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Objective To prioritize genes that were pleiotropically or potentially causally associated with central corneal thickness (CCT). Methods We applied the summary data-based Mendelian randomization (SMR) method integrating summarized data of genome-wide association study (GWAS) on CCT and expression quantitative trait loci (eQTL) data to identify genes that were pleiotropically associated with CCT. We performed separate SMR analysis using CAGE eQTL data and GTEx eQTL data. SMR analyses were done for participants of European and East Asian ancestries, separately. Results We identified multiple genes showing pleiotropic association with CCT in the participants of European ancestry. CLIC3 (ILMN_1796423; P SMR  = 4.15 × 10 − 12 ), PTGDS (ILMN_1664464; P SMR  = 6.88 × 10 − 9 ) and C9orf142 (ILMN_1761138; P SMR  = 8.09 × 10 − 9 ) were the top three genes using the CAGE eQTL data, and RP11-458F8.4 (ENSG00000273142.1; P SMR  = 5.89 × 10 − 9 ), LCNL1 (ENSG00000214402.6; P SMR  = 5.67 × 10 − 8 ), and PTGDS (ENSG00000107317.7; P SMR  = 1.92 × 10 − 7 ) were the top three genes using the GTEx eQTL data. No genes showed significantly pleiotropic association with CCT in the participants of East Asian ancestry after correction for multiple testing. Conclusion We identified several genes pleiotropically associated with CCT, some of which represented novel genes influencing CCT. Our findings provided important leads to a better understanding of the genetic factors influencing CCT, and revealed potential therapeutic targets for the treatment of primary open-angle glaucoma and keratoconus.

This prospective clinical study was to compare the effect of panretinal photocoagulation (PRP) associated with intravitreal conbercept injections versus PRP alone in the treatment of proliferative diabetic retinopathy (PDR). For each of 15 patients included, one eye was randomly assigned to receive treatment with PRP, and the other eye received conbercept combined PRP. Ophthalmic examinations, optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) were performed at baseline and at each monthly visit until 6 months. Fluorescein angiography (FA) was acquired at baseline, 3 months and 6 months. Between group and within group analysis was done by using generalized estimating equations (GEE). The combination group had a significant decrease of neovascularization (NV) leakage area than the PRP group at month 3 and month 6 after treatment, and a better best-corrected visual acuity (BCVA) during the first three months. Within-group analysis indicated a significant decrease in NV leakage at month 3 and month 6 in both groups, and a significant increase in BCVA at 1 month in the combination group. In summary, the combination of intravitreal injection of conbercept and PRP can significantly reduce the NV of PDR patients and achieve better BCVA during the drug’s lifespan compared with PRP alone.

This study explored the interventional role and potential mechanism of total flavonoids from lychee seeds (TFL) on rats with liver fibrosis, focusing on the LPS/TLR2/4 signaling pathway and intestinal mucosal barrier theories. Male Sprague-Dawley (SD) rats were randomly divided into six groups: Control, Model, Silymarin (43.19 mg·kg⁻¹), TFL low dose (TFL-L, 25 mg·kg⁻¹), TFL medium dose (TFL-M, 50 mg·kg⁻¹), and TFL high dose (TFL-H, 100 mg·kg⁻¹). All groups received oral administration once daily for six weeks. Histopathological evaluations of liver tissues were conducted using HE and Masson staining, while fibrosis scores were assessed. Colon tissues were examined by HE staining for signs of inflammation and cellular infiltration. Immunohistochemistry detected the expression of tight junction proteins ZO-1, occludin, claudin 1, and claudin 4 related to the intestinal barrier. Serum levels of HA, IV-C, LN, PC-III, ALT, AST, and LPS were determined via ELISA. RT-qPCR was used to measure gene expression levels of TNF-α, IL-6, IL-1β, Ccl2, Ccl4, TLR2, TLR4 in liver tissue, and ZO-1, occludin, claudin 1, and claudin 4 in colon tissue. Compared to the Control group, the Model group exhibited significantly higher fibrosis scores, increased serum LPS, ALT, AST, LN, HA, IV-C, and PC-III levels, as well as elevated relative expression levels of Ccl2, TLR2, TLR4, IL-6, IL-1β, and TNF-α genes. After treatment with TFL, pathological scores in all TFL groups were significantly reduced, along with decreased serum levels of LPS, ALT, AST, HA, IV-C, and PC-III compared to the Model group. The relative expression levels of Ccl2, TLR2, TLR4, IL-1β, IL-6, and TNF-α genes in the TFL-H group were also notably lower than those in the Model group. No significant differences were observed in the relative expression of Ccl4 across groups. In addition, the expression of various tight junction-related proteins in the colonic mucosa of the Model group was significantly reduced, whereas the TFL-H group showed significantly richer staining compared to the Model group. TFL demonstrates a good anti-fibrotic effect, with a clear dose-response relationship, where the highest dosage produced the best results. Its anti-fibrotic effect may be associated with restoring intestinal mucosal barrier function and inhibiting the LPS/TLR2/4 signaling pathway.

