SNP set analysis for detecting disease association using exon sequence data

Rare variants are believed to play an important role in disease etiology. Recent advances in high-throughput sequencing technology enable investigators to systematically characterize the genetic effects of both common and rare variants. We introduce several approaches that simultaneously test the effects of common and rare variants within a single-nucleotide polymorphism (SNP) set based on logistic regression models and logistic kernel machine models. Gene-environment interactions and SNP-SNP interactions are also considered in some of these models. We illustrate the performance of these methods using the unrelated individuals data from Genetic Analysis Workshop 17. Three true disease genes (FLT1, PIK3C3, and KDR) were consistently selected using the proposed methods. In addition, compared to logistic regression models, the logistic kernel machine models were more powerful, presumably because they reduced the effective number of parameters through regularization. Our results also suggest that a screening step is effective in decreasing the number of false-positive findings, which is often a big concern for association studies

Role of NLRP3 in the pathogenesis and treatment of gout arthritis

Gout arthritis (GA) is a common and curable type of inflammatory arthritis that has been attributed to a combination of genetic, environmental and metabolic factors. Chronic deposition of monosodium urate (MSU) crystals in articular and periarticular spaces as well as subsequent activation of innate immune system in the condition of persistent hyperuricemia are the core mechanisms of GA. As is well known, drugs for GA therapy primarily consists of rapidly acting anti-inflammatory agents and life-long uric acid lowering agents, and their therapeutic outcomes are far from satisfactory. Although MSU crystals in articular cartilage detected by arthrosonography or in synovial fluid found by polarization microscopy are conclusive proofs for GA, the exact molecular mechanism of NLRP3 inflammasome activation in the course of GA still remains mysterious, severely restricting the early diagnosis and therapy of GA. On the one hand, the activation of Nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome requires nuclear factor kappa B (NF-κB)-dependent transcriptional enhancement of NLRP3, precursor (pro)-caspase-1 and pro-IL-1β, as well as the assembly of NLRP3 inflammasome complex and sustained release of inflammatory mediators and cytokines such as IL-1β, IL-18 and caspase-1. On the other hand, NLRP3 inflammasome activated by MSU crystals is particularly relevant to the initiation and progression of GA, and thus may represent a prospective diagnostic biomarker and therapeutic target. As a result, pharmacological inhibition of the assembly and activation of NLRP3 inflammasome may also be a promising avenue for GA therapy. Herein, we first introduced the functional role of NLRP3 inflammasome activation and relevant biological mechanisms in GA based on currently available evidence. Then, we systematically reviewed therapeutic strategies for targeting NLRP3 by potentially effective agents such as natural products, novel compounds and noncoding RNAs (ncRNAs) in the treatment of MSU-induced GA mouse models. In conclusion, our present review may have significant implications for the pathogenesis, diagnosis and therapy of GA

The Effects of Casting and Blending on Properties of Ionomer and the Electromechanical Responses of Ionic Polymer Metal Composite Actuators

As one typical kind of ionic electroactive polymers (iEAPs), ionic polymer metal composites (IPMC) consist of an ionomer and two thin layers of metallic electrode on its both sides. The micro-properties of the ionomer, usually Nafion as the most used ionomer, exert strongly effects on the responses of IPMC actuator. Our works revealed the effects of casting process with different additives (ethylene glycol (EG), dimethyl sulfoxide (DMSO), N, N′-dimethyl formamide (DMF) and N-methyl formamide (NMF)), and blending with sulfonated multi-walled carbon nanotube (sMWCNT) on properties of ionomer and the electromechanical responses of IPMC actuators. Some important properties of casting membrane and sMWCNT/Nafion blending membrane, such as surface morphology, water uptake and ionic exchange capacity, etc., were measured and evaluated. Among the casting membrane-based IPMC actuators, EG based IPMC actuator has larger deformation at 2 V DC voltage. And a trace amount of sMWCNT can improve the performances of IPMCs significantly for realistic applications

Probing the R-parity violating supersymmetric effects in the exclusive c→d/sℓνℓc\to d/s\ell\nu_\ell decays

A lot of branching ratios of the exclusive $c \to d/s\ell\nu_\ell$ ($\ell=e,\mu$) decays have been quite accurately measured by CLEO-c, BELLE, BABAR, BES(I,II,III), ALEPH and MARKIII collaborations. We probe the R-parity violating supersymmetric effects in the exclusive $c \to d/s\ell\nu_\ell$ decays. From the latest experimental measurements, we obtain new upper limits on the relevant R-parity violating coupling parameters within the decays, and many upper limits are obtained for the first time. Using the constrained new parameter spaces, we predict the R-parity violating effects on the observables, which have not been measured or have not been well measured yet. We find that the R-parity violating effects due to slepton exchange could be large on the branching ratios of $D_{d/s}\to e\nu_e$ decays and the normalized forward-backward asymmetries of $D_{u/d}\to \pi/K \ell\nu_\ell$ as well as $D_s\to K \ell\nu_\ell$ decays, and all branching ratios of the relevant semileptonic $D$ decays are sensitive to squark exchange couplings. Our results in this work could be used to probe new physics effects in the leptonic decays as well as the semileptonic decays, and will correlate with searches for direct supersymmetric signals at LHC and BESIII.Comment: 26 pages, 13 figure