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Signaling through the insulin receptor governs central physiological functions related to cell growth and metabolism. Here we show by tandem native protein complex purification approach and super-resolution STED microscopy that insulin receptor activity requires association with the fundamental structural module in muscle, the dystrophin glycoprotein complex (DGC), and the desmosomal component plakoglobin (γ-catenin). The integrity of this high-molecular-mass assembly renders skeletal muscle susceptibility to insulin, because DGC-insulin receptor dissociation by plakoglobin downregulation reduces insulin signaling and causes atrophy. Furthermore, low insulin receptor activity in muscles from transgenic or fasted mice decreases plakoglobin-DGC-insulin receptor content on the plasma membrane, but not when plakoglobin is overexpressed. By masking β-dystroglycan LIR domains, plakoglobin prevents autophagic clearance of plakoglobin-DGC-insulin receptor co-assemblies and maintains their function. Our findings establish DGC as a signaling hub, and provide a possible mechanism for the insulin resistance in Duchenne Muscular Dystrophy, and for the cardiomyopathies seen with plakoglobin mutations. Insulin receptor signaling governs central physiological functions related to cell growth and metabolism. Here the authors use protein complex purification and super-resolution microscopy to show that insulin receptor activity requires association with dystrophin glycoprotein complex and plakoglobin.

The Arf GTPase-activating protein ArfGAP1 and its brain-specific isoform ArfGAP1B play an important role in neurotransmission. Here we analyzed the distribution of ArfGAP1 in the mouse brain. We found high levels of ArfGAP1 in the mouse dentate gyrus where it displayed especially elevated level in the polymorph layer (hilus). Importantly, the ArfGAP1 signal follows the pathway of the granular cell axons so-called mossy fibers which extend from the dentate gyrus to CA3 via stratum lucidum and partially stratum oriens. Additionally, we identified differential expression of ArfGAP1 in the isocortex. Thus, staining with anti-ArfGAP1 antibodies allows distinction between cortical cell layers 1, 2, 3 and 5 from 4 and 6. Taken together, our data suggest that ArfGAP1 can be used as a specific marker of the dentate mossy fibers and as for visualization of cortical layers in immunohistochemical studies.

PI3K-Akt-FoxO-mTOR signaling is the central pathway controlling growth and metabolism in all cells. Activation of this pathway requires ubiquitination of Akt prior to its activation by phosphorylation. Here, we found that the deubiquitinating (DUB) enzyme USP1 removes K63-linked polyubiquitin chains on Akt to sustain PI3K-Akt-FoxO signaling low during prolonged starvation. DUB screening platform identified USP1 as a direct DUB for Akt, and USP1 depletion in atrophying muscle increased Akt ubiquitination, PI3K-Akt-FoxO signaling, and glucose uptake during fasting. Co-immunoprecipitation and mass spectrometry identified Disabled-2 (Dab2) and the tuberous sclerosis complex TSC1/TSC2 as USP1 bound proteins. During starvation, Dab2 was essential for Akt recruitment to USP1/UAF1 complex, and for PI3K-Akt-FoxO inhibition. Additionally, to maintain its own protein levels high, USP1 limits TSC1 levels to sustain mTOR-mediated basal protein synthesis rates. This USP1-mediated suppression of PI3K-Akt-FoxO signaling probably contributes to insulin resistance in catabolic diseases and perhaps to malignancies seen with USP1 mutations.

Signaling through the insulin receptor governs central physiological functions related to cell growth and metabolism. Here we show by tandem native protein complex purification approach and super-resolution STED microscopy that insulin receptor activity requires association with the fundamental structural module in muscle, the dystrophin glycoprotein complex (DGC), and the desmosomal component plakoglobin (gamma-catenin). The integrity of this high-molecular-mass assembly renders skeletal muscle susceptibility to insulin because DGC-insulin receptor dissociation by plakoglobin downregulation reduced insulin signaling and caused atrophy. Furthermore, impaired insulin receptor function in muscles from diabetic mice reduced plakoglobin-DGC-insulin receptor content on the plasma membrane; however, plakoglobin overexpression alone restored DGC association with the insulin receptor, and stimulated glucose uptake. Our findings establish DGC as a signaling hub, containing plakoglobin as an auxiliary subunit, and provide a possible mechanism for the insulin resistance in Duchenne Muscular Dystrophy, and for the cardiomyopathies seen with plakoglobin mutations.

