Maladaptive Stress Research Articles

Metabolic Dysfunctions, Dysregulation of the Autonomic Nervous System, and Echocardiographic Parameters in Borderline Personality Disorder: A Narrative Review.

Borderline personality disorder (BPD) is a complex psychiatric disorder characterized by an unstable sense of self and identity, emotional dysregulation, impulsivity, and disturbed interpersonal relationships. This narrative review examines the interplay between dysregulation of the autonomic nervous system, metabolic changes, and cardiovascular risk in BPD. Altered heart rate variability (HRV), reflecting the dysregulation of the autonomic nervous system, is associated with some BPD core symptoms, such as emotional instability and impulsivity. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, often stemming from early trauma, contributes to chronic inflammation and elevated allostatic load, which further increases cardiovascular risk. Metabolic dysfunctions in BPD, such as elevated body mass index (BMI), high blood pressure, and inflammatory markers like C-reactive protein (CRP), exacerbate these risks. Speckle-tracking echocardiography, particularly global longitudinal strain (GLS) and biomarkers such as homocysteine and epicardial fat, could be considered early predictors of cardiovascular events in individuals with BPD. Chronic stress, inflammation, and maladaptive stress responses further heighten cardiovascular vulnerability, potentially accelerating biological aging and cognitive decline. A literature search covering the period from 2014 to 2024 on PubMed identified 189 studies on this topic, of which 37 articles were deemed eligible for this review. These included cross-sectional, longitudinal, case-control, randomised controlled trials (RCTs), reviews, and meta-analysis designs, with sample sizes ranging from 14 to 5969 participants. The main limitations were that only one database was searched, the time of publications was limited, non-English manuscripts were excluded, and the quality of each paper was not commented on. This narrative review aims to provide an overview of recent evidence obtained on this topic, pointing out a direction for future research.

Influence of Defense Mechanisms on Sport Burnout: A Multiple Mediation Analysis Effects of Resilience, Stress and Recovery.

The aims of this study were: (a) to explore the relationships between adaptive defense mechanisms (ADMs), maladaptive defense mechanisms (MADMs), stress, recovery, resilience, and sport burnout; and (b) to examine resilience, stress, and recovery as mediators of the relationship between defense mechanisms and burnout. One hundred and seventy-five athletes (M = 20.30 years, SD = 3.75) completed self-report questionnaires assessing defense mechanisms, resilience, stress, and recovery. Correlation analysis revealed that MADMs were positively associated with burnout, while ADMs had no significant link with burnout. Concerning mediation analysis, results showed a mediating effect of resilience in the relationship between ADMs and burnout. The findings also demonstrated a mediating effect of resilience and recovery in the relationship between MADMs and burnout. Our study highlighted that certain defenses categorized as adaptive might not be suitable in specific situations, thus underscoring the influence of mediating variables. The findings of mediation analysis demonstrated that resilience appears to serve as a particularly protective factor against burnout. On the contrary, MADMs would have a deleterious influence in the management of stress, which could lead to burnout. Coaches may consider fostering athletes' resilience in conjunction with ADMs and implementing targeted psychological exercises to reduce the use of MADMs.

Reversing Mental Health & Chronic Stress Related Diseases

Most chronic diseases are psychosomatic, arising from persistent maladaptive stress caused by prolonged negative mental health conditions, frequently subconscious, that disrupt physiological functions. Emotions are biochemical manifestations of cognition and thought processes. We transform mental health and chronic illnesses by revising beliefs and cognition while supplying the body with essential cellular nourishment.

Glucocorticoids induce a maladaptive epithelial stress response to aggravate acute kidney injury.

