Cognitive function in soccer athletes determined by sleep disruption and self-reported health, yet not by decision-reinvestment

BackgroundSleep disruption (SD) increases sympathetic activity and cortisol secretion, and delays cognitive functions such as reaction-time (RT). Sympathetic activity of disturbed sleepers, is similar to those of so-called decision-reinvesters. Decision-reinvestment refers to traits in individuals with greater tendency to ruminate and reinvest in their decisions, with significant decrease in both motor-control and cognitive performance. Decision-making quality is a crucial attribute to athletic performance which relies on RT. Consequently, SD affects pitch-performance negatively, particularly in decision-reinvesters. This observational pilot-study examined the relationship between SD and cognitive function, perceived health, as well as reinvestment strategies. The hypothesis was that athletes with lower SD perceive their health better, report lower stress levels, perform better in cognitive tasks, and show lower tendency for decision-reinvestment.MethodsTwenty-one football player recorded their sleep with fit-trackers for 7 nights. Participants self-reported their mental and physical health, decision-reinvestment strategy, sleep behaviour, and perceived stress levels. Athletes then performed a set of cognitive tests to examine memory function (Backwards Corsi), selective attention (STROOP), and cognitive flexibility (Wisconsin Card Sorting Test, WCST). Normality was tested with a Shapiro-Wilk test, and analysed with a Pearson's or Spearman's correlation test.ResultsSignificant correlation appeared between extended sleep-interruptions and Backwards Corsi RT, r = 0.66, p = 0.010, as further in total sleep time and wellbeing r = 0.50, p = 0.029. A negative correlation exist in regard of pain scores and Backwards Corsi scores r = −0.57, p = 0.110. Physical health correlated with error-rates in the WCST, r = 0.69, p ≤ 0.001. Also, reinvestment negatively correlated with physical health, r = −0.80, p ≤ 0.001.ConclusionWellbeing relies on total sleep-time. Athletes with extended sleep-interruptions are slower in recalling memory, and those with greater reported pain have lower memory scores. Participants who rate physical health greater, have more error-rates in the WCST; indicating that cognitive flexibility is enhanced in individuals with inferior perceived health. However, individuals with lower physical health scores also have greater tendency to ruminate and reinvest in decisions, suggesting interrelation between reinvestment and physical health

p38 MAPK Facilitates Crosstalk Between Endoplasmic Reticulum Stress and IL-6 Release in the Intervertebral Disc

Degenerative disc disease is associated with increased expression of pro-inflammatory cytokines in the intervertebral disc (IVD). However, it is not completely clear how inflammation arises in the IVD and which cellular compartments are involved in this process. Recently, the endoplasmic reticulum (ER) has emerged as a possible modulator of inflammation in age-related disorders. In addition, ER stress has been associated with the microenvironment of degenerated IVDs. Therefore, the aim of this study was to analyze the effects of ER stress on inflammatory responses in degenerated human IVDs and associated molecular mechanisms. Gene expression of ER stress marker GRP78 and pro-inflammatory cytokines IL-6, IL-8, IL-1β, and TNF-α was analyzed in human surgical IVD samples (n = 51, Pfirrmann grade 2–5). The expression of GRP78 positively correlated with the degeneration grade in lumbar IVDs and IL-6, but not with IL-1β and TNF-α. Another set of human surgical IVD samples (n = 25) was used to prepare primary cell cultures. ER stress inducer thapsigargin (Tg, 100 and 500 nM) activated gene and protein expression of IL-6 and induced phosphorylation of p38 MAPK. Both inhibition of p38 MAPK by SB203580 (10 µM) and knockdown of ER stress effector CCAAT-enhancer-binding protein homologous protein (CHOP) reduced gene and protein expression of IL-6 in Tg-treated cells. Furthermore, the effects of an inflammatory microenvironment on ER stress were tested. TNF-α (5 and 10 ng/mL) did not activate ER stress, while IL-1β (5 and 10 ng/mL) activated gene and protein expression of GRP78, but did not influence [Ca2+]i flux and expression of CHOP, indicating that pro-inflammatory cytokines alone may not induce ER stress in vivo. This study showed that IL-6 release in the IVD can be initiated following ER stress and that ER stress mediates IL-6 release through p38 MAPK and CHOP. Therapeutic targeting of ER stress response may reduce the consequences of the harsh microenvironment in degenerated IVD

