Faculty Bibliography

Following peripheral nerve injury, Schwann cell (SC) survival is imperative for successful nerve regeneration. The low-density lipoprotein receptor-related protein-1 (LRP1) has been identified as a pro-survival SC plasma membrane signaling receptor, however, the responsible mechanisms underlying SC homeostasis remain incompletely understood. Herein, we establish that LRP1 largely manages mitochondrial dynamics and bioenergetics in SCs by limiting mitochondria fission, maintaining healthy mitochondria membrane potentials, and reducing lactate production associated with peripheral sensitization. When SC LRP1 is suppressed, inner-mitochondria-linked pathways in peripheral nerve proteome are dramatically altered, and cristae integrity in unmyelinated C-fibers is compromised. SC LRP1 protected sensory neurons from mitochondrial dysfunction and modulated mitochondria-related biological pathways in the DRG transcriptome. Conditional deletion of LRP1 in SCs induces pain-related behaviors in mice without nerve injury. Results point to a significant role for LRP1 in SC mitochondrial homeostasis and advance our understanding of the sensory neuron response to alterations in SC bioenergetics.

Perineural invasion (PNI) frequently occurs in head and neck squamous cell carcinoma (HNSCC), which correlates with poor survival and induces intractable pain and numbness. There is no effective treatment for PNI or associated pain. To gain a better understanding of PNI at the molecular and cellular level, we produced an orthotopic, syngeneic mouse model of PNI by inoculating mouse oral cancer cells into the infraorbital nerve (ION), a nerve that is susceptible to cancer invasion in patients with HNSCC. Mice with PNI in the ION exhibited both evoked and spontaneous nociception and impaired oral function, mimicking human conditions. PNI resulted in a drastic reduction in the proportion and altered mechanical thresholds in mechanically sensitive trigeminal neurons; axon and myelin abnormalities, as well as phagocytic cells, were observed. The tumor bed is marked by CD4⁺ and CD8⁺ T cells, CD68⁺ cells, and F4/80⁺ macrophages, while CD4⁺, CD8⁺, and CD68⁺ immune cells can be found surrounding the nerve. The intraneural niche is predominantly marked by CD68 that does not overlap with F4/80 but instead overlaps with NF200 and MPZ and occasionally with DAPI, suggesting these are likely phagocytic macrophages or Schwann cells. Finally, our RNA sequencing pathway analysis in mouse and human HNSCC found perturbed pathways in neuroinflammation, mitochondrial dysfunction, and cellular metabolism. Additionally, ION-PNI exhibits nerve degenerative features with perturbed pathways that are observed in Alzheimer, Parkinson, and prion diseases. In conclusion, we report a novel, anatomically relevant in vivo model that could be used to study the cellular and molecular mechanisms of PNI-induced neuropathies. Importantly, we found that PNI resembles neurodegenerative diseases with features of altered sensory transduction and conduction, neuroinflammation, and mitochondrial dysfunction, which may underlie peripheral neuropathies, such as pain.

BACKGROUND:) pose a major challenge to curing HIV, with many of its mechanisms still unclear. HIV-1 DNA integration and immune responses may alter the host's epigenetic landscape, potentially silencing HIV-1 replication. METHODS:. RESULTS:-associated genes were enriched on the pathways related to immune defence, transcription repression and host-virus interactions. CONCLUSIONS:These findings suggest that HIV-1 reservoir is linked to aberrant DNA methylation in CD4+ T cells, offering new insights into epigenetic mechanisms of HIV-1 latency and potential molecular targets for eradication strategies. KEY POINTS/CONCLUSIONS:Study involved 427 women with HIV. Identified 245 aberrant DNA methylation sites and 85 methylation regions in CD4+ T cells linked to the HIV-1 reservoir. Highlighted genes are involved in viral replication, immune defence, and host genome integration. Findings suggest potential molecular targets for eradication strategies.

