Exercise and Carotid Properties in the Young–The KiGGS-2 Study

Background: Carotid intima-media thickness (cIMT) and stiffness (cS) are predictive markers of early vascular aging and atherosclerotic risk. This study assessed, whether exercise has protective effects on carotid structure and function or on vascular risk in the young. Methods: Volume and change of exercise (recreational and organized sports participation) of German adolescents and young adults was assessed within the prospective population-study KiGGS at KiGGS-Wave-1 (2009–2012) and KiGGS-Wave-2 (2014–2017) using standardized self-reporting questionnaires. CIMT and cS were measured by real-time B-mode ultrasound sequences with semi-automated edge-detection and automatic electrocardiogram-gated quality control in 2,893 participants (14–28 years, 49.6% female). A cumulative index for atherosclerotic risk (CV-R) included z-scores of mean arterial pressure, triglycerides, total/HDL-cholesterol-ratio, body mass index, and HbA1c. Results: At KiGGS-Wave-2 cross-sectional CV-R but not cS and cIMT was lower in all exercise-groups compared to “no exercise” (B = −0.73, 95%-CI = −1.26 to 0.19, p = 0.008). Longitudinal volume of exercise was negatively associated with CV-R (B = −0.37, 95%-CI = −0.74 to 0.00, p = 0.048) but not with cS and cIMT. Cross-sectional relative risk of elevated CV-R but not cS and cIMT was lower in all exercise-groups compared to “no exercise” (RR = 0.80, 95%-CI = 0.66 to 0.98, p = 0.033). High exercise volumes were associated with lower relative risk of elevated CV-R (RR = 0.80, 95%-CI = 0.65–0.97, p = 0.021) and cS in tendency but not with cIMT. Conclusions: Increased levels of exercise are associated with a better cardiovascular risk profile in young individuals, but not with cS and cIMT. Our study confirms previous recommendations on exercise in this age group without demonstrating a clear benefit on surrogate markers of vascular health.Peer Reviewe

Effect of Acute Ozone Induced Airway Inflammation on Human Sympathetic Nerve Traffic: A Randomized, Placebo Controlled, Crossover Study

Background: Ozone concentrations in ambient air are related to cardiopulmonary perturbations in the aging population. Increased central sympathetic nerve activity induced by local airway inflammation may be one possible mechanism. Methodology/Principal Findings: To elucidate this issue further, we performed a randomized, double-blind, cross-over study, including 14 healthy subjects (3 females, age 22-47 years), who underwent a 3 h exposure with intermittent exercise to either ozone (250 ppb) or clean air. Induced sputum was collected 3 h after exposure. Nineteen to 22 hours after exposure, we recorded ECG, finger blood pressure, brachial blood pressure, respiration, cardiac output, and muscle sympathetic nerve activity (MSNA) at rest, during deep breathing, maximum-inspiratory breath hold, and a Valsalva maneuver. While the ozone exposure induced the expected airway inflammation, as indicated by a significant increase in sputum neutrophils, we did not detect a significant estimated treatment effect adjusted for period on cardiovascular measurements. Resting heart rate (clean air: 59 +/- 62, ozone 60 +/- 62 bpm), blood pressure (clean air: 121 +/- 3/71 +/- 2 mmHg; ozone: 121 +/- 2/71 +/- 2mmHg), cardiac output (clean air: 7.42 +/- 0.29 mmHg; ozone: 7.98 +/- 0.60 l/min), and plasma norepinephrine levels (clean air: 213 +/- 21 pg/ml; ozone: 202 +/- 16 pg/ml), were similar on both study days. No difference of resting MSNA was observed between ozone and air exposure (air: 2362, ozone: 2362 bursts/min). Maximum MSNA obtained at the end of apnea (air: 44 +/- 4, ozone: 48 +/- 4 bursts/min) and during the phase II of the Valsalva maneuver (air: 64 +/- 5, ozone: 57 +/- 6 bursts/min) was similar. Conclusions/Significance: Our study suggests that acute ozone-induced airway inflammation does not increase resting sympathetic nerve traffic in healthy subjects, an observation that is relevant for environmental health. However, we can not exclude that chronic airway inflammation may contribute to sympathetic activation

In-depth analysis of <i>Bacillus subtilis</i> proteome identifies new ORFs and traces the evolutionary history of modified proteins

Abstract Bacillus subtilis is a sporulating Gram-positive bacterium widely used in basic research and biotechnology. Despite being one of the best-characterized bacterial model organism, recent proteomics studies identified only about 50% of its theoretical protein count. Here we combined several hundred MS measurements to obtain a comprehensive map of the proteome, phosphoproteome and acetylome of B. subtilis grown at 37 °C in minimal medium. We covered 75% of the theoretical proteome (3,159 proteins), detected 1,085 phosphorylation and 4,893 lysine acetylation sites and performed a systematic bioinformatic characterization of the obtained data. A subset of analyzed MS files allowed us to reconstruct a network of Hanks-type protein kinases, Ser/Thr/Tyr phosphatases and their substrates. We applied genomic phylostratigraphy to gauge the evolutionary age of B. subtilis protein classes and revealed that protein modifications were present on the oldest bacterial proteins. Finally, we performed a proteogenomic analysis by mapping all MS spectra onto a six-frame translation of B. subtilis genome and found evidence for 19 novel ORFs. We provide the most extensive overview of the proteome and post-translational modifications for B. subtilis to date, with insights into functional annotation and evolutionary aspects of the B. subtilis genome

