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SummaryStudies in shift workers and model organisms link circadian disruption to breast cancer. However, molecular rhythms in non-cancerous and cancerous human breast tissues are largely unknown. We reconstructed rhythms informatically, integrating locally collected, time-stamped biopsies with public datasets. For non-cancerous tissue, the inferred order of core-circadian genes matches established physiology. Inflammatory, epithelial-mesenchymal transition (EMT), and estrogen responsiveness pathways show circadian modulation. Among tumors, clock correlation analysis demonstrates subtype-specific changes in circadian organization. Luminal A organoids and informatic ordering of Luminal A samples exhibit continued, albeit disrupted rhythms. However, CYCLOPS magnitude, a measure of global rhythm strength, varied widely among Luminal A samples. Cycling of EMT pathway genes was markedly increased in high-magnitude Luminal A tumors. Patients with high-magnitude tumors had reduced 5-year survival. Correspondingly, 3D Luminal A cultures show reduced invasion following molecular clock disruption. This study links subtype-specific circadian disruption in breast cancer to EMT, metastatic potential, and prognosis.

The accumulation of antibiotics in farmland and its ecological risk have become a research hotspot at home and abroad. The objective of this study was to investigate the occurrence and accumulation of antibiotics and their potential environmental and ecological risks in vegetable fields in Kaizhou district of Chongqing country. The occurrence characteristics of antibiotics including tetracyclines, sulfonamides, quinolones, macrolides, and chloramphenicols were detected using experimental analysis. The results showed that there was an accumulation of antibiotics in the vegetable soil, and 18 antibiotics in five categories were detected (0-42.88 μg·kg

Human catechol-O-methyltransferase (hCOMT) is considered a therapeutic target due to its crucial roles in the metabolic inactivation of endogenous neurotransmitters and xenobiotic drugs. There are nevertheless few safe and effective COMT inhibitors and there lacks a diversity in structure. To discover novel safe and effective hCOMT inhibitors from herbal products, in this study, 53 herbal products were collected and their inhibitory effects against hCOMT were investigated. Among them, Scutellariae radix (SR) displayed the most potent inhibitory effect on hCOMT with an IC50 value of 0.75 μg mL−1. To further determine specific chemicals as COMT inhibitors, an affinity ultrafiltration coupled with liquid chromatography-mass spectrometry method was developed and successfully applied to identify COMT inhibitors from SR extract. The results demonstrated that scutellarein 2, baicalein 9 and oroxylin A 12 were potent COMT inhibitors, showing a high binding index (>3) and very low IC50 values (32.9 ± 3.43 nM, 37.3 ± 4.32 nM and 18.3 ± 2.96 nM). The results of inhibition kinetics assays and docking simulations showed that compounds 2, 9 and 12 were potent competitive inhibitors against COMT-mediated 3-BTD methylation, and they could stably bind to the active site of COMT. These findings suggested that affinity ultrafiltration allows a rapid identification of natural COMT inhibitors from a complex plant extract matrix. Furthermore, scutellarein 2, baicalein 9 and oroxylin A 12 are potent inhibitors of hCOMT in SR, which could be used as promising lead compounds to develop more efficacious non-nitrocatechol COMT inhibitors for biomedical applications.

Perovskite solar cells (PVSCs) have emerged as a promising photovoltaic technology and have attracted wide research interest due to their outstanding photovoltaic performance, low cost, and the ability to fabricate large-area devices. An impressive certified power conversion efficiency (PCE) of 25.2% has been achieved, demonstrating the excellent potential of PVSCs for future applications. Hole-transporting materials play a key role in improving the device performance of PVSCs by facilitating the extraction of photogenerated holes and their transport from the perovskite layer to the anode. This review provides a brief introduction to PVSCs and summarizes the recent progress in small molecule hole-transporting materials (SM-HTMs) bearing various cores and different 4-anisylamino-based end caps. We classify the end caps into N,N-di-4-anisylamino (DAA), 4-(N,N-di-4-anisylamino)benzo (DAB), and N3, N6(or N2, N7)-bis(di-4-anisylamino)-9H-carbazole (3,6-DAC or 2,7-DAC) groups. We also review the core type, end cap position and number, how these affect the overall properties of the SM-HTMs, and the resultant PVSC device performances. Finally, the challenges and perspectives for the future development of SM-HTMs are presented.

