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Myocardial edema is a consequence of many cardiovascular stressors, including myocardial infarction, cardiac bypass surgery, and hypertension. The aim of this study was to establish a murine model of myocardial edema and elucidate the response of cardiac lymphatics and the myocardium. Myocardial edema without infarction was induced in mice by cauterizing the coronary sinus, increasing pressure in the coronary venous system, and inducing myocardial edema. In male mice, there was rapid development of edema 3 h following coronary sinus cauterization (CSC), with associated dilation of cardiac lymphatics. By 24 h, males displayed significant cardiovascular contractile dysfunction. In contrast, female mice exhibited a temporal delay in the formation of myocardial edema, with onset of cardiovascular dysfunction by 24 h. Furthermore, myocardial edema induced a ring of fibrosis around the epicardial surface of the left ventricle in both sexes that included fibroblasts, immune cells, and increased lymphatics. Interestingly, the pattern of fibrosis and the cells that make up the fibrotic epicardial ring differ between sexes. We conclude that a novel surgical model of myocardial edema without infarct was established in mice. Cardiac lymphatics compensated by exhibiting both an acute dilatory and chronic growth response. Transient myocardial edema was sufficient to induce a robust epicardial fibrotic and inflammatory response, with distinct sex differences, which underscores the sex-dependent differences that exist in cardiac vascular physiology. NEW & NOTEWORTHY Myocardial edema is a consequence of many cardiovascular stressors, including myocardial infarction, cardiac bypass surgery, and high blood pressure. Cardiac lymphatics regulate interstitial fluid balance and, in a myocardial infarction model, have been shown to be therapeutically targetable by increasing heart function. Cardiac lymphatics have only rarely been studied in a noninfarct setting in the heart, and so we characterized the first murine model of increased coronary sinus pressure to induce myocardial edema, demonstrating distinct sex differences in the response to myocardial edema. The temporal pattern of myocardial edema induction and resolution is different between males and females, underscoring sex-dependent differences in the response to myocardial edema. This model provides an important platform for future research in cardiovascular and lymphatic fields with the potential to develop therapeutic interventions for many common cardiovascular diseases.

The complex and inaccessible space radiation environment poses an unresolved risk to astronaut cardiovascular health during long-term space exploration missions. To model this risk, healthy male c57BL/6 mice aged six months (corresponding to an astronaut of 34 years) were exposed to simplified galactic cosmic ray (GCR

The enhancements in boiling heat transfer, i.e., critical heat flux (CHF) and heat transfer coefficient (HTC) can bring immediate benefits to improve the safety, efficiency and cost of heat energy transfer and conversion systems, leading to substantial global energy savings and reduction in greenhouse gas emissions. The enhanced boiling surfaces with great durability are highly desired for energy-intensive industrial applications. Here an optimized graphene oxide (GO) self-assembly surface for significantly enhanced boiling is developed, which could be readily fabricated utilizing the nucleate boiling self-assembly method. The optimal GO boiling surface produces remarkable improvements in boiling heat transfer performance (a CHF of 261 W cm-2 and a HTC of 9.1 W cm-2 K−1), which is among the highest values ever reported for pool boiling heat transfer on the planar enhanced surfaces. Additionally, it shows a good durability. The prominent performance can be attributed to the formation of interconnected and highly thermally conductive GO laminate film with moderate thickness on the substrate, which facilitates rapid cooling and rewetting of the local hot/dry regions, as well as bubble nucleation, thereby delay the occurrence of film boiling regime. The proposed strategy in current work is highly scalable and possesses enormous potentials in pragmatic applications.

Reversible ubiquitination of G protein–coupled receptors regulates their trafficking and signaling; whether deubiquitinases regulate myocardial β1-adrenergic receptors (β1ARs) is unknown. We report that ubiquitin-specific protease 20 (USP20) deubiquitinates and attenuates lysosomal trafficking of the β1AR. β1AR-induced phosphorylation of USP20 Ser-333 by protein kinase A-α (PKAα) was required for optimal USP20-mediated regulation of β1AR lysosomal trafficking. Both phosphomimetic (S333D) and phosphorylation-impaired (S333A) USP20 possess intrinsic deubiquitinase activity equivalent to WT activity. However, unlike USP20 WT and S333D, the S333A mutant associated poorly with the β1AR and failed to deubiquitinate the β1AR. USP20–KO mice showed normal baseline systolic function but impaired β1AR-induced contractility and relaxation. Dobutamine stimulation did not increase cAMP in USP20–KO left ventricles (LVs), whereas NKH477-induced adenylyl cyclase activity was equivalent to WT. The USP20 homolog USP33, which shares redundant roles with USP20, had no effect on β1AR ubiquitination, but USP33 was up-regulated in USP20–KO hearts suggesting compensatory regulation. Myocardial β1AR expression in USP20–KO was drastically reduced, whereas β2AR expression was maintained as determined by radioligand binding in LV sarcolemmal membranes. Phospho-USP20 was significantly increased in LVs of wildtype (WT) mice after a 1-week catecholamine infusion and a 2-week chronic pressure overload induced by transverse aortic constriction (TAC). Phospho-USP20 was undetectable in β1AR KO mice subjected to TAC, suggesting a role for USP20 phosphorylation in cardiac response to pressure overload. We conclude that USP20 regulates β1AR signaling in vitro and in vivo. Additionally, β1AR-induced USP20 phosphorylation may serve as a feed-forward mechanism to stabilize β1AR expression and signaling during pathological insults to the myocardium.

