The oxidized phospholipid PGPC impairs endothelial function by promoting endothelial cell ferroptosis via FABP3.

Ferroptosis is a novel cell death mechanism that is mediated by iron-dependent lipid peroxidation. It may be involved in atherosclerosis development. Products of phospholipid oxidation play a key role in atherosclerosis. 1-palmitoyl-2-glutaroyl-sn-glycero-3-phosphocholine (PGPC) is a phospholipid oxidation product present in atherosclerotic lesions. It remains unclear whether PGPC causes atherosclerosis by inducing endothelial cell ferroptosis. In this study, human umbilical vein endothelial cells (HUVECs) were treated with PGPC. Intracellular levels of ferrous iron, lipid peroxidation, superoxide anions (O2•-), and glutathione were detected, and expression of fatty acid binding protein-3 (FABP3), glutathione peroxidase 4 (GPX4), and CD36 were measured. Additionally, the mitochondrial membrane potential (MMP) was determined. Aortas from C57BL6 mice were isolated for vasodilation testing. Results showed that PGPC increased ferrous iron levels, the production of lipid peroxidation and O2•-, and FABP3 expression. However, PGPC inhibited the expression of GPX4 and glutathione production and destroyed normal MMP. These effects were also blocked by ferrostatin-1, an inhibitor of ferroptosis. FABP3 silencing significantly reversed the effect of PGPC. Furthermore, PGPC stimulated CD36 expression. Conversely, CD36 silencing reversed the effects of PGPC, including PGPC-induced FABP3 expression. Importantly, E06, a direct inhibitor of the oxidized 1-palmitoyl-2-arachidonoyl-phosphatidylcholine IgM natural antibody, inhibited the effects of PGPC. Finally, PGPC impaired endothelium-dependent vasodilation, ferrostatin-1 or FABP3 inhibitors inhibited this impairment. Our data demonstrate that PGPC impairs endothelial function by inducing endothelial cell ferroptosis through the CD36 receptor to increase FABP3 expression. Our findings provide new insights into the mechanisms of atherosclerosis and a therapeutic target for atherosclerosis.

Interpretable machine-learning model for Predicting the Convalescent COVID-19 patients with pulmonary diffusing capacity impairment.

INTRODUCTION: The COVID-19 patients in the convalescent stage noticeably have pulmonary diffusing capacity impairment (PDCI). The pulmonary diffusing capacity is a frequently-used indicator of the COVID-19 survivors' prognosis of pulmonary function, but the current studies focusing on prediction of the pulmonary diffusing capacity of these people are limited. The aim of this study was to develop and validate a machine learning (ML) model for predicting PDCI in the COVID-19 patients using routinely available clinical data, thus assisting the clinical diagnosis. METHODS: Collected from a follow-up study from August to September 2021 of 221 hospitalized survivors of COVID-19 18 months after discharge from Wuhan, including the demographic characteristics and clinical examination, the data in this study were randomly separated into a training (80%) data set and a validation (20%) data set. Six popular machine learning models were developed to predict the pulmonary diffusing capacity of patients infected with COVID-19 in the recovery stage. The performance indicators of the model included area under the curve (AUC), Accuracy, Recall, Precision, Positive Predictive Value(PPV), Negative Predictive Value (NPV) and F1. The model with the optimum performance was defined as the optimal model, which was further employed in the interpretability analysis. The MAHAKIL method was utilized to balance the data and optimize the balance of sample distribution, while the RFECV method for feature selection was utilized to select combined features more favorable to machine learning. RESULTS: A total of 221 COVID-19 survivors were recruited in this study after discharge from hospitals in Wuhan. Of these participants, 117 (52.94%) were female, with a median age of 58.2 years (standard deviation (SD) = 12). After feature selection, 31 of the 37 clinical factors were finally selected for use in constructing the model. Among the six tested ML models, the best performance was accomplished in the XGBoost model, with an AUC of 0.755 and an accuracy of 78.01% after experimental verification. The SHAPELY Additive explanations (SHAP) summary analysis exhibited that hemoglobin (Hb), maximal voluntary ventilation (MVV), severity of illness, platelet (PLT), Uric Acid (UA) and blood urea nitrogen (BUN) were the top six most important factors affecting the XGBoost model decision-making. CONCLUSION: The XGBoost model reported here showed a good prognostic prediction ability for PDCI of COVID-19 survivors during the recovery period. Among the interpretation methods based on the importance of SHAP values, Hb and MVV contributed the most to the prediction of PDCI outcomes of COVID-19 survivors in the recovery period.

