Maternal hypothalamic-pituitary-adrenal axis functioning has important implications for maternal and offspring health, yet findings on cortisol responsivity to acute stress during pregnancy are mixed. Further, little is known about how childhood stress exposure relates to physiological stress regulation during this period, particularly among Black and White women. The present study leveraged multiple waves of prospectively gathered data from a large population-based sample to examine associations between degree of exposure to subsistence-, safety- and caregiving-related stress across childhood and cortisol responsivity during a later pregnancy. Participants (N = 338, 69.7% Black, 26.7% White) were enrolled in the longitudinal Pittsburgh Girls Study in middle childhood. Caregivers reported annually on exposure to a range of stressors when participants were 7–17 years of age. During a prenatal laboratory visit in which participants were between 22 and 31 years of age, participants completed the Trier Social Stress Test (TSST) and provided saliva samples for cortisol assay. Adjusting for covariates, the TSST did not produce a significant increase in cortisol levels over time, though 28.3% of participants were classified as responders. Greater exposure to subsistence-related stress (e.g., resource strain, housing instability) across childhood was associated with blunted cortisol levels during pregnancy. Findings suggest that childhood exposure to subsistence-related stress may have enduring effects on physiological stress regulation and underscore the potential value of targeted preventive interventions to promote intergenerational health. Results also highlight the relevance of public health initiatives aimed at reducing population-level differences in subsistence-related stress exposure.
High-grade dysplastic nodules (HGDN) are recognized precursors of hepatocellular carcinoma in cirrhosis, yet their distinction from macro-regenerative nodules (MRN) relies entirely on morphologic features that exist along a continuum rather than as discrete thresholds, with no ancillary marker available to adjudicate this boundary. Whether these lesions represent distinct molecular states remains unknown. We performed whole-transcriptome spatial profiling (GeoMx Digital Spatial Profiler, Bruker) of MRN and HGDN within their native cirrhotic microenvironment in FFPE explant specimens from three patients. Fifteen regions of interest spanning background cirrhosis (n = 2), MRN (n = 3), HGDN (n = 4), and the HGDN–cirrhotic interface (n = 6) underwent exploratory differential expression and gene set enrichment analyses; because MRN and HGDN derived from different patients, lesion class and donor could not be separated. MRN showed a quiescent regenerative program characterized by HGFAC upregulation, depletion of inflammatory and immunoglobulin transcripts, and no significant upregulation of canonical hepatocellular carcinoma markers. HGDN showed PZP, DEPP1, and CDHR5 upregulation and enrichment of interferon signaling. Spatially, HGDN separated into a metallothionein-enriched core and an MHC-I/interferon-enriched interface expressing HLA-B, HLA-C, and IFI6, a pattern that bulk profiling would be expected to obscure; the core–interface distinction persisted when analysis was restricted to a single patient. In this pilot cohort, morphologically defined regenerative and premalignant hepatocellular nodules showed distinct transcriptional profiles, providing preliminary, hypothesis-generating molecular support for a difficult morphologic distinction. These observations, including the MHC-I/interferon-enriched dysplastic interface, identify candidate targets for validation in larger cohorts with paired lesions.
Background Growing evidence suggests the experience of social exclusion is associated with increased risk for developing cardiovascular disease (CVD), however the psycho-neuro-immune mechanisms involved in this process remain unclear. Peripheral blood mononuclear cells (PBMCs) play an important role in the etiology of peripheral artery disease. Previous research has uncovered beta-adrenergic receptor inhibitory control (BARIC) of inflammation is blunted in PBMCs from individuals at greater risk for CVD. Furthermore, perceived social threat is shown to upregulate inflammatory processes in PBMCs. Given the excess burden of chronic inflammation and exposure to social ostracism reported in people living with HIV (PWH), the current study utilized an fMRI task paradigm to evaluate whether magnitude of blood oxygen level dependent (BOLD) response to social exclusion is associated with the time course of BARIC in CD16+ monocytes in relation to peripheral arterial stiffness. Methods BOLD response to the exclusion versus inclusion trials of a modified Cyberball task were measured in 25 PWH (50.8 ± 10.3 yrs) and 19 people living without HIV (PWoH) (52.8 ± 11.9 yrs.). CD16+ monocytes, collected 45 min before, 45 min and 90 min after Cyberball, were isolated using magnetic bead separation (StemCell™) and incubated for 18-hr following co-stimulation with lipopolysaccharide (LPS) and the non-selective beta-receptor agonist isoproterenol. BARIC was operationalized