Acute stress enhances heterodimerization and binding of corticosteroid receptors at glucocorticoid target genes in the hippocampus

A stressful event results in secretion of glucocorticoid hormones, which bind to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) in the hippocampus to regulate cognitive and affective responses to the challenge. MRs are already highly occupied by low glucocorticoid levels under baseline conditions, whereas GRs only become substantially occupied by stress- or circadian-driven glucocorticoid levels. Currently, however, the binding of MRs and GRs to glucocorticoid-responsive elements (GREs) within hippocampal glucocorticoid target genes under such physiological conditions in vivo is unknown. We found that forced swim (FS) stress evoked increased hippocampal RNA expression levels of the glucocorticoid-responsive genes FK506-binding protein 5 (Fkbp5), Period 1 (Per1), and serum- and glucocorticoid-inducible kinase 1 (Sgk1). Chromatin immunoprecipitation (ChIP) analysis showed that this stressor caused substantial gene-dependent increases in GR binding and surprisingly, also MR binding to GREs within these genes. Different acute challenges, including novelty, restraint, and FS stress, produced distinct glucocorticoid responses but resulted in largely similar MR and GR binding to GREs. Sequential and tandem ChIP analyses showed that, after FS stress, MRs and GRs bind concomitantly to the same GRE sites within Fkbp5 and Per1 but not Sgk1. Thus, after stress, MRs and GRs seem to bind to GREs as homo- and/or heterodimers in a gene-dependent manner. MR binding to GREs at baseline seems to be restricted, whereas after stress, GR binding may facilitate cobinding of MR. This study reveals that the interaction of MRs and GRs with GREs within the genome constitutes an additional level of complexity in hippocampal glucocorticoid action beyond expectancies based on ligand–receptor interactions

Molecular and Epigenetic Mechanisms Underlying Cognitive and Adaptive Responses to Stress

Consolidation of contextual memories after a stressful encounter is essential for the survival of an organism and in allowing a more appropriate response to be elicited should the perceived threat reoccur. Recent evidence has explored the complex role that epigenetic mechanisms play in the formation of such memories, and the underlying signaling pathways are becoming more apparent. The glucocorticoid receptor (GR) has been shown to play a key role in these events having both genomic and non-genomic actions in the brain. GR has been shown to interact with the extracellular signal-regulated kinase mitogen-activated protein kinase (ERK MAPK) signaling pathway which, in concert, drives epigenetic modifications and chromatin remodeling, resulting in gene induction and memory consolidation. Evidence indicates that stressful events can have an effect on the offspring in utero, and that epigenetic marks altered early in life may persist into adulthood. A new and controversial area of research, however, suggests that epigenetic modifications could be inherited through the germline, a concept known as transgenerational epigenetics. This review explores the role that epigenetic processes play in the central nervous system, specifically in the consolidation of stress-induced memories, the concept of transgenerational epigenetic inheritance, and the potential role of epigenetics in revolutionizing the treatment of stress-related disorders through the emerging field of pharmacoepigenetics and personalized medical treatment

Trauma mechanism and patient reported outcome in tibial plateau fractures with posterior involvement

Introduction: Posterior tibial plateau fractures (PTPF) have a high impact on functional outcome and the optimal treatment strategy is not well established. The goal of this study was to assess the relationship between trauma mechanism, fracture morphology and functional outcome in a large multicenter cohort and define possible strategies to improve the outcome. Methods: An international retrospective cohort study was conducted in five level-1 trauma centers. All consecutive operatively treated PTPF were evaluated. Preoperative imaging was reviewed to determine the trauma mechanism. Patient reported outcome was scored using the Knee injury and Osteoarthritis Outcome Score (KOOS). Results: A total of 145 tibial plateau fractures with posterior involvement were selected with a median follow-up of 32.2 months (IQR 24.1-43.2). Nine patients (6%) sustained an isolated posterior fracture. Seventy-two patients (49%) sustained a two-column fracture and three-column fractures were diagnosed in 64 (44%) patients. Varus trauma was associated with poorer outcome on the 'symptoms' (p = 0.004) and 'pain' subscales (p = 0.039). Delayed-staged surgery was associated with worse outcome scores for all subscales except 'pain'. In total, 27 patients (18%) were treated with posterior plate osteosynthesis without any significant difference in outcome. Conclusions: Fracture morphology, varus trauma mechanism and delayed-staged surgery (i.e. extensive soft-tissue injury) were identified as important prognostic factors on postoperative outcome in PTPF. In order to assess possible improvement of outcome, future studies with routine preoperative MRI to assess associated ligamentous injury in tibial plateau fractures (especially for varus trauma) are needed. (c) 2021 Elsevier B.V. All rights reserved

