Publications by authors named "Jordan Kohn"

24 Publications

  • Page 1 of 1

Systemic Inflammation and Cognitive Decrements in Patients with Stage B Heart Failure.

Psychosom Med 2021 Oct 12. Epub 2021 Oct 12.

College of Behavioral and Community Sciences, University of South Florida, Tampa, FL, USA Department of Psychiatry, University of California School of Medicine, San Diego, CA, USA Department of Family Medicine and Public Health, University of California School of Medicine, San Diego, CA, USA Division of Cardiology, University of Miami Miller School of Medicine, Miami, FL, USA Behavioral Medicine Research Center, University of Miami, Miami, Florida, USA; Department of Psychology, University of Miami, Coral Gables, Florida, USA; Division of Endocrinology, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, Florida, USA Department of Medicine, University of California School of Medicine, San Diego, CA, USA Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, FL, USA.

Objective: To investigate the role of systemic inflammation in reduced cognitive functioning in patients with early-stage heart failure (HF), while taking associations with other cardiovascular risk factors into account.

Methods: Patients with stage B HF (n = 270; mean age 66.1 ± 10.1) were examined cross-sectionally for relationships among cardiovascular disease (CVD) and psychological risk factors, c-reactive protein (CRP) and Montreal Cognitive Assessment (MoCA) scores. A subsample (n = 83), at high-risk for stage C HF (B-type natriuretic peptide (BNP) levels >65 pg/mL) were followed for 12-months for relationships between CRP levels and cognitive function.

Results: Baseline smoking (c2 = 6.33), unmarried (c2 = 12.0), hypertension (c2 = 5.72), greater body mass index (d = .45), and physical fatigue (d = .25) were related to higher CRP levels (p's < .05). Cross-sectionally, CRP levels were negatively related to MoCA scores, beyond CVD (DR2 = .022, b = -.170, p < .010) and psychological risk factors (DR2 = .016, b = .145, p < .027) and related to MCI criteria (odds ratio = 1.35, 95% CI 1.00 - 1.81, p = .046). Across 12-months, BNP high-risk patients with CRP levels ≥3 mg/L had lower MoCA scores (23.6; 95% CI 22.4 - 24.8) than patients with CRP levels <3 mg/L (25.4; 95% CI 24.4 - 26.5) (p = .024).

Conclusion: Patients with stage B HF and heightened CRP levels had greater cognitive impairment at baseline and follow-up, independent of CVD and potentially psychological risk factors. Low-grade systemic inflammation may be one mechanism involved in cognitive dysfunction at early stages of HF.
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http://dx.doi.org/10.1097/PSY.0000000000001033DOI Listing
October 2021

Improving sleep by fostering social connection for dementia patients in long-term care.

Int Psychogeriatr 2021 10 3;33(10):1005-1007. Epub 2021 Jun 3.

Department of Psychiatry, University of California San Diego, La Jolla, CA, USA.

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http://dx.doi.org/10.1017/S1041610221000211DOI Listing
October 2021

Primate innate immune responses to bacterial and viral pathogens reveals an evolutionary trade-off between strength and specificity.

Proc Natl Acad Sci U S A 2021 03;118(13)

Centre Hospitalier Universitaire Sainte-Justine, University of Montreal, QC H3T 1C5, Montréal, Canada;

Despite their close genetic relatedness, apes and African and Asian monkeys (AAMs) differ in their susceptibility to severe bacterial and viral infections that are important causes of human disease. Such differences between humans and other primates are thought to be a result, at least in part, of interspecies differences in immune response to infection. However, because of the lack of comparative functional data across species, it remains unclear in what ways the immune systems of humans and other primates differ. Here, we report the whole-genome transcriptomic responses of ape species (human and chimpanzee) and AAMs (rhesus macaque and baboon) to bacterial and viral stimulation. We find stark differences in the responsiveness of these groups, with apes mounting a markedly stronger early transcriptional response to both viral and bacterial stimulation, altering the transcription of ∼40% more genes than AAMs. Additionally, we find that genes involved in the regulation of inflammatory and interferon responses show the most divergent early transcriptional responses across primates and that this divergence is attenuated over time. Finally, we find that relative to AAMs, apes engage a much less specific immune response to different classes of pathogens during the early hours of infection, up-regulating genes typical of anti-viral and anti-bacterial responses regardless of the nature of the stimulus. Overall, these findings suggest apes exhibit increased sensitivity to bacterial and viral immune stimulation, activating a broader array of defense molecules that may be beneficial for early pathogen killing at the potential cost of increased energy expenditure and tissue damage.
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http://dx.doi.org/10.1073/pnas.2015855118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020666PMC
March 2021

Searching for host immune-microbiome mechanisms in obsessive-compulsive disorder: A narrative literature review and future directions.

Neurosci Biobehav Rev 2021 06 24;125:517-534. Epub 2021 Feb 24.

Department of Psychiatry, University of California San Diego, La Jolla, California, United States; Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, California, United States.

