Obesity Is a Major Determinant of Impaired Cardiac Energy Metabolism in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a major health problem with limited treatment options. Although optimizing cardiac energy metabolism is a potential approach to treating heart failure, it is poorly understood what alterations in cardiac energy metabolism actually occur in HFpEF. To determine this, we used mice in which HFpEF was induced using an obesity and hypertension HFpEF protocol for 10 weeks. Next, carvedilol, a third-generation ß-blocker and a biased agonist that exhibits agonist-like effects through ß arrestins by activating extracellular signal-regulated kinase, was used to decrease one of these parameters, namely hypertension. Heart function was evaluated by invasive pressure-volume loops and echocardiography as well as by ex vivo working heart perfusions. Glycolysis and oxidation rates of glucose, fatty acids, and ketones were measured in the isolated working hearts. The development of HFpEF was associated with a dramatic decrease in cardiac glucose oxidation rates, with a parallel increase in palmitate oxidation rates. Carvedilol treatment decreased the development of HFpEF but had no major effect on cardiac energy substrate metabolism. Carvedilol treatment did increase the expression of cardiac ß arrestin 2 and proteins involved in mitochondrial biogenesis. Decreasing bodyweight in obese HFpEF mice increased glucose oxidation and improved heart function. This suggests that the dramatic energy metabolic changes in HFpEF mice hearts are primarily due to the obesity component of the HFpEF model. SIGNIFICANCE STATEMENT: Metabolic inflexibility occurs in heart failure with preserved ejection fraction (HFpEF) mice hearts. Lowering blood pressure improves heart function in HFpEF mice with no major effect on energy metabolism. Between hypertension and obesity, the latter appears to have the major role in HFpEF cardiac energetic changes. Carvedilol increases mitochondrial biogenesis and overall energy expenditure in HFpEF hearts.

Stimulating cardiac glucose oxidation lessens the severity of heart failure in aged female mice.

Heart failure is a prevalent disease worldwide. While it is well accepted that heart failure involves changes in myocardial energetics, what alterations that occur in fatty acid oxidation and glucose oxidation in the failing heart remains controversial. The goal of the study are to define the energy metabolic profile in heart failure induced by obesity and hypertension in aged female mice, and to attempt to lessen the severity of heart failure by stimulating myocardial glucose oxidation. 13-Month-old C57BL/6 female mice were subjected to 10 weeks of a 60% high-fat diet (HFD) with 0.5 g/L of Nω-nitro-L-arginine methyl ester (L-NAME) administered via drinking water to induce obesity and hypertension. Isolated working hearts were perfused with radiolabeled energy substrates to directly measure rates of myocardial glucose oxidation and fatty acid oxidation. Additionally, a series of mice subjected to the obesity and hypertension protocol were treated with a pyruvate dehydrogenase kinase inhibitor (PDKi) to stimulate cardiac glucose oxidation. Aged female mice subjected to the obesity and hypertension protocol had increased body weight, glucose intolerance, elevated blood pressure, cardiac hypertrophy, systolic dysfunction, and decreased survival. While fatty acid oxidation rates were not altered in the failing hearts, insulin-stimulated glucose oxidation rates were markedly impaired. PDKi treatment increased cardiac glucose oxidation in heart failure mice, which was accompanied with improved systolic function and decreased cardiac hypertrophy. The primary energy metabolic change in heart failure induced by obesity and hypertension in aged female mice is a dramatic decrease in glucose oxidation. Stimulating glucose oxidation can lessen the severity of heart failure and exert overall functional benefits.

Metabolic flux in macrophages in obesity and type-2 diabetes.

