The Efficacy of Machine Learning Models for Predicting the Prognosis of Heart Failure: A Systematic Review and Meta-Analysis.

INTRODUCTION: Heart failure (HF) is a major global public health concern. The application of machine learning (ML) to identify individuals at high risk and enable early intervention is a promising approach for improving HF prognosis. We aim to systematically evaluate the performance and value of ML models for predicting HF prognosis. METHODS: PubMed, Web of Science, Scopus, and Embase online databases were searched up to April 30, 2023, to identify studies on the use of ML models to predict HF prognosis. HF prognosis primarily encompasses readmission and mortality. The meta-analysis was conducted by MedCalc software. Subgroup analyses include grouping based on types of ML models, time intervals, sample sizes, the number of predictive variables, validation methods, whether to conduct hyperparameter optimization and calibration, data set partitioning methods. RESULTS: A total of 31 studies were included. The most common ML models were random forest, boosting, support vector machine, neural network. The area under the receiver operating characteristic curve (AUC) for predicting HF readmission was 0.675 (95% CI: 0.651-0.699, p < 0.001), and the AUC for predicting HF mortality was 0.790 (95% CI: 0.765-0.816, p < 0.001). Subgroup analyses revealed that models with the prediction time interval of 1 year, sample sizes ≥10,000, the number of predictive variables ≥100, external validation, hyperparameter tuning, calibration adjustment, and data set partitioning using 10-fold cross-validation exhibited favorable performance within their respective subgroups. CONCLUSION: The performance of ML models in predicting HF readmission is relatively poor, while its performance in predicting HF mortality is moderate. The quality of the relevant studies is generally low, it is essential to enhance the predictive capabilities of ML models through targeted improvements in practical applications.

Investigating the Mechanism of Chinese Medicine Formula AACO Against Chronic Heart Failure by Network Pharmacology Analysis and Experimental Validation.

Background: A traditional Chinese medicine (TCM) formula, containing Astragalus membranaceus (Fisch.) Bunge, Aconitum wilsonii Stapf ex Veitch, Curcuma longa L., and Radix ophiopogonis (AACO), has therapeutic value for the treatment of chronic heart failure (CHF). Objective: This study intends to explore the pharmacological mechanism underlying the activity of the AACO formula against CHF. Materials and Methods: Using the TCM Systems Pharmacology database and Bioinformatics Analysis Tool for Molecular Mechanism of TCM, the active ingredients contained in the herbs of the AACO formula were screened. Meanwhile, the target genes related to these active ingredients were identified and genes correlated with CHF were screened. Protein-protein interaction networks were built to elucidate the relationships between the AACO formula and CHF. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway enrichment analysis were carried out using the DAVID database. A "drug-component-target-disease" network was constructed with Cytoscape 3.7.0. The therapeutic effect of the AACO formula was proven by hemodynamic study, echocardiography evaluation, and histological analysis in transverse aortic constriction-induced CHF mice and was validated in vitro. Results: A total of 105 active ingredients and 1026 related targets were screened and identified, and 240 related targets overlapping with CHF were selected. According to GO analysis, the enriched genes participated in gene expression and cardiac contraction regulation by Ca2+ regulation. From KEGG analysis, the calcium axis was identified as one of the main mechanisms through which the AACO formula exerts an anti-CHF effect. AACO was validated to significantly improve cardiac diastolic and systolic functions in vivo via an increase in the rate of Ca2+ reuptake of the myocardial sarcoplasmic reticulum and improved myocardial contractility in vitro. Conclusions: Network pharmacology is a convenient method to study the complex pharmacological mechanisms of TCM. The calcium axis likely participates in the anti-CHF mechanism of AACO.

[Applicability of H2FPEF and HFA-PEFF Scores in Chinese Patients Suffering From Heart Failure With Preserved Ejection Fraction and Heart Failure With Preserved Ejection Fraction Complicated With Atrial Fibrillation].

