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BackgroundTrichomes are excellent model systems for the analysis of cell differentiation and play essential roles in plant protection. From cucumber inbred line ‘WD1’, we identified an EMS-induced trichome abnormally developing mutant,nps, which exhibited smaller, denser and no pyramid-shaped head trichomes.ResultsUsing F2and BC1populations constructed from a cross betweennpsand ‘9930’, the genetic analysis showed that thenpstrait is controlled by a single recessive nuclear gene. We identifiedCsNpsby map-based cloning with 576 individuals of the F2population generated from the cross ofnpsand inbred line ‘9930’. TheCsNpswas located at a 13.4-kb genomic region on chromosome 3, which region contains three predicted genes. Sequence analysis showed that only one single nucleotide mutation (C → T) between 9930 andnpswas found in the second exon ofCsa3G748220, a plant-specific class I HD-Zip gene. The result of allelism test also indicated thatnpsis a novel allelic mutant ofMict(Micro-trichome). Thus,npswas renamedmict-L130F. By comparing the transcriptome ofmict-L130Fvs WD1 and 06–2 (mict) vs 06–1 (wildtype, near-isogenic line of 06–2), several potential target genes that may be related to trichome development were identified.ConclusionsOur results demonstrate thatMict-L130Fis involved in the morphogenesis of trichomes. Map-based cloning of theMict-L130Fgene could promote the study of trichome development in cucumber.

CsSh5.1, which controls hypocotyl elongation under high temperature conditions in cucumber, was mapped to a 57.1 kb region on chromosome 5 containing a candidate gene encoding a xyloglucan galactosyltransferase. Hypocotyl growth is a vital process in seedling establishment. Hypocotyl elongation after germination relies more on longitudinal cell elongation than cell division. Cell elongation is largely determined by the extensibility of the cell wall. Here, we identified a spontaneous mutant in cucumber (Cucumis sativus L.), sh5.1, which exhibits a temperature-insensitive short hypocotyl phenotype. Genetic analysis showed that the phenotype of sh5.1 was controlled by a recessive nuclear gene. CsSh5.1 was mapped to a 57.1 kb interval on chromosome 5, containing eight predicted genes. Sequencing analysis revealed that the Csa5G171710 is the candidate gene of CsSh5.1, which was further confirmed via co-segregation analysis and genomic DNA sequencing in natural cucumber variations. The result indicated that hypocotyl elongation might be controlled by this gene. CsSh5.1 encodes a xyloglucan galactosyltransferase that specifically adds galactose to xyloglucan and forms galactosylated xyloglucans, which determine the strength and extensibility of the cell walls. CsSh5.1 expression in wild-type (WT) hypocotyl was significantly higher than that in sh5.1 hypocotyl under high temperature, suggesting its important role in hypocotyl cell elongation under high temperature. The identification of CsSh5.1 is helpful for elucidating the function of xyloglucan galactosyltransferase in cell wall expansion and understanding the mechanism of hypocotyl elongation in cucumber.

It remains controversial to claim blood pressure (BP) as a leading risk factor for high risk of death in peritoneal dialysis patients, and less is known about the relationship between BP and mortality in Chinese peritoneal dialysis patients.From Zhejiang Renal Data System in China, we collected data on patients treated and followed up at 98 peritoneal dialysis centres from 2008 to 2016. The associations of BP parameters [SBP, DBP, mean arterial pressure (MAP) and pulse pressure (PP)] with all-cause and cardiovascular mortality were examined. We fitted Cox models for mortality with penalized splines using nonparametric smoothers. Several sensitivity analyses were performed to confirm the robustness of our primary findings.A total of 7335 Chinese peritoneal dialysis patients were included. During a median follow-up of 35.8 months, 1281 (17.5%) patients died. SBP, DBP, MAP follow a U-shaped pattern of both all-cause and cardiovascular mortality. PP presents a reverse L-shaped association with all-cause mortality. Either a higher (SBP141, DBP85 or MAP102 mmHg) or lower (SBP119, DBP67 or MAP88 mmHg) BP tends to have a significantly higher all-cause and cardiovascular mortality risk. Higher PP (60 mmHg) is related to a higher risk of all-cause mortality, but not cardiovascular mortality. These associations remain the same in our competing risk analysis and subgroup analyses.These data indicate U-shaped associations of SBP, DBP and MAP with all-cause mortality and cardiovascular mortality, respectively, and a reverse L-shaped association of PP with all-cause mortality. Further studies are needed to reliably establish the optimal BP targets for better hypertension control in peritoneal dialysis patients.

