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BackgroundSex differences in immune-based disorders are well-established, with female sex associated with a markedly heightened risk of autoimmune disease. Female sex is also overrepresented in other conditions associated with elevated inflammation, including depression, chronic pain, and chronic fatigue. The mechanisms underlying these disparities are unclear. This study used an experimental model of inflammatory challenge to interrogate molecular mechanisms that may contribute to female vulnerability to disorders with an inflammatory basis.MethodIn this analysis of a secondary outcome from a randomized controlled trial, 111 participants (67 female) received either a bolus injection of endotoxin (n = 59) or placebo (n = 52). Participants provided blood samples before and 0.5 h post-injection for assessment of differential activation of key pro-inflammatory (i.e., activator protein (AP)-1; nuclear factor (NF)-κB) and immunoregulatory (i.e., glucocorticoid receptor (GR); cAMP response element binding protein (CREB)) signaling pathways via genome-wide expression profiling and promoter-based bioinformatics analyses.ResultsRelative to males, females exhibited greater endotoxin-induced increases in bioinformatic measures of CREB transcription factor activity (p's

BackgroundLatency reversing agents (LRAs) such as protein kinase C (PKC) modulators can reduce rebound-competent HIV reservoirs in small animal models. Furthermore, administration of natural killer (NK) cells following LRA treatment improves this reservoir reduction. It is currently unknown why the combination of a PKC modulator and NK cells is so potent and whether exposure to PKC modulators may augment NK cell function in some way.MethodsPrimary human NK cells were treated with PKC modulators (bryostatin-1, prostratin, or the designed, synthetic bryostatin-1 analog SUW133), and evaluated by examining expression of activation markers by flow cytometry, analyzing transcriptomic profiles by RNA sequencing, measuring cytotoxicity by co-culturing with K562 cells, assessing cytokine production by Luminex assay, and examining the ability of cytokines and secreted factors to independently reverse HIV latency by co-culturing with Jurkat-Latency (J-Lat) cells.ResultsPKC modulators increased expression of proteins involved in NK cell activation. Transcriptomic profiles from PKC-treated NK cells displayed signatures of cellular activation and enrichment of genes associated with the NFκB pathway. NK cell cytotoxicity was unaffected by prostratin but significantly decreased by bryostatin-1 and SUW133. Cytokines from PKC-stimulated NK cells did not induce latency reversal in J-Lat cell lines.ConclusionsAlthough PKC modulators have some significant effects on NK cells, their contribution in "kick and kill" strategies is likely due to upregulating HIV expression in CD4+ T cells, not directly enhancing the effector functions of NK cells. This suggests that PKC modulators are primarily augmenting the "kick" rather than the "kill" arm of this HIV cure approach.

BackgroundEarly-life adversity (ELA) has been linked to higher depression risk across the life span and chronic inflammatory conditions that contribute to earlier mortality. In this study, we characterized innate immune responses to acute social stress in a community sample of adolescents (mean age = 13.9 ± 1.6 years; 46.4% female) as a potential pathway linking ELA and depression pathogenesis.MethodsParents reported their child's exposure to 9 ELAs, and adolescents participated in the Trier Social Stress Test for Children, with blood collected immediately before and then at 60 and 90 minutes thereafter. Overall, 65 adolescents had complete data for analysis of stress-induced changes in gene expression and 84 adolescents had complete data for circulating inflammatory markers.ResultsRelative to adolescents exposed to no ELA (11.9%) or low ELA (ELA = 1-3; 67.9%), those exposed to high ELA (ELA = 4+; 20.2%) showed larger stress-associated increases in expression of both proinflammatory and innate antiviral gene transcripts in circulating blood. Consistent with a potential mediating role of sympathetic nervous system activity, promoter-based bioinformatics analyses implicated CREB transcription factor activity in structuring observed gene expression differences. These effects were accompanied by a smaller initial but protracted increase in circulating interleukin 6 in adolescents with high ELA.ConclusionsResults are consistent with the hypothesis that ELA may enhance cellular and gene regulatory reactivity to stress, which may, in turn, increase vulnerability to depression and other inflammation-related disease processes.

