Conformational study into N-alkyl-N'-aryl ureas to inform drug discovery.

Ureas are an important functional group in small molecule drugs as well as having wider applications in organic chemistry. Understanding of their conformation is of critical importance for rational design of urea-containing bioactive compounds. Whilst the conformational preferences of biaryl ureas have been extensively studied, very little attention has been paid to alkylated analogues. We carried out a systematic study of N-aryl (phenyl and pyridyl)-N'-cyclopentyl ureas with differing N-methylation patterns using Well Tempered Metadynamics at a semi-empirical level in implicit water (GBSA) using Well-Tempered Metadynamics to generate their conformational free-energy landscapes. Geometries and energetics of the most relevant configurations are further refined using DFT level of theory. Validation for the computation was obtained by synthesis of all 8 analogues followed by conformational studies by X-ray crystallography and NMR. These findings reveal that the methylation pattern significantly affects the conformational preference of the system. Most notably, N-phenyl-N'-cyclopentyl urea is shown to adopt both the trans-trans, and cis-trans conformations with equal energy and that the cis-trans conformation can be significantly stabilised by the presence of an internal hydrogen bond to the N'-hydrogen. This study will be of utility for the design of N-alkyl-N'-aryl ureas as drug candidates.

[Application of Correspondence Analysis in the Analysis of Accidental Death of Chinese Residents].

ABSTRACT: Objective To study the preference relation between residence, sex, age and causes of accidental death of Chinese residents. Methods In this study, 72 residence-sex-age groups and 8 causes of accidental death were qualitatively and quantitatively analyzed by correspondence analysis using the official statistical yearbook issued from 2014 to 2018, and the preference values were calculated. Results Among the 576 pairs of correspondences between the residence-sex-age groups and causes of accidental death, 352 pairs （61.11%） showed a preference relation （preference value>0）. In terms of residence and sex, accidental death preference among Chinese residents was higher in rural areas than in urban areas, and males were higher than females. In terms of the causes of accidental death, the overall risk of accidental mechanical asphyxia and motor vehicle accidents was the highest among all age groups of Chinese residents. In terms of age, with the increase of age, the preference value of accidental death of Chinese residents showed a trend of first increasing and then decreasing. The comparative analysis results of the preference values of various causes of accidental death in different age groups showed that motor vehicle traffic accidents, accidental poisoning, death by crush and electric shock were more likely to occur in the working age group between 20 and 59 years old, accidental fall and fire were more likely to occur in the elderly group over 80 years old, and drowning and accidental mechanical asphyxia were more likely to occur in the minor group between 1 and 19 years old. Conclusion There are different preference relations between residence-sex-age groups and causes of accidental death in China. Therefore, effective control strategies and measures should be formulated for Chinese residents with preference for accidental death.

[Learning curve analysis of 73 cases of central pancreatectomy].

Objective: To explore the learning curve of central pancreatectomy (CP) and provide an excellent reference for surgeons to get the point of this operation. Methods: Clinical data of 73 patients who underwent CP in the same operation team from January 2006 to January 2018 were collected and retrospectively analyzed by the moving average method (MAM) and the cumulative sum method (CUSUM). Data was analyzed by statistical package for social science (SPSS) software. Results: According to the MAM and CUSUM curves, the learning process of CP could be divided into two stages. At the first stage (n=1-11), the median operation time was 340 minutes and the median intraoperative hemorrhage was 400 ml. In the second stage (n=12-73), the median operation time was 213 minutes and the median intraoperative hemorrhage was 100 ml. The difference was statistically significant (P<0.001). There were no significant differences between the two stages of patients in terms of other aspects (P>0.05). Conclusions: CP can be mastered after 11 cases of exercises. In the first 11 operations, surgeons should get familiar with the operation process, respond actively to emergencies and accumulate experience to gain this surgical technique fast.

An alternative laser driven photodissociation mechanism of pyrrole via πσ*1∕S0 conical intersection.

