali Sameh S. 
Published: September 2023

AbstractBackgroundCOVID-19 severity and high in-hospital mortality are often associated with severe hypoxemia, hyperlactatemia, and acidosis. Since neutrophil numbers in severe COVID-19 can exceed 80% of the total circulating leukocytes and that they are massively recruited to infected lungs, we investigated whether metabolic acidosis mediated by the glycolytic neutrophils is associated with lung damage and impaired oxygen delivery in critically ill patients.MethodsBased on prospective mortality outcome, 102 critically ill-hospitalized COVID-19 patients were divided into two groups: ICU-Survivors (ICU-S, n=36) and ICU-Non-survivors (ICU-NS, n=66). Blood samples were collected from patients and control subjects to explore correlations between neutrophil counts, lung damage, glycolysis, blood lactate, blood pH, hemoglobin oxygen saturation, and mortality outcome. We also interrogated isolated neutrophils for glycolytic activities and for apoptosis using high-throughput fluorescence imaging complemented with transcriptomic analyses. Stratified survival analyses were conducted to estimate mortality risk associated with higher lactate among predefined subgroups.ResultsNeutrophil counts were consistently higher in critically ill patients while exhibiting remarkably lower apoptosis. Transcriptomic analysis revealed miRNAs associated with downregulation of genes involved in neutrophils apoptosis. Both CT lung damage scores and neutrophil counts predicted mortality. Severinghaus fitting of hemoglobin oxygen saturation curve revealed a right-shift indicating lower oxygen capacity in non-survivors, which is consistent with lower blood-pH observed in the same group. Levels of blood lactate were increased in patients but significantly more in the ICU-NS relative to the control group. ROC analysis followed by Kaplan-Meyer survival analysis stratified to the obtained cut-off values showed that CT damage scores, neutrophil counts, and lactate levels are predictors of mortality within 15 days following blood collection.ConclusionThe current results implicate neutrophilia as a potential player in metabolic acidosis and deranged oxygen delivery associating SARS-CoV-2 infection thus contributing to mortality outcome.
Effectiveness of a Pain Neuroscience Education program on the physical activity of patients with Chronic Low Back Pain compared to a standard back school program, a randomized controlled study - END-LC
Authors: Thébault Guillaume , Duflos Claire , Le Perf Gaël 
Published: September 2023

AbstractIntroductionEducation is recognized as an effective and necessary method in chronic low back pain. Nevertheless, the data on the effectiveness of education in physical activity in the medium or long term are not yet well known, nor the factors that could lead to practice such or such education. Our study aims to measure the effectiveness of a pain neuroscience education compared to a back school on physical activity three months and one year after educational sessions coupled with a multidisciplinary rehabilitation program. The study also seeks to measure the effects of these two types of education on several other factors including the intensity of pain and psycho-behavioral factors. Finally, it aims to identify the determinants of the success of the educational sessions coupled with the rehabilitation program.Methods and analysisThe study will involve eighty-two adults with chronic low back pain. The study will be monocentric, prospective, open, controlled, and randomized, of superiority, with two parallel arms with an experimental group “pain neuroscience education” and a control group “back school”. The primary outcome will be the average number of steps taken at home over a week measured by an actigraph. Secondary outcomes include behavioral assessments. Descriptive and inferential analysis will be carried out on the primary and secondary judgment criteria. Multivariate modeling will be carried out using actimetric data and data from the main and secondary outcomes.Ethics and disseminationa favorable opinion was given by the Committee for Personal Protection of Ile de France VII on June 22, 2023 (National number: 2023-A00346-39). The study was previously registered with the National Agency or the Safety of Medicines and Health Products (IDRCB : 2023-A00346-39). This protocol is the version submitted to the Committee for Personal Protection of Ile de France VII entitled “Protocol Version N°1 of 03/29/2023”.Trial RegistrationNCT05840302.Article SummaryStrengths and limitations of this studyThe use of an actigraph as a measuring tool of physical activity in ecological context to evaluate effectiveness of an education in low back pain.The follow-up at three months and one year after the rehabilitation program.The study includes an analysis of actimetric data, behavioral, occupational and psychological variables to determine the predictive factors for the success of educational sessions.The monocentric design of this study is a limitation.
Longitudinal Changes in the Carotid Arteries of Head and Neck Cancer Patients Following Radiation Therapy: Results from a Prospective Serial Imaging Biomarker Characterization Study
Authors:   MD Anderson Head and Neck Radiation Oncology and Cardiovascular Working Group, Koutroumpakis Efstratios , Mohamed Abdallah Sherif Radwan , Chaftari Peter , Rosenthal David I. , Gujral Dorothy , Nutting Christopher , Kim Peter , Bassett Roland , Fuller Clifton D. , Mouhayar Elie 
Published: September 2023

