Aims
Paclitaxel is a type of broad‐spectrum anticancer drug in short supply. The price of acetyl‐CoA (17 709 677·4 USD mol−1), which is the acetyl group donor for the enzymatic synthesis of the ...intermediate, baccatin Ⅲ, is still the bottleneck of the mass production of paclitaxel. This study reports a novel acetyl group donor, which could substantially reduce the cost of production.
Methods and Results
In this study, a substrate spectrum with 14 kinds of representative acetyl‐donor substitutes predicted by computer‐aided methods was tested in a 10‐deacetylbaccatin Ⅲ‐10‐O‐acetyltransferase (DBAT) heterogeneous‐expressed open‐whole‐cell catalytic system. The results of computer prediction and experimental analysis revealed the rule of the acetyl‐donor compounds based on this substrate spectrum. N‐acetyl‐d‐glucosamine (30·95 USD mol−1, about 572 202‐fold cheaper than acetyl‐CoA) is selected as a suitable substitute under the rule. The yield when using N‐acetyl‐d‐glucosamine as acetyl donor in open‐whole‐cell catalytic system was 2·13‐fold of that when using acetyl‐CoA. In the in vivo system, the yield increased 24·17%, which may indicate its cooperation with acetyl‐CoA.
Conclusion
The success of open‐whole‐cell synthesis and in vivo synthesis of baccatin Ⅲ by adding N‐acetyl‐d‐glucosamine as acetyl substrate demonstrates that it is a useful substrate to improve the yield of baccatin Ⅲ.
Significance and Impact of the Study
All these findings provided a potential acetyl‐donor substitute for acetyl‐CoA, as well as a low cost and efficient method of preparing paclitaxel through baccatin Ⅲ semi‐synthesis.
Major depressive disorder (MDD) is a prevalent psychiatric condition with limited therapeutic options beyond monoaminergic therapies. Although effective in some individuals, many patients fail to ...respond adequately to existing treatments, and new pharmacologic targets are needed. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate excitability in neurons, and blocking HCN channel function has been proposed as a novel antidepressant strategy. However, systemic blockade of HCN channels produces cardiac effects that limit this approach. Knockout (KO) of the brain-specific HCN-channel auxiliary subunit tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) also produces antidepressant-like behavioral effects and suggests that inhibiting TRIP8b function could produce antidepressant-like effects without affecting the heart. We examined the structural basis of TRIP8b-mediated HCN-channel trafficking and its relationship with antidepressant-like behavior using a viral rescue approach in TRIP8b KO mice. We found that restoring TRIP8b to the hippocampus was sufficient to reverse the impaired HCN-channel trafficking and antidepressant-like behavioral effects caused by TRIP8b KO. Moreover, we found that hippocampal expression of a mutated version of TRIP8b further impaired HCN-channel trafficking and increased the antidepressant-like behavioral phenotype of TRIP8b KO mice. Thus, modulating the TRIP8b-HCN interaction bidirectionally influences channel trafficking and antidepressant-like behavior. Overall, our work suggests that small-molecule inhibitors of the interaction between TRIP8b and HCN should produce antidepressant-like behaviors and could represent a new paradigm for the treatment of MDD.
The East China Sea (ECS) and the South China Sea (SCS) are two major marginal seas of the North Pacific with distinct seasonal variations of primary productivity. Based upon field observations ...covering both the ECS and the northern SCS (NSCS) during December 2008–January 2009, we examined southward long-range transport of nutrients from the ECS to the northeastern SCS (NESCS) carried by the China Coastal Current (CCC) driven by the prevailing northeast monsoon in wintertime. These escaped nutrients from the ECS shelf, where primary production (PP) was limited in winter, might however refuel the PP on the NESCS shelf at lower latitude, where the water temperature remained favorable, but river-sourced nutrients were limited. By combining the field observation of nitrate+nitrite (NO3+NO2, DIN) with our best estimate of volume transport of the CCC, we derived a first-order estimate for DIN flux of 1430 ± 1024 mol s−1. Under the assumption that DIN was the limiting nutrient, such southward DIN transport would have stimulated 8.84 ± 6.33 × 1011 gC of new production (NP), accounting for 33–74% of the NP or 14–22% of PP in winter on the NESCS shelf shallower than 100 m.