Progesterone is primarily a pregnancy-related hormone, produced in substantial quantities after ovulation and during gestation. Traditionally known to function via nuclear receptors for transcriptional regulation, there is also evidence of nonnuclear action. A previously identified mitochondrial progesterone receptor (PR-M) increases cellular respiration in cell models. In these studies, we demonstrated that expression of PR-M in rat H9c2 cardiomyocytes resulted in a ligand-dependent increase in oxidative cellular respiration and beta-oxidation. Cardiac expression in a TET-On transgenic mouse resulted in gene expression of myofibril proteins for remodeling and proteins involved in oxidative phosphorylation and fatty acid metabolism. In a model of increased afterload from constant transverse aortic constriction, mice expressing PR-M showed a ligand-dependent preservation of cardiac function. From these observations, we propose that PR-M is responsible for progesterone-induced increases in cellular energy production and cardiac remodeling to meet the physiological demands of pregnancy.

Traditionally, it’s thought that pool boiling is the most efficient technique to solve the heat dissipation in many thermal management systems due to the huge latent heat of evaporation. Employing nanofluids to enhance pool boiling heat transfer has been widely investigated for the last decade. And among the various nanomaterials, carbon nanotubes (CNTs) have been referred to the most promising nanomaterials because of their superior thermal properties.

This paper analyses the unusual mal-operation of the differential protection for transformer current differential protection during the external fault. The mal-operation reason is researched in detail, based on the mathematical analysis, the simulation, and the field recorded fault data analysis. It is disclosed that the CT saturation leads to the maloperation. Based on this, this paper analyses the improvement for the CT saturation identification method, and discusses the CT selection principles. This paper is aimed at attracting the attention on the problem of the CT saturation and proposing the reference of the analysis method the countermeasure for this problem.

This paper discusses on the protection scheme for the novel flexible short circuit current suppression technology, which applies the new-type fast circuit breaker. The challenges of rapidity, selectivity and reliability for the protection are analyzed. The technology principle of the protection is formulated. The improvement project and the logic coordination under different space levels and time scales is proposed. These new method is to guarantee the safe and sound operation of the power system in the new scenario that applies the novel flexible short circuit current suppression technology.

In order to promote the practice on the DG (distributed generation) technology, this paper introduces the theory research and engineering practice on the protection and control method of the DG system, based on an IDC DG engineering. The basic information and the characteristic of the engineering is described. The general control target and the operation mode under different condition is analyzed, considering the operative characteristics and the requirements of the power substation, the DG and the customer. The coordination scheme between the power grid, the DG and the load is proposed innovatively. The priority and the logical sequence of the control from different part are determined. The practical experiment proves that the protection and control system can provide reliable and efficient power and refrigeration supply for the IDC data central via the coordinated control method of the operation mode shift, SPAS (spare power automatic switchover), load transferring and the black-start, with the coordination of the power grid, the DG and the load. Under the extreme case that the outside power is totally lost, the power and refrigeration supply can be recovered within 155 seconds.

Background and purpose Late cardiac toxicity is a major side effect of radiation therapy (RT) for breast cancer. We developed and characterized a mouse model of radiation-induced heart disease that mimics the dose, fractionation, and beam arrangement of left breast and chest wall RT. Material and methods Female wild-type (C57BL6/J) and atherosclerosis-prone apolipoprotein E-deficient (ApoE−/−) mice (on a C57BL/6J background) on regular chow were treated with 2 Gy × 25 fractions of partial-heart irradiation via opposed tangential beams to the left chest wall. The changes in myocardial perfusion and cardiac function of C57BL/6J mice were examined by single-photon emission computed tomography (SPECT) and echocardiography, respectively. In addition to SPECT and echocardiography, the formation of calcified plaques and changes in cardiac function of ApoE−/− mice were examined by dual-energy microCT (DE-CT) and pressure–volume (PV) loop analysis, respectively. The development of myocardial fibrosis was examined by histopathology. Results Compared to unirradiated controls, irradiated C57BL/6J mice showed no significant changes by SPECT or echocardiography up to 18 months after 2 Gy × 25 partial-heart irradiation even though irradiated mice exhibited a modest increase in myocardial fibrosis. For ApoE−/− mice, 2 Gy × 25 partial-heart irradiation did not cause significant changes by SPECT, DE-CT, or echocardiography. However, PV loop analysis revealed a significant decrease in load-dependent systolic and diastolic function measures including cardiac output, dV/dtmax and dV/dt min 12 months after RT. Conclusions Following clinically relevant doses of partial-heart irradiation in C57BL/6J and ApoE−/− mice, assessment with noninvasive imaging modalities such as echocardiography, SPECT, and DE-CT yielded no evidence of decreased myocardial perfusion and cardiac dysfunction related to RT. However, invasive hemodynamic assessment with PV loop analysis indicated subtle, but significant, changes in cardiac function of irradiated ApoE−/− mice. PV loop analysis may be useful for future preclinical studies of radiation-induced heart disease, especially if subtle changes in cardiac function are expected.

