Novel therapeutic targets for primary open-angle glaucoma identified through multicenter proteome-wide mendelian randomization.

Background: This study aimed to identify novel therapeutic targets for primary open-angle glaucoma (POAG). Methods: The summary-data-based Mendelian randomization (SMR) method was used to evaluate the genetic association between plasma proteins and POAG. Two sets of plasma protein quantitative trait loci (pQTLs) data considered exposures were obtained from the Icelandic Decoding Genetics Study and UK Biobank Pharma Proteomics Project. The summary-level genome-wide association studies data for POAG were extracted from the latest Round 10 release of the FinnGen consortium (8,530 cases and 391,275 controls) and the UK Biobank (4,737 cases and 458,196 controls). Colocalization analysis was used to screen out pQTLs that share the same variant with POAG as drug targets identified. The two-sample Mendelian randomization, reverse causality testing and phenotype scanning were performed to further validate the main findings. Protein-protein interaction, pathway enrichment analysis and druggability assessment were conducted to determine whether the identified plasma proteins have potential as drug targets. Results: After systematic analysis, this study identified eight circulating proteins as potential therapeutic targets for POAG. Three causal proteins with strong evidence of colocalization, ROBO1 (OR = 1.38, p = 1.48 × 10-4, PPH4 = 0.865), FOXO3 (OR = 0.35, p = 4.34 × 10-3, PPH4 = 0.796), ITIH3 (OR = 0.89, p = 2.76 × 10-4, PPH4 = 0.767), were considered tier one targets. Five proteins with medium support evidence of colocalization, NCR1 (OR = 1.25, p = 4.18 × 10-4, PPH4 = 0.682), NID1 (OR = 1.38, p = 1.54 × 10-3, PPH4 = 0.664), TIMP3 (OR = 0.91, p = 4.01 × 10-5, PPH4 = 0.659), SERPINF1 (OR = 0.81, p = 2.77 × 10-4, PPH4 = 0.59), OXT (OR = 1.17, p = 9.51 × 10-4, PPH4 = 0.526), were classified as tier two targets. Additional sensitivity analyses further validated the robustness and directionality of these findings. According to druggability assessment, Pimagedine, Resveratrol, Syringaresinol and Clozapine may potentially be important in the development of new anti-glaucoma agents. Conclusion: Our integrated study identified eight potential associated proteins for POAG. These proteins play important roles in neuroprotection, extracellular matrix regulation and oxidative stress. Therefore, they have promising potential as therapeutic targets to combat POAG.

All-optically controlled mode-coupling induced transparency with tunable efficiency in a microsphere resonator.

The optical analogs of electromagnetically induced transparency (EIT) have attracted vast attention recently. The generation and manipulation of EIT in microcavities have sparked research in both fundamental physics and photonic applications, including light storage, slow light propagation, and optical communication. In this Letter, the generation and tuning of an all-optically controlled mode-coupling induced transparency (MCIT) are proposed, experimentally demonstrated, and theoretically analyzed. The MCIT effect originated from the intermodal coupling between the plethora of modes generated in our fabricated optical microcavity, and the tuning of the transparency mode utilized the cavity's thermal bistability nature. Furthermore, based on our method, a novel, to the best of our knowledge, controlling of the mode shifting efficiency is also achieved with an increase up to two times and more. The proposed scheme paves a unique, simple, and efficient way to manipulate the induced transparency mode, which can be useful for applications like cavity lasing and thermal sensing.

Causal relationships between height, screen time, physical activity, sleep and myopia: univariable and multivariable Mendelian randomization.

Background: This study aims to investigate the independent causal relation between height, screen time, physical activity, sleep and myopia. Methods: Instrumental variables (IVs) for exposures and outcome were obtained from the largest publicly available genome-wide association studies (GWAS) databases. First, we performed a bidirectional univariate MR analysis using primarily the inverse variance weighted method (IVW) with height, screen time, physical activity and sleep as the exposure and myopia as the outcome to investigate the causal relationship between exposures and myopia. Sensitivity analysis was used to demonstrate its robustness. Then the multivariable MR (MVMR) and MR-based mediation approach was further used to estimate the mediating effect of potential confounders (education and time outdoors) on causality. Results: The results of univariate MR analysis showed that taller height (OR = 1.009, 95% CI = 1.005-1.012, p = 3.71 × 10-7), longer time on computer (OR = 1.048, 95% CI = 1.029-1.047, p = 3.87 × 10-7) and less moderate physical activity (OR = 0.976, 95% CI = 0.96-0.991 p = 2.37 × 10-3) had a total effect on the increased risk of developing myopia. Meanwhile our results did not have sufficient evidence to support the causal relationship between chronotype (p = 0.637), sleep duration (p = 0.952) and myopia. After adjusting for education, only taller height remains an independent risk factor for myopia. After adjusting for education, the causal relationship between height, screen and myopia still had statistical significance. A reverse causal relationship was not found in our study. Most of the sensitivity analyses showed consistent results with those of the IVW method. Conclusion: Our MR study revealed that genetically predicted taller height, longer time on computer, less moderate physical activity increased the risk of myopia. After full adjustment for confounders, only height remained independently associated with myopia. As a complement to observational studies, the results of our analysis provide strong evidence for the improvement of myopia risk factors and provide a theoretical basis for future measures to prevent and control myopia in adolescents.

