bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integration of Capnography and Continuous Positive Airway Pressure (CPAP) in the Prehospital Setting
Authors: Sethi Sahil , Hobbs Gene , Hubbard Devin , Donnelly Kenneth , Grover Joseph M. , Rizvi Imran 
Published: October 2023

AbstractBACKGROUNDCapnography is one of the most important respiratory monitoring tools used in EMS because changes to end-tidal CO2(ETCO2) generally precede blood oxygen desaturation, and waveform morphology can be used to assess bronchial patency. Many of capnography’s indications overlap with those of continuous positive airway pressure (CPAP) therapy. However, there are currently no convenient methods to administer CPAP while using capnography, and no peer-reviewed studies have examined combining the two technologies in the prehospital setting.METHODS & FINDINGSTwo types of capnography sampler were used to investigate how ETCO2, capnogram shape, and respiration rate (RR) are affected by applying a CPAP mask both with and without oxygen flowing. A traditional nasal-oral cannula (NC) sampler, as well as a novel sampler that does not break the seal between the CPAP mask and the patient’s face (called the CPAP-Capnography Adapter, or CCA), were evaluated on a Human Patient Simulator (HPS). No significant differences between the NC and CCA were found for ETCO2and RR percent error. Placement of a CPAP mask without turning on O2increased ETCO2. During CPAP therapy, the two samplers maintained their RR measurement accuracy, but ETCO2values were significantly reduced and the capnogram depicted an increased β-angle with severe blunting of the inspiratory downstroke.CONCLUSIONSThe HPS had set-point ETCO2and PaCO2values, indicating that the local CO2concentration at the nares was diluted during CPAP and no longer accurately reflected the simulated subject’s breathing. The compromise in waveform morphology could be overcome by further research into interpreting capnogram differences during CPAP between healthy patients and those with respiratory pathologies. However, at this time, our results show that ETCO2values and capnogram shape should be interpreted with caution during CPAP.
Changes in urinary glutathione sulfonamide (GSA) levels between admission and discharge of patients with cystic fibrosis
Authors: Blake Tamara L , Sly Peter D , Andersen Isabella , Wainwright Claire E , Reid David W , Bell Scott C , Kettle Anthony J , Dickerhof Nina 
Published: October 2023

AbstractThere is an urgent need to develop sensitive, non-invasive biomarkers that can track airway inflammatory activity for patients with cystic fibrosis (CF). Urinary GSA levels correlate well with GSA levels in BAL samples and other markers of neutrophilic inflammation, suggesting that this biomarker may be suitable for tracking disease activity in this population.We recruited 102 children (median 11.5 years-old) and 64 adults (median 32.5 years-old) who were admitted to hospital for management of an acute pulmonary exacerbation and/or eradication of infectious agents such asP. aeruginosaorS. aureus. Our aim was to explore how urinary GSA levels changed across admission timepoints. Urine samples were collected at admission and discharge, and GSA measured by liquid chromatography with mass spectrometry. Paired admission-discharge results were compared using Wilcoxon signed-rank test.Paired admission-discharge samples were available for 49 children and 60 adults. A statistically significant difference was observed between admission-discharge for children, but not for adults. Spearman’s correlation analysis identified a correlation between urinary GSA levels and age, sex, inflammatory markers, andP. aeruginosainfection for children only. Our preliminary findings suggest that urinary GSA is responsive to the resolution of an acute pulmonary exacerbation and therefore warrants further studies in this population.
Protocols for Multi-Scale Molecular Dynamics Simulations: A Comparative Study for Intrinsically Disordered Amyloid Beta in Amber & Gromacs on CPU & GPU
Authors: Smardz Pamela , Anila Midhun Mohan , Rogowski Pawel , Li Mai Suan , Różycki Bartosz , Krupa Pawel 
Published: October 2023