Acute kidney injury (AKI) is a frequent and challenging clinical condition associated with high morbidity and mortality and represents a common complication in critically ill patients with COVID-19. In AKI, renal tubular epithelial cells (TECs) are a primary site of damage, and recovery from AKI depends on TEC plasticity. However, the molecular mechanisms underlying adaptation and maladaptation of TECs in AKI remain largely unclear. Here, our study of an autopsy cohort of patients with COVID-19 provided evidence that injury of TECs by myoglobin, released as a consequence of rhabdomyolysis, is a major pathophysiological mechanism for AKI in severe COVID-19. Analyses of human kidney biopsies, mouse models of myoglobinuric and gentamicin-induced AKI, and mouse kidney tubuloids showed that TEC injury resulted in activation of the glucocorticoid receptor by endogenous glucocorticoids, which aggravated tubular damage. The detrimental effect of endogenous glucocorticoids on injured TECs was exacerbated by the administration of a widely clinically used synthetic glucocorticoid, dexamethasone, as indicated by experiments in mouse models of myoglobinuric- and folic acid-induced AKI, human and mouse kidney tubuloids, and human kidney slice cultures. Mechanistically, studies in mouse models of AKI, mouse tubuloids, and human kidney slice cultures demonstrated that glucocorticoid receptor signaling in injured TECs orchestrated a maladaptive transcriptional program to hinder DNA repair, amplify injury-induced DNA double-strand break formation, and dampen mTOR activity and mitochondrial bioenergetics. This study identifies glucocorticoid receptor activation as a mechanism of epithelial maladaptation, which is functionally important for AKI.

Inhibition of PHLDA3 expression in human superoxide dismutase 1-mutant amyotrophic lateral sclerosis astrocytes protects against neurotoxicity.

Pleckstrin homology-like domain family A-member 3 (PHLDA3) has recently been identified as a player in adaptive and maladaptive cellular stress pathways. The outcome of pleckstrin homology-like domain family A-member 3 signalling was shown to vary across different cell types and states. It emerges that its expression and protein level are highly increased in amyotrophic lateral sclerosis (ALS) patient-derived astrocytes. Whether it orchestrates a supportive or detrimental function remains unexplored in the context of neurodegenerative pathologies. To directly address the role of pleckstrin homology-like domain family A-member 3 in healthy and ALS astrocytes, we used overexpression and knockdown strategies. We generated cultures of primary mouse astrocytes and also human astrocytes from control and ALS patient-derived induced pluripotent stem cells harbouring the superoxide dismutase 1 mutation. Then, we assessed astrocyte viability and the impact of their secretome on oxidative stress responses in human stem cell-derived cortical and spinal neuronal cultures. Here, we show that PHLDA3 overexpression or knockdown in control astrocytes does not significantly affect astrocyte viability or reactive oxygen species production. However, PHLDA3 knockdown in ALS astrocytes diminishes reactive oxygen species concentrations in their supernatants, indicating that pleckstrin homology-like domain family A-member 3 can facilitate stress responses in cells with altered homeostasis. In support, supernatants of PHLDA3-silenced ALS and even control spinal astrocytes with a lower pleckstrin homology-like domain family A-member 3 protein content could prevent sodium arsenite-induced stress granule formation in spinal neurons. Our findings provide evidence that reducing pleckstrin homology-like domain family A-member 3 levels may transform astrocytes into a more neurosupportive state relevant to targeting non-cell autonomous ALS pathology.

Congress of multiple dimers is needed for cross-phosphorylation of IRE1α and its RNase activity.

The unfolded protein response can switch from a pro-survival to a maladaptive, pro-apoptotic mode. During ER stress, IRE1α sensors dimerize, become phosphorylated, and activate XBP1 splicing, increasing folding capacity in the ER protein factory. The steps that turn on the IRE1α endonuclease activity against endogenous mRNAs during maladaptive ER stress are still unknown. Here, we show that although necessary, IRE1α dimerization is not sufficient to trigger phosphorylation. Random and/or guided collisions among IRE1α dimers are needed to elicit cross-phosphorylation and endonuclease activities. Thus, reaching a critical concentration of IRE1α dimers in the ER membrane is a key event. Formation of stable IRE1α clusters is not necessary for RNase activity. However, clustering could modulate the potency of the response, promoting interactions between dimers and decreasing the accessibility of phosphorylated IRE1α to phosphatases. The stepwise activation of IRE1α molecules and their low concentration at the steady state prevent excessive responses, unleashing full-blown IRE1 activity only upon intense stress conditions.

