Maladaptive Responses Research Articles

Psychological Risk Factors for Delayed Recovery Among Active Duty Service Members Seeking Treatment for Musculoskeletal Complaints at a Navy Shore-Based Military Medical Treatment Facility.

Musculoskeletal injuries (MSIs) are a leading cause of separation from the U.S. Navy. Data have shown that several psychological responses to MSI are associated with treatment outcomes. Yellow flags are maladaptive psychological responses to injury and predict delayed recovery, whereas pink flags indicate resilience after MSI and are associated with good treatment outcomes. Identifying these factors in patients with MSI would permit early targeted care to address factors that may delay their readiness for deployment and enhance factors that support recovery. Active duty service members with MSI who reported to physical therapy outpatient services at a naval hospital were recruited for the study. Yellow flags were assessed at baseline as part of a larger study. Participants completed the Fear Avoidance Beliefs Questionnaire (with two subscales, physical activity and work), the Pain Catastrophizing Scale, and the Hospital Anxiety and Depression Scale. Clinically relevant cut-off scores were used to indicate risk factors of delayed recovery. Pink flags were assessed with the Pain Self-Efficacy Questionnaire and a measure of positive outcome expectations for recovery. Two hundred and ninety participants responded to some or all of the questionnaires. Of these, 82% exceeded the cut-off scores on the physical activity subscale of the Fear Avoidance Beliefs Questionnaire, and 39% did so on the work subscale. Pain catastrophizing exceeded the cut-off in only 4.9% of the sample. Forty-three percent of these exceeded the cut-off for the anxiety subscale of the Hospital Anxiety and Depression Scale; 27% exceeded the cut-off on the depression subscale of the Hospital Anxiety and Depression Scale. Additionally, 54% endorsed scores greater than 40 on the Pain Self-Efficacy Questionnaire, and 53% endorsed a high score on the positive outcome expectations. A substantial portion of the sample endorsed elevated scores on one or more indicators of delayed recovery from MSI. Most participants showed a fear of physical activity, and approximately half reported pain-related distress (anxiety and depression). In addition, feelings of self-efficacy and positive outcome expectations of treatment were endorsed by only about half of the participants, indicating that the remaining half did not report adaptive responses to MSI. Early identification of these risk factors will allow for targeted treatment approaches that incorporate these yellow flags into treatment and support a psychologically informed approach to physical therapy. This approach is likely to reduce delayed recovery and improve deployment readiness.

The role of microglia in neuronal and cognitive function during high altitude acclimatization

Due to their interactions with the neurovasculature, microglia are implicated in maladaptive responses to hypobaric hypoxia at high altitude (HA). To explore these interactions at HA, pharmacological depletion of microglia with the colony-stimulating factor-1 receptor inhibitor, PLX5622, was employed in male C57BL/6J mice maintained at HA or sea level (SL) for 3-weeks, followed by assessment of ex-vivo hippocampal long-term potentiation (LTP), fear memory recall and microglial dynamics/physiology. Our findings revealed that microglia depletion decreased LTP and reduced glucose levels by 25% at SL but did not affect fear memory recall. At HA, the absence of microglia did not significantly alter HA associated deficits in fear memory or HA mediated decreases in peripheral glucose levels. In regard to microglial dynamics in the cortex, HA enhanced microglial surveillance activity, ablation of microglia resulted in increased chemotactic responses and decreased microglia tip proliferation during ball formation. In contrast, vessel ablation increased cortical microglia tip path tortuosity. In the hippocampus, changes in microglial dynamics were only observed in response to vessel ablation following HA. As the hippocampus is critical for learning and memory, poor hippocampal microglial context-dependent adaptation may be responsible for some of the enduring neurological deficits associated with HA.

Fear generalization modulated by shock intensity and protein synthesis inhibitor.