Key Data Elements in Myeloid Leukemia

Data standards consisting of key data elements for clinical routine and trial documentation harmonize documentation within and across different health care institutions making documentation more efficient and improving scientific data analysis. This work focusses on the field of myeloid leukemia (ML), where a semantic core of common data elements (CDEs) in routine and trial documentation is established by automatic UMLS-based form analysis of existing documentation models. These CDEs (n=227) were initially reviewed and commented by leukemia experts before they were systematically surveyed by an international voting process through seven hematologists of four countries. The total agreement score was 86%. 116 elements (51%) of these share an agreement score of 100%. This work generated CDEs with language-independent semantic codes and international clinical expert review to build a first approach towards an international data standard for ML. A first version of the CDE list is implemented in the data standard Operational Data Model and additional other data formats for reuse in different medical information systems

The FA women's super league : framing developments in elite women's football

In 2009, the Football Association (FA), the national governing body of football in England, announced its plan to introduce the country's first semi-professional women's elite league. Launched in 2010 as the FA Women's Super League (FA WSL), its introduction provided both an opportunity to research whether this evidenced a change of position for the women's elite game within footballing narratives and also to examine the place of the FA within these. This study adopted a critical sociological feminist approach to deconstruct the assumptions, values and practices that frame the female game and the introduction of the FA WSL, while providing new insights into the role of the sport's governing organisation in defining elite women's football. Through observations at matches and interviews with people working within the women's game, an examination of the development and introduction of the FA WSL was undertaken, with valuable early insights provided into the first three years of the new League. The study identified that the introduction of the FA WSL was impacted upon by the complex, closed and gendered nature of the FA's organisational structure. The new League adhered to traditional societal concepts of hegemonic masculinity, heteronormativity and liberal approaches to gender equality. The study also found that the new elite women's structures required the clubs who gained entry into the FA WSL to adhere to commercialised, spectacularised and commodified values which dominate the men's game and neo liberal societal narratives. The increased inclusion of females into elite football structures did not profoundly disrupt traditional discourses or provide evidence of a fundamental challenge to gender inequality in the game

Prognostic impact of <i>CEBPA </i>mutational subgroups in adult AML

Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIP InDel), frameshift InDel or nonsense mutations inducing translational stop (bZIP STOP) or single base-pair missense alterations (bZIP ms), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIP InDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIP InDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIP InDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIP InDel mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIP ms). (Figure presented.)</p

Proteogenomics connects somatic mutations to signalling in breast cancer

Somatic mutations have been extensively characterized in breast cancer, but the effects of these genetic alterations on the proteomic landscape remain poorly understood. We describe quantitative mass spectrometry-based proteomic and phosphoproteomic analyses of 105 genomically annotated breast cancers of which 77 provided high-quality data. Integrated analyses allowed insights into the somatic cancer genome including the consequences of chromosomal loss, such as the 5q deletion characteristic of basal-like breast cancer. The 5q trans effects were interrogated against the Library of Integrated Network-based Cellular Signatures, thereby connecting CETN3 and SKP1 loss to elevated expression of EGFR, and SKP1 loss also to increased SRC. Global proteomic data confirmed a stromal-enriched group in addition to basal and luminal clusters and pathway analysis of the phosphoproteome identified a G Protein-coupled receptor cluster that was not readily identified at the mRNA level. Besides ERBB2, other amplicon-associated, highly phosphorylated kinases were identified, including CDK12, PAK1, PTK2, RIPK2 and TLK2. We demonstrate that proteogenomic analysis of breast cancer elucidates functional consequences of somatic mutations, narrows candidate nominations for driver genes within large deletions and amplified regions, and identifies therapeutic targets

Prognostic impact of CEBPA mutational subgroups in adult AML

Despite recent refinements in the diagnostic and prognostic assessment of CEBPA mutations in AML, several questions remain open, i.e. implications of different types of basic region leucin zipper (bZIP) mutations, the role of co-mutations and the allelic state. Using pooled primary data analysis on 1010 CEBPA-mutant adult AML patients, a comparison was performed taking into account the type of mutation (bZIP: either typical in-frame insertion/deletion (InDel) mutations (bZIPInDel), frameshift InDel or nonsense mutations inducing translational stop (bZIPSTOP) or single base-pair missense alterations (bZIPms), and transcription activation domain (TAD) mutations) and the allelic state (single (smCEBPA) vs. double mutant (dmCEBPA)). Only bZIPInDel patients had significantly higher rates of complete remission and longer relapse free and overall survival (OS) compared with all other CEBPA-mutant subgroups. Moreover, co-mutations in bZIPInDel patients (e.g. GATA2, FLT3, WT1 as well as ELN2022 adverse risk aberrations) had no independent impact on OS, whereas in non-bZIPInDel patients, grouping according to ELN2022 recommendations added significant prognostic information. In conclusion, these results demonstrate bZIPInDel mutations to be the major independent determinant of outcome in CEBPA-mutant AML, thereby refining current classifications according to WHO (including all dmCEBPA and smCEBPA bZIP) as well as ELN2022 and ICC recommendations (including CEBPA bZIPms)