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Muscle function is an important denominator of energy balance and metabolic health. Adapting the proteome to energetic challenges, in response to diet or fasting, is facilitated by programs of proteostasis, but the adaptive role of the ubiquitin-proteasome system (UPS) in muscle remains unclear. Here, using a multi-omics approach, we uncover that the distinct metabolic condition of obesity is associated with recalibration of the UPS in muscle. Interestingly, obesity is associated with the activation of the transcription factor Nuclear factor, erythroid derived 2,- like 1 (Nfe2l1, also known as Nrf1), and loss of myocyte Nfe2l1 diminishes proteasomal activity and leads to hyperubiquitylation. Mice lacking Nfe2l1 display hormetic energy metabolism and resistance to diet-induced obesity, associated with a lean phenotype and muscle fiber type switching. In conclusion, we define a new adaptive role for UPS in remolding of muscle proteome and function, which is controlled by fine-tuning of proteasome function by Nfe2l1.

Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), and clock disruption increases susceptibility to non-alcoholic fatty liver disease (NAFLD) progression in rodent models. We therefore investigated whether time-of-day-dependent transcriptome and metabolome are significantly altered in human NAFL and NASH livers. Liver biopsies, collected within an 8 hour- window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, NAFL or NASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, NAFL and NASH livers. We provide here a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in NAFLD. Transcriptomic analysis showed a robustness of core molecular clock components in NAFL and NASH livers. It also revealed stage-specific, time-of-day- dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intra- cellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFa and PPARγ signaling are predicted as important contributors to altered rhythmicity. NAFLD progression to NASH perturbs time-of-day-dependent processes in human livers, while core molecular clock component differential expression is maintained.