Obsessive-compulsive disorder (OCD) is disabling and often treatment-refractory. Host immunity and gut microbiota have bidirectional communication with each other and with the brain. Perturbations to this axis have been implicated in neuropsychiatric disorders, but immune-microbiome signaling in OCD is relatively underexplored. We review support for further pursuing such investigations in OCD, including: 1) gut microbiota has been associated with OCD, but causal pathogenic mechanisms remain unclear; 2) early environmental risk factors for OCD overlap with critical periods of immune-microbiome development; 3) OCD is associated with increased risk of immune-mediated disorders and changes in immune parameters, which are separately associated with the microbiome; and 4) gut microbiome manipulations in animal models are associated with changes in immunity and some obsessive-compulsive symptoms. Theoretical pathogenic mechanisms could include microbiota programming of cytokine production, promotion of expansion and trafficking of peripheral immune cells to the CNS, and regulation of microglial function. Immune-microbiome signaling in OCD requires further exploration, and may offer novel insights into pathogenic mechanisms and potential treatment targets for this disabling disorder.
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http://dx.doi.org/10.1016/j.neubiorev.2021.02.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8106658PMC
June 2021

Trajectories of Depressive Symptoms, Neurocognitive Function, and Viral Suppression With Antiretroviral Therapy Among Youth With HIV Over 36 months.

J Acquir Immune Defic Syndr 2021 06;87(2):851-859

Department of Psychiatry, University of California San Diego, La Jolla, CA.

Background: Depression and neurocognitive impairment are highly prevalent among persons living with HIV and associated with poorer clinical outcomes; however, longitudinal studies of depression-neurocognition relationships in youth living with HIV (YLWH), and the role of antiretroviral therapy (ART), are lacking. This study tested whether (1) depressive symptomatology, across somatic, cognitive, and affective symptom domains, improved with ART and (2) more severe depressive symptoms at baseline were associated with poorer neurocognitive function and poorer HIV suppression.

Setting: Data were collected from 181 YLWH (18-24 years) who were treatment-naive, a subset of whom (n = 116) initiated ART.

Methods: Participants were categorized into elevated (DS) or nonelevated (non-DS) depressive symptom groups at entry (Beck Depression Inventory-II ≥14) and followed for 36 months. Neurocognition (5-domain battery) and depressive symptoms were repeatedly assessed. Longitudinal models examined depressive symptomatology, neurocognition, and odds of HIV nonsuppression by group.

Results: Greater improvements in depressive symptoms were observed in the DS group over 36 months [beta = -0.14, (-0.24 to -0.03)], particularly within cognitive and affective domains. Verbal learning performance increased in the DS group [beta = 0.13, (0.01 to 0.24)], whereas psychomotor function improved somewhat in the non-DS group [beta = -0.10, (-0.22 to 0.00)]. Adjusted for ART adherence, odds of HIV nonsuppression did not significantly differ by group [odds ratio = 0.22, (0.04 to 1.23)]; however, greater somatic symptoms at study entry were associated with an increased risk of nonsuppression over time [odds ratio = 2.33 (1.07 to 5.68)].

Conclusion: Depressive symptoms were associated with differential neurocognitive trajectories, and somatic depressive symptoms at baseline may predict poorer subsequent HIV suppression. Identifying and treating depressive symptoms at ART initiation may benefit neurocognitive and clinical outcomes in YLWH.
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http://dx.doi.org/10.1097/QAI.0000000000002653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131211PMC
June 2021

Modulatory Effects of Triphala and Manjistha Dietary Supplementation on Human Gut Microbiota: A Double-Blind, Randomized, Placebo-Controlled Pilot Study.

J Altern Complement Med 2020 Nov 18;26(11):1015-1024. Epub 2020 Sep 18.

Department of Dermatology, University of California Davis, Sacramento, CA, USA.

Triphala (which contains and ) and manjistha (), have received increased clinical attention. The aim of the study was to evaluate the effects of triphala, manjistha, or placebo dietary supplementation on gut microbiota as such studies in humans are lacking. This was a 4-week randomized, double-blind, placebo-controlled pilot trial. This trial was conducted at the University of California Davis, Department of Dermatology. A total of 31 healthy human subjects were randomized to 3 groups. The 3 groups were instructed to take 2,000 mg of either triphala, manjistha or placebo daily for 4 weeks. The impact of treatment on gut microbiota composition was evaluated following a 4-week dietary intervention by profiling fecal communities with 16S rRNA profiling in triphala ( = 9), manjistha ( = 9), or placebo ( = 11) treated subjects that completed the intervention. An average of 336 phylotypes were detected in each sample (range: 161 to 648). The analysis of gut microbiota in placebo control and herb-supplemented participants indicated that responses were highly personalized, and no taxa were uniformly altered by the medicinal herb supplementation protocol. Subjects in both treatment groups displayed a trend toward decreased Firmicutes to Bacteroidetes ratio and increased relative abundance of . Both medicinal herb treatments reduced the relative abundance of Rikenellaceae, primarily reflecting changes in spp. Dietary supplementation with medicinal herbs altered fecal microbial communities. Despite the lack of a clear response signature, a group of bacterial taxa were identified that were more commonly altered in herb-supplemented participants compared to placebo controls. Clinicaltrials.gov identifier NCT03477825.
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http://dx.doi.org/10.1089/acm.2020.0148DOI Listing
November 2020

Greater Well-Being in More Physically Active Cancer Patients Who Are Enrolled in Supportive Care Services.