A first principles quantum dynamics study of N-H photodissociation of pyrrole on the S0-1πσ*(A21) coupled electronic states is carried out with the aid of an optimally designed UV-laser pulse. A new photodissociation path, as compared to the conventional barrier crossing on the πσ*1 state, opens up upon electronic transitions under the influence of pump-dump laser pulses, which efficiently populate both the dissociation channels. The interplay of electronic transitions due both to vibronic coupling and the laser pulse is observed in the control mechanism and discussed in detail. The proposed control mechanism seems to be robust, and not discussed in the literature so far, and is expected to trigger future experiments on the πσ*1 photochemistry of molecules of chemical and biological importance. The design of the optimal pulses and their application to enhance the overall dissociation probability is carried out within the framework of optimal control theory. The quantum dynamics of the system in the presence of pulse is treated by solving the time-dependent Schrödinger equation in the semi-classical dipole approximation.

[Comparisons of prevalence and clinical and environmental characteristics between Tibetan and Han Women with polycystic ovarian syndrome in Tibetan Plateau].

Objective: By the preliminary comparison study on the constituent ratio and clinical characteristics of polycystic ovary syndrome (PCOS) in Tibetan and Han women in Tibetan Plateau, we aimed to find the relevance of its pathogenic factors, and to guide the treatment of PCOS in the plateau region and improve the prognosis. Methods: The general situation and clinical data of 165 patients who were diagnosed with PCOS from December 1, 2015 to November 30, 2016 in the Department of Obstetrics and Gynecology of the People's Hospital of Tibet Autonomous Region were analyzed retrospectively. The prevalence of PCOS among Tibetan and Han women in Tibetan Plateau were compared. Results: (1) A total of 1 520 patients were treated in the Tibet Autonomous Region People's Hospital gynecological endocrinology clinics in one year (Tibetan 865 cases, Han 617 cases, other ethnic groups 38 cases), of which patients with PCOS accounted for 10.9% (165/1520). (2) The incidence of Tibetan PCOS patients with oligomenorrhea, infertility, amenorrhea, acne, hairy, LH/FSH inverted, overweight (BMI≥24), and waist circumference >80 cm were 21.2% (35/165), 20.6% (34/165), 16.4% (27/165), 28.5% (47/165), 17% (28/165), 38.2% (63/165), 23.6% (39/165), and 36.4% (60/165), respectively. The incidence of Han PCOS patients with oligomenorrhea, infertility, amenorrhea, acne, hairy, LH/FSH inverted, overweight (BMI≥24), and waist circumference >80 cm were 7.9% (13/165), 10.3% (17/165), 9.1% (15/165), 15.2% (25/165), 9.7% (16/165), 14.5% (24/165), 10.9% (18/165) and 19.4% (32/165), respectively. The proportion of high testosterone in Tibetan PCOS patients was higher than that in Han PCOS patients with statistically significant. (3) The chief complaint of Tibetan PCOS patients were oligomenorrhea and infertility, and the chief complaint of Han PCOS patients were infertility and amenorrhea. (4) The constituent ratio of outpatient clinics in Nyingchi who were with PCOS at an average elevation of about 3 000 meters in the Tibetan Plateau was 7.9% (13/165), and the average constituent ratio in Lhasa, Xigatse and Nagqu over 3 500 meters above sea level was 35.8% (59/165), 16.9% (28/165) and 15.8% (26/165), respectively. Conclusion: The prevalence of PCOS in Tibetan areas is slightly higher than that in the international community. The clinical manifestations of Tibetan patients with PCOS are significantly different from those of Han patients with PCOS. The higher the altitude, the higher the incidence of PCOS.

Salmonella Typhimurium outbreak associated with a contaminated food container in a school in Sichuan Province, China.

On 13 June 2013, a fever and diarrhoea outbreak occurred in a boarding school in Sichuan Province. We conducted a field investigation and compared food exposure of 81 case students and 104 control students (years 7 and 8) in order to identify the source of infection. There were 401 cases identified (399 students and two cooks). The attack rates were 23-46% in nursery, primary, and secondary schools, but 0% in the high school. Eighty-five percent of case students, consumed cowpea salad compared to 60% of control students at lunch on 12 June (odds ratio 3·1, 95% confidence interval 1·3-7·8). The cowpeas were stored at room temperature for 3 h in a bucket previously used to store raw ingredients. The bucket was cleaned using water without a disinfectant. There were two buckets of cowpea, one for the high-school students and another for the other students. This Salmonella outbreak was likely caused by the cowpea salad due to cross-contamination via a storage bucket.