Objective To analyze the diagnostic values of H2FPEF and HFA-PEFF scores for heart failure with preserved ejection fraction (HFpEF) and HFpEF complicated with atrial fibrillation (HFpEF-AF) in Chinese patients and explore the related factors. Methods A cross-sectional study was conducted.A total of 835 consecutive HFpEF patients treated in the Department of Geriatric Cardiology,the First Hospital of Lanzhou University from 2009 to 2020 were selected and assigned to a HFpEF-AF group (n=267) and a HFpEF group (n=568) according to the presence of AF or not.HFA-PEFF and H2FPEF scores were used for retrospective diagnosis and the diagnostic consistency of the two scores was assessed.One hundred and thirty-six healthy volunteers with age and sex matching the patients during the same period were selected as healthy controls.The receiver operating characteristic (ROC) curves were established for H2FPEF and HFA-PEFF scores in diagnosing HFpEF-AF and HFpEF,on the basis of which the diagnostic performance of the two scores was evaluated. Results There was no difference in the HFA-PEFF score between the two groups (P=0.070).However,the HFpEF-AF group had higher mean H2FPEF score and higher proportion of patients with the score no less than 6 than the HFpEF group (P<0.001).According to the ROC curves,HFA-PEFF and H2FPEF scores demonstrated high performance in diagnosing all HFpEF patients,with the area under the curve (AUC) of 0.892 and 0.922 and the optimal cut-offs of 4 and 4,respectively.The HFA-PEFF score showed similar performance in diagnosing HFpEF and HFpEF-AF,with the AUC of 0.899 and 0.911,respectively.The H2FPEF score had higher performance in diagnosing HFpEF-AF (AUC of approximately 1.000) and low performance in diagnosing HFpEF (AUC of 0.885). Conclusions The HFA-PEFF score is applicable in the diagnosis of both HFpEF and HFpEF-AF.The H2FPEF score may underestimate HFpEF in Chinese patients,and its applicability in the Chinese patients with HFpEF alone remains to be investigated.

Deriving particulate backscattering coefficient at 400†nm from small-scale optically shallow waters using Landsat-8 data: a case study at Luhuitou Peninsula, Sanya.

The particulate backscattering coefficient (bbp) plays an important role in the growth of coral reefs by influencing the light field conditions. Small-scale optically shallow waters are commonly found in coastal fringing reefs, making it challenging to monitor the spatial and temporal patterns accurately using Aqua satellites with a low spatial resolution. In this study, six existing optimization-based algorithms for deriving bbp at 400 nm (bbp(400)) were evaluated with three simulated Landsat-8 (spatial resolution = 30 m) data sets and in situ data from the Luhuitou Peninsula, Sanya. The comparison results indicated that the HOPE (hyperspectral optimization process exemplar) (Fix-H-error or Fix-H-error-free) algorithm which sets an input value of the water depth alone outperformed other algorithms. However, the estimated bbp(400) from all the algorithms tended to be either overestimated and underestimated due to the improper the spectral shape value of the backscattering coefficient. The HOPE (Fix-H-error) algorithm estimated-bbp(400) from in situ reflectance also had a good correlation with the in situ total suspended particle concentrations data derived-bbp(400), with a correlation coefficient of 0.83. Therefore, the HOPE (Fix-H-error) algorithm was selected to estimate the bbp(400) from satellite-based Landsat-8 data of the Luhuitou Peninsula, Sanya. Time-series (2014-2021) results from these Landsat-8 images reveal the seasonal variation of bbp(400). The bbp(400) was low from May to September every year. From October to December or January, bbp(400) had an increasing trend, and then it decreased until May. Spatial analysis indicated that bbp(400) decreased with increasing water depth. The spatial and temporal patterns of bbp(400) were consistent with in situ observations reported in the literature. This study preliminarily showed the efficiency of an optimization-based algorithm in deriving bbp(400) in small-scale optically shallow water region using Landsat-8 data.

Fine mapping and candidate gene analysis of a novel fertility restorer gene for C-type cytoplasmic male sterility in maize (Zea mays L.).

