Pathological characteristics of SRY-negative 38,XX-DSD pigs: A family case report.

Disorders of sex development (DSD) are congenital conditions characterized by atypical development of chromosomes, gonads, or anatomical sex. XX-DSD pigs disrupt the production of high-quality breeding pigs and impede the advancement of the pig industry. However, the etiology of XX-DSD pigs remains unclear. Systematic reports on the genetic and pathological characteristics of prepubescent XX-DSD pigs in familial contexts are sparse. This study aimed to investigate the genetic and pathological features of one-month-old XX-DSD pigs within a familial context and to provide phenotypic information to elucidate the pathogenic mechanisms of XX-DSD pigs. The findings revealed that inbreeding within the XX-DSD family may contribute to the pathogenesis of XX-DSD pigs. All XX-DSD pigs in the family had a chromosomal sex of female and were male pseudohermaphrodites. The degree of masculinization of the reproductive organs varied among XX-DSD pigs, demonstrating phenotypic heterogeneity. HE staining showed that the testes of prepubescent XX-DSD pigs contained vesicles in the seminiferous tubules, with or without vestigial germ cells. Ultrastructural analyses indicated that sertoli cells, leydig cells and germ cells in the testes of XX-DSD pigs exhibited pathological damage, confirming impaired testicular function. Immunofluorescence staining revealed high expression of SRY-box transcription factor 9 (SOX9) in XX-DSD pig testicular tissues, while forkhead box L2 (FOXL2) was minimally expressed. Disordered secretion of reproductive hormones in prepubescent XX-DSD pigs indicated abnormal hypothalamic-pituitary-gonadal axis (HPGA) function. This study elucidates the genetic and pathological characteristics of prepubescent XX-DSD pigs in familial case, providing valuable insights for further exploration of the pathogenic mechanisms underlying XX-DSD.

A dual RNA-seq analyses revealed dynamic arms race during the invasion of walnut by Colletotrichum gloeosporioides.

BACKGROUND: Walnut anthracnose caused by Colletotrichum gloeosporioides seriously endangers the yield and quality of walnut, and has now become a catastrophic disease in the walnut industry. Therefore, understanding both pathogen invasion mechanisms and host response processes is crucial to defense against C. gloeosporioides infection. RESULTS: Here, we investigated the mechanisms of interaction between walnut fruits (anthracnose-resistant F26 fruit bracts and anthracnose-susceptible F423 fruit bracts) and C. gloeosporioides at three infection time points (24hpi, 48hpi, and 72hpi) using a high-resolution time series dual transcriptomic analysis, characterizing the arms race between walnut and C. gloeosporioides. A total of 20,780 and 6670 differentially expressed genes (DEGs) were identified in walnut and C. gloeosporioides against 24hpi, respectively. Generous DEGs in walnut exhibited opposite expression patterns between F26 and F423, which indicated that different resistant materials exhibited different transcriptional responses to C. gloeosporioides during the infection process. KEGG functional enrichment analysis indicated that F26 displayed a broader response to C. gloeosporioides than F423. Meanwhile, the functional analysis of the C. gloeosporioides transcriptome was conducted and found that PHI, SignalP, CAZy, TCDB genes, the Fungal Zn (2)-Cys (6) binuclear cluster domain (PF00172.19) and the Cytochrome P450 (PF00067.23) were largely prominent in F26 fruit. These results suggested that C. gloeosporioides secreted some type of effector proteins in walnut fruit and appeared a different behavior based on the developmental stage of the walnut. CONCLUSIONS: Our present results shed light on the arms race process by which C. gloeosporioides attacked host and walnut against pathogen infection, laying the foundation for the green prevention of walnut anthracnose.

SARS-CoV-2 spike protein acts as a ß-adrenergic receptor agonist: A potential mechanism for cardiac sequelae of long COVID.

