Exploring the Diverse Landscape of Fungal Cytochrome P450-Catalyzed Regio- and Stereoselective Dimerization of Diketopiperazines.

Dimeric indole-containing diketopiperazines (di-DKPs) are a diverse group of natural products produced through cytochrome P450-catalyzed C-C or C-N coupling reactions. The regio- and stereoselectivity of these reactions plays a significant role in the structural diversity of di-DKPs. Despite their pivotal role, the mechanisms governing the selectivity in fungi are not fully understood. Employing bioinformatics analysis and heterologous expression experiments, five undescribed P450 enzymes (AmiP450, AcrP450, AtP450, AcP450, and AtuP450) responsible for the regio- and stereoselective dimerization of diketopiperazines (DKPs) in fungi are identified. The function of these P450s is consistent with phylogenetic analysis, highlighting their dominant role in controlling the dimerization modes. Combinatorial biosynthesis-based pathway reconstitution of non-native gene clusters expands the chemical space of fungal di-DKPs and reveals that the regioselectivity is influenced by the substrate. Furthermore, multiple sequence alignment and molecular docking of these enzymes demonstrate a C-terminal variable region near the substrate tunnel entrance in AtuP450 that is crucial for its regioselectivity. These findings not only reveal the secret of fungal di-DKPs diversity but also deepen understanding of the mechanisms and catalytic specificity involved in P450-catalyzed dimerization reactions.

A Fungal Promiscuous UbiA Prenyltransferase Expands the Structural Diversity of Chrodrimanin-Type Meroterpenoids.

Prenyltransferases play important roles in the diversification of natural products and the improvement of biological activities. A UbiA-type prenyltransferase CdnC with substrate promiscuity was identified as the pivotal builder of the noncanonical chrodrimanin skeletons, which carry a benzo-cyclohexanone structure as the nonterpene part. In vitro and heterologous expression studies with CdnC led to the production of a series of novel chrodrimanin-like structures. The discovery of CdnC offers a referable strategy for the biosynthesis and structural diversification of farnesyl-derived meroterpenoids.

Heterologous expression and metabolic engineering tools for improving terpenoids production.

Terpenoids, also referred to as isoprenoids, are the largest group of natural compounds which have contributed significantly to the pharmaceutical industry. The challenges in producing bioactive terpenoids from their original host or by organic synthesis methods spurred the endeavors of producing terpenoids in heterologous host. Modern advances utilizing synthetic biology and biological engineering tools have provided a variety of pharmaceutical terpenoids in large-scale and with diversified structures. In this review, we will summarize the progress in production of typical terpenoids skeletons using heterologous expression method assisted by metabolic engineering techniques, with the purpose of enlightening further efforts in developing advanced cell factories for producing terpenoid based pharmaceuticals.

Overexpression of Global Regulator PbrlaeA Leads to the Discovery of New Polyketide in Fungus Penicillium Brocae HDN-12-143.

Overexpression of the PbrlaeA gene of the fungus Penicillium brocae HDN-12-143 resulted in the isolation of four compounds including fumigatin chlorohydrin (1), whose configuration has not been reported before, and one new compound iso-fumigatin chlorohydrin (2). All structures including absolute configurations were elucidated on the basis of comprehensive spectroscopic data, 13C NMR calculations, and ECD calculations. Compounds 1 and 2 exhibited cytotoxic activity against HL-60 with IC50 of 18.63 and 24.83 µM.

Amphiepicoccins A-J: Epipolythiodioxopiperazines from the Fish-Gill-Derived Fungus Epicoccum nigrum HDN17-88.

Ten new epipolythiodioxopiperazines (ETPs), namely, amphiepicoccins A-J (1-10), were isolated from the fish-gill-derived fungus Epicoccum nigrum HDN17-88. Their structures were deduced from extensive spectroscopic data and electronic circular dichroism (ECD) calculations. Amphiepicoccin A (1) which contains an aromatic indole motif is unprecedented among the epicoccin type of ETPs. Compounds 1, 3, and 6 displayed anti-HSV-2 activities, with IC50 values of 70, 64, and 29 µM, respectively (acyclovir as positive control with an IC50 value of 31 µM), while 5 and 6 also revealed inhibitory activity against Bacillus subtilis with minimum inhibitory concentration (MIC) values of 13 and 25 µM, respectively.

