Dysregulation Of Stress Response Research Articles

Exploring Biopsychosocial Stress Markers in Women With Fibromyalgia

Identification of fibromyalgia has been a challenge for healthcare professionals due to the lack of a clinical biomarker. A well-supported integrative hypothesis holds that this condition is a chronic pain problem partly caused by long-term dysregulation of stress response. Therefore, stress assessment from a biopsychosocial perspective may be a useful approach to recognizing fibromyalgia. A cross-sectional case-control study was conducted to explore stress markers from a multidimensional perspective, including heart rate variability (as a biomarker of stress) as well as psychological distress and social stress. Forty-seven women with fibromyalgia were recruited from support groups and another 47 were recruited as matched pain-free controls. Comparison and discriminant function analyses were performed. The data support the goodness of biopsychosocial stress markers in women with fibromyalgia, resulting in the identification of between 70% and 74.5% of fibromyalgia cases (sensitivity) and 85%-87% pain-free controls (specificity), with medium-high levels of fit (λ = 0.58 and λ = 0.59; p < .00). Women with fibromyalgia were characterized by high levels of psychological distress, social stress (disorder levels), and autonomic dysregulation. Although distress and social stress had a greater weight in discriminant functions, dysregulation in terms of low parasympathetic activity and high sympathetic activity at rest was also relevant. A biopsychosocial approach to stress with an objective biomarker such as heart rate variability may be a useful tool to identify and manage FM.

Metabolic dysfunction and the development of physical frailty: an aging war of attrition.

The World Health Organization recently declared 2021-2030 the decade of healthy aging. Such emphasis on healthy aging requires an understanding of the biologic challenges aging populations face. Physical frailty is a syndrome of vulnerability that puts a subset of older adults at high risk for adverse health outcomes including functional and cognitive decline, falls, hospitalization, and mortality. The physiology driving physical frailty is complex with age-related biological changes, dysregulated stress response systems, chronic inflammatory pathway activation, and altered energy metabolism all likely contributing. Indeed, a series of recent studies suggests circulating metabolomic distinctions can be made between frail and non-frail older adults. For example, marked restrictions on glycolytic and mitochondrial energy production have been independently observed in frail older adults and collectively appear to yield a reliance on the highly fatigable ATP-phosphocreatine (PCr) energy system. Further, there is evidence that age-associated impairments in the primary ATP generating systems (glycolysis, TCA cycle, electron transport) yield cumulative deficits and fail to adequately support the ATP-PCr system. This in turn may acutely contribute to several major components of the physical frailty phenotype including muscular fatigue, weakness, slow walking speed and, over time, result in low physical activity and accelerate reductions in lean body mass. This review describes specific age-associated metabolic declines and how they can collectively lead to metabolic inflexibility, ATP-PCr reliance, and the development of physical frailty. Further investigation remains necessary to understand the etiology of age-associated metabolic deficits and develop targeted preventive strategies that maintain robust metabolic health in older adults.

The cortisol awakening response in a 3 month clinical trial of service dogs for veterans with posttraumatic stress disorder

Recent literature suggests that service dogs may be a valuable complementary intervention option for posttraumatic stress disorder (PTSD) among military veterans due to the potential influence on stress response dysregulation. The aim of this short-term longitudinal study was to quantify the impact of service dogs in US military veterans with PTSD with particular attention to the cortisol awakening response. A sub aim of the study was to empirically evaluate the physiological effects of PTSD service dogs on veteran partners. We conducted a clinical trial (ID: NCT03245814) that assessed the cortisol awakening response for 245 participants at baseline and 3 months follow-up across an intervention group (service dog: veterans n = 88, partners n = 46) and control group (usual care: n = 73, partners n = 38). A total of N = 161 veterans and N = 84 partners collected whole saliva samples via a passive drool collection immediately upon waking, 30 min after waking, and 45 min after waking on three consecutive weekdays at baseline and again at follow-up. Mixed model repeated measures (MMRM) with a fixed effect of the intervention group (service dog or control) were utilized. Covariates considered for the model included time of awakening, sleep duration, sleep efficiency, prior day experiences (measured via ecological momentary assessment), traumatic brain injury, age, gender, race, ethnicity, socioeconomic status, smoking status, alcohol use, physical health, and body mass index. A total of 3951 salivary samples were collected (veterans: 2613, partners: 1338). MMRM results demonstrated that veterans with a service dog had a statistically significant higher cortisol awakening response, including the area under the curve with respect to both increase (AUCi, β = 1.46, p = 0.046) and absolute increase (AINC, β = 0.05, p = 0.035). Results were not statistically significant for partners. Findings suggest that veterans with service dogs have a higher, less blunted CAR in comparison to veterans receiving usual care alone. In veterans with a blunted morning cortisol response, service dog placement could help boost their morning cortisol response.

