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Sample records for distal glut4 trafficking

  1. Lack of CD2AP disrupts Glut4 trafficking and attenuates glucose uptake in podocytes.

    PubMed

    Tolvanen, Tuomas A; Dash, Surjya Narayan; Polianskyte-Prause, Zydrune; Dumont, Vincent; Lehtonen, Sanna

    2015-12-15

    The adapter protein CD2-associated protein (CD2AP) functions in various signaling and vesicle trafficking pathways, including endosomal sorting and/or trafficking and degradation pathways. Here, we investigated the role of CD2AP in insulin-dependent glucose transporter 4 (Glut4, also known as SLC2A4) trafficking and glucose uptake. Glucose uptake was attenuated in CD2AP(-/-) podocytes compared with wild-type podocytes in the basal state, and CD2AP(-/-) podocytes failed to increase glucose uptake in response to insulin. Live-cell imaging revealed dynamic trafficking of HA-Glut4-GFP in wild-type podocytes, whereas in CD2AP(-/-) podocytes, HA-Glut4-GFP clustered perinuclearly. In subcellular membrane fractionations, CD2AP co-fractionated with Glut4, IRAP (also known as LNPEP) and sortilin, constituents of Glut4 storage vesicles (GSVs). We further found that CD2AP forms a complex with GGA2, a clathrin adaptor, which sorts Glut4 to GSVs, suggesting a role for CD2AP in this process. We also found that CD2AP forms a complex with clathrin and connects clathrin to actin in the perinuclear region. Furthermore, clathrin recycling back to trans-Golgi membranes from the vesicular fraction containing GSVs was defective in the absence of CD2AP. This leads to reduced insulin-stimulated trafficking of GSVs and attenuated glucose uptake into CD2AP(-/-) podocytes.

  2. Alternative routes to the cell surface underpin insulin-regulated membrane trafficking of GLUT4

    PubMed Central

    Kioumourtzoglou, Dimitrios; Pryor, Paul R.; Gould, Gwyn W.; Bryant, Nia J.

    2015-01-01

    ABSTRACT Insulin-stimulated delivery of glucose transporters (GLUT4, also known as SLC2A4) from specialized intracellular GLUT4 storage vesicles (GSVs) to the surface of fat and muscle cells is central to whole-body glucose regulation. This translocation and subsequent internalization of GLUT4 back into intracellular stores transits through numerous small membrane-bound compartments (internal GLUT4-containing vesicles; IGVs) including GSVs, but the function of these different compartments is not clear. Cellugyrin (also known as synaptogyrin-2) and sortilin define distinct populations of IGV; sortilin-positive IGVs represent GSVs, but the function of cellugyrin-containing IGVs is unknown. Here, we demonstrate a role for cellugyrin in intracellular sequestration of GLUT4 in HeLa cells and have used a proximity ligation assay to follow changes in pairwise associations between cellugyrin, sortilin, GLUT4 and membrane trafficking machinery following insulin-stimulation of 3T3-L1 adipoctyes. Our data suggest that insulin stimulates traffic from cellugyrin-containing to sortilin-containing membranes, and that cellugyrin-containing IGVs provide an insulin-sensitive reservoir to replenish GSVs following insulin-stimulated exocytosis of GLUT4. Furthermore, our data support the existence of a pathway from cellugyrin-containing membranes to the surface of 3T3-L1 adipocytes that bypasses GSVs under basal conditions, and that insulin diverts traffic away from this into GSVs. PMID:26071524

  3. Role for the microtubule cytoskeleton in GLUT4 vesicle trafficking and in the regulation of insulin-stimulated glucose uptake.

    PubMed Central

    Fletcher, L M; Welsh, G I; Oatey, P B; Tavaré, J M

    2000-01-01

    Insulin stimulates glucose uptake into adipocytes by promoting the translocation of the glucose transporter isoform 4 (GLUT4) from intracellular vesicles to the plasma membrane. In 3T3-L1 adipocytes GLUT4 resides both in an endosomal pool, together with transferrin receptors, and in a unique pool termed 'GLUT4 storage vesicles' (GSVs), which excludes endosomal proteins. The trafficking of GLUT4 vesicles was studied in living 3T3-L1 adipocytes by time-lapse confocal microscopy of GLUT4 tagged with green fluorescent protein. GLUT4 vesicles exhibited two types of motion: rapid vibrations around a point and short (generally less than 10 microm) linear movements. The linear movements were completely blocked by incubation of the cells in the presence of microtubule-depolymerizing agents. This suggests that a subpopulation of GLUT4 vesicles can exhibit motor-driven movements along microtubules. Upon further examination, microtubule depolymerization inhibited insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane by approx. 40%, but had no effect on insulin-induced translocation of the transferrin receptor to the plasma membrane from endosomes. We propose that an intact microtubule cytoskeleton may be required for optimal trafficking of GLUT4 present in the GSV pool, but not that resident in the endosomal pool. PMID:11085918

  4. Characterization of VAMP isoforms in 3T3-L1 adipocytes: implications for GLUT4 trafficking.

    PubMed

    Sadler, Jessica B A; Bryant, Nia J; Gould, Gwyn W

    2015-02-01

    The fusion of GLUT4-containing vesicles with the plasma membrane of adipocytes is a key facet of insulin action. This process is mediated by the formation of functional soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes between the plasma membrane t-SNARE complex and the vesicle v-SNARE or VAMP. The t-SNARE complex consists of Syntaxin4 and SNAP23, and whereas many studies identify VAMP2 as the v-SNARE, others suggest that either VAMP3 or VAMP8 may also fulfil this role. Here we characterized the levels of expression, distribution, and association of all the VAMPs expressed in 3T3-L1 adipocytes to provide the first systematic analysis of all members of this protein family for any cell type. Despite our finding that all VAMP isoforms form SDS-resistant SNARE complexes with Syntaxin4/SNAP23 in vitro, a combination of levels of expression (which vary by >30-fold), subcellular distribution, and coimmunoprecipitation analyses lead us to propose that VAMP2 is the major v-SNARE involved in GLUT4 trafficking to the surface of 3T3-L1 adipocytes.

  5. Characterization of VAMP isoforms in 3T3-L1 adipocytes: implications for GLUT4 trafficking

    PubMed Central

    Sadler, Jessica B. A.; Bryant, Nia J.; Gould, Gwyn W.

    2015-01-01

    The fusion of GLUT4-containing vesicles with the plasma membrane of adipocytes is a key facet of insulin action. This process is mediated by the formation of functional soluble N-ethylmaleimide–sensitive factor attachment protein receptor (SNARE) complexes between the plasma membrane t-SNARE complex and the vesicle v-SNARE or VAMP. The t-SNARE complex consists of Syntaxin4 and SNAP23, and whereas many studies identify VAMP2 as the v-SNARE, others suggest that either VAMP3 or VAMP8 may also fulfil this role. Here we characterized the levels of expression, distribution, and association of all the VAMPs expressed in 3T3-L1 adipocytes to provide the first systematic analysis of all members of this protein family for any cell type. Despite our finding that all VAMP isoforms form SDS-resistant SNARE complexes with Syntaxin4/SNAP23 in vitro, a combination of levels of expression (which vary by >30-fold), subcellular distribution, and coimmunoprecipitation analyses lead us to propose that VAMP2 is the major v-SNARE involved in GLUT4 trafficking to the surface of 3T3-L1 adipocytes. PMID:25501368

  6. Vimentin binds IRAP and is involved in GLUT4 vesicle trafficking

    SciTech Connect

    Hirata, Yohko; Hosaka, Toshio; Iwata, Takeo; Le, Chung T.K.; Jambaldorj, Bayasgalan; Teshigawara, Kiyoshi; Harada, Nagakatsu; Sakaue, Hiroshi; Sakai, Tohru; Yoshimoto, Katsuhiko; Nakaya, Yutaka

    2011-02-04

    Research highlights: {yields} Vimentin is shown to bind to the N-terminus of insulin-responsive aminopeptidase (IRAP), a major cargo protein of GLUT4 vesicles in 3T3-L1 adipocytes. {yields} GLUT4 translocation to the plasma membrane by insulin is decreased in vimentin-depleted adipocytes. {yields} An interaction between vimentin and IRAP functions to sequester GLUT4 vesicles to the peri-nuclear region of the cell. -- Abstract: Insulin-responsive aminopeptidase (IRAP) and GLUT4 are two major cargo proteins of GLUT4 storage vesicles (GSVs) that are translocated from a postendosomal storage compartment to the plasma membrane (PM) in response to insulin. The cytoplasmic region of IRAP is reportedly involved in retention of GSVs. In this study, vimentin was identified using the cytoplasmic domain of IRAP as bait. The validity of this interaction was confirmed by pull-down assays and immunoprecipitation in 3T3-L1 adipocytes. In addition, it was shown that GLUT4 translocation to the PM by insulin was decreased in vimentin-depleted adipocytes, presumably due to dispersing GSVs away from the cytoskeleton. These findings suggest that the IRAP binding protein, vimentin, plays an important role in retention of GSVs.

  7. The cytosolic C-terminus of the glucose transporter GLUT4 contains an acidic cluster endosomal targeting motif distal to the dileucine signal.

    PubMed Central

    Shewan, A M; Marsh, B J; Melvin, D R; Martin, S; Gould, G W; James, D E

    2000-01-01

    The insulin-responsive glucose transporter GLUT4 is targeted to a post-endocytic compartment in adipocytes, from where it moves to the cell surface in response to insulin. Previous studies have identified two cytosolic targeting motifs that regulate the intracellular sequestration of this protein: FQQI(5-8) in the N-terminus and LL(489,490) (one-letter amino acid notation) in the C-terminus. In the present study we show that a GLUT4 chimaera in which the C-terminal 12 amino acids in GLUT4 have been replaced with the same region from human GLUT3 is constitutively targeted to the plasma membrane when expressed in 3T3-L1 adipocytes. To further dissect this domain it was divided into three regions, each of which was mutated en bloc to alanine residues. Analysis of these constructs revealed that the targeting information is contained within the residues TELEYLGP(498-505). Using the transferrin-horseradish peroxidase endosomal ablation technique in 3T3-L1 adipocytes, we show that mutants in which this C-terminal domain has been disrupted are more sensitive to chemical ablation than wild-type GLUT4. These data indicate that GLUT4 contains a targeting signal in its C-terminus, distal to the dileucine motif, that regulates its sorting into a post-endosomal compartment. Similar membrane-distal, acidic-cluster-based motifs are found in the cytosolic tails of the insulin-responsive aminopeptidase IRAP (insulin-regulated aminopeptidase) and the proprotein convertase PC6B, indicating that this type of motif may play an important role in the endosomal sequestration of a number of different proteins. PMID:10926832

  8. The Rab GTPase-activating protein TBC1D4/AS160 contains an atypical phosphotyrosine-binding domain that interacts with plasma membrane phospholipids to facilitate GLUT4 trafficking in adipocytes.

    PubMed

    Tan, Shi-Xiong; Ng, Yvonne; Burchfield, James G; Ramm, Georg; Lambright, David G; Stöckli, Jacqueline; James, David E

    2012-12-01

    The Rab GTPase-activating protein TBC1D4/AS160 regulates GLUT4 trafficking in adipocytes. Nonphosphorylated AS160 binds to GLUT4 vesicles and inhibits GLUT4 translocation, and AS160 phosphorylation overcomes this inhibitory effect. In the present study we detected several new functional features of AS160. The second phosphotyrosine-binding domain in AS160 encodes a phospholipid-binding domain that facilitates plasma membrane (PM) targeting of AS160, and this function is conserved in other related RabGAP/Tre-2/Bub2/Cdc16 (TBC) proteins and an AS160 ortholog in Drosophila. This region also contains a nonoverlapping intracellular GLUT4-containing storage vesicle (GSV) cargo-binding site. The interaction of AS160 with GSVs and not with the PM confers the inhibitory effect of AS160 on insulin-dependent GLUT4 translocation. Constitutive targeting of AS160 to the PM increased the surface GLUT4 levels, and this was attributed to both enhanced AS160 phosphorylation and 14-3-3 binding and inhibition of AS160 GAP activity. We propose a model wherein AS160 acts as a regulatory switch in the docking and/or fusion of GSVs with the PM.

  9. The Rab GTPase-Activating Protein TBC1D4/AS160 Contains an Atypical Phosphotyrosine-Binding Domain That Interacts with Plasma Membrane Phospholipids To Facilitate GLUT4 Trafficking in Adipocytes

    PubMed Central

    Tan, Shi-Xiong; Ng, Yvonne; Burchfield, James G.; Ramm, Georg; Lambright, David G.; Stöckli, Jacqueline

    2012-01-01

    The Rab GTPase-activating protein TBC1D4/AS160 regulates GLUT4 trafficking in adipocytes. Nonphosphorylated AS160 binds to GLUT4 vesicles and inhibits GLUT4 translocation, and AS160 phosphorylation overcomes this inhibitory effect. In the present study we detected several new functional features of AS160. The second phosphotyrosine-binding domain in AS160 encodes a phospholipid-binding domain that facilitates plasma membrane (PM) targeting of AS160, and this function is conserved in other related RabGAP/Tre-2/Bub2/Cdc16 (TBC) proteins and an AS160 ortholog in Drosophila. This region also contains a nonoverlapping intracellular GLUT4-containing storage vesicle (GSV) cargo-binding site. The interaction of AS160 with GSVs and not with the PM confers the inhibitory effect of AS160 on insulin-dependent GLUT4 translocation. Constitutive targeting of AS160 to the PM increased the surface GLUT4 levels, and this was attributed to both enhanced AS160 phosphorylation and 14-3-3 binding and inhibition of AS160 GAP activity. We propose a model wherein AS160 acts as a regulatory switch in the docking and/or fusion of GSVs with the PM. PMID:23045393

  10. The role of phospholipase D in Glut-4 translocation.

    PubMed

    Huang, Ping; Frohman, Michael A

    2003-01-01

    Insulin-stimulated Glut-4 translocation is regulated through a complex pathway. Increasing attention is being paid to the role undertaken in this process by Phospholipase D, a signal transduction-activated enzyme that generates the lipid second-messenger phosphatidic acid. Phospholipase D facilitates Glut-4 translocation at potentially multiple steps in its outward movement. Current investigation is centered on Phospholipase D promotion of Glut-4-containing membrane vesicle trafficking and vesicle fusion into the plasma membrane, in part through activation of atypical protein kinase C isoforms. PMID:14648804

  11. High basal cell surface levels of fish GLUT4 are related to reduced sensitivity of insulin-induced translocation toward GGA and AS160 inhibition in adipocytes

    PubMed Central

    Capilla, Encarnación; Díaz, Mònica; Hou, June Chunqiu; Pessin, Jeffrey E.

    2010-01-01

    Glucose entry into cells is mediated by a family of facilitative transporter proteins (GLUTs). In mammals, GLUT4 is expressed in insulin-sensitive tissues and is responsible for the postprandial uptake of glucose. In fish, GLUT4 also mediates insulin-regulated glucose entry into cells but differs from mammalian GLUT4 in its affinity for glucose and in protein motifs known to be important for the traffic of GLUT4. In this study, we have characterized the intracellular and plasma membrane (PM) traffic of two orthologs of GLUT4 in fish, trout (btGLUT4) and salmon (okGLUT4), that do not share the amino terminal FQQI targeting motif of mammalian GLUT4. btGLUT4 (FQHL) and, to a lesser extent, okGLUT4 (FQQL) showed higher basal PM levels, faster traffic to the PM after biosynthesis, and earlier acquisition of insulin responsiveness than rat GLUT4. Furthermore, btGLUT4 showed a similar profile of internalization than rat GLUT4. Expression of the dominant-interfering AS160-4P mutant caused a significant decrease in the insulin-induced PM levels of okGLUT4 and rat GLUT4 and, to a lesser extent, of btGLUT4, suggesting that btGLUT4 has reduced retention into the IRC. Contrary to rat GLUT4 and okGLUT4, the presence of btGLUT4 at the PM under insulin-stimulated conditions was not affected by coexpression of a dominant-interfering GGA mutant. These data suggest that fish GLUT4 follow a different trafficking pathway to the PM compared with rat GLUT4 that seems to be relatively independent of GGA. These results indicate that the regulated trafficking characteristics of GLUT4 have been modified during evolution from fish to mammals. PMID:20075431

  12. GLUT4 and transferrin receptor are differentially sorted along the endocytic pathway in CHO cells.

    PubMed

    Wei, M L; Bonzelius, F; Scully, R M; Kelly, R B; Herman, G A

    1998-02-01

    The trafficking of GLUT4, a facilitative glucose transporter, is examined in transfected CHO cells. In previous work, we expressed GLUT4 in neuroendocrine cells and fibroblasts and found that it was targeted to a population of small vesicles slightly larger than synaptic vesicles (Herman, G.A, F. Bonzelius, A.M. Cieutat, and R.B. Kelly. 1994. Proc. Natl. Acad. Sci. USA. 91: 12750-12754.). In this study, we demonstrate that at 37 degrees C, GLUT4-containing small vesicles (GSVs) are detected after cell surface radiolabeling of GLUT4 whereas uptake of radioiodinated human transferrin does not show appreciable accumulation within these small vesicles. Immunofluorescence microscopy experiments show that at 37 degrees C, cell surface-labeled GLUT4 as well as transferrin is internalized into peripheral and perinuclear structures. At 15 degrees C, endocytosis of GLUT4 continues to occur at a slowed rate, but whereas fluorescently labeled GLUT4 is seen to accumulate within large peripheral endosomes, no perinuclear structures are labeled, and no radiolabeled GSVs are detectable. Shifting cells to 37 degrees C after accumulating labeled GLUT4 at 15 degrees C results in the reappearance of GLUT4 in perinuclear structures and GSV reformation. Cytosol acidification or treatment with hypertonic media containing sucrose prevents the exit of GLUT4 from peripheral endosomes as well as GSV formation, suggesting that coat proteins may be involved in the endocytic trafficking of GLUT4. In contrast, at 15 degrees C, transferrin continues to traffic to perinuclear structures and overall labels structures similar in distribution to those observed at 37 degrees C. Furthermore, treatment with hypertonic media has no apparent effect on transferrin trafficking from peripheral endosomes. Double-labeling experiments after the internalization of both transferrin and surface-labeled GLUT4 show that GLUT4 accumulates within peripheral compartments that exclude the transferrin receptor (TfR) at

  13. N-Acetylated alpha-linked acidic dipeptidase expressed in rat adipocytes is localized in the insulin-responsive glucose transporter (GLUT4) intracellular compartments and involved in the insulin-stimulated GLUT4 recruitment.

    PubMed

    Park, Seung Y; Ha, Byoung G; Choi, Geum H; Lee, Wan

    2004-04-01

    The GLUT4-containing vesicles purified from rat adipocyte contain many protein species of unknown identity, some of which are likely to play a critical role in the trafficking of GLUT4. Presently, we describe an 85-kDa protein in GLUT4-vesicles of rat adipocytes as a potential GLUT4 traffic regulatory protein. MALDI-TOF MS, RT-PCR, gene cloning, protein sequence analysis, and immunoreactivity assay have identified this protein as N-acetylated alpha-linked acidic dipeptidase (NAALADase) expressed in rat adipocytes. NAALADase in rat adipocytes was mostly membrane-associated and colocalized in discrete GLUT4-compartments with enrichment in putative GLUT4-sorting endosomes (G4G(L)). Total cell lysates of adipocytes exhibited NAALADase activity. Next, we treated rat adipocytes with 2-[phosphonomethy]pentanedionic acid (2-PMPA), a potent NAALADase inhibitor, and studied its effect on the distribution of GLUT4 and 3-O-methyl glucose (3OMG) flux. In 2-PMPA-treated adipocytes, there was a significant reduction (by 40%) in the insulin-stimulated GLUT4 translocation to the plasma membrane. The 3OMG flux in insulin-stimulated adipocytes was also delayed (51% of control) by 2-PMPA treatment, indicating that 2-PMPA impairs insulin-stimulated GLUT4 recruitment and the uptake of glucose. It is suggested that NAALADase may function as a regulator required for the insulin-stimulated GLUT4 vesicle movement and/or its exocytosis, thus may regulate insulin-induced GLUT4 recruitment in rat adipocytes.

  14. Lipid rafts are required for GLUT4 internalization in adipose cells.

    PubMed

    Ros-Baro, A; Lopez-Iglesias, C; Peiro, S; Bellido, D; Palacin, M; Zorzano, A; Camps, M

    2001-10-01

    It has been recently reported that insulin recruits a novel signaling machinery to lipid rafts required for insulin-stimulated GLUT4 translocation [Baumann, A., Ribon, V., Kanzaki, M., Thurmond, D. C., Mora, S., Shigematsu, S., Bickel, P. E., Pessin, J. E. & Saltiel, A. R. (2001) Nature 407, 202-207, 2000; Chiang, S. H., Baumann, C. A., Kanzaki, M., Thurmond, D. C., Watson, R. T., Neudauer, C. L., Macara, I. G., Pessin, J. E. & Saltiel, A. R. (2001) Nature 410, 944-948]. We have assessed the role of lipid rafts on GLUT4 traffic in adipose cells. High GLUT4 levels were detected in caveolae from adipocytes by two approaches, the mechanical isolation of purified caveolae from plasma membrane lawns and the immunogold analysis of plasma membrane lawns followed by freeze-drying. The role of lipid rafts in GLUT4 trafficking was studied by adding nystatin or filipin at concentrations that specifically disrupt caveolae morphology and inhibit caveolae function without altering clathrin-mediated endocytosis. These caveolae inhibitors did not affect the insulin-stimulated glucose transport. However, they blocked both the GLUT4 internalization and the down-regulation of glucose transport triggered by insulin removal in 3T3-L1 adipocytes. Our data indicate that lipid rafts are crucial for GLUT4 internalization after insulin removal. Given that high levels of GLUT4 were detected in caveolae from insulin-treated adipose cells, this transporter may be internalized from caveolae or caveolae may operate as an obligatory transition station before internalization.

  15. Gene gun bombardment-mediated expression and translocation of EGFP-tagged GLUT4 in skeletal muscle fibres in vivo.

    PubMed

    Lauritzen, Hans P M M; Reynet, Christine; Schjerling, Peter; Ralston, Evelyn; Thomas, Stephen; Galbo, Henrik; Ploug, Thorkil

    2002-09-01

    Cellular protein trafficking has been studied to date only in vitro or with techniques that are invasive and have a low time resolution. To establish a gentle method for analysis of glucose transporter-4 (GLUT4) trafficking in vivo in fully differentiated rat skeletal muscle fibres we combined the enhanced green fluorescent protein (EGFP) labelling technique with physical transfection methods in vivo: intramuscular plasmid injection or gene gun bombardment. During optimisation experiments with plasmid coding for the EGFP reporter alone EGFP-positive muscle fibres were counted after collagenase treatment of in vivo transfected flexor digitorum brevis (FDB) muscles. In contrast to gene gun bombardment, intramuscular injection produced EGFP expression in only a few fibres. Regardless of the transfection technique, EGFP expression was higher in muscles from 2-week-old rats than in those from 6-week-old rats and peaked around 1 week after transfection. The gene gun was used subsequently with a plasmid coding for EGFP linked to the C-terminus of GLUT4 (GLUT4-EGFP). Rats were anaesthetised 5 days after transfection and insulin given i.v. with or without accompanying electrical hindleg muscle stimulation. After stimulation, the hindlegs were fixed by perfusion. GLUT4-EGFP-positive FDB fibres were isolated and analysed by confocal microscopy. The intracellular distribution of GLUT4-EGFP under basal conditions as well as after translocation to the plasma membrane in response to insulin, contractions, or both, was in accordance with previous studies of endogenous GLUT4. Finally, GLUT4-EGFP trafficking in quadriceps muscle in vivo was studied using time-lapse microscopy analysis in anaesthetised mice and the first detailed time-lapse recordings of GLUT4-EGFP translocation in fully differentiated skeletal muscle in vivo were obtained.

  16. Demonstration of differential quantitative requirements for NSF among multiple vesicle fusion pathways of GLUT4 using a dominant-negative ATPase-deficient NSF

    SciTech Connect

    Chen Xiaoli; Matsumoto, Hideko; Hinck, Cynthia S.; Al-Hasani, Hadi; St-Denis, Jean-Francois; Whiteheart, Sidney W.; Cushman, Samuel W. . E-mail: sam_cushman@nih.gov

    2005-07-22

    In this study, we investigated the relative participation of N-ethylmaleimide-sensitive factor (NSF) in vivo in a complex multistep vesicle trafficking system, the translocation response of GLUT4 to insulin in rat adipose cells. Transfections of rat adipose cells demonstrate that over-expression of wild-type NSF has no effect on total, or basal and insulin-stimulated cell-surface expression of HA-tagged GLUT4. In contrast, a dominant-negative NSF (NSF-D1EQ) can be expressed at a low enough level that it has little effect on total HA-GLUT4, but does reduce both basal and insulin-stimulated cell-surface HA-GLUT4 by {approx}50% without affecting the GLUT4 fold-translocation response to insulin. However, high expression levels of NSF-D1EQ decrease total HA-GLUT4. The inhibitory effect of NSF-D1EQ on cell-surface HA-GLUT4 is reversed when endocytosis is inhibited by co-expression of a dominant-negative dynamin (dynamin-K44A). Moreover, NSF-D1EQ does not affect cell-surface levels of constitutively recycling GLUT1 and TfR, suggesting a predominant effect of low-level NSF-D1EQ on the trafficking of GLUT4 from the endocytic recycling compared to the intracellular GLUT4-specific compartment. Thus, our data demonstrate that the multiple fusion steps in GLUT4 trafficking have differential quantitative requirements for NSF activity. This indicates that the rates of plasma and intracellular membrane fusion reactions vary, leading to differential needs for the turnover of the SNARE proteins.

  17. Insulin-stimulated plasma membrane fusion of Glut4 glucose transporter-containing vesicles is regulated by phospholipase D1.

    PubMed

    Huang, Ping; Altshuller, Yelena M; Hou, June Chunqiu; Pessin, Jeffrey E; Frohman, Michael A

    2005-06-01

    Insulin stimulates glucose uptake in fat and muscle by mobilizing Glut4 glucose transporters from intracellular membrane storage sites to the plasma membrane. This process requires the trafficking of Glut4-containing vesicles toward the cell periphery, docking at exocytic sites, and plasma membrane fusion. We show here that phospholipase D (PLD) production of the lipid phosphatidic acid (PA) is a key event in the fusion process. PLD1 is found on Glut4-containing vesicles, is activated by insulin signaling, and traffics with Glut4 to exocytic sites. Increasing PLD1 activity facilitates glucose uptake, whereas decreasing PLD1 activity is inhibitory. Diminished PA production does not substantially hinder trafficking of the vesicles or their docking at the plasma membrane, but it does impede fusion-mediated extracellular exposure of the transporter. The fusion block caused by RNA interference-mediated PLD1 deficiency is rescued by exogenous provision of a lipid that promotes fusion pore formation and expansion, suggesting that the step regulated by PA is late in the process of vesicle fusion. PMID:15772157

  18. Rac1 and ROCK are implicated in the cell surface delivery of GLUT4 under the control of the insulin signal mimetic diDCP-LA-PE.

    PubMed

    Tsuchiya, Ayako; Kanno, Takeshi; Shimizu, Tadashi; Tanaka, Akito; Nishizaki, Tomoyuki

    2015-08-01

    The phosphatidylethanolamine derivative 1,2-O-bis-[8-{2-(2-pentyl-cyclopropylmethyl)-cyclopropyl}-octanoyl]-sn-glycero-3-phosphatidylethanolamine (diDCP-LA-PE) promoted GLUT4 translocation to the cell surface in differentiated 3T3-L1-GLUT4myc adipocytes through a pathway along a phosphatidylinositol 3-kinase (PI3K)/3-phosphoinositide-dependent protein kinase-1 (PDK1)/Akt axis, that mimics insulin signaling. Moreover, diDCP-LA-PE-induced GLUT4 translocation was suppressed by inhibitors of the Rho GTPase Rac1 and Rho-associated coiled-coil-containing protein kinase (ROCK) or knocking-down Rac1 and ROCK1. The results of the present study show that Rac1 and ROCK are critical for regulation of GLUT4 trafficking by diDCP-LA-PE as well as insulin.

  19. Myosin IIA participates in docking of Glut4 storage vesicles with the plasma membrane in 3T3-L1 adipocytes

    SciTech Connect

    Chung, Le Thi Kim; Hosaka, Toshio; Harada, Nagakatsu; Jambaldorj, Bayasgalan; Fukunaga, Keiko; Nishiwaki, Yuka; Teshigawara, Kiyoshi; Sakai, Tohru; Nakaya, Yutaka; Funaki, Makoto

    2010-01-01

    In adipocytes and myocytes, insulin stimulation translocates glucose transporter 4 (Glut4) storage vesicles (GSVs) from their intracellular storage sites to the plasma membrane (PM) where they dock with the PM. Then, Glut4 is inserted into the PM and initiates glucose uptake into these cells. Previous studies using chemical inhibitors demonstrated that myosin II participates in fusion of GSVs and the PM and increase in the intrinsic activity of Glut4. In this study, the effect of myosin IIA on GSV trafficking was examined by knocking down myosin IIA expression. Myosin IIA knockdown decreased both glucose uptake and exposures of myc-tagged Glut4 to the cell surface in insulin-stimulated cells, but did not affect insulin signal transduction. Interestingly, myosin IIA knockdown failed to decrease insulin-dependent trafficking of Glut4 to the PM. Moreover, in myosin IIA knockdown cells, insulin-stimulated binding of GSV SNARE protein, vesicle-associated membrane protein 2 (VAMP2) to PM SNARE protein, syntaxin 4 was inhibited. These data suggest that myosin IIA plays a role in insulin-stimulated docking of GSVs to the PM in 3T3-L1 adipocytes through SNARE complex formation.

  20. TUSC5 regulates insulin-mediated adipose tissue glucose uptake by modulation of GLUT4 recycling

    PubMed Central

    Beaton, Nigel; Rudigier, Carla; Moest, Hansjörg; Müller, Sebastian; Mrosek, Nadja; Röder, Eva; Rudofsky, Gottfried; Rülicke, Thomas; Ukropec, Jozef; Ukropcova, Barbara; Augustin, Robert; Neubauer, Heike; Wolfrum, Christian

    2015-01-01

    Objective Failure to properly dispose of glucose in response to insulin is a serious health problem, occurring during obesity and is associated with type 2 diabetes development. Insulin-stimulated glucose uptake is facilitated by the translocation and plasma membrane fusion of vesicles containing glucose transporter 4 (GLUT4), the rate-limiting step of post-prandial glucose disposal. Methods We analyzed the role of Tusc5 in the regulation of insulin-stimulated Glut4-mediated glucose uptake in vitro and in vivo. Furthermore, we measured Tusc5 expression in two patient cohorts. Results Herein, we report that TUSC5 controls insulin-stimulated glucose uptake in adipocytes, in vitro and in vivo. TUSC5 facilitates the proper recycling of GLUT4 and other key trafficking proteins during prolonged insulin stimulation, thereby enabling proper protein localization and complete vesicle formation, processes that ultimately enable insulin-stimulated glucose uptake. Tusc5 knockout mice exhibit impaired glucose disposal and TUSC5 expression is predictive of glucose tolerance in obese individuals, independent of body weight. Furthermore, we show that TUSC5 is a PPARγ target and in its absence the anti-diabetic effects of TZDs are significantly blunted. Conclusions Collectively, these findings establish TUSC5 as an adipose tissue-specific protein that enables proper protein recycling, linking the ubiquitous vesicle traffic machinery with tissue-specific insulin-mediated glucose uptake into adipose tissue and the maintenance of a healthy metabolic phenotype in mice and humans. PMID:26629404

  1. Tiliroside-derivatives enhance GLUT4 translocation via AMPK in muscle cells.

    PubMed

    Shi, Lihuan; Qin, Nan; Hu, Lijuan; Liu, Linjuan; Duan, Hongquan; Niu, Wenyan

    2011-05-01

    Tiliroside isolated from Chinese herb Potentilla chinensis showed therapeutic activities in diabetes. We synthesized 7 tiliroside-derivatives and examined their effects on surface GLUT4myc levels in muscle cells. Derivatives 2a and 3 increased surface GLUT4myc levels, and derivative 3 has the greatest potential. AMPK may be involved in tiliroside-derivatives-regulated GLUT4myc traffic.

  2. Proteomic Analysis of GLUT4 Storage Vesicles Reveals Tumor Suppressor Candidate 5 (TUSC5) as a Novel Regulator of Insulin Action in Adipocytes*

    PubMed Central

    Fazakerley, Daniel J.; Naghiloo, Sheyda; Chaudhuri, Rima; Koumanov, Françoise; Burchfield, James G.; Thomas, Kristen C.; Krycer, James R.; Prior, Matthew J.; Parker, Ben L.; Murrow, Beverley A.; Stöckli, Jacqueline; Meoli, Christopher C.; Holman, Geoffrey D.; James, David E.

    2015-01-01

    Insulin signaling augments glucose transport by regulating glucose transporter 4 (GLUT4) trafficking from specialized intracellular compartments, termed GLUT4 storage vesicles (GSVs), to the plasma membrane. Proteomic analysis of GSVs by mass spectrometry revealed enrichment of 59 proteins in these vesicles. We measured reduced abundance of 23 of these proteins following insulin stimulation and assigned these as high confidence GSV proteins. These included established GSV proteins such as GLUT4 and insulin-responsive aminopeptidase, as well as six proteins not previously reported to be localized to GSVs. Tumor suppressor candidate 5 (TUSC5) was shown to be a novel GSV protein that underwent a 3.7-fold increase in abundance at the plasma membrane in response to insulin. siRNA-mediated knockdown of TUSC5 decreased insulin-stimulated glucose uptake, although overexpression of TUSC5 had the opposite effect, implicating TUSC5 as a positive regulator of insulin-stimulated glucose transport in adipocytes. Incubation of adipocytes with TNFα caused insulin resistance and a concomitant reduction in TUSC5. Consistent with previous studies, peroxisome proliferator-activated receptor (PPAR) γ agonism reversed TNFα-induced insulin resistance. TUSC5 expression was necessary but insufficient for PPARγ-mediated reversal of insulin resistance. These findings functionally link TUSC5 to GLUT4 trafficking, insulin action, insulin resistance, and PPARγ action in the adipocyte. Further studies are required to establish the exact role of TUSC5 in adipocytes. PMID:26240143

  3. Insulin Stimulates Translocation of Human GLUT4 to the Membrane in Fat Bodies of Transgenic Drosophila melanogaster

    PubMed Central

    Crivat, Georgeta; Lizunov, Vladimir A.; Li, Caroline R.; Stenkula, Karin G.; Zimmerberg, Joshua; Cushman, Samuel W.; Pick, Leslie

    2013-01-01

    The fruit fly Drosophila melanogaster is an excellent model system for studies of genes controlling development and disease. However, its applicability to physiological systems is less clear because of metabolic differences between insects and mammals. Insulin signaling has been studied in mammals because of relevance to diabetes and other diseases but there are many parallels between mammalian and insect pathways. For example, deletion of Drosophila Insulin-Like Peptides resulted in ‘diabetic’ flies with elevated circulating sugar levels. Whether this situation reflects failure of sugar uptake into peripheral tissues as seen in mammals is unclear and depends upon whether flies harbor the machinery to mount mammalian-like insulin-dependent sugar uptake responses. Here we asked whether Drosophila fat cells are competent to respond to insulin with mammalian-like regulated trafficking of sugar transporters. Transgenic Drosophila expressing human glucose transporter-4 (GLUT4), the sugar transporter expressed primarily in insulin-responsive tissues, were generated. After expression in fat bodies, GLUT4 intracellular trafficking and localization were monitored by confocal and total internal reflection fluorescence microscopy (TIRFM). We found that fat body cells responded to insulin with increased GLUT4 trafficking and translocation to the plasma membrane. While the amplitude of these responses was relatively weak in animals reared on a standard diet, it was greatly enhanced in animals reared on sugar-restricted diets, suggesting that flies fed standard diets are insulin resistant. Our findings demonstrate that flies are competent to mobilize translocation of sugar transporters to the cell surface in response to insulin. They suggest that Drosophila fat cells are primed for a response to insulin and that these pathways are down-regulated when animals are exposed to constant, high levels of sugar. Finally, these studies are the first to use TIRFM to monitor insulin

  4. Identification and characterization of two distinct intracellular GLUT4 pools in rat skeletal muscle: evidence for an endosomal and an insulin-sensitive GLUT4 compartment.

    PubMed

    Aledo, J C; Lavoie, L; Volchuk, A; Keller, S R; Klip, A; Hundal, H S

    1997-08-01

    In skeletal muscle, acute insulin treatment results in the recruitment of the GLUT4 glucose transporter from intracellular vesicular structures to the plasma membrane. The precise nature of these intracellular GLUT4 stores has, however, remained poorly defined. Using an established skeletal-muscle fractionation procedure we present evidence for the existence of two distinct intracellular GLUT4 compartments. We have shown that after fractionation of crude muscle membranes on a discontinuous sucrose gradient the majority of the GLUT4 immunoreactivity was largely present in two sucrose fractions (30 and 35%, w/w, sucrose; denoted F30 and F35 respectively) containing intracellular membranes of different buoyant densities. Here we show that these fractions contained 44+/-6 and 49+/-7% of the crude membrane GLUT4 reactivity respectively, and could be further discriminated on the basis of their immunoreactivity against specific subcellular antigen markers. Membranes from the F30 fraction were highly enriched in transferrin receptor (TfR) and annexin II, two markers of the early endosome compartment, whereas they were significantly depleted of both GLUT1 and the alpha1-subunit of (Na++K+)-ATPase, two cell-surface markers. Insulin treatment resulted in a significant reduction in GLUT4 content in membranes from the F35 fraction, whereas the amount of GLUT4 in the less dense (F30) fraction remained unaffected by insulin. Immunoprecipitation of GLUT4-containing vesicles from both intracellular fractions revealed that TfR was present in GLUT4 vesicles isolated from membranes from the F30 fraction. In contrast, GLUT4 vesicles from the F35 fraction were devoid of TfR. The aminopeptidase, vp165, was present in GLUT4 vesicles from both F30 and F35; however, vesicles isolated from F30 contained over twice as much vp165 per unit of GLUT4 than those isolated from F35. The biochemical co-localization of vp165/GLUT4 was further substantiated by double-immunogold labelling of ultrathin

  5. Insulin accelerates inter-endosomal GLUT4 traffic via phosphatidylinositol 3-kinase and protein kinase B.

    PubMed

    Foster, L J; Li, D; Randhawa, V K; Klip, A

    2001-11-23

    Insulin enhances plasmalemmal-directed traffic of glucose transporter-4 (GLUT4), but it is unknown whether insulin regulates GLUT4 traffic through endosomal compartments. In L6 myoblasts expressing Myc-tagged GLUT4, insulin markedly stimulated the rate of GLUT4myc recycling. In myoblasts stimulated with insulin to maximize surface GLUT4myc levels, we followed the rates of surface-labeled GLUT4myc endocytosis and chased its intracellular distribution in space and time using confocal immunofluorescence microscopy. Surface-labeled GLUT4myc internalized rapidly (t(12) 3 min), reaching the early endosome by 2 min and the transferrin receptor-rich, perinuclear recycling endosome by 20 min. Upon re-addition of insulin, the t(12) of GLUT4 disappearance from the plasma membrane was unchanged (3 min), but strikingly, GLUT4myc reached the recycling endosome by 10 and left by 20 min. This effect of insulin was blocked by the phosphatidylinositol 3-kinase inhibitor LY294002 or by transiently transfected dominant-negative phosphatidylinositol 3-kinase and protein kinase B mutants. In contrast, insulin did not alter the rate of arrival of rhodamine-labeled transferrin at the recycling endosome. These results reveal a heretofore unknown effect of insulin to accelerate inter-endosomal travel rates of GLUT4 and identify the recycling endosome as an obligatory stage in insulin-dependent GLUT4 recycling.

  6. Lack of cyclical fluctuations of endometrial GLUT4 expression in women with polycystic ovary syndrome: Evidence for direct regulation of GLUT4 by steroid hormones.

    PubMed

    Cui, Peng; Li, Xin; Wang, Xiaoqin; Feng, Yi; Lin, Jin-Fang; Billig, Håkan; Shao, Ruijin

    2015-12-01

    Background Determination of the role of steroid hormones in expression and regulation of endometrial glucose transport 4 (GLUT4) in humans is important for understanding endometrial disorders such as polycystic ovary syndrome (PCOS), a common hormone-imbalance disease. Methods Endometrial biopsy samples were collected from non-PCOS patients with regular menstrual cycles or with hyperplasia and from PCOS patients with or without hyperplasia. In addition, endometrial tissues from postmenopausal women were incubated with human chorionic gonadotropin (hCG, 10 IU/ml), 17β-estradiol (E2, 10 nM), progesterone (P4, 100 nM), or a combination of E2 and P4 for 24 h. The expression of GLUT4 was measured at the mRNA level using quantitative real-time polymerase chain reaction (qRT-PCR) and at the protein level using Western blot analysis and immunohistochemistry. Results A cyclical change in GLUT4 expression pattern was observed in non-PCOS patients, and a high level of GLUT4 expression was seen in the proliferative phase compared to the secretory phase. Low levels of GLUT4 expression were found in PCOS patients compared to menstrual cycle phase-matched non-PCOS patients, and there was no significant change in GLUT4 expression in PCOS patients during the menstrual cycle. GLUT4 was localized in both epithelial and stromal cells, with notable changes in epithelial cells. We postulate that decreased GLUT4 expression might be regulated by steroid hormones. In support of this, we showed that in cultured endometrial tissues hCG and E2 alone had no effect on GLUT4 expression. However, P4 alone and P4 in combination with E2 decreased GLUT4 expression. Compared with non-PCOS controls, PCOS patients with endometrial hyperplasia exhibited decreased GLUT4 expression in particular in the epithelial cells. Conclusion We conclude that P4 can induce changes in endometrial GLUT4 expression during the menstrual cycle and that abnormal hormonal conditions such as PCOS disrupt normal patterns

  7. Lack of cyclical fluctuations of endometrial GLUT4 expression in women with polycystic ovary syndrome: Evidence for direct regulation of GLUT4 by steroid hormones

    PubMed Central

    Cui, Peng; Li, Xin; Wang, Xiaoqin; Feng, Yi; Lin, Jin-Fang; Billig, Håkan; Shao, Ruijin

    2015-01-01

    Background Determination of the role of steroid hormones in expression and regulation of endometrial glucose transport 4 (GLUT4) in humans is important for understanding endometrial disorders such as polycystic ovary syndrome (PCOS), a common hormone-imbalance disease. Methods Endometrial biopsy samples were collected from non-PCOS patients with regular menstrual cycles or with hyperplasia and from PCOS patients with or without hyperplasia. In addition, endometrial tissues from postmenopausal women were incubated with human chorionic gonadotropin (hCG, 10 IU/ml), 17β-estradiol (E2, 10 nM), progesterone (P4, 100 nM), or a combination of E2 and P4 for 24 h. The expression of GLUT4 was measured at the mRNA level using quantitative real-time polymerase chain reaction (qRT-PCR) and at the protein level using Western blot analysis and immunohistochemistry. Results A cyclical change in GLUT4 expression pattern was observed in non-PCOS patients, and a high level of GLUT4 expression was seen in the proliferative phase compared to the secretory phase. Low levels of GLUT4 expression were found in PCOS patients compared to menstrual cycle phase-matched non-PCOS patients, and there was no significant change in GLUT4 expression in PCOS patients during the menstrual cycle. GLUT4 was localized in both epithelial and stromal cells, with notable changes in epithelial cells. We postulate that decreased GLUT4 expression might be regulated by steroid hormones. In support of this, we showed that in cultured endometrial tissues hCG and E2 alone had no effect on GLUT4 expression. However, P4 alone and P4 in combination with E2 decreased GLUT4 expression. Compared with non-PCOS controls, PCOS patients with endometrial hyperplasia exhibited decreased GLUT4 expression in particular in the epithelial cells. Conclusion We conclude that P4 can induce changes in endometrial GLUT4 expression during the menstrual cycle and that abnormal hormonal conditions such as PCOS disrupt normal patterns

  8. The Glucose Transporter (GLUT4) Enhancer Factor Is Required for Normal Wing Positioning in Drosophila

    PubMed Central

    Yazdani, Umar; Huang, Zhiyu; Terman, Jonathan R.

