23834 research outputs found
Sort by
A secretome atlas of cardiac fibroblasts from healthy and infarcted mouse hearts
Full text linkCardiac fibroblasts (CF) are key players after myocardial infarction (MI), but their signaling is only incompletely understood. Here we report a first secretome atlas of CF in control (cCF) and post-MI mouse hearts (miCF), combining a rapid cell isolation technique with SILAC and click chemistry. In CF, numerous paracrine factors involved in immune homeostasis are identified. Comparing secretome, transcriptome (SLAMseq), and cellular proteome disclose protein turnover. In miCF at day 5 post-MI, significantly upregulated proteins include SLIT2, FN1, and CRLF1 in mouse and human samples. Comparing the miCF secretome at days 3 and 5 post-MI reveals the dynamic nature of protein secretion. Specific in-vivo labeling of miCF proteins via biotin ligase TurboID using the POSTN promotor mirrors the in-vitro data. In summary, we identify numerous paracrine factors specifically secreted from CF in mice and humans. This secretome atlas may lead to new biomarkers and/or therapeutic targets for the activated CF
MTOR signaling regulates the development of airway mucous cell metaplasia associated with severe asthma
Full text linkIn asthma, airway epithelial remodeling is characterized by aberrant goblet cell metaplastic differentiation accompanied by epithelial cell hyperplasia and hypertrophy. These pathologic features in severe asthma indicate a loss of control of proliferation, cell size, differentiation, and migration. MTOR is a highly conserved pathway that regulates protein synthesis, cell size, and proliferation. We hypothesized that the balance between MTOR and autophagy regulates mucous cell metaplasia. Airways from individuals with severe asthma showed increased MTOR signaling by RPS6 phosphorylation, which was reproduced using an IL-13-activated model of primary human airway epithelial cells (hAEC). MTOR inhibition by rapamycin led to a decrease of IL-13-mediated cell hypertrophy, hyperplasia, and MUC5AC mucous metaplasia. BrdU labeling during IL-13-induced mucous metaplasia confirmed that MTOR was associated with increased basal-to-apical hAEC migration. MTOR activation by genetic deletion of Tsc2 in cultured mouse AECs increased IL-13-mediated hyperplasia, hypertrophy, and mucous metaplasia. Transcriptomic analysis of IL-13-stimulated hAEC identified MTOR-dependent expression of genes associated with epithelial migration and cytoskeletal organization. In summary, these findings point to IL-13-dependent and -independent roles of MTOR signaling in the development of pathogenic epithelial changes contributing to airway obstruction in severe asthma
Recombinant interleukin-7 treatment of refractory refractory Mycobacterium avium complexlung disease (IMPULSE-7): A pilot phase II, single-center, randomized, clinical trial
Full text linkBACKGROUND: Nontuberculous mycobacteria disease is an emerging opportunistic infection that is often refractory to therapy. Interleukin 7 (IL-7) is a pleiotropic cytokine with broad-ranging effects that enhance immunity and augment monocyte/macrophage anti-
OBJECTIVES: This study evaluated IL-7 in patients with refractory
DESIGN: Prospective, single-center, randomized, study of IL-7 in patients with refractory MAC-LD.
METHODS: Randomization (two sets of 4 weekly IL-7 injections) was stratified based on the presence of pulmonary cavities. The primary outcome was sputum culture conversion to negative within 6 months. Exploratory outcomes included investigation of potential molecular mechanisms of immunosuppression via single-cell RNA sequencing (scRNA-seq).
RESULTS: Of the eight participants enrolled, six completed the IL-7 regimen, one completed one 4-week therapy, and one received a single dose of IL-7. All six participants who completed the regimen showed an increased absolute lymphocyte count (ALC), yet none converted their sputum culture to negative at 6 months. Similarly, there were no differences in secondary outcomes compared to baseline. IL-7 was well tolerated, and two participants showed an increase in time-positivity for MAC in their sputum culture. scRNA-seq revealed increased expression of genes involved in immunosuppressive pathways.
