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Abstract Background Inherited retinal dystrophies (IRDs) are a group of debilitating visual disorders characterized by the progressive degeneration of photoreceptors, which ultimately lead to blindness. Among the causes of this condition, mutations in the PCYT1A gene, which encodes the rate-limiting enzyme responsible for phosphatidylcholine (PC) de novo synthesis via the Kennedy pathway, have been identified. However, the precise mechanisms underlying the association between PCYT1A mutations and IRDs remain unclear. To address this knowledge gap, we focused on elucidating the functions of PCYT1A in the retina. Results We found that PCYT1A is highly expressed in Müller glial (MG) cells in the inner nuclear layer (INL) of the retina. Subsequently, we generated a retina-specific knockout mouse model in which the Pcyt1a gene was targeted (Pcyt1a-RKO or RKO mice) to investigate the molecular mechanisms underlying IRDs caused by PCYT1A mutations. Our findings revealed that the deletion of Pcyt1a resulted in retinal degenerative phenotypes, including reduced scotopic electroretinogram (ERG) responses and progressive degeneration of photoreceptor cells, accompanied by loss of cells in the INL. Furthermore, through proteomic and bioinformatic analyses, we identified dysregulated retinal fatty acid metabolism and activation of the ferroptosis signalling pathway in RKO mice. Importantly, we found that PCYT1A deficiency did not lead to an overall reduction in PC synthesis within the retina. Instead, this deficiency appeared to disrupt free fatty acid metabolism and ultimately trigger ferroptosis. Conclusions This study reveals a novel mechanism by which mutations in PCYT1A contribute to the development of IRDs, shedding light on the interplay between fatty acid metabolism and retinal degenerative diseases, and provides new insights into the treatment of IRDs.

Abstract Mitogen‐activated protein kinase (MAPK) cascade is the center of plant signal transduction system that amplify immune signals into cellular responses by phosphorylating diverse substrates. The MAPK cascade consisting of MAPK kinase kinases (MAPKKKs), MAPK kinases (MAPKKs), and MAPKs is well characterized in plants, in which Raf‐like kinases are generally regarded as MAPKKKs. However, it is rarely reported that Raf‐like MAPKKKs function as middle regulators to link MAPK and its downstream transcription factors in plant immunity. Verticillium wilt, caused by the soil‐borne vascular fungus Verticillium dahliae, is a serious disease in many plants, including cotton. The previous studies showed that GhMPK9 (a MAPK) is involved in the response to Verticillium wilt. Here, the Raf‐like kinase GhRAF39_1 is reported as helper regulates the phosphorylation of WRKY transcription factor GhWRKY40a by GhMPK9. The phosphorylated GhWRKY40a can further activate the transcription of GhERF1b to up‐regulate defense‐related genes while inhibit the transcription of GhABF2 to regulate the stomatal opening, thus improving the resistance to Verticillium wilt in cotton. This study reveals a new signaling module of GhMPK9‐GhRAF39_1‐GhWRKY40a to regulate GhERF1b‐ and GhABF2‐mediated defense responses, which triggers plant defense against Verticillium wilt.

1,5-Anhydroglucitol (1,5-AG) is sensitive to short-term glucose fluctuations and postprandial hyperglycemia, which has great potential in the clinical application of diabetes as a nontraditional blood glucose monitoring indicator. A large number of studies have found that 1,5-AG can be used to screen for diabetes, manage diabetes, and predict the perils of diabetes complications (diabetic nephropathy, diabetic cardiovascular disease, diabetic retinopathy, diabetic pregnancy complications, diabetic peripheral neuropathy, etc.). Additionally, 1,5-AG and β cells are also associated with each other. As a noninvasive blood glucose monitoring indicator, salivary 1,5-AG has much more benefit for clinical application; however, it cannot be ignored that its detection methods are not perfect. Thus, a considerable stack of research is still needed to establish an accurate and simple enzyme assay for the detection of salivary 1,5-AG. More clinical studies will also be required in the future to confirm the normal reference range of 1,5-AG and its role in diabetes complications to further enhance the blood glucose monitoring system for diabetes.

Abstract Lung adenocarcinoma exhibits high incidence and mortality rates, presenting a significant health concern. Concurrently, the COVID-19 pandemic has emerged as a grave global public health challenge. Existing literature suggests that T cells, pivotal components of cellular immunity, are integral to both antiviral and antitumor responses. Yet, the nuanced alterations and consequent functions of T cells across diverse disease states have not been comprehensively elucidated. We gathered transcriptomic data of peripheral blood mononuclear cells from lung adenocarcinoma patients, COVID-19 patients, and healthy controls. We followed a standardized analytical approach for quality assurance, batch effect adjustments, and preliminary data processing. We discerned distinct T cell subsets and conducted differential gene expression analysis. Potential key genes and pathways were inferred from GO and Pathway enrichment analyses. Additionally, we implemented Mendelian randomization to probe the potential links between pivotal genes and lung adenocarcinoma susceptibility. Our findings underscored a notable reduction in mature CD8 + central memory T cells in both lung adenocarcinoma and COVID-19 cohorts relative to the control group. Notably, the downregulation of specific genes, such as TRGV9, could impede the immunological efficacy of CD8 + T cells. Comprehensive multi-omics assessment highlighted genetic aberrations in genes, including TRGV9, correlating with heightened lung adenocarcinoma risk. Through rigorous single-cell transcriptomic analyses, this investigation meticulously delineated variations in T cell subsets across different pathological states and extrapolated key regulatory genes via an integrated multi-omics approach, establishing a robust groundwork for future functional inquiries. This study furnishes valuable perspectives into the etiology of multifaceted diseases and augments the progression of precision medicine.

