Pore-Specific Anisotropic Etching of Zeolitic Imidazolate Frameworks by Carboxylic Acid Vapors.

Anisotropic etching is a powerful way to customize metal-organic frameworks with advanced nanostructures, but it is still in its infancy. Herein, we proposed an unprecedented etching strategy that created anisotropic hollow structures in various zeolitic imidazolate framework (ZIF) nano/single crystals via pore-specific carving. The etching occurred through a newly discovered gas-solid reaction where carboxylic acid vapors bind with ligands in ZIFs at room temperature to form ionic liquid (IL). A series of experiments were conducted to decode the origin of anisotropy and the "hollowing out" effect. We found that large pore openings on {111} facets provide access for the entry of carboxylic acid vapors and the outflow of the IL, resulting in pore-dependent anisotropy features. The unique "etching after adsorption" mechanism and the adsorption capacity of the IL enable acid vapors to hollow out nanocrystals and even single crystals. By altering carboxylic acids and ligands in ZIFs, the etching process can be precisely tuned from the inside out or the outside in. This new method demonstrates broad universality and brings unprecedented morphologies and complexities. It may offer great opportunities for achieving purposeful modification of ZIFs and the rational construction of intricate architectures.

Duck Tembusu virus NS3 protein induces apoptosis by activating the PERK/PKR pathway and mitochondrial pathway.

IMPORTANCE: Duck Tembusu virus (DTMUV) is an emerging pathogenic flavivirus that replicates well in mosquito, bird, and mammalian cells. An in vivo study revealed that BALB/c mice and Kunming mice were susceptible to DTMUV after intracerebral inoculation. Moreover, there are no reports about DTMUV-related human disease, but antibodies against DTMUV and viral RNA were detected in the serum samples of duck industry workers. This information implies that DTMUV has expanded its host range and poses a threat to mammalian health. Thus, understanding the pathogenic mechanism of DTMUV is crucial for identifying potential antiviral targets. In this study, we discovered that NS3 can induce the mitochondria-mediated apoptotic pathway through the PERK/PKR pathway; it can also interact with voltage-dependent anion channel 2 to induce apoptosis. Our findings provide a theoretical basis for understanding the pathogenic mechanism of DTMUV infection and identifying potential antiviral targets and may also serve as a reference for exploring the pathogenesis of other flaviviruses.

Advances in Nanoplatforms for Immunotherapy Applications Targeting the Tumor Microenvironment.

Cancer immunotherapy is a treatment method that activates or enhances the autoimmune response of the body to fight tumor growth and metastasis, has fewer toxic side effects and a longer-lasting efficacy than radiotherapy and chemotherapy, and has become an important means for the clinical treatment of cancer. However, clinical results from immunotherapy have shown that most patients lack responsiveness to immunotherapy and cannot benefit from this treatment strategy. The tumor microenvironment (TME) plays a critical role in the response to immunotherapy. The TME typically prevents effective lymphocyte activation, reducing their infiltration, and inhibiting the infiltration of effector T cells. According to the characteristic differences between the TME and normal tissues, various nanoplatforms with TME targeting and regulation properties have been developed for more precise regulation of the TME and have the ability to codeliver a variety of active pharmaceutical ingredients, thereby reducing systemic toxicity and improving the therapeutic effect of antitumor. In addition, the precise structural design of the nanoplatform can integrate specific functional motifs, such as surface-targeted ligands, degradable backbones, and TME stimulus-responsive components, into nanomedicines, thereby reshaping the tumor microenvironment, improving the body's immunosuppressive state, and enhancing the permeability of drugs in tumor tissues, in order to achieve controlled and stimulus-triggered release of load cargo. In this review, the physiological characteristics of the TME and the latest research regarding the application of TME-regulated nanoplatforms in improving antitumor immunotherapy will be described. Furthermore, the existing problems and further applications perspectives of TME-regulated platforms for cancer immunotherapy will also be discussed.

Recent advances of CREKA peptide-based nanoplatforms in biomedical applications.