Background Hyperbaric oxygen therapy (HBOT) involves patients breathing 100% oxygen in a pressurized chamber, above 1 atmosphere. Many centers are now promoting the use of HBOT for skin rejuvenation. However, the current indications for HBOT do not encompass aesthetic applications. Aim The aim of this evidence‐based review was to assess the existing literature regarding the utilization of HBOT in medical aesthetics and rejuvenation, evaluate its effectiveness and safety, and conduct a cost analysis. Materials and Methods PubMed Interface, Cochrane Library, Google Scholar, and Embase searches were carried out. The Best Bets methodology was used, and the risk of bias was appraised using the Quality Assessment Tool for Quantitative Studies. Results and Main Findings This review included a total of 17 human studies with a total of 766 participants. Three studies were classified as level II evidence, three studies were of level III evidence, and 11 were of level IV evidence. All the included studies were judged at high risk of bias. The most relevant findings supported by level II evidence were that HBOT decreased the shedding rate post‐FUE hair transplant (27.6 ± 2.6% vs. 69.1 ± 2.4%) but this did not affect the final outcome between HBOT (96.9 ± 0.5%) and the control (93.8 ± 0.6%). Moreover, level III evidence demonstrated that following HBOT, there was a significant increase in elastic fiber length (p ≤ 0.0001, effect size = 2.71) and a significant decrease in fiber fragmentation (p = 0.012). There was also a significant increase in collagen fiber density following HBOT (p = 0.0001, effect size = 1.10). However, there was no significant effect of antioxidant vitamins A, C, and E with HBOT. The inflammatory response significantly decreased after 7 days of HBOT with a decreased expression of IL‐12p40, MIP‐1β, and PDGF‐BB and a higher expression of IL‐1Ra. Moreover, HBOT was used prophylactically prior to abdominoplasty to decrease the risk of complications. In this study, complications were decreased from 32.6% (89 patients) to 8.4% (7 patients) with a p < 0.001, and in a multivariate analysis, preoperative HBOT was an independent protective factor against postoperative complications (p < 0.001). Conclusion and Recommendations There is conflicting evidence on how the method of action of HBOT can have a beneficiary effect in aesthetic and whether the treatment is justifiable. To our knowledge, this is the first comprehensive review discussing the available evidence regarding the use of HBOT in many aesthetic clinical scenarios, including preventive, medical, and surgical settings. However, randomized clinical trials with longer follow‐up and better patient selection are needed to be able to generate a reliable conclusion.

Background and aimsTeam-based learning (TBL) is an effective, active learning strategy that has been validated and used in medical schools. It consists of three phases; preparation, readiness assurance tests and application exercise. It follows a ‘flipped classroom’ model where assessment takes place at the beginning and encourages team discussions that emulate clinical practice. TBL has been used in medical education; however, there is a lack of literature on its use specifically in physician associate (PA) education. We therefore explored the perceptions of a Stroke TBL session among PA students in a UK PA Programme.MethodsThe study took place during the COVID-19 pandemic; therefore, TBL was implemented virtually using online video conferencing platforms. The students’ perceptions were then analysed using anonymous online questionnaires sent to them shortly after the session. The questionnaire included specific questions comparing TBL to other teaching methods such as problem-based learning (PBL).ResultsOverall, the students felt that TBL was an effective teaching method that was better than other methods such as lectures and PBL.ConclusionsThis was a small study of a single TBL session that provided rich qualitative data around students’ perceptions. It is a good foundation for developing TBL further in UK PA Programmes. We encourage further use of this strategy with further studies in this area.