[Abstract]: Objective: This study aims to evaluate the efficacy and safety of using a strip-shaped cymba conchae orthosis for the nonsurgical correction of complex auricular deformities. Methods: Clinical data were collected from 2020 to 2021 for 6 patients who underwent correction using a strip-shaped cymba conchae orthosis. The indications, corrective effects, and complications associated with use of the orthosis were analyzed. Results: There were four indications for treatment: cryptotia with helix adhesion; cryptotia with grade I microtia; cryptotia with excessive helix thickness; and auricular deformity beyond the treatment time window (≥6 months). Excellent corrective effects were observed in all 6 patients. Complications occurred in one patient, who recovered after symptomatic treatment. Conclusion: The use of a strip-shaped cymba conchae orthosis alone or combined with a U-shaped helix orthosis presents a feasible approach for correcting complex auricular deformities or deformities beyond the treatment time window in pediatric patients.

Returning livestock manure to the cropland as organic fertilizer is a sustainable and environmentally friendly treatment method, but its application also alters the soil microenvironment. However, the impact of soil microbial community disturbance and pollutant accumulation from different types of organic fertilizers remains largely unknown in South China. To fill this gap, we investigated the effects of organic fertilizers, including chicken manure, pig manure and vermicompost on the soil bacterial and fungal communities and environmental risks. The results show that applying organic fertilizer effectively increases the soil nutrient content. High-throughput sequencing of bacteria and fungi showed that the application of different organic fertilizers had differential effects on microbial community structure, with the highest number of microbe-specific OTUs in the vermicomposting treatment. Additionally, this study found no risk of heavy metal (Cu, Zn, Pb, Cr and Cd) contamination from short-term organic fertilizer application, but there was a risk of antibiotic (ENR and CHL) contamination. Functional microorganisms regulating heavy metals and antibiotics were identified by RDA analysis. This study facilitates the screening of types of organic fertilizers that can be safely returned to the field as well as developing strategies to regulate functional microbes.

In this work, magnetic molecularly imprinted polymers (MIPs) for specific recognition of Hydroxytyrosol (HT) were designed by vinyl-modified magnetic particles (Fe3O4@SiO2@VTEOs) as carrier, ternary deep eutectic solvent (DES) as functional monomer, while ethylene glycol dimethacrylate (EGDMA) as crosslinker. The optimum amount of DES was obtained by adsorption experiments (molar ratio, caffeic acid: choline chloride: formic acid = 1:6:3) which were 140 μL in total. Under the optimized amount of DES, the maximum adsorption capacity of the MIPs particles was 42.43 mg g−1, which was superior to non-imprinted polymer (4.64 mg g−1) and the imprinting factor (IF) is 9.10. Syringin and Oleuropicrin were used as two reference molecules to test the selectivity of the DES-MIPs particles. The adsorption capacity of HT was 40.11 mg g−1. Three repeated experiments show that the polymer has high stability and repeatability (RSD = 5.50).

China consumes 35% of the world’s fertilizer every year; however, most of the nitrogen fertilizers, which are essential for rice cultivation, are not used effectively. In this study, factors affecting the nitrogen leaching loss rate were studied in typical soil and rice varieties in South China. The effects of various irrigation measures on rice growth and nitrogen leaching loss were investigated by conducting experiments with eight groups. These groups included traditional irrigation (TI) and shallow wet irrigation (SWI). The TI is a common irrigation method for farmers in South China, maintaining a water layer of 5-8 cm depth. For SWI, after establishing a shallow water layer usually maintaining at 1-2 cm, paddy is irrigated when the field water level falls to a certain depth, then this process is then repeat as necessary. The nitrogen distribution characteristics were determined using 15N isotope tracing. In addition, the effects of nitrification, denitrification, and microbial composition on soil nitrogen transformation at different depths were studied by microbial functional gene quantification and high-throughput sequencing. The results revealed that in the SWI groups, the total nitrogen leaching loss rate reduced by 0.3-0.8% and the nitrogen use efficiency (NUE) increased by 2.18-4.43% compared with those in the TI groups. After the 15N-labeled nitrogen fertilizer was applied, the main pathways of nitrogen were found to be related to plant absorption and nitrogen residues. Furthermore, paddy soil ammonia-oxidizing archaea were more effective than ammonia-oxidizing bacteria for soil ammonia oxidation by SWI groups. The SWI measures increased the relative abundance of Firmicutes in paddy soil, enhancing the ability of rice to fix nitrogen to produce ammonium nitrogen, thus reducing the dependence of rice on chemical fertilizers. Moreover, SWI enhanced the relative abundance of nirS and nosZ genes within surface soil bacteria, thereby promoting denitrification in the surface soil of paddy fields. SWI also promoted ammonia oxidation and denitrification by increasing the abundance and activity of Proteobacteria, Nitrospirae, and Bacteroidetes. Collectively, SWI effectively reduced the nitrogen leaching loss rate and increase NUE.