BACKGROUND: Currently, pathophysiological mechanisms of post-acute sequelae of coronavirus disease-19-cardiovascular syndrome (PASC-CVS) remain unknown. METHODS AND RESULTS: Patients with PASC-CVS exhibited significantly higher circulating levels of severe acute respiratory syndrome-coronavirus-2 spike protein S1 than the non-PASC-CVS patients and healthy controls. Moreover, individuals with high plasma spike protein S1 concentrations exhibited elevated heart rates and normalized low frequency, suggesting cardiac ß-adrenergic receptor (ß-AR) hyperactivity. Microscale thermophoresis (MST) assay revealed that the spike protein bound to ß1- and ß2-AR, but not to D1-dopamine receptor. These interactions were blocked by ß1- and ß2-AR blockers. Molecular docking and MST assay of ß-AR mutants revealed that the spike protein interacted with the extracellular loop 2 of both ß-ARs. In cardiomyocytes, spike protein dose-dependently increased the cyclic adenosine monophosphate production with or without epinephrine, indicating its allosteric effects on ß-ARs. CONCLUSION: Severe acute respiratory syndrome-coronavirus-2 spike proteins act as an allosteric ß-AR agonist, leading to cardiac ß-AR hyperactivity, thus contributing to PASC-CVS.

[Different levels and clinical significance of growth differentiation factor-15 in patients with atrial fibrillation].

OBJECTIVE: To measure the concentration of growth differentiation factor-15 (GDF-15) in the serum of patients with atrial fibrillation (AF), to study the correlations between the levels of GDF-15 and different factors including basic clinical information, biochemical examinations, and atrial structure, and further to explore the association between GDF-15 and AF types and structural remodeling. METHODS: AF patients who were admitted to the ward of the Department of Cardiology at Peking University Third Hospital between October 2017 and October 2019 were prospectively enrolled. Patients admitted to the ward at the same time with sinus rhythm and no prior AF history were enrolled in the control group. Clinical information and blood samples of the patients were collected. Enzyme-linked immunosorbent assay was used to measure the concentration of GDF-15. SPSS 23.0 was used for statistical analysis. RESULTS: In the study, 156 AF patients (64 persistent AF and 92 paroxysmal AF) and 38 patients of the control group were included. Serum GDF-15 levels in the AF group were significantly higher than in the control group [1 112 (723, 1 525) ng/L vs. 697 (499, 825) ng/L, P < 0.001]. Serum GDF-15 levels in the persistent AF group were significantly higher than in the paroxysmal AF group [1 140 (858, 1 708) ng/L vs. 1 090 (662, 1 374) ng/L, P=0.047]. The area under the curve (AUC) of serum GDF-15 levels for prediction of AF was 0.736 (95%CI: 0.651-0.822, P < 0.001). The cut-off value was 843.2 ng/L with a sensitivity of 68.2% and a specificity of 78.9%. The AUC of serum GDF-15 levels for prediction of persistent AF was 0.594 (95%CI: 0.504-0.684, P=0.047). The cut-off va-lue was 771.5 ng/L with a sensitivity of 82.8% and a specificity of 35.9%. Spearman rank correlation analysis showed that the serum GDF-15 levels were positively correlated with age (r=0.480, P < 0.001), left atrial pressure (LAP, r=0.300, P < 0.001), and also negatively correlated with left atrial appendage flow velocity (LAAV, r=-0.252, P=0.002). Multiple linear regression analysis showed that age and LAP affected the GDF-15 levels significantly (P < 0.05). Logistic regression analysis suggested GDF-15 (OR=1.002, 95%CI: 1.001-1.003, P=0.004) and left atrial diameter (LAD, OR=1.400, 95%CI: 1.214-1.616, P < 0.001) were independent predictors of AF. CONCLUSIONS: Serum GDF-15 levels are higher in AF patients. Meanwhile, serum GDF-15 levels are higher in persistent AF patients than paroxysmal AF patients. GDF-15 is associated with AF and atrial structural remodeling.

JrPHL8-JrWRKY4-JrSTH2L module regulates resistance to Colletotrichum gloeosporioides in walnut.