A decrease in skeletal muscle strength and functional exercise capacity due to aging, frailty, and muscle wasting poses major unmet clinical needs. These conditions are associated with numerous adverse clinical outcomes including falls, fractures, and increased hospitalization. Clenbuterol, a β(2)-adrenergic receptor (β(2)AR) agonist enhances skeletal muscle strength and hypertrophy; however, its clinical utility is limited by side effects such as cardiac arrhythmias mediated by G protein signaling. We recently reported that clenbuterol-induced increases in contractility and skeletal muscle hypertrophy were lost in β-arrestin 1 knockout mice, implying that arrestins, multifunctional adapter and signaling proteins, play a vital role in mediating the skeletal muscle effects of β(2)AR agonists. Carvedilol, classically defined as a βAR antagonist, is widely used for the treatment of chronic systolic heart failure and hypertension, and has been demonstrated to function as a β-arrestin-biased ligand for the β(2)AR, stimulating β-arrestin-dependent but not G protein-dependent signaling. In this study, we investigated whether treatment with carvedilol could enhance skeletal muscle strength via β-arrestin-dependent pathways. In a murine model, we demonstrate chronic treatment with carvedilol, but not other β-blockers, indeed enhances contractile force in skeletal muscle and this is mediated by β-arrestin 1. Interestingly, carvedilol enhanced skeletal muscle contractility despite a lack of effect on skeletal muscle hypertrophy. Our findings suggest a potential unique clinical role of carvedilol to stimulate skeletal muscle contractility while avoiding the adverse effects with βAR agonists. This distinctive signaling profile could present an innovative approach to treating sarcopenia, frailty, and secondary muscle wasting.

An increasing body of evidence suggests that bone marrow–derived myeloid cells play a critical role in the pathophysiology of pulmonary hypertension (PH). However, the true requirement for myeloid cells in PH development has not been demonstrated, and a specific disease-promoting myeloid cell population has not been identified. Using bone marrow chimeras, lineage labeling, and proliferation studies, we determined that, in murine hypoxia-induced PH, Ly6Clo nonclassical monocytes are recruited to small pulmonary arteries and differentiate into pulmonary interstitial macrophages. Accumulation of these nonclassical monocyte–derived pulmonary interstitial macrophages around pulmonary vasculature is associated with increased muscularization of small pulmonary arteries and disease severity. To determine if the sensing of hypoxia by nonclassical monocytes contributes to the development of PH, mice lacking expression of hypoxia-inducible factor-1α in the Ly6Clo monocyte lineage were exposed to hypoxia. In these mice, vascular remodeling and PH severity were significantly reduced. Transcriptome analyses suggest that the Ly6Clo monocyte lineage regulates PH through complement, phagocytosis, Ag presentation, and chemokine/cytokine pathways. Consistent with these murine findings, relative to controls, lungs from pulmonary arterial hypertension patients displayed a significant increase in the frequency of nonclassical monocytes. Taken together, these findings show that, in response to hypoxia, nonclassical monocytes in the lung sense hypoxia, infiltrate small pulmonary arteries, and promote vascular remodeling and development of PH. Our results demonstrate that myeloid cells, specifically cells of the nonclassical monocyte lineage, play a direct role in the pathogenesis of PH.

Cardiac two-pore domain potassium channels (K2P) exist in organisms from Drosophila to humans; however, their role in cardiac function is not known. We identified a K2P gene, CG8713 (sandman), in a Drosophila genetic screen and show that sandman is critical to cardiac function. Mice lacking an ortholog of sandman, TWIK-related potassium channel (TREK-1, also known Kcnk2), exhibit exaggerated pressure overload-induced concentric hypertrophy and alterations in fetal gene expression, yet retain preserved systolic and diastolic cardiac function. While cardiomyocyte-specific deletion of TREK-1 in response to in vivo pressure overload resulted in cardiac dysfunction, TREK-1 deletion in fibroblasts prevented deterioration in cardiac function. The absence of pressure overload-induced dysfunction in TREK-1-KO mice was associated with diminished cardiac fibrosis and reduced activation of JNK in cardiomyocytes and fibroblasts. These findings indicate a central role for cardiac fibroblast TREK-1 in the pathogenesis of pressure overload-induced cardiac dysfunction and serve as a conceptual basis for its inhibition as a potential therapy.

