Our understanding of when and how humans adapted to living on the Tibetan Plateau at altitudes above 2000 to 3000 meters has been constrained by a paucity of archaeological data. Here we report data ...sets from the northeastern Tibetan Plateau indicating that the first villages were established only by 5200 calendar years before the present (cal yr B.P.). Using these data, we tested the hypothesis that a novel agropastoral economy facilitated year-round living at higher altitudes since 3600 cal yr B.P. This successful subsistence strategy facilitated the adaptation of farmers-herders to the challenges of global temperature decline during the late Holocene.
•GSH-deficient mouse models have been developed by targeting GCL, the rate-limiting enzyme of GSH biosynthesis.•Liver-specific Gclc knockout mice have 95% depletion of hepatic GSH and develop ...spontaneous steatohepatitis.•Universal Gclm deleted mice have 15% of normal hepatic GSH and are protected from liver injuries induced by hepatic insults.•Animal studies indicate a potential role of hepatic GSH in fine-tuning metabolic and stress responses to liver injuries.
Glutathione (GSH) is the most abundant cellular thiol antioxidant and it exhibits numerous and versatile functions. Disturbances in GSH homeostasis have been associated with liver diseases induced by drugs, alcohol, diet and environmental pollutants. Until recently, our laboratories and others have developed mouse models with genetic deficiencies in glutamate-cysteine ligase (GCL), the rate-limiting enzyme in the GSH biosynthetic pathway. This review focuses on regulation of GSH homeostasis and, specifically, recent studies that have utilized such GSH-deficient mouse models to investigate the role of GSH in liver disease processes. These studies have revealed a differential hepatic response to distinct profiles of hepatic cellular GSH concentration. In particular, mice engineered to not express the catalytic subunit of GCL in hepatocytes Gclc(h/h) mice experience almostcomplete loss of hepatic GSH (to 5% of normal) and develop spontaneous liver pathologies characteristic of various clinical stages of liver injury. In contrast, mice globally engineered to not express the modifier subunit of GCL Gclm(−/−) mice show a less severe hepatic GSH deficit (to ≈15% of normal) and exhibit overall protection against liver injuries induced by a variety of hepatic insults. Collectively, these transgenic mouse models provide interesting new insights regarding pathophysiological functions of GSH in the liver.
Aims
Poly‐γ‐glutamic acid (γ‐PGA) is an excellent water‐soluble biosynthesis material. To confirm the rate‐limiting steps of γ‐PGA biosynthesis pathway, we introduced a heterologous Bacillus strain ...pathway and employed an enzyme‐modulated dismemberment strategy in Escherichia coli.
Methods and Results
In this study, we heterologously introduced the γ‐PGA biosynthesis pathway of two laboratory‐preserved strains—Bacillus amyloliquefaciens FZB42 and Bacillus subtilis 168 into E. coli, and compared their γ‐PGA production levels. Next, by changing the plasmid copy numbers and supplying sodium glutamate, we explored the effects of gene expression levels and concentrations of the substrate l‐glutamic acid on γ‐PGA production. We finally employed a two‐plasmid induction system using an enzyme‐modulated dismemberment of pgsBCAE operon to confirm the rate‐limiting genes of the γ‐PGA biosynthesis pathway.
Conclusion
Through heterologously over‐expressing the genes of the γ‐PGA biosynthesis pathway and exploring gene expression levels, we produced 0·77 g l−1 γ‐PGA in strain RSF‐EBCAE(BS). We also confirmed that the rate‐limiting genes of the γ‐PGA biosynthesis pathway were pgsB and pgsC.
Significance and Impact of the Study
This work is beneficial to increase γ‐PGA production and study the mechanism of γ‐PGA biosynthesis enzymes.
China has experienced considerable economic losses from a severe deterioration in air quality. To solve this, a comprehensive understanding of the impacts and sources of air pollution is necessary. ...This study aimed to quantify the environmental and human health impacts of PM2.5 and O3 pollution from the six major emission-producing sectors in China. We utilized a chemical transport model to simulate the air quality impacts engendered by sectoral emissions. The consequent impacts on public health and crop production, as well as the corresponding collateral economic costs, were quantified by concentration-response functions. The results show that the sectoral emissions in 2010 caused approximately 1 143 000 (95% confidence interval (CI): 168 000-1 796 000) premature mortalities and a 20 035 (95% CI: 6776-32 166) Gg crop production loss. Of the six sectors, the industrial sector was the largest contributor of air pollution, accounting for 36% of the total impact on health, as well as 41% of crop production loss due to O3 exposure. The impacts attributable to sectoral emissions in China were estimated to cost ∼267 (95% CI: 180-360) billion yuan (0.66% of the annual GDP). Our findings suggest an urgent need to reduce anthropogenic emissions in China, particularly those of the industrial sector. The varying characteristics of impact due to emissions of various sectors highlight the importance of evaluating cobenefits when formulating emission control policies.