Recent literature extensively investigates the crucial role of energy metabolism in determining the inflammatory response and polarization status of macrophages. This rapidly expanding area of research highlights the importance of understanding the link between energy metabolism and macrophage function. The metabolic pathways in macrophages are intricate and interdependent, and they can affect the polarization of macrophages. Previous studies suggested that glucose flux through cytosolic glycolysis is necessary to trigger pro-inflammatory phenotypes of macrophages, and fatty acid oxidation is crucial to support anti-inflammatory responses. However, recent studies demonstrated that this understanding is oversimplified and that the metabolic control of macrophage polarization is highly complex and not fully understood yet. How the metabolic flux through different metabolic pathways (glycolysis, glucose oxidation, fatty acid oxidation, ketone oxidation, and amino acid oxidation) is altered by obesity- and type 2 diabetes (T2D)-associated insulin resistance is also not fully defined. This mini-review focuses on the impact of insulin resistance in obesity and T2D on the metabolic flux through the main metabolic pathways in macrophages, which might be linked to changes in their inflammatory responses. We closely evaluated the experimental studies and methodologies used in the published research and highlighted priority research areas for future investigations.

Equity in prenatal healthcare services globally: an umbrella review.

BACKGROUND: Timely, appropriate, and equitable access to quality healthcare during pregnancy is proven to contribute to better health outcomes of birthing individuals and infants following birth. Equity is conceptualized as the absence of differences in healthcare access and quality among population groups. Healthcare policies are guides for front-line practices, and despite merits of contemporary policies striving to foster equitable healthcare, inequities persist. The purpose of this umbrella review is to identify prenatal healthcare practices, summarize how equities/inequities are reported in relation to patient experiences or health outcomes when accessing or using services, and collate equity reporting characteristics. METHODS: For this umbrella review, six electronic databases were searched (Medline, EMBASE, APA PsychInfo, CINAHL, International Bibliography of the Social Sciences, and Cochrane Library). Included studies were extracted for publication and study characteristics, equity reporting, primary outcomes (prenatal care influenced by equity/inequity) and secondary outcomes (infant health influenced by equity/inequity during pregnancy). Data was analyzed deductively using the PROGRESS-Plus equity framework and by summative content analysis for equity reporting characteristics. The included articles were assessed for quality using the Risk of Bias Assessment Tool for Systematic Reviews. RESULTS: The search identified 8065 articles and 236 underwent full-text screening. Of the 236, 68 systematic reviews were included with first authors representing 20 different countries. The population focus of included studies ranged across prenatal only (n = 14), perinatal (n = 25), maternal (n = 2), maternal and child (n = 19), and a general population (n = 8). Barriers to equity in prenatal care included travel and financial burden, culturally insensitive practices that deterred care engagement and continuity, and discriminatory behaviour that reduced care access and satisfaction. Facilitators to achieve equity included innovations such as community health workers, home visitation programs, conditional cash transfer programs, virtual care, and cross-cultural training, to enhance patient experiences and increase their access to, and use of health services. There was overlap across PROGRESS-Plus factors. CONCLUSIONS: This umbrella review collated inequities present in prenatal healthcare services, globally. Further, this synthesis contributes to future solution and action-oriented research and practice by assembling evidence-informed opportunities, innovations, and approaches that may foster equitable prenatal health services to all members of diverse communities.

Molecular mechanism of miR-203a targeting Runx2 to regulate thiram induced-chondrocyte development.

Thiram is a kind of organic compound, which is commonly used for sterilization, insecticidal and deodorization in daily life. Its toxicology has been broadly studied. Recently, more and more microRNAs have been shown to participate in the regulation of cartilage development. However, the potential mechanism by which microRNA regulates chondrocyte growth is still unclear. Our experiments have demonstrated that thiram can hamper chondrocytes development and cause a significant increase in miR-203a content in vitro and in vivo trials. miR-203a mimic significantly decrease in mRNA and protein expression of Wnt4, Runx2, COL2A1, ß-catenin and ALP, and significantly enhance the mRNA and protein levels of GSK-3ß. It has been observed that overexpression of miR-203a hindered chondrocytes development. In addition, Runx2 was confirmed to be a direct target of miR-203a by dual luciferase report gene assay. Transfection of si-Runx2 into chondrocytes reveals that significant downregulation of genes is associated with cartilage development. Overall, these results suggest that overexpression of miR-203a inhibits the expression of Runx2. These findings are conducive to elucidate the mechanism of chondrocytes dysplasia induced by thiram and provide new research ideas for the toxicology of thiram.