ABSTRACTIntrinsically disordered proteins (IDPs) present challenges to conventional experimental techniques due to their large-scale conformational fluctuations and the transient occurrence of structural elements. This work illustrates computational methods for studying IDPs at various levels of resolution. The included simulation protocol offers a step-by-step guide on how to conduct molecular dynamics (MD) simulations and analyze the results using the Amber and Gromacs packages, employing both all-atom and coarse-grained approaches. This protocol can be easily adapted to study other biomacromolecules, including folded and disordered proteins and peptides.Furthermore, it is discussed in this work how to perform standard molecular modeling operations, such as amino-acid substitutions (mutagenesis) and insertions of residues missing in a protein structure, as well as how to incorporate post-translational modifications into the simulations, such as disulfide bonds, which are often crucial for proteins to attain their physiologically functional structure. In conventional MD studies, disulfide bonds are typically fixed at the preparation step and remain unchanged throughout the simulations, unable to break or reform. Here, in contrast, a dynamic approach is presented. It involves adequate distance restraints applied to the sulfur atoms of selected cysteine residues, allowing disulfide bonds to break and reform during the simulation.The effectiveness of these methodologies is demonstrated by examining a model IDP, the monomeric form of 1-42 amyloid-β (Aβ42), both with and without disulfide bonds, at different levels of resolution. This study not only contributes to our understanding of the role of disulfide bonds but also provides detailed simulation protocols that can serve as a foundation for future investigations.SUMMARYGiven the challenges of experimental studies on intrinsically disordered proteins, this manuscript demonstrates step-by-step protocols for conducting all-atom and coarse-grained molecular dynamics simulations using two widespread packages, Amber and Gromacs. The monomeric form of 1-42 amyloid-β (Aβ42) is used as an example, from which insights into the structure, dynamics and physicochemical properties of this protein can be obtained.
Discovery of CMX990: A Potent SARS-CoV-2 3CL Protease Inhibitor Bearing a Novel Covalent Warhead
Authors: Elshan N. G. R. Dayan , Wolff Karen C. , Riva Laura , Woods Ashley K. , Grabovyi Gennadii , Wilson Katy , Rahimi Alireza , Pedroarena James , Ghorai Sourav , Gupta Anil Kumar , Nazarian Armen , Weiss Frank , Liu Yuyin , Mazumdar Wrickban , Song Lirui , Okwor Neechi , Malvin Jacqueline , Bakowski Malina A. , Beutler Nathan , Kirkpatrick Melanie G. , Gebara-Lamb Amal , Huang Edward , Nguyen-Tran Van , Chi Victor , Li Shuangwei , Rogers Thomas F. , McNamara Case W. , Chen Jian Jeffrey , Joseph Sean B. , Schultz Peter G. , Chatterjee Arnab K. 
Published: October 2023

ABSTRACTThere remains a need to develop novel SARS-CoV-2 therapeutic options that improve upon existing therapies by increased robustness of response, fewer safety liabilities, and global-ready accessibility. Functionally critical viral main protease (Mpro, 3CLpro) of SARS-CoV-2 is an attractive target due to its homology within the coronaviral family, and lack thereof towards human proteases. In this disclosure, we outline the advent of a novel SARS-CoV-2 3CLproinhibitor, CMX990, bearing an unprecedented trifluoromethoxymethyl ketone warhead. Compared with the marketed drug nirmatrelvir (combination with ritonavir = PaxlovidTM), CMX990 has distinctly differentiated potency (∼5x more potent in primary cells) and humanin vitroclearance (>4x better microsomal clearance and >10x better hepatocyte clearance), with goodin vitro-in vivocorrelation. Based on its compelling preclinical profile and projected once or twice a day dosing supporting unboosted oral therapy in humans, CMX990 advanced to a Phase 1 clinical trial as an oral drug candidate for SARS-CoV-2.
Unexpected delayed incursion of highly pathogenic avian influenza H5N1 (clade 2.3.4.4b) in the Antarctic region
Authors: Lisovski Simeon , Günther Anne , Dewar Meagan , Ainley David , Aldunate Fabián , Arce Rodrigo , Ballard Grant , Bauer Silke , Belliure Josabel , Banyard Ashley C. , Boulinier Thierry , Bennison Ashley , Braun Christina , Cary Craig , Catry Paulo , Clessin Augustin , Connan Maelle , Correia Edna , Cox Aidan , Cristina Juan , Elrod Megan , Emerit Julia , Ferreiro Irene , Fowler Zoe , Gamble Amandine , Granadeiro José P. , Hurtado Joaquin , Jongsomjit Dennis , Lesage Célia , Lejeune Mathilde , Kuepfer Amanda , Lescroël Amélie , Li Amy , McDonald Ian R. , Menéndez-Blázquez Javier , Morandini Virginia , Moratorio Gonzalo , Militão Teresa , Moreno Pilar , Perbolianachis Paula , Pennycook Jean , Raslan Maryam , Reid Scott M. , Richards-Babbage Roanna , Schmidt Annie E. , Sander Martha Maria , Smyth Lucy , Soutullo Alvaro , Stanworth Andrew , Streith Léo , Tornos Jérémy , Varsani Arvind , Herzschuh Ulrike , Beer Martin , Wille Michelle 
Published: October 2023