Maladaptive fear responses, including sensitized threat reactions and overgeneralization, contribute to anxiety disorders such as generalized anxiety disorder and post-traumatic stress disorder. Although stress intensity influences the generation and extent of these maladaptive fears, the underlying mechanisms remain unclear. The present study examined whether varying footshock stress intensity and inhibition of protein synthesis have differential effect on fear sensitization and generalization in mice. Mice were subjected to a classic fear conditioning protocol involving five different levels of footshock intensities. Prior to fear acquisition, the protein synthesis inhibitor cycloheximide (CHX) was administered intraperitoneally. Fear sensitization to white noise and fear generalization to tones with frequencies differing from the conditioned tone were assessed at either 2 or 4 days after fear acquisition. The results showed that, although varying shock intensities (except the lowest) led to a similar pattern of increased freezing during auditory cues in fear acquisition, the extent of both fear sensitization and generalization increased with the intensity of the footshock in the following days. As shock intensities increased, there was a proportional rise in sensitized fear to white noise and generalized freezing to tones with frequencies progressively closer to the conditioned stimulus. Mildest shocks did not induce discriminative conditioned fear memory, whereas the most intense shocks led to pronounced fear generalization. Administration of CHX before fear acquisition did not affect sensitized fear but reduced generalization of freezing to tones dissimilar from the conditioned stimulus in the group exposed to the most intense shock. Our results suggest that maladaptive fear responses elicited by varying stress intensities exhibit distinct characteristics. The effect of CHX to prevent overgeneralization without affecting discriminative fear memory points to potential therapeutic approaches for fear-related disorders, suggesting the possibility of mitigating overgeneralization while preserving necessary fear discrimination.

Effect of physical activity in lymphocytes senescence burden in patients with COPD.

Chronic obstructive pulmonary disease (COPD) is regarded as an accelerated-age disease in which chronic inflammation, maladaptive immune responses, and senescence cell burden coexist. Accordingly, cellular senescence has emerged as a potential mechanism involved in COPD pathophysiology. In this study, 25 stable patients with COPD underwent a daily physical activity promotion program for 6 mo. We reported that increase of physical activity was related to a reduction of the senescent cell burden in circulating lymphocytes of patients with COPD. Senescent T-lymphocyte population, characterized by absence of surface expression of CD28, was reduced after physical activity intervention, and the reduction was associated to the increase of physical activity level. In addition, the mRNA expression of cyclin-dependent kinase inhibitors, a hallmark of cell senescence, was reduced and, in accordance, the proliferative capacity of lymphocytes was improved postintervention. Moreover, we observed an increase in functionality in T cells from patients after intervention, including improved markers of activation, enhanced cytotoxicity, and altered cytokine secretions in response to viral challenge. Lastly, physical activity intervention reduced the potential of lymphocytes' secretome to induce senescence in human primary fibroblasts. In conclusion, our study provides, for the first time, evidence of the potential of physical activity intervention in patients with COPD to reduce the senescent burden in circulating immune cells.NEW & NOTEWORTHY For the first time, we identified in patients with COPD a relation between physical activity intervention with respiratory function improvement and cellular senescence burden in lymphocytes that improved the T cell functionality and proliferative capacity of patients. In addition, our experiments highlight the possible impact of T-cell senescence in other cell types which could be related to some of the clinical lung complications observed in COPD.

Understanding sex differences in extinction retention: Pre-extinction stress and sex hormone status

