DISCUSSION These findings show altered M1 in the context of acute moderate to severe pain, suggesting early signs of altered GABAergic inhibitory and glutamatergic facilitatory activities.Whilst susceptibility variants for many complex diseases, such as rheumatoid arthritis (RA), have been well characterised, the mechanism by which risk is mediated is still unclear for many loci. This is especially true for the majority of variants that do not affect protein-coding regions. lncRNA represent a group of molecules that have been shown to be enriched amongst variants associated with RA and other complex diseases, compared to random variants. In order to establish to what degree direct disruption of lncRNA may represent a potential mechanism for mediating RA susceptibility, we chose to further explore this overlap. By testing the ability of annotated features to improve a model of disease susceptibility, we were able to demonstrate a local enrichment of enhancers from immune-relevant cell types amongst RA susceptibility variants (log2 enrichment 3.40). This was not possible for lncRNA annotations in general, however a small, but significant enrichment was observed for immune-enriched lncRNA (log2 enrichment 0.867002). This enrichment was no longer apparent when the model was conditioned on immune-relevant enhancers (log2 enrichment -0.372734), suggesting that direct disruption of lncRNA sequence, independent of enhancer disruption, does not represent a major mechanism by which susceptibility to complex diseases is mediated. Furthermore, we demonstrated that, in keeping with general lncRNA characteristics, immune-enriched lncRNA are expressed at low levels that may not be amenable to functional characterisation.BACKGROUND The epidemic of hand, foot, and mouth disease (HFMD) has become a severe public health problem in the world and has also brought a high economic and health burden. Furthermore, the prevalence of HFMD varies significantly among different locations. However, there have been few investigations of the effects of socioeconomic factors and air pollution factors on the incidence of HFMD. METHODS This study collected data on HFMD in Shenzhen, China, from 2012 to 2015. We selected eleven factors as potential risk factors for HFMD. A Bayesian spatiotemporal model was used to quantify the influence of the factors on HFMD and to identify the relative risks in different districts. RESULTS The risk factors of HFMD were the population, population density, concentration of SO2, and concentration of NO2. The relative risks (RRs) were 1.00473 (95% CI 1.00059-1.00761), 1.00010 (95% CI 1.00002-1.00016), 1.00215 (95% CI 1.00170-1.00232) and 1.00058 (95% CI 1.00028-1.00078), respectively. The protective factors against HFMD were the per capita GDP, the number of public kindergartens, the concentration of PM10, and the concentration of O3. The RRs were 0.98840 (95% CI 0.98660-0.99026), 0.97686 (95% CI 0.96946-0.98403), 0.99108 (95% CI 0.98551-0.99840) and 0.99587 (95% CI 0.99534-0.99610), respectively. The risk of incidence in Longgang district and Pingshan district decreased, while the risk of incidence in Baoan district increased. CONCLUSIONS Studies have confirmed that socioeconomic factors and air pollution factors have an impact on the incidence of HFMD in Shenzhen, China. The results will be of great practical significance to local authorities, which is conducive to accurate prevention and can be used to formulate HFMD early warning systems.Most enzymes act on more than a single substrate. There is frequently a need to block the production of a single pathogenic outcome of enzymatic activity on a substrate but to avoid blocking others of its catalytic actions. Full blocking might cause severe side effects because some products of that catalysis may be vital. Substrate selectivity is required but not possible to achieve by blocking the catalytic residues of an enzyme. That is the basis of the need for "Substrate Selective Inhibitors" (SSI), and there are several molecules characterized as SSI. However, none have yet been designed or discovered by computational methods. We demonstrate a computational approach to the discovery of Substrate Selective Inhibitors for one enzyme, Prolyl Oligopeptidase (POP) (E.C 3.4.21.26), a serine protease which cleaves small peptides between Pro and other amino acids.  https://www.selleckchem.com/MEK.html  Among those are Thyrotropin Releasing Hormone (TRH) and Angiotensin-III (Ang-III), differing in both their binding (Km) and in turnover (kcat). We used our in-house "Iterative Stochastic Elimination" (ISE) algorithm and the structure-based "Pharmacophore" approach to construct two models for identifying SSI of POP. A dataset of ~1.8 million commercially available molecules was initially reduced to less than 12,000 which were screened by these models to a final set of 20 molecules which were sent for experimental validation (five random molecules were tested for comparison). Two molecules out of these 20, one with a high score in the ISE model, the other successful in the pharmacophore model, were confirmed by in vitro measurements. One is a competitive inhibitor of Ang-III (increases its Km), but non-competitive towards TRH (decreases its Vmax).Epithelial cell polarity defects support cancer progression. It is thus crucial to decipher the functional interactions within the polarity protein network. Here we show that Drosophila Girdin and its human ortholog (GIRDIN) sustain the function of crucial lateral polarity proteins by inhibiting the apical kinase aPKC. Loss of GIRDIN expression is also associated with overgrowth of disorganized cell cysts. Moreover, we observed cell dissemination from GIRDIN knockdown cysts and tumorspheres, thereby showing that GIRDIN supports the cohesion of multicellular epithelial structures. Consistent with these observations, alteration of GIRDIN expression is associated with poor overall survival in subtypes of breast and lung cancers. Overall, we discovered a core mechanism contributing to epithelial cell polarization from flies to humans. Our data also indicate that GIRDIN has the potential to impair the progression of epithelial cancers by preserving cell polarity and restricting cell dissemination.