Bayer AG.

DNA methylation is a heritable chromatin modification that maintains chromosome stability, regulates transposon silencing and appears to be involved in gene expression in response to environmental conditions. Environmental stress alters DNA methylation patterns that are correlated with gene expression differences. Here, genome-wide differential DNA-methylation was identified upon prolonged Zn deficiency, leading to hypo- and hyper-methylated chromosomal regions. Preferential CpG methylation changes occurred in gene promoters and gene bodies, but did not overlap with transcriptional start sites. Methylation changes were also prominent in transposable elements. By contrast, non-CG methylation differences were exclusively found in promoters of protein coding genes and in transposable elements. Strongly Zn deficiency-induced genes and their promoters were mostly non-methylated, irrespective of Zn supply. Differential DNA methylation in the CpG and CHG, but not in the CHH context, was found close to a few up-regulated Zn-deficiency genes. However, the transcriptional Zn-deficiency response in roots appeared little correlated with associated DNA methylation changes in promoters or gene bodies. Furthermore, under Zn deficiency, developmental defects were identified in an Arabidopsis mutant lacking non-CpG methylation. The root methylome thus responds specifically to a micro-nutrient deficiency and is important for efficient Zn utilization at low availability, but the relationship of differential methylation and differentially expressed genes is surprisingly poor.

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Association between the (AC) n dinucleotide repeat polymorphism at the 5 0 -end of the aldose reductase gene and the occurrence of diabetic nephropathy was conducted. We examined eight studies consisting of ten Caucasian type 1 diabetes mellitus case-control comparisons and eight studies consisting of nine type 2 diabetes mellitus case-control comparisons, which were based on our inclusion criterion and available in the literature. The meta-analysis demonstrated a large heterogeneity among the studies on the type 1 diabetic subjects and a significant association was observed between the (AC) n dinucleotide repeat polymorphism at the 5 0 -end of the aldose reductase gene and diabetic nephropathy. The ZK2 allele appeared to be a genetic risk factor for susceptibility to diabetic nephropathy with a random effects odds ratio (OR) of 1 . 40 (95% confidence interval, CI (1 . 07, 1 . 84)). The ZC2 allele showed a protective effect on diabetic nephropathy with a random effects OR of 0 . 77 (95% CI (0 . 65, 0 . 91)). The meta-analysis, however, showed no association between the genetic polymorphism and diabetic nephropathy in type 2 diabetic subjects. Neither the risk ZK2 allele nor the protective ZC2 allele in type 1 diabetic subjects appeared to have an effect on nephropathy in type 2 diabetic subjects, while their fixed effects OR was 1 . 09 (95% CI (0 . 96, 1 . 22)) and 0 . 88 (95% CI (0 . 67, 1 . 15)) respectively.The current meta-analysis demonstrated a correlation between the (AC) n dinucleotide repeat polymorphism and the occurrence of diabetic nephropathy in Caucasian type 1 diabetic subjects in contrast to type 2 diabetic subject population in which such an association could not be demonstrated.

The purpose of our study was to evaluate the correlation between the beta-fibrinogen gene -148C/T and -455G/A polymorphisms and susceptibility to coronary artery disease in the Chinese population using a meta-analytic approach. Eligible studies about this correlation were identified by searching the PubMed, EMBASE, and CNKI databases. Of the 13 identified, 7 (with 1488 cases and 1234 controls) involved the -148C/T polymorphism and 9 (with 1023 cases and 1081 controls) involved the -455G/A polymorphism. No publication bias was detectable and heterogeneity testing found significant differences between the ORs for both groups of studies. The combined OR for the 7 studies on susceptibility to coronary artery disease in -148T allele carriers compared to the -148C/C wild-type homozygotes was 1.31 (95%CI: 0.94-1.84, P = 0.11). The combined OR for the 9 studies on susceptibility to coronary artery disease in -455A allele carriers compared to the -455G/G wild-type homozygotes was 1.75 (95%CI: 1.24-2.46, P = 0.001). Our results suggest the absence of an association between the beta-fibrinogen gene -148C/T polymorphism and susceptibility to coronary artery disease and the possibility that -455G/A polymorphism (in particular, allele A) increases susceptibility to this disease in the Chinese population.

