Human exposure risk of organic UV filters: A comprehensive analysis based on primary exposure pathways.

The exposure of organic UV filters has been increasingly confirmed to induce adverse effects on humans. However, the critical exposure pathway and the vulnerable population of organic UV filters are not clearly identified. This paper attempts to evaluate the health risk of commonly used organic UV filters from various exposure routes based on comprehensive analysis strategy. The estimated daily intakes (EDI) and hazard quotient (HQ) values of organic UV filters through four pathways (dermal exposure, indoor dust, indoor air, and drinking water) for various age groups were determined. Although the total HQ values (0.01-0.4) from comprehensive exposure of organic UV filters were below risk threshold (1.0), infants were identified as the most vulnerable population, with EDI (75.71 ng/kg-bw/day) of 2-3 times higher than that of adults. Additionally, the total EDI values of individual exposure pathways were estimated and ranked as follows: indoor air (138.44 ng/kg-bw/day) > sunscreen application (37.2 ng/kg-bw/day) > drinking water (21.87 ng/kg-bw/day) > indoor dust (9.24 ng/kg-bw/day). Moreover, we successfully tailored the Sankey diagram to depict the EDI proportion of individual organic UV filters from four exposure pathways. It was noted that EHMC (ethylhexyl methoxycinnamate) and EHS (ethylhexyl salicylate) dominated the contribution of EDI (72 %) via indoor air exposure routes. This study serves as a crucial reference for enhancing public health risk awareness concerning organic UV filters, with a special focus on the vulnerable populations such as infants and children.

Structural basis of adenine nucleotides regulation and neurodegenerative pathology in ClC-3 exchanger.

The ClC-3 chloride/proton exchanger is both physiologically and pathologically critical, as it is potentiated by ATP to detect metabolic energy level and point mutations in ClC-3 lead to severe neurodegenerative diseases in human. However, why this exchanger is differentially modulated by ATP, ADP or AMP and how mutations caused gain-of-function remains largely unknow. Here we determine the high-resolution structures of dimeric wildtype ClC-3 in the apo state and in complex with ATP, ADP and AMP, and the disease-causing I607T mutant in the apo and ATP-bounded state by cryo-electron microscopy. In combination with patch-clamp recordings and molecular dynamic simulations, we reveal how the adenine nucleotides binds to ClC-3 and changes in ion occupancy between apo and ATP-bounded state. We further observe I607T mutation induced conformational changes and augments in current. Therefore, our study not only lays the structural basis of adenine nucleotides regulation in ClC-3, but also clearly indicates the target region for drug discovery against ClC-3 mediated neurodegenerative diseases.

Comprehensive diagnostic model for osteosarcoma classification using CT imaging features.

Objective: The main objective of this study was to create and assess a detailed diagnostic model with an optimizing feature selection algorithm that combines computed tomography (CT) imaging characteristics, demographic information, and genetic markers to enhance the accuracy of benign and malignant classification of osteosarcoma. This research seeks to enhance the early identification and categorization of benign and malignant of osteosarcoma, ultimately enabling more personalized and efficient treatment approaches. Methods: Data from 225 patients diagnosed with osteosarcoma at two different medical institutions between June 2018 and June 2021 were gathered for this research study. A novel feature selection approach that combined Principal Component Analysis (PCA) with Improved Particle Swarm Optimization (IPSO) was utilized to analyze 1743 image-derived features. The performance of the resulting model was evaluated using metrics such as area under the receiver operating characteristic curve (AUC), accuracy (ACC), sensitivity (SEN), and specificity (SPE), and compared to models developed using conventional feature selection methods. Results: The proposed model showed promising predictive performance with an AUC of 0.87, accuracy of 0.80, sensitivity of 0.75, and specificity of 0.85. These results suggest improved predictive ability compared to models built using traditional feature selection techniques, particularly in terms of accuracy and specificity. However, there is room for improvement in enhancing sensitivity. Conclusion: Our study introduces a novel predictive model for distinguishing between benign and malignant osteosarcoma., emphasizing its potential significance in clinical practice. Through the utilization of CT imaging features, our model shows improved accuracy and specificity, marking progress in the early detection and classification of osteosarcoma as either benign or malignant. Future investigations will concentrate on enhancing the model's sensitivity and validating its effectiveness on a larger dataset, aiming to boost its clinical relevance and support personalized treatment approaches for osteosarcoma.

