Causal association between mental disorders and cerebrovascular diseases: Evidence from Mendelian randomization study.

BACKGROUND AND OBJECTIVE: Observational studies have suggested that mental disorders and cerebrovascular diseases (CVDs) may be risk factors for each other, but genetic evidence of a causal relationship is still lacking. We used Mendelian randomization (MR) studies to explore the causal relationship between mental disorders and CVDs from the genetic perspective. METHODS: To investigate the causal association between major depressive disorder (MDD), anxiety, attention deficit/hyperactivity disorder (ADHD), bipolar disorder and schizophrenia five kinds of mental disorders and CVDs using two-sample two-way MR analysis based on publicly available genome-wide association study (GWAS) data. We used as instrumental variables (IVs) single-nucleotide polymorphisms (SNPs) that were strongly associated with mental disorders and CVDs. IVW method was used as the main analysis method, and MR-IVW, MR-Egger methods, MR-PRESSO test, leave-one-out analysis and funnel plot were used for sensitivity analysis. We further conducted a meta-analysis to summarize the currently available MR analyses. RESULTS: The results of forward MR study showed that there was a significant causal relationship between ADHD and AS (any stroke) (p(AS) = 0.001, OR (95%CI) =1.118 (1.047-1.195)), any ischemic stroke (AIS) (p(AIS) = 0.004, OR (95%CI) =1.118(1.035-1.206)) and large artery stroke (LAS) (p(LAS) = 0.026, OR (95%CI): 1.206(1.023-1.422)). No heterogeneity, pleiotropy and outliers were found in sensitivity analysis. The reverse MR study showed that IA (intracranial aneurysm) (p(IA) = 0.033, OR (95%CI) = 1.123(1.009-1.249)) and UIA (unruptured intracranial aneurysm) (p(UIA) = 0.015, OR (95%CI) =1.040(1.008-1.074)) were risk factors for schizophrenia. Sensitivity analysis showed no pleiotropy, but there was heterogeneity. After excluding outliers, MR analysis showed that IA and UIA were still risk factors for schizophrenia. Our meta-analyses found statistical significance in causal relationships between ADHD and LAS (OR (95%CI) =1.18 (1.06-1.32), p = 0.003), IA and schizophrenia (OR (95%CI) =1.05 (1.02-1.08), p = 0.002) and UIA and schizophrenia (OR (95%CI) =1.03 (1.01-1.06), p = 0.010). CONCLUSION: The MR study and meta-analysis suggest that genetically predicted ADHD is a risk factor for LAS, and IA and UIA increase the risk of schizophrenia. The result has implications for the development of feasible prevention strategies in the future.

Spatiotemporal hologram.

Spatiotemporal structured light has opened up new avenues for optics and photonics. Current spatiotemporal manipulation of light mostly relies on phase-only devices such as liquid crystal spatial light modulators to generate spatiotemporal optical fields with unique photonic properties. However, simultaneous manipulation of both amplitude and phase of the complex field for the spatiotemporal light is still lacking, limiting the diversity and richness of achievable photonic properties. In this work, a simple and versatile spatiotemporal holographic method that can arbitrarily sculpt the spatiotemporal light is presented. The capabilities of this simple yet powerful method are demonstrated through the generation of fundamental and higher-order spatiotemporal Bessel wavepackets, spatiotemporal crystal-like and quasi-crystal-like structures, and spatiotemporal flat-top wavepackets. Fully customizable spatiotemporal wavepackets will find broader application in investigating the dynamics of spatiotemporal fields and interactions between ultrafast spatiotemporal pulses and matters, unveiling previously hidden light-matter interactions and unlocking breakthroughs in photonics and beyond.

Developing a Machine-Learning Prediction Model for Infliximab Response in Crohn's Disease: Integrating Clinical Characteristics and Longitudinal Laboratory Trends.

