Insulin resistance is a fundamental pathogenic factor present in various metabolic disorders including obesity and type 2 diabetes. Although skeletal muscle accounts for 70-90% of insulin-stimulated glucose disposal, the mechanism underlying muscle insulin resistance is poorly understood. Here we show in mice that muscle-specific mitsugumin 53 (MG53; also called TRIM72) mediates the degradation of the insulin receptor and insulin receptor substrate 1 (IRS1), and when upregulated, causes metabolic syndrome featuring insulin resistance, obesity, hypertension and dyslipidaemia. MG53 expression is markedly elevated in models of insulin resistance, and MG53 overexpression suffices to trigger muscle insulin resistance and metabolic syndrome sequentially. Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. Mechanistically, MG53 acts as an E3 ligase targeting the insulin receptor and IRS1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. These findings define MG53 as a novel therapeutic target for treating metabolic disorders and associated cardiovascular complications.

Background: Mitsugumin 53 (MG53 or TRIM72), a striated muscle-specific E3 ligase, promotes ubiquitin-dependent degradation of the insulin receptor and insulin receptor substrate-1 and subsequently induces insulin resistance, resulting in metabolic syndrome and type 2 diabetes mellitus (T2DM). However, it is unknown how MG53 from muscle regulates systemic insulin response and energy metabolism. Increasing evidence demonstrates that muscle secretes proteins as myokines or cardiokines that regulate systemic metabolic processes. We hypothesize that MG53 may act as a myokine/cardiokine, contributing to interorgan regulation of insulin sensitivity and metabolic homeostasis. Methods: Using perfused rodent hearts or skeletal muscle, we investigated whether high glucose, high insulin, or their combination (conditions mimicking metabolic syndrome or T2DM) alters MG53 protein concentration in the perfusate. We also measured serum MG53 levels in rodents and humans in the presence or absence of metabolic diseases, particularly T2DM. The effects of circulating MG53 on multiorgan insulin response were evaluated by systemic delivery of recombinant MG53 protein to mice. Furthermore, the potential involvement of circulating MG53 in the pathogenesis of T2DM was assessed by neutralizing blood MG53 with monoclonal antibodies in diabetic db/db mice. Finally, to delineate the mechanism underlying the action of extracellular MG53 on insulin signaling, we analyzed the potential interaction of MG53 with extracellular domain of insulin receptor using coimmunoprecipitation and surface plasmon resonance assays. Results: Here, we demonstrate that MG53 is a glucose-sensitive myokine/cardiokine that governs the interorgan regulation of insulin sensitivity. First, high glucose or high insulin induces MG53 secretion from isolated rodent hearts and skeletal muscle. Second, hyperglycemia is accompanied by increased circulating MG53 in humans and rodents with diabetes mellitus. Third, systemic delivery of recombinant MG53 or cardiac-specific overexpression of MG53 causes systemic insulin resistance and metabolic syndrome in mice, whereas neutralizing circulating MG53 with monoclonal antibodies has therapeutic effects in T2DM db/db mice. Mechanistically, MG53 binds to the extracellular domain of the insulin receptor and acts as an allosteric blocker. Conclusions: Thus, MG53 has dual actions as a myokine/cardiokine and an E3 ligase, synergistically inhibiting the insulin signaling pathway. Targeting circulating MG53 opens a new therapeutic avenue for T2DM and its complications.

