Biological Dysregulation Research Articles

An integrated approach to understand biological stress system dysregulation across depressive and anxiety disorders

BackgroundAffective disorders involve dysregulation of major biological stress systems (hypothalamic-pituitary-adrenal (HPA)-axis, immune system, autonomic nervous system (ANS)). Suchdysregulationshave rarely beensimultaneously examined across different stress systems. MethodsIn the Netherlands Study of Depression and Anxiety (n=2789), we investigated whether current or remitted depressive and/or anxiety disorders (based on the CIDI semi-structured interview), including specific symptom profiles, were associated with separate markers and cumulative indexes of the HPA-axis (cortisol awakening response, evening cortisol, dexamethasone suppression test cortisol), immune system (C-reactive protein, interleukin-6, tumor necrosis factor-α), and ANS (heart rate, respiratory sinus arrhythmia, pre-ejection period). ResultsDepressive andanxiety disorderswere significantlyassociated with changes in three biological stress systemsincluding HPA-axis hyperactivity, increased inflammatory activity, and a higher ANS tone, particularly for integrative and cumulative indexes of these stress systems (pFDR <.05) vs. controls. The strongest associations were seen with current disorders andcumulative indexes of the HPA-axis (β=.124, pFDR=.001), the immune system (β =.057, pFDR=.032), and total cumulative index across stress systems (β=.102, pFDR=.004). Atypical, energy-related depression severity was linked to immune system markers (pFDR<0.001), melancholic depression severity to HPA-axis markers (pFDR=.032), and anxiety arousal severity to both HPA-axis and immune system markers (pFDR<0.05). Findings were partially explained by poorer lifestyle, more chronic diseases,or (especially for ANS-function) antidepressant use. LimitationsCross-sectional analyses limit examination of temporal associations. ConclusionPatients withdepressive and anxiety disorders showed consistent dysregulation across biological stress systems, particularly for current episodes.To understand stress system functionality in affective disorders, an integrated approach capturing cumulative stress indices within and across biological stress systems is important.

Acute Exposure of Atmospheric Ultrafine Particles Induced Inflammation Response and Dysregulated TGFβ/Smads Signaling Pathway in ApoE-/- Mice.

Ultrafine particles (UFPs) referred to particular matters with aerosol diameter less than 100nm. Because of the lightweight and small size, UFPs have become an occupational inhalation risk. The UFPs will be accumulated in the deep lung through inhalation, and then reach into all the organs via circulation system; some UFPs even stay in the brain. As previous study reported, UFPs exposure is usually associated with cardiovascular disease, such as atherosclerosis (AS). In our study, we tried to understand how acute UFP exposure caused the biological dysregulation in atherosclerosis. Acute exposure of UFPs were applied to mice for 6 consecutive days, mice were sacrificed after 3, 5, 7, and 10days post-exposure. Aorta and serum were collected for histological and biomarkers analysis. Mice aortic adventitial fibroblasts (MAFs) were isolated from mice and used to further study to understand the mechanism of UFPs induced atherosclerosis. Compared to the untreated control, the inflammation responses and nitrate stress were observed after acute exposure of UFPs, with increased IL-6, MCP-1, p47phox, and 3-NT levels in the mice serum. Besides, upregulation of microRNAs: miR-301b-3p and Let-7c-1-3p, and their downstream target: Smad2, Smad3, and TGFβ1 were also observed in mouse aorta after acute exposure of UFPs. Similar results were identified in vitro as well. Acute exposure of UFPs induced the systematic nitrate stress and inflammation responses, along with the changes of vascular permeability. Dysregulated miRNAs and TGFβ/Smads signaling pathway indicated the higher risk of atherosclerosis/vasculature remodeling when exposed to UFPs.