KEY MESSAGE: A novel strong fertility restorer gene Rf12 for C-type cytoplasmic male sterility of maize was finely mapped on chromosome 2. Its best candidate gene Zm00001d007531 is predicted to encode a p-type PPR protein. The lack of strong restorer gene of maize CMS-C greatly limits its application in hybrid seed production. Therefore, the cloning of maize CMS-C novel strong restorer genes is necessary. In this study, a strong restorer line ZH91 for maize CMS-C was found, and the novel restorer gene named Rf12 in ZH91 had been mapped in a 146 kb physical interval on maize chromosome 2. Using the third-generation high-throughput sequencing (ONT), the whole genome sequence of ZH91 was got, and with integrating the annotation information of the reference genome B73_RefGen_v4 and B73_RefGen_v5, four candidate genes were predicted in ZH91 within the mapping region. Then using gene cloning, stranded specific RNA sequencing, qRT-PCR analysis and subcellular localization, Zm00001d007531 was identified as the most likely candidate gene of Rf12. Zm00001d007531 encodes a p-type PPR protein with 19 PPR motifs and targets mitochondria and chloroplast. Stranded specific RNA sequencing and qRT-PCR results both show that the expression of Zm00001d007531 between anthers of near-isogenic lines C478Rf12Rf12 and C478rf12rf12 was significantly difference in pollen mother cell stage. And the result of sequence alignment for Zm00001d007531 gene in 60 materials showed that there are twelve SNPs in CDS region of Zm00001d007531 were tightly linked to the fertility. The finding of a novel strong restorer germplasm resource ZH91 for maize CMS-C can greatly promote the application of maize CMS-C line in maize hybrid seeds production, and the identification of candidate gene Zm00001d007531 can accelerate the backcrossing process of maize CMS-C strong restorer gene Rf12 to some extent.

Circulating interleukins and risk of colorectal cancer: a Mendelian randomization study.

BACKGROUND: Recent studies have suggested a potential causal association between Interleukins (ILs) and Colorectal Cancer (CRC), and thus, it is important to examine the causal relationship between them using a Mendelian randomization (MR) approach. METHODS: The instrumental variables were extracted for IL-1ra, IL-6, IL-6ra, IL-8, IL-16, IL-18, IL-27 from genome-wide association studies of European ancestry. Summary statistics of CRC were also retrieved. An inverse variance-weighted MR approach was implemented as the primary method to compute overall effects from multiple instruments. Additional MR approaches and sensitivity and heterogeneity pleiotropy analyses were also conducted respectively. RESULTS: Our analysis suggested a causal effect between an increase of IL-8 and a reduced risk of CRC (odds ratio 0.65; 95% confidence interval, 0.43-0.98; p = 0.041) and did not provide evidence for causal effects of IL-1ra, IL-6, IL-6ra, IL-16, IL-18, IL-27. Sensitivity analyses suggested the robustness of MR results and that they were unlikely to be affected by unbalanced pleiotropy or significant heterogeneity. CONCLUSIONS: This study investigated the role of ILs in the development of CRC and we found a causal effect between an increase of IL-8 and a reduced risk of CRC but not found evidence for causal effects of IL-1ra, IL-6, IL-6ra, IL-16, IL-18, IL-27. Sensitivity analyses suggested the robustness of MR results and that they were unlikely to be affected by unbalanced pleiotropy or significant heterogeneity.

Neural optimization machine: a neural network approach for optimization and its application in additive manufacturing with physics-guided learning.

Neural networks (NNs) are increasingly used in design to construct the objective functions and constraints, which leads to the needs of optimization of NN models with respect to design variables. A Neural Optimization Machine (NOM) is proposed for constrained single/multi-objective optimization by appropriately designing the NN architecture, activation function and loss function. The NN's built-in backpropagation algorithm conducts the optimization and is seamlessly integrated with the additive manufacturing (AM) process-property model. The NOM is tested using several numerical optimization problems. It is shown that the increase in the dimension of design variables does not increase the computational cost significantly. Next, a brief review of the physics-guided machine learning model for fatigue performance prediction of AM components is given. Finally, the NOM is applied to design processing parameters in AM to optimize the mechanical fatigue properties through the physics-guided NN under uncertainties. One novel contribution of the proposed methodology is that the constrained process optimization is integrated with physics/knowledge and the data-driven AM process-property model. Thus, a physics-compatible process design can be achieved. Another significant benefit is that the training and optimization are achieved in a unified NN model, and no separate process optimization is needed. This article is part of the theme issue 'Physics-informed machine learning and its structural integrity applications (Part 1)'.

Mitochondria-Related Gene MAOB is a Key Biomarker of Osteoarthritis and Inhibition of Its Expression Reduces LPS-induced Chondrocyte Damage.

