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The dysfunction of matriptase, a membrane-anchored protease, is highly related to the progression of skin and breast cancers. Epidermal growth factor (EGF)-induced matriptase activation and cancer invasion are known but with obscure mechanisms. Here, we demonstrate a vesicular-trafficking-mediated interplay between matriptase and EGF signaling in cancer promotion. We found that EGF induces matriptase to undergo endocytosis together with the EGF receptor, followed by acid-induced activation in endosomes. Activated matriptase is then secreted extracellularly on exosomes to catalyze hepatocyte growth factor precursor (pro-HGF) cleavage, resulting in autocrine HGF/c-Met signaling. Matriptase-induced HGF/c-Met signaling represents the second signal wave of EGF, which promotes cancer cell scattering, migration, and invasion. These findings demonstrate a role of vesicular trafficking in efficient activation and secretion of membrane matriptase and a reciprocal regulation of matriptase and EGF signaling in cancer promotion, providing insights into the physiological functions of vesicular trafficking and the molecular pathological mechanisms of skin and breast cancers. [Display omitted] • EGF induces EGFR-facilitated matriptase endocytosis • Matriptase is activated by endosomal acidic conditions and secreted on exosomes • Exosomal matriptase catalyzes pro-HGF maturation to activate the HGF/c-Met pathway • Activated HGF/c-Met pathway—the second signal wave of EGF—induces cancer invasion Ye et al. show that EGF induces matriptase endocytosis together with EGFR for acidic activation in endosomes, followed by exosomal secretion. Exosomal matriptase initiates the second wave of EGF signaling via catalyzing pro-HGF maturation to activate the HGF/c-Met pathway. This vesicle-trafficking-mediated interplay between EGF and matriptase promotes SCC and TNBC invasion. [ABSTRACT FROM AUTHOR]

A large number of studies have reported that the genetic variants in STAT6 gene may be implicated in susceptibility to asthma, but with inconsistent results. Therefore, the aim of this meta-analysis was to determine the likelihood of developing asthma for the individuals with different STAT6 variants. The database including Pubmed, Embase and CNKI (Chinese National Knowledge Infrastructure) were searched to find the relevant papers. Data were extracted by two independent reviewers and the odds radios (ORs) were pooled with 95% confidence intervals (CIs), using random effect or fixed effect models as appropriate, to indicate the risk of asthma for different STAT6 variants. The heterogeneity and bias were tested for each pooled result. Data from 19 studies were pooled that reported associations of rs324015, rs71802646 and rs324011 in STAT6 gene with asthma risk. The results demonstrated that 13GT and short GT in rs71802646 were both associated with increased risk of asthma in overall analysis (OR=1.26 for 13GT and 1.30 for short GT). Further, subgroup analysis showed an increased risk of asthma in Asian population with 13GT (OR=1.21), 14GT (OR=1.97) and short GT (OR=1.27). Besides, 13GT, 14GT and short GT all contributed to higher risk of atopic asthma, with OR 1.50, 2.21 and 1.65 respectively. However, rs324015 (G>A) appeared to be associated with decreased risk for atopic asthma (with OR=0.83, 0.68 and 0.79 for A, AA and AA+AG respectively). Both overall and subgroup analyses indicated no effect of rs324011 on asthma risk. In conclusion, our meta-analyses suggest that short GT repeats of rs71802646 in STAT6 contribute to higher risk for asthma, while rs324015 may have a protective effect on atopic asthma. [ABSTRACT FROM AUTHOR]

The home mathematics environment of preschoolers is related to their mathematical performance. Information about the home mathematics environment in China is sparse, however. Accordingly, we developed and tested a culturally relevant home mathematics environment questionnaire for Chinese families. In Study 1 (n = 376), exploratory factor analysis of the questionnaire revealed four activity factors: Informal, Basic Formal, Advanced Formal, and Spatial. In Study 2 (n = 353), the general structure of the questionnaire was evaluated with confirmatory factor analysis. Some minor changes were made to the questionnaire. In Study 3, 137 caregivers completed the refined questionnaire and their children were tested on fundamental mathematical skills. As in research from Western countries, Chinese parents' reports of the frequency of advanced mathematical activities were positively correlated with their preschoolers' mathematical skills. This study provides comparative data from China about the home mathematics environment and broadens the scope of research beyond Western countries. We developed a questionnaire with high reliability and strong validity, demonstrating that it is a useful tool for assessing the home mathematics environment of Chinese families. The work adds to the literature on the home mathematics environment more generally and provides comparative data from China. We found that the performance of Chinese preschool children on mathematical tasks was related to the frequency of advanced but not basic formal mathematical activities, highlighting the similar relations between the home mathematics environment and children's mathematics performance across the world. • A home mathematics environment questionnaire for Chinese families was developed. • Parents' reports of home math activities were similar to those in other countries. • The frequency of advanced math activities was related to preschoolers' math skills. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the effects of TRAF6 and NLRX1 polymorphisms and their interactions with environmental factors on the susceptibility of type 2 diabetes mellitus (T2DM) vascular complications in a southern Han Chinese population.Methods: Five single nucleotide polymorphisms (SNPs) were genotyped in a case-control study to estimate risk factors of T2DM vascular complications. Gene-gene and gene-environment interactions and haplotype associations were also estimated.Results: The CA genotype of the NLRX1 rs4245191 was identified as a risk factor for T2DM macrovascular complications and diabetic cerebral infarction (OR=2.88, 95% CI=1.15-7.22, P=0.024; OR=4.00, 95% CI=1.04-15.38, P=0.043, respectively). A significantly lower T allele frequency in the TRAF6 rs16928973 was observed in T2DM patients with both microvascular and macrovascular complications compared with patients without any complication under the allelic model (T vs. C: OR=0.36, 95% CI=0.14-0.98, P=0.038). No significant differences in haplotypes, gene-gene interactions and gene-environment interactions were observed among T2DM vascular subgroup patients.Conclusions: Our study provides evidence that the NLRX1 rs4245191 polymorphisms influence the risk of T2DM macrovascular complications and diabetic cerebral infarction. [ABSTRACT FROM AUTHOR]