Background Vancomycin is the standard therapy for methicillin-resistant Staphylococcus aureus (MRSA) infection; however, nephrotoxicity happened with a high incidence of 15%~40%. Weighting the risk before receiving vancomycin treatment facilitates timely prevention of nephrotoxicity, but no standardized strategy exists for this purpose. Methods A retrospective cohort study was performed. A total of 524 hospitalized patients treated with vancomycin were included in this study. They were divided into derivation cohort (n=341) and externally validation cohort (n=183) according to their admission time. Using univariate and multivariable logistic regression, we identified potential predictors of vancomycin-associated acute kidney injury (AKI) and developed a risk score by plotting nomogram. The predictive performance of this novel risk score was assessed and validated by discrimination and calibration. Besides, the risk score was also compared with existing prediction models according to integrated discrimination index (IDI) and net reclassification index (NRI). Results The incidence of AKI was 16.1% (55/341) in the derivation cohort and 16.4% (30/183) in the validation cohort. Three factors (vancomycin serum trough concentration, piperacillin/tazobactam and furosemide) were determined as predictors for vancomycin-associated AKI. The established three-item risk score showed a comparable discrimination in both derivation cohort (AUC=0.793, 95% CI: 0.732-0.855) and validation cohort (AUC=0.788, 95% CI: 0.698-0.877). The risk score also demonstrated a good calibration in the derivation cohort (χ2=6.079, P=0.638>0.05) and validation cohort (χ2=5.665, P=0.686>0.05). Compared with prediction by Cmin alone, this risk score significantly improved reclassification accuracy (IDI=0.050, 95% CI: 0.024-0.076, P

This study aimed to describe the 25‐hydroxyvitamin D (25(OH)D) and parathyroid hormone (PTH) status of Southeast Chinese individuals influenced by season. The secondary aim was to determine the cutoff for sufficient 25(OH)D in a four‐season region. From January 2011 to June 2014, a total of 17 646 individuals were evaluated in our study. The serum levels of PTH were detected simultaneously in 5579 cases. A total of 25(OH)D and intact PTH were measured by the electrochemiluminescent immunoassay. The distribution of the concentration, prevalence and seasonal variability of 25(OH)D and PTH were studied. The mean 25(OH)D concentration in our study was 43.00(30.40) nmol/L. The prevalence of insufficiency (25(OH)D

Ravidasvir (RDV) is a novel oral hepatitis C virus NS5A inhibitor. This study aimed to evaluate the pharmacokinetics and safety of RDV and the drug-drug interactions between RDV and ritonavir-boosted danoprevir (DNVr) in healthy adults. In the 1st study, healthy volunteers were administered single oral doses of 100, 200, and 300 mg of RDV and 200 mg once daily for 7 days. The 2nd study was a randomized, double-blinded, and placebo-controlled sequential design (day 1 for 200 mg of RDV alone, day 7 for 100 mg/100 mg of DNVr, day 13 for 200 mg of RDV plus 100 mg/100 mg DNVr, followed by 200 mg of RDV once daily with 100 mg/100 mg of DNVr twice daily for 10 days). The results showed that RDV exposure increased in a dose-proportional manner following a single dose with no evidence of accumulation with multiple doses. Coadministration with DNVr (100 mg/100 mg, twice daily) resulted in a 2.92-fold and 1.99-fold increase in minimum plasma concentration at steady state (C(min,ss)) and area under the concentration-time curve at steady state (AUC(τ)) of RDV, respectively. With coadministration of RDV, maximum plasma concentration (C(max)) and area under the concentration-time curve from 0 to 12 h (AUC(0–12)) of DNV increased 1.71-fold and 2.33-fold, respectively. We did not observe any significant changes in ritonavir exposure. Both single and multiple doses of RDV with or without DNVr were well tolerated. The favorable pharmacokinetic and safety results support ravidasvir’s continued clinical development and treatment. (The studies described in this paper have been registered at ClinicalTrials.gov under identifiers NCT03430830 and NCT03288636.)

