Thromboelastography-guided antiplatelet therapy for patients with ischemic cerebrocardiovascular diseases: a systematic review and meta-analysis.

BACKGROUND: The effectiveness of thromboelastography (TEG)-guided antiplatelet therapy in patients with ischemic cerebrocardiovascular diseases is not well-established. This systematic review evaluates the efficacy and safety of TEG-guided antiplatelet therapy compared to standard treatment in patients with ischemic cerebrocardiovascular diseases. METHODS: Randomized controlled trials (RCTs) and observational studies comparing TEG-guided antiplatelet therapy with standard therapy in patients suffering from ischemic stroke (IS) or coronary artery disease (CAD) were identified. The primary efficacy measure was a composite of ischemic and hemorrhagic events. Secondary efficacy measures included any ischemic events, while safety was assessed by the occurrence of bleeding events. RESULTS: 10 studies involving 4 RCTs and 6 observational studies with a total of 1,678 patients were included. When considering a composite of ischemic and hemorrhagic events in RCTs, a significant reduction was observed in IS or CAD patients under TEG-guided therapy compared to standard therapy (OR 0.45, 95% CI 0.27 to 0.75, P=0.002). After pooling RCTs and observational studies together, compared to standard antiplatelet therapy, TEG-guided therapy significantly reduced the risk of a composite of ischemic and hemorrhagic events (OR 0.26, 95% CI 0.19 to 0.37; P<0.00001), ischemic events (OR 0.28, 95% CI 0.19 to 0.41; P<0.00001), and bleeding events (OR 0.31, 95% CI 0.16 to 0.62; P=0.0009) in patients with IS or CAD. CONCLUSIONS: TEG-guided antiplatelet therapy appears to be both effective and safe for patients with IS or CAD. These findings support the use of TEG testing to tailor antiplatelet therapy in individuals with ischemic cerebrocardiovascular diseases.

NUAK1 promotes metabolic dysfunction-associated steatohepatitis progression by activating Caspase 6-driven pyroptosis and inflammation.

BACKGROUND: lNUAK1 is strongly associated with organ fibrosis, but its causal mechanism for modulating lipid metabolism and hepatic inflammation underlying MASH has not been fully clarified. METHOD: In our study, human liver tissues from patients with MASH and control subjects were obtained to evaluate NUAK1 expression. MASH models were established using C57BL/6 mice. Liver damage and molecular mechanisms of the NUAK1-Caspase 6 signaling were tested in vivo and in vitro. RESULTS: In the clinical arm, NUAK1 expression was upregulated in liver samples from patients with MASH. Moreover, increased NUAK1 was detected in mouse MASH models. NUAK1 inhibition ameliorated steatohepatitis development in MASH mice accompanied by the downregulation of hepatic steatosis and fibrosis. Intriguingly, NUAK1 was found to facilitate Caspase 6 activation and trigger pyroptosis in MASH-stressed livers. Disruption of hepatocytes Caspase 6 decreased MASH-induced liver inflammation with upregulated TAK1 but diminished RIPK1. Moreover, we found that NUAK1/Caspase 6 axis inhibition could accelerate the interaction between TAK1 and RIPK1, which in turn led to the degradation of RIPK1. CONCLUSIONS: In summary, our study elucidates that NUAK1-Caspase 6 signaling controls inflammation activation in MASH through the interaction between TAK1 and RIPK1, which is crucial for controlling pyroptosis and promoting the progression of MASH.

M1 macrophage-derived exosomes inhibit cardiomyocyte proliferation through delivering miR-155.

