Pathways and mechanism of MRTX1133 binding to KRAS G12D elucidated by molecular dynamics simulations and Markov state models.

KRAS G12D is the most common oncogenic mutation identified in several types of cancer. Therefore, design of inhibitors targeting KRAS G12D represents a promising strategy for anticancer therapy. MRTX1133 is a highly potent inhibitor (approximate experiment Kd ≈ 0.0002 nM) of KRAS G12D and is currently in Phase 1/2 study, however, pathways of the compound binding to KRAS G12D has remained unknown, and the mechanism underlying the complicated dynamic process are challenging to capture experimentally, which hinder the structure-based anti-cancer drug design. Here, using MRTX1133 as a probe, unbiased molecular dynamics (MD) was used to simulate the process of MRTX1133 spontaneously binding to KRAS G12D. In six of 42 independent MD simulation (a total of 99 µs), MRTX1133 was observed to successfully associate with KRAS G12D. The kinetically metastable states refer to the potential pathways of MRTX1133 binding to KRAS G12D were revealed by Markov state models (MSM) analysis. Additionally, 8 key residues that are essential for MRTX1133 recognition and tight binding at the preferred low energy states were identified by MM/GBSA analysis. In sum, this study provides a new perspective on understanding the pathways and mechanism of MRTX1133 binding to KRAS G12D.

Effects of Water and Nitrogen Control on the Growth Physiology, Yields, and Economic Benefits of Lycium barbarum Plants in a Lycium barbarum + Alfalfa System.

In the production of economic forests, there are common issues such as excessive application of water and fertilizer, redundant plant growth, and low economic benefits. Reasonable water and fertilizer management can not only help address these problems but also improve the absorption and use efficiency of water and fertilizer resources by plants, promoting the green and efficient development of the fruit and forestry industry. In order to explore a suitable water and nitrogen management mode for Lycium barbarum, field experiments were conducted in this study from 2021 to 2022. Specifically, four irrigation modes (according to the proportion ratio of soil moisture content to field moisture capacity θf, 45-55% θf (W1, severe water deficiency), 55-65% θf (W2, moderate water deficiency), 65-75% θf (W3, mild water deficiency), and 75-85% θf (W4, sufficient irrigation)) and four nitrogen application levels (0 kg·ha-1 (N0, no nitrogen application), 150 kg·ha-1 (N1, low nitrogen application level), 300 kg·ha-1 (N2, medium nitrogen application level), and 450 kg·ha-1 (N3, high nitrogen application level)) were set up to analyze the influences of water and nitrogen control on the plant height, stem diameter, chlorophyll content, photosynthetic characteristics and yield, and economic benefits of Lycium barbarum in the Lycium barbarum + Alfalfa system. The study results show that the plant height and stem diameter increment of Lycium barbarum increase with the irrigation amount, increasing first and then decreasing with the increase in the nitrogen application level. Meanwhile, the chlorophyll contents in Lycium barbarum continuously increase throughout their growth periods, with Lycium barbarum treated with W4N2 during all growth periods presenting the highest contents of chlorophyll. In a Lycium barbarum + Alfalfa system, the daily variation curve of the Lycium barbarum net photosynthetic rate presents a unimodal pattern, with maximum values of the daily average net photosynthetic rate and daily carboxylation rate appearing among W4N2-treated plants (19.56 µmol·m-2·s-1 and 157.06 mmol·m-2·s-1). Meanwhile, the transpiration rates of Lycium barbarum plants continuously decrease with the increased degree of water deficiency and decreased nitrogen application level. W1N2-treated plants exhibit the highest leaf daily average water use efficiency (3.31 µmol·s-1), presenting an increase of 0.50-10.47% in efficiency compared with plants under other treatments. The coupling of water and nitrogen has significantly improved the yields and economic benefits of Lycium barbarum plants, with W4N2-treated and W3N2-treated plants presenting the highest dried fruit yield (2623.07 kg·ha-1) and net income (50,700 CNY·ha-1), respectively. Furthermore, compared with other treatment methods, these two treatment methods (W4N2 and W3N2) exhibit increases of 4.04-84.08% and 3.89-123.35% in dried fruit yield and net income indexes, respectively. Regression analysis shows that, in a Lycium barbarum + Alfalfa system, both high yields and economic benefits of Lycium barbarum plants can be achieved using an irrigation amount of 4367.33-4415.07 m3·ha-1 and a nitrogen application level of 339.80-367.35 kg·ha-1. This study can provide a reference for improving the productivity of Lycium barbarum plants and achieving a rational supply of water and nitrogen in Lyciun barbarum + Alfalfa systems in the Yellow River Irrigation Area of Gansu, China, and other similar ecological areas.