AbstractThe current highly pathogenic avian influenza H5N1 panzootic has substantial impacts on wild birds and marine mammals. Although major outbreaks occurred in South America, incursion to Antarctica emerged late in the breeding season of 2023/2024 and was confined the wider region of the Antarctic Peninsula. To infer potential underlying processes, we compiled H5N1 surveillance from Antarctica and Sub-Antarctic Islands prior to the first confirmed cases.
Increased tau expression in theAPOE4blood-brain barrier model is associated with reduced anti-tau therapeutic antibody deliveryin vitro
Authors: Wasielewska Joanna M. , Bajracharya Rinie , Johnston Rebecca L. , Chaves Juliana C.S. , Pébay Alice , Oikari Lotta E. , Götz Jürgen , Nisbet Rebecca M. , White Anthony R. 
Published: October 2023

AbstractTau protein is a critical driver of neurodegeneration and an important drug target in Alzheimer’s disease (AD). Tau-specific immunotherapy has emerged as a promising treatment strategy for AD, however the therapeutic efficacy of anti-tau antibodies may be limited by their insufficient delivery across the blood-brain barrier (BBB). The apolipoprotein E4 allele (APOE4) is the strongest genetic risk factor for sporadic AD and is known to influence tau-mediated neurodegeneration. Interestingly, both tau andAPOE4have been implicated in the cerebrovascular pathology observed in AD. Yet, the crosstalk betweenAPOE4and tau at the level of the BBB and its consequences for anti-tau immunotherapeutics delivery, remain poorly understood. Here, we utilisedAPOE3- andAPOE4-carrying human iPSC-derived induced brain endothelial-like cells (iBECs) as a sporadic AD BBB model, determined the levels of endogenous tau in iBECs, and explored the transport of two novel monoclonal anti-tau antibodies, RNF5 and RN2N, across thein vitrobarrier. Our results demonstrate thatMAPTgene transcription, tau protein levels and tau phosphorylation are increased in iBECs in anAPOE4-related manner and are associated with reduced iBEC monolayer integrity and increased permeability to biologically inert fluorescent tracers. Additionally, elevated levels of intracellular tau inAPOE4cells were accompanied by the reduced passive permeability of therapeutic anti-tau antibodies through theAPOE4iBEC monolayer, which could be improved by the application of focused ultrasound and microbubble drug-delivery technology. Together, our study illustrates a new role forAPOE4and tau in human iBECs with potential implications for BBB dysfunction and anti-tau therapeutic antibody delivery.
GRAIGH: Gene Regulation accessibility integrating GeneHancer database
Authors: Martini Lorenzo , Savino Alessandro , Bardini Roberta , Di Carlo Stefano 
Published: October 2023

AbstractSingle-cell assays for transposase-accessible chromatin sequencing data are one of the most powerful tools for studying the epigenetic heterogeneity of cell populations. However, the chromatin accessibility landscape is not well understood and lacks a proper way to interpret it. This work proposes Gene Regulation Accessibility Integrating GeneHancer (GRAIGH), a novel approach to the interpretation of genome accessibility through the integration of the GeneHancer database information, which describes genome-wide enhancer-to-gene associations. Firstly, this paper presents the methods for integrating GeneHancer with scATAC-seq data, creating a new matrix where the features are the GeneHancer elements IDs instead of the accessibility peaks. Secondly, it investigates its capability to analyze the data and detect cellular heterogeneity. In particular, this work shows that the GeneHancer elements are selectively accessible for distinct cell types, and more importantly, their connected genes are precisely known marker genes. Moreover, it investigates the specificity of GeneHancer elements accessibility, demonstrating their high selectivity against the gene activity.
Evolution and Diversification of Carboxylesterase-like [4+2] Cyclases in Aspidosperma and Iboga Alkaloid Biosynthesis
Authors: DeMars Matthew D. , O’Connor Sarah E. 
Published: October 2023

