As a concentrated energy source with high added value, hydrogen has great development prospects, with special emphasis on sustainable microbial production as a replacement for traditional fossil fuels. In this study, λ-Red recombination was used to alter the activity of Complex I by single and combined knockout of nuoE, nuoF and nuoG. In addition, the conversion of malic to pyruvic acid was promoted by overexpressing the maeA gene, which could increase the content of NADH and formic acid in the bacterial cells. Compared to the original strain, hydrogen production was 65% higher in the optimized strain IAM1183-EFG/M, in which the flux of the formic acid pathway was increased by 257%, the flux of the NADH pathway was increased by 13%, and the content of metabolites also changed significantly. In further bioreactor, the total hydrogen production of the scale-up IAM1183-EFG/M after 44 h of fermentation was 4.76 L, which increased by 18% compared with the starting strain. This study provides a new direction for future exploration of microbial hydrogen production by combinatorial modification of multiple genes.
We investigated the distribution of HPV genotypes in Uyghur women in Xinjiang region of China, and behavioral factors which could predispose them to HPV infection. In this cross-sectional study, women aged 15-59 years were recruited by cluster sampling method in Yutian region in 2009. Liquid-based cytology samples were analyzed centrally for HPV genotype with a linear array detector. Univariate and multivariate logistic regression analyses were performed to identify behavioral risk factors for HPV infection. A total of 883 Uyghur women were recruited successfully. The prevalence of high-risk HPV and low-risk HPV were 7.25% and 1.58%, respectively; the most common HPVs were HPV16, 51, 31, 39 and 58. We found that age of first sexual intercourse was a strong predictor for HPV infection (odds ratio of 4.01 for ${\leq}15$ years versus ${\geq}25$). Having sexual partners ${\geq}3$ was the second predictor (OR 3.69, 95% CI 2.24-7.16). Cleaning the vagina after sex showed an increased risk of HPV infection (OR 2.72; 95% CI 1.98-5.13); Using the condom showed protective factors for HPV infection (OR 0.36; 95%CI0.12-0.53). HPV16, 51, 31, 39 and 58 were the priority types; the age of first sexual intercourse was identified as a major risk factor for HPV infection. Other notable risks were number of sexual partners and cleaning the vagina after sex. Changing these behavioral risk factors could help to reduce the occurrence of cervical cancer in this population.
Intramuscular implantation of cultured allogeneic myoblasts derived from pathogen-free muscle biopsies of genetically normal human volunteers demonstrated safety and efficacy in clinical studies of Duchenne muscular dystrophy (DMD), heart failure, ischemic cardiomyopathy, Type-II diabetes, cancer, and aging disfigurement. Through natural cell fusion, donor myoblasts inserted their normal nuclei that supplied the complete human genome to replenish the aberrant gene(s). The replacement gene(s) produced single or multiple gene transcripts, factors, and protein(s) in multiple pathways to effect complementary genetic repair. Donor myoblasts also fused among themselves to form normal myofibers. Applications included diagnostic screening, disease prevention, disease treatment, drug discovery, and selection of superior cell clones for therapies. Only 3-week cyclosporine immunosuppression was necessary to support engraftment, development, and functioning. Improvement in the host included production of repairing structural and regulatory proteins, increases in muscle cell number and function, increases in locomotive capacity, breathing capacity and life span in DMD boys, increases in blood ejection and vascularization in heart failure and ischemic patients, and transfer of biochemicals and ions across the muscle cell membrane in diabetic patients. Intra-tumor implantation of allogeneic human myoblasts induced cancer apoptosis, inhibiting metastasis and tumor growth with cancer patients. FDA currently listed 23 myoblast implantation projects, and EMA listed 6, mostly in Phase II with some in Phase III clinical trials. This unique platform technology, patented for its compositions, methods, and related medical devices of cell/gene therapies, promised to be of great social and economic values in world health and human services.
Abstract Mammalian male germ cell development is a stepwise cell-fate transition process; however, the full-term developmental profile of male germ cells remains undefined. Here, by interrogating the high-precision transcriptome atlas of 11,598 cells covering 28 critical time-points, we demonstrate that cell-fate transition from mitotic to post-mitotic primordial germ cells is accompanied by transcriptome-scale reconfiguration and a transitional cell state. Notch signaling pathway is essential for initiating mitotic arrest and the maintenance of male germ cells’ identities. Ablation of HELQ induces developmental arrest and abnormal transcriptome reprogramming of male germ cells, indicating the importance of cell cycle regulation for proper cell-fate transition. Finally, systematic human-mouse comparison reveals potential regulators whose deficiency contributed to human male infertility via mitotic arrest regulation. Collectively, our study provides an accurate and comprehensive transcriptome atlas of the male germline cycle and allows for an in-depth understanding of the cell-fate transition and determination underlying male germ cell development.