Despite a downward trend in pollutant levels because of a series of emission control policies, the Pearl River Delta (PRD) region continues to suffer from a high number of fine particulate matter ...(PM2.5) events and the resultant public health impacts. To effectively control PM2.5 in the region, a comprehensive understanding of source contribution and PM2.5 responses to various emission species is critical. We applied the Community Multiscale Air Quality Modeling System together with the high-order decoupled direct method, to simulate air quality and PM2.5 sensitivity and examined PM2.5 responses to emission species in the PRD region in the four seasons of 2010. We employed a concentration-response function to quantify the resultant number of premature mortalities attributable to outdoor PM2.5. We estimated that local and transboundary air pollution (TAP) contributed 27% and 73%, respectively, of the region's PM2.5. In absolute terms, the largest impacts from local and TAP occurred in winter. With respect to relative contributions among the different sources, regional TAP (between cities in the region) (R-TAP) and local contributions had the largest effect in summer, whereas superregional TAP (from outside of the region) contributed the most in fall and winter. Outdoor PM2.5 pollution caused 20 160 (95% confidence interval: 5100-39 310) premature mortalities every year in the PRD region. Averaging among cities, 50%, 20%, and 30% of these deaths were attributable to S-TAP, R-TAP, and local contributions, respectively. Precursor gas emissions (i.e. NH3, volatile organic compounds, SO2, and NOx) affect PM2.5 level in a nonlinear manner; thus, individual pollutant control strategies are less effective for improving PM2.5 pollution than an integrated strategy. On the basis of our findings, we recommend that controls for multiple emission species should be implemented to control PM2.5 pollution in the region.
Aims
To establish the biotechnology platforms for production of bio‐based chemicals in various micro‐organisms is considered as a promising target to improve renewable production of isoprene.
Methods ...and Results
In this study, we heterologously expressed the mevalonate (MVA) isoprene biosynthesis pathway, and explored three strategies of increasing isoprene production in Escherichia coli. We first manipulated the expression levels of the MVA pathway genes through changing the gene cassettes and promoters. To introduce cofactor engineering, we then overexpressed NADP‐dependent glyceraldehyde‐3‐phosphate dehydrogenase gene from Clostridium acetobutylicum to supply available NADPH. To reduce the inhibitory by‐product accumulation, we finally knocked out acetate‐producing genes, phosphate acetyl transferase and pyruvate oxidase B in E. coliJM109 (DE3), decreasing acetate accumulation 89% and increasing isoprene production 39%. The strategies described here finally increased the isoprene titre to 92 mg l−1 in two‐gene deletion strain JMAB‐4T7P1Trc, increasing 2·6‐fold comparing to strain JM7T7.
Conclusion
The multimodularly engineering approaches including promoter engineering, cofactor engineering and by‐product reducing could be used to improve isoprene production in E. coli.
Significance and Impact of the Study
The metabolic strategies in this study show us directions for further studies to promote transformation of renewable sources to isoprene.
Runx2, Osx, and Dspp in Tooth Development Chen, S.; Gluhak-Heinrich, J.; Wang, Y.H. ...
Journal of dental research,
10/2009, Letnik:
88, Številka:
10
Journal Article
Recenzirano
Odprti dostop
The transcription factors Runx2 and Osx are necessary for osteoblast and odontoblast differentiation, while Dspp is important for odontoblast differentiation. The relationship among Runx2, Osx, and ...Dspp during tooth and craniofacial bone development remains unknown. In this study, we hypothesized that the roles of Runx2 and Osx in the regulation of osteoblast and odontoblast lineages may be independent of one another. The results showed that Runx2 expression overlapped with Osx in dental and osteogenic mesenchyme from E12 to E16. At the later stages, from E18 to PN14, Runx2 and Osx expressions remained intense in alveolar bone osteoblasts. However, Runx2 expression was down-regulated, whereas Osx expression was clearly seen in odontoblasts. At later stages, Dspp transcription was weakly present in osteoblasts, but strong in odontoblasts where Osx was highly expressed. In mouse odontoblast-like cells, Osx overexpression increased Dspp transcription. Analysis of these data suggests differential biological functions of Runx2, Osx, and Dspp during odontogenesis and osteogenesis.