ABSTRACTINTRODUCTIONWe prospectively evaluated morphologic and functional changes in the carotid arteries of patients treated with unilateral neck radiation therapy (RT) for head and neck cancer.METHODSBilateral carotid artery duplex studies were performed at 0, 3, 6, 12, 18 months and 2, 3, 4, and 5 years following RT. Intima media thickness (IMT); global and regional circumferential, as well as radial strain, arterial elasticity, stiffness, and distensibility were calculated.RESULTSThirty-eight patients were included. A significant difference in the IMT from baseline between irradiated and unirradiated carotid arteries was detected at 18 months (median, 0.073mm vs -0.003mm;P=0.014), which increased at 3 and 4 years (0.128mm vs 0.013mm,P=0.016, and 0.177mm vs 0.023mm,P=0.0002, respectively). A > 0.073mm increase at 18 months was significantly more common in patients who received concurrent chemotherapy (67% vs 25%;P=0.03). A significant transient change was noted in global circumferential strain between the irradiated and unirradiated arteries at 6 months (median difference, -0.89,P=0.023), which did not persist. No significant differences were detected in the other measures of elasticity, stiffness, and distensibility.CONCLUSIONSFunctional and morphologic changes of the carotid arteries detected by carotid ultrasound, such as changes in global circumferential strain at 6 months and carotid IMT at 18 months, may be useful for the early detection of radiation-induced carotid artery injury, can guide future research aiming to mitigate carotid artery stenosis, and should be considered for clinical surveillance survivorship recommendations after head and neck RT.
Can we start to ignore the SARS-CoV-2 disease?
Authors: Nesteruk Igor 
Published: September 2023

ABSTRACTCurrent WHO reports claim a decline in COVID-19 testing. Many countries are reporting no new infections. In particular, USA, China and Japan have registered no cases and COVID-19 related deaths since May 15, 2023. To discuss consequences of ignoring SARS-CoV-2 infection, we compare endemic characteristics of the disease in 2023 with ones estimated before using 2022 datasets. The accumulated numbers of cases and deaths reported to WHO by 10 most infected countries and global figures were used to calculate the average daily numbers of cases and deaths per capita (DCCandDDC) and case fatality rates (CFR) for two periods in 2023. The average values of daily deaths per million still vary between 0.12 and 0.41. It means that annual global number of COVID-19 related deaths is still approximately twice higher than the seasonal influenza mortality. Increase ofCFRvalues in 2023 show that SARS-CoV-2 infection is still dangerous despite of increasing the vaccination level. Very lowCFRfigures in South Korea and very high ones in the UK 4 need further investigations.
Genetic architecture of telomere length in 462,675 UK Biobank whole-genome sequences
Authors: Burren Oliver S. , Dhindsa Ryan S. , Deevi Sri V. V. , Wen Sean , Nag Abhishek , Mitchell Jonathan , Hu Fengyuan , Smith Katherine R. , Razdan Neetu , Olsson Henric , Platt Adam , Vitsios Dimitrios , Wu Qiang ,   AstraZeneca Genomics Initiative, Codd Veryan , Nelson Christopher P , Samani Nilesh J , March Ruth E. , Wasilewski Sebastian , Carss Keren , Fabre Margarete , Wang Quanli , Pangalos Menelas N. , Petrovski Slavé 
Published: September 2023

AbstractTelomeres protect the ends of chromosomes from damage, and genetic regulation of their length is associated with human disease and ageing. We developed a joint telomere length (TL) metric, combining both qPCR and whole genome sequencing (WGS) measurements across 462,675 UK Biobank participants that increased our ability to capture TL heritability by 36% (h2mean=0.058 to h2combined=0.079) and improved predictions of age. Exome-wide rare variant (minor allele frequency<0.001) and gene-level collapsing association studies identified 53 variants and 22 genes significantly associated with TL that included allelic series inACDandRTEL1. Five of the 31 rare-variant TL associated genes (16%) were also known drivers of clonal haematopoiesis (CH), prompting somatic variant analyses. Stratifying by CH clone size, we uncovered novel gene-specific associations with TL, including lengthened telomeres in individuals with largeSRSF2-mutant clones, in contrast to the progressive telomere shortening observed with increasing clonal expansions driven by other CH genes. Our findings demonstrate the impact of rare variants on TL with larger effects in genes associated with CH, a precursor of myeloid cancers and several other non-malignant human diseases. Telomere biology is likely to be an important focus for the prevention and treatment of these conditions.
Exposure to Heavy Metals, Obesity, and Stroke Mortality in the United States
Authors: Cao Ziqin , Bakulski Kelly M. , Paulson Henry L. , Wang Xin 
Published: September 2023