as the difference in TNF-α expressed by LPS-stimulated CD16+ monocytes without vs. with isoproterenol. A repeated measures ANCOVA assessed whether BOLD response to social exclusion in the subgenual anterior cingulate (sgACC), relates to change in BARIC of TNF-α following the encounter. The interactive effect of HIV+ status and BARIC on peripheral arterial stiffness was evaluated using multiple regression while controlling for age and gender. Results Whole-brain analysis revealed sgACC BOLD activation was significantly greater in the sgACC during exclusion compared to inclusion trials surviving FWE small-volume correction (p < 0.05, FWE-SVC). Compared to the middle and highest tercile, individuals within the lowest tercile of sgACC BOLD activation showed an initial BARIC response pre-task followed by a respective decline and recovery in BARIC immediate and 90 minutes post-task (F(1,32) = 5.471, p = .023, η2 = 0.152). Although these neuro-immune associations were not moderated by HIV status, greater BARIC was associated with lower arterial stiffness in PWoH and higher arterial stiffness in PWH (β = −0.89, t = −2.176, p = 0.040). Conclusion This study supports the role of sgACC in processing social exclusion and relevance of this biobehavioral response to the time course of beta-adrenergic receptor-mediated inhibitory control of TNF-α expression in intermediate and non-classical monocytes. Further this study provides preliminary evidence of a paradoxical association between greater BARIC of monocyte inflammation and arterial stiffness in PWH who have not yet developed CVD. Replication of these observations is warranted within a larger cohort to determine the contribution of these processes to the development of CVD.
Severe worry and anxiety in late life are linked to increased risk of Alzheimer’s disease (AD), but underlying neural mechanisms remain unclear. Severe worry is associated with reduced hippocampal volume. One proposed mechanism is stress-related glutamate excitotoxicity, which may contribute to hippocampal atrophy and cognitive decline. This pilot study examined whether anxiety, worry, and cognitive function are associated with markers of glutamate excitotoxicity, specifically hippocampal glutamate and N-acetyl aspartate (NAA). Eighteen older adults with varying worry underwent 7T magnetic resonance spectroscopy of left and right hippocampus and clinical and cognitive assessments. Linear regression analyses examined associations between anxiety, cognitive performance, and hippocampal metabolites, controlling for volume. Exploratory analyses assessed additional metabolites, including creatine, gamma-aminobutyric acid (GABA), glutathione, and myo-inositol. Greater worry severity and lower overall cognitive function were associated with reduced hippocampal NAA levels. Higher global anxiety was associated with lower hippocampal glutamate. Exploratory analyses revealed additional relationships between other metabolites and both mood symptoms and cognition. These preliminary findings suggest hippocampal metabolic markers may play a role in late-life anxiety and worry. However, results provide only partial support for glutamate excitotoxicity as a mechanism linking anxiety to cognitive impairment, highlighting the need for larger studies.
Background Human metapneumovirus (HMPV) is a significant cause of respiratory infection, yet no licensed vaccine exists. Variability across viral subgroups, particularly in the attachment (G) protein, can complicate universal design. We assessed the immunogenetic regions in the fusion (F) and G proteins to identify stable vaccine targets. Methods We analyzed N = 324 Pittsburgh and N = 655 global HMPV genomes (2017–2022) for genome diversity per viral subgroup. Previously identified epitope sequences were obtained from the Immune Epitope DataBase (IEDB) for F and G proteins and sequence similarity was determined. Using NetMHCpan-4.1, we identified and computed inferred human leukocyte antigen (HLA) binding affinities for 15 epitope variants (1 or 2 substitutions) against universally common human alleles. Results The F protein was highly conserved across all subgroups (>96% amino acid sequence identity). In the G protein, we identified a conserved epitope cluster (G3–G7) where epitope G7 was present in 91% of A2 genomes. Functional modeling of the G-protein epitope variants revealed that the majority of HLA alleles maintained or gained binding affinity, a subset exhibited diminished binding (escape), suggesting these regions are subject to ongoing antigenic drift. B-genotypes showed fewer retained binders and were notably underrepresented in the current epitope databases. Conclusion The conserved F protein remains an optimal target for neutralization, while the G3–G7 cluster provides a robust secondary target for T-cell mediated immunity. A bivalent vaccine strategy could pair the stable F protein with these high-frequency G-protein epitopes to elicit an immune response. This approach addresses the A2 subgroup, and incorporating B-genotypes through ongoing surveillance and epitope mapping will be essential to achieve comprehensive, multi-antigen coverage across circulating HMPV strains.
