Inhibition of Ubc13-mediated ubiquitination by GPS2 regulates multiple stages of B cell development

Non-proteolytic ubiquitin signaling mediated by Lys63 ubiquitin chains plays a critical role in multiple pathways that are key to the development and activation of immune cells. Our previous work indicates that GPS2 (G-protein Pathway Suppressor 2) is a multifunctional protein regulating TNF signaling and lipid metabolism in the adipose tissue through modulation of Lys63 ubiquitination events. However, the full extent of GPS2-mediated regulation of ubiquitination and the underlying molecular mechanisms are unknown. Here, we report that GPS2 is required for restricting the activation of TLR and BCR signaling pathways and the AKT/FOXO1 pathway in immune cells based on direct inhibition of Ubc13 enzymatic activity. Relevance of this regulatory strategy is confirmed in vivo by B cell-targeted deletion of GPS2, resulting in developmental defects at multiple stages of B cell differentiation. Together, these findings reveal that GPS2 genomic and non-genomic functions are critical for the development and cellular homeostasis of B cells

A protein functional leap: how a single mutation reverses the function of the transcription regulator TetR

Today's proteome is the result of innumerous gene duplication, mutagenesis, drift and selection processes. Whereas random mutagenesis introduces predominantly only gradual changes in protein function, a case can be made that an abrupt switch in function caused by single amino acid substitutions will not only considerably further evolution but might constitute a prerequisite for the appearance of novel functionalities for which no promiscuous protein intermediates can be envisaged. Recently, tetracycline repressor (TetR) variants were identified in which binding of tetracycline triggers the repressor to associate with and not to dissociate from the operator DNA as in wild-type TetR. We investigated the origin of this activity reversal by limited proteolysis, CD spectroscopy and X-ray crystallography. We show that the TetR mutant Leu17Gly switches its function via a disorder–order mechanism that differs completely from the allosteric mechanism of wild-type TetR. Our study emphasizes how single point mutations can engender unexpected leaps in protein function thus enabling the appearance of new functionalities in proteins without the need for promiscuous intermediates

Health literacy in men and women with cardiovascular diseases and its association with the use of health care services - Results from the population-based GEDA2014/2015-EHIS survey in Germany

Background Health literacy (HL), defined as the ability to access, understand, appraise and apply health information, offers a promising approach to reduce the development of cardiovascular diseases (CVD) and to improve the management of CVD in populations. Design We used data from nationwide cross-sectional German Health Update (GEDA2014/2015-EHIS) survey. 13,577 adults ≥ 40 years completed a comprehensive standardized paper or online questionnaire including the short form of the European Health Literacy Survey Questionnaire (HLS-EU-Q16). Methods We compared participants with and without CVD with regard to their HL. We also analyzed the association between HL level and health care outcomes among individuals with CVD, i.e. frequency of general practitioner or specialist consultations, hospitalization and treatment delay. Results The percentage of “problematic” or “inadequate” HL, defined as “not sufficient” HL, was significantly higher in individuals with CVD compared to without CVD (men 41.8% vs. 33.6%, women 46.7% vs. 33.4%). Having CVD was independently associated with “not sufficient” HL after adjusting for age, education, income, health consciousness and social support (adjusted OR: men 1.36, women 1.64). Among participants with CVD, individuals with “inadequate” HL were more likely to have more than 6 general practitioner consultations (49.3% vs. 28.7%), hospitalization (46.6% vs. 36.0%) in the last 12 months and to experience delay in getting health care because of long waiting lists for an appointment (30.7% vs. 18.5%) compared to participants with “sufficient” HL. Conclusion “Problematic” or “inadequate” HL is independently associated with CVD and health care use. This is a challenge and an opportunity for both CVD prevention and treatment.Peer Reviewe

Expertise of the Robert Koch Institute for the first prevention report: background, aims and approach

Peer Reviewe

Change in the association of body mass index and systolic blood pressure in Germany – national cross-sectional surveys 1998 and 2008–2011