Lihua Wu,1,2,* Chang Xu,1,2,* Guolan Wu,1,2 Huili Zhou,1,2 Duo Lv,1,2 You Zhai,1,2 Yujie Huang,1,2 Wenling Tang,3 Fangqiong Li,4 Jianzhong Shentu1–3 1Research Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Zhejiang Provincial Key Laboratory for Drug Evaluation and Clinical Research, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 3College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 4Clinical Research Department, Haisco Pharmaceutical Group, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jianzhong ShentuResearch Center for Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310003, People’s Republic of ChinaTel +86 571 87236560Fax +86 571 87214223Email stjz@zju.edu.cnPurpose: A fixed-dose combination (FDC) tablet of melitracen/flupentixol has been widely used for depression. The purpose of this study was to assess the safety profile and the relative bioavailability of two FDC products containing 10 mg melitracen and 0.5 mg flupentixol from two different manufacturers, in order to acquire adequate pharmacokinetic evidence for registration approval of the test formulation.Methods: The study was designed as a single-dose, randomized, open-label, 2-period crossover study under fasted or fed conditions in healthy Chinese subjects. Twenty-four subjects (16 men and 8 women) were selected for fasted study, and another 24 cases (16 men and 8 women) were in fed study. Each subject was randomized at the beginning to receive either a single dose of the reference FDC or the test FDC tablet during the first period. Following two-week washout period, all subjects received the alternate formulation during the second period. Blood samples were collected up to 144 hrs after administration. Pharmacokinetic parameters, including Cmax, Tmax, AUC0-t, AUC0-∞, t½, CL/F, and Vd/F were acquired based on the time versus concentration profiles. Then, the geometric mean ratios (GMR) and corresponding 90% CIs were calculated for the determination of bioequivalence analysis. Safety assessment included changes in vital signs and laboratory tests, physical examination findings, and incidence or reports of adverse events (AEs).Results: The present study has clearly indicated the test and the reference FDC products are bioequivalent in terms of rate and extent of drug absorption. GMR of Cmax, AUC0–t, and AUC0-∞ for both flupentixol and melitracen between the two formulation FDC products, and corresponding 90% CIs, were all within the range of 80% to 125% under fasted or fed conditions. Both the test and the reference FDC products indicated good tolerance in all volunteers. Chinese Clinical Trials Registry identifier: CTR20171256.Keywords: bioequivalence, melitracen, flupentixol, pharmacokinetics, fixed-dose combination tablet

Ethnopharmacological usages Fructus Alpiniae oxyphyllae (A. oxyphylla) is an important medicinal plant that is used not only as an edible fruit, but also as an important traditional medicine for benefiting cognitive performance and alleviating a wide spectrum of diseases. Such as; warming kidney, securing essence and arresting polyuria, as well as warming the spleen and stopping diarrhea and saliva. Aims The purpose of this review is to provide updated, comprehensive and categorized information on the traditional uses, phytochemistry and pharmacological research of A. oxyphylla in order to explore their therapeutic potential and establish a solid foundation for directing future research. Materials and methods All the available information on A. oxyphylla was collected via electronic search (using Pubmed, SciFinder, Scirus, Google Scholar and Web of Science) and additionally a number of unpublished resources, (e.g. books, Ph.D. and M.Sc. dissertations, government reports). Results Phytochemical research on A. oxyphylla has led to the isolation of components such as essential oils, terpenes, diarylheptanoids, flavones, nucleobases and nucleosides, steroids and others. Crude extracts, fractions and phytochemical constituents isolated from A. oxyphylla showed a wide spectrum of in vitro and in vivo pharmacological activities like neuroprotective, anti-diarrheal, anti-diuretic, anti-neoplastic, anti-oxidant, anti-inflammatory, anti-allergic, viscera protective and anti-diabetic activities. Neuroprotective, anti-cancer, anti-diarrheal and anti-diuretic effects are major areas of research conducted on A. oxyphylla. Conclusions Modern pharmacological studies have supported many traditional uses of A. oxyphylla, including nervous system, urinary system and gastrointestinal system disease. There was convincing evidence in experimental animal models in support of its neuroprotection, secure essence, reduce urination, and anti-carcinogenic effects. However, all the reported pharmacological activities were carried out at pre-clinical level and the authors urge further investigation in clinical trials about these therapeutic fields of A. oxyphylla.