Walnut anthracnose (Colletotrichum gloeosporioides) reduces walnut yield and quality and seriously threatens the healthy development of the walnut industry. WRKY transcription factors (TFs) are crucial regulatory factors involved in plant-pathogen interactions. Our previous transcriptome analysis results indicate that JrWRKY4 responds to infection by C. gloeosporioides, but its specific regulatory network and disease resistance mechanism are still unclear. Herein, the characteristics of JrWRKY4 as a transcription activator located in the nucleus were first identified. Gain-of-function and loss-of-function analyses showed that JrWRKY4 could enhance walnut resistance against C. gloeosporioides. A series of molecular experiments showed that JrWRKY4 directly interacted with the promoter region of JrSTH2L and positively regulated its expression. In addition, JrWRKY4 interacted with JrVQ4 to form the protein complex, which inhibited JrWRKY4 for the activation of JrSTH2L. Notably, a MYB TF JrPHL8 interacting with the JrWRKY4 promoter has also been identified, which directly bound to the MBS element in the promoter of JrWRKY4 and induced its activity. Our study elucidated a novel mechanism of the JrPHL8-JrWRKY4-JrSTH2L in regulating walnut resistance to anthracnose. This mechanism improves our understanding of the molecular mechanism of WRKY TF mediated resistance to anthracnose in walnut, which provides new insights for molecular breeding of disease-resistant walnuts in the future.

Airborne magnetite nanoparticles induced early vascular pathologies by disrupting lipid metabolism under high-fat dietary patterns.

Magnetite nanoparticles (MNPs) have been extensively detected in the atmospheric environment and implicated as a prominent threat to atherosclerosis, a chronic vascular inflammatory disease. Due to globalization and economic development, the dramatic shift in diet from traditional to high-fat dietary patterns aggravated atherosclerosis progression induced by environmental factors. However, limited knowledge is available regarding vascular risks and underlying mechanisms of airborne MNPs in high-risk populations with high-fat dietary habits. Herein, we demonstrated that MNPs exerted a proatherogenic effect under high-fat dietary patterns, leading to aortic wall thickening, elastic fiber disorganization, macrophage infiltration, and local inflammation. Based on the correlation analysis between MNPs and PM group, we identified that MNPs might be a key PM component in atherogenic toxicity. MNPs exposure disturbed the dynamic process of lipid metabolism, manifested as aortic lipid accumulation, dyslipidemia, and hepatic lipid metabolism disorder, which was modulated by the JAK-STAT pathway. Overall, these findings provide new insight into understanding the cardiovascular risks and mechanisms of MNPs among high-risk populations.

Coronary Artery Disease with Elevated Levels of HDL Cholesterol Is Associated with Distinct Lipid Signatures.

Levels of high-density lipoprotein cholesterol (HDL-C) are inversely associated with the incidence of coronary artery disease (CAD). However, the underlying mechanism of CAD in the context of elevated HDL-C levels is unclear. Our study aimed to explore the lipid signatures in patients with CAD and elevated HDL-C levels and to identify potential diagnostic biomarkers for these conditions. We measured the plasma lipidomes of forty participants with elevated HDL-C levels (men with >50 mg/dL and women with >60 mg/dL), with or without CAD, using liquid chromatography-tandem mass spectrometry. We analyzed four hundred fifty-eight lipid species and identified an altered lipidomic profile in subjects with CAD and high HDL-C levels. In addition, we identified eighteen distinct lipid species, including eight sphingolipids and ten glycerophospholipids; all of these, except sphingosine-1-phosphate (d20:1), were higher in the CAD group. Pathways for sphingolipid and glycerophospholipid metabolism were the most significantly altered. Moreover, our data led to a diagnostic model with an area under the curve of 0.935, in which monosialo-dihexosyl ganglioside (GM3) (d18:1/22:0), GM3 (d18:0/22:0), and phosphatidylserine (38:4) were combined. We found that a characteristic lipidome signature is associated with CAD in individuals with elevated HDL-C levels. Additionally, the disorders of sphingolipid as well as glycerophospholipid metabolism may underlie CAD.

Exercise Training Attenuates Acute ß-Adrenergic Receptor Activation-Induced Cardiac Inflammation via the Activation of AMP-Activated Protein Kinase.

