Randomized, blind, controlled phase III clinical trial: Assessing the immunogenicity and safety of freeze-dried human rabies vaccine (vero cell) with a 4-dose regimen (2-1-1) in a 10-60 year-old demographic.

OBJECTIVE: The aim of this study is to demonstrate that the freeze-dried human rabies vaccine (Vero cell), administered in a four-dose schedule (2-1-1) to the 10-60 years old population, has immunogenicity that is not inferior to the approved five-dose schedule and similar vaccines with a four-dose schedule, and to evaluate its safety. METHOD: A total of 1800 individuals were enrolled and divided into three groups: four-dose test group, four-dose control group, and five-dose control group. The rabies virus neutralizing antibodies were measured using the Rapid Fluorescent Focus Inhibition Test to assess immunogenicity, and the incidence of adverse events and serious adverse events were statistically analyzed. RESULTS: The seroconversion rates 14 days after the first dose and 14 days after the complete course of vaccination were 100% in all three groups. The antibody GMC of the four-dose test group was higher than that of the five-dose control group, but slightly lower than the four-dose control group. Seven days after the first dose, both four-dose regimen groups showed higher seroconversion rates and antibody GMCs compared to the five-dose regimen group, proving that the immunogenic effect of the four-dose regimen seven days post-first vaccination is superior to the five-dose regimen. The overall incidence of adverse events showed no significant difference between the four-dose test group and the five-dose control group, but was significantly lower in the four-dose test group compared to the four-dose control group. CONCLUSION: The vaccine in the four-dose test group is equivalent in immunogenic effect to the four-dose control group vaccine and superior to the five-dose control group vaccine; the safety of the vaccine in the four-dose test group is equivalent to the five-dose control group vaccine and superior to the four-dose control group vaccine. CLINICALTRIALS: gov number: NCT05549908.

Research progress on the mechanisms of fruit glossiness in cucumber.

Cucumber (Cucumis sativus L.) is an important horticultural crop in China. Consumer requirements for aesthetically pleasing appearances of horticultural crops are gradually increasing, and cucumbers having a good visual appearance, as well as flavor, are important for breeding and industry development. The gloss of cucumber fruit epidermis is an important component of its appeal, and the wax layer on the fruit surface plays important roles in plant growth and forms a powerful barrier against external biotic and abiotic stresses. The wax of the cucumber epidermis is mainly composed of alkanes, and the luster of cucumber fruit is mainly determined by the alkane and silicon contents of the epidermis. Several genes, transcription factors, and transporters affect the synthesis of ultra-long-chain fatty acids and change the silicon content, further altering the gloss of the epidermis. However, the specific regulatory mechanisms are not clear. Here, progress in research on the luster of cucumber fruit epidermis from physiological, biochemical, and molecular regulatory perspectives are reviewed. Additionally, future research avenues in the field are discussed.

A novel Mre11 protein from the hyperthermophilic euryarchaeon Thermococcus barophilus Ch5 possesses 5'-3' exonuclease and endonuclease activities.

Mre11 is one of important proteins that are involved in DNA repair and recombination by processing DNA ends to produce 3'-single stranded DNA, thus providing a platform for other DNA repair and recombination proteins. In this work, we characterized the Mre11 protein from the hyperthermophilic euryarchaeon Thermococcus barophilus Ch5 (Tba-Mre11) biochemically and dissected the roles of its four conserved residues, which is the first report on Mre11 proteins from Thermococcus. Tba-Mre11 possesses exonuclease activity for degrading ssDNA and dsDNA in the 5'-3' direction, which contrasts with other reported Mre11 homologs. Maximum degradation efficiency was observed with Mn2+ at 80 °C and at pH 7.5-9.5. In addition to possessing 5'-3' exonuclease activity, Tba-Mre11 has endonuclease activity that nicks plasmid DNA and circular ssDNA. Mutational data show that residues D10, D51 and N86 in Tba-Mre11 are essential for DNA degradation since almost no activity was observed for the D10A, D51A and N86A mutants. By comparison, residue D44 in Tba-Mre11 is not responsible for DNA degradation since the D44A mutant possessed the similar WT protein activity. Notably, the D44A mutant almost completely abolished the ability to bind DNA, suggesting that residue D44 is essential for binding DNA.

Enrichment of Total Flavonoids and Licochalcone A from Glycyrrhiza inflata Bat. Residue Based on a Combined Membrane-Macroporous Resin Process and a Quality-Control Study.