Objective: To explore the differences in the effect of peroral traction-assisted endoscopic submucosal dissection (ESD) and traditional ESD for the treatment of early gastric cancer and precancerous lesions. Methods: 112 patients with early gastric cancer and precancerous lesions treated in our hospital between May 2013 and May 2016 were collected and divided into control group and observation group according to the random number table (n=56). Observation group of patients received peroral traction-assisted ESD, and the control group of patients only received traditional ESD. The intraoperative dissected lesion diameter, mean operation time and intraoperative blood loss of two groups of patients were recorded, enzyme-linked immunosorbent assay was used to detect serum inflammatory factor levels, and RIA was used to detect serum stress hormone levels. Results: Dissected lesion diameter of observation group was greater than that of control group (P

In response to heart injury, inflammation, or mechanical overload, quiescent cardiac fibroblasts (CFs) can become activated myofibroblasts leading to pathological matrix remodeling and decline in cardiac function. Specific targeting of fibroblasts may thus enable new therapeutic strategies to delay or reverse the progression of heart failure and cardiac fibrosis. However, it remains unknown if all CFs are equally responsive to specific pathological insults and if there exist sub-populations of resident fibroblasts in the heart that have distinctive pathogenic phenotypes. Here, we show that in response to transverse aortic constriction (TAC)-induced heart failure, previously uncharacterized Thy1neg (Thy1-/MEFSK4+/CD45-/CD31-) fraction of mouse ventricular fibroblasts became more abundant and attained a more activated, pro-fibrotic myofibroblast phenotype compared to Thy1Pos fraction. In a tissue-engineered 3D co-culture model of healthy cardiomyocytes and freshly isolated CFs, Thy1neg CFs from TAC hearts significantly decreased cardiomyocyte contractile function and calcium transient amplitude, and increased extracellular collagen deposition yielding a profibrotic heart tissue phenotype. In vivo, mice with global knockout of Thy1 developed more severe cardiac dysfunction and fibrosis in response to TAC-induced heart failure than wild-type mice. Taken together, our studies identify cardiac myofibroblasts lacking Thy1 as a pathogenic CF fraction in cardiac fibrosis and suggest important roles of Thy1 in pathophysiology of heart failure.

The Frank-Starling law of the heart is a physiological phenomenon that describes an intrinsic property of heart muscle in which increased cardiac filling leads to enhanced cardiac contractility. Identified more than a century ago, the Frank-Starling relationship is currently known to involve length-dependent enhancement of cardiac myofilament Ca2+ sensitivity. However, the upstream molecular events that link cellular stretch to the length-dependent myofilament Ca2+ sensitivity are poorly understood. Because the angiotensin II type 1 receptor (AT1R) and the multifunctional transducer protein β-arrestin have been shown to mediate mechanosensitive cellular signaling, we tested the hypothesis that these two proteins are involved in the Frank-Starling mechanism of the heart. Using invasive hemodynamics, we found that mice lacking β-arrestin 1, β-arrestin 2, or AT1R were unable to generate a Frank-Starling force in response to changes in cardiac volume. Although wild-type mice pretreated with the conventional AT1R blocker losartan were unable to enhance cardiac contractility with volume loading, treatment with a β-arrestin-biased AT1R ligand to selectively activate β-arrestin signaling preserved the Frank-Starling relationship. Importantly, in skinned muscle fiber preparations, we found markedly impaired length-dependent myofilament Ca2+ sensitivity in β-arrestin 1, β-arrestin 2, and AT1R knockout mice. Our data reveal β-arrestin 1, β-arrestin 2, and AT1R as key regulatory molecules in the Frank-Starling mechanism, which potentially can be targeted therapeutically with β-arrestin-biased AT1R ligands.

