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.

Visualization and analysis of mapping knowledge domains for optic neuritis: a bibliometric research from 2013 to 2022.

PURPOSE: To explore the global research trends, hotspots and frontiers of optic neuritis (ON) over the past decade through qualitative and quantitative analysis of bibliometrics. METHODS: Publications on ON from 2013 to 2022 were retrieved from Web of Science Core Collection (WoSCC). VOSviewer and CiteSpace were mainly used to facilitate bibliometric analysis and visualization. RESULTS: A total of 3027 papers were retrieved from peer-reviewed publications and the annual research output increased over time. Neurosciences neurology was the most published area. The USA was the most productive and influential country, and in the focus of international cooperation. University College London was the most productive organization and Charite Medical University of Berlin had the largest number of cooperating partners. Paul F contributed the largest number of publications and Wingerchuk DM ranked first among the co-cited authors. Multiple Sclerosis and Related Disorders was the most prolific journal publishing ON research. The most co-cited references mainly focused on the diagnostic criteria for neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). The keywords formed the following four clusters: the pathophysiology of MS-ON; the autoantibody markers and diagnostic criteria of NMOSD-ON and myelin oligodendrocyte glycoprotein associated disorder-ON (MOGAD-ON); the epidemiology and clinical characteristics of ON; and the treatment of ON. CONCLUSION: This bibliometrics analysis showed a systematic view of the evolutionary process, research hotspots, and future directions of ON research. It can provide insights for ON research and valuable information for neuro-ophthalmologic specialists to evaluate research policies and promote international cooperation.

Observation of the effect of posterior scleral reinforcement combined with orthokeratology and 0.01% atropine in the treatment of congenital myopia: a case report.

BACKGROUND: Myopia has recently emerged as a significant threat to global public health. The high and pathological myopia in children and adolescents could result in irreversible damage to eye tissues and severe impairment of visual function without timely control. Posterior scleral reinforcement (PSR) can effectively control the progression of high myopia by limiting posterior scleral expansion, improving retrobulbar vascular perfusion, thereby stabilizing the axial length and refraction of the eye. Moreover, orthokeratology and low concentrations of atropine are also effective in slowing myopia progression. CASE PRESENTATION: A female child was diagnosed with binocular congenital myopia and amblyopia at the age of 3 and the patient's vision had never been rectified with spectacles at the first consultation. The patient's ophthalmological findings suggested, high refractive error with low best corrected visual acuity, longer axial length beyond the standard level of her age, and fundus examination suggesting posterior scleral staphyloma with weakened hemodynamics of the posterior ciliary artery. Thereby, PSR was performed to improve fundus health and the combination of orthokeratology and 0.01% atropine were performed to control the development of myopia. Following up to 8 years of clinical treatment and observations, the progression of myopia could be well controlled and fundus health was stable. CONCLUSION: In this report, 8-year of clinical observation indicated that PSR could improve choroidal thickness and hemodynamic parameters of the retrobulbar vessels, postoperative orthokeratology combined with 0.01% atropine treatment strategy may be a good choice for myopia control effectively.

Mapping research trends of chronic ocular graft-versus-host disease from 2009 to 2020: a bibliometric analysis.