BACKGROUND: Achieving long-term clinical remission in Crohn's disease (CD) with antitumor necrosis factor α (anti-TNF-α) agents remains challenging. AIMS: This study aims to establish a prediction model based on patients' clinical characteristics using a machine-learning approach to predict the long-term efficacy of infliximab (IFX). METHODS: Three cohorts comprising 746 patients with CD were included from 3 inflammatory bowel disease (IBD) centers between June 2013 and January 2022. Clinical records were collected from baseline, 14-, 30-, and 52-week post-IFX treatment. Three machine-learning approaches were employed to develop predictive models based on 23 baseline predictors. The SHapley Additive exPlanations (SHAP) algorithm was used to dissect underlying predictors, and latent class mixed model (LCMM) was applied for trajectory analysis of the longitudinal change of blood routine tests along with long-term IFX therapy. RESULTS: The XGBoost model exhibited the best discrimination between long-term responders and nonresponders. In the internal training and testing set, the model achieved an AUC of 0.91 (95% CI, 0.86-0.95) and 0.71 (95% CI, 0.66-0.87), respectively. Moreover, it achieved a moderate predictive performance in the independent external cohort, with an AUC of 0.68 (95% CI, 0.59-0.77). The SHAP algorithm revealed disease-relevant laboratory measurements, notably hemoglobin (HB), white blood cells (WBC), erythrocyte sedimentation rate (ESR), albumin (ALB), and platelets (PLT), alongside age at diagnosis and the Montreal classification, as the most influential predictors. Furthermore, 2 distinct patient clusters based on dynamic laboratory tests were identified for monitoring the long-term remission. CONCLUSIONS: The established prediction model demonstrated remarkable discriminatory power in distinguishing long-term responders from nonresponders to IFX therapy. The identification of distinct patient clusters further emphasizes the need for tailored therapeutic approaches in CD management.

The study developed a machine-learning model using clinical data to predict long-term efficacy of IFX in Crohn's disease. The XGBoost model demonstrated strong discriminatory power, revealing influential predictors and distinct patient clusters, emphasizing the importance of tailored therapeutic approaches in CD management.

Platinum-Metformin Conjugates Acting as Promising PD-L1 Inhibitors through the AMP-Activated Protein Kinase Mediated Lysosomal Degradation Pathway.

With the development of metalloimmunology, the potential of platinum drugs in cancer immunotherapy has attracted extensive attention. Although immunochemotherapy combining PD-1/PD-L1 antibodies with platinum drugs has achieved great success in the clinic, combination therapy commonly brings new problems. Herein, we have developed a platinum-metformin conjugate as a promising alternative to antibody-based PD-L1 inhibitors, not only disrupting PD-1/PD-L1 axis on cell surface but also down-regulating the total PD-L1 levels in non-small cell lung cancer (NSCLC) cells comprehensively, thus achieving highly efficient immunochemotherapy by a single small molecule. Mechanism studies demonstrate that Pt-metformin conjugate can selectively accumulate in lysosomes, promote lysosomal-dependent PD-L1 degradation via the AMPK-TFEB pathway, and modulate the upstream regulatory proteins related to PD-L1 expression (e.g. HIF-1α and NF-κB), eventually decreasing the total abundance of PD-L1 in NSCLC, overcoming tumor hypoxia, and activating anti-tumor immunity in vivo. This work suggests an AMPK-mediated lysosomal degradation pathway of PD-L1 for the first time and provides a unique design perspective for the development of novel platinum drugs for immunochemotherapy.

Identification of A Novel Activated NK-Associated Gene Score Associated with Diagnosis and Biological Therapy Response in Ulcerative Colitis.

