OBJECTIVE: Humans are exposed to complex mixtures of environmental chemicals and other factors that can affect their health. Analysis of these mixture exposures presents several key challenges for environmental epidemiology and risk assessment, including high dimensionality, correlated exposure, and subtle individual effects. METHODS: We proposed a novel statistical approach, the generalized functional linear model (GFLM), to analyze the health effects of exposure mixtures. GFLM treats the effect of mixture exposures as a smooth function by reordering exposures based on specific mechanisms and capturing internal correlations to provide a meaningful estimation and interpretation. The robustness and efficiency was evaluated under various scenarios through extensive simulation studies. RESULTS: We applied the GFLM to two datasets from the National Health and Nutrition Examination Survey (NHANES). In the first application, we examined the effects of 37 nutrients on BMI (2011-2016 cycles). The GFLM identified a significant mixture effect, with fiber and fat emerging as the nutrients with the greatest negative and positive effects on BMI, respectively. For the second application, we investigated the association between four pre- and perfluoroalkyl substances (PFAS) and gout risk (2007-2018 cycles). Unlike traditional methods, the GFLM indicated no significant association, demonstrating its robustness to multicollinearity. CONCLUSION GFLM framework is a powerful tool for mixture exposure analysis, offering improved handling of correlated exposures and interpretable results. It demonstrates robust performance across various scenarios and real-world applications, advancing our understanding of complex environmental exposures and their health impacts on environmental epidemiology and toxicology.
Humans ; Environmental Exposure/analysis* ; Linear Models ; Nutrition Surveys ; Environmental Pollutants ; Body Mass Index

Objective To investigate the effect of dorsal repulsive axon guidance protein(Draxin)on the migration of trunk neural crest cells during the early development of embryonic mouse spinal cord.Methods Immunohistochemistry and in situ hybridization were used to detect the expression characteristics of Draxin in early embryonic spinal cord(8 mice each group);In situ hybridization was used to detect the change of migration characteristics of trunk neural crest cells in early embryonic spinal cord of different types of mouse(5 mice each group);in vitro culture method was used to check the effect of Draxin on the migration characteristics of embryonic mouse trunk neural crest cells(16 mice each group).Resultsβ-galactosidase gene Z(LacZ)gene was introduced when Draxin gene was knocked out to produce Draxin gene knockout mice.β-galactosidase staining was used to detect LacZ gene expression in Draxin knockout embryonic mice,and the result showed that Draxin expression was observed in the spinal cord of early embryonic mice since 9.5 days(E9.5).Draxin expression was obvious in the embryonic mice spinal cord in E10.5 period.In situ hybridization was used to detect the expression of Draxin gene in the spinal cord of wild type embryonic mice,and the result further verified the obvious expression of Draxin in the early embryonic mice spinal cord in El0.5 period.Sox10 in situ hybridization was used to detect neural crest cell migration in the spinal cord of embryonic mice in E10.5 period.The result showed that segmental migration of neural crest cells in the early embryonic spinal cord of some Draxin knockout mice was delayed compared with the wild type mice.The effect of Draxin on the migration of wild type early embryonic mice trunk neural crest cells in vitro was tested.The result showed that Draxin reduced the migration distance of neural crest cells in vitro.Conclusion In the early developmental stage of embryonic spinal cord(E9.5-E10.5),neural crest cells migrated exuberant.At the same time,Draxin plays an important inhibitory function in the formation of the specific migration pathways of trunk neural crest cells by promoting neural crest cells migrating away from Draxin expressing regions.

Objective To quantitatively analyze the impact of environmental hygiene on the occurrence of health-care-associated infections(HAI).Methods Monitoring data of HAI and environmental hygiene from a tertiary first-class hospital from January 2018 to December 2022 were collected,and the impact of environmental bacterial colony forming unit(CFU)on the occurrence of HAI was analyzed by a time-series generalized additive model.Results The single-contamination model showed a significant positive correlation between HAI and staff's hand bacterial CFU(β1=0.009,P=0.012).For an increase of 1 interquartile range(IQR)in the monthly mean CFU per dish(MCFU/Dish)of staffs'hand,the incidence of HAI increased by 13.28％(95％CI:2.82％-24.81％).Subgroup and lag effect analysis showed that when the monthly MCFU/Dish(after hand disinfection)of staffs'hand in-creased by one IQR,the excess risk(ER)of HAI for the month(lag0)was 16.26％(95％CI:15.45％-17.09％).In the multi-contamination model,the correlation between surface contamination and HAI was also statistically sig-nificant.Conclusion There is a significant correlation between hospital environmental hygiene and the occurrence of HAI.