Exercise has proven cardiac benefits, but the underlying mechanisms of exercise that protect the heart from acute sympathetic stress injuries remain unknown. In this study, adult C57BL/6J mice and their AMP-activated protein kinase α2 knockout (AMPKα2-/-) littermates were either subjected to 6 weeks of exercise training or housed under sedentary conditions and then treated with or without a single subcutaneous injection of the ß-adrenergic receptor (ß-AR) agonist isoprenaline (ISO). We investigated the differences in the protective effects of exercise training on ISO-induced cardiac inflammation in wild-type (WT) and AMPKα2-/- mice using histology, enzyme-linked immunosorbent assay (ELISA) and Western blotting analyses. The results indicated that exercise training alleviated ISO-induced cardiac macrophage infiltration, chemokines and the expression of proinflammatory cytokines in wild-type mice. A mechanism study showed that exercise training attenuated the ISO-induced production of reactive oxygen species (ROS) and the activation of NLR Family, pyrin domain-containing 3 (NLRP3) inflammasomes. In cardiomyocytes, the ISO-induced effects on these processes were inhibited by AMP-activated protein kinase (AMPK) activator (metformin) pretreatment and reversed by the AMPK inhibitor (compound C). AMPKα2-/- mice showed more extensive cardiac inflammation following ISO exposure than their wild-type littermates. These results indicated that exercise training could attenuate ISO-induced cardiac inflammation by inhibiting the ROS-NLRP3 inflammasome pathway in an AMPK-dependent manner. Our findings suggested the identification of a novel mechanism for the cardioprotective effects of exercise.

Gas chromatography-mass spectrometry pilot study to identify volatile organic compound biomarkers of childhood obesity with dyslipidemia in exhaled breath.

Objectives: Childhood obesity affects multiple organs in the body and is associated with both significant morbidity and ultimately premature mortality. Childhood obesity, especially dyslipidemia, can lead to early atherosclerosis and premature cardiovascular disease (CVD) in adulthood. The detection of exhaled volatile organic compounds (VOCs) in the breath offers the opportunity for the discovery of novel disease-specific biomarkers. This study aimed to identify VOCs that correlate with childhood obesity accompanied by dyslipidemia. Methods: A total of 82 overweight or obese children between the ages of 8 and 12 years were recruited from the exercise on obesity adolescents in Peking (EXCITING) study (NCT04984005). The breath VOCs of the participants were measured by gas chromatography-mass spectrometry (GC-MS). The classification was performed using principal component analysis (PCA) of the relative abundance of VOCs. The difference between the obese and overweight groups with or without dyslipidemia was analyzed. Results: Among the 82 children, 25 were overweight, of whom 10 had dyslipidemia. The other 57 children were obese, and 17 of them had dyslipidemia. Obese children with dyslipidemia had higher triglycerides and elevated non-high-density lipoprotein-cholesterol compared to overweight children without dyslipidemia. We confirmed 13 compounds based on database well matches (average score > 80) for mass spectra and refractive index. These 13 VOCs were grouped into three chemical functional groups: saturated hydrocarbons, aromatic hydrocarbons and unsaturated aldehydes. For obese children with dyslipidemia, the PCA scatter plot of the three chemical groups was obviously separated from the other groups. Some of the candidates, including heptadecane, naphthalene, and cis-6-nonnenol, were significantly higher in obese children with dyslipidemia than in overweight groups with or without dyslipidemia. Conclusion: A suite of VOCs from three chemical function groups, saturated hydrocarbons, aromatic hydrocarbons, and unsaturated aldehydes, were separated in the obese children with dyslipidemia. Heptadecane, naphthalene, and cis-6-nonenol were significantly elevated in obese children with dyslipidemia. Our findings underscore the potential value of the candidate VOCs for future risk categorization.

Exercise training attenuates angiotensin II-induced cardiac fibrosis by reducing POU2F1 expression.

