Gene and Pathway-Based Analysis: Second Wave of Genome-wide Association Studies

Despite great success of GWAS in identification of common genetic variants associated with complex diseases, the current GWAS have focused on single SNP analysis. However, single SNP analysis often identifies a number of the most significant SNPs that account for only a small proportion of the genetic variants and offers limited understanding of complex diseases. To overcome these limitations, we propose gene and pathway-based association analysis as a new paradigm for GWAS. As a proof of concept, we performed a comprehensive gene and pathway-based association analysis for thirteen published GWAS. Our results showed that the proposed new paradigm for GWAS not only identified the genes that include significant SNPs found by single SNP analysis, but also detected new genes in which each single SNP conferred small disease risk, but their joint actions were implicated in the development of diseases. The results also demonstrated that the new paradigm for GWAS was able to identify biologically meaningful pathways associated with the diseases which were confirmed by gene-set rich analysis using gene expression data

The Activities of Antioxidant Nutrients in Human Plasma Depend on the Localization of Attacking Radical Species

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Knockdown of Ant2 Reduces Adipocyte Hypoxia And Improves Insulin Resistance in Obesity.

Decreased adipose tissue oxygen tension and increased HIF-1α expression can trigger adipose tissue inflammation and dysfunction in obesity. Our current understanding of obesity-associated decreased adipose tissue oxygen tension is mainly focused on changes in oxygen supply and angiogenesis. Here, we demonstrate that increased adipocyte O2 demand, mediated by ANT2 activity, is the dominant cause of adipocyte hypoxia. Deletion of adipocyte Ant2 improves obesity-induced intracellular adipocyte hypoxia by decreasing obesity-induced adipocyte oxygen demand, without effects on mitochondrial number or mass, or oligomycin-sensitive respiration. This led to decreased adipose tissue HIF-1α expression and inflammation with improved glucose tolerance and insulin resistance in both a preventative or therapeutic setting. Our results suggest that ANT2 may be a target for the development of insulin sensitizing drugs and that ANT2 inhibition might have clinical utility

Pre-set extrusion bioprinting for multiscale heterogeneous tissue structure fabrication

Recent advances in three-dimensional bioprinting technology have led to various attempts in fabricating human tissue-like structures. However, current bioprinting technologies have limitations for creating native tissue-like structures. To resolve these issues, we developed a new pre-set extrusion bioprinting technique that can create heterogeneous, multicellular, and multimaterial structures simultaneously. The key to this ability lies in the use of a precursor cartridge that can stably preserve a multimaterial with a pre-defined configuration that can be simply embedded in a syringe-based printer head. The multimaterial can be printed and miniaturized through a micro-nozzle without conspicuous deformation according to the pre-defined configuration of the precursor cartridge. Using this system, we fabricated heterogeneous tissue-like structures such as spinal cords, hepatic lobule, blood vessels, and capillaries. We further obtained a heterogeneous patterned model that embeds HepG2 cells with endothelial cells in a hepatic lobule-like structure. In comparison with homogeneous and heterogeneous cell printing, the heterogeneous patterned model showed a well-organized hepatic lobule structure and higher enzyme activity of CYP3A4. Therefore, this pre-set extrusion bioprinting method could be widely used in the fabrication of a variety of artificial and functional tissues or organs

Screening for fear of cancer recurrence : instrument validation and current status in early stage lung cancer patients

Background Fear of cancer recurrence (FCR) is one of the most distressing concerns for cancer patients. A psychometrically validated brief scale is urgently needed for use in busy clinical oncology settings. This study aimed to (1) develop and validate the 7-item fear of cancer recurrence scale Chinese version (FCR7-C), and (2) explore the severity of FCR in post-operative early-stage lung cancer patients in Taiwan. Methods Early-stage lung cancer patients were recruited from a medical center in Taiwan. The FCR7-C was evaluated for content and construct validity and internal consistency reliability. Construct validity of FCR7-C was determined by the empirically supported correlation and confirmatory factor analysis (CFA). Results A total of 160 subjects were recruited. The FCR7-C was shown to have satisfactory content validity and internal consistency reliability (Cronbach's α = 0.9). The uni-dimensional structure was confirmed by CFA that showed a good fit for the model. The FCR7-C score correlates positively with the degree of most of the physical symptoms, anxiety, and depression, but correlates negatively with patient age, performance status, and quality of life. We found that 81.9% of patients reported at least some FCR, with a mean FCR severity of 15.18 (SD = 7.78). Conclusion FCR7-C is a brief screening tool with good psychometrics. Patients with early-stage lung cancer still revealed mild to moderate level of FCR. Applying the FCR7-C for to screen cancer patients’ distress and further develop personalized psychological interventions would be strongly suggested.Publisher PDFPeer reviewe