    2008-01-01

    Many of the transcription factors and target genes that pattern the developing adult remain unknown. In the present study, we find that an ortholog of the poorly understood transcription factor, glucose transporter (GLUT4) enhancer factor (Glut4EF, GEF) [also known as the Huntington's disease gene regulatory region-binding protein (HDBP) 1], plays a critical role in specifying normal wing positioning in adult Drosophila. Glut4EF proteins are zinc-finger transcription factors named for their ability to regulate expression of GLUT4 but nothing is known of Glut4EF's in vivo physiological functions. Here, we identify a family of Glut4EF proteins that are well conserved from Drosophila to humans and find that mutations in Drosophila Glut4EF underlie the wing-positioning defects seen in stretch mutants. In addition, our results indicate that previously uncharacterized mutations in Glut4EF are present in at least 11 publicly available fly lines and on the widely used TM3 balancer chromosome. These results indicate that previous observations utilizing these common stocks may be complicated by the presence of Glut4EF mutations. For example, our results indicate that Glut4EF mutations are also present on the same chromosome as two gain-of-function mutations of the homeobox transcription factor Antennapedia (Antp) and underlie defects previously attributed to Antp. In fact, our results support a role for Glut4EF in the modulation of morphogenetic processes mediated by Antp, further highlighting the importance of Glut4EF transcription factors in patterning and morphogenesis. PMID:18245850

  9. Overexpression of Vesicle-associated Membrane Protein (VAMP) 3, but Not VAMP2, Protects Glucose Transporter (GLUT) 4 Protein Translocation in an in Vitro Model of Cardiac Insulin Resistance*

    PubMed Central

    Schwenk, Robert W.; Angin, Yeliz; Steinbusch, Laura K. M.; Dirkx, Ellen; Hoebers, Nicole; Coumans, Will A.; Bonen, Arend; Broers, Jos L. V.; van Eys, Guillaume J. J. M.; Glatz, Jan F. C.; Luiken, Joost J. F. P.

    2012-01-01

    Cardiac glucose utilization is regulated by reversible translocation of the glucose transporter GLUT4 from intracellular stores to the plasma membrane. During the onset of diet-induced insulin resistance, elevated lipid levels in the circulation interfere with insulin-stimulated GLUT4 translocation, leading to impaired glucose utilization. Recently, we identified vesicle-associated membrane protein (VAMP) 2 and 3 to be required for insulin- and contraction-stimulated GLUT4 translocation, respectively, in cardiomyocytes. Here, we investigated whether overexpression of VAMP2 and/or VAMP3 could protect insulin-stimulated GLUT4 translocation under conditions of insulin resistance. HL-1 atrial cardiomyocytes transiently overexpressing either VAMP2 or VAMP3 were cultured for 16 h with elevated concentrations of palmitate and insulin. Upon subsequent acute stimulation with insulin, we measured GLUT4 translocation, plasmalemmal presence of the fatty acid transporter CD36, and myocellular lipid accumulation. Overexpression of VAMP3, but not VAMP2, completely prevented lipid-induced inhibition of insulin-stimulated GLUT4 translocation. Furthermore, the plasmalemmal presence of CD36 and intracellular lipid levels remained normal in cells overexpressing VAMP3. However, insulin signaling was not retained, indicating an effect of VAMP3 overexpression downstream of PKB/Akt. Furthermore, we revealed that endogenous VAMP3 is bound by the contraction-activated protein kinase D (PKD), and contraction and VAMP3 overexpression protect insulin-stimulated GLUT4 translocation via a common mechanism. These observations indicate that PKD activates GLUT4 translocation via a VAMP3-dependent trafficking step, which pathway might be valuable to rescue constrained glucose utilization in the insulin-resistant heart. PMID:22936810

  10. Overexpression of vesicle-associated membrane protein (VAMP) 3, but not VAMP2, protects glucose transporter (GLUT) 4 protein translocation in an in vitro model of cardiac insulin resistance.

    PubMed

    Schwenk, Robert W; Angin, Yeliz; Steinbusch, Laura K M; Dirkx, Ellen; Hoebers, Nicole; Coumans, Will A; Bonen, Arend; Broers, Jos L V; van Eys, Guillaume J J M; Glatz, Jan F C; Luiken, Joost J F P

    2012-10-26

    Cardiac glucose utilization is regulated by reversible translocation of the glucose transporter GLUT4 from intracellular stores to the plasma membrane. During the onset of diet-induced insulin resistance, elevated lipid levels in the circulation interfere with insulin-stimulated GLUT4 translocation, leading to impaired glucose utilization. Recently, we identified vesicle-associated membrane protein (VAMP) 2 and 3 to be required for insulin- and contraction-stimulated GLUT4 translocation, respectively, in cardiomyocytes. Here, we investigated whether overexpression of VAMP2 and/or VAMP3 could protect insulin-stimulated GLUT4 translocation under conditions of insulin resistance. HL-1 atrial cardiomyocytes transiently overexpressing either VAMP2 or VAMP3 were cultured for 16 h with elevated concentrations of palmitate and insulin. Upon subsequent acute stimulation with insulin, we measured GLUT4 translocation, plasmalemmal presence of the fatty acid transporter CD36, and myocellular lipid accumulation. Overexpression of VAMP3, but not VAMP2, completely prevented lipid-induced inhibition of insulin-stimulated GLUT4 translocation. Furthermore, the plasmalemmal presence of CD36 and intracellular lipid levels remained normal in cells overexpressing VAMP3. However, insulin signaling was not retained, indicating an effect of VAMP3 overexpression downstream of PKB/Akt. Furthermore, we revealed that endogenous VAMP3 is bound by the contraction-activated protein kinase D (PKD), and contraction and VAMP3 overexpression protect insulin-stimulated GLUT4 translocation via a common mechanism. These observations indicate that PKD activates GLUT4 translocation via a VAMP3-dependent trafficking step, which pathway might be valuable to rescue constrained glucose utilization in the insulin-resistant heart.

  11. Regulation of GLUT4 gene expression by SREBP-1c in adipocytes

    PubMed Central

    Im, Seung-Soon; Kwon, Sool-Ki; Kang, Seung-Youn; Kim, Tae-Hyun; Kim, Ha-Il; Hur, Man-Wook; Kim, Kyung-Sup; Ahn, Yong-Ho

    2006-01-01

    Expression of the GLUT4 (glucose transporter type 4 isoform) gene in adipocytes is subject to hormonal or metabolic control. In the present study, we have characterized an adipose tissue transcription factor that is influenced by fasting/refeeding regimens and insulin. Northern blotting showed that refeeding increased GLUT4 mRNA levels for 24 h in adipose tissue. Consistent with an increased GLUT4 gene expression, the mRNA levels of SREBP (sterol-regulatory-element-binding protein)-1c in adipose tissue were also increased by refeeding. In streptozotocin-induced diabetic rats, insulin treatment increased the mRNA levels of GLUT4 in adipose tissue. Serial deletion, luciferase reporter assays and electrophoretic mobility-shift assay studies indicated that the putative sterol response element is located in the region between bases −109 and −100 of the human GLUT4 promoter. Transduction of the SREBP-1c dominant negative form to differentiated 3T3-L1 adipocytes caused a reduction in the mRNA levels of GLUT4, suggesting that SREBP-1c mediates the transcription of GLUT4. In vivo chromatin immunoprecipitation revealed that refeeding increased the binding of SREBP-1 to the putative sterol-response element in the GLUT4. Furthermore, treating streptozotocin-induced diabetic rats with insulin restored SREBP-1 binding. In addition, we have identified an Sp1 binding site adjacent to the functional sterol-response element in the GLUT4 promoter. The Sp1 site appears to play an additive role in SREBP-1c mediated GLUT4 gene upregulation. These results suggest that upregulation of GLUT4 gene transcription might be directly mediated by SREBP-1c in adipose tissue. PMID:16787385

  12. Insulin-induced cortical actin remodeling promotes GLUT4 insertion at muscle cell membrane ruffles

    PubMed Central

    Tong, Peter; Khayat, Zayna A.; Huang, Carol; Patel, Nish; Ueyama, Atsunori; Klip, Amira

    2001-01-01

    Insulin stimulates glucose uptake by recruiting glucose transporter 4 (GLUT4) from an intracellular compartment to the cell surface; this phenomenon is defective in type 2 diabetes. Here we examine the involvement of actin filaments in GLUT4 translocation and their possible defects in insulin resistance, using L6 myotubes expressing myc-tagged GLUT4. Insulin caused membrane ruffling, a dynamic distortion of the myotube dorsal surface. Fluorescence microscopy and immunogold staining of surface GLUT4myc coupled to backscatter electron microscopy revealed a high density of this protein in membrane ruffles. The t-SNAREs syntaxin4 and SNAP-23 were also abundant in these regions. Below the membrane, GLUT4 and the vesicular protein VAMP2, but not VAMP3, colocalized with the actin structures supporting the membrane ruffles. GLUT4myc externalization and membrane ruffles were reduced by jasplakinolide and by swinholide-A, drugs that affect actin filament stability and prevent actin branching, respectively. Insulin resistance generated by prolonged (24 hours) exposure of myotubes to high glucose and insulin diminished the acute insulin-dependent remodeling of cortical actin and GLUT4myc translocation, reminiscent of the effect of swinholide-A. We propose that GLUT4 vesicle incorporation into the plasma membrane involves insulin-dependent cortical actin remodeling and that defective actin remodeling contributes to insulin resistance. PMID:11489930

  13. Expression, purification, and functional characterization of the insulin-responsive facilitative glucose transporter GLUT4.

    PubMed

    Kraft, Thomas E; Hresko, Richard C; Hruz, Paul W

    2015-12-01

    The insulin-responsive facilitative glucose transporter GLUT4 is of fundamental importance for maintenance of glucose homeostasis. Despite intensive effort, the ability to express and purify sufficient quantities of structurally and functionally intact protein for biophysical analysis has previously been exceedingly difficult. We report here the development of novel methods to express, purify, and functionally reconstitute GLUT4 into detergent micelles and proteoliposomes. Rat GLUT4 containing FLAG and His tags at the amino and carboxy termini, respectively, was engineered and stably transfected into HEK-293 cells. Overexpression in suspension culture yielded over 1.5 mg of protein per liter of culture. Systematic screening of detergent solubilized GLUT4-GFP fusion protein via fluorescent-detection size exclusion chromatography identified lauryl maltose neopentyl glycol (LMNG) as highly effective for isolating monomeric GLUT4 micelles. Preservation of structural integrity and ligand binding was demonstrated via quenching of tryptophan fluorescence and competition of ATB-BMPA photolabeling by cytochalasin B. GLUT4 was reconstituted into lipid nanodiscs and proper folding was confirmed. Reconstitution of purified GLUT4 with amphipol A8-35 stabilized the transporter at elevated temperatures for extended periods of time. Functional activity of purified GLUT4 was confirmed by reconstitution of LMNG-purified GLUT4 into proteoliposomes and measurement of saturable uptake of D-glucose over L-glucose. Taken together, these data validate the development of an efficient means to generate milligram quantities of stable and functionally intact GLUT4 that is suitable for a wide array of biochemical and biophysical analyses.

  14. In vitro analysis of the glucose-transport system in GLUT4-null skeletal muscle.

    PubMed Central

    Ryder, J W; Kawano, Y; Chibalin, A V; Rincón, J; Tsao, T S; Stenbit, A E; Combatsiaris, T; Yang, J; Holman, G D; Charron, M J; Zierath, J R

    1999-01-01

    We have characterized the glucose-transport system in soleus muscle from female GLUT4-null mice to determine whether GLUT1, 3 or 5 account for insulin-stimulated glucose-transport activity. Insulin increased 2-deoxyglucose uptake 2.8- and 2.1-fold in soleus muscle from wild-type and GLUT4-null mice, respectively. Cytochalasin B, an inhibitor of GLUT1- and GLUT4-mediated glucose transport, inhibited insulin-stimulated 2-deoxyglucose uptake by >95% in wild-type and GLUT4-null soleus muscle. Addition of 35 mM fructose to the incubation media was without effect on insulin-stimulated 3-O-methylglucose transport activity in soleus muscle from either genotype, whereas 35 mM glucose inhibited insulin-stimulated (20 nM) 3-O-methylglucose transport by 65% in wild-type and 99% in GLUT4-null mice. We utilized the 2-N-4-1-(1-azi-2,2,2-triflu oroethyl)benzoyl-1, 3-bis(D-mannose-4-yloxy)-2-propylamine (ATB-BMPA) exofacial photolabel to determine if increased cell-surface GLUT1 or GLUT4 content accounted for insulin-stimulated glucose transport in GLUT4-null muscle. In wild-type soleus muscle, cell-surface GLUT4 content was increased by 2.8-fold under insulin-stimulated conditions and this increase corresponded to the increase in 2-deoxyglucose uptake. No detectable cell-surface GLUT4 was observed in soleus muscle from female GLUT4-null mice under either basal or insulin-stimulated conditions. Basal cell-surface GLUT1 content was similar between wild-type and GLUT4-null mice, with no further increase noted in either genotype with insulin exposure. Neither GLUT3 nor GLUT5 appeared to account for insulin-stimulated glucose-transport activity in wild-type or GLUT4-null muscle. In conclusion, insulin-stimulated glucose-transport activity in female GLUT4-null soleus muscle is mediated by a facilitative transport process that is glucose- and cytochalasin B-inhibitable, but which is not labelled strongly by ATB-BMPA. PMID:10455018

  15. The t-SNAREs syntaxin4 and SNAP23 but not v-SNARE VAMP2 are indispensable to tether GLUT4 vesicles at the plasma membrane in adipocyte

    SciTech Connect

    Kawaguchi, Takayuki; Tamori, Yoshikazu; Kanda, Hajime; Yoshikawa, Mari; Tateya, Sanshiro; Nishino, Naonobu; Kasuga, Masato

    2010-01-15

    SNARE proteins (VAMP2, syntaxin4, and SNAP23) have been thought to play a key role in GLUT4 trafficking by mediating the tethering, docking and subsequent fusion of GLUT4-containing vesicles with the plasma membrane. The precise functions of these proteins have remained elusive, however. We have now shown that depletion of the vesicle SNARE (v-SNARE) VAMP2 by RNA interference in 3T3-L1 adipocytes inhibited the fusion of GLUT4 vesicles with the plasma membrane but did not affect tethering of the vesicles to the membrane. In contrast, depletion of the target SNAREs (t-SNAREs) syntaxin4 or SNAP23 resulted in impairment of GLUT4 vesicle tethering to the plasma membrane. Our results indicate that the t-SNAREs syntaxin4 and SNAP23 are indispensable for the tethering of GLUT4 vesicles to the plasma membrane, whereas the v-SNARE VAMP2 is not required for this step but is essential for the subsequent fusion event.

  16. Effect of denervation or unweighting on GLUT-4 protein in rat soleus muscle

    NASA Technical Reports Server (NTRS)

    Henriksen, Erik J.; Rodnick, Kenneth J.; Mondon, Carl E.; James, David E.; Holloszy, John O.

    1991-01-01

    The study is intended to test the hypothesis that the decreased capacity for glucose transport in the denervated rat soleus and the increased capacity for glucose transport in the unweighted rat soleus are related to changes in the expression of the regulatable glucose transporter protein in skeletal muscle (GLUT-4). Results obtained indicate that altered GLUT-4 expression may be a major contributor to the changes in insulin-stimulated glucose transport that are observed with denervation and unweighting. It is concluded that muscle activity is an important factor in the regulation of the GLUT-4 expression in skeletal muscle.

  17. Selective regulation of the perinuclear distribution of glucose transporter 4 (GLUT4) by insulin signals in muscle cells.

    PubMed

    Dugani, Chandrasagar B; Randhawa, Varinder K; Cheng, Alex W P; Patel, Nish; Klip, Amira

    2008-06-01

    Insulin regulates glucose transporter 4 (GLUT4) availability at the surface of muscle and adipose cells. In L6 myoblasts, stably expressed GLUT4myc is detected mostly in a perinuclear region. In unstimulated cells, about half of perinuclear GLUT4myc colocalizes with the transferrin receptor (TfR). Insulin stimulation selectively decreased the perinuclear colocalization of GLUT4myc with TfR determined by 3D-reconstruction of fluorescence images. Perinuclear GLUT4myc adopted two main distributions defined morphometrically as 'conical' and 'concentric'. Insulin rapidly reduced the proportion of cells with conical in favor of concentric perinuclear GLUT4myc distributions in association with the gain in surface GLUT4myc. Upon removal of insulin, the GLUT4myc perinuclear distribution and surface levels reversed in parallel. In contrast, hypertonicity (which like insulin elevates surface GLUT4myc) did not elicit perinuclear GLUT4myc redistribution. Insulin also caused redistribution of perinuclear vesicle-associated membrane protein-2 (VAMP2), without alteration of perinuclear TfR and VAMP3. Inhibitory mutants of phosphatidylinositol-3 kinase (Deltap85) or Akt substrate AS160 (AS160-4P) prevented insulin-mediated perinuclear GLUT4myc redistribution. Tetanus toxin expression did not prevent the perinuclear GLUT4myc redistribution, suggesting that redistribution is independent of GLUT4myc fusion with the plasma membrane. We propose that insulin causes selective, dynamic relocalization of perinuclear GLUT4myc and VAMP2 and perinuclear GLUT4myc redistribution is a direct target of insulin-derived signals.

  18. Loss of GLUT4 induces metabolic reprogramming and impairs viability of breast cancer cells.

    PubMed

    Garrido, Pablo; Osorio, Fernando G; Morán, Javier; Cabello, Estefanía; Alonso, Ana; Freije, José M P; González, Celestino

    2015-01-01

    Metabolic reprogramming strategies focus on the normalization of metabolism of cancer cells and constitute promising targets for cancer treatment. Here, we demonstrate that the glucose transporter 4 (GLUT4) has a prominent role in basal glucose uptake in MCF7 and MDA-MB-231 breast cancer cells. We show that shRNA-mediated down-regulation of GLUT4 diminishes glucose uptake and induces metabolic reprogramming by reallocating metabolic flux to oxidative phosphorylation. This reallocation is reflected on an increased activity of the mitochondrial oxidation of pyruvate and lower lactate release. Altogether, GLUT4 inhibition compromises cell proliferation and critically affects cell viability under hypoxic conditions, providing proof-of-principle for the feasibility of using pharmacological approaches to inhibit GLUT4 in order to induce metabolic reprogramming in vivo in breast cancer models.

  19. Topology mapping of insulin-regulated glucose transporter GLUT4 using computational biology.

    PubMed

    Chakraborty, Chiranjib; Bandyopadhyay, Sanghamitra; Maulik, Ujjwal; Agoramoorthy, Govindasamy

    2013-01-01

    The type 2 diabetes is increasing rapidly around the globe. The primary cause for this is insulin resistance due to the disruption of the insulin signal transduction mechanism. Insulin signal transduction stimulates glucose transport through the glucose transporter GLUT4, by promoting the exocytosis process. Understanding the structural topology of GLUT4 mechanism will increase our understanding of the dynamic activities about glucose transport and its regulation in the membrane environment. However, little is known about the topology of GLUT4. In this article, we have determined the amino acid composition, disulfide topology, structure conformation pattern of GLUT4. The amino acid composition portrays that leucine composition is the highest contributing to 15.5% among all other amino acids. Three cysteine residues such as Cys223, Cys361, and Cys363 were observed and the last two were associated with one disulfide bond formation. We have generated surface cavities to know the clefts/pockets on the surface of this protein that showed few irregular cavities placed mostly in the transmembrane-helical part. Besides, topology mapping of 12 transmembrane-helixes was done to predict N- and O-glycosylation sites and to show the highly glycosylated GLUT4 that includes both N- and O-glycosylation sites. Furthermore, hydrophobic segment and molecular charge distribution were analyzed. This article shows that bioinformatics tools can provide a rapid methodology to predict the topology of GLUT4. It also provides insights into the structural details and structural functioning relationships in the human GLUT4. The results can be of great help to advance future drug development research using GLUT4 as a target protein.

  20. Endoproteolytic Cleavage of TUG Protein Regulates GLUT4 Glucose Transporter Translocation*

    PubMed Central

    Bogan, Jonathan S.; Rubin, Bradley R.; Yu, Chenfei; Löffler, Michael G.; Orme, Charisse M.; Belman, Jonathan P.; McNally, Leah J.; Hao, Mingming; Cresswell, James A.

    2012-01-01

    To promote glucose uptake into fat and muscle cells, insulin causes the translocation of GLUT4 glucose transporters from intracellular vesicles to the cell surface. Previous data support a model in which TUG traps GLUT4-containing vesicles and tethers them intracellularly in unstimulated cells and in which insulin mobilizes this pool of vesicles by releasing this tether. Here we show that TUG undergoes site-specific endoproteolytic cleavage, which separates a GLUT4-binding, N-terminal region of TUG from a C-terminal region previously suggested to bind an intracellular anchor. Cleavage is accelerated by insulin stimulation in 3T3-L1 adipocytes and is highly dependent upon adipocyte differentiation. The N-terminal TUG cleavage product has properties of a novel 18-kDa ubiquitin-like modifier, which we call TUGUL. The C-terminal product is observed at the expected size of 42 kDa and also as a 54-kDa form that is released from membranes into the cytosol. In transfected cells, intact TUG links GLUT4 to PIST and also binds Golgin-160 through its C-terminal region. PIST is an effector of TC10α, a GTPase previously shown to transmit an insulin signal required for GLUT4 translocation, and we show using RNAi that TC10α is required for TUG proteolytic processing. Finally, we demonstrate that a cleavage-resistant form of TUG does not support highly insulin-responsive GLUT4 translocation or glucose uptake in 3T3-L1 adipocytes. Together with previous results, these data support a model whereby insulin stimulates TUG cleavage to liberate GLUT4 storage vesicles from the Golgi matrix, which promotes GLUT4 translocation to the cell surface and enhances glucose uptake. PMID:22610098

  1. GLUT-4 translocation in skeletal muscle studied with a cell-free assay: involvement of phospholipase D.

    PubMed

    Kristiansen, S; Nielsen, J N; Bourgoin, S; Klip, A; Franco, M; Richter, E A

    2001-09-01

    GLUT-4-containing membranes immunoprecipitated from insulin-stimulated rat skeletal muscle produce the phospholipase D (PLD) product phosphatidic acid. In vitro stimulation of PLD in crude membrane with ammonium sulfate (5 mM) resulted in transfer of GLUT-4 (3.0-fold vs. control) as well as transferrin receptor proteins from large to small membrane structures. The in vitro GLUT-4 transfer could be blocked by neomycin (a PLD inhibitor), and neomycin also reduced insulin-stimulated glucose transport in intact incubated soleus muscles. Furthermore, protein kinase B(beta) (PKB(beta)) was found to associate with the GLUT-4 protein and was transferred to small vesicles in response to ammonium sulfate in vitro. Finally, addition of cytosolic proteins, prepared from basal skeletal muscle, and GTP nucleotides to an enriched GLUT-4 membrane fraction resulted in in vitro transfer of GLUT-4 to small membranes (6.8-fold vs. unstimulated control). The cytosol and nucleotide-induced GLUT-4 transfer could be blocked by neomycin and N-ethylmaleimide. In conclusion, we have developed a cell-free assay that demonstrates in vitro GLUT-4 transfer. This transfer may suggest release of GLUT-4-containing vesicles from donor GLUT-4 membranes involving PLD activity and binding of PKB(beta) to GLUT-4.

  2. Suppression of the GLUT4 adaptive response to exercise in fructose-fed rats

    PubMed Central

    Goyaram, Veeraj; Kohn, Tertius A.

    2013-01-01

    Exercise-induced increase in skeletal muscle GLUT4 expression is associated with hyperacetylation of histone H3 within a 350-bp DNA region surrounding the myocyte enhancer factor 2 (MEF2) element on the Glut4 promoter and increased binding of MEF2A. Previous studies have hypothesized that the increase in MEF2A binding is a result of improved accessibility of this DNA segment. Here, we investigated the impact of fructose consumption on exercise-induced GLUT4 adaptive response and directly measured the accessibility of the above segment to nucleases. Male Wistar rats (n = 30) were fed standard chow or chow + 10% fructose or maltodextrin drinks ad libitum for 13 days. In the last 6 days five animals per group performed 3 × 17-min bouts of intermittent swimming daily and five remained untrained. Triceps muscles were harvested and used to measure 1) GLUT4, pAMPK, and HDAC5 contents by Western blot, 2) accessibility of the DNA segment from intact nuclei using nuclease accessibility assays, 3) acetylation level of histone H3 and bound MEF2A by ChIP assays, and 4) glycogen content. Swim training increased GLUT4 content by ∼66% (P < 0.05) but fructose and maltodextrin feeding suppressed the adaptation. Accessibility of the DNA region to MNase and DNase I was significantly increased by swimming (∼2.75- and 5.75-fold, respectively) but was also suppressed in trained rats that consumed fructose or maltodextrin. Histone H3 acetylation and MEF2A binding paralleled the accessibility pattern. These findings indicate that both fructose and maltodextrin modulate the GLUT4 adaptive response to exercise by mechanisms involving chromatin remodeling at the Glut4 promoter. PMID:24326422

  3. Visualization and quantitation of GLUT4 translocation in human skeletal muscle following glucose ingestion and exercise.

    PubMed

    Bradley, Helen; Shaw, Christopher S; Bendtsen, Claus; Worthington, Philip L; Wilson, Oliver J; Strauss, Juliette A; Wallis, Gareth A; Turner, Alice M; Wagenmakers, Anton J M

    2015-05-11

    Insulin- and contraction-stimulated increases in glucose uptake into skeletal muscle occur in part as a result of the translocation of glucose transporter 4 (GLUT4) from intracellular stores to the plasma membrane (PM). This study aimed to use immunofluorescence microscopy in human skeletal muscle to quantify GLUT4 redistribution from intracellular stores to the PM in response to glucose feeding and exercise. Percutaneous muscle biopsy samples were taken from the m. vastus lateralis of ten insulin-sensitive men in the basal state and following 30 min of cycling exercise (65% VO2 max). Muscle biopsy samples were also taken from a second cohort of ten age-, BMI- and VO2 max-matched insulin-sensitive men in the basal state and 30 and 60 min following glucose feeding (75 g glucose). GLUT4 and dystrophin colocalization, measured using the Pearson's correlation coefficient, was increased following 30 min of cycling exercise (baseline r = 0.47 ± 0.01; post exercise r = 0.58 ± 0.02; P < 0.001) and 30 min after glucose ingestion (baseline r = 0.42 ± 0.02; 30 min r = 0.46 ± 0.02; P < 0.05). Large and small GLUT4 clusters were partially depleted following 30 min cycling exercise, but not 30 min after glucose feeding. This study has, for the first time, used immunofluorescence microscopy in human skeletal muscle to quantify increases in GLUT4 and dystrophin colocalization and depletion of GLUT4 from large and smaller clusters as evidence of net GLUT4 translocation to the PM.

  4. Weaning marginally affects glucose transporter (GLUT4) expression in calf muscles and adipose tissues.

    PubMed

    Hocquette, J F; Castiglia-Delavaud, C; Graulet, B; Ferré, P; Picard, B; Vermorel, M

    1997-08-01

    The nutritional regulation of glucose transporter GLUT4 was studied in eight muscles and four adipose tissues from two groups of preruminant (PR) or ruminant (R) calves of similar age (170 d), empty body weight (194 kg) at slaughter, and level of net energy intake from birth onwards. Isocitrate dehydrogenase (EC 1.1.1.41) activity in muscles was not different between PR and R except in masseter muscle from the cheek (+71% in R; P < 0.003), which becomes almost constantly active at weaning for food chewing. Basal and maximally-insulin-stimulated glucose transport rate (GTR) per g tissue wet weight in rectus abdominis muscle were significantly higher in R calves (+31 and 41% respectively; P < 0.05). GLUT4 protein contents did not differ in muscles from PR and R except in masseter (+74% in R; P < 0.05) indicating that the increased GTR in rectus abdominis cannot be accounted for by an enhanced GLUT4 expression. GLUT4 mRNA levels did not differ between the two groups of animals in all muscles suggesting a regulation of GLUT4 at the protein level in masseter. GLUT4 number expressed on a per cell basis was lower in adipose tissue from R calves (-39%; P < 0.05) and higher in internal than in peripheral adipose tissues. In summary, the regulation of GLUT4 in calves at weaning differs markedly from that previously described in rodents (for review, see Girard et al. 1992). Furthermore, significant inter-individual variations were shown for metabolic activities in muscle and for biochemical variables in adipose tissue.

  5. Visualization and quantitation of GLUT4 translocation in human skeletal muscle following glucose ingestion and exercise

    PubMed Central

    Bradley, Helen; Shaw, Christopher S; Bendtsen, Claus; Worthington, Philip L; Wilson, Oliver J; Strauss, Juliette A; Wallis, Gareth A; Turner, Alice M; Wagenmakers, Anton JM

    2015-01-01

    Insulin- and contraction-stimulated increases in glucose uptake into skeletal muscle occur in part as a result of the translocation of glucose transporter 4 (GLUT4) from intracellular stores to the plasma membrane (PM). This study aimed to use immunofluorescence microscopy in human skeletal muscle to quantify GLUT4 redistribution from intracellular stores to the PM in response to glucose feeding and exercise. Percutaneous muscle biopsy samples were taken from the m. vastus lateralis of ten insulin-sensitive men in the basal state and following 30 min of cycling exercise (65% VO2 max). Muscle biopsy samples were also taken from a second cohort of ten age-, BMI- and VO2 max-matched insulin-sensitive men in the basal state and 30 and 60 min following glucose feeding (75 g glucose). GLUT4 and dystrophin colocalization, measured using the Pearson's correlation coefficient, was increased following 30 min of cycling exercise (baseline r = 0.47 ± 0.01; post exercise r = 0.58 ± 0.02; P < 0.001) and 30 min after glucose ingestion (baseline r = 0.42 ± 0.02; 30 min r = 0.46 ± 0.02; P < 0.05). Large and small GLUT4 clusters were partially depleted following 30 min cycling exercise, but not 30 min after glucose feeding. This study has, for the first time, used immunofluorescence microscopy in human skeletal muscle to quantify increases in GLUT4 and dystrophin colocalization and depletion of GLUT4 from large and smaller clusters as evidence of net GLUT4 translocation to the PM. PMID:25969463

  6. Early alterations in soleus GLUT-4, glucose transport, and glycogen in voluntary running rats

    NASA Technical Reports Server (NTRS)

    Henriksen, Erik J.; Halseth, Amy E.

    1994-01-01

    Voluntary wheel running (WR) by juvenile female rats was used as a noninterventional model of soleus muscle functional overload to study the regulation of insulin-stimulated glucose transport activity by the glucose transporter (GLUT-4 isoform) protein level and glycogen concentration. Soleus total protein content was significantly greater (+18%;P greater than 0.05) than in age-matched controls after 1 wk of WR, and this hypertrophic response continued in weeks 2-4 (+24-32%). GLUT-4 protein was 39% greater than in controls in 1-wk WR soleus, and this adaptation was accompanied by a similar increase in in vitro insulin-stimulated glucose transport activity(+29%). After 2 and 4 wk of WR, however, insulin-stimulated glucose transport activity had returned to control levels, despite a continued elevation (+25-28%) of GLUT-4 protein. At these two time points, glycogen concentration was significantly enhanced in WR soleus (+21-42%), which coincided with significant reductions in glycogen synthase activity ratios (-23 to-41%). These results indicate that, in this model of soleus muscle functional overload, the GLUT-4 protein level may initially regulate insulin-stimulated glucose transport activity in the absence of changes in other modifying factors. However,this regulation of glucose transport activity by GLUT-4 protein may be subsequently overridden by elevated glycogen concentration.

  7. Glucose transporters GLUT4 and GLUT8 are upregulated after facial nerve axotomy in adult mice

    PubMed Central

    Gómez, Olga; Ballester-Lurbe, Begoña; Mesonero, José E; Terrado, José

    2011-01-01

    Peripheral nerve axotomy in adult mice elicits a complex response that includes increased glucose uptake in regenerating nerve cells. This work analyses the expression of the neuronal glucose transporters GLUT3, GLUT4 and GLUT8 in the facial nucleus of adult mice during the first days after facial nerve axotomy. Our results show that whereas GLUT3 levels do not vary, GLUT4 and GLUT8 immunoreactivity increases in the cell body of the injured motoneurons after the lesion. A sharp increase in GLUT4 immunoreactivity was detected 3 days after the nerve injury and levels remained high on Day 8, but to a lesser extent. GLUT8 also increased the levels but later than GLUT4, as they only rose on Day 8 post-lesion. These results indicate that glucose transport is activated in regenerating motoneurons and that GLUT4 plays a main role in this function. These results also suggest that metabolic defects involving impairment of glucose transporters may be principal components of the neurotoxic mechanisms leading to motoneuron death. PMID:21740425

  8. Ca²⁺ signals promote GLUT4 exocytosis and reduce its endocytosis in muscle cells.

    PubMed

    Li, Q; Zhu, X; Ishikura, S; Zhang, D; Gao, J; Sun, Y; Contreras-Ferrat, A; Foley, K P; Lavandero, S; Yao, Z; Bilan, P J; Klip, A; Niu, W

    2014-07-15

    Elevating cytosolic Ca(2+) stimulates glucose uptake in skeletal muscle, but how Ca(2+) affects intracellular traffic of GLUT4 is unknown. In tissue, changes in Ca(2+) leading to contraction preclude analysis of the impact of individual, Ca(2+)-derived signals. In L6 muscle cells stably expressing GLUT4myc, the Ca(2+) ionophore ionomycin raised cytosolic Ca(2+) and caused a gain in cell surface GLUT4myc. Extra- and intracellular Ca(2+) chelators (EGTA, BAPTA-AM) reversed this response. Ionomycin activated calcium calmodulin kinase II (CaMKII), AMPK, and PKCs, but not Akt. Silencing CaMKIIδ or AMPKα1/α2 partly reduced the ionomycin-induced gain in surface GLUT4myc, as did peptidic or small molecule inhibitors of CaMKII (CN21) and AMPK (Compound C). Compared with the conventional isoenzyme PKC inhibitor Gö6976, the conventional plus novel PKC inhibitor Gö6983 lowered the ionomycin-induced gain in cell surface GLUT4myc. Ionomycin stimulated GLUT4myc exocytosis and inhibited its endocytosis in live cells. siRNA-mediated knockdown of CaMKIIδ or AMPKα1/α2 partly reversed ionomycin-induced GLUT4myc exocytosis but did not prevent its reduced endocytosis. Compared with Gö6976, Gö6983 markedly reversed the slowing of GLUT4myc endocytosis triggered by ionomycin. In summary, rapid Ca(2+) influx into muscle cells accelerates GLUT4myc exocytosis while slowing GLUT4myc endocytosis. CaMKIIδ and AMPK stimulate GLUT4myc exocytosis, whereas novel PKCs reduce endocytosis. These results identify how Ca(2+)-activated signals selectively regulate GLUT4 exocytosis and endocytosis in muscle cells.

  9. Glut4 is upregulated despite decreased insulin signaling during prolonged fasting in northern elephant seal pups

    PubMed Central

    Vázquez-Medina, José Pablo; Crocker, Daniel E.; Ortiz, Rudy M.

    2011-01-01

    Postprandial cellular glucose uptake is dependent on an insulin-signaling cascade in muscle and adipose tissue, resulting in the translocation of the insulin-dependent glucose transporter 4 (Glut4) into the plasma membrane. Additionally, extended food deprivation is characterized by suppressed insulin signaling and decreased Glut4 expression. Northern elephant seals are adapted to prolonged fasts characterized by high levels of plasma glucose. To address the hypothesis that the fasting-induced decrease in insulin is associated with reduced insulin signaling in prolonged fasted seals, we compared the adipose protein levels of the cellular insulin-signaling pathway, Glut4 and plasma glucose, insulin, cortisol, and adiponectin concentrations between Early (n = 9; 2–3 wks postweaning) and Late (n = 8; 6–8 wks postweaning) fasted seals. Plasma adiponectin (230 ± 13 vs. 177 ± 11 ng/ml), insulin (2.7 ± 0.4 vs. 1.0 ± 0.1 μU/ml), and glucose (9.8 ± 0.5 vs. 8.0 ± 0.3 mM) decreased, while cortisol (124 ± 6 vs. 257 ± 30 nM) doubled with fasting. Glut4 increased (31%) with fasting despite the significant decreases in the cellular content of phosphatidylinositol 3-kinase as well as phosphorylated insulin receptor, insulin receptor substrate-1, and Akt2. Increased Glut4 may have contributed to the decrease in plasma glucose, but the decrease in insulin and insulin signaling suggests that Glut4 is not insulin-dependent in adipose tissue during prolonged fasting in elephant seals. The reduction of plasma glucose independent of insulin may make these animals an ideal model for the study of insulin resistance. PMID:20980624

  10. Karanjin from Pongamia pinnata induces GLUT4 translocation in skeletal muscle cells in a phosphatidylinositol-3-kinase-independent manner.

    PubMed

    Jaiswal, Natasha; Yadav, Prem P; Maurya, Rakesh; Srivastava, Arvind K; Tamrakar, Akhilesh K

    2011-11-16

    Insulin-stimulated glucose uptake in skeletal muscle is decreased in type 2 diabetes due to impaired translocation of insulin-sensitive glucose transporter 4 (GLUT4) from intracellular pool to plasma membrane. Augmenting glucose uptake into this tissue may help in management of type 2 diabetes. Here, the effects of an identified antihyperglycemic molecule, karanjin, isolated from the fruits of Pongamia pinnata were investigated on glucose uptake and GLUT4 translocation in skeletal muscle cells. Treatment of L6-GLUT4myc myotubes with karanjin caused a substantial increase in the glucose uptake and GLUT4 translocation to the cell surface, in a concentration-dependent fashion, without changing the total amount of GLUT4 protein and GLUT4 mRNA. This effect was associated with increased activity of AMP-activated protein kinase (AMPK). Cycloheximide treatment inhibited the effect of karanjin on GLUT4 translocation suggesting the requirement of de novo synthesis of protein. Karanjin-induced GLUT4 translocation was further enhanced with insulin and the effect is completely protected in the presence of wortmannin. Moreover, karanjin did not affect the phosphorylation of AKT (Ser-473) and did not alter the expression of the key molecules of insulin signaling cascade. We conclude that karanjin-induced increase in glucose uptake in L6 myotubes is the result of an increased translocation of GLUT4 to plasma membrane associated with activation of AMPK pathway, in a PI-3-K/AKT-independent manner. PMID:21939653

  11. Insulin Stimulated-Glucose Transporter Glut 4 Is Expressed in the Retina

    PubMed Central

    Sánchez-Chávez, Gustavo; Peña-Rangel, Ma. Teresa; Riesgo-Escovar, Juan R.; Martínez-Martínez, Alejandro; Salceda, Rocío

    2012-01-01

    The vertebrate retina is a very metabolically active tissue whose energy demands are normally met through the uptake of glucose and oxygen. Glucose metabolism in this tissue relies upon adequate glucose delivery from the systemic circulation. Therefore, glucose transport depends on the expression of glucose transporters. Here, we show retinal expression of the Glut 4 glucose transporter in frog and rat retinas. Immunohistochemistry and in situ hybridization studies showed Glut 4 expression in the three nuclear layers of the retina: the photoreceptor, inner nuclear and ganglionar cell layers. In the rat retina immunoprecipitation and Western blot analysis revealed a protein with an apparent molecular mass of 45 kDa. 14C-glucose accumulation by isolated rat retinas was significantly enhanced by physiological concentrations of insulin, an effect blocked by inhibitors of phosphatidyl-inositol 3-kinase (PI3K), a key enzyme in the insulin-signaling pathway in other tissues. Also, we observed an increase in 3H-cytochalasin binding sites in the presence of insulin, suggesting an increase in transporter recruitment at the cell surface. Besides, insulin induced phosphorylation of Akt, an effect also blocked by PI3K inhibition. Expression of Glut 4 was not modified in retinas of a type 1 diabetic rat model. To our knowledge, our results provide the first evidence of Glut4 expression in the retina, suggesting it as an insulin- responsive tissue. PMID:23285235

  12. Eccentric exercise decreases glucose transporter GLUT4 protein in human skeletal muscle.

    PubMed Central

    Asp, S; Daugaard, J R; Richter, E A

    1995-01-01

    1. Eccentric exercise causes impaired postexercise glycogen resynthesis. To study whether changes in muscle concentration of the glucose transporter (GLUT4) protein might be involved, seven healthy young men performed one-legged eccentric exercise by resisting knee flexion enforced by a motor-driven device. 2. The GLUT4 protein concentration in the exercised and in the control thigh was unchanged immediately after exercise. On days 1 and 2 after exercise, the GLUT4 protein concentration in the exercised muscle was 68 +/- 10 and 64 +/- 10% (means +/- S.E.M.; P < 0.05), respectively, of the concentration in the control muscle, and had returned to control values on days 4 and 7. 3. The muscle glycogen concentration decreased from 404 +/- 44 to 336 +/- 44 mmol (kg dry wt)-1 (P < 0.05) during exercise. The glycogen concentration remained significantly lower than in the control thigh on days 1 and 2 after exercise but on days 4 and 7 no differences were found. 4. Although no cause-effect relationship was established, these findings may suggest that decreased muscle concentrations of GLUT4 protein, and, hence, a decreased rate of glucose transport into muscle cells, may be involved in the sustained low glycogen concentration seen after eccentric exercise. Images Figure 1 Figure 4 PMID:7738859

  13. Methotrexate increases skeletal muscle GLUT4 expression and improves metabolic control in experimental diabetes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Long-term administration of 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR) mimics the effects of endurance exercise by activating AMP kinase and by increasing skeletal muscle expression of GLUT4 glucose transporter. AICAR is an intermediate in the purine de novo synthesis, and its tissue conc...

  14. Pongamol from Pongamia pinnata stimulates glucose uptake by increasing surface GLUT4 level in skeletal muscle cells.

    PubMed

    Tamrakar, Akhilesh K; Jaiswal, Natasha; Yadav, Prem P; Maurya, Rakesh; Srivastava, Arvind K

    2011-06-01

    Skeletal muscle is the major site of postprandial glucose disposal and augmenting glucose uptake into this tissue may attenuate insulin resistance that precedes type 2 diabetes mellitus. Here, we investigated the effect of pongamol, an identified lead molecule from the fruits of Pongamia pinnata, on glucose uptake and GLUT4 translocation in skeletal muscle cells. In L6-GLUT4myc myotubes treatment with pongamol significantly promoted both glucose transport and GLUT4 translocation to the cell surface in a concentration-dependent manner, without changing the total amount of GLUT4 protein and GLUT4 mRNA, effects that were also additive with insulin. Cycloheximide treatment inhibited the effect of pongamol on GLUT4 translocation suggesting the requirement of new protein synthesis. The pongamol-induced increase in GLUT4 translocation was completely abolished by wortmannin, and pongamol significantly potentiated insulin-mediated phosphorylation of AKT (Ser-473). We conclude that pongamol-induced increase in glucose uptake in L6 myotubes is the result of an increased translocation of GLUT4 to plasma membrane, driven by a PI-3-K/AKT dependent mechanism. PMID:21497640

  15. Insulin and insulin-like growth factor I (IGF-I) stimulate GLUT4 glucose transporter translocation in Xenopus oocytes.