A comparison of depressive symptom profiles between current major depressive disorder and schizophrenia spectrum disorder

IntroductionDepressive symptoms are highly prevalent and clinically relevant in schizophrenia spectrum disorder (SSD) patients. So far, little is known about to what extent the depressive symptom profile in SSD is comparable to that seen in major depressive disorder (MDD). MethodsData were derived from the Genetic Risk and Outcome of Psychosis study (GROUP) and the Netherlands Study of Depression and Anxiety (NESDA). We examined differences in severity of depressive symptom profiles and distribution of mood/cognition and somatic/vegetative depressive symptoms using the Quick Inventory of Depressive Symptomatology - Self Report (QIDS-SR) within SSD patients (n = 449), MDD patients (n = 816) and healthy controls (n = 417), aged 18 to 50. Within SSD, associations between depression severity and clinical and demographic data were examined. Results60.4% of SSD patients showed substantial depressive symptomatology (QIDS-SR≥6). The difference in mood/cognition symptoms between SSD and MDD was larger (higher symptoms in MDD, effect size = 1.13), than the differences in somatic/vegetative symptoms (effect size 0.74). In patients with SSD, multivariable regression analyses showed that lower social functioning, male gender, use of benzodiazepine and more severe positive symptoms were associated with higher overall depressive symptomatology. The use of antipsychotics or antidepressants was associated with more somatic/vegetative symptoms. ConclusionMore than half of SSD patients have considerable depressive symptomatology, with a relative preponderance of somatic/vegetative symptoms compared to the profile seen in MDD. Future research could explore whether depressive symptom profile in SSD may also be associated with biological dysregulations like in MDD.

Diet Quality and Biological Risk in a National Sample of Older Americans

Biomarkers are sensitive to current health status and capture aspects of health that may precede the development of disease and other health problems. Using comprehensive measures of biological risk, this study aims to investigate the relationship between intake of individual dietary components, overall diet quality, and biological dysregulation. For the analysis, we used nutrition and biomarker data from 3,641 older adults (over age 50) in the Health and Retirement Study. Eleven out of 13 individual dietary components were associated with lower biological risk. After controlling for SES, health behaviors, and access to health care, a high intake of fruits, greens and beans, whole grains, seafood and plant proteins, and fatty acids and a low intake of sodium and saturated fat were still associated with lower biological risk. Respondents with poor/suboptimal quality diet had higher biological risk than those with good quality diet. After controlling for SES, health behaviors, and access to health care, respondents with poor/suboptimal quality diet continued to exhibit higher biological risk than those with good quality diet, though the differences in biological risk were reduced. Findings from this study emphasize the importance of healthy eating in improving health of older adults. Encouraging intake of fruits, greens and beans, whole grains, seafood and plant proteins, and fatty acids, while limiting consumption of sodium and saturated fat would improve overall diet quality and contribute to the prevention of chronic diseases and morbidity.

On the Biopsychosocial Costs of Alienated Labor.

Data from the national, longitudinal Mid-Life in the US (MIDUS) study were used to examine work alienation and its relationship to biological health as well as psychological and social functioning. The alienation measure focuses on the autonomy and creativity the work provides. We hypothesized that alienated work would have negative associations with each of the three domains: in biology, higher 'allostatic load' (biological dysregulation); in psychology, poorer cognitive performance; and socially, negative impacts on family life. The outcomes are generally as predicted, though there are notable differences for men and women.

Abstract 17448: Comprehensive Characterization of Alternative Polyadenylation in Human Right Ventricle Failure

Background: Alternative cleavage and polyadenylation (APA) an emerging post-transcriptional mechanism for gene regulation that generates distinct isoforms of mRNA with different 3’UTR lengths. APA plays an important role in different biological processes and dysregulation of APA leading to many human diseases. However, the functional consequences of APA events in the right ventricle (RV) failure in humans remain unexplored. Objective: To identify whether the 3′UTR length is modulated by APA in the RV failure in humans compared to healthy RV. Methods and Results: We used Poly A tail RNA sequencing and a novel algorithm called DaPars to measure the global patterns of APA in healthy and failing human RV specimens. We revealed 3'UTR shortening and lengthening of many genes in failing RV compared to healthy RV specimens. The lengthened 3’UTR genes were enriched for functional groups such as RNA processing and splicing. Whereas the shortened 3’UTR genes were enriched for nucleic acid metabolic process and chromatin organization. In addition, differential APA events in RV failure regulates many pathways important for the progression of the RV failure. Finally, the regulator proteins of APA including cleavage and polyadenylation specificity factor (CPSF) 6 and 7, cleavage factor Im (CFIm) 25 and 59 have been regulated in RV failure compared to healthy RV specimens. Conclusions: Our results highlight important roles of APA in the progression of RV failure in humans, including RNA processing, splicing, and specific gene expression. Demonstrating that APA mediated 3’UTR length regulation provides the additional layer of gene expressions in RV failure.