Glycyrrhiza inflata Bat. produces a lot of licorice waste after water extraction, which also retains abundant total flavonoids (TFs) and licochalcone A. However, licorice residue is often wasted due to the lack of good utilization of resources in practical applications. This study first screened the optimal membrane pore size and resin type and then explored the mechanism and conditions of the adsorption of TFs on the resin. Then, different combinations and sequences of membrane and macroporous resin (MR) methods were investigated. It was found that using the membrane method for initial purification, followed by the MR method for further purification, yielded the best purification results. Next, response surface methodology was utilized to investigate the resin's dynamic desorption conditions for TFs. Finally, the TF purity increased from 32.9% to 78.2% (2.38-fold) after purification by a combined membrane-MR process; the purity of licochalcone A increased from 11.63 mg·g-1 to 22.70 mg·g-1 (1.95-fold). This study verified the feasibility of enriching TFs and licochalcone A from licorice residue using a membrane-MR coupling method. In addition, a quality-control method was established using a fingerprinting method on the basis of ultrahigh-performance liquid chromatography (UPLC) to ensure the stability of the enrichment process.

Biotransformation and disposition characteristics of HSK7653, a novel long-acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes.

AIM: To investigate the metabolism and disposition characteristics of HSK7653 in healthy male Chinese participants. METHODS: A single oral dose of 80 µCi (25 mg) [14C]HSK7653 capsules was administered to six healthy participants, and blood, plasma, urine and faeces were collected. Quantitative and qualitative analysis was conducted to investigate the pharmacokinetics, blood-to-plasma ratio, mass balance and metabolism of HSK7653. RESULTS: The drug was well absorbed and reached a maximum concentration at 1.25 h. The drug-related components (HSK7653 and its metabolites) were eliminated slowly, with a half-life (t1/2) of 111 h. Unchanged HSK7653 contributed to more than 97% of the total radioactivity in all plasma samples. The blood-to-plasma ratio (0.573-0.845) indicated that HSK7653 did not tend to distribute into blood cells. At 504 h postdose, up to 95.9% of the dose was excreted, including 79.8% in urine and 16.1% in faeces. Most of the radioactivity (75.5% dose) in excreta was unchanged HSK7653. In addition, nine metabolites were detected in urine and faeces. The most abundant metabolite was M6-2, a dioxidation product of HSK7653, which accounted for 4.73% and 2.63% of the dose in urine and faeces, respectively. The main metabolic pathways of HSK7653 in vivo included oxidation, pyrrole ring opening and sulphonamide hydrolysation. CONCLUSION: HSK7653 was well absorbed, slightly metabolized and slowly excreted in humans. The high plasma exposure and long t1/2 of HSK7653 may contribute to its long-lasting efficacy as a long-acting dipeptidyl peptidase-4 inhibitor.

Biochemical characterization and mutational analysis of the NurA protein from the hyperthermophilic euryarchaeon Thermococcus barophilus Ch5.

Archaeal NurA protein plays a key role in producing 3'-single stranded DNA used for homologous recombination repair, together with HerA, Mre11, and Rad50. Herein, we describe biochemical characteristics and roles of key amino acid residues of the NurA protein from the hyperthermophilic euryarchaeon Thermococcus barophilus Ch5 (Tba-NurA). Tba-NurA possesses 5'-3' exonuclease activity for degrading DNA, displaying maximum efficiency at 45 °C-65 °C and at pH 8.0 in the presence of Mn2+. The thermostable Tba-NurA also possesses endonuclease activity capable of nicking plasmid DNA and circular ssDNA. Mutational data demonstrate that residue D49 of Tba-NurA is essential for exonuclease activity and is involved in binding ssDNA since the D49A mutant lacked exonuclease activity and reduced ssDNA binding. The R96A and R129A mutants had no detectable dsDNA binding, suggesting that residues R96 and R129 are important for binding dsDNA. The abolished degradation activity and reduced dsDNA binding of the D120A mutant suggest that residue D120 is essential for degradation activity and dsDNA binding. Additionally, residues Y392 and H400 are important for exonuclease activity since these mutations resulted in exonuclease activity loss. To our knowledge, it is the first report on biochemical characterization and mutational analysis of the NurA protein from Thermococcus.

A Versatile Chitosan-Based Hydrogel Accelerates Infected Wound Healing via Bacterial Elimination, Antioxidation, Immunoregulation, and Angiogenesis.