The mitochondria are an important organelle in cells responsible for producing energy, and its abnormal function is closely related to the occurrence and development of osteoarthritis. Finding key genes associated with mitochondrial dysfunction in osteoarthritis can provide new ideas for the study of its pathogenesis. Firstly, 371 differential expressed genes (DEGs) were obtained through bioinformatics analysis of the GSE12021 and GSE55235 datasets in the GEO database, and 24 mitochondria-related DEGs (Mito-DEGs) were obtained by crossing differential genes with mitochondrial related genes. Next, KEGG and GO analysis of Mito-DEGs showed that upregulated Mito-DEGs were mainly enriched in small molecule catabolic process and tryptophan metabolism, while downregulated Mito-DEGs were mainly enriched in acetyl-CoA metabolic process and fatty acid biosynthesis. Furthermore, the key genes ME2 and MAOB were obtained through protein-protein interaction network analysis and lasso cox analysis of the 24 Mito-DEGs. In addition, the comparison results of immune cell scores showed differences between T cells CD4 memory resting, T cells regulatory (Tregs), Mast cells resting, and Mast cells activated in the OA group and the control group. More importantly, the potential regulatory mechanisms of key genes were studied through GSEA analysis and their correlation with immune infiltrating cells, immune checkpoints, m6A, and ferroptosis. Finally, in LPS-induced C28/I2 cells, silencing MAOB reduced inflammation injury and inhibited mitochondrial damage. Our research findings suggest that MAOB may hold potential as a target for the diagnosis and treatment of osteoarthritis.

[Cardiac Structural and Functional Features in Patients With Type 2 Diabetes Mellitus and Heart Failure With Preserved Ejection Fraction:A Study Based on Propensity Score Matching].

Objective To investigate the cardiac structural and functional characteristics in the patients with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes mellitus (T2DM),and predict the factors influencing the characteristics. Methods A total of 783 HFpEF patients diagnosed in the Department of Geriatric Cardiology,the First Hospital of Lanzhou University from April 2009 to December 2020 were enrolled in this study.Echocardiography and tissue Doppler technique were employed to evaluate cardiac structure and function.According to the occurrence of T2DM,the patients were assigned into a HFpEF+T2DM group (n=332) and a HFpEF group (n=451).Propensity score matching (PSM)(in a 1∶1 ratio) was adopted to minimize confounding effect.According to urinary albumin excretion rate (UAER),the HFpEF+T2DM group was further divided into three subgroups with UAER<20 µg/min,of 20-200 µg/min,and>200 µg/min,respectively.The comorbidities,symptoms and signs,and cardiac structure and function were compared among the groups to clarify the features of diabetes related HFpEF.Multivariate linear regression was conducted to probe the relationship of systolic blood pressure,blood glucose,glycosylated hemoglobin,and UARE with cardiac structural and functional impairment. Results The HFpEF+T2DM group had higher prevalence of hypertension (P=0.001) and coronary heart disease (P=0.036),younger age (P=0.020),and larger body mass index (P=0.005) than the HFpEF group,with the median diabetic course of 10 (3,17) years.After PSM,the prevalence of hypertension and coronary heart disease,body mass index,and age had no significant differences between the two groups(all P>0.05).In addition,the HFpEF+T2DM group had higher interventricular septal thickness (P=0.015),left ventricular posterior wall thickness (P=0.040),and left ventricular mass (P=0.012) and lower early diastole velocity of mitral annular septum (P=0.030) and lateral wall (P=0.011) than the HFpEF group.Compared with the HFpEF group,the HFpEF+T2DM group showed increased ratio of early diastolic mitral filling velocity to early diastolic mitral annular velocity (E/e') (P=0.036).Glycosylated hemoglobin was correlated with left ventricular mass (P=0.011),and the natural logarithm of UAER with interventricular septal thickness (P=0.004),left ventricular posterior wall thickness (P=0.006),left ventricular mass (P<0.001),and E/e' ratio (P=0.049). Conclusion The patients with both T2DM and HFpEF have thicker left ventricular wall,larger left ventricular mass,more advanced left ventricular remodeling,severer impaired left ventricular diastolic function,and higher left ventricular filling pressure than the HFpEF patients without T2DM.Elevated blood glucose and diabetic microvascular diseases might play a role in the development of the detrimental structural and functional changes of the heart.

Interleukin-6 absence triggers intestinal microbiota dysbiosis and mucosal immunity in mice.