PURPOSE: To evaluate the global scientific output of research on ocular chronic Graft versus host disease (cGVHD) and explore the current status and trends in this field over the past decade by bibliometric analysis. METHODS: The bibliometric search was performed in the Web of Science Core Collection (WoSCC) database. VOSviewer v.1.6.16 was used to map the knowledge domain. The annual number of publications and citations, distribution of countries and organizations, productivity of authors and journals, international collaborations, cited references, and keywords in the field of ocular cGVHD were visualized. RESULTS: In total, 398 peer-reviewed publications from 2009 to 2020 on ocular cGVHD were retrieved. The United States among all countries had the highest number of publications and citations, and Keio University was the most effective institution. Dana, R ranks the highest regarding the number of publications and citations on ocular cGVHD. Cornea and Biology of Blood and Marrow Transplantation were the most-cited journals in ocular cGVHD studies from ophthalmology and hematology, respectively. The top-cited references were primarily centered on dry eye. The keywords constituted three clusters: (1) consensus criteria and epidemiology of ocular cGVHD, (2) preclinical medical research of ocular cGVHD, and (3) treatment. CONCLUSION: Based on the data retrieved from WoSCC, a comparative analysis of the quantity and quality of papers on ocular cGVHD was conducted through bibliometric methods. This may contribute to better understanding of the status of ocular cGVHD study. The three major research topics shed new light on the ocular cGVHD study as well as meaningful materials for scholars to identify potential collaborators and promising partner institutions.

Immune-related lncRNAs as predictors of survival in breast cancer: a prognostic signature.

BACKGROUND: Breast cancer is a highly heterogeneous disease, this poses challenges for classification and management. Long non-coding RNAs play acrucial role in the breast cancersdevelopment and progression, especially in tumor-related immune processes which have become the most rapidly investigated area. Therefore, we aimed at developing an immune-related lncRNA signature to improve the prognosis prediction of breast cancer. METHODS: We obtained breast cancer patient samples and corresponding clinical data from The Cancer Genome Atlas (TCGA) database. Immune-related lncRNAs were screened by co-expression analysis of immune-related genes which were downloaded from the Immunology Database and Analysis Portal (ImmPort). Clinical patient samples were randomly separated into training and testing sets. In the training set, univariate Cox regression analysis and LASSO regression were utilized to build a prognostic immune-related lncRNA signature. The signature was validated in the training set, testing set, and whole cohorts by the Kaplan-Meier log-rank test, time-dependent ROC curve analysis, principal component analysis, univariate andmultivariate Cox regression analyses. RESULTS: A total of 937 immune- related lncRNAs were identified, 15 candidate immune-related lncRNAs were significantly associated with overall survival (OS). Eight of these lncRNAs (OTUD6B-AS1, AL122010.1, AC136475.2, AL161646.1, AC245297.3, LINC00578, LINC01871, AP000442.2) were selected for establishment of the risk prediction model. The OS of patients in the low-risk group was higher than that of patients in the high-risk group (p = 1.215e - 06 in the training set; p = 0.0069 in the validation set; p = 1.233e - 07 in whole cohort). The time-dependent ROC curve analysis revealed that the AUCs for OS in the first, eighth, and tenth year were 0.812, 0.81, and 0.857, respectively, in the training set, 0.615, 0.68, 0.655 in the validation set, and 0.725, 0.742, 0.741 in the total cohort. Multivariate Cox regression analysis indicated the model was a reliable and independent indicator for the prognosis of breast cancer in the training set (HR = 1.432; 95% CI 1.204-1.702, p < 0.001), validation set (HR = 1.162; 95% CI 1.004-1.345, p = 0.044), and whole set (HR = 1.240; 95% CI 1.128-1.362, p < 0.001). GSEA analysis revealed a strong connection between the signature and immune-related biological processes and pathways. CONCLUSIONS: We constructed and verified a robust signature of 8 immune-related lncRNAs for the prediction of breast cancer patient survival.

Purification and immobilization of α-amylase in one step by gram-positive enhancer matrix (GEM) particles from the soluble protein and the inclusion body.

Immobilization of the enzyme benefits the catalytic industry a lot. The gram-positive enhancer matrix (GEM) particles could purify and immobilize the recombinant α-amylase in one step without changing the enzymatic character. The enzyme immobilized by GEM particles exhibited good reusability and storage stability. The denaturants dissolved some of the GEM particles and a part of the GEM particles could bear the denaturants. The GEM particles had strong binding ability to the recombination protein with the AcmA tag even when the denaturants existed. The inclusion body was dissolved by urea and then bound by the GEM particles. The GEM particles binding the recombination protein were separated by centrifugation and resuspended in the renaturation solution. GEM particles were recycled by repeating the boiling procedure used in preparing them. The recombination α-amylase without any tag was obtained by digestion and separated via centrifugation. Altogether, our findings suggest that GEM particles have the potential to function as both immobilization and purification materials to bind the soluble recombinant protein with the AcmA tag and the inclusion body dissolved in the denaturants.