BACKGROUND: Exercise training protects against heart failure. However, the mechanism underlying the protective effect of exercise training on angiotensin II (Ang II)-induced cardiac fibrosis remains unclear. METHODS: An exercise model involving C57BL/6N mice and 6 weeks of treadmill training was used. Ang II (1.44 mg/kg/day) was administered to induce cardiac fibrosis. RNA sequencing and bioinformatic analysis were used to identify the key factors mediating the effects of exercise training on cardiac fibrosis. Primary adult mouse cardiac fibroblasts (CFs) were used in vitro. Adeno-associated virus serotype 9 was used to overexpress POU domain, class 2, transcription factor 1 (POU2F1) in vivo. RESULTS: Exercise training attenuated Ang II-induced cardiac fibrosis and reversed 39 gene expression changes. The transcription factor regulating the largest number of these genes was POU2F1. Compared to controls, POU2F1 was shown to be significantly upregulated by Ang II, which is itself reduced by exercise training. In vivo, POU2F1 overexpression nullified the benefits of exercise training on cardiac fibrosis. In CFs, POU2F1 promoted cardiac fibrosis. CCAAT enhancer-binding protein ß (C/EBPß) was predicted to be the transcription factor of POU2F1 and verified using a dual-luciferase reporter assay. In vivo, exercise training activated AMP-activated protein kinase (AMPK) and alleviated the increase in C/EBPß induced by Ang II. In CFs, AMPK agonist inhibited the increase in C/EBPß and POU2F1 induced by Ang II, whereas AMPK inhibitor reversed this effect. CONCLUSION: Exercise training attenuates Ang II-induced cardiac fibrosis by reducing POU2F1. Exercise training inhibits POU2F1 by activating AMPK, which is followed by the downregulation of C/EBPß, the transcription factor of POU2F1.

Early identification of STEMI patients with emergency chest pain using lipidomics combined with machine learning.

OBJECTIVES: To analyze the differential expression of lipid spectrum between ST-segment elevated myocardial infarction (STEMI) and patients with emergency chest pain and excluded coronary artery disease (CAD), and establish the predictive model which could predict STEMI in the early stage. METHODS: We conducted a single-center, nested case-control study using the emergency chest pain cohort of Peking University Third Hospital. Untargeted lipidomics were conducted while LASSO regression as well as XGBoost combined with greedy algorithm were used to select lipid molecules. RESULTS: Fifty-two STEMI patients along with 52 controls were enrolled. A total of 1925 lipid molecules were detected. There were 93 lipid molecules in the positive ion mode which were differentially expressed between the STEMI and the control group, while in the negative ion mode, there were 73 differentially expressed lipid molecules. In the positive ion mode, the differentially expressed lipid subclasses were mainly diacylglycerol (DG), lysophophatidylcholine (LPC), acylcarnitine (CAR), lysophosphatidyl ethanolamine (LPE), and phosphatidylcholine (PC), while in the negative ion mode, significantly expressed lipid subclasses were mainly free fatty acid (FA), LPE, PC, phosphatidylethanolamine (PE), and phosphatidylinositol (PI). LASSO regression selected 22 lipids while XGBoost combined with greedy algorithm selected 10 lipids. PC (15: 0/18: 2), PI (19: 4), and LPI (20: 3) were the overlapping lipid molecules selected by the two feature screening methods. Logistic model established using the three lipids had excellent performance in discrimination and calibration both in the derivation set (AUC: 0.972) and an internal validation set (AUC: 0.967). In 19 STEMI patients with normal cardiac troponin, 18 patients were correctly diagnosed using lipid model. CONCLUSIONS: The differentially expressed lipids were mainly DG, CAR, LPC, LPE, PC, PI, PE, and FA. Using lipid molecules selected by XGBoost combined with greedy algorithm and LASSO regression to establish model could accurately predict STEMI even in the more earlier stage.

The Foam Cell Formation Associated With Imbalanced Cholesterol Homeostasis Due to Airborne Magnetite Nanoparticles Exposure.

Fine particulate matter (PM) is a leading environmental cause for the increased morbidity and mortality of atherosclerosis (AS) worldwide, but little is known about the toxic component and disturbance of PM exposure on foam cell formation, a crucial pathological process in AS. Airborne magnetite nanoparticles (NPs) have been reported to be detected in human serum, which inevitably encounter with macrophages in atherosclerotic plaques, thus throwing potential disturbance on the formation of macrophage-derived foam cells. Here we comprehensively unveiled that the environmental concentrations of PM exposure triggered and potentiated the formation of macrophage-derived foam cells using both real-ambient PM-exposed mice and AS mice models, including high-fat diet-fed mice and apolipoprotein E-deficient mice. The in vitro model further defined the dose-dependent response of PM treatment on foam cell formation. Interestingly, airborne magnetite NPs rather than nonmagnetic NPs at the same concentration were demonstrated to be the key toxic component of PM in the promoted foam cell formation. Furthermore, magnetite NPs exposure led to abnormal cholesterol accumulation in macrophages, which was attributed to the attenuation of cholesterol efflux and enhancement of lipoprotein uptake, but independent of cholesterol esterification. The in-depth data revealed that magnetite NPs accelerated the protein ubiquitination and subsequent degradation of SR-B1, a crucial transporter of cholesterol efflux. Collectively, these findings for the first time identified magnetite NPs as one key toxic component of PM-promoted foam cell formation, and provided new insight of abnormal cholesterol metabolism into the pathogenesis of PM-induced AS.

