Highly Efficient Monolithic Perovskite/Perovskite/Silicon Triple-Junction Solar Cells.

Wide-bandgap metal halide perovskites have demonstrated promise in multijunction photovoltaic (PV) cells. However, photoinduced phase segregation and the resultant low open-circuit voltage (Voc) have greatly limited the PV performance of perovskite-based multijunction devices. Here, a alloying strategy is reported to achieve uniform distribution of triple cations and halides in wide-bandgap perovskites by doping Rb+ and Cl- with small ionic radii, which effectively suppresses halide phase segregation while promoting the homogenization of surface potential. Based on this strategy, a Voc of 1.33 V is obtained from single-junction perovskite solar cells, and a VOC approaching 3.0 V and a power conversion efficiency of 25.0% (obtained from reverse scan direction, certified efficiency: 24.19%) on an 1.04 cm2 photoactive area can be achieved in a perovskite/perovskite/c-Si triple-junction tandem cell, where the certification efficiency is by far the greatest performance of perovskite-based triple-junction tandem solar cells. This work overcomes the performance deadlock of perovskite-based triple-junction tandem cells by setting a materials-by-design paradigm.

Structural Dynamics-Driven Discovery of Anticancer and Antimetastatic Effects of Diltiazem and Glibenclamide Targeting Urokinase Receptor.

Diltiazem and glibenclamide are commonly used hypotensive and antidiabetic drugs. This study reports the discovery of the potential antitumor and antimetastatic effects of these two drugs using a structural dynamics-driven virtual screening targeting urokinase receptor (uPAR). Owing to uPAR's high flexibility, currently resolved crystal structures of uPAR, all in ligand-bound states, provide limited representations of its physiological conformation. To improve the accuracy of screening, we performed a long-timescale molecular dynamics simulation and obtained the representative conformations of apo-uPAR as the targets for our screening. Experimentally, we demonstrated that diltiazem and glibenclamide bound uPAR with KD values in the micromolar range. In addition, both compounds effectively suppressed tumor growth and metastasis in a uPAR-dependent manner in vitro and in vivo. This work not only provides two potent uPAR inhibitors but also reports a proof-of-concept study on the potential off-label antitumor and antimetastatic uses of diltiazem and glibenclamide.

Effect of polyethylene glycol 400 on the pharmacokinetics and tissue distribution of baicalin by intravenous injection based on the enzyme activity of UGT1A8/1A9.

Baicalin (BG) is a bioactive flavonoid extracted from the dried root of the medicinal plant, Scutellaria radix (SR) (dicotyledonous family, Labiatae), and has several biological activities. Polyethylene glycol 400 (PEG400) has been used as a suitable solvent for several traditional Chinese medicines (TCM) and is often used as an excipient for the compound preparation of SR. However, the drug-excipient interactions between BG and PEG400 are still unknown. Herein, we evaluated the effect of a single intravenous PEG400 administration on the BG levels of rats using pharmacokinetic and tissue distribution studies. A liver microsome and recombinant enzyme incubation system were used to further confirm the interaction mechanism between PEG400 and UDP-glucuronosyltransferases (UGTs) (UGT1A8 and UGT1A9). The pharmacokinetic study demonstrated that following the co-intravenous administration of PEG400 and BG, the total clearance (CLz) of BG in the rat plasma decreased by 101.60% (p < 0.05), whereas the area under the plasma concentration-time curve (AUC)0-t and AUC0-inf increased by 144.59% (p < 0.05) and 140.05% (p < 0.05), respectively. Additionally, the tissue distribution study showed that the concentration of BG and baicalein-6-O-ß-D-glucuronide (B6G) in the tissues increased, whereas baicalein (B) in the tissues decreased, and the total amount of BG and its metabolites in tissues altered following the intravenous administration of PEG400. We further found that PEG400 induced the UGT1A8 and UGT1A9 enzyme activities by affecting the maximum enzymatic velocity (Vmax) and Michaelis-Menten constant (Km) values of UGT1A8 and UGT1A9. In conclusion, our results demonstrated that PEG400 interaction with UGTs altered the pharmacokinetic behaviors and tissue distribution characteristics of BG and its metabolites in rats.

Rapid determination and dietary intake risk assessment of 249 pesticide residues in Panax notoginseng.

UPLC-MS/MS and GC-MS/MS were used to establish a method to simultaneously determine various pesticide residues in Panax notoginseng. Results showed that the limits of detection of 249 pesticides were all 5-10 µg/kg. The detection rate of pesticides in 121 P. notoginseng samples was 93.39%, and 19 pesticides were detected. According to the US Code of Federal Regulations, the Chinese Pharmacopoeia recommended algorithm, and the Japanese "positive list system", the pass rates of pesticide residues were 100%, 99.17%, and 89.26%, respectively. The chronic risk quotient (ADI%) and acute risk quotient (ARfD%) of P. notoginseng were 0.00-0.12% and 0.00-0.15%, respectively. In summary, the detection method established in this study can be used for routine analysis of various P. notoginseng pesticide residues. The pesticide residues in the main root samples of P. notoginseng were at a safe level and unlikely pose health risks to consumers.