A new framework for understanding stress and disease: the developmental model of stress as applied to multiple sclerosis.

This paper proposes a new model of stress that integrates earlier models and adds insights from developmental psychology. Previous models describe the behavioral and physical effects of stress events, but have not explained the translation of experiences into stress itself. The Developmental Model of Stress shows how psychosocial developmental challenges in childhood create persistent negative beliefs and behaviors that increase threat perception and maladaptive stress responses. These developmental challenges produce early psychological and physiological predispositions for increased stress responses over time. Ongoing stress leads to dysregulation of physical stress-response systems (allostatic load), which is associated with multiple diseases. High allostatic load provides the necessary preconditions for the diathesis-stress model, which says the addition of an acute stressor to a weakened or predisposed system can lead to disease development. The paper also documents the evolving measurement of stress to better understand the stress-disease relationship, helping to resolve conflicting results between studies. The Developmental Model of Stress was combined with clinician insight and patient reports to build an integrative framework for understanding the role of stress in the development and progression of multiple sclerosis (MS). It includes the first mapping of maladaptive beliefs and behaviors arising from developmental challenges that are common to people with MS. An initial comparison shows these may be distinct from those of people with other chronic diseases. These beliefs and behaviors form the predisposing factors and contribute to the triggering factors, which are the acute stressors triggering disease onset. These often took two forms, a prolonged incident experienced as feeling trapped or stuck, and threat of a breach in a relationship. The reinforcing factors add the stress of a chronic disease with a poor prognosis and seemingly random symptom fluctuation, still managed with the same beliefs and behaviors developed in childhood, increasing physiological dysregulation and symptom severity. A pilot study is described in which these three categories of stress factors in MS were explicitly addressed. This study noted clinically important improvements in physical and mental well-being, providing preliminary support for the Developmental Model. Future research might expand on the pilot using a more robust sample and design.

Occupational Stress, Strain, and Coping among Nursing Personnel: A Hospital-Based Cross-sectional Study

Abstract Background Nurses are the backbone of the health care system and the largest health care force in the world. They work in multidisciplinary areas in hospitals, nursing homes, government and private sectors, and research and development, which makes them the most stressful personnel in clinical areas. Objectives This paper aims to explore occupational stress, strain, and coping among nurses working in a hospital in Bengaluru. Methodology A nonexperimental hospital-based cross-sectional study was conducted from November 2, 2022, to December 2, 2022, using a purposive sampling technique. A total of 77 nurses from different areas participated in the study. Data were collected by the researcher himself through the revised version of the Occupational Stress Inventory scale. Descriptive statistics were used with the mean, standard deviation, frequency, and percentage. To check the association, chi-square analysis was used. Results The research shows that the majority of the nurses had maladaptive stress in terms of role insufficiency, role ambiguity, role boundary, and physical environment (PE). It was observed that there was a high level of vocational strain (VS) and interpersonal strain with an average social support system (SS) among nurses. A significant association was found between gender and occupational role questionnaire (ORQ) factors like PE, designation of the nurse and ORQ in the area of responsibility, and PE of the working area. In the personal strain questionnaire factor, VS was significantly associated with gender. Furthermore, a significant association was also found between gender and personal resources questionnaire factors like self-care coping and SS coping skills. Conclusion Our data suggested a moderate to high level of occupational stress with less SS among nurses. Consequently, it is imperative for health care organizations to acknowledge the existence of occupational stress and collaborate toward devising a resolution, enabling nurses to provide patients with optimal care.

