28-day repeated-dose toxicity of orally administered Jinmao Jiedu granule in Sprague-Dawley rats.

Jinmao Jiedu granule is a Chinese medicine preparation consisting of Actinidia valvata Dunn, Salvia chinensis Benth, Iphigenia indica Kunth, and chicken gizzard. For many years, it has been employed in adjuvant therapy for cancer, especially liver cancer. However, the potential toxicity of the granule has not been reported. The present study aimed to assess the repeated-dose toxicity of orally administered Jinmao Jiedu granules for Sprague-Dawley (SD) rats. SD rats were orally administered Jinmao Jiedu granules at doses of 2.85, 5.70, and 11.40 g/kg in a 28-day subchronic toxicity study. No adverse clinical signs associated with treatment were noted throughout the experiment. There were no treatment-related toxicity alterations in body weight, hematology, clinical biochemistry, urinalysis, necropsy, and histopathology in rats compared with the control group. The No Observed Adverse Effect Level (NOAEL) of the Jinmao Jiedu granule was higher than 11.40 g/kg/day in rats.

Suitable biochar application practices simultaneously alleviate N2O and NH3 emissions from arable soils: A meta-analysis study.

Nitrogen (N) fertilization profoundly improves crop agronomic yield but triggers reactive N (Nr) loss into the environment. Nitrous (N2O) and ammonia (NH3) emissions are the main Nr species that affect climate change and eco-environmental health. Biochar is considered a promising soil amendment, and its efficacy on individual Nr gas emission reduction has been widely reported. However, the interactions and trade-offs between these two Nr species after biochar addition have not been comprehensively analysed. The influencing factors, such as biochar characteristics, environmental conditions, and management measures, remain uncertain. Therefore, 35 publications (145 paired observations) were selected for a meta-analysis to explore the simultaneous mitigation potential of biochar on N2O and NH3 emissions after its application on arable soil. The results showed that biochar application significantly reduced N2O emission by 7.09% while having no significant effect on NH3 volatilisation. Using biochar with a low pH, moderate BET, or pyrolyzed under moderate temperatures could jointly mitigate N2O and NH3 emissions. Additionally, applying biochar to soils with moderate soil organic carbon, high soil total nitrogen, or low cation exchange capacity showed similar responses. The machine-learning model suggested that biochar pH is a dominating moderator of its efficacy in mitigating N2O and NH3 emissions simultaneously. The findings of this study have major implications for biochar application management and aid the further realisation of the multifunctionality of biochar application in agriculture, which could boost agronomic production while lowering environmental costs.

Efficient degradation of tetracycline residues in pharmaceutical wastewater by Ni/Fe bimetallic atomic cluster composite catalysts with enhanced electron transfer pathway.

Metal cluster catalysts have large atomic load, interaction between atomic sites, and wide application of catalysis. In this study, a Ni/Fe bimetallic cluster material was prepared by a simple hydrothermal method and used as an efficient catalyst to activate the degradation system of peroxymonosulfate (PMS), which showed nearly 100% tetracycline (TC) degradation performance over a wide pH range (pH = 3-11). The results of electron paramagnetic resonance test, quenching experiment and density functional theory (DFT) calculation show that the non-free radical pathway electron transfer efficiency of the catalytic system is effectively improved, and a large number of PMS are captured and activated by high density Ni atomic clusters in Ni/Fe bimetallic clusters. The degradation intermediates identified by LC/MS showed that TC was efficiently degraded into small molecules. In addition, the Ni/Fe bimetallic cluster/PMS system has excellent efficiency for degrading various organic pollutants and practical pharmaceutical wastewater. This work opens up a new way for metal atom cluster catalysts to efficiently catalyze the degradation of organic pollutants in PMS systems.

Ultrasonic-assisted nanoencapsulation of kiwi leaves proanthocyanidins in liposome delivery system for enhanced biostability and bioavailability.

The poor biostability and bioavailability of proanthocyanidins limit their application. In this study, it was hypothesized that encapsulation in lecithin-based nanoliposomes using ultrasonic technology improves the above properties. Based on preliminary experiments, the effects of lecithin mass ratio (1-9%, wt.), pH (3.2-6.8), ultrasonic power (0-540 W), and time (0-10 min) on biostability and bioavailability of purified kiwi leaves proanthocyanidins (PKLPs) were determined. Nanoliposomes prepared optimally with lecithin (5%, wt.), pH = 3.2, ultrasonic power (270 W), and time (5 min) demonstrated a significantly (p < 0.05) improved physicochemical stability, homogeneity, and high encapsulation efficiency (73.84%) relative to control. The PKLPs bioaccessibility during in vitro digestion increased by 2.28-3.07-fold, with a remarkable sustained release and delivery to the small intestine. Similar results were obtained by in vivo analyses, showing over 200% increase in PKLPs bioaccessibility compared to the control. Thus, PKLPs-loaded nanoliposomes are promising candidates for foods and supplements for novel applications.

