A high-fat diet promotes cancer progression by inducing gut microbiota-mediated leucine production and PMN-MDSC differentiation.

A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.

Astrocytic Neuroligin-3 influences gene expression and social behavior, but is dispensable for synapse number.

Neuroligin-3 (Nlgn3) is an autism-associated cell-adhesion molecule that interacts with neurexins and is robustly expressed in both neurons and astrocytes. Neuronal Nlgn3 is an essential regulator of synaptic transmission but the function of astrocytic Nlgn3 is largely unknown. Given the high penetrance of Nlgn3 mutations in autism and the emerging role of astrocytes in neuropsychiatric disorders, we here asked whether astrocytic Nlgn3 might shape neural circuit properties in the cerebellum similar to neuronal Nlgn3. Imaging of tagged Nlgn3 protein produced by CRISPR/Cas9-mediated genome editing showed that Nlgn3 is enriched in the cell body but not the fine processes of cerebellar astrocytes (Bergmann glia). Astrocyte-specific knockout of Nlgn3 did not detectably alter the number of synapses, synaptic transmission, or astrocyte morphology in mouse cerebellum. However, spatial transcriptomic analyses revealed a significant shift in gene expression among multiple cerebellar cell types after the deletion of astrocytic Nlgn3. Hence, in contrast to neuronal Nlgn3, astrocytic Nlgn3 in the cerebellum is not involved in shaping synapses but may modulate gene expression in specific brain areas.

Development of an ubiquitin-proteasome system signature for predicting prognosis and providing therapeutic guidance for patients with triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is a pathological subtype with a high mortality, and the development of inhibitors in the ubiquitin-proteasome system (UPS) component could be a novel therapeutic tool. METHODS: Triple-negative breast cancer data were obtained from The Cancer Genome Atlas (TCGA), and subtype analysis was performed by consistent clustering analysis to identify molecular subtypes of TNBC according to UPS characteristics. Differential analysis, COX and least absolute shrinkage and selection operator (LASSO) COX regression analyses were performed to select genes associated with overall survival in TNBC. The final prognostic model (UPS score) was determined using the LASSO COX model. The model performance was assessed using receiver operating characteristic (ROC) curves and survival curves. In addition, the results of the UPS score on analyzing the abundance of immune cell infiltration and immunotherapy were explored. Finally, we developed a nomogram for TNBC survival prediction. RESULTS: Two UPS subtypes (UPSMS1 and UPSMS2) showing significant survival differences were classified. COX regression analysis on differentially expressed genes in UPSMS1 and UPSMS2 filtered five genes that affected overall survival. Based on the regression coefficients and expression data of the five genes, we built a prognostic assessment system (UPS score). The UPS score showed consistent prognostic and therapeutic guidance values. Finally, the ROC curve of the nomogram and UPS score showed the highest predictive efficacy compared with traditional clinical prognostic indicators. CONCLUSION: The UPS score represented a promising prognostic tool to predict overall survival and immune status and guide personalized treatment selection in TNBC patients, and this study may provide a more practical alternative for clinical monitoring and management of TNBC.

Fucosyltransferase 9 promotes neuronal differentiation and functional recovery after spinal cord injury by suppressing the activation of Notch signaling.

Individuals with spinal cord injury (SCI) suffer from permanent disabilities such as severe motor, sensory and autonomic dysfunction. Neural stem cell transplantation has proven to be a potential strategy to promote regeneration of the spinal cord, since NSCs can produce neurotrophic growth factors and differentiate into mature neurons to reconstruct the injured site. However, it is necessary to optimize the differentiation of NSCs before transplantation to achieve a better regenerative outcome. Inhibition of Notch signaling leads to a transition from NSCs to neurons, while the underlying mechanism remains inadequately understood. Our results demonstrate that overexpression of fucosyltransferase 9 (Fut9), which is upregulated by Wnt4, promotes neuronal differentiation by suppressing the activation of Notch signaling through disruption of furin-like enzyme activity during S1 cleavage. In an in vivo study, Fut9-modified NSCs efficiently differentiates into neurons to promote functional and histological recovery after SCI. Our research provides insight into the mechanisms of Notch signaling and a potential treatment strategy for SCI.