Background Pregnancy is associated with higher incidence of failed endotracheal intubation and is exacerbated by labor. However, the influence of labor on airway outcomes with laryngeal mask airway (LMA) for cesarean delivery is unknown. Methods This is a secondary analysis of a prospective cohort study on LMA use during cesarean delivery. Healthy parturients who fasted > 4 h undergoing Category 2 or 3 cesarean delivery with Supreme™ LMA (sLMA) under general anesthesia were included. We excluded parturients with BMI > 35 kg/m2, gastroesophageal reflux disease, or potentially difficult airway (Mallampati score of 4, upper respiratory tract or neck pathology). Anesthesia and airway management reflected clinical standard at the study center. After rapid sequence induction and cricoid pressure, sLMA was inserted as per manufacturer’s recommendations. Our primary outcome was time to effective ventilation (time from when sLMA was picked up until appearance of end-tidal carbon dioxide capnography), and secondary outcomes include first-attempt insertion failure, oxygen saturation, ventilation parameters, mucosal trauma, pulmonary aspiration, and Apgar scores. Differences between labor status were tested using Student’s t-test, Mann-Whitney U test, or Fisher’s exact test, as appropriate. Quantitative associations between labor status and outcomes were determined using univariate logistic regression analysis. Results Data from 584 parturients were analyzed, with 37.8% in labor. Labor did not significantly affect time to effective ventilation (mean (SD) for labor: 16.0 (5.75) seconds; no labor: 15.3 (3.35); mean difference: -0.65 (95%CI: − 1.49 to 0.18); p = 0.1262). However, labor was associated with increased first-attempt insertion failure and blood on sLMA surface. No reduction in oxygen saturation or pulmonary aspiration was noted. Conclusions Although no significant increase in time to effective ventilation was noted, labor may increase the number of insertion attempts and oropharyngeal trauma with sLMA use for cesarean delivery in parturients at low risk of difficult airway. Future studies should investigate the effects of labor on LMA use in high risk parturients. Trial registration The study was prospectively registered at clinicaltrials.gov (NCT02026882) on 3 January 2014.

AIM: To evaluate the quality of life of recruits after refractive surgery. METHODS: Population-based, cross-sectional study. Using the Quality of Life Impact of Refractive Correction (QIRC) questionnaire, the quality of life in 615 recruits underwent refractive surgery was evaluated. The overall score and each question score of QIRC were compared between subgroups of different strength of preoperative refractive error, postoperative interval, type of surgical procedure and postoperative recovery. RESULTS: The mean overall QIRC score of recruits underwent refractive surgery was 49.15±7.89. Significant difference was found for strength of preoperative refractive error (F=4.16, P0.05). Scores of recruits underwent mechanical microkeratome laser in situ keratomileusis (MK-LASIK), Sub-Bowman’s keratomileusis (SBK), femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK), femtosecond lenticule extraction (ReLEx flex) or small-incision lenticule extraction (ReLEx SMILE) procedure showed no significant difference too. Recruits had adverse complaints postoperatively (45.85±6.66) scored lower when compared with all underwent refractive surgery (t=5.28, P

Levels of type 2 cytokines are elevated in the blood and intestinal tissues of ulcerative colitis (UC) patients in the active phase; this phenomenon indicates the participation of type 2 immune response in UC progression. The beneficial effects of melatonin in dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis models have been illustrated, but its role in the oxazolone (Oxa)-induced colitis model (driven by type 2 immune response) remains relatively unknown. We investigated the relationship between melatonin concentration and the severity of UC, revealing a significantly negative correlation. Subsequently, we investigated the effects of melatonin in Oxa-induced colitis mice and the potential underlying mechanisms. Administration of melatonin significantly counteracted body weight loss, colon shortening, and neutrophil infiltration in Oxa-induced colitis mice. Melatonin treatment mitigated Oxa-induced colitis by suppressing type 2 immune response. In addition, melatonin attenuated intestinal permeability by enhancing the expression of ZO-1 and occludin in colitis mice. Interestingly, the protective effect of melatonin was abolished when the mice were co-housed, indicating that the regulation of gut microbiota by melatonin was critical in alleviating Oxa-induced colitis. Subsequently, 16S rRNA sequencing was performed to explore the microbiota composition. Decreased richness and diversity of intestinal microbiota at the operational taxonomic unit (OTU) level resulted from melatonin treatment. Melatonin also elevated the abundance of Bifidobacterium, a well-known probiotic, and reduced proportions of several harmful bacterial genera, such as Desulfovibrio, Peptococcaceae, and Lachnospiraceae. Fecal microbiota transplantation (FMT) was used to explore the role of microbiota in the function of melatonin in Oxa-induced colitis. Microbiota transplantation from melatonin-treated mice alleviated Oxa-induced colitis, suggesting that the microbiome participates in the relief of Oxa-induced colitis by melatonin. Our findings demonstrate that melatonin ameliorates Oxa-induced colitis in a microbiota-dependent manner, suggesting the therapeutic potential of melatonin in treating type 2 immunity-associated UC.