Multiparametric MRI subregion radiomics for preoperative assessment of high-risk subregions in microsatellite instability of rectal cancer patients: a multicenter study.

BACKGROUND: Microsatellite instability (MSI) is associated with treatment response and prognosis in patients with rectal cancer (RC). However, intratumoral heterogeneity limits MSI testing in patients with RC. The authors developed a subregion radiomics model based on multiparametric MRI to preoperatively assess high-risk subregions with MSI and predict the MSI status of patients with RC. METHODS: This retrospective study included 475 patients (training cohort, 382; external test cohort, 93) with RC from two participating hospitals between April 2017 and June 2023. In the training cohort, subregion radiomic features were extracted from multiparametric MRI, which included T2-weighted, T1-weighted, diffusion-weighted, and contrast-enhanced T1-weighted imaging. MSI-related subregion radiomic features, classical radiomic features, and clinicoradiological variables were gathered to build five predictive models using logistic regression. Kaplan-Meier survival analysis was conducted to explore the prognostic information. RESULTS: Among the 475 patients [median age, 64 years (interquartile range, IQR: 55-70 years); 304 men and 171 women], the prevalence of MSI was 11.16% (53/475). The subregion radiomics model outperformed the classical radiomics and clinicoradiological models in both training [area under the curve (AUC)=0.86, 0.72, and 0.59, respectively] and external test cohorts (AUC=0.83, 0.73, and 0.62, respectively). The subregion-clinicoradiological model combining clinicoradiological variables and subregion radiomic features performed the optimal, with AUCs of 0.87 and 0.85 in the training and external test cohorts, respectively. The 3-year disease-free survival rate of MSI groups predicted based on the model was higher than that of the predicted microsatellite stability groups in both patient cohorts (training, P =0.032; external test, P =0.046). CONCLUSIONS: The authors developed and validated a model based on subregion radiomic features of multiparametric MRI to evaluate high-risk subregions with MSI and predict the MSI status of RC preoperatively, which may assist in individualized treatment decisions and positioning for biopsy.

Assessment of blood one-carbon metabolism indexes during mid-to-late pregnancy in 397 Chinese pregnant women.

Objectives: One-carbon metabolism (OCM) significantly influences fetal growth and neurodevelopment through transferring methyl group to biomolecules, during which folate, methionine, choline and betaine function as methyl donor nutrients, while vitamin B2, B6, B12 function as enzyme cofactors, and homocysteine (Hcy) and S-adenosyl methionine (SAM) are functional metabolites. This study aimed to assess blood OCM index levels and explore their relationships among Chinese pregnant women. Methods: Data were obtained from the baseline of the Mother-Child Nutrition and Health Cohort Study. Pregnant women, voluntarily recruited from September 2020 to June 2022 during antenatal examinations in five Chinese cities at 24-32 gestational weeks, provided fasting venous blood samples. Measurements included RBC and serum folate, serum vitamin B2, B6, B12, choline, betaine, methionine, total Hcy (tHcy), and plasma SAM. Sociodemographic characteristics and pregnancy-related conditions were collected via a self-designed questionnaire. Results: Of 397 participants, 82.6% were in mid-pregnancy (24-27 gestational weeks) and 17.4% were in late-pregnancy (28-32 gestational weeks). Serum folate, vitamin B6, and B12 deficiencies were 2.5, 1.3, and 8.3%, respectively. Elevated tHcy (≥10 µmol/L) was observed in 1.8% of pregnant women. Elderly pregnant women (aged 35 and above) exhibited significantly lower serum methionine levels (p < 0.05), while multiparous women had lower RBC folate levels (p < 0.05), and lower serum methionine and vitamin B12 levels (p < 0.10, not statistically significant). Partial correlation analysis revealed positive associations between RBC folate and cofactor vitamin B12 (r = 0.244, p < 0.05) in the folate cycle, as well as significant correlations between two methyl donor paths [serum folate was significantly related to serum choline (r = 0.172) and betaine (r = 0.193)]. As functional biomarkers of OCM, serum tHcy exhibited negative associations with RBC folate (ß = -0.330, p < 0.05) and vitamin B6 (ß = -0.317, p < 0.05), and plasma SAM displayed a positive association with serum betaine (ß = 0.610, p < 0.05), while negatively associated with serum vitamin B6 (ß = -0.181, p < 0.05). Conclusion: The blood OCM exhibited imbalances during mid-to-late pregnancy, characterized by lower levels of folate, vitamin B6, and B12, alongside elevated tHcy levels. Adequate folate and vitamin B6 emerged as significant predictors of lower tHcy levels. Additionally, serum betaine showed a positive correlation with plasma SAM. This suggests the importance of not only ensuring sufficient folate but also optimizing other OCM-related nutrients throughout pregnancy.