    PubMed Central

    Mora, S; Kaliman, P; Chillarón, J; Testar, X; Palacín, M; Zorzano, A

    1995-01-01

    1. The heterologous expression of glucose transporters GLUT4 and GLUT1 in Xenopus oocytes has been shown to cause a differential targeting of these glucose-carrier isoforms to cellular membranes and a distinct induction of glucose transport activity. In this study we have evaluated the effect of insulin and insulin-like growth factor I (IGF-I) on glucose uptake and glucose transporter distribution in Xenopus oocytes expressing mammalian GLUT4 and GLUT1 glucose carriers. 2. Insulin and IGF-I stimulated 2-deoxyglucose uptake in GLUT4-expressing oocytes, but not in GLUT1-expressing oocytes or in water-injected oocytes. The stimulatory effect of insulin and IGF-I on 2-deoxyglucose uptake in GLUT4-expressing oocytes occurred via activation of the IGF-I receptor. 3. Subcellular-fractionation studies indicated that insulin and IGF-I stimulated translocation of GLUT4 to the cell surface of the oocyte. 4. Incubation of intact oocytes with insulin stimulated phosphatidylinositol 3-kinase activity, an effect that was blocked by the additional presence of wortmannin. Furthermore, wortmannin totally abolished the insulin-induced stimulation of 2-deoxyglucose uptake in GLUT4-expressing oocytes. 5. In this study, both the insulin-induced GLUT4 carrier translocation and GLUT4-dependent insulin-stimulated glucose transport have been reconstituted in the Xenopus oocyte. These observations, together with the fact that wortmannin, as found in adipocytes, inhibits insulin-stimulated glucose transport in oocytes, suggest that the heterologous expression of GLUT4 in oocytes is a useful experimental model by which to study the cell biology of insulin-induced GLUT4 translocation. Images Figure 2 Figure 3 PMID:7575481

  16. Effect of Intermittent Hypoxia and Rimonabant on Glucose Metabolism in Rats: Involvement of Expression of GLUT4 in Skeletal Muscle

    PubMed Central

    Wang, Xiaoya; Yu, Qin; Yue, Hongmei; Zeng, Shuang; Cui, Fenfen

    2015-01-01

    Background Obstructive sleep apnea (OSA) and its main feature, chronic intermittent hypoxia (IH) during sleep, is closely associated with insulin resistance (IR) and diabetes. Rimonabant can regulate glucose metabolism and improve IR. The present study aimed to assess the effect of IH and rimonabant on glucose metabolism and insulin sensitivity, and to explore the possible mechanisms. Material/Methods Thirty-two rats were randomly assigned into 4 groups: Control group, subjected to intermittent air only; IH group, subjected to IH only; IH+NS group, subjected to IH and treated with normal saline; and IH+Rim group, subjected to IH and treated with 10 mg/kg/day of rimonabant. All rats were killed after 28 days of exposure. Then, the blood and skeletal muscle were collected. We measured fasting blood glucose levels, fasting blood insulin levels, and the expression of glucose transporter 4 (GLUT4) in both mRNA and protein levels in skeletal muscle. Results IH can slow weight gain, increase serum insulin level, and reduce insulin sensitivity in rats. The expressions of GLUT4 mRNA, total GLUT4, and plasma membrane protein of GLUT4 (PM GLUT4) in skeletal muscle were decreased. Rimonabant treatment was demonstrated to improve weight gain and insulin sensitivity of the rats induced by IH. Rimonabant significantly upregulated the expression of GLUT4 mRNA, PM GLUT4, and total GLUT4 in skeletal muscle. Conclusions The present study demonstrates that IH can cause IR and reduced expression of GLUT4 in both mRNA and protein levels in skeletal muscle of rats. Rimonabant treatment can improve IH – induced IR, and the upregulation of GLUT4 expression may be involved in this process. PMID:26503060

  17. Insulin-sensitive glucose transporter transcript levels in calf muscles assessed with a bovine GLUT4 cDNA fragment.

    PubMed

    Hocquette, J F; Graulet, B; Castiglia-Delavaud, C; Bornes, F; Lepetit, N; Ferre, P

    1996-07-01

    Previous studies have shown that the expression of the insulin-sensitive glucose transporter (GLUT4) is lower in oxidative muscles than in glycolytic muscles in bovines and goats in contrast to observations in rats. Additional experiments in this work provide very strong arguments that the immunoreactive band detected does represent GLUT4 protein, which further validates our previous results. Therefore, to determine the level of regulation, the main objective of the present study was to measure GLUT4 mRNA amounts in various bovine muscles. A 241-bp fragment of the bovine GLUT4 cDNA was cloned by polymerase chain reaction (PCR). It shares 80-90% sequence identity with related sequences in other species. This PCR-amplified bovine GLUT4 probe was used to determine the distribution of GLUT4 mRNA in bovine tissues in comparison with that of GLUT1 mRNA. Moreover, GLUT4 mRNA amounts were quantified by Northern-blot analysis in heart and seven skeletal muscles with various oxidative and glycolytic activities from seven ruminant calves. GLUT4 mRNA was detected by Northern-blot analysis only in calf insulin-sensitive tissues. In contrast, GLUT1 mRNA was detected in all tissues studied except liver. GLUT4 mRNA amount was the highest in masseter and heart, which are oxidative muscles (1.67 +/- 0.16 and 1.53 +/- 0.19 units/g wet tissue weight, respectively) and the lowest in glycolytic or oxido-glycolytic muscles (0.31 +/- 0.04 to 1.00 +/- 0.09 units/g wet tissue weight; SEM, n = 7). These data and our previous results provide evidence for translational and/or post-translational control mechanisms of bovine GLUT4 protein expression in a muscle type-specific manner.

  18. A novel IRS-1-associated protein, DGKζ regulates GLUT4 translocation in 3T3-L1 adipocytes

    PubMed Central

    Liu, TingYu; Yu, BuChin; Kakino, Mamoru; Fujimoto, Hitoshi; Ando, Yasutoshi; Hakuno, Fumihiko; Takahashi, Shin-Ichiro

    2016-01-01

    Insulin receptor substrates (IRSs) are major targets of insulin receptor tyrosine kinases. Here we identified diacylglycerol kinase zeta (DGKζ) as an IRS-1-associated protein, and examined roles of DGKζ in glucose transporter 4 (GLUT4) translocation to the plasma membrane. When DGKζ was knocked-down in 3T3-L1 adipocytes, insulin-induced GLUT4 translocation was inhibited without affecting other mediators of insulin-dependent signaling. Similarly, knockdown of phosphatidylinositol 4-phosphate 5-kinase 1α (PIP5K1α), which had been reported to interact with DGKζ, also inhibited insulin-induced GLUT4 translocation. Moreover, DGKζ interacted with IRS-1 without insulin stimulation, but insulin stimulation decreased this interaction. Over-expression of sDGKζ (short-form DGKζ), which competed out DGKζ from IRS-1, enhanced GLUT4 translocation without insulin stimulation. Taking these results together with the data showing that cellular PIP5K activity was correlated with GLUT4 translocation ability, we concluded that IRS-1-associated DGKζ prevents GLUT4 translocation in the absence of insulin and that the DGKζ dissociated from IRS-1 by insulin stimulation enhances GLUT4 translocation through PIP5K1α activity. PMID:27739494

  19. Dual role for myosin II in GLUT4-mediated glucose uptake in 3T3-L1 adipocytes

    SciTech Connect

    Fulcher, F. Kent; Smith, Bethany T.; Russ, Misty; Patel, Yashomati M.

    2008-10-15

    Insulin-stimulated glucose uptake requires the activation of several signaling pathways to mediate the translocation and fusion of GLUT4 vesicles to the plasma membrane. Our previous studies demonstrated that GLUT4-mediated glucose uptake is a myosin II-dependent process in adipocytes. The experiments described in this report are the first to show a dual role for the myosin IIA isoform specifically in regulating insulin-stimulated glucose uptake in adipocytes. We demonstrate that inhibition of MLCK but not RhoK results in impaired insulin-stimulated glucose uptake. Furthermore, our studies show that insulin specifically stimulates the phosphorylation of the RLC associated with the myosin IIA isoform via MLCK. In time course experiments, we determined that GLUT4 translocates to the plasma membrane prior to myosin IIA recruitment. We further show that recruitment of myosin IIA to the plasma membrane requires that myosin IIA be activated via phosphorylation of the RLC by MLCK. Our findings also reveal that myosin II is required for proper GLUT4-vesicle fusion at the plasma membrane. We show that once at the plasma membrane, myosin II is involved in regulating the intrinsic activity of GLUT4 after insulin stimulation. Collectively, our results are the first to reveal that myosin IIA plays a critical role in mediating insulin-stimulated glucose uptake in 3T3-LI adipocytes, via both GLUT4 vesicle fusion at the plasma membrane and GLUT4 activity.

  20. Quantitative immunofluorescence microscopy of subcellular GLUT4 distribution in human skeletal muscle: effects of endurance and sprint interval training

    PubMed Central

    Bradley, Helen; Shaw, Christopher S.; Worthington, Philip L.; Shepherd, Sam O.; Cocks, Matthew; Wagenmakers, Anton J. M.

    2014-01-01

    Abstract Increases in insulin‐mediated glucose uptake following endurance training (ET) and sprint interval training (SIT) have in part been attributed to concomitant increases in glucose transporter 4 (GLUT4) protein content in skeletal muscle. This study used an immunofluorescence microscopy method to investigate changes in subcellular GLUT4 distribution and content following ET and SIT. Percutaneous muscle biopsy samples were taken from the m. vastus lateralis of 16 sedentary males in the overnight fasted state before and after 6 weeks of ET and SIT. An antibody was fully validated and used to show large (> 1 μm) and smaller (<1 μm) GLUT4‐containing clusters. The large clusters likely represent trans‐Golgi network stores and the smaller clusters endosomal stores and GLUT4 storage vesicles (GSVs). Density of GLUT4 clusters was higher at the fibre periphery especially in perinuclear regions. A less dense punctate distribution was seen in the rest of the muscle fibre. Total GLUT4 fluorescence intensity increased in type I and type II fibres following both ET and SIT. Large GLUT4 clusters increased in number and size in both type I and type II fibres, while the smaller clusters increased in size. The greatest increases in GLUT4 fluorescence intensity occurred within the 1 μm layer immediately adjacent to the PM. The increase in peripheral localisation and protein content of GLUT4 following ET and SIT is likely to contribute to the improvements in glucose homeostasis observed after both training modes. PMID:25052490

  1. Mulberry leaf extract stimulates glucose uptake and GLUT4 translocation in rat adipocytes.

    PubMed

    Naowaboot, Jarinyaporn; Pannangpetch, Patchareewan; Kukongviriyapan, Veerapol; Prawan, Auemduan; Kukongviriyapan, Upa; Itharat, Arunporn

    2012-01-01

    Mulberry (Morus alba L.) leaf tea is promoted for its health benefits and the control of diabetes in Asian nations. The blood glucose lowering activity of mulberry leaf extract (MA) has been proven; however, the molecular basis underlying this effect remains unclear. The aim of the present work is to elucidate its mechanism of the antihyperglycemic action, by examining the effect of MA on glucose uptake and the translocation of glucose transporter 4 protein (GLUT4) to the plasma membrane of adipocytes isolated from diabetic rats. The incubation of adipocytes with 5-45 μg/ml MA resulted in 31-54% increase of glucose uptake in a dose-dependent manner. This glucose uptake enhancing effect was inhibited by the phosphoinositol 3-kinase (PI3-K) inhibitor, wortmannin (100 nM). The GLUT4 protein on the plasma membrane fraction of adipocytes was markedly increased after treatment with 15 μg/ml MA extract. Interestingly, gallic acid, one of the phenolic compounds found in MA extract, increased glucose uptake and enhanced the translocation of GLUT4 at concentrations comparable to the amount of gallic acid in the effective concentration ranges of MA. Thus, it is likely that gallic acid contributes, at least in part, to its antihyperglycemic activity. The present results suggest that the antihyperglycemic action of MA is mediated by increasing glucose uptake via the activation of PI3-K signaling pathway and translocation of GLUT4 to the plasma membrane. These findings are the first molecular evidence supporting the mulberry tea as herbal medicine for diabetic patients. PMID:22298456

  2. Impaired translocation of GLUT4 results in insulin resistance of atrophic soleus muscle.

    PubMed

    Xu, Peng-Tao; Song, Zhen; Zhang, Wen-Cheng; Jiao, Bo; Yu, Zhi-Bin

    2015-01-01

    Whether or not the atrophic skeletal muscle induces insulin resistance and its mechanisms are not resolved now. The antigravity soleus muscle showed a progressive atrophy in 1-week, 2-week, and 4-week tail-suspended rats. Hyperinsulinemic-euglycemic clamp showed that the steady-state glucose infusion rate was lower in 4-week tail-suspended rats than that in the control rats. The glucose uptake rates under insulin- or contraction-stimulation were significantly decreased in 4-week unloaded soleus muscle. The key protein expressions of IRS-1, PI3K, and Akt on the insulin-dependent pathway and of AMPK, ERK, and p38 on the insulin-independent pathway were unchanged in unloaded soleus muscle. The unchanged phosphorylation of Akt and p38 suggested that the activity of two signal pathways was not altered in unloaded soleus muscle. The AS160 and GLUT4 expression on the common downstream pathway also was not changed in unloaded soleus muscle. But the GLUT4 translocation to sarcolemma was inhibited during insulin stimulation in unloaded soleus muscle. The above results suggest that hindlimb unloading in tail-suspended rat induces atrophy in antigravity soleus muscle. The impaired GLUT4 translocation to sarcolemma under insulin stimulation may mediate insulin resistance in unloaded soleus muscle and further affect the insulin sensitivity of whole body in tail-suspended rats.

  3. The beneficial effects of exercise in rodents are preserved after detraining: a phenomenon unrelated to GLUT4 expression

    PubMed Central

    2010-01-01

    Background Although exercise training has well-known cardiorespiratory and metabolic benefits, low compliance with exercise training programs is a fact, and the harmful effects of physical detraining regarding these adaptations usually go unnoticed. We investigated the effects of exercise detraining on blood pressure, insulin sensitivity, and GLUT4 expression in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY). Methods Studied animals were randomized into sedentary, trained (treadmill running/5 days a week, 60 min/day for 10 weeks), 1 week of detraining, and 2 weeks of detraining. Blood pressure (tail-cuff system), insulin sensitivity (kITT), and GLUT4 (Western blot) in heart, gastrocnemius and white fat tissue were measured. Results Exercise training reduced blood pressure (19%), improved insulin sensitivity (24%), and increased GLUT4 in the heart (+34%); gastrocnemius (+36%) and fat (+22%) in SHR. In WKY no change in either blood pressure or insulin sensitivity were observed, but there was an increase in GLUT4 in the heart (+25%), gastrocnemius (+45%) and fat (+36%) induced by training. Both periods of detraining did not induce any change in neither blood pressure nor insulin sensitivity in SHR and WKY. One-week detraining reduced GLUT4 in SHR (heart: -28%; fat: -23%) and WKY (heart: -19%; fat: -22%); GLUT4 in the gastrocnemius was reduced after a 2-week detraining (SHR: -35%; WKY: -25%). There was a positive correlation between GLUT4 (gastrocnemius) and the maximal velocity in the exercise test (r = 0.60, p = 0.004). Conclusions The study findings show that in detraining, despite reversion of the enhanced GLUT4 expression, cardiorespiratory and metabolic beneficial effects of exercise are preserved. PMID:21029425

  4. Effect of 7-10 days of cycle ergometer exercise on skeletal muscle GLUT-4 protein content.

    PubMed

    Gulve, E A; Spina, R J

    1995-11-01

    Previous studies in animals and humans have shown that endurance exercise-training protocols of several weeks to many months in duration induce adaptive increases in skeletal muscle GLUT-4 protein concentration. It is generally assumed that the increase in GLUT-4 concentration is a long-term adaptation to training. The present study examined whether 7-10 days of cycle ergometer exercise could induce increases in skeletal muscle GLUT-4 levels. Eight healthy subjects (4 men, 4 women) aged 31 +/- 2 (SE) yr exercised 2 h daily at 65-70% of peak O2 uptake (VO2peak) for either 7 (n = 3) or 10 (n = 5) consecutive days. Muscle biopsies (vastus lateralis) were obtained before initiation of the exercise program and 36-48 h after the final bout of exercise. Glucose transporter protein was quantitated by Western blotting using antiserum specific for GLUT-4. VO2peak was increased by 10% (from 3.0 +/- 0.2 to 3.3 +/- 0.2 l/min; P < 0.01) in response to the training. Body weight did not change (74.3 +/- 4.6 before vs. 75.0 +/- 4.2 kg after) as a result of training. Muscle GLUT-4 immunoreactivity was increased 98% (from 584 +/- 50 to 1,154 +/- 40 counts per minute 125I/25 micrograms protein; P < 0.001) in response to training. Increase in VO2peak and GLUT-4 protein were similar for 7 and 10 days of training. These results suggest that, given an adequate training stimulus, adaptations in skeletal muscle GLUT-4 protein occur very rapidly. Furthermore, the increase in GLUT-4 after 7-10 days of exercise is as large as that reported in studies employing long-term training protocols.

  5. Reversing the reduced level of endometrial GLUT4 expression in polycystic ovary syndrome: a mechanistic study of metformin action

    PubMed Central

    Li, Xin; Cui, Peng; Jiang, Hong-Yuan; Guo, Yan-Rong; Pishdari, Bano; Hu, Min; Feng, Yi; Billig, Håkan; Shao, Ruijin

    2015-01-01

    Conflicting results have been reported regarding whether or not insulin-regulated glucose transporter 4 (GLUT4) is expressed in human and rodent endometria. There is an inverse relationship between androgen levels and insulin-dependent glucose metabolism in women. Hyperandrogenemia, hyperinsulinemia, and insulin resistance are believed to contribute to endometrial abnormalities in women with polycystic ovary syndrome (PCOS). However, it has been unclear in previous studies if endometrial GLUT4 expression is regulated by androgen-dependent androgen receptors (ARs) and/or the insulin receptor/Akt/mTOR signaling network. In this study, we demonstrate that GLUT4 is expressed in normal endometrial cells (mainly in the epithelial cells) and is down-regulated under conditions of hyperandrogenemia in tissues from PCOS patients and in a 5α-dihydrotestosterone-induced PCOS-like rat model. Western blot analysis revealed reduced endometrial GLUT4 expression and increased AR expression in PCOS patients. However, the reduced GLUT4 level was not always associated with an increase in AR in PCOS patients when comparing non-hyperplasia with hyperplasia. Using a human tissue culture system, we investigated the molecular basis by which GLUT4 regulation in endometrial hyperplasia tissues is affected by metformin in PCOS patients. We show that specific endogenous organic cation transporter isoforms are regulated by metformin, and this suggests a direct effect of metformin on endometrial hyperplasia. Moreover, we demonstrate that metformin induces GLUT4 expression and inhibits AR expression and blocks insulin receptor/PI3K/Akt/mTOR signaling in the same hyperplasia human tissues. These findings indicate that changes in endometrial GLUT4 expression in PCOS patients involve the androgen-dependent alteration of AR expression and changes in the insulin receptor/PI3K/Akt/mTOR signaling network. PMID:26045896

  6. Reversing the reduced level of endometrial GLUT4 expression in polycystic ovary syndrome: a mechanistic study of metformin action.

    PubMed

    Li, Xin; Cui, Peng; Jiang, Hong-Yuan; Guo, Yan-Rong; Pishdari, Bano; Hu, Min; Feng, Yi; Billig, Håkan; Shao, Ruijin

    2015-01-01

    Conflicting results have been reported regarding whether or not insulin-regulated glucose transporter 4 (GLUT4) is expressed in human and rodent endometria. There is an inverse relationship between androgen levels and insulin-dependent glucose metabolism in women. Hyperandrogenemia, hyperinsulinemia, and insulin resistance are believed to contribute to endometrial abnormalities in women with polycystic ovary syndrome (PCOS). However, it has been unclear in previous studies if endometrial GLUT4 expression is regulated by androgen-dependent androgen receptors (ARs) and/or the insulin receptor/Akt/mTOR signaling network. In this study, we demonstrate that GLUT4 is expressed in normal endometrial cells (mainly in the epithelial cells) and is down-regulated under conditions of hyperandrogenemia in tissues from PCOS patients and in a 5α-dihydrotestosterone-induced PCOS-like rat model. Western blot analysis revealed reduced endometrial GLUT4 expression and increased AR expression in PCOS patients. However, the reduced GLUT4 level was not always associated with an increase in AR in PCOS patients when comparing non-hyperplasia with hyperplasia. Using a human tissue culture system, we investigated the molecular basis by which GLUT4 regulation in endometrial hyperplasia tissues is affected by metformin in PCOS patients. We show that specific endogenous organic cation transporter isoforms are regulated by metformin, and this suggests a direct effect of metformin on endometrial hyperplasia. Moreover, we demonstrate that metformin induces GLUT4 expression and inhibits AR expression and blocks insulin receptor/PI3K/Akt/mTOR signaling in the same hyperplasia human tissues. These findings indicate that changes in endometrial GLUT4 expression in PCOS patients involve the androgen-dependent alteration of AR expression and changes in the insulin receptor/PI3K/Akt/mTOR signaling network. PMID:26045896

  7. Exercise training exacerbates tourniquet ischemia-induced decreases in GLUT4 expression and muscle atrophy in rats.

    PubMed

    Tsai, Ying-Lan; Hou, Chien-Wen; Liao, Yi-Hung; Chen, Chung-Yu; Lin, Fang-Ching; Lee, Wen-Chih; Chou, Shih-Wei; Kuo, Chia-Hua

    2006-05-15

    The current study determined the interactive effects of ischemia and exercise training on glycogen storage and GLUT4 expression in skeletal muscle. For the first experiment, an acute 1-h tourniquet ischemia was applied to one hindlimb of both the 1-week exercise-trained and untrained rats. The contralateral hindlimb served as control. For the second experiment, 1-h ischemia was applied daily for 1 week to both trained (5 h post-exercise) and untrained rats. GLUT4 mRNA was not affected by acute ischemia, but exercise training lowered GLUT4 mRNA in the acute ischemic muscle. GLUT4 protein levels were elevated by exercise training, but not in the acute ischemic muscle. Exercise training elevated muscle glycogen above untrained levels, but this increase was reversed by chronic ischemia. GLUT4 mRNA and protein levels were dramatically reduced by chronic ischemia, regardless of whether the animals were exercise-trained or not. Chronic ischemia significantly reduced plantaris muscle mass, with a greater decrease found in the exercise-trained rats. In conclusion, the exercise training effect on muscle GLUT4 protein expression was prevented by acute ischemia. Furthermore, chronic ischemia-induced muscle atrophy was exacerbated by exercise training. This result implicates that exercise training could be detrimental to skeletal muscle with severely impaired microcirculation.

  8. Effects of space flight on GLUT-4 content in rat plantaris muscle

    NASA Astrophysics Data System (ADS)

    Tabata, I.; Kawanaka, Kentaro; Sekiguchi, Chiharu; Nagaoka, Shunji; Ohira, Yoshinobu

    The effects of 14 days of space flight on the glucose transporter protein (GLUT-4) were studied in the plantaris muscle of growing 9-week-old, male Sprague Dawley rats. The rats were randomly separated into five groups: pre-flight vivarium ground controls (PF-VC) sacrificed approximately 2 h after launch; flight groups sacrificed either approximately 5 h (F-R0) or 9 days (F-R9) after the return from space; and synchronous ground controls (SC-R0 and SC-R9) sacrificed at the same time as the respective flight groups. The flight groups F-R0 and F-R9 were exposed to micro-gravity for 14 days in the Spacelab module located in the cargo bay of the shuttle transport system - 58 of the manned Space Shuttle for the NASA mission named ''Spacelab Life Sciences 2''. Body weight and plantaris weight of SC-R0 and F-R0 were significantly higher than those of PF-VC. Neither body weight nor plantaris muscle weight in either group had changed 9 days after the return from space. As a result, body weight and plantaris muscle weight did not differ between the flight and synchronous control groups at any of the time points investigated. The GLUT-4 content (cpm/µg membrane protein) in the plantaris muscle did not show any significant change in response to 14 days of space flight or 9 days after return. Similarly, citrate synthase activity did not change during the course of the space flight or the recovery period. These results suggest that 14 days of space flight does not affect muscle mass or GLUT-4 content of the fast-twitch plantaris muscle in the rat.

  9. Acute resistance exercise-induced IGF1 expression and subsequent GLUT4 translocation.

    PubMed

    Kido, Kohei; Ato, Satoru; Yokokawa, Takumi; Makanae, Yuhei; Sato, Koji; Fujita, Satoshi

    2016-08-01

    Acute aerobic exercise (AE) is a major physiological stimulus for skeletal muscle glucose uptake through activation of 5' AMP-activated protein kinase (AMPK). However, the regulation of glucose uptake by acute resistance exercise (RE) remains unclear. To investigate the intracellular regulation of glucose uptake after acute RE versus acute AE, male Sprague-Dawley rats were divided into three groups: RE, AE, or nonexercise control. After fasting for 12 h overnight, the right gastrocnemius muscle in the RE group was exercised at maximum isometric contraction via percutaneous electrical stimulation (3 × 10 sec, 5 sets). The AE group ran on a treadmill (25 m/min, 60 min). Muscle samples were taken 0, 1, and 3 h after completion of the exercises. AMPK, Ca(2+)/calmodulin-dependent protein kinase II, and TBC1D1 phosphorylation were increased immediately after both forms of exercise and returned to baseline levels by 3 h. Muscle IGF1 expression was increased by RE but not AE, and maintained until 3 h after RE Additionally, Akt and AS160 phosphorylation were sustained for 3 h after RE, whereas they returned to baseline levels by 3 h after AE Similarly, GLUT4 translocation remained elevated 3 h after RE, although it returned to the baseline level by 3 h after AE Overall, this study showed that AMPK/TBC1D1 and IGF1/Akt/AS160 signaling were enhanced by acute RE, and that GLUT4 translocation after acute RE was more prolonged than after acute AE These results suggest that acute RE-induced increases in intramuscular IGF1 expression might be a distinct regulator of GLUT4 translocation. PMID:27550988

  10. Fiber type effects on contraction-stimulated glucose uptake and GLUT4 abundance in single fibers from rat skeletal muscle

    PubMed Central

    Castorena, Carlos M.; Arias, Edward B.; Sharma, Naveen; Bogan, Jonathan S.

    2014-01-01

    To fully understand skeletal muscle at the cellular level, it is essential to evaluate single muscle fibers. Accordingly, the major goals of this study were to determine if there are fiber type-related differences in single fibers from rat skeletal muscle for: 1) contraction-stimulated glucose uptake and/or 2) the abundance of GLUT4 and other metabolically relevant proteins. Paired epitrochlearis muscles isolated from Wistar rats were either electrically stimulated to contract (E-Stim) or remained resting (No E-Stim). Single fibers isolated from muscles incubated with 2-deoxy-d-[3H]glucose (2-DG) were used to determine fiber type [myosin heavy chain (MHC) isoform protein expression], 2-DG uptake, and abundance of metabolically relevant proteins, including the GLUT4 glucose transporter. E-Stim, relative to No E-Stim, fibers had greater (P < 0.05) 2-DG uptake for each of the isolated fiber types (MHC-IIa, MHC-IIax, MHC-IIx, MHC-IIxb, and MHC-IIb). However, 2-DG uptake for E-Stim fibers was not significantly different among these five fiber types. GLUT4, tethering protein containing a UBX domain for GLUT4 (TUG), cytochrome c oxidase IV (COX IV), and filamin C protein levels were significantly greater (P < 0.05) in MHC-IIa vs. MHC-IIx, MHC-IIxb, or MHC-IIb fibers. TUG and COX IV in either MHC-IIax or MHC-IIx fibers exceeded values for MHC-IIxb or MHC-IIb fibers. GLUT4 levels for MHC-IIax fibers exceeded MHC-IIxb fibers. GLUT4, COX IV, filamin C, and TUG abundance in single fibers was significantly (P < 0.05) correlated with each other. Differences in GLUT4 abundance among the fiber types were not accompanied by significant differences in contraction-stimulated glucose uptake. PMID:25491725

  11. Exogenous β-amyloid peptide interferes with GLUT4 localization in neurons.

    PubMed

    Oliveira, Leandro T; Leon, Gabbriela V O; Provance, D William; de Mello, Fernando G; Sorenson, Martha M; Salerno, Verônica P

    2015-07-30

    Aging represents a major risk factor for numerous illnesses that are of increasing importance to society, including two of the most prevalent: diabetes and Alzheimer's disease. Studies have shown that diabetes is a risk factor for spontaneous Alzheimer's disease. While these studies suggest that diabetes can contribute to Alzheimer's disease, the implications of AD on diabetes are practically unexplored. The major mediator of the pathophysiological effects, the Aβ42 peptide, has been shown to enter neurons and lead to an alteration of the intracellular distribution of the molecular motor myosin Vb. Myosin Vb functions in memory and learning by participating in the strengthening of the long-term potentiation (LTP) of synaptic transmissions. It has also been implicated in the translocation of the glucose transporter, GLUT4, to the plasma membrane in response to insulin, a process that is defective in diabetes. Here, the effect on GLUT4 upon entry of the Aβ42 peptide into cultured chick retinal neurons was explored. The results suggest an alteration in distribution and a reduced level at the cell surface, as well as an increased colocalization with myosin Vb, which can partially explain the changes in glucose metabolism associated with AD. It is also shown that the presence of the Aβ40 peptide inhibits the internalization of the Aβ42 peptide in cultured cells. Together, the results provide additional targets for the development of therapeutics against the progression and effects of Alzheimer's disease.

  12. Signal transduction meets vesicle traffic: the software and hardware of GLUT4 translocation.

    PubMed

    Klip, Amira; Sun, Yi; Chiu, Tim Ting; Foley, Kevin P

    2014-05-15

    Skeletal muscle is the major tissue disposing of dietary glucose, a function regulated by insulin-elicited signals that impart mobilization of GLUT4 glucose transporters to the plasma membrane. This phenomenon, also central to adipocyte biology, has been the subject of intense and productive research for decades. We focus on muscle cell studies scrutinizing insulin signals and vesicle traffic in a spatiotemporal manner. Using the analogy of an integrated circuit to approach the intersection between signal transduction and vesicle mobilization, we identify signaling relays ("software") that engage structural/mechanical elements ("hardware") to enact the rapid mobilization and incorporation of GLUT4 into the cell surface. We emphasize how insulin signal transduction switches from tyrosine through lipid and serine phosphorylation down to activation of small G proteins of the Rab and Rho families, describe key negative regulation step of Rab GTPases through the GTPase-activating protein activity of the Akt substrate of 160 kDa (AS160), and focus on the mechanical effectors engaged by Rabs 8A and 10 (the molecular motor myosin Va), and the Rho GTPase Rac1 (actin filament branching and severing through Arp2/3 and cofilin). Finally, we illustrate how actin filaments interact with myosin 1c and α-Actinin4 to promote vesicle tethering as preamble to fusion with the membrane.

  13. Functional characterization of retromer in GLUT4 storage vesicle formation and adipocyte differentiation.

    PubMed

    Yang, Zhe; Hong, Lee Kian; Follett, Jordan; Wabitsch, Martin; Hamilton, Nicholas A; Collins, Brett M; Bugarcic, Andrea; Teasdale, Rohan D

    2016-03-01

    Insulin-stimulated translocation of glucose transporter 4 (GLUT4) storage vesicles (GSVs), the specialized intracellular compartments within mature adipocytes, to the plasma membrane (PM) is a fundamental cellular process for maintaining glucose homeostasis. Using 2 independent adipocyte cell line models, human primary Simpson-Golabi-Behmel syndrome and mouse 3T3-L1 fibroblast cell lines, we demonstrate that the endosome-associated protein-sorting complex retromer colocalizes with GLUT4 on the GSVs by confocal microscopy in mature adipocytes. By use of both confocal microscopy and differential ultracentrifugation techniques, retromer is redistributed to the PM of mature adipocytes upon insulin stimulation. Furthermore, stable knockdown of the retromer subunit-vacuolar protein-sorting 35, or the retromer-associated protein sorting nexin 27, by lentivirus-delivered small hairpin RNA impaired the adipogenesis process when compared to nonsilence control. The knockdown of retromer decreased peroxisome proliferator activated receptor γ expression during differentiation, generating adipocytes with decreased levels of GSVs, lipid droplet accumulation, and insulin-stimulated glucose uptake. In conclusion, our study demonstrates a role for retromer in the GSV formation and adipogenesis. PMID:26581601

  14. Dual-mode of insulin action controls GLUT4 vesicle exocytosis

    PubMed Central

    Xu, Yingke; Rubin, Bradley R.; Orme, Charisse M.; Karpikov, Alexander; Yu, Chenfei

    2011-01-01

    Insulin stimulates translocation of GLUT4 storage vesicles (GSVs) to the surface of adipocytes, but precisely where insulin acts is controversial. Here we quantify the size, dynamics, and frequency of single vesicle exocytosis in 3T3-L1 adipocytes. We use a new GSV reporter, VAMP2-pHluorin, and bypass insulin signaling by disrupting the GLUT4-retention protein TUG. Remarkably, in unstimulated TUG-depleted cells, the exocytic rate is similar to that in insulin-stimulated control cells. In TUG-depleted cells, insulin triggers a transient, twofold burst of exocytosis. Surprisingly, insulin promotes fusion pore expansion, blocked by acute perturbation of phospholipase D, which reflects both properties intrinsic to the mobilized vesicles and a novel regulatory site at the fusion pore itself. Prolonged stimulation causes cargo to switch from ∼60 nm GSVs to larger exocytic vesicles characteristic of endosomes. Our results support a model whereby insulin promotes exocytic flux primarily by releasing an intracellular brake, but also by accelerating plasma membrane fusion and switching vesicle traffic between two distinct circuits. PMID:21555461

  15. Functional characterization of retromer in GLUT4 storage vesicle formation and adipocyte differentiation.

    PubMed

    Yang, Zhe; Hong, Lee Kian; Follett, Jordan; Wabitsch, Martin; Hamilton, Nicholas A; Collins, Brett M; Bugarcic, Andrea; Teasdale, Rohan D

    2016-03-01

    Insulin-stimulated translocation of glucose transporter 4 (GLUT4) storage vesicles (GSVs), the specialized intracellular compartments within mature adipocytes, to the plasma membrane (PM) is a fundamental cellular process for maintaining glucose homeostasis. Using 2 independent adipocyte cell line models, human primary Simpson-Golabi-Behmel syndrome and mouse 3T3-L1 fibroblast cell lines, we demonstrate that the endosome-associated protein-sorting complex retromer colocalizes with GLUT4 on the GSVs by confocal microscopy in mature adipocytes. By use of both confocal microscopy and differential ultracentrifugation techniques, retromer is redistributed to the PM of mature adipocytes upon insulin stimulation. Furthermore, stable knockdown of the retromer subunit-vacuolar protein-sorting 35, or the retromer-associated protein sorting nexin 27, by lentivirus-delivered small hairpin RNA impaired the adipogenesis process when compared to nonsilence control. The knockdown of retromer decreased peroxisome proliferator activated receptor γ expression during differentiation, generating adipocytes with decreased levels of GSVs, lipid droplet accumulation, and insulin-stimulated glucose uptake. In conclusion, our study demonstrates a role for retromer in the GSV formation and adipogenesis.

  16. Trafficking defect of mutant kidney anion exchanger 1 (kAE1) proteins associated with distal renal tubular acidosis and Southeast Asian ovalocytosis.

    PubMed

    Sawasdee, Nunghathai; Udomchaiprasertkul, Wandee; Noisakran, Sansanee; Rungroj, Nanyawan; Akkarapatumwong, Varaporn; Yenchitsomanus, Pa-thai

    2006-11-24

    Compound heterozygous anion exchanger 1 (AE1) SAO/G701D mutations result in distal renal tubular acidosis with Southeast Asian ovalocytosis. Interaction, trafficking and localization of wild-type and mutant (SAO and G701D) kAE1 proteins fused with hemagglutinin, six-histidine, Myc, or green fluorescence protein (GFP) were examined in human embryonic kidney (HEK) 293 cells. When individually expressed, wild-type kAE1 was localized at cell surface while mutant kAE1 SAO and G701D were intracellularly retained. When co-expressed, wild-type kAE1 could form heterodimer with kAE1 SAO or kAE1 G701D and could rescue mutant kAE1 proteins to express on the cell surface. Co-expression of kAE1 SAO and kAE1 G701D also resulted in heterodimer formation but intracellular retention without cell surface expression, suggesting their trafficking defect and failure to rescue each other to the plasma membrane, most likely the molecular mechanism of the disease in the compound heterozygous condition. PMID:17027918

  17. Adaptive responses of GLUT-4 and citrate synthase in fast-twitch muscle of voluntary running rats

    NASA Technical Reports Server (NTRS)

    Henriksen, E. J.; Halseth, A. E.

    1995-01-01

    Glucose transporter (GLUT-4) protein, hexokinase, and citrate synthase (proteins involved in oxidative energy production from blood glucose catabolism) increase in response to chronically elevated neuromuscular activity. It is currently unclear whether these proteins increase in a coordinated manner in response to this stimulus. Therefore, voluntary wheel running (WR) was used to chronically overload the fast-twitch rat plantaris muscle and the myocardium, and the early time courses of adaptative responses of GLUT-4 protein and the activities of hexokinase and citrate synthase were characterized and compared. Plantaris hexokinase activity increased 51% after just 1 wk of WR, whereas GLUT-4 and citrate synthase were increased by 51 and 40%, respectively, only after 2 wk of WR. All three variables remained comparably elevated (+50-64%) through 4 wk of WR. Despite the overload of the myocardium with this protocol, no substantial elevations in these variables were observed. These findings are consistent with a coordinated upregulation of GLUT-4 and citrate synthase in the fast-twitch plantaris, but not in the myocardium, in response to this increased neuromuscular activity. Regulation of hexokinase in fast-twitch muscle appears to be uncoupled from regulation of GLUT-4 and citrate synthase, as increases in the former are detectable well before increases in the latter.

  18. Repression of GLUT4 expression by the endoplasmic reticulum stress response in 3T3-L1 adipocytes

    PubMed Central

    Miller, Ryan S.; Diaczok, Daniel; Cooke, David W.

    2007-01-01

    Expression of GLUT4 is decreased in adipocytes in obesity and type 2 diabetes, contributing to the insulin resistance of these states. Recent investigations suggest a role for activation of the ER stress response in the pathophysiology of type 2 diabetes. We investigated activation of the ER stress response in 3T3-L1 adipocytes. We show that activation of the ER stress response decreased GLUT4 expression at the level of gene transcription. Activation of the ER stress response also increased the expression of CHOP10, an inhibitor of the activity and expression of C/EBPα. As expected, activation of the ER stress response decreased expression of C/EBPα, an activator of GLUT4 expression, providing a mechanism to account for the repression of GLUT4 by ER stress activation. Our studies identify repression of GLUT4 expression as another potential mechanism for obesity-induced activation of the ER stress response to contribute to the insulin resistance of obesity. PMID:17698029

  19. Testosterone stimulates glucose uptake and GLUT4 translocation through LKB1/AMPK signaling in 3T3-L1 adipocytes.

    PubMed

    Mitsuhashi, Kazuteru; Senmaru, Takafumi; Fukuda, Takuya; Yamazaki, Masahiro; Shinomiya, Katsuhiko; Ueno, Morio; Kinoshita, Shigeru; Kitawaki, Jo; Katsuyama, Masato; Tsujikawa, Muneo; Obayashi, Hiroshi; Nakamura, Naoto; Fukui, Michiaki

    2016-01-01

    Decreases in serum testosterone concentrations in aging men are associated with metabolic disorders. Testosterone has been reported to increase GLUT4-dependent glucose uptake in skeletal muscle cells and cardiomyocytes. However, studies on glucose uptake occurring in response to testosterone stimulation in adipocytes are currently not available. This study was designed to determine the effects of testosterone on glucose uptake in adipocytes. Glucose uptake was assessed with 2-[(3)H] deoxyglucose in 3T3-L1 adipocytes. GLUT4 translocation was evaluated in plasma membrane (PM) sheets and PM fractions by immunofluorescence and immunoblotting, respectively. Activation of GLUT4 translocation-related protein kinases, including Akt, AMPK, LKB1, CaMKI, CaMKII, and Cbl was followed by immunoblotting. Expression levels of androgen receptor (AR) mRNA and AR translocation to the PM were assessed by real-time RT-PCR and immunoblotting, respectively. The results showed that both high-dose (100 nM) testosterone and testosterone-BSA increased glucose uptake and GLUT4 translocation to the PM, independently of the intracellular AR. Testosterone and testosterone-BSA stimulated the phosphorylation of AMPK, LKB1, and CaMKII. The knockdown of LKB1 by siRNA attenuated testosterone- and testosterone-BSA-stimulated AMPK phosphorylation and glucose uptake. These results indicate that high-dose testosterone and testosterone-BSA increase GLUT4-dependent glucose uptake in 3T3-L1 adipocytes by inducing the LKB1/AMPK signaling pathway.

  20. In Vitro Evaluations of Cytotoxicity of Eight Antidiabetic Medicinal Plants and Their Effect on GLUT4 Translocation

    PubMed Central

    Kadan, Sleman; Saad, Bashar; Sasson, Yoel; Zaid, Hilal

    2013-01-01

    Despite the enormous achievements in conventional medicine, herbal-based medicines are still a common practice for the treatment of diabetes. Trigonella foenum-graecum, Atriplex halimus, Olea europaea, Urtica dioica, Allium sativum, Allium cepa, Nigella sativa, and Cinnamomum cassia are strongly recommended in the Greco-Arab and Islamic medicine for the treatment and prevention of diabetes. Cytotoxicity (MTT and LDH assays) of the plant extracts was assessed using cells from the liver hepatocellular carcinoma cell line (HepG2) and cells from the rat L6 muscle cell line. The effects of the plant extracts (50% ethanol in water) on glucose transporter-4 (GLUT4) translocation to the plasma membrane was tested in an ELISA test on L6-GLUT4myc cells. Results obtained indicate that Cinnamomon cassia is cytotoxic at concentrations higher than 100 μg/mL, whereas all other tested extracts exhibited cytotoxic effects at concentrations higher than 500 μg/mL. Exposing L6-GLUT4myc muscle cell to extracts from Trigonella foenum-graecum, Urtica dioica, Atriplex halimus, and Cinnamomum verum led to a significant gain in GLUT4 on their plasma membranes at noncytotoxic concentrations as measured with MTT assay and the LDH leakage assay. These findings indicate that the observed anti-diabetic properties of these plants are mediated, at least partially, through regulating GLUT4 translocation. PMID:23606883

  1. Myosin Va mediates Rab8A-regulated GLUT4 vesicle exocytosis in insulin-stimulated muscle cells.

    PubMed

    Sun, Yi; Chiu, Tim T; Foley, Kevin P; Bilan, Philip J; Klip, Amira

    2014-04-01

    Rab-GTPases are important molecular switches regulating intracellular vesicle traffic, and we recently showed that Rab8A and Rab13 are activated by insulin in muscle to mobilize GLUT4-containing vesicles to the muscle cell surface. Here we show that the unconventional motor protein myosin Va (MyoVa) is an effector of Rab8A in this process. In CHO-IR cell lysates, a glutathione S-transferase chimera of the cargo-binding COOH tail (CT) of MyoVa binds Rab8A and the related Rab10, but not Rab13. Binding to Rab8A is stimulated by insulin in a phosphatidylinositol 3-kinase-dependent manner, whereas Rab10 binding is insulin insensitive. MyoVa-CT preferentially binds GTP-locked Rab8A. Full-length green fluorescent protein (GFP)-MyoVa colocalizes with mCherry-Rab8A in perinuclear small puncta, whereas GFP-MyoVa-CT collapses the GTPase into enlarged perinuclear depots. Further, GFP-MyoVa-CT blocks insulin-stimulated translocation of exofacially myc-tagged GLUT4 to the surface of muscle cells. Mutation of amino acids in MyoVa-CT predicted to bind Rab8A abrogates both interaction with Rab8A (not Rab10) and inhibition of insulin-stimulated GLUT4myc translocation. Of importance, small interfering RNA-mediated MyoVa silencing reduces insulin-stimulated GLUT4myc translocation. Rab8A colocalizes with GLUT4 in perinuclear but not submembrane regions visualized by confocal total internal reflection fluorescence microscopy. Hence insulin signaling to the molecular switch Rab8A connects with the motor protein MyoVa to mobilize GLUT4 vesicles toward the muscle cell plasma membrane.

  2. Myosin Va mediates Rab8A-regulated GLUT4 vesicle exocytosis in insulin-stimulated muscle cells

    PubMed Central

    Sun, Yi; Chiu, Tim T.; Foley, Kevin P.; Bilan, Philip J.; Klip, Amira

    2014-01-01

    Rab-GTPases are important molecular switches regulating intracellular vesicle traffic, and we recently showed that Rab8A and Rab13 are activated by insulin in muscle to mobilize GLUT4-containing vesicles to the muscle cell surface. Here we show that the unconventional motor protein myosin Va (MyoVa) is an effector of Rab8A in this process. In CHO-IR cell lysates, a glutathione S-transferase chimera of the cargo-binding COOH tail (CT) of MyoVa binds Rab8A and the related Rab10, but not Rab13. Binding to Rab8A is stimulated by insulin in a phosphatidylinositol 3-kinase–dependent manner, whereas Rab10 binding is insulin insensitive. MyoVa-CT preferentially binds GTP-locked Rab8A. Full-length green fluorescent protein (GFP)–MyoVa colocalizes with mCherry-Rab8A in perinuclear small puncta, whereas GFP–MyoVa-CT collapses the GTPase into enlarged perinuclear depots. Further, GFP–MyoVa-CT blocks insulin-stimulated translocation of exofacially myc-tagged GLUT4 to the surface of muscle cells. Mutation of amino acids in MyoVa-CT predicted to bind Rab8A abrogates both interaction with Rab8A (not Rab10) and inhibition of insulin-stimulated GLUT4myc translocation. Of importance, small interfering RNA–mediated MyoVa silencing reduces insulin-stimulated GLUT4myc translocation. Rab8A colocalizes with GLUT4 in perinuclear but not submembrane regions visualized by confocal total internal reflection fluorescence microscopy. Hence insulin signaling to the molecular switch Rab8A connects with the motor protein MyoVa to mobilize GLUT4 vesicles toward the muscle cell plasma membrane. PMID:24478457

  3. Glucose-transporter (GLUT4) protein content in oxidative and glycolytic skeletal muscles from calf and goat.

    PubMed

    Hocquette, J F; Bornes, F; Balage, M; Ferre, P; Grizard, J; Vermorel, M

    1995-01-15

    It is well accepted that skeletal muscle is a major glucose-utilizing tissue and that insulin is able to stimulate in vivo glucose utilization in ruminants as in monogastrics. In order to determine precisely how glucose uptake is controlled in various ruminant muscles, particularly by insulin, this study was designed to investigate in vitro glucose transport and insulin-regulatable glucose-transporter protein (GLUT4) in muscle from calf and goat. Our data demonstrate that glucose transport is the rate-limiting step for glucose uptake in bovine fibre strips, as in rat muscle. Insulin increases the rate of in vitro glucose transport in bovine muscle, but to a lower extent than in rat muscle. A GLUT4-like protein was detected by immunoblot assay in all insulin-responsive tissues from calf and goat (heart, skeletal muscle, adipose tissue) but not in liver, brain, erythrocytes and intestine. Unlike the rat, bovine and goat GLUT4 content is higher in glycolytic and oxido-glycolytic muscles than in oxidative muscles. In conclusion, using both a functional test (insulin stimulation of glucose transport) and an immunological approach, this study demonstrates that ruminant muscles express GLUT4 protein. Our data also suggest that, in ruminants, glucose is the main energy-yielding substrate for glycolytic but not for oxidative muscles, and that insulin responsiveness may be lower in oxidative than in other skeletal muscles.

