Galveston College

Microglial cells exhibit crucial metabolic adaptations to maintain neural homeostasis. However, their dysregulated activation during infections can lead to neurotoxicity and contribute to the development of neuroinflammatory disorders. Understanding the physiological and metabolic changes of microglia during immune activation is crucial for identifying protective targets against neuroinflammation. This study investigates how the Zika virus (ZIKV) alters microglia metabolism during inflammation, highlighting cellular adaptations that sustain oxidative metabolism linked to cell survival during cellular activation and viral replication. After identifying an enriched abundance of proteins related to oxidative phosphorylation and cellular component organization in the global proteomics of mouse brains following ZIKV exposure, we investigated the relevance of these pathways during in vitro infection of human microglia. ZIKV infection led to cytoskeleton remodeling via β-tubulin reallocation, which characterized an ameboid-like phenotype. Despite the indication of a shift toward increased glycolytic activity due to decreased intracellular glucose, which suggests its consumption, and the accumulation of tricarboxylic acid cycle (TCA) intermediates, ZIKV-infected microglia exhibit enhanced respiratory capacity and an abundance of smaller-sized mitochondria in the perinuclear region. The accumulation of citrate, succinate, and malate, while maintaining mitochondrial function, suggests an important metabolic adaptation that supports biosynthetic pathways and sustains cell viability under stress. Decreased intracellular glutamate abundance supports mitochondrial oxidative metabolism. Pre-treatment with the anti-inflammatory docosahexaenoic acid (DHA) mitigates ZIKV-induced metabolic alterations by reducing pro-inflammatory markers, downregulating viral entry receptors, and lowering microglial activation and viral load. This study reveals that while ZIKV induces cell death in neuronal-like cells, the mitochondrial adaptation observed in microglial infection could be a key to maintaining cell survival throughout neuroinflammation. Our findings elucidate a novel cellular adaptation during ZIKV infection involving β-tubulin reorganization and metabolic dynamics, reflecting microglial flexibility and resistance during neuroinflammation, and demonstrating the therapeutic potential of DHA in mitigating ZIKV-induced pathology.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12035-025-05418-y.

BackgroundPopulation studies of cognitive functioning rely on survey questionnaires to estimate the prevalence of dementia in nationally representative samples. In addition to direct tests of cognitive functioning, the international studies as part of the Harmonized Cognitive Assessment Protocol, also include informant questionnaires, in which a family member or other person close to the research participant are asked about the participant's cognitive functioning. While international harmonized measures of directly assessed cognitive have been developed, there are no statistical harmonizations of informant assessments of cognitive functioning.MethodThis study investigates differences in how informants respond to questions about cognitive functioning in the US and Mexico. Using data from the Harmonized Cognitive Assessment Protocol (HCAP) of the Health and Retirement Study (HRS) (n = 3,183) in the United States and the Mexican Cognitive Aging Study (MexCOG) (n = 1,259) in Mexico, we examined informant reports of cognitive functioning of the Community Screening Instrument for Dementia (CSID). We test for differential item functioning (DIF) using structural equation modeling (SEM) to develop a confirmatory factor analysis (CFA) model of the CSID informant questionnaire in Mexico and the U.S.ResultWe find that a harmonized measure of the CSID has fixed factor loadings between countries but different item thresholds. Our harmonized measure of informant reports of cognitive functioning suggests that informants report less cognitive impairment for older adults in Mexico when controlling for directly assessed cognitive functioning.ConclusionOur results suggests that either the harmonized direct assessment of cognition may underestimate cognitive functioning in Mexico or that informants in Mexico are systematically under reporting symptoms of cognitive decline.

Abstract Objective This study explores the mediating effect of social activities on the association between hearing status and cognitive function across three countries. Method Data from three waves of the HRS (United States), MHAS (Mexico), and CHARLS (China), collected from 2011 to 2021, were analyzed. Multilevel models were used to examine the association between self-reported hearing status (fair/poor vs. good/excellent) and verbal memory. The mediating effects of social activities were assessed using the Karlson-Holm-Breen (KHB) method. Results Fair/poor hearing was associated with lower verbal memory in the HRS (b=-0.145, SE = 0.023) and CHARLS (b=-0.056, SE = 0.020), but not in MHAS (b=-0.001, SE = 0.018). Social activities were positively associated with verbal memory in all three datasets. Fair/poor hearing was associated with reduced social activities in the HRS (OR = 0.838, p < 0.001), MHAS (OR = 0.847, p < 0.01), and CHARLS (OR = 0.779, p < 0.001). The association between self-rated hearing and verbal memory remained statistically significant after adjusting for social activities in the HRS (b=-0.144, SE = 0.023) and CHARLS (b=-0.045, SE = 0.021). Conclusion We did not find universal mediation effects of social activities on the association between hearing status and verbal memory. These findings underscore the need for context-specific approaches to addressing sensory loss and cognitive health.