Bacterial composition of biofilms formed on dairy-processing equipment.

Polymicrobial biofilms often form on the surfaces of food-processing machinery, causing equipment damage and posing a contamination risk for the foods processed by the system. The composition of the microbial communities that make up these biofilms is largely unknown, especially in the dairy industry. To address this deficit, we investigated the bacterial composition of biofilms that form on the surfaces of equipment during dairy processing using Illumina MiSeq sequencing and culture-dependent methods. Illumina sequencing identified eight phyla, comprising six classes, ten orders, fifteen families, eighteen genera, and eighteen species. In contrast, only eight species were isolated from the same samples using the culture-based method. To determine the ability of the identified bacteria to form biofilms, biofilm formation analysis via crystal violet staining was performed. Five of the eight culturable species, Acinetobacter baumannii, Acinetobacter junii, Enterococcus faecalis, Corynebacterium callunae, and Stenotrophomonas maltophilia, were able to form biofilms. Since most of the identified bacteria are potential food-borne or opportunistic pathogens, this study provides guidance for quality control of products produced in dairy processing facilities.

Expression, regulation and function of miR-126 in the mouse choroid vasculature.

MicroRNA miR-126 has been shown to be required for proper angiogenesis in several models. However, its expression, regulation and function in the mouse choroid remain unclear. Our previous data has shown that miR-126 expression is enriched in the endothelial cells (ECs) of the mouse choroid. Here we report that a 5.5 kb Egfl7/miR-126 promoter drives the expression of miR-126 in the choroid ECs during choroidal vascular development. The expression of miR-126 in the ECs is regulated by flow stress likely through Krüppel-like transcriptional factors. miR-126-/- mice show mildly delayed choroidal vascular development, but adult knockout mice develop periphery choroidal vascular lesions. This study suggests that miR-126 is largely dispensable for mouse choroidal development but required for maintaining choroidal vasculature integrity.

Theme trends and knowledge structure on choroidal neovascularization: a quantitative and co-word analysis.

BACKGROUND: The distribution pattern and knowledge structure of choroidal neovascularization (CNV) was surveyed based on literatures in PubMed. METHODS: Published scientific papers about CNV were retrieved from Jan 1st, 2012 to May 31st, 2017. Extracted MeSH terms were analyzed quantitatively by using Bibliographic Item Co-Occurrence Matrix Builder (BICOMB) and high-frequency MeSH terms were identified. Hierarchical cluster analysis was conducted by SPSS 19.0 according to the MeSH term-source article matrix. High-frequency MeSH terms co-occurrence matrix was constructed to support strategic diagram and social network analysis (SNA). RESULTS: According to the searching strategy, all together 2366 papers were included, and the number of annual papers changed slightly from Jan 1st, 2012 to May 31st, 2017. Among all the extracted MeSH terms, 44 high-frequency MeSH terms were identified and hotspots were clustered into 6 categories. In the strategic diagram, clinical drug therapy, pathology and diagnosis related researches of CNV were well developed. In contrast, the metabolism, etiology, complications, prevention and control of CNV in animal models, and genetics related researches of CNV were relatively immature, which offers potential research space for future study. As for the SNA result, the position status of each component was described by the centrality values. CONCLUSIONS: The studies on CNV are relatively divergent and the 6 research categories concluded from this study could reflect the publication trends on CNV to some extent. By providing a quantitative bibliometric research across a 5-year span, it could help to depict an overall command of the latest topics and provide some hints for researchers when launching new projects.