68 The Impact of Pain Catastrophizing on Neuropsychological Performance in Youth with Persistent Post Concussive Symptoms

Objective:Patients with persistent post-concussion symptoms (PPCS) experience prolonged recovery (e.g., headache, fatigue, or dizziness) lasting &gt;2 months post injury. These symptoms are thought to be maintained by several biopsychosocial factors including dysregulated stress responses, such as pain catastrophizing, that may drive behavioral avoidance and contribute to mood symptoms and cognitive difficulties. Conditions with similar symptomatology to PPCS (e.g., anxiety disorders, somatosensory disorders, chronic pain, etc.) also exhibit maladaptive thought patterns like pain catastrophizing as well as decrements in certain aspects of cognitive performance; however little is known about how pain catastrophizing might relate to neuropsychological performance in youth with PPCS. Therefore, the purpose of this study was to examine the relationship between pain catastrophizing and neuropsychological performance in youth participants with PPCS.Participants and Methods:A prospective case-control study design was used to examine 29 participants between the ages of 13 to 23. Participants were divided into two groups: 1) patients with PPCS (2-16 months post-injury; n = 15) and 2) age-matched, non-injured controls (n = 14). Participants completed the Pain Catastrophizing Scale (PCS) to determine degree of catastrophic thinking related to pain experience and the Beck Depression Inventory (BDI). Neuropsychological performance was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and a modified version of the Paced Auditory Serial Addition Test (PASAT) where performance was evaluated by total correct and error type (i.e., commission and omission) across 5 trials. ANCOVA was used to compare group differences in pain catastrophizing and neuropsychological tests scores while controlling for age and linear regressions examined the relationship between PCS total score and each neuropsychological test score while controlling for level of depression.Results:Overall, the PPCS group reported significantly higher levels of pain catastrophizing on the PCS compared to the control group (p &lt; 0.01). For neuropsychological performance, the PPCS group scored significantly lower than the control group on List Learning (p &lt; 0.01), Semantic Fluency (p &lt; 0.05), and List Recall (p &lt; 0.01) on the RBANS and made significantly higher omission errors (but not commission) on the PASAT(p &lt;.01). Higher pain catastrophizing was also associated with poorer neuropsychological performance on the exact same tasks the PPCS group performed worse than controls. There was no significant interaction by group in the impact of PCS scores on neurocognitive performance.Conclusions:Compared to controls, youth PPCS patients reported higher levels of pain catastrophizing. Additionally, pain catastrophizing was associated with poorer neuropsychological performance. These findings suggest that increased pain catastrophizing after head injury could contribute to poorer cognitive performance in youth. As such, interventions that target maladaptive cognitive coping styles like pain catastrophizing may be especially helpful for patients with PPCS.

Triploid Pacific oysters exhibit stress response dysregulation and elevated mortality following heatwaves.

Polyploidy has been suggested to negatively impact environmental stress tolerance, resulting in increased susceptibility to extreme climate events. In this study, we compared the genomic and physiological response of diploid (2n) and triploid (3n) Pacific oysters (Crassostrea gigas) to conditions present during an atmospheric heatwave that impacted the Pacific Northwestern region of the United States in the summer of 2021. Climate stressors were applied either singly (single stressor; elevated seawater temperature, 30°C) or in succession (multiple stressor; elevated seawater temperature followed by aerial emersion at 44°C), replicating conditions present within the intertidal over a tidal cycle during the event. Oyster mortality rate was elevated within stress treatments with respect to the control and was significantly higher in triploids than diploids following multiple stress exposure (36.4% vs. 14.8%). Triploids within the multiple stressor treatment exhibited signs of energetic limitation, including metabolic depression, a significant reduction in ctenidium Na+ /K+ ATPase activity, and the dysregulated expression of genes associated with stress response, innate immunity, glucose metabolism, and mitochondrial function. Functional enrichment analysis of ploidy-specific gene sets identified that biological processes associated with metabolism, stress tolerance, and immune function were overrepresented within triploids across stress treatments. Our results suggest that triploidy impacts the transcriptional regulation of key processes that underly the stress response of Pacific oysters, resulting in downstream shifts in physiological tolerance limits that may increase susceptibility to extreme climate events that present multiple environmental stressors. The impact of chromosome set manipulation on the climate resilience of marine organisms has important implications for domestic food security within future climate scenarios, especially as triploidy induction becomes an increasingly popular tool to elicit reproductive control across a wide range of species used within marine aquaculture.