Abstract Solar radiation varies quantitatively and qualitatively while penetrating through the seawater column and thus is one of the most important environmental factors shaping the vertical distribution pattern of phytoplankton. The haploid and diploid life-cycle phases of coccolithophores might have different vertical distribution preferences. Therefore, the two phases respond differently to high solar photosynthetically active radiation (PAR, 400–700 nm) and ultraviolet radiation (UVR, 280–400 nm). To test this, the haploid and diploid Emiliania huxleyi were exposed to oversaturating irradiance. In the presence of PAR alone, the effective quantum yield was reduced by 10% more due to the higher damage rate of photosystem II in haploid cells than in diploid cells. The addition of UVR resulted in further inhibition of the quantum yield for both haploid and diploid cells in the first 25 min, partly because of the increased damage of photosystem II. Intriguingly, this UVR-induced inhibition of the haploid cells completely recovered half an hour later. This recovery was confirmed by the comparable maximum quantum yields, maximum relative electron transport rates and yields of the haploid cells treated with PAR and PAR + UVR. Our data indicated that photosynthesis of the haploid phase was more sensitive to high visible light than the diploid phase but resistant to UVR-induced inhibition, reflecting the ecological niches to which this species adapts. Graphical Abstract

Abstract Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that affects social interaction and behavior. Mutations in the gene encoding chromodomain helicase DNA-binding protein 8 (CHD8) lead to autism symptoms and macrocephaly by a haploinsufficiency mechanism. However, studies of small animal models showed inconsistent findings about the mechanisms for CHD8 deficiency-mediated autism symptoms and macrocephaly. Using the nonhuman primate as a model system, we found that CRISPR/Cas9-mediated CHD8 mutations in the embryos of cynomolgus monkeys led to increased gliogenesis to cause macrocephaly in cynomolgus monkeys. Disrupting CHD8 in the fetal monkey brain prior to gliogenesis increased the number of glial cells in newborn monkeys. Moreover, knocking down CHD8 via CRISPR/Cas9 in organotypic monkey brain slices from newborn monkeys also enhanced the proliferation of glial cells. Our findings suggest that gliogenesis is critical for brain size in primates and that abnormal gliogenesis may contribute to ASD.

Cashmere goats are valuable genetic resources which are famous worldwide for their high-quality fiber. Runs of homozygosity (ROHs) have been identified as an efficient tool to assess inbreeding level and identify related genes under selection. However, there is limited research on ROHs in cashmere goats. Therefore, we investigated the ROH pattern, assessed genomic inbreeding levels and examined the candidate genes associated with the cashmere trait using whole-genome resequencing data from 123 goats. Herein, the Inner Mongolia cashmere goat presented the lowest inbreeding coefficient of 0.0263. In total, we identified 57,224 ROHs. Seventy-four ROH islands containing 50 genes were detected. Certain identified genes were related to meat, fiber and milk production (FGF1, PTPRM, RERE, GRID2, RARA); fertility (BIRC6, ECE2, CDH23, PAK1); disease or cold resistance and adaptability (PDCD1LG2, SVIL, PRDM16, RFX4, SH3BP2); and body size and growth (TMEM63C, SYN3, SDC1, STRBP, SMG6). 135 consensus ROHs were identified, and we found candidate genes (FGF5, DVL3, NRAS, KIT) were associated with fiber length or color. These findings enhance our comprehension of inbreeding levels in cashmere goats and the genetic foundations of traits influenced by selective breeding. This research contributes significantly to the future breeding, reservation and use of cashmere goats and other goat breeds.

Subgroup J avian leukemia virus (ALV-J) and chicken infectious anemia virus (CIAV) are widely acknowledged as significant immunosuppressive pathogens that commonly co-infect chickens, causing substantial economic losses in the poultry industry. However, whether co-infection of ALV-J and CIAV have synergistic pathogenicity remains uncertain. To explore their synergistic pathogenesis, we established a co-infection model of ALV-J and CIAV in HD11 cells and specific-pathogen-free (SPF) chickens. We discovered that ALV-J and CIAV can synergistically promote the secretion of IL-6, IL-10, IFN-α, and IFN-γ and apoptosis in HD11 cells. In vivo, compared to the ALV-J and CIAV mono-infected group, the mortality increased significantly by 27% (20 to 47%) and 14% (33 to 47%) in the co-infected group, respectively. We also discovered that ALV-J and CIAV synergistically inhibited weight gain and exhibited more severe organ damage in co-infected chickens. Furthermore, we found that CIAV can promote the replication of ALV-J in HD11 cells and significantly enhance ALV-J viral load in blood and tissues of co-infected chickens, but ALV-J cannot promote the replication of CIAV. Moreover, by measuring the immune organ indexes and proportions of blood CD3+CD4+ and CD3+CD8+ lymphocytes, more serious instances of immunosuppression were observed in ALV-J and CIAV co-infected chickens than in mono-infected chickens. Taken together, our findings demonstrate that ALV-J and CIAV synergistically enhance pathogenicity and immunosuppression.