BACKGROUND: M1 macrophages are closely associated with cardiac injury after myocardial infarction (MI). Increasing evidence shows that exosomes play a key role in pathophysiological regulation after MI, but the role of M1 macrophage-derived exosomes (M1-Exos) in myocardial regeneration remains unclear. In this study, we explored the impact of M1 macrophage-derived exosomes on cardiomyocytes regeneration in vitro and in vivo. METHODS: M0 macrophages were induced to differentiate into M1 macrophages with GM-CSF (50 ng/mL) and IFN-γ (20 ng/mL). Then M1-Exos were isolated and co-incubated with cardiomyocytes. Cardiomyocyte proliferation was detected by pH3 or ki67 staining. Quantitative real-time PCR (qPCR) was used to test the level of miR-155 in macrophages, macrophage-derived exosomes and exosome-treated cardiomyocytes. MI model was constructed and LV-miR-155 was injected around the infarct area, the proliferation of cardiomyocytes was counted by pH3 or ki67 staining. The downstream gene and pathway of miR-155 were predicted and verified by dual-luciferase reporter gene assay, qPCR and immunoblotting analysis. IL-6 (50 ng/mL) was added to cardiomyocytes transfected with miR-155 mimics, and the proliferation of cardiomyocytes was calculated by immunofluorescence. The protein expressions of IL-6R, p-JAK2 and p-STAT3 were detected by Western blot. RESULTS: The results showed that M1-Exos suppressed cardiomyocytes proliferation. Meanwhile, miR-155 was highly expressed in M1-Exos and transferred to cardiomyocytes. miR-155 inhibited the proliferation of cardiomyocytes and antagonized the pro-proliferation effect of interleukin 6 (IL-6). Furthermore, miR-155 targeted gene IL-6 receptor (IL-6R) and inhibited the Janus kinase 2(JAK)/Signal transducer and activator of transcription (STAT3) signaling pathway. CONCLUSION: M1-Exos inhibited cardiomyocyte proliferation by delivering miR-155 and inhibiting the IL-6R/JAK/STAT3 signaling pathway. This study provided new insight and potential treatment strategy for the regulation of myocardial regeneration and cardiac repair by macrophages.

Introgression of chromosome 5P from Agropyron cristatum enhances grain weight in a wheat background.

KEY MESSAGE: A grain weight locus from Agropyron cristatum chromosome 5P increases grain weight in different wheat backgrounds and is localized to 5PL (bin 7-12). Thousand-grain weight is an important trait in wheat breeding, with a narrow genetic basis being the main factor limiting improvement. Agropyron cristatum, a wild relative of wheat, harbors many desirable genes for wheat improvement. Here, we found that the introduction of the 5P chromosome from A. cristatum into wheat significantly increased the thousand-grain weight by 2.55-7.10 g, and grain length was the main contributor to grain weight. An increase in grain weight was demonstrated in two commercial wheat varieties, indicating that the grain weight locus was not affected by the wheat background. To identify the chromosome segment harboring the grain weight locus, three A. cristatum 5P deletion lines, two wheat-A. cristatum 5P translocation lines and genetic populations of these lines were used to evaluate agronomic traits. We found that the translocation lines harboring the long arm of A. cristatum chromosome 5P (5PL) exhibited high grain weight and grain length, and the genetic locus associated with increased grain weight was mapped to 5PL (bin 7-12). An increase in grain weight did not adversely affect other agronomic traits in translocation line 5PT2, which is a valuable germplasm resource. Overall, we identified a grain weight locus from chromosome 5PL and provided valuable germplasm for improving wheat grain weight.

Hypoalkaline Phosphatemia Dental Type: A Case Report.

Mutations in dental hypophosphatasia (HPP) have been reported less than those in other types of HPP because the symptoms are mild or the dental lesions are only partial manifestations of other types of HPP. In this case, we observe the clinical manifestation of dental hypoalkaline phosphatase by analyzing the genetic mutation and biochemical parameters in child. The clinical data of the child with odonto HPP were collected and analyzed. The blood samples of the child and his parents were sequenced and verified using Sanger through a specific probe capture and high-throughput second-generation sequencing technology. Major clinical manifestations in the patient were early loss of deciduous teeth, significantly lower serum alkaline phosphatase (ALP) levels, lower active vitamin D, and increased blood phosphorus, but no abnormality was observed in the oral X-ray. Two missense mutations-c.542C>T (p. ser181leu) and c.644 T> C (p.Ile215Thr)-were found in exon 6 of the ALPL gene from the father and mother, respectively. The clinical manifestations of odonto hypophosphatasia were early loss of deciduous teeth and significantly reduced serum ALP levels. Of 2 mutations-c.542C>T (p.ser181leu) and c.644 T> C (p.Ile215Thr)-in the ALPL gene, c.644 T> C (p.Ile215Thr) was a new mutation.

