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Background While eukaryotic noncoding RNAs have recently received intense scrutiny, it is becoming clear that bacterial transcription is at least as pervasive. Bacterial small RNAs and antisense RNAs (sRNAs) are often assumed to be noncoding, due to their lack of long open reading frames (ORFs). However, there are numerous examples of sRNAs encoding for small proteins, whether or not they also have a regulatory role at the RNA level. Methods Here, we apply flexible machine learning techniques based on sequence features and comparative genomics to quantify the prevalence of sRNA ORFs under natural selection to maintain protein-coding function in 14 phylogenetically diverse bacteria. Importantly, we quantify uncertainty in our predictions, and follow up on them using mass spectrometry proteomics and comparison to datasets including ribosome profiling. Results A majority of annotated sRNAs have at least one ORF between 10 and 50 amino acids long, and we conservatively predict that 409±191.7 unannotated sRNA ORFs are under selection to maintain coding (mean estimate and 95% confidence interval), an average of 29 per species considered here. This implies that overall at least 10.3±0.5 % of sRNAs have a coding ORF, and in some species around 20% do. 165±69 of these novel coding ORFs have some antisense overlap to annotated ORFs. As experimental validation, many of our predictions are translated in published ribosome profiling data and are identified via mass spectrometry shotgun proteomics. B. subtilis sRNAs with coding ORFs are enriched for high expression in biofilms and confluent growth, and S. pneumoniae sRNAs with coding ORFs are involved in virulence. sRNA coding ORFs are enriched for transmembrane domains and many are predicted novel components of type I toxin/antitoxin systems. Conclusions We predict over two dozen new protein-coding genes per bacterial species, but crucially also quantified the uncertainty in this estimate. Our predictions for sRNA coding ORFs, along with predicted novel type I toxins and tools for sorting and visualizing genomic context, are freely available in a user-friendly format at http://disco-bac.web.pasteur.fr. We expect these easily-accessible predictions to be a valuable tool for the study not only of bacterial sRNAs and type I toxin-antitoxin systems, but also of bacterial genetics and genomics.

Introduction Telemedicine is being used in an increasing number of healthy lifestyle intervention studies in preventive cardiology. However, the optimal telemedicine-based approach for patients with cardiovascular disease remains unclear. Therefore, the aim of this systematic review is to identify which design features are associated with the acceptance and efficacy of telemedicine in this specific patient population. Methods The databases PubMed/MEDLINE, Embase and the Web of Science Core Collection were searched from 5 October 2010 to 5 October 2020. This systematic review only included randomized controlled or quasi-randomized controlled trials with a comparator to a telemedicine-based intervention group and a designated measure of adherence. We adopted a narrative synthesis approach to define telemedical design features, which were clustered into three main categories (social, exercise related and barrier removal) and compared to adherence (graded as good, medium and bad) and primary outcomes (significant improvement, no significant change). Results We screened a total of 865 records, of which 14 were included in this review, containing 13 identified design features. In 8 studies (57.1%), adherence was graded as good (4 studies medium, 2 studies bad). A positive primary outcome occurred in 10 (71.4%) studies. Personal contact showed the most pronounced (while not statistically significant) positive association with adherence and study outcomes. Conclusion Given the remote nature of telemedical lifestyle intervention studies, including recurring personal contact in the intervention seems to be a key factor in ensuring that adherence levels remain comparable to those seen in centre-based interventions.

β-Site APP-cleaving enzyme 1 (BACE1) inhibition is considered one of the most promising therapeutic strategies for Alzheimer’s disease, but current BACE1 inhibitors also block BACE2. As the localization and function of BACE2 in the brain remain unknown, it is difficult to predict whether relevant side effects can be caused by off-target inhibition of BACE2 and whether it is important to generate BACE1-specific inhibitors. Here, we show that BACE2 is expressed in discrete subsets of neurons and glia throughout the adult mouse brain. We uncover four new substrates processed by BACE2 in cultured glia: vascular cell adhesion molecule 1, delta and notch-like epidermal growth factor–related receptor, fibroblast growth factor receptor 1, and plexin domain containing 2. Although these substrates were not prominently cleaved by BACE2 in healthy adult mice, proinflammatory TNF induced a drastic increase in BACE2-mediated shedding of vascular cell adhesion molecule 1 in CSF. Thus, although under steady-state conditions the effect of BACE2 cross-inhibition by BACE1-directed inhibitors is rather subtle, it is important to consider that side effects might become apparent under physiopathological conditions that induce TNF expression.

