Search

Abstract Many studies have focused on the effects of small molecules, such as amino acids, on metabolism under hypoxia. Recent findings have indicated that phenylalanine levels were markedly elevated in adaptation to chronic hypoxia. This raises the possibility that phenylalanine treatment could markedly improve the hypoxic endurance. However, the importance of hypoxia-regulated phenylalanine is still unclear. This study investigates the role of phenylalanine in hypoxia adaptation using a hypoxic zebrafish model and multi-omics analysis. We found that phenylalanine-related metabolic pathways are significantly up-regulated under hypoxia, contributing to enhanced hypoxic endurance. Phenylalanine treatment reduced ROS levels, improved mitochondrial oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) in hypoxic cells. Western blotting revealed increased phenylalanine uptake via L-type amino transporters (LAT1), activating the LKB1/AMPK signaling pathway. This activation up-regulated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and the Bcl-2/Bax ratio, while down-regulating uncoupling protein 2 (UCP2), thereby improving mitochondrial function under hypoxia. This is the first comprehensive multi-omics analysis to demonstrate phenylalanine’s crucial role in hypoxia adaptation, providing insights for the development of anti-hypoxic drugs. Graphical Abstract

The extreme heavy rainfall weather under the long-term influence of MCS can easily cause serious disasters such as flash floods in complex terrain areas. Detailed study of its characteristics and causes can help better understand and defend against similar disaster weather. In this paper, we use multi-source meteorological observation data to study the MCS evolution characteristics and mechanism of two rainstorm processes on 10-11 August 2020 (process 1) and 4-5 August 2021 (process 2) in the complex terrain area of the eastern slope of the Qinghai Tibet Plateau. The results are as follows. (1) The two processes are warm rainstorm weather processes under the influence of weak weather scale system, and the strong precipitation areas are located in the Pingba River valley to the west of Luochun Mountains. The terrain has a very obvious impact on the strong precipitation areas. Compared with process 2, process 1 has larger precipitation intensity, wider range and more concentrated distribution of precipitation areas. (2) The MCS that caused the two rainstorm both originated in the high altitude windward slope terrain in the west of Ya'an, and maintained development in the west side of Luochun Mountains, but the MCS of process 1 was larger in scale, intensity and duration. (3) The heavy precipitation in process 1 is mainly caused by a larger scale convective (mainly cumulus clouds) MCS with stable and less movement, while process 2 is caused by two successively developing mixed (cumulus layer cloud mixing) MCS passing through the same area. (4) The maintenance mechanism of MCS during the two processes is different. The main mechanism of Process 1 is the continuous formation of deep convective cells under the forced uplift of the Luochun Mountain terrain, which merge with the original MCS1_A and maintain it on the western side of Luochun Mountain for a long time, forming a quasi stationary backward established MCS echo zone; At the same time, the blocking effect of the terrain on the outflow of the cold pool and the bypass effect on the warm and humid air flow also promote the stability and less movement of MCS1_A to a certain extent. The main mechanism for maintaining MCS in process 2 is the feedback effect of high-altitude windward slope terrain.

Abstract Background Diabetic retinopathy (DR) is a common microvascular complication of diabetes mellitus (DM) and a significant cause of acquired blindness in the working-age population worldwide. Aging is considered as an important risk factor for DR development. Macrophages in aged mice bear typical M2 marker proteins but simultaneously express a pro-inflammatory factor profile. This may explain why the level of intraocular inflammation does not decrease during proliferative diabetic retinopathy (PDR) despite the occurrence of neovascularization and fibrosis (M2 activation). α-Klotho (KL) was originally discovered as a soluble anti-aging factor, which is mainly expressed in kidney tubular epithelium, choroid plexus in the brain and secreted in the blood. However, the role of KL in DR pathophysiology has not been previously reported. Methods Type 1 (streptozotocin [STZ]-induced) and type 2 (a high-fat diet along with a low dose of STZ) diabetic mouse models were established and injected with or without KL adenovirus via the tail vein for 12 weeks. Vldlr−/− mice were injected intravitreally with or without soluble KL protein from P8 to P15. The retinal structure and function were analyzed by electroretinogram and optical coherence tomography. The neovascular lesions were analyzed by retinal flat mount and RPE flat mount. The senescence markers, macrophage morphology, and KL expression levels were detected by immunofluorescence staining. A cell model was constructed using RAW264.7 cells stimulated by 4-hydroxynonenal (4HNE) and transfected with or without KL adenovirus. The senescence-associated secretory phenotypes were detected by qRT-PCR. Senescence was detected by SA-β-Gal staining. Serum, aqueous humor, and vitreous humor KL levels of proliferative diabetic retinopathy (PDR) patients were measured by enzyme‐linked immunosorbent assay. Quantitative proteomics and bioinformatics were applied to predict the change of proteins and biological function after overexpression of KL in macrophages. The effects of KL on the HECTD1 binding to IRS1 were analyzed by bioinformatics, molecular docking, and Western Blot. Results Serum, aqueous humor, and vitreous humor KL levels were lower in patients with PDR than in those with cataracts. KL relieved the retinal structure damage, improved retina function, and inhibited retinal senescence in diabetic mice. KL administration attenuated the neovascular lesions in VLDLR−/− mice by decreasing the secretion of VEGFA and FGF2 from macrophages. KL also protected RAW264.7 cells from 4HNE-induced senescence. Additionally, it inhibited E3 ubiquitin ligase HECTD1 expression in both diabetic mouse peripheral blood mononuclear cells and 4HNE-treated RAW264.7 cells. KL inhibited HECTD1 binding to IRS1 and reduced the ubiquitination of IRS1. Conclusions Macrophage aging is involved in DM-induced retinopathy. KL alleviates DM-induced retinal macrophage senescence by downregulating HECTD1 and decreasing IRS1 ubiquitination and degradation. Meanwhile, KL administration attenuated the neovascular lesions by altering the activation state of macrophages and decreasing the expression of VEGFA and FGF2.

Abstract Background A cross-sectional population-based survey in the Beichen district of Tianjin was conducted to estimate the prevalence of dry eye disease (DED) among the population over 50 years old with Dry Eye Workshop (DEWS) II and Chinese expert consensus (CEC) criteria. Methods A total of 5791 subjects over 50 years old were enrolled. Ocular surface disease index (OSDI) questionnaire, lipid layer thickness (LLT), partial blink ratio (PBR), fluorescein tear film breakup time (FBUT), Schirmer I test (SIT), fluorescein staining, meibomian gland dropout, meibomian gland expression scores (MES) and quantity scores (MQS) was assessed. Additionally, basic information, weight, disease history, living habits, anxiety, and depression condition were collected. Results According to the CEC, the prevalence of DED was 39.0%, whereas 44.0% based on DEWS II. The prevalence of DED increased with age and was substantially greater among women (41.1%, 95% CI, 39.5-42.6%) than males (35.1%, 95% CI, 33.1 -37.2%) (p

Abstract Context Polycystic ovary syndrome (PCOS), a common endocrine disorder in women of reproductive age, is closely associated with chronic low-grade inflammation and metabolic disturbances. In PCOS mice, dietary inulin has been demonstrated to regulate intestinal flora and inflammation. However, the efficacy of dietary inulin in clinical PCOS remains unclear. Objective The intestinal flora and related metabolic indexes of obese patients with polycystic ovary syndrome (PCOS) after 3 months of inulin treatment were analyzed. Setting and design To analyze the intestinal flora and related metabolic indexes in healthy controls and obese patients with polycystic ovary syndrome after 3 months of inulin treatment. Results The results showed that dietary inulin improved sex hormone disorders, reduced BMI and WHR levels in obese women with PCOS. In addition, the inulin intervention reduced plasma TNF-α, IL-1β, IL-6, and MCP-1levels. Inulin intervention increased the abundance of Actinobacteria, Fusobacteria, Lachnospira, and Bifidobacterium, as well as decreased the ratio of F/B and the abundance of proteobacteria, Sutterella, and Enterobacter. Correlation analyses showed a strong relationship among plasma inflammatory factors, sex steroid hormones, and the intestinal flora of patients. Conclusions Dietary inulin may improve obese PCOS women disease through the gut flora–inflammation–steroid hormone pathway. The clinical trial registration number: ChiCTR-IOR-17012281.

BackgroundArrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy characterized by high risks of sustained ventricular tachycardia (sVT) and sudden cardiac death. Identifying patients with high risk of sVT is crucial for the management of ACM.MethodsA total of 147 ACM patients were retrospectively enrolled in the observational study and divided into training and validation groups. The least absolute shrinkage and selection operator (LASSO) regression model was employed to identify factors associated with sVT. Subsequently, a nomogram was constructed based on multivariable logistic regression analysis. The performance of the nomogram was evaluated using the area under the curve (AUC) of the receiver operating characteristic (ROC) curve and calibration curve. Decision curve analysis was conducted to assess the clinical utility of the nomogram.ResultsSeven parameters were incorporated into the nomogram: age, male sex, syncope, heart failure, T wave inversion in precordial leads, left ventricular ejection fraction (LVEF), SDNN level. The AUC of the nomogram to predict the probability of sVT was 0.867 (95% CI, 0.797–0.938) in the training group and 0.815 (95% CI, 0.673–0.958) in the validation group. The calibration curve demonstrated a good consistency between the actual clinical results and the predicted outcomes. Decision curve analysis indicated that the nomogram had higher overall net benefits in predicting sVT.ConclusionWe have developed and internally validated a new prediction model for sVT in ACM. This model could serve as a valuable tool to accurately identify ACM patients with high risk of sVT.

Purpose: The aim of this study is to explore the prevalence, associated risk factors, and the influence of urbanization on the epidemiology of diabetic retinopathy (DR) and diabetic macular edema (DME). Methods: This study utilized a cross-sectional design to survey residents aged 50 and older in the Beichen community, Tianjin. Participants underwent thorough examinations, including questionnaire surveys, laboratory blood tests, eye assessments, fundus photography, and optical coherence tomography (OCT) scans. DR was diagnosed using the retinopathy severity scale from fundus photographs based on the Early Treatment Diabetic Retinopathy Study (ETDRS) classification system. DME was identified through medical history records and OCT evaluations. In this study, we analyzed and assessed the prevalence and risk factors associated with DR and DME. Results: The study included 5,648 participants, and 1,182 of these were diagnosed with diabetes. Among the diabetic individuals, the prevalence of DR was 28.8%. Among the eyes of those diagnosed with DR, 37.12% had mild non-proliferative DR (NPDR), 54.81% had moderate NPDR, 6.35% (33 eyes) showed severe NPDR, and 1.73% had proliferative DR (PDR). The prevalence of DME among diabetic patients was 14.13%. Age was negatively correlated with DR (OR, 0.924), while blood glucose levels (OR, 1.123) and the duration of diabetes (OR, 1.090) were positively correlated. Additionally, blood glucose levels (OR, 1.121) and the duration of diabetes (OR, 1.070) were positively associated with DME. Conclusion: In this study, the prevalence of DR and DME was high in the Beichen District of Tianjin than in other parts of China. Maintaining effective glycemic control is the most important modifiable factor in reducing the risk of DR and DME progression and minimizing the risk of vision loss.

Abstract Glaucoma is the leading cause of irreversible blindness and is characterized by progressive retinal ganglion cell (RGC) loss and retinal nerve fiber layer thinning. Currently, no existing treatment is effective for the preservation of RGCs. MicroRNA-22-3p (miR22) and small extracellular vesicles derived from mesenchymal stem cells (MSC-sEVs) have neuroprotective effects. In this study, we apply miR22-overexpressing MSC-sEVs in an N-methyl-D-aspartic acid (NMDA)-induced RGC injury model to assess their short-term therapeutic effects and explore the underlying mechanisms. We find that mice in the miR22-sEVs-treated group have thicker retinas, fewer apoptotic cells, more reserved RGCs, better retinal function, and lower expression levels of Bax and caspase-3. MiR22-sEVs treatment promotes viability, inhibits apoptosis and inhibits Bax and caspase-3 expression in RGC-5 cells. MiR22 targets mitogen-activated protein kinase kinase kinase 12 to inhibit apoptosis by regulating the mitogen-activated protein kinase (MAPK) signaling pathway. Collectively, our results suggest that miR22-sEVs ameliorate NMDA-induced RGC injury through the inhibition of MAPK signaling pathway-mediated apoptosis, providing a potential therapy for glaucoma and other diseases that involve RGC damage.

Abstract Background Brominated Flame Retardants (BFRs) have attracted widespread concern due to their environmental persistence and potential toxicity. This study aims to examine the association between BFRs exposure and hypertension. Methods We used data from the National Health and Nutrition Examination Survey (NHANES) spanning 2005 to 2016 for the cross-sectional analysis. To evaluate the individual and combined impacts of BFRs exposure on hypertension, we utilized multivariate models, including generalized additive models, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) models. Results 9882 individuals (48% male) aged ≥ 20 were included in the final analysis, of whom 4114 had hypertension. After controlling for potential covariates, higher serum concentrations of PBDE100 (OR: 1.26; 95% CI: 1.01, 1.57) and PBDE153 (OR: 1.50; 95% CI: 1.18, 1.88) were significantly associated with hypertension. A nonlinear relationship between PBDE28 and hypertension was observed (P = 0.03). Moreover, BFRs mixture were positively associated with the prevalence of hypertension in both the WQS (β:1.09; 95% CI: 1.02, 1.17; P = 0.02) and BKMR models. Conclusion Our study suggested that BFRs exposure is positively associated with hypertension in the general population. To confirm this association and elucidate the mechanisms, further research is required.

Abstract Background To establish a normative database for macular vessel density (VD) measured by optical coherence tomography angiography (OCTA) and explore the parameters related to the VD. Methods An observational study in epidemiology. 5840 healthy elderly participants in Beichen district, Tianjin, China underwent detailed ophthalmic and systemic examinations. OCTA was performed in all subjects using a 6 × 6-mm line scan mode centered on the macula and the built-in software was used to quantify VD and stratify the retina. Results One thousand four hundred sixty-one healthy elderly citizens (30.4% men) were included, with a median age of 60.0 years (8.0 years) and an age range of 50 to 87 years.VDs in the different plexuses: superficial capillary plexus (SCP) 43.9% (3.2%), deep capillary plexus (DCP) 44.3% (2.8%), outer capillary plexus (OCP) 21.9% (5.9%), choriocapillaris (CC) 52.1% (1.4%). 90% medical reference range of the VDs at different plexuses was reported. Age was correlated with the VDs of each capillary plexus. Sex was correlated with the VDs of DCP and OCP, and the VDs of DCP (p

Borehole instability in naturally fractured rocks poses significant challenges to drilling. Drilling mud invades the surrounding formations through natural fractures under the difference between the wellbore pressure (Pw) and pore pressure (Pp) during drilling, which may cause wellbore instability. However, the weakening of fracture strength due to mud intrusion is not considered in most existing borehole stability analyses, which may yield significant errors and misleading predictions. In addition, only limited factors were analyzed, and the fracture distribution was oversimplified. In this paper, the impacts of mud intrusion and associated fracture strength weakening on borehole stability in fractured rocks under both isotropic and anisotropic stress states are investigated using a coupled DEM (distinct element method) and DFN (discrete fracture network) method. It provides estimates of the effect of fracture strength weakening, wellbore pressure, in situ stresses, and sealing efficiency on borehole stability. The results show that mud intrusion and weakening of fracture strength can damage the borehole. This is demonstrated by the large displacement around the borehole, shear displacement on natural fractures, and the generation of fracture at shear limit. Mud intrusion reduces the shear strength of the fracture surface and leads to shear failure, which explains that the increase in mud weight may worsen borehole stability during overbalanced drilling in fractured formations. A higher in situ stress anisotropy exerts a significant influence on the mechanism of shear failure distribution around the wellbore. Moreover, the effect of sealing natural fractures on maintaining borehole stability is verified in this study, and the increase in sealing efficiency reduces the radial invasion distance of drilling mud. This study provides a directly quantitative prediction method of borehole instability in naturally fractured formations, which can consider the discrete fracture network, mud intrusion, and associated weakening of fracture strength. The information provided by the numerical approach (e.g. displacement around the borehole, shear displacement on fracture, and fracture at shear limit) is helpful for managing wellbore stability and designing wellbore-strengthening operations.