  4. Glucose-transporter (GLUT4) protein content in oxidative and glycolytic skeletal muscles from calf and goat.

    PubMed Central

    Hocquette, J F; Bornes, F; Balage, M; Ferre, P; Grizard, J; Vermorel, M

    1995-01-01

    It is well accepted that skeletal muscle is a major glucose-utilizing tissue and that insulin is able to stimulate in vivo glucose utilization in ruminants as in monogastrics. In order to determine precisely how glucose uptake is controlled in various ruminant muscles, particularly by insulin, this study was designed to investigate in vitro glucose transport and insulin-regulatable glucose-transporter protein (GLUT4) in muscle from calf and goat. Our data demonstrate that glucose transport is the rate-limiting step for glucose uptake in bovine fibre strips, as in rat muscle. Insulin increases the rate of in vitro glucose transport in bovine muscle, but to a lower extent than in rat muscle. A GLUT4-like protein was detected by immunoblot assay in all insulin-responsive tissues from calf and goat (heart, skeletal muscle, adipose tissue) but not in liver, brain, erythrocytes and intestine. Unlike the rat, bovine and goat GLUT4 content is higher in glycolytic and oxido-glycolytic muscles than in oxidative muscles. In conclusion, using both a functional test (insulin stimulation of glucose transport) and an immunological approach, this study demonstrates that ruminant muscles express GLUT4 protein. Our data also suggest that, in ruminants, glucose is the main energy-yielding substrate for glycolytic but not for oxidative muscles, and that insulin responsiveness may be lower in oxidative than in other skeletal muscles. Images Figure 1 Figure 2 PMID:7832761

  5. Role of exercise intensity on GLUT4 content, aerobic fitness and fasting plasma glucose in type 2 diabetic mice.

    PubMed

    Cunha, Verusca Najara; de Paula Lima, Mérica; Motta-Santos, Daisy; Pesquero, Jorge Luiz; de Andrade, Rosangela Vieira; de Almeida, Jeeser Alves; Araujo, Ronaldo Carvalho; Grubert Campbell, Carmen Silvia; Lewis, John E; Simões, Herbert Gustavo

    2015-10-01

    Type 2 diabetes mellitus (T2D) results in several metabolic and cardiovascular dysfunctions, clinically characterized by hyperglycaemia due to lower glucose uptake and oxidation. Physical exercise is an effective intervention for glycaemic control. However, the effects of exercising at different intensities have not yet been addressed. The present study analysed the effects of 8 weeks of training performed at different exercise intensities on type 4 glucose transporters (GLUT4) content and glycaemic control of T2D (ob/ob) and non-diabetic mice (ob/OB). The animals were divided into six groups, with four groups being subjected either to low-intensity (ob/obL and ob/OBL: 3% body weight, three times/week/40 min) or high-intensity (ob/obH and ob/OBH: 6% body weight, three times per week per 20 min) swimming training. An incremental swimming test was performed to measure aerobic fitness. After the training intervention period, glycaemia and the content of GLUT4 were quantified. Although both training intensities were beneficial, the high-intensity regimen induced a more significant improvement in GLUT4 levels and glycaemic profile compared with sedentary controls (p < 0.05). Only animals in the high-intensity exercise group improved aerobic fitness. Thus, our study shows that high-intensity training was more effective for increasing GLUT4 content and glycaemia reduction in insulin-resistant mice, perhaps because of a higher metabolic demand imposed by this form of exercise.

  6. Phosphorylation of the adipose/muscle-type glucose transporter (GLUT4) and its relationship to glucose transport activity.

    PubMed Central

    Schürmann, A; Mieskes, G; Joost, H G

    1992-01-01

    The effects of protein phosphorylation and dephosphorylation on glucose transport activity reconstituted from adipocyte membrane fractions and its relationship to the phosphorylation state of the adipose/muscle-type glucose transporter (GLUT4) were studied. In vitro phosphorylation of membranes in the presence of ATP and protein kinase A produced a stimulation of the reconstituted glucose transport activity in plasma membranes and low-density microsomes (51% and 65% stimulation respectively), provided that the cells had been treated with insulin prior to isolation of the membranes. Conversely, treatment of membrane fractions with alkaline phosphatase produced an inhibition of reconstituted transport activity. However, in vitro phosphorylation catalysed by protein kinase C failed to alter reconstituted glucose transport activity in membrane fractions from both basal and insulin-treated cells. In experiments run under identical conditions, the phosphorylation state of GLUT4 was investigated by immunoprecipitation of glucose transporters from membrane fractions incubated with [32P]ATP and protein kinases A and C. Protein kinase C stimulated a marked phosphate incorporation into GLUT4 in both plasma membranes and low-density microsomes. Protein kinase A, in contrast to its effect on reconstituted glucose transport activity, produced a much smaller phosphorylation of the GLUT4 in plasma membranes than in low-density microsomes. The present data suggest that glucose transport activity can be modified by protein phosphorylation via an insulin-dependent mechanism. However, the phosphorylation of the GLUT4 itself was not correlated with changes in its reconstituted transport activity. Images Fig. 1. Fig. 2. Fig. 3. PMID:1637303

  7. Hyperinsulinemia leads to uncoupled insulin regulation of the GLUT4 glucose transporter and the FoxO1 transcription factor.

    PubMed

    Gonzalez, Eva; Flier, Emily; Molle, Dorothee; Accili, Domenico; McGraw, Timothy E

    2011-06-21

    Insulin resistance is a component of the metabolic syndrome and Type 2 diabetes. It has been recently shown that in liver insulin resistance is not complete. This so-called selective insulin resistance is characterized by defective insulin inhibition of hepatic glucose output while insulin-induced lipogenesis is maintained. How this occurs and whether uncoupled insulin action develops in other tissues is unknown. Here we show in a model of chronic hyperinsulinemia that adipocytes develop selective insulin resistance in which translocation of the GLUT4 glucose transporter to the cell surface is blunted yet nuclear exclusion of the FoxO1 transcription factor is preserved, rendering uncoupled insulin-controlled carbohydrate and lipid metabolisms. We found that in adipocytes FoxO1 nuclear exclusion has a lower half-maximal insulin dose than GLUT4 translocation, and it is because of this inherent greater sensitivity that control of FoxO1 by physiological insulin concentrations is maintained in adipocytes with compromised insulin signaling. Pharmacological and genetic interventions revealed that insulin regulates GLUT4 and FoxO1 through the PI3-kinase isoform p110α, although FoxO1 showed higher sensitivity to p110α activity than GLUT4. Transient down-regulation and overexpression of Akt isoforms in adipocytes demonstrated that insulin-activated PI3-kinase signals to GLUT4 primarily through Akt2 kinase, whereas Akt1 and Akt2 signal to FoxO1. We propose that the lower threshold of insulin activity for FoxO1's nuclear exclusion is in part due to its regulation by both Akt isoforms. Identification of uncoupled insulin action in adipocytes suggests this condition might be a general phenomenon of insulin target tissues contributing to insulin resistance's pathophysiology.

  8. Trafficking of the NMDAR2B Receptor Subunit Distal Cytoplasmic Tail from Endoplasmic Reticulum to the Synapse

    PubMed Central

    Standley, Steve; Petralia, Ronald S.; Hamilton, Rebecca; Wang, Ya-Xian; Schubert, Manfred

    2012-01-01

    NMDA receptor NR2A/B subunits have PDZ-binding domains on their extreme C-termini that are known to interact with the PSD-95 family and other PDZ proteins. We explore the interactions between PSD-95 family proteins and the NR2A/B cytoplasmic tails, and the consequences of these interactions, from the endoplasmic reticulum (ER) through delivery to the synapse in primary rat hippocampal and cortical cultured neurons. We find that the NR2A/B cytoplasmic tails cluster very early in the secretory pathway and interact serially with SAP102 beginning at the intermediate compartment, and then PSD-95. We further establish that colocalization of the distal C-terminus of NR2B and PSD-95 begins at the trans-Golgi Network (TGN). Formation of NR2B/PSD-95/SAP102 complexes is dependent on the PDZ binding domain of NR2B subunits, but association with SAP102 and PSD-95 plays no distinguishable role in cluster pre-formation or initial targeting to the vicinity of the synapse. Instead the PDZ binding domain plays a role in restricting cell-surface clusters to postsynaptic targets. PMID:22761831

  9. Grb10 deletion enhances muscle cell proliferation, differentiation and GLUT4 plasma membrane translocation.

    PubMed

    Mokbel, Nancy; Hoffman, Nolan J; Girgis, Christian M; Small, Lewin; Turner, Nigel; Daly, Roger J; Cooney, Gregory J; Holt, Lowenna J

    2014-11-01

    Grb10 is an intracellular adaptor protein which binds directly to several growth factor receptors, including those for insulin and insulin-like growth factor receptor-1 (IGF-1), and negatively regulates their actions. Grb10-ablated (Grb10(-/-) ) mice exhibit improved whole body glucose homeostasis and an increase in muscle mass associated specifically with an increase in myofiber number. This suggests that Grb10 may act as a negative regulator of myogenesis. In this study, we investigated in vitro, the molecular mechanisms underlying the increase in muscle mass and the improved glucose metabolism. Primary muscle cells isolated from Grb10(-/-) mice exhibited increased rates of proliferation and differentiation compared to primary cells isolated from wild-type mice. The improved proliferation capacity was associated with an enhanced phosphorylation of Akt and ERK in the basal state and changes in the expression of key cell cycle progression markers involved in regulating transition of cells from the G1 to S phase (e.g., retinoblastoma (Rb) and p21). The absence of Grb10 also promoted a faster transition to a myogenin positive, differentiated state. Glucose uptake was higher in Grb10(-/-) primary myotubes in the basal state and was associated with enhanced insulin signaling and an increase in GLUT4 translocation to the plasma membrane. These data demonstrate an important role for Grb10 as a link between muscle growth and metabolism with therapeutic implications for diseases, such as muscle wasting and type 2 diabetes.

  10. Palmitate stimulates glucose transport in rat adipocytes by a mechanism involving translocation of the insulin sensitive glucose transporter (GLUT4)

    NASA Technical Reports Server (NTRS)

    Hardy, R. W.; Ladenson, J. H.; Henriksen, E. J.; Holloszy, J. O.; McDonald, J. M.

    1991-01-01

    In rat adipocytes, palmitate: a) increases basal 2-deoxyglucose transport 129 +/- 27% (p less than 0.02), b) decreases the insulin sensitive glucose transporter (GLUT4) in low density microsomes and increases GLUT4 in plasma membranes and c) increases the activity of the insulin receptor tyrosine kinase. Palmitate-stimulated glucose transport is not additive with the effect of insulin and is not inhibited by the protein kinase C inhibitors staurosporine and sphingosine. In rat muscle, palmitate: a) does not affect basal glucose transport in either the soleus or epitrochlearis and b) inhibits insulin-stimulated glucose transport by 28% (p less than 0.005) in soleus but not in epitrochlearis muscle. These studies demonstrate a potentially important differential role for fatty acids in the regulation of glucose transport in different insulin target tissues.

  11. A potential link between insulin signaling and GLUT4 translocation: Association of Rab10-GTP with the exocyst subunit Exoc6/6b

    SciTech Connect

    Sano, Hiroyuki; Peck, Grantley R.; Blachon, Stephanie; Lienhard, Gustav E.

    2015-09-25

    Insulin increases glucose transport in fat and muscle cells by stimulating the exocytosis of specialized vesicles containing the glucose transporter GLUT4. This process, which is referred to as GLUT4 translocation, increases the amount of GLUT4 at the cell surface. Previous studies have provided evidence that insulin signaling increases the amount of Rab10-GTP in the GLUT4 vesicles and that GLUT4 translocation requires the exocyst, a complex that functions in the tethering of vesicles to the plasma membrane, leading to exocytosis. In the present study we show that Rab10 in its GTP form binds to Exoc6 and Exoc6b, which are the two highly homologous isotypes of an exocyst subunit, that both isotypes are found in 3T3-L1 adipocytes, and that knockdown of Exoc6, Exoc6b, or both inhibits GLUT4 translocation in 3T3-L1 adipocytes. These results suggest that the association of Rab10-GTP with Exoc6/6b is a molecular link between insulin signaling and the exocytic machinery in GLUT4 translocation. - Highlights: • Insulin stimulates the fusion of vesicles containing GLUT4 with the plasma membrane. • This requires vesicular Rab10-GTP and the exocyst plasma membrane tethering complex. • We find that Rab10-GTP associates with the Exoc6 subunit of the exocyst. • We find that knockdown of Exoc6 inhibits fusion of GLUT4 vesicles with the membrane. • The interaction of Rab10-GTP with Exoc6 potentially links signaling to exocytosis.

  12. The effect of adipose cell size on the measurement of GLUT 4 in white adipose tissue of obese mice.

    PubMed

    Fabres-Machado, U; Saito, M

    1995-03-01

    Glucose transporter (GLUT 4) was assessed in subcellular membrane fractions of white adipose tissue (WAT) from obese insulin-resistant aurothioglucose (AuTG)- or monosodium glutamate (MSG)-treated mice. Obesity was demonstrated by increased body weight and/or Lee index, as well as by the heavier WAT and brown adipose tissue in relation to similar weights of gastrocnemius and heart. In vivo insulin-resistance in obese animals was suggested by moderate hyperglycemia and severe hyperinsulinemia. Morphological analyses of adipose cells showed a > 10-fold increase in cell volume of obese mice. Subcellular fractionation indicated a reduced (P < 0.01) protein membrane content in the fat-free extract (FFE) from obese mice. However, the specific activity of 5'nucleotidase, a plasma membrane (PM) marker, in FFE and PM did not differ among groups. In addition, the total PM enzyme activity per unit of cell surface area was also unchanged. The GLUT 4 content, assessed by Western blotting and expressed per microgram membrane protein, was reduced by approximately 50% (P < 0.01) in all membrane fractions from obese animals. However, the total FFE GLUT 4 content per cell was increased (P < 0.01), from 23.5 +/- 1.8 in controls to 62.4 +/- 7.6 and 47.4 +/- 5.9 cpm cell-1 10(-3) in AuTG and MSG, respectively, but the total PM GLUT 4 content per unit of cell surface area was highly reduced (P < 0.01), from 165.1 +/- 16.7 in controls to 53.8 +/- 10.9 and 32.0 +/- 5.3 cpm microns-2 10(-9) in AuTG and MSG, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

  13. Developmental regulation of glucose transporters GLUT3, GLUT4 and GLUT8 in the mouse cerebellar cortex

    PubMed Central

    Gómez, Olga; Ballester-Lurbe, Begoña; Poch, Enric; Mesonero, José E; Terrado, José

    2010-01-01

    Glucose uptake into the mammalian nervous system is mediated by the family of facilitative glucose transporter proteins (GLUT). In this work we investigate how the expression of the main neuronal glucose transporters (GLUT3, GLUT4 and GLUT8) is modified during cerebellar cortex maturation. Our results reveal that the levels of the three transporters increase during the postnatal development of the cerebellum. GLUT3 localizes in the growing molecular layer and in the internal granule cell layer. However, the external granule cell layer, Purkinje cell cytoplasm and cytoplasm of the other cerebellar cells lack GLUT3 expression. GLUT4 and GLUT8 have partially overlapping patterns, which are detected in the cytoplasm and dendrites of Purkinje cells, and also in the internal granule cell layer where GLUT8 displays a more diffuse pattern. The differential localization of the transporters suggests that they play different roles in the cerebellum, although GLUT4 and GLUT8 could also perform some compensatory or redundant functions. In addition, the increase in the levels and the area expressing the three transporters suggests that these roles become more important as development advances. Interestingly, the external granule cells, which have been shown to express the monocarboxylate transporter MCT2, express none of the three main neuronal GLUTs. However, when these cells migrate inwardly to differentiate in the internal granule cells, they begin to produce GLUT3, GLUT4 and GLUT8, suggesting that the maturation of the cerebellar granule cells involves a switch in their metabolism in such a way that they start using glucose as they mature. PMID:20819112

  14. Rosmarinic acid ameliorates hyperglycemia and insulin sensitivity in diabetic rats, potentially by modulating the expression of PEPCK and GLUT4

    PubMed Central

    Runtuwene, Joshua; Cheng, Kai-Chun; Asakawa, Akihiro; Amitani, Haruka; Amitani, Marie; Morinaga, Akinori; Takimoto, Yoshiyuki; Kairupan, Bernabas Harold Ralph; Inui, Akio

    2016-01-01

    Background Rosmarinic acid (RA) is a natural substance that may be useful for treating diabetes mellitus. The present study investigated the effects of RA on glucose homeostasis and insulin regulation in rats with streptozocin (STZ)-induced type 1 diabetes or high-fat diet (HFD)-induced type 2 diabetes. Methods Glucose homeostasis was determined using oral glucose tolerance tests and postprandial glucose tests, and insulin activity was evaluated using insulin tolerance tests and the homeostatic model assessment for insulin resistance. Additionally, the protein expression levels of PEPCK and GLUT4 were determined using Western blot analysis. Results RA administration exerted a marked hypoglycemic effect on STZ-induced diabetic rats and enhanced glucose utilization and insulin sensitivity in HFD-fed diabetic rats. These effects of RA were dose-dependent. Meanwhile, RA administration reversed the STZ- and HFD-induced increase in PEPCK expression in the liver and the STZ- and HFD-induced decrease in GLUT4 expression in skeletal muscle. Conclusion RA reduces hyperglycemia and ameliorates insulin sensitivity by decreasing PEPCK expression and increasing GLUT4 expression. PMID:27462144

  15. The Effect of a High-Protein Diet and Exercise on Cardiac AQP7 and GLUT4 Gene Expression.

    PubMed

    Palabiyik, Orkide; Karaca, Aziz; Taştekin, Ebru; Yamasan, Bilge Eren; Tokuç, Burcu; Sipahi, Tammam; Vardar, Selma Arzu

    2016-10-01

    High-protein (HP) diets are commonly consumed by athletes despite their potential health hazard, which is postulated to enforce a negative effect on bone and renal health. However, its effects on heart have not been known yet. Aquaporin-7 (AQP7) is an aquaglyceroporin that facilitates glycerol and water transport. Glycerol is an important cardiac energy production substrate, especially during exercise, in conjunction with fatty acids and glucose. Glucose transporter 4 (GLUT4) is an insulin-sensitive glucose transporter in heart. We aimed to investigate the effect of HPD on AQP7 and GLUT4 levels in the rat heart subjected to exercise. Male Sprague-Dawley rats were divided into control (n = 12), exercise (E) training (n = 10), HPD (n = 12), and HPD-E training (n = 9) groups. The HPD groups were fed a 45 % protein-containing diet 5 weeks. The HPD-E and E groups were performed the treadmill exercise during the 5-week study period. Real-time polymerase chain reaction and immunohistochemistry techniques were used to determine the gene expression and localization of AQP7 and GLUT4 in heart tissue. Results of relative gene expression were calculated by the 'Pfaffl' mathematical method using the REST program. Differences in AQP7 and GLUT4 gene expression were expressed as fold change compared to the control group. Heart weight/tibia ratio and ventricular wall thickness were evaluated as markers of cardiac hypertrophy. Further, serum glucose, glycerol, and insulin levels were also measured. AQP7 gene expression was found to be increased in the E (3.47-fold, p < 0.001), HPD (5.59-fold, p < 0.001), and HPD-E (3.87-fold, p < 0.001) groups compared to the control group. AQP7 protein expression was also increased in the HPD and HPD-E groups (p < 0.001). Additionally, cardiac mRNA expression levels of GLUT4 showed a significant increase in the E (2.16-fold, p < 0.003), HPD (7.14-fold, p < 0.001), and HPD-E (3.43-fold, p < 0.001) groups compared to the

  16. A complex of Rab13 with MICAL-L2 and α-actinin-4 is essential for insulin-dependent GLUT4 exocytosis

    PubMed Central

    Sun, Yi; Jaldin-Fincati, Javier; Liu, Zhi; Bilan, Philip J.; Klip, Amira

    2016-01-01

    Insulin promotes glucose uptake into skeletal muscle through recruitment of glucose transporter 4 (GLUT4) to the plasma membrane. Rab GTPases are molecular switches mobilizing intracellular vesicles, and Rab13 is necessary for insulin-regulated GLUT4–vesicle exocytic translocation in muscle cells. We show that Rab13 engages the scaffold protein MICAL-L2 in this process. RNA interference–mediated knockdown of MICAL-L2 or truncated MICAL-L2 (MICAL-L2-CT) impaired insulin-stimulated GLUT4 translocation. Insulin increased Rab13 binding to MICAL-L2, assessed by pull down and colocalization under confocal fluorescence and structured illumination microscopies. Association was also visualized at the cell periphery using TIRF microscopy. Insulin further increased binding of MICAL-L2 to α-actinin-4 (ACTN4), a protein involved in GLUT4 translocation. Rab13, MICAL-L2, and ACTN4 formed an insulin-dependent complex assessed by pull down and confocal fluorescence imaging. Of note, GLUT4 associated with the complex in response to insulin, requiring the ACTN4-binding domain in MICAL-L2. This was demonstrated by pull down with distinct fragments of MICAL-L2 and confocal and structured illumination microscopies. Finally, expression of MICAL-L2-CT abrogated the insulin-dependent colocalization of Rab13 with ACTN4 or Rab13 with GLUT4. Our findings suggest that MICAL-L2 is an effector of insulin-activated Rab13, which links to GLUT4 through ACTN4, localizing GLUT4 vesicles at the muscle cell periphery to enable their fusion with the membrane. PMID:26538022

  17. The glucose transporter (GLUT-4) and vesicle-associated membrane protein-2 (VAMP-2) are segregated from recycling endosomes in insulin- sensitive cells

    PubMed Central

    1996-01-01

    Insulin stimulates glucose transport in adipocytes by translocation of the glucose transporter (GLUT-4) from an intracellular site to the cell surface. We have characterized different synaptobrevin/vesicle- associated membrane protein (VAMP) homologues in adipocytes and studied their intracellular distribution with respect to GLUT-4. VAMP-1, VAMP- 2, and cellubrevin cDNAs were isolated from a 3T3-L1 adipocyte expression library. VAMP-2 and cellubrevin were: (a) the most abundant isoforms in adipocytes, (b) detectable in all insulin responsive tissues, (c) translocated to the cell surface in response to insulin, and (d) found in immunoadsorbed GLUT-4 vesicles. To further define their intracellular distribution, 3T3-L1 adipocytes were incubated with a transferrin/HRP conjugate (Tf/HRP) and endosomes ablated following addition of DAB and H2O2. While this resulted in ablation of > 90% of the transferrin receptor (TfR) and cellubrevin found in intracellular membranes, 60% of GLUT-4 and 90% of VAMP-2 was not ablated. Immuno-EM on intracellular vesicles from adipocytes revealed that VAMP-2 was colocalized with GLUT-4, whereas only partial colocalization was observed between GLUT-4 and cellubrevin. These studies show that two different v-SNAREs, cellubrevin and VAMP-2, are partially segregated in different intracellular compartments in adipocytes, implying that they may define separate classes of secretory vesicles in these cells. We conclude that a proportion of GLUT-4 is found in recycling endosomes in nonstimulated adipocytes together with cellubrevin and the transferrin receptor. In addition, GLUT-4 and VAMP-2 are selectively enriched in a postendocytic compartment. Further study is required to elucidate the function of this latter compartment in insulin-responsive cells. PMID:8707843

  18. Differential regulation of adipose tissue glucose transporters in genetic obesity (fatty rat). Selective increase in the adipose cell/muscle glucose transporter (GLUT 4) expression.

    PubMed

    Hainault, I; Guerre-Millo, M; Guichard, C; Lavau, M

    1991-03-01

    Adipocytes from young obese Zucker rats exhibit a hyperresponsive insulin-mediated glucose transport, together with a marked increase in cytochalasin B binding as compared with lean rat adipocytes. Here, we examined in these cells the expression of two isoforms of glucose transporter, the erythroid (GLUT 1) and the adipose cell/muscle (GLUT 4) types, in rats aged 16 or 30 d, i.e., before and after the emergence of hyperinsulinemia. GLUT 1 protein and mRNA levels were identical in the two genotypes at both ages. In contrast, the levels of GLUT 4 protein in obese rat adipocytes were 2.4- and 4.5-fold those of lean littermates at 16 and 30 d of age, respectively, in perfect agreement with the genotype effect on insulin-stimulated glucose transport activity. The levels of GLUT 4 mRNA per fat pad were increased 2.3- and 6.2-fold in obese vs. lean rats 16- and 30-d-old, indicating a pretranslational level of regulation. The obese phenotype was not associated with overexpression of GLUT 4 mRNA in gastrocnemius muscle. This work indicates that the fa gene exerts a differential control on the expression of GLUT 1 and GLUT 4 in adipose tissue and provides evidence that independent of hyperinsulinemia, genotype is a major regulatory factor of GLUT 4 expression in this tissue.

  19. Saffron with resistance exercise improves diabetic parameters through the GLUT4/AMPK pathway in-vitro and in-vivo

    PubMed Central

    Dehghan, Firouzeh; Hajiaghaalipour, Fatemeh; Yusof, Ashril; Muniandy, Sekaran; Hosseini, Seyed Ali; Heydari, Sedigheh; Salim, Landa Zeenelabdin Ali; Azarbayjani, Mohammad Ali

    2016-01-01

    Saffron is consumed as food and medicine to treat several illnesses. This study elucidates the saffron effectiveness on diabetic parameters in-vitro and combined with resistance exercise in-vivo. The antioxidant properties of saffron was examined. Insulin secretion and glucose uptake were examined by cultured RIN-5F and L6 myotubes cells. The expressions of GLUT2, GLUT4, and AMPKα were determined by Western blot. Diabetic and non-diabetic male rats were divided into: control, training, extract treatment, training + extract treatment and metformin. The exercise and 40 mg/kg/day saffron treatments were carried out for six weeks. The antioxidant capacity of saffron was higher compare to positive control (P < 0.01). High dose of saffron stimulated insulin release in RIN-5F cells and improved glucose uptake in L6 myotubes. GLUT4 and AMPKα expressions increased in both doses of saffron (P < 0.01), whereas GLUT2 not changed (p > 0.05). Serum glucose, cholesterol, triglyceride, low-density lipoprotein, very low-density lipoprotein, insulin resistance, and glycated hemoglobin levels decreased in treated rats compared to untreated (p < 0.01). However, no significant differences were observed in the high-density lipoprotein, insulin, adiponectin, and leptin concentration levels in all groups (p > 0.05). The findings suggest that saffron consuming alongside exercise could improve diabetic parameters through redox-mediated mechanisms and GLUT4/AMPK pathway to entrap glucose uptake. PMID:27122001

  20. Saffron with resistance exercise improves diabetic parameters through the GLUT4/AMPK pathway in-vitro and in-vivo.

    PubMed

    Dehghan, Firouzeh; Hajiaghaalipour, Fatemeh; Yusof, Ashril; Muniandy, Sekaran; Hosseini, Seyed Ali; Heydari, Sedigheh; Salim, Landa Zeenelabdin Ali; Azarbayjani, Mohammad Ali

    2016-01-01

    Saffron is consumed as food and medicine to treat several illnesses. This study elucidates the saffron effectiveness on diabetic parameters in-vitro and combined with resistance exercise in-vivo. The antioxidant properties of saffron was examined. Insulin secretion and glucose uptake were examined by cultured RIN-5F and L6 myotubes cells. The expressions of GLUT2, GLUT4, and AMPKα were determined by Western blot. Diabetic and non-diabetic male rats were divided into: control, training, extract treatment, training + extract treatment and metformin. The exercise and 40 mg/kg/day saffron treatments were carried out for six weeks. The antioxidant capacity of saffron was higher compare to positive control (P < 0.01). High dose of saffron stimulated insulin release in RIN-5F cells and improved glucose uptake in L6 myotubes. GLUT4 and AMPKα expressions increased in both doses of saffron (P < 0.01), whereas GLUT2 not changed (p > 0.05). Serum glucose, cholesterol, triglyceride, low-density lipoprotein, very low-density lipoprotein, insulin resistance, and glycated hemoglobin levels decreased in treated rats compared to untreated (p < 0.01). However, no significant differences were observed in the high-density lipoprotein, insulin, adiponectin, and leptin concentration levels in all groups (p > 0.05). The findings suggest that saffron consuming alongside exercise could improve diabetic parameters through redox-mediated mechanisms and GLUT4/AMPK pathway to entrap glucose uptake. PMID:27122001

  1. Single Point Mutations Result in the Miss-Sorting of Glut4 to a Novel Membrane Compartment Associated with Stress Granule Proteins

    PubMed Central

    Song, XiaoMei; Lichti, Cheryl F.; Townsend, R. Reid; Mueckler, Mike

    2013-01-01

    Insulin increases cellular glucose uptake and metabolism in the postprandial state by acutely stimulating the translocation of the Glut4 glucose transporter from intracellular membrane compartments to the cell surface in muscle and fat cells. The intracellular targeting of Glut4 is dictated by specific structural motifs within cytoplasmic domains of the transporter. We demonstrate that two leucine residues at the extreme C-terminus of Glut4 are critical components of a motif (IRM, insulin responsive motif) involved in the sorting of the transporter to insulin responsive vesicles in 3T3L1 adipocytes. Light microscopy, immunogold electron microscopy, subcellular fractionation, and sedimentation analysis indicate that mutations in the IRM cause the aberrant targeting of Glut4 to large dispersed membrane vesicles that are not insulin responsive. Proteomic characterization of rapidly and slowly sedimenting membrane vesicles (RSVs and SSVs) that were highly enriched by immunoadsorption for either wild-type Glut4 or an IRM mutant revealed that the major vesicle fraction containing the mutant transporter (IRM-RSVs) possessed a relatively small and highly distinct protein population that was enriched for proteins associated with stress granules. We suggest that the IRM is critical for an early step in the sorting of Glut4 to insulin-responsive subcellular membrane compartments and that IRM mutants are miss-targeted to relatively large, amorphous membrane vesicles that may be involved in a degradation pathway for miss-targeted or miss-folded proteins or represent a transitional membrane compartment that Glut4 traverses en route to insulin responsive storage compartments. PMID:23874650

  2. Effect of insulin on the rates of synthesis and degradation of GLUT1 and GLUT4 glucose transporters in 3T3-L1 adipocytes.

    PubMed Central

    Sargeant, R J; Pâquet, M R

    1993-01-01

    The effect of continuous insulin stimulation on the rates of turnover and on the total cellular contents of the glucose-transporter proteins GLUT1 and GLUT4 in 3T3-L1 adipocytes was investigated. Pulse-and-chase studies with [35S]methionine followed by immunoprecipitation of GLUT1 and GLUT4 with isoform-specific antibodies revealed the half-lives of these proteins to be 19 h and 50 h respectively. Inclusion of 100 nM insulin in the chase medium resulted in a decrease in the half-lives of both proteins to about 15.5 h. This effect of insulin was specific for the glucose-transporter proteins, as the average half-life of all proteins was found to be 55 h both with and without insulin stimulation. The effect of insulin on the rate of synthesis of the glucose transporters was determined by the rate of incorporation of [35S]methionine. After 24 h of insulin treatment, the rate of synthesis of GLUT1 and GLUT4 were elevated over control levels by 3.5-fold and 2-fold respectively. After 72 h of treatment under the same conditions, the rate of synthesis of GLUT1 remained elevated by 2.5-fold, whereas the GLUT4 synthesis rate was not different from control levels. Western-blot analysis of total cellular membranes revealed a 4.5-fold increase in total cellular GLUT1 content and a 50% decrease in total cellular GLUT4 after 72 h of insulin treatment. These observations suggest that the rates of synthesis and degradation of GLUT1 and GLUT4 in 3T3-L1 adipocytes are regulated independently and that these cells respond to prolonged insulin treatment by altering the metabolism of GLUT1 and GLUT4 proteins in a specific manner. Images Figure 1 Figure 3 Figure 4 Figure 5 PMID:8457217

  3. Insulin and hypertonicity recruit GLUT4 to the plasma membrane of muscle cells by using N-ethylmaleimide-sensitive factor-dependent SNARE mechanisms but different v-SNAREs: role of TI-VAMP.

    PubMed

    Randhawa, Varinder K; Thong, Farah S L; Lim, Dawn Y; Li, Dailin; Garg, Rami R; Rudge, Rachel; Galli, Thierry; Rudich, Assaf; Klip, Amira

    2004-12-01

    Insulin and hypertonicity each increase the content of GLUT4 glucose transporters at the surface of muscle cells. Insulin enhances GLUT4 exocytosis without diminishing its endocytosis. The insulin but not the hypertonicity response is reduced by tetanus neurotoxin, which cleaves vesicle-associated membrane protein (VAMP)2 and VAMP3, and is rescued upon introducing tetanus neurotoxin-resistant VAMP2. Here, we show that hypertonicity enhances GLUT4 recycling, compounding its previously shown ability to reduce GLUT4 endocytosis. To examine whether the canonical soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) mechanism is required for the plasma membrane fusion of the tetanus neurotoxin-insensitive GLUT4 vesicles, L6 myoblasts stably expressing myc-tagged GLUT4 (GLUT4myc) were transiently transfected with dominant negative N-ethylmaleimide-sensitive factor (NSF) (DN-NSF) or small-interfering RNA to tetanus neurotoxin-insensitive VAMP (TI-VAMP siRNA). Both strategies markedly reduced the basal level of surface GLUT4myc and the surface gain of GLUT4myc in response to hypertonicity. The insulin effect was abolished by DN-NSF, but only partly reduced by TI-VAMP siRNA. We propose that insulin and hypertonicity recruit GLUT4myc from partly overlapping, but distinct sources defined by VAMP2 and TI-VAMP, respectively.

  4. Insulin and Hypertonicity Recruit GLUT4 to the Plasma Membrane of Muscle Cells by Using N-Ethylmaleimide-sensitive Factor-dependent SNARE Mechanisms but Different v-SNAREs: Role of TI-VAMP

    PubMed Central

    Randhawa, Varinder K.; Thong, Farah S.L.; Lim, Dawn Y.; Li, Dailin; Garg, Rami R.; Rudge, Rachel; Galli, Thierry; Rudich, Assaf; Klip, Amira

    2004-01-01

    Insulin and hypertonicity each increase the content of GLUT4 glucose transporters at the surface of muscle cells. Insulin enhances GLUT4 exocytosis without diminishing its endocytosis. The insulin but not the hypertonicity response is reduced by tetanus neurotoxin, which cleaves vesicle-associated membrane protein (VAMP)2 and VAMP3, and is rescued upon introducing tetanus neurotoxin-resistant VAMP2. Here, we show that hypertonicity enhances GLUT4 recycling, compounding its previously shown ability to reduce GLUT4 endocytosis. To examine whether the canonical soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) mechanism is required for the plasma membrane fusion of the tetanus neurotoxin-insensitive GLUT4 vesicles, L6 myoblasts stably expressing myc-tagged GLUT4 (GLUT4myc) were transiently transfected with dominant negative N-ethylmaleimide-sensitive factor (NSF) (DN-NSF) or small-interfering RNA to tetanus neurotoxin-insensitive VAMP (TI-VAMP siRNA). Both strategies markedly reduced the basal level of surface GLUT4myc and the surface gain of GLUT4myc in response to hypertonicity. The insulin effect was abolished by DN-NSF, but only partly reduced by TI-VAMP siRNA. We propose that insulin and hypertonicity recruit GLUT4myc from partly overlapping, but distinct sources defined by VAMP2 and TI-VAMP, respectively. PMID:15469990

  5. Gingerols of Zingiber officinale enhance glucose uptake by increasing cell surface GLUT4 in cultured L6 myotubes.

    PubMed

    Li, Yiming; Tran, Van H; Duke, Colin C; Roufogalis, Basil D

    2012-09-01

    In this study we investigate the active constituents of the rhizome of Zingiber officinale, Roscoe (ginger) and determine their activity on glucose uptake in cultured L6 myotubes and the molecular mechanism underlying this action. Freeze-dried ginger powder was extracted with ethyl acetate (1 kg/3 L) to give the total ginger extract, which was then separated into seven fractions, consisting of nonpolar to moderately polar compounds, using a short-column vacuum chromatographic method. The most active fraction (F7) was further purified for identification of its active components. The effect of the extract, fractions, and purified compounds on glucose uptake was evaluated using radioactive labelled 2-[1,2-³H]-deoxy-D-glucose in L6 myotubes. The pungent phenolic gingerol constituents were identified as the major active compounds in the ginger extract enhancing glucose uptake. (S)-[6]-Gingerol was the most abundant component among the gingerols, however, (S)-[8]-gingerol was the most potent on glucose uptake. The activity of (S)-[8]-gingerol was found to be associated primarily with an increase in surface distribution of GLUT4 protein on the L6 myotube plasma membrane, as detected by expression of hemagglutinin epitope-tagged GLUT4 in L6 muscle cells. The enhancement of glucose uptake in L6 rat skeletal muscle cells by the gingerol pungent principles of the ginger extract supports the potential of ginger and its pungent components for the prevention and management of hyperglycemia and type 2 diabetes. PMID:22828920

  6. Sex-Dependent Effects of Dietary Genistein on Echocardiographic Profile and Cardiac GLUT4 Signaling in Mice

    PubMed Central

    Leung, Lana; Martin, Joshua B.; Lawmaster, Todd; Arthur, Kathryn; Broderick, Tom L.

    2016-01-01

    This study aimed to determine whether genistein diet resulted in changes in cardiac function, using echocardiography, and expression of key proteins involved in glucose uptake by the myocardium. Intact male and female C57BL/6J mice (aged 4–6 weeks) were fed either 600 mg genistein/kg diet (600 G) or 0 mg genistein/kg diet (0 G) for 4 weeks. Echocardiography data revealed sex-dependent differences in the absence of genistein: compared to females, hearts from males exhibited increased systolic left ventricle internal dimension (LVIDs), producing a decrease in function, expressed as fractional shortening (FS). Genistein diet also induced echocardiographic changes in function: in female hearts, 600G induced a 1.5-fold (P < 0.05) increase in LVIDs, resulting in a significant decrease in FS and whole heart surface area when compared to controls (fed 0 G). Genistein diet increased cardiac GLUT4 protein expression in both males (1.51-fold, P < 0.05) and females (1.76-fold, P < 0.05). However, no effects on the expression of notable intracellular signaling glucose uptake-regulated proteins were observed. Our data indicate that consumption of genistein diet for 4 weeks induces echocardiographic changes in indices of systolic function in females and has beneficial effects on cardiac GLUT4 protein expression in both males and females. PMID:27471542

  7. Exercise ameliorates insulin resistance via Ca2+ signals distinct from those of insulin for GLUT4 translocation in skeletal muscles.

    PubMed

    Park, Dae-Ryoung; Park, Kwang-Hyun; Kim, Byung-Ju; Yoon, Chung-Su; Kim, Uh-Hyun

    2015-04-01

    Muscle contraction and insulin induce glucose uptake in skeletal muscle through GLUT4 membrane translocation. Beneficial effects of exercise on glucose homeostasis in insulin-resistant individuals are known to be due to their distinct mechanism between contraction and insulin action on glucose uptake in skeletal muscle. However, the underlying mechanisms are not clear. Here we show that in skeletal muscle, distinct Ca(2+) second messengers regulate GLUT4 translocation by contraction and insulin treatment; d-myo-inositol 1,4,5-trisphosphate/nicotinic acid adenine dinucleotide phosphate (NAADP) and cyclic ADP-ribose/NAADP are main players for insulin- and contraction-induced glucose uptake, respectively. Different patterns of phosphorylation of AMPK and Ca(2+)/calmodulin-dependent protein kinase II were shown in electrical stimuli (ES)- and insulin-induced glucose uptake pathways. ES-induced Ca(2+) signals and glucose uptake are dependent on glycolysis, which influences formation of NAD(P)-derived signaling messengers, whereas insulin-induced signals are not. High-fat diet (HFD) induced a defect in only insulin-mediated, but not ES-mediated, Ca(2+) signaling for glucose uptake, which is related to a specifically lower NAADP formation. Exercise decreases blood glucose levels in HFD-induced insulin resistance mice via NAADP formation. Thus we conclude that different usage of Ca(2+) signaling in contraction/insulin-stimulated glucose uptake in skeletal muscle may account for the mechanism by which exercise ameliorates glucose homeostasis in individuals with type 2 diabetes.

  8. Human Trafficking

    MedlinePlus

    ... TRAFFICKING (English) Listen < Back to Search FACT SHEET: HUMAN TRAFFICKING (English) Published: August 2, 2012 Topics: Public Awareness , ... organizations that protect and serve trafficking victims. National Human Trafficking Resource Center at 1.888.373.7888 Last ...

  9. Orexin-A stimulates the expression of GLUT4 in a glucose dependent manner in the liver of orange-spotted grouper (Epinephelus coioides).

    PubMed

    Zhang, Cong; Sun, Caiyun; Wang, Bin; Yan, Peipei; Wu, Amin; Yang, Guokun; Li, Wensheng

    2016-09-01

    Orexins are hypothalamic neuropeptides involved in the central regulation of feeding behavior, sleep-wake cycle and other physiological functions. Orexin-A can regulate energy metabolism and increase glucose uptake, suggesting a role in glucose metabolism. In this study, we investigated the effects of orexin-A on GLUT4 mRNA and protein levels and the intracellular signaling mechanisms mediating orexin-A activity in the hepatocytes of grouper. Our results demonstrate that intraperitoneal injection of orexin-A increased the expression of GLUT4 in the liver, and this effect was significantly enhanced by co-injection of glucose. Treatment of primary cultured hepatocytes with either orexin-A or glucose alone had no effect on the expression of GLUT4, while co-treatment with orexin-A and glucose significantly increased the expression of GLUT4. This stimulatory effect was partially blocked by inhibitors to ERK1/2, JNK or p38 MAPK and was further blocked by an orexin receptor antagonist, which indicates that orexin-A could stimulate the expression of GLUT4 in a glucose dependent manner in primary hepatocytes via ERK1/2, JNK and p38 signaling. Our results suggest that orexin-A could play a pivotal role in stimulating glucose utilization in grouper, for a long-term goal, which might be useful in reducing costs in the aquaculture industry. PMID:27264958

  10. Orexin-A stimulates the expression of GLUT4 in a glucose dependent manner in the liver of orange-spotted grouper (Epinephelus coioides).

    PubMed

    Zhang, Cong; Sun, Caiyun; Wang, Bin; Yan, Peipei; Wu, Amin; Yang, Guokun; Li, Wensheng

    2016-09-01

    Orexins are hypothalamic neuropeptides involved in the central regulation of feeding behavior, sleep-wake cycle and other physiological functions. Orexin-A can regulate energy metabolism and increase glucose uptake, suggesting a role in glucose metabolism. In this study, we investigated the effects of orexin-A on GLUT4 mRNA and protein levels and the intracellular signaling mechanisms mediating orexin-A activity in the hepatocytes of grouper. Our results demonstrate that intraperitoneal injection of orexin-A increased the expression of GLUT4 in the liver, and this effect was significantly enhanced by co-injection of glucose. Treatment of primary cultured hepatocytes with either orexin-A or glucose alone had no effect on the expression of GLUT4, while co-treatment with orexin-A and glucose significantly increased the expression of GLUT4. This stimulatory effect was partially blocked by inhibitors to ERK1/2, JNK or p38 MAPK and was further blocked by an orexin receptor antagonist, which indicates that orexin-A could stimulate the expression of GLUT4 in a glucose dependent manner in primary hepatocytes via ERK1/2, JNK and p38 signaling. Our results suggest that orexin-A could play a pivotal role in stimulating glucose utilization in grouper, for a long-term goal, which might be useful in reducing costs in the aquaculture industry.