A MALDI-TOF mass spectrometry-based method for detection of copy number variations in BRCA1 and BRCA2 genes.

Background: Identifying germline mutations in BRCA1 and BRCA2 genes (BRCAs) would benefit the carriers in multiple aspects. In addition to single-nucleotide variations and small indels, copy number variations (CNVs) is also an indispensable component of identifiable mutations in BRCAs. A sensitive, rapid and throughput-flexible method to detect CNVs would be preferred to meet the rising clinical requirements for BRCAs testing. Methods: We developed a MALDI-TOF-MS-based method (MS assay) which included three steps: first, multiplex end-point PCR followed by a single base extension reaction; second, automated analyte transfer and data acquisition; third, data analysis. We applied MS assay to detect CNVs in BRCAs in 293 Chinese patients with ovarian or pancreatic cancer. All the samples were examined by targeted next-generation sequencing (TS) simultaneously. Samples were further cross-validated by multiplex ligation-dependent probe amplification (MLPA) if the results from MS assay and TS were inconsistent. Long range PCR was then applied to identify the exact breakpoints in BRCAs. Results: MS assay introduced highly multiplexed panels to detect CNVs of BRCAs semi-quantitatively. Simplified on-board data analysis was available for MS assay and no complex bioinformatics was needed. The turnaround time of MS assay was less than 8 hours with a hands-on time of only 40 min. Compared to TS, MS assay exhibited higher sensitivity (100% vs. 75%) and was more flexible in throughput, with the reagent cost per sample remaining constant no matter how many samples were examined per assay. A total of eight CNVs in BRCAs were detected from the 293 samples, and the molecular breakpoints were successfully identified in five samples through long-range PCR followed by Sanger sequencing. Conclusion: Our results suggested that MS assay might be an effective method in primary screening for CNVs in genes such as BRCAs, especially when short turnaround time and/or high sensitivity is a top priority.

Ten-step asymmetric total syntheses of potent antibiotics anthracimycin and anthracimycin B.

The increase in antibiotic resistance calls for the development of novel antibiotics with new molecular structures and new modes of action. However, in the past few decades only a few novel antibiotics have been discovered and progressed into clinically used drugs. The discovery of a potent anthracimycin antibiotic represents a major advance in the field of antibiotics. Anthracimycin is a structurally novel macrolide natural product with an excellent biological activity profile: (i) potent in vitro antibacterial activity (MIC 0.03-1.0 µg mL-1) against many methicillin-resistant Staphylococcus aureus (MRSA) strains, Bacillus anthracis (anthrax), and Mycobacterium tuberculosis; (ii) low toxicity to human cells (IC50 > 30 µM); (iii) a novel mechanism of action (inhibiting DNA/RNA synthesis). While the first total synthesis of anthracimycin was elegantly accomplished by Brimble et al. with 20 steps, we report a 10-step asymmetric total synthesis of anthracimycin and anthracimycin B (first total synthesis). Our convergent strategy features (i) one-pot sequential Mukaiyama vinylogous aldol/intramolecular Diels-Alder reaction to construct trans-decalin with high yield and excellent endo/exo selectivity and (ii) Z-selective ring-closing metathesis to forge the 14-membered ring. In vitro antibacterial evaluation suggested that our synthetic samples exhibited similar antibacterial potency to the naturally occurring anthracimycins against Gram-positive strains. Our short and reliable synthetic route provides a supply of anthracimycins for further in-depth studies and allows medicinal chemists to prepare a library of analogues for establishing structure-activity relationships.

1,5-Allyl Shift by a Sequential Achmatowicz/Oxonia-Cope/Retro-Achmatowicz Rearrangement.

