👤 Steffen Scheer

Disrupted diurnal rest-activity rhythms (RAR), that is, daily 24-h patterns of rest and activity, have been associated with fatigue and decreased quality of life among survivors of colorectal cancer (CRC). To identify potential targets for interventions to improve RAR, we investigated longitudinal associations of time spent in sedentary behavior and physical activity with RAR parameters after CRC treatment. In a prospective cohort study, repeated measurements were performed among 268 survivors of stage I-III CRC at 6 weeks, 6 months, and 1, 2, and 5 years after treatment. Thigh-worn accelerometers were used to determine hours/day spent in sedentary behavior, standing, and total physical activity during waking time, as well as RAR parameters including mesor, amplitude, circadian quotient (CQ), dichotomy index (I < O) and 24 h-autocorrelation (R24). Self-reported light-intensity physical activity (LPA) and moderate-to-vigorous physical activity (MVPA) were determined via the validated SQUASH questionnaire. Longitudinal associations were analyzed using confounder-adjusted linear mixed models. More sedentary time was statistically significantly associated with a lower mesor, amplitude, I < O and R24 over the 5-year post-treatment period. More standing time was associated with a higher mesor, amplitude, CQ, and I < O but not with R24. Higher levels of objectively assessed total physical activity as well as self-reported MVPA were associated with higher values for all RAR parameters. LPA was not associated with any of the RAR parameters. In the years after CRC treatment, less sedentary behavior and more standing and physical activity were generally associated with higher RAR parameters indicating a more robust rhythm. Future studies should provide more insight into causality of these associations as RAR may be a potential new target for interventions to reduce fatigue after CRC.Trial registration: EnCoRe study NL6904 (https://www.Onderzoekmetmensen.nl/). Show less

Chronic sleep disturbances, associated with cardiometabolic diseases, psychiatric disorders and all-cause mortality, affect 25-30% of adults worldwide. Although environmental factors contribute substantially to self-reported habitual sleep duration and disruption, these traits are heritable and identification of the genes involved should improve understanding of sleep, mechanisms linking sleep to disease and development of new therapies. We report single- and multiple-trait genome-wide association analyses of self-reported sleep duration, insomnia symptoms and excessive daytime sleepiness in the UK Biobank (n = 112,586). We discover loci associated with insomnia symptoms (near MEIS1, TMEM132E, CYCL1 and TGFBI in females and WDR27 in males), excessive daytime sleepiness (near AR-OPHN1) and a composite sleep trait (near PATJ (INADL) and HCRTR2) and replicate a locus associated with sleep duration (at PAX8). We also observe genetic correlation between longer sleep duration and schizophrenia risk (r Show less

Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) can both be due to mutations in the genes encoding β-myosin heavy chain (MYH7) or cardiac myosin-binding protein C (MYBPC3). The aim of the present study was to determine the prevalence and spectrum of mutations in both genes in German HCM and DCM patients and to establish novel genotype-to-phenotype correlations. Coding exons and intron flanks of the two genes MYH7 and MYBPC3 of 236 patients with HCM and 652 patients with DCM were sequenced by conventional and array-based means. Clinical records were established following standard protocols. Mutations were detected in 41 and 11% of the patients with HCM and DCM, respectively. Differences were observed in the frequency of splice site and frame-shift mutations in the gene MYBPC3, which occurred more frequently (P< 0.02, P< 0.001, respectively) in HCM than in DCM, suggesting that cardiac myosin-binding protein C haploinsufficiency predisposes to hypertrophy rather than to dilation. Additional novel genotype-to-phenotype correlations were found in HCM, among these a link between MYBPC3 mutations and a particularly large thickness of the interventricular septum (P= 0.04 vs. carriers of a mutation in MYH7). Interestingly, this correlation and a link between MYH7 mutations and a higher degree of mitral valve regurgitation held true for both HCM and DCM, indicating that the gene affected by a mutation may determine the magnitude of structural and functional alterations in both HCM and DCM. A large clinical-genetic study has unravelled novel genotype-to-phenotype correlations in HCM and DCM which warrant future investigation of both the underlying mechanisms and the prognostic use. Show less

Recent evidence indicates that acquisition of artery or vein identity during vascular development is governed, in part, by genetic mechanisms. The artery-specific expression of a number of Notch signaling genes in mouse and zebrafish suggests that this pathway may play a role in arterial-venous cell fate determination during vascular development. We show that loss of Notch signaling in zebrafish embryos leads to molecular defects in arterial-venous differentiation, including loss of artery-specific markers and ectopic expression of venous markers within the dorsal aorta. Conversely, we find that ectopic activation of Notch signaling leads to repression of venous cell fate. Finally, embryos lacking Notch function exhibit defects in blood vessel formation similar to those associated with improper arterial-venous specification. Our results suggest that Notch signaling is required for the proper development of arterial and venous blood vessels, and that a major role of Notch signaling in blood vessels is to repress venous differentiation within developing arteries. Movies available on-line Show less