A Common Variant Of Ubiquinol-Cytochrome c Reductase Complex Is Associated with DDH

Purpose

Genetic basis of Developmental dysplasia of the hip (DDH) remains largely unknown. To find new susceptibility genes for DDH, we carried out a genome-wide association study (GWAS) for DDH.

Methods

We enrolled 386 radiology confirmed DDH patients and 558 healthy controls (Set A) to conduct a genome-wide association study (GWAS). Quality-control was conducted at both the sample and single nucleotide polymorphism (SNP) levels. We then conducted a subsequent case-control study to replicate the association between a promising loci, rs6060373 in UQCC gene and DDH in an independent set of 755 cases and 944 controls (set B).

Results

In the DDH GWAS discovering stage, 51 SNPs showed significance of less than 10^-4, and another 577 SNPs showed significance of less than 10-3. In UQCC, all the 12 genotyped SNPs showed as promising risk loci. Genotyping of rs6060373 in set A showed the minor allele A as a promising risk allele (p = 4.82*10^-7). In set A, the odds ratio of allele A was 1.77. Genotyping of rs6060373 in Set B produced another significant result (p = 0.0338) with an odds ratio of 1.18 for risk allele A. Combining set A and set B, we identified a total p value of 3.63*10^-6 with the odds ratio of 1.35 (1.19–1.53) for allele A.

Conclusion

Our study demonstrates common variants of UQCC, specifically rs6060373, are associated with DDH in Han Chinese population.     

Synergetic utilization of glucose and glycerol for efficient myo-inositol biosynthesis

myo-Inositol (MI) as a dietary supplement can provide various health benefits. One major challenge to its efficient biosynthesis is to achieve proper distribution of carbon flux between growth and production. Herein, this challenge was overcome by synergetic utilization of glucose and glycerol. Specifically, glycerol was catabolized to support cell growth while glucose was conserved as the building block for MI production. Growth and production were coupled via the phosphotransferase system, and both modules were optimized to achieve efficient production. First, the optimal enzyme combination was established for the production module. It was observed that enhancing the production module resulted in both increased MI production and better cell growth. In addition, glucose was shown to inhibit glycerol utilization via carbon catabolite repression and the inhibition was released by over-expressing glycerol kinase. Furthermore, the inducible promoter was replaced by strong constitutive promoters to avoid inducer use. With these efforts, the final strain produced MI with both high titer and yield. In fed-batch cultivation, 76 g/L of MI was produced, showing scale-up potential. This study provides a promising strategy to achieve rational distribution of carbon flux.     

Impacts of main factors on bioethanol fermentation from stalk juice of sweet sorghum by immobilized Saccharomyces cerevisiae (CICC 1308)

In order to attain a higher ethanol yield and faster ethanol fermentation rate, orthogonal experiments of ethanol fermentation with immobilized yeast from stalk juice of sweet sorghum were carried out in the shaking flasks to investigate the effect of main factors, namely, fermentation temperature, agitation rate, particles stuffing rate and pH on ethanol yield and CO(2) weight loss rate. The range analysis and analysis of variance (ANOVA) were applied for the results of orthogonal experiments. Results showed that the optimal condition for bioethanol fermentation should be A(4)B(3)C(3)D(4), namely, fermentation temperature, agitation rate, particles stuffing rate and pH were 37 degrees C, 200rpm, 25% and 5.0, respectively. The verification experiments were carried out in shaking flasks and 5L bioreactor at the corresponding parameters. The results of verification experiments in the shaking flasks showed that ethanol yield and CO(2) weight loss rate were 98.07% and 1.020gh(-1), respectively. The results of ethanol fermentation in the 5L bioreactor showed that ethanol yield and fermentation time were 93.24% and 11h, respectively. As a result, it could be concluded that the determined optimal condition A(4)B(3)C(3)D(4) was suitable and reasonable for the ethanol fermentation by immobilized Saccharomyces cerevisiae. The conclusion in the research would be beneficial for application of ethanol fermentation by immobilized S. cerevisiae from stalk juice of sweet sorghum.     

Characterization of tailoring genes involved in the modification of geldanamycin polyketide in Streptomyces hygroscopicus JCM4427

Geldanamycin and its analogs are important anticancer agents that inhibit the newly targeted, heat-shock protein (Hsp) 90, which is a chaperone protein in eukaryotic cells. To resolve which geldanamycin biosynthetic genes are responsible for particular post-polyketide synthase (PKS) processing steps and in which order the reactions occur, we individually inactivated candidate genes in Streptomyces hygroscopicus subsp. duamyceticus JCM4427, and isolated and elucidated the structures of intermediates from each mutant. The results indicated that gel7 governs at least one of the benzoquinone ring oxidation steps. In addition, gel16 was found to be involved in double-bond formation between C-4 and C-5 of 4,5-dihydrogeldanamycin, which confirmed our previous findings that this double bond reduced during the post-PKS modification of the polyketide assembly. In addition, pro-geldanamycin, which does not possess a double bond at C-4/5, was purified from the gel7 and 8 double-gene-inactivated mutant.     

Carnosine protects against permanent cerebral ischemia in histidine decarboxylase knockout mice by reducing glutamate excitotoxicity

Recently, we showed that carnosine protects against NMDA-induced excitotoxicity in differentiated PC12 cells through a histaminergic pathway. However, whether the protective effect of the carnosine metabolic pathway also occurs in ischemic brain is unknown. Utilizing the model of permanent middle cerebral artery occlusion (pMCAO) in mice, we found that carnosine significantly improved neurological function and decreased infarct size in both histidine decarboxylase knockout and the corresponding wild-type mice to the same extent. Carnosine decreased the glutamate levels and preserved the expression of glutamate transporter-1 (GLT-1) but not the glutamate/aspartate transporter in astrocytes exposed to ischemia in vivo and in vitro. It suppressed the dissipation of ΔΨ_m and generation of mitochondrial reactive oxygen species (ROS) induced by oxygen–glucose deprivation in astrocytes. Furthermore, carnosine also decreased the mitochondrial ROS and reversed the decrease in GLT-1 induced by rotenone. These findings are the first to demonstrate that the mechanism of carnosine action in pMCAO may not be mediated by the histaminergic pathway, but by reducing glutamate excitotoxicity through the effective regulation of the expression of GLT-1 in astrocytes due to improved mitochondrial function. Thus, our study reveals a novel antiexcitotoxic agent in ischemic injury.