Trends and hot spots in research related to aqueous humor from 2014 to 2023: A bibliometric analysis.

Purpose: To analyze publication trends and investigate research hotspots of aqueous humor (AH) studies. Methods: A bibliometric study was conducted based on the Web of Science Core Collection (WOSCC). VOSviewer v. 1.6.18 was utilized to create a knowledge map visualizing the number of annual publications, the distribution of countries, international collaborations, author productivity, source journals and keywords in the field. Results: A grand total of 4020 peer-reviewed papers concerning AH were retrieved from 2014 to 2023. The United States of America secured the top position among the most published countries and Duke University emerged as the most active institution. Stamer, WD contributed the most papers in this area. Investigative Ophthalmology & Visual Science was the most prolific journal in AH research. Retrieved publications mainly concentrated on the correlation between AH as a biomarker carrier and different ocular disorders. Six clusters were formed based on the keywords: (1) the diagnosis of endophthalmitis and AH pharmacokinetics; (2) the association of AH with pathogenesis and prognosis of glaucoma; (3) diagnosis and treatment of AH associated with uveitis; (4) the relationship between AH and refractive diseases of the eye; (5) the association of AH with mechanism and biomarkers of ocular tumorigenesis; (6) the indicators of AH associated with fundus disease. Conclusions: This study unveiled present patterns of global collaboration, emerging frontiers, fundamental knowledge, research hotspots and current trends in AH.

Application of mendelian randomization in ocular diseases: a review.

Ocular disorders can significantly lower patients' quality of life and impose an economic burden on families and society. However, for the majority of these diseases, their prevalence and mechanisms are yet unknown, making prevention, management, and therapy challenging. Although connections between exposure factors and diseases can be drawn through observational research, it is challenging to rule out the interference of confounding variables and reverse causation. Mendelian Randomization (MR), a method of research that combines genetics and epidemiology, has its advantage to solve this problem and thus has been extensively utilized in the etiological study of ophthalmic diseases. This paper reviews the implementation of MR in the research of ocular diseases and provides approaches for the investigation of related mechanisms as well as the intervention strategies.

Exploration of potential novel drug targets for diabetic retinopathy by plasma proteome screening.

The aim of this study is to identify novel potential drug targets for diabetic retinopathy (DR). A bidirectional two-sample Mendelian randomization (MR) analysis was performed using protein quantitative trait loci (pQTL) of 734 plasma proteins as the exposures and clinically diagnosed DR as the outcome. Genetic instruments for 734 plasma proteins were obtained from recently published genome-wide association studies (GWAS), and external plasma proteome data was retrieved from the Icelandic Decoding Genetics Study and UK Biobank Pharma Proteomics Project. Summary-level data of GWAS for DR were obtained from the Finngen Consortium, comprising 14,584 cases and 202,082 population controls. Steiger filtering, Bayesian co-localization, and phenotype scanning were used to further verify the causal relationships calculated by MR. Three significant (p < 6.81 × 10-5) plasma protein-DR pairs were identified during the primary MR analysis, including CFH (OR = 0.8; 95% CI 0.75-0.86; p = 1.29 × 10-9), B3GNT8 (OR = 1.09; 95% CI 1.05-1.12; p = 5.9 × 10-6) and CFHR4 (OR = 1.11; 95% CI 1.06-1.16; p = 1.95 × 10-6). None of the three proteins showed reverse causation. According to Bayesian colocalization analysis, CFH (coloc.abf-PPH4 = 0.534) and B3GNT8 (coloc.abf-PPH4 = 0.638) in plasma shared the same variant with DR. All three identified proteins were validated in external replication cohorts. Our research shows a cause-and-effect connection between genetically determined levels of CFH, B3GNT8 and CFHR4 plasma proteins and DR. The discovery implies that these proteins hold potential as drug target in the process of developing drugs to treat DR.

Association of autoimmune and allergic diseases with senile cataract: a bidirectional two-sample Mendelian randomization study.