Hintergrund: Menschen, die an Multiple Sklerose (MS) erkrankt sind, profitieren nachweislich von regelmäßigem sportlichen Training. Die Trainingseffekte können sich sowohl in einer verbesserten allgemeinen körperlichen Leistungsfähigkeit sowie einer verbesserten Bewältigung der Aktivitäten des täglichen Lebens zeigen als auch auf mögliche Begleiterkrankungen oder den Krankheitsverlauf selbst einwirken. Das Funktionstraining ist ein angeleitetes wöchentliches Training in der Gruppe, welches die Deutsche Multiple Sklerose Gesellschaft (DMSG), Landesverband Hessen e.V., seit 2019 für Menschen mit MS und verwandten Krankheitsbildern anbietet. Das Funktionstraining wird durch den Arzt/die Ärztin für Menschen mit einer chronischen Erkrankung verordnet, um Zugang zu Sport- und Bewegungsangeboten zu ermöglichen sowie konkret die körperliche Leistungsfähigkeit zu erhalten und um Funktionseinschränkungen der Stütz- und Bewegungsorgane zu reduzieren. Methode: Vom 1.10.2019 bis zum 13.3.2020 fand das Funktionstraining an verschiedenen Orten in Hessen statt. Im April 2020 wurden aus den Funktionstrainingsgruppen insgesamt 91 Teilnehmende (TN) und 53 ausgebildete DMSGFunktionstrainer*innen (FTR) schriftlich befragt. TN und FTR bewerteten u. a. die Qualität des Funktionstrainings, die organisatorischen Abläufe, die infrastrukturellen Bedingungen und die Rahmenbedingungen für die Umsetzung des Funktionstrainings. Ergebnisse: Mit einer Rücklaufquote von 86,8 % der befragten TN und 56,6 % der befragten FTR, wurden die Fragebögen von 75 MS-Erkrankten und von 30 FTR für deskriptive Analysen inkludiert. Die Stichprobe der TN wies eine Krankheitsdauer von 17,7 ± 9,9 Jahren, 2,1 ± 1,2 Therapieeinheiten in der Woche und ein Alter von 56,1 ± 7,1 Jahren auf. Das Alter der Stichprobe der FTR betrug 42,73 ± 10,2 Jahre. Die Befragten waren Sport-, Physio-, Ergotherapeut*innen sowie Yogalehrer*innen. Als größte Herausforderung für die FTR zeigte sich die Vereinbarkeit der heterogenen Gruppe, da die unterschiedlichen Einschränkungsgrade in der Mobilität einen hohen Anspruch an die Trainingsorganisation stellen. Sowohl die Stichprobe der TN als auch die der FTR bewerteten die Dynamik und den Austausch in der Gruppe als positiv. Die Inhalte des DMSG-Funktionstrainings empfanden die TN als abwechslungsreich und die FTR wurden als kompetent bewertet. Der Trainingsort war mit einer Entfernung von 8,5 ± 8,4 km für den Großteil der TN gut zu erreichen. Hinsichtlich der Barrierefreiheit variierten die Aussagen. Für die FTR war infrastrukturell die Organisation und Vorbereitung des Funktionstrainings aufwendig. Diskussion: Die Konzeption und Durchführung eines pauschalen Gruppentrainingsangebots für Menschen mit einer Krankheit, die sich in sehr unterschiedlichem Maße auf den Einzelnen auswirkt und individuell stark variierende Symptome hervorruft, stellt eine große Herausforderung dar. Die Ergebnisse der wissenschaftlichen Begleitung einer ersten Entwicklungsphase sind vielversprechend hinsichtlich der Umsetzung und Gestaltung des Trainings. Ebenso besteht eine grundsätzlich hohe Zufriedenheit der TN in Bezug auf das Funktionstraining. Der kritische Punkt liegt vor allem in der (infra-)strukturellen Umsetzung des Trainings und bedarf zukünftig weiterer Optimierung. Die Weiterentwicklung, die sich aus den ersten Evaluationsergebnissen ergibt, sowie die Anpassung an die neuen Gegebenheiten in der Coronapandemie führen zu einer konzeptionellen Überarbeitung des DMSG-Funktionstrainings hin zu einem Online-Angebot. Die wissenschaftliche Begleitung der Projektfortführung stellt weiterhin eine hohe Priorität dar, um einem entsprechenden Qualitätsanspruch in der Gesundheitsversorgung für MS-Erkrankte gerecht zu werden. Abstract Background: People with multiple sclerosis (pwMS) benefit from regular physical exercise. There are positive effects in physical and cognitive performance and in dealing with activities of daily living. In addition, pwMS who exercise regularly prevent themselves from comorbidities such as diabetes, osteoporosis or chronic heart diseases and create biopositive effects in the neurodegenerative disease itself. The head organizations of German health insurances authorized the German Multiple Sclerosis (MS) Society in the state of Hesse providing the ambulant rehabilitation program “DMSG-Funktionstraining” for pwMS in 2019. “DMSGFunktionstraining” (functional training) is an exercise training program developed for people with disabilities or people at risk of disability that takes place weekly and is led by a qualified therapist. It is prescribed by a doctor (duration between 12 and 24 months) and is part of outpatient medical rehabilitation. Methods: From the 1st of October 2019 until the 13th of March 2020 training groups were started throughout the state. In April 2020, 91 participants and 53 qualified coaches were evaluated via questionnaire. Participants and coaches evaluated the value of “DMSG-Funktionstraining,” the organizational strategies, the infrastructural conditions and the framework. Results: The return rate was about 86.8 % by “DMSG-Funktionstraining” participants and 56.6 % by “DMSG-Funktionstraining” coaches. Seventy-five questionnaires by the participants and 30 questionnaires by the coaches were included in descriptive analyses. The sample participant was 56.1 ± 7.1 years old, was diagnosed before 17.7 ± 9.9 years and had 2.1 ± 1.2 therapy units in total per week. The sample coach was 42.73 ± 10.2 years old. The respondents were sport therapists, physiotherapists, ergotherapists and yoga teachers. The big challenge for “DMSG-Funktionstraining” coaches was outlined in the heterogeneity of the group in one common training session. The disabilities were very different in regard to mobility and that meant a high level of training preparation and organization. Both the participants and the coaches evaluated the dynamic and the conversation possibilities in the training group as positive. The training contents were considered to be diversified and the coaches were assessed as competent. The distance between place of living and the training location was about 8.5 ± 8.4 kilometers and seemed to be attainable by the participants. In regard to accessibility, the responses varied. Considering the infrastructure, the organization strategies and the preparation, “Funktionstraining” was described as laborious by the coaches. Discussion: In conclusion, the difficulty with group training for people with a disease that combines highly varied symptomatic outcomes presents a big challenge. The results of this accompanying research in a preliminary project period can be described as auspicious in regard to the implementation of “DMSGFunktionstraining” in the long term. There was a high level of satisfaction among “DMSG-Funktionstraining” participants. The critical point lies especially in the infrastructural implementation and needs further development. Based on the underlying results and the new circumstances due to the corona pandemic, the “DMSG-Funktionstraining” needed a new concept to transfer group training for pwMS to a virtual training room. Furthermore, the accompanying research turns out to have a high priority in order to gain a high-quality level in health care and self-help for pwMS, prospectively.