Aldose reductase inhibition alleviates diabetic cardiomyopathy and is associated with a decrease in myocardial fatty acid oxidation.

BACKGROUND: Cardiovascular diseases, including diabetic cardiomyopathy, are major causes of death in people with type 2 diabetes. Aldose reductase activity is enhanced in hyperglycemic conditions, leading to altered cardiac energy metabolism and deterioration of cardiac function with adverse remodeling. Because disturbances in cardiac energy metabolism can promote cardiac inefficiency, we hypothesized that aldose reductase inhibition may mitigate diabetic cardiomyopathy via normalization of cardiac energy metabolism. METHODS: Male C57BL/6J mice (8-week-old) were subjected to experimental type 2 diabetes/diabetic cardiomyopathy (high-fat diet [60% kcal from lard] for 10 weeks with a single intraperitoneal injection of streptozotocin (75 mg/kg) at 4 weeks), following which animals were randomized to treatment with either vehicle or AT-001, a next-generation aldose reductase inhibitor (40 mg/kg/day) for 3 weeks. At study completion, hearts were perfused in the isolated working mode to assess energy metabolism. RESULTS: Aldose reductase inhibition by AT-001 treatment improved diastolic function and cardiac efficiency in mice subjected to experimental type 2 diabetes. This attenuation of diabetic cardiomyopathy was associated with decreased myocardial fatty acid oxidation rates (1.15 ± 0.19 vs 0.5 ± 0.1 µmol min-1 g dry wt-1 in the presence of insulin) but no change in glucose oxidation rates compared to the control group. In addition, cardiac fibrosis and hypertrophy were also mitigated via AT-001 treatment in mice with diabetic cardiomyopathy. CONCLUSIONS: Inhibiting aldose reductase activity ameliorates diastolic dysfunction in mice with experimental type 2 diabetes, which may be due to the decline in myocardial fatty acid oxidation, indicating that treatment with AT-001 may be a novel approach to alleviate diabetic cardiomyopathy in patients with diabetes.

Clonal Expansion and Dispersal Pathways of Puccinia polysora in China.

Southern corn rust (SCR) caused by Puccinia polysora is one of the most devastating diseases in the world. In recent years, SCR has been upgraded from a minor to a major disease around the world, including in China. However, little is known about its population genetics and structure in China. In this study, we analyzed 288 isolates collected from various localities during 2017 in seven Chinese provinces: Guangxi, Guangdong, Anhui, Hunan, Shandong, Henan, and Shaanxi. The isolates were analyzed using nine microsatellite markers. The population structure, genetic diversity, and reproduction mode of P. polysora were investigated based on genotype data. Strong genotypic diversity was detected and clonal reproduction was dominant. The populations collected from the pathogen's winter-reproductive regions harbored more genotypes than those collected from the pathogen's epidemic regions. The spatial differences in genotypic richness, and evenness among the populations were significant, and showed a decreasing trend from south to north. Most isolates were clustered into two clonal groups. Two high-frequency multilocus genotypes (MLGs), MLG1 and MLG2, were widely distributed in all populations. Our analyses confirmed that P. polysora employed clone dispersal from the pathogen's winter-reproductive regions to the pathogen's epidemic regions, and in addition to the sources from the pathogen's winter-reproductive regions, the pathogen in Anhui and Hunan might also have other sources from areas such as Taiwan, China, or/and Southeast Asia, and the pathogen went through a genetic bottleneck during its dispersal. These findings provide initial insights into the reproduction mode and dispersal pathways of P. polysora in China.

miR-181b-1-3p affects the proliferation and differentiation of chondrocytes in TD broilers through the WIF1/Wnt/ß-catenin pathway.