Pogonatherum crinitum is a promising lead (Pb) hyperaccumulator due to its high Pb tolerance and accumulation ability. However, the mechanisms that support Pb accumulation and tolerance in P. ...crinitum are not yet clearly understood.
An indoor hydroponic experiment was conducted by cultivating P. crinitum seedlings exposed to intermittent Pb stress for 60 days, divided into four stages (T1, T2, T3 and T4), with a 15‐day duration per stage. The following concentrations of Pb were used: 0, 500, 0, 500 mg·l−1 and 0, 1000, 0, 1000 mg·l−1). Antioxidant enzyme activity, Pb concentration and subcellular distribution of Pb were measured at each of the above stages.
The results showed that superoxide dismutase (SOD) activity in shoots, and SOD, peroxidase (POD) and malondialdehyde (MDA) activity in shoots and roots significantly increased from T1 (no Pb stress) to T2 (Pb stress) in both 500 mg·l−1 and 1000 mg·l−1 treatments; however, no significant difference was noted between stages T3 (no Pb stress) and T4 (Pb stress). There was no obvious effect of Pb stress on catalase (CAT) activity in shoots and roots among different stages. The Pb concentration in shoots was up to 5090.90 mg·kg−1 and 7573.57 mg·kg−1, and the bioconcentration factor (BFC) was 10.18 and 7.57 for the 500 mg·l−1 and 1000 mg·l−1 treatments, respectively, which confirmed the Pb hyperaccumulator characteristics of P. crinitum. For plants under Pb stress, most of the Pb was fixed in the cell walls, with a smaller amount in leaves and root vacuoles.
Both SOD and POD scavenging of reactive oxygen radicals and fixing and compartmentalisation of Pb in the cell wall might play important roles in detoxification of P. crinitum seedlings in response to Pb stress. There was no phased response of P. crinitum to intermittent Pb stress and the physiological response to Pb stress may be contiguous.
Persistent hemolytic anemia and a lack of oral treatments are challenges for patients with paroxysmal nocturnal hemoglobinuria who have received anti-C5 therapy or have not received complement ...inhibitors. Iptacopan, a first-in-class oral factor B inhibitor, has been shown to improve hemoglobin levels in these patients.
In two phase 3 trials, we assessed iptacopan monotherapy over a 24-week period in patients with hemoglobin levels of less than 10 g per deciliter. In the first, anti-C5-treated patients were randomly assigned to switch to iptacopan or to continue anti-C5 therapy. In the second, single-group trial, patients who had not received complement inhibitors and who had lactate dehydrogenase (LDH) levels more than 1.5 times the upper limit of the normal range received iptacopan. The two primary end points in the first trial were an increase in the hemoglobin level of at least 2 g per deciliter from baseline and a hemoglobin level of at least 12 g per deciliter, each without red-cell transfusion; the primary end point for the second trial was an increase in hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion.
In the first trial, 51 of the 60 patients who received iptacopan had an increase in the hemoglobin level of at least 2 g per deciliter from baseline, and 42 had a hemoglobin level of at least 12 g per deciliter, each without transfusion; none of the 35 anti-C5-treated patients attained the end-point levels. In the second trial, 31 of 33 patients had an increase in the hemoglobin level of at least 2 g per deciliter from baseline without red-cell transfusion. In the first trial, 59 of the 62 patients who received iptacopan and 14 of the 35 anti-C5-treated patients did not require or receive transfusion; in the second trial, no patients required or received transfusion. Treatment with iptacopan increased hemoglobin levels, reduced fatigue, reduced reticulocyte and bilirubin levels, and resulted in mean LDH levels that were less than 1.5 times the upper limit of the normal range. Headache was the most frequent adverse event with iptacopan.
Iptacopan treatment improved hematologic and clinical outcomes in anti-C5-treated patients with persistent anemia - in whom iptacopan showed superiority to anti-C5 therapy - and in patients who had not received complement inhibitors. (Funded by Novartis; APPLY-PNH ClinicalTrials.gov number, NCT04558918; APPOINT-PNH ClinicalTrials.gov number, NCT04820530.).