Global, regional, and national burden of early-onset gastric cancer.

OBJECTIVE: The burden of gastric cancer (GC) across different age groups needs updating. We determined the GC global, regional, and national burden profiles and changes in incidence for 3 sequential 5-year intervals from 2003 to 2017. METHODS: The latest incidence and mortality estimates of GC from 185 countries and regions were extracted from the GLOBOCAN 2022 database. The 5-year interval age-standardised incidence rates (ASIRs) were evaluated using cancer registry data from volumes X-XII of the Cancer Incidence in Five Continents (CI5). Correlation analysis was used to evaluate the relationship between ASIR or the age-standardised mortality rate (ASMR) and the Human Development Index (HDI). RESULTS: There was an estimated global 968,000 new GC cases and 660,000 deaths in 2022, with male predominance. GC ASIRs and ASMRs were 9.2 and 6.1 per 100,000 persons, respectively. East Asia had the highest burden, with 53.8% of cases and 48.2% of deaths among all geographic regions. There was a significant correlation between ASIR and HDI. Over three 5-year intervals from 2003 to 2017, the incidence of GC notably decreased in most countries but peaked at 2008-2012 in New Zealand, Turkey, and South Africa. Several countries in Europe, Oceania, and America suggest an increasingly concerning trend among younger individuals, especially females. CONCLUSIONS: GC is a significant health issue, especially among males and in geographic regions with an HDI, such as eastern Asia. While the incidence of GC is decreasing in many countries due to prevention efforts and improved treatments, a rising trend persists among younger individuals. Comprehensive prevention strategies tailored to different age patterns are clearly needed.

Overtime work and Chinese workers' physical and mental health: The mediating role of social support and work value awareness.

BACKGROUND: China was once called the world's factory. Chinese workers had long weekly working hours. However, the empirical results of the relationship between overtime work and workers' health are mixed and remain inconclusive. OBJECTIVE: This study aimed to investigate how overtime work influenced workers' physical and mental health and the role of lifestyles, social support, and work value awareness. METHODS: Data from the China Labor-force Dynamics Survey 2016 (N = 14,205) was used. The instrumental variable approach was employed to overcome the endogeneity problem between overtime work and workers' health. The bootstrapping method was conducted to elicit the role of lifestyles, social support, and work value awareness. RESULTS: The results indicated that overtime work significantly and negatively influenced Chinese workers' physical and mental health. The results of the bootstrapping suggested that workers' social support and work value awareness partially mediated the relationship between overtime work and their physical and mental health. However, the mediating role of lifestyles was insignificant. CONCLUSION: Through using big data with national representativeness, this study suggests that overtime work negatively influences Chinese workers' physical and mental health. Our findings provide policy implications for improving workers' health rights and well-being in emerging economies.

Study on the impact of digital transformation on green competitive advantage: The role of green innovation and government regulation.

Digital transformation enables small and medium enterprises (SMEs) to reduce or overcome their reliance on resources and energy, thereby minimizing their environmental impact and providing them with sustainable green competitive advantages. However, the reasons for this phenomenon are not yet clear. To further investigate this issue, we selected 391 Chinese SMEs to examine the relationships among green transformation, green innovation, government regulation, and green competitive advantages. Green innovation includes green product innovation and green process innovation, while government regulation includes incentive regulation, constraint regulation, and guidance regulation. The empirical results show that digital transformation can enhance SMEs' green competitive advantages. Additionally, the hypothesized mediating effect of green product innovation and green process innovation between digital transformation and green competitive advantages is supported, while the moderating effect of incentive regulation, constraint regulation, and guidance regulation on the relationship between digital transformation and green product innovation and green process innovation is also confirmed. The findings of this study may contribute to more effective management of digital transformation and green innovation in SMEs, thereby promoting their development.

