Genome-wide association analysis of insomnia complaints identifies risk genes and genetic overlap with psychiatric and metabolic traits.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked FilesPersistent insomnia is among the most frequent complaints in general practice. To identify genetic factors for insomnia complaints, we performed a genome-wide association study (GWAS) and a genome-wide gene-based association study (GWGAS) in 113,006 individuals. We identify three loci and seven genes associated with insomnia complaints, with the associations for one locus and five genes supported by joint analysis with an independent sample (n = 7,565). Our top association (MEIS1, P < 5 × 10-8) has previously been implicated in restless legs syndrome (RLS). Additional analyses favor the hypothesis that MEIS1 exhibits pleiotropy for insomnia and RLS and show that the observed association with insomnia complaints cannot be explained only by the presence of an RLS subgroup within the cases. Sex-specific analyses suggest that there are different genetic architectures between the sexes in addition to shared genetic factors. We show substantial positive genetic correlation of insomnia complaints with internalizing personality traits and metabolic traits and negative correlation with subjective well-being and educational attainment. These findings provide new insight into the genetic architecture of insomnia.Netherlands Organization for Scientific Research NWO Brain & Cognition 433-09-228 European Research Council ERC-ADG-2014-671084 INSOMNIA Netherlands Scientific Organization (NWO) VU University (Amsterdam, the Netherlands) Dutch Brain Foundation Helmholtz Zentrum Munchen - German Federal Ministry of Education and Research state of Bavaria German Migraine & Headache Society (DMKG) Almirall AstraZeneca Berlin Chemie Boehringer Boots Health Care GlaxoSmithKline Janssen Cilag McNeil Pharma MSD Sharp Dohme Pfizer Institute of Epidemiology and Social Medicine at the University of Munster German Ministry of Education and Research (BMBF) German Restless Legs Patient Organisation (RLS Deutsche Restless Legs Vereinigung) Swiss RLS Patient Association (Schweizerische Restless Legs Selbsthilfegruppe

Sleep, vigilance, and thermosensitivity

The regulation of sleep and wakefulness is well modeled with two underlying processes: a circadian and a homeostatic one. So far, the parameters and mechanisms of additional sleep-permissive and wake-promoting conditions have been largely overlooked. The present overview focuses on one of these conditions: the effect of skin temperature on the onset and maintenance of sleep, and alertness. Skin temperature is quite well suited to provide the brain with information on sleep-permissive and wake-promoting conditions because it changes with most if not all of them. Skin temperature changes with environmental heat and cold, but also with posture, environmental light, danger, nutritional status, pain, and stress. Its effect on the brain may thus moderate the efficacy by which the clock and homeostat manage to initiate or maintain sleep or wakefulness. The review provides a brief overview of the neuroanatomical pathways and physiological mechanisms by which skin temperature can affect the regulation of sleep and vigilance. In addition, current pitfalls and possibilities of practical applications for sleep enhancement are discussed, including the recent finding of impaired thermal comfort perception in insomniacs

Link-Prediction to Tackle the Boundary Specification Problem in Social Network Surveys

Diffusion processes in social networks often cause the emergence of global phenomena from individual behavior within a society. The study of those global phenomena and the simulation of those diffusion processes frequently require a good model of the global network. However, survey data and data from online sources are often restricted to single social groups or features, such as age groups, single schools, companies, or interest groups. Hence, a modeling approach is required that extrapolates the locally restricted data to a global network model. We tackle this Missing Data Problem using Link-Prediction techniques from social network research, network generation techniques from the area of Social Simulation, as well as a combination of both. We found that techniques employing less information may be more adequate to solve this problem, especially when data granularity is an issue. We validated the network models created with our techniques on a number of real-world networks, investigating degree distributions as well as the likelihood of links given the geographical distance between two nodes

Increased OXPHOS activity precedes rise in glycolytic rate in H-RasV12/E1A transformed fibroblasts that develop a Warburg phenotype.