  11. Cardiac fibrosis and down regulation of GLUT4 in experimental diabetic cardiomyopathy are ameliorated by chronic exposures to intermittent altitude

    PubMed Central

    Faramoushi, Mahdi; Amir Sasan, Ramin; Sari Sarraf, Vahid; Karimi, Pouran

    2016-01-01

    Introduction: Chronic intermittent hypoxia is considered as a preconditioning status in cardiovascular health to inducing resistance to the low oxygen supply. Diabetic cardiomyopathy leads to inability of the heart to effective circulation of blood preventing of consequent tissue damages so; the aim of this study was elucidation of effect of chronic exposure to hypoxia on Cardiac fibrosis and expression of GLUT4 in experimental diabetic cardiomyopathy. Methods: A total number of 30 rats were randomly divided into three groups; 1: Normoxia control group (NN, n = 10). 2: Normoxia diabetic group (ND, n = 10) that took fat diet for 2 weeks then were injected by streptozotocin (37 mg/kg) and 3: Hypoxia diabetic group (HD, n = 10): that were exposed to chronic intermittent hypoxia (CIH) (altitude ≈3400 m, 14% oxygen for 8 weeks). After hypoxia challenge, plasma metabolic parameters including: fasting blood glucose (FBS), triglyceride (TG) and total cholesterol (TC) were measured by colorimetric assay. Cardiac expression of GLUT4 protein and cardiac collagen accumulation were determined in the excised left ventricle by western blotting, and Masson trichrome staining respectively. Results: Based on resultant data, FBS, TG and TC were significantly (P < 0.05) decreased in HD vs. ND. Homeostasis Model Assessment (HOMA) were also significantly attenuated after exposed to CIH in HD group compared to ND group (P < 0.05). Significant increase in packed cell volume and hemoglobin concentration was observed in HD group compared to ND group (P < 0.05). Comparison of heart wet weight between three groups showed a significant difference (P < 0.05) with lower amount in HD and ND versus NN. Myocardial fibrosis was significantly more pronounced in ND when compared to NN. Eight weeks exposure to hypoxia ameliorated this increase in HD group. Intermittent hypoxia significantly increased GLUT4 protein expression in HD compared to ND group (P < 0.05). Conclusion: Data suggested that CIH

  12. Antioxidant, antilipidemic and antidiabetic effects of ficusin with their effects on GLUT4 translocation and PPARγ expression in type 2 diabetic rats.

    PubMed

    Irudayaraj, Santiagu Stephen; Stalin, Antony; Sunil, Christudas; Duraipandiyan, Veeramuthu; Al-Dhabi, Naif Abdullah; Ignacimuthu, Savarimuthu

    2016-08-25

    In this study, the antioxidant, antilipidemic and antidiabetic effects of ficusin isolated from Ficus carica leaves and their effects on GLUT4 translocation and PPARγ expression were evaluated in HFD-STZ induced type 2 diabetic rats. Ficusin (20 and 40 mg/kg b. wt.) lowered the levels of fasting blood glucose, plasma insulin and body weight gain, in HFD-STZ induced diabetic rats. Ficusin also significantly lowered the serum antioxidant enzymes (SOD, CAT and GPx) and lipids (TC, TG and FFA) levels to near normal. Ficusin significantly enhanced the PPARγ expression and improved the translocation and activation of GLUT4 in the adipose tissue. Molecular docking analysis exhibited promising interactions of GLUT4 and PPARγ into their active sites. This study suggests that ficusin improved the insulin sensitivity on adipose tissue and it can be used for the treatment of obesity related type 2 diabetes mellitus. PMID:27350165

  13. Insulin elicits a ROS-activated and an IP₃-dependent Ca²⁺ release, which both impinge on GLUT4 translocation.

    PubMed

    Contreras-Ferrat, Ariel; Llanos, Paola; Vásquez, César; Espinosa, Alejandra; Osorio-Fuentealba, César; Arias-Calderon, Manuel; Lavandero, Sergio; Klip, Amira; Hidalgo, Cecilia; Jaimovich, Enrique

    2014-05-01

    Insulin signaling includes generation of low levels of H2O2; however, its origin and contribution to insulin-stimulated glucose transport are unknown. We tested the impact of H2O2 on insulin-dependent glucose transport and GLUT4 translocation in skeletal muscle cells. H2O2 increased the translocation of GLUT4 with an exofacial Myc-epitope tag between the first and second transmembrane domains (GLUT4myc), an effect additive to that of insulin. The anti-oxidants N-acetyl L-cysteine and Trolox, the p47(phox)-NOX2 NADPH oxidase inhibitory peptide gp91-ds-tat or p47(phox) knockdown each reduced insulin-dependent GLUT4myc translocation. Importantly, gp91-ds-tat suppressed insulin-dependent H2O2 production. A ryanodine receptor (RyR) channel agonist stimulated GLUT4myc translocation and insulin stimulated RyR1-mediated Ca(2+) release by promoting RyR1 S-glutathionylation. This pathway acts in parallel to insulin-mediated stimulation of inositol-1,4,5-trisphosphate (IP3)-activated Ca(2+) channels, in response to activation of phosphatidylinositol 3-kinase and its downstream target phospholipase C, resulting in Ca(2+) transfer to the mitochondria. An inhibitor of IP3 receptors, Xestospongin B, reduced both insulin-dependent IP3 production and GLUT4myc translocation. We propose that, in addition to the canonical α,β phosphatidylinositol 3-kinase to Akt pathway, insulin engages both RyR-mediated Ca(2+) release and IP3-receptor-mediated mitochondrial Ca(2+) uptake, and that these signals jointly stimulate glucose uptake.

  14. The amino terminus of GLUT4 functions as an internalization motif but not an intracellular retention signal when substituted for the transferrin receptor cytoplasmic domain

    PubMed Central

    1994-01-01

    Previous studies have demonstrated that the amino-terminal cytoplasmic domain of GLUT4 contains a phenylalanine-based targeting motif that determines its steady state distribution between the surface and the interior of cells (Piper, R. C., C. Tai, P. Kuleza, S. Pang, D. Warnock, J. Baenziger, J. W. Slot, H. J. Geuze, C. Puri, and D. E. James. 1993. J. Cell Biol. 121:1221). To directly measure the effect that the GLUT4 amino terminus has on internalization and subsequent recycling back to the cell surface, we constructed chimeras in which this sequence was substituted for the amino-terminal cytoplasmic domain of the human transferrin receptor. The chimeras were stably transfected into Chinese hamster ovary cells and their endocytic behavior characterized. The GLUT4-transferrin receptor chimera was recycled back to the cell surface with a rate similar to the transferrin receptor, indicating that the GLUT4 sequence was not promoting intracellular retention of the chimera. The GLUT4-transferrin receptor chimera was internalized at half the rate of the transferrin receptor. Substitution of an alanine for phenylalanine at position 5 slowed internalization of the chimera by twofold, to a level characteristic of bulk membrane internalization. However, substitution of a tyrosine increased the rate of internalization to the level of the transferrin receptor. Neither of these substitutions significantly altered the rate at which the chimeras were recycled back to the cell surface. These results demonstrate that the major function of the GLUT4 amino-terminal domain is to promote the effective internalization of the protein from the cell surface, via a functional phenylalanine-based internalization motif, rather than retention of the transporter within intracellular structures. PMID:8120093

  15. Insulin elicits a ROS-activated and an IP₃-dependent Ca²⁺ release, which both impinge on GLUT4 translocation.

    PubMed

    Contreras-Ferrat, Ariel; Llanos, Paola; Vásquez, César; Espinosa, Alejandra; Osorio-Fuentealba, César; Arias-Calderon, Manuel; Lavandero, Sergio; Klip, Amira; Hidalgo, Cecilia; Jaimovich, Enrique

    2014-05-01

    Insulin signaling includes generation of low levels of H2O2; however, its origin and contribution to insulin-stimulated glucose transport are unknown. We tested the impact of H2O2 on insulin-dependent glucose transport and GLUT4 translocation in skeletal muscle cells. H2O2 increased the translocation of GLUT4 with an exofacial Myc-epitope tag between the first and second transmembrane domains (GLUT4myc), an effect additive to that of insulin. The anti-oxidants N-acetyl L-cysteine and Trolox, the p47(phox)-NOX2 NADPH oxidase inhibitory peptide gp91-ds-tat or p47(phox) knockdown each reduced insulin-dependent GLUT4myc translocation. Importantly, gp91-ds-tat suppressed insulin-dependent H2O2 production. A ryanodine receptor (RyR) channel agonist stimulated GLUT4myc translocation and insulin stimulated RyR1-mediated Ca(2+) release by promoting RyR1 S-glutathionylation. This pathway acts in parallel to insulin-mediated stimulation of inositol-1,4,5-trisphosphate (IP3)-activated Ca(2+) channels, in response to activation of phosphatidylinositol 3-kinase and its downstream target phospholipase C, resulting in Ca(2+) transfer to the mitochondria. An inhibitor of IP3 receptors, Xestospongin B, reduced both insulin-dependent IP3 production and GLUT4myc translocation. We propose that, in addition to the canonical α,β phosphatidylinositol 3-kinase to Akt pathway, insulin engages both RyR-mediated Ca(2+) release and IP3-receptor-mediated mitochondrial Ca(2+) uptake, and that these signals jointly stimulate glucose uptake. PMID:24569874

  16. Dehydroepiandrosterone activates AMP kinase and regulates GLUT4 and PGC-1α expression in C2C12 myotubes

    SciTech Connect

    Yokokawa, Takumi; Sato, Koji; Iwanaka, Nobumasa; Honda, Hiroki; Higashida, Kazuhiko; Iemitsu, Motoyuki; Hayashi, Tatsuya; Hashimoto, Takeshi

    2015-07-17

    Exercise and caloric restriction (CR) have been reported to have anti-ageing, anti-obesity, and health-promoting effects. Both interventions increase the level of dehydroepiandrosterone (DHEA) in muscle and blood, suggesting that DHEA might partially mediate these effects. In addition, it is thought that either 5′-adenosine monophosphate-activated protein kinase (AMPK) or peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mediates the beneficial effects of exercise and CR. However, the effects of DHEA on AMPK activity and PGC-1α expression remain unclear. Therefore, we explored whether DHEA in myotubes acts as an activator of AMPK and increases PGC-1α. DHEA exposure increased glucose uptake but not the phosphorylation levels of Akt and PKCζ/λ in C2C12 myotubes. In contrast, the phosphorylation levels of AMPK were elevated by DHEA exposure. Finally, we found that DHEA induced the expression of the genes PGC-1α and GLUT4. Our current results might reveal a previously unrecognized physiological role of DHEA; the activation of AMPK and the induction of PGC-1α by DHEA might mediate its anti-obesity and health-promoting effects in living organisms. - Highlights: • We assessed whether dehydroepiandrosterone (DHEA) activates AMPK and PGC-1α. • DHEA exposure increased glucose uptake in C2C12 myotubes. • The phosphorylation levels of AMPK were elevated by DHEA exposure. • DHEA induced the expression of the genes PGC-1α and GLUT4. • AMPK might mediate the anti-obesity and health-promoting effects of DHEA.

  17. Activation of nuclear receptor NR5A2 increases Glut4 expression and glucose metabolism in muscle cells

    SciTech Connect

    Bolado-Carrancio, A.; Riancho, J.A.; Sainz, J.; Rodríguez-Rey, J.C.

    2014-04-04

    Highlights: • NR5A2 expression in C2C12 is associated with myotube differentiation. • DLPC induces an increase in GLUT4 levels and glucose uptake in C2C12 myotubes. • In high glucose conditions the activation of NR5A2 inhibits fatty acids oxidation. - Abstract: NR5A2 is a nuclear receptor which regulates the expression of genes involved in cholesterol metabolism, pluripotency maintenance and cell differentiation. It has been recently shown that DLPC, a NR5A2 ligand, prevents liver steatosis and improves insulin sensitivity in mouse models of insulin resistance, an effect that has been associated with changes in glucose and fatty acids metabolism in liver. Because skeletal muscle is a major tissue in clearing glucose from blood, we studied the effect of the activation of NR5A2 on muscle metabolism by using cultures of C2C12, a mouse-derived cell line widely used as a model of skeletal muscle. Treatment of C2C12 with DLPC resulted in increased levels of expression of GLUT4 and also of several genes related to glycolysis and glycogen metabolism. These changes were accompanied by an increased glucose uptake. In addition, the activation of NR5A2 produced a reduction in the oxidation of fatty acids, an effect which disappeared in low-glucose conditions. Our results suggest that NR5A2, mostly by enhancing glucose uptake, switches muscle cells into a state of glucose preference. The increased use of glucose by muscle might constitute another mechanism by which NR5A2 improves blood glucose levels and restores insulin sensitivity.

  18. Oleanolic Acid Attenuates Insulin Resistance via NF-κB to Regulate the IRS1-GLUT4 Pathway in HepG2 Cells

    PubMed Central

    Li, Ming; Han, Zongyu; Bei, Weijian; Rong, Xianglu; Guo, Jiao; Hu, Xuguang

    2015-01-01

    The aim of our study is to elucidate the mechanisms of oleanolic acid (OA) on insulin resistance (IR) in HepG2 cells. HepG2 cells were induced with FFA as the insulin resistance model and were treated with OA. Then the glucose content and the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were analyzed. Moreover, protein expression of nuclear factor kappa B (NF-κB), insulin receptor substrate 1(IRS1), and glucose transporter 4 (GLUT4) in cells treated with OA were measured by Western blot analysis. Additionally, IRS1 protein expression exposed to OA was detected after using pyrrolidine dithiocarbamate (PDTC).Our results revealed that OA decreased the glucose content in HepG2 cells in vitro. Moreover, OA reduced the levels of TNF-α and IL-6 and upregulated IRS1 and GLUT4 protein expression. Furthermore, OA also reduced NF-κB protein expression in insulin-resistant HepG2 cells. After blocking NF-κB, the expression of IRS1 protein had no obvious changes when treated with OA. OA attenuated insulin resistance and decreased the levels of TNF-α and IL-6. Meanwhile, OA decreased NF-κB protein expression and upregulated IRS1 and GLUT4 protein expression. Therefore, regulating the IRS1-GLUT4 pathway via NF-κB was the underlying mechanism of OA on insulin resistance. PMID:26843885

  19. PI3K-GLUT4 Signal Pathway Associated with Effects of EX-B3 Electroacupuncture on Hyperglycemia and Insulin Resistance of T2DM Rats

    PubMed Central

    2016-01-01

    Objectives. To explore electroacupuncture's (EA's) effects on fasting blood glucose (FBG) and insulin resistance of type 2 diabetic mellitus (T2DM) model rats and give a possible explanation for the effects. Method. It takes high fat diet and intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) for model preparation. Model rats were randomly divided into T2DM Model group, EA weiwanxiashu (EX-B3) group, and sham EA group (n = 12/group). EA (2 Hz continuous wave, 2 mA, 20 min/day, 6 days/week, 4 weeks) was applied as intervention. FBG, area under curve (AUC) of oral glucose tolerance test (OGTT), insulin resistance index (HOMA-IR), pancreatic B cell function index (HOMA-B), skeletal muscle phosphorylated phosphatidylinositol-3-kinase (PI3K), glucose transporter 4 (GLUT4), and membrane GLUT4 protein expression were measured. Results. EA weiwanxiashu (EX-B3) can greatly upregulate model rat's significantly reduced skeletal muscle PI3K (Y607) and membrane GLUT4 protein expression (P < 0.01), effectively reducing model rats' FBG and AUC of OGTT (P < 0.01). The effects are far superior to sham EA group. Conclusion. EA weiwanxiashu (EX-B3) can upregulate skeletal muscle phosphorylated PI3K protein expression, to stimulate membrane translocation of GLUT4 and thereby increase skeletal muscle glucose intake to treat T2DM.

  20. PI3K-GLUT4 Signal Pathway Associated with Effects of EX-B3 Electroacupuncture on Hyperglycemia and Insulin Resistance of T2DM Rats.

    PubMed

    Cao, Bing-Yan; Li, Rui; Tian, Huan-Huan; Ma, Yan-Jia; Hu, Xiao-Gang; Jia, Ning; Wang, Yue-Ying

    2016-01-01

    Objectives. To explore electroacupuncture's (EA's) effects on fasting blood glucose (FBG) and insulin resistance of type 2 diabetic mellitus (T2DM) model rats and give a possible explanation for the effects. Method. It takes high fat diet and intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) for model preparation. Model rats were randomly divided into T2DM Model group, EA weiwanxiashu (EX-B3) group, and sham EA group (n = 12/group). EA (2 Hz continuous wave, 2 mA, 20 min/day, 6 days/week, 4 weeks) was applied as intervention. FBG, area under curve (AUC) of oral glucose tolerance test (OGTT), insulin resistance index (HOMA-IR), pancreatic B cell function index (HOMA-B), skeletal muscle phosphorylated phosphatidylinositol-3-kinase (PI3K), glucose transporter 4 (GLUT4), and membrane GLUT4 protein expression were measured. Results. EA weiwanxiashu (EX-B3) can greatly upregulate model rat's significantly reduced skeletal muscle PI3K (Y607) and membrane GLUT4 protein expression (P < 0.01), effectively reducing model rats' FBG and AUC of OGTT (P < 0.01). The effects are far superior to sham EA group. Conclusion. EA weiwanxiashu (EX-B3) can upregulate skeletal muscle phosphorylated PI3K protein expression, to stimulate membrane translocation of GLUT4 and thereby increase skeletal muscle glucose intake to treat T2DM. PMID:27656242

  1. PI3K-GLUT4 Signal Pathway Associated with Effects of EX-B3 Electroacupuncture on Hyperglycemia and Insulin Resistance of T2DM Rats

    PubMed Central

    2016-01-01

    Objectives. To explore electroacupuncture's (EA's) effects on fasting blood glucose (FBG) and insulin resistance of type 2 diabetic mellitus (T2DM) model rats and give a possible explanation for the effects. Method. It takes high fat diet and intraperitoneal injection of streptozotocin (STZ, 30 mg/kg) for model preparation. Model rats were randomly divided into T2DM Model group, EA weiwanxiashu (EX-B3) group, and sham EA group (n = 12/group). EA (2 Hz continuous wave, 2 mA, 20 min/day, 6 days/week, 4 weeks) was applied as intervention. FBG, area under curve (AUC) of oral glucose tolerance test (OGTT), insulin resistance index (HOMA-IR), pancreatic B cell function index (HOMA-B), skeletal muscle phosphorylated phosphatidylinositol-3-kinase (PI3K), glucose transporter 4 (GLUT4), and membrane GLUT4 protein expression were measured. Results. EA weiwanxiashu (EX-B3) can greatly upregulate model rat's significantly reduced skeletal muscle PI3K (Y607) and membrane GLUT4 protein expression (P < 0.01), effectively reducing model rats' FBG and AUC of OGTT (P < 0.01). The effects are far superior to sham EA group. Conclusion. EA weiwanxiashu (EX-B3) can upregulate skeletal muscle phosphorylated PI3K protein expression, to stimulate membrane translocation of GLUT4 and thereby increase skeletal muscle glucose intake to treat T2DM. PMID:27656242

  2. The inability of phosphatidylinositol 3-kinase activation to stimulate GLUT4 translocation indicates additional signaling pathways are required for insulin-stimulated glucose uptake.

    PubMed

    Isakoff, S J; Taha, C; Rose, E; Marcusohn, J; Klip, A; Skolnik, E Y

    1995-10-24

    Recent experimental evidence has focused attention to the role of two molecules, insulin receptor substrate 1 (IRS-1) and phosphatidylinositol 3-kinase (PI3-kinase), in linking the insulin receptor to glucose uptake; IRS-1 knockout mice are insulin resistant, and pharmacological inhibitors of PI3-kinase block insulin-stimulated glucose uptake. To investigate the role of PI3-kinase and IRS-1 in insulin-stimulated glucose uptake we examined whether stimulation of insulin-sensitive cells with platelet-derived growth factor (PDGF) or with interleukin 4 (IL-4) stimulates glucose uptake; the activated PDGF receptor (PDGFR) directly binds and activates PI3-kinase, whereas the IL-4 receptor (IL-4R) activates PI3-kinase via IRS-1 or the IRS-1-related molecule 4PS. We found that stimulation of 3T3-L1 adipocytes with PDGF resulted in tyrosine phosphorylation of the PDGFR and activation of PI3-kinase in these cells. To examine whether IL-4 stimulates glucose uptake, L6 myoblasts were engineered to overexpress GLUT4 as well as both chains of the IL-4R (L6/IL-4R/GLUT4); when these L6/IL-4R/GLUT4 myoblasts were stimulated with IL-4, IRS-1 became tyrosine phosphorylated and associated with PI3-kinase. Although PDGF and IL-4 can activate PI3-kinase in the respective cell lines, they do not possess insulin's ability to stimulate glucose uptake and GLUT4 translocation to the plasma membrane. These findings indicate that activation of PI3-kinase is not sufficient to stimulate GLUT4 translocation to the plasma membrane. We postulate that activation of a second signaling pathway by insulin, distinct from PI3-kinase, is necessary for the stimulation of glucose uptake in insulin-sensitive cells.

  3. Comparison of GLUT1, GLUT3, and GLUT4 mRNA and the subcellular distribution of their proteins in normal human muscle

    NASA Technical Reports Server (NTRS)

    Stuart, C. A.; Wen, G.; Gustafson, W. C.; Thompson, E. A.

    2000-01-01

    Basal, "insulin-independent" glucose uptake into skeletal muscle is provided by glucose transporters positioned at the plasma membrane. The relative amount of the three glucose transporters expressed in muscle has not been previously quantified. Using a combination of qualitative and quantitative ribonuclease protection assay (RPA) methods, we found in normal human muscle that GLUT1, GLUT3, and GLUT4 mRNA were expressed at 90 +/- 10, 46 +/- 4, and 156 +/- 12 copies/ng RNA, respectively. Muscle was fractionated by DNase digestion and differential sedimentation into membrane fractions enriched in plasma membranes (PM) or low-density microsomes (LDM). GLUT1 and GLUT4 proteins were distributed 57% to 67% in LDM, whereas GLUT3 protein was at least 88% in the PM-enriched fractions. These data suggest that basal glucose uptake into resting human muscle could be provided in part by each of these three isoforms.

  4. Anti-diabetic property of Tinospora cordifolia and its active compound is mediated through the expression of Glut-4 in L6 myotubes.

    PubMed

    Sangeetha, M K; Priya, C D Mohana; Vasanthi, Hannah R

    2013-02-15

    Tinospora cordifolia is a well reported plant possessing numerous medicinal values including anti-diabetic property. Aim of the present study is to study the mechanism of action of Tinospora cordifolia and its active compound in differentiated myocytes, L6 cells. Key marker of diabetes in cells is the insulin dependent glucose transporter-4 (Glut-4) which also responds to exogenous chemicals, and is over expressed up to 5- and 4-fold, by Tinospora cordifolia and palmatine, respectively. Next to Glut-4, the predominant protein influencing glucose metabolism is PPARα and γ whose expressions were also positively modulated. Further, the inhibitors of insulin pathway prevented glucose uptake mediated by Tinospora cordifolia and palmatine which shows that the activity is majorly mediated through insulin pathway. PMID:23290487

  5. Exercise improved lipid metabolism and insulin sensitivity in rats fed a high-fat diet by regulating glucose transporter 4 (GLUT4) and musclin expression.

    PubMed

    Yu, J; Zheng, J; Liu, X F; Feng, Z L; Zhang, X P; Cao, L L; Zhou, Z P

    2016-01-01

    This study aimed to evaluate the effects of exercise training on triglyceride deposition and the expression of musclin and glucose transporter 4 (GLUT4) in a rat model of insulin resistance. Thirty male Sprague-Dawley rats (8 weeks old, weight 160±10 g) were fed a high-fat diet (40% calories from fat) and randomly divided into high-fat control group and swimming intervention group. Rats fed with standard food served as normal control. We found that 8-week swimming intervention significantly decreased body weight (from 516.23±46.27 to 455.43±32.55 g) and visceral fat content (from 39.36±2.50 to 33.02±2.24 g) but increased insulin sensitivity index of the rats fed with a high-fat diet. Moreover, swimming intervention improved serum levels of TG (from 1.40±0.83 to 0.58±0.26 mmol/L) and free fatty acids (from 837.80±164.25 to 556.38±144.77 μEq/L) as well as muscle triglycerides deposition (from 0.55±0.06 to 0.45±0.02 mmol/g) in rats fed a high-fat diet. Compared with rats fed a standard food, musclin expression was significantly elevated, while GLUT4 expression was decreased in the muscles of rats fed a high-fat diet. In sharp contrast, swimming intervention significantly reduced the expression of musclin and increased the expression of GLUT4 in the muscles of rats fed a high-fat diet. In conclusion, increased musclin expression may be associated with insulin resistance in skeletal muscle, and exercise training improves lipid metabolism and insulin sensitivity probably by upregulating GLUT4 and downregulating musclin.

  6. Exercise improved lipid metabolism and insulin sensitivity in rats fed a high-fat diet by regulating glucose transporter 4 (GLUT4) and musclin expression

    PubMed Central

    Yu, J.; Zheng, J.; Liu, X.F.; Feng, Z.L.; Zhang, X.P.; Cao, L.L.; Zhou, Z.P.

    2016-01-01

    This study aimed to evaluate the effects of exercise training on triglyceride deposition and the expression of musclin and glucose transporter 4 (GLUT4) in a rat model of insulin resistance. Thirty male Sprague-Dawley rats (8 weeks old, weight 160±10 g) were fed a high-fat diet (40% calories from fat) and randomly divided into high-fat control group and swimming intervention group. Rats fed with standard food served as normal control. We found that 8-week swimming intervention significantly decreased body weight (from 516.23±46.27 to 455.43±32.55 g) and visceral fat content (from 39.36±2.50 to 33.02±2.24 g) but increased insulin sensitivity index of the rats fed with a high-fat diet. Moreover, swimming intervention improved serum levels of TG (from 1.40±0.83 to 0.58±0.26 mmol/L) and free fatty acids (from 837.80±164.25 to 556.38±144.77 μEq/L) as well as muscle triglycerides deposition (from 0.55±0.06 to 0.45±0.02 mmol/g) in rats fed a high-fat diet. Compared with rats fed a standard food, musclin expression was significantly elevated, while GLUT4 expression was decreased in the muscles of rats fed a high-fat diet. In sharp contrast, swimming intervention significantly reduced the expression of musclin and increased the expression of GLUT4 in the muscles of rats fed a high-fat diet. In conclusion, increased musclin expression may be associated with insulin resistance in skeletal muscle, and exercise training improves lipid metabolism and insulin sensitivity probably by upregulating GLUT4 and downregulating musclin. PMID:27143172

  7. Exercise improved lipid metabolism and insulin sensitivity in rats fed a high-fat diet by regulating glucose transporter 4 (GLUT4) and musclin expression.

    PubMed

    Yu, J; Zheng, J; Liu, X F; Feng, Z L; Zhang, X P; Cao, L L; Zhou, Z P

    2016-01-01

    This study aimed to evaluate the effects of exercise training on triglyceride deposition and the expression of musclin and glucose transporter 4 (GLUT4) in a rat model of insulin resistance. Thirty male Sprague-Dawley rats (8 weeks old, weight 160±10 g) were fed a high-fat diet (40% calories from fat) and randomly divided into high-fat control group and swimming intervention group. Rats fed with standard food served as normal control. We found that 8-week swimming intervention significantly decreased body weight (from 516.23±46.27 to 455.43±32.55 g) and visceral fat content (from 39.36±2.50 to 33.02±2.24 g) but increased insulin sensitivity index of the rats fed with a high-fat diet. Moreover, swimming intervention improved serum levels of TG (from 1.40±0.83 to 0.58±0.26 mmol/L) and free fatty acids (from 837.80±164.25 to 556.38±144.77 μEq/L) as well as muscle triglycerides deposition (from 0.55±0.06 to 0.45±0.02 mmol/g) in rats fed a high-fat diet. Compared with rats fed a standard food, musclin expression was significantly elevated, while GLUT4 expression was decreased in the muscles of rats fed a high-fat diet. In sharp contrast, swimming intervention significantly reduced the expression of musclin and increased the expression of GLUT4 in the muscles of rats fed a high-fat diet. In conclusion, increased musclin expression may be associated with insulin resistance in skeletal muscle, and exercise training improves lipid metabolism and insulin sensitivity probably by upregulating GLUT4 and downregulating musclin. PMID:27143172

  8. Effect of GLP-1 treatment on GLUT2 and GLUT4 expression in type 1 and type 2 rat diabetic models.

    PubMed

    Villanueva-Peñacarrillo, M L; Puente, J; Redondo, A; Clemente, F; Valverde, I

    2001-07-01

    Glucagon-like peptide-1 (G LP-1) is an incretin with glucose-dependent insulinotropic and insulin-independent antidiabetic properties that exerts insulin-like effects on glucose metabolism in rat liver, skeletal muscle, and fat. This study aimed to search for the effect of a prolonged treatment, 3 ds, with GLP-1 on glucotransporter GLUT2 expression in liver, and on that of GLUT4 in skeletal muscle and fat, in rats. Normal rats and streptozotocin-induced type 1 and type 2 diabetic models were used; diabetic rats were also treated with insulin for comparison. In normal rats, GLP-1 treatment reduced in the three tissues the corresponding glucotransporter protein level, without modifying their mRNA. In the type 2 diabetic model, GLP-1, like insulin, stimulated in liver and fat only the glucotransporter translational process, while in the muscle an effect at the GLUT4 transcriptional level was also observed. In the type 1 diabetic model, GLP-1 apparently exerted in the liver only a posttranslational effect on GLUT2 expression; in muscle and fat, while insulin was shown to have an action on GLUT4 at both transcriptional and translational levels, the effect of GLP-1 was restricted to glucotransporter translation. In normal and diabetic rats, exogenous GLP-1 controlled the glucotransporter expression in extrapancreatic tissues participating in the overall glucose homeostasis-liver, muscle, and fat-where the effect of the peptide seems to be exerted only at the translational and/or posttranslational level; in muscle and fat, the presence of insulin seems to be required for GLP-1 to activate the transcriptional process. The stimulating action of GLP-1 on GLUT2 and GLUT4 expression, mRNA or protein, could be a mechanism by which, at least in part, the peptide exerts its lowering effect on blood glucose.

  9. Intra-uterine undernutrition amplifies age-associated glucose intolerance in pigs via altered DNA methylation at muscle GLUT4 promoter.

    PubMed

    Wang, Jun; Cao, Meng; Yang, Mei; Lin, Yan; Che, Lianqiang; Fang, Zhengfeng; Xu, Shengyu; Feng, Bin; Li, Jian; Wu, De

    2016-08-01

    The present study aimed to investigate the effect of maternal malnutrition on offspring glucose tolerance and the epigenetic mechanisms involved. In total, twelve primiparous Landrace×Yorkshire gilts were fed rations providing either 100 % (control (CON)) or 75 % (undernutrition (UN)) nutritional requirements according to the National Research Council recommendations, throughout gestation. Muscle samples of offspring were collected at birth (dpn1), weaning (dpn28) and adulthood (dpn189). Compared with CON pigs, UN pigs showed lower serum glucose concentrations at birth, but showed higher serum glucose and insulin concentrations as well as increased area under the blood glucose curve during intravenous glucose tolerance test at dpn189 (P<0·05). Compared with CON pigs, GLUT-4 gene and protein expressions were decreased at dpn1 and dpn189 in the muscle of UN pigs, which was accompanied by increased methylation at the GLUT4 promoter (P<0·05). These alterations in methylation concurred with increased mRNA levels of DNA methyltransferase (DNMT) 1 at dpn1 and dpn28, DNMT3a at dpn189 and DNMT3b at dpn1 in UN pigs compared with CON pigs (P<0·05). Interestingly, although the average methylation levels at the muscle GLUT4 promoter were decreased at dpn189 compared with dpn1 in pigs exposed to a poor maternal diet (P<0·05), the methylation differences in individual CpG sites were more pronounced with age. Our results indicate that in utero undernutrition persists to silence muscle GLUT4 likely through DNA methylation during the ageing process, which may lead to the amplification of age-associated glucose intolerance. PMID:27265204

  10. Chronic caffeine intake reverses age-induced insulin resistance in the rat: effect on skeletal muscle Glut4 transporters and AMPK activity.

    PubMed

    Guarino, Maria P; Ribeiro, Maria J; Sacramento, Joana F; Conde, Sílvia V

    2013-10-01

    The role of caffeine consumption on insulin action is still under debate. The hypothesis that chronic caffeine intake reverses aging-induced insulin resistance in the rat was tested in this work. The mechanism by which caffeine restores insulin sensitivity was also investigated. Six groups of rats were used: 3 months old (3 M), 3 months old caffeine-treated (3MCaf), 12 months old (12 M), 12 months old caffeine-treated (12MCaf), 24 months old (24 M), and 24 months old caffeine-treated (24MCaf). Caffeine was administered in drinking water (1 g/l) during 15 days. Insulin sensitivity was assessed by means of the insulin tolerance test. Blood pressure, body weight, visceral and total fat, fasting glycemia and insulinemia, plasma nonesterified fatty acids (NEFA), total antioxidant capacity (TAC), cortisol, nitric oxide, and catecholamines were monitored. Skeletal muscle Glut4 and 5'-AMP activated protein kinase (AMPK) protein expression and activity were also assessed. Aged rats exhibited diminished insulin sensitivity accompanied by hyperinsulinemia and normoglycemia, increased visceral and total fat, decreased TAC and plasma catecholamines, and also decreased skeletal muscle Glut4 and AMPK protein expression. Chronic caffeine intake restored insulin sensitivity and regularized circulating insulin and NEFA in both aging models. Caffeine neither modified skeletal muscle AMPK expression nor activity in aged rats; however, it decreased visceral and total fat in 12 M rats and it restored skeletal muscle Glut4 expression to control values in 24 M rats. We concluded that chronic caffeine intake reverses aging-induced insulin resistance in rats by decreasing NEFA production and also by increasing Glut4 expression in skeletal muscle.

  11. The cholesterol-lowering agent methyl-β-cyclodextrin promotes glucose uptake via GLUT4 in adult muscle fibers and reduces insulin resistance in obese mice.

    PubMed

    Llanos, Paola; Contreras-Ferrat, Ariel; Georgiev, Tihomir; Osorio-Fuentealba, Cesar; Espinosa, Alejandra; Hidalgo, Jorge; Hidalgo, Cecilia; Jaimovich, Enrique

    2015-02-15

    Insulin stimulates glucose uptake in adult skeletal muscle by promoting the translocation of GLUT4 glucose transporters to the transverse tubule (T-tubule) membranes, which have particularly high cholesterol levels. We investigated whether T-tubule cholesterol content affects insulin-induced glucose transport. Feeding mice a high-fat diet (HFD) for 8 wk increased by 30% the T-tubule cholesterol content of triad-enriched vesicular fractions from muscle tissue compared with triads from control mice. Additionally, isolated muscle fibers (flexor digitorum brevis) from HFD-fed mice showed a 40% decrease in insulin-stimulated glucose uptake rates compared with fibers from control mice. In HFD-fed mice, four subcutaneous injections of MβCD, an agent reported to extract membrane cholesterol, improved their defective glucose tolerance test and normalized their high fasting glucose levels. The preincubation of isolated muscle fibers with relatively low concentrations of MβCD increased both basal and insulin-induced glucose uptake in fibers from controls or HFD-fed mice and decreased Akt phosphorylation without altering AMPK-mediated signaling. In fibers from HFD-fed mice, MβCD improved insulin sensitivity even after Akt or CaMK II inhibition and increased membrane GLUT4 content. Indinavir, a GLUT4 antagonist, prevented the stimulatory effects of MβCD on glucose uptake. Addition of MβCD elicited ryanodine receptor-mediated calcium signals in isolated fibers, which were essential for glucose uptake. Our findings suggest that T-tubule cholesterol content exerts a critical regulatory role on insulin-stimulated GLUT4 translocation and glucose transport and that partial cholesterol removal from muscle fibers may represent a useful strategy to counteract insulin resistance.

  12. The In Vivo Antidiabetic Activity of Nigella sativa Is Mediated through Activation of the AMPK Pathway and Increased Muscle Glut4 Content

    PubMed Central

    Benhaddou-Andaloussi, Ali; Martineau, Louis; Vuong, Tri; Meddah, Bouchra; Madiraju, Padma; Settaf, Abdellatif; Haddad, Pierre S.

    2011-01-01

    The antidiabetic effect of N. sativa seed ethanol extract (NSE) was assessed in Meriones shawi after development of diabetes. Meriones shawi were divided randomly into four groups: normal control, diabetic control, diabetic treated with NSE (2 g eq plant/kg) or with metformin (300 mg/kg) positive control, both administered by daily intragastric gavage for 4 weeks. Glycaemia and body weight were evaluated weekly. At study's end, an Oral Glucose Tolerance Test (OGTT) was performed to estimate insulin sensitivity. Upon sacrifice, plasma lipid profile, insulin, leptin, and adiponectin levels were assessed. ACC phosphorylation and Glut4 protein content were determined in liver and skeletal muscle. NSE animals showed a progressive normalization of glycaemia, albeit slower than that of metformin controls. Moreover, NSE increased insulinemia and HDL-cholesterol, compared to diabetic controls. Leptin and adiponectin were unchanged. NSE treatment decreased OGTT and tended to decrease liver and muscle triglyceride content. NSE stimulated muscle and liver ACC phosphorylation and increased muscle Glut4. These results confirm NSE's previously reported hypoglycaemic and hypolipidemic activity. More significantly, our data demonstrate that in vivo treatment with NSE exerts an insulin-sensitizing action by enhancing ACC phosphorylation, a major component of the insulin-independent AMPK signaling pathway, and by enhancing muscle Glut4 expression. PMID:21584245

  13. The diabetogenic effects of excessive ethanol: reducing beta-cell mass, decreasing phosphatidylinositol 3-kinase activity and GLUT-4 expression in rats.

    PubMed

    Zhao, Li-Na; Hao, Li-Ping; Yang, Xue-Feng; Ying, Chen-Jiang; Yu, Dong; Sun, Xiu-Fa

    2009-05-01

    The diabetogenic impact of ethanol remains as a focal point of basic and clinical investigations. In this study, Wistar rats were subjected to daily intragastric ethanol administration (10 ml/kg body weight injection with 0 (control), 10, 20 and 33 % (v/v) ethanol in the injections, respectively) for 19 weeks. At the end of the administration, we found that the fasting plasma glucose level of the 33 % (v/v) ethanol-loaded group was 18 % higher than the control. Insulin sensitivity was decreased in a dose-dependent manner in all the ethanol-loaded groups (r - 0.842, P < 0.001) during intraperitoneal insulin tolerance test. Necrotic/haemorrhagic injury was detected in the pancreas and islet beta-cell mass was significantly reduced in the 33 % (v/v) ethanol-loaded rats by immunohistochemical and morphometric analysis. At the molecular level, we detected a dose-dependent attenuation of phosphatidylinositol 3-kinase activity (r - 0.956, P < 0.001) and GLUT-4 expression (GLUT-4 mRNA, r - 0.899, P < 0.001; GLUT-4 protein, r - 0.964, P < 0.001) in skeletal muscle. These results demonstrated that drinking is a conditional aetiological factor for diabetes and excessive ethanol intake is negatively associated with both insulin sensitivity and beta-cell mass. The whole-body insulin resistance might result from the ethanol-induced insulin signalling defects in muscle.

  14. Fucoidan from sea cucumber Cucumaria frondosa exhibits anti-hyperglycemic effects in insulin resistant mice via activating the PI3K/PKB pathway and GLUT4.

    PubMed

    Wang, Yiming; Wang, Jingfeng; Zhao, Yanlei; Hu, Shiwei; Shi, Di; Xue, Changhu

    2016-01-01

    The present study investigated the anti-hyperglycemic properties and mechanisms of fucoidan, isolated from Cucumaria frondosa (Cf-FUC), in insulin resistant mice. Male C57BL/6J mice were fed regular diet or high-fat/high-sucrose diet for 19 weeks. Model animals were dietary administrated either rosiglitazone (RSG, 1 mg/kg·bw), fucoidan (Cf-FUC, 80 mg/kg·bw) or their combinations. Results showed that Cf-FUC significantly reduced fasting blood glucose and insulin levels, and enhanced glucose tolerance and insulin tolerance in insulin-resistant mice. Quantitative real-time PCR analysis showed that Cf-FUC increased the mRNA expressions of insulin receptors (IR), insulin receptor substrate 1 (IRS-1), phosphatidylinositol 3 kinase (PI3K), protein kinase B (PKB), and glucose transporter 4 (GLUT4). Western blot assays demonstrated that Cf-FUC showed no effect on total protein expression but nevertheless enhanced the phosphorylation of proteins listed above and increased translocation of GLUT4 to the cell membrane. Furthermore, Cf-FUC enhanced the effects of RSG. These results indicated that Cf-FUC exhibited significant anti-hyperglycemic effects via activating PI3K/PKB pathway and GLUT4 in skeletal muscle and adipose tissue.

  15. Defects in processing and trafficking of the AE1 Cl-/HCO3- exchanger associated with inherited distal renal tubular acidosis.

    PubMed

    Shayakul, Chairat; Alper, Seth L

    2004-03-01

    Distal renal tubular acidosis (dRTA) results from impaired urinary acidification by the renal collecting duct. Acquired dRTA can be secondary to diverse pathological processes, including diabetic, ischemic, fibrosing, or immunological processes; less frequently it presents as a familial disorder with either an autosomal recessive or dominant pattern of transmission. Mutations in the SLC4A1/AE1/band 3 Cl(-)/HCO(3)(-) exchanger gene have been identified as causes for both dominant and recessive forms of dRTA. These mutations comprise a group almost entirely distinct from the SLC4A1 mutations that underlie the familial hemolytic anemia of hereditary spherocytosis. Why does one group of mutations express almost exclusively an isolated erythroid phenotype, whereas the second group of mutations expresses almost exclusively a phenotype explicable entirely by defective function of renal collecting duct type A intercalated cells? This review summarizes current research addressing this central question in the pathobiology of inherited dRTA associated with mutations in the SLC4A1 gene. Studying dRTA-associated mutant AE1 polypeptides can provide novel insights into the biology of the intercalated cell and the collecting duct as well as more generally into mechanisms by which epithelial cells generate and maintain functional polarity. PMID:15067510

  16. Chronic growth hormone treatment in normal rats reduces post-prandial skeletal muscle plasma membrane GLUT1 content, but not glucose transport or GLUT4 expression and localization.

    PubMed Central

    Napoli, R; Cittadini, A; Chow, J C; Hirshman, M F; Smith, R J; Douglas, P S; Horton, E S

    1996-01-01

    Whether skeletal muscle glucose transport system is impaired in the basal, post-prandial state during chronic growth hormone treatment is unknown. The current study was designed to determine whether 4 weeks of human growth hormone (hGH) treatment (3.5 mg/kg per day) would impair glucose transport and/or the number of glucose transporters in plasma membrane vesicles isolated from hindlimb skeletal muscle of Sprague-Dawley rats under basal, post-prandial conditions. hGH treatment was shown to have no effect on glucose influx (Vmax or K(m)) determined under equilibrium exchange conditions in isolated plasma membrane vesicles. Plasma membrane glucose transporter number (Ro) measured by cytochalasin B binding was also unchanged by hGH treatment. Consequently, glucose transporter turnover number (Vmax/Ro), a measure of average glucose transporter intrinsic activity, was similar in hGH-treated and control rats. hGH did not change GLUT4 protein content in whole muscle or in the plasma membrane, and muscle content of GLUT4 mRNA also was unchanged. In contrast, GLUT1 protein content in the plasma membrane fraction was significantly reduced by hGH treatment. This was associated with a modest, although not significant, decrease in muscle content of GLUT1 mRNA. In conclusion, high-dose hGH treatment for 4 weeks did not alter post-prandial skeletal muscle glucose transport activity. Neither the muscle level nor the intracellular localization of GLUT4 was changed by the hormone treatment. On the contrary, the basal post-prandial level of GLUT1 in the plasma membrane was reduced by hGH. The mRNA data suggest that this reduction might result from a decrease in the synthesis of GLUT1. PMID:8645183

  17. Hypoglycemic Effects of Three Medicinal Plants in Experimental Diabetes: Inhibition of Rat Intestinal α-glucosidase and Enhanced Pancreatic Insulin and Cardiac Glut-4 mRNAs Expression.