Associations of prenatal and childhood Pb exposure with allostatic load in adolescence: Findings from the ELEMENT cohort study

The biological pathways which link lead (Pb) and long-term outcomes are unclear, though rodent models and a few human studies suggest Pb may alter the body's stress response systems, which over time, can elicit dysregulated stress responses with cumulative impacts. This study examined associations between prenatal and early childhood Pb exposure and adolescent allostatic load, an index of an individual's body burden of stress in multiple biological systems, and further examined sex-based associations. Among 391 (51% male) participants in the ELEMENT birth cohort, we related trimester-specific maternal blood Pb, 1-month postpartum maternal tibia and patella Pb, and child blood Pb at 12–24 months to an allostatic load index in adolescence comprised of biomarkers of cardiovascular, metabolic, neuroendocrine, and immune function. The results were overall mixed, with prenatal exposure, particularly maternal bone Pb, being positively associated with allostatic load, and early childhood Pb showing mixed results for males and females. In adjusted Poisson regression models, 1 mcg/g increase in tibia Pb was associated with a 1% change in expected allostatic load (IRR = 1.01; 95%CI 0.99, 1.02). We found a significant Pb × sex interaction (IRR = 1.05; 95%CI 1.01, 1.10); where males saw an increasing percent change in allostatic load as 12 month Pb levels increased compared to females who saw a decreasing allostatic load. Further examination of allostatic load will facilitate the determination of potential mechanistic pathways between developmental toxicant exposures and later-in-life cardiometabolic outcomes.

Transcriptional time course after rotator cuff repair in 6month old female rabbits.

Introduction: Rotator cuff tears are prevalent in the population above the age of 60. The disease progression leads to muscle atrophy, fibrosis, and fatty infiltration, which is not improved upon with surgical repair, highlighting the need to better understand the underlying biology impairing more favorable outcomes. Methods: In this study, we collected supraspinatus muscle tissue from 6month old female rabbits who had undergone unilateral tenotomy for 8weeks at 1, 2, 4, or 8weeks post-repair (n = 4/group). RNA sequencing and enrichment analyses were performed to identify a transcriptional timeline of rotator cuff muscle adaptations and related morphological sequelae. Results: There were differentially expressed (DE) genes at 1 (819 up/210 down), 2 (776/120), and 4 (63/27) weeks post-repair, with none at 8week post-repair. Of the time points with DE genes, there were 1092 unique DE genes and 442 shared genes, highlighting that there are changing processes in the muscle at each time point. Broadly, 1-week post-repair differentially expressed genes were significantly enriched in pathways of metabolism and energetic activity, binding, and regulation. Many were also significantly enriched at 2weeks, with the addition of NIF/NF-kappaB signaling, transcription in response to hypoxia, and mRNA stability alongside many additional pathways. There was also a shift in transcriptional activity at 4weeks post-repair with significantly enriched pathways for lipids, hormones, apoptosis, and cytokine activity, despite an overall decrease in the number of differentially expressed genes. At 8weeks post-repair there were no DE genes when compared to control. These transcriptional profiles were correlated with the histological findings of increased fat, degeneration, and fibrosis. Specifically, correlated gene sets were enriched for fatty acid metabolism, TGF-B-related, and other pathways. Discussion: This study identifies the timeline of transcriptional changes in muscle after RC repair, which by itself, does not induce a growth/regenerative response as desired. Instead, it is predominately related to metabolism/energetics changes at 1week post-repair, unclear or asynchronous transcriptional diversity at 2weeks post-repair, increased adipogenesis at 4weeks post-repair, and a low transcriptional steady state or a dysregulated stress response at 8weeks post-repair.

Nisin Z Potential for the Control of Diabetic Foot Infections Promoted by Pseudomonas aeruginosa Persisters.

