Targeted nanoprobe for magnetic resonance imaging-guided enhanced antitumor via synergetic photothermal/immunotherapy.

Synergistic photothermal/immunotherapy has garnered significant attention for its potential to enhance tumor therapeutic outcomes. However, the fabrication of an intelligent system with a simple composition that simultaneously exerts photothermal/immunotherapy effect and imaging guidance function still remains a challenge. Herein, a glutathione (GSH)-responsive theranostic nanoprobe, named HA-MnO2/ICG, was elaborately constructed by loading photothermal agent (PTA) indocyanine green (ICG) onto the surface of hyaluronic acid (HA)-modified manganese dioxide nanosheets (HA-MnO2) for magnetic resonance (MR) imaging-guided synergetic photothermal/immuno-enhanced therapy. In this strategy, HA-MnO2 nanosheets were triggered by the endogenous GSH in tumor microenvironment to generate Mn2+ for MR imaging, where the longitudinal relaxation rate of HA-MnO2/ICG was up to 14.97 mM-1s-1 (∼24 times than that found in a natural environment), demonstrating excellent intratumoral MR imaging. Moreover, the HA-MnO2/ICG nanoprobe demonstrates remarkable photothermal therapy (PTT) efficacy, generating sufficient heat to induce immunogenic cell death (ICD) within tumor cells. Meanwhile the released Mn2+ ions from the nanosheets function as potent immune adjuvants, amplifying the immune response against cancer. In vivo experiments validated that HA-MnO2/ICG-mediated PTT was highly effective in eradicating primary tumors, while simultaneously enhancing immunogenicity to prevent the growth of distal metastasis. This hybrid HA-MnO2/ICG nanoprobe opened new avenues in the design of MR imaging-monitored PTT/immuno-enhanced synergistic therapy for advanced cancer.

Critical windows for exposure to chemical composition of ambient particulate matter and human semen quality decline.

BACKGROUND: Critical windows for exposure to chemical components of particulate matter (PM <2.5 µm in diameter [PM2.5]) associated with the human semen quality decline remain unclear. OBJECTIVES: To address this gap, we developed a new analytical framework by integrating a Linear Mixed Model (LMM) with subject- and center-specific intercepts and a Distributed Lag Model (DLM) to fully account for correlations between finely vulnerable exposure windows based on complete profile of the spermatogenesis cycle. METHODS: We constructed a multicenter cohort involving 33,234 sperm donors with 78,952 semen samples covering 6 representative regions across China from 2014 to 2020 to investigate the week-scale critical windows for the exposure. Daily exposure to PM2.5 chemical components of donors was derived from grid data based on 1-km spatial resolution surface measurements. RESULTS: Decreased sperm count was significantly associated with NO3- and SO42- at 9-10 weeks (e.g., ß: -0.05 %, 95%CI: [-0.10 %, -0.00 %] at the 9th week) and 0-2 weeks (e.g., ß: -0.66 %, 95%CI: [-1.24 %, -0.07 %] at the 1st week), respectively. Critical windows of progressive motility decline were 0-10 weeks for BC (e.g., ß: -0.07 %, 95%CI: [-0.11 %, -0.03 %] at the 5th week), Cl- at 1-4 weeks (e.g., ß: -2.21 %, 95%CI: [-3.77 %, -0.66 %] at the 2nd week), 0-6 weeks and 9-10 weeks for NO3- (e.g., ß: -0.05 %, 95%CI: [-0.09 %, -0.01 %] at the 4th week), 1-3 weeks and the 8th week for NH4+ (e.g., ß: -0.06 %, 95%CI: [-0.11 %, -0.01 %] at the 2nd week). Total motility is significantly negatively associated with BC at entire windows, Cl- at 0-3 weeks, the 5th week and 9-10 weeks. CONCLUSIONS: There are week-scale vulnerable windows of exposure to PM2.5 chemical components for human semen quality. This highlights the need for more targeted pollution control strategies addressing PM2.5 and its chemical components.

Early Weaning Inhibits Intestinal Stem Cell Expansion to Disrupt the Intestinal Integrity of Duroc Piglets via Regulating the Keap1/Nrf2 Signaling.

