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Terpene cyclization, one of the most complex chemical reactions in nature, is generally catalyzed by two classes of terpene cyclases (TCs). Cytochrome P450s that act as unexpected TC-like enzymes are known but are very rare. Here, we genome-mined a cryptic bacterial terpenoid gene cluster, named ari, from the thermophilic actinomycete strain Amycolatopsis arida. By employing a heterologous production system, we isolated and characterized three highly oxidized eunicellane-derived diterpenoids, aridacins AC (13), that possess a rare 6/7/5-fused tricyclic scaffold. In vivo and in vitro experiments systematically established a non-canonical two-step biosynthetic pathway for diterpene skeleton formation. First, a class I TC (AriE) cyclizes geranylgeranyl diphosphate (GGPP) into a 6/10-fused bicyclic cis-eunicellane skeleton. Next, a cytochrome P450 (AriF) catalyzes cyclization of the eunicellane skeleton into the 6/7/5-fused tricyclic scaffold via C2-C6 bond formation. Quantum chemical computations support a hydrogen abstraction and subsequent oxidation mechanism for AriF catalyzed carbocation cyclization. The biosynthetic logic of skeleton construction in the aridacin diterpenoids is unprecedented, expanding the catalytic capacity and diversity of P450s and setting the stage to investigate the inherent principles of carbocation generation by P450s in the biosynthesis of terpenoids.

Terpene cyclases (TCs), the extraordinary enzymes that create the structural diversity seen in terpene natural products, are traditionally divided into two classes. Although the structural and mechanistic features in class I TCs are well-known, the corresponding details in class II counterparts have not been fully characterized. Here, we report the genome mining discovery and structural characterization of two class II sesquiterpene cyclases (STCs) from Streptomyces. These drimenyl diphosphate synthases (DMSs) are the first STCs shown to possess β,γ-didomain architecture. High-resolution X-ray crystal structures of SsDMS in complex with both a farnesyl diphosphate and Mg2+ unveiled an induced-fit mechanism with an unprecedented Mg2+ binding mode, finally solving one of the lingering questions in class II TC enzymology. This study supports continued genome mining for novel bacterial TCs and provides new mechanistic insights into canonical class II TCs that will lead to advances in TC engineering and synthetic biology.

The Chinese community-acquired pneumonia (CAP) Diagnosis and Treatment Guideline 2020 recommends quinolone antibiotics as the initial empirical treatment options for CAP. However, patients with pulmonary tuberculosis (PTB) are often misdiagnosed with CAP because of the similarity of symptoms. Moxifloxacin and levofloxacin have inhibitory effects on mycobacterium tuberculosis as compared with nemonoxacin, resulting in delayed diagnosis of PTB. Hence, the aim of this study is to compare the cost-effectiveness of nemonoxacin, moxifloxacin and levofloxacin in the treatment of CAP and to determine the value of these treatments in the differential diagnosis of PTB. Primary efficacy data were collected from phase II-III randomized, double-blind, multi-center clinical trials comparing nemonoxacin to moxifloxacin (CTR20130195) and nemonoxacin to levofloxacin (CTR20140439) for the treatment of Chinese CAP patients. A decision tree was constructed to compare the cost-utility among three groups under the perspective of healthcare system. The threshold for willingness to pay (WTP) is 1–3 times GDP per capita ($11,174–33,521). Scenarios including efficacy and cost for CAP patients with a total of 6% undifferentiated PTB. Sensitivity and scenario analyses were performed to test the robustness of basic analysis. The costs of nemonoxacin, moxifloxacin, and levofloxacin were $903.72, $1053.59, and $1212.06 and the outcomes were 188.7, 188.8, and 188.5 quality-adjusted life days (QALD), respectively. Nemonoxacin and moxifloxacin were dominant compared with levofloxacin, and the ICER of moxifloxacin compared with nemonoxacin was $551,643, which was much greater than WTP; therefore, nemonoxacin was the most cost-effective option. Regarding patients with PTB who were misdiagnosed with CAP, taking nemonoxacin could save $290.76 and $205.51 when compared with moxifloxacin and levofloxacin and resulted in a gain of 2.83 QALDs. Our findings demonstrate that nemonoxacin is the more economical compared with moxifloxacin and levofloxacin, and non-fluoroquinolone antibiotics are cost-saving and utility-increasing compared to fluoroquinolones in the differential diagnosis of PTB, which can help healthcare system in making optimal policies and help clinicians in the medication of patients.

Background: Currently, increasing regions have realized that universal vaccination are necessary to prevent COVID-19. However many of them are facing problems associated with insufficient supply or chaotic allocation of vaccines. This study selected the United States population as an example and explored prioritization strategies of COVID-19 vaccination for different age groups to achieve the highest economic efficiency.Methods: We built a dynamic transmission model to predict the incidence of SARS-CoV-2 infections under the prioritization strategies of vaccination for different ages within a 180-day simulation period. Quality-adjusted life year (QALY) was selected as the outcome. Medical costs included direct medical cost and vaccine cost based on a healthcare system perspective. Data on SARS-CoV-2 epidemiology, vaccine efficacy, and medical costs were derived from publicly available databases and previously published literature. Different COVID-19 vaccines were included in scenario analysis. The robustness of the study results was evaluated by one-way sensitivity analysis and probabilistic sensitivity analysis.Results: COVID-19 vaccination is economical compared with no vaccination. Priority vaccination for adults aged 25–59 years saves $31,664.2 million and that for adults over 60 years old saves $30,082.9 million in medical costs compared with no vaccine intervention. Additionally, priority vaccination for adults aged 25–59 years vs. over 60 years old saves $1,581.3 million. In contrast, priority vaccination for adults aged over 60 years vs. 25–59 years old gains 0.001 QALYs and costs $4.7 per capita, with an incremental cost-effectiveness ratio of $4,829.3/QALY, and it is economical when taking gross domestic product per capita of the United States in 2020 as the willingness-to-pay threshold. The results of sensitivity analysis indicate that the base-case results are robust.Conclusions: From a healthcare system perspective, it is most economical to prioritize adults aged over 60 years for COVID-19 vaccination in the United States, thereby achieving effective resource allocation and saving the government costs.

