Causal Relationship Between Autism Spectrum Disorder and Inflammatory Bowel Disease: A Bidirectional Mendelian Randomization Study.

Patients with autism spectrum disorder (ASD) are often accompanied by inflammatory bowel disease (IBD) in observational research; however, the potential causal link between the two conditions remains unknown. In this study, we used a two-sample bidirectional Mendelian randomization (MR) approach to assess the causal relationship between ASD and IBD and its main subtypes, Crohn's disease (CD), and ulcerative colitis (UC). Independent genetic instruments from a genome-wide association study (GWAS) for IBD (25,042 cases and 34,915 controls) were used to investigate the association of IBD with ASD data obtained from the PGC and the iPSYCH consortia (N = 46,351). The primary analysis employed the random effects inverse variance weighting (IVW) method. Horizontal pleiotropy was detected using the MR Egger regression and the MR-pleiotropy residual sum and outlier (MR-PRESSO) analysis while heterogeneity was detected using Cochran's Q. The IVW method indicated a positive causal relationship of IBD with ASD (odds ratio (OR) = 1.028, 95% confidence interval (CI) = 1.001-1.056, p = 0.042). In subtype analyses, CD was positively related to ASD (OR = 1.036; 95% CI = 1.004-1.069; p = 0.02); however, UC showed no relationship (OR = 1.021; 95% CI = 0.999-1.044; p = 0.065). In contrast, no evidence of a causal relationship between ASD and IBD or its subtypes (p > 0.05) was found. Our findings provided evidence in support of potential causal associations between IBD/CD and ASD.

Study of kaempferol in the treatment of rheumatoid arthritis through modulation of the NLRP3/CASP1/GSDMD axis and T-cell activation: Based on network pharmacology, single-cell analysis, and experimental validation.

BACKGROUND: Kaempferol (Kae) is a natural flavonol compound with excellent anti-inflammatory and immunomodulatory effects, which is of great importance in the treatment of inflammatory diseases. The efficacy of Kae in the treatment of rheumatoid arthritis (RA) has been demonstrated. However, its relevant pharmacodynamic mechanism requires further investigation. PURPOSES: This study aimed to further explore the potential mechanism of action of Kae in the treatment of RA using network pharmacology, single-cell analysis, and animal experiments. METHODS: Drug target genes were downloaded and screened from the Comparative Toxicogenomics Database (CTD), SwissTargetPrediction database, BindingDB database, and TargetNet database. Transcriptome data from GEO databases (GSE55235, GSE89408, and GSE200815) were selected for disease transcriptome analysis and single-cell matrix data. Network pharmacology and molecular docking were used to investigate the potential mechanism of action of Kae in treating RA. Single-cell analysis, immune infiltration co-expression analyses, and Mendelian-Randomization (MR) studies were conducted to explore the relationship between Kae's target genes and immune cells. Collagen-induced arthritis (CIA) was induced in DBA/1 mouse models through enhanced immunization. Therapeutic efficacy of Kae was assessed using arthritis score, paw swelling index, body weight monitoring, microCT, hematoxylin and eosin (HE) staining, Safranin O-Fast green staining, and Tartrate-resistant acid phosphatase (TRAP) staining. Tissue immunofluorescence and flow cytometry were used to detect expression levels of key genes and immune cell activation status. RESULTS: In vivo experiments demonstrated the efficacy of Kae in treating CIA mice. Network pharmacology indicated that Kae might exert anti-inflammatory effects through the NLRP3/CASP1/GSDMD axis. Immune infiltration, single-cell, and MR analyses revealed close associations between Kae's target genes and CD4+, CD8+, and regulatory T cells. Kae inhibited cellular pyroptosis in joint tissues and down-regulated NLRP3, CASP1, and GSDMD expression. Flow cytometry results showed decreased CD4/CD8 ratio, reduced proportion of CD4+ effector memory T cells (Tem), and increased naïve and regulatory T cells (Treg). CONCLUSION: Kae might exert anti-inflammatory effects by modulating the NLRP3/CASP1/GSDMD axis to inhibit pyroptosis and suppress overactive immune responses by regulating T-cell proliferation. In summary, Kae demonstrated significant therapeutic efficacy in treating RA.