Molecular Characteristics and Pathogenicity of Staphylococcus aureus Exotoxins.

Staphylococcus aureus stands as one of the most pervasive pathogens given its morbidity and mortality worldwide due to its roles as an infectious agent that causes a wide variety of diseases ranging from moderately severe skin infections to fatal pneumonia and sepsis. S. aureus produces a variety of exotoxins that serve as important virulence factors in S. aureus-related infectious diseases and food poisoning in both humans and animals. For example, staphylococcal enterotoxins (SEs) produced by S. aureus induce staphylococcal foodborne poisoning; toxic shock syndrome toxin-1 (TSST-1), as a typical superantigen, induces toxic shock syndrome; hemolysins induce cell damage in erythrocytes and leukocytes; and exfoliative toxin induces staphylococcal skin scalded syndrome. Recently, Panton-Valentine leucocidin, a cytotoxin produced by community-associated methicillin-resistant S. aureus (CA-MRSA), has been reported, and new types of SEs and staphylococcal enterotoxin-like toxins (SEls) were discovered and reported successively. This review addresses the progress of and novel insights into the molecular structure, biological activities, and pathogenicity of both the classic and the newly identified exotoxins produced by S. aureus.

Diagnostic value of platelet-lymphocyte ratio and hemoglobin-platelet ratio in patients with rectal cancer.

BACKGROUND: This study aimed to investigate the diagnostic value of platelet-lymphocyte ratio (PLR) and hemoglobin-platelet ratio (HPR) combined or not with carcinoembryonic antigen (CEA) in rectal cancer. METHODS: We recruited 235 patients pathologically diagnosed with rectal cancer, 113 patients with benign rectal diseases, and 229 healthy control patients in this retrospective analysis. Then, the correlation between PLR, HPR, and clinicopathological findings was analyzed. Receiver operating characteristic (ROC) curve was used to assess the diagnostic value of PLR and HPR combined or not with CEA in rectal cancer patients. RESULTS: The levels of PLR, HPR, and CEA were higher in rectal cancer patients than those in the subjects with benign rectal diseases (P < .001) and the healthy controls (P < .001). Platelet-lymphocyte ratio and HPR were associated with lymph node metastasis and tumor stage, rather than serosa invasion, distant metastasis, or tumor size. PLR or HPR combined with CEA produced larger area under curve (AUC) (AUCPLR+CEA  = 0.75, 95% CI = 0.70-0.79, AUCHPR+CEA  = 0.76, 95% CI = 0.71-0.80) than PLR (P < .0001), HPR (P < .0001), or CEA (P = .024) alone. CONCLUSION: Our results suggest that PLR or HPR combined with CEA can increase diagnostic efficacy and may be a useful diagnostic marker for patients with rectal cancer.

Activation of the PP2A catalytic subunit by ivabradine attenuates the development of diabetic cardiomyopathy.

Hyperglycemia-induced apoptosis plays a critical role in the pathogenesis of diabetic cardiomyopathy (DCM). Our previous study demonstrated that ivabradine, a selective If current antagonist, significantly attenuated myocardial apoptosis in diabetic mice, but the underlying mechanisms remained unknown. This study investigated the underlying mechanisms by which ivabradine exerts anti-apoptotic effects in experimental DCM. Pretreatment with ivabradine, but not ZD7288 (an established If current blocker), profoundly inhibited high glucose-induced apoptosis via inactivation of nuclear factor (NF)-κB signaling in neonatal rat cardiomyocytes. The effect was abolished by transfection of an siRNA targeting protein phosphatase 2A catalytic subunit (PP2Ac). In streptozotocin-induced diabetic mice, ivabradine treatment significantly inhibited left ventricular hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) and HCN4 (major components of the If current), activated PP2Ac, and attenuated NF-κB signaling activation and apoptosis, in line with improved histological abnormalities, fibrosis, and cardiac dysfunction without affecting hyperglycemia. These effects were not observed in diabetic mice with virus-mediated knockdown of HCN2 or HCN4 after myocardial injection, but were alleviated by knockdown of PP2Acα. Molecular docking and phosphatase activity assay confirmed direct binding of ivabradine to, and activation of, PP2Ac. In conclusion, ivabradine may directly activate PP2Ac, leading to inhibition of NF-κB signaling activation, myocardial apoptosis, and fibrosis, and eventually improving cardiac function in experimental DCM. Taken together, the present findings suggest that ivabradine may be a promising drug for treatment of DCM.