Enhanced anti-tumor activity mediated by combination chimeric antigen receptor T cells targeting GD2 and GPC2 in high-risk neuroblastoma.

BACKGROUND AIMS: Chimeric antigen receptor T (CAR-T) cells targeting single antigens show limited activity against solid tumors due to poor T cell persistence, low efficiency infiltration, and exhaustion together with heterogeneous tumor-associated antigen (TAA) expression. This is also true in high-risk neuroblastoma (HRNB), a lethal pediatric extracranial malignancy. To overcome these obstacles, a combinational strategy using GD2-specific and GPC2-specific CAR-T cells was developed to improve immunotherapeutic efficacy. METHODS: We individually developed GD2-specific and GPC2-specific CARs containing a selective domain (sCAR) which was a peptide of 10 amino acids derived from human nuclear autoantigen La/SS-B. These constructs allowed us to generate two different HRNB antigen-specific CAR-T cells with enhanced biological activity through stimulating sCAR-engrafted T cells via a selective domain-specific monoclonal antibody (SmAb). Binding affinity and stimulation of GD2- and GPC2-specific sCARs by SmAb were measured, and transient and persistent anti-tumor cytotoxicity of GD2sCAR-T and GPC2sCAR-T cells were quantified in neuroblastoma cell lines expressing different TAA levels. The anti-tumor pharmaceutical effects and cellular mechanisms mediated by single or combinational sCAR-T cells were evaluated in vitro and in vivo. RESULTS: GD2- and GPC2-specific sCARs had antigen-specific binding affinity similar to their parental counterparts and were recognized by SmAb. SmAb-mediated stimulation selectively activated sCAR-T proliferation and increased central memory T cells in the final products. SmAb-stimulated sCAR-T cells had enhanced transient cytolytic activity, and combination therapy extended long-term anti-tumor activity in vitro through TNF-α and IL-15 release. Stimulated sCAR-T cells overcame heterogeneous antigen expression in HRNB, and the multi-TAA-targeting strategy was especially efficacious in vivo, inducing apoptosis through the caspase-3/PARP pathway and inhibiting the release of several tumor-promoting cytokines. CONCLUSIONS: These data suggest that combined targeting of multiple TAAs is a promising strategy to overcome heterogenous antigen expression in solid tumors and extend CAR-T cell persistence for HRNB immunotherapy.

Treatment of metastatic hormone-sensitive prostate cancer: from doublet therapy to triplet therapy.

For metastatic prostate cancer, androgen deprivation therapy (ADT) is the key strategy to control the disease. However, after 18-24 months of treatment, most patients will progress from metastatic hormone-sensitive prostate cancer (mHSPC) to metastatic castration-resistant prostate cancer (mCRPC) even with ADT. Once patients enter into mCRPC, they face with significant declines in quality of life and a dramatically reduced survival period. Thus, doublet therapy, which combines ADT with new hormone therapy (NHT) or ADT with docetaxel chemotherapy, substitutes ADT alone and has become the "gold standard" for the treatment of mHSPC. In recent years, triplet therapy, which combines ADT with NHT and docetaxel chemotherapy, has also achieved impressive effects in mHSPC. This article provides a comprehensive review of the recent applications of the triplet therapy in the field of mHSPC.

Intelligent electrospinning nanofibrous membranes for monitoring and promotion of the wound healing.