The leaf is an important photosynthetic organ and plays an essential role in the growth and development of plants. Leaf color mutants are ideal materials for studying chlorophyll metabolism, chloroplast development, and photosynthesis. In this study, we identified an EMS-induced mutant, yl2.1, which exhibited yellow cotyledons and true leaves that did not turn green with leaf growth. The yl2.1 locus was controlled by a recessive nuclear gene. The CsYL2.1 was mapped to a 166.7-kb genomic region on chromosome 2, which contains 24 predicted genes. Only one non-synonymous single nucleotide polymorphism (SNP) was found between yl2.1 and wt-WD1 that was located in Exon 7 of Csa2G263900, resulting in an amino acid substitution. CsYL2.1 encodes a plastid isoform of triose phosphate isomerase (pdTPI), which catalyzes the reversible conversion of dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (GAP) in chloroplasts. CsYL2.1 was highly expressed in the cotyledons and leaves. The mesophyll cells of the yl2.1 leaves contained reduced chlorophyll and abnormal chloroplasts. Correspondingly, the photosynthetic efficiency of the yl2.1 leaves was impaired. Identification of CsYL2.1 is helpful in elucidating the function of ptTPI in the chlorophyll metabolism and chloroplast development and understanding the molecular mechanism of this leaf color variant in cucumber.

The leaf is an important photosynthetic organ and plays an essential role in the growth and development of plants. Leaf color mutants are ideal materials for studying chlorophyll metabolism, chloroplast development, and photosynthesis. In this study, we identified an EMS-induced mutant, yl2.1, which exhibited yellow cotyledons and true leaves that did not turn green with leaf growth. The yl2.1 locus was controlled by a recessive nuclear gene. The CsYL2.1 was mapped to a 166.7-kb genomic region on chromosome 2, which contains 24 predicted genes. Only one non-synonymous single nucleotide polymorphism (SNP) was found between yl2.1 and wt-WD1 that was located in Exon 7 of Csa2G263900, resulting in an amino acid substitution. CsYL2.1 encodes a plastid isoform of triose phosphate isomerase (pdTPI), which catalyzes the reversible conversion of dihydroxyacetone phosphate (DHAP) to glyceraldehyde-3-phosphate (GAP) in chloroplasts. CsYL2.1 was highly expressed in the cotyledons and leaves. The mesophyll cells of the yl2.1 leaves contained reduced chlorophyll and abnormal chloroplasts. Correspondingly, the photosynthetic efficiency of the yl2.1 leaves was impaired. Identification of CsYL2.1 is helpful in elucidating the function of ptTPI in the chlorophyll metabolism and chloroplast development and understanding the molecular mechanism of this leaf color variant in cucumber.

Background: The trichomes of cucumber fruits are also called spines. Cucumber has important commercial value, and its fruit spines represent a classical tissue with which to study the cell division and differentiation mode of multicellular trichomes. Although there have been many studies on the development of unicellular trichomes in model plants, the molecular mechanism of multicellular trichome formation remains elusive. In this study, we used a pair of cucumber materials defined as having hard (Ts, wild type) or tender (ts, mutant) spines in a previous study. The whole developmental process of fruit spines was continuously observed by microscopy and SEM. In an attempt to define the developmental stages of fruit spines, transcriptome profiles at different stages were determined to explore the molecular mechanisms underlying the process of spine development. Results: According to significant phenotypic differences, the developmental process of fruit spines was clearly defined as involving four stages. Comparison of transcriptome profiles showed that 803 and 722 genes were upregulated in the stalk (stage II and stage III) and base (stage IV) developmental stages of fruit spines, respectively. Functional analysis of differentially expressed genes (DEGs) showed that for all developmental stages of fruit spines, lipid metabolism, amino acid metabolism, and signal transduction were the most noticeable pathways. However, during the development of the stalk, genes related to auxin polar transport and HD-ZIP transcription factors were significantly upregulated. bHLH transcription factors and cytoskeleton-related genes were significantly upregulated during the development of the base. In addition, stage III was the key point for differentiating between the wild type and mutant. We detected 628 DEGs between the wild type and mutant at this stage. These DEGs are mainly involved in calcium signaling of the cytoskeleton and auxin polar transport, indicating that the main reason for the disorder of the fruit spine developmental pattern in the mutant was a change in cell polarity caused by blocked intercellular signal transmission.Conclusions: Our study defines in great detail the developmental stages of cucumber fruit spines. At the same time, transcriptome profiles are used to present the gene regulatory networks at different developmental stages of cucumber fruit spines. In addition, we analyzed transcriptomic data of a wild type and mutant to elucidate the biological pathways involving C-type lectin receptor-like kinase that regulate the development of fruit spines.