TRPV4 mediates cell damage induced by hyperphysiological compression and regulates COX2/PGE2 in intervertebral discs

Background Aberrant mechanical loading of the spine causes intervertebral disc (IVD) degeneration and low back pain. Current therapies do not target the mediators of the underlying mechanosensing and mechanotransduction pathways, as these are poorly understood. This study investigated the role of the mechanosensitive transient receptor potential vanilloid 4 (TRPV4) ion channel in dynamic compression of bovine nucleus pulposus (NP) cells in vitro and mouse IVDs in vivo. Methods Degenerative changes and the expression of the inflammatory mediator cyclooxygenase 2 (COX2) were examined histologically in the IVDs of mouse tails that were dynamically compressed at a short repetitive hyperphysiological regime (vs sham). Bovine NP cells embedded in an agarose-collagen hydrogel were dynamically compressed at a hyperphysiological regime in the presence or absence of the selective TRPV4 antagonist GSK2193874. Lactate dehydrogenase (LDH) and prostaglandin E2 (PGE2) release, as well as phosphorylation of mitogen-activated protein kinases (MAPKs), were analyzed. Degenerative changes and COX2 expression were further evaluated in the IVDs of trpv4-deficient mice (vs wild-type; WT). Results Dynamic compression caused IVD degeneration in vivo as previously shown but did not affect COX2 expression. Dynamic compression significantly augmented LDH and PGE2 releases in vitro, which were significantly reduced by TRPV4 inhibition. Moreover, TRPV4 inhibition during dynamic compression increased the activation of the extracellular signal-regulated kinases 1/2 (ERK) MAPK pathway by 3.13-fold compared to non-compressed samples. Trpv4-deficient mice displayed mild IVD degeneration and decreased COX2 expression compared to WT mice. Conclusions TRPV4 therefore regulates COX2/PGE2 and mediates cell damage induced by hyperphysiological dynamic compression, possibly via ERK. Targeted TRPV4 inhibition or knockdown might thus constitute promising therapeutic approaches to treat patients suffering from IVD pathologies caused by aberrant mechanical stress

Effects of Early Life Stress on Bone Homeostasis in Mice and Humans

Bone pathology is frequent in stressed individuals. A comprehensive examination of mechanisms linking life stress, depression and disturbed bone homeostasis is missing. In this translational study, mice exposed to early life stress (MSUS) were examined for bone microarchitecture (μCT), metabolism (qPCR/ELISA), and neuronal stress mediator expression (qPCR) and compared with a sample of depressive patients with or without early life stress by analyzing bone mineral density (BMD) (DXA) and metabolic changes in serum (osteocalcin, PINP, CTX-I). MSUS mice showed a significant decrease in NGF, NPYR1, VIPR1 and TACR1 expression, higher innervation density in bone, and increased serum levels of CTX-I, suggesting a milieu in favor of catabolic bone turnover. MSUS mice had a significantly lower body weight compared to control mice, and this caused minor effects on bone microarchitecture. Depressive patients with experiences of childhood neglect also showed a catabolic pattern. A significant reduction in BMD was observed in depressive patients with childhood abuse and stressful life events during childhood. Therefore, future studies on prevention and treatment strategies for both mental and bone disease should consider early life stress as a risk factor for bone pathologies

Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes

Usher syndrome (USH) is the most common form of monogenic deaf-blindness. Loss of vision is untreatable and there are no suitable animal models for testing therapeutic strategies of the ocular constituent of USH, so far. By introducing a human mutation into the harmonin-encoding USH1C gene in pigs, we generated the first translational animal model for USH type 1 with characteristic hearing defect, vestibular dysfunction, and visual impairment. Changes in photoreceptor architecture, quantitative motion analysis, and electroretinography were characteristics of the reduced retinal virtue in USH1C pigs. Fibroblasts from USH1C pigs or USH1C patients showed significantly elongated primary cilia, confirming USH as a true and general ciliopathy. Primary cells also proved their capacity for assessing the therapeutic potential of CRISPR/Cas-mediated gene repair or gene therapy in vitro. AAV-based delivery of harmonin into the eye of USH1C pigs indicated therapeutic efficacy in vivo

Glow up: does a professional photoshoot intervention affect self-esteem and emotions among adolescent psychiatric patients?—A longitudinal intervention study