Interleukin-6 (IL-6) in mucosal immune cells is involved in post-injury intestinal regeneration, inflammation responses, and gastric homeostasis. However, the interaction between IL-6 and the dynamic balance of gut microbiota (GM) remains unexplored. Intestinal pathology was assessed by hematoxylin and eosin and periodic acid-Schiff staining in wild-type (WT) and IL-6 gene knockout (KO) C57BL/6J mice. GM profiles were established via high-throughput sequencing of the fecal bacterial 16S rRNA gene. Intestinal α- and ß-defensins were measured by quantitative real-time PCR; further, flow cytometry was performed to analyze isolated intraepithelial lymphocytes (IELs). Compared with the WT, IL-6 KO did not obviously change gut structures, but significantly reduced GM diversity, resulting in reduced metabolic pathways with decreased gram-positive but elevated gram-negative bacteria. More taxa alterations included differences at the phyla (e.g., increased Verrucomicrobia and decreased Firmicutes) and genera (e.g., increased Akkermansia and decreased Lactobacillus) levels. Absence of IL-6 also significantly increased intestinal expression of defensins α3 and α4 (Defa3 and Defa4) and the percentage of natural TCRγδ+ IELs, providing a molecular basis for triggering mucosal immune response. Therefore, IL-6 loss remodels GM composition and alters IEL maintenance, identifying IL-6 as a crucial cytokine for GM dysbiosis and mucosal immunity.

GRK5 Controls SAP97-Dependent Cardiotoxic ß1 Adrenergic Receptor-CaMKII Signaling in Heart Failure.

RATIONALE: Cardiotoxic ß1 adrenergic receptor (ß1AR)-CaMKII (calmodulin-dependent kinase II) signaling is a major and critical feature associated with development of heart failure. SAP97 (synapse-associated protein 97) is a multifunctional scaffold protein that binds directly to the C-terminus of ß1AR and organizes a receptor signalosome. OBJECTIVE: We aim to elucidate the dynamics of ß1AR-SAP97 signalosome and its potential role in chronic cardiotoxic ß1AR-CaMKII signaling that contributes to development of heart failure. METHODS AND RESULTS: The integrity of cardiac ß1AR-SAP97 complex was examined in heart failure. Cardiac-specific deletion of SAP97 was developed to examine ß1AR signaling in aging mice, after chronic adrenergic stimulation, and in pressure overload hypertrophic heart failure. We show that the ß1AR-SAP97 signaling complex is reduced in heart failure. Cardiac-specific deletion of SAP97 yields an aging-dependent cardiomyopathy and exacerbates cardiac dysfunction induced by chronic adrenergic stimulation and pressure overload, which are associated with elevated CaMKII activity. Loss of SAP97 promotes PKA (protein kinase A)-dependent association of ß1AR with arrestin2 and CaMKII and turns on an Epac (exchange protein directly activated by cAMP)-dependent activation of CaMKII, which drives detrimental functional and structural remodeling in myocardium. Moreover, we have identified that GRK5 (G-protein receptor kinase-5) is necessary to promote agonist-induced dissociation of SAP97 from ß1AR. Cardiac deletion of GRK5 prevents adrenergic-induced dissociation of ß1AR-SAP97 complex and increases in CaMKII activity in hearts. CONCLUSIONS: These data reveal a critical role of SAP97 in maintaining the integrity of cardiac ß1AR signaling and a detrimental cardiac GRK5-CaMKII axis that can be potentially targeted in heart failure therapy. Graphical Abstract: A graphical abstract is available for this article.

Genome sequencing sheds light on the contribution of structural variants to Brassica oleracea diversification.

BACKGROUND: Brassica oleracea includes several morphologically diverse, economically important vegetable crops, such as the cauliflower and cabbage. However, genetic variants, especially large structural variants (SVs), that underlie the extreme morphological diversity of B. oleracea remain largely unexplored. RESULTS: Here we present high-quality chromosome-scale genome assemblies for two B. oleracea morphotypes, cauliflower and cabbage. Direct comparison of these two assemblies identifies ~ 120 K high-confidence SVs. Population analysis of 271 B. oleracea accessions using these SVs clearly separates different morphotypes, suggesting the association of SVs with B. oleracea intraspecific divergence. Genes affected by SVs selected between cauliflower and cabbage are enriched with functions related to response to stress and stimulus and meristem and flower development. Furthermore, genes affected by selected SVs and involved in the switch from vegetative to generative growth that defines curd initiation, inflorescence meristem proliferation for curd formation, maintenance and enlargement, are identified, providing insights into the regulatory network of curd development. CONCLUSIONS: This study reveals the important roles of SVs in diversification of different morphotypes of B. oleracea, and the newly assembled genomes and the SVs provide rich resources for future research and breeding.

Comparative genomic analysis of the tricarboxylic acid cycle members in four Solanaceae vegetable crops and expression pattern analysis in Solanum tuberosum.

