Geschlechterunterschiede in der physiologischen und psychologischen Stressreaktion im experimentellen und naturalistischen Setting unter Berücksichtigung der Faktoren Schlaf und kognitive Bewertung

Hintergrund: Viele Studien weisen darauf hin, dass Frauen physiologisch geringer, psychologisch jedoch stärker auf Stress reagieren als Männer. Geprüft wurde dies vermehrt mittels psychosozialer Laborstressoren. Es ist nur wenig erforscht, ob Frauen und Männer auch unterschiedlich auf andere typisch stressreiche Ereignisse reagieren, welche Rolle die kognitive Bewertung dabei spielt und ob sich die Stressoren geschlechtsspezifisch auf den Schlaf auswirken. Zielsetzung: Diese Arbeit möchte ein umfangreiches Bild liefern zur physiologischen und psychologischen Stressreaktion von Männern und Frauen. Dabei sollen nicht nur etablierte Laborstressoren wie der TSST betrachtet werden, sondern auch naturalistische Stressoren (Referate) sowie Schlafdeprivation. Zudem sollen in diesem Zusammenhang bisher vernachlässigte Faktoren wie kognitive Bewertung und Schlaf berücksichtigt werden. Methode: Es wurden mehrere Studien durchgeführt. Zunächst wurden anhand eines Laborstressors, des TSSTs, 42 Frauen und 46 Männer hinsichtlich ihrer Stressreaktion verglichen. In einer anschließenden Studie wurde geprüft, welche kurzfristigen (kognitiven, sozialen oder rein informellen) Interventionen zu einer Verringerung des Stresses bei Frauen (n = 131) im TSST führen. Eine weitere Studie untersuchte den Geschlechtsunterschied (24 Frauen, 22 Männer) bezüglich des Haltens eines Referates und verglich dies mit einer Kontrollbedingung (Zusehen beim Referat eines Kommilitonen). Schließlich wurde untersucht, ob Frauen und Männer (jeweils n = 16) unterschiedlich auf Schlafdeprivation reagieren; dabei wurde ebenfalls eine Kontrollbedingung (normale Schlafnacht) erhoben. Als Stressindikatoren dienten in jeder Studie Cortisol und subjektives Stressempfinden sowie vereinzelt auch Alpha-Amylase, kognitive Bewertung, Blutdruck und Herzrate. Zudem wurden Schlafparameter abgefragt. Zuletzt sollte mittels einer Onlineerhebung (656 Frauen, 141 Männer) die Frage beantwortet werden, ob Männer und Frauen den Einfluss von Stress auf die Gesundheit generell unterschiedlich einschätzen. Ergebnisse: Männer reagierten physiologisch größtenteils stärker auf die Stressoren als Frauen, während Frauen sich emotional und kognitiv gestresster zeigten und Stress zudem als gesundheitsschädlicher bewerteten. Frauen empfanden die Stresssituationen anderer Personen als ähnlich bedrohlich und herausfordernd wie die eigene Stresssituation. Sie gaben an, anfälliger für stressbezogene Schlafstörungen zu sein, berichteten aber vor als auch nach den Stressoren nicht von einem schlechteren Schlaf als Männer. Schlussfolgerung: Frauen und Männer gehen mit Stress auf unterschiedliche Weise um. Dieser Unterschied ist womöglich ein Zusammenspiel der Aufgabenverteilung von Männern und Frauen, wie sie in der frühen Menschheitsgeschichte vorherrschte, zusammen mit einer geschlechtsspezifischen Sozialisation.Sex differences concerning the physiological and psychological stress reaction in an experimental and naturalistic setting in consideration of the aspects sleep and cognitive appraisal Background: Many studies imply that women are psychologically more, yet physiologically less stressed than men when it comes to stressful situations. This finding was analyzed frequently by using psychosocial stressors. Studies analyzing a sex difference concerning other typical stressful events, cognitive appraisal and the influence of the stressors on sleep are scarce. Objective: The goal of this dissertation is to present a comprehensive picture of the physiological and psychological stress reactions of men and women. Thereby, laboratory stressors like the TSST will be considered as well as naturalistic stressors (oral presentations) and sleep deprivation. Furthermore, previous neglected aspects like cognitive appraisal and sleep shall be taken into account. Methods: Several studies have been conducted. First, the stress reactions of 42 women and 46 men were compared via a laboratory stressor, the TSST. One subsequent study tested which short-term intervention (cognitive, social or informal) would lead to a reduced TSST-stress reaction in women (n = 131). Another study analyzed the sex difference in reaction to giving an oral presentation (24 women, 22 men) and compared it to a control condition (watching an oral presentation of a fellow student). Eventually, it was examined, if men and women (both groups with n = 16) react differently to sleep deprivation which was also compared to a control condition (normal night of sleep). Indicators for stress such as cortisol and subjective stress feelings were assessed in every study and in some cases also alpha-amylase, cognitive appraisal, blood pressure and heartrate. Additionally, subjects provided information concerning their sleep. At last, an online study (656 women, 141 men) analyzed, if men and women appraise the influence of stress on health differently. Results: From a physiologically perspective, men tended to react stronger to the stressors than women did, whereas women showed a stronger emotional and cognitive stress response and evaluated stress as more harmful. Women appraised the stress situations of others as threatening as their own stress situations. Women indicated to be more vulnerable to stress related sleep disorders but did not report worse sleep than men did before or after the stressors. Conclusion: Men and women handle stress differently. The sex differences regarding stress may display an interaction of the delegation of tasks, common for the early human history, and a gender typical socialization