INTRODUCTION: Natural killer (NK) cells are associated with the pathogenesis of ulcerative colitis (UC); however, their precise contributions remain unclear. The present study aimed to investigate the diagnostic value of the activated NK-associated gene (ANAG) score in UC and evaluate its predictive value in response to biological therapy. METHODS: Bulk RNA-seq and scRNA-seq datasets were obtained from the Gene Expression Omnibus (GEO) and Single Cell Portal (SCP) databases. In the bulk RNA-seq, differentially expressed genes (DEGs) were screened by the "Batch correction" and "Robust rank aggregation" (RRA) methods. The immune infiltration landscape was estimated using single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT. DEGs that correlated with activated NK cells were identified as activated NK-associated genes (ANAGs). Protein-protein interaction (PPI) analysis and least absolute shrinkage and selection operator (LASSO) regression were used to screen key ANAGs and establish an ANAG score. The expression levels of the four key ANAGs were validated in human samples by real-time quantitative polymerase chain reaction (RT-qPCR) and immunofluorescence. The potential therapeutic drugs for UC were identified using the DSigDB database. Through scRNA-seq data analysis, the cell scores based on the ANAGs were calculated by "AddModuleScore" and "AUCell". RESULTS: Immune infiltration analysis revealed a higher abundance of activated NK cells in non-inflamed UC tissues (ssGSEA, P<0.001; CIBERSORT, P<0.01). Fifty-four DEGs correlated with activated NK cells were identified as ANAGs. The ANAG score was established using four key ANAGs (SELP, TIMP1, MMP7, and ABCG2). The ANAG scores were significantly higher in inflamed tissues (P<0.001) and in biological therapy non-responders (NR) tissues before treatment (golimumab, P<0.05; ustekinumab, P<0.001). The ANAG score demonstrated an excellent diagnostic value (AUC = 0.979). Patients with higher ANAG scores before treatment were more likely to experience a lack of response to golimumab or ustekinumab (golimumab, P<0.05; ustekinumab, P<0.001). CONCLUSION: This study established a novel ANAG score with the ability to precisely diagnose UC and distinguish the efficacy of biological treatment.

The contribution of dietary advanced glycation end-products and genetic risk in the development of inflammatory bowel disease: a prospective cohort study.

BACKGROUND: Dietary advanced glycation end products (AGEs) may promote oxidative stress and inflammation in the gastrointestinal tract. AIMS: The aim of this study is to investigate the association between dietary AGE intake and the risk of inflammatory bowel disease (IBD). METHODS: We included 121,978 participants without IBD at baseline from the UK Biobank. We estimated consumption of three common AGEs (Nε-(carboxymethyl)-lysine (CML), Nε-(1-carboxyethyl)-lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1)) by matching 24-h dietary questionnaires to a validated dietary AGE database. We used Cox proportional hazards regression models to calculate the hazard ratio (HR) and 95% CI of the association between dietary AGEs and IBD risk. RESULTS: During a median follow-up of 13.72 years, 671 participants developed IBD (192 with Crohn's disease (CD) and 478 with ulcerative colitis (UC)). Among the assessed dietary AGEs, only CEL was associated with an increased risk of IBD (HR = 1.09, 95% CI: 1.01-1.18, p = 0.020) and CD (HR = 1.18, 95% CI: 1.03-1.36, p = 0.014), particularly for participants who were overweight, physically inactive, and non-smokers. Among participants at a high genetic risk of CD, HRs (95% CI) of CD were 1.26 (1.00-1.57) for CML, 1.41 (1.12-1.77) for CEL, and 1.28 (1.01-1.62) for MG-H1 (p < 0.05 for each). However, none of the dietary AGEs was significantly associated with UC risk, irrespective of genetic predisposition. CONCLUSIONS: Dietary CEL was associated with an increased risk of IBD and CD, but not UC. Further interventional studies are required to support the potential benefit of AGE restriction, especially for individuals at a high genetic risk of CD.

Dosimetric Study and Robustness Analysis of Base Note Intensive Locked Field Radiotherapy for Left Breast Cancer.

Background: The locked vision plan can make the left breast cancer heart and lung organs dose. Objective: The aim of the present study was to compare the dosimetric differences between field-locked and field-split plans in intensity-modulated radiotherapy for left-sided breast cancer, to explore the effect of field-locking on the low-dose region, and to evaluate its robustness to the radiotherapy target, in order to provide a reference for the selection of clinical radiotherapy protocols. Methods: A total of 30 patients were selected after radical left breast cancer surgery, and 7-field locked-field and split-field plans were developed to compare the dose difference (∆D) between the target area and each organ at risk, and to introduce offsets of 3, 5 and 7 mm in six directions and recalculate the perturbed dose distributions, and to compare the ∆D between the original and the perturbed plans according to the robustness of the plans. Results: The results revealed that the D98%, D95% and Dmean values of the planning target volume (PTV) of the two plans differed little and were not statistically different. The locked field plan provided better protection for the left lung, right lung, heart, right breast and left anterior descending coronary artery. For PTV∆D98%, PTV∆D95%, PTV∆Dmean, the ∆D was higher for the Locked Fields plan, and for LungL∆5, LungL∆20 and Heart∆mean, the ∆D was higher for the original plan. Discussion: It was concluded that the field-locking plan could reduce the low-dose area of the affected lung and provide improved protection to the remaining critical organs, and the field-locking plan was more robust in protecting critical organs. Meanwhile, the field-locking plan showed higher sensitivity to positional deviation for target PTV.