Nanomedicine technology is a rapidly developing field of research and application that uses nanoparticles as a platform to facilitate the diagnosis and treatment of diseases. Nanoparticles loaded with drugs and imaging contrast agents have already been used in clinically, but they are essentially passive delivery carriers. To make nanoparticles smarter, an important function is the ability to actively locate target tissues. It enables nanoparticles to accumulate in target tissues at higher concentrations, thereby improving therapeutic efficacy and reducing side effects. Among the different ligands, the CREKA peptide (Cys-Arg-Glu-Lys-Ala) is a desirable targeting ligand and has a good targeting ability for overexpressed fibrin in different models, such as cancers, myocardial ischemia-reperfusion, and atherosclerosis. In this review, the characteristic of the CREKA peptide and the latest reports regarding the application of CREKA-based nanoplatforms in different biological tissues are described. In addition, the existing problems and future application perspectives of CREKA-based nanoplatforms are also addressed.

Effects of blood pressure and antihypertensive drugs on osteoarthritis: a mendelian randomized study.

BACKGROUND: Previous studies have suggested that antihypertensive drugs may play a role in the treatment of osteoarthritis, but these studies may be limited by confounding factors and lead to biased results. Therefore, we conducted a Mendelian randomization study to investigate the effects of blood pressure and antihypertensive drugs on osteoarthritis. METHODS: We used published large-scale genome-wide association data and applied univariate and multivariate Mendelian randomization methods. The main analysis model was inverse variance weighting, and the reliability of the results was tested using MR-Egger intercept analysis, Cochran's Q test, and leave-one-out analysis. We comprehensively evaluated the relationship between systolic blood pressure, diastolic blood pressure, 12 antihypertensive drugs, and osteoarthritis. We also conducted verification in the independent queue of UK Biobank and built a simple linear regression model to obtain an independent comparison. RESULTS: We found no evidence that systolic and diastolic blood pressure significantly affected osteoarthritis. However, among antihypertensive drugs, we observed a significant positive correlation between potassium-preserving diuretics and aldosterone antagonists and all osteoarthritis (OR: 0.560, 95% CI 0.406-0.772, P = 0.0004). Sensitivity analysis showed no horizontal pleiotropy or heterogeneity, and the leave-one-out analysis demonstrated the reliability of the results. This result was replicated with nominally statistical significance in the validation cohort and exhibited significant correlation in the linear regression analysis. CONCLUSIONS: Our study suggested that controlling the protein targets of potassium-sparing diuretics and aldosterone antagonists may have beneficial results for osteoarthritis. These findings provide valuable medication strategies for the control of hypertension in patients with osteoarthritis.

RNA-Seq analysis of duck embryo fibroblast cells gene expression during duck Tembusu virus infection.

Duck Tembusu virus (DTMUV), a member of the family Flaviviridae and an economically important pathogen with a broad host range, leads to markedly decreased egg production. However, the molecular mechanism underlying the host-DTMUV interaction remains unclear. Here, we performed high-throughput RNA sequencing (RNA-Seq) to study the dynamic changes in host gene expression at 12, 24, 36, 48 and 60 h post-infection (hpi) in duck embryo fibroblasts (DEF) infected with DTMUV. A total of 3129 differentially expressed genes (DEG) were identified after DTMUV infection. Gene Ontology (GO) category and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis revealed that these DEG were associated with multiple biological functions, including signal transduction, host immunity, virus infection, cell apoptosis, cell proliferation, and pathogenicity-related and metabolic process signaling pathways. This study analyzed viral infection and host immunity induced by DTMUV infection from a novel perspective, and the results provide valuable information regarding the mechanisms underlying host-DTMUV interactions, which will prove useful for the future development of antiviral drugs or vaccines for poultry, thus benefiting the entire poultry industry.

Duck Tembusu virus infection induces mitochondrial-mediated and death receptor-mediated apoptosis in duck embryo fibroblasts.