Analysis of the Adsorption Behavior of Phenanthrene on Microplastics Based on Two-Dimensional Correlation Spectroscopy.

Microplastics (MPs), an emerging pollutant, widely co-occur with polycyclic aromatic hydrocarbons (PAHs) in the environment. Therefore, the interaction between MPs and PAHs has been the focus of much attention in recent years. In this study, three types of MPs, i.e., polypropylene, polystyrene, and poly(vinyl chloride), with the same main chain were selected as the adsorbents, with phenanthrene (PHE) as the representative PAHs. The adsorption mechanisms were explored from the perspective of the molecular spectral level using a combination of Fourier transform infrared spectroscopy (FT-IR) with a two-dimensional correlation technique. The adsorption kinetics results showed that the adsorption of PHE on the three MPs was dominated by chemisorption. However, the FT-IR analysis results indicated that no new covalent bond was created during the adsorption process. Based on the above research, a generalized two-dimensional (2D) correlation spectral technique was employed to investigate the sequence of functional group changes during the adsorption process for different MPs. Furthermore, the hybrid 2D correlation spectral technique explored the effect of side groups attached to the main chain molecules of MPs on adsorption. The results showed that for all three MPs, the functional groups in the side chain have a higher affinity for PHE, which is due to their higher hydrophobicity. This study provides a feasible way to analyze the adsorption of pollutants on MPs, and the results are important for understanding the adsorption interaction between PAHs and MPs in the aquatic environment.

Clinicopathological features and outcomes of PLA2R-related membranous nephropathy with renal glycosuria.

BACKGROUND: Membranous nephropathy (MN) is an immune complex-mediated disease. Massive proteinuria can lead to Fanconi syndrome, clinically manifesting as renal glycosuria. The prevalence and prognosis of M-type phospholipase A2 receptor (PLA2R)-related MN with renal glycosuria remain unknown. MATERIALS AND METHODS: Patients diagnosed with PLA2R-related MN with renal glycosuria were reviewed, and the control group comprised patients with MN without renal glycosuria who were randomly selected at a ratio of 1 : 3. RESULTS: 50 patients diagnosed with PLA2R-related MN with renal glycosuria from January 2015 to January 2020 were included, with a prevalence of 2.3%. Compared with patients without renal glycosuria, those with renal glycosuria exhibited greater proteinuria, lower estimated glomerular filtration rate (eGFR), and higher use of diuretics, anticoagulants, antibiotics, traditional Chinese medicine, and tacrolimus within 3 months prior to renal biopsy (all p < 0.05). Histologically, patients with renal glycosuria exhibited more severe pathological stages, acute/chronic tubulointerstitial lesions, and tubulointerstitial inflammation (all p < 0.05). Of the 10 patients treated with rituximab (RTX), proteinuria remission was maintained in 6 (60%) patients, and urine glucose remission was achieved in 5 of these 6 patients (83.3%). Multivariate Cox regression analysis showed that renal glycosuria and age > 50 years were independent risk factors for end-stage renal disease (ESRD) or a 30% reduction in the eGFR in patients with PLA2R-related MN. CONCLUSION: PLA2R-related MN patients with renal glycosuria presented with more severe clinicopathological manifestations and worse prognoses. Nephrotoxic drugs should be administered rationally, and RTX should be considered as a promising treatment option.

Evaluation of transurethral GreenLight laser-selective vaporization for refractory overactive bladder in women.