The adverse inflammatory response of tobacco smoking in COVID-19 patients: biomarkers from proteomics and metabolomics.

Whether tobacco smoking affects the occurrence and development of coronavirus disease 2019 (COVID-19) is still a controversial issue, and potential biomarkers to predict the adverse outcomes of smoking in the progression of COVID-19 patients have not yet been elucidated. To further uncover their linkage and explore the effective biomarkers, three proteomics and metabolomics databases (i.e. smoking status, COVID-19 status, and basic information of population) from human serum proteomic and metabolomic levels were established by literature search. Bioinformatics analysis was then performed to analyze the interactions of proteins or metabolites among the above three databases and their biological effects. Potential confounding factors (age, body mass index (BMI), and gender) were controlled to improve the reliability. The obtained data indicated that smoking may increase the relative risk of conversion from non-severe to severe COVID-19 patients by inducing the dysfunctional immune response. Seven interacting proteins (C8A, LBP, FCN2, CRP, SAA1, SAA2, and VTN) were found to promote the deterioration of COVID-19 by stimulating the complement pathway and macrophage phagocytosis as well as inhibiting the associated negative regulatory pathways, which can be biomarkers to reflect and predict adverse outcomes in smoking COVID-19 patients. Three crucial pathways related to immunity and inflammation, including tryptophan, arginine, and glycerophospholipid metabolism, were considered to affect the effect of smoking on the adverse outcomes of COVID-19 patients. Our study provides novel evidence and corresponding biomarkers as potential predictors of severe disease progression in smoking COVID-19 patients, which is of great significance for preventing further deterioration in these patients.

The R93C Variant of PCSK9 Reduces the Risk of Premature MI in a Chinese Han Population.

Background: Dyslipidemia is a common risk factor for premature myocardial infarction (PMI). Our previous work has shown that single-nucleotide polymorphisms (SNPs) of LDLR, APOB, and PCSK9 are associated with dyslipidemia, but how these SNPs correlate with risk for PMI is unknown. Objective: This study aims to evaluate the association between SNPs of LDLR, APOB, and PCSK9 and risk of PMI in Chinese Han population. Methods: Two cohorts were established. In Cohort 1 (413 in the PMI group and 1,239 in the control group), SNPs of APOB, LDLR, and PCSK9 with minor allele frequency (MAF) > 1%, which has been shown to impact the risk of PMI in a Chinese Han population, were thoroughly examined, and gene-environment interactions were analyzed. A model for PMI risk prediction was developed in Cohort 1 and externally validated in Cohort 2 (577 in the PMI group and 270 in the control group). Results: The distribution of the T allele at the PCSK9 R93C variant (rs151193009, C > T) was lower in the PMI group than that in the control group (PMI vs. Control in Cohort 1, 0.8% vs. 2.3%, P adjust < 0.05; in Cohort 2, 1.0% vs. 2.4%, P adjust < 0.05). The T allele at PCSK9 R93C variant (rs151193009, C > T) reduced the risk of PMI by ∼60% regardless of adjusting for confounding factors (in Cohort 1, adjusted odds ratio (OR) 0.354, 95% confidence interval (CI) 0.139-0.900, p = 0.029; in Cohort 2, adjusted OR 0.394, 95% CI 0.157-0.987, p = 0.047). No gene-environment interactions were observed between the R93C variant and diabetes/hypertension/smoking in PMI occurrence in this Chinese Han population. Our model showed good performance in predicting the risk of PMI in Cohort 1 (AUC 0.839, 95% CI 0.815-0.862, p < 0.001) and in an external cohort (AUC 0.840, 95% CI 0.810-0.871, p < 0.001). Conclusions: The PCSK9 R93C variant was associated with significantly reduced risk of PMI in the Chinese Han population, and the model we developed performed well in predicting PMI risk in this Chinese Han population.