The recently emerged Omicron (B.1.1.529) variant has rapidly surpassed Delta to become the predominant circulating SARS-CoV-2 variant, given the higher transmissibility rate and immune escape ability, resulting in breakthrough infections in vaccinated individuals. A new generation of SARS-CoV-2 vaccines targeting the Omicron variant are urgently needed. Here, we developed a subunit vaccine named RBD-HR/trimer by directly linking the sequence of RBD derived from the Delta variant (containing L452R and T478K) and HR1 and HR2 in SARS-CoV-2 S2 subunit in a tandem manner, which can self-assemble into a trimer. In multiple animal models, vaccination of RBD-HR/trimer formulated with MF59-like oil-in-water adjuvant elicited sustained humoral immune response with high levels of broad-spectrum neutralizing antibodies against Omicron variants, also inducing a strong T cell immune response in vivo. In addition, our RBD-HR/trimer vaccine showed a strong boosting effect against Omicron variants after two doses of mRNA vaccines, featuring its capacity to be used in a prime-boost regimen. In mice and non-human primates, RBD-HR/trimer vaccination could confer a complete protection against live virus challenge of Omicron and Delta variants. The results qualified RBD-HR/trimer vaccine as a promising next-generation vaccine candidate for prevention of SARS-CoV-2, which deserved further evaluation in clinical trials. The SARS-CoV-2 Omicron variant has quickly become the predominant circulating variant, due to the high transmissibility and immune escape. Here, the authors develop a trimeric protein vaccine candidate and show a sustained humoral immune response, and protection from challenge (Omicron and Delta) in various animal models.

Previous genome-wide association studies (GWAS) have identified potential genetic variants associated with the risk of major depressive disorder (MDD), but the underlying biological interpretation remains largely unknown. We aimed to prioritize genes that were pleiotropically or potentially causally associated with MDD. We applied the summary data-based Mendelian randomization (SMR) method integrating GWAS and gene expression quantitative trait loci (eQTL) data in 13 brain regions to identify genes that were pleiotropically associated with MDD. In addition, we repeated the analysis by using the meta-analyzed version of the eQTL summary data in the brain (brain-eMeta). We identified multiple significant genes across different brain regions that may be involved in the pathogenesis of MDD. The prime-specific gene BTN3A2 (corresponding probe: ENSG00000186470.9) was the top hit showing pleiotropic association with MDD in 9 of the 13 brain regions and in brain-eMeta, after correction for multiple testing. Many of the identified genes are located in the human major histocompatibility complex (MHC) region on chromosome 6 and are mainly involved in the immune response. Our SMR analysis indicated that multiple genes showed pleiotropic association with MDD across the brain regions. These findings provided important leads to a better understanding of the mechanism of MDD and revealed potential therapeutic targets for the prevention and effective treatment of MDD.

Mucosal immunity plays a significant role in the first-line defense against viruses transmitted and infected through the respiratory system, such as SARS-CoV-2. However, the lack of effective and safe adjuvants currently limits the development of COVID-19 mucosal vaccines. In the current study, we prepare an intranasal vaccine containing cationic crosslinked carbon dots (CCD) and a SARS-CoV-2 antigen, RBD-HR with spontaneous antigen particlization. Intranasal immunization with CCD/RBD-HR induces high levels of antibodies with broad-spectrum neutralization against authentic viruses/pseudoviruses of Omicron-included variants and protects immunized female BALB/c mice from Omicron infection. Despite strong systemic cellular immune response stimulation, the intranasal CCD/RBD-HR vaccine also induces potent mucosal immunity as determined by the generation of tissue-resident T cells in the lungs and airway. Moreover, CCD/RBD-HR not only activates professional antigen-presenting cells (APCs), dendritic cells, but also effectively targets nasal epithelial cells, promotes antigen binding via sialic acid, and surprisingly provokes the antigen-presenting of nasal epithelial cells. We demonstrate that CCD is a promising intranasal vaccine adjuvant for provoking strong mucosal immunity and might be a candidate adjuvant for intranasal vaccine development for many types of infectious diseases, including COVID-19. Lei et al. show that intranasal immunisation with their vaccine candidate is able to broadly protect mice from SARS-CoV-2 infection, including Omicron variants.

Accurate prediction of the Sharpe ratio, a key metric for risk-adjusted returns in financial markets, remains a significant challenge due to the complex and stochastic nature of stock price movements. This paper introduces a novel deep learning model, the Temporal Fusion Transformer with Adaptive Sharpe Ratio Optimization (TFT-ASRO), designed to address this challenge. The model incorporates real-time market sensor data and financial indicators as input signals, leveraging multiple data streams including price sensors, volume sensors, and market sentiment sensors to capture the complete market state. Using a comprehensive dataset of US historical stock prices and earnings data, we demonstrate that TFT-ASRO outperforms traditional methods and existing deep learning models in predicting Sharpe ratios across various time horizons. The model’s multi-task learning framework, which simultaneously predicts returns and volatility, provides a more nuanced understanding of risk-adjusted performance. Furthermore, our adaptive optimization approach effectively balances the trade-off between return maximization and risk minimization, leading to more robust predictions. Empirical results show that TFT-ASRO achieves a 18% improvement in Sharpe ratio prediction accuracy compared to state-of-the-art baselines, with particularly strong performance in volatile market conditions. The model also demonstrates superior uncertainty quantification, providing reliable confidence intervals for its predictions. These findings have significant implications for portfolio management and investment strategy optimization, offering a powerful tool for financial decision-makers in the era of data-driven investing.