Difficulties in fear regulation can sometimes result in maladaptive fear responses. To better understand how to improve fear regulation, it is important to determine how known factors, such as sex hormone status and stress, might interact to influence fear memory. Research has shown that women with high estradiol levels (mid-cycle) and men exhibit better extinction retention compared to women with low estradiol levels (women in the early follicular cycle or using oral contraceptives). Stress has also been demonstrated to affect both the learning and retention of extinction. Despite documented interactions between stress and sex hormones, their combined effects have not been thoroughly studied. This study aims to examine the impact of stress as a function of sex hormone status on extinction learning and retention.A total of 168 non-clinical participants were studied, including men (n = 46), women using oral contraceptives (n = 38), women in the early follicular phase (n = 40), and women in mid-cycle (n = 44). On Day 1, fear acquisition training was performed. On day 2, prior to extinction training, half of the participants were exposed to a psychosocial stressor, while the other half performed a non-stressful control task. On day 3, extinction retention was tested. Fear was quantified using skin conductance responses, while stress hormones were quantified through saliva samples.Exposure to stress prior to extinction training did not affect extinction learning, regardless of sex hormone status. In contrast, pre-extinction stress exposure had different effects on extinction retention depending on hormone status. Stressed men showed impairment in extinction retention compared to controls, while the experimental condition had no effect on naturally cycling women. Regardless of stress exposure, early follicular women exhibited a deficit in fear regulation, while mid-cycle women showed effective fear regulation. Among women using oral contraceptives, the stress group demonstrated better extinction retention compared to the control group.These results demonstrate the importance of considering sex hormone status and stress exposure during extinction learning, as both components may modulate extinction retention. These results could help identifying hormonal conditions that may enhance the effectiveness of extinction-based psychological therapies used in the treatment of fear-related disorders.

Flibanserin conquers murine depressive pseudodementia by amending HPA axis, maladaptive inflammation and AKT/GSK/STAT/BDNF trajectory: Center-staging of the serotonergic/adrenergic circuitry

Depressive pseudodementia (DPD) is a debilitating cognitive dysfunction that accompanies major and/or frequent depressive attacks. DPD has gained significant research attention owing to its negative effects on the patients' quality of life and productivity. This study tested the procognitive potential of Flibanserin (FBN), the serotonin (5HT) receptor modulator, against propranolol (PRP), as β/5HT1A receptors blocker. Serving this purpose, female Wistar Albino rats were subjected to chronic unpredictable stress (CUS) and subsequently treated with FBN only (3 mg/kg/day, p.o), PRP only (10 mg/kg/day, p.o), or PRP followed by FBN, using the same doses. FBN ameliorated the behavioral/cognitive alterations and calmed the hypothalamic-pituitary-adrenal (HPA) axis storm by reducing the levels of stress-related hormones, viz, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT) parallel to epinephrine (EPI) hyperstimulation. The maladaptive inflammatory response, comprising of interleukin (IL)-1β/6, and tumor necrosis factor (TNF)-α, was consequently blunted. This was contemporaneous to the partial restoration of the protein kinase-B (AKT)/glycogen synthase kinase (GSK)3β/signal transducer and activator of transcription (STAT)-3 survival trajectory and the reinstatement of the levels of brain derived neurotrophic factor (BDNF). Microscopically, FBN repaired the hippocampal architecture and lessened CD68/GFAP immunoreactivity. Pre-administration of PRP partially abolished FBN effect along the estimated parameters, except for 5HT2A receptor expression and epinephrine level, to prove 5HT1A receptor as a fulcrum initiator of the investigated pathway, while its sole administration worsened the underlying condition. Ultimately, these findings highlight the immense procognitive potential of FBN, offering a new paradigm for halting DPD advancement via synchronizing adrenergic/serotonergic circuitry.

Dynamic landscape of a competing endogenous RNA (ceRNA) network in Early-Onset Preeclampsia under hypoxia conditions