Optimization and purification of glucansucrase produced by Leuconostoc mesenteroides DRP2-19 isolated from Chinese Sauerkraut.

Strain DRP2-19 was detected to produce high yield of glucansucrase in MRS broth, which was identified to be Leuconostoc mesenteroides. In order for industrial glucansucrase production of L. mesenteroides DRP2-19, a one-factor test was conducted, then response surface method was applied to optimize its yield and discover the best production condition. Based on Plackett-Burman (PB) experiment, sucrose, Ca2+, and initial pH were found to be the most significant factors for glucansucrase production. Afterwards, effects of the three main factors on glucansucrase activity were further investigated by central composite design and the optimum composition was sucrose 35.87 g/L, Ca2+ 0.21 mmol/L, and initial pH 5.56. Optimum results showed that glucansucrase activity was increased to 3.94 ± 0.43 U/mL in 24 hr fermentation, 2.66-fold higher than before. In addition, the crude enzyme was purified using ammonium sulfate precipitation, ion-exchange chromatography, and gel filtration. The molecular weight of glucansucrase was determined as approximately 170 kDa by Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The enzyme was purified 15.77-fold and showed a final specific activity of 338.56 U/mg protein.

Optimization and partial characterization of ca-independent α-amylase from Bacillus amyloliquefaciens BH1.

Strain Bacillus amyloliquefaciens BH1 was evaluated for the generation of α-amylase. Culture conditions and medium components were optimized by a statistical approach for the optimal generation of α-amylase with response surface methodology (RSM) method. The Plackett-Burman (PB) design was executed to select the fermentation variables and Central composite design (CCD) for optimizing significant factors influencing production. The optimum levels for highest generation of α-amylase activity (198.26 ± 3.54 U/mL) were measured. A 1.69-fold improve generation was acquired in comparison with the non-optimized. Partial characterization of the α-amylase indicated optimal pH and temperature at 7.0 and 40 °C, respectively. Crude α-amylase maintained a constant pH range 5.0-8.0 and 30-70 °C. The α-amylase was independent of Ca2+, and the activity was inhibited by Fe3+, Co2+, Cu2+, and Hg2+. The thermo and pH stability of the α-amylase indicate its extensive application in the food and pharmaceutical industries.

Strand and Cell Type-specific Function of microRNA-126 in Angiogenesis.

microRNAs or miRs have been shown to be pivotal modulators of vascular development. The strand and cell type-specific function of miR-126 in angiogenesis, especially pathological angiogenesis, remains poorly defined. We characterized the retinal vascular phenotype of miR-126-/- mice, and tested the function of miR-126 strands (miR-126-3p and -5p) using in vitro angiogenesis models and a mouse model of neovascular age-related macular degeneration. We found that miR-126 is critical for retinal vascular development but has dual function in pathological angiogenesis. miR-126-/- mice showed defective postnatal retinal vascular development and remodeling, which is partially rescued by genetic knockout of its target gene Spred-1. Surprisingly, either silencing miR-126-3p by LNA-antimiR or overexpressing miR-126-3p by miRNA mimic repressed laser-induced choroidal neovascularization. To dissect the underlying mechanism, we found in endothelial cells, silencing of miR-126-3p repressed angiogenesis, while overexpression of miR-126-5p enhanced angiogenesis. However, in retinal pigment epithelial cells, miR-126-3p repressed vascular endothelial growth factor (VEGF-A) expression via a novel mechanism of regulating αB-Crystallin promoter activity and by directly targeting VEGF-A 3'-untranslated region. These findings provide first genetic evidence that miR-126 is required for the development of different retinal vascular layers, and also uncover a strand and cell type-specific function of miR-126 in ocular pathological angiogenesis.

Modulation of airway epithelial antiviral immunity by fungal exposure.