Weathering in Detroit: Place, Race, Ethnicity, and Poverty as Conceptually Fluctuating Social Constructs Shaping Variation in Allostatic Load.

US population health inequity remains entrenched, despite mandates to eliminate it. To promote a public health approach of consequence in this domain, stakeholders call for moving from risk-factor epidemiology toward consideration of dynamic local variations in the physiological impacts of structured lived experience. Using a community-based, participatory research approach, we collected and analyzed a unique data set of 239 black, white, and Mexican adults from a stratified, multistage probability sample of three Detroit, Michigan, neighborhoods. We drew venous blood, collected saliva, took anthropometric measurements, and assayed specimens to measure allostatic load (AL), an indicator of stress-mediated biological dysregulation, linking participants' AL scores and survey responses. In a series of nested Poisson models, we regressed AL on socioeconomic, psychosocial, neighborhood, and behavioral stressors to test the hypothesis that race/ethnicity and poverty-to-income ratio (PIR) are conceptually fluctuating variables whose impacts on AL are sensitive to structured lived experience. White and Mexican Detroit participants with PIR < 1 have higher AL than counterparts nationally; black participants in Detroit and nationwide had comparable AL. Within Detroit, disparities by PIR were higher in whites than blacks, with no significant difference by PIR in Mexicans. The size of estimated effects of having PIR < 1 for whites is 58 percentage points greater than that of Mexicans and twice that of blacks. Structurally rooted unobserved heterogeneity bias threatens the validity of independent main effects interpretations of associations between race/ethnicity, socioeconomic characteristics, or place and health. One-size-fits-all analytic or policy models developed from the perspective of the dominant social group insufficiently address the experiences of diverse populations in specific settings and historical moments; nor do they recognize culturally mediated protective resources residents may have developed against material and psychosocial hardship.

Dopaminergic, Noradrenergic, Adrenal, and Thyroid Abnormalities in Psychotic and Affective Disorders.

BackgroundThis study aimed to assess hypothalamic-pituitary dopaminergic (DA), noradrenergic (NA), thyroid (HPT), and adrenal (HPA) activity in schizophrenia, in schizoaffective disorder, and in bipolar disorder.MethodWe investigated a combined approach of hormone responses to (1) apomorphine (APO), a short-acting DA receptor agonist which decreases prolactin secretion (PRL), and stimulates secretion of growth hormone (GH), adrenocorticotropin (ACTH), and cortisol; (2) clonidine (CLO), an alpha 2-adrenoceptor agonist which stimulates GH secretion; (3) 8 AM and 11 PM protirelin (TRH) which stimulates thyrotropin (TSH) secretion; and (4) dexamethasone which suppresses cortisol secretion, in 13 hospitalized healthy male controls and 39 untreated male inpatients: 13 with DSM-IV paranoid schizophrenia, 13 with DSM-IV schizoaffective disorder (bipolar subtype, depressed at the time of the study), and 13 with DSM-IV bipolar disorder (depressed).ResultsCompared to controls, paranoid schizophrenic patients showed (1) lower APO-induced ACTH and cortisol stimulation, and (2) higher post-dexamethasone cortisol values. Compared to controls, schizoaffective and bipolar patients showed (1) lower ΔΔTSH values (i.e., difference between 11 PM and 8 AM TRH-TSH responses), (2) lower APO-induced PRL suppression, (3) lower CLO-induced GH stimulation, and (4) higher post-dexamethasone cortisol values.ConclusionsAlthough results must be interpreted with caution because of the small sample, this preliminary study suggests that depressed bipolar and schizoaffective patients share common biological dysregulations, distinct from that of paranoid schizophrenic patients. From a pathophysiological viewpoint, paranoid schizophrenic patients can be characterized by hyposensitivity of the hypothalamic DA receptors (possibly resulting from an increase in presynaptic DA release) associated with increased HPA axis activity, while depressed bipolar and schizoaffective patients can be characterized by hyposensitivity of the pituitary TRH and DA-D2 receptors (possibly linked to the activation of the hypothalamic TRH and tuberoinfundibular DA neurons, respectively), together with subsensitive postsynaptic α2-adrenoreceptors at the hypothalamic level (possibly secondary to an erratic release of NA) and increased HPA axis activity.

