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Comparative single-cell immune responses in peripheral blood and lymph node of immunized SARS-CoV-2 challenged infant rhesus macaques
Get PDFA better understanding of post-exposure immune responses in vaccinated individuals, particularly infants, is needed. Using a rhesus macaque model, we compared recipients of mRNA- or protein-based SARS-CoV-2 vaccines administered in infancy with unvaccinated controls 7 days post-SARS-CoV-2 virus challenge. Mass cytometry profiling of peripheral blood mononuclear cells and dissociated mediastinal lymph node cells at 7 days post-challenge revealed tissue-specific differences between groups, representing a snapshot of immune activity at this point. Vaccinated animals showed lower frequencies of activated CD8+ T cells in blood and lower levels of monocyte and B cell subsets in lymph nodes, aligning with lower viral loads and milder pathology. Plasmacytoid dendritic cells—commonly depleted in circulation during severe human COVID-19—were preserved in the blood of vaccinated groups. Ex vivo stimulation demonstrated heightened inflammatory cell signaling from unvaccinated rhesus macaques, correlating with worse clinical outcomes. These findings enhance our understanding of a critical nonhuman primate model and underscore the utility of single-cell, tissue-level analyses in evaluating next-generation pediatric SARS-CoV-2 vaccine strategies
The association of physical activity fragmentation with all-cause mortality in Hispanics: a prospective cohort study
Get PDFBackground Physical activity fragmentation represents the frequency of transitioning from an active to sedentary state. The prognostic information of physical activity fragmentation is unclear in Hispanics/Latinos. This study examined the association of PA fragmentation with all-cause mortality in Hispanic/Latino adults. Methods We investigated 11,992 participants from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (18–74 yr; 52.2% women), from four United States urban communities (Bronx, New York; Chicago, Illinois; Miami, Florida; San Diego, California), that wore an accelerometer for one week. Physical activity fragmentation was calculated using the active-to-sedentary transition probability (ASTP) as the reciprocal of the average active bout duration. Daily total log-transformed activity count (TLAC) was used as a measure of total physical activity. The residual of ASTP regressed on TLAC (TLAC-adjusted ASTP) was explored to investigate the association of ASTP independent of total physical activity. Deaths were identified from annual follow-up interviews, obituary searches, or matches to the National Death Index through December 31, 2021. Cox regression models were fitted according to physical activity fragmentation. Findings There were 745 deaths (6.2%) over a mean follow-up of 11.2 (SD 2.2) years. The highest compared to the lowest tertile of ASTP showed a HR of 1.45 (95% CI 1.10–1.92) of all-cause mortality after accounting for confounders. The mortality risk also increased for each 0.10-unit increase of ASTP, as a continuous variable, by 22% (HR 1.22; 95% CI 1.07–1.39). The results were similar considering TLAC-adjusted ASTP. Interpretation Among Hispanic/Latino adults, more fragmented physical activity was associated with elevated all-cause mortality, independent of total physical activity volume. Funding HCHS/SOL was supported by the National Institutes of Health
Sex-based brain iron differences and inhibitory control in ADHD adolescents
No full textADHD affects children across sexes but is often underdiagnosed in girls, potentially due to differences in neurobiology and behavioral presentation. This study investigated whether there are sex-dependent differences in regional brain iron concentrations among children with ADHD and whether these differences predict performance on a Go/No-Go inhibitory control task. Using BrainMAP neuroimaging data, tissue iron levels were compared across three brain regions in males and females with ADHD. Results revealed that females had significantly lower brain iron concentrations than males in all regions, with all comparisons reaching statistical significance. However, no significant differences were observed in omission rates between sexes, and no correlations were found between brain iron levels and inhibitory control performance. These findings highlight a potential disconnect between biological markers and behavioral measures and underscore the importance of incorporating sex-specific neurobiological data into ADHD assessment frameworks. This work contributes to efforts to improve equitable diagnosis and intervention, particularly for girls whose symptoms may go unrecognized by behavior-based tools alone
Association of Lp(a) With Stroke and Cerebral Injury on MRI: Insights From the HCHS/SOL (Hispanic Community Health Study/Study of Latinos) and Investigation of Neurocognitive Aging MRI (SOL-INCA MRI).