Carboxylesterase 2 (CES2) is one of the most important Phase I drug metabolizing enzymes in the carboxylesterase family. It plays crucial roles in the bioavailability of oral ester prodrugs and the therapeutic effect of some anticancer drugs such as irinotecan (CPT11) and capecitabine. In addition to the well-known roles of CES2 in xenobiotic metabolism, the enzyme also participates in endogenous metabolism and the production of lipids. In this study, we synthesized a series of pyrazolones and assayed their inhibitory effects against CES2 in vitro. Structure-activity relationship analysis of these pyrazolones reveals that the introduction of 4-methylphenyl unit (R1), 4-methylbenzyl (R2) and cyclohexyl (R3) moieties are beneficial for CES2 inhibition. Guided by these SARs results, 1-cyclohexyl-4-(4-methylbenzyl)-3-p-tolyl-1H- pyrazol-5(4H)-one (27) was designed and synthesized. Further investigations demonstrated that the compound 27 exhibited stronger CES2 inhibition activity with a lower IC50 value (0.13 μM). The inhibition kinetic study demonstrated that compound 27 inhibited the hydrolysis of CES2-fluorescein diacetate (FD) through non-competitive inhibition. In addition, the molecular docking showed that the core of pyrazolone, the cyclohexane moiety, 4-methylbenzyl and 4-methylphenyl groups in compound 27 all played important roles with the amino acid residues of CSE2. Also, compound 27 could inhibit adipocyte adipogenesis induced by mouse preadipocytes. In brief, we designed and synthesized a novel pyrazolone compound with a strong inhibitory ability on CES2 and could inhibit the adipogenesis induced by mouse preadipocytes, which can be served as a promising lead compound for the development of more potent pyrazolone-type CES2 inhibitors, and also used as a potential tool for exploring the biological functions of CES2 in human being.

Human catechol

Catechol-O-methyltransferase (COMT) is a major drug metabolizing enzyme in humans. COMT expression is directedly associated with various mental diseases and cancers due to its essential role in catalyzing metabolic inactivation of endogenous catecholamines and catechol estrogens. However, a practical method to precisely measure COMT activities in biological samples is lacking. In the current study, we established a liquid chromatography-fluorescence detection (LC-FD) method based on fluorometric detection of the methylated product of 3-BTD, a fluorescent probe for COMT, to sensitively quantify COMT activities in human erythrocytes and cell homogenates. Assay validation of the established LC-FD based method was conducted for selectivity and sensitivity, range of linearity, precision and accuracy, recovery, biological matrices effect and stability. The limit of quantification for 3-BTMD (the methylated product of 3-BTD by COMT) of this method was 0.0083 nM, which is nearly 10-fold lower than that for previously published methods. The method was precise with intra- and inter-day relative standard deviation (RSD) lower than 5%. In addition, this method showed an excellent anti-interference ability with no effects of the endogenous substances on the fluorometric detection of 3-BTMD. The practical use of this method was established by its successful application for the measurement of COMT activities in individual human erythrocytes (n = 13), and in cell homogenates generated from four different human cell lines. Our results suggest that this method will be of great value in accurately determining the native activity of COMT in biological samples, which is beneficial for a complete understand of the role of COMT both in physiological and pathological conditions.

