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Abstract Background The pathogenesis of diabetic cardiomyopathy is closely linked to abnormal glycosylation modifications. N-acetylglucosaminyltransferase V (GnT-V), which catalyzes the production of N-linked -1–6 branching of oligosaccharides, is involved in several pathophysiological mechanisms of many disorders, including cardiac hypertrophy and heart failure. However, the mechanism by which GnT-V regulates cardiac hypertrophy in diabetic cardiomyopathy is currently poorly understood. In this study, we investigated the role of GnT-V on myocardial hypertrophy in diabetic cardiomyopathy and elucidated the underlying mechanisms. Material and methods Streptozotocin (STZ) was intraperitoneally injected into mice to induce diabetic cardiomyopathy. An adeno-associated virus (AAV) carrying negative control small hairpin RNA (shNC) or GnT-V-specifc small hairpin RNA (shGnT-V) was used to manipulate GnT-V expression. In our study, forty male C57BL/6J mice were randomly divided into four groups (10 mice per group): control mice with AAV-shNC, diabetic cardiomyopathy mice with AAV-shNC, control mice with AAV-shGnT-V, and diabetic cardiomyopathy mice with AAV-shGnT-V. In addition, H9C2 cells and primary neonatal cardiac fibroblasts treated with high glucose were used as a cell model of diabetes. Analysis of cardiac hypertrophy and fibrosis, as well as functional studies, were used to investigate the underlying molecular pathways. Results AAV-mediated GnT-V silencing dramatically improved cardiac function and alleviated myocardial hypertrophy and fibrosis in diabetic mice. In vitro experiments demonstrated that GnT-V was elevated in cardiomyocytes and induced cardiomyocyte hypertrophy in response to high glucose stimulation. GnT-V knockdown significantly reduced the expression of the integrinβ1 signaling pathway, as evidenced by decreased downstream ERK1/2 activity, which inhibited cardiomyocyte hypertrophy accompanied by reduced ANP, BNP, and β-MHC expression. Furthermore, knocking down GnT-V expression lowered the TGF-β1-Smads signaling pathway, which reduced the expression of α-SMA, collagen I, and collagen III. Conclusions Overall, our research indicated that GnT-V may be a useful therapeutic target to treat diabetic cardiomyopathy, primarily in the inhibition of myocardial hypertrophy and fibrosis.

[Introduction] The application scenarios of peak shaving and valley filling by energy storage connected to the distribution network are studied to clarify the influence of energy storage access on network losses and voltage quality on the distribution network side. [Method] The paper analyzed the change trend of network loss power with the energy storage injection current and access position during peak hours of energy storage discharge, and then analyzed the change trend of network loss power with the energy storage injection current and access position when the energy storage system was connected and charged during valley hours. For the influence of energy storage connected to the distribution network for peak shaving and valley filling on the voltage of the distribution network, the influence of different energy storage injection currents and access positions on the voltage distribution along the distribution network was studied from the perspective of energy storage discharge during peak hours and energy storage charging during valley hours. Finally, considering the total voltage deviation index of the distribution network, the influence on the total voltage deviation index after the distribution network which was connected to energy storage was studied. [Result] Through simulation calculations, the influence trend of energy storage participating in peak shaving and valley filling for the distribution network on network loss power and voltage loss is analyzed when different fixed or continuous values of energy storage current and access position are taken, and it is compared with theoretical analysis. [Conclusion] The study will provide useful references for the coordinated planning and optimized operation of various energy storage facilities in the distribution network, and it has good engineering reference value.

Abstract Background Sheep milk is a nutritional and health-promoting food source for humans. The DEATH superfamily is a conserved protein family, and some of its members are closely related to lactation. Systematic studies of the members of the DEATH superfamily are important for further understanding its functions in the mammary gland during lactation; however, there studies are currently lacking. Results Herein, 74 members of the DEATH superfamily were identified in sheep, and phylogenetic analyses indicated that four subfamilies were strongly correlated in evolution. The Ka/Ks calculations demonstrated that negative selection was the primary pressure acting on DEATH members; however, the immune-related gene IFI203 was undergoing strong positive selection in sheep. Furthermore, in the late pregnancy and lactation period, these DEATH genes exhibited similar expression patterns under different nutritional conditions in the mammary gland, and four subfamilies were positively correlated in expression patterns. Additionally, half or more DEATH genes were upregulated in the lactation period, which implied their crucial roles in the lactation of sheep. Conclusions The current research contributes to a better understanding of the evolutionary characteristics of the DEATH superfamily and their roles in sheep lactation, and it also provides potential target genes for the molecular breeding of dairy sheep. Graphical Abstract