Drug-resistant bacterial infection of cutaneous wounds causes great harm to the human body. These infections are characterized by a microenvironment with recalcitrant bacterial infections, persistent oxidative stress, imbalance of immune regulation, and suboptimal angiogenesis. Treatment strategies available to date are incapable of handling the healing dynamics of infected wounds. A Schiff base and borate ester cross-linked hydrogel, based on phenylboronic acid-grafted chitosan (CS-PBA), dibenzaldehyde-grafted poly(ethylene glycol), and tannic acid (TA), is fabricated in the present study. Customized phenylboronic acid-modified zinc oxide nanoparticles (ZnO) are embedded in the hydrogel prior to gelation. The CPP@ZnO-P-TA hydrogel effectively eliminates methicillin-resistant Staphylococcus aureus (MRSA) due to the pH-responsive release of Zn2+ and TA. Killing is achieved via membrane damage, adenosine triphosphate reduction, leakage of intracellular components, and hydrolysis of bacterial o-nitrophenyl-ß-d-galactopyranoside. The CPP@ZnO-P-TA hydrogel is capable of scavenging reactive oxygen and nitrogen species, alleviating oxidative stress, and stimulating M2 polarization of macrophages. The released Zn2+ and TA also induce neovascularization via the PI3K/Akt pathway. The CPP@ZnO-P-TA hydrogel improves tissue regeneration in vivo by alleviating inflammatory responses, stimulating angiogenesis, and facilitating collagen deposition. These findings suggest that this versatile hydrogel possesses therapeutic potential for the treatment of MRSA-infected cutaneous wounds.

X-chromosome and kidney function: evidence from a multi-trait genetic analysis of 908,697 individuals reveals sex-specific and sex-differential findings in genes regulated by androgen response elements.

X-chromosomal genetic variants are understudied but can yield valuable insights into sexually dimorphic human traits and diseases. We performed a sex-stratified cross-ancestry X-chromosome-wide association meta-analysis of seven kidney-related traits (n = 908,697), identifying 23 loci genome-wide significantly associated with two of the traits: 7 for uric acid and 16 for estimated glomerular filtration rate (eGFR), including four novel eGFR loci containing the functionally plausible prioritized genes ACSL4, CLDN2, TSPAN6 and the female-specific DRP2. Further, we identified five novel sex-interactions, comprising male-specific effects at FAM9B and AR/EDA2R, and three sex-differential findings with larger genetic effect sizes in males at DCAF12L1 and MST4 and larger effect sizes in females at HPRT1. All prioritized genes in loci showing significant sex-interactions were located next to androgen response elements (ARE). Five ARE genes showed sex-differential expressions. This study contributes new insights into sex-dimorphisms of kidney traits along with new prioritized gene targets for further molecular research.

The Recent Advances of Polymer-POSS Nanocomposites With Low Dielectric Constant.

This study provides a comprehensive overview of the preparation methods for polyhedral oligomeric silsesquioxane (POSS) monomers and polymer/POSS nanocomposites. It focuses on the latest advancements in using POSS to design polymer nanocomposites with reduced dielectric constants. The study emphasizes exploring the potential of POSS, either alone or in combination with other materials, to decrease the dielectric constant and dielectric loss of various polymers, including polyimides, bismaleimide resins, poly(aryl ether)s, polybenzoxazines, benzocyclobutene resins, polyolefins, cyanate ester resins, and epoxy resins. In addition, the research investigates the impact of incorporating POSS on improving the thermal properties, mechanical properties, surface properties, and other aspects of these polymers. The entire study is divided into two parts, discussing systematically the role of POSS in reducing dielectric constants during the preparation of POSS composites using both physical blending and chemical synthesis methods. The goal of this research is to provide valuable strategies for designing a new generation of low dielectric constant materials suitable for large-scale integrated circuits in the semiconductor materials domain.

Anthropogenic multipollutant input to the offshore South China Sea.