AbstractMonoterpene indole alkaloids (MIAs) are a large and diverse class of plant natural products, and their biosynthetic construction has been a subject of intensive study for many years. The enzymatic basis for the production of aspidosperma and iboga alkaloids, which are produced exclusively by members of the Apocynaceae plant family, has recently been discovered. Three carboxylesterase (CXE)-like enzymes fromCatharanthus roseusandTabernanthe ibogacatalyze regio- and enantiodivergent [4+2] cycloaddition reactions to generate the aspidosperma (tabersonine synthase, TS) and iboga (coronaridine synthase, CorS; catharanthine synthase, CS) scaffolds from a common biosynthetic intermediate. Here, we use a combined phylogenetic and biochemical approach to investigate the evolution and functional diversification of these cyclase enzymes. Through ancestral sequence reconstruction, we provide evidence for initial evolution of TS from an ancestral CXE followed by emergence of CorS in two separate lineages, leading in turn to CS exclusively in theCatharanthusgenus. This progression from aspidosperma to iboga alkaloid biosynthesis is consistent with the chemotaxonomic distribution of these MIAs. We subsequently generate and test a panel of chimeras based on the ancestral cyclases to probe the molecular basis for differential cyclization activity. Finally, we show through partial heterologous reconstitution of tabersonine biosynthesis using non-pathway enzymes how aspidosperma alkaloids could have first appeared as “underground metabolites” via recruitment of promiscuous enzymes from common protein families. Our results provide insight into the evolution of biosynthetic enzymes and how new secondary metabolic pathways can emerge through small but important sequence changes following co-option of preexisting enzymatic functions.
TheStaphylococcus aureusregulatory program in a human skin-like environment
Authors: Costa Flavia G. , Mills Krista B. , Crosby Heidi A. , Horswill Alexander R. 
Published: October 2023

AbstractStaphylococcus aureusis a Gram-positive pathogen responsible for the majority of skin and soft tissue infections (SSTIs).S. aureuscolonizes the anterior nares of approximately 20-30% of the population and transiently colonizes the skin, thereby increasing the risk of developing SSTIs and more serious infections. Current laboratory models that mimic the skin surface environment are expensive, require substantial infrastructure, and limit the scope of bacterial physiology studies under human skin conditions. To overcome these limitations, we developed a cost-effective, open-source, chemically defined media recipe termed skin-like media (SLM) that incorporates key aspects of the human skin surface environment and supports growth of several Staphylococcal species. We utilized SLM to investigate the transcriptional response of methicillin-resistantS. aureus(MRSA) following growth in SLM compared to a commonly used laboratory media. Through RNA-seq analysis, we observed the upregulation of several virulence factors, including genes encoding functions involved in adhesion, proteolysis, and cytotoxicity. To further explore these findings, we conducted qRT-PCR experiments to determine the influence of media composition, pH, and temperature on the transcriptional response of key factors involved in adhesion and virulence. We also demonstrated that MRSA primed in SLM adhered better to human corneocytes and demonstrated adhesin-specific phenotypes that previously required genetic manipulation. These results support the potential utility of SLM as anin vitromodel for assessing Staphylococcal physiology and metabolism on human skin.ImportanceStaphylococcus aureusis the major cause of skin diseases, and its increased prevalence in skin colonization and infections present a need to understand its physiology in this environment. The work presented here outlinesS. aureusupregulation of colonization and virulence factors using a newly developed media that strives to replicate the human skin surface environment, and demonstrates roles for adhesins ClfA, SraP, and Fnbps in human corneocyte adherence.
Non-essential kinetochore proteins contribute to meiotic chromosome condensation through polo-like kinase
Authors: Trakroo Deepika , Agarwal Prakhar , Alekar Anushka , Ghosh Santanu Kumar 
Published: October 2023