Early life stress (ELS) is common in the United States and worldwide, and contributes to the development of psychopathology in individuals with these experiences and their offspring. A growing body of research suggests that early life stress may contribute to adverse health partly through modulation of immune (and particularly inflammatory) responses. Therefore, increased maternal prenatal inflammation has been proposed as a mechanistic pathway by which the observed cross-generational effects of parental early life stress on child neuropsychiatric outcomes may be exerted. We examined associations between early life stress and molecular markers of inflammation (specifically pro-inflammatory gene expression and receptor-mediated transcription factor activity) and a commonly studied circulating marker of inflammation (C-Reactive Protein) in a diverse group of women in or near their third trimester of pregnancy, covarying for age, race/ethnicity, BMI, concurrent infection, concurrent perceived stress, and per capita household income. Mothers who experienced higher levels of early life stress had significantly increased pro-inflammatory (NF-κB) and decreased anti-viral (IRF) transcription factor activity. Transcripts that were up or down regulated in mothers with high ELS were preferentially derived from both CD16+ and CD16- monocytes. Early life stress was not associated with elevated CRP. Taken together, these findings provide preliminary evidence for an association between ELS and a pro-inflammatory transcriptional phenotype during pregnancy that may serve as a mechanistic pathway for cross-generational transmission of the effects of early life stress on mental and physical health.

Slow paced breathing via heart rate variability (HRV) biofeedback stimulates vagus-nerve pathways that counter noradrenergic stress and arousal pathways that can influence production and clearance of Alzheimer's disease (AD)-related proteins. Thus, we examined whether HRV biofeedback intervention affects plasma Αβ40, Αβ42, total tau (tTau), and phosphorylated tau-181 (pTau-181) levels. We randomized healthy adults (N = 108) to use slow-paced breathing with HRV biofeedback to increase heart rate oscillations (Osc+) or to use personalized strategies with HRV biofeedback to decrease heart rate oscillations (Osc-). They practiced 20-40 min daily. Four weeks of practicing the Osc+ and Osc- conditions produced large effect size differences in change in plasma Aβ40 and Aβ42 levels. The Osc+ condition decreased plasma Αβ while the Osc- condition increased Αβ. Decreases in Αβ were associated with decreases in gene transcription indicators of β-adrenergic signaling, linking effects to the noradrenergic system. There were also opposing effects of the Osc+ and Osc- interventions on tTau for younger adults and pTau-181 for older adults. These results provide novel data supporting a causal role of autonomic activity in modulating plasma AD-related biomarkers.Trial registration: NCT03458910 (ClinicalTrials.gov); first posted on 03/08/2018.

BackgroundThe Pathways to Wellness trial tested the efficacy of 2 interventions for younger breast cancer survivors: mindful awareness practices (MAPs) and survivorship education (SE). This planned secondary analysis examines intervention effects on stress, positive psychological outcomes, and inflammation (Clincaltrials.gov NCT03025139).MethodsWomen diagnosed with breast cancer at or before age 50 years who had completed treatment and had elevated depressive symptoms were randomly assigned to 6 weeks of MAPs, SE, or wait-list control (WLC). Assessments conducted at pre- and postintervention and at 3- and 6-month follow-up measured general stress perceptions, cancer-related intrusive thoughts and worry, positive affect, meaning and peace in life, altruism and empathy, and markers of inflammation. Analyses compared change in outcomes over time in each intervention group relative to WLC using linear mixed models.ResultsA total 247 women were randomly assigned to MAPs (n = 85), SE (n = 81), or WLC (n = 81). MAPs statistically significantly decreased intrusive thoughts and worry at postintervention and 3-month follow-up relative to WLC (P

A growing body of work has addressed human adaptations to diverse environments using genomic data, but few studies have connected putatively selected alleles to phenotypes, much less among underrepresented populations such as Amerindians. Studies of natural selection and genotype-phenotype relationships in underrepresented populations hold potential to uncover previously undescribed loci underlying evolutionarily and biomedically relevant traits. Here, we worked with the Tsimane and the Moseten, two Amerindian populations inhabiting the Bolivian lowlands. We focused most intensively on the Tsimane, because long-term anthropological work with this group has shown that they have a high burden of both macro and microparasites, as well as minimal cardiometabolic disease or dementia. We therefore generated genome-wide genotype data for Tsimane individuals to study natural selection, and paired this with blood mRNA-seq as well as cardiometabolic and immune biomarker data generated from a larger sample that included both populations. In the Tsimane, we identified 21 regions that are candidates for selective sweeps, as well as 5 immune traits that show evidence for polygenic selection (e.g., C-reactive protein levels and the response to coronaviruses). Genes overlapping candidate regions were strongly enriched for known involvement in immune-related traits, such as abundance of lymphocytes and eosinophils. Importantly, we were also able to draw on extensive phenotype information for the Tsimane and Moseten and link five regions (containing PSD4, MUC21 and MUC22, TOX2, ANXA6, and ABCA1) with biomarkers of immune and metabolic function. Together, our work highlights the utility of pairing evolutionary analyses with anthropological and biomedical data to gain insight into the genetic basis of health-related traits.

