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Background: Airway epithelial cells are critical in host defense against bacteria including Mycoplasma pneumoniae (Mp) in chronic obstructive pulmonary disease (COPD) and asthma. beta2-agonists are mainstay of COPD and asthma therapy, but whether beta2-agonists directly affect airway epithelial host defense functions is unclear.Methods: Epithelial cells from bronchial brushings of normal (n = 8), asthma (n = 8) and COPD (n = 8) subjects were grown in air-liquid interface cultures, and treated with cigarette smoke extract (CSE) and/or Th2 cytokine IL-13, followed by Mp infection and treatment with beta2-agonists albuterol and formoterol for up to seven days. Mp and host defense proteins short palate, lung, and nasal epithelial clone 1 (SPLUNC1) and beta-defensin-2 were quantified. Expression of beta2-adrenergic receptors was also measured by real-time quantitative RT-PCR.Results: (R)- or racemic albuterol and (R,R)- or racemic formoterol significantly decreased Mp levels in normal and asthma epithelial cells. Normal cells treated with Mp and (R)- or racemic albuterol showed an increase in SPLUNC1, but not in beta-defensin-2. COPD cells did not respond to drug treatment with a significant decrease in Mp or an increase in SPLUNC1. IL-13 attenuated drug effects on Mp, and markedly decreased SPLUNC1 and beta2-adrenergic receptors.Conclusions: These results for the first time show that beta2-agonists enhance host defense functions of primary bronchial epithelial cells from normal and asthma subjects, which is attenuated by IL-13. [ABSTRACT FROM AUTHOR]

Context: Health professionals are exposed to critical influences and pressures when socialized into their work environments. Little is known about the organizational socialization of certified athletic trainers (ATs) in the collegiate context.Objective: To discuss the organizational influences and quality-of-life issues as each relates to the professional socialization of ATs working in the National Collegiate Athletic Association Division I setting.Design: A qualitative design of in-depth interviews and follow-up electronic interviews was used to examine the organizational socialization of ATs.Setting: Participants associated with Division I athletic programs from 4 National Athletic Trainers' Association districts volunteered for the study.Participants: A total of 11 men and 5 women participated in the study, consisting of 14 ATs and 2 athletic directors.Data Collection and Analysis: Interviews were transcribed verbatim and analyzed inductively. A peer review, member checks, and data source triangulation were performed to establish trustworthiness.Results: Two categories emerged that provide insight into the experiences that affected the professional socialization of the ATs: organizational influences and quality-of-life issues. The data indicate that the participants in this study were heavily influenced by the bureaucratic tendencies of the Division I athletic organizations in which they worked. The participants were extremely concerned about the diminished quality of life that may result from being an AT in this context. They were, however, able to maintain a commitment to delivering quality care to the student-athletes despite these influences. High work volume and low administrative support were commonly cited as problems, thus creating concern about diminished quality of life and the fear of burnout.Conclusions: The AT's role appears not only rewarding but also challenging. The reward is working closely with patients and developing an interpersonal bond; the challenge is dealing with a bureaucratic structure and balancing one's professional and personal lives to prevent burnout. Thought should be given to using intervention strategies to mitigate the negative influences on the AT's role. [ABSTRACT FROM AUTHOR]

Objective: Torus Palatinus (TP) is a common trait with an unclear aetiology. Although prior studies suggest a hereditary component, the genetic factors that influence TP risk remain unknown. The purpose of this study is to identify genetic variants associated with TP., Materials and Methods: We assessed the TP status of 829 individuals from various ancestral backgrounds using 3D palate scans. We then carried out a genome-wide association study (GWAS) to identify common variants associated with TP. We also performed gene-based tests across the exome to investigate the role of low-frequency coding variants., Results: Our GWAS did not identify any genome-wide significant signals but identified suggestive associations including hits on chromosomes 2, 5 and 17 with p-values less than 5 × 10 -6 . Candidate genes at these suggestive loci have been implicated in normal-range craniofacial features, syndromes with facial and oral malformations, and bone density. We did not find evidence that low-frequency coding variants influence TP risk. In addition, we failed to replicate associations identified in prior genetic studies of TP., Conclusion: These findings suggest that multiple genes likely influence the development of TP. Independent replication will be required to confirm our suggestive associations., (© 2024 The Author(s). Orthodontics & Craniofacial Research published by John Wiley & Sons Ltd.)