Objective: Early-onset preeclampsia (EOPE) manifests as elevated blood pressure and indications of organ damage, predominantly in the kidneys, in women before 34 weeks of gestation. A growing body of evidence suggests that hypoxia triggers a series of maladaptive responses culminating in the progression of EOPE. However, the precise mechanisms underlying these processes remain largely undefined. This study aimed to map the dynamic interplay within the competing endogenous RNA (ceRNA) network in EOPE under hypoxic conditions to provide insights into its molecular etiology. Methods: To investigate the oxidative stress response in EOPE, RNA sequencing data (ID: GSE119265) were retrieved from the Gene Expression Omnibus (GEO) database for exhaustive analysis. Oxygen-sensitive differential expressed genes (DEGs) were identified by comparing EOPE samples to controls at 5% and 20% O2 concentrations, respectively. Furthermore, the STRING database facilitated the construction of a protein-protein interaction network, highlighting critical hub genes among the identified DEGs. Results: An intricate ceRNA network encompassing four representative DEGs (AOC1, DCN, TGFB1, and SYNE3) and seven differentially expressed long non-coding RNAs (HCG27, MEG3, XIST, LINC01119, LINC00964, LINC01118, and LINC01588) was established. Conclusions: Our analysis revealed a set of long non-coding RNA that respond to hypoxic stress, shedding light on their possible roles in the oxygen-dependent pathophysiology of EOPE. These insights offer new avenues for targeted EOPE diagnosis and treatment. Further studies are required to elucidate their precise functions.

Integrated multi-omics analysis reveals molecular changes associated with chronic lipid accumulation following contusive spinal cord injury

Functional and pathological recovery after spinal cord injury (SCI) is often incomplete due to the limited regenerative capacity of the central nervous system (CNS), which is further impaired by several mechanisms that sustain tissue damage. Among these, the chronic activation of immune cells can cause a persistent state of local CNS inflammation and damage. However, the mechanisms that sustain this persistent maladaptive immune response in SCI have not been fully clarified yet.In this study, we integrated histological analyses with proteomic, lipidomic, transcriptomic, and epitranscriptomic approaches to study the pathological and molecular alterations that develop in a mouse model of cervical spinal cord hemicontusion.We found significant pathological alterations of the lesion rim with myelin damage and axonal loss that persisted throughout the late chronic phase of SCI. This was coupled by a progressive lipid accumulation in myeloid cells, including resident microglia and infiltrating monocyte-derived macrophages. At tissue level, we found significant changes of proteins indicative of glycolytic, tricarboxylic acid cycle (TCA), and fatty acid metabolic pathways with an accumulation of triacylglycerides with C16:0 fatty acyl chains in chronic SCI. Following transcriptomic, proteomic, and epitranscriptomic studies identified an increase of cholesterol and m6A methylation in lipid-droplet-accumulating myeloid cells as a core feature of chronic SCI.By characterizing the multiple metabolic pathways altered in SCI, our work highlights a key role of lipid metabolism in the chronic response of the immune and central nervous system to damage.

Macrophage-fibroblast crosstalk drives Arg1-dependent lung fibrosis via ornithine loading.

Monocyte-derived macrophages recruited to injured tissues induce a maladaptive fibrotic response characterized by excessive production of collagen by local fibroblasts. Macrophages initiate this programming via paracrine factors, but it is unknown whether reciprocal responses from fibroblasts enhance profibrotic polarization of macrophages. We identify macrophage-fibroblast crosstalk necessary for injury-associated fibrosis, in which macrophages induced interleukin 6 ( IL-6 ) expression in fibroblasts via purinergic receptor P2rx4 signaling, and IL-6, in turn, induced arginase 1 ( Arg1 ) expression in macrophages. Arg1 contributed to fibrotic responses by metabolizing arginine to ornithine, which fibroblasts used as a substrate to synthesize proline, a uniquely abundant constituent of collagen. Imaging of idiopathic pulmonary fibrosis (IPF) lung samples confirmed expression of ARG1 in myeloid cells, and arginase inhibition suppressed collagen expression in cultured precision-cut IPF lung slices. Taken together, we define a circuit between macrophages and fibroblasts that facilitates cross-feeding metabolism necessary for injury-associated fibrosis.