Stress can lead to depression, in part because of activation of inflammatory mechanisms. It is therefore critical to identify resilience factors that can buffer against these effects, but no research to date has evaluated whether psychosocial resilience mitigates the effects of stress on inflammation-associated depressive symptoms. We therefore examined psychosocial resources known to buffer against stress in a longitudinal study of women with breast cancer (N = 187). Depressive symptoms and inflammation were measured over a 2-year period extending from after diagnosis into survivorship. Cancer-related stress and psychosocial resources-social support, optimism, positive affect, mastery, self-esteem, and mindfulness-were measured after diagnosis. As hypothesized, women who reported having more psychosocial resources showed weaker associations between stress and depressive symptoms and weaker associations between stress and inflammation-related depressive symptoms. Results highlight the importance of psychosocial resilience by demonstrating a relationship between psychosocial resources and sensitivity to inflammation-associated depressive symptoms.

BackgroundInflammation contributes to poor behavioral, functional, and clinical outcomes in cancer survivors. We examined whether standard cancer treatments-radiation and chemotherapy-led to acute and persistent changes in circulating markers of inflammation in breast cancer patients.MethodsA total of 192 women diagnosed with early stage breast cancer provided blood samples before and after completion of radiation and/or chemotherapy and at 6-, 12-, and 18-month posttreatment follow-ups. Samples were assayed for circulating inflammatory markers, including tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, downstream markers of their activity (soluble TNF receptor type II [sTNF-RII], C reactive protein), and other inflammatory mediators (IL-8, interferon-γ [IFN-γ]). Analyses evaluated within-group changes in inflammatory markers in 4 treatment groups: no radiation or chemotherapy (n = 39), radiation only (n = 77), chemotherapy only (n = 18), and chemotherapy with radiation (n = 58).ResultsPatients treated with chemotherapy showed statistically significant increases in circulating concentrations of TNF-α, sTNF-RII, IL-6, and IFN-γ from pre- to posttreatment, with parameter estimates in standard deviation units ranging from 0.55 to 1.20. Those who received chemotherapy with radiation also showed statistically significant increases in IL-8 over this period. Statistically significant increases in TNF-α, sTNF-RII, IL-6, IFN-γ, and IL-8 persisted at 6, 12, and 18 months posttreatment among patients treated with chemotherapy and radiation (all P < .05). Patients treated with radiation only showed a statistically significant increase in IL-8 at 18 months posttreatment; no increases in any markers were observed in patients treated with surgery only.ConclusionsChemotherapy is associated with acute increases in systemic inflammation that persist for months after treatment completion in patients who also receive radiation therapy. These increases may contribute to common behavioral symptoms and other comorbidities in cancer survivors.

The low-dose mixture hypothesis of carcinogenesis proposes that exposure to an environmental chemical that is not individually oncogenic may nonetheless be capable of enabling carcinogenesis when it acts in concert with other factors. A class of ubiquitous environmental chemicals that are hypothesized to potentially function in this low-dose capacity are synthesized polybrominated diphenyl ethers (PBDEs). PBDEs can affect correlates of carcinogenesis that include genomic instability and inflammation. However, the effect of low-dose PBDE exposure on such correlates in mammary tissue has not been examined. In the present study, low-dose long-term (16 weeks) administration of PBDE to mice modulated transcriptomic indicators of genomic integrity and innate immunity in normal mammary tissue. PBDE increased transcriptome signatures for the Nuclear Factor Erythroid 2 Like 2 (NFE2L2) response to oxidative stress and decreased signatures for non-homologous end joining DNA repair (NHEJ). PBDE also decreased transcriptome signatures for the cyclic GMP-AMP Synthase - Stimulator of Interferon Genes (cGAS-STING) response, decreased indication of Interferon Stimulated Gene Factor 3 (ISGF3) and Nuclear Factor Kappa B (NF-κB) transcription factor activity, and increased digital cytometry estimates of immature dendritic cells (DCs) in mammary tissue. Replication of the PBDE exposure protocol in mice susceptible to mammary carcinogenesis resulted in greater tumor development. The results support the notion that ongoing exposure to low levels of PBDE can disrupt facets of genomic integrity and innate immunity in mammary tissue. Such effects affirm that synthesized PBDEs are a class of environmental chemicals that reasonably fit the low-dose mixture hypothesis.