BACKGROUND: The tricarboxylic acid (TCA) cycle is crucial for energy supply in animal, plant, and microbial cells. It is not only the main pathway of carbohydrate catabolism but also the final pathway of lipid and protein catabolism. Some TCA genes have been found to play important roles in the growth and development of tomato and potato, but no comprehensive study of TCA cycle genes in Solanaceae crops has been reported. RESULTS: In this study, we analyzed TCA cycle genes in four important Solanaceae vegetable crops (potato (Solanum tuberosum), tomato (Solanum lycopersicum), eggplant (Solanum melongena), and pepper (Capsicum annuum)) based on comparative genomics. The four Solanaceae crops had a total of 180 TCA cycle genes: 43 in potato, 44 in tomato, 40 in eggplant, and 53 in pepper. Phylogenetic analysis, collinearity analysis, and tissue expression patterns revealed the conservation of and differences in TCA cycle genes between the four Solanaceae crops and found that there were unique subgroup members in Solanaceae crops that were independent of Arabidopsis genes. The expression analysis of potato TCA cycle genes showed that (1) they were widely expressed in various tissues, and some transcripts like Soltu.DM.01G003320.1(SCoAL) and Soltu.DM.04G021520.1 (SDH) mainly accumulate in vegetative organs, and some transcripts such as Soltu.DM.12G005620.3 (SDH) and Soltu.DM.02G007400.4 (MDH) are preferentially expressed in reproductive organs; (2) several transcripts can be significantly induced by hormones, such as Soltu.DM.08G023870.2 (IDH) and Soltu.DM.06G029290.1 (SDH) under ABA treatment, and Soltu.DM.07G021850.2 (CSY) and Soltu.DM.09G026740.1 (MDH) under BAP treatment, and Soltu.DM.02G000940.1 (IDH) and Soltu.DM.01G031350.4 (MDH) under GA treatment; (3) Soltu.DM.11G024650.1 (SDH) can be upregulated by the three disease resistance inducers including Phytophthora infestans, acibenzolar-S-methyl (BTH), and DL-ß-amino-n-butyric acid (BABA); and (4) the levels of Soltu.DM.01G045790.1 (MDH), Soltu.DM.01G028520.3 (CSY), and Soltu.DM.12G028700.1 (CSY) can be activated by both NaCl and mannitol. The subcellular localization results of three potato citrate synthases showed that Soltu.DM.01G028520.3 was localized in mitochondria, while Soltu.DM.12G028700.1 and Soltu.DM.07G021850.1 were localized in the cytoplasm. CONCLUSIONS: This study provides a scientific foundation for the comprehensive understanding and functional studies of TCA cycle genes in Solanaceae crops and reveals their potential roles in potato growth, development, and stress response.

Deficiency of platelet adhesion molecule CD226 causes megakaryocyte development and platelet hyperactivity.

This study used constitutive CD226 gene knockout (KO) mice as a model to investigate the functions and mechanisms of CD226 in megakaryocyte (MK) maturation and platelet activation. Although CD226 deficiency did not cause MK polyploidization or platelet granule abnormalities, increased MK counts were detected in the femora bone marrow (BM) and spleen of CD226 KO mice. Particularly, CD226 KO mice have a more extensive membrane system in MKs and platelets than wild-type (WT) mice. We also demonstrated that CD226 KO mice displayed increased platelet counts, shortened bleeding time, and enhanced platelet aggregation. CD226 KO platelets had an increased mature platelet ratio compared to the control platelets. In addition, the observed reduction in bleeding time may be due to decreased nitric oxide (NO) production in the platelets. Platelet-specific CD226-deficient mice showed similar increased MK counts, shortened bleeding time, enhanced platelet aggregation, and decreased NO production in platelets. Furthermore, we performed middle cerebral artery occlusion-reperfusion surgery on WT and CD226 KO mice to explore the potential effect of CD226 on acute ischemia-reperfusion injury; the results revealed that CD226 deficiency led to significantly increased infarct area. Thus, CD226 is a promising candidate for the treatment of thrombotic disorders.

Total White Blood Cell Count Mediated the Association Between Increased Arterial Stiffness and Risk of Type 2 Diabetes Mellitus in Chinese Adults.