Simulation of Laptev Sea polynya dynamics using the FESOM model with different atmospheric forces

The Laptev Sea polynyas play a key role for the shelf areas of the Siberian Arctic due to their impact on ice production. Changes in polynya dynamics result in modified fluxes of energy, momentum and matter in the atmosphere-ocean-sea ice system. An improved understanding and quantification of polynya effects in the Laptev Sea can be achieved by high-resolution sea ice-ocean models. Here we use the well-established Finite Element Sea Ice-Ocean Model FESOM (5 km x 5 km) (AWI Bremerhaven). It consists of a hydrostatic primitive-equation ocean model and a dynamic-thermodynamic sea ice model. In our study the model is forced by 6-hourly GME analyses (0.5° x 0.5°), daily and 6-hourly NCEP/NCAR reanalyses (2.5° x 2.5°) and hourly COSMO data (5 km x 5 km) to investigate a polynya event during the TRANSDRIFT winter experiment 2008. The input data consists of 10 m-wind, 2 m-temperature and specific humidity, total cloudiness and precipitation rate. In order to test the quality of the forcing data, comparisons with in-situ have been performed. They show shortcomings of the atmospheric analyses model data with respect to the daily course of the temperature, but very good agreement for the wind. The opening process of a main polynya event on 29 April 2008 is represented with all atmospheric forcing fields (except the daily NCEP data) in a similarly good way. However, there are differences in direction and velocity of the icedrift and in the location and development of the polynyas. Small-scale structures are best represented by applying the high-resolution COSMO data. The maximum sensible heat flux is 220 W/m2, the maximum latent heat flux is 120 W/m2, the maximum advective ice thickness reduction is 5 cm/h and the maximum thermal ice thickness production is 5 mm/h

SPECT myocardial perfusion imaging as an adjunct to coronary calcium score for the detection of hemodynamically significant coronary artery stenosis