CONCLUSION: In adults with refractory MAC-LD, IL-7 did not result in sputum culture conversion. IL-7 reversed the underlying lymphopenia associated with MAC-LD and led to a sustained increase in ALC. The study was limited by a small sample size, and although a longer course of IL-7 combined with newer antimicrobials for may warrant further investigation, structural lung disease may be a stronger predictor of cure than immune dysfunction in MAC-LD.
TRIAL REGISTRATION: The trial was registered in clinicaltrials.gov (NCT04154826)
Vibrotactile auricular vagus nerve stimulation alters limbic system connectivity in humans: A pilot study
Full text linkVibration offers a potential alternative modality for transcutaneous auricular vagus nerve stimulation (taVNS). However, mechanisms of action are not well-defined. The goal of this pilot study was to evaluate the potential of vibrotactile stimulation of the outer ear as a method for activating central brain regions similarly to established vagal nerve stimulation methods. Seven patients with intractable epilepsy undergoing stereotactic electroencephalography (sEEG) monitoring participated in the study. Vibrotactile taVNS was administered across five vibration frequencies (2, 6, 12, 20, and 40 Hz) following a randomized stimulation pattern with 30 trials per frequency. Spectral coherence during stimulation was analyzed across theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz), and broadband gamma (70-170 Hz) frequency bands. At the group level, vibrotactile taVNS significantly increased coherence in theta (effect sizes 6 Hz: r = 0.311; 20 Hz: r = 0.316; 40 Hz: r = 0.264) and alpha bands (effect sizes 20 Hz: r = 0.455; 40 Hz: r = 0.402). Anatomically, multiple limbic brain regions exhibited increased coherence during taVNS compared to baseline. The percentage of total electrode pairs demonstrating increased coherence was also quantified at the individual level. Twenty Hz vibration resulted in the highest percentage of responder pairs across low-frequency coherence measures, with a group-average of 33% of electrode pairs responding, though inter-subject variability was present. Overall, vibrotactile taVNS induced significant low-frequency coherence increases involving several limbic system structures. Further, parametric characterization revealed the presence of inter-subject variability in terms of identifying the vibration frequency with the greatest coherence response. These findings encourage continued research into vibrotactile stimulation as an alternative modality for noninvasive vagus nerve stimulation
Fatty acid 2-hydroxylase facilitates rotavirus uncoating and endosomal escape
Full text linkDespite the clinical significance of many nonenveloped viruses, the molecular mechanisms of their internalization and membrane penetration are not well understood. Rotaviruses (RVs) are nonenveloped double-stranded RNA viruses and the leading cause of severe dehydrating diarrhea in infants and young children. We identified fatty acid 2-hydroxylase (encoded b
Allele-specific vitamin D receptor binding is associated with pediatric-onset multiple sclerosis
Full text linkBACKGROUND AND OBJECTIVES: The genetic basis of adult-onset multiple sclerosis (MS) is well-studied, but less is known about pediatric-onset MS (pedMS), comprising approximately 5% of all MS onsets. Mendelian randomization (MR) studies have demonstrated evidence for a causal association between MS and both 25-hydroxyvitamin D [25(OH)D] serum levels and genetic variation related to vitamin D receptor (VDR) binding. The objective was to identify whether VDR binding variants (VDR-BVs) previously implicated in adult-onset MS were associated with pedMS using genetic instrumental variables (GIVs).
METHODS: Using previously identified VDR-BVs to construct individual GIVs with two-sample MR, we investigated associations with pedMS in 725 cases and 592 controls of European ancestry from the US Network of Pediatric MS Centers. Associations between each VDR-BV and pedMS were estimated using logistic regression adjusting for the first three genome-wide principal components. A significant interaction between a VDR-BV and 25(OH)D GIV provided evidence for a causal association unbiased by pleiotropy.
RESULTS: One VDR-BV, rs2531804, previously associated with adult-onset MS, was also significantly associated with pedMS after multiple testing correction.