There are different stress resistance among different breeds of pigs. Changes in intestinal stem cells (ISCs) are still unclear among various breeds of piglets after early weaning. In the current study, Taoyuan Black and Duroc piglets were slaughtered at 21 days of age (early weaning day) and 24 days of age (3 days after early weaning) for 10 piglets in each group. The results showed that the rate of ISC-driven epithelial renewal in local Taoyuan Black pigs hardly changed after weaning for 3 days. However, weaning stress significantly reduced the weight of the duodenum and jejunum in Duroc piglets. Meanwhile, the jejunal villus height, tight junction-related proteins (ZO-1, Occludin, and Claudin1), as well as the trans-epithelial electrical resistance (TEER) values, were down-regulated after weaning for 3 days in Duroc piglets. Moreover, compared with Unweaned Duroc piglets, the numbers of Olfm4+ ISC cells, PCNA+ mitotic cells, SOX9+ secretory progenitor cells, and Villin+ absorptive cells in the jejunum were reduced significantly 3 days after weaning. And ex vivo jejunal crypt-derived organoids exhibited growth disadvantages in weaned Duroc piglets. Notably, the Keap1/Nrf2 signaling activities and the expression of HO-1 were significantly depressed in weaned Duroc piglets compared to Unweaned Duroc piglets. Thus, we can conclude that ISCs of Duroc piglets were more sensitive to weaning stress injury than Taoyuan Black piglets, and Keap1/Nrf2 signaling is involved in this process.

Epicardial transplantation of antioxidant polyurethane scaffold based human amniotic epithelial stem cell patch for myocardial infarction treatment.

Myocardial infarction (MI) is a leading cause of death globally. Stem cell therapy is considered a potential strategy for MI treatment. Transplantation of classic stem cells including embryonic, induced pluripotent and cardiac stem cells exhibited certain repairing effect on MI via supplementing cardiomyocytes, however, their clinical applications were blocked by problems of cell survival, differentiation, functional activity and also biosafety and ethical concerns. Here, we introduced human amniotic epithelial stem cells (hAESCs) featured with immunomodulatory activities, immune-privilege and biosafety, for constructing a stem cell cardiac patch based on porous antioxidant polyurethane (PUR), which demonstrated decent hAESCs compatibility. In rats, the administration of PUR-hAESC patch significantly reduced fibrosis and facilitated vascularization in myocardium after MI and consequently improved cardiac remodeling and function. Mechanistically, the patch provides a beneficial microenvironment for cardiac repair by facilitating a desirable immune response, paracrine modulation and limited oxidative milieu. Our findings may provide a potential therapeutic strategy for MI.

Exotic mangrove Laguncularia racemosa litter input accelerates nutrient cycling in mangrove ecosystems.

Exotic plant litter presents different chemical and physical properties relative to native plant litter and alters ecosystem processes and functions that may facilitate exotic plant dispersal. However, these effects are largely unknown, especially within wetland ecosystems. This study examines whether introducing litter from the exotic mangrove Laguncularia racemosa could result in (1) accelerated community litter decomposition rates and increased nutrient cycling rates and (2) microbial community structure changes in the invaded areas. A single decomposition experiment using litterbags was conducted to examine the short-term effects of L. racemosa litter in the native mangrove forest ecosystem. The soil nutrients and microbial communities of Rhizophora stylosa, L. racemosa, and mixed forests were also compared to explore the long-term cumulative effects of L. racemosa litter in native ecosystems. The results indicated that L. racemosa has lower-quality leaf litter than R. stylosa and a significantly faster decomposition rate. This may result from changes in the soil microbial community structure caused by L. racemosa leaf litter input, which favors the decomposition of its own litter. Both the short-term and cumulative effect experiments demonstrated that L. racemosa leaf litter significantly increased the relative abundance of microbes related to litter decomposition, such as Proteobacteria and Bdellovibrionota, and enhanced the alpha diversity of soil fungi, thus creating a microbial environment conducive to L. racemosa leaf litter decomposition. Moreover, the accumulation of soil nutrients was lower under L. racemosa than under R. stylosa over several years. This may be related to the more rapid growth of L. racemosa, which causes soil nutrient absorption and storage within the plant tissues, thereby reducing the soil nutrient content. Inputting exotic mangrove L. racemosa leaf litter reduced the soil blue carbon content, potentially adversely affecting global climate change. L. racemosa may employ a unique strategy to lower soil nutrient levels in native mangroves based on its low-quality leaf litter, thereby weakening the competitive ability of native plants that are intolerant to low-nutrient conditions and enhancing its own competitive advantage to further spread into these areas. In summary, the input of exotic L. racemosa leaf litter accelerates nutrient cycling in local mangroves.