[Surgical treatment and prognosis of pancreatic neuroendocrine carcinoma].

Objective: Pancreatic neuroendocrine carcinoma (pNEC) is a highly malignant tumor.This study aimed to evaluate the role of surgery and the prognosis for patients with pancreatic neuroendocrine carcinoma (pNEC). Methods: We collected and reviewed all clinical data of patients who underwent radical surgery for pNEC from Jan 2000 through Jan 2016 in our hospital. Cox-regression analysis wasused to evaluate the factors potentially influencing survival. Results: Twenty patients including 11 males and 9 females (median age, 62.5 years) were included in this study. All patients underwent radical surgery and 17 cases received postoperative platinum-based chemotherapy.The median follow-up time was 41 months (range, 1 to 127 months). The 1-, 3-, and 5-year survival rates of the patients were 66.7%, 51.5% and 28.1%, with a median survival time of 75.3 months.The multivariate analysis indicated that tumor size and Ki-67 index were of prognostic significance. Conclusions: Pancreatic neuroendocrine carcinomas are rare but increasing in incidence. Patients with localized nonmetastatic primary tumors seem to benefit from surgery. Early diagnosis and multimodality therapy are key points of an improved survival.

Application of high-throughput, high-resolution and cost-effective next generation sequencing-based large-scale HLA typing in donor registry.

Next generation sequencing (NGS)-based human leukocyte antigen (HLA) typing was used for ultra large-scale genotyping of registry donors for the China Marrow Donor Program (CMDP). More than 79,000 samples were subjected to HLA genotyping at 4-digit allelic level without ambiguities for HLA-A, -B, -C, DRB1 and DQB1 loci, with throughput up to 2068 samples per lane in a HiSeq flow cell (eight lanes per run), and cost reduced by 95% compared with that of Sanger-based typing. Two percent of randomly selected samples were quality control (QC) tested at 4-digit allelic level by the CMDP QC laboratory, yielded a concordance of 99.72%. These results demonstrate that NGS is a cost effective and valuable tool for HLA typing of registry donors.

Effect of surface free energies on the heterogeneous nucleation of water droplet: a molecular dynamics simulation approach.

Heterogeneous nucleation of water droplet on surfaces with different solid-liquid interaction intensities is investigated by molecular dynamics simulation. The interaction potentials between surface atoms and vapor molecules are adjusted to obtain various surface free energies, and the nucleation process and wetting state of nuclei on surfaces are investigated. The results indicate that near-constant contact angles are already established for nano-scale nuclei on various surfaces, with the contact angle decreasing with solid-liquid interaction intensities linearly. Meanwhile, noticeable fluctuation of vapor-liquid interfaces can be observed for the nuclei that deposited on surfaces, which is caused by the asymmetric forces from vapor molecules. The formation and growth rate of nuclei are increasing with the solid-liquid interaction intensities. For low energy surface, the attraction of surface atoms to water molecules is comparably weak, and the pre-existing clusters can depart from the surface and enter into the bulk vapor phase. The distribution of clusters within the bulk vapor phase becomes competitive as compared with that absorbed on surface. For moderate energy surfaces, heterogeneous nucleation predominates and the formation of clusters within bulk vapor phase is suppressed. The effect of high energy particles that embedded in low energy surface is also discussed under the same simulation system. The nucleation preferably initiates on the high energy particles, and the clusters that formed on the heterogeneous particles are trapped around their original positions instead of migrating around as that observed on smooth surfaces. This feature makes it possible for the heterogeneous particles to act as fixed nucleation sites, and simulation results also suggest that the number of nuclei increases monotonously with the number of high energy particles. The growth of nuclei on high energy particles can be divided into three sub-stages, beginning with the formation of a wet-spot, increase of contact angle with near-constant contact line, and finally growth with constant contact angle. The growth rate of nuclei also increases with the size of high energy particles.

Risk factors for infection in patients undergoing shoulder arthroscopy: a systematic review and meta-analysis.

