Alzheimer's disease as a causal risk factor for diabetic retinopathy: a Mendelian randomization study.

Objectives: This study aims to investigate the causal relationship between Alzheimer's Disease (AD) and Diabetic Retinopathy (DR). Methods: Employing Mendelian Randomization (MR), Generalized Summary-data-based Mendelian Randomization (GSMR), and the MR-Steiger test, this study scrutinizes the genetic underpinnings of the hypothesized causal association between AD and DR, as well as its Proliferative DR (PDR) and Non-Proliferative DR (NPDR) subtypes. Comprehensive data from Genome-Wide Association Studies (GWAS) were analyzed, specifically AD data from the Psychiatric Genomics Consortium (71,880 cases/383,378 controls), and DR, PDR, and NPDR data from both the FinnGen consortium (FinnGen release R8, DR: 5,988 cases/314,042 controls; PDR: 8,383 cases/329,756 controls; NPDR: 3,446 cases/314,042 controls) and the IEU OpenGWAS (DR: 14,584 cases/176,010 controls; PDR: 8,681 cases/204,208 controls; NPDR: 2,026 cases/204,208 controls). The study also incorporated Functional Mapping and Annotation (FUMA) for an in-depth analysis of the GWAS results. Results: The MR analyses revealed that genetic susceptibility to AD significantly increases the risk of DR, as evidenced by GWAS data from the FinnGen consortium (OR: 2.5090; 95% confidence interval (CI):1.2102-5.2018, false discovery rate P-value (PFDR)=0.0201; GSMR: bxy=0.8936, bxy_se=0.3759, P=0.0174), NPDR (OR: 2.7455; 95% CI: 1.3178-5.7197, PFDR=0.0166; GSMR: bxy=0.9682, bxy_se=0.3802, P=0.0126), and PDR (OR: 2.3098; 95% CI: 1.2411-4.2986, PFDR=0.0164; GSMR: bxy=0.7962, bxy_se=0.3205, P=0.0129) using DR GWAS from FinnGen consortium. These results were corroborated by DR GWAS datasets from IEU OpenGWAS. The MR-Steiger test confirmed a significant association of all identified instrumental variables (IVs) with AD. While a potential causal effect of DR and its subtypes on AD was identified, the robustness of these results was constrained by a low power value. FUMA analysis identified OARD1, NFYA, TREM1 as shared risk genes between DR and AD, suggesting a potential genetic overlap between these complex diseases. Discussion: This study underscores the contribution of AD to an increased risk of DR, as well as NPDR and PDR subtypes, underscoring the necessity of a holistic approach in the management of patients affected by these conditions.

Recycling Valuable Alkylbenzenes from Polystyrene through Methanol-Assisted Depolymerization.

The vast bulk of polystyrene (PS), a major type of plastic polymers, ends up in landfills, which takes up to thousands of years to decompose in nature. Chemical recycling promises to enable lower-energy pathways and minimal environmental impacts compared with traditional incineration and mechanical recycling. Herein, we demonstrated that methanol as a hydrogen supplier assisted the depolymerization of PS (denoted as PS-MAD) into alkylbenzenes over a heterogeneous catalyst composed of Ru nanoparticles on SiO2. PS-MAD achieved a high yield of liquid products which accounted for 93.2 wt % of virgin PS at 280 °C for 6 h with the production rate of 118.1 mmolcarbon gcatal. -1 h-1. The major components were valuable alkylbenzenes (monocyclic aromatics and diphenyl alkanes), the sum of which occupied 84.3 wt % of liquid products. According to mechanistic studies, methanol decomposition dominates the hydrogen supply during PS-MAD, thereby restraining PS aromatization which generates by-products of fused polycyclic arenes and polyphenylenes.

The association between epilepsy and COVID-19: analysis based on Mendelian randomization and FUMA.