Laparoscopic anatomical right hepatectomy using a four-incision anterior approach: Technical details and surgical outcomes (with Video).

With the continuous advancements of laparoscopic techniques, many surgeons have enhanced the feasibility and safety of this approach for carefully selected patients. This study aims to offer a comprehensive account of the technical aspects and surgical outcomes associated with laparoscopic anatomical right hepatectomy, explicitly utilizing a four-incision anterior approach. The surgical procedure involved several maneuvers, including blocking the Glissonean pedicle, ligation of the right hepatic artery, right branch of the portal vein, and the right hepatic duct, removal of the liver parenchyma along the ischemic line, and determination of the liver section based on four anatomical landmarks: the right anterior Glissonian pedicle, middle hepatic vein, root of the right hepatic vein, and retrohepatic inferior vena cava. The article provides clear visualization of these anatomical landmarks following right hepatectomy. Proper patient positioning and precise incision placement are crucial factors for ensuring the success of the laparoscopic right anterior hepatectomy procedure. The separation of the extrahepatic Glissonean pedicle at the liver hilum to determine the hepatic resection ischemia line, as well as the identification of liver sections using four anatomical landmarks are essential steps in the liver resection process. The laparoscopic anatomical right hepatectomy using a four-incision anterior approach was performed smoothly, with standard intraoperative techniques completed. Measures are in place to address any complications that may arise during the surgery.

Efficacy of intravenous acetaminophen on postoperative shivering: A meta-analysis of randomized controlled trials.

PURPOSE: Postoperative shivering (POS) is a common and vital complication after anesthesia, which may result in serious consequences and uncomfortable experiences. Acetaminophen has been used to treat fever and mild to moderate pain. However, there is not enough evidence to prove its advantage for POS. This meta-analysis aimed to explore the prophylactic use of acetaminophen as a valid agent for POS. METHODS: Two researchers independently searched PubMed, the Cochrane Library, and Embase for controlled clinical trials. The meta-analysis of randomized controlled trials (RCTs) was performed by Review Manager. RESULTS: Nine trials with 856 patients were included in our meta-analysis. Acetaminophen significantly reduced POS compared with placebo (pooled risk ratio [RR]: 0.43, 95% confidence interval [CI]: 0.35-0.52). What is more, not only 15 mg/kg but also 1000 mg intravenous acetaminophen could reduce the incidence of shivering compared with placebo. CONCLUSION: Our present meta-analysis demonstrates that the intravenous prophylactic infusion of acetaminophen may prevent POS, and the results may provide new evidence to expand the clinical value of acetaminophen in addition to its routine usage.

Differences of clinical phenotype between familial and sporadic Crohn's disease in East China.

PURPOSE: Family history is one of the strongest risk factors for inflammatory bowel diseases (IBD) while studies about the clinical phenotype of familial IBD are limited. This study aimed to compare the phenotypic features of familial Crohn's disease (CD) with sporadic CD. METHODS: Familial CD was defined as CD patients having one or more first, second, third, fourth degree, or above relatives with CD. Sporadic CD patients hospitalized during the same period were matched 1:3 by age and gender. Differences in clinical characteristics, phenotype distribution, extraintestinal manifestations, and complications at diagnosis, as well as treatment regimen and surgery, were compared between familial and sporadic CD. RESULTS: The familial CD was associated with a higher rate of past appendectomy history (P = 0.009), more intestinal perforation at onset (P = 0.012), more MRI results of anal lesion (P = 0.023), and gastrointestinal perforation (P = 0.040) at diagnosis, higher rate of past intestinal surgery history (P = 0.007), more number of intestinal surgeries (P = 0.037), longer duration of follow-up (P = 0.017), lower rate of taking biologicals for current maintenance (P = 0.043), lower tendency to upgrade to biologicals during follow-up (P = 0.013), higher possibility to experience gastrointestinal obstruction (P = 0.047), and abdominal abscess during follow-up (P = 0.045). CONCLUSION: Familial CD is associated with a more aggressive clinical phenotype.

Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn's Disease.

BACKGROUND: The efficacy and safety of risankizumab as compared with ustekinumab in patients with Crohn's disease are unknown. METHODS: In this phase 3b, multicenter, open-label, randomized, controlled trial with blinded assessment of end points, patients with moderate-to-severe Crohn's disease who had had an inadequate response to anti-tumor necrosis factor (TNF) therapy or unacceptable side effects with such therapy were randomly assigned to receive risankizumab or ustekinumab at standard doses for 48 weeks. The two primary end points, which were tested sequentially, were clinical remission at week 24 (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]), which was analyzed in the first 50% of patients to complete the week 24 visit, with a noninferiority margin of 10 percentage points; and endoscopic remission at week 48 (defined as a score of ≤4, a decrease of ≥2 points from baseline, and no subscore >1 in any individual variable on the Simple Endoscopic Score for Crohn's Disease [range, 0 to 56, with higher scores indicating more severe disease]), which was analyzed for superiority in 100% of the patients. Safety was assessed in all patients who received at least one dose of risankizumab or ustekinumab. RESULTS: In the full intention-to-treat population for the efficacy analysis, 230 of 255 patients (90.2%) who received risankizumab and 193 of 265 patients (72.8%) who received ustekinumab completed all the assigned treatments. Both primary end points were met; risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 (58.6% vs. 39.5%; adjusted difference, 18.4 percentage points; 95% confidence interval [CI], 6.6 to 30.3) and superior to ustekinumab with respect to endoscopic remission at week 48 (31.8% vs. 16.2%; adjusted difference, 15.6 percentage points; 95% CI, 8.4 to 22.9; P<0.001). The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: In this head-to-head clinical trial of risankizumab and ustekinumab involving patients with moderate-to-severe Crohn's disease who had had unacceptable side effects with anti-TNF therapy or an inadequate response to such therapy, risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 and superior with respect to endoscopic remission at week 48. (Funded by AbbVie; ClinicalTrials.gov number, NCT04524611.).

ETS1 and RBPJ transcriptionally regulate METTL14 to suppress TGF-ß1-induced epithelial-mesenchymal transition in human bronchial epithelial cells.

Asthma is a chronic respiratory disease characterized by airway inflammation and remodeling. Epithelial-mesenchymal transition (EMT) of bronchial epithelial cells is considered to be a crucial player in asthma. Methyltransferase-like 14 (METTL14), an RNA methyltransferase, is implicated in multiple pathological processes, including EMT, cell proliferation and migration. However, the role of METTL14 in asthma remains uncertain. This research aimed to explore the biological functions of METTL14 in asthma and its underlying upstream mechanisms. METTL14 expression was down-regulated in asthmatic from three GEO datasets (GSE104468, GSE165934, and GSE74986). Consistent with this trend, METTL14 was decreased in the lung tissues of OVA-induced asthmatic mice and transforming growth factor-ß1 (TGF-ß1)-stimulated human bronchial epithelial cells (Beas-2B) in this study. Overexpression of METTL14 caused reduction in mesenchymal markers (FN1, N-cad, Col-1 and α-SMA) in TGF-ß1-treated cells, but caused increase in epithelial markers (E-cad), thus inhibiting EMT. Also, METTL14 suppressed the proliferation and migration ability of TGF-ß1-treated Beas-2B cells. Two transcription factors, ETS1 and RBPJ, could both bind to the promoter region of METTL14 and drive its expression. Elevating METTL14 expression could reversed EMT, cell proliferation and migration promoted by ETS1 or RBPJ deficiency. These results indicate that the ETS1/METTL14 and RBPJ/METTL14 transcription axes exhibit anti-EMT, anti-proliferation and anti-migration functions in TGF-ß1-induced bronchial epithelial cells, implying that METTL14 may be considered an alternative candidate target for the treatment of asthma.

