A Penalized Multi-trait Mixed Model for Association Mapping in Pedigree-based GWAS

In genome-wide association studies (GWAS), penalization is an important approach for identifying genetic markers associated with trait while mixed model is successful in accounting for a complicated dependence structure among samples. Therefore, penalized linear mixed model is a tool that combines the advantages of penalization approach and linear mixed model. In this study, a GWAS with multiple highly correlated traits is analyzed. For GWAS with multiple quantitative traits that are highly correlated, the analysis using traits marginally inevitably lose some essential information among multiple traits. We propose a penalized-MTMM, a penalized multivariate linear mixed model that allows both the within-trait and between-trait variance components simultaneously for multiple traits. The proposed penalized-MTMM estimates variance components using an AI-REML method and conducts variable selection and point estimation simultaneously using group MCP and sparse group MCP. Best linear unbiased predictor (BLUP) is used to find predictive values and the Pearson's correlations between predictive values and their corresponding observations are used to evaluate prediction performance. Both prediction and selection performance of the proposed approach and its comparison with the uni-trait penalized-LMM are evaluated through simulation studies. We apply the proposed approach to a GWAS data from Genetic Analysis Workshop (GAW) 18

miR-638 is a new biomarker for outcome prediction of non-small cell lung cancer patients receiving chemotherapy.

MicroRNAs (miRNAs), a class of small non-coding RNAs, mediate gene expression by either cleaving target mRNAs or inhibiting their translation. They have key roles in the tumorigenesis of several cancers, including non-small cell lung cancer (NSCLC). The aim of this study was to investigate the clinical significance of miR-638 in the evaluation of NSCLC patient prognosis in response to chemotherapy. First, we detected miR-638 expression levels in vitro in the culture supernatants of the NSCLC cell line SPC-A1 treated with cisplatin, as well as the apoptosis rates of SPC-A1. Second, serum miR-638 expression levels were detected in vivo by using nude mice xenograft models bearing SPC-A1 with and without cisplatin treatment. In the clinic, the serum miR-638 levels of 200 cases of NSCLC patients before and after chemotherapy were determined by quantitative real-time PCR, and the associations of clinicopathological features with miR-638 expression patterns after chemotherapy were analyzed. Our data helped in demonstrating that cisplatin induced apoptosis of the SPC-A1 cells in a dose- and time-dependent manner accompanied by increased miR-638 expression levels in the culture supernatants. In vivo data further revealed that cisplatin induced miR-638 upregulation in the serum derived from mice xenograft models, and in NSCLC patient sera, miR-638 expression patterns after chemotherapy significantly correlated with lymph node metastasis. Moreover, survival analyses revealed that patients who had increased miR-638 levels after chemotherapy showed significantly longer survival time than those who had decreased miR-638 levels. Our findings suggest that serum miR-638 levels are associated with the survival of NSCLC patients and may be considered a potential independent predictor for NSCLC prognosis

Donor–Acceptor Fluorophores for Energy-Transfer-Mediated Photocatalysis

Triplet–triplet energy transfer (EnT) is a fundamental activation pathway in photocatalysis. In this work, we report the mechanistic origins of the triplet excited state of carbazole-cyanobenzene donor–acceptor (D–A) fluorophores in EnT-based photocatalytic reactions and demonstrate the key factors that control the accessibility of the 3LE (locally excited triplet state) and 3CT (charge-transfer triplet state) via a combined photochemical and transient absorption spectroscopic study. We found that the energy order between 1CT (charge transfer singlet state) and 3LE dictates the accessibility of 3LE/3CT for EnT, which can be effectively engineered by varying solvent polarity and D–A character to depopulate 3LE and facilitate EnT from the chemically more tunable 3CT state for photosensitization. Following the above design principle, a new D–A fluorophore with strong D–A character and weak redox potential is identified, which exhibits high efficiency for Ni(II)-catalyzed cross-coupling of carboxylic acids and aryl halides with a wide substrate scope and high selectivity. Our results not only provide key fundamental insight on the EnT mechanism of D–A fluorophores but also establish its wide utility in EnT-mediated photocatalytic reactions