Contains fulltext : 80248.pdf (publisher's version ) (Open Access)BACKGROUND: The Warburg phenotype in cancer cells has been long recognized, but there is still limited insight in the consecutive metabolic alterations that characterize its establishment. We obtained better understanding of the coupling between metabolism and malignant transformation by studying mouse embryonic fibroblast-derived cells with loss-of-senescence or H-RasV12/E1A-transformed phenotypes at different stages of oncogenic progression. RESULTS: Spontaneous immortalization or induction of senescence-bypass had only marginal effects on metabolic profiles and viability. In contrast, H-RasV12/E1A transformation initially caused a steep increase in oxygen consumption and superoxide production, accompanied by massive cell death. During prolonged culture in vitro, cell growth rate increased gradually, along with tumor forming potential in in vitro anchorage-independent growth assays and in vivo tumor formation assays in immuno-deficient mice. Notably, glucose-to-lactic acid flux increased with passage number, while cellular oxygen consumption decreased. This conversion in metabolic properties was associated with a change in mitochondrial NAD+/NADH redox, indicative of decreased mitochondrial tricarboxic acid cycle and OXPHOS activity. CONCLUSION: The high rate of oxidative metabolism in newly transformed cells is in marked contrast with the high glycolytic rate in cells in the later tumor stage. In our experimental system, with cells growing under ambient oxygen conditions in nutrient-rich media, the shift towards this Warburg phenotype occurred as a step-wise adaptation process associated with augmented tumorigenic capacity and improved survival characteristics of the transformed cells. We hypothesize that early-transformed cells, which potentially serve as founders for new tumor masses may escape therapies aimed at metabolic inhibition of tumors with a fully developed Warburg phenotype

Sleep estimates using microelectromechanical systems (MEMS).

Study Objectives: Although currently more affordable than polysomnography, actigraphic sleep estimates have disadvantages. Brand-specific differences in data reduction impede pooling of data in large-scale cohorts and may not fully exploit movement information. Sleep estimate reliability might improve by advanced analyses of three-axial, linear accelerometry data sampled at a high rate, which is now feasible using microelectrome-chanical systems (MEMS). However, it might take some time before these analyses become available. To provide ongoing studies with backward compatibility while already switching from actigraphy to MEMS accelerometry, we designed and validated a method to transform accelerometry data into the traditional actigraphic movement counts, thus allowing for the use of validated algorithms to estimate sleep parameters. Design: Simultaneous actigraphy and MEMS-accelerometry recording. Setting: Home, unrestrained. Participants: Fifteen healthy adults (23-36 y, 10 males, 5 females). Interventions: None. Measurements: Actigraphic movement counts/15-sec and 50-Hz digitized MEMS-accelerometry. Analyses: Passing-Bablok regression optimized transformation of MEMS-accelerometry signals to movement counts. Kappa statistics calculated agreement between individual epochs scored as wake or sleep. Bland-Altman plots evaluated reliability of common sleep variables both between and within actigraphs and MEMS-accelerometers. Results: Agreement between epochs was almost perfect at the low, medium, and high threshold (kappa = 0.87 ± 0.05, 0.85 ± 0.06, and 0.83 ± 0.07). Sleep parameter agreement was better between two MEMS-accelerometers or a MEMS-accelerometer and an actigraph than between two actigraphs. Conclusions: The algorithm allows for continuity of outcome parameters in ongoing actigraphy studies that consider switching to MEMS-accel-erometers. Its implementation makes backward compatibility feasible, while collecting raw data that, in time, could provide better sleep estimates and promote cross-study data pooling

Nuclear envelope rupture and repair during cancer cell migration

During cancer metastasis, tumor cells penetrate tissues through tight interstitial spaces, which requires extensive deformation of the cell and its nucleus. Here, we investigated mammalian tumor cell migration in confining microenvironments in vitro and in vivo. Nuclear deformation caused localized loss of nuclear envelope (NE) integrity, which led to the uncontrolled exchange of nucleo-cytoplasmic content, herniation of chromatin across the NE, and DNA damage. The incidence of NE rupture increased with cell confinement and with depletion of nuclear lamins, NE proteins that structurally support the nucleus. Cells restored NE integrity using components of the endosomal sorting complexes required for transport III (ESCRT III) machinery. Our findings indicate that cell migration incurs substantial physical stress on the NE and its content and requires efficient NE and DNA damage repair for cell survival