Human Amniotic Epithelial Stem Cells Promote Colonic Recovery in Experimental Colitis via Exosomal MiR-23a-TNFR1-NF-κB Signaling.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, manifests as chronic intestinal inflammation with debilitating symptoms, posing a significant burden on global healthcare. Moreover, current therapies primarily targeting inflammation can lead to immunosuppression-related complications. Human amniotic epithelial stem cells (hAESCs), which exhibit low immunogenicity and ethical acceptability, have gained attention as potential therapeutics. In this study, it is demonstrated that their encapsulation in a hydrogel and administration via anal injection enhanced the colonic mucosal barrier repair in a murine colitis model induced by dextran sodium sulfate during the recovery phase. The underlying mechanism involved the release of exosomes from hAESCs enriched with microRNA-23a-3p, which post-transcriptionally reduced tumor necrosis factor receptor 1 expression, suppressing the nuclear factor-κB pathway in colonic epithelial cells, thus played a key role in inflammation. The novel approach shows potential for IBD treatment by restoring intestinal epithelial homeostasis without the immunosuppressive therapy-associated risks. Furthermore, the approach provides an alternative strategy to target the key molecular pathways involved in inflammation and promotes intestinal barrier function using hAESCs and their secreted exosomes. Overall, this study provides key insights to effectively treat IBD, addresses the unmet needs of patients, and reduces related healthcare burden.

Direct response of liquid crystal to pH changes for wide range pH sensing via the whispering gallery mode.

pH sensing is essential in various fields including healthcare, environmental monitoring, food safety, and agriculture. In this Letter, we propose a method for a wide-range pH measurement based on the direct response of liquid crystal (LC) to pH variations via the whispering gallery mode (WGM). The liquid crystal 4-cyano-4'-pentylbiphenyl (5CB) is selected for its excellent optoelectronic properties and the birefringence of 5CB microdroplets serving as spherical resonators. This sensor achieves wide-range pH sensing without any intermediaries. Polarized optical microscopy (POM) and WGM provide a qualitative morphological analysis and accurate quantitative spectral measurements. Under alkaline conditions (pH 7.6 to 13.3), POM images of 5CB microdroplets show a complete transition from bipolar to radial structures, with an average sensitivity of 1.78 nm/pH of redshift in WGM spectra. In acidic conditions (pH 6.65 to 1.5), structural changes observed by POM are minor, with a sensitivity of 1.06 nm/pH of blueshift in WGM spectra. This difference is attributed to the varying refractive indices of HCl and NaOH solutions. This method offers a reference for theoretical studies on pH and LC interactions and holds promise for the development of LC-based pH sensors.

Injectable hydrogel microsphere-bomb for MRSA-infected chronic osteomyelitis.

Biofilm and bone tissue defect induced by the bacterial infection severely impede chronic osteomyelitis treatment. It is critical to break though the densely and obstinate biofilm so that the target drugs can deliver to the infected bone more effectively. Herein, an acoustically responsive multifunctional hydrogel microsphere-bomb (EMgel) was designed and prepared by microfluidic technology, which could be injected to the focus of bone infection, and blasted into the nidus deeply to destroy the bacterial biofilm matrix barrier under penetrating ultrasound, so the encapsulated natural polyphenolic EGCG and bioactive MoS2 released to repair the damaged bone. The results proved the hydrogel microsphere-bomb exhibited controlling drug release, favorable antibacterial (as high as 99 %), high biofilm resistance, fascinating antioxidation, good cytocompatibility, and osteogenic differentiation. The acoustically responsive microsphere-bomb further proved their fantastic ability to eradicate biofilm and promote bone regeneration in the Methicillin-resistant Staphylococcus aureus (MRSA) infected chronic osteomyelitis model due to the synergy effects of EGCG and bioactive MoS2. Especially, immunohistochemical staining showed lower inflammatory reaction and higher expression of OCN in EMgel group treated with ultrasound wave. This study presents a new design of hydrogel microsphere-based intelligence drug delivery for osteomyelitis treatment, which exhibit great promising potential for dealing with chronic orthopedic infections, drug delivery system and tissue engineering.