Thiram is a plant fungicide, its excessive use has exceeded the required environmental standards. It causes tibial dyschondroplasia (TD) in broilers which is a common metabolic disease that affects the growth plate of tibia bone. It has been studied that many microRNAs (miRNAs) are involved in the differentiation of chondrocytes however, their specific roles and mechanisms have not been fully investigated. The selected features of tibial chondrocytes of broilers were studied in this experiment which included the expression of miR-181b-1-3p and the genes related to WIF1/Wnt/ß-catenin pathway in chondrocytes through qRT-PCR, western blot and immunofluorescence. The correlation between miR-181b-1-3p and WIF1 was determined by dual luciferase reporter gene assay whereas, the role of miR-181b-1-3p and WIF1/Wnt/ß-catenin in chondrocyte differentiation was determined by mimics and inhibitor transfection experiments. Results revealed that thiram exposure resulted in decreased expression of miR-181b-1-3p and increased expression of WIF1 in chondrocytes. A negative correlation was also observed between miR-181b-1-3p and WIF1. After overexpression of miR-181b-1-3p, the expression of ACAN, ß-catenin and Col2a1 increased but the expression of GSK-3ß decreased. It was observed that inhibition of WIF1 increased the expression of ALP, ß-catenin, Col2a1 and ACAN but decreased the expression of GSK-3ß. It is concluded that miR-181b-1-3p can reverse the inhibitory effect of thiram on cartilage proliferation and differentiation by inhibiting WIF1 expression and activating Wnt/ß-catenin signaling pathway. This study provides a new molecular target for the early diagnosis and possible treatment of TD in broilers.

Vitamin C intake and multiple health outcomes: an umbrella review of systematic reviews and meta-analyses.

The purpose of this article was to assess the existing systematic reviews and meta-analyses for the association between vitamin C intake and multiple health outcomes. A total of 76 meta-analyses (51 papers) of randomised controlled trials and observational studies with 63 unique health outcomes were identified. Dose-response analysis showed that vitamin C intake was associated with reduced risk of all-cause mortality, cardiovascular disease (CVD), oesophageal cancer, gastric cancer, cervical cancer and lung cancer with an increment of 50-100 mg per day. Beneficial associations were also identified for respiratory, neurological, ophthalmologic, musculoskeletal, renal and dental outcomes. Harmful associations were found for breast cancer and kidney stones for vitamin C supplement intake. The benefits of vitamin C intake outweigh the disadvantages for a range of health outcomes. However, the recommendation of vitamin C supplements needs to be cautious. More prospective studies and well-designed randomised controlled trials (RCTs) are needed.

MicroRNA-16 is involved in the pathogenesis of pre-eclampsia via regulation of Notch2.

In recent years, the role of microRNAs (miRNAs) in pre-eclampsia (PE) has been demonstrated, while the relevant mechanisms of miR-16 in PE await to be unearthed. Thus, the aim of this study is to explore whether miR-16 exerts its function in PE, and we assumed that miR-16 may be implicated in the occurrence of PE by adjusting the biological functions of trophoblast cells via modulating Notch2. Placental tissues of pregnant women with normal pregnancy and PE were collected to detect the expression of miR-16, Notch2, and Notch3. The effects of miR-16 and Notch2 on the biological functions of BeWo and JEG-3 cells were further determined. Expression of miR-16 and Notch2 in trophoblast cells was detected by reverse transcription quantitative polymerase chain reaction and western blot assay. Downregulated Notch2 and upregulated miR-16 and Notch3 were found in placental tissues of PE. There was a negative correlation between Notch2 and miR-16 expression (r = -0.769), and a positive correlation between Notch3 and miR-16 expression (r = 0.676; p < .05). Overexpression of miR-16 inhibited proliferation, migration, and invasion, and facilitated the apoptosis of BeWo and JEG-3 cells, but overexpression of Notch2 reversed this trend. Overexpression of miR-16 inhibited Notch2 expression in BeWo and JEG-3 cells, and Notch2 was the target gene of miR-16. Our study highlights that overexpression of miR-16 is involved in PE by regulating the biological functions of trophoblast cells via inhibition of Notch2. This paper provides a new idea for further study of the pathogenesis of PE.