Unscrambling the Dynamics of Danger: Scientific Foundations and Evidence for the Looming Vulnerability Model and Looming Cognitive Style in Anxiety

BackgroundA revised looming vulnerability model is described that updates the original conceptual model and synthesizes new findings and evidence. The revised model extends the notion of dynamic threat by describing the role of cognitive-perceptual distortions. Moreover, it suggests that dynamic threat perceptions, particularly that threats are approaching, serve as warning signals that lower the threshold for appraising threat, influencing negative emotional responses (primarily but not only anxiety and fear), cognitive-affective processing, behavior, and maladaptive coping. Individual differences in “looming cognitive style” can lead to transdiagnostic vulnerability to anxiety (and less so, to depression), maladaptive defensive reactions, cognitive-affective (experiential) avoidance, and stress generation.MethodsThis article reviews the conceptualization proposed by the revised looming vulnerability model, and comprehensively reviews its scientific foundation, and current supporting evidence that has accrued for the model across diverse research domains.ResultsThe revised conceptualization of the looming vulnerability model is amply supported by the accumulated research, which highlights the importance of dynamic stimuli for attention, memory, emotional, and neurological response. Likewise, the looming cognitive style is supported by a substantial number of studies, linking it to cognitive vulnerability to anxiety, biased threat processing, maladaptive coping and cognitive-affective avoidance, and developmental antecedents.ConclusionsThe review of evidence supports the revised looming vulnerability model's tenets about the importance of dynamic stimulusi features, which previous models have neglected, and of the looming cognitive style, which is proposed as a distinct cognitive vulnerability Clinical implications and future research directions are discussed.

Abnormal Morphology and Synaptogenic Signaling in Astrocytes Following Prenatal Opioid Exposure.

In recent decades, there has been a dramatic rise in the rates of children being born after in utero exposure to drugs of abuse, particularly opioids. Opioids have been shown to have detrimental effects on neurons and glia in the central nervous system (CNS), but the impact of prenatal opioid exposure (POE) on still-developing synaptic circuitry is largely unknown. Astrocytes exert a powerful influence on synaptic development, secreting factors to either promote or inhibit synapse formation and neuronal maturation in the developing CNS. Here, we investigated the effects of the partial µ-opioid receptor agonist buprenorphine on astrocyte synaptogenic signaling and morphological development in cortical cell culture. Acute buprenorphine treatment had no effect on the excitatory synapse number in astrocyte-free neuron cultures. In conditions where neurons shared culture media with astrocytes, buprenorphine attenuated the synaptogenic capabilities of astrocyte-secreted factors. Neurons cultured from drug-naïve mice showed no change in synapses when treated with factors secreted by astrocytes from POE mice. However, this same treatment was synaptogenic when applied to neurons from POE mice, indicating a complex neuroadaptive response in the event of impaired astrocyte signaling. In addition to promoting morphological and connectivity changes in neurons, POE exerted a strong influence on astrocyte development, disrupting their structural maturation and promoting the accumulation of lipid droplets (LDs), suggestive of a maladaptive stress response in the developing CNS.

USING THE METHOD OF PSYCHOCONSTITUTIONAL THERAPY IN THE EARLY ACUTE PERIOD OF POST-TRAUMATIC DISORDER

In this study, we investigated the effectiveness of psychoconstitutional therapy (PCT) in the early acute phase of Post-Traumatic Stress Disorder (PTSD) within a biopsychosocial framework, considering individual psychological and constitutional differences. Participants were categorized into "Flowers," "Pots," and "Gardeners" based on their stress response behaviours and received tailored interventions aimed at modulating amygdala activity and revising maladaptive stress responses. The results showed statistically significant improvements in stress response behaviours, PTSD symptomatology across various clusters, and overall psychological well-being, as measured by the Psychological General Well-Being Index. This study highlights the potential of psychoconstitutional therapy not only to reduce PTSD symptoms but also to enhance general mental health. It supports the inclusion of this therapy in current psychiatric practices and aligns with the growing trend towards personalized treatment approaches, offering new hope for effective PTSD management

Coping styles do not interact with the association between childhood trauma history and the immune-inflammatory phenotype of schizophrenia: Findings from a cross-sectional study