Single-atom oxide-decorated AuNPs for universal enhancement in SERS detection of pesticide residues.

BACKGROUND: In the context of modern agriculture, the proliferation of chemical use calls for enhanced pesticide detection to safeguard food quality and public health. The development of accurate testing methodologies is imperative to mitigate the environmental impact of pesticides and ensure the integrity of ecosystems, thereby reflecting the pressing need for advancements in agricultural safety protocols. Therefore, the development of highly sensitive monitoring technology for detecting pesticide residues in agricultural products is necessary for safeguarding human health, ensuring food safety, and maintaining environmental sustainability. RESULTS: Herein, a controllable surface charge on single tungsten atom-modified gold nanoparticles was used to create an electrostatic force with positively charged pesticide residues. Moreover, hydrogen bonds formed by single-atom sites can induce analyte-adsorbed nanoparticle aggregation, and the sizes of single-tungsten-atom-decorated AuNPs can maintain a gap between each other, resulting in improved SERS detection sensitivity through analyte enrichment at gold nanoparticle hotspots. In terms of the detection limits for pesticide residue analysis, we can effectively achieve an ultrahigh sensitivity of 0.1 ppb for acetamiprid, paraquat and carbendazim, which is among the best SERS sensitivities at the state of the art. For apple sample analysis, our work demonstrated good reproductivity (RSD<6 %) and a strong linear relationship (R2 ≥ 0.97) for 4 pesticide residues after optimizing the pretreatment process, which proves the enormous potential in quantitative analysis. SIGNIFICANCE: Single-atom sites hotspot are firstly successfully achieved and uniformly dispersed between Au nanoparticle, which can effectively increase the sensitivity, keep stability of the Raman scattering signals and possess a significant improvement beyond that of undecorated hotspots when applied in pesticide residue detection. This method can be employed as a universal strategy to capture pesticide residues at hotspots for SERS detection.

Circular RNA-encoded oncogenic PIAS1 variant blocks immunogenic ferroptosis by modulating the balance between SUMOylation and phosphorylation of STAT1.

BACKGROUND: The clinical response rate to immune checkpoint blockade (ICB) therapy in melanoma remains low, despite its widespread use. Circular non-coding RNAs (circRNAs) are known to play a crucial role in cancer progression and may be a key factor limiting the effectiveness of ICB treatment. METHODS: The circRNAs that were downregulated after coadministration compared with single administration of PD-1 inhibitor administration were identified through RNA-seq and Ribo-seq, and thus the circPIAS1 (mmu_circ_0015773 in mouse, has_circ_0008378 in human) with high protein coding potential was revealed. Fluorescence in situ hybridization (FISH) assays were conducted to determine the localization of circPIAS1 in human and mouse melanoma cells, as well as its presence in tumor and adjacent tissues of patients. Validation through dual-luciferase reporter assay and LC-MS/MS confirmed the ability of circPIAS1 to encode a novel 108 amino acid polypeptide (circPIAS1-108aa). Specific antisense oligonucleotides (ASOs) targeting the junction site of circPIAS1 were developed to reduce its intracellular levels. Proliferation changes in melanoma cells were assessed using CCK8, EdU, and colony formation assays. The impact of circPIAS1-108aa on the ferroptosis process of melanoma cells was studied through GSH, MDA, and C11-BODIPY staining assays. Western Blot, Immunoprecipitation (IP), and Immunoprecipitation-Mass Spectrometry (IP-MS) techniques were employed to investigate the impact of circPIAS1-108aa on the P-STAT1/SLC7A11/GPX4 signaling pathway, as well as its influence on the balance between STAT1 SUMOylation and phosphorylation. Additionally, a melanoma subcutaneous transplanted tumor mouse model was utilized to examine the combined effect of reducing circPIAS1 levels alongside PD-1 inhibitor. RESULTS: Compared with the group treated with PD-1 inhibitor alone, circPIAS1 was significantly down-regulated in the coadministration group and demonstrated higher protein coding potential. CircPIAS1, primarily localized in the nucleus, was notably upregulated in tumor tissues compared to adjacent tissues, where it plays a crucial role in promoting cancer cell proliferation. This circRNA can encode a unique polypeptide consisting of 108 amino acids, through which it exerts its cancer-promoting function and impedes the effectiveness of ICB therapy. Mechanistically, circPIAS1-108aa hinders STAT1 phosphorylation by recruiting SUMO E3 ligase Ranbp2 to enhance STAT1 SUMOylation, thereby reactivating the transduction of the SLC7A11/GPX4 signaling pathway and restricting the immunogenic ferroptosis induced by IFNγ. Furthermore, the combination of ASO-circPIAS1 with PD-1 inhibitor effectively inhibits melanoma growth and significantly enhances the efficacy of immune drugs in vivo. CONCLUSIONS: Our study uncovers a novel mechanism regarding immune evasion in melanoma driven by a unique 108aa peptide encoded by circPIAS1 in melanoma that dramatically hinders immunogenic ferroptosis triggered by ICB therapy via modulating the balance between SUMOylation and phosphorylation of STAT1. This work reveals circPIAS1-108aa as a critical factor limiting the immunotherapeutic effects in melanoma and propose a promising strategy for improving ICB treatment outcomes.