SnoopLigase Enables Highly Efficient Generation of C-C-Linked Bispecific Nanobodies Targeting TNF-α and IL-17A.

Bispecific antibodies (bis-Nbs) have been extensively developed since the concept was devised over the decades. Taking advantage of the superior characteristics of nanobodies, bis-Nbs exhibit an emerging tendency to become the new generation of research and diagnostic tools. Traditional strategies to connect the homo- or heterogeneous monomers are commonly applied, but there are still technical issues to generate the bispecific molecules as efficiently as designed. Here, we utilize SnoopLigase to directly tether the C terminus (C-C) of the tagged nanobodies against tumor necrosis factor-α (TNF-α) and interleukin-17A (IL-17A). Under optimal conditions, the yield of C-C-linked bis-Nbs can reach as high as 70% due to the existence of SnoopLigase. The prepared bis-Nbs possessed similar or even higher affinity as the monomers and significantly inhibited the proliferation and migration of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) induced by TNF-α and IL-17A. This study provides an innovative route for using SnoopLigase to realize a highly efficient generation of C-C-linked bis-Nbs. The approach can be applied to different and multicomponent systems for their potential applications in disease diagnosis and treatment.

Copper-Mediated Cyclization of o-Hydroxyaryl Enaminones with 3-Indoleacetic Acids toward the Synthesis of 3-Indolmethyl-Chromones.

Here, we describe a copper-mediated tandem decarboxylative coupling/annulation protocol of o-hydroxyaryl enaminones with 3-indoleacetic acids. A series of 3-indolmethyl-chromones were afforded in up to 97% yield. A one-pot method for 3-indolmethyl-chromones from o-hydroxy acetophenones, N, N-dimethylformamide dimethyl acetal, and 3-indoleacetic acids was also developed. Derivatization of the products was conducted to provide various indolmethyl-substituted pyrimidines. Moreover, a biological evaluation revealed that some compounds had anti-influenza viral activities.

Transition Metal Catalyst-Free C-3 Sulfonylmethylation of Imidazo[1,2-a]pyridines with Glyoxylic Acid and Sodium Sulfinates in Water.

Herein, we describe an efficient and benign protocol for direct C-3 sulfonylmethylation of imidazo[1,2-a]pyridines with glyoxylic acid and sodium sulfinates. Various sulfonylmethylated imidazo[1,2-a]pyridines were synthesized in water under transition metal catalyst-free conditions. This multicomponent reaction featured available substrates, good functional group tolerance, moderate to excellent yields, and mild reaction conditions.

A new method for C(sp2)-H sulfonylmethylation with glyoxylic acid and sodium sulfinates.

We herein describe a C4 sulfonylmethylation of pyrazol-5-amines with glyoxylic acid and sodium sulfinates. The reaction only needed water as a solvent, and it featured mild reaction conditions, simple operation, and high regioselectivity. Various C4 sulfonylmethylated pyrazol-5-amines were obtained in good to excellent yields. Moreover, this sulfonylmethylation method was applicable for C(sp2)-H sulfonylmethylation of other substrates such as enamines, indoles, and antipyrines by adding a catalyst and changing the solvent. Biological evaluation revealed that some products had antiproliferative activity against cancer cell lines.

WKYMVm/FPR2 Alleviates Spinal Cord Injury by Attenuating the Inflammatory Response of Microglia.

Spinal cord injury (SCI) is a common traumatic disease of the nervous system. The pathophysiological process of SCI includes primary injury and secondary injuries. An excessive inflammatory response leads to secondary tissue damage, which in turn exacerbates cellular and organ dysfunction. Due to the irreversibility of primary injury, current research on SCI mainly focuses on secondary injury, and the inflammatory response is considered the primary target. Thus, modulating the inflammatory response has been suggested as a new strategy for the treatment of SCI. In this study, microglial cell lines, primary microglia, and a rat SCI model were used, and we found that WKYMVm/FPR2 plays an anti-inflammatory role and reduces tissue damage after SCI by suppressing the extracellular signal-regulated kinases 1 and 2 (ERK1/2) and nuclear factor-κB (NF-κB) signaling pathways. FPR2 was activated by WKYMVm, suppressing the secretion of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) by inhibiting M1 microglial polarization. Moreover, FPR2 activation by WKYMVm could reduce structural disorders and neuronal loss in SCI rats. Overall, this study illustrated that the activation of FPR2 by WKYMVm repressed M1 microglial polarization by suppressing the ERK1/2 and NF-κB signaling pathways to alleviate tissue damage and locomotor decline after SCI. These findings provide further insight into SCI and help identify novel treatment strategies.