Adverse childhood experiences (ACEs) are a well-known risk factor of schizophrenia. Moreover, individuals with schizophrenia are likely to use maladaptive stress coping strategies. Although it has been reported that a history of ACEs might be associated with a pro-inflammatory phenotype in patients with schizophrenia, the interacting effect of coping styles on this association has not been tested so far. In the present study, we aimed to investigate the levels of immune-inflammatory markers in patients with schizophrenia and healthy controls (HCs), taking into consideration a history of ACEs and coping strategies. Participants included 119 patients with schizophrenia and 120 HCs. Serum levels of 26 immune-inflammatory markers were determined. A history of any categories of ACEs was significantly more frequent in patients with schizophrenia. Moreover, patients with schizophrenia were significantly more likely to use emotion-focused coping and less likely to use active coping strategies compared to HCs. The levels of interleukin(IL)-6, RANTES, and tumor necrosis factor-α (TNF-α), appeared to be elevated in patients with schizophrenia after adjustment for potential confounding factors in all tested models. Participants reporting a history of any ACEs had significantly higher levels of TNF-α and IL-6. No significant main and interactive effects of active strategies as the predominant coping on immune-inflammatory markers with altered levels in patients with schizophrenia were found. Findings from the present study indicate that ACEs are associated with elevated TNF-α and IL-6 levels regardless of schizophrenia diagnosis and predominant coping styles.

Recapitulating and reversing human brain ribosomopathy defects via the maladaptive integrated stress response.

Animal or human models recapitulating brain ribosomopathies are incomplete, hampering development of urgently needed therapies. Here, we generated genetic mouse and human cerebral organoid models of brain ribosomopathies, caused by mutations in small nucleolar RNA (snoRNA) SNORD118. Both models exhibited protein synthesis loss, proteotoxic stress, and p53 activation and led to decreased proliferation and increased death of neural progenitor cells (NPCs), resulting in brain growth retardation, recapitulating features in human patients. Loss of SNORD118 function resulted in an aberrant upregulation of p-eIF2α, the mediator of integrated stress response (ISR). Using human iPSC cell-based screen, we identified small-molecule 2BAct, an ISR inhibitor, which potently reverses mutant NPC defects. Targeting ISR by 2BAct mitigated ribosomopathy defects in both cerebral organoid and mouse models. Thus, our SNORD118 mutant organoid and mice recapitulate human brain ribosomopathies and cross-validate maladaptive ISR as a key disease-driving mechanism, pointing to a therapeutic intervention strategy.

The relationship between maladaptive health beliefs, pandemic-related stress, and health anxiety during the COVID-19 pandemic.

Research has demonstrated that people experience specific distress and anxiety regarding COVID-19. This distress may consist of interconnected symptom categories corresponding to a COVID stress syndrome. Susceptibility to COVID stress syndrome may be related to one's maladaptive health beliefs; however, no research has investigated the association between maladaptive health beliefs and COVID stress. The present study explored the impact of health beliefs on COVID stress, health anxiety, and associated psychological constructs. This cross-sectional survey study included 221 adults (M age = 20.59, SD = 2.28). Participants completed an online survey including demographic questionnaires and self-report measures of health beliefs, COVID stress, health anxiety, and related psychological constructs. Health anxiety, anxiety sensitivity, state/trait anxiety, intolerance of uncertainty, and depression accounted for significant variance in COVID stress (F(6, 214) = 11.18, R2 = .24, p < .001). Health beliefs (i.e., perceived likelihood of illness, medical service inadequacy, and difficulty coping) were associated with greater COVID stress, although health beliefs were not found to mediate the relationship between health anxiety and COVID stress. Health beliefs were associated with greater COVID stress, although health beliefs did not mediate the relationship between health anxiety and COVID stress. The relationship between health anxiety and COVID stress may be better explained by other COVID-related cognitions (e.g., vaccine efficacy, dangerousness of COVID-19). The findings highlight the importance of peoples' health beliefs during the pandemic. Given anxiety's influence on peoples' behavioural responses to the pandemic, further research should identify COVID-specific cognitions for prevention of COVID stress and health anxiety.

The brain, gut, and bladder health nexus: A conceptual model linking stress and mental health disorders to overactive bladder in women.