The ideal path to a good death: An international meta-synthesis of rural residents' perspectives.

BACKGROUND: Rural areas frequently encounter restricted access to healthcare and end-of-life services. Given current pressing realities, understanding their unique perspectives on what constitutes a good death is essential. Existing research has largely overlooked the voices of rural residents. AIM: To obtain a more comprehensive understanding of rural residents' expectations regarding a good death. DESIGN: A meta-synthesis. By exploring the logic within relevant content, the stages of the life course serve as the framework for integration. DATA SOURCES: PubMed, Web of Science Core Collection, Embase, Cochrane Library, CINAHL (EBSCO), PsycINFO (EBSCO), China National Knowledge Infrastructure (CNKI), WanFang, and China Biology Medicine disc (CBM) were systematically searched from their inception to May 2023. RESULT: Of the 1100 articles retrieved, 8 studies were included. This paper outlines "the path to a rural good death": (1) When death is perceived as distant: acknowledge its inevitability while striving to achieve a successful and complete life journey. (2) As death approaches: maintain composure and have the capacity and support to face it. (3) When death truly arrives: depart in an envisioned scenario. (4) What's left behind: be properly arranged. CONCLUSION: The essential characteristics of a rural good death align with previous interpretations. However, distinct aspects emerge: communities play a significant role, characterized by reciprocal relationships; the role of medicine is less emphasized; and "rurality" deeply shapes residents' expectations of a good death. The pathway to a good death presented in this article is aspirational, requiring collaborative efforts to make it a tangible reality.

Informing or concealing - Dynamics of telling disease-related bad news among family members of older cancer patients: A qualitative study.

BACKGROUND: With the dramatic rise in the number of older cancer patients, the question of whether or not to tell older patients of bad news becomes an urgent and common challenge. However, existing studies concentrated on the three types of disclosure decisions and their reasons, including full disclosure, partial disclosure, and avoidance of disclosure, and the evolution process and factors influencing family members' disclosure decisions are unclear. OBJECTIVE: Explore the experience and factors of the shift between disclosure and concealment among family members of older cancer patients. METHODS: A qualitative study was employed. Semi-structured interviews were conducted with 33 family members at two general hospitals and one community hospital between December 2022 and June 2023. The interview data were analyzed using a content analysis approach. RESULTS: The treatment plan symbolizes the "hope of survival" and it is the fundamental factor for the shift between concealment and disclosure. There are three themes of family members in making decisions during the diagnostic and therapeutic process: (a) When bad news is approaching: Keep calm in the midst of chaos, (b) when a treatment plan is determined: Hope for survival dictates disclosure decisions, and (c) when the patient's disease deteriorated: Finding hope in hopelessness. CONCLUSIONS: Disclosure and concealment are a complex and dynamic process. The factor of the shift lies in the "hope of survival" symbolized by the treatment plan. The key to disclosure by family members is to give patients enough hope to control or cure a patient's disease, or prolong the life of patients and improve their quality of life.

Oropharyngeal microbiome profiling and its association with age and heart failure in the elderly population from the northernmost province of China.