The superior boiling surfaces obtained by facile, efficient and economical approaches are highly desirable in large-scale industrial applications. Here, a microporous copper surface for enhanced boiling was readily and rapidly prepared by utilizing a single-step and low-cost wire cutting electric discharge machining process. The saturated pool boiling tests on the microporous and plain copper surfaces were conducted at atmospheric pressure using distilled water as working fluid. The significant boiling performance enhancements are demonstrated on the microporous copper surface. It achieves a heat transfer coefficient (HTC) of 16.7 W cm−2 K−1, a critical heat flux (CHF) of 185.7 W cm−2 and a onset of nucleate boiling (ONB) at 4.4 K, indicating a 198% higher HTC, a 61% higher CHF, as well as a 47% lower ONB compared with the plain surface. The enhanced boiling mechanism is explained based on the surface characteristics. The formation of numerous microscale cavities facilitates bubble nucleation, departure for reducing ONB and increasing HTC, and improves surface wettability for delaying CHF. The visualization investigations of bubble behaviors were also conducted for further verifying our analysis. The results show the microporous copper surface exhibits a larger nucleation density, departure frequency, and a smaller departure diameter of bubble.

The graphene oxide (GO) nanocoating surface was fabricated by GO nanoparticles self-assembly on plain copper surface under nucleate pool boiling. Saturated and subcooled pool boiling experiments on GO nanocoating surface with distilled water at atmospheric pressure were conducted. Saturated pool boiling performance indicated enhancements of 78% in critical heat flux (CHF) and 41% in maximum heat transfer coefficient (HTC) when compared with the plain copper surface. It was found that the enhancement was mainly attributed to the improved wettability and high thermal conductivity of GO nanocoating, as well as the increased surface roughness. Subcooled pool boiling results showed that the liquid subcooling had significant effect on heat transfer performance of GO nanocoating surface. The CHF increased linearly with the increased subcooling degree, and the maximum HTC increased almost linearly with the increased subcooling degree. The CHF reached 274 W/cm2 at subcooling degree of 19 K, which translated an enhancement of 128% when compared with the plain copper surface. This high CHF can address the heat dissipation bottleneck in ultra high-power density electronic devices. To better understand the subcooling effect on nucleate boiling, visualization studies on bubble growth characteristics at subcooled pool boiling were investigated with a high-speed digital camera. It was shown that bubbles were smaller and grew more slowly with the increase of liquid subcooling, and microbubble jets were observed at moderate heat flux regime.

Background β2-adrenergic receptors (β2ARs) are the target of catecholamines and play fundamental roles in cardiovascular, pulmonary, and skeletal muscle physiology. An important action of β2AR stimulation on skeletal muscle is anabolic growth, which has led to the use of agonists such as clenbuterol by athletes to enhance muscle performance. While previous work has demonstrated that β2ARs can engage distinct signaling and functional cascades mediated by either G proteins or the multifunctional adaptor protein, β-arrestin, the precise role of β-arrestin in skeletal muscle physiology is not known. Here, we tested the hypothesis that agonist activation of the β2AR by clenbuterol would engage β-arrestin as a key transducer of anabolic skeletal muscle growth. Methods The contractile force of isolated extensor digitorum longus muscle (EDL) and calcium signaling in isolated flexor digitorum brevis (FDB) fibers were examined from the wild-type (WT) and β-arrestin 1 knockout mice (βarr1KO) followed by chronic administration of clenbuterol (1 mg/kg/d). Hypertrophic responses including fiber composition and fiber size were examined by immunohistochemical imaging. We performed a targeted phosphoproteomic analysis on clenbuterol stimulated primary cultured myoblasts from WT and βarr1KO mice. Statistical significance was determined by using a two-way analysis with Sidak’s or Tukey’s multiple comparison test and the Student’s t test. Results Chronic administration of clenbuterol to WT mice enhanced the contractile force of EDL muscle and calcium signaling in isolated FDB fibers. In contrast, when administered to βarr1KO mice, the effect of clenbuterol on contractile force and calcium influx was blunted. While clenbuterol-induced hypertrophic responses were observed in WT mice, this response was abrogated in mice lacking β-arrestin 1. In primary cultured myoblasts, clenbuterol-stimulated phosphorylation of multiple pro-hypertrophy proteins required the presence of β-arrestin 1. Conclusions We have identified a previously unappreciated role for β-arrestin 1 in mediating β2AR-stimulated skeletal muscle growth and strength. We propose these findings could have important implications in the design of future pharmacologic agents aimed at reversing pathological conditions associated with skeletal muscle wasting. Electronic supplementary material The online version of this article (10.1186/s13395-018-0184-8) contains supplementary material, which is available to authorized users.