The incidence of chronic wound healing is promoted by the growing trend of elderly population, obesity, and type II diabetes. Although numerous wound dressings have been studied over the years, it is still challenging for many wound dressings to perfectly adapt to the healing process due to the dynamic and complicated wound microenvironment. Aiming at an optimal reproduction of the physiological environment, multifunctional electrospinning nanofibrous membranes (ENMs) have emerged as a promising platform for the wound treatment owing to their resemblance to extracellular matrix (ECM), adjustable preparation processes, porousness, and good conformability to the wound site. Moreover, profiting from the booming development of human-machine interaction and artificial intelligence, a next generation of intelligent electrospinning nanofibrous membranes (iENMs) based wound dressing substrates that could realize the real-time monitoring of wound proceeding and individual-based wound therapy has evoked a surge of interest. In this regard, general wound-related biomarkers and process are overviewed firstly and representative iENMs stimuli-responsive materials are briefly summarized. Subsequently, the emergent applications of iENMs for the wound healing are highlighted. Finally, the opportunities and challenges for the development of next-generation iENMs as well as translating iENMs into clinical practice are evaluated.

The CaMK Family Differentially Promotes Necroptosis and Mouse Cardiac Graft Injury and Rejection.

Organ transplantation is associated with various forms of programmed cell death which can accelerate transplant injury and rejection. Targeting cell death in donor organs may represent a novel strategy for preventing allograft injury. We have previously demonstrated that necroptosis plays a key role in promoting transplant injury. Recently, we have found that mitochondria function is linked to necroptosis. However, it remains unknown how necroptosis signaling pathways regulate mitochondrial function during necroptosis. In this study, we investigated the receptor-interacting protein kinase 3 (RIPK3) mediated mitochondrial dysfunction and necroptosis. We demonstrate that the calmodulin-dependent protein kinase (CaMK) family members CaMK1, 2, and 4 form a complex with RIPK3 in mouse cardiac endothelial cells, to promote trans-phosphorylation during necroptosis. CaMK1 and 4 directly activated the dynamin-related protein-1 (Drp1), while CaMK2 indirectly activated Drp1 via the phosphoglycerate mutase 5 (PGAM5). The inhibition of CaMKs restored mitochondrial function and effectively prevented endothelial cell death. CaMKs inhibition inhibited activation of CaMKs and Drp1, and cell death and heart tissue injury (n = 6/group, p < 0.01) in a murine model of cardiac transplantation. Importantly, the inhibition of CaMKs greatly prolonged heart graft survival (n = 8/group, p < 0.01). In conclusion, CaMK family members orchestrate cell death in two different pathways and may be potential therapeutic targets in preventing cell death and transplant injury.

Pectolinarigenin ameliorated airway inflammation and airway remodeling to exhibit antitussive effect.

Cough is a common symptom of several respiratory diseases. However, frequent coughing from acute to chronic often causes great pain to patients. It may turn into cough variant asthma, which seriously affects people's quality of life. For cough treatment, it is dominated by over-the-counter antitussive drugs, such as asmeton, but most currently available antitussive drugs have serious side effects. Thus, there is a great need for the development of new drugs with potent cough suppressant. BALB/c mice were used to construct mice model with cough to investigate the pharmacological effects of pectolinarigenin (PEC). Hematoxylin-eosin and Masson staining were used to assess lung injury and airway remodeling, and ELISA was used to assess the level of inflammatory factor release. In addition, inflammatory cell counts were measured to assess airway inflammation. Airway hyperresponsiveness assay was used to assess respiratory resistance in mice. Finally, we used Western blotting to explore the potential mechanisms of PEC. We found that PEC could alleviate lung tissue injury and reduce the release of inflammatory factors, inhibit of cough frequency and airway wall collagen deposition in mice model with cough. Meanwhile, PEC inhibited the Ras/ERK/c-Fos pathway to exhibit antitussive effect. Therefore, PEC may be a potential drug for cough suppression.

Pre-breeding of spontaneous Robertsonian translocations for density planting architecture by transferring Agropyron cristatum chromosome 1P into wheat.

