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Emilio Trignano - One of the best experts on this subject based on the ideXlab platform.
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transverse upper gracilis flap with implant in postmastectomy breast reconstruction a case report
Microsurgery, 2014Co-Authors: Emilio Trignano, Nefer Fallico, Corrado Rubino, Luca Andrea Dessy, Andrea F Armenti, Nicolo Scuderi, Venkat RamakrishnanAbstract:Autologous flaps can be used in combination with prosthesis in postmastectomy breast reconstruction. The deep inferior epigastric perforator (DIEP) flap is considered the preferred choice among autologous tissue transfer techniques. However, in patients with a peculiar figure (moderately large breasts and large thighs with flat stomach), who cannot use their abdominal tissue, the transverse upper gracilis (Tug) flap with implant is investigated as a further option for breast reconstruction. This report presents a patient who underwent the Tug flap plus implant reconstruction. A bilateral skin-sparing mastectomy was performed removing 340 g for each breast. The volume of the Tug flaps was 225 g (left) and 250 g (right). Preoperative volumes were restored by placing under the Tug muscle a round textured implant. No complications occurred during the postoperative period both in the recipient and donor site and the outcomes of the procedure were good. In cases where the use of the DIEP flap is not possible because of past laparotomies or inadequate abdominal volume, the Tug flap plus implant may be considered as a valid alternative. © 2013 Wiley Periodicals, Inc. Microsurgery 34:149–152, 2014.
Samuel Hafner - One of the best experts on this subject based on the ideXlab platform.
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Eternal peace in the Tug-of-war?
Economic Theory, 2020Co-Authors: Samuel HafnerAbstract:The Tug-of-war in which single players repeatedly compete in all-pay auctions is known to have a non-cooperative Markov-perfect equilibrium in which neither player expends positive effort and the Tug-of-war remains unresolved, provided that the winner and loser prizes, the tie-breaking rule, the lead required for victory, and the initial state are chosen appropriately. In this paper, we show that such peaceful equilibria do not exist if the Tug-of-war is between teams with pairwise matched players. The reason for this phenomenon is that the members of the teams can externalize future effort costs while the single players cannot. For a restricted number of states, our analysis also highlights the impact of the discount factor on the expected trajectory of the Tug-of-war, the dynamics of the expected effort, and the equilibrium utility.
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a Tug of war team contest
Games and Economic Behavior, 2017Co-Authors: Samuel HafnerAbstract:This paper analyzes a Tug-of-war contest between two teams. In each round of the Tug-of-war, a pair of agents from the opposing teams competes in a private value all-pay auction with asymmetric value distributions and effort effectiveness. Whichever team arrives first at a given lead in terms of battle victories over the opponent wins the Tug-of-war. There exists a unique Markov-perfect equilibrium in bidding strategies which depend on the respective player's valuation and the current state of the Tug-of-war. We derive rich comparative statics for this equilibrium by using the fact that the state of the Tug-of-war evolves according to a time-homogeneous absorbing Markov chain.
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a Tug of war team contest
Research Papers in Economics, 2015Co-Authors: Samuel HafnerAbstract:This paper analyzes a Tug of war contest between two teams. In each round of the Tug of war a pair of agents from the opposing teams competes in a private value all-pay auction with asymmetric type distributions and e ort e ectiveness. Whichever team arrives fi rst at a given lead in terms of battle victories over the opponent wins the Tug of war. There exists a unique Markov-perfect equilibrium in bidding strategies that depend on the player's valuation and on the history through the current state of the Tug of war only. We derive rich comparative statics for this equilibrium by using the fact that the states of the Tug of war evolve according to a time-homogeneous absorbing Markov chain.
Jonathan S. Bogan - One of the best experts on this subject based on the ideXlab platform.