Background: Coronary artery calcifications (CAC) are markers of coronary atherosclerosis, but do not correlate well with stenosis severity. This study intended to evaluate clinical situations where a combined approach of coronary calcium scoring (CS) and nuclear stress test (SPECT-MPI) is useful for the detection of relevant CAD. Methods: Patients with clinical indication for invasive coronary angiography (ICA) were included into our study during 08/2005- 09/2008. At first all patients underwent CS procedure as part of the study protocol performed by either using a multidetector computed tomography (CT) scanner or a dual-source CT imager. CAC were automatically defined by dedicated software and the Agatston score was semi-automatically calculated. A stress-rest SPECT-MPI study was performed afterwards and scintigraphic images were evaluated quantitatively. Then all patients underwent ICA. Thereby significant CAD was defined as luminal stenosis >= 75% in quantitative coronary analysis (QCA) in >= 1 epicardial vessel. To compare data lacking Gaussian distribution an unpaired Wilcoxon-Test (Mann-Whitney) was used. Otherwise a Students t-test for unpaired samples was applied. Calculations were considered to be significant at a p-value of 0 significant CAD was confirmed by ICA, and excluded in 152/284 (53.5%) patients. Sensitivity for CAD detection by CS alone was calculated as 99.2%, specificity was 30.3%, and negative predictive value was 98.5%. An additional SPECT in patients with CS>0 increased specificity to 80.9% while reducing sensitivity to 87.9%. Diagnostic accuracy was 84.2%. Conclusions: In patients without CS=0 significant CAD can be excluded with a high negative predictive value by CS alone. An additional SPECT-MPI in those patients with CS>0 leads to a high diagnostic accuracy for the detection of CAD while reducing the number of patients needing invasive diagnostic procedure

Apple B-box factors regulate light-responsive anthocyanin biosynthesis genes

Environmentally-responsive genes can affect fruit red colour via the activation of MYB transcription factors. The apple B-box (BBX) gene, BBX33/CONSTANS-like 11 (COL11) has been reported to influence apple red-skin colour in a light- and temperature-dependent manner. To further understand the role of apple BBX genes, other members of the BBX family were examined for effects on colour regulation. Expression of 23 BBX genes in apple skin was analysed during fruit development. We investigated the diurnal rhythm of expression of the BBX genes, the anthocyanin biosynthetic genes and a MYB activator, MYB10. Transactivation assays on the MYB10 promoter, showed that BBX proteins 1, 17, 15, 35, 51, and 54 were able to directly function as activators. Using truncated versions of the MYB10 promoter, a key region was identified for activation by BBX1. BBX1 enhanced the activation of MYB10 and MdbHLH3 on the promoter of the anthocyanin biosynthetic gene DFR. In transformed apple lines, over-expression of BBX1 reduced internal ethylene content and altered both cyanidin concentration and associated gene expression. We propose that, along with environmental signals, the control of MYB10 expression by BBXs in 'Royal Gala' fruit involves the integration of the expression of multiple BBXs to regulate fruit colour.Peer reviewe

Recognition of microbial viability via TLR8 drives TFH cell differentiation and vaccine responses

Live attenuated vaccines are generally highly efficacious and often superior to inactivated vaccines, yet the underlying mechanisms of this remain largely unclear. Here we identify recognition of microbial viability as a potent stimulus for follicular helper T cell (TFH cell) differentiation and vaccine responses. Antigen-presenting cells (APCs) distinguished viable bacteria from dead bacteria through Toll-like receptor 8 (TLR8)-dependent detection of bacterial RNA. In contrast to dead bacteria and other TLR ligands, live bacteria, bacterial RNA and synthetic TLR8 agonists induced a specific cytokine profile in human and porcine APCs, thereby promoting TFH cell differentiation. In domestic pigs, immunization with a live bacterial vaccine induced robust TFH cell and antibody responses, but immunization with its heat-killed counterpart did not. Finally, a hypermorphic TLR8 polymorphism was associated with protective immunity elicited by vaccination with bacillus Calmette-Guérin (BCG) in a human cohort. We have thus identified TLR8 as an important driver of TFH cell differentiation and a promising target for TFH cell–skewing vaccine adjuvants