1,3-Allyl and 1,2-allyl shifts through [3,3]- and [2,3]-sigmatropic rearrangements are well-established and widely used in organic synthesis. In contrast, 1,5-allyl shift through related [3,5]-sigmatropic rearrangement is unknown because [3,5]-sigmatropic rearrangement is thermally Woodward-Hoffmann forbidden. Herein, we report an unexpected discovery of a formal 1,5-allyl shift of allyl furfuryl alcohol through a 2-step sequential rearrangement. Mechanistically, this formal 1,5-allyl shift is achieved through a sequential ring expansion/contraction rearrangement: 1) Achmatowicz rearrangement (ring expansion), and 2) cascade oxonia-Cope rearrangement/retro-Achmatowicz rearrangement (ring contraction). This new 1,5-allyl shift method is demonstrated with >20 examples and expected to find applications in organic synthesis and materials chemistry.

Case Report: Torsade de Pointes Induced by the Third-Generation Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor Osimertinib Combined With Litsea Cubeba.

Torsades de Pointes (TdP) occurred in a 68-year-old female with epidermal growth factor receptor (EGFR) mutant lung cancer administered osimertinib, the third-generation EGFR tyrosine kinase inhibitor (TKI). Electrocardiogram (ECG) recorded at Tdp showed QT prolongation (QTc = 515 ms), to which a Traditional Chinese Medicine (TCM) named "Litsea Cubeba" may have contributed. After discontinuation of osimertinib and Litsea Cubeba, magnesium supplementation, potassium supplementation, lidocaine infusion, and the pacemaker frequency adjustment, Tdp terminated. However, QT prolongation sustained at discharge (QTc = 528 ms), partly because of the emergency use of amiodarone. Osimertinib may prolong the QT interval leading to TdP, especially when multiple risk factors to lengthen QT interval are incidentally overlapped. Thus, regular monitoring of ECG and appropriate management of concomitant drugs are highly recommended.

Preparation, characterization, and antibacterial activity of tigecycline-loaded, ultrasound-activated microbubbles.

Central nervous system infectious disease caused by the multidrug-resistant Acinetobacter baumannii (AB) seriously threatens human life in clinic. Tigecycline has good sensitivity in killing AB, but due to its wide tissue distribution and blood-brain barrier, concentration in cerebrospinal fluid is low, therefore, the clinical effect is limited. Herein, we designed micro-bubbled tigecycline, aimed to enhance its anti-MDRAB effects under ultrasound. The lipid microbubbles with different ratios of lipids to drugs (a ratio of 10:1, 20:1, and 40:1) were prepared by the mechanical shaking method. The morphology, zeta potential and particle size of microbubbles were tested to screen out the much better formulation. Encapsulation efficiency and drug loading amount were determined by ultracentrifugation combined with high-performance liquid chromatography. Then the in vitro antibacterial activity against AB was conducted using the selected ultrasound-activated microbubble. Results showed the selected microbubbles with high encapsulation efficiency and good stability. The mechanical shaking method is feasible for preparation of drug-loaded and ultrasound-activated lipid microbubbles. Using 0.2 mg/mL microbubbles, combined with 1 MHz, 2.5 W/cm2 and 1 min of ultrasound exhibited a potent anit-AB in vitro. This study indicates that tigecycline treatment in form of ultrasound-activated microbubble is a promising strategy against AB infections.

Catalytic asymmetric coupling of vinylogous species via deconjugated butenolide addition to vinylogous imines in situ generated from arylsulfonyl indoles.

An efficient catalytic asymmetric coupling of vinylogous species is developed via deconjugated butenolide addition to vinylogous imines in situ generated from arylsulfonyl indoles. With quinine-derived bifunctional squaramide as the catalyst, a series of structurally diverse enantioenriched sec-alkyl-3-substituted indoles containing valuable γ,γ-disubstituted butenolide moieties and adjacent quaternary-tertiary stereocenters are obtained in synthetically viable results (up to 97% yield, 77 : 23 dr and 97% ee).

Benzylidene succinimides as 3C synthons for the asymmetric tandem Mannich reaction/transamidation of cyclic trifluoromethyl ketimines to obtain F3C-containing polycyclic dihydroquinazolinones.

By taking advantage of benzylidene succinimides as a new class of 3C synthons, a highly diastereo- and enantioselective tandem Mannich reaction/transamidation has been established by reacting them with cyclic trifluoromethyl N-acyl ketimines. Using a Cinchona alkaloid-derived squaramide as the catalyst, the tandem reaction proceeded smoothly under mild conditions and afforded a range of F3C-containing chiral polycyclic dihydroquinazolinones with excellent results (up to 99% yield, all cases >20 : 1 dr, up to 99% ee).

A Paeonia ostii caffeoyl-CoA O-methyltransferase confers drought stress tolerance by promoting lignin synthesis and ROS scavenging.