Multiple pathogens, such as bacteria, fungi, and viruses, have been frequently found in asthmatic airways and are associated with the pathogenesis and exacerbation of asthma. Among these pathogens, Alternaria alternata (Alt), a universally present fungus, and human rhinovirus have been extensively studied. However, their interactions have not been investigated. In the present study, we tested the effect of Alt exposure on virus-induced airway epithelial immunity using live virus and a synthetic viral mimicker, double-stranded RNA (dsRNA). Alt treatment was found to significantly enhance the production of proinflammatory cytokines (e.g., IL-6 and IL-8) induced by virus infection or dsRNA treatment. In contrast to this synergistic effect, Alt significantly repressed type I and type III IFN production, and this impairment led to elevated viral replication. Mechanistic studies suggested the positive role of NF-κB and mitogen-activated protein kinase pathways in the synergism and the attenuation of the TBK1-IRF3 pathway in the inhibition of IFN production. These opposite effects are caused by separate fungal components. Protease-dependent and -independent mechanisms appear to be involved. Thus, Alt exposure alters the airway epithelial immunity to viral infection by shifting toward more inflammatory but less antiviral responses.

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.

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.

Degradation Mechanism of Aflatoxin M1 by Recombinant Catalase from Bacillus pumilusE-1-1-1: Food Applications in Milk and Beer.

A bacteria capable of degrading aflatoxin M1 (AFM1) was isolated from African elephant manure. It was identified as Bacillus pumilus by 16s rDNA sequencing and named B. pumilusE-1-1-1. Compared with physical and chemical methods, biological methods have attracted much attention due to their advantages, such as thorough detoxification, high specificity, and environmental friendliness. This work aimed to study the effects of a recombinant catalase (rCAT) from B. pumilusE-1-1-1 on the degradation of AFM1 in pattern solution. The degradation mechanism was further explored and applied to milk and beer. Kinetic Momentum and Virtual Machine Maximum values for rCAT toward AFM1 were 4.1 µg/mL and 2.5 µg/mL/min, respectively. The rCAT-mediated AFM1 degradation product was identified as C15H14O3. Molecular docking simulations suggested that hydrogen and pi bonds played major roles in the steadiness of AFM1-rCAT. In other work, compared with identical density of AFM1, survival rates of Hep-G2 cells incubated with catalase-produced AFM1 degradation products increased by about 3 times. In addition, degradation rates in lager beer and milk were 31.3% and 47.2%, respectively. Therefore, CAT may be a prospective substitute to decrease AFM1 contamination in pattern solution, milk, and beer, thereby minimizing its influence on human health.

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.

Synthesis of dextran of different molecular weights by recombinant dextransucrase DsrB.

Leuconostoc citreum JZ-002 was extracted from artisanal orange wine. This strain was used to synthesize dextran with a purification extraction of 27.9 g/L. The resulting dextran had a molecular weight of 2.45 × 106 Da. A significant portion, amounting to 64 % of the structure, is constituted by the main chain, with α-(1,6) glycosidic bonds acting as the linkages. In contrast, the branched chain, comprising 34 % of the entire molecule, is characterized by the presence of α-(1,3) glycosidic bonds. The dextransucrase DsrB, believed to be accountable for the formation of the dextran backbone, was successfully cloned into the pET-28a-AcmA vector. The recombinant expression of the enzyme was achieved. Purified recombinant enzymes and immobilized in a single go using the gram-positive enhancer matrix (GEM). The maximum yield of dextran produced by suchimmobilized enzyme was 191.9 g/L. The composition featured a dextran connected via α-(1,6) glycosidic linkages. Molecular weight controlled synthesis was achieved with sucrose concentrations of 100-2000 mM and enzyme concentrations of 320-1280 U. The Mw of the synthesized dextran extended from 4680 to 1,320,000 Da. By controlling the ratio between enzyme concentration and sucrose concentration, dextrans with diverse Mw can be enzymatically generated.

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.

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.