DISCUSSION: This study is the first to use VDR-BVs from previous MR studies to demonstrate causal differences in VDR binding at a locus contributing to pedMS susceptibility
Dexamethasone-eluting cochlear implants reduce inflammation and foreign body response in human and murine cochleae
Full text linkThe inflammatory foreign body response (FBR) following cochlear implantation (CI) can negatively impact CI outcomes, including increased electrode impedances. This study aims to investigate the long-term efficacy of dexamethasone-eluting cochlear implant and locally delivered dexamethasone, a potent anti-inflammatory glucocorticoid, on the intracochlear FBR and electrical impedance post-implantation in a murine model. Preliminary impedance data in humans are also provided as a complement to the murine data to illustrate generalizability and reinforce implications related to clinical application. The left ears of CX3CR
Dataset and analysis of automated and manual methods to differentiate wide QRS complex tachycardias
Full text linkThe differentiation of wide complex tachycardias (WCTs) into ventricular tachycardia (VT) and supraventricular wide tachycardia (SWCT) via 12-lead ECG (electrocardiogram) interpretation is a crucial yet demanding clinical task. Decades of research have been dedicated to simplifying and improving this differentiation via manual algorithms. Despite such research, the effectiveness of such algorithms still remains limited, primarily due to reliance on user expertise. To combat this limitation, automated algorithms have been created that show promise as alternatives to manual ECG interpretation. However, direct comparison of the methods\u27 diagnostic performances has not been undertaken. A recent publication (LoCoco et al., 2024) compared the diagnostic performance between traditional manual ECG interpretation approaches (i.e. Brugada, Vereckei aVR, and VT Score) to novel automated wide QRS complex tachycardia differentiation algorithms (i.e. WCT Formula I, WCT Formula II, VT Prediction Model, Solo Model, and Paired Model). Two electrophysiologists independently applied the 3 manual WCT differentiation approaches to 213 ECGs. Simultaneously, computerized data from the same paired WCT with baseline ECGs were processed by the 5 automated WCT differentiation algorithms. Following these analyses, the diagnostic performance of automated algorithms was compared with manual ECG interpretation approaches. In this article, a summary of data components relating to diagnostic performance of the methods tested is presented
WashU Epigenome Browser update 2025
Full text linkThe WashU Epigenome Browser (https://epigenomegateway.wustl.edu/) is a web-based tool for exploring genomic data and providing visualization, investigation, and analysis of epigenomic datasets. Since its 2018 update, the redesigned user interface and newly developed features have enhanced how investigators interact with both the Browser and the extensive genomic data it hosts. The rapid evolution of the JavaScript ecosystem has presented new challenges and opportunities in maintaining and developing the WashU Epigenome Browser. In this update, we present a completely rewritten codebase. This new codebase minimizes the use of external libraries whenever possible, resulting in a significantly smaller code bundle size after production compilation. The reduced code size improves loading efficiency and boosts the Browser\u27s performance, with improved scripting, graphics rendering, and painting performance. Lowering external dependencies also allows for faster and more straightforward installation. Additionally, the update includes a redesign of the user interface to further enhance user experience and features a new modular design in the codebase that enables the Browser to be exported as stand-alone modules for use in other web applications. Several novel track types for long-read methylation data and single-cell methylation data visualization have been added, and we continue to update and expand the data hubs we host for major consortia. We constructed the first data hub to systematically compare genomic data mapped to different genome assemblies, focusing on comparisons between hg38 and the first human T2T genome, chm13, using our new comparative genomics track function. The WashU Epigenome Browser also serves as a foundation for other genomics platforms, such as the WashU Virus Genome Browser, developed for SARS-COV-2 research, the WashU Comparative Epigenome Browser, and the WashU Repeat Browser
Autoregulation of RPL7B by inhibition of a structural splicing enhancer
Full text linkYeast ribosomal protein gene RPL7B is autoregulated by inhibition of splicing. The first intron has a zipper stem that brings the 5\u27 splice site near the branch point (BP) and serves as an enhancer of splicing that is required for efficient splicing because the intron has a nonconsensus BP sequence of UGCUAAC. The intron also contains an alternative, and mutually exclusive, structure that is conserved across many yeast species. That conserved structure is a binding site for the Rpl7 protein so that when the protein is in excess over what is required for ribosomes, the protein binds to the conserved structure which eliminates the enhancer structure and represses splicing and gene expression