SETD2 is essential for terminal differentiation of erythroblasts during fetal erythropoiesis.

SET domain-containing 2 (SETD2), the primary methyltransferase for histone 3 lysine-36 trimethylation (H3K36me3) in mammals, is associated with many hematopoietic diseases when mutated. Previous works have emphasized its role in maintaining adult hematopoietic stem cells or tumorigenesis, however, whether and how SETD2 regulates erythropoiesis during embryonic development is relatively unexplored. In this study, using a conditional SETD2 knockout (KO) mouse model, we reveal that SETD2 plays an essential role in fetal erythropoiesis. Loss of Setd2 in hematopoietic cells ablates H3K36me3, and leads to anemia with a significant decrease in erythroid cells in the peripheral blood at E18.5. This is due to impaired erythroblast differentiation in both spleen and liver. We also find increased proportions of nucleated erythrocytes in the blood of Setd2 KO embryos. Lastly, we ascribe embryonic erythropoiesis-related genes Vegfc, Vegfr3, and Prox1, as likely downstream targets of SETD2 regulation. Our study reveals a critical role of SETD2 in fetal erythropoiesis that precedes adult hematopoiesis, and provide unique insights into the defects in erythroid lineages, such as anemia.

Development of a handheld compression optical coherence elastography probe with a disposable stress sensor.

Optical coherence elastography (OCE) is a functional extension of optical coherence tomography (OCT). OCE measures a sample's deformation under force stimuli. Compression is often used to generate the force stimuli in OCE. In this Letter, we report the development of a handheld quantitative compression OCE probe with a novel stress senor, dedicated to measuring the force. The stress sensor consists of a circular glass window and a metal ring which are connected with polyurethane spokes. This sensor is mounted on the tip of the OCT sample arm as an imaging window, so that the force applied to the sample through the window can be measured by detecting the window displacement from the OCT image. The force-displacement function was first developed through simulation on COMSOL Multiphysics and eventually calibrated experimentally. A phase-sensitive OCT technique was employed to measure both the window displacement and the sample deformation. The performance of an OCE probe with this stress sensor was evaluated on a two-layer phantom. The results show that it is extremely capable of measuring the sample Young's modulus. Finally, we successfully measured the elasticity of the human fingertip, indicating a good potential of this OCE probe for in vivo elastogram measurement on human skin.

Neoadjuvant everolimus plus letrozole versus fluorouracil, epirubicin and cyclophosphamide for ER-positive, HER2-negative breast cancer: a randomized pilot trial.

BACKGROUND: Here we evaluated the feasibility, efficacy, tolerability, and treatment-mediated immune modulation of neoadjuvant everolimus plus letrozole versus chemotherapy in treating postmenopausal patients with ER-positive, HER2-negative breast cancer. METHODS: Postmenopausal women with ER-positive, HER2-negative breast cancer who had a primary tumor > 2 cm or positive axillary lymph node(s) proofed by biopsy were randomly (1,1) enrolled to receive neoadjuvant everolimus plus letrozole for 18 weeks or fluorouracil, epirubicin plus cyclophosphamide (FEC) for 6 cycles before surgery. Primary outcome was feasibility of the trial. Secondary outcome included ultrasound response rate, pathological complete response rate, breast-conserving surgery rate, toxicities, treatment-mediated immune modulation and biomarkers. RESULTS: Forty patients were randomized. Completion rate was 90.0% in the neoadjuvant endocrine therapy (NET) arm but 70.0% in the neoadjuvant chemotherapy (NAC) arm. The ultrasound response rate was 65.0% in NET arm and 40.0% in FEC arm, respectively. In terms of the adverse events, clearly favored NET arm. Everolimus plus letrozole increased the ratio of peripheral Tregs to CD4+ T cells and tumor PD-L1 expression, and decreased Ki67 index and tumor-infiltrating Tregs, and patients with a greater increase of tumor-specific CTLs showed more sensitive to NET. CONCLUSION: This pilot trial showed that neoadjuvant everolimus plus letrozole might achieve a favorable ultrasound response rate with low toxicities in treating postmenopausal ER-positive, HER2-negative breast cancer patients. Everolimus plus letrozole might have positive antitumoral immunity effects. Further large randomized controlled trials are needed to confirm our findings. TRAIL REGISTRATION: A Trial of Neoadjuvant Everolimus Plus Letrozole Versus FEC in Women With ER-positive, HER2-negative Breast Cancer, registered on 07/04/2016 and first posted on 18/04/2016, NCT02742051 .