Objective: A multitude of observational studies have underscored a substantial comorbidity between COVID-19 and epilepsy. This study was aimed at establishing a conclusive causal link between these two conditions. Methods: We employed Mendelian randomization (MR) to evaluate the causal link between COVID-19 and epilepsy, as well as its focal and generalized subtypes. The GWAS for epilepsy and its subtypes database were abstracted from both FinnGen consortium and ILAE. Additionally, we leveraged functional mapping and annotation (FUMA) to integrate information from genome-wide association studies (GWAS) results. Results: The MR analyses revealed that genetic liability to COVID-19 infection conferred a causal effect on epilepsy [FinnGen: OR: 1.5306; 95% confidence interval (CI): 1.1676-2.0062, PFDR (false discovery rate) = 0.0076; ILAE: OR: 1.3440; 95% CI: 1.0235-1.7649, PFDR = 0.0429], and generalized epilepsy (FinnGen: OR: 2.1155; 95% CI: 1.1734-3.8139, PFDR = 0.0327; ILAE: OR: 1.1245; 95% CI: 1.0444-1.2108, PFDR = 0.0114). Genetic liability to COVID-19 hospitalization conferred a causal effect on epilepsy (FinnGen: OR: 1.0934; 95% CI: 1.0097-1.1841, PFDR = 0.0422; ILAE: OR: 1.7381; 95% CI: 1.0467-2.8862, PFDR = 0.0451), focal epilepsy (ILAE: OR: 1.7549; 95% CI: 1.1063-2.7838, PFDR = 0.0338), and generalized epilepsy (ILAE: OR: 1.1827; 95% CI: 1.0215-1.3693, PFDR = 0.0406). Genetic liability to COVID-19 severity conferred a causal effect on epilepsy (FinnGen consortium: OR: 1.2454; 95% CI: 1.0850-1.4295, PFDR = 0.0162; ILAE: OR: 1.2724; 95% CI: 1.0347-1.5647, PFDR = 0.0403), focal epilepsy (FinnGen: OR: 1.6818; 95% CI: 1.1478-2.4642, PFDR = 0.0231; ILAE: OR: 1.6598; 95% CI: 1.2572-2.1914, PFDR = 0.0054), and generalized epilepsy (FinnGen: OR: 1.1486; 95% CI: 1.0274-1.2842, PFDR = 0.0335; ILAE: OR: 1.0439; 95% CI: 1.0159-1.0728, PFDR = 0.0086). In contrast, no causal linkage of epilepsy on COVID-19 was observed. Further, FUMA analysis identified six overlapping genes, including SMEK2, PNPT1, EFEMP1, CCDC85A, VRK2, and BCL11A, shared between COVID-19 and epilepsy. Tissue-specific expression analyses revealed that the disease-gene associations of COVID-19 were significantly enriched in lung, ovary, and spleen tissue compartments, while being significantly enriched in brain tissue for epilepsy. Conclusion: Our study demonstrates that COVID-19 can be a contributing factor to epilepsy, but we found no evidence that epilepsy contributes to COVID-19.

PD-L1-mediated immune evasion in triple-negative breast cancer is linked to the loss of ZNF652.

The intrinsic regulation of programmed death ligand-1 (PD-L1) expression remains unclear. Here, we report that zinc-finger protein 652 (ZNF652) is a potent transcription repressor of PD-L1. ZNF652 frequently experiences loss of heterozygosity (LOH) in various cancers. Higher LOH rate and lack of estrogen-inducible transcription lead to suppressed expression of ZNF652 in triple-negative breast cancer (TNBC). Mechanistically, ZNF652 is physically associated with the NuRD transcription co-repressor complex to repress a cohort of genes, including PD-L1. Overexpression of ZNF652 inhibits PD-L1 transcription, whereas depletion of ZNF652 upregulates PD-L1. Loss of ZNF652 in TNBC unleashes PD-L1-mediated immune evasion both in vitro and in vivo. Significantly, ZNF652 expression is progressively lost during breast cancer progression, and a low ZNF652 level is correlated with elevated PD-L1 expression, less infiltrated CD8+ T cells, and poor prognosis in TNBC. Our study provides insights into PD-L1 regulation and supports the pursuit of ZNF652 as a potential biomarker and drug target for breast cancer immunotherapy.

RAGE: a potential target for Epimedium's anti-neuroinflammation role in vascular dementia-insights from network pharmacology and molecular simulation.

Vascular dementia (VaD), a cognitive impairment resulting from cerebrovascular issues, could be mitigated by Epimedium. This study investigates Epimedium's efficacy in VaD management through a systematic review, network pharmacology, molecular docking, and molecular dynamic simulations (MDS). Comprehensive literature searches were conducted across various databases. Epimedium's pharmacological properties were analyzed using the TCMSP database. Integration with the Aging Atlas database enabled the identification of shared targets between Epimedium and VaD. A protein-protein interaction (PPI) network was constructed, and central targets' topological attributes were analyzed using Cytoscape 3.9.1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were conducted using "ClusterProfiler" R package. The interactions between Epimedium and central targets were assessed by Molecular docking and MDS. Epimedium and its 23 bioactive components counteracted oxidative stress, neuroinflammation, and neuronal damage, thereby attenuating cognitive deterioration in VaD. A total of 78 common targets were identified, with 22 being significantly related to aging. Enrichment analysis identified 1769 GO terms and 139 KEGG pathways, highlighting the AGE-RAGE signaling pathway. Molecular docking revealed that 23 bioactive components, except Linoleyl acetate, effectively interacted with top central targets (JUN, MAPK14, IL6, FOS, TNF). MDS demonstrated that flavonoids Icariin, Kaempferol, Luteolin, and Quercetin formed stable complexes with RAGE. The study identifies RAGE as a novel therapeutic target for Epimedium in the mitigation of VaD via its anti-inflammatory properties.