Background The Supreme™ laryngeal mask airway (SLMA) is a single-use LMA with double lumen design that allows separation of the respiratory and the alimentary tract, hence potentially reducing the gastric volume and risk of aspiration. The purpose of this prospective cohort study is to evaluate the the role of the SLMA as an airway technique for women undergoing category 2 and 3 Cesarean delivery under general anesthesia. Methods We recruited 584 parturients who underwent category 2 or 3 Cesarean delivery under general anesthesia, in which 193 parturients underwent category 2 and 391 parturients underwent category 3 Cesarean delivery. The primary outcome was insertion success rate at 1st attempt in SLMA insertion. The secondary outcomes included anaesthetic, obstetric outcomes and maternal side effects associated with airway device. Results The 1st attempt insertion success rate was 98.3%, while the overall insertion success rate was 100%. The mean (Standard deviation) time to effective ventilation was 15.6 (4.4) seconds. Orogastric tube insertion was successful at the 1st attempt in all parturients. There was no clinical evidence of aspiration or regurgitation. No episodes of hypoxemia, laryngospasm or bronchospasm were observed intra-operatively. The incidence of complications was low and with good maternal satisfaction reported. Conclusions The SLMA could be an alternative effective airway in category 2 and 3 parturients emergency Cesarean Delivery under general anesthesia in a carefully-selected obstetric population. Trial registration Clinical Trials Registration: Clinicaltrials.gov Registration NCT02026882 . Registered on December 31, 2013.

The present study was performed to explore the role of galanin and galanin receptor 1 (GalR 1) in nociceptive modulation in the central nucleus of amygdala (CeA) in normal rats and rats with neuropathy, and the involvement of GalR 1 and PKC was also investigated. The hindpaw withdrawal latencies (HWLs) to thermal and mechanical stimulations were increased in a dose-dependent manner after intra-CeA injection of galanin in both normal rats and rats with neuropathy. The increased HWLs were significantly attenuated by intra-CeA injection of galanin receptor antagonist M40, indicating an involvement of galanin receptor in nociceptive modulation in CeA. Furthermore, intra-CeA administration of the GalR 1 agonist M 617 induced increases in HWLs in normal rats, suggesting that GalR 1 may be involved in galanin-induce antinociception in CeA. Additionally, intra-CeA injection of the PKC inhibitor inhibited galanin-induced antinociception, showing an involvement of PKC in galanin-induced antinociception in CeA of normal rats. Moreover, there was a significant increase in GalR1 content in CeA in rats with neuropathy than that in normal rats. These results illustrated that galanin induced antinociception in CeA in normal rats and rats with neuropathy, and there is an up-regulation of GalR1 expression in rats with neuropathy.

Obstetric dfficult airway is a leading cause of maternal morbidity and mortality. The laryngeal mask airway (LMA) is often used as a rescue airway device after failed intubation, however, little is known about predictors of difficult LMA insertion, particularly in obstetrics. Since Mallampati scores of III/IV has been associated with difficult tracheal intubation, our present study aims to investigate if Mallampati score (MP) could predict airway outcomes for LMA use in obstetrics. This prospective cohort study was performed at a single-center: Quanzhou Women’s and Children’s Hospital, Fujian Province, China. Five hundred and eighty-four parturients undergoing elective cesarean section under general anesthesia were recruited. The primary outcome was time to effective ventilation, and secondary outcomes included first attempt insertion success, seal pressure, ventilation and hemodynamic parameters, occurrence of clinical aspiration, and maternal and fetal outcomes. The parturients were classified into two groups based on MP of III/IV (High MP: 61) versus I/II (Low MP: 523). BMI was higher in the High MP group than in the Low MP group (mean (SD) 29.3 (7.0) vs 26.8 (3.1), p

Myeloid cell leukemia-1 (Mcl-1) is a validated and attractive target for cancer therapy. Over-expression of Mcl-1 in many cancers allows cancer cells to evade apoptosis and contributes to their resistance to current chemotherapeutics. In this study, more than thirty coumarin derivatives with different substituents were designed and synthesized, and their Mcl-1 inhibitory activities evaluated using a fluorescence polarization-based binding assay. The results showed that the catechol group was a key constituent for Mcl-1 inhibitory activity of the coumarins, and methylation of the catechol group led to decreased inhibitory activity. The introduction of a hydrophobic electron-withdrawing group at the C-4 position of 6,7-dihydroxycoumarin, enhanced Mcl-1 inhibitory capacity, and a hydrophilic group in this position was unbeneficial to the inhibitory potency. In addition, the introduction of a nitrogen-containing group to the C-5 or C-8 position, which allowed an intramolecular hydrogen bond, was also unfavorable for Mcl-1 inhibition. Among all coumarins tested, 4-trifluoromethyl-6,7-dihydroxycoumarin (Cpd 4) displayed the most potent inhibitory activity towards Mcl-1 (Ki = 0.21 ± 0.02 μM, IC50 = 1.21 ± 0.56 μM, respectively), for which the beneficial effect on taxol resistance was also validated in A549 cells. A strong interaction between Cpd 4 and Mcl-1 in docking simulations further supported the observed potent Mcl-1 inhibition ability of Cpd 4. 3D-QSAR analysis of all tested coumarin derivatives further provides new insights into the relationships linking the inhibitory effects on Mcl-1 and the steric-electrostatic properties of coumarins. These findings could be of great value for medicinal chemists for the design and development of more potent Mcl-1 inhibitors for biomedical applications.