Pulmonary artery denervation improves pulmonary arterial hypertension induced right ventricular dysfunction by modulating the local renin-angiotensin-aldosterone system.

BACKGROUND: Pulmonary arterial hypertension (PAH) is commonly accompanied with the activation of the renin-angiotensin-aldosterone system (RAAS). Renal sympathetic denervation (RSD) reduces PAH partly through the inhibition of RAAS. Analogically, we hypothesized that pulmonary artery denervation (PADN) could reverse PAH and PAH-induced right ventricular (RV) dysfunction by downregulating the local RAAS activity. METHODS: Twenty-five beagle dogs were randomized into two groups: control group (intra-atrial injection of N-dimethylacetamide, 3 mg/kg, n = 6) and test group (intra-atrial injection of dehydrogenized-monocrotaline, 3 mg/kg, n = 19). Eight weeks later, dogs in the test group with mean pulmonary arterial pressure (mPAP) ≥25 mmHg (n = 16) were reassigned into the sham (n = 8) and PADN groups (n = 8) by chance. After another 6 weeks, the hemodynamics, pulmonary tissue morphology and the local RAAS expression in lung and right heart tissue were measured. RESULTS: PADN reduced the mPAP (25.94 ± 3.67 mmHg vs 33.72 ± 5.76 mmHg, P < 0.05) and the percentage of medial wall thickness (%MWT) (31.0 ± 2.6 % vs 37.9 ± 2.8 %, P < 0.05) compared with the sham group. PADN attenuated RV dysfunction, marked with reduced atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and ratio of right ventricular to left ventricular plus septum weight [RV/(LV + S)]. Moreover, the local RAAS expression was activated in PAH dogs while inhibited after PADN. CONCLUSIONS: PADN improves hemodynamics and relieves RV dysfunction in dogs with PAH, which can be associated with the downregulating RAAS activity in local tissue.

Efficiencies and Complications of Dual Chamber versus Single Chamber Implantable Cardioverter Defibrillators in Secondary Sudden Cardiac Death Prevention: A Meta-analysis.

BACKGROUND: Dual chamber implantable cardioverter defibrillators (ICDs) are considered to have better clinical outcomes than single chamber ICDs, however, an individual trial may not have sufficient power to prove it. This meta-analysis aimed to compare clinical outcomes of dual chamber ICDs (DC-ICDs) with single chamber ICDs (SC-ICDs) in secondary sudden cardiac death (SCD) prevention. METHODS: We searched Medline, the Cochrane Library, and other internet sources, without language or date restrictions for articles comparing clinical outcomes between DC-ICDs and SC-ICDs. Studies were selected for inclusion based on the following criteria: Randomised controlled trial.; Controlled design was used to compare SC-ICDs and DC-ICDs; Retrospective study if the survival analysis was performed. Efficacy endpoints were mortality, appropriate therapy, inappropriate detection of SVT, inappropriate therapy. Safety endpoints were lead-related complication and all complications. Relative risk (RR) or odds ratios (ORs) with 95% confidence intervals (CI) were calculated, and a χ2-based test of homogeneity was performed. RESULTS: We identified nine trials (n=2594) with a weighted mean follow-up of 18.9 months. Compared with DC-ICDs, SC-ICDs were associated with a significant reduction in lead complications (RR:3.30; 95% CI: 1.17-9.30; p=0.02). However, both groups had similar rates of mortality (OR: 0.91; 95%CI: 0.91-1.51; p=0.73), appropriate therapy (RR: 0.90; 95%CI: 0.73-1.11; p=0.32), inappropriate detection of SVT (RR: 1.82; 95%CI: 0.71-4.62; p=0.21), inappropriate therapy (RR: 2.08; 95%CI: -0.22-0.19; p=0.86) and all complications (OR: 1.27; 95%CI: 0.19-8.67; p=0.81). CONCLUSIONS: Besides more lead-related complications, DC-ICDs had similar efficacy and all complications as SC-ICDs in secondary sudden cardiac death prevention.

[Effect of Tanshinone IIA in Preventing and Treating Oxaliplatin Induced Peripheral Neuropathy].