The co-transport of contaminants by soil colloids can generate substantial environmental risk, and this behavior is greatly affected by environmental conditions. In this study, AF4-ICP-MS was used to investigate the size distribution and composition of Cd/Pb-bearing colloids; saturated sand column experiments were used to investigate the impact of soil colloids on the transport of Cd/Pb under different pH and ionic strength conditions. AF4-ICP-MS characterization showed that natural colloids were primarily associated with two sizes ranges: 0.3–35 KDa (F1, fine nanoparticles) and 280 KDa–450 nm (F2, larger nanoparticles), which mainly consisted of organic matter (OM), iron (Fe), and manganese (Mn) (oxy)hydroxides and clay minerals. Fine nanoparticles could strongly adsorb Cd and Pb under all environmental conditions. Mn and Fe (oxy)hydroxides generally formed under neutral to alkaline conditions and exhibited adsorption capabilities for Cd and Pb, respectively. Transport experiments were conducted under different pH and ionic strength conditions. At pH 3.0, soil colloids had little effect on the transport of Cd2+ and Pb2+. At pH 5.0, soil colloids inhibited the transport of Cd2+ by 16.1%, and Pb2+ recovery was still 0.0%. At pH 7.0 and 9.0, soil colloids facilitated the transport of Cd2+ by 15.6% and 29.6%, facilitated Pb2+ by 1.3% and 6.4%. At an ionic strength of 0, 0.005, and 0.01 mol L−1 NaNO3, soil colloids facilitated the transport of Cd2+ by 77.7%, 45.8%, and 15.6%, only facilitated the transport of Pb2+ by 46.2% at an ionic strength of 0 mol L−1 NaNO3. At an ionic strength of 0.05 mol L−1 NaNO3, soil colloids inhibited the transport of Cd2+ and Pb2+ by 33.1% and 21.0%, respectively. The transport of Cd2+ and Pb2+ facilitated by soil colloids was clearly observed under low ionic strength and non-acidic conditions, which can generate a potential environmental risk.

Acidic soils cover approximately 50 % of the arable land with high N2O emission potential. 3,4-dimethylpyrazole phosphate (DMPP) inhibits N2O emission from soils; however, its efficiency is affected by acidity. Liming is used for soil conditioning to ameliorate the effects of acidity. In the present study, we investigated the effects of liming on the efficiency of DMPP in inhibiting N2O emission in acidic soils and the mechanisms involved. We evaluated the impact of liming, DMPP, and combined application and its microbial responses in two acidic soils from Zengcheng (ZC) and Shaoguan (SG) City, Guangdong Province, China. Soils were subjected to four treatments: un-limed soil (low soil pH) + urea (LU), un-limed soil + urea + DMPP (LD), limed soil (high soil pH) + urea (HU), and limed soil + urea + DMPP (HD) for analyses of the mineral N, N2O emissions, and full-length 16S and metagenome sequencing. The results revealed that, HU significantly decreased and increased the N2O emission by 17.8 % and 235.0 % in ZC and SG, respectively, compared with LU. This was caused by a trade-off between N2O production and consumption after liming, where microbial communities and N-cycling functional genes show various compositions in different acidic soils. LD reduced N2O emission by 23.5 % in ZC, whereas decreased 1.5 % was observed in SG. Interestingly, DMPP efficiency considerably improved after liming in two acidic soils. Compared with LU, HD significantly reduced N2O emissions by 61.2 % and 48.5 % in ZC and SG, respectively. Synergy of mitigation efficiency was observed by lime and DMPP application, which was attributed to the changes in the dominant nitrifiers and the increase in N2O consumption by denitrifiers. The combined application of lime and DMPP is a high-efficiency strategy for N2O mitigation can ensure agricultural sustainability in acidic arable soils with minimal environmental damage.

In this paper, we consider the multiplicity of homoclinic solutions for the following damped vibration problems $$ \ddot{x}(t)+B\dot{x}(t)-A(t)x(t)+H_{x}(t,x(t))=0,$$ where $A(t)\in (\mathbb{R},\mathbb{R}^{N})$ is a symmetric matrix for all $t\in \mathbb{R}$, $B=[b_{ij}]$ is an antisymmetric $N \times N$ constant matrix, and $H(t,x)\in C^{1}(\mathbb{R}\times B_{\delta},\mathbb{R})$ is only locally defined near the origin in $x$ for some $\delta>0$. With the nonlinearity $H(t,x)$ being partially sub-quadratic at zero, we obtain infinitely many homoclinic solutions near the origin by using a Clark's theorem.