Peritoneal adhesions commonly occur following abdominal or pelvic surgery and can cause serious complications. Currently, physical barriers are the primary approach used in clinical practice to prevent adhesion, although their effectiveness is frequently inadequate. In this study, we developed an injectable peptide-loaded hydrogel with multiple functions, including self-fusion, tissue-adhesiveness, anti-inflammation, anti-cell adhesion and anti-angiogenesis. To assess the effectiveness of these hydrogels, which are stabilized by dynamic imine bonds and acetal connections, in preventing postoperative abdominal adhesions, we utilized both a rat abdominal adhesion model and a rat model simulating repeated-injury adhesions. In comparison to the commercially available HA hydrogel, as-prepared hydrogels exhibited significant reductions in inflammation, fibrosis, and angiogenesis, leading to an obvious decrease in peritoneal adhesions. Moreover, this peptide-loaded hydrogel demonstrated an ideal degradation time, maintaining an in vivo viability for about 10 days. We believe this peptide-loaded hydrogel presents a promising solution for the challenging clinical issue of postoperative abdominal adhesions.

Purpose: To investigate the global and regional correlations between longitudinal structure-function (S-F) and vasculature-function (V-F) using circumpapillary retinal nerve fiber layer (cpRNFL) thickness measurements, circumpapillary vessel density (cpVD) and the corresponding/final visual outcomes at different stages of nonarteritic anterior ischemic optic neuropathy (NAION). Methods: Thirty eyes of 30 patients with acute NAION were included. LogMAR best-corrected visual acuity(BCVA), mean deviation (MD) and visual field index (VFI), cpRNFL thickness and cpVD across different retinal layers were examined at baseline, 2 weeks and 1 month after diagnosis. Potential correlations between the Optical coherence tomography (OCT) and optical coherence tomography angiography (OCTA) parameters and visual outcomes were investigated in both acute and sub-acute NAION. Results: Significant global and regional correlations in S-F relationship were identified exclusively in sub-acute stage (p < 0.05). However, among the OCTA parameters for the acute NAION, the temporal cpVD in superficial vessel complex (SVC) and inner retinal layer (IRL) exhibited positive correlations with corresponding and final visual acuity and visual field outcomes. In the sub-acute stage of NAION, the cpVD of global or temporal section in radial peripapillary capillary (RPC), SVC and IRL were positively correlated with visual outcomes. Conclusion: Significant longitudinal V-F relationships exist both globally and regionally, in acute and sub-acute NAION. The cpVD parameters of the SVC and IRL are potentially valuable for evaluating corresponding and final visual outcomes and highlights the importance of monitoring cpVD over cpRNFL thickness in acute NAION.

Abstract Background While serum Ca has proven to be a reliable predictor of mortality across various diseases, its connection with the clinical outcomes of ischemic stroke (IS) remains inconclusive. Our research aimed to explore the relationships between serum total Ca (tCa) and serum ionized Ca (iCa) and mortality among acute IS (AIS) patients. Methods We gathered data from 1773 AIS patients in the Medical Information Mart for Intensive Care Database IV, including baseline demographic data, comorbidities, vital signs, laboratory-based data, and scoring systems. Endpoints for the study encompassed 30-d, 90-d, and 365-d all-cause mortalities. Employing restricted cubic spline Cox regression, we explored potential nonlinear relationships between admission serum iCa and tCa levels and mortality. Participants were categorized into four groups based on serum iCa and tCa quartiles. Multivariable Cox regression analysis was then conducted to evaluate the independent association of iCa and tCa quartiles with all-cause mortality. Results The restricted cubic spline revealed a U-shaped association between iCa and 30-d and 90-d mortality (P

Abstract Background We aimed to investigate the anatomical features of optical coherence tomography (OCT) and vitreous cytokine levels as predictors of outcomes of combined phacovitrectomy with intravitreal dexamethasone (DEX) implants for idiopathic epiretinal membrane (iERM) treatment. Methods A prospective, single-masked, randomized, controlled clinical trial included 48 eyes. They were randomly assigned in a 1:1 ratio to undergo the DEX group (combined phacovitrectomy with ERM peeling and Ozurdex implantation) and control group (phacovitrectomy only). Best-corrected visual acuity (BCVA) and central macular thickness (CMT) were assessed at 1 d, 1 week, 1 month, and 3 months. The structural features of OCT before surgery were analysed for stratified analysis. Baseline soluble CD14 (sCD14) and sCD163 levels in the vitreous fluid were measured using ELISA. Results BCVA and CMT were not significantly different in the DEX and control groups. Eyes with hyperreflective foci (HRF) at baseline achieved better BCVA (P time*group=0.746; P group=0.043, Wald χ²=7.869) and lower CMT (Ptime*group = 0.079; Pgroup = 0.001, Wald χ²=6.774) responses to DEX during follow-up. In all patients, the mean vitreous level of sCD163 in eyes with HRF was significantly higher than that in eyes without HRF (P = 0.036, Z=-2.093) at baseline. In the DEX group, higher sCD163 predicted greater reduction in CMT from baseline to 1 month (r = 0.470, P = 0.049). Conclusions We found that intraoperative DEX implantation did not have beneficial effects on BCVA and CMT over a 3-month period in all patients with iERM, implying that the use of DEX for all iERM is not recommended. In contrast, for those with HRF on OCT responded better to DEX implants at the 3-month follow-up and thier vitreous fluid expressed higher levels of sCD163 at baseline. These data support the hypothesis that DEX implants may be particularly effective in treating cases where ERM is secondary to inflammation. Trial registration The trail has been registered at Chinese Clinical Trail Registry( https://www.chictr.org.cn ) on 2021/03/12 (ChiCTR2100044228). And all patients in the article were enrolled after registration.

Abstract Purpose To investigate the effects of vitrectomy and intravitreal dexamethasone (DEX) implantation on retinal biomarkers in patients with advanced idiopathic epiretinal membrane (IERM) and to evaluate this treatment’s anatomical and functional outcomes. Methods This retrospective study included 41 patients with advanced IERM who underwent vitrectomy and were divided into a pars plana vitrectomy (PPV) group (20 eyes) and a dexamethasone (DEX) group (21 eyes) based on intravitreal DEX implantation. We collected data on best-corrected visual acuity (BCVA), central macular thickness (CMT), disorganization of the retinal inner layers (DRIL), subretinal fluid, intraretinal cystoid changes (IRC), integrity of the inner-outer segment layer, and intraocular pressure. Results BCVA improved significantly in both groups; the DEX group had a higher visual acuity gain at 1 and 6 months (P = 0.002 and 0.023, respectively). Postoperative CMT gradually decreased in both groups, with the DEX group showing a greater decrease at 1 and 6 months (P = 0.009 and 0.033, respectively). Six months after surgery, the DRIL and IRC grades in the DEX group were significantly improved compared to those in the PPV group (P = 0.037 and 0.038, respectively). Multivariate regression analyses revealed that patients with intraoperative DEX implants were more likely to have a significant CMT reduction (≥ 100 μm) from baseline (odds ratio (OR), 9.44; 95% confidence intervals (CI), 1.58–56.56; P = 0.014) at 6 months and less likely to exhibit DRIL at 6 months postoperatively (OR, 0.08; 95% CI, 0.01–0.68; P = 0.021). Conclusion Vitrectomy combined with intravitreal DEX implantation facilitates the recovery of postoperative visual acuity and improvement of anatomical outcomes in patients with advanced IERM, effectively reducing CMT and improving DRIL.

Abstract Background Viral infection elicits the type I interferon (IFN-I) response in host cells and subsequently inhibits viral infection through inducing hundreds of IFN-stimulated genes (ISGs) that counteract many steps in the virus life cycle. However, most of ISGs have unclear functions and mechanisms in viral infection. Thus, more work is required to elucidate the role and mechanisms of individual ISGs against different types of viruses. Results Herein, we demonstrate that poliovirus receptor-like protein4 (PVRL4) is an ISG strongly induced by IFN-I stimulation and various viral infections. Overexpression of PVRL4 protein broadly restricts growth of enveloped RNA and DNA viruses, including vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), influenza A virus (IAV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) whereas deletion of PVRL4 in host cells increases viral infections. Mechanistically, it suppresses viral entry by blocking viral-cellular membrane fusion through inhibiting endosomal acidification. The vivo studies demonstrate that Pvrl4-deficient mice were more susceptible to the infection of VSV and IAV. Conclusion Overall, our studies not only identify PVRL4 as an intrinsic broad-spectrum antiviral ISG, but also provide a candidate host-directed target for antiviral therapy against various viruses including SARS-CoV-2 and its variants in the future.