OBJECTIVE: To observe preventive and therapeutic effects of Tanshinone IIA (T II A) on oxaliplatin induced peripheral neuropathy (OlPN) and to explore its effects on the expression of calcitonin gene related peptide (CGRP) and never growth factor (NGF). METHODS: Totally 36 phase II - III patients with malignant tumor of digestive tract undergoing chemotherapy program with oxaliplatin, were equally assigned to the T II A group (using THA at 80 mg/day 1 day before oxaliplatin chemotherapy for 3 successive days) and the control group (using chemotherapy program with oxaliplatin alone) by segmented randomization. After 4 cycles of chemotherapy, the incidence degree and incidence of OlPN were evaluated. Sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity ( MNCV) were tested by EMG evoked potential device. Serum levels of CGRP and NGF were also detected in the two groups before and after chemotherapy. The correlation of serum levels of CGRP and NGF to OIPN was assessed using linear correlation analysis. RESULTS: After chemotherapy the OlPN incidence was 27.8% (5/18 cases) in the T II A group, obviously lower than that in the control group (55.6%, 10/18 cases; P < 0.05). Compared with before treatment in the same group, SNCV and MNCV of common peroneal nerve were slowed down, serum NGF levels decreased, and serum CGRP levels obviously increased in the two groups (all P < 0.05). Compared with the control group after treatment, SNCV and MNCV of common peroneal nerve were obviously accelerated, serum NGF levels increased, and serum CGRP levels obviously decreased in the THA group (all P < 0.05). Results of linear correlation analysis indicated serum NGF level was negatively correlated with peripheral neuropathy (PN), serum CGRP expression was positively correlated with neurotoxicity (P < 0.05). CONCLUSION: T II A could reduce the incidence of OlPN, which might be associated with inhibiting the expression of CGRP and up-regulating NGF activities.

Interleukin-6, but not C-reactive protein, predicts the occurrence of cardiovascular events after drug-eluting stent for unstable angina.

BACKGROUND: Evidences concerning the predictive value of baseline inflammatory biomarkers after drug-eluting stent (DES) placement are controversial, mainly because the use of statin was not precisely defined. OBJECTIVES: The aim was to compare the differences between interleukin (IL)-6 and high-sensitivity C-reactive protein (hs-CRP) in predicting cardiovascular events 2 years after stenting in patients with unstable angina (UA) who had not received statin pretreatment. METHODS: There were 1,896 patients included in this study. The primary end-point was the occurrence of cardiac death or myocardial infarction (MI). Secondary endpoints included all-cause death, stent thrombosis (ST), target lesion revascularization (TLR), target vessel revascularization (TVR), or a composite of major adverse cardiac events (MACE) at 2 years after the procedure. RESULTS: During the median follow-up of 2.77 years, 96 patients experienced cardiac death (n = 37, 1.95%) or MIs (n = 70, 3.69%), 94 TLRs, 123 TVRs, 215 MACEs, and 21 definite or probable STs. In multivariable Cox proportional-hazards models and discrimination analysis, elevated IL-6 levels were superior to hs-CRP in predicting the occurrence not only of cardiac death or MI (HR 1.337, 95% CI 1.234-1.449, P < 0.001), but also of MACE and late-occurring definite/probable ST. Incorporation of IL-6 into conventional variables resulted in significantly increased c statistic for the prediction of end-points, with the exception of TLR and TVR. CONCLUSION: Elevated IL-6 levels were independent predictors of cardiac death or MI, MACE, and late ST in patients with UA who had not received statin pretreatment, suggesting a role for IL-6 in the inflammatory risk assessment. Pathological studies have confirmed that atherosclerosis is a chronic inflammatory disease. Serum levels of high-sensitivity C-reactive protein (hs-CRP), matrix metalloproteinase, plasminogen activator inhibitor-1, the complement components C3a or C5a, and interleukin(IL)-6 were reported to provide strong and independent indications of the risk for future cardiovascular (CV) events, even among individuals who are thought to be free of vascular disease.

I(f) current channel inhibitor (ivabradine) deserves cardioprotective effect via down-regulating the expression of matrix metalloproteinase (MMP)-2 and attenuating apoptosis in diabetic mice.