Моделирование наземных испытаний рефлекторов антенн космических аппаратов на стенде с активной системой обезвешивания

Объектом исследования является стенд для раскрытия рефлектора антенны с восемью спицами диаметром 8,6 метров. Цель работы – моделирование наземных испытаний рефлекторов антенн космического аппарата (КА) на стенде с активной системой обезвешивания. В процессе исследования проводился анализ существующих способов обезвешивания элементов конструкций КА, разрабатывался алгоритм обезвешивания спицы, определялись кинематические зависимости углов механизма раскрытия спиц от перемещения мачты при раскрытии рефлектора антенны КА, разрабатывалась модель системы раскрытия спицы.The object of this study is to stand for the opening of the reflector antenna with eight spokes with a diameter of 8.6 meters. Objective - ground test simulation of the spacecraft antenna reflectors (CA) on a stand with an active obezveshivaniya system. The study analyzed the existing methods obezveshivaniya elements of spacecraft structures, developed an algorithm obezveshivaniya spokes, were determined according to the disclosure of the kinematic mechanism of the angles of the spokes on the displacement of the mast during the opening of the reflector antenna spacecraft designed spokes model disclosure system

Poor sporting abilities after tibial plateau fractures involving the posterior column: how can we do better?

Purpose: Tibial plateau fractures with the involvement of the posterior column are an important prognostic factor towards poor functional outcome. We aimed to assess the sporting abilities postoperatively with special emphasis on the type of sports and sport-specific movements, as well as time needed to resume sports, restricting factors in sports engagement, and patient satisfaction. We aimed to provide prognostic information on return to sports. Methods: Demographic, clinical and radiological variables were retrospectively collected from 82 multicentric patients between 2014 and 2016. Prospectively, sporting abilities before and after surgery were determined using questionnaires at a mean follow-up of 33 months postoperatively. Results: Involvement in sports significantly decreased, with only 68.4% of patients resuming sports (p < 0.001). The mean time needed to partially or fully resume sports was 6–9 and 9–12 months, respectively. The ability to resume at the pre-injury level of effort and performance was 22% and 12%, respectively. Restricting factors were pain (66%), fear of re-injury (37%), limited range of motion (26%), and instability (21%). The majority (59%) of patients were unsatisfied with their physical abilities. Significantly worse outcomes were observed in patients playing high-impact sports, experiencing knee pain during physical activity, suffering from extension/valgus or flexion/varus trauma. Conclusions: Tibial plateau fractures with the involvement of the posterior column significantly hamper the patients’ sporting abilities, leaving the majority of patients unsatisfied. Preoperative counseling about prognosis, setting realistic expectations, optimizing rehabilitation and pain management postoperatively, and advising low-impact sports might improve engagement in physical activities and emotional impact on patients. Level of evidence: 3

Exercise Improves Cognitive Responses to Psychological Stress through Enhancement of Epigenetic Mechanisms and Gene Expression in the Dentate Gyrus