OBJECTIVE: Type 2 diabetes mellitus (T2DM) is known to be related to increased arterial stiffness. However, little is known about the risk of T2DM due to accelerated arterial stiffness and the underlying mechanism involved. We aimed to examine arterial stiffness, as determined by brachial-ankle pulse wave velocity (baPWV), in relation to T2DM among a community-based population and whether the association was mediated by white blood cell (WBC) counts. Approach and results: A total of 1036 Chinese adults aged 64.3 years with complete data were qualified in the present study. The dose-response association between baPWV levels, WBC counts, and risk of T2DM were explored using generalized linear models or multivariate logistic regression models. A mediation analysis was conducted to investigate the role of WBC counts on the association between baPWV and T2DM. After multivariate adjustments, we observed a dose-responsive relationship between increased baPWV and elevated risk of T2DM: comparing extreme tertiles of baPWV, the adjusted odds ratio for T2DM risk was 2.29 (95% CI, 1.32-3.98; P for trend =0.005). In addition, significant dose-dependent relationships were found across baPWV tertiles with increasing total or differential WBC counts, which in turn, were positively related to higher risk of T2DM (all P for trend <0.05). Mediation analyses indicated that total WBC count mediated 4.5% of the association between increased baPWV and elevated T2DM risk. CONCLUSIONS: Increased arterial stiffness might increase T2DM risk among middle-aged and older Chinese adults, which was partially mediated by total WBC count.

Glucose Homeostasis Is Dysregulated in Ducks Infected with Duck Hepatitis B Virus.

INTRODUCTION: The association between hepatitis B virus (HBV) infection and the development of diabetes remains controversial. This study examined the effect of HBV infection on glucose homeostasis using a duck HBV (DHBV) model. METHODS: Plasma DHBV DNA was detected by quantitative polymerase chain reaction (PCR). Tissue infection of DHBV was determined by detecting DHBV covalently closed circular DNA (cccDNA) with a method of rolling circle amplification combined with cross-gap PCR, and verified by fluorescence in situ hybridization assay. An intravenous injection glucose tolerance test (GTT) was used to analyze the effect of DHBV infection on glucose tolerance. RESULTS: Of the finally included 97 domestic ducks, 53 (54.6%) were congenitally infected by DHBV. The positive rate of DHBV cccDNA in the liver, kidney, pancreas, and skeletal muscle of the infected ducks was 100, 75.5, 67.9, and 47.2%, respectively. The DHBV-infected ducks had higher blood glucose levels at 15 and 30 min post-load glucose (p < 0.01 and p < 0.001, respectively) in the GTT, much more individuals with greater glucose area under curve (p < 0.01), and a 57% impaired glucose tolerance (IGT) rate, as compared with noninfected controls. In addition, the subgroups of the infected ducks with DHBV cccDNA positive in skeletal muscle maintained the higher blood glucose level up to 2 h post-load glucose during the GTT and had a 76% IGT rate. CONCLUSION: These results suggest that DHBV intrahepatic and extrahepatic infection impairs glucose tolerance, and thus evidence the association of DHBV infection with the dysregulation of glucose metabolism.

A New Method to Bound the Integrity Risk for Residual-Based ARAIM.

This paper develops a tight integrity risk bound for Residual-Based (RB) Advanced Receiver Autonomous Integrity Monitoring (ARAIM). ARAIM measurement models include nominal biases accounting for unknown but bounded errors, and faults of unbounded magnitude. In RB methods, upper bounding the integrity risk requires that one finds the worst-case directions of both the multi-satellite fault vector and of the all-in-view nominal bias vector. Previous methods only account for the worst-case fault direction assuming zero nominal bias. To address this issue, in this paper, we derive a new bounding method in parity space. The method establishes a direct relationship between mean estimation error and RB test statistic non-centrality parameter, which accounts for both faults and nominal errors. ARAIM performance is evaluated to quantify the improvement provided by the proposed method over previous approaches.

A label-free protamine-assisted colorimetric sensor for highly sensitive detection of S1 nuclease activity.

A label-free, sensitive, simple and general colorimetric method was reported to monitor S1 nuclease activity based on protamine-assisted aggregation of gold nanoparticles (AuNPs). Here, protamine, a linear polycation, was used as a medium for causing the aggregation of negatively charged AuNPs by electrostatic interactions, resulting in changes in the surface plasmon resonance (SPR) absorption bands as well as the color of AuNPs. Here, the AuNPs were employed as an indicator to detect the level of S1 nuclease in the solution. Substrate DNA could be cleaved into small fragments by the specific S1 nuclease, which effectively prevents the electrostatic interaction between DNA and protamine and thus facilitates the interaction between protamine and AuNPs. The quantitative analysis of S1 nuclease activity can be performed via directly measuring the changes in the absorption spectra of the AuNPs. Using S1 nuclease as a model analyte, the limit of detection was estimated to be 1.0 × 10-4 U mL-1. Furthermore, the proposed concept has been successfully applied in S1 nuclease analysis of serum samples, offering an ultrasensitive strategy for the speedy detection of the nuclease activity and providing a new avenue for high-throughput screening of nucleases and drugs with potential inhibition properties.