Copper-Catalyzed C-3 Functionalization of Imidazo[1,2-a]pyridines with 3-Indoleacetic Acids.

A copper-catalyzed C-3 functionalization of imidazo[1,2-a]pyridines with 3-indoleacetic acids through an aerobic oxidative decarboxylative process has been developed. The protocol provided a series of 3-(1H-indol-3-ylmethyl)-imidazo[1,2-a]pyridines in moderate to good yields under simple reaction conditions. Importantly, some products exhibited potent antiproliferative activity in cancer cell lines.

Efficacy of a virtual reality-based basic and clinical fused curriculum for clinical education on the lumbar intervertebral disc.

OBJECTIVE: Today, minimally invasive procedures have become mainstream surgical procedures. Percutaneous endoscopic transforaminal discectomy for lumbar disc herniation (LDH) requires profound knowledge of the laparoscopic lumbar anatomy. Immersive virtual reality (VR) provides three-dimensional patient-specific models to help in the process of preclinical surgical preparation. In this study, the authors investigated the efficacy of VR application in LDH for training orthopedic residents and postgraduates. METHODS: VR images of the lumbar anatomy were created with immersive VR and mAnatomy software. The study was conducted among 60 residents and postgraduates. A questionnaire was developed to assess the effect of and satisfaction with this VR-based basic and clinical fused curriculum. The teaching effect was also evaluated through a postlecture test, and the results of the prelecture surgical examination were taken as baselines. RESULTS: All participants in the VR group agreed that VR-based education is practical, attractive, and easy to operate, compared to traditional teaching, and promotes better understanding of the anatomical structures involved in LDH. Learners in the VR group achieved higher scores on an anatomical and clinical fusion test than learners in the traditional group (84.67 ± 14.56 vs 76.00 ± 16.10, p < 0.05). CONCLUSIONS: An immersive VR-based basic and clinical fused curriculum can increase residents' and postgraduates' interest and support them in mastering the structural changes and complicated symptoms of LDH. However, a simplified operational process and more realistic haptics of the VR system are necessary for further surgical preparation and application.

Elevated Expression Levels of Long Non-Coding RNA, Loc554202, Are Predictive of Poor Prognosis in Cervical Cancer.

Cervical cancer remains one of the most common causes of gynecological cancer-associated death. Long non-coding RNA Loc554202 (lncRNA Loc554202) has been reported to be involved in the development of several types of cancer. However, the role of Loc554202 in cervical cancer remains unclear. In this study, we measured the expression levels of Loc554202 in cervical cancer tissues from 120 patients. The quantitative real-time PCR analysis showed the expression levels of Loc554202 were significantly higher in cervical cancer tissues compared with the adjacent non-tumor tissues. Elevated expression levels of Loc554202 were significantly associated with tumor size (p = 0.006), FIGO stage (p = 0.015), HPV (p = 0.001), and lymph node metastasis (p = 0.002). Kaplan-Meier analysis clearly illustrated that patients with high expression levels of Loc554202 had a lower overall survival rate compared to patients with lower expression (p = 0.0013). Furthermore, we show that Loc554202 is an independent poor prognostic factor through multivariate analysis. Subsequently, using cervical cancer cell lines, HeLa and ME-180, we decreased the expression levels of Loc554202 with siRNA. As results, the proliferation ability of cervical cancer cells was inhibited and apoptosis was induced after Loc554202 knockdown, as judged by viability assay, colony formation, and flow cytometry. Moreover, knockdown of Loc554202 expression down-regulated Bcl-2 expression and conversely up-regulated Bax expression in cervical cancer cells using Western blotting analysis. In conclusion, elevated levels of Loc554202 are predictive of poor prognosis in cervical cancer. We suggest that Loc554202 may serve as a potential therapeutic target for cervical cancer.