Cost-effectiveness analysis of continuing bevacizumab plus chemotherapy versus chemotherapy alone after first progression of metastatic colorectal cancer.

BACKGROUND: Continuation of bevacizumab plus second-line chemotherapy has significantly improved overall and progression-free survival in patients with metastatic colorectal cancer (mCRC). However, the cost-effectiveness of such high cost therapy is still uncertain in China; so this analysis was performed to evaluate the cost-effectiveness of these treatment options from the Chinese health care system perspective. METHODS: A cost-effectiveness analysis was conducted using data from the ML18147 trial (ClinicalTrials.gov identifier NCT00700102) by modeling a partitioned survival model. Main evaluation indicators were quality-adjusted life years (QALYs) and incremental cost-effectiveness ratio (ICER) with a willingness to pay (WTP) threshold of $38,201 per QALY. One-way and probabilistic sensitivity analyses were conducted to assess the robustness and stability of the model. Subgroup and scenario analyses were also performed to make our study more relevant. RESULTS: Bevacizumab plus chemotherapy increased 0.12 QALYs and an incremental cost of $22,761.62 compared with chemotherapy, resulting in an ICER of $188,904.09 per QALY. The model was most sensitive to the utility of progression-free survival and the cost of bevacizumab. Compared with chemotherapy, bevacizumab plus chemotherapy had a 0% cost-effectiveness probability, and no cost-effectiveness in subgroups at the WTP threshold of $38,201 per QALY. The scenario analysis found that bevacizumab biosimilar gained an ICER of $126,397.38 per QALY when assuming the cost of drugs was calculated at the most affordable price. CONCLUSIONS: At the WTP threshold of $38,201 per QALY, continuation of bevacizumab plus chemotherapy is unlikely considered cost-effective for patients after first progression of mCRC.

The economic burden of autism spectrum disorder with and without intellectual disability in China: A nationwide cost-of-illness study.

OBJECTIVE: The economic burden of autism spectrum disorder (ASD) on individuals, their families and society as a whole is poorly understood. Accurate figures are crucial for economic estimates and service planning. METHODS: The total lifetime individual costs and annual societal costs of ASD in China were estimated with a prevalence-based, gross cost of illness approach and data from multiple sources. The direct medical costs in outpatient and inpatient settings from the electronic health records (EHRs) of hospitals, and direct nonmedical costs from a national survey were included. The indirect costs were from both the national survey and the estimation using human capital methods. Age-specific lifetime incremental societal costs were measured. Comorbidity-related and unrelated costs were analyzed separately. RESULTS: The discounted lifetime cost for an individual with ASD in China was $2.65 million (at 2020 prices, $) for those without intellectual disability (ID) and $4.61 million (at 2020 prices, $) for those with ID. The total cost of ASD amounted to $41.8 billion in 2020. Productivity loss were major cost drivers for ASD individuals without ID. Direct nonmedical costs (rehabilitation or adult care costs etc.) were major drivers for ASD individuals with ID. In a lifetime course, the total annual costs for middle aged and elderly (>42 years) were highest, followed by transitional adults (18-29 years) and preschoolers, both for individuals with or without ID. The distribution of costs over the lifespan varied by the cost category. CONCLUSIONS: ASD imposes a substantial economic burden on families and health care systems. Sectors and services coordination should be given policy considerations.