A small, but growing literature links stressors and mental health disorders (MHDs) across the life course to overactive bladder (OAB) and urinary incontinencesymptoms. Mechanisms by which stressors and MHDs may impact bladder health are not fully understood, limiting novel prevention and treatment efforts. Moreover, potential biopsychosocial mechanisms involving the brain and gut have not been considered in an integrated, comprehensive fashion. Members of the prevention of lower urinary tract symptomsResearch Consortium developed conceptual models to inform research on biopsychosocial mechanisms through which stress and MDHs may impact bladder health among girls and women, focusing on brain and gut physiology. Two conceptual models were developed-one to explain central (brain-based) and peripheral (gut-based) mechanisms linking stressors and MHDs to OAB and bladder health, and one to highlight bidirectional communication between the brain, gut, and bladder. Traumatic events, chronic stressors, and MHDs may lead to a maladaptive stress response, including dysregulated communication and signaling between the brain, gut, and bladder. Gut bacteria produce molecules and metabolites that alter production of neurotransmitters, amino acids, short-chain fatty acids, and inflammatory immune response molecules that mediate communication between the gut and brain. Microbiota signal neurogenesis, microglia maturation, and synaptic pruning; they also calibrate brain-gut-bladder axis communication through neurotransmission and synaptogenesis, potentially influencing bladder symptom development. Life course trajectories of risk may be prevented or interrupted by central and peripheral resources for neuropsychological resilience. Depicted pathways, including brain-gut-bladder communication, have implications for research and development of novel prevention and treatment approaches.

Abstract 15172: P21 Activated Kinase 2 Mediates Cardioprotection in Heart Failure With Preserved Ejection Fraction by Modulating Endoplasmic Reticulum Stress Response

Introduction: Heart failure with preserved ejection fraction (HFpEF) is a type of heart failure characterised by diastolic dysfunction but normal systolic function. Endoplasmic reticulum (ER) stress has been implicated in the pathophysiology of HFpEF. Previous studies have reported that P21 activated kinase 2 (Pak2) confers cardioprotection against the endoplasmic reticulum stress response. Hypothesis: Pak2 protein can potentially alleviate the adverse effects of maladaptive ER stress in HFpEF. Methods: The HFpEF model was developed by feeding C57/BL6N male mice with a high-fat diet (HFD) and a constitutive nitric oxide inhibitor, L-NAME, in drinking water for 15 weeks. Cardiac function was assessed by echocardiography and hemodynamics. Heart and lung structure was detected by H&amp;E staining and Masson staining. Electron microscopy, immunoblotting, and RNA sequencing were used to investigate the ER structure and function. Cardiomyocyte-specific Pak2 knockout (Pak2 CKO ) mice and adeno-associated virus (AAV) 9 for Pak2 overexpression were used to investigate the role of Pak2 in the heart. Results: After 15 weeks of feeding, mice on the HFD+L-NAME diet developed an HFpEF phenotype, as indicated by cardiac hypertrophy, impaired diastolic function but preserved systolic function, and pulmonary remodelling. The ER structure and the IRE1/XBP1s pathway were impaired in the cardiomyocytes of HFD+L-NAME mice. Pak2CKO mice exhibited the HFpEF phenotype at 10 weeks. In addition, Pak2 overexpression prevented diastolic dysfunction after 15 weeks and preserved the activation of the IRE1/XBP1s pathway under stress conditions. Conclusions: HFD + L-NAME diet for 15 weeks recapitulated the features of HFpEF in mice. Pak2 plays a protective role in HFpEF progression by modulating the cardiomyocyte ER stress response through the IRE1/XBP1s signaling pathway.