[Seasonal changes of ammonia-oxidizing bacterial communities during tropical forest restoration]. / 热带森林恢复过程中氨氧化细菌群落的季节变化.

In this study, we used a high-throughput sequencing technology to survey the dry-wet seasonal change characteristics of soil ammonia-oxidizing bacteria (AOB) communities in the three restoration stages [i.e., Mallotus paniculatus community (early stage), Millettia leptobotrya community (middle stage), and Syzygium oblatum community (later stage)] of Xishuangbanna tropical forest ecosystems. We analyzed the effects of soil physicochemical characteristics on AOB community composition and diversity during tropical forest restoration. The results showed that tropical forest restoration significantly affected the relative abundance of dominant AOB phyla and their dry-wet seasonal variation. The maximum relative abundance of Proteobacteria (71.3%) was found in the early recovery stage, while that of Actinobacteria was found in the late recovery stage (1.0%). The abundances of Proteobacteria and Actinobacteria had the maximum ranges of dry-wet seasonal variation in the early and late stages, respectively. The abundance of dominant AOB genera and its dry-wet seasonal variation varied across tropical forest restoration stages. The maximum average relative abundance of Nitrosospira and Nitrosomonas in the late recovery stage was 66.2% and 1.5%, respectively. In contrast, the abundance of Nitrosovibrio reached its maximum (25.6%) in the early recovery stage. The maximum dry-wet seasonal variation in relative abundance of Nitrosospira and Nitrosomonas occurred in the early recovery stage, while that of Nitrosovibrio occurred in the middle recovery stage. The Chao1, Shannon, and Simpson diversity indices of AOB communities increased along the restoration stages, which were significantly higher in the wet season than in the dry season. The results of canonical correspondence analysis showed that soil easily oxidized carbon was the main factor controlling AOB community diversity and Actinobacteria abundance. Soil bulk density and temperature were the main factors affecting Proteobacteria abundance. Soil pH, microbial biomass carbon, water content, ammonium nitrogen, bulk density, and temperature were the main factors controlling the abundances of Nitrosospira, Nitrosomonas, and Nitrosovibrio. Therefore, tropical forest restoration can regulate the change of relative abundance of dominant AOB taxa via mediating the changes of soil temperature, bulk density, and readily oxidized carbon, leading to an increase in soil AOB community diversity.

Aspirin prevents colorectal cancer by regulating the abundance of Enterococcus cecorum and TIGIT+Treg cells.

Although aspirin can reduce the incidence of colorectal cancer (CRC), there is still uncertainty about its significance as a treatment for CRC, and the mechanism of aspirin in CRC is not well understood. In this study, we used aspirin to prevent AOM/DSS-induced CRC in mice, and the anti-CRC efficacy of aspirin was assessed using haematoxylin and eosin (H&E) staining and by determining the mouse survival rate and tumour size. 16S rDNA sequencing, flow cytometry (FCM), and Western blotting were also conducted to investigate the changes in the gut microbiota, tumour immune microenvironment, and apoptotic proteins, respectively. The results demonstrated that aspirin significantly exerted anti-CRC effects in mice. According to 16S rDNA sequencing, aspirin regulated the composition of the gut microbiota and dramatically reduced the abundance of Enterococcus cecorum. FCM demonstrated that there were more CD155 tumour cells and CD4 + CD25 + Treg cells showed increased TIGIT levels. Moreover, increased TIGIT expression on Treg cells is associated with reduced Treg cell functionality. Importantly, the inhibition of Treg cells is accompanied by the promotion of CD19 + GL-7 + B cells, CD8 + T cells, CD4 + CCR4 + Th2 cells, and CD4 + CCR6 + Th17 cells. Overall, aspirin prevents colorectal cancer by regulating the abundance of Enterococcus cecorum and TIGIT + Treg cells.

Causal relationship between sleep disorders and the risk of Alzheimer's disease: A Mendelian randomization study.