Mutations in GABRB3

Objective: To examine the role of mutations in GABRB3 encoding the b3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. Methods: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. Results: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands frommultiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy withmyoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant beta(3), together with alpha(5) and gamma(2s) subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations. Conclusions: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism

The spectrum of intermediate SCN8A-related epilepsy

Objective: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies. Methods: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.Peer reviewe

16p11.2 600 kb Duplications confer risk for typical and atypical Rolandic epilepsy

Rolandic epilepsy (RE) is the most common idiopathic focal childhood epilepsy. Its molecular basis is largely unknown and a complex genetic etiology is assumed in the majority of affected individuals. The present study tested whether six large recurrent copy number variants at 1q21, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 previously associated with neurodevelopmental disorders also increase risk of RE. Our association analyses revealed a significant excess of the 600 kb genomic duplication at the 16p11.2 locus (chr16: 29.5-30.1 Mb) in 393 unrelated patients with typical (n = 339) and atypical (ARE; n = 54) RE compared with the prevalence in 65 046 European population controls (5/393 cases versus 32/65 046 controls; Fisher's exact test P = 2.83 × 10−6, odds ratio = 26.2, 95% confidence interval: 7.9-68.2). In contrast, the 16p11.2 duplication was not detected in 1738 European epilepsy patients with either temporal lobe epilepsy (n = 330) and genetic generalized epilepsies (n = 1408), suggesting a selective enrichment of the 16p11.2 duplication in idiopathic focal childhood epilepsies (Fisher's exact test P = 2.1 × 10−4). In a subsequent screen among children carrying the 16p11.2 600 kb rearrangement we identified three patients with RE-spectrum epilepsies in 117 duplication carriers (2.6%) but none in 202 carriers of the reciprocal deletion. Our results suggest that the 16p11.2 duplication represents a significant genetic risk factor for typical and atypical R

Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci

Background: A Xist RNA decorated Barr body is the structural hallmark of the compacted inactive X territory in female mammals. Using super resolution three-dimensional structured illumination microscopy (3D-SIM) and quantitative image analysis, we compared its ultrastructure with active chromosome territories (CTs) in human and mouse somatic cells, and explored the spatio-temporal process of Barr body formation at onset of inactivation in early differentiating mouse embryonic stem cells (ESCs). Results: We demonstrate that all CTs are composed of structurally linked chromatin domain clusters (CDCs). In active CTs the periphery of CDCs harbors low-density chromatin enriched with transcriptionally competent markers, called the perichromatin region (PR). The PR borders on a contiguous channel system, the interchromatin compartment (IC), which starts at nuclear pores and pervades CTs. We propose that the PR and macromolecular complexes in IC channels together form the transcriptionally permissive active nuclear compartment (ANC). The Barr body differs from active CTs by a partially collapsed ANC with CDCs coming significantly closer together, although a rudimentary IC channel system connected to nuclear pores is maintained. Distinct Xist RNA foci, closely adjacent to the nuclear matrix scaffold attachment factor-A (SAF-A) localize throughout Xi along the rudimentary ANC. In early differentiating ESCs initial Xist RNA spreading precedes Barr body formation, which occurs concurrent with the subsequent exclusion of RNA polymerase II (RNAP II). Induction of a transgenic autosomal Xist RNA in a male ESC triggers the formation of an `autosomal Barr body' with less compacted chromatin and incomplete RNAP II exclusion. Conclusions: 3D-SIM provides experimental evidence for profound differences between the functional architecture of transcriptionally active CTs and the Barr body. Basic structural features of CT organization such as CDCs and IC channels are however still recognized, arguing against a uniform compaction of the Barr body at the nucleosome level. The localization of distinct Xist RNA foci at boundaries of the rudimentary ANC may be considered as snap-shots of a dynamic interaction with silenced genes. Enrichment of SAF-A within Xi territories and its close spatial association with Xist RNA suggests their cooperative function for structural organization of Xi