Background/AimsPyogenic liver abscess (PLA) is a serious, life threatening condition with a high mortality rate that represents a diagnostic and therapeutic challenge. The aim of this study was to collect demographic data and clinical, laboratory and microbiological characteristics of PLA patients treated between 2000 and 2010. We also aimed to collect information regarding our management experience of these cases.MethodsAs a retrospective review, 47 patients with PLA in a tertiary referral center were examined to determine their demographic characteristics, clinical features, and laboratory, imaging, and microbiologic findings as well as the treatment outcome.ResultsCryptogenic PLA was the most frequently identified type of PLA, while benign biliary tract disease was the most frequently identifiable cause of PLA (18/47 patients; 38.3%). Leukocytosis and elevated alanine transaminase were common laboratory findings and were observed in 35 (74.5%) and 22 (46.8%) patients, respectively. Increased fibrinogen was also detected in 11 of 15 investigated cases (73.3%). Notably, infection-induced thrombocytopenia occurred in 8 patients (17%). Diabetes mellitus was associated with the occurrence of infection induced shock when compared to the non-diabetic group (p<0.05). Patients with two or more comorbid diseases had longer hospitalizations when compared to patients with one comorbid disease or those without comorbidities (p<0.001). The number of days needed to establish diagnosis was correlated with the length of hospitalization (p<0.001). The overall hospital mortality rate was 2.1% (1/47).ConclusionsCharacteristics of PLA patients from the past 10 years are presented. The number of days needed to establish a PLA diagnosis was correlated with the length of the hospital stay. The hospital stay of PLA patients can be further improved by early diagnosis and effective treatments during the early stages of PLA progression.

The extraordinary transmission in density-near-zero (DNZ) acoustic metamaterials (AMs) provides possibilities to manipulate acoustic signals with extremely large effective phase velocity and wavelength. Here, we report compact transformable acoustic logic gates with a subwavelength size as small as 0.82λ based on DNZ AMs. The basic acoustic logic gates, composed of a tri-port structure filled with space-coiling DNZ AMs, enable precise direct linear interference of input signals with considerably small phase lag and wavefront distortion. We demonstrate both theoretically and experimentally the basic Boolean logic operations such as OR, AND, XOR, and NOT with wide operational frequency ranges and controllability, by adjusting the phase difference between two input signals. More complex logic calculus, such as “I1 + I2 × I3,” are also realized by cascading of the basic logic gates. Our proposal provides diverse routes to construct devices for acoustic signal computing and manipulations.

Organotin compounds such as tributyltin (TBT) and triphenyltin can induce diabetes and insulin resistance. However, the development of diabetes caused by organotins and its underlying mechanisms remain unclear. In the present study, male KM mice were orally administered with TBT (0.5, 5, and 50 μg/kg) once every 3 days for 45 days. Their body weights increased and reached a significant difference compared to the control, and the fasting blood glucose levels were significantly elevated. The fasting levels of serum insulin and adiponectin increased, while glucagon levels decreased in the animals treated with TBT. The expression of the insulin receptor (IR) signaling cascade, including IR, IR substrate, phosphatidylinositol 3-kinase, Akt, and glucose transporter 4, was inhibited both in the skeletal muscle and the liver, which might be a main reason for the hyperglycemia and hyperinsulinemia. After removing the TBT stress for 60 days, the animals which had received exposure to TBT could recover normoglycemia, accompanied with a recovery of the suppressed IR signal pathway and fasting insulin levels. However, the fasting levels of serum adiponectin and glucagon were lower than that of the control mice, which would remain a potential risk inducing the disruption of glucose homeostasis.

Remote sensing land-use scene classification has a wide range of applications including forestry, urban-growth analysis, and weather forecasting. This paper presents an effective image representation method, Gabor-filtering-based completed local binary patterns (GCLBP), for land-use scene classification. It employs the multi-orientation Gabor filters to capture the global texture information from an input image. Then, a local operator called completed local binary patterns (CLBP) is utilized to extract the local texture features, such as edges and corners, from the Gabor feature images and the input image. The resulting CLBP histogram features are concatenated to represent an input image. Experimental results on two datasets demonstrate that the proposed method is superior to several existing methods for landuse scene classification.

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(1) Comparing with nicorandil, urapidil and diltiazem, nitroglycerin caused a significant relaxation in all three graft vessels tested. (2) Nitroglycerin, nicorandil and urapidil were more effective in preventing RA spasm than diltiazem.