Reversible ubiquitination of G protein–coupled receptors regulates their trafficking and signaling; whether deubiquitinases regulate myocardial β(1)-adrenergic receptors (β(1)ARs) is unknown. We report that ubiquitin-specific protease 20 (USP20) deubiquitinates and attenuates lysosomal trafficking of the β(1)AR. β(1)AR-induced phosphorylation of USP20 Ser-333 by protein kinase A-α (PKAα) was required for optimal USP20-mediated regulation of β(1)AR lysosomal trafficking. Both phosphomimetic (S333D) and phosphorylation-impaired (S333A) USP20 possess intrinsic deubiquitinase activity equivalent to WT activity. However, unlike USP20 WT and S333D, the S333A mutant associated poorly with the β(1)AR and failed to deubiquitinate the β(1)AR. USP20–KO mice showed normal baseline systolic function but impaired β(1)AR-induced contractility and relaxation. Dobutamine stimulation did not increase cAMP in USP20–KO left ventricles (LVs), whereas NKH477-induced adenylyl cyclase activity was equivalent to WT. The USP20 homolog USP33, which shares redundant roles with USP20, had no effect on β(1)AR ubiquitination, but USP33 was up-regulated in USP20–KO hearts suggesting compensatory regulation. Myocardial β(1)AR expression in USP20–KO was drastically reduced, whereas β(2)AR expression was maintained as determined by radioligand binding in LV sarcolemmal membranes. Phospho-USP20 was significantly increased in LVs of wildtype (WT) mice after a 1-week catecholamine infusion and a 2-week chronic pressure overload induced by transverse aortic constriction (TAC). Phospho-USP20 was undetectable in β(1)AR KO mice subjected to TAC, suggesting a role for USP20 phosphorylation in cardiac response to pressure overload. We conclude that USP20 regulates β(1)AR signaling in vitro and in vivo. Additionally, β(1)AR-induced USP20 phosphorylation may serve as a feed-forward mechanism to stabilize β(1)AR expression and signaling during pathological insults to the myocardium.

Type 1 diabetes (T1D) is an autoimmune disease in which cells of the immune system destroy pancreatic β cells, which secrete insulin. The high prevalence of T1D in developed societies may be explained by environmental changes, including lower exposure to helminths. Indeed, infection by helminths such as Schistosoma, Filaria, and Heligmosomoides polygyrus and their by-products has been reported to ameliorate or prevent the development of T1D in human and animal models. Helminths can trigger distinct immune regulatory pathways, often involving adaptive immune cells that include T helper 2 (Th2) cells and regulatory T cells (Tregs) and innate immune cells that include dendritic cells, macrophages, and invariant natural killer T cells, which may act synergistically to induce Tregs in a Toll-like receptor-dependent manner. Cytokines such as interleukin (IL)-4, IL-10, and transforming growth factor (TGF)-β also play an important role in protection from T1D. Herein, we provide a comprehensive review of the effects and mechanisms underlying protection against T1D by helminths.

The oncoprotein Mdm2 is a RING domain-containing E3 ubiquitin ligase that ubiquitinates G protein-coupled receptor kinase 2 (GRK2) and β-arrestin2, thereby regulating β-adrenergic receptor (βAR) signaling and endocytosis. Previous studies showed that cardiac Mdm2 expression is critical for controlling p53-dependent apoptosis during early embryonic development, but the role of Mdm2 in the developed adult heart is unknown. We aimed to identify if Mdm2 affects βAR signaling and cardiac function in adult mice. Using Mdm2/p53-KO mice, which survive for 9-12 months, we identified a critical and potentially novel role for Mdm2 in the adult mouse heart through its regulation of cardiac β1AR signaling. While baseline cardiac function was mostly similar in both Mdm2/p53-KO and wild-type (WT) mice, isoproterenol-induced cardiac contractility in Mdm2/p53-KO was significantly blunted compared with WT mice. Isoproterenol increased cAMP in left ventricles of WT but not of Mdm2/p53-KO mice. Additionally, while basal and forskolin-induced calcium handling in isolated Mdm2/p53-KO and WT cardiomyocytes were equivalent, isoproterenol-induced calcium handling in Mdm2/p53-KO was impaired. Mdm2/p53-KO hearts expressed 2-fold more GRK2 than WT. GRK2 polyubiquitination via lysine-48 linkages was significantly reduced in Mdm2/p53-KO hearts. Tamoxifen-inducible cardiomyocyte-specific deletion of Mdm2 in adult mice also led to a significant increase in GRK2, and resulted in severely impaired cardiac function, high mortality, and no detectable βAR responsiveness. Gene delivery of either Mdm2 or GRK2-CT in vivo using adeno-associated virus 9 (AAV9) effectively rescued β1AR-induced cardiac contractility in Mdm2/p53-KO. These findings reveal a critical p53-independent physiological role of Mdm2 in adult hearts, namely, regulation of GRK2-mediated desensitization of βAR signaling.

