A unifying framework for robust association testing,estimation, and genetic model selection using the generalized linear model

The analysis of genome-wide genetic association studies generally starts with univariate statistical tests of each single-nucleotide polymorphism. The standard approach is the Cochran-Armitage trend test or its logistic regression equivalent although this approach can lose considerable power if the underlying genetic model is not additive. An alternative is the MAX test, which is robust against the three basic modes of inheritance. Here, the asymptotic distribution of the MAX test is derived using the generalized linear model together with the Delta method and multiple contrasts. The approach is applicable to binary, quantitative, and survival traits. It may be used for unrelated individuals, family-based studies, and matched pairs. The approach provides point and interval effect estimates and allows selecting the most plausible genetic model using the minimum P-value. R code is provided. A Monte-Carlo simulation study shows that the asymptotic MAX test framework meets type I error levels well, has good power, and good model selection properties for minor allele frequencies ≥0.3. Pearson''s χ²-test is superior for lower minor allele frequencies with low frequencies for the rare homozygous genotype. In these cases, the model selection procedure should be used with caution. The use of the MAX test is illustrated by reanalyzing findings from seven genome-wide association studies including case–control, matched pairs, and quantitative trait data.     

Sintering and Mechanical Properties of (SiC + TiCx)p/Fe Composites Synthesized from Ti3AlC2, SiC,and Fe Powders

Ceramic-particle-reinforced iron matrix composites (CPR-IMCs) have been used in many fields due to their excellent performance. In this study, using the fast resistance-sintering technology developed by our team, iron matrix composites (IMCs) reinforced by both SiC and TiC_x particles were fabricated via the addition of SiC and Ti₃AlC₂ particles, and the resulting relative densities of the sintering products were up to 98%. The XRD and EDS analyses confirmed the in situ formation of the TiC_x from the decomposition of Ti₃AlC₂ during sintering. A significant hybrid reinforcing effect was discovered in the (SiC + TiC_x)_p/Fe composites, where the experimental strength and hardness of the (SiC + TiC_x)_p/Fe composites were higher than the composites of monolithic SiC_p/Fe and (TiC_x)_p/Fe. While, under the condition of constant particle content, the elongation of the samples reinforced using TiC_x was the best, those reinforced by SiC was the lowest, and those reinforced by (SiC + TiC_x) fell in between, which means the plastic response of (SiC + TiC_x)_p/Fe composites obeyed the rule of mixture. The successful preparation of IMCs based on the hybrid reinforcement mechanism provides an idea for the optimization of IMCs.     

Synthesis and Characterization of a Nearly Single Bulk Ti2AlN MAX Phase Obtained from Ti/AlN Powder Mixture through Spark Plasma Sintering

MAX phases are an advanced class of ceramics based on ternary carbides or nitrides that combine some of the ceramic and metallic properties, which make them potential candidate materials for many engineering applications under severe conditions. The present work reports the successful synthesis of nearly single bulk Ti₂AlN MAX phase (>98% purity) through solid-state reaction and from a Ti and AlN powder mixture in a molar ratio of 2:1 as starting materials. The mixture of Ti and AlN powders was subjected to reactive spark plasma sintering (SPS) under 30 MPa at 1200 °C and 1300 °C for 10 min in a vacuum atmosphere. It was found that the massive formation of Al₂O₃ particles at the grain boundaries during sintering inhibits the development of the Ti₂AlN MAX phase in the outer zone of the samples. The effect of sintering temperature on the microstructure and mechanical properties of the Ti₂AlN MAX phase was investigated and discussed.     