We conducted a meta-analysis to determine the risk of infection following shoulder arthroscopy and to identify risk factors for infection. We systematically searched the PubMed/Medline, Embase and Cochrane Library databases, as well as the reference lists of previous systematic reviews and meta-analyses; manual searches were also performed. A random-effects model was employed to estimate pooled odds ratios (ORs), based on sample size, the P-value of Egger's test and heterogeneity among studies. Of the 29,342 articles screened, 16 retrospective studies comprising 74,759 patients were included. High-quality evidence showed that patients with diabetes (OR, 1.30; 95% confidence interval (CI), 1.20-1.41) or hypertension (OR, 1.26; 95% CI, 1.10-1.44) had a higher risk of infection, while moderate quality evidence showed that patients with obesity (body mass index ≥30 kg/m2) (OR, 1.42; 95% CI, 1.28-1.57), those who were male (OR, 1.65; 95% CI, 1.12-2.44), those who had an American Society of Anesthesiologists (ASA) class ≥3 (OR, 2.02; 95% CI, 1.02-3.99) and those who had a history of smoking (OR, 2.44; 95% CI, 1.39-4.28) had a higher risk of infection. The meta-analysis revealed that there was no association between age, time of surgery, or alcohol consumption and infection. This meta-analysis identified six significant risk factors for infection following shoulder arthroscopy including diabetes, obesity, hypertension, male sex, ASA class, history of smoking. These patient-related risk factors may help identify postoperative patients at higher risk for infection following shoulder arthroscopy.

The effects of 1,4-cyclohexanediol on frozen ram spermatozoa.

In order to improve the quality of frozen spermatozoa of Yunnan semi-fine wool sheep, 1, 4-cyclohexanediol (1, 4-CHD) as a synthetic ice blocker was used for cryopreservation of ram spermatozoa in this study. Briefly, following collection by electric stimulation, equilibration at 5℃ following dilution with the freezing extender, and pre-freezing in liquid nitrogen vapor, the ram spermatozoa were preserved in liquid nitrogen for one month. In addition, the effects of osmolarity of the diluting extenders used for evaluation of frozen spermatozoa quality were also assessed. The results indicated addition of 1, 4-CHD could not increase the motility of ram spermatozoa after cryopreservation and thawing. With the elevation of the concentrations of 1, 4-CHD, the motility and moving velocity of frozen ram spermatozoa showed a steady decrease. Additionally, the presence of 1, 4-CHD cannot increase the percentage of frozen spermatozoa with intact acrosome and membrane. When the isotonic binding buffer was used to dilute the thawed spermatozoa, the percentage of cells labeled with propidium iodide (PI) after cryopreservation in the presence of 1, 4-CHD was significantly higher than that of spermatozoa frozen in the absence of 1, 4-CHD (P < 0.05). However, the percentage of frozen-thawed spermatozoa with exposed PS in the presence of 1, 4-CHD was significantly less than that of spermatozoa frozen in the absence of 1, 4-CHD (P < 0.01). When the basic extenders with an osmolarity of 404mOsm, 528mOsm, 648mOsm, or 853mOsm were used to dilute the frozen-thawed spermatozoa respectively, there is no significant difference between the four groups with respect to the moving velocity and membrane integrity (P > 0.05). In conclusion, the presence of 1, 4-CHD cannot improve the motility, moving velocity, acrosome staus, and membrane integrity of frozen ram spermatozoa. However, 1, 4-CHD may inhibit apoptosis caused by freezing and thawing.

[Dealcoholized red wine inhibits occurrence and progression of hepatocellular carcinoma possibly by inducing cell cycle arrest and apoptosis].