Father presence, adolescent girls' resilience, psychological security, and achievement goal orientation: examining direct and indirect associations.

In the developmental research, studies on the importance of fathers in the parent-child relationship is insufficient, especially the father-daughter relationship. Thus far, a few studies have investigated whether father presence influences adolescent daughters' resilience. Therefore, this study investigated the extent to which intermediary factors affect the relationship between father presence and daughters' resilience. A total of 718 Chinese female high school students participated in a questionnaire survey. The results showed father presence was positively related to resilience in female high school students. Additionally, psychological security fully mediated the relationship between father presence and daughters' resilience, whereas achievement goal orientation partially mediated this relationship; specifically, the mastery-approach and performance-approach orientations. The results highlight the importance of considering the meaning and implications of father presence and daughter's resilience in Chinese culture.

STASCAN deciphers fine-resolution cell distribution maps in spatial transcriptomics by deep learning.

Spatial transcriptomics technologies have been widely applied to decode cellular distribution by resolving gene expression profiles in tissue. However, sequencing techniques still limit the ability to create a fine-resolved spatial cell-type map. To this end, we develop a novel deep-learning-based approach, STASCAN, to predict the spatial cellular distribution of captured or uncharted areas where only histology images are available by cell feature learning integrating gene expression profiles and histology images. STASCAN is successfully applied across diverse datasets from different spatial transcriptomics technologies and displays significant advantages in deciphering higher-resolution cellular distribution and resolving enhanced organizational structures.

Risk Factors of Postoperative Atrial Fibrillation After Isolated Coronary Artery Bypass Grafting Surgery in the Recent 10 Years: Clinical Analysis of 6229 Patients.

BACKGROUND: Postoperative atrial fibrillation (POAF) is a common complication after coronary artery bypass grafting (CABG) that prolongs hospitalization and increases expenses. HYPOTHESIS: Perioperative risk factors may predict POAF. METHODS: From March 2015 to January 2023, 6229 patients who underwent isolated CABG and were in sinus rhythm before CABG were included in this retrospective study. The preoperative and postoperative variants of patients were collected and analyzed by univariate analyses between the patients with and without POAF. Multivariate logistic regression analysis was then used to study the independent risk factors for POAF. RESULTS: The incidence of POAF in this group of patients was 30.94%. Univariate analyses demonstrated that age (p < 0.001), hypertension (p < 0.001), smoking (p < 0.05), cardiopulmonary bypass (CPB) time (p < 0.01), and ejection fraction (EF, p < 0.01) were the risk factors for POAF. Multivariate logistic regression analysis determined the independent risk factors associated with POAF were old age (odds ratio [OR] = 1.062, p = 0.000) and low EF (OR = 0.980; p = 0.008). CONCLUSIONS: In the current era, after isolated CABG surgery, there is still a quite high incidence of POAF (30.94% in this group of CABG patients). The main risk factors correlating to POAF include age, hypertension, smoking, CPB time, and EF. Among these factors, multivariate analysis identified old age and low EF as the independent risk factors associated with POAF. Particular care should be taken in the perioperative period for these patients in the prevention of POAF.

Genetic analysis of selection bias in a natural experiment: Investigating in-utero famine effects on elevated body mass index in the Dutch Hunger Winter Families Study.