Dimensions of acculturation and biological dysregulation among Latina/os: the role of ethnic background, gender, and immigrant generation

ABSTRACT Objective: Research examining how different dimensions of acculturative beliefs and behaviors influence the risk of biological dysregulation among Latina/os is limited. This study examined associations between three types of acculturation and allostatic load (i.e. a multisystem index of biological dysregulation) across gender and Latina/o ethnic groups. Multiplicative models were also included in order to determine whether immigrant generation moderates acculturation-allostatic load relationships. Design: Data were drawn from the Hispanic Community Health Study/ Study of Latina/os. The sample consisted of 11,841 Latina/os from five ethnic groups: Cuban, Puerto Rican, Dominican, Mexican, and South/Central American. The measure for allostatic load was derived from 15 biomarker and anthropometric measures that were designed to capture cardiometabolic risk, glucose metabolism, cardiopulmonary function, inflammation, and organ function. Acculturation measures, immigrant generation, gender, ethnic background, and other covariates were derived from self-reports. Survey corrected ordinary least squares regressions were used to assess relationships between different dimensions of acculturation and allostatic load. Results: Results demonstrate dimensions of acculturation play a significant role in the risk of biological dysregulation for Latina/os with divergent results across gender and ethnic background. Estimates from the multiplicative models show immigrant generation moderates acculturation-allostatic load relationships, and relationships are dependent on gender and ethnic background. Conclusion: The study contributes to the understanding of how different dimensions of acculturation, as well as other important structural determinants of health, influence the risk of biological dysregulation among Latina/os. Finding from this study can inform targeted strategies designed to reduce the physiological consequences of chronic stress among Latina/os.

Allostatic load and mental health: a latent class analysis of physiological dysregulation

This study explored the associations between specific profiles of biological dysregulation and mental health outcomes in a national, community sample of healthy adults in the United States. A latent class analysis of data from the Midlife Development in the United States study (n = 1,757) was conducted to determine classes of biological dysregulation. Multinomial logistic regressions of class membership were employed to determine associations with measures related to depression, including whether or not individuals had sought treatment, Center for Epidemiological Studies Depression Scale, and both the generalized distress and anhedonia subscales of the Mood and Anxiety Symptoms Questionnaire. Four classes of dysregulation emerged: baseline/low dysregulation, metabolic and inflammatory dysregulation, parasympathetic dysregulation, and SAM pathway dysregulation. Individuals who met the criteria for depression measures were more likely to be in the metabolic and immune dysregulation and parasympathetic dysregulation groups as compared to the baseline group. The results suggest that mental health outcomes, such as depression, are differentially associated with specific profiles of biological dysregulation. A more nuanced approach to profiles of dysregulation could better inform treatment decisions. Lay summary Higher levels of allostatic load, which represents the cumulative wear and tear of exposure to stress, are associated with increased rates of depression and anhedonia. Specifically, parasympathetic dysregulation and immunometabolic dysregulation are associated with negative mental health outcomes

Physical Activity Buffers the Adverse Impacts of Racial Discrimination on Allostatic Load Among Indigenous Adults.

BackgroundRacial discrimination has been associated with biological dysfunction among ethnic minorities. The extent to which regular physical activity (PA) may buffer this association is unknown.PurposeTo examine the association between past-year racial discrimination and allostatic load (AL) stratified by PA within a sample of Indigenous adults.MethodsData were collected from Indigenous adults attending university in a city in western Canada between 2015 and 2017. The Experiences of Discrimination Scale was used to assess discrimination and the Godin–Shephard Leisure-Time Physical Activity Questionnaire assessed PA. A composite of seven biomarkers assessing neuroendocrine, cardiovascular, metabolic, and immune system function measured AL. Linear regression models examined associations adjusted for confounders (N = 150).ResultsIn the insufficiently active group, every 1 point increase in racial discrimination (up to a maximum of 9) resulted in approximately one third of a point increase in AL score. In the sufficiently active group, the association between racial discrimination and AL score was not statistically significant.ConclusionsA growing body of research suggests racial discrimination is associated with multisystem biological dysregulation and health risks. Increased action to address racism in society is a priority. As that work unfolds, there is a need to identify effective tools that racialized groups can use to buffer the effects of racism on their health. The present findings suggest that engagement in regular PA may attenuate the pernicious effects of discrimination on biological dysfunction.

Depressive symptoms and their relationship with negative and other psychotic symptoms in early onset psychosis.

