Assembly dynamics of PML nuclear bodies in living cells

The mammalian cell nucleus contains a variety of organelles or nuclear bodies which contribute to key nuclear functions. Promyelocytic leukemia nuclear bodies (PML NBs) are involved in the regulation of apoptosis, antiviral responses, the DNA damage response and chromatin structure, but their precise biochemical function in these nuclear pathways is unknown. One strategy to tackle this problem is to assess the biophysical properties of the component parts of these macromolecular assemblies in living cells. In this study we determined PML NB assembly dynamics by live cell imaging, combined with mathematical modeling. For the first time, dynamics of PML body formation were measured in cells lacking endogenous PML. We show that all six human nuclear PML isoforms are able to form nuclear bodies in PML negative cells. All isoforms exhibit individual exchange rates at NBs in PML positive cells but PML I, II, III and IV are static at nuclear bodies in PML negative cells, suggesting that these isoforms require additional protein partners for efficient exchange. PML V turns over at PML Nbs very slowly supporting the idea of a structural function for this isoform. We also demonstrate that SUMOylation of PML at Lysine positions K160 and/or K490 are required for nuclear body formation in vivo.We propose a model in which the isoform specific residence times of PML provide both, structural stability to function as a scaffold and flexibility to attract specific nuclear proteins for efficient biochemical reactions at the surface of nuclear bodies

Prenatal and Postnatal Hair Steroid Levels Predict Post-Partum Depression 12 Weeks after Delivery

Within three to six months after delivery, 13%-19% of women suffer from post-partum depression (PPD), understood as a dysfunctional adaptation to the postpartum condition and motherhood. In the present cross-sectional study, we compared the hair steroid levels of women 12 weeks before and after delivery and with or without PPD.; The present study was a cross-sectional study conducted twelve weeks after delivery. At that time, 48 women (mean age: 25.9 years) with PPD and 50 healthy controls (mean age: 25.2 years) completed questionnaires on depressive symptoms. Further, at the same time point, 6 cm lengths of hair strands were taken, providing samples of hair steroids 12 weeks before and 12 weeks after delivery in order to analyze hair steroids (cortisol, cortisone, progesterone, testosterone, and dehydroepiandrosterone (DHEA)).; Compared to those of women without PPD, hair steroid levels (cortisol, cortisone, progesterone) were significantly lower in women with PPD both before and after delivery. Lower prenatal cortisone and progesterone levels predicted higher depression scores 12 weeks after delivery. Lower prenatal levels of cortisol and progesterone and higher levels of DHEA, and postnatal lower levels of cortisol, cortisone, and progesterone, along with higher levels of DHEA predicted PPD-status with an accuracy of 98%.; PPD is associated with blunted hair cortisol, cortisone, and progesterone secretions both pre- and postpartum. Such blunted steroid levels appear to reflect a stress responsivity that is less adaptive to acute and transient stressors. It follows that prenatally assessed low hair cortisol and progesterone levels, along with high DHEA levels, are reliable biomarkers of post-partum depression 12 weeks after delivery

Influence of Regular Physical Activity on Mitochondrial Activity and Symptoms of Burnout - An Interventional Pilot Study

Occupational burnout is both a serious public and individual health concern. Psychopharmacological and psychological interventions are often employed, while interventions involving physical activity have been less frequently studied. The aims of the present study were (1) to investigate the effects of physical activity on mitochondrial activity levels and symptoms of burnout, (2) to compare the mitochondrial activity levels and symptoms of burnout of individuals suffering burnout with those of healthy controls (HCs), and (3) to explore the associations between mitochondrial activity and burnout symptoms.; Twelve males with burnout (mean age: M = 45.8 years) took part in the study. At baseline and after 12 weeks of an intervention involving physical activity, participants completed questionnaires covering symptoms of burnout and depression. In parallel, blood samples were taken to measure changes in mitochondrial functional outcomes, such as ATP levels, oxygen consumption and complex I. For comparison, baseline values of healthy controls (HCs; depression and burnout questionnaires; blood samples) were assessed.; Over time, symptoms of burnout (emotional exhaustion and depersonalization) and depression significantly decreased in participants with burnout (large effect sizes) but remained significantly higher than those of HCs (medium to large effect sizes). Personal accomplishment increased over time (medium effect size) but was still lower than for HCs (large effect size). At baseline and compared to HCs, individuals with burnout had significantly lower ATP levels of mitochondrial functional outcomes. Over time, mitochondrial activity levels increased among individuals with burnout. High baseline mitochondrial activity was significantly correlated with lower depression and burnout scores both at baseline and at the end of the study.; In individuals with burnout, regular physical activity had positive effects on mitochondrial activity and on symptoms of burnout and depression. However, when compared to healthy controls, full remission was not achieved