P02.26.B METABOLIC PLASTICITY IN GLIOBLASTOMA TUMOR-INITIATING CELL AND RESISTANCE TO LSD1-DIRECTED THERAPY

Abstract BACKGROUND Glioblastoma (GBM), the most common primary brain tumor in adults, remains incurable despite multimodal therapy. There is a pressing unmet medical need for new therapeutic strategies, especially because patients experience only short-term benefit after primary treatment and the vast majority inevitably relapse. Adaptation to harsh microenvironmental conditions, including nutrient deprivation, proteostasis perturbation, hypoxia and drug treatment, induce molecular and metabolic changes in glioblastoma that lead to the acquisition of a tolerance to stress and resistance to drug. In this context, we demonstrated that Lysine-specific histone demethylase 1 (LSD1) is a regulator of tumor-initiating cell (TICs) survival, adaptation and recovery from stress. LSD1 pharmacological inhibition with a specific and brain penetrant inhibitor (LSD1i) induces a maladaptive integrated stress response (ISR) which leads to the death of TICs exposed to ER stress or nutrient deficiency. MATERIAL AND METHODS Given the high GBM heterogeneity, we analyzed different patient-derived TICs grown in vitro as sphere and characterized for their genetic landscape and in vitro/in vivo stem cell-like features. We applied mechanistically different strategies, including biological, metabolic and pharmacological approaches, as well as transcriptomic and proteomic profiling. Zebrafish and GBM xenografts have been exploited as in vivo models. RESULTS LSD1i treatment induces physical and functional rearrangements of mitochondria, culminating into their enhanced bioenergetic activity and ATP production that predispose to cell death. Interestingly, only a subset of patient-derived TICs benefits from LSD1i therapy. These samples are largely dependent on glycolysis and, upon LSD1i administration, they are unable to further enhance it when mitochondrial energy production is inhibited. The samples resistant to LSD1i maintain their cellular behavior unaltered even upon prolonged treatment. They display reduced susceptibility to the stressful cues represented by either LSD1i and the known ER stressors Thapsigargin and Tunicamycin, by efficiently restoring energy homeostasis and properly activating the Activating Transcription Factor 4 (ATF4)-dependent ISR. Remarkably, LSD1i resistant samples display metabolic flexibility and switch between glycolytic and oxidative metabolism to ensure their survival. CONCLUSION The identification of specific metabolic vulnerabilities could offer unique opportunities for therapeutic intervention: the selective LSD1i vulnerability relies on the preferential dependence on glycolysis, while the great metabolic plasticity of LSD1i resistant TICs coordinates changes that favor their adaptation to stressful microenvironments and therapeutic insults.

Wellbeing, social media addiction and coping strategies among Chilean adolescents during the pandemic.

During the COVID-19 pandemic, adolescents had to deal with a range of mental health problems that has increased social media addiction levels with adverse effects on life satisfaction. Previous studies have explored coping mechanisms to deal with this addiction problem, but did not consider the need to simultaneously cope with different dimensions. Therefore, our study aimed to examine the moderating effect of various coping mechanisms on the relationship between social media addiction and adolescent life satisfaction. Self-report questionnaires were applied to 1290 secondary school students (age mean = 16.03, SD = 1.27, range: 14 to 19; and 57% female). An exploratory and a confirmatory factor analysis were performed to determine the factor structure of the Brief-Cope 28 scale. Then, a descriptive and correlational analysis of the variables and a multiple linear regression analysis was performed. We found that the social media addiction risk was negatively associated with life satisfaction, adaptive strategies were positively correlated to life satisfaction, and maladaptive strategies were negatively correlated to it. Also, a moderation model was evaluated in which four stress management strategies, namely acceptance and perspective-taking, seeking socio-emotional support, active coping, and maladaptive strategies all conditioned the relationship between social media addiction risk and life satisfaction after controlling for demographic variables and the specific strategies of using comedy, religion and substance use. Results indicate additive and multiplicative effects of management strategies for stressful situations in the studied relationship. Seeking socio-emotional support and active coping were positively related to life satisfaction and maladaptive strategies were negatively associated with it. Multiplicative effects indicate that the relationship between the social media addiction risk and life satisfaction depends only on the acceptance and perspective taking that adolescents report. When adolescents reported having low or average levels of acceptance and perspective taking, there was a negative correlation with general life satisfaction, a connection that grew markedly stronger. In contrast, no connection between social media addiction and life satisfaction was detected for adolescents who report higher levels of acceptance and perspective-taking. Abuse of social media and the use of maladaptive stress coping strategies were risk factors that decreased life satisfaction among adolescents during the COVID-19 pandemic period.