Integr Cancer Ther 2020 Jan-Dec;19:1534735420921439

University of California San Diego, La Jolla, CA, USA.

Cancers are one of the leading causes of mortality worldwide. Cancer patients are increasingly seeking integrative care clinics to promote their health and well-being during and after treatment. To examine relationships between physical activity (PA) and quality of life (QoL) in a sample of cancer patients enrolling in integrative care in a supportive care clinic. Also, to explore circulating inflammatory biomarkers and heart rate variability (HRV) in relationship to PA and QoL. A cross-sectional design of adult patients who sought care in the InspireHealth clinic, Vancouver, British Columbia, Canada. Patients with complete PA data (n = 118) answered psychosocial questionnaires, provided blood samples, and received HRV recordings before enrollment. Patients were stratified into "less" versus "more" active groups according to PA guidelines (150 minutes of moderate or 75 minutes of vigorous PA or an equivalent combination). Breast (33.1%) and prostate (10.2%) cancers were the most prevalent primary diagnoses. Patients engaging in more PA reported better physical ( = 1265.5, = .013), functional ( = 1306.5, = .024), and general QoL ( = 1341, = .039), less fatigue ( = 1268, = .014), fewer physical cancer-related symptoms ( = 2.338, = .021), and less general distress ( = 2.061, = .021). Between PA groups, type of primary cancer diagnosis differed (χ = 41.79, = .014), while stages of cancer did not (χ = 3.95, = .412). Fewer patients reported depressed mood within the more active group (χ = 6.131, = .047). More active patients were also less likely to have ever used tobacco (χ = 7.41, = .025) and used fewer nutritional supplements (χ = 39.74, ≤ .001). An inflammatory biomarker index was negatively correlated with vigorous PA ( = -0.215, = .022). Multivariable linear regression ( = 0.71) revealed that age (β = 0.22; = .001), fatigue (β = -0.43; ≤ .001), anxiety (β = -0.14; = .048), and social support (β = 0.38; = .001) were significant correlates of QoL.
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http://dx.doi.org/10.1177/1534735420921439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265567PMC
July 2021

Are we facing a crashing wave of neuropsychiatric sequelae of COVID-19? Neuropsychiatric symptoms and potential immunologic mechanisms.

Brain Behav Immun 2020 07 13;87:34-39. Epub 2020 Apr 13.

Department of Psychiatry, University of California San Diego, 9500 Gilman Dr. MC0804, La Jolla, CA 92093-0804, USA; Department of Family Medicine and Public Health, Department of Psychiatry, University of California San Diego, 9500 Gilman Dr. MC0804, La Jolla, CA 92093-0804, USA. Electronic address:

The coronavirus disease 19 (COVID-19) pandemic is a significant psychological stressor in addition to its tremendous impact on every facet of individuals' lives and organizations in virtually all social and economic sectors worldwide. Fear of illness and uncertainty about the future precipitate anxiety- and stress-related disorders, and several groups have rightfully called for the creation and dissemination of robust mental health screening and treatment programs for the general public and front-line healthcare workers. However, in addition to pandemic-associated psychological distress, the direct effects of the virus itself (several acute respiratory syndrome coronavirus; SARS-CoV-2), and the subsequent host immunologic response, on the human central nervous system (CNS) and related outcomes are unknown. We discuss currently available evidence of COVID-19 related neuropsychiatric sequelae while drawing parallels to past viral pandemic-related outcomes. Past pandemics have demonstrated that diverse types of neuropsychiatric symptoms, such as encephalopathy, mood changes, psychosis, neuromuscular dysfunction, or demyelinating processes, may accompany acute viral infection, or may follow infection by weeks, months, or longer in recovered patients. The potential mechanisms are also discussed, including viral and immunological underpinnings. Therefore, prospective neuropsychiatric monitoring of individuals exposed to SARS-CoV-2 at various points in the life course, as well as their neuroimmune status, are needed to fully understand the long-term impact of COVID-19, and to establish a framework for integrating psychoneuroimmunology into epidemiologic studies of pandemics.
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http://dx.doi.org/10.1016/j.bbi.2020.04.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7152874PMC
July 2020

Differing salivary microbiome diversity, community and diurnal rhythmicity in association with affective state and peripheral inflammation in adults.

Brain Behav Immun 2020 07 14;87:591-602. Epub 2020 Feb 14.

Department of Psychiatry, United States; Center for Microbiome Innovation, United States; Department of Family Medicine and Public Health, University of California, San Diego, United States. Electronic address:

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http://dx.doi.org/10.1016/j.bbi.2020.02.004DOI Listing
July 2020

Higher soluble CD14 levels are associated with lower visuospatial memory performance in youth with HIV.