Diabetic foot ulcers (DFU) are a major complication of diabetes mellitus and a public health concern worldwide. The ability of P. aeruginosa to form biofilms is a key factor responsible for the chronicity of diabetic foot infections (DFIs) and frequently associated with the presence of persister cells. These are a subpopulation of phenotypic variants highly tolerant to antibiotics for which new therapeutic alternatives are urgently needed, such as those based on antimicrobial peptides. This study aimed to evaluate the inhibitory effect of nisin Z on P. aeruginosa DFI persisters. To induce the development of a persister state in both planktonic suspensions and biofilms, P. aeruginosa DFI isolates were exposed to carbonyl cyanide m-chlorophenylhydrazone (CCCP) and ciprofloxacin, respectively. After RNA extraction from CCCP-induced persisters, transcriptome analysis was performed to evaluate the differential gene expression between the control, persisters, and persister cells exposed to nisin Z. Nisin Z presented a high inhibitory effect against P. aeruginosa persister cells but was unable to eradicate them when present in established biofilms. Transcriptome analysis revealed that persistence was associated with downregulation of genes related to metabolic processes, cell wall synthesis, and dysregulation of stress response and biofilm formation. After nisin Z treatment, some of the transcriptomic changes induced by persistence were reversed. In conclusion, nisin Z could be considered as a potential complementary therapy for treating P. aeruginosa DFI, but it should be applied as an early treatment or after wound debridement.

The cortisol switch between vulnerability and resilience.

In concert with neuropeptides and transmitters, the end products of the hypothalamus-pituitary-adrenal (HPA) axis, the glucocorticoid hormones cortisol and corticosterone (CORT), promote resilience: i.e., the ability to cope with threats, adversity, and trauma. To exert this protective action, CORT activates mineralocorticoid receptors (MR) and glucocorticoid receptors (GR) that operate in a complementary manner -as an on/off switch- to coordinate circadian events, stress-coping, and adaptation. The evolutionary older limbic MR facilitates contextual memory retrieval and supports an on-switch in the selection of stress-coping styles at a low cost. The rise in circulating CORT concentration after stress subsequently activates a GR-mediated off-switch underlying recovery of homeostasis by providing the energy for restraining the primary stress reactions and promoting cognitive control over emotional reactivity. GR activation facilitates contextual memory storage of the experience to enable future stress-coping. Such complementary MR-GR-mediated actions involve rapid non-genomic and slower gene-mediated mechanisms; they are time-dependent, conditional, and sexually dimorphic, and depend on genetic background and prior experience. If coping fails, GR activation impairs cognitive control and promotes emotional arousal which eventually may compromise resilience. Such breakdown of resilience involves a transition to a chronic stress construct, where information processing is crashed; it leads to an imbalanced MR-GR switch and hence increased vulnerability. Novel MR-GR modulators are becoming available that may reset a dysregulated stress response system to reinstate the cognitive flexibility required for resilience.

Psychological, endocrine and polygenic predictors of emotional well-being during the COVID-19 pandemic in a longitudinal birth cohort

The COVID-19 pandemic severely affected the lives of families and the well-being of both parents and their children. Various factors, including prenatal stress, dysregulated stress response systems, and genetics may have influenced how the stress caused by the pandemic impacted the well-being of different family members. The present work investigated if emotional well-being during the COVID-19 pandemic could be predicted by developmental stress-related and genetic factors. Emotional well-being of 7–10 year-old children (n = 263) and mothers (n = 241) (participants in a longitudinal German birth cohort (POSEIDON)) was assessed during the COVID-19 pandemic using the CRISIS questionnaire at two time periods (July 2020–October 2020; November 2020–February 2021). Associations of the children’s and mothers’ well-being with maternal perceived stress, of the children’s well-being with their salivary and morning urine cortisol at 45 months, and polygenic risk scores (PRSs) for depression, schizophrenia, loneliness were investigated. Lower emotional well-being was observed in both children and mothers during compared to before the pandemic, with the children’s but not the mothers’ emotional well-being improving over the course of the pandemic. A positive association between the child and maternal emotional well-being was found. Prenatally assessed maternal perceived stress was associated with a lower well-being in children, but not in mothers. Cortisol measures and PRSs were not significantly associated with the children’s emotional well-being. The present study confirms that emotional well-being of children and mothers are linked, and were negatively affected by the COVID-19 pandemic, with differences in development over time.

Impact of acute stress on neural indices of positive and negative reinforcement processing in cannabis users.