IntroductionGuidelines recommend lifestyle intervention in chronic ischaemic heart disease (CIHD) and type 2 diabetes mellitus (T2DM). However, evidence from randomised controlled trials is scarce in patients with combined entities.Methods and analysisThe Lifestyle Intervention in Chronic Ischaemic Heart Disease and Type 2 Diabetes (LeIKD) trial is a prospective, multicentre study that will randomise (1:1) patients with CIHD (ICD-10: I20-I25) and T2DM (ICD-10: E11) from one health insurance company into a lifestyle intervention (LS) or usual care (UC). Active LS consists of an individual combined exercise programme of strength and endurance training and nutritional counselling with regular feedback for 6 months. Intervention is supported by telemedicine. Follow-up without individualised feedback will continue for 6 months. The study aims to investigate whether an individualised telemedical supported LS intervention is superior to UC in improving cardiovascular risk factors, physical activity, quality of life, health literacy, major cardiovascular events and health economics in patients with both CIHD and T2DM. Primary endpoint is the change in HbA1c from baseline to 6 months.Ethics and disseminationThe study has been approved by the ethics committee of the Technical University of Munich (registration number: 144/18-S) and at each study site. The study will be conducted according to the World Medical Association Declaration of Helsinki, and results will be published in articles and reports. It is funded by the Federal Joint Committee (www.innovationsfonds.g-ba.de), reference number 01NVF17015, which has no impact on data collection, analysis or interpretation. Dissemination is independent of the funding source.Trial registration numberClinical trials.gov identifier: NCT03835923. German registry for clinical studies (DRKS): DRKS00015140.

Aims Exercise training improves aerobic capacity (V̇O2peak) in patients with heart failure and preserved ejection fraction (HFpEF), but underlying mechanisms remain unclear. We aimed to evaluate whether exercise training could improve systolic and diastolic function during exercise. Methods This was a substudy of the multicentre Optimizing Exercise Training in HFpEF (OptimEx‐Clin) trial, in which 180 patients with HFpEF were randomized 1:1:1 to guideline control, moderate continuous training or high‐intensity interval training. All patients included at two out of five participating sites underwent exercise echocardiography at baseline and 3 months. Patients of both training groups were pooled and compared with guideline control. Results A total of 61 patients (mean age 73 ± 7 years, 72% female) were included. At baseline, E/e′ increased from 17.0 ± 5.7 to 19.5 ± 6.1 and systolic pulmonary artery pressure from 31 ± 8 to 51 ± 11 mmHg (both P < 0.001). Right ventricular function did not change significantly (maximal tricuspid annular plane systolic excursion 24.7 ± 4.0 mm, P = 0.051 vs. baseline). At 3 months, patients randomized to exercise training improved V̇O2peak (control +0.2, training +2.7 mL/kg/min, P = 0.006) and demonstrated small but significant improvements in exercise E/e′ (control 21.7 ± 7.5 to 22.8 ± 9.2, training 18.3 ± 5.0 to 17.2 ± 4.1, P = 0.044). No significant changes were observed in ejection fraction, mitral or tricuspid annular plane systolic excursion, S′, A′ or systolic pulmonary artery pressure (P > 0.05). Changes in E/e′ were not associated with the change in V̇O2peak. Conclusions In patients with HFpEF, exercise echocardiography revealed increases in filling pressures as well as a failure to augment right ventricular function during exercise. After 3 months of exercise training, HFpEF patients demonstrated a small improvement in diastolic function (exercise E/e′), but this did not explain the improved aerobic capacity. Training‐induced change of diastolic function in HFpEF. HIIT, high‐intensity interval training; HFpEF, heart failure with preserved ejection fraction; LVEF, left ventricular ejection fraction; MCT, moderate continuous training; TAPSE, tricuspid annular plane systolic excursion; V̇O2peak, peak oxygen uptake.

Aims Exercise training (ET) has been consistently shown to increase peak oxygen consumption (V̇O2) in patients with heart failure with preserved ejection fraction (HFpEF); however, inter‐individual responses vary significantly. Because it is unlikely that ET‐induced improvements in peak V̇O2 are significantly mediated by an increase in peak heart rate (HR), we aimed to investigate whether baseline peak O2‐pulse (V̇O2 × HR−1, reflecting the product of stroke volume and arteriovenous oxygen difference), not baseline peak V̇O2, is inversely associated with the change in peak V̇O2 (adjusted by body weight) following ET versus guideline control (CON) in patients with HFpEF. Methods and results This was a secondary analysis of the OptimEx‐Clin (Optimizing Exercise Training in Prevention and Treatment of Diastolic Heart Failure, NCT02078947) trial, including all 158 patients with complete baseline and 3 month cardiopulmonary exercise testing measurements (106 ET, 52 CON). Change in peak V̇O2 (%) was analysed as a function of baseline peak V̇O2 and its determinants (absolute peak V̇O2, peak O2‐pulse, peak HR, weight, haemoglobin) using robust linear regression analyses. Mediating effects on change in peak V̇O2 through changes in peak O2‐pulse, peak HR and weight were analysed by a causal mediation analysis with multiple correlated mediators. Change in submaximal exercise tolerance (V̇O2 at the ventilatory threshold, VT1) was analysed as a secondary endpoint. Among 158 patients with HFpEF (66% female; mean age, 70 ± 8 years), changes in peak O2‐pulse explained approximately 72% of the difference in changes in peak V̇O2 between ET and CON [10.0% (95% CI, 4.1 to 15.9), P = 0.001]. There was a significant interaction between the groups for the influence of baseline peak O2‐pulse on change in peak V̇O2 (interaction P = 0.04). In the ET group, every 1 mL/beat higher baseline peak O2‐pulse was associated with a decreased mean change in peak V̇O2 of −1.45% (95% CI, −2.30 to −0.60, P = 0.001) compared with a mean change of −0.08% (95% CI, −1.11 to 0.96, P = 0.88) following CON. None of the other factors showed significant interactions with study groups for the change in peak V̇O2 (P > 0.05). Change in V̇O2 at VT1 was not associated with any of the investigated factors (P > 0.05). Conclusions In patients with HFpEF, the easily measurable peak O2‐pulse seems to be a good indicator of the potential for improving peak V̇O2 through exercise training. While changes in submaximal exercise tolerance were independent of baseline peak O2‐pulse, patients with high O2‐pulse may need to use additional therapies to significantly increase peak V̇O2.