Get PDFBACKGROUND: Lp(a) (lipoprotein[a]) is a risk factor for cardiovascular disease; however, its association with cerebrovascular disease is not as well established. METHODS: Data from a population-based cohort of Hispanics/Latinos included 16 333 individuals with baseline Lp(a) levels (nmol/L) and self-reported prevalent stroke or transient ischemic attack (TIA). A subset of 2642 individuals with brain magnetic resonance imaging was also included. Linear and multivariate logistic regression assessed the association of Lp(a) with (1) self-reported stroke or TIA, (2) cerebral injury defined as self-reported stroke or TIA or evidence of a stroke on brain magnetic resonance imaging, (3) white matter hyperintensity volume, and (4) silent brain infarcts. Sampling weights were utilized given the HCHS/SOL (Hispanic Community Health Study/Study of Latinos) complex sample design. RESULTS: Mean age±SE was 41.1±0.3 years, 52.0% female, and median interquartile range (Q1, Q3) Lp(a) level of 19.7 (7.3-60.6) nmol/L; brain magnetic resonance imaging subset mean age±SE was 49.9±0.4 years, 56.4% female, and median (interquartile range) Lp(a) level of 21.7 (8.1-62.9) nmol/L. Each unit increase in log-transformed Lp(a) was associated with higher odds of self-reported stroke or TIA (odds ratio, 1.13 [95% CI, 1.01-1.27]; P=0.03). Lp(a) levels in the highest quintile (>77 nmol/L) were significantly associated with higher odds of prevalent stroke or TIA compared with Lp(a) <6 nmol/L (first quintile: odds ratio, 1.74 [95% CI, 1.09-2.77]; P=0.02). The highest proportion of cerebral injury was noted in Q5, while the lowest proportion was noted in Q2. When comparing Lp(a) >77 nmol/L with Lp(a) of 6 to <13 nmol/L (second quintile), a significant association was found between Lp(a) and cerebral injury that persisted after fully adjusted models (odds ratio, 2.03 [95% CI, 1.05-3.93]; P=0.03). Each unit increase in log-Lp(a) was associated with a 0.10 increase in log-white matter hyperintensity (β, 0.10; P=0.005). No significant association was found between Lp(a) and silent brain infarcts. CONCLUSIONS: Lp(a) is independently and significantly associated with prevalent stroke/TIA, and white matter hyperintensity, in a large diverse population of Hispanics/Latinos
Prediction of Ambient PM2.5 Chemical Components in Southern California Using Machine Learning
Get PDFFine particulate matter (PM2.5, particulate matter with an aerodynamic diameter ≤2.5 μm) poses major public health and environmental risks, yet the toxicity of its chemical components remains poorly understood due to limited chemical speciation data. In this study we apply an extreme gradient boosting (XGBoost) machine learning framework to predict key PM2.5 components including organic carbon, elemental carbon, nitrate, sulfate, ammonium, and metals, using readily available predictors: total PM2.5 mass concentrations, meteorological variables, trace gas measurements, and indicators of exceptional events (e.g., wildfires, fireworks). Leveraging a decade of data from two monitoring sites in Southern California (Los Angeles and Rubidoux), the models achieved strong predictive performance, particularly for nitrate, ammonium, and elemental carbon. Among the most influential predictors across components were total PM2.5 mass, relative humidity, and boundary layer height. This approach has promise for enhancing satellite remote sensing applications, improving chemical transport model inputs, and generating cost-effective estimates of PM2.5 components during sampling gaps and in regions lacking frequent monitoring. Further research is needed to assess the generalizability of this framework across diverse geographic and climatic settings
HIV-1 accessory protein Vpr possesses a cryptic p300-dependent transcription-promoting activity that is blocked by histone deacetylases in CD4+ T cells