OBJECTIVE:This cross-sectional study investigated the associations of neighborhood-level factors with immune activation, systemic inflammation, and leukocyte telomere length in 110 sexual minority men with human immunodeficiency virus. METHOD/METHODS:From 2013 to 2017, sexual minority men with human immunodeficiency virus who used stimulants were recruited in San Francisco, California and provided blood samples to measure the markers of immune activation, systemic inflammation, and leukocyte telomere length. To measure neighborhood-level indices, the home address for each participant was geocoded and linked to data from the Centers for Disease Control and Prevention. Hierarchical linear modeling was employed to investigate the associations of neighborhood-level factors with systemic inflammation and leukocyte telomere length. RESULTS:After adjusting for age, stimulant use, self-reported income, level of education, and race and ethnicity, residing in neighborhoods with greater percentages of poverty (β = .33, p < .001) and a higher proportion of racial/ethnic minority residents (β = .26, p < .05) were independently associated with higher levels of interleukin-6. Additionally, residing in neighborhoods with higher percentage of uninsured individuals was independently associated with higher tumor necrosis factor-alpha (β = .24, p < .05). Indices of neighborhood-level adversity were additionally associated with providing a urine sample that was reactive for stimulants (OR = 1.31, p = .002), which was, in turn, associated with shorter leukocyte telomere length (β = -.31, p < .05). CONCLUSIONS:Future longitudinal research should examine the biobehavioral pathways linking neighborhood-level factors and stimulant use with systemic inflammation and cellular aging. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

OBJECTIVE:Past correlational research has shown that minority stress has direct and indirect effects on the biology of sexual minority people. This pilot randomized controlled trial (RCT) examined the potential of AWARENESS, a nine-session cognitive behavioral intervention to reduce intersectional minority stress, to alter gene expression related to immune function, inflammation, and HIV disease progression. METHOD/METHODS:Between 2016 and 2019, 25 sexual minority men living with HIV with recent substance use (n = 12 in AWARENESS and n = 13 in control) were enrolled, a subset with complete gene expression data among the 41 individuals within the parent RCT. Blood samples were taken prior to the intervention, at the 9-week conclusion of the intervention, and at 4 months postrandomization, and leukocyte RNA was sequenced for all samples. The authors examined differential expression analyses of single genes and overrepresentation analysis of gene sets. RESULTS:Neither AWARENESS nor the control condition was related to the differential expression of single genes. Overrepresentation analysis suggested that AWARENESS was related to changes over time in gene expression in leukocyte RNA in 52 gene sets (q < .05), many of which are related to immune function, while the active control condition was related to changes in gene expression among genes in only one gene set. When AWARENESS was compared to the control condition, four gene sets evidenced an overrepresentation of genes reflecting change over time. CONCLUSIONS:This RCT suggests that AWARENESS is associated with changes in gene expression, primarily focused on changes in genes associated with immune processes. (PsycInfo Database Record (c) 2025 APA, all rights reserved).

BACKGROUND:Depression affects 33% of women with type 2 diabetes (T2D) and leads to increased risks of premature mortality. Fluctuation and variation of depressive presentations can hinder clinical identification. PURPOSE/OBJECTIVE:We aimed to identify and examine subgroups characterized by distinct depressive symptom trajectories among women with T2D. METHODS:This retrospective analysis leveraged the Women's Interagency HIV Study data to identify depressive symptom trajectories based on the Center for Epidemiological Studies Depression scores (2014-2019) among women with and without HIV. Descriptive statistics characterized sample demographics (eg, age, race, income), clinical indices (eg, hemoglobin A1C [HbA1c], BMI, HIV status), and psychosocial experiences (eg, discrimination, social support, anxiety, pain). We used growth mixture modeling to identify groups defined by distinct depressive symptom trajectories and parametric and non-parametric tests to examine demographic, clinical, and psychosocial differences across subgroups. RESULTS:Among the 630 women included, the mean age was 50.4 (SD = 8.3) years, 72.4% identified as Black and non-Hispanic, and 68.2% were living with HIV. Five subgroups were identified and distinguished by severity and symptom type. Participants with lower incomes (P = .01), lower employment (P < .0001), lower social support (P = .0001), and experiences of discrimination (P < .0001) showed greater membership in threshold, moderate, and severe depressive subgroups. Subgroup membership was not associated with metabolic indices (BMI, HbA1c) or HIV status. Anxiety, pain, and loneliness (all P = .0001) were worse in subgroups with higher depressive symptoms. CONCLUSIONS:Among women with T2D, depressive symptom trajectories differ across clinical and social contexts. This study advances precision by delineating subgroups within a broad clinical category.