BACKGROUND: Ivabradine (IVBD), a novel I(f)-channel inhibitor and specific heart rate-lowering agent, is known to have anti-oxidative activity that promotes endothelial function. However, the molecular mechanism through which IVBD acts on cardiac function has yet to be elucidated, especially in experimental diabetic animals. METHODS: For this reason, twenty diabetic mice were randomly assigned to IVBD-treated (10 mg/kg/day) and control (saline) groups. After a 3-month treatment, microarray assay was performed to identify differentia expressed genes, and cardiac function was measured by echocardiography, with subsequent immunohistochemistry analysis and western blotting. RESULTS: Our results showed that ivabradine treatment attenuated the expression and staining score of matrix metalloproteinase (MMP)-2, induced the dephosphorylation of caspase 3, BAX and MMP-2, and enhanced the phosphorylation of NF-κB. Ivabradine treatment led to a significant improvement in cardiac function. CONCLUSION: Ivabradine significantly improved cardiac function by attenuating apoptosis and inhibiting the expression and activity of MMP-2 in diabetic mice, which underscored the novel clinical implications of ivabradine for diabetic patients.

Implications of the changes in serum neutrophil gelatinase-associated lipocalin and cystatin C in patients with chronic kidney disease.

AIM: Early intervention in patients with chronic kidney disease (CKD) significantly improves the prognosis. The present widely used markers of renal function, such as serum creatinine (sCr), fail to reflect early renal damage and predict the progression of disease. The authors aimed to evaluate whether neutrophil gelatinase-associated lipocalin (NGAL), a novel specific biomarker of acute kidney injury, could predict the progression of CKD. METHODS: We identified 92 patients with stage 2-4 CKD caused by primary chronic glomerulonephritis. The patients were followed for 2 years, the changes in NGAL levels in the progressive and non-progressive groups were compared. RESULTS: First, the serum NGAL levels of patients with stage 2-4 CKD were significantly increased compared with the control group. Second, based on Pearson correlation analysis, positive correlations existed between NGAL and cystatin C levels and between NGAL and sCr levels. Third, bounded by the progress of renal function, the area under the curve of serum NGAL was 0.872 (95% confidence interval, 0.786-0.933), which suggests a blood NGAL cut-off level of 246 ng/mL (sensitivity 85.19%, specificity 81.54%). Fourth, Kaplan-Meier survival curve analysis showed that the serum NGAL level was closely related to the end-point of renal function in patients with CKD. Fifth, Cox multivariate regression analysis showed that the estimated glomerular filtration rate and blood NGAL are associated with progression of CKD. CONCLUSION: Serum NGAL is an effective biomarker for detecting early-stage renal damage in CKD patients. Serum NGAL was significantly correlated with the severity of renal damage and the progression of renal function deterioration.

Critical Involvement of the Thioredoxin Reductase Gene (trxB) in Salmonella Gallinarum-Induced Systemic Infection in Chickens.

Salmonella enterica serovar Gallinarum biovar Gallinarum (SG) causes fowl typhoid, a notifiable infectious disease in poultry. However, the pathogenic mechanism of SG-induced systemic infection in chickens remains unclear. Thioredoxin reductase (TrxB) is a redox protein crucial for regulating various enzyme activities in Salmonella serovar, but the role in SG-induced chicken systemic infection has yet to be determined. Here, we constructed a mutant SG strain lacking the trxB gene (trxB::Cm) and used chicken embryo inoculation and chicken oral infection to investigate the role of trxB gene in the pathogenicity of SG. Our results showed that trxB::Cm exhibited no apparent differences in colony morphology and growth conditions but exhibited reduced tolerance to H2O2 and increased resistance to bile acids. In the chicken embryo inoculation model, there was no significant difference in the pathogenicity of trxB::Cm and wild-type (WT) strains. In the chicken oral infection, the WT-infected group exhibited typical clinical symptoms of fowl typhoid, with complete mortality between days 6 and 9 post infection. In contrast, the trxB::Cm group showed a 100% survival rate, with no apparent clinical symptoms or pathological changes observed. The viable bacterial counts in the liver and spleen of the trxB::Cm-infected group were significantly reduced, accompanied by decreased expression of cytokines and chemokines (IL-1ß, IL-6, IL-12, CXCLi1, TNF-α, and IFN-γ), which were significantly lower than those in the WT group. These results show that the pathogenicity of the trxB-deficient strain was significantly attenuated, indicating that the trxB gene is a crucial virulence factor in SG-induced systemic infection in chickens, suggesting that trxB may become a potentially effective target for controlling and preventing SG infection in chickens.