Background: Many observational studies have been reported that patients with autoimmune or allergic diseases seem to have a higher risk of developing senile cataract, but the views are not consistent. In order to minimize the influence of reverse causality and potential confounding factors, we performed Mendelian Randomization (MR) analysis to investigate the genetic causal associations between autoimmune, allergic diseases and senile cataract. Methods: Single nucleotide polymorphisms associated with ten common autoimmune and allergic diseases were obtained from the IEU Open genome-wide association studies (GWAS) database. Summary-level GWAS statistics for clinically diagnosed senile cataract were obtained from the FinnGen research project GWAS, which consisted of 59,522 individuals with senile cataracts and 312,864 control individuals. MR analysis was conducted using mainly inverse variance weighted (IVW) method and further sensitivity analysis was performed to test robustness. Results: As for ten diseases, IVW results confirmed that type 1 diabetes (OR = 1.06; 95% CI = 1.05-1.08; p = 2.24×10-12), rheumatoid arthritis (OR = 1.05; 95% CI = 1.02-1.08; p = 1.83×10-4), hypothyroidism (OR = 2.4; 95% CI = 1.42-4.06; p = 1.12×10-3), systemic lupus erythematosus (OR = 1.02; 95% CI = 1.01-1.03; p = 2.27×10-3), asthma (OR = 1.02; 95% CI = 1.01-1.03; p = 1.2×10-3) and allergic rhinitis (OR = 1.07; 95% CI = 1.02-1.11; p = 2.15×10-3) were correlated with the risk of senile cataract. Celiac disease (OR = 1.04; 95% CI = 1.01-1.08; P = 0.0437) and atopic dermatitis (OR = 1.05; 95% CI = 1.01-1.10; P = 0.0426) exhibited a suggestive connection with senile cataract after Bonferroni correction. These associations are consistent across weighted median and MR Egger methods, with similar causal estimates in direction and magnitude. Sensitivity analysis further proved that these associations were reliable. Conclusions: The results of the MR analysis showed that there were causal relationships between type 1 diabetes, rheumatoid arthritis, hypothyroidism, systemic lupus erythematosus, asthma, allergic rhinitis and senile cataract. To clarify the possible role of autoimmune and allergy in the pathophysiology of senile cataract, further studies are needed.

A review on the mechanisms underlying the antitumor effects of natural products by targeting the endoplasmic reticulum stress apoptosis pathway.

Cancer poses a substantial risk to human life and wellbeing as a result of its elevated incidence and fatality rates. Endoplasmic reticulum stress (ERS) is an important pathway that regulates cellular homeostasis. When ERS is under- or overexpressed, it activates the protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-, inositol-requiring enzyme 1 (IRE1)- and activating transcription Factor 6 (ATF6)-related apoptotic pathways to induce apoptosis. Tumor cells and microenvironment are susceptible to ERS, making the modulation of ERS a potential therapeutic approach for treating tumors. The use of natural products to treat tumors has substantially progressed, with various extracts demonstrating antitumor effects. Nevertheless, there are few reports on the effectiveness of natural products in inducing apoptosis by specifically targeting and regulating the ERS pathway. Further investigation and elaboration of its mechanism of action are still needed. This paper examines the antitumor mechanism of action by which natural products exert antitumor effects from the perspective of ERS regulation to provide a theoretical basis and new research directions for tumor therapy.

Development of corneal contact lens materials and current clinical application of contact lenses: A review.

Unlike conventional glasses, corneal contact lenses (CLs) can directly contact the surface of the tear film through the application of biopolymer materials, to achieve therapeutic and cosmetic purposes. Since the advent of polymethylmethacrylate, a material that has gained widespread use and attention, statistically, there are now more than 150 × 106 people around the world who wear corneal contact lenses. However, the associated complications caused by the interaction of contact lenses with the ocular surface, tear film, endogenous and environmental microorganisms, and components of the solution affect nearly one-third of the wearer population. The application of corneal contact lenses in correcting vision and myopia control has been widely recognized. With the development of related materials, corneal contact lenses are applied to the treatment of ocular surface diseases, including corneal bandage lenses, drug-loaded corneal contact lenses, biosensors, and other new products, while minimizing the side effects associated with CL wear. This paper summarized the development history and material properties of CLs, focused on the current main clinical applications and mechanisms, as well as clarified the possible complications in wearing therapeutic contact lenses and the direction for improvement in the future.

A bibliometric and visual analysis of cancer-associated fibroblasts.