Duck Tembusu virus (DTMUV) is a pathogenic flavivirus that has caused enormous economic losses in Southeast Asia. Our previous study showed that DTMUV could induce duck embryo fibroblast (DEF) apoptosis, but the specific mechanism was not clear. In this study, we confirmed that DTMUV could induce the apoptosis of DEFs by DAPI staining and TUNEL staining. Furthermore, we found that the expression levels of cleaved-caspase-3/7/8/9 were significantly upregulated after DTMUV infection. After treatment of cells with an inhibitor of caspase-8 or caspase-9, DTMUV-induced apoptosis rates were significantly decreased, indicating that the caspase-8-mediated death receptor apoptotic pathway and caspase-9-mediated mitochondrial apoptotic pathway were involved in DTMUV-induced apoptosis. Moreover, we found that DTMUV infection not only caused the release of mitochondrial cytochrome C (Cyt C) and the downregulation of the apoptosis-inhibiting protein Bcl-2 but also reduced the mitochondrial membrane potential (MMP) and the accumulation of intracellular reactive oxygen species (ROS). Key genes in the mitochondrial apoptotic pathway and death receptor apoptotic pathway were upregulated to varying degrees, indicating the activation of the mitochondrial apoptosis pathway and death receptor apoptosis pathway. In conclusion, this study clarifies the molecular mechanism of DTMUV-induced apoptosis and provides a theoretical basis for revealing the pathogenic mechanism of DTMUV infection.

Computed tomography-guided radiofrequency ablation of cervical intervertebral discs for the treatment of refractory cervicogenic headache: A retrospective chart review.

OBJECTIVE: To evaluate the feasibility and efficacy of computed tomography (CT)-guided radiofrequency ablation (RFA) of cervical intervertebral discs for the treatment of discogenic cervicogenic headache (CEH). BACKGROUND: Some patients with CEH experience no obvious therapeutic effect after conventional therapy, particularly patients with refractory CEH originating from abnormal cervical intervertebral discs. Treatment for this type of CEH remains poorly characterized. METHODS: Using a single intervention arm, pretest/posttest design, we retrospectively analyzed the data of patients who underwent CT-guided RFA of cervical intervertebral discs for CEH at the Pain Medicine Center of Zhejiang Provincial People's Hospital from January 2017 to April 2021. If conservative treatment failed in patients with discogenic CEH, we classified the patients as having refractory CEH and performed RFA of cervical intervertebral discs. We used a numeric rating scale (NRS) to assess pain intensity for 6 months. We also compared therapeutic outcome of patients with different characteristics. RESULTS: A total of 44 patients who underwent CT-guided RFA of cervical intervertebral discs were enrolled and 41 of them were analyzed in the present study. The preoperative median (25th, 75th) NRS score was 4 (4, 5), and it was significantly reduced to 1 (0, 4) 6 months after RFA (p < 0.001). The number of patients with ≥50% of their pain relieved after 6 months was 28 of 41 (68%). No serious treatment-related complications occurred in this study. Compared with single-level RFA, multi-level RFA shows greater effects on pain intensity reduction (p = 0.032) and pain relief rate (p = 0.047) of patients. CONCLUSION: In patients who have discogenic CEH, CT-guided RFA of the cervical intervertebral discs appears to be a promising treatment with no serious complications.

Linking doctor-patient relationship to medical residents' work engagement: The influences of role overload and conflict avoidance.

BACKGROUND: Chinese residents' practical work experiences are different from those described in Western studies. To explore potential mechanisms underlying the effects of doctor-patient relationships on medical residents' work engagement, verifying a posited mediating effect of role overload, and moderating effect of conflict avoidance, in the Chinese context. METHODS: Based on the conservation of resources theory, a composite model was constructed. This study's data were collected from four different Chinese tertiary hospitals; 195 residents undergoing regularization training took this survey. Hierarchical moderated and mediated regression analyses were utilized. RESULTS: Doctor-patient relationship were found to be positively related to residents' work engagement (ß=0.31, p≤0.001). Role overload partially mediated the effect of these relationships on work engagement, and the moderating role of conflict avoidance in the relationship between doctor-patient relationship and conflict avoidance was negative. CONCLUSION: Maintaining good doctor-patient relationship can prompt residents to increase their engagement in work in order to meet their patients' needs. Furthermore, role overload has a particular influence in early career stages. Not only is it necessary for residents to gain a sense of recognition and support while they carry out their job responsibilities, especially while dealing with complex doctor-patient relationship, but it is also important to create work environments that can help residents shape their professional competency.

[Comparison between peel and pulp of Aurantii Fructus Immaturus by UPLC fingerprint and multicomponent quantitative analysis].