The commercial availability of high quality 150 mm 4H SiC wafers has aided in the growth of SiC power device fabrication. The progress of 150 mm 4H SiC wafer development at Dow Corning is reviewed. Defect densities compare well to those typical for 100 mm wafers, with even lower threading screw dislocation densities observed in 150 mm wafers. Resistivity data shows a comparable range from 0.012 – 0.025 ohm.cm, and excellent shape control is highlighted for wafer thicknesses of 350 μm and 500 μm.

To reduce potential mis-registration from differences in the breathing pattern between two complementary PET and CT data sets, patients are generally allowed to breathe quietly during a dual-modality scan using a combined PET/CT tomograph. Frequently, however, local mis-registration between the CT and the PET is observed. We have evaluated the appearance, magnitude, and frequency of respiration-induced artefacts in CT images of dual-modality PET/CT studies of 62 patients. Combined PET/CT scans during normal respiration were acquired in 43 subjects using single- or dual-slice CT. Nineteen patients were scanned with a special breathing protocol (limited breath-hold technique) on a single-slice PET/CT tomograph. All subjects were injected with approximately 370 MBq of FDG, and PET/CT scanning commenced 1 h post injection. The CT images were reconstructed and, after appropriate scaling, used for on-line attenuation correction of the PET emission data. We found that respiration artefacts can occur in the majority of cases if no respiration protocol is used. When applying the limited breath-hold technique, the frequency of severe artefacts in the area of the diaphragm was reduced by half, and the spatial extent of respiration-induced artefacts was reduced by at least 40% compared with the acquisition protocols without any breathing instructions. In conclusion, special breathing protocols are effective and should be used for CT scans as part of combined imaging protocols using a dual-modality PET/CT tomograph. The results of this study can also be applied to multi-slice CT to potentially reduce further breathing artefacts in PET/CT imaging and to improve overall image quality.

Synchrotron white beam x-ray topography images show that faint needle-like surface morphological features observed on the Si-face of 4H-SiC homoepitaxial layers using Nomarski optical microscopy are associated with V-shaped stacking faults in the epilayer. KOH etching of the V-shaped defects reveals small oval pits connected by a shallow trench which correspond to the surface intersections of two partial dislocations and the stacking fault connecting them. Transmission electron microscopy (TEM) specimens from regions containing the V-shaped defects prepared using focused ion beam milling show stacking sequences of (85), (50) and (63) at the faulted region using high resolution TEM. In order to study the formation mechanism of the V-shaped defects, low dislocation density 4H-SiC substrates were chosen for epitaxial growth, and the corresponding regions before and after epitaxy growth are compared in SWBXT images. It is found that no defects in the substrate are directly associated with the formation of the V-shaped defects. Simulation results of the contrast from the two partial dislocations associated with V-shaped defects in synchrotron monochromatic beam x-ray topography reveals the opposite sign nature of their Burgers vectors. Therefore, a mechanism of 2D nucleation during epitaxy growth is postulated for the formation of the V-shaped defects, which requires elimination of non-sequential c /4[0001] bilayers from the original structure to create the observed faulted stacking sequence.

Fibroblasts are the main matrix producing cells of the dermis and are also strongly regulated by their matrix environment which can be used to improve and guide skin wound healing processes. Here, we systematically investigated the molecular effects on primary dermal fibroblasts in response to high-sulfated hyaluronan [HA] (hsHA) by quantitative proteomics. The comparison of non- and high-sulfated HA revealed regulation of 84 of more than 1,200 quantified proteins. Based on gene enrichment we found that sulfation of HA alters extracellular matrix remodeling. The collagen degrading enzymes cathepsin K, matrix metalloproteinases-2 and -14 were found to be down-regulated on hsHA. Additionally protein expression of thrombospondin-1, decorin, collagen types I and XII were reduced, whereas the expression of trophoblast glycoprotein and collagen type VI were slightly increased. This study demonstrates that global proteomics provides a valuable tool for revealing proteins involved in molecular effects of growth substrates for further material optimization.