Background We have shown previously that exercise benefits stress resistance and stress coping capabilities. Furthermore, we reported recently that epigenetic changes related to gene transcription are involved in memory formation of stressful events. In view of the enhanced coping capabilities in exercised subjects we investigated epigenetic, gene expression and behavioral changes in 4-weeks voluntarily exercised rats. Methodology/Principal Findings Exercised and control rats coped differently when exposed to a novel environment. Whereas the control rats explored the new cage for the complete 30-min period, exercised animals only did so during the first 15 min after which they returned to sleeping or resting behavior. Both groups of animals showed similar behavioral responses in the initial forced swim session. When re-tested 24 h later however the exercised rats showed significantly more immobility behavior and less struggling and swimming. If rats were killed at 2 h after novelty or the initial swim test, i.e. at the peak of histone H3 phospho-acetylation and c-Fos induction, then the exercised rats showed a significantly higher number of dentate granule neurons expressing the histone modifications and immediate-early gene induction. Conclusions/Significance Thus, irrespective of the behavioral response in the novel cage or initial forced swim session, the impact of the event at the dentate gyrus level was greater in exercised rats than in control animals. Furthermore, in view of our concept that the neuronal response in the dentate gyrus after forced swimming is involved in memory formation of the stressful event, the observations in exercised rats of enhanced neuronal responses as well as higher immobility responses in the re-test are consistent with the reportedly improved cognitive performance in these animals. Thus, improved stress coping in exercised subjects seems to involve enhanced cognitive capabilities possibly resulting from distinct epigenetic mechanisms in dentate gyrus neurons

Fluid-structure interaction simulation of prosthetic aortic valves : comparison between immersed boundary and arbitrary Lagrangian-Eulerian techniques for the mesh representation

In recent years the role of FSI (fluid-structure interaction) simulations in the analysis of the fluid-mechanics of heart valves is becoming more and more important, being able to capture the interaction between the blood and both the surrounding biological tissues and the valve itself. When setting up an FSI simulation, several choices have to be made to select the most suitable approach for the case of interest: in particular, to simulate flexible leaflet cardiac valves, the type of discretization of the fluid domain is crucial, which can be described with an ALE (Arbitrary Lagrangian-Eulerian) or an Eulerian formulation. The majority of the reported 3D heart valve FSI simulations are performed with the Eulerian formulation, allowing for large deformations of the domains without compromising the quality of the fluid grid. Nevertheless, it is known that the ALE-FSI approach guarantees more accurate results at the interface between the solid and the fluid. The goal of this paper is to describe the same aortic valve model in the two cases, comparing the performances of an ALE-based FSI solution and an Eulerian-based FSI approach. After a first simplified 2D case, the aortic geometry was considered in a full 3D set-up. The model was kept as similar as possible in the two settings, to better compare the simulations' outcomes. Although for the 2D case the differences were unsubstantial, in our experience the performance of a full 3D ALE-FSI simulation was significantly limited by the technical problems and requirements inherent to the ALE formulation, mainly related to the mesh motion and deformation of the fluid domain. As a secondary outcome of this work, it is important to point out that the choice of the solver also influenced the reliability of the final results

The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus of male mice

Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic, and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), the main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. We here demonstrate that the deletion of Fkbp5 in Sim1(+) neurons dampens the acute stress response and increases GR sensitivity. In contrast, Fkbp5 overexpression in the PVN results in a chronic HPA axis over-activation, and a PVN-specific rescue of Fkbp5 expression in full Fkbp5 KO mice normalizes the HPA axis phenotype. Single-cell RNA sequencing revealed the cell-type-specific expression pattern of Fkbp5 in the PVN and showed that Fkbp5 expression is specifically upregulated in Crh(+) neurons after stress. Finally, Crh-specific Fkbp5 overexpression alters Crh neuron activity, but only partially recapitulates the PVN-specific Fkbp5 overexpression phenotype. Together, the data establish the central and cell-type-specific importance of Fkbp5 in the PVN in shaping HPA axis regulation and the acute stress response

Use of satellite observations for operational oceanography: recent achievements and future prospects

The paper gives an overview of the development of satellite oceanography over the past five years focusing on the most relevant issues for operational oceanography. Satellites provide key essential variables to constrain ocean models and/or serve downstream applications. New and improved satellite data sets have been developed and have directly improved the quality of operational products. The status of the satellite constellation for the last five years was, however, not optimal. Review of future missions shows clear progress and new research and development missions with a potentially large impact for operational oceanography should be demonstrated. Improvement of data assimilation techniques and developing synergetic use of high resolution satellite observations are important future priorities