KEY MESSAGE: We developed T1AL·1PS and T1AS·1PL Robertsonian translocations by breakage-fusion mechanism based on wheat-A. cristatum 1P(1A) substitution line with smaller leaf area, shorter plant height, and other excellent agronomic traits Agropyron cristatum, a wild relative of wheat, is a valuable germplasm resource for improving wheat genetic diversity and yield. Our previous study confirmed that the A. cristatum chromosome 1P carries alien genes that reduce plant height and leaf size in wheat. Here, we developed T1AL·1PS and T1AS·1PL Robertsonian translocations (RobTs) by breakage-fusion mechanism based on wheat-A. cristatum 1P (1A) substitution line II-3-1c. Combining molecular markers and cytological analysis, we identified 16 spontaneous RobTs from 911 F2 individuals derived from the cross of Jimai22 and II-3-1c. Fluorescence in situ hybridization (FISH) was applied to detect the fusion structures of the centromeres in wheat and A. cristatum chromosomes. Resequencing results indicated that the chromosomal junction point was located at the physical position of Triticum aestivum chromosome 1A (212.5 Mb) and A. cristatum chromosome 1P (230 Mb). Genomic in situ hybridization (GISH) in pollen mother cells showed that the produced translocation lines could form stable ring bivalent. Introducing chromosome 1PS translocation fragment into wheat significantly increased the number of fertile tillers, grain number per spike, and grain weight and reduced the flag leaf area. However, introducing chromosome 1PL translocation fragment into wheat significantly reduced flag leaf area and plant height with a negative effect on yield components. The pre-breeding of two spontaneous RobTs T1AL·1PS and T1AS·1PL was important for wheat architecture improvement.

2022 Shandong Province university medical technical skills competition nursing track: An effective project to improve core competencies of nursing students.

Background: The core competencies of nursing students have gradually become the focus of attention of nursing educators. Nursing skills competitions are an important form of educational and teaching activity in universities and the nursing track at the Shandong Provincial University Students' Medical Technical Skills Competition gives nursing students an opportunity to demonstrate their clinical skills and knowledge. This study aims to describe the organisation and procedures of the nursing track, analyse the competition results and explore the impact the competition has on the core competencies of the nursing students. This will provide new ideas for future nursing professional education. Methods: Statistical analysis of the competition results was performed as a means of understanding the current status of theoretical knowledge and clinical skills of nursing students in Shandong Province. The impact of the competition on the core competencies of participating students was analysed by distributing questionnaires to universities in Shandong Province that participated in the competition. Results: 14 universities with nursing programmes participated in the competition, including eight public universities and six private universities. 220 questionnaires were distributed to nursing students at the participating universities and 218 were ultimately included, demonstrating an efficiency rate of 99.09%. Conclusions: The 2022 nursing track included the addition of a comprehensive written examination as a means of judging the competencies of nursing students in Shandong Province from a variety of aspects. Skills competitions are effective for improving the core competencies of nursing students and they will become an important means for nursing educators to reform education and improve the core competencies of nursing students in the future.

Association between beta-blocker utilization and heart failure mortality in the peritoneal dialysis population: a cohort study.

Background: The prognostic significance of beta(ß)-blocker therapy in patients at end-stage renal disease, specifically those receiving peritoneal dialysis (PD) and presenting with heart failure, remains inadequately elucidated due to limited research conducted thus far. Methods: A retrospective analysis was performed on a cohort comprising 608 patients receiving PD between September 2007 and March 2019, with a subsequent follow-up period extending until December 2020. Cox regression and propensity score matching weighted analysis was used to model adjusted hazard ratios for ß-blocker use with heart failure-related mortality. Competing risk analysis and subgroup analysis were carried out to further elucidate the correlation. Results: ß-blockers were prescribed for 56.1% of the peritoneal dialysis patients. Heart failure occurred in 43.4% of the total population and 15.5% of deaths were due to heart failure. The prescription of ß-blockers was associated with a 43% lower adjusted hazard ratio (HR) for heart failure death within the cohort (95% confidence interval [CI] = 0.36-0.89; P = 0.013). Even after accounting for competing risk events, patients in the group using ß-blockers demonstrated a significantly lower cumulative risk of heart failure-related mortality compared to those not using ß-blockers (P = 0.007). This protective effect of ß-blockers was also observed in subgroup analyses. Conversely, ß-blocker use had no statistically significant associations with all-cause mortality. Conclusion: The use of ß-blockers was associated with a reduced risk of heart failure-related mortality in the PD population. Future randomized clinical trials are warranted to confirm the beneficial effect of ß-blockers in the context of PD.

