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X-linked retinitis pigmentosa (XLRP) is the most severe form of Retinitis Pigmentosa (RP) and one of the leading causes of blindness in the world. Currently, there is no effective treatment for RP. In the present study, we recruited a XLRP family and identified a 4 bp deletion mutation (c. 2234_2237del) in RPGR ORF15 with Sanger sequencing, which was located in the exact same region as the missing XES (X chromosome exome sequencing) coverage. Then, we generated cell lines harboring the identified mutation and corrected it via enhanced prime editing system (ePE). Collectively, Sanger sequencing identified a pathogenic mutation in RPGR ORF15 for XLRP which was corrected with ePE. This study provides a valuable insight for genetic counseling of the afflicted family members and prenatal diagnosis, also paves a way for applying prime editing based gene therapy in those patients.

Rapid enhancement of the thermostability of enzymes by the CREATE strategy.

Purpose: This study aimed to investigate the value of combined detection of HCY and NRG4 in the diagnosis of early diabetic kidney disease (DKD) and to explore the association between the ratio of HCY/NRG4 and DKD. Methods: A total of 140 diabetic patients and 43 healthy people were prospectively enrolled. The plasma HCY level, NRG4 level and HCY/NRG4 of them were measured to compare their differences and analyze the correlation with DKD. The independent influencing factors of patients with DKD were screened, and the nomograph of DKD occurrence was constructed. Results: The levels of HCY and HCY/NRG4 in diabetic patients were significantly increased, while the level of NRG4 was significantly decreased (p < 0.01). The AUCs of HCY/NRG4 predicted for DKD were 0.961. HCY/NRG4 and the course of DM were independent risk factors for DKD. A predictive nomograph of DKD was constructed, and decision curve analysis (DCA) showed good clinical application value. HCY/NRG4 was positively correlated with Scr, UACR, TG, UA, BUN, TCHOL and LDL and negatively correlated with eGFR and HDL (p < 0.05). Conclusions: The level of HCY and NRG4 is closely related to the severity of DM, and combined detection of HCY/NRG4 can identify patients with DKD at an early stage.

Atherosclerosis is a major contributor to morbidity and mortality worldwide. Although several molecular markers associated with atherosclerosis have been developed in recent years, the lack of robust evidence hinders their clinical applications. For these reasons, identification of novel and robust biomarkers will directly contribute to atherosclerosis management in the context of predictive, preventive, and personalized medicine (PPPM). This integrative analysis aimed to identify critical genetic markers of atherosclerosis and further explore the underlying molecular immune mechanism attributing to the altered biomarkers.Gene Expression Omnibus (GEO) series datasets were downloaded from GEO. Firstly, differential expression analysis and functional analysis were conducted. Multiple machine-learning strategies were then employed to screen and determine key genetic markers, and receiver operating characteristic (ROC) analysis was used to assess diagnostic value. Subsequently, cell-type identification by estimating relative subsets of RNA transcript (CIBERSORT) and a single-cell RNA sequencing (scRNA-seq) data were performed to explore relationships between signatures and immune cells. Lastly, we validated the biomarkers' expression in human and mice experiments.A total of 611 overlapping differentially expressed genes (DEGs) included 361 upregulated and 250 downregulated genes. Based on the enrichment analysis, DEGs were mapped in terms related to immune cell involvements, immune activating process, and inflaming signals. After using multiple machine-learning strategies, dehydrogenase/reductase 9 (DHRS9) and protein tyrosine phosphatase receptor type J (PTPRJ) were identified as critical biomarkers and presented their high diagnostic accuracy for atherosclerosis. From CIBERSORT analysis, both DHRS9 and PTPRJ were significantly related to diverse immune cells, such as macrophages and mast cells. Further scRNA-seq analysis indicated DHRS9 was specifically upregulated in macrophages of atherosclerotic lesions, which was confirmed in atherosclerotic patients and mice.Our findings are the first to report the involvement of DHRS9 in the atherogenesis, and the proatherogenic effect of DHRS9 is mediated by immune mechanism. In addition, we confirm that DHRS9 is localized in macrophages within atherosclerotic plaques. Therefore, upregulated DHRS9 could be a novel potential target for the future predictive diagnostics, targeted prevention, patient stratification, and personalization of medical services in atherosclerosis.The online version contains supplementary material available at 10.1007/s13167-022-00289-y.