Twenty batches of Aurantii Fructus Immaturus(AFI) were collected, with their peel and pulp taken as research objects. Ultra-high performance liquid chromatography(UPLC) fingerprints of peel and pulp of AFI were established with 17 common peaks in peel and 10 in pulp. Six kinds of flavonoids were identified, i.e., narirutin, naringin, rhoifolin, hesperidin, neohesperidin and nobiletin. The Similarity Evaluation System for Chromatographic Fingerprint of Traditional Chinese Medicine was employed for similarity analysis, which showed that the chromatographic peaks of peel and pulp were basically similar to their respective reference fingerprints, with all similarities greater than 0.90. The similarity between peel and pulp of the same batch of AFI ranged from 0.850 to 0.983. Cluster analysis(CA), principal component analysis(PCA), and orthogonal partial least squares discriminant analysis(OPLS-DA) were conducted on the common peaks of peel and pulp of AFI with SPSS 17.0 and SIMCA 14.1. Combined with the reference fingerprints, these analyses revealed 12 differential components regarding peel and pulp. Further, the content of the 6 flavonoids and synephrine was determined. The proposed method integrating UPLC fingerprint and multicomponent quantitative analysis is applicable to the quality evaluation of AFI. The results provide a certain basis for the scientific connotation about the appearance characteristic of AFI.

Exposure of tomato (Lycopersicon esculentum) to silver nanoparticles and silver nitrate: physiological and molecular response.

Silver nanoparticles (AgNPs) are among the most widely used nanomaterials, with applications in sectors as diverse as communications, energy, medicine, and agriculture. This diverse application of AgNPs increases the risk of the release of these materials into the environment and raises the potential for transfer into plants and, subsequently, the human body. To better understand the effects of NPs in agricultural systems, this study investigates plant physiological and molecular responses upon exposure to AgNPs in comparison to silver nitrate (AgNO3). Tomato seedlings (Lycopersison esculentum) were exposed to 10, 20, or 30 mg/L silver (Ag), AgNO3, or AgNPs in hydroponic media for 7 days. A number of endpoints were measured, including plant growth, photosynthetic pigments, oxidative and antioxidant responses. The results showed 2-7 times lower growth rate in plants exposed to silver compared to the control. H2O2 and malondialdehyde as oxidative stress indicators were, respectively, 1.7 and 4 times higher in plants exposed to all forms of silver compared to the control. The antioxidative responses increased significantly in plants exposed to Ag and AgNPs compared to the control. However, plants exposed to AgNO3 showed up to 50% lower enzymatic antioxidant activity. At the molecular level, the expression of genes involved in defense responses, including ethylene-inducing xylanase (EIX), peroxidase 51 (POX), and phenylalanine ammonia lyase, were significantly upregulated upon exposure to silver. The molecular and physiological data showed exposure to all forms of silver resulted in oxidative stress and exposure to AgNPs induced antioxidative and defense responses. However, exposure to AgNO3 resulted in phytotoxicity and failure in antioxidative responses. It indicates the higher reactivity and phytotoxicity of the ionic form of silver compared to NPs. The findings of this study add important information to efforts in attempting to characterize the exposure and risk associated with the release of nanomaterials in the environment.

C14orf93 (RTFC) is identified as a novel susceptibility gene for familial nonmedullary thyroid cancer.

The genetic causes for familial nonmedullary thyroid cancer (FNMTC) remain largely unknown. Through genetic linkage analysis and exome sequencing, C14orf93 (RTFC), PYGL, and BMP4 were identified as susceptibility gene candidates in a FNMTC family. By examining the expression and the oncogenic functions of these candidate genes, PYGL and BMP4 were excluded. We further characterized the functions of the uncharacterized gene RTFC in thyroid cancer. RTFC promotes thyroid cancer cell survival under starving conditions, and thyroid cancer cell migration. The R115Q, V205M and G209D RTFC mutants enhance the colony forming capacity of thyroid cancer cells, and are able to transform normal thyroid cells. In summary, our data suggest the roles of RTFC in thyroid carcinogenesis.

CT-Guided Radiofrequency Ablation Targeting the Herniation Edge of the Cervical Disc for the Treatment of Neck Pain: A Retrospective Study.