Abstract Objective ObjectiveThis study intends to examine the education gradients in functional limitations for older adults in Mexico by comparing effect size between two birth cohorts age 60-76 in 2001 versus 2018. Methods Data were drawn from the Mexican Health and Aging Study (MHAS) 2001 and 2018 waves. Tobit model was used to estimate the education gradient in functional limitations. Living conditions in childhood (pluming in house, parents’ education, and serious health conditions), chronic conditions, and the longest work were adjusted for. The cohort difference was tested by including interaction effects and propensity matching scores. Results Compared to the 2001 cohort, the 2018 cohort presented lower proportion of no education, and higher proportion in each level of education, especially the secondary and tertiary education. Education gradients were significant in functional limitations for each birth cohort, but the education gradient was attenuated for the 2018 cohort compared to the 2001 cohort. Living conditions in childhood have long-term effects on functional limitations in later life. Agricultural and industrial work contribute to greater functional limitations. No different effects of primary job/work and early life conditions between the cohorts were detected. Conclusion Disregarding the average higher levels of education within the 2018 wave birth cohort, the education gradients in functional limitations decreased compared to the early birth cohort in 2001 wave.

Background: Cancer therapy–related cardiac dysfunction (CTRCD) is a well-recognized adverse effect of HER2-targeted therapies, particularly trastuzumab. While current guidelines recommend serial left ventricular ejection fraction (LVEF) monitoring every 3 months during treatment, such uniform surveillance may lead to overutilization in low-risk patients. Objective: This study aimed to externally validate a nomogram from Memorial Sloan Kettering to predict CTRCD in a contemporary cohort of patients with HER2-positive breast cancer. Methods: This retrospective study included women with HER2-positive breast cancer treated with trastuzumab between 2013&2022 at a large cancer center. The primary endpoint was 1-year CTRCD-free survival, with CTRCD defined as an LVEF decline ≥10% to <53% or a ≥16% reduction from baseline. Patients were stratified into risk groups based on total nomogram points. Model performance was evaluated in the validation cohort using Kaplan-Meier estimates, calibration plots, concordance index (C-index), and area under the ROC curve (AUC). Results: The derivation and validation cohorts demonstrated notable differences in baseline characteristics. Patients in the validation cohort (n=356) had a higher mean BMI (39.6% vs. 22.9%) and greater prevalence of cardiovascular comorbidities, including hypertension (34.8% vs. 23.5%), diabetes (11.5% vs. 7.2%), and hyperlipidemia (24.7% vs. 17.1%) but with substantially lower anthracycline exposure (31.5% vs. 77.8%) compared to the derivation cohort. 9.6% of patients developed CTRCD within 395 days of trastuzumab initiation, which was defined as the 1-year CTRCD event. The 1-year CTRCD event rates across increasing quartiles of the nomogram score were 6.0%, 4.4%, 9.6%, and 19.5%, respectively, indicating effective risk stratification. Kaplan-Meier–estimated 1-year CTRCD-free survival was 90.1%, closely aligned with the nomogram-predicted probability of 87.8%. The model demonstrated excellent discriminative performance, with a C-index of 0.68 (95% CI, 0.49–0.86) and an AUC of 0.69 (95% CI, 0.58–0.78) (Figure A, B). Conclusion: The novel CTRCD nomogram demonstrated excellent discriminatory power and generalizable to an independent, real-world patient population. These findings support its utility for personalized CTRCD risk stratification and suggest its potential to guide less frequent LVEF monitoring in low-risk patients receiving HER2-targeted therapy.

Introduction and Objective: Barriers to accessibility and communication hinder diabetes care in underserved communities. Integrating mobile health (mHealth) and community health workers (CHWs) into care models offers significant potential to address these challenges but requires thorough evaluation. We assessed the effectiveness of an mHealth-driven feedback loop connecting participants, CHWs, and clinicians across multiple health systems Methods: A total of 258 uninsured Hispanic participants with type 2 diabetes were randomly assigned to either standard care at their community clinic (control) or a 12-month comprehensive diabetes education program. This program included group education, YouTube video highlights, and a weekly mHealth-driven Participant-CHW-Clinician feedback loop to identify participant concerns. Outcomes measured included (1) HbA1c (primary) from baseline to 12 months, (2) adherence to pre-defined ADA preventive care measures, and (3) the execution of feedback loops to identify and resolve participant issues. Results: *Compared to the control arm, intervention participants showed a significant improvement in HbA1c (intervention:−1.0% vs. control:−0.1%, p = 0.002) and demonstrated better adherence to preventive care for diabetes foot exams (p<0.01) and statin therapy (p=0.04). CHWs identified 815 issues (average=6.5 per participant) and resolved 90% of them through the feedback loop model. The majority of issues were related to supplies (25%), physical health (20%), and medication access (20%). *final data will be completed by April 30, 2025 Conclusion: An mHealth-based feedback loop connecting participants, CHWs, and clinicians was associated with improved HbA1c levels, better adherence to ADA guidelines, and the identification and resolution of participant issues. Future research is needed to identify implementation strategies that can enhance the sustainability of the program. Disclosure E.M. Vaughan: None. C. Johnston: None. A. Amspoker: None. A. Balasubramanyam: None. S. Virani: None. C.M. Ballantyne: Research Support; Abbott Diagnostics. Consultant; Abbott Diagnostics, 89bio, Inc. Research Support; Akcea Thearpeutics, Inc, Amgen Inc. Consultant; Amarin Corporation, Amgen Inc. Research Support; Arrowhead Pharmaceuticals, Inc. Consultant; Arrowhead Pharmaceuticals, Inc, AstraZeneca, Denka Seiken, ESPERION Therapeutics, Inc., Genentech, Inc, Illumina. Research Support; Ionis Pharmaceuticals. Consultant; Ionis Pharmaceuticals, Eli Lilly and Company. Research Support; Merck & Co., Inc. Consultant; Merck & Co., Inc. Research Support; NewAmsterdam Pharma. Consultant; NewAmsterdam Pharma. Research Support; Novartis Pharmaceuticals Corporation. Consultant; Novartis Pharmaceuticals Corporation. Research Support; Novo Nordisk. Consultant; Novo Nordisk. Research Support; Roche Diagnostics. Consultant; Roche Diagnostics. L.R. Porterfield: None. Funding NIH/NIDDK (R01 DK129474)