OBJECTIVE: To investigate the inhibitory effect of dealcoholized red wine (DRW) on occurrence and progression of hepatocellular carcinoma (HCC) and explore its possible mechanisms. METHODS: Three HCC cell lines (Huh7, HepG2 and SKHep-1) treated with 5, 10, 25, 50 and 100 µL/mL DRW were examined for changes in proliferation and colony formation ability using CCK-8 assay and colony formation assay. A nude mouse model bearing subcutaneous HCC xenograft was used to test the effect of 300 µL/day DRW for 4 weeks on tumor growth. The inhibitory effect of 300 µL/day DRW for 6 weeks on tumor growth was also observed in a mouse model of chemically induced HCC by examining the tumor number, largest tumor diameter and the liver/body ratio. RNA-seq technique was used for transcriptome sequencing of Huh7 cells treated with DRW (75 µL/mL) for 48 h, and gene-set enrichment analysis (GSEA) was performed to identify the changes in genes and pathways. Flow cytometry assay was used to analyze the changes in cell cycle and apoptosis of the cells. RESULTS: DRW inhibited the proliferation of the HCC cell lines in a concentration-and time-dependent manner, and concentration-dependently inhibited colony formation of the cells. Treatment with DRW significantly reduced the volume of subcutaneous tumor xenograft in the tumor-bearing nude mice (P < 0.05), and lowered the number of tumors (P < 0.001), the largest tumor diameter (P < 0.05) and the liver/body ratio (P < 0.01) in mice with chemically induced HCC. RNA-seq showed that 634 genes were significantly up-regulated and 478 were down-regulated in Huh7 cells after treatment with DRW. Gene-set enrichment analysis revealed that DRW significantly down-regulated cell cycle-related pathways (E2F Targets, G2M Checkpoint and MYC Targets) and up-regulated apoptosis pathways. Flow cytometry assay showed that DRW induced cell cycle arrest in G1 phase and apoptosis of Huh7 cells. CONCLUSION: DRW inhibits the occurrence and progression of HCC, and this effect is mediated possibly by inducing cell cycle arrest and apoptosis.

Comparison of the efficacy of febuxostat vs. benzbromarone in the treatment of gout: a meta-analysis in Chinese gout patients.

OBJECTIVE: Febuxostat and benzbromarone are two common drugs for the treatment of gout, but the clinical efficacy of these two drugs is controversial. This meta-analysis aimed to compare the efficacy of febuxostat and benzbromarone in the treatment of gout. MATERIALS AND METHODS: PubMed, Embase, and the Cochrane Library were searched for articles related to febuxostat and benzbromarone in the treatment of gout from inception to January 7, 2023. Titles and abstracts were reviewed in accordance with predesigned inclusion and exclusion criteria, and data were extracted independently. The Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the studies, and the continuous variables were expressed as the standard mean square error (SMD) by STATA 16 (Stata Corp., College Station, TX, USA). The sensitivity analysis was conducted by randomly removing a study, and the heterogeneity was analyzed by funnel plots and Egger's test. RESULTS: According to the search strategy, a total of 1,043 publications were retrieved from the three aforementioned databases, of which 45 publications were excluded due to duplication. Fourteen studies remained after screening titles and abstracts, and a total of 7 studies met the inclusion criteria after a comprehensive evaluation of the 14 studies. Meta-analysis showed that the uric acid (UA)-reducing effect of febuxostat is better than that of benzbromarone, while febuxostat showed a better ability to improve the estimated glomerular filtration rate (eGFR) and reduce Cr and blood urea nitrogen (BUN). In terms of hepatotoxicity, benzbromarone was not as potent as febuxostat in increasing alanine transaminase (ALT) and aspartate transaminase (AST), suggesting that benzbromarone has less hepatotoxicity. Moreover, there was no significant difference in the effect on blood lipid levels between the two drugs. CONCLUSIONS: The beneficial effect of febuxostat on renal function-related indexes such as the eGFR, Cr and BUN is significant, while benzbromarone is more effective in reducing UA and has relatively less hepatotoxicity. The specific efficacy of the two drugs needs to be confirmed by further research.

Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release.

A major drawback of cytotoxic chemotherapy is the lack of selectivity toward noncancerous cells. The targeted delivery of cytotoxic drugs to tumor cells is a longstanding goal in cancer research. We proposed that covalent inhibitors could be adapted to deliver cytotoxic agents, conjugated to the ß-position of the Michael acceptor, via an addition-elimination mechanism promoted by covalent binding. Studies on model systems showed that conjugated 5-fluorouracil (5FU) could be released upon thiol addition in relevant time scales. A series of covalent epidermal growth factor receptor (EGFR) inhibitors were synthesized as their 5FU derivatives. Achieving the desired release of 5FU was demonstrated to depend on the electronics and geometry of the compounds. Mass spectrometry and NMR studies demonstrated an anilinoquinazoline acrylate ester conjugate bound to EGFR with the release of 5FU. This work establishes that acrylates can be used to release conjugated molecules upon covalent binding to proteins and could be used to develop targeted therapeutics.