Crystal structure of the cytokinin-producing enzyme "lonely guy" (LOG) from Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) is an extremely successful intracellular pathogen that cause a large number of death worldwide. It is interesting that this non-phytopathogen can synthesize cytokinin by "lonely guy" (LOG) protein. The cytokinin biosynthesis pathway in Mtb is not clear. Here we determined the crystal structure of LOG from Mtb (MtLOG) at a high resolution of 1.8 Å. MtLOG exists as dimer which belongs to type-I LOG and shows a typical α-ß Rossmann fold. Like other LOGs, MtLOG also contains a conserved "PGGXGTXXE" motif that contributes to the formation of an active site. For the first time, we found that the MtLOG binds to Mg2+ in the negative potential pocket. According to the docking result, we found that Arg78, Arg98 and Tyr162 should be the key amino acid involved in substrate binding. Our findings provide a structural basis for cytokinin study in Mtb and will play an important role in design and development of enzyme inhibitors.

The empirical support for the radical cure strategy for eliminating Plasmodium vivax in China.

BACKGROUND: With the recent certification by World Health Organization that the People's Republic of China is malaria-free, it is timely to consider how elimination of malaria was completed in People's Republic of China over the last 7 decades. Of the four widespread species of human malaria, Plasmodium vivax was the last to be eliminated by the national program of China. Understanding the incubation periods and relapses patterns of P. vivax through historical data from China is relevant for planning disease elimination in other malaria-endemic countries, with residual P. vivax malaria. METHODS: We collated data from both published and unpublished malaria parasite inoculation experiments conducted between 1979 and 1988 with parasites from different regions of the People's Republic of China. The studies had at least two years of follow-up. We categorized P. vivax incubation patterns via cluster analysis and investigated relapse studies by adapting a published within-host relapse model for P. vivax temperate phenotypes. Each model was fitted using the expectation-maximization (EM) algorithm initialized by hierarchical model-based agglomerative clustering. RESULTS: P. vivax parasites from the seven studies of five southern and central provinces in the People's Republic of China covering geographies ranging from the south temperate to north tropical zones. The parasites belonged to two distinct phenotypes: short- (10-19 days) or long-incubation (228-371 days). The larger the sporozoite inoculation, the more likely short incubation periods were observed, and with more subsequent relapses (Spearman's rank correlation between the number of inoculated sporozoites and the number of relapses of 0.51, p-value = 0.0043). The median of the posterior distribution for the duration of the first relapse interval after primary infection was 168.5 days (2.5% quantile: 89.7; 97.5% quantile: 227.69 days). The predicted survival proportions from the within-host model fit well to the original relapse data. The within-host model also captures the hypnozoite activation rates and relapse frequencies, which consequently influences the transmission possibility of P. vivax. CONCLUSIONS: Through a within-host model, we demonstrate the importance of clearance of hypnozoites. A strategy of two rounds of radical hypnozoite clearance via mass drug administration (MDA) deployed during transmission (summer and autumn) and non-transmission (late spring) seasons had a pronounced effect on outbreaks during the malaria epidemics in China. This understanding can inform malaria control strategies in other endemic countries with similar settings.

[Distribution and Ecological Risk Assessment of Antibiotics in the Songhua River Basin of the Harbin Section and Ashe River].

Solid phase extraction (SPE) and high-performance liquid chromatography-mass spectrometry (HPLC-MS) were used to detect and analyze the distribution of 10 antibiotics including sulfonamides, fluoroquinolones, and macrolides in the Harbin section of Songhua River basin and Ashe River, a tributary of Songhua River. The correlation between the antibiotic concentration and water quality indexes was analyzed and the ecological risks were evaluated. The results showed that only six antibiotics were detected in the entry section of Harbin city on the Songhua River and the concentration was relatively low. However, nine antibiotics were detected in the exit section and only sulfamethazine (SM1) was not detected. The concentrations of macrolide antibiotics increased most significantly, followed by those of sulfonamides and fluoroquinolones. The inflow of three tributaries in Harbin city was the direct cause of the increase in antibiotic concentration in the Songhua River. Only sulfapyridine (SMPD) was not detected in the upper section of Ashe River. Ten antibiotics were detected in the section where the Ashe River enters the Songhua River. The other nine antibiotics were the highest except norfloxacin (NOR). Wastewater discharged from four sewage treatment plants along Ashe River is an important factor affecting the concentration of antibiotics in the Ashe River. Correlation analysis shows that three kinds of antibiotics in the Songhua River have certain positive correlations with ammonia nitrogen, total phosphorus, and total organic carbon. There is a significant positive correlation between the three kinds of antibiotics and ammonia nitrogen and total phosphorus in the Ashe River system, indicating that the water quality indexes of the Harbin section of Songhua River and Ashe River are closely related to their antibiotic concentrations. The results of ecological risk assessment showed that macrolide antibiotics in the Harbin section of Songhua and Ashe Rivers had certain ecological risks.

