Epigenetic regulation of F2RL3 associates with myocardial infarction and platelet function

DNA hypomethylation at the F2RL3 (F2R like thrombin or trypsin receptor 3) locus has been associated with both smoking and atherosclerotic cardiovascular disease; whether these smoking-related associations form a pathway to disease is unknown. F2RL3 encodes protease-activated receptor 4, a potent thrombin receptor expressed on platelets. Given the role of thrombin in platelet activation and the role of thrombus formation in myocardial infarction, alterations to this biological pathway could be important for ischemic cardiovascular disease. METHODS: We conducted multiple independent experiments to assess whether DNA hypomethylation at F2RL3 in response to smoking is associated with risk of myocardial infarction via changes to platelet reactivity. Using cohort data (N=3205), we explored the relationship between smoking, DNA hypomethylation at F2RL3, and myocardial infarction. We compared platelet reactivity in individuals with low versus high DNA methylation at F2RL3 (N=41). We used an in vitro model to explore the biological response of F2RL3 to cigarette smoke extract. Finally, a series of reporter constructs were used to investigate how differential methylation could impact F2RL3 gene expression. RESULTS: Observationally, DNA methylation at F2RL3 mediated an estimated 34% of the smoking effect on increased risk of myocardial infarction. An association between methylation group (low/high) and platelet reactivity was observed in response to PAR4 (protease-activated receptor 4) stimulation. In cells, cigarette smoke extract exposure was associated with a 4.9% to 9.3% reduction in DNA methylation at F2RL3 and a corresponding 1.7-(95% CI, 1.2–2.4, P=0.04) fold increase in F2RL3 mRNA. Results from reporter assays suggest the exon 2 region of F2RL3 may help control gene expression. CONCLUSIONS: Smoking-induced epigenetic DNA hypomethylation at F2RL3 appears to increase PAR4 expression with potential downstream consequences for platelet reactivity. Combined evidence here not only identifies F2RL3 DNA methylation as a possible contributory pathway from smoking to cardiovascular disease risk but from any feature potentially influencing F2RL3 regulation in a similar manner

Noncommutative solitons on Kahler manifolds

We construct a new class of scalar noncommutative multi-solitons on an arbitrary Kahler manifold by using Berezin's geometric approach to quantization and its generalization to deformation quantization. We analyze the stability condition which arises from the leading 1/hbar correction to the soliton energy and for homogeneous Kahler manifolds obtain that the stable solitons are given in terms of generalized coherent states. We apply this general formalism to a number of examples, which include the sphere, hyperbolic plane, torus and general symmetric bounded domains. As a general feature we notice that on homogeneous manifolds of positive curvature, solitons tend to attract each other, while if the curvature is negative they will repel each other. Applications of these results are discussed.Comment: 26 pages, 3 figures, harvmac; references adde

Scanning the horizon: towards transparent and reproducible neuroimaging research

Functional neuroimaging techniques have transformed our ability to probe the neurobiological basis of behaviour and are increasingly being applied by the wider neuroscience community. However, concerns have recently been raised that the conclusions that are drawn from some human neuroimaging studies are either spurious or not generalizable. Problems such as low statistical power, flexibility in data analysis, software errors and a lack of direct replication apply to many fields, but perhaps particularly to functional MRI. Here, we discuss these problems, outline current and suggested best practices, and describe how we think the field should evolve to produce the most meaningful and reliable answers to neuroscientific questions

Teaching Thinking and Reasoning Skills More Effectively

Political pundits whine that the world would be a better place if only more people thought like them. A clever engineer once told me that the world needs (his arms come together in a weight lifting pose, hands rounded together) more circles! Me? I want a world full of wise, thinking individuals. This is a world of minds that have an inner balance wheel ; minds that protect themselves from extremes and under-use. Rudyard Kipling set up the model of a well-trained mind, If you can keep your head while all around you are losing theirs and blaming it on you... Thinking and reasoning aptitude can be built within a person like a physical muscle (Goodman and Goodman, 1991). Human beings can learn, develop, and enhance these capabilities as part of their maturity