Osteoclast stimulatory transmembrane protein (OC-STAMP) is a promising molecular prognostic indicator for multiple myeloma.

BACKGROUND: Currently, the prognostic stratification and therapeutic evaluation systems for multiple myeloma (MM) lack specific molecular indicators. OC-STAMP is a new gene and is also highly expressed in MM. METHODS: A total of 160 MM patients have been investigated with both quantitative reverse transcription PCR (RT-qPCR), flow cytometry (FCM) and cytogenetic FISH on the same mononuclear cells isolated from bone marrow specimens. RESULTS: We found that OC-STAMP mRNA levels were significantly higher in newly diagnosed cases of MM than in healthy donors (median, 0.52% vs. 0.02%, P < .001). Moreover, the changes in the OC-STAMP mRNA levels paralleled the disease stages and minimal residual disease, as detected by FCM. Furthermore, we found that patients with high OC-STAMP mRNA levels were more likely to develop ≥3 bone lesions, be diagnosed with Durie-Salmon stages III, and have the P53 (17p13) deletion. In addition, advanced stage patients with high OC-STAMP mRNA levels had a lower 4-year progression-free survival (5.6% vs. 22.9%, P = .0055) and a worse 4-year overall survival (25.8% vs. 48.8%, P = .0137) compared to patients with low mRNA levels of this indicator. CONCLUSIONS: OC-STAMP may be a promising molecular indicator to monitor treatment effects and participate in the prognostic stratification of MM.

Influenced CD cells and ICAM-1 by pulmonary surfactant combined with high-frequency oscillatory ventilation and its effects on immune function in children with neonatal respiratory distress syndrome.

This study aimed to explore the clinical efficacy of pulmonary surfactant combined with high-frequency oscillatory ventilation (HFOV) on neonatal respiratory distress syndrome (NRDS) and its influence on immune function in children. Children admitted to our hospital from March 2017 to March 2019 who received HFOV combined with pulmonary surfactant therapy as a research group. Sixty-two children received conventional nasal continuous positive pressure combined with pulmonary surfactant therapy as a control group. Clinical efficacy, blood gas and immune function of patients were compared between the two groups. The clinical efficacy of the research group was better than that of the control group (P< 0.050). PaO2 and PaO2/FiO2 were both higher after treatment (P< 0.050). CD3+ and NK cells in the research group were higher than those in the control group, while CD8+ cells and ICAM-1 were lower than those in the control group (P< 0.050). CD3+, CD4+ and NK cells decreased in both groups after treatment, while CD8+ cells and ICAM-1 increased (P< 0.050). HFOV combined with pulmonary surfactant has significant clinical efficacy and high safety on NRDS, and has a certain protective effect on children's immune function. Hence, it is worthy of being the first choice for the clinical treatment of NRDS in the future.

Alcohol Consumption by Beverage Type and Risk of Breast Cancer: A Dose-Response Meta-Analysis of Prospective Cohort Studies.