Novel Eu-dipeptide assemblies for a fluorescence sensing strategy to ultrasensitive determine trace sulfamethazine.

Self-assembled Eu-dipeptide (tryptophan-phenylalanine) microparticles with multi-emission fluorescence was prepared and modified with a single-stranded DNA corresponding to the sulfamethazine (SMZ) adapter (Eu-PMPs@cDNA). Aptamer-functionalized magnetic Fe3O4 (MNPs@aptamer) was used to specifically bind the target SMZ. Using Eu-PMPs@cDNA as fluorescent signal probe and MNPs@aptamer as catcher, a noncompetitive fluorescence sensing strategy was developed for determination of SMZ with good sensitivity, accuracy, selectivity, and stability. Under the optimized conditions, fluorescence increases linearly in the 0-20 ng/mL SMZ concentration range, and the detection limit is 0.014 ng/mL. The fluorescence sensing method was applied to analysis of water and fish muscle samples, and recoveries ranged from 81.78 to 119.46 % with relative standard deviations below 4.2 %. This study offered a reliable and sensitive fluorescence sensing strategy for SMZ determination in food samples, which owns great potential for wide-ranging application in harmful compounds assay by simply changing the type of aptamer and its complementary single-stranded DNA.

Mediating effect of psychological capital on the relationship between mental health literacy and coping styles among newly recruited nurses.

BACKGROUND: Newly recruited nurses face multiple sources of stress and their coping styles need to be focused on to ensure good mental health. This study aimed to examine the relationship among mental health literacy, psychological capital and coping styles in newly recruited nurses. METHODS: A cross-sectional study was conducted in August and September 2022. A total of 315 newly recruited nurses were recruited in a tertiary hospital in Henan Province, central China, employing the convenience sampling method. The self-reported questionnaires were sent through a QR code, including the Mental Health Literacy Scale for Healthcare Students, Psychological Capital Questionnaire, and Simplified Coping Style Questionnaire. Pearson correlation analysis was used to evaluate the relationships among the variables. Mediation analysis was performed to identify the mediating effect of psychological capital on the relationship between mental health literacy and coping styles. RESULTS: Positive coping showed a positive relationship with psychological capital and mental health literacy, while negative coping showed a negative relationship with psychological capital and mental health literacy. For positive coping, psychological capital was a partial mediator with an effect of 0.140, accounting for 62.8%. For negative coping, a full mediating effect was shown by psychological capital between mental health literacy and negative coping, with an indirect effect of -0.048. CONCLUSION: Psychological capital plays a partial and complete mediating role between mental health literacy and different coping styles among newly recruited nurses. Diversified training and personalized guidance in improving mental health literacy and increasing psychological capital simultaneously can be provided to newly recruited nurses continuously to adjust their coping styles.

Chromosomal mapping of a major genetic locus from Agropyron cristatum chromosome 6P that influences grain number and spikelet number in wheat.