Natural-experiment designs that compare survivors of in-utero famine exposure to unaffected controls suggest that in-utero undernutrition predisposes to development of obesity. However, birth rates drop dramatically during famines. Selection bias could arise if factors that contribute to obesity also protect fertility and/or fetal survival under famine conditions. We investigated this hypothesis using genetic analysis of a famine-exposed birth cohort. We genotyped participants in the Dutch Hunger Winter Families Study (DHWFS, N=950; 45% male), of whom 51% were exposed to the 1944-1945 Dutch Famine during gestation and 49% were their unexposed same-sex siblings or "time controls" born before or after the famine in the same hospitals. We computed body-mass index (BMI) polygenic indices (PGIs) in DHWFS participants and compared BMI PGIs between famine-exposed and control groups. Participants with higher polygenic risk had higher BMIs (Pearson r=0.42, p<0.001). However, differences between BMI PGIs of famine-exposed participants and controls were small and not statistically different from zero across specifications (Cohen's d=0.10, p>0.092). Our findings did not indicate selection bias, supporting the validity of the natural-experiment design within DHWFS. In summary, our study outlines a novel approach to explore the presence of selection bias in famine and other natural experiment studies.

Epidemiological characteristics and transmission dynamics of dengue fever in China.

China has experienced successive waves of dengue epidemics over the past decade. Nationwide data on 95,339 dengue cases, 89 surveillance sites for mosquito density and population mobility between 337 cities during 2013-20 were extracted. Weekly dengue time series including time trends and harmonic terms were fitted using seasonal regression models, and the amplitude and peak timing of the annual and semiannual cycles were estimated. A data-driven model-inference approach was used to simulate the epidemic at city-scale and estimate time-evolving epidemiological parameters. We found that the geographical distribution of dengue cases was expanding, and the main imported areas as well as external sources of imported cases changed. Dengue cases were predominantly concentrated in southern China and it exhibited an annual peak of activity, typically peaking in September. The annual amplitude of dengue epidemic varied with latitude (F = 19.62, P = 0.0001), mainly characterizing by large in southern cities and small in northern cities. The effective reproduction number Reff across cities is commonly greater than 1 in several specific months from July to November, further confirming the seasonal fluctuations and spatial heterogeneity of dengue epidemics. The results of this national study help to better informing interventions for future dengue epidemics in China.

Electronic Engineering of Crystalline/Amorphous CoP/FeCoPx Nanoarrays for Efficient Water Electrolysis.

The development of bifunctional, non-noble metal-based electrocatalysts for hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) through morphology and electronic engineering is highly attractive for efficient water splitting. Herein, hierarchical nanoarrays consisting of crystalline cobalt phosphide nanorods covered by amorphous Fe-doped cobalt phosphide nanocuboids (CoP/FeCoPx) are constructed as bifunctional catalysts for both HER and OER. Experimental results and theoretical calculations reveal that the catalysts exhibit balanced dual-catalytic properties due to simultaneous introduction of Fe doping and phosphorus vacancies, leading to an optimized electronic structure of the CoP/FeCoPx. Furthermore, the hierarchical nanoarrays made of crystalline/amorphous heterostructures significantly enhance the performance of the electrocatalysts. As a result, the CoP/FeCoPx catalyst demonstrates remarkable performance in both HER and OER, with overpotentials of 74 and 237 mV at 10 mA cm-2 in 1 m KOH, respectively, as well as a low cell voltage of 1.53 V at 10 mA cm-2 for alkaline overall water splitting. This work integrates the morphology engineering involving design of hierarchical crystalline/amorphous nanoarrays and the electronic engineering through Fe doping and phosphorus vacancies for efficient water electrolysis. It may open a new route toward rational design and feasible fabrication of high-performance, multifunctional, non-noble metal-based electrocatalysts for energy conversion.

Tuning nanoparticle core composition drives orthogonal fluorescence amplification for enhanced tumour imaging.

Tumour detection with high selectivity and sensitivity is crucial for delineating tumour margins and identifying metastatic foci during image-guided surgery. Optical nanoprobes with preferential tumour accumulation is often limited by inefficient amplification of biological signals. Here, we report the design of a library of hydrophobic core-tunable ultra-pH-sensitive nanoprobes (HUNPs) for orthogonally amplifying tumour microenvironmental signals on multiple tumour models. We find that tuning the hydrophobicity of nanoparticle core composition with non-ionizable monomers can enhance cellular association of HUNPs by more than ten-fold, resulting in a high cellular internalization efficiency of HUNPs with up to 50% in tumours. Combining high tumour accumulation and high cell internalization efficiency, HUNPs show orthogonally amplified fluorescence signals, permitting the precise locating and delineating margins between malignant lesions and normal tissues with high contrast-to-noise ratio and resolution. Our study provides key strategies to design nanomedicines with high intracellular bioavailability for cancer detection, drug/gene delivery, and therapy.