The effects of multiple-dose administration of tenofovir disoproxil fumarate (TDF) on the pharmacokinetics of morinidazole (MOR) were compared in healthy subjects. MOR exposure was similar, with an area under the curve from 0 h to infinity (AUC0-∞) treatment ratio for MOR+TDF/MOR of 1.01 (90% confidence interval, 0.97 to 1.06). No relevant differences were observed regarding plasma exposure of metabolites. Renal clearances of MOR and its metabolites were not affected by TDF., The effects of multiple-dose administration of tenofovir disoproxil fumarate (TDF) on the pharmacokinetics of morinidazole (MOR) were compared in healthy subjects. MOR exposure was similar, with an area under the curve from 0 h to infinity (AUC0-∞) treatment ratio for MOR+TDF/MOR of 1.01 (90% confidence interval, 0.97 to 1.06). No relevant differences were observed regarding plasma exposure of metabolites. Renal clearances of MOR and its metabolites were not affected by TDF. No unexpected safety or tolerability issues were observed.

Cucumber is one of the most important vegetables in the world. The C2H2 zinc finger protein (C2H2-ZFP) family plays an important role in the growth development and abiotic stress responses of plants. However, there have been no systematic studies on cucumber. In this study, we performed a genome-wide study of C2H2-ZFP genes and analyzed their chromosomal location, gene structure, conservation motif, and transcriptional expression. In total, 101 putative cucumber C2H2-ZFP genes were identified and divided into six groups (I&ndash, VI). RNA-seq transcriptome data on different organs revealed temporal and spatial expression specificity of the C2H2-ZFP genes. Expression analysis of sixteen selected C2H2-ZFP genes in response to cold, drought, salt, and abscisic acid (ABA) treatments by real-time quantitative polymerase chain reaction showed that C2H2-ZFP genes may be involved in different signaling pathways. These results provide valuable information for studying the function of cucumber C2H2-ZFP genes in the future.

Cucumber is one of the most important vegetables in the world. The C2H2 zinc finger protein (C2H2-ZFP) family plays an important role in the growth development and abiotic stress responses of plants. However, there have been no systematic studies on cucumber. In this study, we performed a genome-wide study of C2H2-ZFP genes and analyzed their chromosomal location, gene structure, conservation motif, and transcriptional expression. In total, 101 putative cucumber C2H2-ZFP genes were identified and divided into six groups (I–VI). RNA-seq transcriptome data on different organs revealed temporal and spatial expression specificity of the C2H2-ZFP genes. Expression analysis of sixteen selected C2H2-ZFP genes in response to cold, drought, salt, and abscisic acid (ABA) treatments by real-time quantitative polymerase chain reaction showed that C2H2-ZFP genes may be involved in different signaling pathways. These results provide valuable information for studying the function of cucumber C2H2-ZFP genes in the future.

Meihua Lin, Duo Lv, Yunliang Zheng, Minglan Wu, Chang Xu, Qiao Zhang, Lihua Wu Research Center of Clinical Pharmacy, State Key Laboratory for Diagnosis and Treatment of Infectious Disease, First Affiliated Hospital, Zhejiang University, Hangzhou, China Background: Cancer cells often have characteristic changes in metabolism. Besides Warburg effect, abnormal lipid metabolism is also considered as one of the most typical metabolic symbols of cancer. Thus, understanding the mechanisms of cell metabolic reprogramming may provide a potential avenue for cancer treatment. Materials and methods: In total, 41 pairs of matched samples of primary hepatocellular carcinoma (HCC) and adjacent non-cancerous liver tissues were collected. Afterward, we performed quantitative reverse transcriptase polymerase chain reaction to investigate carnitine palmitoyltransferase-2 (CPT2) expression and then systematically analyzed its relationship with clinicopathologic features. We further performed proliferation, colony formation, migration and invasion, drug resistance, and lipogenesis assays to determine the function of CPT2 in HCC. Results: In this study, we have identified CPT2 which is the rate-limiting enzyme of fatty acid oxidation, downregulated in HCC and was significantly associated with tumor histological differentiation and venous invasion. In vitro studies demonstrated that knockdown of CPT2 remarkably enhanced the tumorigenic activity and metastatic potential of hepatoma cells. In addition, CPT2 silencing induced chemoresistance to cisplatin. Mechanistically, low expression of CPT2 promoted cancer cell lipogenesis via upregulation of stearoyl-CoA desaturase-1, the key enzyme involved in the synthesis of monounsaturated fatty acids, at both mRNA and protein levels in hepatoma cell line. Conclusion: Altogether, our findings demonstrate that CPT2 has a critical role in HCC progression and chemoresistance and may potentially serve as a novel prognostic marker and therapeutic target for HCC treatment. Keywords: lipid metabolism, CPT2, HCC, SCD1, chemoresistance