Toll-like receptor 3 (TLR3) is involved in type I interferon-β (IFN-β) via TIR-domain-containing adapter-inducing interferon-β (TRIF) and Tumor necrosis factor receptor–associated factor 3 (TRAF3), culminating in inflammation and immunity reactions. TLR3 is implicated in insulin resistance and type 2 diabetes mellitus (T2DM). Eight SNPs of these genes were detected in 552 T2DM patients and 552 matched healthy control subjects. Gene-gene and gene-environment interactions and haplotype associations were also evaluated. We identified a 21% increased risk of T2DM for the T allele of rs12435483 in the TRAF3 gene (OR: 1.21; 95% CI: 1.01–1.44; P = 0.036). The GA genotype and GA + AA genotype of TRAF3 rs12147254 were found to increase the risk of coronary heart disease (CHD) among T2DM patients (GA vs. GG: OR = 4.17, 95% CI: 1.04–16.79, P = 0.045; GA + AA vs. GG: OR = 3.97, 95% CI: 1.02–15.48, P = 0.047). However, the GACGAC haplotype in TRAF3 had a protective effect on T2DM micro-macrovascular complications (OR = 0.33, 95% CI: 0.13–0.85, P = 0.017). Two-factor (TRAF3 rs12435483 and LDL) and three-factor (TRAF3 rs12435483, BMI and HDL) interactions of the risk of T2DM were identified. In conclusion, the genetic variants in the TLR3-TRIF-TRAF3-INF-β signaling pathway and interactions with some particular environmental factors (LDL, BMI and HDL) may contribute to susceptibility to T2DM and vascular complications in the Han Chinese population. [ABSTRACT FROM AUTHOR]

Retinoid X receptor alpha (RXRα), a nuclear receptor of transcription factor, controls various physiological and pathological pathways including cellular growth, proliferation, differentiation, and apoptosis. Here, we report that RXRα is phosphorylated at its N-terminal A/B domain by cyclin-dependent kinase 1 (Cdk1) at the onset of mitosis, triggering its translocation to the centrosome, where phosphorylated-RXRα (p-RXRα) interacts with polo-like kinase 1 (PLK1) through its N-terminal A/B domain by a unique mechanism. The interaction promotes PLK1 activation, centrosome maturation, and mitotic progression. Levels of p-RXRα are abnormally elevated in cancer cell lines, during carcinogenesis in animals, and in clinical tumor tissues. An RXRα ligand XS060, which specifically inhibits p-RXRα/PLK1 interaction but not RXRα heterodimerization, promotes mitotic arrest and catastrophe in a tumor-specific manner. These findings unravel a transcription-independent action of RXRα at the centrosome during mitosis and identify p-RXRα as a tumor-specific vulnerability for developing mitotic drugs with improved therapeutic index. • Cdk1 phosphorylation of RXRα induces its translocation to centrosome during mitosis • Centrosomal RXRα modulates mitosis by interacting with PLK1 • Cdk1-phosphorylated RXRα confers tumor cells with vulnerability to RXRα inhibitors • An RXRα ligand promotes mitotic catastrophe by inhibiting p-RXRα/PLK1 interaction Xie and Zhou et al. report a transcription-independent function of RXRα. Upon phosphorylation by Cdk1 at the onset of mitosis, RXRα translocates to the centrosome, where it interacts with PLK1 to promote centrosome maturation and mitotic progression. The authors also identify Cdk1-phosphorylated RXRα as a tumor-specific vulnerability to an RXRα inhibitor. [ABSTRACT FROM AUTHOR]