The roles of neural adaptation and sensitization in contact lens discomfort

PurposeTo investigate the roles of neural adaptation and sensitization in contact lens discomfort (CLD). MethodsCooling stimuli (20 °C) were applied to the cornea in a group comprising 24 symptomatic and 25 asymptomatic contact lens (CL) wearers as well as 15 non-CL wearing controls, using a computerized Belmonte esthesiometer. The adaptation paradigm consisted of 20 repetitive stimuli at threshold, sub- and supra-threshold levels. The sensitization paradigm involved five levels of suprathreshold stimuli ranging between 1x to 2x threshold. Following each stimulus, participants rated the sensation magnitude regarding intensity, coolness and irritation. Measurements were taken with habitual CL (BL_CL), after 2 weeks of no-CL (No_CL) and after restarting habitual CL wear (ReSt_CL). ResultsThe symptomatic subjects exhibited a lower threshold but reported enhanced sensations during the adaptation and sensitization paradigm, compared to the asymptomatic and control groups (all p ≤ 0.021). At the BL_CL and ReSt_CL visits, they showed increased ratings to repeated subthreshold stimuli (p = 0.025) and greater irritation during the sensitization paradigm (p ≤ 0.032). Ratings in asymptomatic and control groups were relatively unchanged over time (p ≥ 0.181). Logistic regression revealed a link between the augmented sensory responses and increased likelihood with CLD. ConclusionThe maladaptive sensory responses seen in CLD subjects, with reduced adaptation and heightened sensitization to ocular surface stimulation, suggest an imbalance between sensitization and adaptation in CLD. As CLD may represent a reversible subcategory of dry eye, it can serve as a human dry eye model for studying the neurosensory effect of ocular surface stimulation.

Cellular Senescence and Extracellular Vesicles in the Pathogenesis and Treatment of Obesity-A Narrative Review.

This narrative review explores the pathophysiology of obesity, cellular senescence, and exosome release. When exposed to excessive nutrients, adipocytes develop mitochondrial dysfunction and generate reactive oxygen species with DNA damage. This triggers adipocyte hypertrophy and hypoxia, inhibition of adiponectin secretion and adipogenesis, increased endoplasmic reticulum stress and maladaptive unfolded protein response, metaflammation, and polarization of macrophages. Such feed-forward cycles are not resolved by antioxidant systems, heat shock response pathways, or DNA repair mechanisms, resulting in transmissible cellular senescence via autocrine, paracrine, and endocrine signaling. Senescence can thus affect preadipocytes, mature adipocytes, tissue macrophages and lymphocytes, hepatocytes, vascular endothelium, pancreatic β cells, myocytes, hypothalamic nuclei, and renal podocytes. The senescence-associated secretory phenotype is closely related to visceral adipose tissue expansion and metaflammation; inhibition of SIRT-1, adiponectin, and autophagy; and increased release of exosomes, exosomal micro-RNAs, pro-inflammatory adipokines, and saturated free fatty acids. The resulting hypernefemia, insulin resistance, and diminished fatty acid β-oxidation lead to lipotoxicity and progressive obesity, metabolic syndrome, and physical and cognitive functional decline. Weight cycling is related to continuing immunosenescence and exposure to palmitate. Cellular senescence, exosome release, and the transmissible senescence-associated secretory phenotype contribute to obesity and metabolic syndrome. Targeted therapies have interrelated and synergistic effects on cellular senescence, obesity, and premature aging.

Working knowledge, uncertainty and ontological politics: An ethnography of UK long covid clinics.