INTRODUCTION: Sinuvertebral nerve overactivation is one of the mechanisms of neck pain caused by cervical disc herniation. Radiofrequency ablation (RFA) of sinuvertebral nerves has shown efficacy for the treatment of discogenic low back pain. However, relatively few studies evaluated the efficacy of RFA of sinuvertebral nerves for the treatment of chronic neck pain caused by cervical disc herniation. METHODS: Clinical data were retrospectively collected from 168 patients diagnosed with cervical disc herniated neck pain from January 1, 2019, to September 1, 2022, who were treated with computed tomography (CT)-guided cervical disc RFA of at the Pain Medicine Center of Zhejiang Provincial People's Hospital. A 22-G RFA needle (Inomed, Emmendingen, Germany) was inserted between the carotid artery and trachea to the intervertebral disc under the direction of CT the scanner. Depending on the position of the protruding nucleus pulposus or the rupture of the annulus fibrosus, the needle was inserted into the posterior side of the intervertebral disc until the tip of the needle reached the target position. The numeric rating scale (NRS) score, pain relief and appearance of complications after RFA were evaluated. RESULTS: A total of 168 patients underwent CT-guided RFA for cervical disc herniation. The average duration of pain was 67.07 ± 70.42 months. At 6 months of follow-up, the median preoperative NRS score decreased significantly from preoperative 5.41 ± 1.08 to postoperative 1.341 ± 1.25 at 1 month, 1.4 ± 1.38 at 3 months and 1.72 ± 1.41 at 6 months after RFA (p < 0.01). The numbers of patients with ≥ 50% of their neck pain relieved were 84% (141/168), 87% (147/168), 87% (147/168) and 79% (133/168) at 1 day, 1 month, 3 months and 6 months after RFA, respectively. No serious complications related to treatment or long-term complications were observed. CONCLUSIONS: This study highlights that CT-guided RFA targeting the edge of cervical disc herniation to destroy the sinuvertebral nerves can effectively relieve neck pain, and the computed tomography (CT)-guided RFA treatment strategy has the advantages of having few complications.

Differential distribution of characteristic constituents in peel and pulp of Aurantii Fructus Immaturus (Citrus aurantium L.) using MALDI mass spectrometry imaging.

Aurantii Fructus Immaturus (AFI) was structurally divided into two parts named "peel" and "pulp". The exocarp and mesocarp of materials named "peel". The endocarp separated into multiple compartments and the cystic hair attached to it named "pulp". In order to explore the distribution and content of constituents in AFI, an efficient method to explore the distribution of constituents was developed based on matrix assisted laser desorption/ionization fourier transform ion cyclotron resonance mass spectrometry imaging (MALDI-FTICR-MSI). After simple processing, thirty-two constituents with distinct localization in the mass range of 101-1200 Da were identified by MALDI-FTICR-MSI. In addition, the identified four flavnoids (poncirin, sinensetin, 3,5,6,7,8,3',4'-heptemthoxyflavone, and tangeritin) were analyzed for differences between using LC-MS. Quantitative analysis results supported the quantitative results from MALDI-FT-ICR-MSI. The results implied that different parts had different constituents in AFI, and demonstrated MALDI-MSI have high potential in the direct analysis of constituents.

Exploring the association between grip strength and adverse pregnancy and perinatal outcomes: A Mendelian randomization study.

Background: Previous observational studies have demonstrated an association between grip strength and detrimental pregnancy and perinatal outcomes. However, the causality of this relationship remains uncertain. Objective: This study aims to investigate if there is a causal relationship between grip strength and adverse pregnancy and perinatal outcomes, providing evidence to support active intervention for adverse pregnancy outcomes. Study design: A two-sample Mendelian randomization method was used to select GWAS data from the UK Biobank and the FinnGen Biobank as data sources. The inverse variance weighting method was used as the main analysis method. The reliability of the results was verified through sensitivity analysis, including Cochran's Q test, MR-egger intercept regression analysis, leave-one-out analysis, and funnel plot. Independent queues are also used to verify the reliability of the results. Results: The study demonstrated a significant positive correlation between genetically predicted hand grip strength and offspring birth weight, specifically left-hand grip strength (ß = 0.193, 95 % CI: 0.099-0.286, p = 0.0001) and right-hand grip strength (ß = 0.310, 95 % CI: 0.235-0.384, p = 3.27E-16). Sensitivity analysis indicated no horizontal multi-effect, and leave-one-out analysis along with the funnel plot showed no abnormalities. The verification queue also yielded similar results. Conclusion: This study revealed a significant association between grip strength-related traits and offspring birth weight, suggesting a potential protective effect. Moreover, a negative predictive trend was observed for other adverse pregnancy outcomes. Modifying grip strength through an active lifestyle and continuous monitoring of pregnant women's grip strength may have implications for improving pregnancy outcomes. However, further research is warranted to investigate these findings more comprehensively.