Background: Cancer-associated fibroblasts (CAFs) represent the predominant stromal component within the tumour microenvironment (TME), exhibiting considerable heterogeneity and plasticity that significantly impact immune response and metabolic reprogramming within the TME, thereby influencing tumour progression. Consequently, investigating CAFs is of utmost importance. The objective of this study is to employ bibliometric analysis in order to evaluate the current state of research on CAFs and predict future areas of research and emerging trends. Methods: Conduct a comprehensive search for scholarly publications within the Web of Science Core Collection database, encompassing the time period from January 1, 2001, to December 31, 2022. Apply VOSviewer, CiteSpace, R software and Microsoft Excel for bibliometric analysis and visualisation. Results: This study involved a comprehensive analysis of 5,925 publications authored by 33,628 individuals affiliated with 4,978 institutions across 79 countries/regions. These publications were published in 908 journals, covering 14,495 keywords and 203,947 references. Notably, there was a significant increase in articles published between 2019 and 2022. China had the highest count of articles, while the United States emerged as the most frequently cited country. The primary research institutions in this field were Shanghai Jiao Tong University, Harvard University, and the University of Texas MD Anderson Cancer Center. Sotgia, Federica and Lisanti, Michael P from the University of Manchester, and Martinet, Wim from the University of Antwerp were the most prolific and highly cited authors. The journal Cancers had the highest number of publications, while Cancer Research was the most frequently cited journal. Molecular, biology, immunology, medicine and genetics were the main research disciplines in the field of CAFs. Key directions in CAFs research encompassed the study of transforming growth factor-ß, Fibroblast Activation Protein, breast cancer, as well as growth and metastasis. The findings from the analysis of keyword co-occurrence and literature co-citation have revealed several emerging hotspots and trends within the field of CAFs. These include STAT3, multidrug resistance, pancreatic ductal adenocarcinoma, pan-cancer analysis, preclinical evaluation, ionizing radiation, and gold nanoparticles. Conclusion: Targeting CAFs is anticipated to be a novel and effective strategy for cancer treatment. This study provides a comprehensive overview of the existing research on CAFs from 2001 to 2022, utilizing bibliometric analysis. The study identified the prominent areas of investigation and anticipated future research directions, with the aim of providing valuable insights and recommendations for future studies in the field of CAFs.

Time-domain convolution model for studying oscillation dynamics in an injection-locked optoelectronic oscillator.

A time-domain convolution model is proposed to study the oscillation dynamics in the injection-locked optoelectronic oscillator (OEO). The model has the ability to calculate multiple characteristics of the oscillation signal, such as the spectrum and the phase noise. Based on the model, the injection locking, the frequency pulling and the asymmetrical spectrum generation phenomena are numerically simulated in success. The simulation results fit in with the experimental results, indicating that the proposed model accurately describes the oscillation dynamics in the injection-locked OEO. In addition, the building-up process of the oscillation signal in the OEO is simulated. Alternating appearance of the sidebands on both sides of the primary oscillation mode is observed for the first time in the asymmetrical spectrum generation. This model is a powerful tool to study the oscillation dynamics in the injection-locked OEO.

Andrographolide, a natural anti-inflammatory agent: An Update.

Botanicals have attracted much attention in the field of anti-inflammatory due to their good pharmacological activity and efficacy. Andrographis paniculata is a natural plant ingredient that is widely used around the world. Andrographolide is the main active ingredient derived from Andrographis paniculata, which has a good effect on the treatment of inflammatory diseases. This article reviews the application, anti-inflammatory mechanism and molecular targets of andrographolide in different inflammatory diseases, including respiratory, digestive, immune, nervous, cardiovascular, skeletal, and tumor system diseases. And describe its toxicity and explain its safety. Studies have shown that andrographolide can be used to treat inflammatory lesions of various systemic diseases. In particular, it acts on many inflammation-related signalling pathways. The future direction of andrographolide research is also introduced, as is the recent research that indicates its potential clinical application as an anti-inflammatory agent.

Highly enantioselective aldol reactions between acetaldehyde and activated acyclic ketones catalyzed by chiral primary amines.

Highly enantioselective cross-aldol reactions between acetaldehyde and activated acyclic ketones are reported for the first time. Various acyclic ketones, such as saturated and unsaturated keto esters, reacted with acetaldehyde in the presence of a chiral primary amine and a Brønsted acid to afford optically enriched tertiary alcohols in good yields and with excellent enantioselectivities. Trifluoromethyl ketones were tolerable under the reaction conditions, thereby affording the trifluoromethyl carbinol in good-to-excellent yields and enantioselectivities. Structural modification of the chiral amines from the same chiral source switched the stereoselectivity of the products. The utility of aldol chemistry was demonstrated in the brief synthesis of functionally enriched δ-lactones. Theoretical calculations on the transition-state structure indicated that the protonated tertiary amine could effectively activate the carbonyl group of a keto ester to promote the addition process through hydrogen-bonding interaction and, simultaneously, provide an appropriate attacking pattern for the approach of the keto ester to the enamine, which is formed from acetaldehyde and the chiral catalyst, on a particular face, resulting in high enantioselectivity.