Group size planning for breedings of gene-modified mice and other organisms following Mendelian inheritance

Colony management of gene-modified animals is time-consuming, costly and affected by random events related to Mendelian genetics, fertility and litter size. Careful planning is mandatory to ensure successful outcomes using the least number of animals, hence adhering to the 3R principles of animal welfare. Here we have developed an R package, accessible also through an interactive public website, that optimizes breeding design by providing information about the optimal number of breedings needed to obtain defined breeding outcomes, taking into account specific species, strain, or line properties and success probability. Our software also enables breeding planning for balanced male-to-female ratio or single-sex experiments. We show that, for single-sex designs, the necessary number of breedings is at least doubled compared to the use of all born animals. While the presented tool provides preset parameters for the laboratory mouse, it can be readily used for any other species

NeurOscientific Workflow Assistance (NOWA)

In dem Infrastrukturprojekt NOWA (NeurOscientific Workflow Assistance) des von der DFG geförderten SFB/TRR 135 "Kardinale Mechanismen der Wahrnehmung: Prädiktion, Bewertung, Kategorisierung" werden Werkzeuge für die gemeinsame Nutzung von Forschungsdaten entwickelt. Um die Reproduzierbarkeit aller Schritte im Lebenszyklus einer wissenschaftlichen Studie zu verbessern – d.h. von der Planung bis zur Veröffentlichung von Forschungsdaten – zielt NOWA darauf ab, einen organisatorischen und technologischen Rahmen zu schaffen, der die Arbeitsabläufe entlang des gesamten Forschungsdatenlebenszyklus unterstützt. Ziel ist es, Forschungsdaten von Beginn an innerhalb der Arbeitsgruppen und des SFB zu teilen und sie zum Zeitpunkt der Veröffentlichung der Ergebnisse "auf Knopfdruck" öffentlich zugänglich zu machen. Die geplante Workflow-Unterstützung realisiert sich in einer Reihe von Leitlinien für das Forschungsdatenmanagement, die einerseits durch Sensibilisierung, Support und Schulung und andererseits durch eine kohärente Sammlung von Datenverarbeitungswerkzeugen umgesetzt werden. Das Poster präsentiert den Status Quo des INF-Projekts sowie die aktuelle prototypische Implementierung des digitalen Assistenzsystems

Potential of fibre metal laminates in root joints of wind energy turbine rotor blades

The length of rotor blades is showing continuous growth for future wind energy turbines leading to high bending moments, which must be transferred to the hub by the root section. As the growth of the root diameter is limited by factors such as transportability, motivation to improve the load carrying capacity without changing the geometry is high. Hybridisation with metals shows a possibility to intrinsically increase the bearing strength of fibre-reinforced plastics. This publication presents experimental investigations into hybrid laminates to be used in so-called T-joints for connecting rotor blades to the hub of the nacelle of a wind energy turbine. An overview is given about the bearing strength of several material combinations hybridising glass- and carbon fibre-reinforced plastics (GFRP, CFRP) with aluminium, titanium and steel alloys. A GFRP-steel-hybrid can be identified as a material with a high reinforcing effect even for low amounts of steel. A hybrid T-joint demonstrator is manufactured by resin infusion and tested under static tension. In comparison with a GFRP reference, a joining strength increase of about 33% is achieved for a steel content of 3%. Further coupon level tests reveal a weak spot in the transition zone between the monolithic GFRP region and full hybrid region as the static and fatigue resistance clearly decreases in comparison with monolithic GFRP and full hybrid references

Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study

Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2-3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2-2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA.Peer reviewe

Association of Human FOS Promoter Variants with the Occurrence of Knee-Osteoarthritis in a Case Control Association Study