Innovation in biomedical research has increased markedly over the last few decades. However, clinical, therapeutic, and public health advances have often not yielded expected improvements in health outcomes nor reduced disparities. Translational science was developed to improve social benefits related to research and development. We propose a practical model for socially responsible translational science that aims to better align research with its expected social benefits. Scientists and community members from the Houston-Galveston region participated in 12 focus groups and a one-day Deliberative Dialogue Summit to examine the expected social benefits of science, establish the factors and practices of social responsibility, and design an empirical model for socially responsible translational science. Researchers and community members discussed three distinct fields of research - HIV, maternal health, and mental health and substance use disorders. We conducted deductive qualitative data analysis based on theoretical social responsibility criteria of translational science, namely: relevance, usability, and sustainability. We then developed inductive codes to capture the factors and practices identified during discussions as necessary for the translation of research to increase social benefit. First, participants explored ways to broaden the scope of biomedical research beyond a narrow emphasis on scientific impact to also consider social impacts and determinants of health; this heightens the relevance of research and underscores its responsibility to address social needs and reduce inequities. Second, to improve usability of translational research, participants suggested increasing access to research products, processes, and participation. They also recommended modifying the research infrastructure to incorporate other systems that can assist with translation including the system of care and the broader community-based systems. Third and finally, for the long-term sustainability of research practices, co-development and co-funding of research was promoted to include local community needs, cultures, knowledges and preferences from project commencement to completion.

Abstract Introduction/Rationale of the study: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in young children. Several cytokines, innate and inflammatory mediators have been detected in the nasopharyngeal secretions (NPS) of RSV-infected patients, but their origin and physical status in fluid or other subcellular components of the NPS secretome remain to be determined. Extracellular vesicles (EVs) are nanoparticle released by cells and carry a cargo of molecules that can modulate the responses of target cells to viral infection. In this study, we used a model of RSV-infected human nose organoids-derived epithelial cells (HNO-EPI) and NPS of RSV-infected children to analyze the protein composition of secreted EVs. Methods: EVs were isolated from the supernatant of an uninfected (mock-EVs) and RSV-infected (RSV-EVs) pediatric HNO-EPI cultured in air liquid interface (24h at MOI of 1) and from NPS samples of ten hospitalized children < 2 years who were tested positive for RSV and from six control uninfected children. EVs were purified using a two-step method: precipitation followed by CD63 exosome capture beads and characterized for particle number, size and specific EV markers by Exocheck arrays. EV-associated cytokines and inflammatory mediators were determined by Proximity Extension Assay (PEA) technology and multiplex antibody-based arrays (Luminex), along with LC-MS/MS analysis of NPS EV proteome. Results: PEA and Luminex arrays showed increased levels of several chemokines, including CCL2, CCL20, CXCL5, CX3CL1 and CXCL6 in EVs secreted by RSV-infected HNO-EPI compared to Mock HNO-EPI. EVs derived from RSV-infected HNO-EPI were also enriched in other proteins, such as MMP-1, MMP-10, uPA, Flt3L, ARNT and CD40. Analysis of samples from RSV infected children showed that some proteins such as CCL3, CCL20, CXCL8, uPA, VEGFA, were mostly concentrated in the EV fraction of the NPS secretome. LC-MS/MS followed by bioinformatics/Gene Ontology suggest that that NPS-EVs of children with RSV infections come from different cellular sources, with the most abundant proteins originating from neutrophils end epithelial cells. Conclusions: Understanding the protein cargo in EVs from upper airways will enhance insight into virus-mediated mechanisms of disease in young RSV patients. The packaging of innate immune mediators, such as cytokines, in EVs could protect them from cellular degradation and be indeed a crucial mechanism for regulating innate and antiviral responses both locally and distantly from the initial site of viral entry, which might otherwise evade targeting by cytokines in their soluble, circulating form.