Quinoa is an annual self-pollinating plant rich in polyphenols, flavonoids, saponins, and amino acids; its protein balance closely aligns with the ideal recommendation set by the Food and Agriculture Organization. Therefore, quinoa is considered the most suitable “all-nutrient food”. Phosphorus fertilization plays an important role in restricting the growth and development of quinoa; however, the effects of phosphorus fertilizer on quinoa growth remain unclear. Therefore, we conducted metabolome and transcriptome analyses on quinoa leaves during the filling stage, subjecting plants to different doses of phosphorus fertilizer. Overall, phosphorus treatment exerted a significant impact on the phenotypic characteristics of quinoa. Specifically, through a combined analysis of ultra-performance liquid chromatography–tandem mass spectrometry and transcriptome analysis, we identified the alteration and regulation of specific metabolites and genes within flavonoid biosynthesis pathways; this comprehensive evaluation helped elucidate the response mechanism of quinoa leaves during the grouting stage under various phosphorus conditions. Ultimately, the results of this study provide a reference for the selection of quinoa cultivars that exhibit tolerance to low- or high-phosphorus stress; additionally, we offer a theoretical basis for the rational application of phosphorus fertilizer and the enhancement of phosphorus utilization efficiency.

The ROP (rate of penetration) within the horizontal section of shale gas wells in the Luzhou oil field is low, seriously delaying the exploration and development process. It is proved that reducing mud density mitigates the bottom-hole differential pressure (ΔP) and increases the ROP during overbalanced drilling. However, wellbore collapse may occur when wellbore pressure is excessively low. It is urgent to ascertain the optimal equilibrium point between improving ROP and maintaining wellbore stability. The safe mud weight window and the lower limit of mud density in the horizontal section of the Luzhou block are predicted using the piecewise fitting method based on conventional logging data. Then, the accuracy of the collapse pressure prediction was verified using the distinct element method (DEM), and the effect of wellbore pressure, in-situ stress, rock cohesion, and natural fracture density on borehole collapse was investigated. Finally, a fitting model of ΔP and ROP of the horizontal section in the Luzhou block is established to predict ROP promotion potential after mud density reduction. The field application of this approach, demonstrated in 8 horizontal wells in the Luzhou block, effectively validates the efficiency of reducing mud density for ROP improvement. This study provides a useful method for simultaneously improving ROP and maintaining wellbore stability and offers significant insights for petroleum engineers in the design of drilling parameters.

Abstract Background Catheter ablation is recommended in patients with frequent and symptomatic ventricular arrhythmias (VAs) in an otherwise normal heart. Right or left outflow tract (OT) are the most common origins, and catheter ablation is highly effective with low complication rates. However, outcome of catheter ablation of VAs other than the OT (non-OTVAs) is limited. The aim of this single-center study was to assess the safety and mid-term outcome of catheter ablation for non-OTVAs. Method and Results From 2013 to 2018, 251 patients who underwent catheter ablation for idiopathic non-OTVAs were enrolled and grouped according to the origins including His-Purkinje system (HPS, n = 108), papillary muscle / moderator band (PM/MB, n = 47), tricuspid annulus (TA, n = 70), and mitral annulus (MA, n = 26), 244 (97.2%) had acute elimination of VAs. The time of VAs recurrence of the single procedure was 1.69 (0.12,9.72) months, with 66% occurring within the first 3 months. The recurrence rate was significantly higher in the PM/MB group than in the TA (p = 0.025) and MA groups (p = 0.023). The single procedure success rate in all patients was 70.1%, in which 66.7%, 59.6%, 80%, and 76.9% were achieved in the HPS, PM/MB, TA, and MA groups, respectively (p = 0.284). After multiple procedures, the total success rate was 76.5% at the follow-up of 4.38 ± 2.42 years. The rate was significantly lower in the PM/MB group than in the TA group (p = 0.035). In subgroup analysis, no significant difference was observed in the recurrence rate of single procedure in patients with different VA origins within the PM/MB (log-rank test, p = 0.546). Conclusion Despite a certain percentage of recurrences observed in the mid-term follow-up, catheter ablation remained feasible and effective for idiopathic non-OTVAs.

Abstract Artificial intelligence (AI)-based diagnostic systems have been reported to improve fundus disease screening in previous studies. This multicenter prospective self-controlled clinical trial aims to evaluate the diagnostic performance of a deep learning system (DLS) in assisting junior ophthalmologists in detecting 13 major fundus diseases. A total of 1493 fundus images from 748 patients were prospectively collected from five tertiary hospitals in China. Nine junior ophthalmologists were trained and annotated the images with or without the suggestions proposed by the DLS. The diagnostic performance was evaluated among three groups: DLS-assisted junior ophthalmologist group (test group), junior ophthalmologist group (control group) and DLS group. The diagnostic consistency was 84.9% (95%CI, 83.0% ~ 86.9%), 72.9% (95%CI, 70.3% ~ 75.6%) and 85.5% (95%CI, 83.5% ~ 87.4%) in the test group, control group and DLS group, respectively. With the help of the proposed DLS, the diagnostic consistency of junior ophthalmologists improved by approximately 12% (95% CI, 9.1% ~ 14.9%) with statistical significance (P

Abstract Purpose To compare the effectiveness and safety of a 27-gauge (27G) beveled-tip microincision vitrectomy surgery (MIVS) with a 25-gauge (25G) flat-tip MIVS for the treatment of proliferative diabetic retinopathy (PDR). Methods A prospective, single-masked, randomized, controlled clinical trial included 52 eyes (52 patients) with PDR requiring proliferative membrane removal. They were randomly assigned in a 1:1 ratio to undergo the 27G beveled-tip and or 25G flat-tip MIVS (the 27G group and the 25G group, respectively). During surgery, the productivity of cutting the membrane, the number of vitrectomy probe (VP) exchanges to microforceps, total operation time, vitrectomy time and intraoperative complications were measured. Best-corrected visual acuity (BCVA), intraocular pressure (IOP) and postoperative complications were also assessed to month 6. Results Forty-seven eyes (47 patients) completed the follow-up, including 25 in the 27G group and 22 in the 25G group. During surgery in the 27G group, cutting the membrane was more efficient (P = 0.001), and the number of VP exchanges to microforceps was lower (P = 0.026). The occurrences of intraoperative hemorrhages and electrocoagulation also decreased significantly (P = 0.004 and P = 0.022). There were no statistical differences in the total operation time or vitrectomy time between the two groups (P = 0.275 and P = 0.372), but the former was slightly lower in the 27G group. Additionally, the 27G group required fewer wound sutures (P = 0.044). All the follow-up results revealed no significant difference between the two groups. Conclusions Compared with the 25G flat-tip MIVS, the 27G beveled-tip MIVS could be more efficient in removing the proliferative membrane while reducing the occurrence of intraoperative hemorrhages and electrocoagulation using appropriate surgical techniques and instrument parameters. Its vitreous removal performance was not inferior to that of the 25G MIVS and might offer potential advantages in total operation time. In terms of patient outcomes, advanced MIVS demonstrates equal effectiveness and safety to 25G flat-tip MIVS. Trial registration The clinical trial has been registered at Clinicaltrials.gov (NCT0544694) on 07/07/2022. And all patients in the article were enrolled after registration.

Abstract Curriculum standards are a critical component of a nation’s educational system and directly impact talent development and overall national development. Most studies on curriculum standards focus on a single competency. This study aims to understand the extent to which the competencies outlined in the OECD 2030-oriented learning framework are reflected in China’s compulsory education biology curriculum as a whole and within individual content subjects. In this study, we conducted a content analysis of China’s National Biology Curriculum Standards (Grades 7–9). The result shows that the standards cover 20 of the 28 competencies, focusing on foundational literacies, transformative competencies and competency development. We found that certain competencies, such as Action, Literacy, and Problem-solving, were emphasized across content subjects, while other competencies were uniquely emphasized within specific content subjects. This study provides a comprehensive view of China’s National Biology Curriculum Standards (Grades 7–9) from the perspective of future literacy development and can inform efforts to reform the curriculum.