Long covid (persistent COVID-19) is a new disease with contested aetiology and variable prognosis. We report a 2-year ethnography of UK long covid clinics. Using a preformative lens, we show that multidisciplinary teams (MDTs) built working knowledge based on shared practices, mutual trust, distributed cognition (e.g. emails, record entries), relational knowledge of what was at stake for the patient, and harnessing uncertainty to open new discursive spaces. Most long covid MDTs performed the working knowledge of 'rehabilitation', a linked set of practices oriented to ensuring that the patient understood and strove to 'correct' maladaptive physiological responses (e.g. through breathing exercises) and pursued recovery goals, supported by physiotherapists, psychologists and generalist clinicians. Some MDTs with a higher proportion of doctors (e.g. cardiologists, neurologists, immunologists) enacted the working knowledge of 'microscopic damage', seeking to elucidate and rectify long covid's underlying molecular and cellular pathology. They justified non-standard investigations and medication in selected patients by co-constructing an evidentiary narrative based on biological mechanisms. Working knowledge was ontologically concordant within MDTs but sometimes discordant between MDTs. Overt ontological conflict occurred mostly when patients attending 'rehabilitation' clinics invoked the working knowledge of microscopic damage that had been generated and circulated in online support communities.

Serial Mediation Analysis of Psychological Inflexibility and Daytime Insomnia Rumination in the Relationship Between Dysfunctional Beliefs About Sleep and Insomnia in College Students.

Emerging research suggests that psychological inflexibility may be a factor contributing to the development and maintenance of insomnia. However, less is known about the potential cognitive pathways that may explain this relationship. In this study, we investigated the serial mediating effects of psychological inflexibility and daytime insomnia-related rumination on the association between dysfunctional beliefs and attitudes about sleep (DBAS) and insomnia symptoms. The sample included 490 college students who underwent assessments at two time points over a 1-month period. The results of our mediational tests yielded significant indirect effects, supporting the prediction that psychological inflexibility and daytime insomnia rumination serially mediate the relationship between DBAS and insomnia. The study provides insights into potential mechanisms for insomnia, emphasizing the role of psychological inflexibility in perpetuating maladaptive cognitive processes associated with insomnia. Future researchers should explore other maladaptive responses to insomnia-related concerns and distress, such as worry and safety behaviors, and replicate findings in clinically elevated insomnia samples.

Successive association of adaptive/maladaptive response styles to depressive mood and decentering: a preliminary study of Japanese university students

Response styles to depressive mood, which are ruminative or distractive responses, have both adaptive and maladaptive forms. The adaptiveness of ruminative/distractive responses is associated with decentering. However, whether decentering increases using adaptive response styles or adaptive (maladaptive) response styles heighten (lower) decentering levels remains unclear. This short-term longitudinal survey examined the sequential influence of decentering on response styles and the indirect effect of decentering on depression through response styles. One hundred twenty-six Japanese undergraduates completed questionnaires on response styles, decentering, and depressive symptoms at two points in time, four weeks apart. Cross-lagged panel analyses indicated that decentering predicted lower maladaptive ruminative and distractive responses and a higher adaptive ruminative response. Adaptive ruminative response predicted higher decentering. Furthermore, mediation analyses showed that decentering influenced depression through adaptive/maladaptive ruminative responses. Results suggest that an individual’s decentering level partly determines which response style is likely to be used when an initial depressive mood is experienced.

Developmental relations of achievement goals and affect in physical education

ObjectiveThis study aimed to examine the developmental relationships between achievement goals and affect in school physical education. MethodThe study sample comprised 1063 (girls 546) Finnish Grade 6 students (M = 12.27 years ± 0.33 at the beginning of the study). The participants in the study were asked to provide annual assessments about their perceptions of achievement goals, enjoyment, and anxiety. The assessments were conducted four times over three consecutive years. ResultsThe results indicated that mastery-approach goals were positively associated with enjoyment (between-level), whereas both mastery-avoidance and performance-avoidance goals were positively associated with anxiety (between-level). Additionally, the associations between repeated measures (within-level) of mastery-approach goals and enjoyment were similar each year, whereas mastery- and performance-approach/avoidance goals were consistently associated with anxiety within the same year. Girls reported lower performance-approach goals and enjoyment but higher mastery-avoidance goals and anxiety than boys. ConclusionThe findings suggest that mastery approach goals exhibit a positive correlation with favorable affective reactions, while performance-avoidance goals demonstrate a connection with maladaptive responses. Physical education teachers should endeavor to establish mastery-oriented goals for their students from the outset of the educational process.