The remote region of the South China Sea (SCS), situated far from urban mainland areas, is commonly perceived to experience minimal pollution. However, this may evolve into a considerably polluted region owing to increasing anthropogenic pollutants. In this study, we employ a multidisciplinary approach to analyze the surface sediments collected from the offshore area of the southern SCS. Our aim is to explore potential anthropogenic pollutants, their interactions, and the related controlling factors. This research endeavors to enhance our understanding of the current pollution status in the SCS and help making relevant policy management decisions. Comparison with previous reports reveals that now, the area is more extensively and increasingly contaminated by petroleum hydrocarbons and heavy metals (Cd and As) than before. For the first time, we report the recognition of coprostanol and long-chain alkyl mid-chain ketones, unveiling the noticeable incorporation of sewage fecal matter and biomass burning into offshore sediments. Moreover, sedimentary multipollutants (except ketones) exhibit strong correlations with terrestrial elements and fine-sized particles, displaying a roughly high-west/low-east spatial variability in pollutant accumulation or enrichment. These signatures evidently demonstrate the major impact of river discharges (e.g., the Mekong River to the west and the Pearl and Red Rivers to the north) on the SCS. They have hydrodynamic effects on the subsequent basin-wide dispersal of pollutants, driven by monsoon-induced large- and regional-scale currents. The different behavior of burning-related ketones may be partly due to their aerosol form, leading to atmospheric transportation. Because anthropogenic multipollutants pose compounded threats, exacerbating oceanic warming and acidification to marine ecosystems such as the widespread coral reefs in the southern SCS, scientific management of urban emissions is required to mitigate ecosystem degradation in the Anthropocene era.

Hypomethylation of glycine dehydrogenase promoter in peripheral blood mononuclear cells is a new diagnostic marker of hepatitis B virus-associated hepatocellular carcinoma.

BACKGROUND: Glycine dehydrogenase (GLDC) plays an important role in the initiation and proliferation of several human cancers. In this study, we aimed to detect the methylation status of GLDC promoter and its diagnostic value for hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC). METHODS: We enrolled 197 patients, 111 with HBV-HCC, 51 with chronic hepatitis B (CHB), and 35 healthy controls (HCs). The methylation status of GLDC promoter in peripheral mononuclear cells (PBMCs) was identified by methylation specific polymerase chain reaction (MSP). The mRNA expression was examined using real-time quantitative polymerase chain reaction (qPCR). RESULTS: The methylation frequency of the GLDC promoter was significantly lower in HBV-HCC patients (27.0%) compared to that in CHB patients (68.6%) and HCs (74.3%) (P < 0.001). The methylated group had lower alanine aminotransferase level (P = 0.035) and lower rates of tumor node metastasis (TNM) III/IV (P = 0.043) and T3/T4 (P = 0.026). TNM stage was identified to be an independent factor for GLDC promoter methylation. GLDC mRNA levels in CHB patients and HCs were significantly lower than those in HBV-HCC patients (P = 0.022 and P < 0.001, respectively). GLDC mRNA levels were significantly higher in HBV-HCC patients with unmethylated GLDC promoters than those with methylated GLDC promoters (P = 0.003). The diagnostic accuracy of alpha-fetoprotein (AFP) combined with GLDC promoter methylation for HBV-HCC was improved compared with that of AFP alone (AUC: 0.782 vs. 0.630, P < 0.001). In addition, GLDC promoter methylation was an independent predictor for overall survival of HBV-HCC patients (P = 0.038). CONCLUSIONS: The methylation frequency of GLDC promoter was lower in PBMCs from HBV-HCC patients than that from patients with CHB and HCs. The combination of AFP and GLDC promoter hypomethylation significantly improved the diagnostic accuracy of HBV-HCC.

Interaction of 2D nanomaterial with cellular barrier: Membrane attachment and intracellular trafficking.

The cell membrane serves as a barrier against the free entry of foreign substances into the cell. Limited by factors such as solubility and targeting, it is difficult for some drugs to pass through the cell membrane barrier and exert the expected therapeutic effect. Two-dimensional nanomaterial (2D NM) has the advantages of high drug loading capacity, flexible modification, and multimodal combination therapy, making them a novel drug delivery vehicle for drug membrane attachment and intracellular transport. By modulating the surface properties of nanocarriers, it is capable of carrying drugs to break through the cell membrane barrier and achieve precise treatment. In this review, we review the classification of various common 2D NMs, the primary parameters affecting their adhesion to cell membranes, and the uptake mechanisms of intracellular transport. Furthermore, we discuss the therapeutic potential of 2D NMs for several major disorders. We anticipate this review will deepen researchers' understanding of the interaction of 2D NM drug carriers with cell membrane barriers, and provide insights for the subsequent development of novel intelligent nanomaterials capable of intracellular transport.

Is Kidney Function Associated with Age-Related Macular Degeneration?: Findings from the Asian Eye Epidemiology Consortium.