Tnt1 is an active retrotransposon originally identified in tobacco (Nicotiana tabacum L.) (Grandbastien et al., 1989), but its transposition activity could be activated through tissue culture in other plant species. The insertions are stable and inheritable in the progeny, which has made it a valuable and versatile tool for developing insertional mutagenesis libraries in several plant species. Here, we explored its utility for mutagenesis in cucumber (Cucumis sativus L.). T3 Tnt1 transgenic cucumber plants were subjected to tissue culture to regenerate self-pollinated progeny. With PCR and analyses and Southern hybridization, we found regenerated plants maintained the original Tnt1 insertion and created new insertions suggesting characteristic re-transposition activity of Tnt1 during this process. Using genome walking, some flanking sequences of Tnt1 insertions were recovered in regenerated plants. The results demonstrated that Tnt1 could be stably inherited and re-transposable during tissue culture in cucumber and that it is feasible to use for developing an insertional mutagenesis library for cucumber. Keywords: cucumber, Tnt1, retrotransposon, tissue culture, mutagenesis library

Using map-based cloning of ts gene, we identified a new sort of gene involved in the initiation of multicellular tender spine in cucumber. The cucumber (Cucumis sativus L.) fruit contains spines on the surface, which is an extremely valuable quality trait affecting the selection of customers. In this study, we elaborated cucumber line NC072 with wild type (WT) hard fruit spines and its spontaneous mutant NC073, possessing tender and soft spines on fruits. The mutant trait was named as tender spines (ts), which is controlled by a single recessive nuclear gene. We identified the gene ts by map-based cloning with an F2 segregating population of 721 individuals generated from NC073 and WT line SA419-2. It was located between two markers Indel6239679 and Indel6349344, 109.7 kb physical distance on chromosome 1 containing fifteen putative genes. With sequencing and quantitative reverse transcription-polymerase chain reaction analysis, the Csa1G056960 gene was considered as the most possible candidate gene of ts. In the mutant, Csa1G056960 has a nucleotide change in the 5′ splicing site of the second intron, which causes different splicing to delete the second exon, resulting in a N-terminal deletion in the predicted amino acid sequence. The gene encodes a C-type lectin receptor-like tyrosine-protein kinase which would play an important role in the formation of cucumber fruit. This is firstly reported of a receptor kinase gene regulating the development of multicellular spines/trichomes in plants. The ts allele could accelerate the molecular breeding of cucumber soft spines.

Metabolic syndrome (MetS), a cluster of metabolic disturbances that increase the risk for cardiovascular disease and diabetes, was because of genetic susceptibility and environmental risk factors. To identify the genetic variants associated with MetS and metabolic components, we conducted a genome‐wide association study followed by replications in totally 12,720 participants from the north, north‐eastern and eastern China. In combined analyses, independent of the top known signal at rs651821 on APOA5, we newly identified a secondary triglyceride‐associated signal at rs180326 on BUD13 (P combined = 2.4 × 10−8). Notably, by an integrated analysis of the genotypes and the serum levels of APOA5, BUD13 and triglyceride, we observed that BUD13 was another potential mediator, besides APOA5, of the association between rs651821 and serum triglyceride. rs671 (ALDH2), an east Asian‐specific common variant, was found to be associated with MetS (P combined = 9.7 × 10−22) in Han Chinese. The effects of rs671 on metabolic components were more prominent in drinkers than in non‐drinkers. The replicated loci provided information on the genetic basis and mechanisms of MetS and metabolic components in Han Chinese.