Tissue injury triggers activation of mesenchymal lineage cells into wound-repairing myofibroblasts, whose unrestrained activity leads to fibrosis. Although this process is largely controlled at the transcriptional level, whether the main transcription factors involved have all been identified has remained elusive. Here, we report multi-omics analyses unraveling Basonuclin 2 (BNC2) as a myofibroblast identity transcription factor. Using liver fibrosis as a model for in-depth investigations, we first show that BNC2 expression is induced in both mouse and human fibrotic livers from different etiologies and decreases upon human liver fibrosis regression. Importantly, we found that BNC2 transcriptional induction is a specific feature of myofibroblastic activation in fibrotic tissues. Mechanistically, BNC2 expression and activities allow to integrate pro-fibrotic stimuli, including TGFβ and Hippo/YAP1 signaling, towards induction of matrisome genes such as those encoding type I collagen. As a consequence, Bnc2 deficiency blunts collagen deposition in livers of mice fed a fibrogenic diet. Additionally, our work establishes BNC2 as potentially druggable since we identified the thalidomide derivative CC-885 as a BNC2 inhibitor. Altogether, we propose that BNC2 is a transcription factor involved in canonical pathways driving myofibroblastic activation in fibrosis.

Increased prefabrication and modularization have resulted in fabrication shops producing more complex assemblies with tighter tolerances. Most measurements in fabrication shops are still done using manual tools that are not accurate enough for engineering tolerance specifications, which can lead to rework. Three dimensional (3D) scanning and measurement systems can provide increased accuracy and digital integration capabilities, however they do not sufficiently support fast and accurate dimensional quality assurance (DQA) of pipe spool fabrication. This is because no dimensional quality assurance methods to date have focused solely on termination points for pipe spool assemblies. In the present article, a new scan-vs-BIM method is developed to accurately estimate termination points for 3D scanned cylindrical assemblies. This method relies on statistically fitting circular features at termination points and thus eliminating conventional issues with target placement for laser trackers and measurement readings for tape measures. The method is tested in an industrial-scale experiment, where 30 pipe spool assemblies were fabricated, and more than 400 quality control steps completed. The accuracy of termination point detection was benchmarked against results from a laser tracker and compared against commercial scan-to-BIM software. Results show that the developed method has an average accuracy of 1.01 mm and is significantly better than the scan-to-BIM software with an average accuracy of 4.75 mm.