Underwater image enhancement via red channel maximum attenuation prior and multi-scale detail fusion.

The underwater environment poses great challenges, which have a negative impact on the capture and processing of underwater images. However, currently underwater imaging systems cannot adapt to various underwater environments to guarantee image quality. To address this problem, this paper designs an efficient underwater image enhancement approach that gradually adjusts colors, increases contrast, and enhances details. Based on the red channel maximum attenuation prior, we initially adjust the blue and green channels and correct the red channel from the blue and green channels. Subsequently, the maximum and minimum brightness blocks are estimated in multiple channels to globally stretch the image, which also includes our improved guided noise reduction filtering. Finally, in order to amplify local details without affecting the naturalness of the results, we use a pyramid fusion model to fuse local details extracted from two methods, taking into account the detail restoration effect of the optical model. The enhanced underwater image through our method has rich colors without distortion, effectively improved contrast and details. The objective and subjective evaluations indicate that our approach surpasses the state-of-the-art methods currently. Furthermore, our approach is versatile and can be applied to diverse underwater scenes, which facilitates subsequent applications.

Efficient solvent- and hydrogen-free upcycling of high-density polyethylene into separable cyclic hydrocarbons.

Plastic pollution is a planetary threat that has been exacerbated by the COVID-19 pandemic due to the surge in medical waste, personal protective equipment and takeaway packaging. A socially sustainable and economically viable method for plastic recycling should not use consumable materials such as co-reactants or solvents. Here we report that Ru nanoparticles on zeolitic HZSM-5 catalyse the solvent- and hydrogen-free upcycling of high-density polyethylene into a separable distribution of linear (C1 to C6) and cyclic (C7 to C15) hydrocarbons. The valuable monocyclic hydrocarbons accounted for 60.3 mol% of the total yield. Based on mechanistic studies, the dehydrogenation of polymer chains to form C=C bonds occurs on both Ru sites and acid sites in HZSM-5, whereas carbenium ions are generated on the acid sites via the protonation of the C=C bonds. Accordingly, optimizing the Ru and acid sites promoted the cyclization process, which requires the simultaneous existence of a C=C bond and a carbenium ion on a molecular chain at an appropriate distance, providing high activity and cyclic hydrocarbon selectivity.

High-power femtosecond vortices generated from a Kerr-lens mode-locked solid-state Hermite-Gaussian oscillator.

We report the generation of high-order transverse modes from a Kerr-lens mode-locked femtosecond laser. Two different orders of Hermite-Gaussian modes were realized by non-collinear pumping, which were converted into the corresponding Laguerre-Gaussian vortex modes using a cylindrical lens mode converter. The mode-locked vortex beams, with an average power of 1.4 W and 0.8 W, contained pulses as short as 126 fs and 170 fs at the first and second Hermite-Gaussian mode orders, respectively. This work demonstrates the possibility of developing Kerr-lens mode-locked bulk lasers with various pure high-order modes and paves the way for generating ultrashort vortex beams.

Direct synthesis of extra-heavy olefins from carbon monoxide and water.

Extra-heavy olefins (C12+=), feedstocks to synthesize a wide range of value-added products, are conventionally generated from fossil resources via energy-intensive wax cracking or multi-step processes. Fischer-Tropsch synthesis with sustainably obtained syngas as feed-in provides a potential way to produce C12+=, though there is a trade-off between enhancing C-C coupling and suppressing further hydrogenation of olefins. Herein, we achieve selective production of C12+= via the overall conversion of CO and water, denoted as Kölbel-Engelhardt synthesis (KES), in polyethylene glycol (PEG) over a mixture of Pt/Mo2N and Ru particles. KES provides a continuously high CO/H2 ratio, thermodynamically favoring chain propagation and olefin formation. PEG serves as a selective extraction agent to hinder hydrogenation of olefins. Under an optimal condition, the yield ratio of CO2 to hydrocarbons reaches the theoretical minimum, and the C12+= yield reaches its maximum of 1.79 mmol with a selectivity (among hydrocarbons) of as high as 40.4%.