Contemporary breast cancer surgical procedures vary greatly by the amount of tissue removed, anesthesia time, and reconstruction. Despite historical literature comparing the health-related quality of life (HRQOL) after lumpectomy and mastectomy, HRQOL data are limited regarding contemporary surgical procedures. Further, biological processes (e.g., inflammation) associated with HRQOL outcomes have not been described. We conducted two studies to examine differences in post-operative physical and mental functioning, pain, fatigue, and systemic inflammatory markers including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP) in women with early-stage breast cancer. Study 1 assessed women before and after surgery (n = 27) and Study 2 used a large cross-sectional sample (n = 240) to confirm findings from Study 1 and included a no-surgery comparison group. In Study 1, women who received mastectomy had lower physical functioning than lumpectomy (ps

Parasympathetic nervous system activity can downregulate inflammation, but it remains unclear how parasympathetic nervous system activity relates to antiviral activity. The present study examined associations between parasympathetic nervous system activity and cellular antiviral gene regulation in 90 adolescents (Mage = 16.28, SD = 0.73; 51.1% female) who provided blood samples and measures of cardiac respiratory sinus arrhythmia (RSA), twice, five weeks apart. Using a multilevel analytic framework, we found that higher RSA (an indicator of higher parasympathetic nervous system activity)-both at rest and during paced breathing-was associated with higher expression of Type I interferon (IFN) response genes in circulating leukocytes, even after adjusting for demographic and biological covariates. RSA was not associated with a parallel measure of inflammatory gene expression. These results identify a previously unrecognized immunoregulatory aspect of autonomic nervous system function and highlight a potential biological pathway by which parasympathetic nervous system activity may relate to health.

BackgroundStress precipitates depression and may do so in part by increasing susceptibility to inflammation-induced depressive symptoms. However, this has not been examined among individuals facing a major life stressor. Accordingly, the present study tested the moderating role of stress on the longitudinal association between inflammation and depressive symptoms among women with breast cancer.MethodsWomen recently diagnosed with early-stage breast cancer (N = 187) were enrolled before starting adjuvant/neoadjuvant treatment. Blood draws and self-reported depressive symptoms were collected pre-treatment, post-treatment, and at 6, 12, and 18-month post-treatment follow ups. C-reactive protein (CRP) was used to index inflammation. Measures of psychological stress, including cancer-related stress, general stress perceptions, and childhood stress, were administered pre-treatment.ResultsStress moderated the association between CRP and depressive symptoms, such that higher levels of CRP were associated with elevated depressive symptoms only among women who reported high cancer-related stress (β = 0.080, p = .002) and perceived stress (β = 0.053, p = .044); childhood stress effects were non-significant. Moreover, elevated CRP was associated with increased odds of exhibiting clinically significant depressive symptoms (OR = 1.64, p

BackgroundFatigue is a common and expected side effect of cancer treatment. However, the majority of studies to date have focused on average levels of fatigue, which may obscure important individual differences in the severity and course of fatigue over time. The current study was designed to identify distinct trajectories of fatigue from diagnosis into survivorship in a longitudinal study of women with early-stage breast cancer.MethodsWomen with stage 0 to stage IIIA breast cancer (270 women) were recruited before (neo)adjuvant therapy with radiotherapy, chemotherapy, and/or endocrine therapy and completed assessments at baseline; posttreatment; and at 6 months, 12 months, and 18 months of follow-up. Growth mixture modeling was used to identify trajectories of fatigue, and differences among the trajectory groups with regard to demographic, medical, and psychosocial variables were examined.ResultsFive distinct trajectories of fatigue were identified: Stable Low (66%), with low levels of fatigue across assessments; Stable High (13%), with high fatigue across assessments; Decreasing (4%), with high fatigue at baseline that resolved over time; Increasing (9%), with low fatigue at baseline that increased over time; and Reactive (8%), with increased fatigue after treatment that resolved over time. Both psychological and treatment-related factors were found to be associated with fatigue trajectories, with psychological factors most strongly linked to high fatigue at the beginning of and over the course of treatment.ConclusionsThere is considerable variability in the experience of fatigue among women with early-stage breast cancer. Although the majority of women report relatively low fatigue, those with a history of depression and elevated psychological distress may be at risk of more severe and persistent fatigue.