White Mulberry Root-bark (WMR) is an edible Chinese herbal used for the treatment of inflammation, nephritis and asthma. This study aimed to investigate the inhibitory effects of ethanol extract from WMR against human carboxylesterase 2 (hCE2), as well as to identity and character natural hCE2 inhibitors in this herbal. Our results demonstrated that the ethanol extract of WMR displayed potent inhibitory effects against hCE2, while three major bioactive constitutes in WMR were identified on the basis of LC fingerprinting combined with activity-based screening of LC fractions. Three bioactive compounds including SD, KG and SC were efficiently identified by comparison of LC retention times, UV and MS spectral data, with the help of authentic standards. The inhibition potentials and inhibition types of these natural compounds against hCE2 were further investigated in human liver microsomes. The results demonstrated that these bioactive compounds are potent non-competitive inhibitors against hCE2, with the Ki values ranging from 0.76μM to 1.09μM. All these findings suggested that three abundant natural compounds in WMR displayed potent inhibitory effects against hCE2, which could be used as lead compounds to develop more potent hCE2 inhibitors for the alleviation of hCE2-mediated severe delayed-onset diarrhea.

This paper presents and verifies a new idea for constructing an ultrasonic motor (USM). The stator contains several vibrators fabricated by bonding piezoelectric ceramics (PZTs) to a metal base. When two alternating current (AC) voltages with a 90° phase difference are applied to the PZTs, longitudinal and bending modes are excited in the vibrator. The bending vibrations of the vibrators are stacked to form the torsional vibration of the stator, ultimately generating longitudinal-torsional composite vibration. Both vibrators and the stator are excited to the resonance state. A standing wave is formed by superposition of longitudinal and torsional modes. The proposed motor is an in-plane vibration motor because the vibrations of the stator are in the circumferential plane. The finite element method (FEM) is used to validate the feasibility of the proposed motor. The fabricated stator contains five vibrators. The tested resonance frequencies of longitudinal and torsional modes are 44.42 kHz and 43.83 kHz, respectively. The stall torque is 0.3 N·m and no-load speed is 45 r/min. The highest efficiency is 30%. The applied driving voltage is 100 Vo-p (peak voltage) at 43.9 kHz. The designed motor is a parallel-actuated integral motor. It allows the vibrators to operate synchronously, and overcomes asynchronous issues that occur in traditional multi-vibrator motors.

Esculentoside B (EsB, also named phytolaccagenin 3- O -β- d -xylopyranoside), a pentacyclic triterpene isolated from herbal medicine Radix phytolaccae , has been found to possess multiple pharmacological activities. Nonetheless, the low content in nature and the difficulties in the total synthesis of EsB strongly limit its extensive investigations and further development as a drug candidate. This study aims to provide a practical method for highly efficient preparation of EsB using esculentoside A (EsA, phytolaccagenin 3- O -β- d -glucopyranosyl (1 → 4)-β- d -xylopyranoside) as the starting material. β- d -glucosidase from snailase was used to catalyze the formation of EsB, and the product was then purified and fully characterized by both HRMS and NMR. To prepare EsB in a more cost-effective way, response surface methodology (RSM) was used to explore the potential effects of the reaction conditions (such as reaction temperature, pH, enzyme load, and reaction time) on the conversion rates of EsA. The highest EsB yield of 0.66 mg/ml was obtained experimentally under optimized conditions as follows: temperature 48.28 °C, pH 6.4, enzyme load 4.43%, and reaction time 2.73 h. This result agreed well with the predicted yield of 0.68 mg/ml by RSM. The enzymatic kinetics of this biotransformation was characterized at the optimum pH and temperature. The S 50 value was evaluated as 167.4 μM, while the V max value was 345.6 nmol/min/mg. In summary, this study provided a mild and practical method for the highly efficient preparation of EsB from EsA, which held great promise for large scale production of EsB.