Multi-omics analyses reveal the mechanisms of Arsenic-induced male reproductive toxicity in mice.

Arsenic (As), a widespread environmental contaminant, can induce serious male reproductive injury; however, the underlying mechanisms remain unclear. Multi-omics analyses, including transcriptome, proteome, and phosphoproteome could promote our understanding of As-induced male reproductive toxicity. Here, we established the reproductive injured mice model by intraperitoneal injection of NaAsO2 (8 mg/kg body weight), which was validated by reduced reproductive cells, sperm motility, and litter size. The followed multi-omics analyses of mice revealed that As exposure inhibited ATP production by decreasing the expression of proteins HK1, and GAPDHS, and the enzymatic activities of PDH and SDH. The inhibition of mitochondrial activity and increase in HDAC2 and MTA3 dysregulated the lysine acetylation levels of histone and global proteins. Specifically, the downregulated histones H4K5ac and H4K12ac and upregulated histone H3K9ac disordered the distribution of TP1 to interfere with spermatogenesis. Moreover, As could reduce the expression of COL1A1, RAB13, and LSR to disrupt the junctions between seminiferous tubules, and thereinto, the inhibition of RAB13 increased PKA-dependent phosphorylation. Our study reveals that As causes male reproductive toxicity through decreasing energy production, altering histone acetylation, and impairing cell junctions. Our findings provide basic data for further studies on As reproductive toxicity.

Ca2+ ionophore A23187 inhibits ATP generation reducing mouse sperm motility and PKA-dependent phosphorylation.

Male infertility is a global problem in modern society of which capacitating defects are a major cause. Previous studies have demonstrated that Ca2+ ionophore A23187 can make mouse sperm capable of fertilizing in vitro, which may aid in clinical treatment of capacitating defects. However, the detailed role and mechanism of Ca2+ in the capacitating process are still unclear especially how A23187 quickly renders sperm immotile and inhibits cAMP/PKA-mediated phosphorylation. We report that A23187 induces a Ca2+ flux in the mitochondria enriched sperm tail and excess Ca2+ inhibits key metabolic enzymes involved in acetyl-CoA biosynthesis, TCA cycle and electron transport chain pathways resulting in reduced ATP and overall energy production, however this flux does not destroy the structure of the sperm tail. Due to the decrease in ATP production, which is the main phosphate group donator and the power of sperm, the sperm is rendered immobile and PKA-mediated phosphorylation is inhibited. Our study proposed a possible mechanism through which A23187 reduces sperm motility and PKA-mediated phosphorylation from ATP generation, thus providing basic data for exploring the functional roles of Ca2+ in sperm in the future.

Lead-mediated inhibition of lysine acetylation and succinylation causes reproductive injury of the mouse testis during development.

Lead (Pb), a widespread heavy metal, may induce serious diseases, particularly male reproductive injury. However, the mechanisms by which Pb induces testicular injury remain unclear. In this paper, we established a mouse model of Pb-induced testicular injury via an intraperitoneal injection of lead chloride at a concentration of 1.5 mg/kg body weight. We confirmed that Pb could induce a series of injuries, including a low litter size, smaller testes, more weak offspring, direct injury, and aberrant spermiogenesis. Our study demonstrated that Pb could inhibit lysine acetylation (Kac) and succinylation (Ksuc) via western blot (WB) and immunofluorescence (IF) analyses. We subsequently separated different germ cells that contained Pre-meiotic spermatogonia (SPG), meiotic spermatocyte (SPC), and round spermatid (RS) into the Pb-treated and control groups and verified that Pb inhibited Kac in SPC, RS, and particularly, during meiosis. Furthermore, our results regarding the inhibition of pyruvate kinase and mitochondrial electron transport chain complex I and II in the Pb-treated groups suggested that Pb may restrain key enzymes to block the TCA cycle and that the low TCA cycle activity could reduce the contents of two important metabolites, acetyl-CoA and succinyl-CoA, to inhibit Kac and Ksuc. Moreover, we examined the influences of the inhibition of Kac and Ksuc on spermiogenesis, which indicated that decreased Kac and Ksuc could impede the replacement of transition proteins in elongating sperm and disorder the distribution of germ cells in the seminiferous tubule. Our research provides novel insights into the mechanisms of Pb reproductive toxicity with respect to lysine acetylation and succinylation.