CYP4CS5-mediated thiamethoxam and clothianidin resistance is accompanied by fitness cost in the whitefly Bemisia tabaci.

BACKGROUND: Understanding the trade-offs between insecticide resistance and the associated fitness is of particular importance to sustainable pest control. One of the most devastating pest worldwide, the whitefly Bemisia tabaci, has developed resistance to various insecticides, especially the neonicotinoid group. Although neonicotinoid resistance often is conferred by P450s-mediated metabolic resistance, the relationship between such resistance and the associated fitness phenotype remains largely elusive. By gene cloning, quantitative reverse transcription (qRT)-PCR, RNA interference (RNAi), transgenic Drosophila melanogaster, metabolism capacity in vitro and 'two sex-age stage' life table study, this study aims to explore the molecular role of a P450 gene CYP4CS5 in neonicotinoid resistance and to investigate whether such resistance mechanism carries fitness costs in the whitefly. RESULTS: Our bioassay tests showed that a total of 13 field-collected populations of B. tabaci MED biotype displayed low-to-moderate resistance to thiamethoxam and clothianidin. Compared to the laboratory susceptible strain, we then found that an important P450 CYP4CS5 was remarkably upregulated in the field resistant populations. Such overexpression of CYP4CS5 had a good match with the resistance level among the whitefly samples. Further exposure to the two neonicotinoids resulted in an increase in CYP4CS5 expression. These results implicate that overexpression of CYP4CS5 is closely correlated with thiamethoxam and clothianidin resistance. RNAi knockdown of CYP4CS5 increased mortality of the resistant and susceptible populations after treatment with thiamethoxam and clothianidin in bioassay, but obtained an opposite result when using a transgenic line of D. melanogaster expressing CYP4CS5. Metabolic assays in vitro revealed that CYP4CS5 exhibited certain capacity of metabolizing thiamethoxam and clothianidin. These in vivo and in vitro assays indicate an essential role of CYP4CS5 in conferring thiamethoxam and clothianidin resistance in whitefly. Additionally, our life-table analysis demonstrate that the field resistant whitefly exhibited a prolonged development time, shortened longevity and reduced fecundity compared to the susceptible, suggesting an existing fitness cost as a result of the resistance. CONCLUSION: Collectively, in addition to the important role of CYP4CS5 in conferring thiamethoxam and clothianidin resistance, this resistance mechanism is associated with fitness costs in the whitefly. These findings not only contribute to the development of neonicotinoids resistance management strategies, but also provide a new target for sustainable whitefly control. © 2023 Society of Chemical Industry.

High-throughput analytical methodology of monoalkyl phthalate esters and the composite risk assessment with their parent phthalate esters in aquatic organisms and seawater.

A sensitive, robust, and highly efficient analytical methodology involving solid phase extraction coupled to ultra-high performance liquid chromatography tandem mass spectrometry was successfully established to detect 13 monoalkyl phthalate esters (MPAEs) in aquatic organisms and seawater. After the organisms were preprocessed using enzymatic deconjugation with ß-glucuronidase, extraction, purification, and qualitative and quantitative optimization procedures were performed. Under optimal conditions, the limits of detection varied from 0.07 to 0.88 µg/kg (wet weight) and 0.04-1.96 ng/L in organisms and seawater, respectively. Collectively, MPAEs achieved acceptable recovery values (91.0-102.7%) with relative standard deviations less than 10.4% and matrix effects ranging from 0.93 to 1.07 in the above matrix. Furthermore, MPAEs and phthalate esters were detected by the developed methodology and gas chromatography-triple quadrupole tandem mass spectrometer in practical samples, respectively. Mono-n-butyl phthalate and mono-iso-butyl phthalate were the most predominant congeners, accounting for 24.8-35.2% in aquatic organisms and seawater. Comprehensive health and ecological risks were higher after the MPAEs were incorporated than when phthalate esters were considered separately, and greater than their risk threshold. Therefore, the risks caused by substances and their metabolites in multiple media, with analogous structure-activity relationships, should be considered to ensure the safety of aquatic organisms and consumers.

Benefit-Risk Assessment of Chinese Medicine Injections for Primary Liver Cancer Based on Multi-criteria Decision Analysis.