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coordinated regulation of vasopressin inactivation and glucose uptake by action of Tug protein in muscle
Journal of Biological Chemistry, 2015Co-Authors: Estifanos N Habtemichael, Jonathan P Belman, Abel R Alcazarroman, Michael G Loffler, Bradley R Rubin, Laura R Grossi, Omar Julca, Naiwen Chi, Varman T Samuel, Jonathan S. BoganAbstract:In adipose and muscle cells, insulin stimulates the exocytic translocation of vesicles containing GLUT4, a glucose transporter, and insulin-regulated aminopeptidase (IRAP), a transmembrane aminopeptidase. A substrate of IRAP is vasopressin, which controls water homeostasis. The physiological importance of IRAP translocation to inactivate vasopressin remains uncertain. We previously showed that in skeletal muscle, insulin stimulates proteolytic processing of the GLUT4 retention protein, Tug, to promote GLUT4 translocation and glucose uptake. Here we show that Tug proteolysis also controls IRAP targeting and regulates vasopressin action in vivo. Transgenic mice with constitutive Tug proteolysis in muscle consumed much more water than wild-type control mice. The transgenic mice lost more body weight during water restriction, and the abundance of renal AQP2 water channels was reduced, implying that vasopressin activity is decreased. To compensate for accelerated vasopressin degradation, vasopressin secretion was increased, as assessed by the cosecreted protein copeptin. IRAP abundance was increased in T-tubule fractions of fasting transgenic mice, when compared with controls. Recombinant IRAP bound to Tug, and this interaction was mapped to a short peptide in IRAP that was previously shown to be critical for GLUT4 intracellular retention. In cultured 3T3-L1 adipocytes, IRAP was present in Tug-bound membranes and was released by insulin stimulation. Together with previous results, these data support a model in which Tug controls vesicle translocation by interacting with IRAP as well as GLUT4. Furthermore, the effect of IRAP to reduce vasopressin activity is a physiologically important consequence of vesicle translocation, which is coordinated with the stimulation of glucose uptake. Background: Insulin stimulates the exocytic translocation of vesicles containing GLUT4 glucose transporters and insulin-regulated aminopeptidase (IRAP). Results: Insulin acts through Tug proteins to control IRAP targeting, similar to GLUT4; the activity of vasopressin, an IRAP substrate, is reduced in mice with disrupted Tug action in muscle. Conclusion: Tug regulates vasopressin action. Significance: Exocytic translocation of vesicles in muscle coordinates vasopressin inactivation with glucose uptake.
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acetylation of Tug protein promotes the accumulation of glut4 glucose transporters in an insulin responsive intracellular compartment
Journal of Biological Chemistry, 2015Co-Authors: Jonathan P Belman, Rachel R Bian, Estifanos N Habtemichael, Michael J Jurczak, Abel R Alcazarroman, Leah Mcnally, Gerald I Shulman, Jonathan S. BoganAbstract:Insulin causes the exocytic translocation of GLUT4 glucose transporters to stimulate glucose uptake in fat and muscle. Previous results support a model in which Tug traps GLUT4 in intracellular, insulin-responsive vesicles termed GLUT4 storage vesicles (GSVs). Insulin triggers Tug cleavage to release the GSVs; GLUT4 then recycles through endosomes during ongoing insulin exposure. The Tug C terminus binds a GSV anchoring site comprising Golgin-160 and possibly other proteins. Here, we report that the Tug C terminus is acetylated. The Tug C-terminal peptide bound the Golgin-160-associated protein, ACBD3 (acyl-CoA-binding domain-containing 3), and acetylation reduced binding of Tug to ACBD3 but not to Golgin-160. Mutation of the acetylated residues impaired insulin-responsive GLUT4 trafficking in 3T3-L1 adipocytes. ACBD3 overexpression enhanced the translocation of GSV cargos, GLUT4 and insulin-regulated aminopeptidase (IRAP), and ACBD3 was required for intracellular retention of these cargos in unstimulated cells. Sirtuin 2 (SIRT2), a NAD+-dependent deacetylase, bound Tug and deacetylated the Tug peptide. SIRT2 overexpression reduced Tug acetylation and redistributed GLUT4 and IRAP to the plasma membrane in 3T3-L1 adipocytes. Mutation of the acetylated residues in Tug abrogated these effects. In mice, SIRT2 deletion increased Tug acetylation and proteolytic processing. During glucose tolerance tests, glucose disposal was enhanced in SIRT2 knock-out mice, compared with wild type controls, without any effect on insulin concentrations. Together, these data support a model in which Tug acetylation modulates its interaction with Golgi matrix proteins and is regulated by SIRT2. Moreover, acetylation of Tug enhances its function to trap GSVs within unstimulated cells and enhances insulin-stimulated glucose uptake.