Background: Refractory overactive bladder (OAB) in women is a common yet challenging condition for which traditional treatments have been unsatisfactory. This study aimed to evaluate the efficacy and safety of transurethral bladder mucosal GreenLight laser-selective vaporization for treating refractory OAB in women. Methods: The female patients with refractory OAB who were admitted to the Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University between May 2022 and July 2023 were examined retrospectively in this study. Transurethral bladder mucosal GreenLight laser-selective vaporization was used to treat the patients, and the perioperative and postoperative parameters were reviewed and compared. Bladder mucosa was examined by immunohistochemical staining to explore the expressions of TRPV1, P2X3, tumor necrosis factor alpha (TNF-α), and interleukin 6 (IL-6) before and after treatments. Results: Surgeries were performed successfully for all 32 patients in 57.38±11.22 minutes with minimal intraoperative bleeding. Twelve weeks post-surgery, there was a significant decrease (P<0.05) in the patients' Overactive Bladder Symptom Score (OABSS), 3-day bladder diary (daytime frequency, nocturia, urgency, and urgency incontinence), and Overactive Bladder questionnaire Short Form (OAB-qSF) score. After treatments, both first desire to void (FDV) and maximum bladder pressure capacity (MCBC) increased significantly (P<0.05). The immunohistochemical analysis revealed that the GreenLight laser significantly reduced the expressions of TRPV1, P2X3, TNF-α, and IL-6 in the bladder mucosa (P<0.05). No severe complications were observed after interventions. Conclusions: For female patients with refractory OAB who have shown poor response to conventional treatment approaches, transurethral bladder mucosal GreenLight laser-selective vaporization may represent a promising alternative treatment option.

Machine learning identifies key cells and therapeutic targets during ferroptosis after spinal cord injury.

Ferroptosis, a type of cell death that mainly involves iron metabolism imbalance and lipid peroxidation, is strongly correlated with the phagocytic response caused by bleeding after spinal cord injury. Thus, in this study, bulk RNA sequencing data (GSE47681 and GSE5296) and single-cell RNA sequencing data (GSE162610) were acquired from gene expression databases. We then conducted differential analysis and immune infiltration analysis. Atf3 and Piezo1 were identified as key ferroptosis genes through random forest and least absolute shrinkage and selection operator algorithms. Further analysis of single-cell RNA sequencing data revealed a close relationship between ferroptosis and cell types such as macrophages/microglia and their intrinsic state transition processes. Differences in transcription factor regulation and intercellular communication networks were found in ferroptosis-related cells, confirming the high expression of Atf3 and Piezo1 in these cells. Molecular docking analysis confirmed that the proteins encoded by these genes can bind cycloheximide. In a mouse model of T8 spinal cord injury, low-dose cycloheximide treatment was found to improve neurological function, decrease levels of the pro-inflammatory cytokine inducible nitric oxide synthase, and increase levels of the anti-inflammatory cytokine arginase 1. Correspondingly, the expression of the ferroptosis-related gene Gpx4 increased in macrophages/microglia, while the expression of Acsl4 decreased. Our findings reveal the important role of ferroptosis in the treatment of spinal cord injury, identify the key cell types and genes involved in ferroptosis after spinal cord injury, and validate the efficacy of potential drug therapies, pointing to new directions in the treatment of spinal cord injury.

Pterostilbene Alleviates Dextran Sodium Sulfate (DSS)-Induced Intestinal Barrier Dysfunction Involving Suppression of a S100A8-TLR-4-NF-κB Signaling Cascade.

Intestinal barrier hemostasis is the key to health. As a resveratrol analogue, pterostilbene (PT) has been reported to prevent dextran sodium sulfate (DSS)-induced intestinal barrier dysfunction mainly associated with the intestinal NF-κB signaling pathway. However, the exact underlying mechanisms are not yet well-defined yet. In this study, we performed RNA-sequencing analysis and unexpectedly found that alarmin S100A8 sensitively responded to DSS-induced intestinal injury. Accordingly, histologic assessments suggested that the high expression of S100A8 was accompanied by increased intestinal infiltration of macrophages, upregulated intestinal epithelial Toll-like receptor 4 (TLR-4), and activated NF-κB signaling pathway. Interestingly, the above phenomena were effectively counteracted upon the addition of PT. Furthermore, by using a coculture system of macrophage THP-1 cells and HT-29 colon cells, we identified macrophage-secreted S100A8 activated intestinal epithelial NF-κB signaling pathway through TLR-4. Taken together, these findings suggested that PT ameliorated DSS-induced intestinal barrier injury through suppression of the macrophage S100A8-intestinal epithelial TLR-4-NF-κB signaling cascade.