    PubMed

    Moradabadi, Leila; Montasser Kouhsari, Shideh; Fehresti Sani, Mohammad

    2013-01-01

    Garlic (Allium sativum L., Alliaceae), Persian shallot (Allium ascalonicum L., Alliaceae ) and Sage (Salvia officinalis L., Lamiaceae) are believed to have hypoglycemic properties and have been used traditionally as antidiabetic herbal medicines in Iran. In this study, diabetes was induced by subcutaneous injection of alloxan monohydrate (100 mg kg(-1)) to male Wistar rats. Antidiabetic effects of methanolic extracts of the above mentioned three plants on alloxan-diabetic rats was investigated in comparison with the effects of antidiabetic drugs such as acarbose, glibenclamide and metformin by measuring postprandial blood glucose (PBG), oral glucose tolerance test (OGTT), inhibition of rat intestinal α-glucosidase enzymes activities and pancreatic Insulin and cardiac Glut-4 mRNAs expression. In short term period, hypoglycemic effects of A. sativum and A. ascalonicum showed significant reduction of PBG similar to glibenclamide (5 mg kg(-1) bw) while S. officinalis significantly reduced PBG similar to acarbose (20 mg kg(-1) bw). After 3 weeks of treatment by methanolic plant extracts, significant chronic decrease in the PBG was observed similar to metformin (100 mg kg(-1) bw). For OGTT, S. officinalis reduced PBG in a similar way as acarbose (20 mg kg(-1) bw). Intestinal sucrase and maltase activities were inhibited significantly by A. sativum, A. ascalonicum and S. officinalis. In addition, we observed increased expression of Insulin and Glut-4 genes in diabetic rats treated with these plants extracts. Up regulation of Insulin and Glut-4 genes expression and inhibition of α-glucosidaseactivities are the two mechanisms that play a considerable role in hypoglycemic action of garlic, shallot and sage.

  18. Intense electroacupuncture normalizes insulin sensitivity, increases muscle GLUT4 content, and improves lipid profile in a rat model of polycystic ovary syndrome.

    PubMed

    Johansson, Julia; Feng, Yi; Shao, Ruijin; Lönn, Malin; Billig, Håkan; Stener-Victorin, Elisabet

    2010-10-01

    Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and insulin resistance, possibly reflecting defects in skeletal muscle and adipocyte insulin signaling. Low-frequency (2 Hz) electroacupuncture (EA) increases insulin sensitivity in female rats with dihydrotestosterone (DHT)-induced PCOS, but the mechanism is unclear. We hypothesized that low-frequency EA regulates mediators involved in skeletal muscle glucose uptake and metabolism and alters the lipid profile in rats with DHT-induced PCOS. To test this hypothesis, we implanted in prepubescent female rats 90-day continuous-release pellets containing DHT (PCOS). At 70 days of age, the rats were randomly subdivided into two groups: one received low-frequency EA (evoking muscle twitches) for 20-25 min five times/wk for 4-5 wk; the other did not. Controls were implanted with pellets containing vehicle only. All three groups were otherwise handled similarly. Lipid profile was measured in fasting blood samples. Insulin sensitivity was determined by euglycemic hyperinsulinemic clamp, soleus muscle protein expression of glucose transporter 4 (GLUT4), and phosphorylated and nonphosphorylated Akt, and Akt substrate of 160 kDa was determined by Western blot analysis and GLUT4 location by immunofluorescence staining. PCOS EA rats had normalized insulin sensitivity, lower levels of total high-density lipoprotein and low-density lipoprotein cholesterol, and increased expression of GLUT4 in different compartments of skeletal muscle compared with PCOS rats. Total weight and body composition did not differ in the groups. Thus, in rats with DHT-induced PCOS, low-frequency EA has systemic and local effects involving intracellular signaling pathways in muscle that may, at least in part, account for the marked improved insulin sensitivity. PMID:20663984

  19. Hypoglycemic Effects of Three Medicinal Plants in Experimental Diabetes: Inhibition of Rat Intestinal α-glucosidase and Enhanced Pancreatic Insulin and Cardiac Glut-4 mRNAs Expression.

    PubMed

    Moradabadi, Leila; Montasser Kouhsari, Shideh; Fehresti Sani, Mohammad

    2013-01-01

    Garlic (Allium sativum L., Alliaceae), Persian shallot (Allium ascalonicum L., Alliaceae ) and Sage (Salvia officinalis L., Lamiaceae) are believed to have hypoglycemic properties and have been used traditionally as antidiabetic herbal medicines in Iran. In this study, diabetes was induced by subcutaneous injection of alloxan monohydrate (100 mg kg(-1)) to male Wistar rats. Antidiabetic effects of methanolic extracts of the above mentioned three plants on alloxan-diabetic rats was investigated in comparison with the effects of antidiabetic drugs such as acarbose, glibenclamide and metformin by measuring postprandial blood glucose (PBG), oral glucose tolerance test (OGTT), inhibition of rat intestinal α-glucosidase enzymes activities and pancreatic Insulin and cardiac Glut-4 mRNAs expression. In short term period, hypoglycemic effects of A. sativum and A. ascalonicum showed significant reduction of PBG similar to glibenclamide (5 mg kg(-1) bw) while S. officinalis significantly reduced PBG similar to acarbose (20 mg kg(-1) bw). After 3 weeks of treatment by methanolic plant extracts, significant chronic decrease in the PBG was observed similar to metformin (100 mg kg(-1) bw). For OGTT, S. officinalis reduced PBG in a similar way as acarbose (20 mg kg(-1) bw). Intestinal sucrase and maltase activities were inhibited significantly by A. sativum, A. ascalonicum and S. officinalis. In addition, we observed increased expression of Insulin and Glut-4 genes in diabetic rats treated with these plants extracts. Up regulation of Insulin and Glut-4 genes expression and inhibition of α-glucosidaseactivities are the two mechanisms that play a considerable role in hypoglycemic action of garlic, shallot and sage. PMID:24250646

  20. Hypoglycemic Effects of Three Medicinal Plants in Experimental Diabetes: Inhibition of Rat Intestinal α-glucosidase and Enhanced Pancreatic Insulin and Cardiac Glut-4 mRNAs Expression

    PubMed Central

    Moradabadi, Leila; Montasser Kouhsari, Shideh; Fehresti Sani, Mohammad

    2013-01-01

    Garlic (Allium sativum L., Alliaceae), Persian shallot (Allium ascalonicum L., Alliaceae ) and Sage (Salvia officinalis L., Lamiaceae) are believed to have hypoglycemic properties and have been used traditionally as antidiabetic herbal medicines in Iran. In this study, diabetes was induced by subcutaneous injection of alloxan monohydrate (100 mg kg−1) to male Wistar rats. Antidiabetic effects of methanolic extracts of the above mentioned three plants on alloxan-diabetic rats was investigated in comparison with the effects of antidiabetic drugs such as acarbose, glibenclamide and metformin by measuring postprandial blood glucose (PBG), oral glucose tolerance test (OGTT), inhibition of rat intestinal α-glucosidase enzymes activities and pancreatic Insulin and cardiac Glut-4 mRNAs expression. In short term period, hypoglycemic effects of A. sativum and A. ascalonicum showed significant reduction of PBG similar to glibenclamide (5 mg kg−1 bw) while S. officinalis significantly reduced PBG similar to acarbose (20 mg kg−1 bw). After 3 weeks of treatment by methanolic plant extracts, significant chronic decrease in the PBG was observed similar to metformin (100 mg kg−1 bw). For OGTT, S. officinalis reduced PBG in a similar way as acarbose (20 mg kg−1 bw). Intestinal sucrase and maltase activities were inhibited significantly by A. sativum, A. ascalonicum and S. officinalis. In addition, we observed increased expression of Insulin and Glut-4 genes in diabetic rats treated with these plants extracts. Up regulation of Insulin and Glut-4 genes expression and inhibition of α-glucosidaseactivities are the two mechanisms that play a considerable role in hypoglycemic action of garlic, shallot and sage. PMID:24250646

  1. Proteolytic cleavage of cellubrevin and vesicle-associated membrane protein (VAMP) by tetanus toxin does not impair insulin-stimulated glucose transport or GLUT4 translocation in rat adipocytes.

    PubMed Central

    Hajduch, E; Aledo, J C; Watts, C; Hundal, H S

    1997-01-01

    Acute insulin stimulation of glucose transport in fat and skeletal muscle occurs principally as a result of the hormonal induced translocation of the GLUT4 glucose transporter from intracellular vesicular stores to the plasma membrane. The precise mechanisms governing the fusion of GLUT4 vesicles with the plasma membrane are very poorly understood at present but may share some similarities with synaptic vesicle fusion, as vesicle-associated membrane protein (VAMP) and cellubrevin, two proteins implicated in the process of membrane fusion, are resident in GLUT4-containing vesicles isolated from rat and murine 3T3-L1 adipocytes respectively. In this study we show that proteolysis of both cellubrevin and VAMP, induced by electroporation of isolated rat adipocytes with tetanus toxin, does not impair insulin-stimulated glucose transport or GLUT4 translocation. The hormone was found to stimulate glucose uptake by approx. 16-fold in freshly isolated rat adipocytes. After a single electroporating pulse, the ability of insulin to activate glucose uptake was lowered, but the observed stimulation was nevertheless nearly 5-fold higher than the basal rate of glucose uptake. Electroporation of adipocytes with 600 nM tetanus toxin resulted in a complete loss of both cellubrevin and VAMP expression within 60 min. However, toxin-mediated proteolysis of both these proteins had no effect on the ability of insulin to stimulate glucose transport which was elevated approx. 5-fold, an activation of comparable magnitude to that observed in cells electroporated without tetanus toxin. The lack of any significant change in insulin-stimulated glucose transport was consistent with the finding that toxin-mediated proteolysis of both cellubrevin and VAMP had no detectable effect on insulin-induced translocation of GLUT4 in adipocytes. Our findings indicate that, although cellubrevin and VAMP are resident proteins in adipocyte GLUT4-containing vesicles, they are not required for the acute insulin

  2. Non-invasive assessment of animal exercise stress: real-time PCR of GLUT4, COX2, SOD1 and HSP70 in avalanche military dog saliva.

    PubMed

    Diverio, S; Guelfi, G; Barbato, O; Di Mari, W; Egidi, M G; Santoro, M M

    2015-01-01

    Exercise has been shown to increase mRNA expression of a growing number of genes. The aim of this study was to assess if mRNA expression of the metabolism- and oxidative stress-related genes GLUT4 (glucose transporter 4), COX2 (cyclooxygenase 2), SOD1 (superoxide dismutase 1) and HSP70 (heat shock protein 70) in saliva changes following acute exercise stress in dogs. For this purpose, 12 avalanche dogs of the Italian Military Force Guardia di Finanza were monitored during simulation of a search for a buried person in an artificial avalanche area. Rectal temperature (RT) and saliva samples were collected the day before the trial (T0), immediately after the descent from a helicopter at the onset of a simulated avalanche search and rescue operation (T1), after the discovery of the buried person (T2) and 2 h later (T3). Expressions of GLUT4, SOD1, COX2 and HSP70 were measured by real-time PCR. The simulated avalanche search and rescue operation was shown to exert a significant effect on RT, as well as on the expression of all metabolism- and oxidative stress-related genes investigated, which peaked at T2. The observed expression patterns indicate an acute exercise stress-induced upregulation, as confirmed by the reductions in expression at T3. Moreover, our findings indicate that saliva is useful for assessing metabolism- and oxidative stress-related genes without the need for restraint, which could affect working dog performance.

  3. α-Mangostin Improves Glucose Uptake and Inhibits Adipocytes Differentiation in 3T3-L1 Cells via PPARγ, GLUT4, and Leptin Expressions

    PubMed Central

    Taher, Muhammad; Mohamed Amiroudine, Mohamed Zaffar Ali; Tengku Zakaria, Tengku Muhamad Faris Syafiq; Ichwan, Solachuddin J. A.; Kaderi, Mohd Arifin; Ahmed, Qamar Uddin; Zakaria, Zainul Amiruddin

    2015-01-01

    Obesity has been often associated with the occurrence of cardiovascular diseases, type 2 diabetes, and cancer. The development of obesity is also accompanied by significant differentiation of preadipocytes into adipocytes. In this study, we investigated the activity of α-mangostin, a major xanthone component isolated from the stem bark of G. malaccensis, on glucose uptake and adipocyte differentiation of 3T3-L1 cells focusing on PPARγ, GLUT4, and leptin expressions. α-Mangostin was found to inhibit cytoplasmic lipid accumulation and adipogenic differentiation. Cells treated with 50 μM of α-mangostin reduced intracellular fat accumulation dose-dependently up to 44.4% relative to MDI-treated cells. Analyses of 2-deoxy-D-[3H] glucose uptake activity showed that α-mangostin significantly improved the glucose uptake (P < 0.05) with highest activity found at 25 μM. In addition, α-mangostin increased the amount of free fatty acids (FFA) released. The highest glycerol release level was observed at 50 μM of α-mangostin. qRT-PCR analysis showed reduced lipid accumulation via inhibition of PPARγ gene expression. Induction of glucose uptake and free fatty acid release by α-mangostin were accompanied by increasing mRNA expression of GLUT4 and leptin. These evidences propose that α-mangostin might be possible candidate for the effective management of obesity in future. PMID:25873982

  4. Non-invasive assessment of animal exercise stress: real-time PCR of GLUT4, COX2, SOD1 and HSP70 in avalanche military dog saliva.

    PubMed

    Diverio, S; Guelfi, G; Barbato, O; Di Mari, W; Egidi, M G; Santoro, M M

    2015-01-01

    Exercise has been shown to increase mRNA expression of a growing number of genes. The aim of this study was to assess if mRNA expression of the metabolism- and oxidative stress-related genes GLUT4 (glucose transporter 4), COX2 (cyclooxygenase 2), SOD1 (superoxide dismutase 1) and HSP70 (heat shock protein 70) in saliva changes following acute exercise stress in dogs. For this purpose, 12 avalanche dogs of the Italian Military Force Guardia di Finanza were monitored during simulation of a search for a buried person in an artificial avalanche area. Rectal temperature (RT) and saliva samples were collected the day before the trial (T0), immediately after the descent from a helicopter at the onset of a simulated avalanche search and rescue operation (T1), after the discovery of the buried person (T2) and 2 h later (T3). Expressions of GLUT4, SOD1, COX2 and HSP70 were measured by real-time PCR. The simulated avalanche search and rescue operation was shown to exert a significant effect on RT, as well as on the expression of all metabolism- and oxidative stress-related genes investigated, which peaked at T2. The observed expression patterns indicate an acute exercise stress-induced upregulation, as confirmed by the reductions in expression at T3. Moreover, our findings indicate that saliva is useful for assessing metabolism- and oxidative stress-related genes without the need for restraint, which could affect working dog performance. PMID:25245143

  5. Evidence for an insulin receptor substrate 1 independent insulin signaling pathway that mediates insulin-responsive glucose transporter (GLUT4) translocation.

    PubMed Central

    Morris, A J; Martin, S S; Haruta, T; Nelson, J G; Vollenweider, P; Gustafson, T A; Mueckler, M; Rose, D W; Olefsky, J M

    1996-01-01

    Interaction of the activated insulin receptor (IR) with its substrate, insulin receptor substrate 1 (IRS-1), via the phosphotyrosine binding domain of IRS-1 and the NPXY motif centered at phosphotyrosine 960 of the IR, is important for IRS-1 phosphorylation. We investigated the role of this interaction in the insulin signaling pathway that stimulates glucose transport. Utilizing microinjection of competitive inhibitory reagents in 3T3-L1 adipocytes, we have found that disruption of the IR/IRS-1 interaction has no effect upon translocation of the insulin-responsive glucose transporter (GLUT4). The activity of these reagents was demonstrated by their ability to block insulin stimulation of two distinct insulin bioeffects, membrane ruffling and mitogenesis, in 3T3-L1 adipocytes and insulin-responsive rat 1 fibroblasts. These data suggest that phosphorylated IRS-1 is not an essential component of the metabolic insulin signaling pathway that leads to GLUT4 translocation, yet it appears to be required for other insulin bioeffects. Images Fig. 1 Fig. 2 Fig. 3 PMID:8710883

  6. Acute regulation by insulin of phosphatidylinositol-3-kinase, Rad, Glut 4, and lipoprotein lipase mRNA levels in human muscle.

    PubMed

    Laville, M; Auboeuf, D; Khalfallah, Y; Vega, N; Riou, J P; Vidal, H

    1996-07-01

    We have investigated the acute regulation by insulin of the mRNA levels of nine genes involved in insulin action, in muscle biopsies obtained before and at the end of a 3-h euglycemic hyperinsulinemic clamp. Using reverse transcription-competitive PCR, we have measured the mRNAs encoding the two insulin receptor variants, the insulin receptor substrate-1, the p85alpha subunit of phosphatidylinositol-3-kinase, Ras associated to diabetes (Rad), the glucose transporter Glut 4, glycogen synthase, 6-phosphofructo-l-kinase, lipoprotein lipase, and the hormone-sensitive lipase. Insulin infusion induced a significant increase in the mRNA level of Glut 4 (+56 +/- 13%), Rad (+96 +/- 25%), the p85alpha subunit of phosphatidylinositol-3-kinase (+92 +/- 18%) and a decrease in the lipoprotein lipase mRNA level (-49 +/- 5%), while the abundance of the other mRNAs was unaffected. The relative expression of the two insulin receptor variants was not modified. These results demonstrate an acute coordinated regulation by insulin of the expression of genes coding key proteins involved in its action in human skeletal muscle and suggest that Rad and the p85alpha regulatory subunit of phosphatidylinositol-3-kinase can be added to the list of the genes controlled by insulin. PMID:8690802

  7. Human Trafficking

    ERIC Educational Resources Information Center

    Wilson, David McKay

    2011-01-01

    The shadowy, criminal nature of human trafficking makes evaluating its nature and scope difficult. The U.S. State Department and anti-trafficking groups estimate that worldwide some 27 million people are caught in a form of forced servitude today. Public awareness of modern-day slavery is gaining momentum thanks to new abolitionist efforts. Among…

  8. Exercise training increases glycogen synthase activity and GLUT4 expression but not insulin signaling in overweight nondiabetic and type 2 diabetic subjects.

    PubMed

    Christ-Roberts, Christine Y; Pratipanawatr, Thongchai; Pratipanawatr, Wilailak; Berria, Rachele; Belfort, Renata; Kashyap, Sangeeta; Mandarino, Lawrence J

    2004-09-01

    Exercise training improves insulin sensitivity in subjects with and without type 2 diabetes. However, the mechanism by which this occurs is unclear. The present study was undertaken to determine how improved insulin signaling, GLUT4 expression, and glycogen synthase activity contribute to this improvement. Euglycemic clamps with indirect calorimetry and muscle biopsies were performed before and after 8 weeks of exercise training in 16 insulin-resistant nondiabetic subjects and 6 type 2 diabetic patients. Training increased peak aerobic capacity (Vo(2peak)) in both nondiabetic (from 34 +/- 2 to 39 +/- 2 mL O(2)/kg fat-free mass [FFM]/min, 14% +/- 2%, P <.001) and diabetic (from 26 +/- 3 to 34 +/- 3 mL O(2)/kg FFM/min, 32% +/- 4%) subjects. Training also increased insulin-stimulated glucose disposal in nondiabetic (from 6.2 +/- 0.5 to 7.1 +/- 0.7 mg/kg FFM/min) and diabetic subjects (from 4.3 +/- 0.6 to 5.5 +/- 0.6 mg/kg FFM/min). Total glycogen synthase activity was increased by 46% +/- 17% and 45% +/- 12% in nondiabetic and diabetic subjects, respectively, in response to training (P <.01 v before training). Moreover, after training, glycogen synthase fractional velocity was correlated with insulin-stimulated glucose storage (r = 0.53, P <.05) and the training-induced improvement in glucose disposal was accounted for primarily by increased insulin-stimulated glucose storage. Training also increased GLUT4 protein by 38% +/- 8% and 22% +/- 10% in nondiabetic and diabetic subjects, respectively (P <.05 v. before training). Akt protein expression, which was decreased by 29% +/- 3% (P <.05) in the diabetic subjects before training (compared to the nondiabetics), increased significantly in both groups (P <.001). In contrast, exercise training did not enhance the ability of insulin to stimulate insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3 (PI 3)-kinase activity. The present data are consistent with a working model whereby 8 weeks of exercise

  9. Downregulation of GLUT4 contributes to effective intervention of estrogen receptor-negative/HER2-overexpressing early stage breast disease progression by lapatinib.

    PubMed

    Acharya, Sunil; Xu, Jia; Wang, Xiao; Jain, Shalini; Wang, Hai; Zhang, Qingling; Chang, Chia-Chi; Bower, Joseph; Arun, Banu; Seewaldt, Victoria; Yu, Dihua

    2016-01-01

    Tamoxifen and aromatase inhibitors (AIs) have shown efficacy in prevention of estrogen receptor-positive (ER+) breast cancer; however, there exists no proven prevention strategy for estrogen receptor-negative (ER-) breast cancer. Up to 40% of ER- breast cancers have human epidermal growth factor receptor 2 overexpression (HER2+), suggesting HER2 signaling might be a good target for chemoprevention for certain ER- breast cancers. Here, we tested the feasibility of the HER2-targeting agent lapatinib in prevention and/or early intervention of an ER-/HER2+ early-stage breast disease model. We found that lapatinib treatment forestalled the progression of atypical ductal hyperplasia (ADH)-like acini to ductal carcinoma in situ (DCIS)-like acini in ER-/HER2+ human mammary epithelial cells (HMECs) in 3D culture. Mechanistically, we found that inhibition of HER2/Akt signaling by lapatinib led to downregulation of GLUT4 and a reduced glucose uptake in HER2-overexpressing cells, resulting in decreased proliferation and increased apoptosis of these cells in 3D culture. Additionally, our data suggest that HER2-driven glycolytic metabolic dysregulation in ER-/HER2+ HMECs might promote early-stage breast disease progression, which can be reversed by lapatinib treatment. Furthermore, low-dose lapatinib treatment, starting at the early stages of mammary grand transformation in the MMTV-neu* mouse model, significantly delayed mammary tumor initiation and progression, extended tumor-free survival, which corresponded to effective inhibition of HER2/Akt signaling and downregulation of GLUT4 in vivo. Taken together, our results indicate that lapatinib, through its inhibition of key signaling pathways and tumor-promoting metabolic events, is a promising agent for the prevention/early intervention of ER-/HER2+ breast cancer progression. PMID:27293993

  10. Nutritional status induces divergent variations of GLUT4 protein content, but not lipoprotein lipase activity, between adipose tissues and muscles in adult cattle.

    PubMed

    Bonnet, Muriel; Faulconnier, Yannick; Hocquette, Jean-François; Bocquier, François; Leroux, Christine; Martin, Patrice; Chilliard, Yves

    2004-10-01

    Metabolic adaptations to variations in food supply are incompletely understood in ruminant animal adipose tissue (AT) and muscle. To explore this, we studied lipid metabolism and glucose transport potential in one internal and one external AT, as well as in one oxidative and one glycolytic muscle from control, 7 d underfed and 21 d refed adult cows. Refeeding increased (+79 to +307 %) the activities of enzymes involved in de novo lipogenesis (fatty acid synthase, malic enzyme, glucose-6-phosphate dehydrogenase) in perirenal and subcutaneous AT; underfeeding did not modify these variables. Underfeeding decreased the activities of lipoprotein lipase (LPL) in perirenal AT (-70 %) and cardiac muscle (-67 %), but did not modify the activities in subcutaneous AT and longissimus thoracis. Refeeding increased LPL activities in all tissues (+40 to +553 %) to levels comparable with (cardiac muscle) or greater than (AT, longissimus thoracis) those observed in control cows. Such variations in perirenal and cardiac muscle LPL activities did not result from variations in LPL mRNA levels, but suggest a post-transcriptional regulation of LPL in these nutritional conditions. Underfeeding did not modify GLUT4 contents in perirenal AT and muscles, while refeeding increased it only in perirenal AT (+250 %). Our present results contrast with previous results in rats, where LPL is regulated in opposite directions in AT and muscles, and GLUT4 is generally increased by fasting and decreased by refeeding in skeletal muscles. The present results highlight the bovine specificity of the response, which probably arises in part from peculiarities of ruminant animals for nutrient digestion and absorption.

  11. Downregulation of GLUT4 contributes to effective intervention of estrogen receptor-negative/HER2-overexpressing early stage breast disease progression by lapatinib

    PubMed Central

    Acharya, Sunil; Xu, Jia; Wang, Xiao; Jain, Shalini; Wang, Hai; Zhang, Qingling; Chang, Chia-Chi; Bower, Joseph; Arun, Banu; Seewaldt, Victoria; Yu, Dihua

    2016-01-01

    Tamoxifen and aromatase inhibitors (AIs) have shown efficacy in prevention of estrogen receptor-positive (ER+) breast cancer; however, there exists no proven prevention strategy for estrogen receptor-negative (ER-) breast cancer. Up to 40% of ER- breast cancers have human epidermal growth factor receptor 2 overexpression (HER2+), suggesting HER2 signaling might be a good target for chemoprevention for certain ER- breast cancers. Here, we tested the feasibility of the HER2-targeting agent lapatinib in prevention and/or early intervention of an ER-/HER2+ early-stage breast disease model. We found that lapatinib treatment forestalled the progression of atypical ductal hyperplasia (ADH)-like acini to ductal carcinoma in situ (DCIS)-like acini in ER-/HER2+ human mammary epithelial cells (HMECs) in 3D culture. Mechanistically, we found that inhibition of HER2/Akt signaling by lapatinib led to downregulation of GLUT4 and a reduced glucose uptake in HER2-overexpressing cells, resulting in decreased proliferation and increased apoptosis of these cells in 3D culture. Additionally, our data suggest that HER2-driven glycolytic metabolic dysregulation in ER-/HER2+ HMECs might promote early-stage breast disease progression, which can be reversed by lapatinib treatment. Furthermore, low-dose lapatinib treatment, starting at the early stages of mammary grand transformation in the MMTV-neu* mouse model, significantly delayed mammary tumor initiation and progression, extended tumor-free survival, which corresponded to effective inhibition of HER2/Akt signaling and downregulation of GLUT4 in vivo. Taken together, our results indicate that lapatinib, through its inhibition of key signaling pathways and tumor-promoting metabolic events, is a promising agent for the prevention/early intervention of ER-/HER2+ breast cancer progression. PMID:27293993

  12. Oral chromium picolinate improves carbohydrate and lipid metabolism and enhances skeletal muscle Glut-4 translocation in obese, hyperinsulinemic (JCR-LA corpulent) rats.

    PubMed

    Cefalu, William T; Wang, Zhong Q; Zhang, Xian H; Baldor, Linda C; Russell, James C

    2002-06-01

    Human studies suggest that chromium picolinate (CrPic) decreases insulin levels and improves glucose disposal in obese and type 2 diabetic populations. To evaluate whether CrPic may aid in treatment of the insulin resistance syndrome, we assessed its effects in JCR:LA-corpulent rats, a model of this syndrome. Male lean and obese hyperinsulinemic rats were randomly assigned to receive oral CrPic [80 microg/(kg. d); n = 5 or 6, respectively) in water or to control conditions (water, n = 5). After 3 mo, a 120-min intraperitoneal glucose tolerance test (IPGTT) and a 30-min insulin tolerance test were performed. Obese rats administered CrPic had significantly lower fasting insulin levels (1848 +/- 102 vs. 2688 +/- 234 pmol/L; P < 0.001; mean +/- SEM) and significantly improved glucose disappearance (P < 0.001) compared with obese controls. Glucose and insulin areas under the curve for IPGTT were significantly less for obese CrPic-treated rats than in obese controls (P < 0.001). Obese CrPic-treated rats had lower plasma total cholesterol (3.57 +/- 0.28 vs. 4.11 +/- 0.47 mmol/L, P < 0.05) and higher HDL cholesterol levels (1.92 +/- 0.09 vs. 1.37 +/- 0.36 mmol/L, P < 0.01) than obese controls. CrPic did not alter plasma glucose or cholesterol levels in lean rats. Total skeletal muscle glucose transporter (Glut)-4 did not differ among groups; however, CrPic significantly enhanced membrane-associated Glut-4 in obese rats after insulin stimulation. Thus, CrPic supplementation enhances insulin sensitivity and glucose disappearance, and improves lipids in male obese hyperinsulinemic JCR:LA-corpulent rats.

  13. Co-activator binding protein PIMT mediates TNF-α induced insulin resistance in skeletal muscle via the transcriptional down-regulation of MEF2A and GLUT4

    PubMed Central

    Kain, Vasundhara; Kapadia, Bandish; Viswakarma, Navin; Seshadri, Sriram; Prajapati, Bhumika; Jena, Prasant K; Teja Meda, Chandana Lakshmi; Subramanian, Maitreyi; Kaimal Suraj, Sashidhara; Kumar, Sireesh T; Prakash Babu, Phanithi; Thimmapaya, Bayar; Reddy, Janardan K; Parsa, Kishore V. L.; Misra, Parimal

    2015-01-01

    The mechanisms underlying inflammation induced insulin resistance are poorly understood. Here, we report that the expression of PIMT, a transcriptional co-activator binding protein, was up-regulated in the soleus muscle of high sucrose diet (HSD) induced insulin resistant rats and TNF-α exposed cultured myoblasts. Moreover, TNF-α induced phosphorylation of PIMT at the ERK1/2 target site Ser298. Wild type (WT) PIMT or phospho-mimic Ser298Asp mutant but not phospho-deficient Ser298Ala PIMT mutant abrogated insulin stimulated glucose uptake by L6 myotubes and neonatal rat skeletal myoblasts. Whereas, PIMT knock down relieved TNF-α inhibited insulin signaling. Mechanistic analysis revealed that PIMT differentially regulated the expression of GLUT4, MEF2A, PGC-1α and HDAC5 in cultured cells and skeletal muscle of Wistar rats. Further characterization showed that PIMT was recruited to GLUT4, MEF2A and HDAC5 promoters and overexpression of PIMT abolished the activity of WT but not MEF2A binding defective mutant GLUT4 promoter. Collectively, we conclude that PIMT mediates TNF-α induced insulin resistance at the skeletal muscle via the transcriptional modulation of GLUT4, MEF2A, PGC-1α and HDAC5 genes. PMID:26468734

  14. Two chalcones, 4-hydroxyderricin and xanthoangelol, stimulate GLUT4-dependent glucose uptake through the LKB1/AMP-activated protein kinase signaling pathway in 3T3-L1 adipocytes.

    PubMed

    Ohta, Mitsuhiro; Fujinami, Aya; Kobayashi, Norihiro; Amano, Akiko; Ishigami, Akihito; Tokuda, Harukuni; Suzuki, Nobutaka; Ito, Fumitake; Mori, Taisuke; Sawada, Morio; Iwasa, Koichi; Kitawaki, Jo; Ohnishi, Katsunori; Tsujikawa, Muneo; Obayashi, Hiroshi

    2015-07-01

    4-Hydroxyderricin (4HD) and xanthoangelol (XAG) are major components of n-hexane/ethyl acetate (5:1) extract of the yellow-colored stem juice of Angelica keiskei. 4-Hydroxyderricin and XAG have been reported to increase glucose transporter 4 (GLUT4)-dependent glucose uptake in 3T3-L1 adipocytes, but the detailed mechanism of this phenomenon remains unknown. This present study was aimed at clarifying the detailed mechanism by which 4HD and XAG increase GLUT4-dependent glucose uptake in 3T3-L1 adipocytes. Both 4HD and XAG increased glucose uptake and GLUT4 translocation to the plasma membrane. 4-Hydroxyderricin and XAG also stimulated the phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) and its downstream target acetyl-CoA carboxylase. In addition, phosphorylation of liver kinase B1 (LKB1), which acts upstream of AMPK, was also increased by 4HD and XAG treatment. Small interfering RNA knockdown of LKB1 attenuated 4HD- and XAG-stimulated AMPK phosphorylation and suppressed glucose uptake. These findings demonstrate that 4HD and XAG can increase GLUT4-dependent glucose uptake through the LKB1/AMPK signaling pathway in 3T3-L1 adipocytes. PMID:26077869

  15. Zinc stimulates glucose consumption by modulating the insulin signaling pathway in L6 myotubes: essential roles of Akt-GLUT4, GSK3β and mTOR-S6K1.

    PubMed

    Wu, Yuntang; Lu, Huizi; Yang, Huijun; Li, Chunlei; Sang, Qian; Liu, Xinyan; Liu, Yongzhe; Wang, Yongming; Sun, Zhong

    2016-08-01

    The present study was performed to evaluate the insulin-like effects of zinc in normal L6 myotubes as well as its ability to alleviate insulin resistance. Glucose consumption was measured in both normal and insulin-resistant L6 myotubes. Western blotting and immunofluorescence revealed that zinc exhibited insulin-like glucose transporting effects by activating key markers that are involved in the insulin signaling cascade (including Akt, GLUT4 and GSK3β), and downregulating members of the insulin signaling feedback cascade such as mammalian target of rapamycin (mTOR) and ribosomal protein S6 kinase (S6K1). In normal L6 myotubes, zinc enhanced glucose consumption via a mechanism that might involve the activation of Akt phosphorylation, glucose transporter 4 (GLUT4) translocation and GSK3β phosphorylation. In contrast, zinc exerted insulin-mimetic effects in insulin-resistant L6 myotubes by upregulating Akt phosphorylation, GLUT4 translocation and GSK3β phosphorylation, and downregulating the expression of mTOR and S6K1. In conclusion, zinc might enhance glucose consumption by modulating insulin signaling pathways including Akt-GLUT4, GSK3β, mTOR and S6K1.

  16. Distribution patterns of the glucose transporters GLUT4 and GLUT1 in skeletal muscles of rats (Rattus norvegicus), pigs (Sus scrofa), cows (Bos taurus), adult goats, goat kids (Capra hircus), and camels (Camelus dromedarius).

    PubMed

    Duehlmeier, R; Sammet, K; Widdel, A; von Engelhardt, W; Wernery, U; Kinne, J; Sallmann, H-P

    2007-02-01

    Earlier studies demonstrated that forestomach herbivores are less insulin sensitive than monogastric omnivores. The present study was carried out to determine if different distribution patterns of the glucose transporters GLUT1 and GLUT4 may contribute to these different insulin sensitivities. Western blotting was used to measure GLUT1 and GLUT4 protein contents in oxidative (masseter, diaphragm) and glycolytic (longissimus lumborum, semitendinosus) skeletal muscle membranes of monogastric omnivores (rats and pigs), and of forestomach herbivores (cows, adult goats, goat kids, and camels). Muscles were characterized biochemically. Comparing red and white muscles, the isocitrate dehydrogenase (ICDH) activity was 1.5-15-times higher in oxidative muscles of all species, whereas lactate dehydrogenase (LDH) activity was 1.4-4.4-times higher in glycolytic muscles except in adult goats. GLUT4 levels were 1.5-6.3-times higher in oxidative muscles. GLUT1 levels were 2.2-8.3-times higher in glycolytic muscles in forestomach herbivores but not in monogastric animals. We conclude that GLUT1 may be the predominant glucose transporter in glycolytic muscles of ruminating animals. The GLUT1 distribution patterns were identical in adult and pre-ruminant goats, indicating that GLUT1 expression among these muscles is determined genetically. The high blood glucose levels of camels cited in literature may be due to an "NIDDM-like" impaired GLUT4 activity in skeletal muscle.

  17. Leptin Reduces the Expression and Increases the Phosphorylation of the Negative Regulators of GLUT4 Traffic TBC1D1 and TBC1D4 in Muscle of ob/ob Mice

    PubMed Central

    Sáinz, Neira; Rodríguez, Amaia; Catalán, Victoria; Becerril, Sara; Ramírez, Beatriz; Lancha, Andoni; Burgos-Ramos, Emma; Gómez-Ambrosi, Javier; Frühbeck, Gema

    2012-01-01

    Leptin improves insulin sensitivity in skeletal muscle. Our goal was to determine whether proteins controlling GLUT4 traffic are altered by leptin deficiency and in vivo leptin administration in skeletal muscle of wild type and ob/ob mice. Leptin-deficient ob/ob mice were divided in three groups: control, leptin-treated (1 mg/kg/d) and leptin pair-fed ob/ob mice. Microarray analysis revealed that 1,546 and 1,127 genes were regulated by leptin deficiency and leptin treatment, respectively. Among these, we identified 24 genes involved in intracellular vesicle-mediated transport in ob/ob mice. TBC1 domain family, member 1 (Tbc1d1), a negative regulator of GLUT4 translocation, was up-regulated (P = 0.001) in ob/ob mice as compared to wild types. Importantly, leptin treatment reduced the transcript levels of Tbc1d1 (P<0.001) and Tbc1d4 (P = 0.004) in the leptin-treated ob/ob as compared to pair-fed ob/ob animals. In addition, phosphorylation levels of TBC1D1 and TBC1D4 were enhanced in leptin-treated ob/ob as compared to control ob/ob (P = 0.015 and P = 0.023, respectively) and pair-fed ob/ob (P = 0.036 and P = 0.034, respectively) mice. Despite similar GLUT4 protein expression in wild type and ob/ob groups a different immunolocalization of this protein was evidenced in muscle sections. Leptin treatment increased GLUT4 immunoreactivity in gastrocnemius and extensor digitorum longus sections of leptin-treated ob/ob mice. Moreover, GLUT4 protein detected in immunoprecipitates from TBC1D4 was reduced by leptin replacement compared to control ob/ob (P = 0.013) and pair-fed ob/ob (P = 0.037) mice. Our findings suggest that leptin enhances the intracellular GLUT4 transport in skeletal muscle of ob/ob animals by reducing the expression and activity of the negative regulators of GLUT4 traffic TBC1D1 and TBC1D4. PMID:22253718

  18. Intracellular Trafficking Network of Protein Nanocapsules: Endocytosis, Exocytosis and Autophagy

    PubMed Central

    Zhang, Jinxie; Zhang, Xudong; Liu, Gan; Chang, Danfeng; Liang, Xin; Zhu, Xianbing; Tao, Wei; Mei, Lin

    2016-01-01

    The inner membrane vesicle system is a complex transport system that includes endocytosis, exocytosis and autophagy. However, the details of the intracellular trafficking pathway of nanoparticles in cells have been poorly investigated. Here, we investigate in detail the intracellular trafficking pathway of protein nanocapsules using more than 30 Rab proteins as markers of multiple trafficking vesicles in endocytosis, exocytosis and autophagy. We observed that FITC-labeled protein nanoparticles were internalized by the cells mainly through Arf6-dependent endocytosis and Rab34-mediated micropinocytosis. In addition to this classic pathway: early endosome (EEs)/late endosome (LEs) to lysosome, we identified two novel transport pathways: micropinocytosis (Rab34 positive)-LEs (Rab7 positive)-lysosome pathway and EEs-liposome (Rab18 positive)-lysosome pathway. Moreover, the cells use slow endocytosis recycling pathway (Rab11 and Rab35 positive vesicles) and GLUT4 exocytosis vesicles (Rab8 and Rab10 positive) transport the protein nanocapsules out of the cells. In addition, protein nanoparticles are observed in autophagosomes, which receive protein nanocapsules through multiple endocytosis vesicles. Using autophagy inhibitor to block these transport pathways could prevent the degradation of nanoparticles through lysosomes. Using Rab proteins as vesicle markers to investigation the detail intracellular trafficking of the protein nanocapsules, will provide new targets to interfere the cellular behaver of the nanoparticles, and improve the therapeutic effect of nanomedicine.

  19. Intracellular Trafficking Network of Protein Nanocapsules: Endocytosis, Exocytosis and Autophagy

    PubMed Central

    Zhang, Jinxie; Zhang, Xudong; Liu, Gan; Chang, Danfeng; Liang, Xin; Zhu, Xianbing; Tao, Wei; Mei, Lin

    2016-01-01

    The inner membrane vesicle system is a complex transport system that includes endocytosis, exocytosis and autophagy. However, the details of the intracellular trafficking pathway of nanoparticles in cells have been poorly investigated. Here, we investigate in detail the intracellular trafficking pathway of protein nanocapsules using more than 30 Rab proteins as markers of multiple trafficking vesicles in endocytosis, exocytosis and autophagy. We observed that FITC-labeled protein nanoparticles were internalized by the cells mainly through Arf6-dependent endocytosis and Rab34-mediated micropinocytosis. In addition to this classic pathway: early endosome (EEs)/late endosome (LEs) to lysosome, we identified two novel transport pathways: micropinocytosis (Rab34 positive)-LEs (Rab7 positive)-lysosome pathway and EEs-liposome (Rab18 positive)-lysosome pathway. Moreover, the cells use slow endocytosis recycling pathway (Rab11 and Rab35 positive vesicles) and GLUT4 exocytosis vesicles (Rab8 and Rab10 positive) transport the protein nanocapsules out of the cells. In addition, protein nanoparticles are observed in autophagosomes, which receive protein nanocapsules through multiple endocytosis vesicles. Using autophagy inhibitor to block these transport pathways could prevent the degradation of nanoparticles through lysosomes. Using Rab proteins as vesicle markers to investigation the detail intracellular trafficking of the protein nanocapsules, will provide new targets to interfere the cellular behaver of the nanoparticles, and improve the therapeutic effect of nanomedicine. PMID:27698943

  20. Rat white adipocytes activate p85/p110 PI3K and induce PM GLUT4 in response to adrenoceptor agonists or aluminum fluoride.

    PubMed

    Ohsaka, Y; Nomura, Y

    2016-03-01

    Adipocyte responses to adrenergic and ß-adrenoceptor(-AR) (adrenoceptor) regulation are not sufficiently understood, and information helpful for elucidating the adrenoceptor-responsive machinery is insufficient. Here we show by using immunoprecipitated kinase analysis with a phosphatidylinositol 3-kinase (PI3K) p85 antibody that PI3K activation was induced by treatment with 10 or 100 µM norepinephrine (NE) for 15 min or with 10 mM aluminum fluoride (AF, a guanosine triphosphate (GTP)-binding (G) protein activator) for 20 min in white adipocytes (rat epididymal adipocytes) and that treatment with pertussis toxin (PTX, a G-protein inactivator) inhibited PI3K activation induced by the 20-min treatment with AF in the cells. In addition, western blot analysis revealed that glucose transporter 4 (GLUT4) level in the adipocyte plasma membrane (PM) fraction was increased by treatment with 10 µM NE, 100 µM dobutamine (DOB, a ß1-AR agonist), or 0.1 µM CL316243 (CL, a ß3-AR agonist) for 30 min or with 10 mM AF for 20 min. NE or AF treatment triggered 2-deoxyglucose (2-DG) uptake into adipocytes under the above conditions. Our results advance the understanding of responses to adrenoceptor regulation in white adipocytes and provide possible clues for clarifying the machinery involved in adrenergic and ß-AR responses in the cells. PMID:27030626

  1. Subacute static magnetic field exposure in rat induces a pseudoanemia status with increase in MCT4 and Glut4 proteins in glycolytic muscle.

    PubMed

    Elferchichi, Miryam; Mercier, Jacques; Ammari, Mohamed; Belguith, Hatem; Abdelmelek, Hafedh; Sakly, Mohsen; Lambert, Karen

    2016-01-01

    The purpose of this study was to investigate the effect of subacute exposure to static magnetic fields (SMF) on hematological and muscle biochemical parameters in rats. Male Wistar rats, daily exposed to SMF, were exposed to SMF (128 mT, 1 h/day) during 15 consecutive days. SMF-exposed rats showed a significant decrease in red blood cell (RBC) count, hemoglobin (Hb), and hematocrit (Ht) values compared to sham-exposed rats (p < 0.05). Concomitant decreases of plasma iron level against increase in transferrin amount were also observed after SMF exposure (p < 0.0.05). In postprandial condition, SMF-exposed rats presented higher plasma lactate (p < 0.01). Additionally, SMF exposure increased monocarboxylate transporters (MCT4) and glucose transporter 4 (Glut4)'s contents only in glycolytic muscle (p < 0.05). SMF exposure induced alteration of hematological parameters; importantly, we noticed a pseudoanemia status, which seems to affect tissue oxygen delivery. Additionally, SMF exposure seems to favor the extrusion of lactate from the cell to the blood compartment. Given that, these arguments advocate for an adaptive response to a hypoxia status following SMF exposure.

  2. GLUT4 Expression in Adipocytes Regulates De Novo Lipogenesis and Levels of a Novel Class of Lipids With Antidiabetic and Anti-inflammatory Effects.

