Search

The majority of exercise physiology research has been conducted in males, resulting in a skewed biological representation of how exercise impacts the physiological system. Extrapolating male-centric physiological findings to females is not universally appropriate and may even be detrimental. Thus, addressing this imbalance and taking into consideration sex as a biological variable is mandatory for optimization of precision exercise interventions and/or regimens. Our present analysis focused on establishing multiomic profiles in young, exercise-naïve males (n=23) and females (n=17) at rest and following acute exercise. Sex differences were characterized at baseline and following exercise using skeletal muscle and extracellular vesicle transcriptomics, whole blood methylomics, and serum metabolomics. Sex-by-time analysis of the acute exercise response revealed notable overlap, as well as divergent molecular responses between males and females. An exploratory comparison of two combined exercise regimens (high-intensity: HITT and traditional: TRAD) was then performed using singular value decomposition, revealing latent data structures that suggest a complex dose-by-sex interaction response to exercise. These findings lay the groundwork for an understanding of key differences in responses to acute exercise exposure between sexes. This may be leveraged in designing optimal training strategies, understanding common and divergent molecular interplay guiding exercise responses, and elucidating the role of sex hormones and/or other sex-specific attributes in responses to acute and chronic exercise.

Extracellular vesicles (EVs), membrane-encapsulated nanoparticles shed from all cells, are tightly involved in critical cellular functions. Moreover, EVs have recently emerged as exciting therapeutic modalities, delivery vectors, and biomarker sources. However, EVs are difficult to characterize, because they are typically small and heterogeneous in size, origin, and molecular content. Recent advances in single EV methods have addressed some of these challenges by providing sensitive tools for assessing individual vesicles; one example is our recently developed Single Extracellular VEsicle Nanoscopy (SEVEN) approach. However, these tools are typically not universally available to the general research community, as they require highly specialized equipment. Here, we show how single EV studies may be democratized via a novel method that employs super-resolution radial fluctuations (SRRF) microscopy and advanced data analysis. SRRF is compatible with a wide range of microscopes and fluorophores. We herein quantified individual EVs by combining affinity isolation (analytical protocol based on SEVEN) with SRRF microscopy and new analysis algorithms supported by machine learning-based EV assessment. Using SEVEN, we first optimized the workflow and validated the data obtained on wide-field and total internal reflection fluorescence microscopes. We further demonstrated that our approach, which we call the SEVEN-Universal Protocol (SEVEN-UP), can robustly assess the number, size, and content of plasma and recombinant EVs. Finally, we used the platform to assess RNA in EVs from conditioned cell culture media. Using SYTO RNASelect dye, we found that 18% of EVs from HEK 293T cells appear to contain RNA; these EVs were significantly larger compared with the general EV population. Altogether, we developed an economical, multiparametric, single EV characterization approach for the research community.

Introduction: While there may be microbial contributions to Alzheimer's disease (AD), findings have been inconclusive. We recently reported an AD-associated CD83(+) microglia subtype associated with increased immunoglobulin G4 (IgG4) in the transverse colon (TC)., Methods: We used immunohistochemistry (IHC), IgG4 repertoire profiling, and brain organoid experiments to explore this association., Results: CD83(+) microglia in the superior frontal gyrus (SFG) are associated with elevated IgG4 and human cytomegalovirus (HCMV) in the TC, anti-HCMV IgG4 in cerebrospinal fluid, and both HCMV and IgG4 in the SFG and vagal nerve. This association was replicated in an independent AD cohort. HCMV-infected cerebral organoids showed accelerated AD pathophysiological features (Aβ42 and pTau-212) and neuronal death., Discussion: Findings indicate complex, cross-tissue interactions between HCMV and the adaptive immune response associated with CD83(+) microglia in persons with AD. This may indicate an opportunity for antiviral therapy in persons with AD and biomarker evidence of HCMV, IgG4, or CD83(+) microglia., Highlights: Cross-tissue interaction between HCMV and the adaptive immune response in a subset of persons with AD. Presence of CD83(+) microglial associated with IgG4 and HCMV in the gut. CD83(+) microglia are also associated presence of HCMV and IgG4 in the cortex and vagal nerve. Replication of key association in an independent cohort of AD subjects. HCMV infection of cerebral organoids accelerates the production of AD neuropathological features., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)