Analysis of the recombination and evolution of the new type mutant pseudorabies virus XJ5 in China.

Pseudorabies have caused enormous economic losses in China's pig industry and have recurred on many large pig farms since late 2011. The disease is caused by highly pathogenic, antigenic variant pseudorabies virus (vPRV) strains. Our laboratory isolated a pseudorabies virus in 2015 and named it XJ5. The pathogenic ability of this mutant strain was much stronger than that of the original isolate. After we sequenced its whole genome (GenBank accession number: OP512542), we found that its overall structure was not greatly changed compared with that of the previous strain Ea (KX423960.1). The whole genome alignment showed that XJ5 had a strong genetic relationship with the strains isolated in China after 2012 reported in GenBank. Based on the isolation time of XJ5 and the mutation and recombination analysis of programs, we found that the whole genome homology of XJ5 and other strains with Chinese isolates was greater than 95%, while the homology with strains outside Asia was less than 94%, which indicated that there may be some recombination and mutation patterns. We found that virulent PRV isolates emerged successively in China in 2011 and formed two different evolutionary clades from foreign isolates. At the same time, this may be due to improper immunization and the presence of wild strains in the field, and recent reports have confirmed that Bartha vaccine strains recombine with wild strains to obtain new pathogenic strains. We performed genetic evolution analysis of XJ5 isolated and sequenced in our laboratory to trace its possible mutations and recombination. We found that XJ5 may be the result of natural mutation of a virus in a branch of mutant strains widely existing in China.

The current therapeutic cancer vaccines landscape in non-small cell lung cancer.

Currently, conventional immunotherapies for the treatment of non-small cell lung cancer (NSCLC) have low response rates and benefit only a minority of patients, particularly those with advanced disease, so novel therapeutic strategies are urgent deeded. Therapeutic cancer vaccines, a form of active immunotherapy, harness potential to activate the adaptive immune system against tumor cells via antigen cross-presentation. Cancer vaccines can establish enduring immune memory and guard against recurrences. Vaccine-induced tumor cell death prompts antigen epitope spreading, activating functional T cells and thereby sustaining a cancer-immunity cycle. The success of vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rendered cancer vaccines a promising avenue, especially when combined with immunotherapy or chemoradiotherapy for NSCLC. This review delves into the intricate antitumor immune mechanisms underlying therapeutic cancer vaccines, enumerates the tumor antigen spectrum of NSCLC, discusses different cancer vaccines progress and summarizes relevant clinical trials. Additionally, we analyze the combination strategies, current limitations, and future prospects of cancer vaccines in NSCLC treatment, aiming to offer fresh insights for their clinical application in managing NSCLC. Overall, cancer vaccines offer promising potential for NSCLC treatment, particularly combining with chemoradiotherapy or immunotherapy could further improve survival in advanced patients. Exploring inhaled vaccines or prophylactic vaccines represents a crucial research avenue.

Targeting S100A12 to Improve Angiogenesis and Accelerate Diabetic Wound Healing.

Long-term inflammation and impaired angiogenesis are thought to be the causes of delayed healing or nonhealing of diabetic wounds. S100A12 is an essential pro-inflammatory factor involved in inflammatory reactions and serves as a biomarker for various inflammatory diseases. However, whether high level of S100A12 exists in and affects the healing of diabetic wounds, as well as the underlying molecular mechanisms, remain unclear. In this study, we found that the serum concentration of S100A12 is significantly elevated in patients with type 2 diabetes. Exposure of stratified epidermal cells to high glucose environment led to increased expression and secretion of S100A12, resulting in impaired endothelial function by binding to the advanced glycation endproducts (RAGE) or Toll-like receptor 4 (TLR4) on endothelial cell. The transcription factor Krüpple-like Factor 5 (KLF5) is highly expressed in the epidermis under high glucose conditions, activating the transcriptional activity of the S100A12 and boost its expression. By establishing diabetic wounds model in alloxan-induced diabetic rabbit, we found that local inhibition of S100A12 significantly accelerated diabetic wound healing by promoting angiogenesis. Our results illustrated the novel endothelial-specific injury function of S100A12 in diabetic wounds and suggest that S100A12 is a potential target for the treatment of diabetic wounds.