Objectives: Network pharmacology is essential for understanding the multi-target and multi-pathway therapeutic mechanisms of traditional Chinese medicine. This study aims to evaluate the influence of database quality on target identification and to explore the therapeutic potential of rhynchophylline (Rhy) in treating overactive bladder (OAB). Methods: An OAB dataset was constructed through extensive literature screening. Using this dataset, we applied network pharmacology to predict potential targets for Rhy, which is known for its therapeutic effects but lacks a well-defined target profile. Predicted targets were validated through in vitro experiments, including DARTS and CETSA. Results: Our analysis identified Rhy as a potential modulator of the M3 receptor and TRPM8 channel in the treatment of OAB. Validation experiments confirmed the interaction between Rhy and these targets. Additionally, the GeneCards database predicted other targets that are not directly linked to OAB, corroborated by the literature. Conclusions: We established a more accurate and comprehensive dataset of OAB targets, enhancing the reliability of target identification for drug treatments. This study underscores the importance of database quality in network pharmacology and contributes to the potential therapeutic strategies for OAB.

Abstract Background Diabetic macular edema (DME) is the main cause of vision loss in diabetic patients. Currently, anti-vascular endothelial growth factor (VEGF) intravitreal injection stands as the first-line therapy for DME. However, some patients exhibit insufficient response to anti-VEGF agents and often require multiple injections, imposing psychological and economic burdens. While microinvasive pars plana vitrectomy (PPV) has been shown to be safe and effective in treating refractory DME, scant research has explored its application to treatment-naïve DME. The purpose of this study is to determine whether early PPV combined with internal limiting membrane (ILM) peeling can lessen the therapeutic burden of DME patients, prevent vision loss, and maintain long-term stabilization of diabetic retinopathy. Methods This is a single-center, prospective, parallel-group, non-inferiority randomized controlled trial involving 102 DME participants. Participants will be randomly assigned to either the study group (PPV combined with ILM peeling) or the control group (conbercept intravitreal injection (IVC)) at a 1:1 ratio, with a scheduled follow-up at 12 months post-operation. Comparative analysis of results between the two groups will be conducted at months 1, 3, 6, and 12 after the intervention. The primary outcomes involve evaluating the changes in central subfield thickness (CST) and best corrected visual acuity (BCVA). The secondary outcomes include assessment of optical coherence tomography (OCT) and OCT angiography (OCTA) biomarkers, re-treatment and adverse events rates, diabetic retinopathy (DR) development, cost-effectiveness analysis, and vision-related quality of life (VRQL). Discussion Some patients do not respond well to anti-VEGF drugs and repeated intravitreal injections increase the treatment burden for patients. The VVV study aims to explore whether PPV combined with ILM peeling could become an initial treatment option for treatment-naïve DME patients. Trial registration ClinicalTrials.gov NCT05728476. Registered on 15 February 2023.

Abstract Long non-coding RNAs (lncRNAs) interaction with RNA-Binding proteins (RBPs) plays an important role in immunological processes. The generation of antigen-specific Th17 cells is closely associated with autoimmune pathogenesis. However, the function of lncRNA-RBP interactions in the regulation of pathogenic Th17 cell responses during autoimmunity remains poorly understood. Here, we found that lncRNA Neat1, highly expressed in Th17 cells, promoted antigen-specific Th17 cell responses. Both global and CD4+ T cell-specific knockdown of Neat1 protected mice against the development of experimental autoimmune uveitis (EAU). Mechanistically, Neat1 regulated RNA-Binding protein NonO, thus relieving IL-17 and IL-23R from NonO-mediated transcriptional repression and supporting antigen-specific Th17 cell responses. In addition, Neat1 also modulated miR-128-3p/NFAT5 axis to increase the expression of IL-17 and IL-23R, leading to augmented Th17 cell responses. Our findings elucidate a previously unrecognized mechanistic insight into the action of Neat1 in promoting antigen-specific Th17 responses and autoimmunity, and may facilitate the development of therapeutic targets for T cell-mediated autoimmune diseases.

Abstract Background Several common retinal diseases that cause blindness are characterised by pathological neovascularisation accompanied by inflammation and neurodegeneration, including retinopathy of prematurity (ROP), diabetic retinopathy (DR), age-related macular degeneration (AMD), and retinal vein occlusion (RVO). The current treatment strategies for these diseases have limited benefits. Thus, safer and more effective alternative approaches are required. In this study, we loaded small extracellular vesicles (sEVs) derived from mesenchymal stem cell (MSC) with pigment epithelium-derived factor (PEDF), and tested the therapeutic effect of PEDF-loaded sEVs (PEDF-sEVs) using an oxygen induced retinopathy (OIR) mouse model, aiming to establish a new therapy strategy for the treatment of retinal pathological angiogenesis. Results We formulated PEDF-loaded sEVs (PEDF-sEVs) containing high concentrations of PEDF and evaluated their effects through in vivo and in vitro experiments. In OIR mice, PEDF-sEVs showed significantly better effects on retinal avascular areas, inflammation, and neuronal degeneration compared with the anti-vascular endothelial growth factor (VEGF) drug, which may indicate a possible advantage of PEDF-sEVs over anti-VEGF drugs in the treatment of pathological neovascularisation. In vitro, PEDF-sEVs greatly inhibited endothelial cell (EC) proliferation, migration, and tube formation by suppressing the VEGF-induced phosphorylation of extracellular signal-regulated kinase (ERK) and AKT (also known as Protein Kinase B). All experiments and analyses were performed in triplicate. PEDF-sEVs were more effective than PEDF or sEVs alone, both in vitro and in vivo. Furthermore, to determine the distribution of PEDF-sEVs, we used DiD-labelled sEVs and FITC-labelled PEDF to track the sEVs and PEDF, respectively. We found that PEDF-sEVs effectively reduced the degradation of PEDF. Conclusions Loading PEDF on sEVs effectively enhanced the anti-angiogenic, anti-inflammatory, and neuroprotective effects of PEDF by increasing the stability and penetrability. These results suggest a potential role for PEDF-sEVs in retinal pathological neovascularisation. Graphical Abstract

Abstract Background Epiretinal membranes in patients with proliferative vitreoretinopathy (PVR) consist of extracellular matrix and a number of cell types including retinal pigment epithelial (RPE) cells and fibroblasts, whose contraction causes retinal detachment. In RPE cells depletion of platelet-derived growth factor (PDGF) receptor (PDGFR)β suppresses vitreous-induced Akt activation, whereas in fibroblasts Akt activation through indirect activation of PDGFRα by growth factors outside the PDGF family (non-PDGFs) plays an essential role in experimental PVR. Whether non-PDGFs in the vitreous, however, were also able to activate PDGFRβ in RPE cells remained elusive. Methods The CRISPR/Cas9 technology was utilized to edit a genomic PDGFRB locus in RPE cells derived from an epiretinal membrane (RPEM) from a patient with PVR, and a retroviral vector was used to express a truncated PDGFRβ short of a PDGF-binding domain in the RPEM cells lacking PDGFRβ. Western blot was employed to analyze expression of PDGFRβ and α-smooth muscle actin, and signaling events (p-PDGFRβ and p-Akt). Cellular assays (proliferation, migration and contraction) were also applied in this study. Results Expression of a truncated PDGFRβ lacking a PDGF-binding domain in the RPEM cells whose PDGFRB gene has been silent using the CRISPR/Cas9 technology restores vitreous-induced Akt activation as well as cell proliferation, epithelial-mesenchymal transition, migration and contraction. In addition, we show that scavenging reactive oxygen species (ROS) with N-acetyl-cysteine and inhibiting Src family kinases (SFKs) with their specific inhibitor SU6656 blunt the vitreous-induced activation of the truncated PDGFRβ and Akt as well as the cellular events related to the PVR pathogenesis. These discoveries suggest that in RPE cells PDGFRβ can be activated indirectly by non-PDGFs in the vitreous via an intracellular pathway of ROS/SFKs to facilitate the development of PVR, thereby providing novel opportunities for PVR therapeutics. Conclusion The data shown here will improve our understanding of the mechanism by which PDGFRβ can be activated by non-PDGFs in the vitreous via an intracellular route of ROS/SFKs and provide a conceptual foundation for preventing PVR by inhibiting PDGFRβ transactivation (ligand-independent activation).