    PubMed

    Moraes-Vieira, Pedro M; Saghatelian, Alan; Kahn, Barbara B

    2016-07-01

    Adipose tissue (AT) regulates systemic insulin sensitivity through multiple mechanisms, and alterations in de novo lipogenesis appear to contribute. Mice overexpressing GLUT4 in adipocytes (AG4OX) have elevated AT lipogenesis and enhanced glucose tolerance despite being obese and having elevated circulating fatty acids. Lipidomic analysis of AT identified a structurally unique class of lipids, branched fatty acid esters of hydroxy-fatty acids (FAHFAs), which were elevated in AT and serum of AG4OX mice. Palmitic acid esters of hydroxy-stearic acids (PAHSAs) are among the most upregulated FAHFA families in AG4OX mice. Eight PAHSA isomers are present in mouse and human tissues. PAHSA levels are reduced in insulin resistant people, and levels correlate highly with insulin sensitivity. PAHSAs have beneficial metabolic effects. Treatment of obese mice with PAHSAs lowers glycemia and improves glucose tolerance while stimulating glucagon-like peptide 1 and insulin secretion. PAHSAs also reduce inflammatory cytokine production from immune cells and ameliorate adipose inflammation in obesity. PAHSA isomer concentrations are altered in physiological and pathophysiological conditions in a tissue- and isomer-specific manner. The mechanisms most likely involve changes in PAHSA biosynthesis, degradation, and secretion. The discovery of PAHSAs reveals the existence of previously unknown endogenous lipids and biochemical pathways involved in metabolism and inflammation, two fundamental physiological processes. PMID:27288004

  3. Leucine stimulates PPARβ/δ-dependent mitochondrial biogenesis and oxidative metabolism with enhanced GLUT4 content and glucose uptake in myotubes.

    PubMed

    Schnuck, Jamie K; Sunderland, Kyle L; Gannon, Nicholas P; Kuennen, Matthew R; Vaughan, Roger A

    2016-01-01

    Leucine stimulates anabolic and catabolic processes in skeletal muscle, however little is known about the effects of leucine on peroxisome proliferator-activated receptor (PPAR) activity. This work characterized the effects of 24-h leucine treatment on metabolic parameters and protein expression in cultured myotubes. Leucine significantly increased PPARβ/δ expression as well as markers of mitochondrial biogenesis, leading to significantly increased mitochondrial content and oxidative metabolism in a PPARβ/δ-dependent manner. However, leucine-treated cells did not display significant alterations in uncoupling protein expression or oxygen consumed per relative mitochondrial content suggesting leucine-mediated increases in oxidative metabolism are a function of increased mitochondrial content and not altered mitochondrial efficiency. Leucine treatment also increased GLUT4 content and glucose uptake as well as PPARγ and FAS expression leading to increased total lipid content. Leucine appears to activate PPAR activity leading to increased mitochondrial biogenesis and elevated substrate oxidation, while simultaneously promoting substrate/lipid storage and protein synthesis. PMID:27345255

  4. VAMP3 null mice display normal constitutive, insulin- and exercise-regulated vesicle trafficking.

    PubMed

    Yang, C; Mora, S; Ryder, J W; Coker, K J; Hansen, P; Allen, L A; Pessin, J E

    2001-03-01

    To investigate the physiological function of the VAMP3 vesicle SNARE (v-SNARE) isoform in the regulation of GLUT4 vesicle trafficking, we generated homozygotic VAMP3 null mice by targeted gene disruption. The VAMP3 null mice had typical growth rate and weight gain, with normal maintenance of fasting serum glucose and insulin levels. Analysis of glucose disposal and insulin sensitivity demonstrated normal insulin and glucose tolerance, with no evidence for insulin resistance. Insulin stimulation of glucose uptake in isolated primary adipocytes was essentially the same for the wild-type and VAMP3 null mice. Similarly, insulin-, hypoxia-, and exercise-stimulated glucose uptake in isolated skeletal muscle did not differ significantly. In addition, other general membrane trafficking events including phagocytosis, pinocytosis, and transferrin receptor recycling were also found to be unaffected in the VAMP3 null mice. Taken together, these data demonstrate that VAMP3 function is not necessary for either regulated GLUT4 translocation or general constitutive membrane recycling. PMID:11238894

  5. Modulation of GLUT4 expression by oral administration of Mg(2+) to control sugar levels in STZ-induced diabetic rats.

    PubMed

    Solaimani, Haniah; Soltani, Nepton; MaleKzadeh, Kianoosh; Sohrabipour, Shahla; Zhang, Nina; Nasri, Sema; Wang, Qinghua

    2014-06-01

    It has been previously shown that oral magnesium administration decreases the levels of glucose in the plasma. However, the mechanisms are not fully understood. The aim of this study was to determine the potential role of GLUT4 on plasma glucose levels by orally administering magnesium sulfate to diabetic rats. Animals were distributed among 4 groups (n = 10 rats per group): one group served as the non-diabetic control, while the other groups had diabetes induced by streptozotocin (intraperitoneal (i.p.) injection). The diabetic rats were either given insulin by i.p. injection (2.5 U·(kg body mass)(-1)·day(-1)), or magnesium sulfate in their drinking water (10 g·L(-1)). After 8 weeks of treatment, we conducted an i.p. glucose tolerance test (IPGTT), measured blood glucose and plasma magnesium levels, and performed in-vitro and in-vivo insulin level measurements by radioimmunoassay. Gastrocnemius (leg) muscles were isolated for the measurement of GLU4 mRNA expression using real-time PCR. Administration of magnesium sulfate improved IPGTT and lowered blood glucose levels almost to the normal range. However, the insulin levels were not changed in either of the in-vitro or in-vivo studies. The expression of GLU4 mRNA increased 23% and 10% in diabetic magnesium-treated and insulin-treated groups, respectively. Our findings suggest that magnesium lowers blood glucose levels via increased GLU4 mRNA expression, independent to insulin secretion.

  6. Modulation of GLUT4 expression by oral administration of Mg(2+) to control sugar levels in STZ-induced diabetic rats.

    PubMed

    Solaimani, Haniah; Soltani, Nepton; MaleKzadeh, Kianoosh; Sohrabipour, Shahla; Zhang, Nina; Nasri, Sema; Wang, Qinghua

    2014-06-01

    It has been previously shown that oral magnesium administration decreases the levels of glucose in the plasma. However, the mechanisms are not fully understood. The aim of this study was to determine the potential role of GLUT4 on plasma glucose levels by orally administering magnesium sulfate to diabetic rats. Animals were distributed among 4 groups (n = 10 rats per group): one group served as the non-diabetic control, while the other groups had diabetes induced by streptozotocin (intraperitoneal (i.p.) injection). The diabetic rats were either given insulin by i.p. injection (2.5 U·(kg body mass)(-1)·day(-1)), or magnesium sulfate in their drinking water (10 g·L(-1)). After 8 weeks of treatment, we conducted an i.p. glucose tolerance test (IPGTT), measured blood glucose and plasma magnesium levels, and performed in-vitro and in-vivo insulin level measurements by radioimmunoassay. Gastrocnemius (leg) muscles were isolated for the measurement of GLU4 mRNA expression using real-time PCR. Administration of magnesium sulfate improved IPGTT and lowered blood glucose levels almost to the normal range. However, the insulin levels were not changed in either of the in-vitro or in-vivo studies. The expression of GLU4 mRNA increased 23% and 10% in diabetic magnesium-treated and insulin-treated groups, respectively. Our findings suggest that magnesium lowers blood glucose levels via increased GLU4 mRNA expression, independent to insulin secretion. PMID:24821133

  7. Suppression of Very Early Stage Of Adipogenesis by Baicalein, a Plant-Derived Flavonoid through Reduced Akt-C/EBPα-GLUT4 Signaling-Mediated Glucose Uptake in 3T3-L1 Adipocytes

    PubMed Central

    2016-01-01

    Baicalein has been used as a Chinese medicine, and is an abundant plant flavonoid present in fruits and vegetables. Here, we examined the effects of baicalein in adipogenesis and investigated its molecular mechanism in adipocytes. Baicalein lowered the intracellular lipid accumulation and decreased the transcription levels of the adipocyte-specific genes in mouse 3T3-L1 adipocytes. Glucose uptake mediated by glucose transporter 4 (GLUT4) was reduced, causing down-regulation of the intracellular lipid accumulation. These reductions were also observed even when baicalein was added in only early stage of adipogenesis (0–2 days) of 6-day-adipogenesis. Chromatin immunoprecipitation assay showed that baicalein decreased the binding level of C/EBPα protein to the promoter region of the GLUT4 gene. Phosphorylation of Akt at 1 h after the initiation of adipogenesis was inhibited by the treatment with baicalein. Inhibition during only the first 1.5 h after the initiation of adipogenesis by baicalein or an Akt inhibitor was enough to decrease the lipid contents in the cells undergoing adipocyte differentiation for 6 days. These results indicate that baicalein decreased the intracellular lipid accumulation by down-regulation of glucose uptake via repression of Akt-C/EBPα-GLUT4 signaling in the very early stage of adipogenesis of 3T3-L1 adipocytes. PMID:27669565

  8. Economics of human trafficking.

    PubMed

    Wheaton, Elizabeth M; Schauer, Edward J; Galli, Thomas V

    2010-01-01

    Because freedom of choice and economic gain are at the heart of productivity, human trafficking impedes national and international economic growth. Within the next 10 years, crime experts expect human trafficking to surpass drug and arms trafficking in its incidence, cost to human well-being, and profitability to criminals (Schauer and Wheaton, 2006: 164-165). The loss of agency from human trafficking as well as from modern slavery is the result of human vulnerability (Bales, 2000: 15). As people become vulnerable to exploitation and businesses continually seek the lowest-cost labour sources, trafficking human beings generates profit and a market for human trafficking is created. This paper presents an economic model of human trafficking that encompasses all known economic factors that affect human trafficking both across and within national borders. We envision human trafficking as a monopolistically competitive industry in which traffickers act as intermediaries between vulnerable individuals and employers by supplying differentiated products to employers. In the human trafficking market, the consumers are employers of trafficked labour and the products are human beings. Using a rational-choice framework of human trafficking we explain the social situations that shape relocation and working decisions of vulnerable populations leading to human trafficking, the impetus for being a trafficker, and the decisions by employers of trafficked individuals. The goal of this paper is to provide a common ground upon which policymakers and researchers can collaborate to decrease the incidence of trafficking in humans.

  9. Economics of human trafficking.

    PubMed

    Wheaton, Elizabeth M; Schauer, Edward J; Galli, Thomas V

    2010-01-01

    Because freedom of choice and economic gain are at the heart of productivity, human trafficking impedes national and international economic growth. Within the next 10 years, crime experts expect human trafficking to surpass drug and arms trafficking in its incidence, cost to human well-being, and profitability to criminals (Schauer and Wheaton, 2006: 164-165). The loss of agency from human trafficking as well as from modern slavery is the result of human vulnerability (Bales, 2000: 15). As people become vulnerable to exploitation and businesses continually seek the lowest-cost labour sources, trafficking human beings generates profit and a market for human trafficking is created. This paper presents an economic model of human trafficking that encompasses all known economic factors that affect human trafficking both across and within national borders. We envision human trafficking as a monopolistically competitive industry in which traffickers act as intermediaries between vulnerable individuals and employers by supplying differentiated products to employers. In the human trafficking market, the consumers are employers of trafficked labour and the products are human beings. Using a rational-choice framework of human trafficking we explain the social situations that shape relocation and working decisions of vulnerable populations leading to human trafficking, the impetus for being a trafficker, and the decisions by employers of trafficked individuals. The goal of this paper is to provide a common ground upon which policymakers and researchers can collaborate to decrease the incidence of trafficking in humans. PMID:20645472

  10. Fisetin Suppresses Lipid Accumulation in Mouse Adipocytic 3T3-L1 Cells by Repressing GLUT4-Mediated Glucose Uptake through Inhibition of mTOR-C/EBPα Signaling.

    PubMed

    Watanabe, Marina; Hisatake, Mitsuhiro; Fujimori, Ko

    2015-05-27

    3,7,3',4'-Tetrahydroxyflavone (fisetin) is a flavonoid found in vegetables and fruits having broad biological activities. Here the effects of fisetin on adipogenesis and its regulatory mechanism in mouse adipocytic 3T3-L1 cells are studied. Fisetin inhibited the accumulation of intracellular lipids and lowered the expression of adipogenic genes such as peroxisome proliferator-activated receptor γ and CCAAT/enhancer-binding protein (C/EBP) α and fatty acid-binding protein 4 (aP2) during adipogenesis. Moreover, the mRNA levels of genes such as acetyl-CoA carboxylase, fatty acid synthase, and stearoyl-CoA desaturase involved in the fatty acid biosynthesis (lipogenesis) were reduced by the treatment with fisetin. The expression level of the glucose transporter 4 (GLUT4) gene was also decreased by fisetin, resulting in down-regulation of glucose uptake. Furthermore, fisetin inhibited the phosphorylation of the mammalian target of rapamycin (mTOR) and that of p70 ribosomal S6 kinase, a target of the mTOR complex, the inhibition of which was followed by a decreased mRNA level of the C/EBPα gene. The results obtained from a chromatin immunoprecipitation assay demonstrated that the ability of C/EBPα to bind to the GLUT4 gene promoter was reduced by the treatment with fisetin, which agreed well with those obtained when 3T3-L1 cells were allowed to differentiate into adipocytes in medium in the presence of rapamycin, an inhibitor for mTOR. These results indicate that fisetin suppressed the accumulation of intracellular lipids by inhibiting GLUT4-mediated glucose uptake through inhibition of the mTOR-C/EBPα signaling in 3T3-L1 cells.

  11. Effects of isoleucine on glucose uptake through the enhancement of muscular membrane concentrations of GLUT1 and GLUT4 and intestinal membrane concentrations of Na+/glucose co-transporter 1 (SGLT-1) and GLUT2.

    PubMed

    Zhang, Shihai; Yang, Qing; Ren, Man; Qiao, Shiyan; He, Pingli; Li, Defa; Zeng, Xiangfang

    2016-08-01

    Knowledge of regulation of glucose transport contributes to our understanding of whole-body glucose homoeostasis and human metabolic diseases. Isoleucine has been reported to participate in regulation of glucose levels in many studies; therefore, this study was designed to examine the effect of isoleucine on intestinal and muscular GLUT expressions. In an animal experiment, muscular GLUT and intestinal GLUT were determined in weaning pigs fed control or isoleucine-supplemented diets. Supplementation of isoleucine in the diet significantly increased piglet average daily gain, enhanced GLUT1 expression in red muscle and GLUT4 expression in red muscle, white muscle and intermediate muscle (P<0·05). In additional, expressions of Na+/glucose co-transporter 1 and GLUT2 were up-regulated in the small intestine when pigs were fed isoleucine-supplemented diets (P<0·05). C2C12 cells were used to examine the expressions of muscular GLUT and glucose uptake in vitro. In C2C12 cells supplemented with isoleucine in the medium, cellular 2-deoxyglucose uptake was increased (P<0·05) through enhancement of the expressions of GLUT4 and GLUT1 (P<0·05). The effect of isoleucine was greater than that of leucine on glucose uptake (P<0·05). Compared with newborn piglets, 35-d-old piglets have comparatively higher GLUT4, GLUT2 and GLUT5 expressions. The results of this study demonstrated that isoleucine supplementation enhanced the intestinal and muscular GLUT expressions, which have important implications that suggest that isoleucine could potentially increase muscle growth and intestinal development by enhancing local glucose uptake in animals and human beings. PMID:27464458

  12. The Transcriptional Effects of PCB118 and PCB153 on the Liver, Adipose Tissue, Muscle and Colon of Mice: Highlighting of Glut4 and Lipin1 as Main Target Genes for PCB Induced Metabolic Disorders.

    PubMed

    Mesnier, Aurélia; Champion, Serge; Louis, Laurence; Sauzet, Christophe; May, Phealay; Portugal, Henri; Benbrahim, Karim; Abraldes, Joelle; Alessi, Marie-Christine; Amiot-Carlin, Marie-Josephe; Peiretti, Franck; Piccerelle, Philippe; Nalbone, Gilles; Villard, Pierre-Henri

    2015-01-01

    Epidemiological studies have associated environmental exposure to polychlorinated biphenyls (PCBs) with an increased risk of type 2 diabetes; however, little is known about the underlying mechanisms involved in the metabolic side-effects of PCB. Our study evaluated the transcriptional effects of a subchronic exposure (gavage at Day 0 and Day 15 with 10 or 100 μmol/Kg bw) to PCB118 (dioxin-like PCB), PCB153 (non-dioxin-like PCB), or an equimolar mixture of PCB118 and PCB153 on various tissues (liver, visceral adipose tissue, muscle, and colon) in mice. Our results showed that a short-term exposure to PCB118 and/or PCB153 enhanced circulating triglyceride levels but did not affect glycemia. Among the studied tissues, we did not observe any modification of the expression of inflammation-related genes, such as cytokines or chemokines. The main transcriptional effects were observed in visceral adipose and liver tissues. We found a downregulation of lipin1 and glut4 expression in these two target organs. In adipose tissue, we also showed a downregulation of Agpat2, Slc25a1, and Fasn. All of these genes are involved in lipid metabolism and insulin resistance. In muscles, we observed an induction of CnR1 and Foxo3 expression, which may be partly involved in PCB metabolic effects. In summary, our results suggest that lipin1 and glut4, notably in adipose tissue, are the main targeted genes in PCB-induced metabolic disorders, however, further studies are required to fully elucidate the mechanisms involved.

  13. The Transcriptional Effects of PCB118 and PCB153 on the Liver, Adipose Tissue, Muscle and Colon of Mice: Highlighting of Glut4 and Lipin1 as Main Target Genes for PCB Induced Metabolic Disorders

    PubMed Central

    Mesnier, Aurélia; Champion, Serge; Louis, Laurence; Sauzet, Christophe; May, Phealay; Portugal, Henri; Benbrahim, Karim; Abraldes, Joelle; Alessi, Marie-Christine; Amiot-Carlin, Marie-Josephe; Peiretti, Franck; Piccerelle, Philippe; Nalbone, Gilles; Villard, Pierre-Henri

    2015-01-01

    Epidemiological studies have associated environmental exposure to polychlorinated biphenyls (PCBs) with an increased risk of type 2 diabetes; however, little is known about the underlying mechanisms involved in the metabolic side-effects of PCB. Our study evaluated the transcriptional effects of a subchronic exposure (gavage at Day 0 and Day 15 with 10 or 100 μmol/Kg bw) to PCB118 (dioxin-like PCB), PCB153 (non-dioxin-like PCB), or an equimolar mixture of PCB118 and PCB153 on various tissues (liver, visceral adipose tissue, muscle, and colon) in mice. Our results showed that a short-term exposure to PCB118 and/or PCB153 enhanced circulating triglyceride levels but did not affect glycemia. Among the studied tissues, we did not observe any modification of the expression of inflammation-related genes, such as cytokines or chemokines. The main transcriptional effects were observed in visceral adipose and liver tissues. We found a downregulation of lipin1 and glut4 expression in these two target organs. In adipose tissue, we also showed a downregulation of Agpat2, Slc25a1, and Fasn. All of these genes are involved in lipid metabolism and insulin resistance. In muscles, we observed an induction of CnR1 and Foxo3 expression, which may be partly involved in PCB metabolic effects. In summary, our results suggest that lipin1 and glut4, notably in adipose tissue, are the main targeted genes in PCB-induced metabolic disorders, however, further studies are required to fully elucidate the mechanisms involved. PMID:26086818

  14. Distal splenorenal shunt

    MedlinePlus

    ... shunt procedure; Renal - splenic venous shunt; Warren shunt; Cirrhosis - distal splenorenal; Liver failure - distal splenorenal ... hepatitis Blood clots Certain congenital disorders Primary biliary cirrhosis When blood cannot flow normally through the portal ...

  15. Distal Convoluted Tubule

    PubMed Central

    Ellison, David H.

    2014-01-01

    The distal convoluted tubule is the nephron segment that lies immediately downstream of the macula densa. Although short in length, the distal convoluted tubule plays a critical role in sodium, potassium, and divalent cation homeostasis. Recent genetic and physiologic studies have greatly expanded our understanding of how the distal convoluted tubule regulates these processes at the molecular level. This article provides an update on the distal convoluted tubule, highlighting concepts and pathophysiology relevant to clinical practice. PMID:24855283

  16. An adipocentric view of signaling and intracellular trafficking.

    PubMed

    Mora, Silvia; Pessin, Jeffrey E

    2002-01-01

    molecules (leptin and adiponectin) and on one of the most intensively studied regulated membrane proteins, the GLUT4 glucose transporter.

  17. Distal Myopathies: Case Studies.

    PubMed

    Shaibani, Aziz

    2016-08-01

    About 15% of myopathies present with distal weakness. Lack of sensory deficit, and preservation of sensory responses and deep tendon reflexes, favors a myopathic cause for distal weakness. Electromyogram confirms this diagnosis. Profuse spontaneous discharges are common in inflammatory, metabolic, and myofibrillar myopathy (MFM). If the clinical picture indicates a specific disease such as facioscapulohumeral muscular dystrophy (FSHD), genetic testing provides the quickest diagnosis. Otherwise, muscle biopsy can distinguish specific features. The common causes of myopathic distal weakness are FSHD, myotonic dystrophy, and inclusion body myositis. Other causes include MFM, distal muscular dystrophies, metabolic myopathies, and congenital myopathies. PMID:27445241

  18. Crystal Structures of Human TBC1D1 and TBC1D4 (AS160) RabGTPase-activating Protein (RabGAP) Domains Reveal Critical Elements for GLUT4 Translocation

    SciTech Connect

    S Park; W Jin; S Shoelson

    2011-12-31

    We have solved the x-ray crystal structures of the RabGAP domains of human TBC1D1 and human TBC1D4 (AS160), at 2.2 and 3.5 {angstrom} resolution, respectively. Like the yeast Gyp1p RabGAP domain, whose structure was solved previously in complex with mouse Rab33B, the human TBC1D1 and TBC1D4 domains both have 16 {alpha}-helices and no {beta}-sheet elements. We expected the yeast Gyp1p RabGAP/mouse Rab33B structure to predict the corresponding interfaces between cognate mammalian RabGAPs and Rabs, but found that residues were poorly conserved. We further tested the relevance of this model by Ala-scanning mutagenesis, but only one of five substitutions within the inferred binding site of the TBC1D1 RabGAP significantly perturbed catalytic efficiency. In addition, substitution of TBC1D1 residues with corresponding residues from Gyp1p did not enhance catalytic efficiency. We hypothesized that biologically relevant RabGAP/Rab partners utilize additional contacts not described in the yeast Gyp1p/mouse Rab33B structure, which we predicted using our two new human TBC1D1 and TBC1D4 structures. Ala substitution of TBC1D1 Met{sup 930}, corresponding to a residue outside of the Gyp1p/Rab33B contact, substantially reduced catalytic activity. GLUT4 translocation assays confirmed the biological relevance of our findings. Substitutions with lowest RabGAP activity, including catalytically dead RK and Met{sup 930} and Leu{sup 1019} predicted to perturb Rab binding, confirmed that biological activity requires contacts between cognate RabGAPs and Rabs beyond those in the yeast Gyp1p RabGAP/mouse Rab33B structure.

  19. Distal biceps brachii.

    PubMed

    Brigido, Monica Kalume; De Maeseneer, Michel; Morag, Yoav

    2013-02-01

    There has been a renewed interest in the recent literature with regard to the normal anatomy of the distal biceps tendon. Cadaveric studies have demonstrated that a large percentage of individuals have two independent muscle bellies, the short and the long head, with two distinct separate tendons attaching at the radial tuberosity. To avoid diagnostic errors that may have an impact on patient management in case of tendon injury, it is important to keep this anatomical variant in mind. Ultrasonography has been shown to be a useful imaging modality in the evaluation of disorders of the distal biceps brachii muscle and tendon. In this article, we review the relevant anatomy of the distal biceps brachii, the ultrasound technique with alternative approaches for optimum visualization of the distal tendon, and the most common pathologies in this region.

  20. Transphyseal Distal Humerus Fracture.

    PubMed

    Abzug, Joshua; Ho, Christine Ann; Ritzman, Todd F; Brighton, Brian

    2016-01-01

    Transphyseal distal humerus fractures typically occur in children younger than 3 years secondary to birth trauma, nonaccidental trauma, or a fall from a small height. Prompt and accurate diagnosis of a transphyseal distal humerus fracture is crucial for a successful outcome. Recognizing that the forearm is not aligned with the humerus on plain radiographs may aid in the diagnosis of a transphyseal distal humerus fracture. Surgical management is most commonly performed with the aid of an arthrogram. Closed reduction and percutaneous pinning techniques similar to those used for supracondylar humerus fractures are employed. Cubitus varus caused by a malunion, osteonecrosis of the medial condyle, or growth arrest is the most common complication encountered in the treatment of transphyseal distal humerus fractures. A corrective lateral closing wedge osteotomy can be performed to restore a nearly normal carrying angle.

  1. Distal humeral epiphyseal separation.

    PubMed

    Moucha, Calin S; Mason, Dan E

    2003-10-01

    Distal humeral epiphyseal separation is an uncommon injury that is often misdiagnosed upon initial presentation. To make a timely, correct diagnosis, the treating physician must have a thorough understanding of basic anatomical relationships and an awareness of the existence of this injury. This is a case of a child who sustained a separation of the distal humeral epiphysis, as well as multiple other bony injuries, secondary to child abuse.

  2. Lysosomal Trafficking Regulator (LYST).

    PubMed

    Ji, Xiaojie; Chang, Bo; Naggert, Jürgen K; Nishina, Patsy M

    2016-01-01

    Regulation of vesicle trafficking to lysosomes and lysosome-related organelles (LROs) as well as regulation of the size of these organelles are critical to maintain their functions. Disruption of the lysosomal trafficking regulator (LYST) results in Chediak-Higashi syndrome (CHS), a rare autosomal recessive disorder characterized by oculocutaneous albinism, prolonged bleeding, severe immunodeficiency, recurrent bacterial infection, neurologic dysfunction and hemophagocytic lympohistiocytosis (HLH). The classic diagnostic feature of the syndrome is enlarged LROs in all cell types, including lysosomes, melanosomes, cytolytic granules and platelet dense bodies. The most striking CHS ocular pathology observed is an enlargement of melanosomes in the retinal pigment epithelium (RPE), which leads to aberrant distribution of eye pigmentation, and results in photophobia and decreased visual acuity. Understanding the molecular function of LYST and identification of its interacting partners may provide therapeutic targets for CHS and other diseases associated with the regulation of LRO size and/or vesicle trafficking, such as asthma, urticaria and Leishmania amazonensis infections. PMID:26427484

  3. Health implications of human trafficking.

    PubMed

    Richards, Tiffany A

    2014-01-01

    Freedom is arguably the most cherished right in the United States. But each year, approximately 14,500 to 17,500 women, men and children are trafficked into the United States for the purposes of forced labor or sexual exploitation. Human trafficking has significant effects on both physical and mental health. This article describes the features of human trafficking, its physical and mental health effects and the vital role nurses can play in providing care to this vulnerable population. PMID:24750655

  4. Health implications of human trafficking.

    PubMed

    Richards, Tiffany A

    2014-01-01

    Freedom is arguably the most cherished right in the United States. But each year, approximately 14,500 to 17,500 women, men and children are trafficked into the United States for the purposes of forced labor or sexual exploitation. Human trafficking has significant effects on both physical and mental health. This article describes the features of human trafficking, its physical and mental health effects and the vital role nurses can play in providing care to this vulnerable population.

  5. Septin 7 forms a complex with CD2AP and nephrin and regulates glucose transporter trafficking.

    PubMed

    Wasik, Anita A; Polianskyte-Prause, Zydrune; Dong, Meng-Qiu; Shaw, Andrey S; Yates, John R; Farquhar, Marilyn G; Lehtonen, Sanna

    2012-09-01

    Podocytes are insulin-sensitive and take up glucose in response to insulin. This requires nephrin, which interacts with vesicle-associated membrane protein 2 (VAMP2) on GLUT4 storage vesicles (GSVs) and facilitates their fusion with the plasma membrane. In this paper, we show that the filament-forming GTPase septin 7 is expressed in podocytes and associates with CD2-associated protein (CD2AP) and nephrin, both essential for glomerular ultrafiltration. In addition, septin 7 coimmunoprecipitates with VAMP2. Subcellular fractionation of cultured podocytes revealed that septin 7 is found in both cytoplasmic and membrane fractions, and immunofluorescence microscopy showed that septin 7 is expressed in a filamentous pattern and is also found on vesicles and the plasma membrane. The filamentous localization of septin 7 depends on CD2AP and intact actin organization. A 2-deoxy-d-glucose uptake assay indicates that depletion of septin 7 by small interfering RNA or alteration of septin assembly by forchlorfenuron facilitates glucose uptake into cells and further, knockdown of septin 7 increased the interaction of VAMP2 with nephrin and syntaxin 4. The data indicate that septin 7 hinders GSV trafficking and further, the interaction of septin 7 with nephrin in glomeruli suggests that septin 7 may participate in the regulation of glucose transport in podocytes.

  6. 31 CFR 536.311 - Narcotics trafficking.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Narcotics trafficking. 536.311 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.311 Narcotics trafficking. The term narcotics trafficking means any activity...

  7. 31 CFR 536.311 - Narcotics trafficking.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Narcotics trafficking. 536.311 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.311 Narcotics trafficking. The term narcotics trafficking means any activity...

  8. 31 CFR 536.311 - Narcotics trafficking.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false Narcotics trafficking. 536.311 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.311 Narcotics trafficking. The term narcotics trafficking means any activity...

  9. 31 CFR 536.311 - Narcotics trafficking.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Narcotics trafficking. 536.311 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.311 Narcotics trafficking. The term narcotics trafficking means any activity...

  10. 31 CFR 536.311 - Narcotics trafficking.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Narcotics trafficking. 536.311... OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING SANCTIONS REGULATIONS General Definitions § 536.311 Narcotics trafficking. The term narcotics trafficking means any...

  11. Illicit Trafficking of Natural Radionuclides

    SciTech Connect

    Friedrich, Steinhaeusler; Lyudmila, Zaitseva

    2008-08-07

    Natural radionuclides have been subject to trafficking worldwide, involving natural uranium ore (U 238), processed uranium (yellow cake), low enriched uranium (<20% U 235) or highly enriched uranium (>20% U 235), radium (Ra 226), polonium (Po 210), and natural thorium ore (Th 232). An important prerequisite to successful illicit trafficking activities is access to a suitable logistical infrastructure enabling an undercover shipment of radioactive materials and, in case of trafficking natural uranium or thorium ore, capable of transporting large volumes of material. Covert en route diversion of an authorised uranium transport, together with covert diversion of uranium concentrate from an operating or closed uranium mines or mills, are subject of case studies. Such cases, involving Israel, Iran, Pakistan and Libya, have been analyzed in terms of international actors involved and methods deployed. Using international incident data contained in the Database on Nuclear Smuggling, Theft and Orphan Radiation Sources (DSTO) and international experience gained from the fight against drug trafficking, a generic Trafficking Pathway Model (TPM) is developed for trafficking of natural radionuclides. The TPM covers the complete trafficking cycle, ranging from material diversion, covert material transport, material concealment, and all associated operational procedures. The model subdivides the trafficking cycle into five phases: (1) Material diversion by insider(s) or initiation by outsider(s); (2) Covert transport; (3) Material brokerage; (4) Material sale; (5) Material delivery. An Action Plan is recommended, addressing the strengthening of the national infrastructure for material protection and accounting, development of higher standards of good governance, and needs for improving the control system deployed by customs, border guards and security forces.

  12. Illicit Trafficking of Natural Radionuclides

    NASA Astrophysics Data System (ADS)

    Friedrich, Steinhäusler; Lyudmila, Zaitseva

    2008-08-01

    Natural radionuclides have been subject to trafficking worldwide, involving natural uranium ore (U 238), processed uranium (yellow cake), low enriched uranium (<20% U 235) or highly enriched uranium (>20% U 235), radium (Ra 226), polonium (Po 210), and natural thorium ore (Th 232). An important prerequisite to successful illicit trafficking activities is access to a suitable logistical infrastructure enabling an undercover shipment of radioactive materials and, in case of trafficking natural uranium or thorium ore, capable of transporting large volumes of material. Covert en route diversion of an authorised uranium transport, together with covert diversion of uranium concentrate from an operating or closed uranium mines or mills, are subject of case studies. Such cases, involving Israel, Iran, Pakistan and Libya, have been analyzed in terms of international actors involved and methods deployed. Using international incident data contained in the Database on Nuclear Smuggling, Theft and Orphan Radiation Sources (DSTO) and international experience gained from the fight against drug trafficking, a generic Trafficking Pathway Model (TPM) is developed for trafficking of natural radionuclides. The TPM covers the complete trafficking cycle, ranging from material diversion, covert material transport, material concealment, and all associated operational procedures. The model subdivides the trafficking cycle into five phases: (1) Material diversion by insider(s) or initiation by outsider(s); (2) Covert transport; (3) Material brokerage; (4) Material sale; (5) Material delivery. An Action Plan is recommended, addressing the strengthening of the national infrastructure for material protection and accounting, development of higher standards of good governance, and needs for improving the control system deployed by customs, border guards and security forces.

  13. Sex trafficking in South Asia.

    PubMed

    Huda, S

    2006-09-01

    Economic and social inequalities and political conflicts have led to the movement of persons within each country and across the borders in South Asia. Globalization has encouraged free mobility of capital, technology, experts and sex tourism. Illiteracy, dependency, violence, social stigma, cultural stereotypes, gender disparity and endemic poverty, among other factors, place women and children in powerless, non-negotiable situations that have contributed to the emergence and breeding of the cavernous problem of sex trafficking in the entire region. This alarming spread of sex trafficking has fuelled the spread of HIV infection in South Asia, posing a unique and serious threat to community health, poverty alleviation and other crucial aspects of human development. Although the SAARC (South Asian Association for Regional Cooperation) Convention on Trafficking in Women and Children has been an important breakthrough, most of the countries in the region do not have anti-trafficking legislation or means to protect the victims. Countries of the region should make a concerted effort to treat trafficking victims as "victims" of human rights violations in all anti-trafficking strategies and actions.

  14. To discuss illicit nuclear trafficking

    SciTech Connect

    Balatsky, Galya I; Severe, William R; Wallace, Richard K

    2010-01-01

    The Illicit nuclear trafficking panel was conducted at the 4th Annual INMM workshop on Reducing the Risk from Radioactive and Nuclear Materials on February 2-3, 2010 in Washington DC. While the workshop occurred prior to the Nuclear Security Summit, April 12-13 2010 in Washington DC, some of the summit issues were raised during the workshop. The Communique of the Washington Nuclear Security Summit stated that 'Nuclear terrorism is one of the most challenging threats to international security, and strong nuclear security measures are the most effective means to prevent terrorists, criminals, or other unauthorized actors from acquiring nuclear materials.' The Illicit Trafficking panel is one means to strengthen nuclear security and cooperation at bilateral, regional and multilateral levels. Such a panel promotes nuclear security culture through technology development, human resources development, education and training. It is a tool which stresses the importance of international cooperation and coordination of assistance to improve efforts to prevent and respond to incidents of illicit nuclear trafficking. Illicit trafficking panel included representatives from US government, an international organization (IAEA), private industry and a non-governmental organization to discuss illicit nuclear trafficking issues. The focus of discussions was on best practices and challenges for addressing illicit nuclear trafficking. Terrorism connection. Workshop discussions pointed out the identification of terrorist connections with several trafficking incidents. Several trafficking cases involved real buyers (as opposed to undercover law enforcement agents) and there have been reports identifying individuals associated with terrorist organizations as prospective plutonium buyers. Some specific groups have been identified that consistently search for materials to buy on the black market, but no criminal groups were identified that specialize in nuclear materials or isotope smuggling

  15. Functional rescue of a kidney anion exchanger 1 trafficking mutant in renal epithelial cells.

    PubMed

    Chu, Carmen Y S; King, Jennifer C; Berrini, Mattia; Alexander, R Todd; Cordat, Emmanuelle

    2013-01-01

    Mutations in the SLC4A1 gene encoding the anion exchanger 1 (AE1) can cause distal renal tubular acidosis (dRTA), a disease often due to mis-trafficking of the mutant protein. In this study, we investigated whether trafficking of a Golgi-retained dRTA mutant, G701D kAE1, or two dRTA mutants retained in the endoplasmic reticulum, C479W and R589H kAE1, could be functionally rescued to the plasma membrane of Madin-Darby Canine Kidney (MDCK) cells. Treatments with DMSO, glycerol, the corrector VX-809, or low temperature incubations restored the basolateral trafficking of G701D kAE1 mutant. These treatments had no significant rescuing effect on trafficking of the mis-folded C479W or R589H kAE1 mutants. DMSO was the only treatment that partially restored G701D kAE1 function in the plasma membrane of MDCK cells. Our experiments show that trafficking of intracellularly retained dRTA kAE1 mutants can be partially restored, and that one chemical treatment rescued both trafficking and function of a dRTA mutant. These studies provide an opportunity to develop alternative therapeutic solutions for dRTA patients. PMID:23460825

  16. Trafficking: a perspective from Asia.

    PubMed

    Skeldon, R

    2000-01-01

    The main theme of this article is market development and trafficking as a business. It touches upon most of the aspects of the phenomenon, which have been encountered elsewhere, and translates them into the relatively unfamiliar context of many of the Asian and South-East Asian economies. Equally, the literature cited is also probably unfamiliar. Themes touched upon include democratization, inter-state relations, human rights, and scale and perspectives, together with the problems of definitions, theory, and the reliability of data. The directions and characteristics of trafficking flows together with routes and border control are also considered. Coordinated official responses to criminality and criminal organizations, as well as to trafficked individuals, are beginning to emerge. There is a note of caution sounded that contextual and cultural perspectives, particularly on sex workers, must be viewed somewhat differently to those in Western societies. The article concludes that as long as countries in Asia maintain their policies of restrictive immigration, trafficking can be expected to continue and almost certainly increase. This is because accelerating development creates demand for labor at various skill levels and because even in times of recession migrants and brokers will seek to side-step attempts to expel immigrants and restrict access to labor markets. The elimination of trafficking is unlikely to be realistically achieved through legislation and declarations of intent but by improvements in the socioeconomic status of the population.

  17. Trafficking in persons: a health concern?

    PubMed

    Zimmerman, Cathy; Kiss, Ligia; Houssain, Mazeda; Watts, Charlotte

    2009-01-01

    Human trafficking is a phenomenon that has now been documented in most regions in the world. Although trafficking of women and girls for sexual exploitation is the most commonly recognised form of trafficking, it is widely acknowledged that human trafficking also involves men, women and children who are trafficked for various forms of labour exploitation and into other abusive circumstances. Despite the violence and harm inherent in most trafficking situations, there remains extremely little evidence on the individual and public health implications of any form of human trafficking. The Brazilian government has recently launched a national plan to combat human trafficking. However, because the health risks associated with human trafficking have not been well-recognised or documented, there is extremely limited reliable data on the health needs of trafficked persons to inform policy and practices.. Brazilian policy-makers and service providers should be encouraged to learn about the likely range of health impacts of trafficking, and incorporate this into anti-trafficking protection and response strategies. As well as prevention activities, the government, international and local organisations should work together with the public health research community to study the health needs of trafficked persons and explore opportunities to provide safe and appropriate services to victims in need of care. PMID:19721944

  18. Gallic acid attenuates high-fat diet fed-streptozotocin-induced insulin resistance via partial agonism of PPARγ in experimental type 2 diabetic rats and enhances glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway.

    PubMed

    Gandhi, Gopalsamy Rajiv; Jothi, Gnanasekaran; Antony, Poovathumkal James; Balakrishna, Kedike; Paulraj, Michael Gabriel; Ignacimuthu, Savarimuthu; Stalin, Antony; Al-Dhabi, Naif Abdullah

    2014-12-15

    In this study, the therapeutic efficacy of gallic acid from Cyamopsis tetragonoloba (L.) Taub. (Fabaceae) beans was examined against high-fat diet fed-streptozotocin-induced experimental type 2 diabetic rats. Molecular-dockings were done to determine the putative binding modes of gallic acid into the active sites of key insulin-signaling markers. Gallic acid (20 mg/kg) given to high-fat diet fed-streptozotocin-induced rats lowered body weight gain, fasting blood glucose and plasma insulin in diabetic rats. It further restored the alterations of biochemical parameters to near normal levels in diabetic treated rats along with cytoprotective action on pancreatic β-cell. Histology of liver and adipose tissues supported the biochemical findings. Gallic acid significantly enhanced the level of peroxisome proliferator-activated receptor γ (PPARγ) expression in the adipose tissue of treated rat compared to untreated diabetic rat; it also slightly activated PPARγ expressions in the liver and skeletal muscle. Consequently, it improved insulin-dependent glucose transport in adipose tissue through translocation and activation of glucose transporter protein 4 (GLUT4) in phosphatidylinositol 3-kinase (PI3K)/phosphorylated protein kinase B (p-Akt) dependent pathway. Gallic acid docked with PPARγ; it exhibited promising interactions with the GLUT4, glucose transporter protein 1 (GLUT1), PI3K and p-Akt. These findings provided evidence to show that gallic acid could improve adipose tissue insulin sensitivity, modulate adipogenesis, increase adipose glucose uptake and protect β-cells from impairment. Hence it can be used in the management of obesity-associated type 2 diabetes mellitus.

  19. Understanding human trafficking in the United States.

    PubMed

    Logan, T K; Walker, Robert; Hunt, Gretchen

    2009-01-01

    The topic of modern-day slavery or human trafficking has received increased media and national attention. However, to date there has been limited research on the nature and scope of human trafficking in the United States. This article describes and synthesizes nine reports that assess the U.S. service organizations' legal representative knowledge of, and experience with, human trafficking cases, as well as information from actual cases and media reports. This article has five main goals: (a) to define what human trafficking is, and is not; (b) to describe factors identified as contributing to vulnerability to being trafficked and keeping a person entrapped in the situation; (c) to examine how the crime of human trafficking differs from other kinds of crimes in the United States; (d) to explore how human trafficking victims are identified; and, (e) to provide recommendations to better address human trafficking in the United States.

  20. Understanding human trafficking in the United States.

    PubMed

    Logan, T K; Walker, Robert; Hunt, Gretchen

    2009-01-01

    The topic of modern-day slavery or human trafficking has received increased media and national attention. However, to date there has been limited research on the nature and scope of human trafficking in the United States. This article describes and synthesizes nine reports that assess the U.S. service organizations' legal representative knowledge of, and experience with, human trafficking cases, as well as information from actual cases and media reports. This article has five main goals: (a) to define what human trafficking is, and is not; (b) to describe factors identified as contributing to vulnerability to being trafficked and keeping a person entrapped in the situation; (c) to examine how the crime of human trafficking differs from other kinds of crimes in the United States; (d) to explore how human trafficking victims are identified; and, (e) to provide recommendations to better address human trafficking in the United States. PMID:19056686

  1. Small GTPases in vesicle trafficking.

    PubMed

    Molendijk, Arthur J; Ruperti, Benedetto; Palme, Klaus

    2004-12-01

    Plant small GTPases belonging to the Rop, Arf, and Rab families are regulators of vesicle trafficking. Rop GTPases regulate actin dynamics and modulate H(2)O(2) production in polar cell growth and pathogen defence. A candidate Rop GDP to Rop GTP exchange factor (RopGEF) SPIKE1 is involved in the morphogenesis of leaf epidermal cells. The ArfGEF GNOM regulates the endosomal recycling of the PIN proteins, which are involved in polar auxin transport. Intracellular localisation of small GTPases and functional studies using dominant mutant versions of Arf and Rab GTPases are defining novel plant-specific membrane compartments, especially those that participate in endosomal vesicle trafficking.

  2. Distal convoluted tubule.

    PubMed

    McCormick, James A; Ellison, David H

    2015-01-01

    The distal convoluted tubule (DCT) is a short nephron segment, interposed between the macula densa and collecting duct. Even though it is short, it plays a key role in regulating extracellular fluid volume and electrolyte homeostasis. DCT cells are rich in mitochondria, and possess the highest density of Na+/K+-ATPase along the nephron, where it is expressed on the highly amplified basolateral membranes. DCT cells are largely water impermeable, and reabsorb sodium and chloride across the apical membrane via electroneurtral pathways. Prominent among this is the thiazide-sensitive sodium chloride cotransporter, target of widely used diuretic drugs. These cells also play a key role in magnesium reabsorption, which occurs predominantly, via a transient receptor potential channel (TRPM6). Human genetic diseases in which DCT function is perturbed have provided critical insights into the physiological role of the DCT, and how transport is regulated. These include Familial Hyperkalemic Hypertension, the salt-wasting diseases Gitelman syndrome and EAST syndrome, and hereditary hypomagnesemias. The DCT is also established as an important target for the hormones angiotensin II and aldosterone; it also appears to respond to sympathetic-nerve stimulation and changes in plasma potassium. Here, we discuss what is currently known about DCT physiology. Early studies that determined transport rates of ions by the DCT are described, as are the channels and transporters expressed along the DCT with the advent of molecular cloning. Regulation of expression and activity of these channels and transporters is also described; particular emphasis is placed on the contribution of genetic forms of DCT dysregulation to our understanding.