Summary: Biliary epithelial cells (BECs) are a potential source to repair the damaged liver when hepatocyte proliferation is compromised. Promotion of BEC-to-hepatocyte transdifferentiation could be beneficial to the clinical therapeutics of patients with end-stage liver diseases. However, mechanisms underlying the initiation of BEC transdifferentiation remain largely unknown. Here, we show that upon extreme hepatocyte injury, vegfaa and vegfr2/kdrl are notably induced in hepatic stellate cells and BECs, respectively. Pharmacological and genetic inactivation of vascular endothelial growth factor (VEGF) signaling would disrupt BEC dedifferentiation and proliferation, thus restraining hepatocyte regeneration. Mechanically, VEGF signaling regulates the activation of the PI3K-mammalian target of rapamycin complex 1 (mTORC1) axis, which is essential for BEC-to-hepatocyte transdifferentiation. In mice, VEGF signaling exerts conserved roles in oval cell activation and BEC-to-hepatocyte differentiation. Taken together, this study shows VEGF signaling as an initiator of biliary-mediated liver regeneration through activating the PI3K-mTORC1 axis. Modulation of VEGF signaling in BECs could be a therapeutic approach for patients with end-stage liver diseases.

Abstract Background Sheep milk is an attractive nutritional and functional food source. Some Dishevelled, Egl-10 and pleckstrin (DEP) domain-containing proteins can regulate lactation performance in mammals. However, systematic study of the role of sheep DEP family members in regulating lactation is currently lacking. This study aimed to reveal the roles of sheep DEP family members in lactation by exploring their genetic characteristics and functional features at the whole genome-wide level. Results Twenty DEP family members were identified in the sheep genome, and they can be divided into four major groups. Ka/Ks calculations suggest that the purifying selection is the main pressure acting on DEP genes. In the late pregnancy and lactation periods, the expression levels of eight DEP genes exhibited significant differences in the mammary gland. In addition, nutritional conditions have a great influence on the expression of DEP family members, and the DEP gene family underwent more expansion than the average gene family in the early stages of biological evolution. The Mirrortree assays indicated that the DEP family members coevolved in biological evolution. Conclusions Our research provides a better understanding of the characters of the DEP domain-containing protein family and their potential roles in regulating lactation in sheep. Moreover, these results of our study may contribute to the genetic improvement of milk performance in dairy sheep breed. Graphical Abstract

Abstract Background Arginine vasopressin (AVP) is elevated in patients with heart failure, and the increase in the AVP concentration in plasma is positively correlated with disease severity and mortality. Metoprolol (Met) is a beta blocker that is widely used in the clinic to treat pathological cardiac hypertrophy and to improve heart function. However, the specific mechanism by which Met alleviates AVP-induced pathological cardiac hypertrophy is still unknown. Our current study aimed to evaluate the inhibitory effects of Met on AVP-induced cardiomyocyte hypertrophy and the underlying mechanisms. Methods AVP alone or AVP plus Met was added to the wild type or AKT1-overexpressing rat cardiac H9C2 cell line. The cell surface areas and ANP/BNP/β-MHC expressions were used to evaluate the levels of hypertrophy. Western bolting was used to analyze AKT1/P-AKT1, AKT2/P-AKT2, total AKT, SERCA2, and Phospholamban (PLN) expression. Fluo3-AM was used to measure the intracellular Ca2+ stores. Results In the current study, we found that AKT1 but not AKT2 mediated the pathogenesis of AVP-induced cardiomyocyte hypertrophy. Sustained stimulation (48 h) with AVP led to hypertrophy in the H9C2 rat cardiomyocytes, resulting in the downregulation of AKT1 (0.48 fold compared to control) and SERCA2 (0.62 fold), the upregulation of PLN (1.32 fold), and the increase in the cytoplasmic calcium concentration (1.52 fold). In addition, AKT1 overexpression increased the expression of SERCA2 (1.34 fold) and decreased the expression of PLN (0.48 fold) in the H9C2 cells. Moreover, we found that Met could attenuate the AVP-induced changes in AKT1, SERCA2 and PLN expression and decreased the cytoplasmic calcium concentration in the H9C2 cells. Conclusions Our results demonstrated that the AKT1–SERCA2 cascade served as an important regulatory pathway in AVP-induced pathological cardiac hypertrophy.