From Plasmodium vivax outbreak to elimination: lessons learnt from a retrospective analysis of data from Guantang.

BACKGROUND: Malaria was once a serious public health problem in China, with Plasmodium vivax the major species responsible for more than 90% of local transmission. Following significant integrated malaria control and elimination programmes, malaria burden declined, and since 2017 China has not recorded any indigenous case. To understand the historical malaria transmission patterns and epidemic characteristics in China and insights useful to guide P. vivax malaria control and elimination elsewhere, a retrospective study was carried out. METHODS: Historical data from a pilot study conducted in Guantang, Luyi in central China from 1971-1995, were digitized. The data included monthly numbers of reported cases, febrile cases, parasite carriage rates, the neonatal infection rate, and entomological data regarding Anopheles sinensis. RESULTS: Following 25 years of continuous integrated malaria control activities, malaria incidence in Guantang decreased from 4,333 cases per 10,000 in 1970 before integrated implementation to 0.23 cases per 10,000 in 1991, and no cases in 1992-1995. Some fluctuations in incidence were observed between 1977 and 1981. During the period parasite rates, antibody levels and the neonatal infection rate also decreased. The pattern of seasonality confirmed that P. vivax in Henan Province was primarily of the long incubation type (temperate) during non-transmission period. The findings retrospectively provide a scientific basis for the implementation of mass campaigns of liver stage hypnozoite clearance. Entomological studies indicated that An. sinensis was the only vector, and it preferred bovine to human hosts, predominantly biting and resting outdoors. Mosquito densities declined between 1971 and 1984. CONCLUSION: The integrated malaria control approach in Guantang effectively controlled malaria and achieved elimination. Analysis of the effectiveness of the programme can provide guidance to other regions or countries with similar ecological settings aiming to move from malaria control to elimination. There is a potential challenge in the maintenance of non-transmission status owing to imported cases and the long dormancy of liver stage hypnozoites.

A nanometer-sized protease inhibitor for precise cancer diagnosis and treatment.

Inhibition of pro-cancer proteases is a potent anticancer strategy. However, protease inhibitors are mostly developed in the forms of small molecules or peptides, which normally suffer from insufficient metabolic stability. The fast clearance significantly impairs the antitumor effects of these inhibitors. In this study, we report a nanometer-sized inhibitor of a pro-cancer protease, suppressor of tumorigenicity 14 (st14), which has been reported as a potent prognostic marker for multiple cancers. This st14 inhibitor was fabricated by conjugating a recombinant st14 inhibitor (KD1) with carbon quantum dots (CQDs). CQD-KD1 not only demonstrated high potency of inhibiting st14 activity in biochemical experiments, but also remarkably suppressed the invasion of breast cancer cells. In contrast to the original recombinant KD1, CQD-KD1 demonstrated a prolonged retention time in plasma and at the tumor site because of the reduced renal clearance. Consistently, CQD-KD1 demonstrated enhanced efficacies of suppressing tumor growth and cancer metastases in vivo. In addition, CQD-KD1 precisely imaged tumor tissues in cancer-grafted mice by specifically targeting the over-expressed st14 on the tumor cell surface, which indicates CQD-KD1 as a potent probe for the fluorescence guided surgery of tumor resection. In conclusion, this study demonstrates that CQD-KD1 is a highly potent diagnostic and therapeutic agent for cancer treatments.

A novel ELISA for the detection of active form of plasminogen activator inhibitor-1 based on a highly specific trapping agent.

Plasminogen activator inhibitor-1 (PAI-1) is a labile molecule that exists in four different forms: active, latent, cleaved and target bound form. Although there have been many methods to measure the total PAI-1, the measurement of active form of PAI-1 antigen is still challenging. Here we developed a novel ELISA to detect the active form of PAI-1 based on a highly specific PAI-1 capturing agent which binds to active PAI-1 with high affinity. We also used a highly stable PAI-1 mutant as an assay calibrator to enhance the method's reproducibility. This ELISA has the advantage of measuring both the antigen level and activity of PAI-1 at the same time. The assay had a sensitivity of 0.167 ng/ml and a working range of 0.195-25 ng/ml. The intra- and inter-assay variations were 6.7% and 11.3% respectively. The mean recovery of spiked standard was 102%. We used this strategy to measure the active PAI-1 level in plasma of healthy donors, and had an interesting observation: the PAI-1 level reduced by half after plasma storage for 6 h at room temperature. This finding represents the first observation of activity loss in plasma PAI-1 samples, and may explain large variations in PAI-1 levels (0-100 ng/ml) observed in human samples using commercial assays.