Hard capsules of traditional Chinese medicine(TCM) have different degrees of hygroscopicity, which affects the stability and efficacy of drugs. In this paper, 30 kinds of commercially available TCM capsules were used as the research object. The hygroscopicity curves of capsule contents, capsule shells, and capsules were tested respectively, and the first-order kinetic equation was used for fitting. The results show that during the 24 h hygroscopicity process, the capsule shell can reduce the weight gain caused by the hygroscopicity of the contents by 0.80%-53.0% and the hygroscopicity rate of the capsule contents by 1.74%-91.3%, indicating that the capsule shell has a strong delay effect on the hygroscopicity of the contents of the TCM capsules. Seven physical parameters of the contents of 30 kinds of TCM capsules were determined, and 14 prescription process-related parameters were sorted out. A partial least squares model for predicting the hygroscopicity rate of the contents of TCM capsules(with shell) for 24 h was established. It is found that the hygroscopicity rate of the capsule shell is positively correlated with the hygroscopicity of the contents of TCM capsules(with shell), suggesting that the capsule shell with a low hygroscopicity rate is helpful for moisture prevention. In addition, the pre-treatment process route of the preparation and the type of molding raw materials affect the hygroscopicity. A larger proportion of the extract in the capsule content and a smaller proportion of the fine powder of the decoction pieces indicate stronger hygroscopicity of the capsule content. The 24 h hygroscopicity rate of 15% was used as the classification node of hygroscopicity strength, and the hygroscopicity rate constant of 0.58 was used as the classification node of hygroscopicity speed. The classification system of hygroscopicity behaviors of TCM capsules was established: the varieties with strong and fast hygroscopicity accounted for about 6.67%, while those with strong and slow hygroscopicity accounted for about 33.3%; the varieties with weak and fast hygroscopicity accounted for about 26.7%, while those with weak and slow hygroscopicity accounted for about 33.3%. The classification system is helpful to quantify and compare the hygroscopicity behavior of different TCM capsules and provides a reference for the quality improvement, moisture prevention technologies, and material research of TCM capsules.
Medicine, Chinese Traditional ; Wettability ; Capsules ; Powders ; Technology ; Drugs, Chinese Herbal

The mixing process is a critical link in the formation of oral solid preparations of traditional Chinese medicine. This paper took the extract powder of Guizhi Fuling Capsules and Paeonol powder as research objects. The angle of repose, loose packing density, and particle size of the two powders were measured to calibrate discrete element simulation parameters for the mixing process. The discrete element method was used to calibrate the simulated solid density of Paeonol powder and extract powder of Guizhi Fuling Capsules based on the Hertz-Mindlin with JKR V2 contact model and particle scaling. The Plackett-Burman experimental design was used to screen out the critical contact parameters that had a significant effect on the simulation of the angle of repose. The regression model between the critical contact parameters and the simulated angle of repose was established by the Box-Behnken experimental design, and the critical contact parameters of each powder were optimized based on the regression model. The best combination of critical contact parameters of the extract powder of Guizhi Fuling Capsules was found to be 0.51 for particle-particle static friction coefficient, 0.31 for particle-particle rolling friction coefficient, and 0.64 for particle-stainless steel static friction coefficient. For Paeonol powder, the best combination of critical contact parameters was 0.4 for particle-particle static friction coefficient and 0.19 for particle-particle rolling friction coefficient. The best combination of contact parameters between Paeonol powder and extract powder of Guizhi Fuling Capsules was 0.27 for collision recovery coefficient, 0.49 for static friction coefficient, and 0.38 for rolling friction coefficient. The verification results show that the relative error between the simulated value and the measured value of the angle of repose of the two single powders is less than 1%, while the relative error between the simulated value and the measured value of the angle of repose of the mixed powder with a mass ratio of 1∶1 is less than 4%. These research results provide reliable physical property simulation data for the mixed simulation experiment of extract powder of Guizhi Fuling Capsules and Paeonol powder.
Wolfiporia ; Calibration ; Powders ; Medicine, Chinese Traditional ; Capsules

Objective: To analyze and compare therapy responses, outcomes, and incidence of severe hematologic adverse events of flumatinib and imatinib in patients newly diagnosed with chronic phase chronic myeloid leukemia (CML) . Methods: Data of patients with chronic phase CML diagnosed between January 2006 and November 2022 from 76 centers, aged ≥18 years, and received initial flumatinib or imatinib therapy within 6 months after diagnosis in China were retrospectively interrogated. Propensity score matching (PSM) analysis was performed to reduce the bias of the initial TKI selection, and the therapy responses and outcomes of patients receiving initial flumatinib or imatinib therapy were compared. Results: A total of 4 833 adult patients with CML receiving initial imatinib (n=4 380) or flumatinib (n=453) therapy were included in the study. In the imatinib cohort, the median follow-up time was 54 [interquartile range (IQR), 31-85] months, and the 7-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.2%, 88.4%, 78.3%, and 63.0%, respectively. The 7-year FFS, PFS, and OS rates were 71.8%, 93.0%, and 96.9%, respectively. With the median follow-up of 18 (IQR, 13-25) months in the flumatinib cohort, the 2-year cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) were 95.4%, 86.5%, 58.4%, and 46.6%, respectively. The 2-year FFS, PFS, and OS rates were 80.1%, 95.0%, and 99.5%, respectively. The PSM analysis indicated that patients receiving initial flumatinib therapy had significantly higher cumulative incidences of CCyR, MMR, MR(4), and MR(4.5) and higher probabilities of FFS than those receiving the initial imatinib therapy (all P<0.001), whereas the PFS (P=0.230) and OS (P=0.268) were comparable between the two cohorts. The incidence of severe hematologic adverse events (grade≥Ⅲ) was comparable in the two cohorts. Conclusion: Patients receiving initial flumatinib therapy had higher cumulative incidences of therapy responses and higher probability of FFS than those receiving initial imatinib therapy, whereas the incidence of severe hematologic adverse events was comparable between the two cohorts.
Adult ; Humans ; Adolescent ; Imatinib Mesylate/adverse effects* ; Incidence ; Antineoplastic Agents/adverse effects* ; Retrospective Studies ; Pyrimidines/adverse effects* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy* ; Treatment Outcome ; Benzamides/adverse effects* ; Leukemia, Myeloid, Chronic-Phase/drug therapy* ; Aminopyridines/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*