To develop a practical method to prepare tilianin by highly selective and efficient hydrolysis of the C-7 rhamnosyl group from linarin.Naringinase was utilized to selectively catalyze the formation of tilianin using linarin as the starting material. The reaction conditions, including temperature, pH, metal ions, substrate concentration and enzyme concentration, were optimized. At 60 °C, naringinase showed enhanced α-L-rhamnosidase activity while the β-D-glucosidase activity was abrogated. The addition of Mg(2+), Fe(2+) and Co(2+) was also beneficial for selective biotransformation of linarin to tilianin. Under the optimized conditions (pH 7.0 at 60 °C), linarin could be nearly completely transformed to tilianin with excellent selectivity (98.9 %), while that of the by-product acacetin was less than 1.1 %. In addition, the structure of target product tilianin was fully characterized by HR-MS and (1)H-NMR.A highly selective and efficient biotransformation of linarin to tilianin was developed by the proper control of incubation temperature, which enhanced the α-L-rhamnosidase activity of naringinase and blocked its β-D-glucosidase activity.

The performance of a new kind of confined stabilized soil (CSS) was investigated which was constructed by filling the stabilized soil, which was made by mixing soil with a binder containing a high content of expansive component, into an engineering plastic pipe. Cube compressive strength of the stabilized soil formed with constraint and axial compression performance of stabilized soil cylinders confined with the constraint pipe were measured. The results indicated that combining the constraint pipe and the binder containing expansion component could achieve such effects: higher production of expansive hydrates could be adopted so as to fill more voids in the stabilized soil and improve its strength; at the same time compressive prestress built on the core stabilized soil, combined of which hoop constraint provided effective radial compressive force on the core stabilized soil. These effects made the CSS acquire plastic failure mode and more than twice bearing capacity of ordinary stabilized soil with the same binder content.

As an edible traditional Chinese herb, Fructus psoraleae (FP) has been widely used in Asia for the treatment of vitiligo, bone fracture and osteoporosis. Several cases on markedly elevated bilirubin and acute liver injury following administration of FP and its related proprietary medicine have been reported, but the mechanism in FP-associated toxicity has not been well investigated yet. This study aimed to investigate the inhibitory effects of FP extract and its major constituents against human UDP-glucuronosyltransferase 1A1 (UGT1A1), the key enzyme responsible for metabolic elimination of bilirubin. To this end, N-(3-carboxy propyl)-4-hydroxy-1,8-naphthalimide (NCHN), a newly developed specific fluorescent probe for UGT1A1, was used to evaluate the inhibitory effects of FP extract or its fractions in human liver microsomes (HLM), while LC-UV fingerprint and UGT1A1 inhibition profile were combined to identity and characterize the naturally occurring inhibitors of UGT1A1 in FP. Our results demonstrated that both the extract of FP and five major components of FP displayed evident inhibitory effects on UGT1A1 in HLM. Among these five identified naturally occurring inhibitors, bavachin and corylifol A were found to be strong inhibitors of UGT1A1 with the inhibition kinetic parameters (Ki) values lower than 1 μM, while neobavaisoflavone, isobavachalcone, and bavachinin displayed moderate inhibitory effects against UGT1A1 in HLM, with the Ki values ranging from 1.61 to 9.86μM. These findings suggested that FP contains natural compounds with potent inhibitory effects against human UGT1A1, which may be one of the important reasons for triggering FP-associated toxicity, including elevated bilirubin levels and liver injury.

Fructus Psoraleae (FP) is an edible Chinese herbal which is widely used in Asia for the treatment of various diseases including asthma, diarrhea, and osteoporosis. This study aimed to investigate the inhibitory effects of the crude ethanol extract from FP on human carboxylesterase 2 (hCE2), as well as to identity and characterize the naturally occurring inhibitors of hCE2 in FP. Our results demonstrated that the ethanol extract of FP displayed potent inhibitory effects towards hCE2, while five major bioactive constitutes in FP were efficiently identified by LC-DAD-ESI-MS/MS, with the aid of LC-based activity profiling. The identified bioactive compounds including neobavaisoflavone, isobavachalcone, bavachinin, corylifol A and bakuchiol were found to be naturally occurring potent inhibitors of hCE2, with low Ki values ranging from 0.62μM to 3.89μM. This is the first report of the chemical constitutes in FP as potent inhibitors of hCE2.