AbstractWe investigated the associations between blood concentrations of lead and cadmium with stroke mortality, and potential effect modification by obesity. Our study analyzed data from 23,437 individuals aged 40 and above, using the National Health and Nutrition Examination Survey (NHANES 1999-2016) linked to the National Death Index. During a median follow-up period of 8.3 years, 336 stroke-related deaths were reported. After adjusting for potential confounders, we found that higher baseline concentrations of lead and cadmium were significantly associated with increased stroke mortality. Specifically, the hazard ratios (HRs) per doubling of metal concentrations were 1.16 (95% CI: 1.11, 1.20) for lead and 1.31 (95% CI: 1.26, 1.36) for cadmium. Stratified analysis showed that stronger associations were observed among participants who were normal weight or overweight, relative to those who were obese. In conclusion, our study demonstrates that elevated blood concentrations of lead and cadmium are significantly associated with an increased risk of stroke mortality, especially among individuals who are normal weight or overweight.
Failure ofR0near the epidemic threshold in the classical SIS model
Authors: Mohammed Mozzamil 
Published: September 2023

AbstractThe primary predictor of a disease outbreak and severity is the basic reproduction numberR0, which represents the average number of secondary cases produced by introducing an infected individual into an entirely susceptible population. According to the classical SIS model, a disease withR0less than one will eventually die out and persist ifR0is greater than one. Using the pair-approximation method, we reconstruct the classical SIS model by explicitly accounting for neighbourhood interactions between susceptible and infected individuals. Specifically, the disease can only be transmitted, with some transmission probability, if a susceptible individual is surrounded by at least one infected individual within its direct neighborhoods. Despite the simplicity of the SIS model present here, results produced by the pair-approximation model deviates significantly from predictions by the mean-field approximation model, particularly near the epidemic threshold. Contrasting the standard SIS model based on the mean-field approach, we find scenarios where the disease dies out even ifR0is greater than one. We suggest a crucial need for redefining the basic reproduction number on a smaller spatial scale and taking the averageR0over a global scale, rather than applying it globally to an entire population. However, in the realm of more intricate models of infectious diseases, it remains an open question to what extent mean-field approximation predictions diverge from predictions produced by models that consider neighborhood interactions.
CCAR1 promotes DNA repair via an unanticipated role in alternative splicing
Authors: Karasu Mehmet E. , Joseph Brian J. , Mironov Aleksei , Schroeder Markus S. , Gvozdenovic Ana , Zavolan Mihaela , Corn Jacob E. 
Published: September 2023

SummaryDNA repair is directly performed by hundreds of core factors and indirectly regulated by thousands of others. We massively expanded a CRISPR inhibition and Cas9-editing screening system to discover factors indirectly modulating homology directed repair (HDR) in the context of ∼18’000 individual gene knockdowns. We focused onCCAR1,a poorly understood gene that we found reduced both HDR and interstrand crosslink repair, phenocopying the loss of the Fanconi Anemia pathway.CCAR1loss abrogated FANCA protein without substantial reduction in the level of its mRNA or that of other FA genes. We instead found that CCAR1 prevents inclusion of a poison exon inFANCA. Transcriptomic analysis revealed that the CCAR1 splicing modulatory activity is not limited to FANCA, and it instead regulates widespread changes in alternative splicing that would damage coding sequences in mouse and human cells. CCAR1 therefore has an unanticipated function as a splicing fidelity factor.
Escherichia coliself-organizes developmental rosettes
Authors: Puri Devina , Allison Kyle R. 
Published: September 2023

AbstractRosettes are self-organizing, circular multicellular communities that initiate developmental processes, like organogenesis and embryogenesis, in complex organisms. Their formation results from the active repositioning of adhered sister cells and is thought to distinguish multicellular organisms form unicellular ones. Though common in eukaryotes, this multicellular behavior has not been reported in bacteria. In this study, we discovered thatEscherichia coliforms rosettes by active sister cell repositioning. After division, sister cells “fold” to actively align at the 2- and 4-cell stages of clonal division, thereby producing rosettes with characteristic quatrefoil configuration. Analysis revealed folding follows an angular random walk, comprised of ∼1-µm strokes and directional randomization. We further showed that this motion was produced by the flagellum, the extracellular tail whose rotation generates swimming motility. Rosette formation was found to requirede novoflagella synthesis suggesting it must balance the opposing forces ofAg43adhesion and flagellar propulsion. We went on to show that proper rosette formation was developmentally required for subsequent morphogenesis of multicellular chains,rpoSexpression, and formation of hydrostatic clonal-chain biofilms. Moreover, we discovered self-folding rosette-like communities in the standard motility assay, indicating this behavior may be general to hydrostatic environments. This study establishes that self-organization of developmental rosettes is a cross-kingdom multicellular behavior. Our findings indicate the potential of targeting bacterial rosettes to interrupt biofilms or reduce their antibiotic tolerance.