AIDS 2019 12;33(15):2363-2374

aDivision of Allergy, Immunology, and Pulmonary Medicine, Department of Pediatrics, Duke University School of Medicine, Durham bUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina cUniversity of California San Diego, La Jolla, California dChildren's Diagnostic & Treatment Center, Fort Lauderdale, Florida eHunter College, CUNY, New York, New York fUniversity of Houston, Houston, Texas gNIH, Bethesda, Maryland, USA.

Objective: HIV-associated neurocognitive disorders persist despite early antiretroviral therapy (ART) and optimal viral suppression. We examined the relationship between immunopathogenesis driven by various pathways of immune activation and discrete neurocognitive performance domains in youth with HIV (YWH).

Design: Observational cross-sectional study.

Methods: YWH, ages 20-28 years, enrolled in Adolescent Medicine Trials Network 071/101 were assessed for biomarkers of macrophage, lymphocyte activation, and vascular inflammation using ELISA/multiplex assays. Standardized neurocognitive tests were performed, and demographically adjusted z-scores were combined to form indices of attention, motor, executive function, verbal, and visuospatial memory. Cross-sectional analysis of the relationship between 18 plasma inflammatory biomarkers and each neurocognitive domain was performed. Linear regression models were fit for each combination of log-transformed biomarker value and neurocognitive domain score, and were adjusted for demographics, socioeconomic status, substance use, depression, CD4 T-cell count, HIV viral load, and ART status.

Results: Study included 128 YWH [mean age 23.8 (SD 1.7) years, 86% men, 68% African American]. Verbal and visuospatial memory domains were most significantly impaired in the cohort (z = -1.59 and -1.0, respectively). Higher sCD14 was associated with impaired visuospatial memory, which remained robust after adjusting for other biomarkers, demographics, and HIV-associated covariates. Among biomarkers of vascular inflammation, sICAM-1 was negatively associated with verbal memory and attention, whereas sVCAM-1 was positively associated with executive function and visuospatial memory. Specific neurocognitive domains were not associated with sCD163, LPS, or CCL2 levels.

Conclusion: Impaired visuospatial memory in YWH is associated with immune activation, as reflected by higher sCD14.
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http://dx.doi.org/10.1097/QAD.0000000000002371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6905124PMC
December 2019

Self-reported sleep disturbances are associated with poorer cognitive performance in older adults with hypertension: a multi-parameter risk factor investigation.

Int Psychogeriatr 2020 07;32(7):815-825

Department of Psychiatry, University of California, San Diego, USA.

Objectives: Given the evidence of multi-parameter risk factors in shaping cognitive outcomes in aging, including sleep, inflammation, cardiometabolism, and mood disorders, multidimensional investigations of their impact on cognition are warranted. We sought to determine the extent to which self-reported sleep disturbances, metabolic syndrome (MetS) factors, cellular inflammation, depressive symptomatology, and diminished physical mobility were associated with cognitive impairment and poorer cognitive performance.

Design: This is a cross-sectional study.

Setting: Participants with elevated, well-controlled blood pressure were recruited from the local community for a Tai Chi and healthy-aging intervention study.

Participants: One hundred forty-five older adults (72.7 ± 7.9 years old; 66% female), 54 (37%) with evidence of cognitive impairment (CI) based on Montreal Cognitive Assessment (MoCA) score ≤24, underwent medical, psychological, and mood assessments.

Measurements: CI and cognitive domain performance were assessed using the MoCA. Univariate correlations were computed to determine relationships between risk factors and cognitive outcomes. Bootstrapped logistic regression was used to determine significant predictors of CI risk and linear regression to explore cognitive domains affected by risk factors.

Results: The CI group were slower on the mobility task, satisfied more MetS criteria, and reported poorer sleep than normocognitive individuals (all p < 0.05). Multivariate logistic regression indicated that sleep disturbances, but no other risk factors, predicted increased risk of evidence of CI (OR = 2.00, 95% CI: 1.26-4.87, 99% CI: 1.08-7.48). Further examination of MoCA cognitive subdomains revealed that sleep disturbances predicted poorer executive function (β = -0.26, 95% CI: -0.51 to -0.06, 99% CI: -0.61 to -0.02), with lesser effects on visuospatial performance (β = -0.20, 95% CI: -0.35 to -0.02, 99% CI: -0.39 to 0.03), and memory (β = -0.29, 95% CI: -0.66 to -0.01, 99% CI: -0.76 to 0.08).

Conclusions: Our results indicate that the deleterious impact of self-reported sleep disturbances on cognitive performance was prominent over other risk factors and illustrate the importance of clinician evaluation of sleep in patients with or at risk of diminished cognitive performance. Future, longitudinal studies implementing a comprehensive neuropsychological battery and objective sleep measurement are warranted to further explore these associations.
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http://dx.doi.org/10.1017/S1041610219001492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011648PMC
July 2020

Social history and exposure to pathogen signals modulate social status effects on gene regulation in rhesus macaques.