Background: NAFLD affects nearly 25% of the global population. Cardiovascular disease (CVD) is the most common cause of death among patients with NAFLD, in line with highly prevalent dyslipidemia in this population. Increased plasma triglyceride (TG)-rich lipoprotein (TRL) concentrations, an important risk factor for CVD, are closely linked with hepatic TG content. Therefore, it is of great interest to identify regulatory mechanisms of hepatic TRL production and remnant uptake in the setting of hepatic steatosis. Approach and Results: To identify liver-regulated pathways linking intrahepatic and plasma TG metabolism, we performed transcriptomic analysis of liver biopsies from two independent cohorts of obese patients. Hepatic encoding apolipoprotein F (APOF) expression showed the fourth-strongest negatively correlation with hepatic steatosis and the strongest negative correlation with plasma TG levels. The effects of adenoviral-mediated human ApoF (hApoF) overexpression on plasma and hepatic TG were assessed in C57BL6/J mice. Surprisingly, hApoF overexpression increased both hepatic very low density lipoprotein (VLDL)-TG secretion and hepatic lipoprotein remnant clearance, associated a similar to 25% reduction in plasma TG levels. Conversely, reducing endogenous ApoF expression reduced VLDL secretion in vivo, and reduced hepatocyte VLDL uptake by similar to 15% in vitro. Transcriptomic analysis of APOF-overexpressing mouse livers revealed a gene signature related to enhanced ApoB-lipoprotein clearance, including increased expression of Ldlr and Lrp1, among others. Conclusion: These data reveal a previously undescribed role for ApoF in the control of plasma and hepatic lipoprotein metabolism by favoring VLDL-TG secretion and hepatic lipoprotein remnant particle clearance.

This study develops a framework for asset management strategy of wastewater collection networks comprised of three interconnected decision-making layers: (1) Visions & Values, (2) Function, and (3) Performance, which are set according to the established concepts of strategic targets, policy levers, sustainability and life cycle. The asset management strategy framework is implemented and validated through demonstration of functionality and value by using the wastewater collection networks of three utilities in Ontario, Canada, to drive management simulations. A borrowing management strategy is used to benchmark the utilities against each other in terms of infrastructure, sociopolitical, and financial performance over a 100-year benchmarking period. It is found that a borrowing management strategy can enable the utility to accelerate their capital works, reduce the volume of inflow and infiltration and their associated expenses and sustainably meet their strategic targets over the life cycle of the assets. Using contour plots, the impact of maximum debt capacity on two infrastructure and financial benchmarking performance indicators is also investigated to explore the “optimal” combination of allowable fee hikes and preferred rehabilitation rates. Furthermore, using a borrowing management strategy, a business case for asset management of wastewater collection networks is developed to explore the “optimal” combination of allowable fee-hike and rehabilitation rates, using a developed inflow and infiltration expenditures (I&IEx) saving ratio contour plots. The results indicate that a borrowing management strategy competes as long as the combinations of allowable fee-hike and preferred rehabilitation rates lead to a positive value of I&IEx saving ratio.

Verifying geometric compliance in offsite manufacturing (OSM) is key for ensuring adequate fit-up, structural integrity, building system performance, and assembly alignment on site. The use of a ge...