BACKGROUND AND OBJECTIVE: Epidemiological studies have shown that sleep disorders are risk factors for Alzheimer's disease (AD), but the causal relationship between sleep disorders and AD risk is unknown. We aim to assess the potential genetic causal association between sleep characteristics and AD, which may contribute to early identification and prediction of risk factors for AD. METHODS: Seven sleep-related traits and the outcome phenotype AD were selected from published genome-wide association studies (GWASs). These sleep-related characteristics and instrumental variables (IVs) for AD were extracted. Two-sample and multivariate Mendelian randomization (MR) analyses were performed to assess the causal relationships between sleep characteristics and AD. The inverse variance weighted (IVW), weighted median (WME), weighted mode (WM), MR-Egger regression (MR-Egger) and simple mode (SM) models were used to evaluate causality. The existence of pleiotropy was detected and corrected by MR-Egger regression, MR pleiotropy residuals and outliers. RESULTS: A two-sample MR study revealed a positive causal association between sleep duration and the onset of AD (OR = 1.002, 95 % CI: 1.000-1.004), and the risk of AD increased with increasing sleep duration. The MR-Egger regression method and MR-PRESSO were used to identify and correct pleiotropy, indicating that there was no horizontal pleiotropy. Heterogeneity was evaluated by Cochran's Q, which indicated no heterogeneity. In a multivariate MR study with seven sleep characteristics corrected for each other, we found that sleep duration remained causally associated with AD (OR = 1.004, 95 % CI: 1.000-1.007). Moreover, we found that after mutual correction, daytime napping had a causal relationship with the onset of AD, and daytime napping may reduce the risk of AD (OR = 0.995, 95 % CI: 0.991-1.000). CONCLUSION: This study is helpful for the early identification and prediction of risk factors for AD, long sleep durations are a risk factor for AD, and daytime napping can reduce the risk of AD.

G-quadruplex-guided cisplatin triggers multiple pathways in targeted chemotherapy and immunotherapy.

G-quadruplexes (G4s) are atypical nucleic acid structures involved in basic human biological processes and are regulated by small molecules. To date, pyridostatin and its derivatives [e.g., PyPDS (4-(2-aminoethoxy)-N 2,N 6-bis(4-(2-(pyrrolidin-1-yl) ethoxy) quinolin-2-yl) pyridine-2,6-dicarboxamide)] are the most widely used G4-binding small molecules and considered to have the best G4 specificity, which provides a new option for the development of cisplatin-binding DNA. By combining PyPDS with cisplatin and its analogs, we synthesize three platinum complexes, named PyPDSplatins. We found that cisplatin with PyPDS (CP) exhibits stronger specificity for covalent binding to G4 domains even in the presence of large amounts of dsDNA compared with PyPDS either extracellularly or intracellularly. Multiomics analysis reveals that CP can effectively regulate G4 functions, directly damage G4 structures, activate multiple antitumor signaling pathways, including the typical cGAS-STING pathway and AIM2-ASC pathway, trigger a strong immune response and lead to potent antitumor effects. These findings reflect that cisplatin-conjugated specific G4 targeting groups have antitumor mechanisms different from those of classic cisplatin and provide new strategies for the antitumor immunity of metals.

Advances in the interaction of glycolytic reprogramming with lactylation.

Lactylation is a novel post-translational modification (PTM) involving proteins that is induced by lactate accumulation. Histone lysine lactylation alters chromatin spatial configuration, influencing gene transcription and regulating the expression of associated genes. This modification plays a crucial role as an epigenetic regulatory factor in the progression of various diseases. Glycolytic reprogramming is one of the most extensively studied forms of metabolic reprogramming, recognized as a key hallmark of cancer cells. It is characterized by an increase in glycolysis and the inhibition of the tricarboxylic acid (TCA) cycle, accompanied by significant lactate production and accumulation. The two processes are closely linked by lactate, which interacts in various physiological and pathological processes. On the one hand, lactylation levels generally correlate positively with the extent of glycolytic reprogramming, being directly influenced by the lactate concentration produced during glycolytic reprogramming. On the other hand, lactylation can also regulate glycolytic pathways by affecting the transcription and structural functions of essential glycolytic enzymes. This review comprehensively outlines the mechanisms of lactylation and glycolytic reprogramming and their interactions in tumor progression, immunity, and inflammation, with the aim of elucidating the relationship between glycolytic reprogramming and lactylation.