Proc Natl Acad Sci U S A 2020 09 14;117(38):23317-23322. Epub 2019 Oct 14.

Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC, Canada H3T1C5;

Social experience is an important predictor of disease susceptibility and survival in humans and other social mammals. Chronic social stress is thought to generate a proinflammatory state characterized by elevated antibacterial defenses and reduced investment in antiviral defense. Here we manipulated long-term social status in female rhesus macaques to show that social subordination alters the gene expression response to ex vivo bacterial and viral challenge. As predicted by current models, bacterial lipopolysaccharide polarizes the immune response such that low status corresponds to higher expression of genes in NF-κB-dependent proinflammatory pathways and lower expression of genes involved in the antiviral response and type I IFN signaling. Counter to predictions, however, low status drives more exaggerated expression of both NF-κB- and IFN-associated genes after cells are exposed to the viral mimic Gardiquimod. Status-driven gene expression patterns are linked not only to social status at the time of sampling, but also to social history (i.e., past social status), especially in unstimulated cells. However, for a subset of genes, we observed interaction effects in which females who fell in rank were more strongly affected by current social status than those who climbed the social hierarchy. Taken together, our results indicate that the effects of social status on immune cell gene expression depend on pathogen exposure, pathogen type, and social history-in support of social experience-mediated biological embedding in adulthood, even in the conventionally memory-less innate immune system.
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http://dx.doi.org/10.1073/pnas.1820846116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7519294PMC
September 2020

Sex-specific roles of cellular inflammation and cardiometabolism in obesity-associated depressive symptomatology.

Int J Obes (Lond) 2019 10 14;43(10):2045-2056. Epub 2019 May 14.

Department of Psychiatry, University of California San Diego, La Jolla, 92093, California, United States.

Background: Obesity and depression are complex conditions with stronger comorbid relationships among women than men. Inflammation and cardiometabolic dysfunction are likely mechanistic candidates for increased depression risk, and their prevalence differs by sex. Whether these relationships extend to depressive symptoms is poorly understood. Therefore, we analyzed sex in associations between inflammation and metabolic syndrome (MetS) criteria on depressive symptomatology. Specifically, we examined whether sex positively moderates the relationship between depressive symptoms and inflammation among women, and whether MetS has parallel effects among men.

Methods: Depressive symptoms, MetS, and inflammation were assessed in 129 otherwise healthy adults. Depressive symptoms were assessed using Beck Depression Inventory (BDI-Ia). Monocyte inflammation regulation (BARIC) was quantified using flow cytometry measurement of TNF-α suppression by β-agonist. Moderation effects of sex on associations between BARIC, MetS criteria, and BDI were estimated using two-way ANOVA and linear regression, adjusting for BMI, and by sex subgroup analyses.

Results: Obese individuals reported more depressive symptoms. Sex did not formally moderate this relationship, though BDI scores tended to differ by BMI among women, but not men, in subgroup analysis. Poorer inflammation control and higher MetS criteria were correlated with somatic depressive symptoms. Sex moderated associations between MetS criteria and somatic symptoms; among men, MetS criteria predicted somatic symptoms, not among women. Subgroup analysis further indicated that poorer inflammation control tended to be associated with higher somatic symptoms in women.

Conclusions: These results indicate that obesity-related inflammation and MetS factors have sex-specific effects on depressive symptoms in a non-clinical population. Although pathophysiological mechanisms underlying sex differences remain to be elucidated, our findings suggest that distinct vulnerabilities to depressive symptoms exist between women and men, and highlight the need to consider sex as a key biological variable in obesity-depression relationships. Future clinical studies on comorbid obesity and depression should account for sex, which may optimize therapeutic strategies.
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http://dx.doi.org/10.1038/s41366-019-0375-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774832PMC
October 2019

Social affiliation predicts mitochondrial DNA copy number in female rhesus macaques.

Biol Lett 2019 01;15(1):20180643

1 Department of Biology, Duke University , Durham, NC 27708 , USA.

In many social mammals, social adversity predicts compromised health and reduced fitness. These effects are thought to be driven in part by chronic social stress, but their molecular underpinnings are not well understood. Recent work suggests that chronic stress can affect mitochondrial copy number, heteroplasmy rates and function. Here, we tested the first two possibilities for the first time in non-human primates. We manipulated dominance rank in captive female rhesus macaques ( n = 45), where low rank induces chronic social stress, and measured mitochondrial DNA (mtDNA) copy number and heteroplasmy in five peripheral blood mononuclear cell types from each study subject. We found no effect of dominance rank on either mtDNA copy number or heteroplasmy rates. However, grooming rate, a measure of affiliative social behaviour predicted by high social status, was positively associated with mtDNA copy number in B cells, cytotoxic T cells and monocytes. Our results suggest that social interactions can influence mtDNA regulation in immune cells. Further, they indicate the importance of considering both affiliative and competitive interactions in investigating this relationship.
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http://dx.doi.org/10.1098/rsbl.2018.0643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371908PMC
January 2019

Compassion Meditation Training for Emotional Numbing Symptoms Among Veterans with Post-Traumatic Stress Disorder.