The importance of depression in adult people with first-episode psychosis (FEP) has been demonstrated. However, it has hardly been studied in children and adolescents. There is a need to broaden knowledge of the relationship between psychotic symptoms and specific depression symptomatology. The aims of study were (a) to examine the frequency of presence and type of depressive symptoms in early onset FEP, and (b) to assess the relationship between depressive symptoms and psychotic symptomatology, and specifically negative symptoms. An observational cross-sectional study was performed in 62 FEP cases. Inclusion criteria were two or more psychotic symptoms, age 7-17years old, first mental health service consultation, and fewer than 6months from the first contact with the service. Participants were assessed with clinical and socio-demographic questionnaires: the Positive and Negative Syndrome Scale (PANSS) and the Children Depression Inventory (CDI). A Student t test was performed to compare psychotic symptoms in both groups: presence of depression and the absence of depression. A Pearson correlation was performed in order to relate subscales of the PANSS and each of the depression subscales and factors, as well the relation between negative and depressive symptoms. Our results show that a high percentage of people with an early onset of a FEP scored positively for depression. The most prevalent depressive symptoms were associated with schooling. The presence of depression was associated with negative, affective, and excited symptoms. Self-esteem, school problems, negative affect, and biological dysregulation were associated with psychotic symptoms. Finally, depressive items related to social functioning were more closely associated with negative symptoms of the PANSS. In conclusion, owing to the high incidence of depression in FEP in those suffering early onset of psychosis, there is a need for instruments to measure the depression more specifically in children and adolescent, and to uncover the clinical characteristics of depression in this population.

The mediating effect of allostatic load on the relationship between neighborhood perceptions and depression.

Neighborhood perceptions is an important predictor of both allostatic load in the form of biological dysregulation and major depressive disorder. Furthermore, biological dysregulation is predictive of major depressive disorder. Yet to date, the use of biological dysregulation as one potential causal pathway linking neighborhood perceptions to depression has not been explored. This study examined the relationship between neighborhood perception, biological dysregulation in the form of allostatic load, and depression among individuals who participated in the three waves of the Midlife Development in the United States study (1996–2014). Two-to-one propensity score matching was employed prior the use of causal mediation analyses. Lower neighborhood perceptions at wave one were associated with increased allostatic load at wave two. Allostatic load at wave two is associated with depression at wave three. The mediation analysis shows that 6.0% of the relationship between neighborhood perception and depression is mediated by biological dysregulation. These results can inform future prevention and treatment methods by supporting efforts to integrate individuals and community-level interventions to aid in addressing both the environmental conditions and biological factors associated with depression.

Determination of the phenotypic age in residents of Mexico City: effect of accelerated ageing on lung function and structure.

IntroductionPhenotypic age better represents age-related biological dysregulation than chronological age. Recently, a multisystem-based ageing measure, which integrates chronological age and nine biomarkers, was proposed.MethodsPhenotypic age was determined in 774 residents of Mexico City over 60 years old and without respiratory problems. We arbitrarily classified as “accelerated” ageing, those showing >4 years compared with their chronological age, and “slowed” ageing, those with <4 years compared with chronological age. Demographic risk factors were analysed with structured questionnaires. Lung structure was evaluated by high-resolution computed tomography and functional competence was analysed by forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), diffusion capacity of carbon monoxide (DLCO), and the 6-minute walk test (6MWT).ResultsOverall, 13% of this cohort showed accelerated ageing, which was corroborated with four independent biomarkers of ageing, 42% had normal ageing and 46% had slowed ageing. Risk factors associated with accelerated ageing were male sex (OR 4.4, 95% CI 2.4–7.9; p<0.01), diabetes mellitus (OR 9.7, 95% CI 5.5–17.2; p<0.01), and long-term sleep duration (OR 2.9 95% CI 1.34–6.35, p<0.01). Among smokers, there was a slight but significant association with the number of pack-years. Subjects with accelerated ageing showed decreased FVC (p<0.0001), FEV1 (p<0.0001), DLCO (p<0.02) and walking distance in the 6MWT (p=0.0001). Slowed-ageing subjects presented less frequently with emphysematous lesions compared with those with accelerated ageing.ConclusionsA small but significant proportion of residents of Mexico City age rapidly, which is associated with male sex, diabetes, and long-term sleep duration. They exhibit lower levels of lung function and develop emphysema more frequently.