KEY MESSAGE: A novel locus on Agropyron cristatum chromosome 6P that increases grain number and spikelet number was identified in wheat-A. cristatum derivatives and across 3 years. Agropyron cristatum (2n = 4x = 28, PPPP), which has the characteristics of high yield with multiple flowers and spikelets, is a promising gene donor for wheat high-yield improvement. Identifying the genetic loci and genes that regulate yield could elucidate the genetic variations in yield-related traits and provide novel gene sources and insights for high-yield wheat breeding. In this study, cytological analysis and molecular marker analysis revealed that del10a and del31a were wheat-A. cristatum chromosome 6P deletion lines. Notably, del10a carried a segment of the full 6PS and 6PL bin (1-13), while del31a carried a segment of the full 6PS and 6PL bin (1-8). The agronomic characterization and genetic population analysis confirmed that the 6PL bin (9-13) brought about an increase in grain number per spike (average increase of 10.43 grains) and spikelet number per spike (average increase of 3.67) over the three growing seasons. Furthermore, through resequencing, a multiple grain number locus was mapped to the physical interval of 593.03-713.89 Mb on chromosome 6P of A. cristatum Z559. The RNA-seq analysis revealed the expression of 537 genes in the del10a young spike tissue, with the annotation indicating that 16 of these genes were associated with grain number and spikelet number. Finally, a total of ten A. cristatum-specific molecular markers were developed for this interval. In summary, this study presents novel genetic material that is useful for high-yield wheat breeding initiatives to meet the challenge of global food security through enhanced agricultural production.

Machine learning model and nomogram to predict the risk of heart failure hospitalization in peritoneal dialysis patients.

INTRODUCTION: The study presented here aimed to establish a predictive model for heart failure (HF) and all-cause mortality in peritoneal dialysis (PD) patients with machine learning (ML) algorithm. METHODS: We retrospectively included 1006 patients who initiated PD from 2010 to 2016. XGBoost, random forest (RF), and AdaBoost were used to train models for assessing risk for 1-year and 5-year HF hospitalization and mortality. The performance was validated using fivefold cross-validation. The optimal ML algorithm was used to construct the models to predictive the risk of the HF and all-cause mortality. The prediction performance of ML methods and Cox regression was compared. RESULTS: Over a median follow-up of 49 months. Two hundred and ninety-eight patients developed HF required hospitalization; 199 patients died during the follow-up. The RF model (AUC = 0.853) was the best performing model for predicting HF, and the XGBoost model (AUC = 0.871) was the best model for predicting mortality. Baseline moderate or severe renal disease, systolic blood pressure (SBP), body mass index (BMI), age, Charlson Comorbidity Index (CCI) score were strongly associated with HF hospitalization, whereas age, CCI score, creatinine, age, high-density lipoprotein cholesterol (HDL-C), total cholesterol, baseline estimated glomerular filtration rate (eGFR) were the most significant predictors of mortality. For all the above endpoints, the ML models demonstrated better discrimination than Cox regression. CONCLUSIONS: We developed and validated a novel method to predict the risk factors of HF and all-cause mortality that integrates readily available clinical, laboratory, and electrocardiographic variables to predict the risk of HF among PD patients.

Construction of magnetic azo-linked porous polymer for highly-efficient enrichment and separation of phenolic endocrine disruptors from environmental water and fish.

Developing effective methods for highly sensitive detection of phenolic endocrine disruptors (EDCs) is especially urgent. Herein, a magnetic hydroxyl-functional porous organic polymer (M-FH-POP) was facilely synthesized by green diazo-couple reaction using basic fuchsin and hesperetin as monomer for the first time. M-FH-POP delivered superior adsorption performance for phenolic EDCs. The adsorption mechanism was hydrogen bonds, hydrophobic interaction and π-π interplay. With M-FH-POP as adsorbent, a magnetic solid phase extraction method was established for extracting trace phenolic EDCs (bisphenol A, 4-tert-butylphenol, bisphenol F and bisphenol B) in water and fish before ultra-high performance liquid chromatography tandem mass spectrometry analysis. The method displayed low detection limit (S/N = 3) of 0.05-0.15 ng mL-1 for water and 0.08-0.3 ng g-1 for fish. The spiked recoveries were 88.3 %-109.8 % with the relative standard deviations of 2.4 %-6.4 %. The method offers a new strategy for sensitive determination of phenolic EDCs in water and fish samples.

Integrating Network Pharmacology and Experimental Verification to Explore the Pharmacological Mechanisms of Cordycepin against Pulmonary Arterial Hypertension in Rats.