Our aim was to analyse (i) the presence of single nucleotide polymorphisms (SNPs) in the JUN and FOS core promoters in patients with rheumatoid arthritis (RA), knee-osteoarthritis (OA), and normal controls (NC); (ii) their functional influence on JUN/FOS transcription levels; and (iii) their associations with the occurrence of RA or knee-OA. JUN and FOS promoter SNPs were identified in an initial screening population using the Non-Isotopic RNase Cleavage Assay (NIRCA); their functional influence was analysed using reporter gene assays. Genotyping was done in RA (n = 298), knee-OA (n = 277), and NC (n = 484) samples. For replication, significant associations were validated in a Finnish cohort (OA: n = 72, NC: n = 548). Initially, two SNPs were detected in the JUN promoter and two additional SNPs in the FOS promoter in perfect linkage disequilibrium (LD). JUN promoter SNP rs4647009 caused significant downregulation of reporter gene expression, whereas reporter gene expression was significantly upregulated in the presence of the FOS promoter SNPs. The homozygous genotype of FOS promoter SNPs showed an association with the susceptibility for knee-OA (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.2–3.7, p = 0.0086). This association was successfully replicated in the Finnish Health 2000 study cohort (allelic OR 1.72, 95% CI 1.2–2.5, p = 0.006). FOS Promoter variants may represent relevant susceptibility markers for knee-OA

Short-term outcomes of physical activity counseling in in-patients with Major Depressive Disorder: Results from the PACINPAT randomized controlled trial

IntroductionA physical activity counseling intervention based on a motivation-volition model was developed and delivered to in-patients with Major Depressive Disorders with the aim of increasing lifestyle physical activity. The aim of this study is to evaluate the short-term outcomes of this intervention.MethodsA multi-center randomized controlled trial was conducted in four Swiss psychiatric clinics. Adults who were initially insufficiently physically active and were diagnosed with Major Depressive Disorder according to ICD-10 were recruited. The sample consisted of 113 participants in the intervention group (Mage = 42 years, 56% women) and 107 in the control group (Mage = 40 years, 49% women). Motivation and volition determinants of physical activity were assessed with questionnaires. Implicit attitudes were assessed with an Implicit Association Test. Physical activity was self-reported and measured with hip-worn accelerometers over 7 consecutive days starting on the day following the data collection.ResultsAccording to accelerometer measures, step count decreased on average 1,323 steps less per day (95% CI = −2,215 to −431, p < 0.01) over time in the intervention group compared to the control group. A trend was recognized indicating that moderate-to-vigorous physical activity decreased on average 8.37 min less per day (95% CI = −16.98 to 0.23, p < 0.06) over time in the intervention group compared to the control group. The initial phase of the intervention does not seem to have affected motivational and volitional determinants of and implicit attitudes toward physical activity.ConclusionPhysical activity counseling may be considered an important factor in the transition from in-patient treatment. Methods to optimize the intervention during this period could be further explored to fulfill the potential of this opportunity.Clinical trial registrationhttps://www.isrctn.com/ISRCTN10469580, identifier ISRCTN10469580

High baseline BDNF serum levels and early psychopathological improvement are predictive of treatment outcome in major depression

Rationale: Major depressive disorder has been associated with low serum levels of brain-derived neurotrophic factor (sBDNF), which is functionally involved in neuroplasticity. Although sBDNF levels tend to normalize following psychopathological improvement with antidepressant treatment, it is unclear how closely sBDNF changes are associated with treatment outcome. Objectives: To examine whether baseline sBDNF or early changes in sBDNF are predictive of response to therapy. Methods: Twenty-five patients with major depressive disorder underwent standardized treatment with duloxetine. Severity of depression, measured by the Hamilton Depression Rating Scale, and sBDNF were assessed at baseline, and after 1, 2, and 6weeks of treatment. Therapy outcome after 6weeks was defined as response (≥50% reduction in baseline Hamilton Depression Rating score) and remission (Hamilton Depression Rating score <8). The predictive values for treatment outcome of baseline sBDNF, and early (i.e., ≤2weeks) changes in sBDNF and Hamilton Depression Rating score were also assessed. Results: At baseline, sBDNF correlated with Hamilton Depression Rating scores. Treatment response was associated with a higher baseline sBDNF concentration, and a greater Hamilton Depression Rating score reduction after 1 and 2weeks. A greater early rise in sBDNF correlated with a decreased early Hamilton Depression Rating score reduction. Conclusions: Even though higher baseline sBDNF levels are associated with more severe depression, they may reflect an increased capacity to respond to treatment. In contrast, changes in sBDNF over the full course of treatment are not associated with psychopathological improvement