From macroautophagy to mitophagy: Unveiling the hidden role of mitophagy in gastrointestinal disorders.

In this editorial, we comment on an article titled "Morphological and biochemical characteristics associated with autophagy in gastrointestinal diseases", which was published in a recent issue of the World Journal of Gastroenterology. We focused on the statement that "autophagy is closely related to the digestion, secretion, and regeneration of gastrointestinal cells". With advancing research, autophagy, and particularly the pivotal role of the macroautophagy in maintaining cellular equilibrium and stress response in the gastrointestinal system, has garnered extensive study. However, the significance of mitophagy, a unique selective autophagy pathway with ubiquitin-dependent and independent variants, should not be overlooked. In recent decades, mitophagy has been shown to be closely related to the occurrence and development of gastrointestinal diseases, especially inflammatory bowel disease, gastric cancer, and colorectal cancer. The interplay between mitophagy and mitochondrial quality control is crucial for elucidating disease mechanisms, as well as for the development of novel treatment strategies. Exploring the pathogenesis behind gastrointestinal diseases and providing individualized and efficient treatment for patients are subjects we have been exploring. This article reviews the potential mechanism of mitophagy in gastrointestinal diseases with the hope of providing new ideas for diagnosis and treatment.

Exosomal miR-17-92 Cluster from BMSCs Alleviates Apoptosis and Inflammation in Spinal Cord Injury.

Spinal cord injury (SCI) involves neuronal apoptosis and axonal disruption, leading to severe motor dysfunction. Studies indicate that exosomes transport microRNAs (miRNAs) and play a crucial role in intercellular communication. This study aimed to explore whether the bone marrow mesenchymal stem cell (BMSCs)-exosomal miR-17-92 cluster can protect against SCI and to explain the underlying mechanisms. In vivo and in vitro SCI models were established and treated with control exosomes (con-exo) or exosomes derived from BMSCs transfected with miR-17-92 cluster plasmid (miR-17-92-exo). Rat BMSCs were isolated and positive markers were identified by flow cytometry. BMSC-derived exosomes were extracted and verified using transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and western blotting. The expression of the miR-17-92 cluster was validated by quantitative reverse transcription PCR (qRT-PCR). Spinal cord function, histopathological changes, apoptotic cells, and inflammatory cytokines release in spinal cord tissues were assessed using the Basso-Beattie-Bresnahan (BBB) score, hematoxylin and eosin (HE) staining, terminal deoxynucleotide transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining, enzyme-linked immunosorbent assay (ELISA), and qRT-PCR. In PC12 cells, cell proliferation, apoptosis, apoptosis-related proteins cleaved-Caspase3 expression, and inflammatory factors secretion were analyzed using a cell counting kit-8 (CCK8) assay, flow cytometry, western blotting, and ELISA. Our data revealed that the exosomes were successfully isolated from rat BMSCs. The BMSC-exosomal miR-17-92 cluster improved neural functional recovery after SCI, as evidenced by an increased BBB score, improved pathological damage, reduced neuronal apoptosis, and decreased inflammatory factors release. Additionally, miR-17-92-exo treatment significantly inhibited lipopolysaccharide (LPS)-induced reduction in cell viability, increase in cell apoptosis, and upregulation of inflammatory factors in PC12 cells. The exosomal miR-17-92 cluster derived from BMSCs improved functional recovery and exhibited neuroprotective effects in SCI by alleviating apoptosis and inflammation.