Chronic cannabis use is maintained in part through dysregulated stress and reward response systems. Specifically, stress-related negative affect is thought to act as a salient motivator for chronic substance use. Models of addiction posit that the transition from positive to negative reinforcement motives for substance use is a key mechanism of disordered use. However, research in substance-using samples has not assessed stress-related neural processing of both positive and negative reinforcement. Therefore, the present study utilized laboratory stress induction to examine how stress affects the reward positivity, an event-related potential sensitive to both positive (RewP) and negative (relief-RewP) reinforcement, in 87 cannabis users (58.10% female, Mage = 19.40) varying in cannabis use disorder (CUD) severity and, as part of larger study aims, history of traumatic brain injury (TBI). We predicted greater CUD severity would be associated with a blunted RewP and enhanced relief-RewP, particularly after stress induction, independent of TBI status. Findings indicated that CUD severity was not associated with RewP/relief-RewP amplitude regardless of acute stress. Exploratory analyses revealed, however, that among those with history of TBI +, CUD severity was associated with greater stress-elicited blunting of the RewP and enhancement of the relief-RewP. Although initial findings contradict current allostatic models of addiction, exploratory findings suggest that history of TBI, and potentially other confounding variables related to increased risk of TBI experience, may influence the extent to which stressful experiences modulate the neurophysiology of both positive and negative reinforcement reward processing in CUD. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Mitochondrial DNA as a marker for treatment-response in post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a serious mental health condition thought to be mediated by a dysregulated stress response system. Stress, especially chronic stress, affects mitochondrial activity and their efficiency in duplicating their genomes. Human cells contain numerous mitochondria that harbor multiple copies of their own genome, which consist of a mixture of wild type and variant mtDNA - a condition known as mitochondrial heteroplasmy. Number of mitochondrial genomes in a cell and the degree of heteroplasmy may serve as an indicator of mitochondrial allostatic load. Changes in mtDNA copy number and the proportion of variant mtDNA may be related to mental disorders and symptom severity, suggesting an involvement of mitochondrial dysfunction also in PTSD. Therefore, we examined number and composition of mitochondrial DNA before and after six weeks of inpatient psychotherapy treatment in a cohort of 60 female PTSD patients. We extracted DNA from isolated monocytes before and after inpatient treatment and quantified cellular mtDNA using multiplex qPCR. We hypothesized that treatment would lead to changes in cellular mtDNA levels and that change in mtDNA level would be associated with PTSD symptom severity and treatment response. It could be shown that mtDNA copy number and the ratio of variant mtDNA decreased during therapy, however, this change did not correlate with treatment response. Our results suggest that inpatient treatment can reduce signs of mitochondrial allostatic load, which could have beneficial effects on mental health. The quantification of mtDNA and the determination of cellular heteroplasmy could represent valuable biomarkers for the molecular characterization of mental disorders in the future.

Perfectionism, Prolonged Stress Reactivity, and Depression: A Two-Wave Cross-Lagged Analysis.

Perfectionism is a vulnerability factor for a wide array of psychopathology. Despite much evidence suggesting dysregulated stress response as an intermediary process that links perfectionism to psychopathology, the lack of a cross-lagged examination deterred researchers from making causal interpretations. This study examined the directionality of effects among perfectionism dimensions, stress reactivity, and depression. A total of 189 participants at time 1 and 94 at time 2 completed an online survey that consisted of measures of perfectionism, stress reactivity, and depression, one month apart. Cross-lagged analysis results showed that personal standards perfectionism predicted later prolonged stress reactivity but not depression at time 2. Self-critical perfectionism predicted later depression but not prolonged stress reactivity at time 2. Rather, prolonged stress reactivity at time 1 predicted self-critical perfectionism at time 2. Findings suggest that perfectionism dimensions are distinct in creating a dysregulated stress process. Future studies could incorporate other stress-related variables (e.g., coping) to further explicate the stress-generation process, in conjunction with stress reactivity.

Elucidating the Neurobiologic Etiology of Comorbid PTSD and Substance Use Disorders.

Early childhood maltreatment and other traumatic event experiences (“trauma”) are common among youth, including those with substance use problems including substance use disorders (SUD). Particularly, interpersonal violence is associated with high rates of comorbidity between posttraumatic stress disorder (PTSD) and SUD, and these comorbid disorders exhibit high levels of overlapping symptomatology. Theoretical models proposed to explain the bidirectional relationship between PTSD and SUD include the self-medication hypothesis and susceptibility hypothesis. In this article, we explore neurobiologic changes associated with trauma, PTSD, and SUD that underly dysregulated stress response. Examining lessons learned from recent translational and clinical research, we propose that further elucidating the neurobiologic etiology of comorbid PTSD and SUD will require a collaborative, interdisciplinary approach, including the integration of preclinical and clinical studies, exploration of biologic markers in clinical studies, and accumulation of larger studies and longitudinal studies with the power to study PTSD and SUD. Such research can transform the field and ultimately reduce high rates and costly impairment of co-occurring PTSD and SUD across the lifespan.