Get PDFAntiretroviral therapy (ART) has dramatically improved the clinical prognosis for people with HIV and prevents HIV transmission. However, ART does not cure HIV infection because of a persistent, latent viral reservoir in long-lived cells such as central memory CD4+ T (TCM) cells. Eliminating or preventing reservoir formation will require a better understanding of HIV-1 latency establishment. We and others have recently shown that host cell factors such as histone deacetylases (HDACs) are critical cellular factors that allow HIV-1 entry into latency. Whether HDACs interact with specific viral factors to regulate latency establishment, however, is unknown. To examine the role of individual HIV-1 accessory proteins, we constructed a panel of HIV-1 reporter strains, each expressing a single HIV-1 accessory protein, and examined them in a primary CD4+ T-cell latency model. Interestingly, we found that the HDAC inhibitor (HDACi) vorinostat potently enhances the effect of the HIV-1 protein Vpr in promoting HIV expression in infected cells, suggesting that Vpr possesses a cryptic transcription-promoting activity that is restricted by HDACs. This activity was dependent on a p300-binding domain of Vpr and inhibited by a selective p300 histone acetyltransferase inhibitor. Interestingly, Vpr expression also resulted in a significant increase in the proportion of infected cells with a central memory (TCM) phenotype. Furthermore, we observed that TCM cells were more resistant to Vpr-induced apoptosis/cell death than other CD4+ T-cell subtypes, indicating that Vpr expression during reservoir formation selects for latent proviruses in TCM cells. Overall, these findings suggest that Vpr plays an important role in shaping the latent reservoir and that HIV-1 latency results, in part, from an HDAC-mediated restriction of Vpr’s transcription-promoting activity. Understanding how viral factors shape the latent reservoir and how host and viral factors interact during HIV-1 latency establishment in CD4+ T cells will aid in the development of new latency-targeting therapies.Author summaryAlthough antiretroviral therapy is effective at treating HIV, a cure remains elusive. The primary obstacle to HIV cure is the presence of a long-lived reservoir of latently infected cells in which the virus persists despite therapy. Recent work has shown that a sizable fraction of this latent reservoir forms near the time that therapy is initiated, suggesting it may be possible to prevent some of the reservoir from forming. However, latency prevention will require a better understanding of how HIV enters latency, including how viral gene expression is silenced. We therefore sought to examine the role of the interaction between viral proteins and host factors in turning off viral gene expression and found that, whereas the HIV protein Vpr turns on viral gene expression, host histone deacetylases block this activity. Second, we observed that Vpr expression in infected cells leads to an increase in the relative proportion of central memory CD4+ T cells, a cell type that harbors latent virus. Our findings on the role of the viral protein Vpr in the silencing of viral gene expression and the persistence of certain memory cell types during infection will be important for developing new approaches to targeting latently infected cells
PEGylation technology: addressing concerns, moving forward
Get PDFPEGylation technology, that is grafting of poly(ethylene glycol)(PEG) to biologics, vaccines and nanopharmaceuticals, has become a cornerstone of modern medicines with over thirty products used in the clinic. PEGylation of therapeutic proteins, nucleic acids and nanopharmaceuticals improves their stability, pharmacokinetic and biodistribution. While PEGylated medicines are safe in the majority of patients, there are growing concerns about the emergence of anti-PEG antibodies and their impact on the therapeutic efficacy of PEGylated medicines as well as broader immune responses, particularly in complement activation and hypersensitivity reactions. These concerns are beginning to scrutinize the future viability of PEGylation technology in medicine design. Here, we outline these concerns, encourage more efforts into looking for comprehensive scientific evidence on the role of anti-PEG antibodies in hypersensitivity reactions, discuss alternatives to PEG and propose strategies for moving PEGylation technology forward
Data Resource Profile: The Finnish TwinRegistry Project.