Respiratory tract infections are the most common triggers for heart failure in elderly people. The healthy respiratory commensal microbiota can prevent invasion by infectious pathogens and decrease the risk of respiratory tract infections. However, upper respiratory tract (URT) microbiome in the elderly is not well understood. To comprehend the profiles of URT microbiota in the elderly, and the link between the microbiome and heart failure, we investigated the oropharyngeal (OP) microbiome of these populations in Heilongjiang Province, located in the North-East of China, a high-latitude and cold area with a high prevalence of respiratory tract infection and heart failure. Taxonomy-based analysis showed that six dominant phyla were represented in the OP microbial profiles. Compared with young adults, the OP in the elderly exhibited a significantly different microbial community, mainly characterized by highly prevalent Streptococcus, unidentified_Saccharibacteria, Veillonella, unidentified_Pre votellaceae, and Neisseria. While unidentified_Prevotellaceae dominated in the young OP microbiome. There was competition for niche dominance between Streptococcus and member of Prevotellaceae in the OP. Correlation analysis revealed that the abundance of unidentified_Saccharibacteria was positive, while Streptococcus was negatively correlated to age among healthy elderly. The bacterial structure and abundance in the elderly with heart failure were much like healthy controls. Certain changes in microbial diversity indicated the potential OP microbial disorder in heart failure patients. These results presented here identify the respiratory tract core microbiota in high latitude and cold regions, and reveal the robustness of OP microbiome in the aged, supplying the basis for microbiome-targeted interventions.IMPORTANCETo date, we still lack available data on the oropharyngeal (OP) microbial communities in healthy populations, especially the elderly, in high latitude and cold regions. A better understanding of the significantly changed respiratory tract microbiota in aging can provide greater insight into characteristics of longevity and age-related diseases. In addition, determining the relationship between heart failure and OP microbiome may provide novel prevention and therapeutic strategies. Here, we compared OP microbiome in different age groups and elderly people with or without heart failure in northeastern China. We found that OP microbial communities are strongly linked to healthy aging. And the disease status of heart failure was not a powerful factor affecting OP microbiome. The findings may provide basic data to reveal respiratory bacterial signatures of individuals in a cold geographic region.

Virtual-screening of xanthine oxidase inhibitory peptides: Inhibition mechanisms and prediction of activity using machine-learning.

Xanthine oxidase (XO) inhibitory peptides can prevent XO-mediated hyperuricemia. Currently, QSAR about XO inhibitory peptides with different lengths remains to be enriched. Here, XO inhibitory peptides were obtained from porcine visceral proteins through virtual-screening. A prediction model was established by machine-learning. Virtual-screening retained four lengths of peptides, including 3-6. Molecular-docking recognized their binding sites with XO and showed residues W, F, and G were the key amino acids. Datasets of XO inhibitory peptides therewith were established. The optimal model was used to generalize the peptides reported. Results showed that the R2 of the tripeptide, tetrapeptide, pentapeptide and hexapeptide in the generalisation test were R2 = 0.81, R2 = 0.82, R2 = 0.83 and R2 = 0.83, respectively. Overall, this work can serve as a reference for explaining the activity mechanism of XO inhibitory peptides and predicting the activity of XO inhibitory peptides.

The dual role of cellular senescence in human tumor progression and therapy.

Cellular senescence, one of the hallmarks of cancer, is characterized by cell cycle arrest and the loss of most normal cellular functions while acquiring a hypersecretory, proinflammatory phenotype. The function of senescent cells in cancer cells varies depending on the cellular conditions. Before the occurrence of cancer, senescent cells act as a barrier to prevent its development. But once cancer has occurred, senescent cells play a procancer role. However, few of the current studies have adequately explained the diversity of cellular senescence across cancers. Herein, we concluded the latest intrinsic mechanisms of cellular senescence in detail and emphasized the senescence-associated secretory phenotype as a key contributor to heterogeneity of senescent cells in tumor. We also discussed five kinds of inducers of cellular senescence and the advancement of senolytics in cancer, which are drugs that tend to clear senescent cells. Finally, we summarized the various effects of senescent cells in different cancers and manifested that their functions may be diametrically opposed under different circumstances. In short, this paper contributes to the understanding of the diversity of cellular senescence in cancers and provides novel insight for tumor therapy.