Oxygen sensors mediated HIF-1α accumulation and translocation: A pivotal mechanism of fine particles-exacerbated myocardial hypoxia injury.

Epidemiological studies have demonstrated a strong association of ambient fine particulate matter (PM2.5) exposure with the increasing mortality by ischemic heart disease (IHD), but the involved mechanisms remain poorly understood. Herein, we found that the chronic exposure of real ambient PM2.5 led to the upregulation of hypoxia-inducible factor-1 alpha (HIF-1α) protein in the myocardium of mice, accompanied by obvious myocardial injury and hypertrophy. Further data from the hypoxia-ischemia cellular model indicated that PM2.5-induced HIF-1α accumulation was responsible for the promotion of myocardial hypoxia injury. Moreover, the declined ATP level due to the HIF-1α-mediated energy metabolism remodeling from ß-oxidation to glycolysis had a critical role in the PM2.5-increased myocardial hypoxia injury. The in-depth analysis delineated that PM2.5 exposure decreased the binding of prolyl hydroxylase domain 2 (PHD2) and HIF-1α and subsequent ubiquitin protease levels, thereby leading to the accumulation of HIF-1α. Meanwhile, factor-inhibiting HIF1 (FIH1) expression was down-regulated by PM2.5, resulting in the enhanced translocation of HIF-1α to the nucleus. Overall, our study provides valuable insight into the regulatory role of oxygen sensor-mediated HIF-1α stabilization and translocation in PM-exacerbated myocardial hypoxia injury, we suggest this adds significantly to understanding the mechanisms of haze particles-caused burden of cardiovascular disease.

Increased hemoglobin A1c level associates with low left atrial appendage flow velocity in patients of atrial fibrillation.

BACKGROUND AND AIMS: High hemoglobin A1c (HbAlc) level is associated with increased cardiovascular disease risk and thromboembolic events [1]. The study sought to explored the association between HbAlc and left atrial appendage flow velocity (LAAV) among non-valvular atrial fibrillation (AF) patients. METHODS AND RESULTS: A total of 249 consecutive non-valvular AF patients who underwent transesophageal echocardiography (TEE) were divided into two subgroups according to the median of LAAV level (<45 cm/s, ≥45 cm/s). Blood samples and other baseline clinical data of all patients were collected and analyzed. The low LAAV group included 126 patients and the high LAAV group included 123 patients. Patients in the low LAAV group were older and had a higher percentage of persistent AF, chronic heart failure, and higher CHA2DS2-VASc score (P < 0.05). HbAlc level in the low LAAV group was significantly higher than the high LAAV group [6.1 (5.7-6.5)% vs 5.9 (5.6-6.2)%, P = 0.010]. The low LAAV group had larger left atrial diameter (LAD), left atrial area (LAA), higher left atrial pressure (LAP), and lower left ventricular ejection fraction (LVEF) (P < 0.05). Spearman rank correlation analysis showed that the HbAlc level was negatively correlated with LAAV (r = -0.211, P = 0.001). Multivariate analysis indicated that female gender (OR = 2.233, 95% CI 1.110-4.492, P = 0.024), persistent AF (OR = 6.610, 95% CI 3.109-14.052, P < 0.001), and HbAlc (OR = 1.903, 95% CI 1.092-3.317, P = 0.023) were independent factors that associated with low LAAV in AF patients. CONCLUSION: Increased HbAlc level is associated with decreased LAAV and may reflect a low contractile function of the left atrial appendage.

Surface charge-dependent mitochondrial response to similar intracellular nanoparticle contents at sublethal dosages.