After kidney transplantation, infection and death are important clinical complications, especially for the growing numbers of older patients with limited resilience to withstand adverse events. Evaluation of changes in gene expression in immune cells can reveal the underlying mechanisms behind vulnerability to infection. A cohort of 60 kidney transplant recipients was evaluated. Gene expression in peripheral blood mononuclear cells 3 months after kidney transplantation was analyzed to compare differences between patients with infection and those who were infection-free in the first-year post-transplant. Pro-inflammatory genes such as IL1B, CCL4, and TNF were found to be downregulated in post-transplant PBMC from patients who developed infection. In contrast, genes involved in metabolism, HLA genes, and transcripts involved in type I interferon innate antiviral responses were found to be upregulated. Promoter-based bioinformatic analyses implicated increased activity of interferon regulatory factors, erythroid nuclear factor (E2), and CCAAT-enhancer-binding protein (C/EBP) in patients who developed infections. Differential patterns of gene expression were observed in patients who developed infection after kidney transplantation, with patterns distinct from changes associated with patient age, suggesting possible mechanisms behind vulnerability to infection. Assessment of gene expression in blood may offer an approach for patient risk stratification and monitoring after transplantation.

Despite growing public and scientific interest in the positive benefits of prosociality, there has been little research on the causal effects of performing kind acts for others on psychological well-being during adolescence. Developmental changes during adolescence, such as greater perspective taking, can promote prosociality. It was hypothesized that performing kind acts for others would improve adolescent well-being (positive and negative affect, perceived stress) and increase prosocial giving. As part of a randomized controlled trial, 97 adolescents (Mage = 16.224, SD = 0.816, range 14-17; 53.608% female) were assigned to either perform kind acts for others (Kindness to Others, N = 33), perform kind acts for themselves (Kindness to Self, N = 34), or report on daily activities (Daily Report, N = 30) three times per week for four weeks. Well-being factors were measured weekly and giving was tested post-intervention. Overall, changes over time in well-being did not differ across conditions. However, altruism emerged as a significant moderator such that altruistic adolescents in the Kindness to Others condition showed increased positive affect, decreased negative affect, and decreased stress. Increased positive affect was also linked to greater prosocial giving for Kindness to Others adolescents. These findings identify individual differences that may shape the effects of doing kind acts for others on well-being during adolescence.

The risk for breast cancer is significantly reduced in persons who engage in greater amounts of physical activity, and greater physical activity before or after diagnosis associates with reduced disease-specific mortality. Previous mechanistic studies indicate that components of innate immunity can mediate an inhibitory effect of physical activity on several types of tumor. However, in breast cancer specifically, the myeloid compartment of innate immunity is thought to exhibit high propensity for an immunosuppressive role that obstructs anti-tumor immunity. Thus, we tested the notion that greater physical activity alters mononuclear phagocytes in mammary tissue when inhibiting nascent tumor in a murine model of breast cancer. To model greater physical activity, we placed an angled running wheel in each mouse's home cage for two weeks before tumor engraftment with EO771 mammary cancer cells that express luciferase for bioluminescent detection. Fully immunocompetent mice and mice with compromised adaptive immunity showed significantly less mammary tumor signal when given access to running wheels, although the effect size was smaller in this latter group. To investigate the role of the myeloid compartment, mononuclear phagocytes were ablated by systemic injection of clodronate liposomes at 24 h before tumor engraftment and again at the time of tumor engraftment, and this treatment reversed the inhibition in wheel running mice. However, clodronate also inhibited mammary tumor signal in sedentary mice, in conjunction with an expected decrease in gene and protein expression of the myeloid antigen, F4/80 (Adgre1), in mammary tissue. Whole transcriptome digital cytometry with CIBERSORTx was used to analyze myeloid cell populations in mammary tissue following voluntary wheel running and clodronate treatment, and this approach found significant changes in macrophage and monocyte populations. In exploratory analyses, whole transcriptome composite scores for monocytic myeloid-derived suppressor cell (M-MDSC), macrophage lactate timer, and inflammation resolution gene expression programs were significantly altered. Altogether, the results support the hypothesis that physical activity inhibits nascent mammary tumor growth by enhancing the anti-tumor potential of mononuclear phagocytes in mammary tissue.

Inflammation has been shown to predict depression, but sensitivity to inflammation varies across individuals. Experimental studies administering potent pro-inflammatory agents have begun to characterize this sensitivity. However, risk factors for inflammation-associated depression in naturalistic contexts have not been determined. The present study examined key psychological and behavioral risk factors (state anxiety, perceived stress, negative affect, disturbed sleep, and childhood adversity) as potential moderators of the relationship between inflammation and depressive symptoms in a prospective longitudinal study of breast cancer survivors. Women with early stage breast cancer were recruited after completing primary cancer treatment (nfinal = 161). Depressive symptoms, inflammatory markers (CRP, IL-6, and sTNF-RII), and key risk factors were assessed post treatment (T1), at 6 and 12-month follow-ups (T2 and T3), and during a final follow-up (TF) 3-6 years after T1; childhood adversity was measured only at T3. Inflammatory markers were combined into a single inflammatory index prior to analyses. Women who reported higher levels of state anxiety, perceived stress, negative affect, and/or sleep disturbance at T1 (post-treatment) exhibited higher depressive symptoms at times when inflammation was higher than typical (interaction βs ranged from .06 to .08; all ps