Fall efficacy and influencing factors among Chinese community-dwelling elders with knee osteoarthritis.

Low fall efficacy can lead to activity restriction and loss of independence, which may cause severe adverse consequences. The purpose of this study was to explore fall efficacy among elders with knee osteoarthritis and influential factors in three communities in Beijing, China. A correlational descriptive study design was used with a sample of 117 participants from July 2014 to November 2014. Results showed that participants had low fall efficacy and that fall efficacy correlated with age, gender, body mass index, marital status, education, disease duration, frequency of falls, number of co-morbidities, pain, stiffness, physical function, depression, lower-extremity muscle strength and balance (r = -0.594 to 0.234, P < 0.05 to 0.001). Multiple regression analysis revealed that 52% of variance in fall efficacy was explained by fall frequency, age, body mass index, gender, pain and balance function. Findings suggest that strategies to prevent falls, reduce body weight, improve effective pain management and enhance balance function may improve fall efficacy in this population.

Current situation and influencing factors of each turnover of kindergarten teachers - a questionnaire survey.

Objective: Frequent teacher turnover may damage the development of teachers and the regular operation of kindergartens. This original research presented kindergarten teachers' first, second, and third turnover rates and occurrence times. This research analyzed the relationship between socio-demographic variables and the varying frequency of kindergarten teacher turnover. These data were used to investigate the characteristics of first, second, and third kindergarten turnover. This research evaluated kindergarten teachers' occupational ambition, emotional attachment, and self-efficacy. Likewise, this research also analyzed the social context, organizational support, management mechanism, reward, and occupational stress of kindergarten. These data were used to determine the key factors affecting kindergarten teachers' turnover. Methods: This research recruited 1,118 kindergarten teachers (mean age = 31.67, sd = 5.02; 3.85% male, 96.14% female) from China. Based on the existing scales, this research developed the Questionnaire of Kindergarten Teachers' Turnover and Influencing Factors for the survey. Kindergarten teachers reported basic information and the impact factors of their first, second, and third turnover through online questionnaires. The Chi-square test was used to analyze the correlation between socio-demographic variables and different frequencies of kindergarten teacher turnover. The binary logistic regression explored the eight factors affecting kindergarten teachers' first, second, and third turnover. Results: The results showed that 43.65% of kindergarten teachers had resigned. In detail, 25.60% of kindergarten teachers resigned once, 10.64% of kindergarten teachers resigned twice, and 8.41% of kindergarten teachers resigned thrice. Gender and marital status were significantly correlated with the three frequencies of kindergarten teacher turnover. Occupational stress, reward, management mechanisms, and ambition consistently affected kindergarten teachers' first, second, and third turnover. Conclusion: The relevant management departments should pay attention to the high turnover rate of kindergarten teachers and put forward more strategies to improve their stability. Women and married can be favored in the recruitment of kindergarten teachers. It is crucial to reduce pressure and improve rewards for kindergarten teachers. Also, kindergartens should provide the space to display teachers' talents and improve management mechanisms. These results provide empirical support for proposing effective policies to promote the stability of kindergarten teachers' construction.

Biparatopic Nanobody-Based Immunosorbent for the Highly Selective Elimination of Tumor Necrosis Factor-α.

Removing the overexpressed TNF-α by hemoperfusion positively affects clinical treatments for diseases such as autoimmune disease and sepsis. However, clearance ratios of adsorbents targeting TNF-α were limited by the extremely low concentration of TNF-α (mostly <1000 ng/L in sepsis) and hydrophobic interactions. In this work, biparatopic nanobodies (NbC21) with a high affinity of 19.9 pM, which bind to two distinct sites of TNF-α, were constructed as high-affinity ligands for the immunosorbent. The theoretical maximum adsorption capacity estimated from the Langmuir isotherm was up to 18.22 mg/g gel. The prepared immunosorbent (NbC21-sorbent) had an outstanding TNF-α clearance ratio of approximately 96% during the dynamic adsorption test, with a sorbent-to-serum ratio of 1:1000. Additionally, it demonstrated favorable hemocompatibility and a prolonged storage capability. The results indicated that the biparatopic nanobody immunosorbent exhibited significant potential for clinical applications as it met the stringent criteria for both efficacy and safety.