BACKGROUND: Considering the inevitability for humans to be frequently exposed to nanoparticles (NPs), understanding the biosafety of NPs is important for rational usage. As an important part of the innate immune system, macrophages are widely distributed in vital tissues and are also a dominant cell type that engulfs particles. Mitochondria are one of the most sensitive organelles when macrophages are exposed to NPs. However, previous studies have mainly reported the mitochondrial response upon high-dose NP treatment. Herein, with gold nanoparticles (AuNPs) as a model, we investigated the mitochondrial alterations induced by NPs at a sublethal concentration. RESULTS: At a similar internal exposure dose, different AuNPs showed distinct degrees of effects on mitochondrial alterations, including reduced tubular mitochondria, damaged mitochondria, increased reactive oxygen species, and decreased adenosine triphosphate. Cluster analysis, two-way ANOVA, and multiple linear regression suggested that the surface properties of AuNPs were the dominant determinants of the mitochondrial response. Based on the correlation analysis, the mitochondrial response was increased with the change in zeta potential from negative to positive. The alterations in mitochondrial respiratory chain proteins indicated that complex V was an indicator of the mitochondrial response to low-dose NPs. CONCLUSION: Our current study suggests potential hazards of modified AuNPs on mitochondria even under sublethal dose, indicates the possibility of surface modification in biocompatibility improvement, and provides a new way to better evaluation of nanomaterials biosafety.

An Asian-specific MPL genetic variant alters JAK-STAT signaling and influences platelet count in the population.

Genomic discovery efforts for hematological traits have been successfully conducted through genome-wide association study on samples of predominantly European ancestry. We sought to conduct unbiased genetic discovery for coding variants that influence hematological traits in a Han Chinese population. A total of 5257 Han Chinese subjects from Beijing, China were included in the discovery cohort and analyzed by an Illumina ExomeChip array. Replication analyses were conducted in 3827 independent Chinese subjects. We analyzed 12 hematological traits and identified 22 exome-wide significant single-nucleotide polymorphisms (SNP)-trait associations with 15 independent SNPs. Our study provides replication for two associations previously reported but not replicated. Further, one association was identified and replicated in the current study, of a coding variant in the myeloproliferative leukemia (MPL) gene, c.793C > T, p.Leu265Phe (L265F) with increased platelet count (ß = 20.6 109 cells/l, Pmeta-analysis = 2.6 × 10-13). This variant is observed at ~2% population frequency in East Asians, whereas it has not been reported in gnomAD European or African populations. Functional analysis demonstrated that expression of MPL L265F in Ba/F3 cells resulted in enhanced phosphorylation of Stat3 and ERK1/2 as compared with the reference MPL allele, supporting altered activation of the JAK-STAT signal transduction pathway as the mechanism underlying the novel association between MPL L265F and platelet count.

Ring finger protein 152-dependent degradation of TSPAN12 suppresses hepatocellular carcinoma progression.

BACKGROUND: Hepatocellular carcinoma (HCC) is the third cause of cancer death in the world, and few molecularly targeted anticancer therapies have been developed to treat it. The E3 ubiquitin ligase RNF152 has been reported to regulate the activity of the mechanistic target of rapamycin complex 1 (mTORC1), induce autophagy and apoptosis. However, the relationship between RNF152 and HCC is unclear. METHODS: Transcriptome RNA-sequencing data of HCC samples and normal tissues were used to detect the mRNA expression of RNF152. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to determine the transcriptional regulation of RNF152 in HCC by FoxO1. RNAi, cell proliferation, colony formation and transwell assays were used to determine the in vitro functions of RNF152. Mouse xenograft models were used to study the in vivo effects of RNF152. The immunoprecipitation assay was used to determine the interaction between RNF152 and TSPAN12. The in vivo ubiquitination assay was performed to determine the regulation of TSPAN12 by RNF152. RESULTS: We found that RNF152 is significantly down-regulated in clinic HCC samples, and its down-regulation is associated with pool overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS) in HCC patients. The transcription factor FoxO1 was significantly positively correlated RNF152 expression in HCC tissues. FoxO1 recognizes a classic insulin response element (IRE) on the RNF152 promoter to regulate its expression in HCC. RNF152 suppressed HCC cell proliferation, clonogenic survival, invasion in vitro, and tumorigenesis in vivo. Mechanistically, RNF152 interacted with TSPAN12 and targeted it for ubiquitination and proteasomal degradation, thereby inhibiting TSPAN12-dependent CXCL6 expression and HCC progression. CONCLUSION: Collectively, our data revealed a tumor suppressor role of RNF152 and a connection between RNF152 and FoxO1 in HCC. Our results support an important role of the FoxO1-RNF152-TSPAN12 axis in the development of HCC. Therapeutic targeting this axis may be an effective means of treating HCC.