OBJECTIVE: To evaluate the benefit-risk of 3 commonly used Chinese medicine injections, Aidi Injection (ADI), Cinobufagin Injection (CINI) and Compound Kushen Injection (CKI), in the treatment of primary liver cancer (PLC), so as to provide a reference for clinical decision-making. METHODS: Randomized controlled trials (RCTs) of ADI, CINI and CKI in the treatment of PLC published in the databases of China National Knowledge Infrastructure, Wanfang, China Science and Technology Journal Database, SinoMed, PubMed, Cochrane Library, and Web of Science were retrieved from January 2020 to October 2022. The data of benefit and risk indicators were combined to obtain the effect value. The multi-criteria decision analysis (MCDA) model was applied to build the decision tree. The benefit value, risk value and benefit risk value of the 3 injections in PLC treatment were calculated. Monte Carlo simulation was carried out to calculate the 95% confidence interval and probability of differences among the 3 injections, so as to optimize the evaluation results. RESULTS: A total of 71 RCTs were included. The benefit values of ADI, CINI and CKI combined with transcatheter arterial chemoembolization (TACE) were 42, 38 and 36, respectively. The risk values were 42, 25 and 37, respectively. The benefit risk values were 42, 31 and 37, respectively. The benefit risk differences of ADI vs. CINI, ADI vs. CKI, and CKI vs. CINI were 11 (-0.86, 17.75), 5 (-5.01, 11.09), and 6 (-1.87, 12.63), respectively. The probability that ADI superior to CINI, ADI superior to CKI, and CKI superior to CINI was 96.26%, 77.27%, and 92.62%, respectively. CONCLUSION: Based on the results of MCDA model, CINI combined with TACE has the greatest risk in the treatment of the PLC. Considering the efficacy and safety, the possible priority of the 3 Chinese medicine injections combined with TACE in the treatment of PLC is ADI, CKI and CINI.

Assessment of Prior Infection With Hepatitis B Virus and Fecundability in Couples Planning Pregnancy.

IMPORTANCE: The association of hepatitis B virus (HBV) infection with reduced fecundability among reproductive-aged couples lacks large-population, in-depth study evidence. OBJECTIVE: To investigate the association of HBV infection with time to pregnancy in couples planning pregnancy, and to explore whether this association varied by gravidity, health statuses, or lifestyles. DESIGN, SETTING, AND PARTICIPANTS: This is a population-based cohort study of Chinese couples participating in the National Free Preconception Check-up Projects during 2015 to 2017. They were planning pregnancy and were followed-up every 3 months until getting pregnant, as confirmed by gynecologic ultrasonography, or were followed-up for 1 year. Data were analyzed between March 1, 2022, and September 30, 2022. MAIN OUTCOMES AND MEASURES: The main outcome was time to pregnancy, assessed using fecundability hazard ratios (HRs). The Cox proportional hazards regression models were used to estimate the association of HBV infection with fecundability. RESULTS: Among 2 419 848 couples (mean [SD] age, 27.87 [5.20] years for women and 29.58 [5.50] years for men), 126 728 women (5.24%) and 156 572 men (6.47%) were infected with HBV. Compared with the HBV-negative group, the fecundability of both women and men in the HBV-positive group decreased by 5% (HR, 0.95; 95% CI, 0.94-0.95). Compared with couples in which both partners were HBV negative, the fecundability of those in which both partners were HBV positive declined by 6% (HR, 0.94; 95% CI, 0.93-0.96) among all couples, by 3% (HR, 0.97; 95% CI, 0.95-0.99) among nulligravidas couples, and by 7% (HR, 0.93; 95% CI, 0.91-0.95) among multigravidas couples. Both the female-male and couple models suggested that the association of HBV infection with decreased fecundability was more pronounced in couples with multigravidas. The negative association was greater in people with overweight and obesity and was inconsistent in certain subgroups; in particular, it was more pronounced in women with reproductive tract infections, normal fasting plasma glucose, and no alcohol intake and in men with normal blood pressure. CONCLUSIONS AND RELEVANCE: In this population-based cohort study, HBV infection was associated with decreased fecundability in a general reproductive-aged population, especially in couples with multigravidas. For women and men with certain health statuses and lifestyles, a comprehensive consideration of this association is recommended to provide personalized fertility guidance.