Dysregulation of CDK6 plays crucial roles in the carcinogenesis of many kinds of human malignancies. However, the role of CDK6 in esophageal squamous cell carcinoma (ESCC) is not well known. We investigated the frequency and prognostic value of CDK6 amplification to improve the risk stratification in patients with ESCC. Pan-cancer analysis of CDK6 was conducted on The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx) and Gene Expression Omnibus (GEO) databases. CDK6 amplification was detected in 502 ESCC samples by Fluorescence in situ hybridization (FISH) through tissue microarrays (TMA). Pan-cancer analysis revealed that CDK6 mRNA level was much higher in multiple kinds of cancers and higher CDK6 mRNA level indicated a better prognosis in ESCC. In this study, CDK6 amplification was detected in 27.5% (138/502) of patients with ESCC. CDK6 amplification was significantly correlated with tumor size (p = 0.044). Patients with CDK6 amplification tended to have a longer disease-free survival (DFS) (p = 0.228) and overall survival (OS) (p = 0.200) compared with patients without CDK6 amplification but of no significance. When further divided into I–II and III–IV stage, CDK6 amplification was significantly associated with longer DFS and OS in III-IV stage group (DFS, p = 0.036; OS, p = 0.022) rather than in I-II stage group (DFS, p = 0.776; OS, p = 0.611). On univariate and multivariate analysis of Cox hazard model, differentiation, vessel invasion, nerve invasion, invasive depth, lymph node metastasis and clinical stage were significantly associated with DFS and OS. Moreover, invasion depth was an independent factor for ESCC prognosis. Taken together, for ESCC patients in III-IV stage, CDK6 amplification indicated a better prognosis.

Purpose: Age-related macular degeneration (AMD) is a leading cause of vision loss. A Previous study based on the co-localization analysis of the genome-wide association study (GWAS) and eQTL genetic signals have reported that single nucleotide polymorphisms (SNPs), including rs760975, rs11528744, rs3761159, rs7212510, rs6965458, rs7559693, rs56108400, rs28495773, rs9928736, rs11777697, rs4381465 are associated with AMD in Americans. The aim of this study was to investigate the association of these SNPs in a Han Chinese population.Methods: There were 576 patients with wet AMD and 572 healthy controls collected in this study. All SNPs were genotyped by flight mass spectrum. Hardy–Weinberg equilibrium was applied to evaluate allele distributions for both AMD and control groups. The genotype and allele frequencies were evaluated using the χ2 tests. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated for the risk of genotype and allele.Results: Three of the 11 SNPs (rs11528744 in HTRA1, rs9928736 in BCRA1 and rs4381465 in B3GLCT) were found to be significantly associated with AMD in the allelic model (corrected p = 0.001, OR = 1.391, 95%CI = 1.179–1.640 for rs11528744; corrected p = 0.004, OR = 0.695, 95%CI = 0.544–0.888 for rs9928736; corrected p = 0.002, OR = 0.614, 95%CI = 0.448–0.841 for rs4381465). There were no differences for the remaining eight SNPs between AMD cases and healthy controls.Conclusion: Our results showed that HTRA1 rs11528744, BCRA1 rs9928736, and B3GLCT rs4381465 were associated with wet AMD, suggesting that HTRA1, BCRA1, and B3GLCT genes may be involved in the development of AMD.

Coronavirus disease 2019 (COVID-19) swept across the world and posed a serious threat to human health. Health and elderly care enterprises are committed to continuously improving people's health. With the rapid development of the digital economy, many enterprises have established digital product-service ecosystems after combining “Internet +,” big data, cloud computing, and the big health industry. This paper uses the case study method to analyze the overseas market value mining mode of health and elderly care enterprises through in-depth research on leading health and elderly care enterprises. This study explores the value mining mode of the leading enterprise's global big health market using a cluster analysis and Bayesian model with the support of data on geographical characteristics, users' sleep habits, and national big health. This paper theoretically summarizes the successful cases of health and elderly care enterprises through digital transformation, which provides a useful reference for the intelligent transformation of the health and elderly care industry.

The primary purpose of this paper is to investigate energy regeneration and conversion technologies based on mechanical–electric–hydraulic hybrid energy storage systems in vehicles. There has been renewed interest in hydraulic storage systems since evidence has been presented that shows that they have the distinct advantages of high energy output and energy recuperation compared to electrical energy recovery systems, which are widely applied in electric vehicles; however, they are known to be high-cost, with a complicated structure and not zero carbon. In this paper, we first review recent research on hydraulic energy regeneration and conversion technologies. Secondly, as the main part of this paper, the latest technological progress and breakthroughs of the mechanical–electric–hydraulic hybrid energy storage systems in vehicles—which are divided into four categories: passenger, minibus and bus, commercial vehicle and special vehicle—are analyzed and discussed in depth. In addition, the current research status of energy management techniques is presented and summarized. Finally, prospects and challenges are suggested and explained. It is evident from the literature review that the mechanical–electric–hydraulic hybrid systems perform excellently in vehicles. Clearly, this review will be helpful to understand, explore and define the hydraulic vehicle of the future concerning energy optimization and environmental friendliness.