Utility of Continuous Paravertebral Block After Retroperitoneal Abdominal Aortic Aneurysm Repair

Open abdominal aortic aneurysm (AAA) repairs can be associated with significant pain and morbidity. Previous studies have demonstrated utility of adjunctive epidural analgesia (EA) in addition to general anesthesia (GA) to reduce pain and blunt the maladaptive surgical stress response. However, EA may be complicated by epidural hematomas and severe hypotension. Recently, we started using continuous paravertebral block (PVB) for perioperative analgesia after retroperitoneal AAA repair. PVB has some distinct advantages over EA such as unilateral localization, reduced risk of hypotension, and minimal risk of epidural hematoma in the setting of systemic heparinization. This study aimed to examine the utility of PVB by comparing total opioid consumption in the postoperative period among patients who received GA+PVB and those who received GA alone. This retrospective matched cohort study included 62 patients who underwent elective retroperitoneal AAA repair between January 2019 and August 2022. Thirty-one subjects managed with GA+PVB were compared with 31 control subjects treated with GA alone, matched on following criteria: age, sex, and cross-clamp location. Outcome measures included total opioid analgesics administered during their inhospital postoperative course, time to extubation, time to return to baseline activity, time to normal bowel function, and length of stay. Opioid doses were converted to morphine milligram equivalents (MMEs). The GA+PVB group required significantly less opioid analgesics (81±53 MME) than the GA group (171±121 MME) (P<0.001). Compared to GA alone, GA+PVB was superior in every clinical metric examined: time to extubation (3 vs. 1hr, P<0.001), recovery of bowel function (3 vs. 2days, P=0.002), recovery of baseline physical activity (4 vs. 2days, P=0.019), and length of stay (5 vs. 3days, P<0.001). Continuous paravertebral block provides better pain management with significantly decreased opioid requirements in the postoperative period compared to GA-alone for patients undergoing elective retroperitoneal AAA repair.

The human circadian system: physiology, pathophysiology and interactions with sleep and stress reactivity

The dramatic fluctuations in the energy demands of living organisms by the rhythmic succession of night and day on our planet has prompted a geophysical evolutionary need for a biological temporal organization necessary for maintenance of homeostasis and adaptation to environmental changes across phylogeny. The intrinsic circadian system (CS) represents a highly conserved and complex internal biological "clock", adjusted to the 24-hour rotation of the earth about itself. This system creates and maintains cellular and organismal rhythmicity and enables a nyctohemeral coordination of multi-level physiologic processes, ranging from gene expression to behaviour. The suprachiasmatic nucleus (SCN) of the hypothalamus is the primary pacemaker of the circadian system of the organism, while a ubiquitous peripheral oscillating network of cellular molecular clocks participates in a complex circadian hierarchy. A critical loss of this harmoniously timed circadian order at different organizational levels is defined as "chronodisruption", a condition that may alter the fundamental properties of basic homeostatic systems at molecular, cellular and organismal levels, and lead to a breakdown of biobehavioral adaptive mechanisms, resulting in maladaptive stress regulation and increased sensitivity and vulnerability to stress. Chronodisruption has been linked to neuroendocrine, immune, cardiometabolic and autonomic dysregulation, with blunted diurnal rhythms, specific sleep pattern pathologies and cognitive deficits, as well as with altered circadian gene expression. This condition may, thus, play a central role in the development of mental and somatic disease. Nevertheless, circadian and sleep disturbances are often clinically considered as "secondary" manifestations in most disorders, neglecting the potentially important pathophysiological role of CS. Understanding the pathophysiologic mechanisms of circadian dysregulation and their role in stress-related, systemic disease could provide new insights into disease mechanisms and could help advance chronobiological treatment possibilities and preventive strategies in populations at risk.