BackgroundChildhood adversity is reliably associated with immune alterations in adulthood, including increases in inflammatory processes. However, relatively few studies have investigated these associations in clinical populations such as cancer patients who are at risk for negative immune-related health outcomes. The current study tested the hypothesis that childhood maltreatment would be associated with alterations in immune-related gene expression in monocytes from women with breast cancer.MethodsWomen (n = 86) were recruited after diagnosis with early-stage breast cancer but before onset of adjuvant therapy with radiation, chemotherapy, and/or endocrine therapy. Participants completed questionnaires to assess childhood maltreatment (Childhood Trauma Questionnaire; CTQ) and depressive symptoms (Center for Epidemiologic Studies Depression Scale; CES-D) and provided blood samples for immune assessment. CD14+ monocytes were isolated for RNA extraction and gene expression analyses.ResultsBased on responses to the CTQ, 28% of participants were classified as experiencing physical and/or emotional abuse or neglect and 7% as experiencing sexual abuse. Genome-wide transcriptional profiling of isolated monocytes identified 202 gene transcripts that differed in average expression level by > 25% over the range of maltreatment exposure. Bioinformatics analyses of those gene transcripts identified a significantly greater prevalence of NF-κB-binding motifs within the promoters of up-regulated vs. down-regulated genes (p = .028) in women exposed to childhood maltreatment, indicating greater inflammatory signaling. Parallel analyses of Type I interferon signaling also indicated greater prevalence of Interferon Response Factor (IRF)-related binding sites in women with a childhood maltreatment history (p = .020). Results remained significant in analyses controlling for current depression; however, NF-κB and IRF-related gene expression was higher in women with both maltreatment exposure and current depression.ConclusionsIn women recently diagnosed with early-stage breast cancer, childhood maltreatment was associated with increases in the classical NF-kB-related pro-inflammatory signaling pathway and with increases in the Type I interferon system. These results suggest a broad pattern of chronic immunologic activation in breast cancer patients with a history of childhood maltreatment, particularly those who are currently experiencing clinically significant depressive symptoms. These findings have implications for the long-term health and well-being of maltreatment exposed breast cancer patients.

Chronic stress can accelerate biological aging, offering one mechanism through which stress may increase age-related disease risk. Chronic activation of the sympathoadrenal system increases cellular energy production, resulting in cell stress that can initiate cellular senescence, a permanent state of cell growth arrest. Our previous research linked psychosocial stress with increased expression of senescence marker p16INK4a; however, less is known about the role of protective psychosocial factors in biological aging. We examined relationship closeness (perceived interconnectedness with one's spouse) as a protective buffer of the effects of stress on expression of the p16INK4a-encoding gene (CDKN2A) and transcription control pathways activated under cell stress. Seventy parents (Mage=43.2) completed interview-based and questionnaire measures of psychosocial stress and relationship closeness. Blood samples assessed CDKN2A expression and inferred activity of a priori-selected transcription factors Nrf2 and heat shock factors (HSFs) via genome-wide transcriptome profiling. Random intercept models adjusting for age, sex, and ethnicity/race revealed that perceived stress was associated with elevated CDKN2A expression for parents with low but not high closeness. Secondary bioinformatics analyses linked the interaction of perceived stress and relationship closeness to Nrf2 and HSF-1 activity. Findings identify relationship closeness as a protective factor that may buffer the impact of stress on cellular stress and senescence pathways.

The purpose of this study was to characterize the association between recent major life events and depressive symptoms during early adulthood, and to determine whether adolescents with chronically low positive affect or persistent sleep disturbance were more vulnerable to the link between stress and depressive symptoms. Adolescents (n = 147; 63.9% female; 33.7% non-Hispanic white) were recruited in 10th-11th grade and re-assessed 2 and 4 years later. At each assessment, adolescents completed measures of positive affect and sleep disturbances. At the final assessment, participants reported on their exposure to major life events in the past 12 months. Exposure to more major life events in the past year was associated with greater depressive symptoms in early adulthood. Chronically low positive affect and persistent sleep disturbances throughout adolescence each independently moderated this relationship. Specifically, only participants reporting low positive affect across the three assessments showed a positive and significant association between major life events and depressive symptoms. Further, only participants reporting sleep disturbances at all three assessments showed a positive and significant association between major life events and depressive symptoms. Chronically low positive affect and persistent sleep disturbances during adolescence may be useful indicators of risk for depression during early adulthood. Further, interventions targeting adolescent sleep disturbances and improving positive affect may be useful in reducing the risk for depression following life stress during this high risk developmental phase.