Cost-effectiveness analysis of selexipag for the combined treatment of pulmonary arterial hypertension.

Objective: Adding selexipag to the combined treatment of endothelin receptor antagonists (ERA) and phosphodiesterase 5 inhibitor (PDE5i) reduces the risk of clinical worsening events in patients with pulmonary arterial hypertension (PAH) but at a considerably higher cost. This study evaluated the cost-effectiveness of adding selexipag to the combined treatment of ERA and PDE5i in patients with PAH from a Chinese healthcare system perspective. Methods: A Markov model was developed to assess costs and quality-adjusted life years (QALYs) of macitentan + tadalafil + selexipag vs. macitentan + tadalafil for the treatment of PAH. Markov states included WHO Functional Class (FC) (I-IV) and death. Transition probabilities were based on data from the TRITON trial. Mortality rates, costs, and utilities were obtained from published literature and public databases. Results: In the base case analysis, compared with macitentan + tadalafil, selexipag + macitentan + tadalafil increased costs ($357,807.588 vs. $116,534.543, respectively) and QALYs (7.234 QALYs vs. 6.666 QALYs, respectively). The resulting incremental cost-effectiveness ratio was $424,746.070 per QALY, which was higher than the willingness-to-pay (WTP) of $38,223.339 per QALY. The results were most sensitive to HR for mortality of patients with FC IV relative to the general population, discount rate, and the cost of selexipag. The probability was greater than 50% for the selexipag + macitentan + tadalafil only if the WTP was more significant than $426,019.200 per QALY. Conclusion: In China, adding selexipag may not be cost-effective for patients with PAH who failed to control their condition after combined treatment of ERA and PDE5i. Results of the analysis can aid discussions on the value and position of selexipag for the combined treatment of PAH.

Dietary exposure risk assessment of pyrethroids in fruits and vegetables: a national scale investigation.

The pyrethroids (PYRs) were extensively used to increase agriculture outputs. However, the cumulative exposures of PYRs would bring about potential risks through food intake. It is an urgent requirement to explore the cumulative exposures on the fruits and vegetables. In this study, a total of 1720 samples incorporating eight primary fruits and vegetables collected around China were investigated to assess the health risk for adults and children from eight PYRs. The relative potency factor (RPF) method was employed to reveal both chronic and acute cumulative exposure. As a result, the hazard index (HI) were 0.004 ~ 0.200% and 11.85 ~ 99.19% for chronic and acute cumulative dietary exposure, respectively. The national wide investigation indicated the cumulative assessments were not hazardous. Besides, the acute intake of pear, grape, and lettuce should be paid on more attention, particularly. This study provides compelling evidence to develop relative policy and regulation to improve the food quality and safety.

Direct and indirect costs for families of children with autism spectrum disorder in China.

LAY ABSTRACT: This is the first comprehensive national study to explore the direct and indirect costs for families of children with autism spectrum disorder in China. The increasing prevalence of autism spectrum disorder highlights a growing need for resources to provide care for families of children with autism spectrum disorder. The medical and nonmedical costs and parents' productivity loss have caused a serious burden on their families. Our objective is to estimate the direct and indirect costs for the families of children with autism spectrum disorder in China. The target population was parents of children with autism spectrum disorder. We analyzed the costs using cross-sectional data from a Chinese national family survey with children aged 2-6 years (N = 3236) who were clinically diagnosed with autism spectrum disorder. Family data from 30 provinces in China were obtained. Cost items included direct medical costs, direct nonmedical costs, and indirect costs. In this study, we found that the largest part of family costs for autism spectrum disorder are nonmedical costs and productivity loss. Autism spectrum disorder has imposed a huge economic burden on parents having children with autism spectrum disorder in China, who need more support than the current health care system provides.

Effect of feeding a dried distillers' grains with solubles diet on the metabolism of the intestinal wall in Guanling crossbred cattle: a preliminary assessment.