[Treatment of thoracolumbar tuberculosis with robot-assisted and minimally invasive access via transforaminal expansion approach].

Objective: To investigate the feasibility and effectiveness of robot-assisted posterior minimally invasive access in treatment of thoracolumbar tuberculosis via transforaminal expansion approach. Methods: A clinical data of 40 patients with thoracolumbar tuberculosis admitted between January 2017 and May 2022 and met the selection criteria was retrospectively analyzed. Among them, 15 cases were treated with robot-assisted and minimally invasive access via transforaminal expansion approach for lesion removal, bone graft, and internal fixation (robotic group), and 25 cases were treated with traditional transforaminal posterior approach for lesion removal and intervertebral bone grafting (traditional group). There was no significant difference in the baseline data between the two groups ( P>0.05) in terms of gender, age, lesion segment, and preoperative American Spinal Injury Association (ASIA) grading, Cobb angle, visual analogue scale (VAS) score, erythrocyte sedimentation rate (ESR), and C reactive protein (CRP). The outcome indicators were recorded and compared between the two groups, including operation time, intraoperative bleeding volume, hospital stay, postoperative bedtime, complications, ESR and CRP before operation and at 1 week after operation, the level of serum albumin at 3 days after operation, VAS score and ASIA grading of neurological function before operation and at 6 months after operation, the implant fusion, fusion time, Cobb angle of the lesion, and the loss of Cobb angle observed by X-ray films and CT. The differences of ESR, CRP, and VAS score (change values) between pre- and post-operation were calculated and compared. Results: Compared with the traditional group, the operation time and intraoperative bleeding volume in the robotic group were significantly lower and the serum albumin level at 3 days after operation was significantly higher ( P<0.05); the postoperative bedtime and the length of hospital stay were also shorter, but the difference was not significant ( P>0.05). There were 2 cases of poor incision healing in the traditional group, but no complication occurred in the robotic group, and the difference in the incidence of complication between the two groups was not significant ( P>0.05). There were significant differences in the change values of ESR and CRP between the two groups ( P<0.05). All Patients were followed up, and the follow-up time was 12-18 months (mean, 13.0 months) in the traditional group and 12-16 months (mean, 13.0 months) in the robotic group. Imaging review showed that all bone grafts fused, and the difference in fusion time between the two groups was not significant ( P>0.05). The difference in Cobb angle between the pre- and post-operation in the two groups was significant ( P<0.05); and the Cobb angle loss was significant more in the traditional group than in the robotic group ( P<0.05). The VAS scores of the two groups significantly decreased at 6 months after operation when compared with those before operation ( P<0.05); the difference in the change values of VAS scores between the two groups was not significant ( P>0.05). There was no occurrence or aggravation of spinal cord neurological impairment in the two groups after operation. There was a significant difference in ASIA grading between the two groups at 6 months after operation compared to that before operation ( P<0.05), while there was no significant difference between the two groups ( P>0.05). Conclusion: Compared with traditional posterior open operation, the use of robot-assisted minimally invasive access via transforaminal approach for lesion removal and bone grafting internal fixation in the treatment of thoracolumbar tuberculosis can reduce the operation time and intraoperative bleeding, minimizes surgical trauma, and obtain definite effectiveness.

Recurrence in Eyelid Sebaceous Carcinoma: A Multicentric Study of 418 Patients.