Job Satisfaction Among Doctors from Jiangsu Province in China.

BACKGROUND Doctors' job satisfaction has an important effect on medical and health services. This study assessed the level of job satisfaction in Chinese doctors and explored how influencing factors differ between general practitioners and specialists. MATERIAL AND METHODS The Minnesota Satisfaction Questionnaire (MSQ) on job satisfaction was distributed to 1883 doctors in Jiangsu province, including 850 general practitioners and 1033 specialists. Data analysis was performed with SPSS 20.0. A one-way ANOVA was used to analyze doctors' job satisfaction and logistic regression analysis was used for multivariate analysis. Correlation analysis was done on the 5 dimensions of satisfaction. RESULTS The average MSQ score of all surveyed doctors was 3.11±0.87, with general practitioners (GPs) and specialists scores of 2.81±0.84 and 3.35±0.82, respectively. Analysis of doctor satisfaction indicated that gender, age, marital status, educational attainment, professional title, and seniority were statistically significant (P<0.05). Overall satisfaction was most closely related to the job itself (r=0.96); work, work environment, and interpersonal relationship were closely related with lead management. CONCLUSIONS The level of job satisfaction of Chinese doctors, especially general practitioners, needs to be improved. Measures such as improving education levels, work environment, and relationships should to be taken soon to improve doctors' job satisfaction in China.

Impact of Community-Based Integrated Traditional Chinese and Western Medicine Metabolic Syndrome Intervention Technology in Rural Residents in Southern Jiangsu, China.

BACKGROUND: To explore the feasibility and efficiency of community-based integrated traditional Chinese medicine (TCM) and Western medicine metabolic syndrome (MS) intervention in rural residents. MATERIAL AND METHODS: The MS intervention was administered to 598 rural community residents aged 45 years and older in Zhoushi from 2011 to 2013. Subjects completed a health examination and health behavior questionnaire before and after the intervention. In the intervention, we designed a "healthy life self-help program" using TCM appropriate technologies for the subjects. RESULTS: After 2 years of intervention by means of integrated traditional Chinese and Western medicine, 57.0% (341 persons) of the subjects no longer suffered from MS. The recovery rate of BMI, blood pressure, FBG, TG, and HDL-C were 22.1%, 40.5%, 37.9%, 32.8%, and 62.4%, respectively. There were statistically significant differences in exercise, smoking, and alcohol drinking between baseline and 2 years later. CONCLUSIONS: The integrated traditional Chinese and Western medicine MS intervention was effective in deceasing most of the parameters of MS, especially blood pressure, and helping people to do more exercise. The program would be useful to implement in other similar populations.

WITHDRAWN: Effects of motivational interviewing on lifestyle modification and diabetes prevention in adults with pre-diabetes.

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Trend in distribution of primary health care professionals in Jiangsu province of eastern China.

INTRODUCTION: Since the late 1990 s, the Chinese government has carried out several reforms on the primary health care, which is greatly improved but still left much to be desired, especially for the health workforces. The aim of this study was to analyze the number of health workforces and the trends in distribution of health workforces in Jiangsu province of eastern China from 2008 to 2012. METHODS: The time trends in number and distribution of health professionals were compared in study period. Lorenz curves were plotted and Gini coefficient, Atkinson index and Theil index were calculated for inequalities in the distribution of health workforces to population and area. RESULTS: The number of health workforces increased every year and the inequality in the distribution of health workforces showed a decline trend from 2008 to 2012. After 2009, these trends changed more rapidly. There was the disproportionality between physicians and nurses. The values of three inequality indicators based on area were larger than those based on population. CONCLUSION: The health reform in 2009 might play an important role in increasing the number of health workforces and improving the distribution of health workforces in primary health care facilities. The disproportionality between physicians and nurses was related to the shortage of number of nurses.