J Altern Complement Med 2019 04 13;25(4):441-443. Epub 2019 Feb 13.

6 Emory-Tibet Partnership, Department of Religion, Emory University, Atlanta, GA.

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http://dx.doi.org/10.1089/acm.2018.0425DOI Listing
April 2019

Social status alters chromatin accessibility and the gene regulatory response to glucocorticoid stimulation in rhesus macaques.

Proc Natl Acad Sci U S A 2019 01 11;116(4):1219-1228. Epub 2018 Dec 11.

Department of Evolutionary Anthropology, Duke University, Durham, NC 27708;

Low social status is an important predictor of disease susceptibility and mortality risk in humans and other social mammals. These effects are thought to stem in part from dysregulation of the glucocorticoid (GC)-mediated stress response. However, the molecular mechanisms that connect low social status and GC dysregulation to downstream health outcomes remain elusive. Here, we used an in vitro GC challenge to investigate the consequences of experimentally manipulated social status (i.e., dominance rank) for immune cell gene regulation in female rhesus macaques, using paired control and GC-treated peripheral blood mononuclear cell samples. We show that social status not only influences immune cell gene expression but also chromatin accessibility at hundreds of regions in the genome. Social status effects on gene expression were less pronounced following GC treatment than under control conditions. In contrast, social status effects on chromatin accessibility were stable across conditions, resulting in an attenuated relationship between social status, chromatin accessibility, and gene expression after GC exposure. Regions that were more accessible in high-status animals and regions that become more accessible following GC treatment were enriched for a highly concordant set of transcription factor binding motifs, including motifs for the GC receptor cofactor AP-1. Together, our findings support the hypothesis that social status alters the dynamics of GC-mediated gene regulation and identify chromatin accessibility as a mechanism involved in social stress-driven GC resistance. More broadly, they emphasize the context-dependent nature of social status effects on gene regulation and implicate epigenetic remodeling of chromatin accessibility as a contributing factor.
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http://dx.doi.org/10.1073/pnas.1811758115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347725PMC
January 2019

3,4-Methylenedioxymethamphetamine Increases Affiliative Behaviors in Squirrel Monkeys in a Serotonin 2A Receptor-Dependent Manner.

Neuropsychopharmacology 2017 Sep 20;42(10):1962-1971. Epub 2017 Apr 20.

Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.

3,4-Methylenedioxymethamphetamine (MDMA) increases sociality in humans and animals. Release of serotonin (5-HT) is thought to have an important role in the increase in social behaviors, but the mechanisms underlying these effects are poorly understood. Despite the advantages of nonhuman primate models, no studies have examined the mechanisms of the social effects of MDMA in nonhuman primates. The behavior and vocalizations of four group-housed squirrel monkeys were examined following administration of MDMA, its enantiomers, and methamphetamine. 5-HT receptor antagonists and agonists were given as drug pretreatments. Data were analyzed using linear mixed-effects models. MDMA and its enantiomers increased affiliative social behaviors and vocalizations, whereas methamphetamine had only modest effects on affiliative behaviors. Pretreatment with a 5-HT receptor antagonist and a 5-HT receptor agonist attenuated the MDMA-induced increase in social behaviors, while a 5-HT receptor antagonist did not alter affiliative vocalizations and increased MDMA-induced social contact. Nonhuman primates show MDMA-specific increases in affiliative social behaviors following MDMA administration, in concordance with human and rodent studies. MDMA-induced increases in social behaviors are 5-HT, but not 5-HT, receptor dependent. Understanding the neurochemical mechanisms mediating the prosocial effects of MDMA could help in the development of novel therapeutics with the unique social effects of MDMA but fewer of its limitations.
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http://dx.doi.org/10.1038/npp.2017.80DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561347PMC
September 2017

Social status alters immune regulation and response to infection in macaques.

Science 2016 11;354(6315):1041-1045

Department of Evolutionary Anthropology, Duke University, Durham, NC 27708, USA.

Social status is one of the strongest predictors of human disease risk and mortality, and it also influences Darwinian fitness in social mammals more generally. To understand the biological basis of these effects, we combined genomics with a social status manipulation in female rhesus macaques to investigate how status alters immune function. We demonstrate causal but largely plastic social status effects on immune cell proportions, cell type-specific gene expression levels, and the gene expression response to immune challenge. Further, we identify specific transcription factor signaling pathways that explain these differences, including low-status-associated polarization of the Toll-like receptor 4 signaling pathway toward a proinflammatory response. Our findings provide insight into the direct biological effects of social inequality on immune function, thus improving our understanding of social gradients in health.
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http://dx.doi.org/10.1126/science.aah3580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5498102PMC
November 2016

Dominance rank causally affects personality and glucocorticoid regulation in female rhesus macaques.