The High-Cycle Tensile-Shear Fatigue Properties and Failure Mechanism of Resistance Spot-Welded Advanced High-Strength Steel with a Zn Coating.

Advanced high-strength steels (AHSSs) with Zn coatings are commonly joined by the resistance spot welding (RSW) technique. However, Zn coatings could possibly cause the formation of liquid metal embrittlement (LME) cracks during the RSW process. The role of a Zn coating in the tensile-shear fatigue properties of a welding joint has not been systematically explored. In this study, the fatigue properties of tensile-shear RSW joints for bare and Zn-coated advanced high-strength steel (AHSS) specimens were comparatively studied. In particular, more severe LME cracks were triggered by employing a tilted welding electrode because much more stress was caused in the joint. LME cracks had clearly occurred in the Zn-coated steel RSW joints, as observed via optical microscopy. On the contrary, no LME cracks could be found in the RSW joints prepared with the bare steel sheets. The fatigue test results showed that the tensile-shear fatigue properties remained nearly unchanged, regardless of whether bare or Zn-coated steel was used for the RSW joints. Furthermore, Zn mapping adjacent to the crack initiation source was obtained by an electron probe micro-analyzer (EPMA), and it showed no segregation of the Zn element. Thus, the failure of the RSW joints with the Zn coating had not initiated from the LME cracks. It was concluded that the fatigue cracks were initiated by the stress concentration in the notch position between the two bonded steel sheets.

Silver nanoparticle-functionalized covalent organic frameworks for the inhibition of foodborne pathogenic bacteria and their application in green grape preservation.

Foodborne pathogens continue to pose a significant threat to human health. This study aims to enhance the antimicrobial activity of low-dose silver nanoparticles (AgNPs) against foodborne pathogens and use the enhanced AgNPs to preserve green grapes. A chemical delivery carrier for covalent organic frameworks (COFs) impregnated with AgNPs was developed. We investigated the bacteriostatic properties (minimum bacteriostatic concentration, bacteriostatic growth curve), the mechanism of action of the bacteriostatic agent, and the performance of the bacteriostatic film. The bacteriostatic preservation rate of the AgNPs@COFs composite on green grapes was evaluated. The minimum bacteriostatic concentration of the AgNPs@COFs composite was 10 µg/mL, and the bacteriostatic rate varied between 94.01 % and 98.77 %. The developed antibacterial AgNPs@COFs composite has potential applications in food packaging and preservation.

Decoding plant-induced transcriptomic variability and consistency in two related polyphagous mites differing in host ranges.

The diet breadth of generalist herbivores when compared to specialists tends to be associated with greater transcriptional plasticity. Here, we consider whether it may also contribute to variation in host range among two generalists with different levels of polyphagy. We examined two related polyphagous spider mites with different host ranges, Tetranychus urticae (1200 plants) and Tetranychus truncatus (90 plants). Data from multiple populations of both species domesticated on common beans and transferred to new plant hosts (cotton, cucumber, eggplant) were used to investigate transcriptional plasticity relative to population-based variation in gene expression. Compared to T. truncatus, T. urticae exhibited much higher transcriptional plasticity. Populations of this species also showed much more variable expression regulation in response to a plant host, particularly for genes related to detoxification, transport, and transcriptional factors. In response to the different plant hosts, both polyphagous species showed enriched processes of drug/xenobiotics metabolism, with T. urticae orchestrating a relatively broader array of biological pathways. Through co-expression network analysis, we identified gene modules associated with host plant response, revealing shared hub genes primarily involved in detoxification metabolism when both mites fed on the same plants. After silencing a shared hub CYP gene related to eggplant exposure, the performance of both species on the original bean host improved, but the fecundity of T. truncatus decreased when feeding on eggplant. The extensive transcriptomic variation shown by T. urticae might serve as a potential compensatory mechanism for a deficiency of hub genes in this species. This research points to nuanced differences in transcriptomic variability between generalist herbivores.