A randomized, double-blind study of larazotide acetate to prevent the activation of celiac disease during gluten challenge.

OBJECTIVES: In patients with celiac disease, enteropathy is caused by the entry of gluten peptides into the lamina propria of the intestine, in which their immunogenicity is potentiated by tissue transglutaminase (tTG) and T-helper type 1-mediated immune responses are triggered. Tight junction disassembly and paracellular permeability are believed to have an important role in the transport of gluten peptides to the lamina propria. Larazotide acetate is a tight-junction regulator peptide that, in vitro, prevents the opening of intestinal epithelial tight junctions. The aim of this study was to evaluate the efficacy and tolerability of larazotide acetate in protecting against gluten-induced intestinal permeability and gastrointestinal symptom severity in patients with celiac disease. METHODS: In this dose-ranging, placebo-controlled study, 86 patients with celiac disease controlled through diet were randomly assigned to larazotide acetate (0.25, 1, 4, or 8 mg) or placebo three times per day with or without gluten challenge (2.4 g/day) for 14 days. The primary efficacy outcome was the urinary lactulose/mannitol (LAMA) fractional excretion ratio. Secondary endpoints included gastrointestinal symptom severity, quality-of-life measures, and antibodies to tTG. RESULTS: LAMA measurements were highly variable in the outpatient setting. The increase in LAMA ratio associated with the gluten challenge was not statistically significantly greater than the increase in the gluten-free control. Among patients receiving the gluten challenge, the difference in the LAMA ratios for the larazotide acetate and placebo groups was not statistically significant. However, larazotide acetate appeared to limit gluten-induced worsening of gastrointestinal symptom severity as measured by the Gastrointestinal Symptom Rating Scale at some lower doses but not at the higher dose. Symptoms worsened significantly in the gluten challenge-placebo arm compared with the placebo-placebo arm, suggesting that 2.4 g of gluten per day is sufficient to induce reproducible gluten toxicity. Larazotide acetate was generally well tolerated. No serious adverse events were observed. The most common adverse events were headache and urinary tract infection. CONCLUSIONS: LAMA variability in the outpatient setting precluded accurate assessment of the effect of larazotide acetate on intestinal permeability. However, some lower doses of larazotide acetate appeared to prevent the increase in gastrointestinal symptom severity induced by gluten challenge.

Theoretical analysis of photoinduced H-atom elimination in thiophenol.

The photoinduced hydrogen elimination reaction in thiophenol via the conical intersections of the dissociative (1)πσ∗ excited state with the bound (1)ππ∗ excited state and the electronic ground state has been investigated with ab initio electronic-structure calculations and time-dependent quantum wave-packet calculations. A screening of the coupling constants of the symmetry-allowed coupling modes at the (1)ππ∗-(1)πσ∗ and (1)πσ∗-S(0) conical intersection shows that the SH torsional mode is by far the most important coupling mode at both conical intersections. A model including three intersecting potential-energy surfaces (S(0), (1)ππ∗, (1)πσ∗) and two nuclear degrees of freedom (SH stretch and SH torsion) has been constructed on the basis of ab initio complete-active-space self-consistent field and multireference second-order perturbation theory calculations. The nonadiabatic quantum wave-packet dynamics initiated by optical excitation of the (1)ππ∗ and (1)πσ∗ states has been explored for this three-state two-coordinate model. The photodissociation dynamics is characterized in terms of snapshots of time-dependent wave packets, time-dependent electronic population probabilities, and the branching ratio of the (2)σ/(2)π electronic states of the thiophenoxyl radical. The dependence of the timescale of the photodissociation process and the branching ratio on the initial excitation of the SH stretching and SH torsional vibrations has been analyzed. It is shown that the node structure, which is imposed on the nuclear wave packets by the initial vibrational preparation as well as by the transitions through the conical intersections, has a profound effect on the photodissociation dynamics. The effect of additional weak coupling modes of CC twist (ν(16a)) and ring-distortion (ν(16b)) character has been investigated with three-dimensional and four-dimensional time-dependent wave-packet calculations, and has been found to be minor.