A novel design of PDC bit with hollowed cutters is presented that uses the principle of hydraulic lubricating and water jetting mechanism to improve ROP. Engineering results show its advantage compared to solid fixed cutters which are commonly used in today’s drilling industry. The structure of the new PDC bit is as follows: each cutter contains a specific fluid channel, which is tailor made; the bit body contains many fluid channels; Compared with the existing conventional PDC bit, the main distinctive features are: the cutters are hollowed, each cutter contains a fluid channel in the centre of itself; and the bit body has fluid passages which are communicating with each hollowed cutter, allowing the drilling fluid flows from the inside of the bit to the outside of each cutter. The failures of a PDC bit are mostly due to premature wear or cracks of compound cutters; the wear or cracks are due to mechanical and thermal effects. To improve the service life of cutters can effectively increase the life of the drill bit. According to thermal stress analysis, the position where the frictional heat concentrated is in the centre of the cutter, which will result in the generation and expansion of thermal cracks, which in turn leads to failure of the cutter and loss of ROP. Therefore, the cutter with fluid passage will improve the way of thermal concentration and expansion, thereby prolonging the life of the drill bit, reducing the number of trips, improving single run drilling footage, therefore the drilling efficiency is increased. During the drilling operation, the rock cuttings cannot flow out timely, and may accumulate on the drill bit, which is commonly referred to as mud balling. The presence of mud balling will reduce the cutting capability of the drill bit and decrease the ROP. The new PDC bit with hollowed cutters has self-cooling and self-cleaning functions to mitigate the thermal effect, while the pressurized flow from the micro-hole of the cutter has the effect of water jetting, which in turn increases the ROP. The novelty of the new PDC bit is in the capability to solve the issues of low ROP and short service life of today’s tough drilling conditions, to meet the requirement of a single trip to complete the total depth.

Objective: Prolylcarboxypeptidase (PRCP) is both involved in the Kallikrein-Kinin system (KKS) and renin-angiotensin-aldosterone system (RAAS). This study aimed to determine the genetic impact of PRCP gene polymorphisms on essential hypertension (EH) in an isolated population from a remote region of China. Methods: A haplotype-based study was investigated in 346 EH patients and 346 normal subjects and all samples were Hani minority residents in Southwest China. A total of 11 tag single nucleotide polymorphisms (SNPs) in PRCP gene were tested by polymerase chain reaction-restriction fragment length polymorphism method. Results: Single site analysis found that PRCP gene 3′UTR SNP rs3750931 was associated with EH. The minor allele G of rs3750931 was more prevalent in the EH patients compared to control subjects after Bonferroni correction ( p Conclusion: The present study indicated PRCP gene rs3750931 was associated with the risk of EH. This SNP G allele could be considered as one of risk markers for EH in Hani population.

Temps croisés II reprend certaines des réflexions produites dans le cadre de l’« Université d’automne », programme de formation, d’échanges et de recherche qui se tient depuis plus de cinq ans à Shanghai et qui associe enseignants, chercheurs et étudiants européens et chinois. Les représentations du temps constituaient l’axe privilégié du premier volume. Celui-ci s’attache à l’une des grandes questions internationales actuelles : la tendance, plus ou moins contrariée, à l’intégration régionale, ses réussites et ses difficultés. Historiens français et européens (Russie, Italie, Allemagne, Royaume-Uni) mêlent leurs analyses à celles des historiens chinois, sur l’Europe comme sur l’Asie. L’aventure de la construction européenne est à penser sur la durée et dans ses limites géopolitiques, externes et internes. Mais la construction européenne est surtout une volonté, celle de ses acteurs, un rythme, ponctué pat quelques grands moments comme l’unification allemande en 1990, et pat de grands enjeux à considérer à l’échelle planétaire. L’Asie est-elle dans le même état d’esprit ? Malgré l’existence de l’ASEAN et son implication dans un espace asiatique plus large, l’expérience européenne y est diversement appréciée. Il est vrai que la Chine, qu’il faut sans doute redéfinit à l’heure des réformes, est beaucoup plus vaste et plus peuplée que l’Europe elle-même. L’expérience européenne bute sur les réalités asiatiques. Comme l’Université d’automne, dont provient l’essentiel de ces textes, cet ouvrage témoigne sur ce sujet du dialogue intellectuel qui se développe entre chercheurs des deux mondes, européen et chinois

Grand pays européen, un des douze pays membres fondateurs de l’Union européenne, l’Angleterre reste la note la moins en accord dans le processus de l’intégration européenne : elle se met volontairement en dehors de la zone euro et de l’espace Schengen. La singularité de l’Angleterre, portée par sa forte identité forgée au cours de sa longue histoire, fait qu’à l’intérieur, les tensions communautaristes ne se désamorcent pas au sein du Royaume-Uni, et qu’à l’extérieur, le pays insulaire rentre...