PURPOSE: Chronic kidney disease (CKD) may elevate susceptibility to age-related macular degeneration (AMD) because of shared risk factors, pathogenic mechanisms, and genetic polymorphisms. Given the inconclusive findings in prior studies, we investigated this association using extensive datasets in the Asian Eye Epidemiology Consortium. DESIGN: Cross-sectional study. PARTICIPANTS: Fifty-one thousand two hundred fifty-three participants from 10 distinct population-based Asian studies. METHODS: Age-related macular degeneration was defined using the Wisconsin Age-Related Maculopathy Grading System, the International Age-Related Maculopathy Epidemiological Study Group Classification, or the Beckman Clinical Classification. Chronic kidney disease was defined as estimated glomerular filtration rate (eGFR) of less than 60 ml/min per 1.73 m2. A pooled analysis using individual-level participant data was performed to examine the associations between CKD and eGFR with AMD (early and late), adjusting for age, sex, hypertension, diabetes, body mass index, smoking status, total cholesterol, and study groups. MAIN OUTCOME MEASURES: Odds ratio (OR) of early and late AMD. RESULTS: Among 51 253 participants (mean age, 54.1 ± 14.5 years), 5079 had CKD (9.9%). The prevalence of early AMD was 9.0%, and that of late AMD was 0.71%. After adjusting for confounders, individuals with CKD were associated with higher odds of late AMD (OR, 1.46; 95% confidence interval [CI], 1.11-1.93; P = 0.008). Similarly, poorer kidney function (per 10-unit eGFR decrease) was associated with late AMD (OR, 1.12; 95% CI, 1.05-1.19; P = 0.001). Nevertheless, CKD and eGFR were not associated significantly with early AMD (all P ≥ 0.149). CONCLUSIONS: Pooled analysis from 10 distinct Asian population-based studies revealed that CKD and compromised kidney function are associated significantly with late AMD. This finding further underscores the importance of ocular examinations in patients with CKD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Changes in Diversity and Composition of Rhizosphere Bacterial and Fungal Community between Resistant and Susceptible Pakchoi under Plasmodiophora brassicae.

Plasmodiophora brassicae (P. brassicae) is a soil-born pathogen worldwide and can infect most cruciferous plants, which causes great yield decline and economic losses. It is not well known how microbial diversity and community composition change during P. brassicae infecting plant roots. Here, we employed a resistant and a susceptible pakchoi cultivar with and without inoculation with P. brassicae to analyze bacterial and fungal diversity using 16S rRNA V3-V4 and ITS_V1 regions, respectively. 16S rRNA V3-V4 and ITS_V1 regions were amplified and sequenced separately. Results revealed that both fungal and bacterial diversity increased, and composition was changed in the rhizosphere soil of the susceptible pakchoi compared with the resistant cultivar. In the four groups of R_mock, S_mock, R_10d, and S_10d, the most relatively abundant bacterium and fungus was Proteobacteria, accounting for 61.92%, 58.17%, 48.64%, and 50.00%, respectively, and Ascomycota, accounting for 75.11%, 63.69%, 72.10%, and 90.31%, respectively. A total of 9488 and 11,914 bacteria were observed uniquely in the rhizosphere soil of resistant and susceptible pakchoi, respectively, while only 80 and 103 fungi were observed uniquely in the correlated soil. LefSe analysis showed that 107 and 49 differentially abundant taxa were observed in bacteria and fungi. Overall, we concluded that different pakchoi cultivars affect microbial diversity and community composition, and microorganisms prefer to gather around the rhizosphere of susceptible pakchoi. These findings provide a new insight into plant-microorganism interactions.

Cardiovascular disease and thinning of retinal nerve fiber layer in a multi-ethnic Asian population: the Singapore epidemiology of eye diseases study.