Friedelin, the most rearranged pentacyclic triterpene, also exhibits remarkable pharmacological and anti-insect activities. In particular, celastrol with friedelin as the skeleton, which is derived from the medicinal plant Tripterygium wilfordii, is a promising drug due to its anticancer and antiobesity activities. Although a previous study achieved friedelin production using engineered Saccharomyces cerevisiae, strains capable of producing high-level friedelin have not been stably engineered. In this study, a combined strategy was employed with integration of endogenous pathway genes into the genome and knockout of inhibiting genes by CRISPR/Cas9 technology, which successfully engineered multiple strains. After introducing an efficient TwOSC1T502E, all strains with genetic integration (tHMG1, ERG1, ERG20, ERG9, POS5, or UPC2.1) showed a 3.0∼6.8-fold increase in friedelin production compared with strain BY4741. Through further double knockout of inhibiting genes, only strains GD1 and GD3 produced higher yields. Moreover, strains GQ1 and GQ3 with quadruple mutants (bts1; rox1; ypl062w; yjl064w) displayed similar increases. Finally, the dominant strain GQ1 with TwOSC1T502E was cultured in an optimized medium in shake flasks, and the final yield of friedelin reached 63.91 ± 2.45 mg/L, which was approximately 65-fold higher than that of the wild-type strain BY4741 and 229% higher than that in ordinary SD-His-Ura medium. It was the highest titer for friedelin production to date. Our work provides a good example for triterpenoid production in microbial cell factories and lays a solid foundation for the mining, pathway analysis, and efficient production of valuable triterpenoids with friedelin as the skeleton.

The amino dicarbonylation of aryl halides affording α-ketoamides with Pd catalysts is highly dependent on the stereoelectronic properties of the involved ligands. Ionic diphosphine ligand L4 can serve as precursor of a hemilabile P,C (phosphine, carbene)-hybrid ligand to form a stable Pd(II)complex, Pd-L4. In contrast, analogues L1−L3 with a similar 1-(thiophen-3-yl)-benzimidazolyl skeleton behave as typical (mono/ di)phosphines. The catalytic system resulting from the complexation of PdCl 2 (MeCN) 2 and L4 exhibits good catalytic performance in terms of aryl iodides conversion (81−95%) and αketoamide selectivity (80−91%), as well as the available recyclability in the RTIL of [Bpy]BF 4 . The in situ FT-IR analysis reveals that the PdCl 2 (MeCN) 2 −L4 catalytic system favors the amino dicarbonylation toward α-ketoamides according to the proposed mechanism of cycle I, which involves two independent COinsertion steps.

Colorectal cancer (CRC) is one of the most common malignant tumors in the world. Cases of colon cancer have experienced dramatic growth for the past few decades in China, while the rate of rectal cancer descends 3% every year in the West. The purpose of this study is to reveal the potential impact of miR-21-5p on the occurrence process of CRC and its connection with a close homolog of L1 (CHL1). In this study, the expression level of the miR-151-3p was found to be significantly higher in colon adenocarcinoma tissue compared with adjacent normal tissues, while the CHL1 was lower in colon adenocarcinoma tissues. The expression of miR-151-3p was inversely correlated with the expression of CHL-1, as it was confirmed with correlation analysis. miR-151-3p deregulates the expression of CHL1. CHL1 overexpression can restrain the proliferation and invasion of CRC. Tumorigenesis experiments showed that the tumor growth rate of CHL1-OV was significantly reduced in mice, and its effect could be reversed by miR-151-3p mimics. Taken together, our study may provide new insights into the potential mechanisms of progression of CRC, and may provide a theory for targeted drug therapy.