Psychoneuroendocrinology 2016 12 12;74:179-188. Epub 2016 Sep 12.

Yerkes National Primate Research Center, Emory University, Atlanta, GA, 30322, USA; Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, Atlanta, GA, 30322, USA.

Low social status is frequently associated with heightened exposure to social stressors and altered glucocorticoid regulation by the hypothalamic-pituitary-adrenal (HPA) axis. Additionally, personality differences can affect how individuals behave in response to social conditions, and thus may aggravate or protect against the effects of low status on HPA function. Disentangling the relative importance of personality from the effects of the social environment on the HPA axis has been challenging, since social status can predict aspects of behavior, and both can remain stable across the lifespan. To do so here, we studied an animal model of social status and social behavior, the rhesus macaque (Macaca mulatta). We performed two sequential experimental manipulations of dominance rank (i.e., social status) in 45 adult females, allowing us to characterize personality and glucocorticoid regulation (based on sensitivity to the exogenous glucocorticoid dexamethasone) in each individual while she occupied two different dominance ranks. We identified two behavioral characteristics, termed 'social approachability' and 'boldness,' which were highly social status-dependent. Social approachability and a third dimension, anxiousness, were also associated with cortisol dynamics in low status females, suggesting that behavioral tendencies may sensitize individuals to the effects of low status on HPA axis function. Finally, we found that improvements in dominance rank increased dexamethasone-induced acute cortisol suppression and glucocorticoid negative feedback. Our findings indicate that social status causally affects both behavioral tendencies and glucocorticoid regulation, and that some behavioral tendencies also independently affect cortisol levels, beyond the effects of rank. Together, they highlight the importance of considering personality and social status together when investigating their effects on HPA axis function.
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http://dx.doi.org/10.1016/j.psyneuen.2016.09.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494262PMC
December 2016

Common methods for fecal sample storage in field studies yield consistent signatures of individual identity in microbiome sequencing data.

Sci Rep 2016 08 16;6:31519. Epub 2016 Aug 16.

Institute of Primate Research, National Museums of Kenya, Nairobi 00502, Kenya.

Field studies of wild vertebrates are frequently associated with extensive collections of banked fecal samples-unique resources for understanding ecological, behavioral, and phylogenetic effects on the gut microbiome. However, we do not understand whether sample storage methods confound the ability to investigate interindividual variation in gut microbiome profiles. Here, we extend previous work on storage methods for gut microbiome samples by comparing immediate freezing, the gold standard of preservation, to three methods commonly used in vertebrate field studies: lyophilization, storage in ethanol, and storage in RNAlater. We found that the signature of individual identity consistently outweighed storage effects: alpha diversity and beta diversity measures were significantly correlated across methods, and while samples often clustered by donor, they never clustered by storage method. Provided that all analyzed samples are stored the same way, banked fecal samples therefore appear highly suitable for investigating variation in gut microbiota. Our results open the door to a much-expanded perspective on variation in the gut microbiome across species and ecological contexts.
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http://dx.doi.org/10.1038/srep31519DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4985740PMC
August 2016

Social status drives social relationships in groups of unrelated female rhesus macaques.

Anim Behav 2016 Jan;111:307-317

Department of Evolutionary Anthropology, Duke University, Durham, NC, U.S.A.; Department of Biology, Duke University, Durham, NC, U.S.A.; Institute of Primate Research, National Museums of Kenya, Nairobi, Kenya; Duke Population Research Institute, Duke University, Durham, NC, U.S.A.

Strong social relationships confer health and fitness benefits in a number of species, motivating the need to understand the processes through which they arise. In female cercopithecine primates, both kinship and dominance rank are thought to influence rates of affiliative behaviour and social partner preference. Teasing apart the relative importance of these factors has been challenging, however, as female kin often occupy similar positions in the dominance hierarchy. Here, we isolated the specific effects of rank on social relationships in female rhesus macaques by analysing grooming patterns in 18 social groups that did not contain close relatives, and in which dominance ranks were experimentally randomized. We found that grooming was asymmetrically directed towards higher-ranking females and that grooming bouts temporarily decreased the likelihood of aggression between grooming partners, supporting the idea that grooming is associated with social tolerance. Even in the absence of kin, females formed the strongest grooming relationships with females adjacent to them in rank, a pattern that was strongest for the highest-ranking females. Using simulations, we show that three rules for allocating grooming based on dominance rank recapitulated most of the relationships we observed. Finally, we evaluated whether a female's tendency to engage in grooming behaviour was stable across time and social setting. We found that one measure, the rate of grooming females provided to others (but not the rate of grooming females received), exhibited modest stability after accounting for the primary effect of dominance rank. Together, our findings indicate that dominance rank has strong effects on social relationships in the absence of kin, suggesting the importance of considering social status and social connectedness jointly when investigating their health and fitness consequences.
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http://dx.doi.org/10.1016/j.anbehav.2015.10.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4707678PMC
January 2016

Ancestral founder mutations in calpain-3 in the Indian Agarwal community: historical, clinical, and molecular perspective.