Introduction: Our study aimed to examine the relationship between cardiovascular diseases (CVD) with peripapillary retinal fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) thickness profiles in a large multi-ethnic Asian population study. Methods: 6,024 Asian subjects were analyzed in this study. All participants underwent standardized examinations, including spectral domain OCT imaging (Cirrus HD-OCT; Carl Zeiss Meditec). In total, 9,188 eyes were included for peripapillary RNFL analysis (2,417 Malays; 3,240 Indians; 3,531 Chinese), and 9,270 eyes (2,449 Malays, 3,271 Indians, 3,550 Chinese) for GCIPL analysis. History of CVD was defined as a self-reported clinical history of stroke, myocardial infarction, or angina. Multivariable linear regression models with generalized estimating equations were performed, adjusting for age, gender, ethnicity, diabetes, hypertension, hyperlipidaemia, chronic kidney disease, body mass index, current smoking status, and intraocular pressure. Results: We observed a significant association between CVD history and thinner average RNFL (ß = -1.63; 95% CI, -2.70 to -0.56; p = 0.003). This association was consistent for superior (ß = -1.79, 95% CI, -3.48 to -0.10; p = 0.038) and inferior RNFL quadrant (ß = -2.14, 95% CI, -3.96 to -0.32; p = 0.021). Of the CVD types, myocardial infarction particularly showed significant association with average (ß = -1.75, 95% CI, -3.08 to -0.42; p = 0.010), superior (ß = -2.22, 95% CI, -4.36 to -0.09; p = 0.041) and inferior (ß = -2.42, 95% CI, -4.64 to -0.20; p = 0.033) RNFL thinning. Among ethnic groups, the association between CVD and average RNFL was particularly prominent in Indian eyes (ß = -1.92, 95% CI, -3.52 to -0.33; p = 0.018). CVD was not significantly associated with average GCIPL thickness, albeit a consistent negative direction of association was observed (ß = -0.22, 95% CI, -1.15 to 0.71; p = 0.641). Discussion: In this large multi-ethnic Asian population study, we observed significant association between CVD history and RNFL thinning. This finding further validates the impact of impaired systemic circulation on RNFL thickness.

International incidence and temporal trends for rhegmatogenous retinal detachment: A systematic review and meta-analysis.

We set out to estimate the international incidence of rhegmatogenous retinal detachment (RRD) and to evaluate its temporal trend over time. There is a lack of robust estimates on the worldwide incidence and trend for RRD, a major cause of acute vision loss. We conducted a systematic review of RRD incidence. The electronic databases PubMed, Scopus, and Thomson Reuters' Web of Science were searched from inception through 2nd June 2022. Random-effects meta-analysis model with logit transformation was performed to obtain pooled annual incidence estimates of RRD. Pooled analysis was performed to evaluate the temporal trend of RRD incidence of the 20,958 records identified from the database searches; 33 studies from 21 countries were included for analysis (274,836 cases of RRD in 273,977 persons). Three of the 6 global regions as defined by WHO had studies that met the inclusion and exclusion criteria of the study. The annual international incidence of RRD was estimated to be 12.17 (95% confidence interval [CI] 10.51-14.09) per 100,000 population; with an increasing temporal trend of RRD at 5.4 per 100,000 per decade (p 0.001) from 1997 to 2019. Amongst world regions, the RRD incidence was highest in Europe (14.52 [95% CI 11.79 - 17.88] per 100,000 population), followed by Western Pacific (10.55 [95% CI 8.71-12.75] per 100,000 population) and Regions of Americas (8.95 [95% CI 6.73-11.92] per 100,000 population). About one in 10,000 persons develop RRD each year. There is evidence of increasing trend for RRD incidence over time, with possibly doubling of the current incidence rate within the next 2 decades.

Six-Year Incidence of Visual Impairment in a Multiethnic Asian Population: The Singapore Epidemiology of Eye Diseases Study.