[Construction of a risk assessment indicator system for re-establishment of imported malaria].

OBJECTIVE: To create a risk assessment indicator system for re-establishment of imported malaria. METHODS: The risk assessment indicator system for re-establishment of imported malaria was preliminarily constructed through literature review and thematic discussions. A total of 26 malaria control experts were selected to carry out a two-round Delphi consultation of the indicator system. The active coefficient, authority coefficient and coordination coefficient of the experts and the coefficient of variation on each indicator were calculated for indicator screening and the weight of each indicator was calculated. The reliability of the indicator system was evaluated using Cronbach's coefficient α, and the content validity of the indicator system was evaluated using the authority coefficient of the expert, while the structural validity of the indicator system was evaluated using Kaiser-Meyer-Olkin (KMO) test and factor analysis. RESULTS: Two rounds of Delphi expert consultations were completed by 23 malaria control experts, and a risk assessment indicator system for re-establishment of imported malaria was constructed, including 3 primary indicators, 7 secondary indicators, and 21 tertiary indicators. The active coefficient (100.00% vs. 88.46%; P < 0.01) and coordination coefficient of the expert (0.372 vs. 0.286; P < 0.01) were significantly greater in the second round of the Delphi expert consultation than in the first round. After the second round of the Delphi expert consultation, the authority coefficient of the experts ranged from 0.757 to 0.930 on each indicator, and the coefficients of variation were 0.098 to 0.136, 0.112 to 0.276 and 0.139 to 0.335 for the primary, secondary and tertiary indicators, respectively. The overall Cronbach's coefficient α of the indicator system was 0.941, and there were significant differences in the KMO values for primary (KMO value = 0.523; χ2 = 18.192, P < 0.05), secondary (KMO value = 0.694, χ2 = 51.499, P < 0.01) and tertiary indicators (KMO value = 0.519; χ2 = 477.638, P < 0.01), while the cumulative contribution rate of six principal components in the tertiary indicators was 84.23%. The normalized weights of three primary indicators of the source of infection, transmission condition and control capability were 0.337, 0.333 and 0.329, and the three secondary indicators with the greatest normalized weights included the number of imported cases and malaria parasite species (0.160), introduction of imported cases in China and medical care seeking (0.152), vector species and density (0.152), while the five tertiary indicators with the greatest normalized weights included the malaria parasite species of imported cases (0.065), vector populations (0.064), and the time interval from onset to medical care seeking (0.059), number of imported cases (0.056), and the time interval from medical care seeking to definitive diagnosis (0.055). CONCLUSIONS: A risk assessment indicator system for re-establishment of imported malaria is successfully created, which provides insights into the assessment of the risk of re-establishment of imported malaria and management of key high-risk factors in malaria-eliminated areas.

[Inhibition of TAK1 aggravates airway inflammation by increasing RIPK1 activity and promoting macrophage death in a mouse model of toluene diisocyanate-induced asthma].