ProblemAltered maternal immune function predicts risk for shorter gestation and low birthweight. Few studies examine associations between prenatal immune cell gene expression and gestational length or birthweight. No studies examine which cell types drive associations. The purpose of this study is to explore associations between peripheral blood immune cell gene expression and gestational length and birthweight, using transcript origin analysis.Method of studyEighty-nine women were drawn from the Community Child Health Network cohort. Third trimester maternal dried blood spots were used for genome-wide transcriptional (mRNA) profiling. Gestational length and birthweight were obtained from medical charts. Covariates were age, race/ethnicity, pre-pregnancy body mass index, smoking, gestational age at blood sampling, and pregnancy infections. Associations between gene expression profiles and gestational length and birthweight were tested using general linear models. The Transcription Element Listening System (TELiS) bioinformatics analysis quantified upstream transcription factor activity. Transcript origin analysis identified leukocyte subsets mediating observed effects.ResultsShorter gestation was predicted by increased NF-kB (TFBM ratio = -0.582 ± 0.172, P

Systemic inflammation is associated with increasing age. Yet, there are limited data about the association between age and systemic inflammation within older adults, and whether older age is also associated with cellular and nuclear signaling markers of inflammation. In community-dwelling older adults (N = 262, 60-88 years), systemic levels of C-reactive protein, interleukin-6, and soluble tumor necrosis factor receptor II; levels of toll-like receptor-4-stimulated monocytic production of interleukin-6 and tumor necrosis factor α; and resting nuclear levels of activated nuclear factor kappa B and signal transducer and activator of transcription (STAT1, STAT3, STAT5) were evaluated. Adjusting for demographic and clinical factors, multivariate linear regression tested the association between age and each inflammatory marker. Age was positively associated with increased levels of interleukin-6 and soluble tumor necrosis factor receptor II (p's < .05) and with increases in STAT1, STAT3, and STAT5 activation (p's < .05). However, no relationship was found between age and C-reactive protein, toll-like receptor-4-stimulated interleukin-6/tumor necrosis factor alpha α production, or nuclear factor kappa B. Within a community-dwelling sample of older adults, older age is associated with increases in STAT activation, along with increases of systemic inflammatory cytokines. In older adults, heterogeneity in age-related increases in inflammatory disease risk may be related to individual variability in inflammation.

The experiences of mothers and fathers are different in ways that could affect their well-being. Yet few studies have comprehensively examined gender differences in parents' well-being. In the current research, we investigated such gender differences in a large representative sample (Study 1a; N = 13,007), in a community sample using validated well-being measures (Study 1b; N = 472), and in a large experience sampling study measuring happiness during caregiving activities and during interactions with children (Study 2; N = 4,930). Fathers reported greater happiness, subjective well-being, psychological need satisfaction, and daily uplifts than did men without children (Studies 1a and 1b). During caregiving experiences, fathers reported greater happiness, whereas mothers reported lower happiness, compared with their other activities. Fathers also reported relatively higher happiness when interacting with their children than did mothers (Study 2). Across all three studies and more than 18,000 participants, parenthood was associated with more positive well-being outcomes for fathers than for mothers.

BackgroundRates of depression increase and peak during late adolescence and alterations in immune processes are thought to be both a risk factor and outcome of depression. However, few studies have examined depression-immune dynamics among adolescents. Using a functional genomics approach, the current study examined whether depressive symptoms were associated with activation of a gene expression profile, characterized by upregulated expression of pro-inflammatory-related genes and downregulated expression of antiviral-related genes in a sample of older adolescents (Mage = 18.37, SD = 0.51).MethodParticipants (n = 87) reported on their depressive symptoms during the past week using the CES-D, and provided blood samples for genome-wide transcriptional profiling of mRNA.ResultsAdolescents with clinically-significant levels of depressive symptoms (CES-D ≥ 16) exhibited upregulated expression of inflammation-related genes and downregulated expression of antiviral-related genes compared to their peers with lower levels of depressive symptoms (CES-D