Background Prompt and precise differential diagnosis of biliary atresia (BA) among cholestatic patients is of great importance. Matrix metalloproteinase-7 (MMP-7) holds great promise as a diagnostic marker for BA. This study aimed to investigate the accuracy of age-specific serum MMP-7 for discriminating BA from other cholestatic pediatric patients. Methods This was a single center diagnostic accuracy and validation study including both retrospective and prospective cohorts. Serum MMP-7 concentrations were measured using an ELISA kit, the trajectory of which with age was investigated in a healthy infants cohort aged 0 to 365 days without hepatobiliary diseases ( n  = 284). Clinical BA diagnosis was based on intraoperative cholangiography and subsequent histological examinations. The diagnostic accuracy of age-specific cutoffs of serum MMP-7 were assessed in a retrospective cohort of cholestatic patients ( n  = 318, with 172 BA) and validated in a prospective cohort ( n  = 687, including 395 BA). Results The MMP-7 concentration declines non-linearly with age, showing higher levels in healthy neonates as well as higher cutoff value in neonatal cholestasis. The area under the ROC curve (AUROC) was 0.967 (95% confidence interval [CI]: 0.946–0.988) for the retrospective cohort, and the cutoff of 18 ng/mL yielded 93.0% (95%CI: 88.1-96.3%), 93.8% (95%CI: 88.6-97.1%), 94.7% (95%CI: 90.1-97.5%), and 91.9% (95%CI: 86.4-95.8%) for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), respectively. The performance of MMP-7 was successfully validated in the larger prospective cohort, resulting in a diagnostic sensitivity of 95.9% (379/395; 95% CI: 93.5–97.7%), a specificity of 87.3% (255/292; 95% CI: 83.0–90.9%), a PPV of 91.1% (379/416; 95% CI: 87.9–93.7%), and a NPV of 94.1% (255/271; 95% CI: 90.6–96.6%), respectively. Besides, higher cutoff value of 28.1 ng/mL achieved the best sensitivity, specificity, PPV, and NPV for infants aged 0–30 days, which was 86.4% (95% CI: 75.0–94.0%), 95.5% (95% CI: 77.2–99.9%), 98.1% (95% CI: 89.7–100%), and 72.4% (95% CI: 52.8–87.3%), respectively. Conclusions The serum MMP-7 is accurate and reliable in differentiating BA from non-BA cholestasis, showing its potential application in the diagnostic algorithm for BA and significant role in the future research regarding pathogenesis of BA.

The immune escape capacities of XBB variants necessitate the authorization of vaccines with these antigens. In this study, we produce three recombinant trimeric proteins from the RBD sequences of Delta, BA.5, and XBB.1.5, formulating a trivalent vaccine (Tri-Vac) with an MF59-like adjuvant at a 1:1:4 ratio. Tri-Vac demonstrates immunogenicity in female NIH mice, inducing cross-neutralization against various SARS-CoV-2 variants, including pre-Omicron and Omicron BA.2.75, BA.5, and XBB lineages. It elicits measurable antigen-specific T cell responses, germinal center B cell responses, and T follicular helper responses, effectively protecting against live Omicron XBB.1.16 challenges. Protective immunity is maintained long-term, with sustained neutralizing antibodies and T cell responses, as well as memory B cells and long-lived plasma cells observed by day 210 post-immunization. Tri-Vac also serves as a candidate booster for enhancing immunity after three doses of inactivated virus or mRNA vaccines. A phase 1 investigator-initiated trial was initiated to assess safety and immunogenicity in humans, focusing on the primary endpoint of adverse reactions within 7 days and key secondary endpoints including the geometric mean titers (GMTs) of serum neutralizing antibodies within 30 days and 6 months post-vaccination, as well as adverse events within 30 days and serious adverse events within 6 months post-vaccination. Preliminary data indicate Tri-Vac has good safety and immunogenicity, improving neutralization against multiple variants, including JN.1, in previously vaccinated individuals, highlighting its clinical potential for protecting against SARS-CoV-2 variants. The registration number of this clinical trial is ChiCTR2200067245. SARS-CoV-2 evolves into new subtypes necessitating further vaccine development. Here the authors generate a trivalent vaccine with Receptor Binding Domains from Delta, BA.5 and XBB.1.5 variants and characterize immunogenicity and protection in mice and safety in a phase I vaccine trial in humans.