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the ubiquitin regulatory x ubx domain containing protein Tug regulates the p97 atpase and resides at the endoplasmic reticulum golgi intermediate compartment
Journal of Biological Chemistry, 2012Co-Authors: Charisse M Orme, Jonathan S. BoganAbstract:p97/VCP is a hexameric ATPase that is coupled to diverse cellular processes, such as membrane fusion and proteolysis. How p97 activity is regulated is not fully understood. Here we studied the potential role of Tug, a widely expressed protein containing a UBX domain, to control mammalian p97. In HEK293 cells, the vast majority of Tug was bound to p97. Surprisingly, the Tug UBX domain was neither necessary nor sufficient for this interaction. Rather, an extended sequence, comprising three regions of Tug, bound to the p97 N-terminal domain. The Tug C terminus resembled the Arabidopsis protein PUX1. Similar to the previously described action of PUX1 on AtCDC48, Tug caused the conversion of p97 hexamers into monomers. Hexamer disassembly was stoichiometric rather than catalytic and was not greatly affected by the p97 ATP-binding state or by Tug N-terminal regions in vitro. In HeLa cells, Tug localized to the endoplasmic reticulum-to-Golgi intermediate compartment and endoplasmic reticulum exit sites. Although siRNA-mediated Tug depletion had no marked effect on total ubiquitylated proteins or p97 localization, Tug overexpression caused an accumulation of ubiquitylated substrates and targeted both Tug and p97 to the nucleus. A physiologic role of Tug was revealed by siRNA-mediated depletion, which showed that Tug is required for efficient reassembly of the Golgi complex after brefeldin A removal. Together, these data support a model in which Tug controls p97 oligomeric status at a particular location in the early secretory pathway and in which this process regulates membrane trafficking in various cell types.
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the glucose transporter 4 regulating protein Tug is essential for highly insulin responsive glucose uptake in 3t3 l1 adipocytes
Journal of Biological Chemistry, 2007Co-Authors: James Cresswell, Michael G Loffler, Jonathan S. BoganAbstract:Insulin stimulates glucose uptake in fat and muscle by redistributing GLUT4 glucose transporters from intracellular membranes to the cell surface. We previously proposed that, in 3T3-L1 adipocytes, Tug retains GLUT4 within unstimulated cells and insulin mobilizes this retained GLUT4 by stimulating its dissociation from Tug. Yet the relative importance of this action in the overall control of glucose uptake remains uncertain. Here we report that transient, small interfering RNA-mediated depletion of Tug causes GLUT4 translocation and enhances glucose uptake in unstimulated 3T3-L1 adipocytes, similar to insulin. Stable Tug depletion or expression of a dominant negative fragment likewise stimulates GLUT4 redistribution and glucose uptake, and insulin causes a 2-fold further increase. Microscopy shows that Tug governs the accumulation of GLUT4 in perinuclear membranes distinct from endosomes and indicates that it is this pool of GLUT4 that is mobilized by Tug disruption. Interestingly, in addition to translocating GLUT4 and enhancing glucose uptake, Tug disruption appears to accelerate the degradation of GLUT4 in lysosomes. Finally, we find that Tug binds directly and specifically to a large intracellular loop in GLUT4. Together, these findings demonstrate that Tug is required to retain GLUT4 intracellularly in 3T3-L1 adipocytes in the absence of insulin and further implicate the insulin-stimulated dissociation of Tug and GLUT4 as an important action by which insulin stimulates glucose uptake.
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Functional cloning of Tug as a regulator of GLUT4 glucose transporter trafficking
Nature, 2003Co-Authors: Jonathan S. Bogan, Natalie Hendon, Adrienne E. Mckee, Tsu Shuen Tsao, Harvey F LodishAbstract:Insulin stimulates glucose uptake in fat and muscle by mobilizing the GLUT4 glucose transporter. GLUT4 is sequestered intracellularly in the absence of insulin, and is redistributed to the plasma membrane within minutes of insulin stimulation. But the trafficking mechanisms that control GLUT4 sequestration have remained elusive. Here we describe a functional screen to identify proteins that modulate GLUT4 distribution, and identify Tug as a putative tether, containing a UBX domain, for GLUT4. In truncated form, Tug acts in a dominant-negative manner to inhibit insulin-stimulated GLUT4 redistribution in Chinese hamster ovary cells and 3T3-L1 adipocytes. Full-length Tug forms a complex specifically with GLUT4; in 3T3-L1 adipocytes, this complex is present in unstimulated cells and is largely disassembled by insulin. Endogenous Tug is localized with the insulin-mobilizable pool of GLUT4 in unstimulated 3T3-L1 adipocytes, and is not mobilized to the plasma membrane by insulin. Distinct regions of Tug are required to bind GLUT4 and to retain GLUT4 intracellularly in transfected, non-adipose cells. Our data suggest that Tug traps endocytosed GLUT4 and tethers it intracellularly, and that insulin mobilizes this pool of retained GLUT4 by releasing this tether.