BackgroundIn our clinical work, we found that cancer patients were susceptible to coronary atherosclerotic heart disease (CAD). However, less is known about the relationship between CAD and cancer. The present study aimed to identify the risk factors for CAD and cancer, as well as the relationship between CAD and cancer.MethodsIn this retrospective study, 1600 patients between January 2012 and June 2019 were enrolled and divided into groups according to whether they had CAD or cancer. Single-factor and multivariate analysis methods were applied to examine the risk factors for CAD and cancer.Results(1) Cancer prevalence was significantly higher in patients with CAD than in patients without CAD (47.2 vs. 20.9%). The prevalence of CAD in cancer and non-cancer patients was 78.9 and 52.4%, respectively. (2) Multivariable logistic regression showed that patients with cancer had a higher risk of developing CAD than non-cancer patients (OR: 2.024, 95% CI: 1.475 to 2.778, p < 0.001). Respiratory (OR: 1.981, 95% CI: 1.236–3.175, p = 0.005), digestive (OR: 1.899, 95% CI: 1.177–3.064, p = 0.009) and urogenital (OR: 3.595, 95% CI: 1.696–7.620, p = 0.001) cancers were significantly associated with a higher risk of CAD compared with no cancer. (3) Patients with CAD also had a higher risk of developing cancer than non-CAD patients (OR = 2.157, 95% CI: 1.603 to 2.902, p < 0.001). Patients in the Alanine aminotransferase (ALT) level ≥ 40 U/L group had a lower risk of cancer than patients in the ALT level < 20 U/L group (OR: 0.490, 95% CI: 0.333–0.722, p < 0.001). (4) An integrated variable (Y = 0.205 × 10–1 age − 0.595 × 10–2 HGB − 0.116 × 10–1 ALT + 0.135 FIB) was identified for monitoring the occurrence of cancer among CAD patients, with an AUC of 0.720 and clinical sensitivity/specificity of 0.617/0.711.Conclusion(1) We discovered that CAD was an independent risk factor for cancer and vice versa. (2) Digestive, respiratory and urogenital cancers were independent risk factors for CAD. (3) We created a formula for the prediction of cancer among CAD patients. (4) ALT, usually considered a risk factor, was proven to be a protective factor for cancer in this study.

The Wnt signaling pathway is an evolutionarily conserved signaling pathway that plays essential roles in embryonic development, organogenesis, and many other biological activities. Both Wnt proteins and DIX proteins are important components of Wnt signaling. Systematic studies of Wnt and DIX families at the genome-wide level may provide a comprehensive landscape to elucidate their functions and demonstrate their relationships, but they are currently lacking. In this report, we describe the correlations between mouse Wnt and DIX genes in family expansion, molecular evolution, and expression levels in cardiac hypertrophy at the genome-wide scale. We observed that both the Wnt and DIX families underwent more expansion than the overall average in the evolutionarily early stage. In addition, mirrortree analyses suggested that Wnt and DIX were co-evolved protein families. Collectively, these results would help to elucidate the evolutionary characters of Wnt and DIX families and demonstrate their correlations in mediating cardiac hypertrophy.

This paper presents an extension of the double Heston stochastic volatility model by combining Hull-White stochastic interest rates. By the change of numeraire and quadratic exponential scheme, this paper develops a new simulation scheme for the extended model. By combining control variates and antithetic variates, this paper provides an efficient Monte Carlo simulation algorithm for pricing barrier options. Based on the differential evolution algorithm the extended model is calibrated to S&P 500 index options to obtain the model parameter values. Numerical results show that the proposed simulation scheme outperforms the Euler scheme, the proposed simulation algorithm is efficient for pricing barrier options, and the extended model is flexible to fit the implied volatility surface. [ABSTRACT FROM AUTHOR]