Baicalein (BA), a natural flavonoid compound, possesses many desirable pharmacological activities. However, poor solubility and extensive metabolism by human UDP-glucuronosyltransferases (UGTs) strongly restrict the clinical applications of BA. We previously reported that two C-8 Mannich base derivatives of BA (BA-a and BA-j) displayed enhanced solubility and anti-cyclin dependent kinase 1 activity, yet the metabolic stabilities of these compounds remained unknown. This study aimed to evaluate the in vitro glucuronidation stability of these BA derivatives and to explore the key factors affecting the UGT-mediated biotransformation. The results showed that the glucuronidation stabilities of these BA derivatives were much higher than BA. BA-a exhibited 12-fold and BA-j exhibited 5-fold improved stability in human liver S9, while in human intestine S9, BA-a and BA-j exhibited 42-fold and 33-fold improved stability, respectively. Further investigations found that the major glucuronidation site(s) were changed from 7-OH and 6-OH in BA to 6-OH in the BA derivatives. Also, both the involved enzymes and their catalytic efficacy in 6-O-glucuronidation of BA derivatives were much lower than that of BA. The formation of an intramolecular hydrogen bond between the C-8 Mannich base substituents and C-7 phenolic groups played a predominant role in these glucuronidation changes. The calculated bond dissociation energy (BDE) of each phenolic group in BA and its derivatives agreed well with their glucuronidation activities. All these findings bring new insights into the structure–glucuronidation relationship and provide a practical strategy for the structural modification to improve the glucuronidation stability of drug candidates, especially for those phenolic compounds.

A practical two-photon fluorescent probe was developed for highly sensitive and selective sensing of the activities of catechol-O-methyltransferase (COMT) in complex biological samples. To this end, a series of 3-substituted 7,8-dihydroxycoumarins were designed and synthesized. Among them, 3-BTD displayed the best combination of selectivity, sensitivity, reactivity, and fluorescence response following COMT-catalyzed 8-O-methylation. The newly developed two-photon fluorescent probe 3-BTD can be used for determining the activities of COMT in complex biological samples and bio-imaging of endogenous COMT in living cells and tissue slices with good cell permeability, low cytotoxicity, and high imaging resolution. All these findings suggest that 3-BTD holds great promise for developing therapeutic molecules that target COMT, as well as for exploring COMT-associated biological processes and its biological functions in living systems. Furthermore, the strategy also sheds new light on the development of fluorescent probes for other conjugative enzymes.

Enters sells saves themanagement system includes the basic information, stock management, salesmanagement, inventory management, query statistics, system management, andother six most. Database concept design includes entity, the use ofPowerDesigner build system model, etc.; Main form design contains basicinformation module suppliers, add, modify and delete, stock management module,etc.Java and JSP are used in the design of the complete portable networkshopping system .

Forming effect of square parts is influenced greatly by technical parameters in hydraulic deep drawing, and it is significative to investigate the parameters. The technical parameters which influence the cold forming effect (wall thickness difference and minimum wall thickness) were introduced in detail by numerical simulation method, including the load method of blank holder force, drawing speed, hydraulic pressure, etc. Furthermore, the reasonable technological parameters were concluded and the wall thickness distribution of magnesium alloy square parts was discussed in this paper. The results show that the cold formability of AZ31B magnesium alloy square parts could be improved when adopt reasonable technological parameters and blank holder force load path in hydraulic deep drawing.

Wind rose analysis method, two dimensional hydrodynamic model and particle tracer model are adopted to systematically study wind field features, flow field variation, and migration, spreading and accumulation processes of the internal and external cyanobacterial boom in Dianshan Lake. The results show that the wind direction in Dianshan Lake varies with seasons; the main wind direction is ESE in summer and autumn, and is NNW in winter and spring. Wind has great effects on the circulation patterns of the lake. In the case of no wind, the lake is mainly influenced by the upstream and downstream flows. River flow enters into the lake during flood tide, while the lake discharges during ebb tide, and there is no circulation occurred; the clockwise and counterclockwise circulations are generated respectively in the north and south of the lake under southeast wind, and similarly for northwest wind only the circulation directions are opposite. Upon different wind and flow fields, cyanobacterial boom is drifting to the windward lakeshore, and is prone to form the algae accumulation area.