The differentiation of Lgr5+ progenitor cells on nanostructures of self-assembled silica beads.

Supporting cells(SCs) have been demonstrated to be a reliable source for regenerating hair cells(HCs). Previous research has reported that Lgr5+ SCs can regenerate HCs both in vitro and in vivo. However, there is limited knowledge about the impact of the material on Lgr5+ cells. In this study, Lgr5+ cells were isolated from neonatal Lgr5-EGFP-CreERT2 transgenic mice by flow cytometry and then plated on self-assembled silica beads (SB). Lgr5+ cell differentiation was observed by immunofluorescence. We found that in the direct differentiation assay, the SB group generated more hair cells than the control group(*p < 0.05). Especially in the SB group, Lgr5+ progenitors generated significantly more Myo7a+ HCs outside of the colony than in the control group(**p < 0.01). In the sphere differentiation assay, we found that the diameter of spheres in the SB group was significantly larger compared to those of the control group(**p < 0.01). However, the difference in the ratio of myo7a+ cell counts was not obvious(P>0.05). The experiment proved that the self-assembled silica beads could promote the differentiation of Lgr5+ progenitors in vitro. Our findings implicate that nanostructures of self-assembled silica beads can be used as vectors for stem cell research in the inner ear.

Ultrasound image-based nomogram combining clinical, radiomics, and deep transfer learning features for automatic classification of ovarian masses according to O-RADS.

Background: Accurate and rapid discrimination between benign and malignant ovarian masses is crucial for optimal patient management. This study aimed to establish an ultrasound image-based nomogram combining clinical, radiomics, and deep transfer learning features to automatically classify the ovarian masses into low risk and intermediate-high risk of malignancy lesions according to the Ovarian- Adnexal Reporting and Data System (O-RADS). Methods: The ultrasound images of 1,080 patients with 1,080 ovarian masses were included. The training cohort consisting of 683 patients was collected at the South China Hospital of Shenzhen University, and the test cohort consisting of 397 patients was collected at the Shenzhen University General Hospital. The workflow included image segmentation, feature extraction, feature selection, and model construction. Results: The pre-trained Resnet-101 model achieved the best performance. Among the different mono-modal features and fusion feature models, nomogram achieved the highest level of diagnostic performance (AUC: 0.930, accuracy: 84.9%, sensitivity: 93.5%, specificity: 81.7%, PPV: 65.4%, NPV: 97.1%, precision: 65.4%). The diagnostic indices of the nomogram were higher than those of junior radiologists, and the diagnostic indices of junior radiologists significantly improved with the assistance of the model. The calibration curves showed good agreement between the prediction of nomogram and actual classification of ovarian masses. The decision curve analysis showed that the nomogram was clinically useful. Conclusion: This model exhibited a satisfactory diagnostic performance compared to junior radiologists. It has the potential to improve the level of expertise of junior radiologists and provide a fast and effective method for ovarian cancer screening.

Causal impact of human blood metabolites and metabolic pathways on serum uric acid and gout: a mendelian randomization study.