Challenges in optimizing sample preparation and LC‐MS/MS conditions for the analysis of carglumic acid,an N‐acetyl glutamate derivative in human plasma

This paper describes a systematic approach to overcoming challenges in developing a robust and selective liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method for reliable and precise determination of carglumic acid in human plasma. Sample extraction was tested on several reversed‐phase solid‐phase extraction (SPE) sorbents with different chemistries, such as hydrophobic C18, hydrophilic‐lipophilic balance, and mixed‐mode cation and anion exchange. The best recovery under the optimized extraction conditions was obtained with Oasis MAX (30 mg, 1cc) mixed‐mode anion exchange (~ 50%) cartridge, compared to other sorbents from 100 μL plasma sample. Complete analytical separation of carglumic acid and carglumic acid‐13C5 15N as an internal standard (IS) from endogenous plasma components was achieved on ACE 5CN (150 × 4.6 mm, 5 µm) column under isocratic conditions using acetonitrile:methanol (50:50, v/v) ? 0.1% acetic acid in water [80:20, v/v] as the mobile phase. The deprotonated precursor → product ion transitions for carglumic acid (189/146) and IS (195/152) were monitored in the negative ionization mode on a triple quadrupole mass spectrometer. The regression curves were linear over a concentration range of 6.00‐6000 ng/mL (r² ≥ 0.9987). Matrix effect was evaluated in terms of IS‐normalized matrix factors, which ranged from 0.95 to 1.01 across four quality control levels. Intra‐ and inter‐batch accuracy and precision, and the stability of carglumic acid in spiked plasma samples were assessed under different conditions. The method was applied to assess the pharmacokinetics of 100 mg/kg body weight carglumic acid in a healthy Indian subject. Copyright © 2015 John Wiley & Sons, Ltd.     

Microstructure and Mechanical Properties of Composites Obtained by Spark Plasma Sintering of Ti3SiC2-15 vol.%Cu Mixtures

Method of soft metal (Cu) strengthening of Ti₃SiC₂ was conducted to increase the hardness and improve the wear resistance of Ti₃SiC₂. Ti₃SiC₂/Cu composites containing 15 vol.% Cu were fabricated by Spark Plasma Sintering (SPS) in a vacuum. The effect of the sintering temperature on the phase composition, microstructure and mechanical properties of the composites was investigated in detail. The as-synthesized composites were thoroughly characterized by scanning electron micrography (SEM), optical micrography (OM) and X-ray diffractometry (XRD), respectively. The results indicated that the constituent of the Ti₃SiC₂/Cu composites sintered at different temperatures included Ti₃SiC₂, Cu₃Si and TiC. The formation of Cu₃Si and TiC originated from the reaction between Ti₃SiC₂ and Cu, which was induced by the presence of Cu and the de-intercalation of Si atoms Ti₃SiC₂. OM analysis showed that with the increase in the sintering temperature, the reaction between Ti₃SiC₂ and Cu was severe, leading to the Ti₃SiC₂ getting smaller and smaller. SEM measurements illustrated that the uniformity of the microstructure distribution of the composites was restricted by the agglomeration of Cu, controlling the mechanical behaviors of the composites. At 1000 °C, the distribution of Cu in the composites was relatively even; thus, the composites exhibited the highest density, relatively high hardness and compressive strength. The relationships of the temperature, the current and the axial dimension with the time during the sintering process were further discussed. Additionally, a schematic illustration was proposed to explain the related sintering characteristic of the composites sintered by SPS. The as-synthesized Ti₃SiC₂/Cu composites were expected to improve the wear resistance of polycrystalline Ti₃SiC₂.     

Efficient Approximation of P-value of the Maximum of Correlated Tests, with Applications to Genome-Wide Association Studies

Genome-wide association study (GWAS), typically involving 100,000 to 500,000 single-nucleotide polymorphisms (SNPs), is a powerful approach to identify disease susceptibility loci. In a GWAS, single-marker analysis, which tests one SNP at a time, is usually used as the first stage to screen SNPs across the genome in order to identify a small fraction of promising SNPs with relatively low p-values for further and more focused studies. For single-marker analysis, the trend test derived for an additive genetic model is often used. This may not be robust when the additive assumption is not appropriate for the true underlying disease model. A robust test, MAX, based on the maximum of three trend test statistics derived for recessive, additive, and dominant models, has been proposed recently for GWAS. But its p-value has to be evaluated through a resampling-based procedure, which is computationally challenging for the analysis of GWAS. Obtaining the p-value for MAX with adjustment for the covariates can be even more time-consuming. In this article, we provide a simple approximation for the p-value of the MAX test with or without adjusting for the covariates. The new method avoids resampling steps and thus makes the MAX test readily applicable to GWAS. We use simulation studies as well as real datasets on 17 confirmed disease-associated SNPs to assess the accuracy of the proposed method. We also apply the method to the GWAS of coronary artery disease.     