Office hours are an integral component of science, technology, engineering, and math (STEM) courses at nearly all colleges and universities. Despite their ubiquity as a support mechanism, there has only been limited work examining how instructors approach office hours and what shapes these approaches. Here, we conduct a phenomenographic study to investigate how instructors of STEM courses experience office hours and how these experiences may impact their approaches to promoting and managing office hours. We identified variations in how instructors promoted office hours, the modality of office hours (i.e., when and where office hours were held), and how instructors facilitated learning during office hours. These variations spanned from student-centric (strategies instructors use with students' interest in mind, e.g., wanting to increase student learning, accessibility, comfort, etc.) to instructor-centric (strategies the instructors use with their own self-interest in mind, e.g., saving time and/or bandwidth, personal needs, comfort, etc.). Additionally, we identify several challenges and barriers, including a lack of formal training or opportunities to discuss office hour approaches with other faculty, and conclude with general recommendations for instructors and administrators in STEM departments for engaging and supporting students during office hours., Competing Interests: Conflicts of interest: The authors declare no conflicts of interest.

The cGMP-AMP Synthase (cGAS)-Stimulator of Interferon Genes (STING) pathway plays a critical role in sensing dsDNA localized to the cytosol, resulting in the activation of a robust inflammatory response. While cGAS-STING signaling is essential for antiviral immunity, aberrant STING activation is observed in amyotrophic lateral sclerosis (ALS), lupus, and autoinflammatory diseases such as Aicardi-Goutières syndrome (AGS) and STING associated vasculopathy with onset in infancy (SAVI). Significant efforts have therefore focused on the development of STING inhibitors. In a concurrent submission, we reported that BB-Cl-amidine inhibits STING-dependent signaling in the nanomolar range, both in vitro and in vivo. Considering this discovery, we sought to generate analogs with higher potency and proteome-wide selectivity. Herein, we report the development of LB244 , which displays nanomolar potency and inhibits STING signaling with markedly enhanced proteome-wide selectivity. Moreover, LB244 mirrored the efficacy of BB-Cl-amidine in vivo . In summary, our data identify novel chemical entities that inhibit STING signaling and provide a scaffold for the development of therapeutics for treating STING-dependent inflammatory diseases.

Macrophages (MΦ) play a role in neonatal etiologies of obstructive cholestasis, however, the role for precise MΦ subsets remains poorly defined. We developed a neonatal murine model of bile duct ligation (BDL) to characterize etiology-specific differences in neonatal cholestatic MΦ polarization. Neonatal BDL surgery was performed on female BALB/c mice at 10 days of life (DOL) with sham laparotomy as controls. Comparison was made to the Rhesus Rotavirus (RRV)-induced murine model of biliary atresia (BA). Evaluation of changes at day 7 after surgery (BDL and sham groups) and murine BA (DOL14) included laboratory data, histology (H&E, anti-CD45 and anti-CK19 staining), flow cytometry of MΦ subsets by MHCII and Ly6c expression, and single cell RNA-sequencing (scRNA-seq) analysis. Neonatal BDL achieved a 90% survival rate; mice had elevated bile acids, bilirubin, and alanine aminotransferase (ALT) versus controls (p < 0.05 for all). Histology demonstrated hepatocellular injury, CD45+ portal infiltrate, and CK19+ bile duct proliferation in neonatal BDL. Comparison to murine BA showed increased ALT in neonatal BDL despite no difference in histology Ishak score. Neonatal BDL had significantly lower MHCII-Ly6c+ MΦ versus murine BA, however, scRNA-seq identified greater etiology-specific MΦ heterogeneity with increased endocytosis in neonatal BDL MΦ versus cellular killing in murine BA MΦ. We generated an innovative murine model of neonatal obstructive cholestasis with low mortality. This model enabled comparison to murine BA to define etiology-specific cholestatic MΦ function. Further comparisons to human data may enable development of immune modulatory therapies to improve patient outcomes., (© 2023. Springer Nature Limited.)

Protein citrullination is a post-translational modification of arginine that controls a diverse array of cellular processes, including gene regulation, protein stability, and neutrophil extracellular trap (NET) formation. Histone citrullination promotes chromatin decondensation and NET formation, a pro-inflammatory form of cell death that is aberrantly increased in numerous immune disorders. This review will provide insights into NETosis and how this novel form of cell death contributes to inflammatory diseases, with a particular emphasis on its role in thrombosis. We will also discuss recent efforts to develop PAD-specific inhibitors., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Paul R Thompson reports financial support was provided by National Institute of General Medical Sciences, authored several patents for PAD inhibitors, and holds an equity interest in Padlock Therapeutics a wholly owned subsidiary of Bristol Myers Squibb. R. Madison Green reports financial support from the National Heart, Lung, and Blood Institute., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors. In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = 0.010) as per interim efficacy analysis. The ChemoID assay-guided group has a significantly lower risk of death (hazard ratio [HR] = 0.44; 95% CI, 0.24-0.81; p = 0.008). Results of this study offer a promising way to provide more affordable treatment for patients with rGBM in lower socioeconomic groups in the US and around the world., Competing Interests: Declaration of interests P.P.C. and J.V. report ownership of intellectual property rights on the CSC platform technology licensed to Cordgenics, LLC., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)