Inflammation and elevated expression of high temperature requirement A serine peptidase 1 (HTRA1) are known high risk factors for age-related macular degeneration (AMD). However, the specific mechanism that HTRA1 causes AMD and the relationship between HTRA1 and inflammation remains unclear. We found that lipopolysaccharide (LPS) induced inflammation enhanced the expression of HTRA1, NF-κB, and p-p65 in ARPE-19 cells. Overexpression of HTRA1 up-regulated NF-κB expression, and on the other hand knockdown of HTRA1 down-regulated the expression of NF-κB. Moreover, NF-κB siRNA has no significant effect on the expression of HTRA1, suggesting HTRA1 works upstream of NF-κB. These results demonstrated that HTRA1 plays a pivotal role in inflammation, explaining possible mechanism of overexpressed HTRA1-induced AMD. Celastrol, a very common anti-inflammatory and antioxidant drug, was found to suppress inflammation by inhibiting phosphorylation of p65 protein efficaciously in RPE cells, which may be applied to the therapy of age-related macular degeneration.

Abstract Background With the rapid development of medical treatment, many patients not only consider the survival time, but also care about the quality of life. Changes in physical, psychological and social functions after and during treatment have caused a lot of troubles to patients and their families. Based on the bio-psycho-social medical model theory, mental health plays an important role in treatment. Therefore, it is necessary for medical staff to know the diseases which have high potential to cause psychological trauma and social avoidance (PTSA). Results Firstly, we obtained diseases which can cause PTSA from literatures. Then, we calculated the similarities of related-diseases to build a disease network. The similarities between diseases were based on their known related genes. Then, we obtained these diseases-related proteins from UniProt. These proteins were extracted as the features of diseases. Therefore, in the disease network, each node denotes a disease and contains the information of its related proteins, and the edges of the network are the similarities of diseases. Then, graph convolutional network (GCN) was used to encode the disease network. In this way, each disease’s own feature and its relationship with other diseases were extracted. Finally, Xgboost was used to identify PTSA diseases. Conclusion We developed a novel method ‘GCN-Xgboost’ and compared it with some traditional methods. Using leave-one-out cross-validation, the AUC and AUPR were higher than some existing methods. In addition, case studies have been done to verify our results. We also discussed the trajectory of social avoidance and distress during acute survival of breast cancer patients.

As plug-in electric vehicles (PEVs) become more and more popular, there is a growing interest in the management of their charging power. Many models exist nowadays to manage the charging of plug-in electric vehicles, and it is important that these models are implemented in a better way. This paper investigates a price-driven charging management model in which all plug-in electric vehicles are informed of the charging strategies of neighboring plug-in electric vehicles and adjust their own strategies to minimize the cost, while an aggregator determines the unit price based on overall electricity consumption to coordinate the charging strategies of the plug-in electric vehicles. In this article, we used an asynchronous distributed generalized Nash game algorithm to investigate a charging management model for plug-in electric vehicles in a smart charging station (SCS). In a charging management model, we need to consider constraints on the charge and discharge rates of plug-in electric vehicles, the battery capacity, the amount of charge per plug-in electric vehicle, and the maximum electrical load that the whole system can allow. Meeting the constraints of plug-in electric vehicles and smart charging stations, the model coordinates the charging strategy of each plug-in electric vehicle to ultimately reduce the cost of smart charging stations, which is the cost that the smart charging station should pay to the higher-level power supply facility. To the best of our knowledge, this algorithm used in this paper has not been used to solve this model, and it has better performance than the generalized Nash equilibria (GNE) seeking algorithm originally used for this model, which is called a fast alternating direction multiplier method (Fast-ADMM). In the simulation results, the asynchronous algorithm we used showed a correlation error of 0.0076 at the 713th iteration, compared to 0.0087 for the synchronous algorithm used for comparison, and the cost of the smart charging station was reduced to USD 4800.951 after coordination using the asynchronous algorithm, which was also satisfactory. We used an asynchronous algorithm to better implement a plug-in electric vehicle charging management model; this also demonstrates the potential advantages of using an asynchronous algorithm for solving the charging management model for plug-in electric vehicles.

Surface runoff is one of the predominant routes for agricultural nitrogen (N) and phosphorus (P) losses, yet their characteristics and corresponding control measures are not fully understood. In 2019 and 2020, field-scale plot experiments were performed at Dongjiang Basin in South China to investigate the characteristics of N and P runoff losses from paddy and maize cropping systems. The results showed that N and P losses from maize fields via surface runoff (27.85 and 1.24 kg ha−1 year−1) were significantly higher than those from paddy fields (15.37 and 0.8 kg ha−1 year−1). The main forms of N losses were nitrate (NO3--N) and ammonium (NH4+-N) in paddy and maize fields, respectively, whereas particulate P form predominated in surface runoff losses from both the paddy and maize fields. Considerable proportions of agricultural N and P (71–83% of the total runoff loss) were lost during basal fertilization and first topdressing application. Moreover, frequent rainfall events following fertilizer application triggered N and P losses from the monitored fields. About 26.22 and 37.48% of N fertilizer was recovered from grains and straw of paddy and maize, respectively, whereas only 12.35 and 19.51% of P fertilizer were recovered during the crop harvesting stage. Surface runoff was one of the dominant liquid pathways in N loss, whereas most of P loss (introduced from fertilizers without crops utilization) was fixed in the soil. Principal component analysis (PCA) proved that the primary sources of N and P losses were fertilizers rather than N and P in the soil. The current results suggest controlled management relating to fertilization, irrigation, and tillage strategies are effective measures for reducing N and P losses, thereby controlling agricultural non-point source pollution. It is hoped that this study will provide comprehensive field-based inputs on characteristics of N and P runoff losses and formulate appropriate control strategies to protect aquatic environments from eutrophication.