Purpose: To examine the 6-year incidence of visual impairment (VI) and identify risk factors associated with VI in a multiethnic Asian population. Design: Prospective, population-based, cohort study. Participants: Adults aged ≥ 40 years were recruited from the Singapore Epidemiology of Eye Diseases cohort study at baseline. Eligible subjects were re-examined after 6 years. Subjects included in the final analysis had a mean age of 56.1 ± 8.9 years, and 2801 (50.5%) were female. Methods: All participants underwent standardized examination and interviewer-administered questionnaire at baseline. Incidences were standardized to the Singapore Population Census 2010. A Poisson binomial regression model was used to evaluate the associations between baseline factors and incident presenting VI. Main Outcome Measures: Incident presenting VI was assessed at the 6-year follow-up visit. Visual impairment (presenting visual acuity < 20/40), low vision (presenting visual acuity < 20/40 but ≥ 20/200), and blindness (presenting visual acuity < 20/200) were defined based on United States definition. Results: A total of 5551 subjects (2188 Chinese, 1837 Indians, and 1526 Malays) were evaluated, of whom 514 developed incident presenting VI over 6 years. Malays had a higher incidence of low vision and blindness (13.0%; 0.6%) than Indians (7.0%; 0.1%) and Chinese (7.7%; 0.2%). Among Malay individuals with VI at baseline, 52.8% remained visually impaired after 6 years, which was considerably higher than Chinese (32.4%) and Indians (37.2%). Older age (per decade; relative risk [RR] = 1.59), a history of cardiovascular disease (RR = 1.38), current smoking (RR = 1.31), smaller housing type (1- to 2-room public flat; RR = 2.01), and no formal education (RR = 1.63) at baseline were associated with a higher risk of incident VI (all P ≤ 0.027). Older age (> 60 years) contributed the highest population attributable risk to incident VI (27.1%), followed by lower monthly income (Singapore dollar < $2000; 26.4%) and smaller housing type (24.7%). Overall, undercorrected refractive error (49.1%) and cataract (82.6%) were leading causes for low vision and blindness, respectively. This was consistently observed across the 3 ethnicities. Conclusions: In this multiethnic Asian population, Malays had a higher VI incidence compared to Indians and Chinese. Leading causes of VI are mostly treatable, suggesting that more efforts are needed to further mitigate preventable visual loss. Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article.

Pharmacokinetics, Mass Balance and Metabolism of [14C]HSK21542, a Novel Kappa Opioid Receptor Agonist, in Humans.

BACKGROUND AND OBJECTIVE: HSK21542, a synthetic short-chain polypeptide, is a selective peripheral kappa opioid receptor (KOR) agonist. In this single-centre, non-randomized, open-label study, the pharmacokinetics, mass balance, metabolism and excretion of HSK21542 were investigated. METHODS: A single intravenous dose of 2 µg/0.212 µCi/kg [14C]HSK21542 was administered to six healthy male subjects. Samples of blood, urine and faeces were collected for quantitative determination of total radioactivity and unchanged HSK21542, and identification of metabolites. RESULTS: The mean total recovery was 81.89% of the radiolabelled dose over 240 h post-dose, with 35.60% and 46.30% excreted in faeces and urine, respectively. The mean maximum concentration (Cmax), the half-life (t1/2) and the area under the concentration-time curve (AUC0-t) of total radioactivity (TRA) in plasma were 20.4 ±4.16 ng Eq./g, 1.93 ± 0.322 h and 21.8 ± 2.93 h·ng Eq./g, respectively, while the Cmax, t1/2 and the AUC0-t of unchanged HSK21542 were 18.3 ± 3.36 ng/mL, 1.66 ± 0.185 h and 18.4 ± 2.24 h·ng/mL, respectively. The blood-to-plasma ratios of TRA at several times ranged from 0.46 to 0.54. [14C]HSK21542 was detected as the main circulating substance in plasma, accounting for 92.17% of the AUC of TRA. The unchanged parent compound was the only major radioactive chemical in urine (100.00% of TRA) and faeces (93.53% of TRA). Metabolites were very minor components. CONCLUSIONS: HSK21542 was barely metabolized in vivo and mainly excreted with unchanged HSK21542 as its main circulating component in plasma. It was speculated that renal excretion was the principal excretion pathway, and faecal excretion was the secondary pathway. CLINICAL TRIAL REGISTRATION NUMBER: NCT05835934.

H3K27 acetylation-induced FSTL1 upregulation by P300/RUNX1 co-activation exacerbated autophagy-mediated neuronal damage and NF-κB-stimulated inflammation in Alzheimer's disease.

Follistatin-like protein 1 (FSTL1) has been demonstrated to participate in the pathogenesis of several neurological diseases. The current study informed the role of H3K27 acetylation-induced FSTL1 upregulation in Alzheimer's disease (AD). Our investigation discovered the upregulated FSTL1 expression and enhanced autophagy activity in AD. FSTL1 knockdown successfully attenuated the injuries of Aß1-42-challenged SH-SY5Y cells through the inhibition of autophagy activity. Besides, FSTL1 deficiency suppresses the inflammatory response and NF-κB signaling in AD. Moreover, it was found that p300 was recruited by transcriptional factor RUNX1 to stimulate the H3K27 acetylation in FSTL1 promoter region, which caused the upregulation of FSTL1 in AD. To summarize, p300 acted as a co-activator of RUNX1 to trigger the activation of FSTL1 in AD, resulting in the exacerbated injuries and inflammatory responses of Aß1-42-induced SH-SY5Y cells.