LAIR-1 overexpression inhibits epithelial-mesenchymal transition in osteosarcoma via GLUT1-related energy metabolism.

BACKGROUND: Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a collagen receptor belonging to the immunoglobulin superfamily. Although previous studies have evaluated the biological role of LAIR in solid tumors, the precise mechanisms underlying the functions of LAIR-1 as a regulator of tumor biological functions remain unclear. METHODS: LAIR-1 expression was evaluated by immunohistochemical analysis using an osteosarcoma (OS) tissue microarray. Wound healing and transwell migration assays were performed to evaluate tumor cell migration. Quantitative real-time polymerase chain reaction (qPCR) and western blotting were conducted to detect the expression of epithelial-mesenchymal transition (EMT)-related molecules. RNA-sequencing (RNA-seq) was conducted to evaluate the mRNA expression profiles after overexpressing LAIR-1 in OS cells. Glucose transporter (Glut)1 expression in OS cells was evaluated by western blotting. RESULTS: LAIR-1 expression was significantly different between the T1 and T2 stages of OS tumors, and it inhibited OS cell migration. LAIR-1 expression was inversely correlated with the expression of Twist1, an EMT-associated transcription factor, via the Forkhead box O1 signal transduction pathway. Furthermore, RNA-seq and qPCR demonstrated that the expression of EMT energy metabolism-related molecules was significantly reduced after LAIR-1 overexpression. CONCLUSIONS: LAIR-1 overexpression decreased the expression of Glut1 and inhibited the expression of EMT-related molecules in OS cells. These findings provide new insights into the molecular mechanism underlying OS progression.

Identification and characterization of the TCA cycle genes in maize.

BACKGROUND: The tricarboxylic acid (TCA) cycle is crucial for cellular energy metabolism and carbon skeleton supply. However, the detailed functions of the maize TCA cycle genes remain unclear. RESULTS: In this study, 91 TCA genes were identified in maize by a homology search, and they were distributed on 10 chromosomes and 1 contig. Phylogenetic results showed that almost all maize TCA genes could be classified into eight major clades according to their enzyme families. Sequence alignment revealed that several genes in the same subunit shared high protein sequence similarity. The results of cis-acting element analysis suggested that several TCA genes might be involved in signal transduction and plant growth. Expression profile analysis showed that many maize TCA cycle genes were expressed in specific tissues, and replicate genes always shared similar expression patterns. Moreover, qPCR analysis revealed that some TCA genes were highly expressed in the anthers at the microspore meiosis phase. In addition, we predicted the potential interaction networks among the maize TCA genes. Next, we cloned five TCA genes located on different TCA enzyme complexes, Zm00001d008244 (isocitrate dehydrogenase, IDH), Zm00001d017258 (succinyl-CoA synthetase, SCoAL), Zm00001d025258 (α-ketoglutarate dehydrogenase, αKGDH), Zm00001d027558 (aconitase, ACO) and Zm00001d044042 (malate dehydrogenase, MDH). Confocal observation showed that their protein products were mainly localized to the mitochondria; however, Zm00001d025258 and Zm00001d027558 were also distributed in the nucleus, and Zm00001d017258 and Zm00001d044042 were also located in other unknown positions in the cytoplasm. Through the bimolecular fluorescent complimentary (BiFC) method, it was determined that Zm00001d027558 and Zm00001d044042 could form homologous dimers, and both homologous dimers were mainly distributed in the mitochondria. However, no heterodimers were detected between these five genes. Finally, Arabidopsis lines overexpressing the above five genes were constructed, and those transgenic lines exhibited altered primary root length, salt tolerance, and fertility. CONCLUSION: Sequence compositions, duplication patterns, phylogenetic relationships, cis-elements, expression patterns, and interaction networks were investigated for all maize TCA cycle genes. Five maize TCA genes were overexpressed in Arabidopsis, and they could alter primary root length, salt tolerance, and fertility. In conclusion, our findings may help to reveal the molecular function of the TCA genes in maize.