In mitochondria, the sirtuin SIRT5 is an NAD+-dependent protein deacylase that controls several metabolic pathways. Although a wide range of SIRT5 targets have been identified, the overall function of SIRT5 in organismal metabolic homeostasis remains unclear. Given that SIRT5 expression is highest in the heart and that sirtuins are commonly stress-response proteins, we used an established model of pressure overload-induced heart muscle hypertrophy caused by transverse aortic constriction (TAC) to determine SIRT5's role in cardiac stress responses. Remarkably, SIRT5KO mice had reduced survival upon TAC compared with wild-type mice but exhibited no mortality when undergoing a sham control operation. The increased mortality with TAC was associated with increased pathological hypertrophy and with key abnormalities in both cardiac performance and ventricular compliance. By combining high-resolution MS-based metabolomic and proteomic analyses of cardiac tissues from wild-type and SIRT5KO mice, we found several biochemical abnormalities exacerbated in the SIRT5KO mice, including apparent decreases in fatty acid oxidation and glucose oxidation as well as an overall decrease in mitochondrial NAD+/NADH. Together, these abnormalities suggest that SIRT5 deacylates protein substrates involved in cellular oxidative metabolism to maintain mitochondrial energy production. Overall, the functional and metabolic results presented here suggest an accelerated development of cardiac dysfunction in SIRT5KO mice in response to TAC, explaining increased mortality upon cardiac stress. Our findings reveal a key role for SIRT5 in maintaining cardiac oxidative metabolism under pressure overload to ensure survival.

Increasing NAD+ levels by supplementing with the precursor nicotinamide mononucleotide (NMN) improves cardiac function in multiple mouse models of disease. While NMN influences several aspects of mitochondrial metabolism, the molecular mechanisms by which increased NAD+ enhances cardiac function are poorly understood. A putative mechanism of NAD+ therapeutic action exists via activation of the mitochondrial NAD+-dependent protein deacetylase sirtuin 3 (SIRT3). We assessed the therapeutic efficacy of NMN and the role of SIRT3 in the Friedreich's ataxia cardiomyopathy mouse model (FXN-KO). At baseline, the FXN-KO heart has mitochondrial protein hyperacetylation, reduced Sirt3 mRNA expression, and evidence of increased NAD+ salvage. Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels. To determine whether SIRT3 is required for NMN therapeutic efficacy, we generated SIRT3-KO and SIRT3-KO/FXN-KO (double KO [dKO]) models. The improvement in cardiac function upon NMN treatment in the FXN-KO is lost in the dKO model, demonstrating that the effects of NMN are dependent upon cardiac SIRT3. Coupled with cardio-protection, SIRT3 mediates NMN-induced improvements in both cardiac and extracardiac metabolic function and energy metabolism. Taken together, these results serve as important preclinical data for NMN supplementation or SIRT3 activator therapy in Friedreich's ataxia patients.

In response to chronic pressure overload, the heart undergoes pathological hypertrophy associated with adverse remodeling, fibrosis, and cardiac dysfunction. Caveolae, membrane invaginations that organize protective signaling pathways and provide a reservoir to buffer membrane tension, can ameliorate maladaptive hypertrophy. However, the factors that govern caveolae assembly in the heart are not fully understood. Here, we report that the fibroblast growth factor (FGF) homologous factor FGF13 is a negative regulator of caveolae density in cardiomyocytes. Adult mice lacking FGF13 in the heart have increased caveolae abundance in cardiomyocytes and are thereby protected from the pathological effects of chronic pressure overload. Our findings, identifying an unexpected role for FGF13, provide insight into the mechanisms underlying caveolae-mediated adaptation to cardiac stress.

The fibroblast growth factor (FGF) homologous factor FGF13, a noncanonical FGF, has been best characterized as a voltage-gated Na+ channel auxiliary subunit. Other cellular functions have been suggested, but not explored. In inducible, cardiac-specific Fgf13 knockout mice, we found-even in the context of the expected reduction in Na+ channel current-an unanticipated protection from the maladaptive hypertrophic response to pressure overload. To uncover the underlying mechanisms, we searched for components of the FGF13 interactome in cardiomyocytes and discovered the complete set of the cavin family of caveolar coat proteins. Detailed biochemical investigations showed that FGF13 acts as a negative regulator of caveolae abundance in cardiomyocytes by controlling the relative distribution of cavin 1 between the sarcolemma and cytosol. In cardiac-specific Fgf13 knockout mice, cavin 1 redistribution to the sarcolemma stabilized the caveolar structural protein caveolin 3. The consequent increase in caveolae density afforded protection against pressure overload-induced cardiac dysfunction by two mechanisms: (i) enhancing cardioprotective signaling pathways enriched in caveolae, and (ii) increasing the caveolar membrane reserve available to buffer membrane tension. Thus, our results uncover unexpected roles for a FGF homologous factor and establish FGF13 as a regulator of caveolae-mediated mechanoprotection and adaptive hypertrophic signaling.