Insights into treatment-specific prognostic somatic mutations in NSCLC from the AACR NSCLC GENIE BPC cohort analysis.

BACKGROUND: Treatment of non-small lung cancer (NSCLC) has evolved in recent years, benefiting from advances in immunotherapy and targeted therapy. However, limited biomarkers exist to assist clinicians and patients in selecting the most effective, personalized treatment strategies. Targeted next-generation sequencing-based genomic profiling has become routine in cancer treatment and generated crucial clinicogenomic data over the last decade. This has made the development of mutational biomarkers for drug response possible. METHODS: To investigate the association between a patient's responses to a specific somatic mutation treatment, we analyzed the NSCLC GENIE BPC cohort, which includes 2,004 tumor samples from 1,846 patients. RESULTS: We identified somatic mutation signatures associated with response to immunotherapy and chemotherapy, including carboplatin-, cisplatin-, pemetrexed- or docetaxel-based chemotherapy. The prediction power of the chemotherapy-associated signature was significantly affected by epidermal growth factor receptor (EGFR) mutation status. Therefore, we developed an EGFR wild-type-specific mutation signature for chemotherapy selection. CONCLUSION: Our treatment-specific gene signatures will assist clinicians and patients in selecting from multiple treatment options.

Brain network functional connectivity changes in long illness duration chronic schizophrenia.

Introduction: Chronic schizophrenia has a course of 5 years or more and has a widespread abnormalities in brain functional connectivity. This study aimed to find characteristic functional and structural changes in a long illness duration chronic schizophrenia (10 years or more). Methods: Thirty-six patients with a long illness duration chronic schizophrenia and 38 healthy controls were analyzed by independent component analysis of brain network functional connectivity. Correlation analysis with clinical duration was performed on six resting state networks: auditory network, default mode network, dorsal attention network, fronto-parietal network, somatomotor network, and visual network. Results: The differences in the resting state network between the two groups revealed that patients exhibited enhanced inter-network connections between default mode network and multiple brain networks, while the inter-network connections between somatomotor network, default mode network and visual network were reduced. In patients, functional connectivity of Cuneus_L was negatively correlated with illness duration. Furthermore, receiver operating characteristic curve of functional connectivity showed that changes in Thalamus_L, Rectus_L, Frontal_Mid_R, and Cerebelum_9_L may indicate a longer illness duration chronic schizophrenia. Discussion: In our study, we also confirmed that the course of disease is significantly associated with specific brain regions, and the changes in specific brain regions may indicate that chronic schizophrenia has a course of 10 years or more.

An integrative multi-context Mendelian randomization method for identifying risk genes across human tissues.

Mendelian randomization (MR) provides valuable assessments of the causal effect of exposure on outcome, yet the application of conventional MR methods for mapping risk genes encounters new challenges. One of the issues is the limited availability of expression quantitative trait loci (eQTLs) as instrumental variables (IVs), hampering the estimation of sparse causal effects. Additionally, the often context- or tissue-specific eQTL effects challenge the MR assumption of consistent IV effects across eQTL and GWAS data. To address these challenges, we propose a multi-context multivariable integrative MR framework, mintMR, for mapping expression and molecular traits as joint exposures. It models the effects of molecular exposures across multiple tissues in each gene region, while simultaneously estimating across multiple gene regions. It uses eQTLs with consistent effects across more than one tissue type as IVs, improving IV consistency. A major innovation of mintMR involves employing multi-view learning methods to collectively model latent indicators of disease relevance across multiple tissues, molecular traits, and gene regions. The multi-view learning captures the major patterns of disease relevance and uses these patterns to update the estimated tissue relevance probabilities. The proposed mintMR iterates between performing a multi-tissue MR for each gene region and joint learning the disease-relevant tissue probabilities across gene regions, improving the estimation of sparse effects across genes. We apply mintMR to evaluate the causal effects of gene expression and DNA methylation for 35 complex traits using multi-tissue QTLs as IVs. The proposed mintMR controls genome-wide inflation and offers insights into disease mechanisms.