Abstract Background To develop a deep learning (DL) model based on preoperative optical coherence tomography (OCT) training to automatically predict the 6-month postoperative visual outcomes in patients with idiopathic epiretinal membrane (iERM). Methods In this retrospective cohort study, a total of 442 eyes (5304 images in total) were enrolled for the development of the DL and multimodal deep fusion network (MDFN) models. All eyes were randomized into a training dataset with 265 eyes (60.0%), a validation dataset with 89 eyes (20.1%), and an internal testing dataset with the remaining 88 eyes (19.9%). The input variables for prediction consisted of macular OCT images and diverse clinical data. Inception-Resnet-v2 network was utilized to estimate the 6-month postoperative best-corrected visual acuity (BCVA). Concurrently, a regression model was developed using the clinical data and OCT parameters in the training data set for predicting postoperative BCVA. The reliability of the models was subsequently evaluated using the testing dataset. Results The prediction DL algorithm exhibited a mean absolute error (MAE) of 0.070 logMAR and root mean square error (RMSE) of 0.11 logMAR in the testing dataset. The DL model demonstrated a robust promising performance with R2 = 0.80, notably superior to R2 = 0.49 of the regression model. The percentages of BCVA prediction errors within ± 0.20 logMAR amounted to 94.32% in the testing dataset. Conclusions The OCT-based DL model demonstrated sensitivity and accuracy in predicting postoperative BCVA in iERM patients. This innovative DL model exhibits substantial potential for integration into surgical planning protocols.

Retinitis pigmentosa (RP) is a degenerative disease, caused by genetic mutations that lead to a loss in photoreceptors. For research on RP, rd10 mice, which carry mutations in the phosphodiesterase (PDE) gene, exhibit degenerative patterns comparable to those of patients with RP, making them an ideal model for investigating potential treatments. Although numerous studies have reported the potential of biochemical drugs, gene correction, and stem cell transplantation in decelerating rd10 retinal degeneration, a comprehensive review of these studies has yet to be conducted. Therefore, here, a comparative analysis of rd10 mouse treatment research over the past decade was performed. Our findings suggest that biochemical drugs capable of inhibiting the inflammatory response may be promising therapeutics. Additionally, significant progress has been made in the field of gene therapy; nevertheless, challenges such as strict delivery requirements, bystander editing, and off-target effects still need to be resolved. Nevertheless, secretory function is the only unequivocal protective effect of stem cell transplantation. In summary, this review presents a comprehensive analysis and synthesis of the treatment approaches employing rd10 mice as experimental subjects, describing a clear pathway for future RP treatment research and identifies potential clinical interventions.

Abstract Background Uveitis and posterior scleritis are sight-threatening diseases with undefined pathogenesis and accurate diagnosis remains challenging. Methods Two plasma-derived extracellular vesicle (EV) subpopulations, small and large EVs, obtained from patients with ankylosing spondylitis-related uveitis, Behcet's disease uveitis, Vogt-Koyanagi-Harada syndrome, and posterior scleritis were subjected to proteomics analysis alongside plasma using SWATH-MS. A comprehensive bioinformatics analysis was performed on the proteomic profiles of sEVs, lEVs, and plasma. Candidate biomarkers were validated in a new cohort using ELISA. Pearson correlation analysis was performed to analyze the relationship between clinical parameters and proteomic data. Connectivity map database was used to predict therapeutic agents. Results In total, 3,668 proteins were identified and over 3000 proteins were quantified from 278 samples. When comparing diseased group to healthy control, the proteomic profiles of the two EV subgroups were more correlated with disease than plasma. Comprehensive bioinformatics analysis highlighted potential pathogenic mechanisms for these diseases. Potential biomarker panels for four diseases were identified and validated. We found a negative correlation between plasma endothelin-converting enzyme 1 level and mean retinal thickness. Potential therapeutic drugs were proposed, and their targets were identified. Conclusions This study provides a proteomic landscape of plasma and EVs involved in ankylosing spondylitis-related uveitis, Behcet's disease uveitis, Vogt-Koyanagi-Harada syndrome, and posterior scleritis, offers insights into disease pathogenesis, identifies valuable biomarker candidates, and proposes promising therapeutic agents.

To report a case of anaphylactic shock caused by the treatment of plantar warts with local injection of pingyangmycin and review the relevant literature. A 30-year-old male had two horny growths on the front sole for 2 months and was diagnosed with plantar wart. Patient was healthy without a history of allergy to foods or drugs. He was treated with local injection of Pingyangmycin in the interval of 3~4 weeks at our hospital in May 2021. After three treatments, the patient did not continue the treatment because of the disappearance of the lesions. In July 2022, plantar wart recurred and the patient received the injection of pingyangmycin again. However, about 5 minutes after the fifth injection, patient developed symptoms of anaphylactic shock such as blurred vision, dyspnea, and blood pressure dropping. Dexamethasone (5 mg IV) and epinephrine (0.5 mg IM) were given immediately. About 1 hour later, the symptoms were gradually relieved and his vital signs were stable.

Abstract Metastatic propagation is the leading cause of death for most cancers. Prediction and elucidation of metastatic process is crucial for the treatment of cancer. Even though somatic mutations have been linked to tumorigenesis and metastasis, it is less explored whether metastatic events can be identified through genomic mutational signatures, which are concise descriptions of the mutational processes. Here, we developed MetaWise, a Deep Neural Network (DNN) model, by applying mutational signatures as input features calculated from Whole-Exome Sequencing (WES) data of TCGA and other metastatic cohorts. This model can accurately classify metastatic tumors from primary tumors and outperform traditional machine learning (ML) models and a deep learning (DL) model, DiaDeL. Signatures of non-coding mutations also have a major impact on the model’s performance. SHapley Additive exPlanations (SHAP) and Local Surrogate (LIME) analyses identify several mutational signatures which are directly correlated to metastatic spread in cancers, including APOBEC-mutagenesis, UV-induced signatures, and DNA damage response deficiency signatures.

Isoliquiritigenin (ISL) has excellent neuroprotective effects. However, its limitations, including poor solubility, low bioavailability, and low accumulation in the brain, restrict its clinical promotion. In this study, a novel type of ISL-loaded liposome (ISL-LP) modified with the brain-targeting polypeptide angiopep-2 was prepared to improve these properties. The zeta potential, morphology, particle size, encapsulation efficiency, drug loading, and in vitro release of ISL-LP were evaluated. The pharmacokinetics and tissue distribution of ISL and ISL-LP were also investigated. The results demonstrated that ISL-LP had an average particle size of 89.36 ± 5.04 nm, a polymer dispersity index of 0.17 ± 0.03, a zeta potential of −20.27 ± 2.18 mV, and an encapsulation efficiency of 75.04 ± 3.28%. The in vitro release experiments indicate that ISL-LP is a desirable sustained-release system. After intravenous administration, LPC-LP prolonged the circulation time of ISL in vivo and enhanced its relative brain uptake. In conclusion, ISL-LP could serve as a promising brain-targeting system for the treatment and prevention of central nervous system (CNS) disorders.

Abstract Patients with metabolic syndrome (MetS) undergoing surgery are at high risk of developing peritoneal adhesions and other severe postoperative complications. However, the single shielding function and absence of physiological activity render conventional methods less useful in preventing adhesions in patients with MetS. To address this challenge, a convenient method is introduced for developing a novel tissue‐adhesive hydrogel called oxidized dextran–metformin (ODE–ME) via Schiff base linkages. This injectable ODE–ME hydrogel exhibits excellent tissue‐adhesive properties and various physiological functions, particularly enhanced antibacterial effects. Furthermore, in vivo experiments demonstrate that the hydrogel can effectively alleviate hyperglycemia, reduce excessive inflammation, and improve fibrinolytic activity in MetS mice, thereby preventing adhesions and promoting incisional healing. The hydrogel concurrently isolates injured tissues and lowers the blood glucose levels immediately after surgery in mice. Therefore, the ODE–ME hydrogel functions as a multifunctional barrier material and has potential for preventing postoperative peritoneal adhesions in patients with MetS in clinical settings.

Seed number per silique (SNPS) is one of seed yield components in rapeseed, but its genetic mechanism remains elusive. Here a double haploid (DH) population derived from a hybrid between female 6Q006 with 35–40 SNPS and male 6W26 with 10–15 SNPS was investigated for SNPS in the year 2017, 2018, 2019 and 2021, and genotyped with Brassica 60K Illumina Infinium SNP array. An overlapping major QTL (qSNPS.C09) explaining 51.50% of phenotypic variance on average was narrowed to a 0.90 Mb region from 44.87 Mb to 45.77 Mb on chromosome C09 by BSA-seq. Subsequently, two DEGs in this interval were detected between extreme individuals in DH and F2 populations by transcriptome sequencing at 7 and 14 days after pollination siliques. Of which, BnaC09g45400D encoded an adenine phosphoribosyltransferase 5 (APT5) has a 48-bp InDel variation in the promoter of two parents. Candidate gene association analysis showed that this InDel variation was associated with SNPS in a nature population of rapeseed, where 54 accessions carrying the same haplotype as parent 6Q006 had higher SNPS than 103 accessions carrying the same haplotype as parent 6W26. Collectively, the findings are helpful for rapeseed molecular breeding of SNPS, and provide new insight into the genetic and molecular mechanism of SNPS in rapeseed.