β-Hydroxybutyrate and melatonin suppress maladaptive UPR, excessive autophagy and pyroptosis in Aβ 1-42 and LPS-Induced SH-SY5Y cells.

Alzheimer's disease is a neurological disease characterized by the build-up of amyloid beta peptide (Aβ) and lipopolysaccharide (LPS), which causes synapse dysfunction, cell death, and neuro-inflammation. A maladaptive unfolded protein response (UPR), excessive autophagy, and pyroptosis aggravate the disease. Melatonin (MEL) and hydroxybutyrate (BHB) have both shown promise in terms of decreasing Aβ pathology. The goal of this study was to see how BHB and MEL affected the UPR, autophagy, and pyroptosis pathways in Aβ1-42 and LPS-induced SH-SY5Y cells. Human neuroblastoma SH-SY5Y cells were treated with BHB, MEL, or a combination of the two after being exposed to A β1-42 and LPS. Cell viability was determined using the MTT test, and gene expression levels of UPR (ATF6, PERK, and CHOP), autophagy (Beclin-1, LC3II, P62, and Atg5), and pyroptosis-related markers (NLRP3, TXNIP, IL-1β, and NFκB1) were determined using quantitative Real-Time PCR (qRT-PCR). For statistical analysis, one-way ANOVA was employed, followed by Tukey's post hoc test. BHB and MEL significantly increased SH-SY5Y cell viability in the presence of A β1-42 and LPS. Both compounds inhibited the expression of maladaptive UPR and autophagy-related genes, as well as inflammatory and pyroptotic markers caused by Aβ1-42 and LPS-induced SH-SY5Y cells. BHB and MEL rescue neurons in A β1-42 and LPS-induced SH-SY5Y cells by reducing maladaptive UPR, excessive autophagy, and pyroptosis. More research is needed to fully comprehend the processes behind their beneficial effects and to discover their practical applications in the treatment of neurodegenerative disorders.

Energetic Costs of Stress in Developing Fishes: Quantifying Allostasis and Allostatic Load.

Stress exerts negative effects on fish health through stimulation of the hypothalamic-pituitary-interrenal axis and autonomic nervous system, resulting in heightened neural and neuroendocrine responses. Energetic investment and physiological adaptation are then required to re-establish homeostatic stability or reach a new allostatic state. The cost of the energetic investment is referred to as allostatic load (AL). While determining the sources of stress and assessing their consequences have resulted in estimates of AL, most of this work has been conducted in adult mammals and humans; no ALs exist for developing fish. From a series of experiments on a model species, zebrafish (Danio rerio), whose yolk-sac larvae were exposed to two chronic stressors (high-temperature and hypoxia), ALs were quantified based on biomarkers of ontogenetic changes in growth, morphometrics, and metabolic activities. Results showed that for zebrafish yolk-sac larvae, chronic stress imposed high AL and, thus, high total allostatic energetic costs, (Rt (AL)), because of prolonged energy demand in the face of limited resources (e.g., yolk). Under severe chronic stress, energetic costs were sufficiently large that energy-limited developing fish may not be able to fully compensate, resulting in maladaptive responses from allostatic overload, leading either to death or to novel allostatic states, possibly more resilient to environmental change.

Disease-specific T cell receptors maintain pathogenic T helper cell responses in postinfectious Lyme arthritis.