AIMS: Alcohol intake has been shown to increase the risk of breast cancer. However, the dose-response analysis of different alcoholic beverages (spirits, wine and beer) is not clear. Our meta-analysis aims to provide a dose-response estimation between different alcohols and breast cancer risk. METHODS: Search of PubMed and Web of Science and manual searches were conducted up to 1 December 2018, and summary relative risks (RRs) and attributable risk percentage (ARP) for alcohol intake on the development of breast cancer were calculated. Dose-response meta-analysis modeled relationships between drinking type and breast cancer risk. Sources of heterogeneity were explored, and sensitivity analyses were conducted to test the robustness of findings. RESULTS: In total, 22 cohort studies and 45,350 breast cancer cases were included. Current drinkers for ER+ had an increased risk compared with never drinkers. In dose-response analysis, there was a statistically significant linear trend with breast cancer risk increasing gradually by total alcohol and wine dose: when adding 10 g per day, the risk increased by 10.5% (RR = 1.10, 95%CI = 1.08-1.13) in total alcohol and 8.9% (RR = 1.08, 95%CI = 1.04-1.14) in wine. For postmenopausal women, the risk increases by 11.1% (RR = 1.11, 95%CI = 1.09-1.13) with every 10 g of total alcohol increase. Furthermore, the breast cancer alcohol-attributed percentage is higher in Europe than in North America and Asia. CONCLUSIONS: The effect of drinking on the incidence of breast cancer is mainly manifested in ER+ breast cancer. Quantitative analysis showed total drinking had a significant risk for breast cancer, especially for postmenopausal women. However, for different alcohols, just wine intake has the similar results.

A dose-response meta-analysis of green tea consumption and breast cancer risk.

Whether drinking green tea (GT) could reduce the risk of breast cancer (BC) is still controversial. The search was performed using PubMed, Embase and Web of Science databases. The generalised least square method and constrained cubic spline model were performed to assess the dose-response trends between GT consumption and BC risk. The attributable risk proportion (ARP) was also calculated. A total of 16 studies were included and the pooled relative risks was 0.86 (95%CI: 0.75-0.99) for BC risk at the highest vs. lowest levels of GT consumption. GT consumption (pnonlinearity = .110), drinking GT years (pnonlinearity = .393) and BC risk were both negatively linearly correlated. Moreover, The ARP results demonstrated in China, people who drink GT do not suffer from BC, 23.5% of which may be attributed to drinking GT. In conclusion, drinking GT may have a positive effect on reducing BC risk, especially in long-term, high doses.

Multi-scale adversarial learning with difficult region supervision learning models for primary tumor segmentation.

Objective.Recently, deep learning techniques have found extensive application in accurate and automated segmentation of tumor regions. However, owing to the variety of tumor shapes, complex types, and unpredictability of spatial distribution, tumor segmentation still faces major challenges. Taking cues from the deep supervision and adversarial learning, we have devised a cascade-based methodology incorporating multi-scale adversarial learning and difficult-region supervision learning in this study to tackle these challenges.Approach.Overall, the method adheres to a coarse-to-fine strategy, first roughly locating the target region, and then refining the target object with multi-stage cascaded binary segmentation which converts complex multi-class segmentation problems into multiple simpler binary segmentation problems. In addition, a multi-scale adversarial learning difficult supervised UNet (MSALDS-UNet) is proposed as our model for fine-segmentation, which applies multiple discriminators along the decoding path of the segmentation network to implement multi-scale adversarial learning, thereby enhancing the accuracy of network segmentation. Meanwhile, in MSALDS-UNet, we introduce a difficult region supervision loss to effectively utilize structural information for segmenting difficult-to-distinguish areas, such as blurry boundary areas.Main results.A thorough validation of three independent public databases (KiTS21, MSD's Brain and Pancreas datasets) shows that our model achieves satisfactory results for tumor segmentation in terms of key evaluation metrics including dice similarity coefficient, Jaccard similarity coefficient, and HD95.Significance.This paper introduces a cascade approach that combines multi-scale adversarial learning and difficult supervision to achieve precise tumor segmentation. It confirms that the combination can improve the segmentation performance, especially for small objects (our codes are publicly availabled onhttps://zhengshenhai.github.io/).

Investigation on activation characterization, secondary electron yield, and surface resistance of novel quinary alloy Ti-Zr-V-Hf-Cu non-evaporable getters.