BACKGROUND: Pulmonary Arterial Hypertension (PAH) is a fatal disease with high morbidity and mortality. Cordycepin has anti-inflammatory, antioxidant and immune enhancing effects. However, the role of Cordycepin in the treatment of PAH and its mechanism is not clear. METHODS: The Cordycepin structure and PAH-related gene targets were obtained from public databases. The KEGG and GO enrichment analysis of common targets was performed in DAVID. PPI networks were also mapped using the STRING platform. AutoDock Vina, AutoDockTools, ChemBio3D and Pymol tools were selected for molecular docking of key targets. The therapeutic effects of Cordycepin on PAH were observed in Monocrotaline(MCT)-induced PAH rats and platelet-derived growth factor BB (PDGFBB)-induced rat pulmonary artery smooth muscle cells (PASMCs). The right ventricular systolic pressure (RVSP) was detected. HE staining, Western Blot, Scratch assay, EDU and TUNEL assays were used respectively. RESULTS: Through Network Pharmacology and molecular docking , the Cordycepin-PAH core genes were found to be TP53, AKT1, CASP3, BAX and BCL2L1. In MCT-induced PAH rats, the administration of Cordycepin significantly reduced RVSP, and inhibited pulmonary vascular remodeling. In PDGFBB-induced PASMCs, Cordycepin reduced the migration and proliferation of PASMCs and promoted apoptosis. After the Cordycepin treatment, the protein expressions of TP53, Cleaved CASP3 and BAX were significantly increased, while the protein expressions of p-AKT1 and BCL2L1 were significantly decreased in MCT-PAH rats and PDGFBB-induced PASMCs. CONCLUSION: This study identified that TP53, AKT1, CASP3, BAX, and BCL2L1 were the potential targets of Cordycepin against PAH by ameliorating pulmonary vascular remodeling, inhibiting the abnormal proliferation and migration of PASMCs and increasing apoptosis of PASMCs. which provided a new understanding of the pharmacological mechanisms of Cordycepin in the treatment of PAH.

Lrg1 silencing attenuates ischemia-reperfusion renal injury by regulating autophagy and apoptosis through the TGFß1- Smad1/5 signaling pathway.

BACKGROUND: Dysfunction in the processes of autophagy and apoptosis within renal tubular epithelial cells (RTEc) contributes to renal ischemia-reperfusion injury (IRI). However, the factors influencing this dysfunction remain unclear. Leucine-rich alpha-2-glycoprotein 1 (Lrg1) plays a role in the progression of diabetic nephropathy and kidney fibrosis by modulating the activin receptor-like kinase 1 (ALK1)-Smad1/5/8 and TGF-ß1/Smad3 pathways, respectively. Therefore, we aimed to investigate whether Lrg1 is involved in the pathological mechanisms of renal IRI and whether its effects are related to the dysregulation of autophagy and apoptosis in RTEc. METHODS: We conducted in vitro and in vivo experiments using CoCl2-induced hypoxic human kidney-2 (HK-2) cells and mice with renal IRI, respectively. Lrg1 was silenced using siRNA and lentiviral vectors in HK-2 cells and mouse kidneys. Rapamycin (Rapa) and methyladenine were applied to regulate autophagy in renal IRI models. RESULTS: Increased Lrg1 expression was observed in hypoxic HK-2 cells and in the kidneys of mice with renal IRI. Silencing of Lrg1 through siRNA and lentiviral approaches restored autophagy and suppressed apoptosis in CoCl2-induced hypoxic HK-2 cells and renal IRI models. Additionally, reduced Lrg1 expression alleviated kidney damage caused by renal IRI. The downregulation of Lrg1 expression restrained the TGFß-Smad1/5 signaling pathway in hypoxic-induced HK-2 cells and renal IRI by reducing ALK1 expression. Lastly, the enhancement of autophagy, achieved through Rapa treatment, provided protection against renal IRI in mice. CONCLUSIONS: Our findings suggest that Lrg1 silencing can be applied as a potential therapeutic target to inhibit the TGFß1-Smad1/5 pathway, thereby enhancing autophagy and decreasing apoptosis in patients with acute kidney injury.