Muscle Nerve 2013 Jun 11;47(6):931-7. Epub 2013 May 11.

Department of Human Genetics, Emory University School of Medicine, 615 Michael Street, Atlanta, Georgia 30322, USA.

Introduction: Clinical heterogeneity of limb-girdle muscular dystrophies (LGMDs, 24 known subtypes), which includes overlapping phenotypes and varying ages of onset and morbidity, adds complexity to clinical and molecular diagnoses.

Methods: To diagnose LGMD subtype, protein analysis, using immunohistochemistry (IHC) and immunoblotting, was followed by gene sequencing through a panel approach (simultaneous sequencing of known LGMD genes) in 9 patients from unrelated families of the Indian Agarwal community. Haplotype studies were performed by targeted SNP genotyping to establish mutation segregation.

Results: We identified 2 founder mutations in CAPN3, a missense (c.2338G>C; p.D780H) and a splice-site (c.2099-1G>T) mutation, on 2 different haplotype backgrounds. The patients were either heterozygous for both or homozygous for either of these mutations.

Conclusions: Founder mutations have immediate clinical application, at least in selected population groups. Clinically available gene panels may provide a definitive molecular diagnosis for heterogeneous disorders such as LGMD.
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http://dx.doi.org/10.1002/mus.23763DOI Listing
June 2013

Predictors of depression in breast cancer patients treated with radiation: role of prior chemotherapy and nuclear factor kappa B.

Cancer 2013 Jun 19;119(11):1951-9. Epub 2013 Mar 19.

Department of Radiation Oncology, Emory University, Atlanta, GA 30322, USA.

Background: Depression is common during and after breast cancer treatment. However, the role of specific therapeutic modalities and related biologic mechanisms remains unclear. Radiation is an essential component of breast-conserving therapy and may contribute to depression in patients with breast cancer through the activation of inflammatory pathways.

Methods: Depressive symptoms and inflammatory mediators, including nuclear factor kappa B (NF-κB), were assessed at baseline (before radiation), during radiation, and 6 weeks after radiation in 64 women who had stage 0 through IIIA breast cancer.

Results: No significant increases in depressive symptoms occurred during or after radiation, although a number of patients exhibited moderate-to-severe depression throughout the study. Multivariate analyses of baseline factors predictive of depression revealed that educational status, perceived stress, prior chemotherapy, and peripheral blood NF-κB DNA binding all were independent predictors of persistent depressive symptoms after radiation (all P < .05). Of these factors, only prior chemotherapy was associated with inflammatory mediators, including NF-κB DNA binding, soluble tumor necrosis factor-alpha receptor 2, and interleukin-6, which, in univariate analyses predicted depressive symptoms after radiation (all P < .05). Chemotherapy-treated patients also exhibited an over-representation of gene transcripts regulated by NF-κB.

Conclusions: Radiation was not associated with increased depressive symptoms in the current study, but of disease and treatment-related factors, prior chemotherapy predicted significant depression after radiation. Longitudinal studies are warranted to investigate the relationship among prior chemotherapy, inflammation, and persistent depression after breast cancer treatment.
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http://dx.doi.org/10.1002/cncr.28003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663885PMC
June 2013

Aberrant firing of replication origins potentially explains intragenic nonrecurrent rearrangements within genes, including the human DMD gene.

Genome Res 2012 Jan 16;22(1):25-34. Epub 2011 Nov 16.

Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, USA.

Non-allelic homologous recombination (NAHR), non-homologous end joining (NHEJ), and microhomology-mediated replication-dependent recombination (MMRDR) have all been put forward as mechanisms to explain DNA rearrangements associated with genomic disorders. However, many nonrecurrent rearrangements in humans remain unexplained. To further investigate the mutation mechanisms of these copy number variations (CNVs), we performed breakpoint mapping analysis for 62 clinical cases with intragenic deletions in the human DMD gene (50 cases) and other known disease-causing genes (one PCCB, one IVD, one DBT, three PAH, one STK11, one HEXB, three DBT, one HRPT1, and one EMD cases). While repetitive elements were found in only four individual cases, three involving DMD and one HEXB gene, microhomologies (2-10 bp) were observed at breakpoint junctions in 56% and insertions ranging from 1 to 48 bp were seen in 16 of the total 62 cases. Among these insertions, we observed evidence for tandem repetitions of short segments (5-20 bp) of reference sequence proximal to the breakpoints in six individual DMD cases (six repeats in one, four repeats in three, two repeats in one, and one repeat in one case), strongly indicating attempts by the replication machinery to surpass the stalled replication fork. We provide evidence of a novel template slippage event during replication rescue. With a deeper insight into the complex process of replication and its rescue during origin failure, brought forward by recent studies, we propose a hypothesis based on aberrant firing of replication origins to explain intragenic nonrecurrent rearrangements within genes, including the DMD gene.
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http://dx.doi.org/10.1101/gr.123463.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3246204PMC
January 2012
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