OBJECTIVES: To investigate the effects of an intratympanic injection of dexamethasone combined with gentamicin on the expression level of serum P0 protein antibodies in patients with Meniere’s disease (MD). METHODS: A total of 136 patients with MD treated in our hospital were enrolled in this study. Among them, 68 patients were treated with an intratympanic injection of dexamethasone combined with gentamicin (observation group). Another 68 patients were treated with gentamicin alone (control group). RESULTS: After treatment, the expression levels of IgG and IgM in the two groups significantly decreased (p0.05). CONCLUSION: For patients with MD, dexamethasone combined with gentamicin can reduce the incidence of vertigo, tinnitus, and gait instability, but it has no effect on the efficacy or number of vertigo attacks 6 months after treatment. Therefore, the levels of myelin P0 protein antibodies after treatment can be used as predictors of vertigo at 6 months after treatment.

This study was conducted to assess the levels of inflammatory factors and angiogenic factors in patients with severe hemophilia A and evaluate their diagnostic values for acute joint bleeding. This study included a total of 144 patients with severe hemophilia A. Of them, 66 had acute joint bleeding. Ninety healthy volunteers were recruited as control. The levels of leukocytes, monocytes, platelets, hemoglobin, phagocyte migration inhibitory factor (MIF), plasminogen, fibrin/fibrinogen degradation products, d -dimer, and α2 antifibrinolytic enzyme were measured using hematology analyzer. Thrombomodulin, endostatin, intercellular adhesion molecule 1, and vascular endothelial growth factor (VEGF) were assessed using enzyme-linked immunosorbent assay. Logistic regression analysis was performed to analyze the factors affecting acute joint bleeding. Compared with healthy volunteers, the levels of leukocytes, C-reactive protein (CRP), MIF, and VEGF were significantly ( P < .05) elevated in the patients with severe hemophilia A and were significantly higher in patients with joint bleeding than in patients with nonbleeding ( P < .05). Multivariate analysis showed that CRP and VEGF were independent risk factors for acute joint bleeding ( P < .05). The area under the curve, sensitivity, and specificity of CRP for the diagnosis of acute joint bleeding were 0.829, 88.43%, and 67.87%, respectively, and those of VEGF were 0.758, 82.8%, and 68.3%, respectively. The levels of inflammatory factors and angiogenesis factors are elevated in patients with severe hemophilia A and both CRP and VEGF are closely related to acute joint bleeding and may be used as potential biomarkers for predicting acute joint bleeding in patients with severe hemophilia A.

Nonsyndromic orofacial cleft (NSOFC) is a severe birth defect that occurs early in embryonic development and includes the subtypes cleft palate only (CPO), cleft lip only (CLO) and cleft lip with cleft palate (CLP). Given a lack of specific genetic factor analysis for CPO and CLO, the present study aimed to dissect the landscape of genetic factors underlying the pathogenesis of these two subtypes using 6,986 cases and 10,165 controls. By combining a genome-wide association study (GWAS) for specific subtypes of CPO and CLO, as well as functional gene network and ontology pathway analysis, we identified 18 genes/loci that surpassed genome-wide significance (P < 5 × 10-8) responsible for NSOFC, including nine for CPO, seven for CLO, two for both conditions and four that contribute to the CLP subtype. Among these 18 genes/loci, 14 are novel and identified in this study and 12 contain developmental transcription factors (TFs), suggesting that TFs are the key factors for the pathogenesis of NSOFC subtypes. Interestingly, we observed an opposite effect of the genetic variants in the IRF6 gene for CPO and CLO. Moreover, the gene expression dosage effect of IRF6 with two different alleles at the same single-nucleotide polymorphism (SNP) plays important roles in driving CPO or CLO. In addition, PAX9 is a key TF for CPO. Our findings define subtypes of NSOFC using genetic factors and their functional ontologies and provide a clue to improve their diagnosis and treatment in the future.