Spatiotemporal optical vortices with controllable radial and azimuthal quantum numbers.

Optical spatiotemporal vortices with transverse photon orbital angular momentum (OAM) have recently become a focal point of research. In this work we theoretically and experimentally investigate optical spatiotemporal vortices with radial and azimuthal quantum numbers, known as spatiotemporal Laguerre-Gaussian (STLG) wavepackets. These 3D wavepackets exhibit phase singularities and cylinder-shaped edge dislocations, resulting in a multi-ring topology in its spatiotemporal profile. Unlike conventional ST optical vortices, STLG wavepackets with non-zero p and l values carry a composite transverse OAM consisting of two directionally opposite components. We further demonstrate mode conversion between an STLG wavepacket and an ST Hermite-Gaussian (STHG) wavepacket through the application of strong spatiotemporal astigmatism. The converted STHG wavepacket is de-coupled in intensity in space-time domain that can be utilized to implement the efficient and accurate recognition of ultrafast STLG wavepackets carried various p and l . This study may offer new insights into high-dimensional quantum information, photonic topology, and nonlinear optics, while promising potential applications in other wave phenomena such as acoustics and electron waves.

Treponema pallidum recombinant protein Tp0768 enhances the ability of HUVECs to promote neutrophil chemotaxis through TLR2/ER stress signaling pathway.

Neutrophils are essential cells involved in inflammation. However, the specific mechanism of neutrophil chemotaxis induced by Treponema Pallidum (T. pallidum) remains unknow. In this study, human umbilical vein endothelial cells (HUVECs) were utilized as target cells to investigate the expression levels of chemokines when stimulated with different concentrations of Tp0768(also known as TpN44.5 or TmpA, a T. pallidum infection dependent antigen). The results indicated that Tp0768 treatment enhanced neutrophil chemotaxis in HUVECs, which was closely associated with the expression levels of CXCL1(C-X-C Motif Chemokine Ligand 1), CXCL2(C-X-C Motif Chemokine Ligand 2), and CXCL8(C-X-C Motif Chemokine Ligand 8, also known as interleukin-8). At the same time, the results show that Toll Like Receptor 2 (TLR2) signaling pathway is activated and endoplasmic reticulum stress (ER stress) occurs. Furthermore, the findings revealed that the use of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and Immunoglobulin-Regulated Enhancer 1 (IRE1) inhibitors reduced the expression levels of CXCL1, CXCL2, and CXCL8. Additionally, inhibiting TLR2 significantly decreased the expression levels of ER stress-related proteins (PERK and IRE1), CXCL1, CXCL2, and CXCL8. Consequently, neutrophil chemotaxis was significantly inhibited after treatment with TLR2, PERK, and IRE1 inhibitors. These findings shed light on the role of Tp0768 in enhancing neutrophil chemotaxis in endothelial cells, providing a foundation for further exploration of syphilis pathogenesis and offering a new direction for the diagnosis and treatment of T. pallidum infection.

Serofast status in syphilis: Pathogenesis to therapeutics.

Syphilis, a sexually transmitted infection caused by Treponema pallidum, has been experiencing a rise in prevalence in recent years. "Syphilis serofast" describes a unique serological reaction in patients with syphilis whose clinical symptoms have resolved following consistent anti-syphilitic therapy, but the non-Treponema pallidum antigen serologic test is still positive. Syphilis serofast is a risk factor for syphilis recurrence, neurosyphilis, and multisystem involvement. Considering the current lack of comprehensive knowledge about the epidemiological characteristics, pathogenesis, and therapies of syphilis serofast, we conducted an online search of research relating to syphilis serofast over the last twenty years. Previous research has shown that the pathogenesis of syphilis serofast is mainly related to clinical factors, immune factors, syphilis subtypes, and T.pallidum membrane protein repeat gene antigen. There are two distinct viewpoints on the treatment of serofast: no excessive treatment and active treatment. In addition, serofast patients also showed two clinical outcomes: syphilis recurrence and persistent serofast status. This article systematically reviews the related factors, treatment, and clinical outcomes of syphilis serofast, provides a theoretical basis for its research, diagnosis, and treatment, and helps clinicians develop a follow-up treatment management plan for syphilis serofast.