The performance of next-generation particle accelerators has been adversely affected by the occurrence of electron multipacting and vacuum instabilities. Particularly, minimization of secondary electron emission (SEE) and reduction of surface resistance are two critical issues to prevent some of the phenomena such as beam instability, reduction of beam lifetime, and residual gas ionization, all of which occur as a result of these adverse effects in next-generation particle accelerators. For the first time, novel quinary alloy Ti-Zr-V-Hf-Cu non-evaporable getter (NEG) films were prepared on stainless steel substrates by using the direct current magnetron sputtering technique to reduce surface resistance and SEE yield with an efficient pumping performance. Based on the experimental findings, the surface resistance of the quinary Ti-Zr-V-Hf-Cu NEG films was established to be 6.6 × 10-7 Ω m for sample no. 1, 6.4 × 10-7 Ω m for sample no. 2, and 6.2 × 10-7 Ω m for sample no. 3. The δmax measurements recorded for Ti-Zr-V-Hf-Cu NEG films are 1.33 for sample no. 1, 1.34 for sample no. 2, and 1.35 for sample no. 3. Upon heating the Ti-Zr-V-Hf-Cu NEG film to 150 °C, the XPS spectra results indicated that there are significant changes in the chemical states of its constituent metals, Ti, Zr, V, Hf, and Cu, and these chemical state changes continued with heating at 180 °C. This implies that upon heating at 150 °C, the Ti-Zr-V-Hf-Cu NEG film becomes activated, showing that novel quinary NEG films can be effectively employed as getter pumps for generating ultra-high vacuum conditions.

Ketones provide an extra source of fuel for the failing heart without impairing glucose oxidation.

BACKGROUND: Cardiac glucose oxidation is decreased in heart failure with reduced ejection fraction (HFrEF), contributing to a decrease in myocardial ATP production. In contrast, circulating ketones and cardiac ketone oxidation are increased in HFrEF. Since ketones compete with glucose as a fuel source, we aimed to determine whether increasing ketone concentration both chronically with the SGLT2 inhibitor, dapagliflozin, or acutely in the perfusate has detrimental effects on cardiac glucose oxidation in HFrEF, and what effect this has on cardiac ATP production. METHODS: 8-week-old male C57BL6/N mice underwent sham or transverse aortic constriction (TAC) surgery to induce HFrEF over 3 weeks, after which TAC mice were randomized to treatment with either vehicle or the SGLT2 inhibitor, dapagliflozin (DAPA), for 4 weeks (raises blood ketones). Cardiac function was assessed by echocardiography. Cardiac energy metabolism was measured in isolated working hearts perfused with 5 mM glucose, 0.8 mM palmitate, and either 0.2 mM or 0.6 mM ß-hydroxybutyrate (ßOHB). RESULTS: TAC hearts had significantly decreased %EF compared to sham hearts, with no effect of DAPA. Glucose oxidation was significantly decreased in TAC hearts compared to sham hearts and did not decrease further in TAC hearts treated with high ßOHB or in TAC DAPA hearts, despite ßOHB oxidation rates increasing in both TAC vehicle and TAC DAPA hearts at high ßOHB concentrations. Rather, increasing ßOHB supply to the heart selectively decreased fatty acid oxidation rates. DAPA significantly increased ATP production at both ßOHB concentrations by increasing the contribution of glucose oxidation to ATP production. CONCLUSION: Therefore, increasing ketone concentration increases energy supply and ATP production in HFrEF without further impairing glucose oxidation.

Mitochondrial fatty acid oxidation is the major source of cardiac adenosine triphosphate production in heart failure with preserved ejection fraction.