Brown adipose tissue (BAT) activity contributes to cardiovascular health by its energy-dissipating capacity but how BAT modulates vascular function and atherosclerosis through endocrine mechanisms remains poorly understood. Here we show that BAT-derived neuregulin-4 (Nrg4) ameliorates atherosclerosis in mice. BAT-specific Nrg4 deficiency accelerates vascular inflammation and adhesion responses, endothelial dysfunction and apoptosis and atherosclerosis in male mice. BAT-specific Nrg4 restoration alleviates vascular inflammation and adhesion responses, attenuates leukocyte homing and reduces endothelial injury and atherosclerosis in male mice. In endothelial cells, Nrg4 decreases apoptosis, inflammation and adhesion responses induced by oxidized low-density lipoprotein. Mechanistically, protein kinase B (Akt)–nuclear factor-κB signaling is involved in the beneficial effects of Nrg4 on the endothelium. Taken together, the results reveal Nrg4 as a potential cross-talk factor between BAT and arteries that may serve as a target for atherosclerosis.

BackgroundGiven the arrival of the aging population has caused a series of social and economic problems, we aimed to explore the key genes underlying cognitively normal brain aging and its potential molecular mechanisms.MethodsGSE11882 was downloaded from Gene Expression Omnibus (GEO). The data from different brain regions were divided into aged and young groups for analysis. Co-expressed differentially expressed genes (DEGs) were screened. Functional analysis, protein–protein interaction (PPI) network, microRNA (miRNA)-gene, and transcription factor (TF)-gene networks were performed to identify hub genes and related molecular mechanisms. AlzData database was used to elucidate the expression of DEGs and hub genes in the aging brain. Animal studies were conducted to validate the hub genes.ResultsCo-expressed DEGs contained 7 upregulated and 87 downregulated genes. The enrichment analysis indicated DEGs were mainly involved in biological processes and pathways related to immune-inflammatory responses. From the PPI network, 10 hub genes were identified: C1QC, C1QA, C1QB, CD163, FCER1G, VSIG4, CD93, CD14, VWF, and CD44. CD44 and CD93 were the most targeted DEGs in the miRNA-gene network, and TIMP1, HLA-DRA, VWF, and FGF2 were the top four targeted DEGs in the TF-gene network. In AlzData database, the levels of CD44, CD93, and CD163 in patients with Alzheimer’s disease (AD) were significantly increased than those in normal controls. Meanwhile, in the brain tissues of cognitively normal mice, the expression of CD44, CD93, and CD163 in the aged group was significantly lower than those in the young group.ConclusionThe underlying molecular mechanisms for maintaining healthy brain aging are related to the decline of immune-inflammatory responses. CD44, CD93, and CD 163 are considered as potential biomarkers. This study provides more molecular evidence for maintaining cognitively normal brain aging.