Dried distillers' grains with solubles (DDGS)-based diets are nutritious and can improve the inflammations and intestinal immunity in livestock. However, there is limited research examining the effect of feeding DDGS-based diets on changes in intestinal metabolites and related pathways in livestock. In this study, six Guanling crossbred cattle (Guizhou Guanling Yellow cattle × Simmental cattle) were selected and divided into a basal diet (BD) group and an experimental group fed with DDGS replacing 25% of the daily ration concentrates (DDGS) (n=3), respectively. Fresh jejunum (J), ileum (I) and cecum (C) tissues were collected for metabolomic analysis. Differential metabolites and metabolic pathways were explored by means of univariate and multivariate statistical analysis. In comparison to the J-BD group, 123 differential metabolites (VIP > 1, p < 0.05) were identified in the J-DDGS group, which (top 20) were mainly divided into superclasses, including lipids and lipid-like molecules, organic acids and derivatives, and organoheterocyclic compounds. Compared with the I-BD group, 47 differential metabolites were obtained in the I-DDGS group, which were mainly divided into superclasses, including lipids and lipid-like molecules and organic acids and derivatives. The C-DDGS vs. C-BD comparison revealed 88 differential metabolites, which were mainly divided into superclasses, including lipids and lipid-like molecules, organic oxygen compounds, and nucleosides. A total of 34 significant metabolic pathways were found (p < 0.05, -log(p) > 1.3). Among them, 3 significant pathways were significantly enriched in the J-DDGS group, 11 significant pathways were significantly enriched in the I-DDGS group, and 20 significant pathways were significantly enriched in the C-DDGS group. Importantly, primary bile acid biosynthesis, linoleic acid metabolism, and arachidonic acid metabolism correlated with intestinal inflammation and immunity by regulating gut microbiota, prostaglandin synthesis, and cell signaling. The data suggest that DDGS-fed cattle unregulated three metabolic pathways mentioned above and that a DDGS-based diet was able to maintain a balance of these three metabolic pathways, thus resulting in improvement of intestinal inflammation and enhanced immunity in cattle. In conclusion, the DDGS diet has the potential to improve intestinal inflammation and enhance the immunity of Guanling crossbred cattle by regulating the metabolic patterns of lipids and lipid-like molecules, organic acids and derivatives, and related metabolic pathways. These results allude to potential metabolic regulatory mechanisms of DDGS diets and also provide a theoretical basis for the application of DDGS in livestock feed.

The impact of COVID-19 on cultural industries: An empirical research based on stock market returns.

The COVID-19 virus has challenged the development of the cultural industries seriously, so far, however few studies have used empirical methods to analyze the impact of the pandemic on the overall cultural industries. Based on the panel data of listed companies, this paper explores the impact of COVID-19 on cultural industries from the perspective of stock market returns. The empirical results show that the pandemic has a significant negative impact on the stock market returns of cultural industries, but the degrees of impact on various creative sub-sectors are significantly different. The findings also indicate that digitalization can effectively reduce the negative impact of COVID-19 on cultural companies, and the epidemic has bigger negative impacts on small and newly-established cultural companies. Moreover, we find that the stock market returns of cultural industries have an inverted U-shaped relationship with the daily growth in total confirmed cases and in total cases of death caused by COVID-19, indicating that the negative marginal impact of COVID-19 on the cultural industries increases firstly and then gradually decreases. Finally, implications for companies and governments are presented respectively based on the findings.

An Analysis of Injury Trends and Disease Burden From Three Surveillance Hospitals in Urumqi From 2006 to 2018.

Objective: To investigate injury trends, injury distribution, and disease burden from three surveillance hospitals in Urumqi from 2006 to 2018. Method: Injury data from the National Injury Surveillance System (NISS) from three hospitals in Urumqi (2006 to 2018) were collected to analyze changes in the characteristics of outpatient injury cases. Years of potential life lost (YPLL) were calculated to determine the disease burden of the injury cases. Results: A total of 161,400 injury cases were recorded over 13 years, and the average age of the patient seeking medical attention was 32.4 years old. Male patients outnumbered female patients with a ratio of 1.6:1, but the proportion of female patients was greater after 45 years of age. The highest number of cases occurred in patients 15-29 years of age, accounting for 26.8% of all injury cases. Injury in females occurred most frequently in the home. A total of 41.4% of injury cases occurred while doing housework. The top three causes of injury were falls (49.7%), blunt force of an object, (13.7%), and motor vehicle accidents (MVA) (13.5%). Years of potential life lost from injury accounted for 7.39% of the total YPLL in the three hospitals. Conclusion: Males should be targeted for injury prevention and intervention in Urumqi. The prevention of falls, blunt force of objects, and MVA should be made a priority. Injury prevention strategies and targeted projects should be developed to reduce the disease burden of injury.