Signature Construction and Disulfidptosis-Related Molecular Cluster Identification for Better Prediction of Prognosis in Glioma.

Disulfidptosis is a newly discovered form of regulatory cell death. However, the identification of disulfidptosis-related molecular subtypes and potential biomarkers in gliomas and their prognostic predictive potential need to be further elucidated. RNA sequencing profiles and the relevant clinical data were obtained from the Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA). Disulfidptosis-related clusters were identified by unsupervised clustering analysis. Immune cell infiltration analysis and drug sensitivity analysis were used to explore the differences between clusters. Gene set enrichment analysis (GSEA) of differential genes between clusters was performed to explore the potential biological functions and signaling. A disulfidptosis-related scoring system (DRSS) was constructed based on a combined COX and LASSO analysis. Mendelian randomization (MR) analyses were used to further explore the causal relationship between levels of genes in DRSS and an increased risk of glioma. A prognosis nomogram was constructed based on the DRSS and 3 clinical features (age, WHO stage, and IDH status). The accuracy and stability of the prognosis nomogram were also validated in different cohorts. We identified two clusters that exhibited different prognoses, drug sensitivity profiles, and tumor microenvironment infiltration profiles. The overall survival (OS) of Cluster2 was significantly better than Cluster1. Cluster1 had an overall greater infiltration of immune cells compared to Cluster2. However, the Monocytes, activated B cells had higher infiltration abundance in Cluster2. GSEA results showed significant enrichment of immune-related biological processes in Cluster1, while Cluster2 was more enriched for functions related to neurotransmission and regulation. PER3, RAB34, NKX3-2, GPX7, FRA10AC1, and TGIF1 were finally included to construct DRSS. DRSS was independently related to prognosis. There was a significant difference in overall survival between the low-risk score group and the high-risk score group. Among six genes in DRSS, GPX7 levels were demonstrated to have a causal relationship with an increased risk of glioma. GPX7 may become a more promising biomarker for gliomas. The prognosis nomogram constructed based on the DRSS and three clinical features has considerable potential for predicting the prognosis of patients with glioma. Free online software for implementing this nomogram was established:  https://yekun-zhuang.shinyapps.io/DynNomapp/ . Our study established a novel glioma classification based on the disulfidptosis-related molecular subtypes. We constructed the DRSS and the prognosis nomogram to accurately stratify the prognosis of glioma patients. GPX7 was identified as a more promising biomarker for glioma. We provide important insights into the treatment and prognosis of gliomas.

Association of non-essential metals with Chinese schizophrenia: A case-control study.

BACKGROUND: The potential link between environmental pollutants, including metals, and schizophrenia development remains debated. This study aimed to explore the association between plasma levels of three non-essential metals-barium (Ba), tungsten (W), and uranium (U)-and schizophrenia risk among Chinese individuals. METHOD: We recruited a total of 221 patients and 219 healthy controls. Plasma levels of three non-essential metals were measured using inductively coupled plasma mass spectrometry. We employed unconditional logistic regression and Bayesian kernel machine regression (BKMR) to explore the relationship between exposure to multiple metals and the risk of schizophrenia. RESULTS: Logistic regression analysis revealed that the highest quartile (Q4) of W had an odds ratio (OR) of 1.87 (95% CI: 1.08-3.21) compared to the lowest quartile (Q1), with a significant P-trend of 0.017. For U, the ORs (95% CI) for Q2, Q3, and Q4 were 2.06 (1.19-3.56), 1.99 (1.15-3.44), and 1.74 (1.00-3.00), respectively. BKMR analyses revealed a progressive increase in the risk of schizophrenia with increasing cumulative levels of the three metals at concentrations below 35%, with U playing a major role in this association. U showed a non-linear positive correlation with schizophrenia, particularly at the 75th percentile level. Moreover, potential interactions were observed between W and Ba, as well as between W and U. CONCLUSION: Higher plasma W and U concentrations were positively associated with the risk of schizophrenia, which was potentially related to the severity of symptoms in schizophrenic patients.