Abstract 2,3-Butanediol (2,3-BDO) is an important gateway molecule for many chemical derivatives. Currently, microbial production is gradually being recognized as a green and sustainable alternative to petrochemical synthesis, but the titer, yield, and productivity of microbial 2,3-BDO remain suboptimal. Here, we used systemic metabolic engineering strategies to debottleneck the 2,3-BDO production in Enterobacter aerogenes . Firstly, the pyruvate metabolic network was reconstructed by deleting genes for by-product synthesis to improve the flux toward 2,3-BDO synthesis, which resulted in a 90% increase of the product titer. Secondly, the 2,3-BDO productivity of the IAM1183-LPCT/D was increased by 55% due to the heterologous expression of DR1558 which boosted cell resistance to abiotic stress. Thirdly, carbon sources were optimized to further improve the yield of target products. The IAM1183-LPCT/D showed the highest titer of 2,3-BDO from sucrose, 20% higher than that from glucose, and the yield of 2,3-BDO reached 0.49 g/g. Finally, the titer of 2,3-BDO of IAM1183-LPCT/D in a 5-L fermenter reached 22.93 g/L, 85% higher than the wild-type strain, and the titer of by-products except ethanol was very low. Key points Deletion of five key genes in E. aerogenes improved 2,3-BDO production The titer of 2,3-BDO was increased by 90% by regulating metabolic flux Response regulator DR1558 was expressed to increase 2,3-BDO productivity Graphical abstract
Anti-Aging Regenerative Cosmetology (AARC) is a patented technology for beautifying and strengthening the human body using live cells to enhance the appearance and function of various body parts to provide health and aestheticism to the individual throughout life. It is a combined cosmetic and preventive medicine to intervene with and correct the undesirable phenotypic expression of aging. The intrinsic properties of myoblasts and foreskin fibroblasts in development and regeneration are harnessed to formulate a genetic cell therapy program that is safe and efficacious, as previously tested in FDA Phase III clinical trials. Myoblasts are selected for strength development and foreskin fibroblasts for tenacity and smooth-to-the-touch. Both cell types are highly mitotic and non-carcinogenic. In addition to providing large quantities of nuclei as regenerative gene medicine and mitochondria as energy generators, myoblasts secret tumor necrosis factor-alpha (TNF-α) for skin whitening and melanoma prevention. Myoblasts, because of their small size, spindle shape, and resilience, grow readily on collagen and laminin within wrinkles of skin surfaces, thus enhancing the color, luster, and texture of the skin "plated" with them. Alternatively, they can be injected subcutaneously as cell fillers to reduce wrinkles. Intramuscular injection of myoblasts can augment muscle groups' size, shape, consistency, tone, and strength, improving the lines, contours, and vitality to sculpt a youthful appearance. By improving cell genetics and organ functions, the program promises to sustain the human subject in good health and appearance, with a good quality of life and prolonged life.
Evidence for the association between long-term exposure to ozone (O3) and cause-specific cardiovascular disease (CVD) mortality is inconclusive, and this association has rarely been evaluated at high O3 concentrations. We aim to evaluate the associations between long-term O3 exposure and cause-specific CVD mortality in a Chinese population. From 2009 to 2018, 744,882 subjects (median follow-up of 7.72 years) were included in the CHinese Electronic health Records Research in Yinzhou (CHERRY) study. The annual average concentrations of O3 and fine particulate matter (PM2.5), which were estimated using grids with a resolution up to 1 × 1 km, were assigned to the community address for each subject. The outcomes were deaths from CVD, ischemic heart disease (IHD), myocardial infarction (MI), stroke, and hemorrhagic/ischemic stroke. Time-varying Cox model adjusted for PM2.5 and individual-level covariates was used. The mean of annual average O3 concentrations was 68.05 μg/m3. The adjusted hazard ratio per 10 μg/m3 O3 increase was 1.22 (95% confidence interval [CI]: 1.13–1.33) for overall CVD mortality, 1.08 (0.91–1.29) for IHD, 1.21 (0.90–1.63) for MI, 1.28 (1.15–1.43) for overall stroke, 1.39 (1.16–1.67) for hemorrhagic stroke and 1.22 (1.00–1.49) for ischemic stroke, respectively. The study showed that subjects without hypertension had a higher risk for CVD mortality associated with long-term O3 exposure (1.66 vs. 1.15, p = 0.01). We observed the association between long-term exposure to high O3 concentrations and cause-specific CVD mortality in China, independent of PM2.5 and other CVD risk factors. This suggested an urgent need to control O3 pollution, especially in developing countries.
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