TAX1BP1 downregulation by STAT3 in cardiac fibroblasts contributes to diabetes-induced heart failure with preserved ejection fraction.

Heart failure (HF) with preserved ejection fraction (HFpEF) is now the most common form of HF and has been reported to be closely related to diabetes. Accumulating evidence suggests that HFpEF patients exhibit cardiac fibrosis. This study investigates whether direct targeted inhibition of the activation of cardiac fibroblasts (CFs), the main effector cells in cardiac fibrosis, improves diabetes-induced HFpEF and elucidates the underlying mechanisms. Twenty-week-old db/db mice exhibited HFpEF, as confirmed by echocardiography and hemodynamic measurements. Proteomics was performed on CFs isolated from the hearts of 20-week-old C57BL/6 and db/db mice. Bioinformatic prediction was used to identify target proteins. Experimental validation was performed in both high glucose (HG)-treated neonatal mouse CFs (NMCFs) and diabetic hearts. TAX1 binding protein 1 (TAX1BP1) was identified as the most significantly differentially expressed protein between 20-week-old C57BL/6 and db/db mice. TAX1BP1 mRNA and protein were markedly downregulated in CFs from diabetic hearts and HG-cultured NMCFs. Overexpression of TAX1BP1 profoundly inhibited HG/diabetes-induced NF-κB nuclear translocation and collagen synthesis in CFs, improved cardiac fibrosis, hypertrophy, inflammation and HFpEF in diabetic mice. Mechanistically, signal transducer and activator of transcription 3 (STAT3), which is phosphorylated and translocated from the cytoplasm into the nucleus under hyperglycemic conditions, bound to TAX1BP1 promoter and blocked TAX1BP1 transcriptional activity, consequently promoting NF-κB nuclear translocation and collagen synthesis in CFs, aggravating cardiac fibrosis, hypertrophy and inflammation, leading to HFpEF in db/db mice. Taken together, our findings demonstrate that targeting regulation of STAT3-TAX1BP1-NF-κB signaling in CFs may be a promising therapeutic approach for diabetes-induced HFpEF.

Salmonella pathogenicity island-14 is a critical virulence factor responsible for systemic infection in chickens caused by Salmonella gallinarum.

Salmonella enterica serovar Gallinarum (S. gallinarum) is an important host-specific pathogen that causes fowl typhoid, a severe systemic, septicemic, and fatal infection, in chickens. S. gallinarum causes high morbidity and mortality in chickens and poses a significant burden and economic losses to the poultry industry in many developing countries. However, the virulence factors and mechanisms of S. gallinarum-induced systemic infection in chickens remain poorly understood. In this study, we constructed a Salmonella pathogenicity island-14 (SPI-14) mutant strain (mSPI-14) of S. gallinarum and evaluated the pathogenicity of mSPI-14 in the chicken systemic infection model. The mSPI-14 exhibited the same level of bacterial growth and morphological characteristics but significantly reduced resistance to bile acids compared with the wild-type (WT) strain in vitro. The virulence of mSPI-14 was significantly attenuated in the chicken oral infection model in vivo. Chickens infected with WT showed typical clinical symptoms of fowl typhoid, with all birds succumbing to the infection within 6 to 9 days post-inoculation, and substantial increases in bacterial counts and significant pathological changes in the liver and spleen were observed. In contrast, all mSPI-14-infected chickens survived, the bacterial counts in the organs were significantly lower, and no significant pathological changes were observed in the liver and spleen. The expression of interleukin (IL)-1ß, IL-12, CXCLi1, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ in the liver of mSPI-14-infected chickens were significantly lower than those in the WT-infected chickens. These results indicate that SPI-14 is a crucial virulence factor in systemic infection of chickens, and avirulent mSPI-14 could be used to develop a new attenuated live vaccine to prevent S. gallinarum infection in chickens.

Multi-omics approaches to understand pathogenicity during potato early blight disease caused by Alternaria solani.