Background and Objective This study was performed in healthy Chinese subjects to evaluate the safety and pharmacokinetic/pharmacodynamic characteristics of a novel injection formulation of dexlansoprazole in the context of single and multiple administration, compared with the original lansoprazole injection. Methods Helicobacter pylori-negative healthy volunteers were recruited, and 70 participants were enrolled into five dosing groups (seven males and seven females in each group), including 15 mg once daily (qd), 15 mg every 12 h (q12h), 30 mg qd and 30 mg q12h of dexlansoprazole treatment for 5 days, as well as 30 mg q12h of lansoprazole treatment for 5 days. Blood samples were collected at scheduled time spots postdose on day 1 (first dose) and day 5 (last dose). Twenty-four-hour intragastric pH was continuously monitored on day 0 (baseline) and days 1 and 5. Dexlansoprazole and S-lansoprazole in human plasma were determined by validated chiral liquid chromatography with tandem mass spectrometry, and the pharmacokinetic parameters were determined by a non-compartmental method using Phoenix WinNonlin software. Safety assessment included changes in vital signs and laboratory tests, physical examination findings, and incidence or reports of adverse events. Results The half-life (t½) and clearance (CL) of dexlansoprazole were 1.76–2.06 h and 4.52–5.40 L/h, respectively, while the t½ and CL of S-lansoprazole were 0.87–1.02 h and 34.66–35.98 L/h, respectively. No drug accumulation after repeated administration was noted. Administration of lansoprazole 30 mg resulted in higher area under the concentration-time curve from time zero to the last measurable concentration (AUCt) of dexlansoprazole than that of dexlansoprazole 15 mg (p = 0.026). Zero to 24 h after q12h multiple dosing, median and mean intragastric pH, percentage of time with the intragastric pH above 4.0 [TpH ≥ 4.0(%)] and percentage of time with the intragastric pH above 6.0 [TpH ≥ 6.0(%)] in the dexlansoprazole 15 mg q12h group were 6.07 ± 0.61, 5.70 ± 0.76, 83.58 ± 12.34, and 53.70 ± 17.06, respectively, which was similar to the lansoprazole 30 mg q12h group, i.e. 6.15 ± 0.62, 5.88 ± 0.67, 87.26 ± 12.08 and 57.00 ± 16.35, respectively. A weak positive correlation between dexlansoprazole AUCt and baseline-adjusted TpH ≥ 4.0(%) over 0–24 h was observed, with Pearson correlation coefficients of 0.437 (p = 0.029), while no correlation was observed between AUCt and baseline-adjusted TpH ≥ 6.0(%) over 0–24 h. Conclusion Every 12 h intravenous dosing of dexlansoprazole up to 30 mg for 5 days was safe and well-tolerated in healthy Chinese subjects. Every 12 h dosing of dexlansoprazole 15 mg has a comparable effect of gastric acid inhibition as lansoprazole 30 mg q12h. Trial Registration ClinicalTrials.gov ID NCT03120273.

An analysis was conducted to investigate the flow and heat transfer of a turboramjet pre-cooler and a new concept pre-cooler used controllable octahedron porous media structure is developed. The pressure and temperature distribution of the pre-cooler is investigated with both numerical and experimental method. Additionally an optimization theory and evaluate factor of porous media structure was developed and applied into the pre-cooler optimization. At the present work the CFD results regarding the pressure drop and heat transfer performance were compared to available experimental data and were found to be in agreement. Thus, the porous media pre-cooler could be applicable to the turboramjet.

Background Pedicel orientation can affect the female flower orientation and seed yield in cucumber. A spontaneous mutant possessing upward growth of pedicels was identified in the wild type inbred strain 9930 and named upward-pedicel (up). The morphological and genetic analyses of up were performed in this study. In order to clone the up gene, 933 F2 individuals and 524 BC1 individuals derived from C-8-6 (WT) and up were used for map-based cloning. Results up was mapped to a 35.2 kb physical interval on chromosome 1, which contains three predicted genes. Sequencing analysis revealed that a 5-bp deletion was found in the second exon of Csa1G535800, and it led to a frameshift mutation resulting in a premature stop codon. The candidate gene of CsUp (Csa1G535800) was further confirmed via genomic and cDNA sequencing in biparental and natural cucumber populations. Sequencing data showed that a 4-bp deletion was found in the sixth exon of Csa1G535800 in CGN19839, another inbred line, and there was also a mutation of an amino acid in Csa1G535800 that could contribute to the upward growth of pedicels in CGN19839. Moreover, it was found that Csa1G535800 exhibited strong expression in the pedicel of WT, suggesting its important role in development of pedicel orientation. Thus, Csa1G535800 was considered to be the candidate gene of CsUp. Conclusions CsUp encodes an Auxilin-like protein and controls pedicel orientation in cucumber. The identification of CsUp may help us to understand the mechanism of pedicel orientation development and allow for investigation of novel functions of Auxilin-like proteins in cucumber.