Purpose: Local recurrence predicts dismal prognosis in eyelid sebaceous carcinoma (SC). Recurrence predictors vary across studies. Accurate recurrence estimation is essential for individualized therapy in eyelid SC. This study aims to identify recurrence predictors and develop a nomogram for personalized prediction in eyelid SC. Methods: We conducted a multicenter retrospective cohort study. Chart reviews were performed in 418 consecutive patients with eyelid SC. All patients were followed up after their initial surgery. Multivariate Cox regression was used to explore the independent predictors of recurrence. A nomogram for recurrence prediction was developed and validated with bootstrap resampling. The predictive accuracy and discriminative ability were compared with the Tumor, Node, Metastasis (TNM) staging system. Results: Over a median of 60-month follow-up, 167 patients (40%) had local recurrence. The median time from diagnosis to recurrence was 14 months. The 1-year cumulative recurrence rate was 18%. Diagnostic delay (hazard ratio [HR] = 1.01, 95% confidence interval [CI] = 1.00-1.01, P = 0.001), orbital involvement (HR = 4.47, 95% CI = 3.04-6.58, P < 0.001), Ki67 (HR = 1.01, 95% CI = 1.00-1.02, P = 0.008) and initial surgery of Mohs micrographic surgery with intraoperative frozen section control (HR = 0.53, 95% CI = 0.35-0.80, P = 0.003) were independent influencing factors of recurrence. A nomogram integrating these four factors combined with pagetoid spread displayed satisfactory discriminative ability (C-index = 0.80-0.83; area under the curve [AUC] = 0.82-0.84), which compared favorably than TNM staging (all P < 0.05). Conclusions: The recurrence rate is high in eyelid SC. Early detection and primary resection with Mohs micrographic surgery are recommended in controlling recurrence. Patients with orbital involvement, high Ki67 expression, and pagetoid spread may require adjuvant measures. This nomogram offers more accurate recurrence estimates, aiding in therapeutic decision making.

Research advances on signaling pathways regulating the polarization of tumor-associated macrophages in lung cancer microenvironment.

Lung cancer (LC) is one of the most common cancer worldwide. Tumor-associated macrophages (TAMs) are important component of the tumor microenvironment (TME) and are closely related to the stages of tumor occurrence, development, and metastasis. Macrophages are plastic and can differentiate into different phenotypes and functions under the influence of different signaling pathways in TME. The classically activated (M1-like) and alternatively activated (M2-like) represent the two polarization states of macrophages. M1 macrophages exhibit anti-tumor functions, while M2 macrophages are considered to support tumor cell survival and metastasis. Macrophage polarization involves complex signaling pathways, and blocking or regulating these signaling pathways to enhance macrophages' anti-tumor effects has become a research hotspot in recent years. At the same time, there have been new discoveries regarding the modulation of TAMs towards an anti-tumor phenotype by synthetic and natural drug components. Nanotechnology can better achieve combination therapy and targeted delivery of drugs, maximizing the efficacy of the drugs while minimizing side effects. Up to now, nanomedicines targeting the delivery of various active substances for reprogramming TAMs have made significant progress. In this review, we primarily provided a comprehensive overview of the signaling crosstalk between TAMs and various cells in the LC microenvironment. Additionally, the latest advancements in novel drugs and nano-based drug delivery systems (NDDSs) that target macrophages were also reviewed. Finally, we discussed the prospects of macrophages as therapeutic targets and the barriers to clinical translation.

Higher Vitamin E Intake Reduces Risk of All-Cause Mortality and Chronic Lower Respiratory Disease Mortality in Chronic Obstructive Pulmonary Disease: NHANES (2008-2018).

Background: In human health, vitamins play a vital role in various metabolic and regulatory processes and in the proper functioning of cells. Currently, the effect of Vitamin E (VE) intake on multiple causes of death in Chronic obstructive pulmonary disease (COPD) patients is unclear. Therefore, this paper aims to investigate the relationship between VE and multiple causes of death in COPD patients, to guide the rationalization of dietary structure and reduce the risk of COPD death. Methods: This study screened patients with COPD aged ≥40 years from the National Health and Nutrition Examination Survey (NHANES) database 2008-2018. Weighted COX regression was used to analyze the association between VE intake and multiple causes of death in COPD. The restricted cubic spline(RCS) is drawn to show their relationship. Finally, we conducted a subgroup analysis for further verification. Results: A total of 1261 participants were included in this study. After adjustment for multiple covariates, VE intake was associated with all-cause death in COPD patients, and chronic lower respiratory disease (CLRD) deaths were linearly associated with cardiovascular disease (CVD) deaths there was no such correlation. Subgroup analyses showed no interaction between subgroups, further validating the robustness of the relationship. Conclusion: In COPD patients, VE intake was negatively associated with all-cause mortality and CLRD death. Higher VE intake reduces the risk of all-cause mortality and CLRD death in COPD patients.