At the M2 terminal of the macrophage activation spectrum, expression of genes is regulated by transcription factors that include STAT6, CREB, and C/EBPβ. Signaling through β-adrenergic receptors drives M2 activation of macrophages, but little is known about the transcription factors involved. In the present study, we found that C/EBPβ regulates the signaling pathway between β-adrenergic stimulation and expression of Arg1 and several other specific genes in the greater M2 transcriptome. β-adrenergic signaling induced Cebpb gene expression relatively early with a peak at 1 h post-stimulation, followed by peak Arg1 gene expression at 8 h. C/EBPβ transcription factor activity was elevated at the enhancer region for Arg 1 at both 4 and 8 h after stimulation but not near the more proximal promoter region. Knockdown of Cebpb suppressed the β-adrenergic-induced peak in Cebpb gene expression as well as subsequent accumulation of C/EBPβ protein in the nucleus, which resulted in suppression of β-adrenergic-induced Arg1 gene expression. Analysis of genome-wide transcriptional profiles identified 20 additional M2 genes that followed the same pattern of regulation by β-adrenergic- and C/EBPβ-signaling. Promoter-based bioinformatic analysis confirmed enrichment of binding motifs for C/EBPβ transcription factor across these M2 genes. These findings pinpoint a mechanism that may be targeted to redirect the deleterious influence of β-adrenergic signaling on macrophage involvement in M2-related diseases such as cancer.

Racial disparities in health outcomes between African Americans and European Americans have been well-documented, but not fully understood. Chronic inflammation contributes to several of the diseases showing racial disparities (e.g., Human Immunodeficiency Virus [HIV]), and racial differences in stress exposure (e.g., experiences of racial discrimination) that stimulate pro-inflammatory processes that may contribute to differential health outcomes. We performed a cross-sectional bioinformatic analyses relating perceived discrimination (as measured by the Perceived Ethnic Discrimination Questionnaire [PED-Q]) to the activity of pro-inflammatory, neuroendocrine, and antiviral transcription control pathways relevant to the conserved transcriptional response to adversity (CTRA) in peripheral blood leukocytes. Subjects were 71 individuals (37 HIV-seropositive (HIV+); 34 HIV-seronegative (HIV-)) (mean age = 53 years, range 27-63), who self-identified either as African American/Black (n = 48) or European American/White (n = 23). This provided the opportunity to examine the independent effects of race and HIV, as well as the modifying role of perceived discrimination on pathways involved in CTRA. Exploratory analysis examined the interactive effects of HIV and race on pathways involved in CTRA. Relative to European Americans, African Americans showed increased activity of two key pro-inflammatory transcription control pathways (NF- кB and AP-1) and two stress-responsive signaling pathways (CREB and glucocorticoid receptor); these effects did not differ significantly as a function of HIV infection (HIV x Race interaction, all p > .10). Results suggested that differences in experiences of racial discrimination could potentially account for more than 50% of the total race-related difference in pro-inflammatory transcription factor activity. In sum, differential exposure to racial discrimination may contribute to racial disparities in health outcomes in part by activating threat-related molecular programs that stimulate inflammation and contribute to increased risk of chronic illnesses.

BACKGROUND:The conserved transcriptional response to adversity (CTRA), characterized by increased expression of proinflammatory genes and decreased expression of antiviral and antibody-related genes, is upregulated in the context of chronic adversity and distress and has been linked to cancer progression. Several studies suggest that the CTRA may also be down-regulated in association with some positive psychological states, particularly eudaimonic well-being. However, it is not clear if the link between inter-individual differences in the CTRA and eudaimonic well-being can be extended to intra-individual change. Using a standardized mindfulness-based intervention, the current study tested whether mindfulness-related increases in eudaimonic well-being related to intra-individual reduction in the CTRA in a sample of younger breast cancer survivors. METHODS:Participants were 22 women who had been diagnosed and treated for early-stage breast cancer at or before age 50 (Mage = 46.6 years) and had no evidence of active disease. Women completed self-report questionnaires and provided peripheral blood samples before and after a 6-week mindfulness meditation intervention. Regression analyses were used to quantify associations between the magnitude of change in eudaimonic well-being and the magnitude of change in the global CTRA score. RESULTS:Women reported significant increases in eudaimonic well-being and showed decreased expression of the pro-inflammatory subcomponent of the CTRA from pre- to post-intervention. The magnitude of increase in eudaimonic well-being was associated with the magnitude of decrease in the composite CTRA score, and this relationship was driven primarily by increased expression of the antiviral/antibody-related CTRA subcomponent. While the intervention was also associated with reduced depressive symptoms, there was no association between change in depressive symptoms and change in the overall CTRA composite score or either of its subcomponents. CONCLUSIONS:Results are consistent with the hypothesis that eudaimonic well-being may be an important mechanism in interventions aimed at enhancing health in vulnerable groups, and contribute to our understanding of how psychological well-being may influence physical health in cancer patients.