Obstructive sleep apnea and 19 gastrointestinal diseases: a Mendelian randomization study.

Background: Alterations gastrointestinal diseases (GDs) were reported in individuals with obstructive sleep apnea (OSA), however, the genetic background between OSA and GDs is still unclear. Methods: This investigation employed Mendelian randomization (MR) analyses to evaluate the causal effect between OSA and 19 types of GDs (gastroesophageal reflux disease (GERD), ulcerative colitis, celiac disease, Crohn's disease, chronic gastritis, irritable bowel syndrome, primary biliary cholangitis, diverticular disease, gastroduodenal ulcer, acute pancreatitis, non-alcoholic fatty liver disease, primary sclerosing cholangitis, cirrhosis, calculus of bile duct, calculus of gallbladder, pancreatic cancer, gastric cancer, colorectal cancer, and esophageal cancer). The inverse-variance weighted (IVW) method was used to evaluate the main effects model of causality. Results: This MR study suggests that OSA may play a causal role inflammation-related GDs (GERD, PIVW=5.94×10-9; gastroduodenal ulcer, PIVW=1×10-4; chronic gastritis, PIVW=0.0214; ulcerative colitis, PIVW=0.0296), and gallstones (calculi of the gallbladder, PIVW=0.0429; calculi of the bile duct, PIVW=0.0068). After accounting for obesity, type 2 diabetes, smoking, and alcohol consumption, the multivariate MR (MVMR) analysis identified that OSA is an independent risk factor for GERD, gastroduodenal ulcer, and calculus of the bile duct. The reverse MVMR analysis showed a causal effect of GERD on OSA. Besides, we did not find that the predisposition to OSA was associated with 4 cancers. Conclusion: This MR analysis provides compelling evidence of an independent causal relationship between genetically predicted OSA and an elevated risk of inflammation-related GDs. Besides, no causal association was observed between OSA and cancers. Further studies should be carried out to verify our findings.

ALOX5 contributes to glioma progression by promoting 5-HETE-mediated immunosuppressive M2 polarization and PD-L1 expression of glioma-associated microglia/macrophages.

BACKGROUND: Oxylipin metabolism plays an essential role in glioma progression and immune modulation in the tumor microenvironment. Lipid metabolic reprogramming has been linked to macrophage remodeling, while the understanding of oxylipins and their catalyzed enzymes lipoxygenases in the regulation of glioma-associated microglia/macrophages (GAMs) remains largely unexplored. METHODS: To explore the pathophysiological relevance of oxylipin in human glioma, we performed Ultra-high performance liquid chromatography-MS/MS (UHPLC-MS/MS) analysis in human glioma and non-tumor brain tissues. To comprehensively investigate the role of arachidonate lipoxygenase 5 (ALOX5) in glioma, we performed in vivo bioluminescent imaging, immunofluorescence staining and flow cytometry analysis on tumors from orthotopic glioma-bearing mice. We developed an ALOX5-targeted nanobody, and tested its anti-glioma efficacy of combination therapy with α-programmed cell death protein-1 (PD-1). RESULTS: In this study, we found that ALOX5 and its oxylipin 5-hydroxyeicosatetraenoic acid (5-HETE) are upregulated in glioma, accumulating programmed death-ligand 1 (PD-L1)+ M2-GAMs and orchestrating an immunosuppressive tumor microenvironment. Mechanistically, 5-HETE derived from ALOX5-overexpressing glioma cells, promotes GAMs migration, PD-L1 expression, and M2 polarization by facilitating nuclear translocation of nuclear factor erythroid 2-related factor 2. Additionally, a nanobody targeting ALOX5 is developed that markedly suppresses 5-HETE efflux from glioma cells, attenuates M2 polarization of GAMs, and consequently ameliorates glioma progression. Furthermore, the combination therapy of the ALOX5-targeted nanobody plus α-PD-1 exhibits superior anti-glioma efficacy. CONCLUSIONS: Our findings reveal a pivotal role of the ALOX5/5-HETE axis in regulating GAMs and highlight the ALOX5-targeted nanobody as a potential therapeutic agent, which could potentiate immune checkpoint therapy for glioma.