Supplemental Digital Content is available in the text, To develop a classification model for accurately discriminating common infectious diseases in Zhejiang province, China. Symptoms and signs, abnormal lab test results, epidemiological features, as well as the incidence rates were treated as predictors, and were collected from the published literature and a national surveillance system of infectious disease. A classification model was established using naïve Bayesian classifier. Dataset from historical outbreaks was applied for model validation, while sensitivity, specificity, accuracy, area under the receiver operating characteristic curve (AUC) and M-index were presented. A total of 146 predictors were included in the classification model, for discriminating 25 common infectious diseases. The sensitivity ranged from 44.44% for hepatitis E to 96.67% for measles. The specificity varied from 96.36% for dengue fever to 100% for 5 diseases. The median of total accuracy was 97.41% (range: 93.85%–99.04%). The AUCs exceeded 0.98 in 11 of 12 diseases, except in dengue fever (0.613). The M-index was 0.960 (95%CI 0.941–0.978). A novel classification model was constructed based on Bayesian approach to discriminate common infectious diseases in Zhejiang province, China. After entering symptoms and signs, abnormal lab test results, epidemiological features and city of disease origin, an output list of possible diseases ranked according to the calculated probabilities can be provided. The discrimination performance was reasonably good, making it useful in epidemiological applications.

Both genetic predisposition and lifestyle factors are associated with the risk for obesity. Multiple obesity loci have been identified using genome-wide association studies mainly in European populations. The aims of this study were to examine the associations of these loci with obesity and gene×dietary behavior interactions among Chinese children and adolescents. Nineteen candidate SNPs were genotyped using Sequenom technology in the Chinese children (N=2977, 853 obese and 2124 controls, aged 7-17). Dietary behaviors were assessed using self-administered questionnaires. After adjusting for age, sex and multiple testing, MC4R rs17782313, SEC16B rs543874, MAP2K5 rs2241423 and KCTD15 rs11084753 were associated with obesity and obesity-related traits (all P

Objective: A generic vaginal progesterone gel has recently been developed in China. Little is known about its pharmacokinetic properties in Chinese subjects. The purpose of our study was to investigate the pharmacokinetics of three forms of vaginal progesterone gel (test formulations at 4 and 8% strength vs. a reference formulation: Crinone 8%) in Chinese healthy post-menopausal women. Methods: This study consisted of two parts study. The part 1 study was a single-center, open-label, 3-period study. Twelve healthy post-menopausal women were to evaluate the safety and pharmacokinetics of 45 mg vaginal progesterone gel (Test 4%) following single dose and multiple doses administered once every other day (q.o.d.) for six times or once daily (q.d.) for 6 days. The part 2 study was a randomized, open-label, 3-stage crossover study. Twelve post-menopausal women received 90 mg vaginal progesterone gel (Test 8%) or 90 mg Crinone (Reference 8%) following single dose and multiple doses (q.o.d. or q.d.). Plasma concentrations of progesterone were measured up to 72 h by using a validated liquid chromatography tandem-mass spectrometry method. The primary pharmacokinetic parameters, maximum plasma concentration (Cmax) and area under the plasma concentration–time curve (AUC) from time zero to last measurable concentration (AUC0-t) and extrapolated to infinity (AUC0-∞) were compared by an analysis of variance using log-transformed data. Results: Totally 24 subjects were enrolled in and completed the study. Following single dose, The geometric mean Cmax values for Test 4%, Test 8%, and Crinone 8% were 6.35, 10.34, 10.45 ng/mL, and their geometric mean AUC0-t (AUC0-∞) were 113.73 (118.00), 169.39 (173.98), and 190.07 (201.13) ng⋅h/mL, respectively. The mean T1/2 values of progesterone were 11.00, 10.92, and 11.40 h, respectively. For 8% test formulation vs. reference, the 90% CIs of the least squares mean test/reference ratios of Cmax, AUC0-t, and AUC0-∞ were 78.32–124.85%, 54.31–146.24%, and 53.64–137.75, respectively. The most frequent adverse events were increased vaginal secretions, most of which were of mild intensity and considered related to treatment. Conclusion: Results with single and multiple doses of vaginal progesterone gel suggest similar pharmacokinetics properties between test formulations and Crinone 8%. Overall, vaginal progesterone gel was well tolerated.