Malignant perivascular epithelioid cell tumor of the retroperitoneum.

Perivascular epithelioid cell tumors (PEComas) are a rare type of mesenchymal neoplasms characterized by a proliferation of perivascular cells with an epithelioid phenotype and expression of myo-melanocytic markers. The majority of PEComas seem to be benign and usually their prognosis is good. Malignant cases are extremely rare, exhibiting a malignant course with local recurrences and distant metastases. We herein report a case of a malignant PEComa arising in the retroperitoneum. The patient was a 55-year-old woman experiencing abdominal discomfort for approximately one month. Ultrasound and computer tomography (CT) scans of the abdomen revealed a solid mass arising from the retroperitoneum. Microscopically, the tumor was composed of epithelioid cells mixed with spindled cells. The nucleus had significant atypia, and the mitoses were obvious. The focal intravascular tumor embolus was visible. Immunohistochemically, the epithelioid tumor cells were positive for HMB45 and Melan-A, and the spindled tumor celLs were positive for SMA and desmin. Seven months after a surgical resection, an ultrasound revealed liver metastases. In conclusion, the malignant PEComas of the retroperitoneum is a very rare neoplasm with unique morphological and immunohistochemical characteristics. It should be differentiated from other epithelioid cell tumors of the retroperitoneum.

[Use of limited sampling strategy for estimating area under concentration-versus-time curve of mycophenolate sodium in renal allograft recipients].

OBJECTIVE: To establish a formula for estimating area under the concentration-versus-time curve (AUC) of mycophenolate sodium in Chinese renal allograft recipients with a limited sampling model. METHODS: A total of 35 renal allograft recipients were recruited from 2010 to 2013 to receive enteric-coated mycophenolate sodium (EC-MPS), calcineurin (CNI) and prednisone as immunosuppressive triple therapy. The serum concentration of mycophenolic acid (MPA) was assayed by enzyme multiplied immunoassay technique (EMIT) at pre-dose (C0), 0.5 (C0.5), 1.0 (C1), 1.5 (C1.5), 2.0 (C2), 3.0 (C3), 4.0 (C4), 6.0 (C6), 8.0 (C8) and 12.0 (C12) h post-dose respectively. Pharmacokinetic parameters of MPA (C0, C12, Cmax, Tmax, AUC0-12 h) were calculated by software WINNOLIN. Simplified formulae for estimation of MPA-AUC in tacrolimus (Tac) group or cyclosporin A (CsA) group were established by multiple stepwise regression analysis. RESULTS: There were variable MPA AUC0-12 h levels between 14 and 67 mg×h/L (mean: 37 ± 14). The MPA trough level (C0) had no correlations with MPA AUC0-12 h (r(2) = 0.090) . The simplified MPA AUC formula for Tac group was AUC = 5.678+1.718×C4+2.853×C6+1.812×C8+3.413×C12 with four sampling points (C4, C6, C8, C12). Estimated AUC with the formula had correlations with AUC0-12 h (r(2) = 0.890). The mean absolute predict error (APE) was 3.45% (0.41%-24.71%) and the proportion of APE above 15% stood at 11.1% (2/18) . In CsA group, the simplified MPA AUC formula was AUC = 7.072+1.525×C3+1.558×C4+ 1.573×C6+2.285×C8. The correlation was r(2) = 0.952, mean APE was 6.50% (0.02%-12.91%) and proportion of APE above 15% stood at 0. The above formulae were observed to have agreement with AUC0-12 h by Bland-Altman analysis. CONCLUSION: The simplified MPA AUC formulae with 4-point sampling provide an effective approach for estimating full MPA AUC0-12 h in Chinese renal recipients on EC-MPS plus tacrolimus or cyclosporin A.

Malaria control in Henan Province, People's Republic of China.

We analyzed malaria prevalence and evaluated the effect of malaria control measures in Henan Province, People's Republic of China between 1993 and 2004. Data relating to malaria epidemics, malaria control measures and their effects, and vector surveillance between 1993 and 2004 were collected and analyzed. Mean malaria incidence during this period was 2.96/100,000. After integrated vector control measures and appropriate treatment of malaria cases were carried out, the number of malaria cases in Henan Province decreased from 4,815 in 2000 to 2,112 in 2004. The parasite-positive rate and the density of Anopheles anthropophagus were also reduced. Malaria control measures were effective and malaria incidence decreased in Henan. However, there are still more cases in this province than in 1992. Local malaria outbreaks and epidemics have occurred in areas where Anopheles anthropophagus and An. sinensis are present. Thus, malaria control measures should be strengthened.