Potato early blight (PEB), a foliar disease of potato during the growing period, caused by Alternaria sp., is common in major potato-producing areas worldwide. Effective agents to control this disease or completely resistant potato varieties are absent. Large-scale use of fungicides is limited due to possibility of increase in pathogen resistance and the requirements of ecological agriculture. In this study, we focused on the composition and infection characteristics of early blight pathogens in Yunnan Province and screened candidate pathogenesis-related pathways and genes. We isolated 85 strains of Alternaria sp. fungi from typical early blight spots in three potato-growing regions in Yunnan Province from 2018 to 2022, and identified 35 strains of Alternaria solani and 50 strains of Alternaria alternata by morphological characterization and ITS sequence comparison, which were identified as the main and conditional pathogens causing early blight in potato, respectively. Scanning electron microscope analysis confirmed only A. solani producing appressorium at 4 h after inoculation successfully infected the leaf cells. Via genome assembly and annotation, combine transcriptome and proteomic analysis, the following pathogenicity-related unit, transcription factors and metabolic pathway were identified: (1) cell wall-degrading enzymes, such as pectinase, keratinase, and cellulase; (2) genes and pathways related to conidia germination and pathogenicity, such as ubiquitination and peroxisomes; and (3) transcription factors, such as Zn-clus, C2H2, bZIP, and bHLH. These elements were responsible for PEB epidemic in Yunnan.

Baicalin Blocks Colon Cancer Cell Cycle and Inhibits Cell Proliferation through miR-139-3p Upregulation by Targeting CDK16.

Baicalin was reported to facilitate the apoptosis of colon cells and inhibit tumor growth in vivo. This study aimed to explore the specific mechanism and function of baicalin on colon cells. Relative mRNA levels were tested via qPCR. Cell proliferation, viability, and cell cycle phases were evaluated using MTT, colony formation, and flow cytometry assays, respectively. The interaction between miR-139-3p and cyclin-dependent kinase 16 (CDK16) was measured via a dual-luciferase reporter assay. Immunohistochemistry was used to count the positivity cells in tumor tissues collected from treated xenografted tumor mice. The results showed that baicalin increased miR-139-3p expression while also decreasing CDK16 levels, blocking the cell cycle, and inhibiting cell proliferation in colon cancer cells. miR-139-3p silencing or CDK16 overexpression abolished the inhibitory effects of baicalin on colon cancer proliferation. miR-139-3p directly targeted and interacted with CDK16 at the cellular level. The protective functions of miR-139-3p knockdown on tumor cells were abrogated by silencing CDK16. The combination of baicalin treatment and CDK16 knockdown further inhibited tumor growth of xenografted tumor mice compared with the groups injected with only sh-CDK16 or baicalin in vivo. In conclusion, baicalin inhibited colon cancer growth by modulating the miR-139-3p/CDK16 axis.

High-density lipoprotein regulates angiogenesis by long non-coding RNA HDRACA.

Normal high-density lipoprotein (nHDL) can induce angiogenesis in healthy individuals. However, HDL from patients with coronary artery disease undergoes various modifications, becomes dysfunctional (dHDL), and loses its ability to promote angiogenesis. Here, we identified a long non-coding RNA, HDRACA, that is involved in the regulation of angiogenesis by HDL. In this study, we showed that nHDL downregulates the expression of HDRACA in endothelial cells by activating WW domain-containing E3 ubiquitin protein ligase 2, which catalyzes the ubiquitination and subsequent degradation of its transcription factor, Kruppel-like factor 5, via sphingosine 1-phosphate (S1P) receptor 1. In contrast, dHDL with lower levels of S1P than nHDL were much less effective in decreasing the expression of HDRACA. HDRACA was able to bind to Ras-interacting protein 1 (RAIN) to hinder the interaction between RAIN and vigilin, which led to an increase in the binding between the vigilin protein and proliferating cell nuclear antigen (PCNA) mRNA, resulting in a decrease in the expression of PCNA and inhibition of angiogenesis. The expression of human HDRACA in a hindlimb ischemia mouse model inhibited the recovery of angiogenesis. Taken together, these findings suggest that HDRACA is involved in the HDL regulation of angiogenesis, which nHDL inhibits the expression of HDRACA to induce angiogenesis, and that dHDL is much less effective in inhibiting HDRACA expression, which provides an explanation for the decreased ability of dHDL to stimulate angiogenesis.

Angioscopy study from a large patient population comparing sirolimus-eluting stent with biodegradable versus durable polymer.