OBJECTIVE: To explore the effect of transforming growth factor-ß (TGF-ß)-activated kinase 1 (TAK1) on toluene diisocyanate (TDI)-induced allergic airway inflammation in mice. METHODS: Thirty-two mice were randomly divided into AOO group, AOO+5Z-7-Oxozeaenol group, TDI group, and TDI+5Z-7-Oxozeaenol group. Another 32 mice were randomly divided into AOO group, TDI group, TDI +5Z-7-Oxozeaenol group, and TDI +5Z-7-Oxozeaenol + Necrostatin-1 group. TAK1 inhibitor (5Z-7-Oxozeaenol, 5 mg/kg) and/or RIPK1 inhibitor (Necrostatin-1, 5 mg/kg) were used before each challenge. Airway responsiveness, airway inflammation and airway remodeling were assessed after the treatments. We also examined the effect of TDI-human serum albumin (TDI-HSA) conjugate combined with TAK1 inhibitor on the viability of mouse mononuclear macrophages (RAW264.7) using CCK8 assay. The expressions of TAK1, mitogen-activated protein kinase (MAPK) and receptor interacting serine/threonine protease 1 (RIPK1) signal pathway in the treated cells were detected with Western blotting. The effects of RIPK1 inhibitor on the viability of RAW264.7 cells and airway inflammation of the mouse models of TDI-induced asthma were evaluated. RESULTS: TAK1 inhibitor aggravated TDI-induced airway inflammation, airway hyper responsiveness and airway remodeling in the mouse models (P < 0.05). Treatment with TAK1 inhibitor significantly decreased the viability of RAW264.7 cells, which was further decreased by co-treatment with TDI-HSA (P < 0.05). TAK1 inhibitor significantly decreased the level of TAK1 phosphorylation and activation of MAPK signal pathway induced by TDI-HSA (P < 0.05). Co-treatment with TAK1 inhibitor and TDI-HSA obviously increased the level of RIPK1 phosphorylation and caused persistent activation of caspase 8 (P < 0.05). RIPK1 inhibitor significantly inhibited the reduction of cell viability caused by TAK1 inhibitor and TDI-HSA (P < 0.05) and alleviated the aggravation of airway inflammation induced by TAK1 inhibitors in TDI-induced mouse models (P < 0.05). CONCLUSION: Inhibition of TAK1 aggravates TDI-induced airway inflammation and hyperresponsiveness and may increase the death of macrophages by enhancing the activity of RIPK1 and causing persistent activation of caspase 8.

Predictive capability of material screening by fast neutron activation analysis using laser-driven neutron sources.

Bright, short-pulsed neutron beams from laser-driven neutron sources (LANSs) provide a new perspective on material screening via fast neutron activation analysis (FNAA). FNAA is a nondestructive technique for determining material elemental composition based on nuclear excitation by fast neutron bombardment and subsequent spectral analysis of prompt γ-rays emitted by the active nuclei. Our recent experiments and simulations have shown that activation analysis can be used in practice with modest neutron fluences on the order of 105 n/cm2, which is available with current laser technology. In addition, time-resolved γ-ray measurements combined with picosecond neutron probes from LANSs are effective in mitigating the issue of spectral interference between elements, enabling highly accurate screening of complex samples containing many elements. This paper describes the predictive capability of LANS-based activation analysis based on experimental demonstrations and spectral calculations with Monte Carlo simulations.

Antidiabetic effects of duodenojejunal bypass in an experimental model of diabetes induced by a high-fat diet.

BACKGROUND: Obese patients with type II diabetes who undergo bariatric surgery revert to normal blood glucose and insulin levels, and develop a dramatic increase in insulin sensitivity. However, the mechanisms involved are unknown. This study characterized pancreatic islet and duodenojejunal enteroendocrine cells in normal mice and those with diabetes induced by a high-fat diet (HFD) following duodenojejunal bypass (DJB). METHODS: C57BL/6J mice, fed for 8 weeks either a normal diet (n = 10) or a HFD (n = 10) resulting in a hyperglycaemic state, underwent DJB (connection of the distal end of the jejunum to the distal stomach and direction of biliopancreatic secretions to the distal jejunum). Metabolic and immunohistological analyses were carried out on the pancreas and gastrointestinal tract. RESULTS: A significant decrease in fasting blood glucose was observed in normal-DJB and HFD-DJB mice 1 week after the operation, with improved glucose tolerance at 4 weeks. There were no changes in pancreatic ß-cell mass, but an increase in the ratio of α-cell to ß-cell mass was observed in the DJB groups. Furthermore, the number of cells expressing Pdx-1, glucagon-like peptide 1, pancreatic polypeptide and synaptophysin was increased in the bypassed duodenum and/or gastrojejunum of the DJB groups. CONCLUSION: Both normal and obese diabetic mice that underwent DJB displayed improved glucose tolerance and a reduction in fasting blood glucose, which mimicked findings in obese diabetic patients following bariatric surgery. The present data suggest that an increase in specific enteroendocrine cell populations may play a critical role in normalizing glucose homeostasis.