In this study we assessed the atherogenic index of plasma (AIP) in relation to retinopathy and nephropathy in patients with type 2 diabetes mellitus (T2DM).In this cross-sectional study there were 4,358 inpatients with T2DM. The patients were divided into 4 groups: T2DM without complications (DM group), T2DM complicated with retinopathy alone and nephropathy alone (DR-alone and DN-alone groups) and T2DM complicated with both DR and DN (DRN group). AIP was calculated by the formula of log [triglyceride / high-density lipoprotein cholesterol].AIPs in the DR-alone, DN-alone and DRN groups were significantly higher than in the DM group, with the DRN group having the highest AIP level. Moreover, patients with proliferative DR had higher AIPs than patients with nonproliferative DR in the DR-alone and DRN groups, and patients with macroalbuminuria had higher AIPs than patients with microalbuminuria in DN-alone and DRN groups. The highest AIP quartile group had the highest proportion of DRN compared with the other quartile groups. The DRN group had a maximal area under the curve (AUC) for AIP on receiver operating characteristic curve analysis (AUC=0.735). In the subgroup analyses by age, the AUCs of patients65 years of age were all greater than those of patients ≥65 years of age. Logistic regression analysis showed that AIP had the highest correlation with age65 years in individuals with DRN, and this association remained significant after adjustment with 3 models.AIP is positively associated with both occurrence and severity of diabetic microvascular complications. It can predict their presence in T2DM, especially in those65 years of age with DRN.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used drugs due to their values in attenuating pain, fever and inflammation. Unfortunately, conspicuous adverse effects, such as gastrointestinal (GI) damage and/or cardiovascular events have impeded their application in clinic. M378 is a novel hydrogen sulfide-releasing NSAIDs with uncompromised potency and negligible toxicity compared to the existing NSAIDs. However, its anti-inflammatory activity and mechanism are still an enigma. Here we investigated the effect of M378 on the NLRP3 inflammasome signaling pathway and addressed the underlying molecular mechanism. Our data in vitro showed that M378 dose-dependently inhibited the cleavage of Caspase-1 and the secretion of active IL-1β and blocked NLRP3-dependent pyroptosis in LPS-primed J774A.1 macrophages. Furthermore, M378 remarkably inhibited upstream ASC oligomerization and ROS production regarding the process of NLRP3 inflammasome assembly. Our data in vivo demonstrated that M378 protected mice from acute liver injury, reducing the levels of ALT/AST and IL-1β and improving hepatic pathological damages. Immunoblot analysis revealed that M378 inhibited the expressions of Caspase-1 and IL-1β in liver tissues of ALI mice. We also showed that M378 alleviated IL-1β secretion and peritoneal neutrophils infiltration in MSU-elicited acute peritonitis mice. In conclusion, M378 exerted its anti-inflammatory effect both in vitro and in vivo and its mechanisms are at least connected to its inhibitory performance on the generation of ASC oligomers and ROS production. These findings give an insight. into the molecular mechanism of hydrogen sulfide-releasing NSAIDs and support a potent therapeutic role of M378 in the treatment of NLRP3-driven inflammatory diseases.

Trace metal (loid) contamination in the atmosphere is widely monitored, but there is a gap in understanding its long-term patterns, especially in North China, which is currently a global contamination hotspot mainly caused by heavy industry emissions and coal combustion. Herein, historical trends of atmospheric As, Cd, Cr, Cu, Hg, Ni, Pb and Zn contamination in North China over the past ∼500 years are comparatively studied with sediment cores from two subalpine lakes (Gonghai and Muhai). Arsenic, Pb, Cd and Hg were main pollutants according to Pb isotopes and enrichment factors. Mercury contamination has increased continuously since the late 1800s and increasing As, Pb and Cd contamination started in the 1950s in Gonghai. In contrast, the contamination in Muhai lagged two decades for As, Cd and Pb and a half-century for Hg behind that in Gonghai, although the trends were similar. This contamination lag was attributed to the low sensitivity of Muhai sediment to early weak atmospheric metal contamination under 2.1-fold higher detrital sedimentation. As, Pb and Cd contamination has intensified since the 1980s, and the metals showed similar sedimentary fluxes in the cores. However, sedimentary fluxes of Hg contamination were 3.4-fold higher in Gonghai than in Muhai due to combination with organic matter. No obvious Cr, Cu and Ni contamination in the cores was mainly because of the low atmospheric deposition from anthropogenic sources relative to detrital input, although some of their atmospheric emissions were higher than those of As, Cd and Hg. Atmospheric As, Pb and Cd contamination was mainly from domestic sources of coal combustion and nonferrous smelting. Mercury contamination was mainly from global and Asian sources in the first half of the 20th century, and domestic emissions gradually dominated Hg contamination after the mid-1900s.

Inorganic P is adsorbed by a variety of soil minerals. For acidic subtropical Alfisols with high contents of both (hydr)oxides and clay minerals, there is an underappreciated understanding of the importance of clay minerals to P species and availability varying with soil pH and P concentration. In this study, the rate and equilibrium of P adsorption in a subtropical Alfisol were investigated by combining soil incubation with three types of P fertilizer with multi-surface modelling. Phosphorus species analysis revealed that most of the P was present in the forms of Al-P and Fe-P in the subtropical Alfisol. The multi-surface model calculation showed that goethite, kaolinite, and illite were the most important soil constituents responsible for the immobilization of P. Clay minerals were as important as Al/Fe (hydr)oxides for P adsorption in the subtropical Alfisol. In addition, there was a highly positive linear correlation between P adsorbed by illite and Olsen P, with a slope of approximately to 1. The model analysis also showed that >99% of the P adsorbed by illite was in the form of - S O 2 P O 2 2 - . These results suggest the important role of illite in controlling P availability and that P adsorption by illite may serve as an indicator of P availability in the subtropical Alfisol.