Overcoming Cancer Persister Cells by Stabilizing the ATF4 Promoter G-quadruplex.

Persister cells (PS) selected for anticancer therapy have been recognized as a significant contributor to the development of treatment-resistant malignancies. It is found that imposing glutamine restriction induces the generation of PS, which paradoxically bestows heightened resistance to glutamine restriction treatment by activating the integrated stress response and initiating the general control nonderepressible 2-activating transcription factor 4-alanine, serine, cysteine-preferring transporter 2 (GCN2-ATF4-ASCT2) axis. Central to this phenomenon is the stress-induced ATF4 translational reprogramming. Unfortunately, directly targeting ATF4 protein has proven to be a formidable challenge because of its flat surface. Nonetheless, a G-quadruplex structure located within the promoter region of ATF4 (ATF4-G4) is uncovered and resolved, which functions as a transcriptional regulator and can be targeted by small molecules. The investigation identifies the natural compound coptisine (COP) as a potent binder that interacts with and stabilizes ATF4-G4. For the first time, the high-resolution structure of the COP-ATF4-G4 complex is determined. The formation of this stable complex disrupts the interaction between transcription factor AP-2 alpha (TFAP2A) and ATF4-G4, resulting in a substantial reduction in intracellular ATF4 levels and the eventual death of cancer cells. These seminal findings underscore the potential of targeting the ATF4-G4 structure to yield significant therapeutic advantages within the realm of persister cancer cells induced by glutamine-restricted therapy.

Construction of IRAK4 inhibitor activity prediction model based on machine learning.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a crucial serine/threonine protein kinase that belongs to the IRAK family and plays a pivotal role in Toll-like receptor (TLR) and Interleukin-1 receptor (IL-1R) signaling pathways. Due to IRAK4's significant role in immunity, inflammation, and malignancies, it has become an intriguing target for discovering and developing potent small-molecule inhibitors. Consequently, there is a pressing need for rapid and accurate prediction of IRAK4 inhibitor activity. Leveraging a comprehensive dataset encompassing activity data for 1628 IRAK4 inhibitors, we constructed a prediction model using the LightGBM algorithm and molecular fingerprints. This model achieved an R2 of 0.829, an MAE of 0.317, and an RMSE of 0.460 in independent testing. To further validate the model's generalization ability, we tested it on 90 IRAK4 inhibitors collected in 2023. Subsequently, we applied the model to predict the activity of 13,268 compounds with docking scores less than - 9.503 kcal/mol. These compounds were initially screened from a pool of 1.6 million molecules in the chemdiv database through high-throughput molecular docking. Among these, 259 compounds with predicted pIC50 values greater than or equal to 8.00 were identified. We then performed ADMET predictions on these selected compounds. Finally, through a rigorous screening process, we identified 34 compounds that adhere to the four complementary drug-likeness rules, making them promising candidates for further investigation. Additionally, molecular dynamics simulations confirmed the stable binding of the screened compounds to the IRAK4 protein. Overall, this work presents a machine learning model for accurate prediction of IRAK4 inhibitor activity and offers new insights for subsequent structure-guided design of novel IRAK4 inhibitors.

Multiplex cerebrospinal fluid proteomics identifies biomarkers for diagnosis and prediction of Alzheimer's disease.

Recent expansion of proteomic coverage opens unparalleled avenues to unveil new biomarkers of Alzheimer's disease (AD). Among 6,361 cerebrospinal fluid (CSF) proteins analysed from the ADNI database, YWHAG performed best in diagnosing both biologically (AUC = 0.969) and clinically (AUC = 0.857) defined AD. Four- (YWHAG, SMOC1, PIGR and TMOD2) and five- (ACHE, YWHAG, PCSK1, MMP10 and IRF1) protein panels greatly improved the accuracy to 0.987 and 0.975, respectively. Their superior performance was validated in an independent external cohort and in discriminating autopsy-confirmed AD versus non-AD, rivalling even canonical CSF ATN biomarkers. Moreover, they effectively predicted the clinical progression to AD dementia and were strongly associated with AD core biomarkers and cognitive decline. Synaptic, neurogenic and infectious pathways were enriched in distinct AD stages. Mendelian randomization did not support the significant genetic link between CSF proteins and AD. Our findings revealed promising high-performance biomarkers for AD diagnosis and prediction, with implications for clinical trials targeting different pathomechanisms.