Inhibition of Hippocampal Neurogenesis Starting in Adolescence Increases Anxiodepressive Behaviors Amid Stress.

Stressors during the adolescent period can affect development of the brain and have long-lasting impacts on behavior. Specifically, adolescent stress impairs hippocampal neurogenesis and can increase risk for anxiety, depression, and a dysregulated stress response in adulthood. In order to model the functional effects of reduced hippocampal neurogenesis during adolescence, a transgenic neurogenesis ablation rat model was used to suppress neurogenesis during the adolescent period and test anxiodepressive behaviors and stress physiology during adulthood. Wildtype and transgenic (TK) rats were given valganciclovir during the first two weeks of adolescence (4-6 weeks old) to knock down neurogenesis in TK rats. Starting in young adulthood (13 weeks old), blood was sampled for corticosterone at several time points following acute restraint stress to measure negative feedback of the stress response, and rats were tested on a battery of anxiodepressive tests at baseline and following acute restraint stress. Although TK rats had large reductions in both cell proliferation during adolescence, as measured by bromodeoxyuridine (BrdU), and ongoing neurogenesis in adulthood (by doublecortin), resulting in decreased volume of the dentate gyrus, negative feedback of the stress response following acute restraint was similar across all rats. Despite similar stress responses, TK rats showed higher anxiety-like behavior at baseline. In addition, only TK rats had increased depressive-like behavior when tested after acute stress. Together, these results suggest that long-term neurogenesis ablation starting in adolescence produces hippocampal atrophy and increases behavioral caution and despair amid stressful environments.

Cortisol awakening response and developmental outcomes at 6-7 years in children born extremely preterm.

Extremely preterm (EPT) birth has been related to dysregulation of stress responses and behavioral/learning problems at school age. Early adverse experiences can blunt HPA axis reactivity. We hypothesized that an attenuated cortisol awakening response would be associated with developmental and behavioral problems at school age in EPT children. This secondary analysis of a sub-cohort of the SUPPORT study included children born between 24 and 27 weeks, evaluated at 6-7 years with a neurodevelopmental battery and cortisol measures. Differences were tested between EPT and a term-born group. Relationships of cortisol awakening response to test scores were analyzed. Cortisol was measured in 110 EPT and 29 term-born 6-7 year olds. Unadjusted WISC-IV and NEPSY-II scores were significantly worse among EPT children only. Conners Parent Rating Scale behavior scores were significantly worse among EPT children. After adjusting for covariates, blunted cortisol awakening responses were found to be associated with poorer scores on memory tests and greater problems with inattention for the EPT group (p < 0.05) only. Among children born EPT, we identified an association of blunted cortisol awakening response with memory and inattention problems. This may have implications related to stress reactivity and its relationship to learning problems in children born EPT. Extended Follow-up at School Age for the SUPPORT Neuroimaging and Neurodevelopmental Outcomes (NEURO) Cohort: NCT00233324. In children born EPT, stress reactivity may have a relationship to learning problems. Cortisol awakening response should be a component for follow-up in EPT born children. Components of executive function, such as memory and attention, are related to stress reactivity.

RshA mutations contributing to tigecycline resistance in Mycobacteroides abscessus.

Tigecycline is an important rescue antibiotic for many bacterial infections. In Mycobacteroides abscessus, tigecycline resistance has been associated with dysregulated stress response caused by aberrations in the interaction of the SigH and RshA factors. In this study, two tigecycline-resistant mutants of M. abscessus (CL5A and CL6A) with mutations in the rshA gene were studied using gene complementation, RT-qPCR and the bacterial adenylate cyclase two-hybrid (BACTH) system. The results supported the premise that mutations in the rshA interrupt the RshA-SigH interaction to cause the overexpression of the sigH gene that leads to tigecycline resistance or reduced susceptibility.

Smokers show an altered hemodynamic profile to active stress: Evidence of a dysregulated stress response in young adults.