BackgroundToday, online communication is shaped by a billion-dollar social media (SM) and social networking site (SNS) industry. Visual content consumed by children and adolescents has been shown to influence behavioral patterns, state emotions, and self-esteem (SE). In this study, we introduced a novel intervention creating visual content through a professional photoshoot and investigated its impact on state emotions and SE in child and adolescent psychiatric (CAP) patients.MethodsStandardized and validated self-rating questionnaires were used to assess SE, state emotions, coping mechanisms, psychopathological symptoms, and internet use behavior at baseline. SE and state emotions were monitored at different time points around a professional photoshoot within 45 CAP patients (30 female patients; mean age, 15.1 years) using a longitudinal design.ResultsWithin-subject repeated-measures ANOVA and bootstrapped paired-sample t-tests showed a significant fluctuation in state emotions and SE throughout the intervention. Spearman correlations and univariate logistic regressions revealed that internalizing symptomatology and maladaptive coping significantly worsened the outcome of the intervention on state emotions and SE in girls. Internet-related variables heightened the positive effect of the intervention in boys and lowered SE in girls during the intervention.ConclusionThe photo intervention had various gender-specific effects. Boys did benefit from the intervention in terms of longitudinal outcome on positive state emotions (PE) and SE, even positively influenced by SNS and SM. Thus, it might be concluded that online social comparison was processed more beneficial in boys. In contrast, when working with visual content in girls, psychopathology and coping must be considered. Internet consumption in general, especially SM and SNS, was related to low SE in girls. Nevertheless, when therapeutically accompanied, the “glow up moment” during the shoot (high on PE and SE; low on negative state emotions) could be used as an index moment for therapeutic reflection

Lymphocyte Subsets Show Different Response Patterns to In Vivo Bound Natalizumab—A Flow Cytometric Study on Patients with Multiple Sclerosis

Natalizumab is an effective monoclonal antibody therapy for the treatment of relapsing- remitting multiple sclerosis (RRMS) and interferes with immune cell migration into the central nervous system by blocking the α4 subunit of very-late activation antigen-4 (VLA-4). Although well tolerated and very effective, some patients still suffer from relapses in spite of natalizumab therapy or from unwanted side effects like progressive multifocal leukoencephalopathy (PML). In search of a routine-qualified biomarker on the effectiveness of natalizumab therapy we applied flow cytometry and analyzed natalizumab binding to α4 and α4 integrin surface levels on T-cells, B-cells, natural killer (NK) cells, and NKT cells from 26 RRMS patients under up to 72 weeks of therapy. Four-weekly infusions of natalizumab resulted in a significant and sustained increase of lymphocyte-bound natalizumab (p<0.001) which was paralleled by a significant decrease in detectability of the α4 integrin subunit on all lymphocyte subsets (p<0.001). We observed pronounced natalizumab accumulations on T and B cells at single measurements in all patients who reported clinical disease activity (n = 4). The natalizumab binding capacity of in vitro saturated lymphocytes collected during therapy was strongly diminished compared to treatment-naive cells indicating a therapy-induced reduction of α4. Summing up, this pilot study shows that flow cytometry is a useful method to monitor natalizumab binding to lymphocytes from RRMS patients under therapy. Investigating natalizumab binding provides an opportunity to evaluate the molecular level of effectiveness of natalizumab therapy in individual patients. In combination with natalizumab saturation experiments, it possibly even provides a means of studying the feasability of patient-tailored infusion intervals. A routine-qualified biomarker on the basis of individual natalizumab saturation on lymphocyte subsets might be an effective tool to improve treatment safety

Inhibition of ADAM17 impairs endothelial cell necroptosis and blocks metastasis

Metastasis is the major cause of death in cancer patients. Circulating tumor cells need to migrate through the endothelial layer of blood vessels to escape the hostile circulation and establish metastases at distant organ sites. Here, we identified the membrane-bound metalloprotease ADAM17 on endothelial cells as a key driver of metastasis. We show that TNFR1-dependent tumor cell–induced endothelial cell death, tumor cell extravasation, and subsequent metastatic seeding is dependent on the activity of endothelial ADAM17. Moreover, we reveal that ADAM17-mediated TNFR1 ectodomain shedding and subsequent processing by the γ-secretase complex is required for the induction of TNF-induced necroptosis. Consequently, genetic ablation of ADAM17 in endothelial cells as well as short-term pharmacological inhibition of ADAM17 prevents long-term metastases formation in the lung. Thus, our data identified ADAM17 as a novel essential regulator of necroptosis and as a new promising target for antimetastatic and advanced-stage cancer therapie