Senescent endothelial cells promote liver metastasis of uveal melanoma in single-cell resolution.

BACKGROUND: Uveal melanoma (UM), the most common adult intraocular tumor, is characterized by high malignancy and poor prognosis in advanced stages. Angiogenesis is critical for UM development, however, not only the role of vascular endothelial dysfunction in UM remains unknown, but also their analysis at the single-cell level has been lacking. A comprehensive analysis is essential to clarify the role of the endothelium in the development of UM. METHODS: By using single-cell RNA transcriptomics data of 11 cases of primary and liver metastasis UM, we analyzed the endothelial cell status. In addition, we analyzed and validated ECs in the in vitro model and collected clinical specimens. Subsequently, we explored the impact of endothelial dysfunction on UM cell migration and explored the mechanisms responsible for the endothelial cell abnormalities and the reasons for their peripheral effects. RESULTS: UM metastasis has a significantly higher percentage of vascular endothelial cells compared to in situ tumors, and endothelial cells in metastasis show significant senescence. Senescent endothelial cells in metastatic tumors showed significant Krüppel-like factor 4 (KLF4) upregulation, overexpression of KLF4 in normal endothelial cells induced senescence, and knockdown of KLF4 in senescent endothelium inhibited senescence, suggesting that KLF4 is a driver gene for endothelial senescence. KLF4-induced endothelial senescence drove tumor cell migration through a senescence-associated secretory phenotype (SASP), of which the most important component of the effector was CXCL12 (C-X-C motif chemokine ligand 12), and participated in the composition of the immunosuppressive microenvironment. CONCLUSION: This study provides an undesirable insight of senescent endothelial cells in promoting UM metastasis.

Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults.

The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing of 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG which is associated with atopic dermatitis and asthma, showed converging evidence from both rare and common variants. 91 genes exerted significant effects on longitudinal outcomes (interquartile range of Hazard Ratio: 1.12-5.89). Mendelian randomization identified five causal genes, of which four were approved drug targets (CDSN, DDR1, LTA, and IL18BP). Proteomic analysis indicated that mutations associated with specific IMDs might also affect protein expression in other IMDs. For example, DXO (celiac disease-related gene) and PSMB9 (alopecia areata-related gene) could modulate CDSN (autoimmune hypothyroidism-, psoriasis-, asthma-, and Graves' disease-related gene) expression. Identified genes predominantly impact immune and biochemical processes, and can be clustered into pathways of immune-related, urate metabolism, and antigen processing. Our findings identified protein-coding variants which are the key to IMDs pathogenesis and provided new insights into tailored innovative therapies.

Genome-wide meta-analysis identifies ancestry-specific loci for Alzheimer's disease.

INTRODUCTION: Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. METHODS: We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. RESULTS: In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. DISCUSSION: The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. HIGHLIGHTS: Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.

Exome sequencing identifies novel genetic variants associated with varicose veins.

BACKGROUND: Varicose veins (VV) are one of the common human diseases, but the role of genetics in its development is not fully understood. METHODS: We conducted an exome-wide association study of VV using whole-exome sequencing data from the UK Biobank, and focused on common and rare variants using single-variant association analysis and gene-level collapsing analysis. FINDINGS: A total of 13,823,269 autosomal genetic variants were obtained after quality control. We identified 36 VV-related independent common variants mapping to 34 genes by single-variant analysis and three rare variant genes (PIEZO1, ECE1, FBLN7) by collapsing analysis, and most associations between genes and VV were replicated in FinnGen. PIEZO1 was the closest gene associated with VV (P = 5.05 × 10-31), and it was found to reach exome-wide significance in both single-variant and collapsing analyses. Two novel rare variant genes (ECE1 and METTL21A) associated with VV were identified, of which METTL21A was associated only with females. The pleiotropic effects of VV-related genes suggested that body size, inflammation, and pulmonary function are strongly associated with the development of VV. CONCLUSIONS: Our findings highlight the importance of causal genes for VV and provide new directions for treatment.