AIMS: Heart failure with preserved ejection fraction (HFpEF) is a prevalent disease worldwide. While it is well established that alterations of cardiac energy metabolism contribute to cardiovascular pathology, the precise source of fuel used by the heart in HFpEF remains unclear. The objective of this study was to define the energy metabolic profile of the heart in HFpEF. METHODS AND RESULTS: Eight-week-old C57BL/6 male mice were subjected to a '2-Hit' HFpEF protocol [60% high-fat diet (HFD) + 0.5 g/L of Nω-nitro-L-arginine methyl ester]. Echocardiography and pressure-volume loop analysis were used for assessing cardiac function and cardiac haemodynamics, respectively. Isolated working hearts were perfused with radiolabelled energy substrates to directly measure rates of fatty acid oxidation, glucose oxidation, ketone oxidation, and glycolysis. HFpEF mice exhibited increased body weight, glucose intolerance, elevated blood pressure, diastolic dysfunction, and cardiac hypertrophy. In HFpEF hearts, insulin stimulation of glucose oxidation was significantly suppressed. This was paralleled by an increase in fatty acid oxidation rates, while cardiac ketone oxidation and glycolysis rates were comparable with healthy control hearts. The balance between glucose and fatty acid oxidation contributing to overall adenosine triphosphate (ATP) production was disrupted, where HFpEF hearts were more reliant on fatty acid as the major source of fuel for ATP production, compensating for the decrease of ATP originating from glucose oxidation. Additionally, phosphorylated pyruvate dehydrogenase levels decreased in both HFpEF mice and human patient's heart samples. CONCLUSION: In HFpEF, fatty acid oxidation dominates as the major source of cardiac ATP production at the expense of insulin-stimulated glucose oxidation.

High level of winter warming aggravates soil carbon, nitrogen loss and changes greenhouse gas emission characteristics in seasonal freeze-thaw farmland soil.

Changes in the soil environment caused by winter warming is affecting the carbon and nitrogen cycles of seasonal freeze-thaw farmland soil. A field experiment was conducted in a seasonal freeze-thaw farmland soil of northeast China to investigate the effects caused from different levels of warming (W1 + 1.77 °C, W2 + 0.69 °C and C + 0 °C) on soil carbon and nitrogen dynamics, microbial biomass and greenhouse gases fluxes. During the early and middle winter, the contents of all kinds of soil carbon and nitrogen (Ammonium, nitrate, total nitrogen, dissolved organic carbon, readily oxidizable organic carbon and soil organic carbon) tended to increase with the increase of warming level, while during the late winter, their contents under different temperature treatments roughly present trend of W2 ≥C > W1. Except for the late thawing period, warming increased the contents of soil microbial biomass carbon and nitrogen, during the late thawing period, with the increase of warming level, MBC and MBN decreased significantly. Warming would stimulate the release of greenhouse gases from soil. But due to the differences of soil environmental conditions in each period and soil nutrient dynamics under different treatments, which made the effects of different levels of warming on soil GHGs fluxes in different periods are different. Our study suggested that low-level warming improved the availability of soil carbon and nitrogen, increased the contents of microbial biomass and greenhouse gas emissions. However, although high-level winter warming showed a similar phenomenon in the early and middle winter to the low-level warming, during the late winter, high-level warming increased soil nutrients loss and broke the seasonal coupling relationship between crop nutrient acquisition and soil microbial nutrient supply, and even led to the adaptation of soil CO2 release to it. This is of great significance for exploring the carbon and nitrogen cycle mechanisms of global terrestrial ecosystem.

Water Corrosion of Tungsten Target for Accelerator-Driven Neutron Source.

The water corrosion of tungsten as a target material can affect the safe operation of accelerator-driven neutron source. This paper reported the corrosion behaviors of tungsten in ultrapure water and tap water for 7, 14, 21, 30 and 60 days. Moreover, ICP-MS, XRD, XPS, SEM-EDS and LSCM were used to analyze the components in solutions, crystalline structures, chemical compositions and surface morphologies. It was found that the dissolution of tungsten, due to corrosion, reached its maximum between 30 days and 60 days in both solutions. The cube-shape substance, CaWO4, was the main corrosion product after tungsten in tap water. The tungsten oxide was changed from WO3 to WO2 during the corrosion of tungsten in ultrapure water. Compared with tungsten in ultrapure water, tungsten in tap water had its surface completely destroyed, with a dense diamond shape. Therefore, based on the analysis from this study, the corrosion mechanisms of tungsten in ultrapure and tap water were revealed.