Cells isolated from patients with ataxia telangiectasia are exquisitely sensitive to ionizing radiation. Kinase inhibitors of ATM, the gene mutated in ataxia telangiectasia, can sensitize tumor cells to radiation therapy, but concern that inhibiting ATM in normal tissues will also increase normal tissue toxicity from radiation has limited their clinical application. Endothelial cell damage can contribute to the development of long-term side effects after radiation therapy, but the role of endothelial cell death in tumor response to radiation therapy remains controversial. Here, we developed dual recombinase technology using both FlpO and Cre recombinases to generate primary sarcomas in mice with endothelial cell-specific deletion of Atm to determine whether loss of Atm in endothelial cells sensitizes tumors and normal tissues to radiation. Although deletion of Atm in proliferating tumor endothelial cells enhanced the response of sarcomas to radiation, Atm deletion in quiescent endothelial cells of the heart did not sensitize mice to radiation-induced myocardial necrosis. Blocking cell cycle progression reversed the effect of Atm loss on tumor endothelial cell radiosensitivity. These results indicate that endothelial cells must progress through the cell cycle in order to be radiosensitized by Atm deletion.

Noninvasive small animal imaging techniques are essential for evaluation of cardiac disease and potential therapeutics. A novel preclinical iodinated contrast agent called eXIA 160 has recently been developed, which has been evaluated for micro-CT cardiac imaging. eXIA 160 creates strong contrast between blood and tissue immediately after its injection and is subsequently taken up by the myocardium and other metabolically active tissues over time. We focus on these properties of eXIA and show its use in imaging myocardial infarction in mice. Five C57BL/6 mice were imaged ~2 weeks after left anterior descending coronary artery ligation. Six C57BL/6 mice were used as controls. Immediately after injection of eXIA 160, an enhancement difference between blood and myocardium of ~340 HU enabled cardiac function estimation via 4D micro-CT scanning with retrospective gating. Four hours post-injection, the healthy perfused myocardium had a contrast difference of ~140 HU relative to blood while the infarcted myocardium showed no enhancement. These differences allowed quantification of infarct size via dual-energy micro-CT. In vivo micro-SPECT imaging and ex vivo triphenyl tetrazolium chloride (TTC) staining provided validation for the micro-CT findings. Root mean squared error of infarct measurements was 2.7% between micro-CT and SPECT, and 4.7% between micro-CT and TTC. Thus, micro-CT with eXIA 160 can be used to provide both morphological and functional data for preclinical studies evaluating myocardial infarction and potential therapies. Further studies are warranted to study the potential use of eXIA 160 as a CT molecular imaging tool for other metabolically active tissues in the mouse. Copyright © 2014 John Wiley & Sons, Ltd.

We report the synthesis of 2-(3-sulfonatomesityl)-5-sulfonatoindenyl)dicyclohexylphosphine hydrate sodium salt and its use in palladium-catalyzed Suzuki-Miyaura and Sonogashira coupling reactions in water (and biphasic water-organic solvent mixtures) to prepare a variety of functionalized biaryls and aryl alkynes in excellent yield.

Advanced thermal management solutions for various applications in energy systems have promoted the developments of novel hybrid wicks for two-phase heat transfer devices (TPHTD). In this study, a novel micro-nano hybrid wick combined rectangular microgrooves with superhydrophilic copper hydroxide nano-textured surfaces is developed. Comparative experiments on the axial wetting lengths, evaporating flow characteristics and evaporating heat transfer performance are systematically conducted for different microgrooves-based wick samples, i.e., the pristine rectangular microgrooves (RMs) and rectangular microgrooves with superhydrophilic nano-textured surfaces (RMSNSs). The distilled water and ethanol are both used as working fluids. The experimental results indicate that the RMSNSs wick produces remarkable increases in axial wetting lengths compared to the pristine RMs wick. Under the unheated condition, the total wetting length (Lt) of water in RMSNSs is more than 4 times of that in RMs. Under the same condition of heat flux, the Lt of RMSNSs is also distinctly larger. The improved axial wetting characteristics can be attributed to the effect of surface wettability enhancement, which have a critical influence on the evaporating heat transfer. The sample temperature of RMSNSs is much lower at each given heat flux and the decrement is more than 15 °C. The maximum incremental ratio of heat transfer coefficient can approach 100%. The enhanced evaporating heat transfer highly depends on the significantly increased thin liquid film area. Furthermore, a theoretical model is presented to facilitate the understanding on axial wetting and heat transfer enhancements effect of RMSNSs. The proposed model is applicable and satisfactorily accurate to predict the axial wetting lengths for microgrooves-based wick sample under the evaporating heat transfer condition. This study provides an in-depth insight into the enhanced axial flow and heat transfer characteristics of micro-nano hybrid wick incorporating microgrooves and nanostructures, and consequently can facilitate the further optimization design of microgrooves-based wick for advanced TPHTD. It is believed that this superior hybrid wick with advantages of facile and rapid fabrication is highly promising in the applications of heat energy transfer, conversion and management.