Summary
The aims of our meta‐analysis were (i) to quantify the predictability of childhood overweight and obesity on the risk of incident asthma; and (ii) to evaluate the gender difference on this ...relationship. The selection criteria included prospective cohort paediatric studies which use age‐ and sex‐specific body mass index (BMI) as a measure of childhood overweight and the primary outcome of incident asthma. A total of 1,027 studies were initially identified through online database searches, and finally 6 studies met the inclusion criteria. The combined result of reported relative risk from the 6 included studies revealed that overweight children conferred increased risks of incident asthma as compared with non‐overweight children (relative risk, 1.19; 95% confidence interval CI, 1.03–1.37). The relationship was further elevated for obesity vs. non‐obesity (relative risk, 2.02; 95% CI, 1.16–3.50). A dose–responsiveness of elevated BMI on asthma incidence was observed (P for trend, 0.004). Obese boys had a significantly larger effect than obese girls (relative risk, boys: 2.47; 95% CI, 1.57–3.87; girls: 1.25; 95% CI, 0.51–3.03), with significant dose‐dependent effect. Proposed mechanisms of gender difference could be through pulmonary mechanics, sleep disordered breathing and leptin. Further research might be needed to better understand the exact mechanism of gender difference on the obesity–asthma relationship.
Eggerthella lenta is a prevalent human gut Actinobacterium implicated in drug, dietary phytochemical, and bile acid metabolism and associated with multiple human diseases. No genetic tools are ...currently available for the direct manipulation of E. lenta. Here, we construct shuttle vectors and develop methods to transform E. lenta and other Coriobacteriia. With these tools, we characterize endogenous E. lenta constitutive and inducible promoters using a reporter system and construct inducible expression systems, enabling tunable gene regulation. We also achieve genome editing by harnessing an endogenous type I-C CRISPR-Cas system. Using these tools to perform genetic knockout and complementation, we dissect the functions of regulatory proteins and enzymes involved in catechol metabolism, revealing a previously unappreciated family of membrane-spanning LuxR-type transcriptional regulators. Finally, we employ our genetic toolbox to study the effects of E. lenta genes on mammalian host biology. By greatly expanding our ability to study and engineer gut Coriobacteriia, these tools will reveal mechanistic details of host-microbe interactions and provide a roadmap for genetic manipulation of other understudied human gut bacteria.
Background and purpose
The aim was to investigate relationships between serum fibulin‐5 concentration and the severity or prognosis in patients with acute intracerebral haemorrhage (ICH).
Methods
...Consecutive ICH patients and healthy controls were included and clinical data were collected. National Institute of Health Stroke Scale (NIHSS) and Glasgow Coma Scale (GCS) were assessed at admission time within 3 days after bleeding. Cerebral haemorrhage volume was calculated and serum fibulin‐5 concentration was measured at the same time. Multivariate linear regression analyses were performed to determine risk factors for serum fibulin‐5 concentration and Spearman correlation coefficients were obtained to explore the relationships between fibulin‐5 concentration and NIHSS or GCS scores. Patients were followed up for 3 months and the modified Rankin Scale was evaluated for all survivors. Receiver operating characteristic (ROC) curves were obtained to explore fibulin‐5 concentration in predicting prognosis.
Results
Serum fibulin‐5 concentration had increased in ICH patients compared with healthy controls (65.86 ± 26.39 μg/l vs. 40.66 ± 5.03 μg/l, P = 0.00) and was mainly influenced by haemorrhage volume (β = 0.905, P = 0.000) and extension to ventricles (β = 10.173, P = 0.097). Serum fibulin‐5 concentration was positively correlated with NIHSS score (r = 0.511, P = 0.000) but inversely correlated with GCS score (r = −0.585, P = 0.000). Based on the ROC curves, the optimal cut‐off point was 80.68 μg/l for death, and the sensitivity and specificity values of serum fibulin‐5 were 77.8% and 93.2%, whilst the optimal cut‐off point was 48.45 μg/l for poor prognosis and the sensitivity and specificity values were 86.4% and 54.1%, respectively.
Conclusions
Serum fibulin‐5 concentration can be regarded as a biomarker for evaluating disease severity and predicting prognosis in ICH patients.
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