This prognostic study evaluates whether psychosis transition can be predicted in patients with clinical high-risk syndromes or recent-onset depression by multimodal machine learning that optimally integrates clinical and neurocognitive data, structural magnetic resonance imaging, and polygenic risk scores for schizophrenia.

Skeletal muscle tissue demonstrates global hypermethylation with age. However, methylome changes across the time-course of differentiation in aged human muscle derived cells, and larger coverage arrays in aged muscle tissue have not been undertaken. Using 850K DNA methylation arrays we compared the methylomes of young (27 ± 4.4 years) and aged (83 ± 4 years) human skeletal muscle and that of young/aged heterogenous muscle-derived human primary cells (HDMCs) over several time points of differentiation (0, 72 h, 7, 10 days). Aged muscle tissue was hypermethylated compared with young tissue, enriched for; pathways-in-cancer (including; focal adhesion, MAPK signaling, PI3K-Akt-mTOR signaling, p53 signaling, Jak-STAT signaling, TGF-beta and notch signaling), rap1-signaling, axon-guidance and hippo-signalling. Aged cells also demonstrated a hypermethylated profile in pathways; axon-guidance, adherens-junction and calcium-signaling, particularly at later timepoints of myotube formation, corresponding with reduced morphological differentiation and reductions in MyoD/Myogenin gene expression compared with young cells. While young cells showed little alterations in DNA methylation during differentiation, aged cells demonstrated extensive and significantly altered DNA methylation, particularly at 7 days of differentiation and most notably in focal adhesion and PI3K-AKT signalling pathways. While the methylomes were vastly different between muscle tissue and HDMCs, we identified a small number of CpG sites showing a hypermethylated state with age, in both muscle tissue and cells on genes KIF15, DYRK2, FHL2, MRPS33, ABCA17P. Most notably, differential methylation analysis of chromosomal regions identified three locations containing enrichment of 6–8 CpGs in the HOX family of genes altered with age. With HOXD10, HOXD9, HOXD8, HOXA3, HOXC9, HOXB1, HOXB3, HOXC-AS2 and HOXC10 all hypermethylated in aged tissue. In aged cells the same HOX genes (and additionally HOXC-AS3) displayed the most variable methylation at 7 days of differentiation versus young cells, with HOXD8, HOXC9, HOXB1 and HOXC-AS3 hypermethylated and HOXC10 and HOXC-AS2 hypomethylated. We also determined that there was an inverse relationship between DNA methylation and gene expression for HOXB1, HOXA3 and HOXC-AS3. Finally, increased physical activity in young adults was associated with oppositely regulating HOXB1 and HOXA3 methylation compared with age. Overall, we demonstrate that a considerable number of HOX genes are differentially epigenetically regulated in aged human skeletal muscle and HDMCs and increased physical activity may help prevent age-related epigenetic changes in these HOX genes.

Recent proteomic applications have demonstrated their potential for revealing the molecular mechanisms underlying neurodegeneration. The present study quantifies cerebellar protein changes in mice that are deficient in plasma membrane calcium ATPase 2 (PMCA2), an essential neuronal pump that extrudes calcium from cells and is abundantly expressed in Purkinje neurons. PMCA2-null mice display motor dyscoordination and unsteady gait deficits observed in neurological diseases such as multiple sclerosis and ataxia. We optimized an amine-specific isobaric tags (iTRAQ ™ )-based shotgun proteomics workflow for this study. This workflow took consideration of analytical variance as a function of ion signal intensity and employed biological repeats to aid noise reduction. Even with stringent protein identification criteria, we could reliably quantify nearly 1000 proteins, including many neuronal proteins that are important for synaptic function. We identified 21 proteins that were differentially expressed in PMCA2-null mice. These proteins are involved in calcium homeostasis, cell structure and chromosome organization. Our findings shed light on the molecular changes that underlie the neurological deficits observed in PMCA2-null mice. The optimized workflow presented here will be valuable for others who plan to implement the iTRAQ method.

BackgroundSuboptimal health status (SHS) is recognized as a subclinical, reversible stage of chronic disease. Association has been confirmed between SHS and cardiovascular risk factors, indicating that SHS may contribute to the development of cardiovascular disease. This study explored integrated risk assessment of cardiovascular disease by combining SHS questionnaire-25 (SHSQ-25) and indicators of endothelial dysfunction.MethodsA community-based cross-sectional study was conducted in a sample of 459 residents of Samara, Russia, who had no history of clinical diagnosed disease and did not receive any treatment in the last 2 weeks. The SHS score was derived from the data collected in the SHSQ-25. Blood pressure, body mass index, and glucose and lipid levels (total cholesterol, low density lipoprotein, cholesterol and triglycerides) were measured by physical examination and laboratory performance. The relationship between SHS and endothelial dysfunction was examined using Pearson’s correlation linear regression analysis. Cluster analysis was performed to identify systemic patterns arising from exposure to a variety of risk factors.ResultsSignificant correlations were observed between index of endothelial function and the overall performance of SHS (r = −0.31, p < 0.05), and individual scales of the questionnaire SHSQ-25: fatigue (r = −0.36, p < 0.05), mental (r = −0.29, p < 0.05), and the cardiovascular system (r = −0.36). Based on cluster analysis, all subjects were grouped into five clusters: (1) optimal health status, (2) SHS at low risk of disease states, (3) SHS with a high risk of non-cardiac pathologies profile, (4) SHS of low risk of cardiovascular disease, and (5) SHS with high risk of cardiovascular disease.ConclusionsSHS is associated with endothelial dysfunction. Integration of suboptimal health status and endothelial dysfunction provides a novel tool to allow people to get a more holistic picture of both subjective and objective health measures, and also can be applied to routine screening for risks of cardiovascular diseases.