Association between prolonged separation from parents and allostatic load among children in China

ObjectiveTo capture the association of exposure to prolonged separation from both parents early in life and allostatic load (AL), a measure of biological multi-system dysregulation. MethodsWe used data from 557 7-12-year-old children enrolled in rural area of Chizhou city, Anhui Province, China. We computed an AL score based on eleven biomarkers representing four regulatory systems: immune/inflammatory system (high sensitivity C-reactive protein); metabolic system (body mass index; high density lipoprotein; low density lipoprotein, total cholesterol; triglycerides; fasting glucose; glycated hemoglobin; insulin) and cardiovascular system (systolic and diastolic blood pressure). Child’s experiences of parent-child separation were collected a brief online questionnaire by parents of children. ResultsMore than 1 in 3 of our participants separated with both parents at age 6 or younger and nearly 1 in 10 persistently separated from both parents after birth. The AL score was significantly higher among children separated from both parents during early childhood (3.25 ± 1.98) or persistently since birth (3.48 ± 1.92), compared with those who did not separated from both parents (2.34 ± 1.53, F = 12.992, P<0.001). After adjustment of demographic covariates, body mass index as well as parent frequency of communication and parental warmth, children who separated from both parents in early childhood (β = 0.84, 95%CI:0.40, 1.28, P < 0.001) or persistently into adolescence (β = 1.27, 95%CI:0.43, 2.12, P = 0.003) evinced the highest levels of AL. ConclusionThis study is the first to show an association between prolonged parent-child separation and physiological wear-and-tear as measured by AL, which provides potential insights into the biological mechanisms underpinning long-term health outcomes in contexts of parent-child separation.

Oxidative stress status in hypertensive patients on amlodipine treatment

Background: Oxidative stress may contribute to the etiology of hypertension in humans. Oxidative stress is an imbalance between reactive oxygen species (ROS) and antioxidant defense mechanisms, causing damage to biological macromolecules and dysregulation of normal metabolism and physiology. Amlodipine as an antihypertensive agent is a long-acting calcium channel blocker that dilates blood vessels and improves blood flow. The aim of this study was to assess the oxidative stress in hypertensive patients on Amlodipine treatment through the assessment of salivary Malondialdehyde (MDA) and superoxide dismutase (SOD) as a marker of oxidative stress.&#x0D; Material and method: 60 individuals were included in this study, divided into two groups; the first group composed of 30 hypertensive patients on Amlodipine antihypertensive agent. The second group, the control group, composed of 30 healthy subjects without any systemic disease and with almost healthy oral hygiene. Intraoral examination was done for each individual and salivary samples were collected with the salivary flow rate (F/R) which was calculated in ml per minute and pH was measured by pH meter. Salivary MDA and SOD were analyzed by using ELISA kit based on the principle of competitive enzyme immunoassay technique; the concentrations of markers were measured by spectrophotometer at 450nm in a microplate reader.&#x0D; Results: Salivary MDA was significantly higher in hypertensive patients compared to control, while salivary SOD was significantly lower in patients than control group. Salivary flow rate and pH was significantly lower in patients as compared to the control group.&#x0D; Conclusions: There is a relation between oxidative stress and hypertension. Salivary MDA and SOD can be used as potential marker for monitoring patients with Hypertension.&#x0D; Keywords: hypertension, Oxidative stress, Amlodipine, MDA and SOD

A history of childhood trauma and allostatic load in patients with psychotic disorders with respect to stress coping strategies

Elevated allostatic load (AL) index, which is a cumulative measure of biological dysregulations associated with stress exposure, has been demonstrated in patients with psychosis. However, it remains unknown whether a history of childhood trauma (CT) might contribute to elevated AL index in psychosis. Therefore, we aimed to investigate the association between AL index, a history of CT and coping styles in patients with psychotic disorders. Participants were 65 patients with schizophrenia-spectrum disorders and 56 healthy controls (HCs). The AL index was computed based on percentile distributions of 15 biomarkers in HCs. The AL index was significantly higher in patients with psychosis. A history of parental antipathy was associated with elevated AL index in both groups of participants. A history of any categories of CT and sexual abuse were associated with higher AL index only in patients with psychosis. Social diversion (seeking social interactions in case of stressful experiences) mediated the association between sexual abuse and the AL index in the group of patients. There was a significant direct effect of sexual abuse on the AL index (this specific CT was associated with higher AL index). However, indirect effect of sexual trauma on AL through social diversion was opposite to direct effect. Childhood adversities, especially sexual abuse and parental antipathy, might contribute to elevated AL index in patients with psychosis. The effect of sexual abuse on the AL index might be specific to psychosis. Engagement in social interactions in case of stressful situations might alleviate biological dysregulations associated with CT.