Get PDFThe Older Finnish Twin Cohort was established 50 years ago and includes twins born in Finland before 1958. Members of the cohort have responded to detailed questionnaires about their health, habits, and lifestyle up to four times, in 1975, 1981, 1991, and 2011. In 2019, the Finnish Parliament approved the Act on the Secondary Use of Health and Social Data, which enables wider use of data from national social and healthcare registers as well as various patient systems and social services. This data resource article describes the linkage of the Older Finnish Twin Cohort to numerous social and healthcare registers, alongside linked data from their families and the broader Finnish population born in 1945-1957, which serves as a reference population for generalizability and other analyses
Emotional Intelligence as a Cornerstone of Success in Ultrarunning: A Synthesis of Meta-Analytic Evidence and Psychological Theory
Get PDFThe sport of ultrarunning, defined as any footrace exceeding the traditional 42.195-kilometer marathon distance, represents one of the most formidable challenges in human endurance.1 These events often traverse demanding and variable terrains, from mountain trails with significant elevation changes to deserts with extreme temperatures, subjecting competitors to profound physiological and psychological stress.3 Athletes routinely face challenges such as dehydration, insufficient energy intake, sleep deprivation, gastrointestinal distress, and intense, often unwanted, emotional states over durations that can extend from several hours to multiple days.5 This extreme context pushes participants to the absolute limits of their physical and mental capabilities, establishing a unique environment where psychological fortitude is not merely an asset but a fundamental component of performance.1
In recent years, a growing body of research has begun to explore the psychological dimensions of endurance sports, moving beyond a purely physiological paradigm to understand what enables athletes to succeed in such grueling conditions.3 Despite a surge in the popularity of ultrarunning, with participation growing over 345% in a single decade, dedicated psychological research has not kept pace, leaving significant gaps in the scientific understanding of these athletes.3 While the importance of psychological factors is widely acknowledged anecdotally—often summarized by the maxim that ultrarunning is "90% mind, and 10% body"—the empirical evidence base remains fragmented.
Identifying and exploiting combinatorial synthetic lethality by characterizing adaptive kinome rewiring of EGFRvIII-driven glioblastoma
Get PDFGBM is an aggressive primary malignant brain tumor that has a poor prognosis. Molecular characterization of GBM has shown that EGFR mutations are present in over 50% of tumors. However, EGFR inhibitors have not shown clinical efficacy in contrast to other EGFR-driven neoplasms due to the unique EGFR biology found in GBM. Upfront combinatorial therapy featuring EGFR tyrosine kinase inhibitors (TKI) may overcome these challenges. To identify combinatorial drug targets within the kinome, we temporally characterized drug-induced kinome rewiring in isogenic, genetically engineered Cdkn2a-deleted mouse astrocytes expressing human EGFRvIII. We utilize RNA sequencing and multiplex inhibitor beads, coupled with mass spectrometry, to demonstrate that kinome rewiring exhibits both shared and unique kinases after acquired resistance develops to EGFR TKI, despite using models with a common genetic background. Additionally, we noted that kinases altered in the acute setting are distinct from those in acquired resistance. By identifying kinome vulnerabilities throughout the acute, dynamic drug response process, we generated a kinase signature associated with EGFR inhibition. Further molecular interrogation of signature genes revealed that drug treatment induces an unexpected increase in Cdk6 protein, but not mRNA, despite live cell imaging and transcriptomic evidence indicating decreased proliferation. Survival experiments with orthotopic allografts show that upfront combination inhibition of Cdk6, using abemaciclib, and EGFR, using neratinib, significantly prolonged median survival compared to neratinib alone. Our findings suggest that identifying and inhibiting targets with synthetic lethality in the upfront combinatorial setting is a viable approach for precision oncology and may help provide an avenue to overcome the resistance mechanisms that contributed to the failures of EGFR as a molecular target in GBM