Genomic DNA functions as a universal external standard in quantitative real-time PCR

Real-time quantitative PCR (qPCR) is a powerful tool for quantifying specific DNA target sequences. Although determination of relative quantity is widely accepted as a reliable means of measuring differences between samples, there are advantages to being able to determine the absolute copy numbers of a given target. One approach to absolute quantification relies on construction of an accurate standard curve using appropriate external standards of known concentration. We have validated the use of tissue genomic DNA as a universal external standard to facilitate quantification of any target sequence contained in the genome of a given species, addressing several key technical issues regarding its use. This approach was applied to validate mRNA expression of gene candidates identified from microarray data and to determine gene copies in transgenic mice. A simple method that can assist achieving absolute quantification of gene expression would broadly enhance the uses of real-time qPCR and in particular, augment the evaluation of global gene expression studies

Gate-dependent spin Hall induced nonlocal resistance and the symmetry of spin-orbit scattering in Au-clustered graphene

Engineering the electron dispersion of graphene to be spin-dependent is crucial for the realization of spin-based logic devices. Enhancing spin-orbit coupling in graphene can induce spin Hall effect, which can be adapted to generate or detect a spin current without a ferromagnet. Recently, both chemically and physically decorated graphenes have shown to exhibit large nonlocal resistance via the spin Hall and its inverse effects. However, these nonlocal transport results have raised critical debates due to the absence of field dependent Hanle curve in subsequent studies. Here, we introduce Au clusters on graphene to enhance spin-orbit coupling and employ a nonlocal geometry to study the spin Hall induced nonlocal resistance. Our results show that the nonlocal resistance highly depends on the applied gate voltage due to various current channels. However, the spin Hall induced nonlocal resistance becomes dominant at a particular carrier concentration, which is further confirmed through Hanle curves. The obtained spin Hall angle is as high as similar to 0.09 at 2 K. Temperature dependence of spin relaxation time is governed by the symmetry of spin-orbit coupling, which also depends on the gate voltage: asymmetric near the charge neutral point and symmetric at high carrier concentration. These results inspire an effective method for generating spin currents in graphene and provide important insights for the spin Hall effect as well as the symmetry of spin scattering in physically decorated graphene

Insights on Distinct Left Atrial Remodeling Between Atrial Fibrillation and Heart Failure With Preserved Ejection Fraction

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) commonly coexist with overlapping pathophysiology like left atrial (LA) remodeling, which might differ given different underlying mechanisms. OBJECTIVES: We sought to investigate the different patterns of LA wall remodeling in AF vs. HFpEF. METHODS: We compared LA wall characteristics including wall volume (LAWV), wall thickness (LAWT), and wall thickness heterogeneity (LAWT[SD]) and LA structure, function among the controls (without AF or HFpEF, n = 115), HFpEF alone (n = 59), AF alone (n = 37), and HFpEF+AF (n = 38) groups using multi-detector computed tomography and echocardiography. RESULTS: LA wall remodeling was most predominant and peak atrial longitudinal strain (PALS) was worst in HFpEF+AF patients as compared to the rest. Despite lower E/e' (9.8 ± 3.8 vs. 13.4 ± 6.4) yet comparable LA volume, LAWT and PALS in AF alone vs. HFpEF alone, LAWV [12.6 (11.6–15.3) vs. 12.0 (10.2–13.7); p = 0.01] and LAWT(SD) [0.68 (0.61–0.71) vs. 0.60 (0.56–0.65); p < 0.001] were significantly greater in AF alone vs. HFpEF alone even after multi-variate adjustment and propensity matching. After excluding the HFpEF+AF group, both LAWV and LAWT [SD] provided incremental values when added to PALS or LAVi (all p for net reclassification improvement <0.05) in discriminating AF alone, with LAWT[SD] yielding the largest C-statistic (0.78, 95% CI: 0.70–0.86) among all LA wall indices. CONCLUSIONS: Despite a similar extent of LA enlargement and dysfunction in HFpEF vs. AF alone, larger LAWV and LAWT [SD] can distinguish AF from HFpEF alone, suggesting the distinct underlying pathophysiological mechanism of LA remodeling in AF vs. HFpEF