AIMS: This study aimed to compare the neointimal coverage (NIC), subclinical thrombus, color of plaque underneath the stent at 9-month after implantation of sirolimus-eluting stent (SES) either with durable or with biodegradable polymer (BDPM). METHODS: A total of 175 patients were assigned as Cypher (n = 81, 97 stents with durable polymer) and Excel (n = 94, 112 stents with BDPM) stent at 9-month after indexed procedure. NIC was classified from grade 0-3. Color of plaque was divided into white, light-yellow, yellow, and dark yellow. Thrombus was diagnosed as white or red material with cotton-like or ragged appearance. Incomplete NIC (grade 0/1) circled by a blush was termed by "inflaming." RESULTS: There were significant differences in unstable angina (90.5 vs. 52.4%, P = 0.015), previous myocardial infarction (33.3 vs. 4.0%, P = 0.045) and left ventricular eject fraction (55.2 ± 7.8 vs. 62.6 ± 6.3%, P = 0.021) between the Excel and Cypher groups. The minimal- and maximal-NIC grades in the Cypher group were 0.67 ± 0.58 and 2.29 ± 0.46, respectively, when compared with 1.45 ± 0.67 (P < 0.001) and 2.64 ± 0.49 (P = 0.023) in the Excel group. The percentage of yellow plaque, thrombus, "inflaming" and NIC grade of 0 in the Excel and Cypher groups, respectively, were as follows: 8.0 vs. 26.8% (P = 0.031), 9.8 vs. 32.9% (P = 0.024), 8.0 vs. 38.1% (P = 0.017), and 38.1 vs. 0% (P < 0.001). Of the stents with "inflaming," 63.6% had thrombus when compared with 20.1% of the non-erosion stents (P < 0.001). Overlapping segments had the lowest NIC grades and more "inflaming" demonstrating a significant difference between Cypher vs. Excel stents. NIC grade was positively correlated with thrombus. CONCLUSIONS: SES with BDPM has improved NIC resulting in less yellow plaque, thrombus, and "inflaming." Overlapping segments had the lowest NIC grade and more "inflaming."

The in vivo performance of small-caliber nanofibrous polyurethane vascular grafts.

BACKGROUND: In a previous in vitro study, we confirmed that small-caliber nanofibrous polyurethane (PU) vascular grafts have favorable mechanical properties and biocompatibility. In the present study, we examined the in vivo biocompatibility and stability of these grafts. METHODS: Forty-eight adult male beagle dogs were randomly divided into two groups receiving, respectively, polyurethane (PU) or polytetrafluoroethylene (PTFE) grafts (n = 24 animals / group). Each group was studied at 4, 8, 12, and 24 weeks after graft implantation. Blood flow was analyzed by color Doppler ultrasound and computed tomography angiography. Patency rates were judged by animal survival rates. Coverage with endothelial and smooth muscle cells was characterized by hematoxylin-eosin and immunohistological staining, and scanning electron microscopy (SEM). RESULTS: Patency rates were significantly higher in the PU group (p = 0.02 vs. PTFE group). During the first 8 weeks, endothelial cells gradually formed a continuous layer on the internal surface of PU grafts, whereas coverage of PTFE graft by endothelial cells was inhomogeneous. After 12 weeks, neointimal thickness remained constant in the PU group, while PTFE group showed neointimal hyperplasia. At 24 weeks, some anastomotic sites of PTFE grafts became stenotic (p = 0.013 vs. PU group). Immunohistological staining revealed a continuous coverage by endothelial cells and an orderly arrangement of smooth muscle cells on PU grafts. Further, SEM showed smooth internal surfaces in PU grafts without thrombus or obvious neointimal hyperplasia. CONCLUSIONS: Small-caliber nanofibrous PU vascular grafts facilitate the endothelialization process, prevent excessive neointimal hyperplasia, and improve patency rates.

High response organic deep ultraviolet photodetector with PEDOT:PSS anode.

We have fabricated an organic deep ultraviolet photodetector (PD) using PEDOT:PSS (PH 1000) as a transparent anode. NPB and PBD were employed as electron donor and acceptor, respectively. The PD exhibits a dark current of 0.0829 µA/cm(2) and a photocurrent of 85.3 µA/cm(2) at -12 V under 280 nm light illumination with an intensity of 0.488 mW/cm(2). A high response at 248-370 nm with its peak of 0.18 A/W at 280 nm and a detectivity of 1.1×10(12) cm Hz(1/2) W(-1) were achieved. The more detailed mechanism of harvesting high performance and the dependence of photocurrent density on illumination intensity are also discussed.