Construction of the Public Management Performance Assessment Algorithm Using Fuzzy Clustering.

This paper analyzes the limitations of the current public management performance evaluation system, puts forward a public management performance evaluation model based on fuzzy clustering, and expounds on the theoretical framework and principle of this method. In addition, this paper introduces the concept and method of public management performance evaluation into the evaluation content system of government under the rule of law and realizes the combination of government under the rule of law theory and public management performance evaluation methodology. At the same time, through the analysis of the organizational system, technical system, institutional mechanism, result orientation, public satisfaction, and related index content, a public management performance evaluation index system is designed. Through macro and micro, qualitative and quantitative analysis and evaluation, the performance evaluation index system is improved, which provides an objective basis for forecasting and decision-making, control, and adjustment. The research shows that the highest accuracy of this clustering method can reach about 96%, and its accuracy is about 10% higher than that of the ID3 algorithm. It is expected that this research can make some contributions to the research of the public management performance evaluation index system. At the same time, it highlights the importance of research on performance evaluation of government ruled by law.

Assessment about bioindicator capacity of acrocarpous moss Campylopus schmidii exposed to abandoned pyritic tailings.

Terrestrial mosses are promising species to study concerning metal deposition, absorption, and soil fertility as moss biocrusts. However, acrocarpous moss, as a kind of terrestrial mosses, has not yet been well understood, both in environmental monitoring and ecological application, especially exposed to an abandoned pyrite mining. Herein, we investigated the concentrations of different heavy metals in soil underlying acrocarpous moss Campylopus schmidii at three distances from an abandoned pyrite mine tailings (0.5, 1, 2 km) by sampling analysis, as well as the accumulation properties of heavy metals in different parts of mosses and soil nutrients under intact mosses and moss-free layers. The results indicated that the soil we researched was heavily polluted by Cr, Cu, and Cd, which was 4.46, 4.18, and 1.77 times higher than the standard of risk screening values for soil environment quality in China. And there was a marked difference in the concentrations and distribution of heavy metals in mosses, with higher concentrations of Cr, Cu, Ni and Pb mainly in the ageing parts. In addition, mosses can effectively promote soil fertility. Compared with the bare soil without the moss layer, the total organic matter and total potassium concentrations of the soil covered by the intact moss layer were significantly increased, by 113.91% and 186.08% respectively. Correlation analysis indicated that similar pollution sources for Zn, Cd, Cu, and Pb, and the concentrations of these heavy metals in soil connected with the distance from the source of pollution. Overall, we expected that these findings could assess the greater potential of single native dominant moss species C.schmidii to act as biomonitors in specific pyrite mine tailings characterized by barren soil with strong acids (pH < 4.0) and polymetallic pollution. Meanwhile, our results revealed may serve as a possibility reference for similar areas and is recommended for developing a vegetative cover utilizing local acrocarpous mosses to achieve greening of degraded tailings in the future, as well as environmental management and protection.

Tripartite Evolutionary Game Analysis of Financial Support for Science-Tech Enterprises' Innovation with Government Participation.

In this study, we use a tripartite evolutionary game model to analyze the financial support for science-tech enterprises' innovation with government participation. Based on the game model, the study uses replication dynamics to analyze the stability of evolutionary trajectory in the eight scenarios of enterprises, the government, and the financial institutes. Then, we discuss the effect of the reputation multiplier, the efficiency of firms' innovation output, and the positive socio-economic externalities multiplier by simulation as the important innovative points in this study. The study draws the following conclusions: (1) enterprises will choose high R&D intensity instead of low R&D intensity if the output of former exceeds that of the latter, (2) enterprises' R&D output is closely related to the strategy choices of the government and financial institutes, and (3) enterprises can attract government subsidy by boosting economic and social externalities. The government subsidies to enterprises with high R&D intensity will improve the innovation output by the innovation investment and reputation multiplier. So, the government can implement subsidy policy to boost high-intensive R&D activity. Financial institutes' strategy choice between equity investment and debt investment is influenced by investment yield difference and can influence enterprises' R&D intensity choices.