Abstract Background Previous reports have indicated that disrupting the Wnt/β-catenin pathway in dendritic cells (DCs) may affect the progression of autoimmune inflammation; however, the factors and timing that regulate Wnt/β-catenin signaling have not been clearly understood. Methods Experimental autoimmune uveitis (EAU) mice and Vogt–Koyanagi–Harada disease (VKH) patient samples were used to detect the expression of Wnt/β-catenin pathway genes. Western blot, real-time PCR, flow cytometry, and ELISA were performed to examine the expression of components of the Wnt/β-catenin pathway and inflammatory factors. DC-specific β-catenin knockout mice and 6-bromoindirubin-3′-oxime (BIO) administered mice were used to observe the effect of disrupting the Wnt pathway on EAU pathogenesis. Results Wnt/β-catenin signaling was inhibited in DCs during the induction phase of EAU. The inhibition was mediated by pertussis toxin (PTX), which promoted DC maturation, in turn promoting pathogenic T cell proliferation and differentiation. In vivo experiments confirmed that deleting β-catenin in DCs enhanced EAU severity, and pre-injection of PTX advanced EAU onset. Administration of a Wnt activator (BIO) limited the effects of PTX, in turn ameliorating EAU. Conclusions Our results demonstrate that PTX plays a key role as a virulence factor in initiating autoimmune inflammation via DCs by inhibiting Wnt/β-catenin signaling in EAU, and highlight the potential mechanism by which infection can trigger apparent autoimmunity.

Here the authors investigated the direct collaboration between ubiquitinated histone H2B (ubH2B) with FACT at the nucleosome level. They found ubH2B enhances FACT’s chaperone property, recruits FACT to form a stable altered nucleosome state, and provides a key platform for transcription.

Abstract Background Early exercise for acute deep venous thrombosis (DVT) improves the patient’s symptoms and does not increase the risk of pulmonary embolism. However, information about its effect on thrombus resolution is limited. The aim of this study was to investigate the role of resistance exercise (RE) in thrombus resolution and recanalization and determine its underlying mechanisms. Methods Ninety-six C57BL/6 J mice were randomly divided into four groups: Control group (C, n = 24); DVT group (D, n = 24); RE + DVT group (ED, n = 24); and inhibitor + RE + DVT group (IED, n = 24). A DVT model was induced by stenosis of the inferior vena cava (IVC). After undergoing IVC ultrasound within 24 h post-operation to confirm DVT formation, mice without thrombosis were excluded. Other mice were sacrificed and specimens were obtained 14 or 28 days after operation. Thrombus-containing IVC was weighed, and the thrombus area and recanalization rate were calculated using HE staining. Masson’s trichrome staining was used to analyze the collagen content. RT-PCR and ELISA were performed to examine IL-6, TNF-α, IL-10, and VEGF expression levels. SIRT1 expression was assessed using immunohistochemistry staining and RT-PCR. VEGF-A protein expression and CD-31-positive microvascular density (MVD) in the thrombus were observed using immunohistochemistry. Results RE did not increase the incidence of pulmonary embolism. It reduced the weight and size of the thrombus and the collagen content. Conversely, it increased the recanalization rate. It also decreased the levels of the pro-inflammatory factors IL-6 and TNF-α and increased the expression levels of the anti-inflammatory factor IL-10. RE enhanced VEGF and SIRT1 expression levels and increased the MVD in the thrombosis area. After EX527 (SIRT1 inhibitor) was applied, the positive effects of exercise were suppressed. Conclusions RE can inhibit inflammatory responses, reduce collagen deposition, and increase angiogenesis in DVT mice, thereby promoting thrombus resolution and recanalization. Its underlying mechanism may be associated with the upregulation of SIRT1 expression.

Synthetic lethal (SL) pairs are pairs of genes whose simultaneous loss-of-function results in cell death, while a damaging mutation of either gene alone does not affect the cell’s survival. This makes SL pairs attractive targets for precision cancer therapies, as targeting the unimpaired gene of the SL pair can selectively kill cancer cells that already harbor the impaired gene. Limited by the difficulty of finding true SL pairs, especially on specific cell types, current computational approaches provide only limited insights because of overlooking the crucial aspects of cellular context dependency and mechanistic understanding of SL pairs. As a result, the identification of SL targets still relies on expensive, time-consuming experimental approaches. In this work, we applied cell-line specific multi-omics data to a specially designed deep learning model to predict cell-line specific SL pairs. Through incorporating multiple types of cell-specific omics data with a self-attention module, we represent gene relationships as graphs. Our approach achieves the prediction of SL pairs in a cell-specific manner and demonstrates the potential to facilitate the discovery of cell-specific SL targets for cancer therapeutics, providing a tool to unearth mechanisms underlying the origin of SL in cancer biology. The code and data of our approach can be found at https://github.com/promethiume/SLwise

Abstract Background The aim of this study was to report the clinical profile and outcomes of retinal pigment epithelial detachment (PED) in Vogt-Koyanagi-Harada (VKH) disease, and to evaluate the correlation between PED and the subsequent development of central serous chorioretinopathy (CSC) throughout the whole corticosteroid treatment course. Methods The retrospective study enrolled a total of 470 eyes with VKH, and 12 eyes with VKH and PED were recruited. Patients were divided into two groups according to the CSC onset or not throughout the whole course (the CSC group and non-CSC group). Best-corrected visual acuity (BCVA) improvement, and PED angle (PEDA, the angle between the two lines of the vertex of the lifted retinal pigment epithelium to the two edge points of the Bruch membrane) were compared between the two groups. Results CSC developed at the site of the PED in 5 of the 12 eyes with PED, while in the remaining 7 eyes PED gradually resolved following therapy. The prevalence of PED and CSC in VKH was 2.55% (12/470) and 1.06% (5/470), respectively. BCVA improvement in the non-CSC group was greater than that in the CSC group, but without a statistical difference (P = 0.25). PEDA was significantly smaller in the CSC group than in the non-CSC group (P = 0.03). Conclusion PEDA is an ideal parameter to reflect hydrostatic pressure and stretches for RPE. As PED predisposes to the development of CSC in selected VKH eyes, PEDA may be a valuable predictive factor for the development of classic CSC in VKH cases.

Background: Volatile organic compounds (VOCs) contain hundreds of chemicals and human exposure to VOCs is pervasive. However, most studies have considered only a single chemical or a class of similar chemicals. Objective: We aimed to investigate the association between urinary volatile organic compound metabolites (mVOCs) and the risk of cardiovascular disease (CVD) in the general population. Methods: The data in this study were collected from the National Health and Nutrition Examination Survey in 2011–2018. Eligible patients were aged ≥20 years for whom complete data for 20 types of urinary mVOCs and CVD outcomes were available. Multivariate logistic regression models were used to elucidate the association between mVOCs and CVD. Generalized additive models were used to examine the nonlinear relationships between mVOCs and CVD. Results: 6814 indiviuals were included in the final analysis, of whom 508 had CVD. Higher urinary concentrations of N-acetyl-S-(2-carboxyethyl)-L-cysteine (CEMA) and N-Acetyl-S-(2-cyanoethyl)-l-cysteine (CYMA) and a lower urinary concentration of 2-aminothiazoline-4-carboxylic acid (ATCA) were associated with CVD outcomes after the adjustment for potential confounding factors. A nonlinear relationship and a threshold effect were only observed between N-acetyl-S-(N-methylcarbamoyl)-l-cysteine (AMCC) and CVD among 20 types of mVOCs. There was a significantly positive correlation between AMCC and CVD when AMCC concentration was >2.32 g/mL. Conclusion: The findings of this study suggested a significant correlation between urinary VOC metabolites and CVD. Urinary mVOCs may indicate hazardous exposure or distinct metabolic traits in patients with CVD.