Maaike Schilperoort - One of the best experts on this subject based on the ideXlab platform.
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the gpr120 agonist Tug 891 promotes metabolic health by stimulating mitochondrial respiration in brown fat
Embo Molecular Medicine, 2018Co-Authors: Maaike Schilperoort, Geerte Hoeke, Anthony Okolo, Natarin Caengprasath, Yiwah Chan, Sami Damak, Aylin C Hanyaloglu, Irina G Shabalina, Anne Reifel MillerAbstract:Abstract Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein‐coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120‐mediated signaling in BAT. We found that activation of GPR120 by the selective agonist Tug‐891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT. Stimulation of brown adipocytes in vitro with Tug‐891 acutely induced O 2 consumption, through GPR120‐dependent and GPR120‐independent mechanisms. Tug‐891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist Tug‐891 is a promising strategy to increase lipid combustion and reduce obesity.
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The GPR120 agonist Tug‐891 promotes metabolic health by stimulating mitochondrial respiration in brown fat
Embo Molecular Medicine, 2018Co-Authors: Maaike Schilperoort, Geerte Hoeke, Anthony Okolo, Natarin Caengprasath, Aylin C Hanyaloglu, Irina G Shabalina, Yiwah ChanAbstract:Abstract Brown adipose tissue (BAT) activation stimulates energy expenditure in human adults, which makes it an attractive target to combat obesity and related disorders. Recent studies demonstrated a role for G protein‐coupled receptor 120 (GPR120) in BAT thermogenesis. Here, we investigated the therapeutic potential of GPR120 agonism and addressed GPR120‐mediated signaling in BAT. We found that activation of GPR120 by the selective agonist Tug‐891 acutely increases fat oxidation and reduces body weight and fat mass in C57Bl/6J mice. These effects coincided with decreased brown adipocyte lipid content and increased nutrient uptake by BAT, confirming increased BAT activity. Consistent with these observations, GPR120 deficiency reduced expression of genes involved in nutrient handling in BAT. Stimulation of brown adipocytes in vitro with Tug‐891 acutely induced O 2 consumption, through GPR120‐dependent and GPR120‐independent mechanisms. Tug‐891 not only stimulated GPR120 signaling resulting in intracellular calcium release, mitochondrial depolarization, and mitochondrial fission, but also activated UCP1. Collectively, these data suggest that activation of brown adipocytes with the GPR120 agonist Tug‐891 is a promising strategy to increase lipid combustion and reduce obesity.
Venkat Ramakrishnan - One of the best experts on this subject based on the ideXlab platform.
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transverse upper gracilis flap with implant in postmastectomy breast reconstruction a case report
Microsurgery, 2014Co-Authors: Emilio Trignano, Nefer Fallico, Corrado Rubino, Luca Andrea Dessy, Andrea F Armenti, Nicolo Scuderi, Venkat RamakrishnanAbstract:Autologous flaps can be used in combination with prosthesis in postmastectomy breast reconstruction. The deep inferior epigastric perforator (DIEP) flap is considered the preferred choice among autologous tissue transfer techniques. However, in patients with a peculiar figure (moderately large breasts and large thighs with flat stomach), who cannot use their abdominal tissue, the transverse upper gracilis (Tug) flap with implant is investigated as a further option for breast reconstruction. This report presents a patient who underwent the Tug flap plus implant reconstruction. A bilateral skin-sparing mastectomy was performed removing 340 g for each breast. The volume of the Tug flaps was 225 g (left) and 250 g (right). Preoperative volumes were restored by placing under the Tug muscle a round textured implant. No complications occurred during the postoperative period both in the recipient and donor site and the outcomes of the procedure were good. In cases where the use of the DIEP flap is not possible because of past laparotomies or inadequate abdominal volume, the Tug flap plus implant may be considered as a valid alternative. © 2013 Wiley Periodicals, Inc. Microsurgery 34:149–152, 2014.