Zusammenfassung Einleitung: Eine Vielzahl an Studien weist darauf hin, dass Sport einen positiven Effekt auf verschiedene Symptome der Multiplen Sklerose (MS) hat. Das Ziel dieser Studie war es herauszufinden, welchen Einfluss ein selbstreguliertes sportliches Training auf den Gang, die Gehfähigkeit, die Selbstwirksamkeit, die sportbezogene Selbstwirksamkeit und die Fatigue von MS-Erkrankten hat. Patienten und Methoden: Zunächst erfolgte eine sportorientierte Kompaktschulung (SpoKs) im Wochenend-Workshop-Design für die teilnehmenden MS-Erkrankten, um sie auf eine selbstgesteuerte Trainingsphase vorzubereiten. Daraufhin trainierten die Probanden eigenständig für 12 Wochen. Für die Messungen wurden das Functional Gait Assessment (FGA), der 10-Meter-Gehtest (10MWT), der 6-Minuten-Gehtest (6MWT), die Multiple Sclerosis Self-efficacy Scale (MSSES), die Skala für die Selbstwirksamkeit zur sportlichen Aktivität (SSA) und die Fatigue Severity Scale (FSS) vor (T0) und 12 Wochen nach Beginn der Schulung (T1) durchgeführt. Ergebnisse: Die Ergebnisse zeigten bei allen motorischen Tests signifikante Unterschiede zwischen T0 und T1 (FGA [p < 0,001], 6MWT [p < 0,05], 10MWTs [p < 0,001], 10MWTf [p < 0,05]). Zusätzlich ist eine signifikante Verbesserung der FSS (p < 0,05) nach dem Interventionszeitraum zu erkennen. Hinsichtlich der MSSES- und SSA-Skala zeigten sich keine signifikanten Veränderungen. Diskussion: Ein selbstreguliertes sportliches Training stellt eine Option dar, den Gang und die Gehfähigkeit bei MS-Patienten zu verbessern. Zudem hat es mildernde Effekte auf die Fatigue- Symptomatik dieser Patientengruppe. Künftige Studien sollten den Ansatz des selbstregulierten Trainings aufgreifen, um weitere positive Effekte aufzudecken. Schlüsselwörter: Multiple Sklerose, Sport, Patientenschulung, selbstreguliertes Training Abstract Introduction: Numerous studies indicate a positive effect of exercise training on various symptoms in multiple sclerosis (MS). The aim of this study was to find out the impact of a self-regulated exercise training on gait, walking ability, self-efficacy, self-efficacy towards physical exercise, and fatigue in people with MS. Materials and methods: Initially, the participants completed an education program to be prepared for a period of self-regulated exercise. After the education program, the patients were encouraged to perform selfregulated exercises for twelve weeks. Measurements, using functional gait assessment (FGA), the 10-minute walk test (10MWT), 6-minute walk test (6MWT), Multiple Sclerosis Self-Efficacy Scale (MSSES), self-efficacy towards physical exercise scale (SSA) and Fatigue Severity Scale (FSS), were performed before (T0) and 12 weeks after the education program (T1). Results: All results of the physical tests showed a significant change between T0 and T1 (FGA (p < 0.001), 6MWT (p < 0.05), 10MWTs (p < 0.001), 10MWTf (p < 0.05)). In addition, there was a significant improvement in FSS (p < 0.05) after the intervention period. There were no significant changes on the MSSES and SSA scales. Discussion: Self-regulated exercise training is an option for improving gait and walking ability in patients with MS. Additionally, there were mitigating effects on fatigue in this patient sample. Future studies should continue to investigate the approach of self-regulated training to reveal further positive effects. Keywords: multiple sclerosis, exercise training, patient education, selfregulated exercise training

Background Little is known about the bleeding risk in patients with inflammatory bowel disease (IBD) and venous thromboembolism (VTE) treated with anticoagulation. Our aim was to elucidate the rate of major bleeding (MB) events in a well-defined cohort of patients with IBD during anticoagulation after VTE. Methods This study is a retrospective follow-up analysis of a multicenter cohort study investigating the incidence and recurrence rate of VTE in IBD. Data on MB and IBD- and VTE-related parameters were collected via telephone interview and chart review. The objective of the study was to evaluate the impact of anticoagulation for VTE on the risk of MB by comparing time periods with anticoagulation vs those without anticoagulation. A random-effects Poisson regression model was used. Results We included 107 patients (52 women, 40 with ulcerative colitis, 64 with Crohn disease, and 3 with unclassified IBD) in the study. The overall observation time was 388 patient-years with and 1445 patient-years without anticoagulation. In total, 23 MB events were registered in 21 patients, among whom 13 MB events occurred without anticoagulation and 10 occurred with anticoagulation. No fatal bleeding during anticoagulation was registered. The incidence rate for MB events was 2.6/100 patient-years during periods exposed to anticoagulation and 0.9/100 patient-years during the unexposed time. Exposure to anticoagulation (adjusted incidence rate ratio, 3.7; 95% confidence interval, 1.5-9.0; P = 0.003) and ulcerative colitis (adjusted incidence rate ratio, 3.5; 95% confidence interval, 1.5-8.1; P = 0.003) were independent risk factors for MB events. Conclusion The risk of major but not fatal bleeding is increased in patients with IBD during anticoagulation. Our findings indicate that this risk may be outweighed by the high VTE recurrence rate in patients with IBD.