Background: A recent weakening and even decoupling of the association of body mass index (BMI) and systolic blood pressure (SBP) in population data was reported, i. a. for Western Europe. Methods: The association of BMI and SBP in recent cross-sectional population data from Germany was investigated in participants aged 18–79 years with BMI 17.5-40 kg/m 2 from national health examination surveys 1998 (n = 6,931) and 2008–2011 (n = 6,861) in Germany. The association was analyzed both in the overall samples and in participants without antihypertensive medication. Results: From 1998 to 2008–11, age- and sex-standardized mean SBP decreased from 129.0 (CI 128.2-129.7) to 124.1 (123.5-124.6) mmHg in all participants and from 126.0 (125.4-126.7) to 122.3 (121.7-122.8) mmHg among persons not on antihypertensive medication. The proportion of persons treated with antihypertensives augmented from 19.2 % (17.7-20.8) to 25.3 % (24.0-26.6). Mean BMI remained constant at around 27 kg/m 2 with a slight increase in obesity prevalence. BMI was positively associated with SBP both in 1998 and 2008–11, yet the association tended to level out with increasing BMI suggesting a non-linear association. The strength of the BMI-SBP-association decreased over time in all and untreated men. In women, the association weakened in the overall sample, but remained similarly strong in untreated women. The unadjusted linear regression models were used to estimate the increase in SBP within 5-unit BMI increases. E. g. for men in 1998, SBP was higher by 7.0 mmHg for a BMI increase from 20 to 25 kg/m 2 and by 3.6 mmHg for BMI 30 to 35 kg/m 2 . The corresponding values for 2008–11 were 3.8 mmHg and 1.7 mmHg. Conclusions: The cross-sectional association of BMI and SBP decreased between 1998 and 2008–11 in Germany, however it did not disappear and it is in part explained by improvements in the diagnosis and treatment of high blood pressure

Expertise des Robert Koch-Instituts für den ersten Präventions- bericht: Hintergrund, Ziele und Herangehensweise

Peer Reviewe

Predicted 10-year risk of cardiovascular mortality in the 40 to 69 year old general population without cardiovascular diseases in Germany

Aims: To estimate the 10-year risk of fatal cardiovascular disease (CVD) in the 40 to 69 year old general population in Germany stratified by sex and to analyze differences between socio-economic status (SES), region and community size in individuals without CVD. The analysis is based on the newly recalibrated SCORE Deutschland risk charts and considered other comorbidities for the classification of the high CVD risk group according to the guidelines of the European Society of Cardiology. Methods and results: In 3,498 participants (40–69 years) from the German Health Examination Survey for Adults 2008–2011 (DEGS1) without a history of CVD (myocardial infarction, coronary heart disease, heart failure, stroke) we estimated the proportion with a low (SCOR

ALIXE: a phase-combination tool for fragment-based molecular replacement.

Fragment-based molecular replacement exploits the use of very accurate yet incomplete search models. In the case of the ARCIMBOLDO programs, consistent phase sets produced from the placement and refinement of fragments with Phaser can be combined in order to increase their signal before proceeding to the step of density modification and autotracing with SHELXE. The program ALIXE compares multiple phase sets, evaluating mean phase differences to determine their common origin, and subsequently produces sets of combined phases that group consistent solutions. In this work, its use on different scenarios of very partial molecular-replacement solutions and its performance after the development of a much-optimized set of algorithms are described. The program is available both standalone and integrated within the ARCIMBOLDO programs. ALIXE has been analysed to identify its rate-limiting steps while exploring the best parameterization to improve its performance and make this software efficient enough to work on modest hardware. The algorithm has been parallelized and redesigned to meet the typical landscape of solutions. Analysis of pairwise correlation between the phase sets has also been explored to test whether this would provide additional insight. ALIXE can be used to exhaustively analyse all partial solutions produced or to complement those already selected for expansion, and also to reduce the number of redundant solutions, which is particularly relevant to the case of coiled coils, or to combine partial solutions from different programs. In each case parallelization and optimization to provide speedup makes its use amenable to typical hardware found in crystallography. ARCIMBOLDO_BORGES and ARCIMBOLDO_SHREDDER now call on ALIXE by default

ALIXE: a phase-combination tool for fragment-based molecular replacement.

Fragment-based molecular replacement exploits the use of very accurate yet incomplete search models. In the case of the ARCIMBOLDO programs, consistent phase sets produced from the placement and refinement of fragments with Phaser can be combined in order to increase their signal before proceeding to the step of density modification and autotracing with SHELXE. The program ALIXE compares multiple phase sets, evaluating mean phase differences to determine their common origin, and subsequently produces sets of combined phases that group consistent solutions. In this work, its use on different scenarios of very partial molecular-replacement solutions and its performance after the development of a much-optimized set of algorithms are described. The program is available both standalone and integrated within the ARCIMBOLDO programs. ALIXE has been analysed to identify its rate-limiting steps while exploring the best parameterization to improve its performance and make this software efficient enough to work on modest hardware. The algorithm has been parallelized and redesigned to meet the typical landscape of solutions. Analysis of pairwise correlation between the phase sets has also been explored to test whether this would provide additional insight. ALIXE can be used to exhaustively analyse all partial solutions produced or to complement those already selected for expansion, and also to reduce the number of redundant solutions, which is particularly relevant to the case of coiled coils, or to combine partial solutions from different programs. In each case parallelization and optimization to provide speedup makes its use amenable to typical hardware found in crystallography. ARCIMBOLDO_BORGES and ARCIMBOLDO_SHREDDER now call on ALIXE by default