Evaluation of the BD MAX GBS assay to detect Streptococcus group B in LIM broth-enriched antepartum vaginal-rectal specimens

The BD MAX GBS real-time polymerase chain reaction assay was evaluated concomitantly with Centers for Disease Control and Prevention-endorsed culture methods to detect Streptococcus group B from LIM broth-enriched antepartum vaginal-rectal specimens. The sensitivity of both methods exceeded 98%.     

Structural Stability,Electronic, Mechanical,Phonon, and Thermodynamic Properties of the M2GaC (M = Zr,Hf) MAX Phase: An ab Initio Calculation

The novel ternary carbides and nitrides, known as MAX phase materials with remarkable combined metallic and ceramic properties, offer various engineering and technological applications. Using ab initio calculations based on generalized gradient approximation (GGA), local density approximation (LDA), and the quasiharmonic Debye model; the electronic, structural, elastic, mechanical, and thermodynamic properties of the M₂GaC (M = Zr, Hf) MAX phase were investigated. The optimized lattice parameters give the first reference to the upcoming theocratical and experimental studies, while the calculated elastic constants are in excellent agreement with the available data. Moreover, obtained elastic constants revealed that both the Zr₂GaC and Hf₂GaC MAX phases are brittle. The band structure and density of states analysis showed that these MAX phases are electrical conductors, having strong directional bonding between M-C (M = Zr, Hf) atoms due to M-d and C-p hybridization. Formation and cohesive energies, and phonon calculations showed that Zr₂GaC and Hf₂GaC MAX phases’ compounds are thermodynamically and dynamically stable and can be synthesized experimentally. Finally, the effect of temperature and pressure on volume, heat capacity, Debye temperature, Grüneisen parameter, and thermal expansion coefficient of M₂GaC (M = Zr, Hf) are evaluated using the quasiharmonic Debye model from the nonequilibrium Gibbs function in the temperature and pressure range 0–1600 K and 0–50 GPa respectively.     

毛蕊花苷通过上调Max蛋白抑制口腔鳞癌细胞的迁移和侵袭

【】目的 分析毛蕊花苷通过上调MAX蛋白表达抑制口腔鳞癌细胞的迁移和侵袭。方法 质谱分析空白对照组及毛蕊花苷处理组口腔鳞癌细胞HN4中蛋白的表达谱,筛选毛蕊花苷处理后丰度高且表达显著增加的蛋白,用Western blotting验证质谱分析的结果,并在口腔鳞癌细胞HN4中运用shRNA干扰关键蛋白的表达,分析毛蕊花苷的处理对鳞癌细胞HN4迁移和侵袭的作用。结果 分析质谱检测的结果筛选经毛蕊花苷处理后,在口腔鳞癌HN4细胞中表达显著升高的MAX蛋白,蛋白印记检测发现与质谱芯片结果相一致,毛蕊花苷处理组鳞癌细胞HN4中MAX的表达明显增加;shRNA干扰口腔鳞癌HN4细胞中MAX的表达,qRT-PCR和Western blotting检测发现HN4细胞中MAX的表达明显下调,运用毛蕊花苷进一步刺激HN4细胞,发现HN4细胞的迁移和侵袭能力显著被抑制。结论 毛蕊花苷可能是通过增强口腔鳞癌细胞中MAX的表达抑制口腔鳞癌细胞的迁移和侵袭。