Carnosine has been demonstrated to play an antitumorigenic role in certain types of cancer. However, its underlying mechanism is unclear. In this study, the roles of carnosine in cell proliferation and its underlying mechanism were investigated in the cultured human cervical gland carcinoma cells HeLa and cervical squamous carcinoma cells SiHa. The results showed that carnosine exerted a significant inhibitory effect on the proliferation of HeLa cells, whereas its inhibitory action on the proliferation of SiHa cells was much weaker. Carnosine decreased the ATP content through inhibiting both mitochondrial respiration and glycolysis pathways in cultured HeLa cells but not SiHa cells. Carnosine reduced the activities of isocitrate dehydrogenase and malate dehydrogenase in TCA (tricarboxylic acid) cycle and the activities of mitochondrial electron transport chain complex I, II, III, and IV in HeLa cells but not SiHa cells. Carnosine also decreased the mRNA and protein expression levels of ClpP, which plays a key role in maintaining the mitochondrial function in HeLa cells. In addition, carnosine induced G1 arrest by inhibiting the G1-S phase transition in both HeLa and SiHa cells. Taken together, these findings suggest that carnosine has a strong inhibitory action on the proliferation of human cervical gland carcinoma cells rather than cervical squamous carcinoma cells. Mitochondrial bioenergetics and glycolysis pathways and cell cycle may be involved in the carnosine action on the cell proliferation in cultured human cervical gland carcinoma cells HeLa.

It remains uncertain if the contralesional primary sensorimotor cortex (CL_PSMC) contributes to motor recovery after stroke. Here we investigated longitudinal changes in the resting-state functional connectivity (rsFC) of the CL_PSMC and their association with motor recovery. Thirteen patients who had experienced subcortical stroke underwent a series of resting-state fMRI and clinical assessments over a period of 1 year at 5 time points, i.e., within the first week, at 2 weeks, 1 month, 3 months, and 1 year after stroke onset. Thirteen age- and gender-matched healthy subjects were recruited as controls. The CL_PSMC was defined as a region centered at the voxel that had greatest activation during hand motion task. The dynamic changes in the rsFCs of the CL_PSMC within the whole brain were evaluated and correlated with the Motricity Index (MI) scores. Compared with healthy controls, the rsFCs of the CL_PSMC with the bilateral PSMC were initially decreased, then gradually increased, and finally restored to the normal level 1 year later. Moreover, the dynamic change in the inter-hemispheric rsFC between the bilateral PSMC in these patients was positively correlated with the MI scores. However, the intra-hemispheric rsFC of the CL_PSMC was not correlated with the MI scores. This study shows dynamic changes in the rsFCs of the CL_PSMC after stroke and suggests that the increased inter-hemispheric rsFC between the bilateral PSMC may facilitate motor recovery in stroke patients. However, generalization of our findings is limited by the small sample size of our study and needs to be confirmed.

The motor function is controlled by the motor system that comprises a series of cortical and subcortical areas interacting via anatomical connections. The motor function will be disturbed when the stroke lesion impairs either any of these areas or their connections. More and more evidence indicates that the reorganization of the motor network including both areas and their anatomical and functional connectivity might contribute to the motor recovery after stroke. Here, we review recent studies employing models of anatomical, functional, and effective connectivity on neuroimaging data to investigate how ischemic stroke influences the connectivity of motor areas and how changes in connectivity relate to impaired function and functional recovery. We suggest that connectivity changes constitute an important pathophysiological aspect of motor impairment after stroke and important mechanisms of motor recovery. We also demonstrate that therapeutic interventions may facilitate motor recovery after stroke by modulating the connectivity among the motor areas. In conclusion, connectivity analyses improved our understanding of the mechanisms of motor recovery after stroke and may help to design hypothesis-driven treatment strategies and sensitive measures for outcome prediction in stroke patients.

The transition from the closed to open state greatly alters the intra- and inter-subunit interactions of the P2X receptor (P2XR). The interactions that occur in the transmembrane domain of the P2X2R remain unclear. We used substituted cysteine mutagenesis disulfide mapping to identify pairs of residues that are in close proximity within the transmembrane domain of rP2X2R and compared our results to the predicted positions of these amino acids obtained from a rat P2X2R homology model of the available open and closed zebrafish P2X4R structures. Alternations in channel function were measured as a change in the ATP-gated current before and after exposure to dithiothreitol. Thirty-six pairs of double mutants of rP2X2R expressed in HEK293 cells produced normal functioning channels. Thirty-five pairs of these mutants did not exhibit a functionally detectable disulfide bond. The double mutant H33C/S345C formed redox-dependent cross-links in the absence of ATP. Dithiothreitol ruptured the disulfide bond of H33C/S345C and induced a 2 to 3-fold increase in current. The EC50 for H33C/S345C before dithiothreitol treatment was ~2-fold higher than that after dithiothreitol treatment. Dithiothreitol reduced the EC50 to wild-type levels. Furthermore, expression of trimeric concatamer receptors with Cys mutations at some but not all six positions showed that the more disulfide bond formation sites within the concatamer, the greater current potentiation after dithiothreitol incubation. Immunoblot analysis of H33C/S345C revealed one monomer band under nonreducing conditions strongly suggesting that disulfide bonds are formed within single subunits (intra-subunit) and not between two subunits (inter-subunit). Taken together, these data indicate that His33 and Ser345 are proximal to each other across an intra-subunit interface. The relative movement between the first transmembrane and the second transmembrane in the intra-subunit is likely important for transmitting the action of ATP binding to the opening of the channel.