Paeonia ostii is an emerging woody oil crop, but drought severely inhibits its growth and promotion in arid or semiarid areas, and little is known about the mechanism governing this inhibition. In this study, the full-length cDNA of a caffeoyl-CoA O-methyltransferase gene (CCoAOMT) from P. ostii was isolated, and determined to be comprised of 987 bp. PoCCoAOMT encoded a 247-amino acid protein, which was located in the nucleus and cytosol. Significantly higher PoCCoAOMT transcription was detected in P. ostii treated with drought stress. Subsequently, the constitutive overexpression of PoCCoAOMT in tobacco significantly conferred drought stress tolerance. Under drought stress, transgenic lines exhibited lower reactive oxygen species (ROS) accumulation, and higher antioxidant enzyme activities and photosynthesis. Moreover, the expression levels of senescence-associated genes were significantly downregulated, whereas the expression levels of lignin biosynthetic genes and PoCCoAOMT were significantly upregulated in transgenic lines. Similarly, transgenic lines produced significantly higher lignin, especially guaiacyl-lignin. These results suggest that PoCCoAOMT is a vital gene in promoting lignin synthesis and ROS scavenging to confer drought stress tolerance in P. ostii.

Organocatalytic asymmetric tandem α-functionalization/1,3-proton shift reaction of benzylidene succinimides with ß-trifluoromethyl enones.

A bifunctional thiourea-catalyzed asymmetric tandem α-functionalization/1,3-proton shift reaction of benzylidene succinimides with ß-trifluoromethyl enones has been developed. A series of F3C-containing chiral Rauhut-Currier type products were obtained in moderate to high yields (up to 98%) with excellent enantioselectivities (up to >99% ee). This represents the first example of benzylidene succinimides undergoing tandem α-functionalization/1,3-proton shift in catalytic enantioselective transformation.

Effects of fulvic acid on the photosynthetic and physiological characteristics of Paeonia ostii under drought stress.

PAEONIA OST II: has become an economically important oil crop in recent years, but its growth is seriously affected by drought stress in dry areas. In this study, the alleviating effect of fulvic acid (FA) on potted P. ostii under natural drought stress was investigated. The natural drought stress adopted in this experiment was mainly characterized by the low soil water content, and the roots of plants cannot absorb enough water to compensate for the consumption of transpiration, which affects the normal physiological activities and causes damage. The results showed that FA treatment significantly increased the leaf water content and antioxidant enzyme activities and decreased reactive oxygen species (ROS) accumulation, the proline (Pro) content, and the relative electrical conductivity (REC). Moreover, FA treatment improved photosynthetic parameters and chlorophyll (Chl) fluorescence parameters, maintained the integrity of chloroplasts and mesophyll cells, and increased the expression level of drought-tolerant genes. These results indicated that FA treatment could induce antioxidant enzymes to eliminate ROS, reduce membrane lipid peroxidation and decrease damage to photosynthesis in P. ostii under drought stress, which would provide a measure for alleviating the damage of P. ostii caused by drought stress.

Highly enantioselective sequential vinylogous aldol reaction/transesterification of methyl-substituted olefinic butyrolactones with isatins for the construction of chiral spirocyclic oxindole-dihydropyranones.

A highly stereoselective sequential vinylogous aldol reaction/transesterification of methyl-substituted olefinic butyrolactones and isatins was developed. With this developed protocol, a series of chiral spirocyclic oxindole-dihydropyranones were obtained in good to excellent yields (73-99%) and enantioselectivities (71-97% ee).

A spatiotemporal meta-analysis of HIV/syphilis epidemic among men who have sex with men living in mainland China.

BACKGROUND: Geographic differences in HIV, syphilis and condomless sex among men who have sex with men in China remained unknown. We aimed to elucidate these spatiotemporal changing patterns in China. METHODS: We conducted a spatiotemporal meta-analysis. We searched four databases for studies conducted between 2001 and 2015. We included studies that reported original data of HIV/syphilis prevalence in China, the study's area/province, and period of data collection. We grouped studies into six regions and four time periods. We examined the changing patterns of national and regional prevalence of HIV, syphilis and condomless sex. RESULTS: Search results yielded 2119 papers, and 272 were included in the meta-analysis. The sample sizes of the studies ranged from 19 to 47,231. National HIV prevalence increased from 3.8% (95% CI 3.0-4.8) in 2001-07 to 6.6% (5.6-7.7) in 2013-15. In most regions, the rise occurred before 2010 and the HIV prevalence remained relatively stable afterwards, except for the Northwest which showed a considerable increase since 2008. National syphilis prevalence decreased from 12.3% (10.2-14.9) in 2001-07 to 7.1% (5.6-8.9) in 2013-15. CONCLUSIONS: The trends of HIV and syphilis infections have been effectively curbed in MSM in most regions of China. Continuous efforts, particularly promotion of condom use, are needed to further reduce these infections.