Under the assumption that investors have the logarithm utility function, this paper adopts the methodology of nonparametric estimation and the expected utility maximization (EUM) model to explore a portfolio engineering problem with bankruptcy control. First, we obtain the nonparametric estimated calculation formula for expected utility by using the nonparametric estimation. Then, sequential quadratic programming (SQP) algorithm for the optimal investment strategy of the EUM model is given. Finally, a numerical portfolio engineering example based on real data of Chinese stock market is presented.

Hammerhead ribozymes have been shown to silence human immunodeficiency virus-1 (HIV-1) gene expression by site-specific cleavage of viral mRNA. The two major factors that determine whether ribozymes will be effective for post-transcriptional gene silencing are colocalization of the ribozyme and the target RNAs, and the choice of an appropriate target site on the mRNA. An effective screening strategy for potential targets on the viral genome is the use of ribozyme libraries in cell culture. Capitalizing on previous findings that HIV-1 and ribozymes can be colocalized in the nucleolus, we created a novel hammerhead ribozyme library by inserting hammerhead ribozymes with fully randomized stems 1 and 2 into the body of the U16 small nucleolar RNA (snoRNA). Following three rounds of cotransfection with an HIV-1 proviral DNA harboring the herpes simplex virus thymidine kinase (HSV-TK) gene, we selected for gancyclovir-resistant cells and identified a ribozyme sequence that could potentially target both the U5 and gag genes of HIV-1 regions on the HIV-1 genome through partial homologies with these targets. When the ribozymes were converted to full complementarity with the targets, they provided potent inhibition of HIV-1 replication in cell culture. These results provide a novel approach for identifying ribozyme targets in HIV-1.

Human carboxylesterases 1 (hCE1), one of the most important human drug metabolizing enzymes, catalyzes the hydrolysis of a large number of structurally diverse of endogenous and exogenous substrates. However, a practical, reliable and sensitive method for the precise measurement of hCE1 activities in complex biological samples has been rarely reported. In this study, a liquid chromatography-fluorescence detection (LC-FD) based method was developed for highly selective and sensitive measurement of hCE1 activities in human tissue and cell preparations. This method was based on the fluorimetric detection of HMBT, the hydrolyzed product of BMBT which was a newly developed specific probe substrate for hCE1. The developed LC-FD method was fully validated in terms of specificity, sensitivity, linearity, precision, recovery and stability. With the help of LC separation, most polar endogenous compounds in biological samples could be eluted in the column dead time, which is very beneficial for accurate determination of hCE1 activities in complex biological samples. The lower limit of quantification for HMBT (product of hCE1) of this LC-FD based method was as low as 20nM, which was quite lower than other reported methods. The method also exhibited good precision, both intra- and inter- assay variances were both lower than 2.5%. Furthermore, the newly developed method was successfully applied to measure hCE1 activity in human liver preparations from individual donors (n=12), as well as in homogenates from eleven different human cell lines. All these findings combined with this practical method are very helpful for the deep understanding of the expression and function of hCE1 in human biological samples.

Brachymystax tsinlingensis Li, 1966 is revalidated and redescribed. It can be distinguished from all congeners by the following combination of characteristics: no spots on operculum; gill rakers 15-20; lateral-line scales 98-116; pyloric caeca 60-71. Unique morphological characters and genetic divergence of this species are discussed. This species has a limited distribution in several streams of the middle part of the Qinling Mountains in China. Methods for management and protection of B. tsinlingensis need to be re-evaluated.

To compare the variations of cardiovascular responses and vascular angiotensin II (AngII) in hypertensive patients during tracheal intubation with intubating laryngeal mask airway (ILMA) versus direct laryngoscope (DLS).A total of 120 hypertensive patients undergoing abdominal surgery were randomly divided into 2 groups, i.e.intubating laryngeal mask airway (Group I) and direct laryngoscope (Group D).Variations of invasive arterial blood pressure and angiotensin II were compared between two groups before and after intubation.The variations of cardiovascular responses and vascular angiotensin II (AngII) during tracheal intubation used of ILMA (T4) and DLS (T4) in an instant, tracheal intubation were immediately accomplished in two groups (T5). The variations of group I were significantly lower than those of group D (P0.05). And statistical significance existed between two groups.Tracheal intubation with intubating laryngeal mask airway (ILMA) can significantly reduce violent cardiovascular reactions and avoid cardiovascular accidents.