Objective: Hyperuricaemia and gout are common metabolic disorders. However, the causal relationships between blood metabolites and serum urate levels, as well as gout, remain unclear. A systematic evaluation of the causal connections between blood metabolites, hyperuricemia, and gout could enhance early screening and prevention of hyperuricemia and gout in clinical settings, providing novel insights and approaches for clinical treatment. Methods: In this study, we employed a bidirectional two-sample Mendelian randomization analysis utilizing data from a genome-wide association study involving 7,286 participants, encompassing 486 blood metabolites. Serum urate and gout data were sourced from the Chronic Kidney Disease Genetics consortium, including 288,649 participants for serum urate and 9,819 African American and 753,994 European individuals for gout. Initially, LDSC methodology was applied to identify blood metabolites with a genetic relationship to serum urate and gout. Subsequently, inverse-variance weighting was employed as the primary analysis method, with a series of sensitivity and pleiotropy analyses conducted to assess the robustness of the results. Results: Following LDSC, 133 blood metabolites exhibited a potential genetic relationship with serum urate and gout. In the primary Mendelian randomization analysis using inverse-variance weighting, 19 blood metabolites were recognized as potentially influencing serum urate levels and gout. Subsequently, the IVW p-values of potential metabolites were corrected using the false discovery rate method. We find leucine (IVW P FDR = 0.00004), N-acetylornithine (IVW P FDR = 0.0295), N1-methyl-3-pyridone-4-carboxamide (IVW P FDR = 0.0295), and succinyl carnitine (IVW P FDR = 0.00004) were identified as significant risk factors for elevated serum urate levels. Additionally, 1-oleoylglycerol (IVW P FDR = 0.0007) may lead to a substantial increase in the risk of gout. Succinyl carnitine exhibited acceptable weak heterogeneity, and the results for other blood metabolites remained robust after sensitivity, heterogeneity, and pleiotropy testing. We conducted an enrichment analysis on potential blood metabolites, followed by a metabolic pathway analysis revealing four pathways associated with serum urate levels. Conclusion: The identified causal relationships between these metabolites and serum urate and gout offer a novel perspective, providing new mechanistic insights into serum urate levels and gout.

Noncovalently particle-anchored cytokines with prolonged tumor retention safely elicit potent antitumor immunity.

Preclinical studies have shown that immunostimulatory cytokines elicit antitumor immune responses but their clinical use is limited by severe immune-related adverse events upon systemic administration. Here, we report a facile and versatile strategy for noncovalently anchoring potent Fc-fused cytokine molecules to the surface of size-discrete particles decorated with Fc-binding peptide for local administration. Following intratumoral injection, particle-anchored Fc cytokines exhibit size-dependent intratumoral retention. The 1-micrometer particle prolongs intratumoral retention of Fc cytokine for over a week and has minimal systemic exposure, thereby eliciting antitumor immunity while eliminating systemic toxicity caused by circulating cytokines. In addition, the combination of these particle-anchored cytokines with immune checkpoint blockade antibodies safely promotes tumor regression in various syngeneic tumor models and genetically engineered murine tumor models and elicits systemic antitumor immunity against tumor rechallenge. Our formulation strategy renders a safe and tumor-agnostic approach that uncouples cytokines' immunostimulatory properties from their systemic toxicities for potential clinical application.

Ultrasound radiomics-based artificial intelligence model to assist in the differential diagnosis of ovarian endometrioma and ovarian dermoid cyst.

Background: Accurately differentiating between ovarian endometrioma and ovarian dermoid cyst is of clinical significance. However, the ultrasound appearance of these two diseases is variable, occasionally causing confusion and overlap with each other. This study aimed to develop a diagnostic classification model based on ultrasound radiomics to intelligently distinguish and diagnose the two diseases. Methods: We collected ovarian ultrasound images from participants diagnosed as patients with ovarian endometrioma or ovarian dermoid cyst. Feature extraction and selection were performed using the Mann-Whitney U-test, Spearman correlation analysis, and the least absolute shrinkage and selection operator (LASSO) regression. We then input the final features into the machine learning classifiers for model construction. A nomogram was established by combining the radiomic signature and clinical signature. Results: A total of 407 participants with 407 lesions were included and categorized into the ovarian endometriomas group (n = 200) and the dermoid cyst group (n = 207). In the test cohort, Logistic Regression (LR) achieved the highest area under curve (AUC) value (0.981, 95% CI: 0.963-1.000), the highest accuracy (94.8%), and the highest sensitivity (95.5%), while LightGBM achieved the highest specificity (97.1%). A nomogram incorporating both clinical features and radiomic features achieved the highest level of performance (AUC: 0.987, 95% CI: 0.967-1.000, accuracy: 95.1%, sensitivity: 88.0%, specificity: 100.0%, PPV: 100.0%, NPV: 88.0%, precision: 93.6%). No statistical difference in diagnostic performance was observed between the radiomic model and the nomogram (P > 0.05). The diagnostic indexes of radiomic model were comparable to that of senior radiologists and superior to that of junior radiologist. The diagnostic performance of junior radiologists significantly improved with the assistance of the model. Conclusion: This ultrasound radiomics-based model demonstrated superior diagnostic performance compared to those of junior radiologists and comparable diagnostic performance to those of senior radiologists, and it has the potential to enhance the diagnostic performance of junior radiologists.