Acute sporadic hepatitis E (ASHE) cases induced by hepatitis E virus genotype 4 (HEV-4) are increasing in China. Our study aimed to estimate the duration of HEV-4 viraemia in Chinese ASHE. A total of ...619 serum specimens from 499 ASHE patients were examined for the presence of HEV RNA. The association between viraemia detection and serum sampling time was compared between subtypes. The cumulative probability of HEV viraemia detection was determined using Kaplan–Meier survival analysis, and the viraemia duration was estimated. A total of 42.7 % of serum specimens were positive for HEV RNA and all the isolated strains were identified as genotype 4 and subsequently assigned to five subtypes. Among the patients infected with subtypes 4d and 4i, the time interval from the initiation of clinical symptoms to serum specimen sampling was shorter than that among the patients with subtypes 4a, 4b and 4h. Kaplan–Meier analysis was conducted with 101 sequential specimens as well as with both 101 sequential specimens and 236 single negative specimens. The cumulative probability of HEV-4 viraemia detection was estimated to decline quickly to approximately 10 % within 32 days after the initiation of clinical symptoms and then to decline very slowly to 5 % by the 41st day and to zero by the 131st day. The majority of ASHE cases maintain detectable HEV-4 viraemia within one month after onset, whereas a small portion of cases maintain long-term viraemia and may act as a reservoir for further transmission.
Girth weld cracking of mechanically lined pipe was occurred after 75days operation in a gasfield gathering system in China. Failure causes were analyzed based on operation histories, field documents, ...and laboratory tests. Results showed that the girth weld failure was mainly due to two aspects, girth weld martensite microstructure and external stress. The crack was initiated from sealing pass zone and filling pass zone, which is a hard and brittle martensite structure with hardness of HV 350–450. The failed pipe area had undergone the heavy rain for 2days, pulling stress, bending stress, and shear stress generated by soil movement resulted in high stress concentration at girth weld. The girth weld cracking failure was initiated from outer carbon steel, and propagated along the weld-fusion line in intergranular mode, which is a typical stress corrosion cracking failure.
•The mechanically lined pipe crack initiated from outer carbon steel, and propagated in intergranular mode along the weld-fusion line•Martensite structure formed at sealing pass zone and filling pass zone is the root cause of mechanically lined pipe cracking failure•Pulling stress, bending stress, and shear stress caused by soil movement resulted in high stress concentration at girth weld
A Mg9Ag alloy is employed as a medium for both production of hydrogen and preparation of Ag nanoparticles through hydrolysis. Mg9Ag milled under H2 exhibits very favorable structural characteristics, ...i.e., yielding a fine nanocrystal powder and partial hydrogen-induced phase decomposition. As a result, a hydrogen yield of 730 mL g−1 is obtained in 25 min at 298 K, a much higher rate than produced by samples not milled or milled under argon. Moreover, the hydrolysis by-product can be recycled to obtain Ag nanoparticles by removing insoluble Mg(OH)2 using an added HCl solution. These results show that this process provides a highly efficient method for economically produce hydrogen and Ag nanoparticles.
•Mg9Ag alloy is employed for both hydrogen generation and Ag NPs preparation.•Hydrogen yield reaches 730 mL g−1 within 25 min at 298 K for H2-milled Mg9Ag.•Ag NPs with a size of less than 50 nm were obtained for H2-milled Mg9Ag.
Land in urban fringe area is the primary source for land supply and development. In Hong Kong (HK), nine new towns have been built in New Territories since 1970s, providing 172.6 km2 built-up land ...and large amount of residences for 3.4 million people. However, due to land scarcity, development restriction, and social opposition, New Development Area (NDA), as the small-scale extension of New Town (NT), was designated as one of the main approaches for HK medium and long term land supply. To demonstrate the characteristics of urban fringe land use transitions in Hong Kong, literature review and case study were used in this research. The history of new town development and the scheme of new development areas were introduced firstly. Afterwards, the land use features of NT and NDA were compared and the case of Hung Shui Kiu NDA was illustrated. It is concluded that while housing, infrastructure and facility were the main elements in NTs, employment, vibrancy and environment were suggested to be the new compulsory elements in NDAs integrated to the traditional planning concepts. As for the development approach, lease modification was adopted in NDA to allow private landowners directly develop their land, in addition to the traditional development approach of land resumption in NT. It is suggested to ensure the development of NDA, the proposed development plan should be persuasive to provide the optimal land use distribution as a trade-off among the profits of developers, the interests of local villager, government concern and the provision of land for future residents. Also, community engagement will play a more important role in NDA planning process. Referring to the analysis of urban fringe land use transitions and strategies for planning and development, the study would also be helpful to others growing cities.
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