AbstractChromosome condensation plays a pivotal role during faithful chromosome segregation, hence understanding the factors that drive condensation is crucial to get mechanistic insight into chromosome segregation. Previously we showed that in budding yeast, the absence of the non-essential kinetochore proteins affects chromatin-condensin association in meiosis but not in mitosis. A differential organization of the kinetochores, that we and others observed earlier during mitosis and meiosis may contribute to the meiotic-specific role. Here, with our in-depth investigation using in vivo chromosome condensation assays in cells sans a non-essential kinetochore protein, Ctf19, we establish that these proteins have roles in achieving a higher meiotic condensation without influencing much of the mitotic condensation. We further observed an accumulation of the polo-like kinase Cdc5 owing to its higher protein stability inctf19Δmeiotic cells. High Cdc5 activity causes hyper-phosphorylation of the condensin resulting in its reduced stability and concomitant decreased association with the chromatin. Overall, our findings highlight the role of Ctf19 in promoting meiotic chromosome condensation by influencing the activity of Cdc5 and thereby affecting the stability and association of condensin with the chromatin.
Spindle architecture constrains karyotype in budding yeast
Authors: Helsen Jana , Reza Md Hashim , Carvalho Ricardo , Sherlock Gavin , Dey Gautam 
Published: October 2023

AbstractThe eukaryotic cell division machinery must rapidly and reproducibly duplicate and partition the cell’s chromosomes in a carefully coordinated process. However, chromosome number varies dramatically between genomes, even on short evolutionary timescales. We sought to understand how the mitotic machinery senses and responds to karyotypic changes by using a series of budding yeast strains in which the native chromosomes have been successively fused. Using a combination of cell biological profiling, genetic engineering, and experimental evolution, we show that chromosome fusions are well tolerated up until a critical point. Cells with fewer than five centromeres lack the necessary number of kinetochore-microtubule attachments needed to counter outward forces in the metaphase spindle, triggering the spindle assembly checkpoint and prolonging metaphase. Our findings demonstrate that spindle architecture is a constraining factor for karyotype evolution.
The impact of quality on health-insurance users' satisfaction in Saudi Arabia: the mediating role of brand image and utilitarian value
Authors: Abourokbah Safinaz Hassan , Husain Khalid Sami 
Published: October 2023

PurposeThis study assesses the quality of health-insurance services and their impact on customer satisfaction, examining the mediating role of utilitarian value and brand image in this relationship.Design/methodology/approachSurvey data were collected from 345 health-insurance companies' customers selected through convenience sampling and were analyzed using SmartPLS.FindingsService quality statistically significantly influences customer satisfaction with health insurance in Saudi Arabia, whereas brand image and utilitarian value partially mediate this relationship. The structural path between service quality and brand image was statistically significant and positive. The utilitarian dimension positively affects customer satisfaction and service quality.Practical implicationsThis study is significant to the management, as it provides insight into the expectations of health-insurance users. The focus is to gain a competitive advantage by improving customer service and brand image.Originality/valueThis investigation contributes to the field by exploring the mediating role of utilitarian value and brand image in the relationship between health-insurance quality and customer satisfaction based on the information provided by insurance policyholders in Saudi Arabia.
CEO personality and corporate sustainability performance
Authors: Venugopal Ajith , Nerur Sridhar , Yasar Mahmut , Rasheed Abdul A. 
Published: October 2023

PurposeThis study aims to examine how chief executive officer's (CEO) personality traits influence the corporate sustainability performance (CSP) of firms. The paper also examines the moderating effect of board power on this relationship.Design/methodology/approachUsing a linguistic tool (IBM's Watson Personality Insight Service), the authors measured the personality traits of 229 CEOs from 176 firms from 2009 to 2018. Firm-level CSP are obtained from the Sustainalytics database. The hypotheses are tested using multiple regression analysis. The robustness of the results of the study is confirmed by addressing endogeneity concerns and by validating the measurement of CEO personality traits using Personality Recognizer, an alternative linguistic tool.FindingsThe results show that CEO personality traits of extraversion and neuroticism are significant predictors of CSP. The paper also identifies board power as a contingent factor that influences the suggested relationships.Originality/valueUsing upper echelon theory and cybernetic big five theory, this paper identifies CEO personality traits as important antecedents of corporate sustainability performance and adds to the micro-foundations of corporate sustainability literature. To the authors’ understanding, this is the first study that examines the influence of CEO personality on CSP using a comprehensive trait framework. The paper also demonstrates the usefulness of text-analytic tools to measure CEO personality traits, thereby contributing to the progress of upper echelon theory.