Tobacco smoking has been associated with lower cardiovascular reactivity to psychological stress in middle‐aged samples, but its impact on cardiovascular reactivity to stress in young adults remains unclear. The present study examined whether young healthy adults showed differing cardiovascular stress reaction profiles depending on their smoking status. Across two laboratory studies (N = 64 and N = 114), we asked participants to complete cognitive stress‐tasks while undergoing continuous hemodynamic monitoring. In both studies, there was not a statistically signification association between systolic blood pressure, diastolic blood pressure, or heart rate reactivity to stress (all ps > .05). However, examination of the underlying hemodynamic profile of the stress response suggested differences between non‐smokers and smokers in both studies. In Study 1, non‐smokers exhibited the expected myocardial response to the active stress‐task; however, smokers exhibited a mixed hemodynamic profile. In Study 2, smokers evidenced a weaker myocardial profile to the active stress‐tasks compared to non‐smokers. However, the examination of the continuous hemodynamic profile score (HP) did not identify statistical differences. These results highlight that any level of the smoking habit is associated with an altered hemodynamic profile in response to stress in smokers, which may have important implications for long‐term cardiovascular health. The findings also suggest that controlling for smoking behavior in reactivity research examining blood pressure and heart rate responses to stress in young adults is not necessary.

The Effect of Adverse Mental Health and Resilience on Perceived Stress by Sexual Violence History.

Sexual violence, including nonconsensual sexual initiation and rape, remains pervasive, with impacts including adverse mental health and dysregulated stress response. Resilience is a promising interventional target. To advance the science, we examined the potential for resilience as an interventional tool by estimating associations between resilience, adverse mental health, and perceived stress among women by sexual violence history and partner perpetration. We analyzed 2018–2020 baseline survey data from 65 women enrolled in a prospective case-control study of sexual violence and HIV susceptibility in San Diego, CA. Multiple linear regressions were performed to examine associations, stratified by sexual violence history. About half of women experienced nonconsensual sexual initiation and/or rape; half of rapes were partner-perpetrated. Post-traumatic stress disorder (PTSD) was significantly associated with perceived stress among survivors (in regressions with depression and resilience, nonconsensual initiation: β = 6.514, p = 0.003, R2 = 0.616; rape: β = 5.075, p = 0.030, R2 = 0.611). Resilience was associated with lower perceived stress for all women; the effect appeared stronger among survivors of sexual violence (nonconsensual initiation: β = −0.599, p < 0.001 vs. β = −0.452, p = 0.019; rape: β = −0.624, p < 0.001 vs. β = −0.421, p = 0.027). Partner perpetration of rape was not associated with perceived stress. Our findings support leveraging resilience and addressing PTSD to reduce perceived stress among women with lifetime experiences of sexual violence.

Deficiency of N-glycanase 1 perturbs neurogenesis and cerebral development modeled by human organoids

Mutations in N-glycanase 1 (NGLY1), which deglycosylates misfolded glycoproteins for degradation, can cause NGLY1 deficiency in patients and their abnormal fetal development in multiple organs, including microcephaly and other neurological disorders. Using cerebral organoids (COs) developed from human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), we investigate how NGLY1 dysfunction disturbs early brain development. While NGLY1 loss had limited impact on the undifferentiated cells, COs developed from NGLY1-deficient hESCs showed defective formation of SATB2-positive upper-layer neurons, and attenuation of STAT3 and HES1 signaling critical for sustaining radial glia. Bulk and single-cell transcriptomic analysis revealed premature neuronal differentiation accompanied by downregulation of secreted and transcription factors, including TTR, IGFBP2, and ID4 in NGLY1-deficient COs. NGLY1 malfunction also dysregulated ID4 and enhanced neuronal differentiation in CO transplants developed in vivo. NGLY1-deficient CO cells were more vulnerable to multiple stressors; treating the deficient cells with recombinant TTR reduced their susceptibility to stress from proteasome inactivation, likely through LRP2-mediated activation of MAPK signaling. Expressing NGLY1 led to IGFBP2 and ID4 upregulation in CO cells developed from NGLY1-deficiency patient’s hiPSCs. In addition, treatment with recombinant IGFBP2 enhanced ID4 expression, STAT3 signaling, and proliferation of NGLY1-deficient CO cells. Overall, our discoveries suggest that dysregulation of stress responses and neural precursor differentiation underlies the brain abnormalities observed in NGLY1-deficient individuals.