PurposeThis study aimed to investigate the safety and efficacy of three-dimensional (3D) surgical video systems for proliferative diabetic retinopathy (PDR).MethodsThis retrospective clinical case study included 30 patients (30 eyes) with PDR. Patients were divided into two groups: one underwent surgery using a 3D surgical video system (14 cases, 14 eyes), while the other underwent traditional microscope surgery (16 cases, 16 eyes). Safety and efficacy were assessed through predetermined surgical parameters, including surgical duration, intraoperative membrane removal rate, and occurrences during intraoperative and postoperative phases.ResultsOur study revealed noteworthy differences in various aspects between the 3D surgical video system group and the traditional microscope surgery group. Specifically, the mean surgical time was 30.25 ± 14.43 mins in the 3D surgical video system group, while it was 38.56 ± 18.71 mins in the traditional microscope surgery group (p = 0.051). Furthermore, the mean membrane removal time was significantly shorter in the 3D group at 2.53 ± 1.52 mins, as compared to 3.23 ± 1.76 mins in the traditional group (p = 0.042). Importantly, the membrane removal rate also displayed a significant difference, with the 3D group at 0.55 ± 0.07 and the traditional group at 0.41 ± 0.11 (p = 0.018). However, no notable differences were observed between the two groups in terms of intraoperative and postoperative incidences.ConclusionThe safety and efficacy obtained using the 3D surgical video system in PDR surgery were comparable to those obtained in traditional microscopic surgery.

Introduction: It has been a decade since the first patient with colon cancer underwent colectomy by hybrid transvaginal natural orifice transluminal endoscopic surgery (hvNOTES). However, the efficacy and safety of this procedure is not well established. Methods: This study is an open-label, multicenter, single-arm, phase 2 trial undertaken at six centers in China. Female patients aged over 18 years and below 80 years old with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, with pathologically proven, resectable, cT1-3N0-2M0 disease who have previously untreated colon cancer are eligible for inclusion. The primary endpoint is a composite of major intraoperative and postoperative complications (greater than grade III, the Common Terminology Criteria for Adverse Events [CTCAE], version 5.0). Secondary endpoints include conversion to laparoscopic or open surgery, postoperative concentration of C-Reactive Protein and procalcitonine, complete pathological assessment of complete mesocolic excision specimens, postoperative pain, amount of narcotic pain medication administered, time to first flatus after surgery, number of harvested lymph nodes, R0 resection rate, length of hospital stay, sexual function assessment, quality of recovery, satisfaction with surgical scars, quality of life, postoperative recurrence patterns, relapse-free survival, and overall survival. Ethics and dissemination: The study was approved by the Research Ethics Committee, Renmin Hospital of Wuhan University, China, number: WDRY2022-K053. All patients will receive written information of the trial and provide informed consent before enrollment. The results of this trial will be disseminated in academic conferences and peer-reviewed medical journals.Trial registration number NCT04048421.

Photoreceptors (PRs) degeneration is central to visual impairment and loss in most blind retinal diseases, including age-related macular disease (AMD) and diabetic retinopathy (DR). PRs are susceptible to oxidative stress owing to their unique metabolic features. Accumulating evidence has demonstrated that the targeting oxidative stress is a promising treatment strategy for PR degeneration. Herein, we introduced potent antioxidative platinum nanoparticles (Pt NPs) to treat PRs degeneration in this study. The Pt NPs exhibited multi-enzymatic antioxidant activity and protected PRs from H2O2-induced oxidative damage in vitro assays. Based on the same mechanism, the intravitreal injection of Pt NPs significantly reduced cell apoptosis, maintained retinal structure and preserved retinal function in a mouse model of light-induced retinal degeneration (LIRD). Most importantly, the results of RNA sequencing showed that the transcription of antioxidative genes was upregulated, and metabolic reprogramming occurred in the LIRD-retina after treatment with Pt NPs, both of which benefited retinal survival from oxidative damage. The results indicated that Pt NPs were indeed potent therapeutic candidates for PRs degeneration in blind retinal diseases.

PurposeWe aimed to evaluate the risk factors and develop a prognostic nomogram of long-term low vision after diabetic vitrectomy.MethodsThis retrospective study included 186 patients (250 eyes) that underwent primary vitrectomy for proliferative diabetic retinopathy with a minimum follow-up period of one year. Patients were assigned to the training cohort (200 eyes) or validation cohort (50 eyes) at a 4:1 ratio randomly. Based on a cutoff value of 0.3 in best-corrected visual acuity (BCVA) measurement, the training cohort was separated into groups with or without low vision. Univariate and multivariate logistic regression analyses were performed on preoperative systemic and ocular characteristics to develop a risk prediction model and nomogram. The calibration curve and the area under the receiver operating characteristic curves (AUC) were used to evaluate the calibration and discrimination of the model. The nomogram was internally validated using the bootstrapping method, and it was further verified in an external cohort.ResultsFour independent risk factors were selected by stepwise forward regression, including tractional retinal detachment (β=1.443, OR=4.235, P

There is an urgent need to address coastal dynamics as a fundamental interaction between physical and biological processes, particularly when trying to predict future biological–physical linkages under anticipated changes in environmental forcing. More integrated modelling, support for observational networks and the use of management interventions as controlled experimental exercises should now be vigorously pursued.

ObjectiveOur aim was to evaluate associations of different risk factors with odds of diabetic retinopathy (DR) diagnosis and retinal neurodegeneration represented by macular ganglion cell-inner plexiform layer (mGCIPL).MethodsThis cross-sectional study analyzed data from individuals aged over 50 years examined between June 2020 and February 2022 in the community-based Beichen Eye Study on ocular diseases. Baseline characteristics included demographic data, cardiometabolic risk factors, laboratory findings, and medications at enrollment. Retinal thickness in both eyes of all participants was measured automatically via optical coherence tomography. Risk factors associated with DR status were investigated using multivariable logistic regression. Multivariable linear regression analysis was performed to explore associations of potential risk factors with mGCIPL thickness.ResultsAmong the 5037 included participants with a mean (standard deviation, SD) age of 62.6 (6.7) years (3258 women [64.6%]), 4018 (79.8%) were control individuals, 835 (16.6%) were diabetic individuals with no DR, and 184 (3.7%) were diabetic individuals with DR. The risk factors significantly associated with DR status were family history of diabetes (odds ratio [OR], 4.09 [95% CI, 2.44-6.85]), fasting plasma glucose (OR, 5.88 [95% CI, 4.66-7.43]), and statins (OR, 2.13 [95% CI, 1.03-4.43]) relative to the control individuals. Compared with the no DR, diabetes duration (OR, 1.17 [95% CI, 1.13-1.22]), hypertension (OR, 1.60 [95% CI, 1.26-2.45]), and glycated hemoglobin A1C (HbA1c) (OR, 1.27 [95% CI, 1.00-1.59]) were significantly correlated with DR status. Furthermore, age (adjusted β = -0.19 [95% CI, -0.25 to -0.13] μm; P < 0.001), cardiovascular events (adjusted β = -0.95 [95% CI, -1.78 to -0.12] μm; P = 0.03), and axial length (adjusted β = -0.82 [95% CI, -1.29 to -0.35] μm; P = 0.001) were associated with mGCIPL thinning in diabetic individuals with no DR.ConclusionMultiple risk factors were associated with higher odds of DR development and lower mGCIPL thickness in our study. Risk factors affecting DR status varied among the different study populations. Age, cardiovascular events, and axial length were identified as potential risk factors for consideration in relation to retinal neurodegeneration in diabetic patients.

Diabetic retinopathy (DR) is a leading cause of blindness worldwide and a costly complication of diabetes mellitus (DM). DR severity is associated with DM duration; thus, DR has become more devastating to individuals and healthcare systems owing to the aging population and the significantly increased human lifespan.Aging is an irreversible cellular state characterized by long-term stagnation of the cell cycle from excessive stress or damage. Furthermore, aging plays a critical role in developing age-related diseases, but its effects (direct or indirect) on DR development remain considerably understudied. Nonetheless, some studies have demonstrated that aging-related degeneration and DR development share common risk factors, which helps explain the increased prevalence of DR and visual impairment in the elderly population.This review aims to provide some conceptual insight into aging and DR development, two intertwined pathophysiological processes, and discusses potential therapeutic strategies for DR, including prevention and treatment, during this era of longevity.