Antibiotic-Refractory Lyme Arthritis (ARLA) involves a complex interplay of T cell responses targeting Borrelia burgdorferi antigens succeeding towards autoantigens by epitope spreading. However, the precise molecular mechanisms driving the pathogenic T cell response in ARLA remain unclear. Our aim was to elucidate the molecular program of disease-specific Th cells. Using flow cytometry, high-throughput T cell receptor (TCR) sequencing and scRNA-seq of CD4+ Th cells isolated from the joints of European ARLA patients, we aimed at inferring antigen specificity through unbiased analysis of TCR repertoire patterns, identifying surrogate markers for disease-specific TCRs and connecting TCR specificity to transcriptional patterns. PD-1hiHLA-DR+CD4+ effector T cells were clonally expanded within the inflamed joints and persisted throughout disease course. Among these cells, we identified a distinct TCRβ motif restricted to HLA-DRB1*11 or *13 alleles. These alleles, being underrepresented in North American ARLA patients, were unexpectedly prevalent in our European cohort. The identified TCRβ motif served as surrogate marker for a convergent TCR response specific to ARLA, distinguishing it from other rheumatic diseases. In the scRNA-seq dataset, the TCRβ motif particularly mapped to peripheral T helper (TPH) cells displaying signs of sustained proliferation, continuous TCR signaling, and expressing CXCL13 and IFN-γ. By inferring disease-specific TCRs from synovial T cells we identified a convergent TCR response in the joints of ARLA patients that continuously fueled the expansion of TPH cells expressing a pathogenic cytokine effector program. The identified TCRs will aid in uncovering the major antigen targets of the maladaptive immune response. Supported by the German Research Foundation (DFG) MO 2160/4-1; the Federal Ministry of Education and Research (BMBF; Advanced Clinician Scientist-Program INTERACT; 01EO2108) embedded in the Interdisciplinary Center for Clinical Research (IZKF) of the University Hospital Würzburg; the German Center for Infection Research (DZIF; Clinical Leave Program; TI07.001_007) and the Interdisciplinary Center for Clinical Research (IZKF) Würzburg (Clinician Scientist Program, Z-2/CSP-30).

Strategies to attenuate maladaptive inflammatory response associated with cardiopulmonary bypass.

Cardiopulmonary bypass (CPB) initiates an intense inflammatory response due to various factors: conversion from pulsatile to laminar flow, cold cardioplegia, surgical trauma, endotoxemia, ischemia-reperfusion injury, oxidative stress, hypothermia, and contact activation of cells by the extracorporeal circuit. Redundant and overlapping inflammatory cascades amplify the initial response to produce a systemic inflammatory response, heightened by coincident activation of coagulation and fibrinolytic pathways. When unchecked, this inflammatory response can become maladaptive and lead to serious postoperative complications. Concerted research efforts have been made to identify technical refinements and pharmacologic interventions that appropriately attenuate the inflammatory response and ultimately translate to improved clinical outcomes. Surface modification of the extracorporeal circuit to increase biocompatibility, miniaturized circuits with sheer resistance, filtration techniques, and minimally invasive approaches have improved clinical outcomes in specific populations. Pharmacologic adjuncts, including aprotinin, steroids, monoclonal antibodies, and free radical scavengers, show real promise. A multimodal approach incorporating technical, circuit-specific, and pharmacologic strategies will likely yield maximal clinical benefit.

Tactile temporal predictions: The influence of conditional probability.

Predicting the timing of incoming information allows brain to optimize information processing in dynamic environments. However, the effects of temporal predictions on tactile perception are not well established. In this study, two experiments were conducted to determine how temporal predictions interact with conditional probabilities in tactile perceptual processing. In Experiment 1, we explored the range of the interval between preceding ready cues and imperative targets in which temporal prediction effects can be observed. This prediction effect was observed for intervals of 500 and 1,000 ms. In Experiment 2, we investigated the benefits of temporal predictions on tactile perception while manipulating the conditional probability (setting the stimulus onset earlier or later than the predicted moment in short and long intervals). Our results revealed that this effect became stronger as the probability of the stimulus at the predicted time point increased under short-interval conditions. Together, our results show that the difficulty of transferring processing resources increases in temporally dynamic environments, suggesting a greater subjective cost associated with maladaptive responses to temporally uncertain events.