(±)-Bicoryanhunine B (1), a new dimeric benzylisoquinoline alkaloid was isolated from the dried tubers of Corydalis yanhusuo by various chromatographic methods, including silica gel, Sephadex LH-20, reverse phase C18, and semi-preparative HPLC. Its structure was determined by spectroscopic methods, including UV, IR, ESI-MS, HR-ESI-MS and 1D/2D NMR. (±)-Bicoryanhunine B (1) was a moderate PD-1/PD-L1 interaction inhibitor with an IC₅₀ value of 7.80 ± 0.49 μmol·L^-1. In addition, 1 exhibited potent inhibitory activities against LPS-induced NO production in RAW 264.7 macrophages with an IC₅₀ value of 4.83 ± 2.21 μmol·L^-1.

The TEA domain (TEAD) family proteins (TEAD1‒4) are essential transcription factors that control cell differentiation and organ size in the Hippo pathway. Although the sequences and structures of TEAD family proteins are highly conserved, each TEAD isoform has unique physiological and pathological functions. Therefore, the development and discovery of subtype selective inhibitors for TEAD protein will provide important chemical probes for the TEAD-related function studies in development and diseases. Here, we identified a novel TEAD1/3 covalent inhibitor (DC-TEADin1072) with biochemical IC

Bupleuri Radix, serving as the sovereign medicinal in many antidepressant compound preparations, has been proved effective in treating depression in mice, but its effect on the intestinal flora remains unclear. The present study aimed to investigate the effects of Bupleurum chinense(one of the original materials of Bupleuri Radix) on the behaviors and the diversity of intestinal flora of depressed mice. A depression mouse model was induced by repeated social defeat stress. Specifically, C57 BL/6 J male mice were exposed to the attack from the CD-1 mice. Then, C57 BL/6 J male mice were divided into a depression group and a B. chinense group, with normal saline and B. chinense administered(ig) respectively. Sucrose preference test and tail suspension test were conducted during and after the experiment respectively, to analyze the effects of B. chinense on the behaviors of the depressed mice. The feces were collected after the experiment. The V3-V4 16 S rDNA regions of intestinal flora of mice in each group were sequenced by Ion S5 TMXL for the analysis of the number of operational taxonomic units(OTUs), richness, alpha and beta diversity indexes, and differential phyla and genera. The results indicated that B. chinense could decrease depressive-like behaviors of mice, increase sucrose preference, and shorten the time of immobility in tail suspension test. After B. chinense intervention, the relative abundance of Firmicutes was significantly decreased, while that of Bacteroidetes was increased at the phylum level. At the genus level, the relative abundance of Lactobacillus and Lachnoclostridium decreased(P<0.05), while that of Bacteroides, Alistopes, etc. was elevated(P<0.05). The findings demonstrate that B. chinense can regulate the intestinal flora and improve the depressive-like behaviors of mice with depression.
Animals ; Bupleurum ; Feces ; Gastrointestinal Microbiome ; Lactobacillus ; Mice ; Mice, Inbred C57BL

OBJECTIVE: To compare the clinical effect on the joint attention and social communication in children with autism spectrum disorder (ASD) between the combined treatment of acupoint catgut embedding therapy with rehabilitation training and the simple application of rehabilitation training. METHODS: A total of 60 children with ASD were randomized into an observation group and a control group, 30 cases in each one. In the control group, the routine ASD rehabilitation training was adopted, including conductive education, speech training and music therapy, once a day. In the observation group, on the base of the treatment as the control group, the catgut embedding therapy was applied to Shenting (GV 24), Baihui (GV 20), Shenmen (HT 7) and the optic area (the point of scalp acupuncture), once a week. In the two groups, the treatment for 4 weeks was as one course, at the interval of 1 week between the courses. A total of 3 courses of treatment were required. The social domain of the autism treatment evaluation checklist (ATEC) and the autism behavior checklist (ABC) were adopted to assess the therapeutic effect of the two groups. RESULTS: After treatment, the scores of each item of the social domain in ATEC and the scores of ABC (feeling, communication, physical movement, language and healthy behavior) were all lower than those before treatment in the two groups (<0.01). The scores of each item in the observation group were lower than those in the control group after treatment (<0.05). CONCLUSION The combined treatment of acupoint catgut embedding therapy with the rehabilitation training effectively improves in the joint attention and social communication. The therapeutic effect of this combined treatment is better than the simple application of rehabilitation training.