Competitive McLafferty-type rearrangements of sodium adduct of anti-2,3-dihydroxy-1-phenylpentane-1,4-dione compounds in tandem mass spectrometry.

Sodium adducts of anti-2,3-dihydroxy-1-phenylpentane-1,4-dione compounds with different substituents were studied by collision-induced dissociation. McLafferty-type rearrangements preceding fragmentation were found as their main fragmentation pathway. Coordination of sodium cation to the oxygen functions may either lead to formation of a five-membered or a six-membered ring. Two McLafferty-type rearrangement product ions exhibiting a mass difference of 2 u indicated that two competitive McLafferty-type rearrangements through a six-membered ring coordination occurred. Relative abundances of the corresponding product ions were studied by energy-resolved collision-induced dissociation experiments and density functional theory calculations. Furthermore, the influence of different substituents was probed.

Mortality among People Living with HIV and AIDS in China: Implications for Enhancing Linkage.

To assess the patterns and predictors of AIDS-related mortality and identify its correlates among adult people living with HIV/AIDS (PLWHA) in China, a retrospective record-based cohort study was conducted among 18 years or older PLWHA, who had at least one follow up reported to the national database between January-1989 and June-2012. Cumulative Incidence Function was used to calculate AIDS-related mortality rate. Gray's test was used to determine the variation in cumulative incidence across strata. The Fine and Gray model was used to measure the burden of cumulative incidence of AIDS-related mortality and strength of its association with potential correlates. Among 375,629 patients, 107,634 died during study period, of which 54,759 (50.87%) deaths were AIDS-related. Cumulative mortality rates of AIDS-related death at one, two, five, 10 and 15 years post-diagnosis were 5.7%, 8.2%, 14.3%, 22.9% and 30.9%, respectively. Among PLWHA, male gender, ethnic minority and having AIDS were associated with significantly higher mortality. Further, homosexual transmission, being on ART and increasing CD4-testing frequency were associated with lower mortality. To reduce mortality among PLWHA, efficient interventions targeting males, ethnic minority, heterosexually infected and AIDS patients should be combined with immunologic monitoring, enhancement of coverage of HIV-testing and ART.

Pre-exposure prophylaxis of HIV: A right way to go or a long way to go?

Antiretroviral drugs are being tried as candidates for the pre-exposure prophylaxis (PrEP) against HIV for a considerable period, due to their potential for immediate inhibition of viral replication. Discrepancies in the findings called for a critical review of the relevant efforts and their outcomes. A systematic literature search identified 143 eligible articles of which only 5 reported complete findings while another 11 were still on-going. Observed moderate efficacy and good safety profile seemed to identify PrEP as a promising step for minimizing the spread of HIV to relatively unaffected population and controlling the epidemic among high risk population groups. But the duration of this efficacy was found to depend heavily on the availability, adherence and other related issues like cost, political commitment, ethical consideration etc. To prevent potential cultural and behavioral modifications, proper pre-administration counseling also seemed critical for the success of PrEP as a cost-effective intervention with adequate coverage.

[Compliance of antiviral therapy and influencing factors in people living with HIV/AIDS in Nanjing].

OBJECTIVE: To understand the compliance of highly active anti-retroviral therapy (HAART) and influencing factors in people living with HIV/AIDS (PLWHA) in Nanjing. METHODS: PLWHA receiving HAART in No. 2 Hospital of Nanjing during May-June 2014 were recruited in this study. Self-administrated questionnaire was used to collect the data about HAART compliance and socio-demographic characteristics of PLWHA surveyed. Descriptive and multivariate statistical analysis were conducted to examine the effects of the factors on self-reported HAART adherence. RESULTS: A total of 276 PLWHA were surveyed, According to the evaluation criterion of Center for Adherence Support Evaluation (CASE), 252 cases showed good compliance (91.3%). logistic regression analysis revealed that smoking, progress of the disease and side effects, reminding of taking drug and age were correlated with self-reported HAART adherence. CONCLUSION: It is suggested to strengthen the education about antiviral therapy compliance in PLWHA with mild infection and those who are smokers and young, suffer from side effects, have no reminding methods for taking drug.