Timing of parental incarceration and allostatic load: a developmental life course approach

PurposeWe examined whether the timing of when a person experienced the loss of a parent to incarceration was significantly associated with allostatic load, a multisystem index of biological dysregulation. MethodsData were drawn from waves I and IV of National Longitudinal Study of Adolescent to Adult Health, a nationally representative sample of adolescents in 1994. The final analytic sample was restricted to responses with valid responses and valid sampling weights (n = 13,365). Survey-corrected negative binomial regressions were used to assess relationships between timings of parental incarceration and allostatic load. ResultsCompared with respondents with no history of parent incarceration, reporting the incarceration of a parent in childhood was associated with higher allostatic load scores, whereas losing a parent to incarceration in adulthood was associated with significantly lower allostatic load scores. ConclusionsThe physiological consequences of parental incarceration are associated with the developmental period in which the incarceration occurred. The risk of biological dysregulation may be greatest among those who experience the loss of a parent to incarceration in childhood.

Exploration of the selective binding mechanism of GSK3β via molecular modeling and molecular dynamics simulation studies

Kinase inhibitor selectivity is a major concern for the design of small-molecule compounds. As a member of serine/threonine protein kinase family, glycogen synthase kinase 3β (GSK3β) is involved in diverse biological processes and abnormal dysregulation of its activity has been associated with several pathologies, including type II diabetes, Alzheimer’s disease, bipolar disorders, and cancers. A small-molecule PF-367 significantly inhibited the GSK3 enzymatic activity over its closest cyclin-dependent kinase 2 (CDK2) with >1000-fold selectivity. However, the PF-367 selectively binding to GSK3β over CDK2 has remained unclear. Here, molecular docking, molecular dynamics (MD) simulations, and molecular mechanics_generalized born/surface area (MM_GBSA) binding free energy calculations, as well as the decomposition of binding free energies were performed to investigate the selective binding mechanism of PF-367 to the ATP-binding site of GSK3β over CDK2. The results revealed that the exposure of the terminal triazole ring of PF-367 into the solvent environment may be responsible for the weak binding complex of CDK2−PF-367, which was further confirmed by the binding free energy calculations and the identified key residues (Phe67, Lys85, Thr138, and Arg141) contributing to the binding interaction. The obtained data can not only decipher the origin of selectivity, but also be used for the design of more potent and selective GSK3β inhibitors.

Effects of working memory training on cognitive, affective, and biological responses to stress in major depression: A novel cognitive bias modification protocol

BackgroundOver 320 million individuals are living with Major Depressive Disorder (MDD), a leading cause of disability worldwide. Thus, there is a crucial need to identify processes that contribute to the maintenance of depressive episodes. Difficulty removing negative information from working memory (WM) is posited to exacerbate affective, cognitive, and biological dysregulation in Major Depressive Disorder (MDD), but this has not yet been tested empirically. MethodsIn this study we examined whether training depressed individuals to remove negative information from WM (RNI training) would reduce symptoms of depression and levels of rumination, and would be associated with attenuated biological responsivity to stress. Individuals diagnosed with MDD were randomly assigned to complete Real-RNI training or Sham-RNI training for six days. ResultsAcross conditions, participants exhibited significant improvements from pre- to post-training in removing negative information from WM, symptoms of depression, and rumination. Furthermore, participants in the Real-RNI condition showed a more attenuated pattern of cortisol and respiratory sinus arrhythmia (RSA) responses to stress than did participants in the Sham-RNI training condition. LimitationsWe did not assess the long-term effects of training. It will be important for future research to examine whether the documented training-related effects persist across time. ConclusionsThis study is the first to examine the effects of RNI training on clinical symptoms and biological responses to stress in MDD, and it provides experimental evidence that training individuals with depression to remove negative information from WM can help to modulate the heightened biological responses to stress seen in depression.