  3. Sex trafficking and the exploitation of adolescents.

    PubMed

    McClain, Natalie M; Garrity, Stacy E

    2011-01-01

    Human trafficking affects a surprisingly large number of adolescents around the globe. Women and girls make up the majority of sex trafficking victims. Nurses must be aware of sex trafficking as a form of sexual violence in the adolescent population. Nurses can play a role in identifying, intervening, and advocating for victims of human trafficking as they currently do for patients that are the victims of other types of violent crimes. PMID:21284727

  4. Genetics Home Reference: distal arthrogryposis type 1

    MedlinePlus

    ... Conditions distal arthrogryposis type 1 distal arthrogryposis type 1 Enable Javascript to view the expand/collapse boxes. ... Open All Close All Description Distal arthrogryposis type 1 is a disorder characterized by joint deformities (contractures) ...

  5. 31 CFR 598.310 - Narcotics trafficking.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false Narcotics trafficking. 598.310 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.310 Narcotics trafficking. The term narcotics trafficking means any illicit activity...

  6. 31 CFR 598.310 - Narcotics trafficking.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Narcotics trafficking. 598.310 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.310 Narcotics trafficking. The term narcotics trafficking means any illicit activity...

  7. 31 CFR 598.310 - Narcotics trafficking.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Narcotics trafficking. 598.310 Section... FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.310 Narcotics trafficking. The term narcotics trafficking means any illicit activity...

  8. 31 CFR 598.310 - Narcotics trafficking.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Narcotics trafficking. 598.310 Section 598.310 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE... General Definitions § 598.310 Narcotics trafficking. The term narcotics trafficking means any...

  9. 31 CFR 598.310 - Narcotics trafficking.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Narcotics trafficking. 598.310 Section 598.310 Money and Finance: Treasury Regulations Relating to Money and Finance (Continued) OFFICE OF... Definitions § 598.310 Narcotics trafficking. The term narcotics trafficking means any illicit activity...

  10. Human trafficking and the healthcare professional.

    PubMed

    Barrows, Jeffrey; Finger, Reginald

    2008-05-01

    Despite the legislation passed in the 19th century outlawing human slavery, it is more widespread today than at the conclusion of the civil war. Modern human slavery, termed human trafficking, comes in several forms. The most common type of human trafficking is sex trafficking, the sale of women and children into prostitution. Labor trafficking is the sale of men, women, and children into hard labor for which they receive little or no compensation. Other forms of trafficking include child soldiering, war brides, and organ removal. Healthcare professionals play a critical role in both finding victims of human trafficking while they are still in captivity, as well as caring for their mental and physical needs upon release. Those working in the healthcare profession need to be educated regarding how a trafficking victim may present, as well as their unique healthcare needs.

  11. Human trafficking and the healthcare professional.

    PubMed

    Barrows, Jeffrey; Finger, Reginald

    2008-05-01

    Despite the legislation passed in the 19th century outlawing human slavery, it is more widespread today than at the conclusion of the civil war. Modern human slavery, termed human trafficking, comes in several forms. The most common type of human trafficking is sex trafficking, the sale of women and children into prostitution. Labor trafficking is the sale of men, women, and children into hard labor for which they receive little or no compensation. Other forms of trafficking include child soldiering, war brides, and organ removal. Healthcare professionals play a critical role in both finding victims of human trafficking while they are still in captivity, as well as caring for their mental and physical needs upon release. Those working in the healthcare profession need to be educated regarding how a trafficking victim may present, as well as their unique healthcare needs. PMID:18414161

  12. Trafficking of Vesicular Neurotransmitter Transporters

    PubMed Central

    Fei, Hao; Grygoruk, Anna; Brooks, Elizabeth S.; Chen, Audrey; Krantz, David E.

    2010-01-01

    Vesicular neurotransmitter transporters are required for the storage of all classical and amino acid neurotransmitters in secretory vesicles. Transporter expression can influence neurotransmitter storage and release, and trafficking targets the transporters to different types of secretory vesicles. Vesicular transporters traffic to synaptic vesicles as well as large dense core vesicles, and are recycled to synaptic vesicles at the nerve terminal. Some of the intrinsic signals for these trafficking events have been defined and include a dileucine motif present in multiple transporter subtypes, an acidic cluster in the neural isoform of the vesicular monoamine transporter (VMAT2) and a polyproline motif in the vesicular glutamate transporter VGLUT1. The sorting of VMAT2 and the vesicular acetylcholine transporter (VAChT) to secretory vesicles is regulated by phosphorylation. In addition, VGLUT1 uses alternative endocytic pathways for recycling back to synaptic vesicles following exocytosis. Regulation of these sorting events has the potential to influence synaptic transmission and behavior. PMID:18507811

  13. [Distal humerus fractures in children].

    PubMed

    Schneidmueller, D; Boettger, M; Laurer, H; Gutsfeld, P; Bühren, V

    2013-11-01

    Fractures of the distal humerus belong to the most common injuries of the upper arm in childhood. Most frequently occurring is the supracondylar fracture of the distal humerus. In these cases and in the second most common epicondylar fractures, the metaphysis is affected and these fractures are therefore extra-articular. They have to be distinguished from articular fractures regarding therapy and prognosis. The growth potential of the distal epiphysis is very limited as is the possibility of spontaneous correction so that major dislocations should not be left uncorrected. Unstable and especially dislocated articular fractures must be anatomically reconstructed employing various osteosynthetic techniques, mostly combined with immobilization. Insufficient reconstruction, growth disturbance and non-union can result in axial deformities, such as cubitus valgus and varus, restriction of motion, pain and nerve palsy.

  14. Viral subversion of nucleocytoplasmic trafficking.

    PubMed

    Yarbrough, Melanie L; Mata, Miguel A; Sakthivel, Ramanavelan; Fontoura, Beatriz M A

    2014-02-01

    Trafficking of proteins and RNA into and out of the nucleus occurs through the nuclear pore complex (NPC). Because of its critical function in many cellular processes, the NPC and transport factors are common targets of several viruses that disrupt key constituents of the machinery to facilitate viral replication. Many viruses such as poliovirus and severe acute respiratory syndrome (SARS) virus inhibit protein import into the nucleus, whereas viruses such as influenza A virus target and disrupt host mRNA nuclear export. Current evidence indicates that these viruses may employ such strategies to avert the host immune response. Conversely, many viruses co-opt nucleocytoplasmic trafficking to facilitate transport of viral RNAs. As viral proteins interact with key regulators of the host nuclear transport machinery, viruses have served as invaluable tools of discovery that led to the identification of novel constituents of nuclear transport pathways. This review explores the importance of nucleocytoplasmic trafficking to viral pathogenesis as these studies revealed new antiviral therapeutic strategies and exposed previously unknown cellular mechanisms. Further understanding of nuclear transport pathways will determine whether such therapeutics will be useful treatments for important human pathogens.

  15. Protein trafficking in kinetoplastid protozoa.

    PubMed Central

    Clayton, C; Häusler, T; Blattner, J

    1995-01-01

    The kinetoplastid protozoa infect hosts ranging from invertebrates to plants and mammals, causing diseases of medical and economic importance. They are the earliest-branching organisms in eucaryotic evolution to have either mitochondria or peroxisome-like microbodies. Investigation of their protein trafficking enables us to identify characteristics that have been conserved throughout eucaryotic evolution and also reveals how far variations, or alternative mechanisms, are possible. Protein trafficking in kinetoplastids is in many respects similar to that in higher eucaryotes, including mammals and yeasts. Differences in signal sequence specificities exist, however, for all subcellular locations so far examined in detail--microbodies, mitochondria, and endoplasmic reticulum--with signals being more degenerate, or shorter, than those of their higher eucaryotic counterparts. Some components of the normal array of trafficking mechanisms may be missing in most (if not all) kinetoplastids: examples are clathrin-coated vesicles, recycling receptors, and mannose 6-phosphate-mediated lysosomal targeting. Other aspects and structures are unique to the kinetoplastids or are as yet unexplained. Some of these peculiarities may eventually prove to be weak points that can be used as targets for chemotherapy; others may turn out to be much more widespread than currently suspected. PMID:7565409

  16. Viral Subversion of Nucleocytoplasmic Trafficking

    PubMed Central

    Yarbrough, Melanie L.; Mata, Miguel A.; Sakthivel, Ramanavelan; Fontoura, Beatriz M. A.

    2014-01-01

    Trafficking of proteins and RNA into and out of the nucleus occurs through the nuclear pore complex (NPC). Due to its critical function in many cellular processes, the NPC and transport factors are common targets of several viruses that disrupt key constituents of the machinery to facilitate viral replication. Many viruses such as poliovirus and severe acute respiratory syndrome (SARS) virus inhibit protein import into the nucleus, while viruses such as influenza A virus target and disrupt host mRNA nuclear export. Current evidence indicates that these viruses may employ such strategies to avert the host immune response. Conversely, many viruses co-opt nucleocytoplasmic trafficking to facilitate transport of viral RNAs. Since viral proteins interact with key regulators of the host nuclear transport machinery, viruses have served as invaluable tools of discovery that led to the identification of novel constituents of nuclear transport pathways. In addition, this review explores the importance of nucleocytoplasmic trafficking to viral pathogenesis as these studies revealed new antiviral therapeutic strategies and exposed previously unknown cellular mechanisms. Further understanding of nuclear transport pathways will determine whether such therapeutics will be useful treatments for important human pathogens. PMID:24289861

  17. Agonist-trafficking and hallucinogens.

    PubMed

    González-Maeso, Javier; Sealfon, Stuart C

    2009-01-01

    Seven transmembrane domain receptors, also termed G protein-coupled receptors (GPCRs), represent the most common molecular target for therapeutic drugs. The generally accepted pharmacological model for GPCR activation is the ternary complex model, in which GPCRs exist in a dynamic equilibrium between the active and inactive conformational states. However, the demonstration that different agonists sometimes elicit a different relative activation of two signaling pathways downstream of the same receptor has led to a revision of the ternary complex model. According to this agonist- trafficking model, agonists stabilize distinct activated receptor conformations that preferentially activate specific signaling pathways. Hallucinogenic drugs and non-hallucinogenic drugs represent an attractive experimental system with which to study agonist-trafficking of receptor signaling. Thus many of the behavioral responses induced by hallucinogenic drugs, such as lysergic acid diethylamide (LSD), psilocybin or mescaline, depend on activation of serotonin 5-HT(2A) receptors (5-HT2ARs). In contrast, this neuropsychological state in humans is not induced by closely related chemicals, such as lisuride or ergotamine, despite their similar in vitro activity at the 5-HT2AR. In this review, we summarize the current knowledge, as well as unresolved questions, regarding agonist-trafficking and the mechanism of action of hallucinogenic drugs.

  18. Regulation of aquaporin-2 trafficking.

    PubMed

    Nedvetsky, Pavel I; Tamma, Grazia; Beulshausen, Sven; Valenti, Giovanna; Rosenthal, Walter; Klussmann, Enno

    2009-01-01

    Principal cells lining renal collecting ducts control the fine-tuning of body water homeostasis by regulating water reabsorption through the water channels aquaporin-2 (AQP2), aquaporin-3 (AQP3), and aquaporin-4 (AQP4). While the localization of AQP2 is subject to regulation by arginine-vasopressin (AVP), AQP3 and AQP4 are constitutively expressed in the basolateral plasma membrane. AVP adjusts the amount of AQP2 in the plasma membrane by triggering its redistribution from intracellular vesicles into the plasma membrane. This permits water entry into the cells and water exit through AQP3 and AQP4. The translocation of AQP2 is initiated by an increase in cAMP following V2R activation through AVP. The AVP-induced rise in cAMP activates protein kinase A (PKA), which in turn phosphorylates AQP2, and thereby triggers the redistribution of AQP2. Several proteins participating in the control of cAMP-dependent AQP2 trafficking have been identified; for example, A kinase anchoring proteins (AKAPs) tethering PKA to cellular compartments; phosphodiesterases (PDEs) regulating the local cAMP level; cytoskeletal components such as F-actin and microtubules; small GTPases of the Rho family controlling cytoskeletal dynamics; motor proteins transporting AQP2-bearing vesicles to and from the plasma membrane for exocytic insertion and endocytic retrieval; SNAREs inducing membrane fusions, hsc70, a chaperone, important for endocytic retrieval. In addition, cAMP-independent mechanisms of translocation mainly involving the F-actin cytoskeleton have been uncovered. Defects of AQP2 trafficking cause diseases such as nephrogenic diabetes insipidus (NDI), a disorder characterized by a massive loss of hypoosmotic urine.This review summarizes recent data elucidating molecular mechanisms underlying the trafficking of AQP2. In particular, we focus on proteins involved in the regulation of trafficking, and physiological and pathophysiological stimuli determining the cellular localization of AQP2

  19. Human Trafficking in the Emergency Department

    PubMed Central

    Patel, Ronak B.; Ahn, Roy; Burke, Thomas F.

    2010-01-01

    Human trafficking continues to persist, affecting up to 200 million people worldwide. As clinicians in emergency departments commonly encounter victims of intimate partner violence, some of these encounters will be with trafficking victims. These encounters provide a rare opportunity for healthcare providers to intervene and help. This case report of a human trafficking patient from a teaching hospital illustrates the complexity in identifying these victims. Clinicians can better identify potential trafficking cases by increasing their awareness of this phenomenon, using qualified interpreters, isolating potential victims by providing privacy and using simple clear reassuring statements ensuring security. A multidisciplinary approach can then be mobilized to help these patients. PMID:21293753

  20. Molybdenum Trafficking for Nitrogen Fixation†

    PubMed Central

    Hernandez, Jose A.; George, Simon J.; Rubio, Luis M.

    2009-01-01

    The molybdenum nitrogenase is responsible for most biological nitrogen fixation, a prokaryotic metabolic process that determines the global biogeochemical cycles of nitrogen and carbon. Here we describe the trafficking of molybdenum for nitrogen fixation in the model diazotrophic bacterium Azotobacter vinelandii. The genes and proteins involved in molybdenum uptake, homeostasis, storage, regulation, and nitrogenase cofactor biosynthesis are reviewed. Molybdenum biochemistry in A. vinelandii reveals unexpected mechanisms and a new role for iron-sulfur clusters in the sequestration and delivery of molybdenum. PMID:19772354

  1. Optical Control of Peroxisomal Trafficking.

    PubMed

    Spiltoir, Jessica I; Strickland, Devin; Glotzer, Michael; Tucker, Chandra L

    2016-07-15

    The blue-light-responsive LOV2 domain of Avena sativa phototropin1 (AsLOV2) has been used to regulate activity and binding of diverse protein targets with light. Here, we used AsLOV2 to photocage a peroxisomal targeting sequence, allowing light regulation of peroxisomal protein import. We generated a protein tag, LOV-PTS1, that can be appended to proteins of interest to direct their import to the peroxisome with light. This method provides a means to inducibly trigger peroxisomal protein trafficking in specific cells at user-defined times. PMID:26513473

  2. Genetics Home Reference: Laing distal myopathy

    MedlinePlus

    ... for This Page GeneReview: Laing Distal Myopathy Laing NG, Laing BA, Meredith C, Wilton SD, Robbins P, ... T, Bridges LR, Fabian V, Rozemuller A, Laing NG. Laing early onset distal myopathy: slow myosin defect ...

  3. Preliminary Validation of the Sex Trafficking Attitudes Scale.

    PubMed

    Houston-Kolnik, Jaclyn D; Todd, Nathan R; Wilson, Midge

    2016-09-01

    This study presents the Sex Trafficking Attitudes Scale (STAS), assessing cognitive, behavioral, and affective attitudes toward the sex trafficking of women and girls. Across two studies, exploratory and confirmatory factor analyses revealed and confirmed six subscales: (a) Knowledge About Sex Trafficking, (b) Awareness of Sex Trafficking, (c) Attitudes Toward Ability to Leave Sex Trafficking, (d) Attitudes Toward Helping Survivors, (e) Empathic Reactions Toward Sex Trafficking, and (f) Efficacy to Reduce Sex Trafficking. Results showed support for convergent validity as the subscales were associated with related measures. The STAS holds promise to expand research and inform efforts to support trafficking survivors.

  4. Distal clavicle fractures in children☆

    PubMed Central

    Labronici, Pedro José; da Silva, Ricardo Rodrigues; Franco, Marcos Vinícius Viana; Labronici, Gustavo José; Pires, Robinson Esteves Santos; Franco, José Sergio

    2015-01-01

    Objective To analyze fractures of the distal clavicle region in pediatric patients. Methods Ten patients between the ages of five to eleven years (mean of 7.3 years) were observed. Nine patients were treated conservatively and one surgically. All the fractures were classified using the Nenopoulos classification system. Results All the fractures consolidated without complications. Conservative treatment was used for nine patients, of whom three were in group IIIB, three IIb, two IIa and one IV. The only patient who was treated surgically was a female patient of eleven years of age with a group IV fracture. Conclusion The treatment indication for distal fractures of the clavicle in children should be based on the patient's age and the displacement of the fragments. PMID:26962489

  5. Distal esophageal spasm: an update.

    PubMed

    Achem, Sami R; Gerson, Lauren B

    2013-09-01

    Distal esophageal spasm (DES) is an esophageal motility disorder that presents clinically with chest pain and/or dysphagia and is defined manometrically as simultaneous contractions in the distal (smooth muscle) esophagus in ≥20% of wet swallows (and amplitude contraction of ≥30 mmHg) alternating with normal peristalsis. With the introduction of high resolution esophageal pressure topography (EPT) in 2000, the definition of DES was modified. The Chicago classification proposed that the defining criteria for DES using EPT should be the presence of at least two premature contractions (distal latency<4.5 s) in a context of normal EGJ relaxation. The etiology of DES remains insufficiently understood, but evidence links nitric oxide (NO) deficiency as a culprit resulting in a disordered neural inhibition. GERD frequently coexists in DES, and its role in the pathogenesis of symptoms needs further evaluation. There is some evidence from small series that DES can progress to achalasia. Treatment remains challenging due in part to lack of randomized placebo-controlled trials. Current treatment agents include nitrates (both short and long acting), calcium-channel blockers, anticholinergic agents, 5-phosphodiesterase inhibitors, visceral analgesics (tricyclic agents or SSRI), and esophageal dilation. Acid suppression therapy is frequently used, but clinical outcome trials to support this approach are not available. Injection of botulinum toxin in the distal esophagus may be effective, but further data regarding the development of post-injection gastroesophageal reflux need to be assessed. Heller myotomy combined with fundoplication remains an alternative for the rare refractory patient. Preliminary studies suggest that the newly developed endoscopic technique of per oral endoscopic myotomy (POEM) may also be an alternative treatment modality. PMID:23892829

  6. Intracellular trafficking of nucleic acids.

    PubMed

    Zhou, Rui; Geiger, R Christopher; Dean, David A

    2004-11-01

    Until recently, the attention of most researchers has focused on the first and last steps of gene transfer, namely delivery to the cell and transcription, in order to optimise transfection and gene therapy. However, over the past few years, researchers have realised that the intracellular trafficking of plasmids is more than just a "black box" and is actually one of the major barriers to effective gene delivery. After entering the cytoplasm, following direct delivery or endocytosis, plasmids or other vectors must travel relatively long distances through the mesh of cytoskeletal networks before reaching the nuclear envelope. Once at the nuclear envelope, the DNA must either wait until cell division, or be specifically transported through the nuclear pore complex, in order to reach the nucleoplasm where it can be transcribed. This review focuses on recent developments in the understanding of these intracellular trafficking events as they relate to gene delivery. Hopefully, by continuing to unravel the mechanisms by which plasmids and other gene delivery vectors move throughout the cell, and by understanding the cell biology of gene transfer, superior methods of transfection and gene therapy can be developed.

  7. Chondroblastoma of the distal phalanx.

    PubMed

    Gregory, James R; Lehman, Thomas P; White, Jeremy R; Fung, Kar-Ming

    2014-05-01

    Chondroblastoma is a rare, benign primary bone tumor that usually occurs at the epiphysis of long bones. The authors present an example of the diagnosis and successful treatment of this neoplasm in an exceedingly rare location in the distal phalanx. Clinical and radiographic outcomes after 68 months of follow-up are presented. A 15-year-old, right hand-dominant, boy developed painful swelling of the right ring finger. Radiographs revealed a radiolucent lesion of the distal phalanx with expansile remodeling of the bone. An excisional biopsy was performed with curettage and bone grafting of the lesion. The diagnosis of chondroblastoma was made based on pathologic evaluation of the biopsy specimen. Sixty-six months after surgical treatment, the patient was free of recurrence and metastatic disease with excellent clinical and functional outcomes. To the authors' knowledge, this represents only the second reported case of chondroblastoma of the distal phalanx. The diagnosis of chondroblastoma in this rare location was made by pathologic review of the resection specimen. It is imperative to confirm the diagnosis of any resected bone specimen even when the concern for an aggressive or malignant lesion is low. A tumor presenting in an unusual location may require a change in treatment or surveillance.

  8. Chondroblastoma of the distal phalanx.

    PubMed

    Gregory, James R; Lehman, Thomas P; White, Jeremy R; Fung, Kar-Ming

    2014-05-01

    Chondroblastoma is a rare, benign primary bone tumor that usually occurs at the epiphysis of long bones. The authors present an example of the diagnosis and successful treatment of this neoplasm in an exceedingly rare location in the distal phalanx. Clinical and radiographic outcomes after 68 months of follow-up are presented. A 15-year-old, right hand-dominant, boy developed painful swelling of the right ring finger. Radiographs revealed a radiolucent lesion of the distal phalanx with expansile remodeling of the bone. An excisional biopsy was performed with curettage and bone grafting of the lesion. The diagnosis of chondroblastoma was made based on pathologic evaluation of the biopsy specimen. Sixty-six months after surgical treatment, the patient was free of recurrence and metastatic disease with excellent clinical and functional outcomes. To the authors' knowledge, this represents only the second reported case of chondroblastoma of the distal phalanx. The diagnosis of chondroblastoma in this rare location was made by pathologic review of the resection specimen. It is imperative to confirm the diagnosis of any resected bone specimen even when the concern for an aggressive or malignant lesion is low. A tumor presenting in an unusual location may require a change in treatment or surveillance. PMID:24810830

  9. Examining the Risk of Nuclear Trafficking

    SciTech Connect

    Balatsky, Galya; Severe, William R; Schoeneck, Jeffery

    2009-01-01

    The need to stop illicit trafficking of nuclear and radioactive materials around the world is undeniable and urgent. This issue is particularly evident due to the highly dangerous consequences of the risks involved, the known interest of terrorist groups in acquiring such materials and the vulnerability of theft and diversion of such materials. Yet the phenomenon of nuclear trafficking remains a subject where the unknown dominates what is known on the subject. The trafficking panel at the Institute for Nuclear Materials Management (INMM) Workshop on Reducing the Risk of Radioactive and Nuclear Materials that took place in Albuquerque, New Mexico, March 10-11, 2009, dealt with some of the issues associated with nuclear trafficking. Different points of view on how to better address trafficking and thwart perpetrator efforts were discussed. This paper presents some of these views and addresses practical measures that should be considered to improve the situation.

  10. Trafficking to the Ciliary Membrane

    PubMed Central

    Nachury, Maxence V.; Seeley, E. Scott; Jin, Hua

    2010-01-01

    The primary cilium organizes numerous signal transduction cascades and an understanding of signaling receptors trafficking to cilia is now emerging. A defining feature of cilia is the periciliary diffusion barrier that separates the ciliary and plasma membranes despite the topological continuity between these two membranes. Although lateral transport through this barrier may take place, polarized exocytosis to the base of the cilium has been the prevailing model for delivering membrane proteins to cilia. Key players for this polarized exocytosis model include the GTPases Rab8 and Rab11, the exocyst and possibly the intraflagellar tranport machinery. Sorting membrane proteins to cilia critically relies on the recognition of ciliary targeting signals by sorting machines such as the BBSome coat complex or the GTPase Arf4. Finally, signaling at the cilium entails the bidirectional movement of proteins between cytoplasm and cilia and ubiquitination may promote exit from cilia. PMID:19575670

  11. Female sex trafficking: conceptual issues, current debates, and future directions.

    PubMed

    Meshkovska, Biljana; Siegel, Melissa; Stutterheim, Sarah E; Bos, Arjan E R

    2015-01-01

    Female sex trafficking is a pressing concern. In this article, we provide a comprehensive overview of relevant issues regarding the concept of female sex trafficking and research in the field of human trafficking, drawing on a variety of disciplines, including economics, gender and sexuality studies, psychology, sociology, law, and social work. We discuss the debates surrounding the definition of human trafficking, compare and contrast it with human smuggling, and outline connections between female sex trafficking and the issue of sex work and prostitution. We further discuss the history and current estimations of female sex trafficking. We then outline the main actors in female sex trafficking, including trafficked persons, traffickers, clients, and service providers, and we overview the trafficking process from recruitment to identification, recovery, and (re)integration. Finally, we conclude with recommendations for future research that tie together the concepts of vulnerability, exploitation, and long-term recovery and (re)integration. PMID:25897567

  12. Female sex trafficking: conceptual issues, current debates, and future directions.

    PubMed

    Meshkovska, Biljana; Siegel, Melissa; Stutterheim, Sarah E; Bos, Arjan E R

    2015-01-01

    Female sex trafficking is a pressing concern. In this article, we provide a comprehensive overview of relevant issues regarding the concept of female sex trafficking and research in the field of human trafficking, drawing on a variety of disciplines, including economics, gender and sexuality studies, psychology, sociology, law, and social work. We discuss the debates surrounding the definition of human trafficking, compare and contrast it with human smuggling, and outline connections between female sex trafficking and the issue of sex work and prostitution. We further discuss the history and current estimations of female sex trafficking. We then outline the main actors in female sex trafficking, including trafficked persons, traffickers, clients, and service providers, and we overview the trafficking process from recruitment to identification, recovery, and (re)integration. Finally, we conclude with recommendations for future research that tie together the concepts of vulnerability, exploitation, and long-term recovery and (re)integration.

  13. Polybasic trafficking signal mediates golgi export, ER retention or ER export and retrieval based on membrane-proximity.

    PubMed

    Parmar, Hirendrasinh B; Barry, Chris; Duncan, Roy

    2014-01-01

    Trafficking of integral membrane proteins between the ER and Golgi complex, and protein sorting and trafficking between the TGN and endosomal/lysosomal compartments or plasma membranes, are dependent on cis-acting, linear amino acid sorting signals. Numerous sorting signals of this type have been identified in the cytoplasmic domains of membrane proteins, several of which rely on basic residues. A novel Golgi export signal that relies on a membrane-proximal polybasic motif (PBM) was recently identified in the reptilian reovirus p14 protein, a representative of an unusual group of bitopic fusion-associated small transmembrane (FAST) proteins encoded by fusogenic orthoreoviruses and responsible for cell-cell fusion and syncytium formation. Using immunofluorescence microscopy, cell surface immunofluorescence, and endoglycosidase H assays, we now show the p14 PBM can mediate several distinct trafficking functions depending on its proximity to the transmembrane domain (TMD). When present within 4-residues of the TMD it serves as a Golgi export signal, but when located at the C-terminus of the 68-residue p14 cytoplasmic endodomain it functions as an ER retention signal. The PBM has no effect on protein trafficking when located at an internal position in the cytoplasmic domain. When present in both membrane-proximal and -distal locations, the PBMs promote export to, and efficient retrieval from, the Golgi complex. Interestingly, the conflicting trafficking signals provided by two PBMs induces extensive ER tubulation and segregation of ER components. These studies highlight how a single trafficking signal in a simple transmembrane protein can have remarkably diverse, position-dependent effects on protein trafficking and ER morphogenesis.

  14. Trafficking of cell surface beta-amyloid precursor protein: retrograde and transcytotic transport in cultured neurons

    PubMed Central

    1995-01-01

    Amyloid beta-protein (A beta), the principal constituent of senile plaques seen in Alzheimer's disease (AD), is derived by proteolysis from the beta-amyloid precursor protein (beta PP). The mechanism of A beta production in neurons, which are hypothesized to be a rich source of A beta in brain, remains to be defined. In this study, we describe a detailed localization of cell surface beta PP and its subsequent trafficking in primary cultured neurons. Full-length cell surface beta PP was present primarily on perikarya and axons, the latter with a characteristic discontinuous pattern. At growth cones, cell surface beta PP was inconsistently detected. By visualizing the distribution of beta PP monoclonal antibodies added to intact cultures, beta PP was shown to be internalized from distal axons or terminals and retrogradely transported back to perikarya in organelles which colocalized with fluid-phase endocytic markers. Retrograde transport of beta PP was shown in both hippocampal and peripheral sympathetic neurons, the latter using a compartment culture system that isolated cell bodies from distal axons and terminals. In addition, we demonstrated that beta PP from distal axons was transcytotically transported to the surface of perikarya from distal axons in sympathetic neurons. Indirect evidence of this transcytotic pathway was obtained in hippocampal neurons using antisense oligonucleotide to the kinesin heavy chain to inhibit anterograde beta PP transport. Taken together, these results demonstrate novel aspects of beta PP trafficking in neurons, including retrograde axonal transport and transcytosis. Moreover, the axonal predominance of cell surface beta PP is unexpected in view of the recent report of polarized sorting of beta PP to the basolateral domain of MDCK cells. PMID:7721945

  15. Human trafficking law and social structures.

    PubMed

    Wooditch, Alese

    2012-08-01

    Human trafficking has only recently emerged at the forefront of policy reform, even in developed nations. Yet, heightened awareness of the issue has not translated into effective policy as the majority of nations have ineffective antitrafficking practices; many countries have failed to criminalize human trafficking, whereas others do not actively enforce statutes in place. By applying Black's theory of law, this study offers a preliminary understanding into the variation of global prosecutorial efforts in human trafficking and adequacy of antitrafficking law. To isolate this relationship, the effects of trafficking markets are controlled. As with prior research, the study finds limited support for the theory. The article concludes with a discussion on the implications of the quantity of antitrafficking law and morphology association for policy development.

  16. Committee opinion no. 507: human trafficking.

    PubMed

    2011-09-01

    Human trafficking is a widespread problem with estimates ranging from 14,000 to 50,000 individuals trafficked into the United States annually. This hidden population involves the commercial sex industry, agriculture, factories, hotel and restaurant businesses, domestic workers, marriage brokers, and some adoption firms. Because 80% of trafficked individuals are women and girls, women’s health care providers may better serve their diverse patient population by increasing their awareness of this problem. The exploitation of people of any race, gender, sexual orientation, or ethnicity is unacceptable at any time, in any place. The members of the American College of Obstetricians and Gynecologists should be aware of this problem and strive to recognize and assist their patients who are victims or who have been victims of human trafficking. PMID:21860320

  17. Committee opinion no. 507: human trafficking.

    PubMed

    2011-09-01

    Human trafficking is a widespread problem with estimates ranging from 14,000 to 50,000 individuals trafficked into the United States annually. This hidden population involves the commercial sex industry, agriculture, factories, hotel and restaurant businesses, domestic workers, marriage brokers, and some adoption firms. Because 80% of trafficked individuals are women and girls, women’s health care providers may better serve their diverse patient population by increasing their awareness of this problem. The exploitation of people of any race, gender, sexual orientation, or ethnicity is unacceptable at any time, in any place. The members of the American College of Obstetricians and Gynecologists should be aware of this problem and strive to recognize and assist their patients who are victims or who have been victims of human trafficking.

  18. Sex trafficking of women and girls.

    PubMed

    Deshpande, Neha A; Nour, Nawal M

    2013-01-01

    Sex trafficking involves some form of forced or coerced sexual exploitation that is not limited to prostitution, and has become a significant and growing problem in both the United States and the larger global community. The costs to society include the degradation of human and women's rights, poor public health, disrupted communities, and diminished social development. Victims of sex trafficking acquire adverse physical and psychological health conditions and social disadvantages. Thus, sex trafficking is a critical health issue with broader social implications that requires both medical and legal attention. Healthcare professionals can work to improve the screening, identification, and assistance of victims of sex trafficking in a clinical setting and help these women and girls access legal and social services. PMID:23687554

  19. Ovarian Cystadenoma in a Trafficked Patient.

    PubMed

    Titchen, Kanani E; Katz, Douglas; Martinez, Kidian; White, Krishna

    2016-05-01

    The topic of child sex trafficking is receiving increased attention both in the lay press and in research articles. Recently, a number of physician organizations have issued policy statements calling for the education and involvement of physicians in combating this form of "modern-day slavery." Primary care and emergency medicine physicians have led these efforts, but a number of these victims may present to surgeons. Surgeons are in a unique position to identify trafficked patients; during the process of undraping, intubation, and surgical preparation, signs of trafficking such as tattoos, scars, dental injuries, and bruising may be evident. In addition, these patients may have specific needs in terms of anesthesia and postoperative care due to substance abuse. Here, we report the case of an 18-year-old girl with a history of sexual exploitation who presents for cystadenoma excision. To our knowledge, this is the first report of a sex-trafficked pediatric patient presenting for surgery. PMID:27244785

  20. Sex Trafficking of Women and Girls

    PubMed Central

    Deshpande, Neha A; Nour, Nawal M

    2013-01-01

    Sex trafficking involves some form of forced or coerced sexual exploitation that is not limited to prostitution, and has become a significant and growing problem in both the United States and the larger global community. The costs to society include the degradation of human and women’s rights, poor public health, disrupted communities, and diminished social development. Victims of sex trafficking acquire adverse physical and psychological health conditions and social disadvantages. Thus, sex trafficking is a critical health issue with broader social implications that requires both medical and legal attention. Healthcare professionals can work to improve the screening, identification, and assistance of victims of sex trafficking in a clinical setting and help these women and girls access legal and social services. PMID:23687554

  1. Peripheral nerve blocks for distal extremity surgery.

    PubMed

    Offierski, Chris

    2013-10-01

    Peripheral nerve block is well suited for distal extremity surgery. Blocking the nerves at the distal extremity is easily done. It does not require ultrasound or stimulators to identify the nerve. Blocking nerves in the distal extremity is safe with low risk of toxicity. The effect of the nerve block is limited to the distribution of the nerve. The distal nerves in the lower extremity are sensory branches of the sciatic nerve. This provides a sensory block only. This has the advantage of allowing the patient to actively contract tendons in the foot and ambulate more quickly after surgery. PMID:24093651

  2. The hidden crime: human trafficking.

    PubMed

    Clause, Kristen J; Lawler, Kate Byrnes

    2013-01-01

    As the primary contact in the health care system, nurses can play a role in combating this crime and assisting the victims. Assessment for abuse, neglect, trauma, recurrent sexually transmitted infections (STIs) and fear of a controlling partner is critical. Following up on "red flags" and understanding methods of safe questioning can make the difference between slavery and recovery for victims. Nurses must also know the professional referrals in their areas once a potential victim has been identified. This may be a very dangerous undertaking and must be handled by experienced personnel. Referrals to forensic nurses or physicians, domestic violence professionals or law enforcement may be indicated. Initially, a nurse may want to consult with the agency social worker for guidance. Human trafficking is a human rights crime. Unfortunately, it is more prevalent in all types of communities than most people suspect. Nurses can be heroes to the victims through understanding of this crime and vigilance in the assessment and care of all people they encounter in their practices. PMID:24218718

  3. The hidden crime: human trafficking.

    PubMed

    Clause, Kristen J; Lawler, Kate Byrnes

    2013-01-01

    As the primary contact in the health care system, nurses can play a role in combating this crime and assisting the victims. Assessment for abuse, neglect, trauma, recurrent sexually transmitted infections (STIs) and fear of a controlling partner is critical. Following up on "red flags" and understanding methods of safe questioning can make the difference between slavery and recovery for victims. Nurses must also know the professional referrals in their areas once a potential victim has been identified. This may be a very dangerous undertaking and must be handled by experienced personnel. Referrals to forensic nurses or physicians, domestic violence professionals or law enforcement may be indicated. Initially, a nurse may want to consult with the agency social worker for guidance. Human trafficking is a human rights crime. Unfortunately, it is more prevalent in all types of communities than most people suspect. Nurses can be heroes to the victims through understanding of this crime and vigilance in the assessment and care of all people they encounter in their practices. To learn more or to help with this cause, visit the Somaly Mam Foundation at www.somaly.org or the U.S. Department of State at www. state.gov. PMID:23977773

  4. The hidden crime: human trafficking.

    PubMed

    Clause, Kristen J; Lawler, Kate Byrnes

    2013-01-01

    As the primary contact in the health care system, nurses can play a role in combating this crime and assisting the victims. Assessment for abuse, neglect, trauma, recurrent sexually transmitted infections (STIs) and fear of a controlling partner is critical. Following up on "red flags" and understanding methods of safe questioning can make the difference between slavery and recovery for victims. Nurses must also know the professional referrals in their areas once a potential victim has been identified. This may be a very dangerous undertaking and must be handled by experienced personnel. Referrals to forensic nurses or physicians, domestic violence professionals or law enforcement may be indicated. Initially, a nurse may want to consult with the agency social worker for guidance. Human trafficking is a human rights crime. Unfortunately, it is more prevalent in all types of communities than most people suspect. Nurses can be heroes to the victims through understanding of this crime and vigilance in the assessment and care of all people they encounter in their practices. To learn more or to help with this cause, visit the Somaly Mam Foundation at www.somaly.org or the U.S. Department of State at www. state.gov.

  5. The hidden crime: human trafficking.

    PubMed

    Clause, Kristen J; Lawler, Kate Byrnes

    2013-01-01

    As the primary contact in the health care system, nurses can play a role in combating this crime and assisting the victims. Assessment for abuse, neglect, trauma, recurrent sexually transmitted infections (STIs) and fear of a controlling partner is critical. Following up on "red flags" and understanding methods of safe questioning can make the difference between slavery and recovery for victims. Nurses must also know the professional referrals in their areas once a potential victim has been identified. This may be a very dangerous undertaking and must be handled by experienced personnel. Referrals to forensic nurses or physicians, domestic violence professionals or law enforcement may be indicated. Initially, a nurse may want to consult with the agency social worker for guidance. Human trafficking is a human rights crime. Unfortunately, it is more prevalent in all types of communities than most people suspect. Nurses can be heroes to the victims through understanding of this crime and vigilance in the assessment and care of all people they encounter in their practices.

  6. Lymphatic Regulation of Cellular Trafficking

    PubMed Central

    Jackson, David G.

    2016-01-01

    Lymphatic vessels play vital roles in immune surveillance and immune regulation by conveying antigen loaded dendritic cells, memory T cells, macrophages and neutrophils from the peripheral tissues to draining lymph nodes where they initiate as well as modify immune responses. Until relatively recently however, there was little understanding of how entry and migration through lymphatic vessels is organized or the specific molecular mechanisms that might be involved. Within the last decade, the situation has been transformed by an explosion of knowledge generated largely through the application of microscopic imaging, transgenic animals, specific markers and function blocking mAbs that is beginning to provide a rational conceptual framework. This article provides a critical review of the recent literature, highlighting seminal discoveries that have revealed the fascinating ultrastructure of leucocyte entry sites in lymphatic vessels, as well as generating controversies over the involvement of integrin adhesion, chemotactic and haptotactic mechanisms in DC entry under normal and inflamed conditions. It also discusses the major changes in lymphatic architecture that occur during inflammation and the different modes of leucocyte entry and trafficking within inflamed lymphatic vessels, as well as presenting a timely update on the likely role of hyaluronan and the major lymphatic endothelial hyaluronan receptor LYVE-1 in leucocyte transit.

  7. In vivo neuron-wide analysis of synaptic vesicle precursor trafficking.

    PubMed

    Maeder, Celine I; San-Miguel, Adriana; Wu, Emily Ye; Lu, Hang; Shen, Kang

    2014-03-01

    During synapse development, synaptic proteins must be targeted to sites of presynaptic release. Directed transport as well as local sequestration of synaptic vesicle precursors (SVPs), membranous organelles containing many synaptic proteins, might contribute to this process. Using neuron-wide time-lapse microscopy, we studied SVP dynamics in the DA9 motor neuron in Caenorhabditis elegans. SVP transport was highly dynamic and bi-directional throughout the entire neuron, including the dendrite. While SVP trafficking was anterogradely biased in axonal segments prior to the synaptic domain, directionality of SVP movement was stochastic in the dendrite and distal axon. Furthermore, frequency of movement and speed were variable between different compartments. These data provide evidence that SVP transport is differentially regulated in distinct neuronal domains. It also suggests that polarized SVP transport in concert with local vesicle capturing is necessary for accurate presynapse formation and maintenance. SVP trafficking analysis of two hypomorphs for UNC-104/KIF1A in combination with mathematical modeling identified directionality of movement, entry of SVPs into the axon as well as axonal speeds as the important determinants of steady-state SVP distributions. Furthermore, detailed dissection of speed distributions for wild-type and unc-104/kif1a mutant animals revealed an unexpected role for UNC-104/KIF1A in dendritic SVP trafficking.

  8. A Novel Pulse-Chase Paradigm to Visualize the Trafficking of Transport Vesicles in Neurons

    NASA Astrophysics Data System (ADS)

    Al-Bassam, Sarmad

    In neurons transmembrane proteins are targeted to dendrites in vesicles that traffic solely within the somatodendritic compartment. How these vesicles are retained within the somatodendritic domain is unknown. Here we adapt a novel pulse chase system that allows synchronous release of exogenous transmembrane proteins from the endoplasmic reticulum using FKBP12 and Rapamycin. We demonstrate proof-of-concept and establish protein trafficking controls in incremental steps. We demonstrate the utility of this approach in studying protein trafficking and establish parameters for analysis of time-lapse images. We implement this novel pulse-chase strategy to track the movements of post-Golgi transport vesicles. Surprisingly, we found that post-Golgi vesicles carrying dendritic proteins were equally likely to enter axons and dendrites. However, once such vesicles entered the axon they very rarely moved beyond the axon initial segment, but instead either halted or reversed direction in an actin and Myosin Va-dependent manner. In contrast, vesicles carrying either an axonal or a nonspecifically localized protein only rarely halted or reversed and instead generally proceeded to the distal axon. Thus, our results are consistent with the axon initial segment behaving as a vesicle filter that mediates the differential trafficking of transport vesicles.

  9. Distal metatarsal synostosis: a case report.

    PubMed

    Aspros, Dimitrios; Ananda-Rajan, Ethan; Jnr, Zdenak Klezl; Rajan, Rohan

    2014-09-01

    We report a rare case of distal metatarsal synostosis of the 4th and 5th metatarsals in an 11 year old male. He was referred with forefoot pain. Clinical examination and radiographs have confirmed an osseous connection of the distal 4th and 5th metatarsal. This was treated surgically with bony bridge excision and the patient is now asymptomatic.

  10. Distal symphalangism: a report of two families.

    PubMed

    Poush, J R

    1991-01-01

    This study describes distal symphalangism in 36 individuals in two families, one of which is the largest pedigree of this rare defect yet documented. Distal symphalangism is ankylosis or rigidity of the distal interphalangeal joints of the hands and/or feet. The findings of this report substantiate the mutation as an autosomal dominant phenotype. Several manifestations of distal symphalangism were observed, including the lack of cutaneous creases over affected joints, brachydactyly, fourth-finger hypophalangism, absent nails, and rudimentary nails. Variability ranged from just toes affected, to a single finger affected, to all fingers and all lesser toes affected. The most common expression of the mutant gene was rigid index fingers. Craniosynostosis, premature closure of the sutures of the skull, was encountered twice in the larger of the two families. It is a possible pleiotropic effect of distal symphalangism. PMID:2061594

  11. Distal symphalangism: a report of two families.

    PubMed

    Poush, J R

    1991-01-01

    This study describes distal symphalangism in 36 individuals in two families, one of which is the largest pedigree of this rare defect yet documented. Distal symphalangism is ankylosis or rigidity of the distal interphalangeal joints of the hands and/or feet. The findings of this report substantiate the mutation as an autosomal dominant phenotype. Several manifestations of distal symphalangism were observed, including the lack of cutaneous creases over affected joints, brachydactyly, fourth-finger hypophalangism, absent nails, and rudimentary nails. Variability ranged from just toes affected, to a single finger affected, to all fingers and all lesser toes affected. The most common expression of the mutant gene was rigid index fingers. Craniosynostosis, premature closure of the sutures of the skull, was encountered twice in the larger of the two families. It is a possible pleiotropic effect of distal symphalangism.

  12. Robotic distal pancreatectomy: a valid option?

    PubMed

    Jung, M K; Buchs, N C; Azagury, D E; Hagen, M E; Morel, P

    2013-10-01

    Although reported in the literature, conventional laparoscopic approach for distal pancreatectomy is still lacking widespread acceptance. This might be due to two-dimensional vision and decreased range of motion to reach and safely dissect this highly vascularized retroperitoneal organ by laparoscopy. However, interest in minimally invasive access is growing ever since and the robotic system could certainly help overcome limitations of the laparoscopic approach in the challenging domain of pancreatic resection, notably in distal pancreatectomy. Robotic distal pancreatectomy with and without spleen preservation has been reported with encouraging outcomes for benign and borderline malignant disease. As a result of upgraded endowristed manipulation and three-dimensional visualization, improved outcome might be expected with the launch of the robotic system in the procedure of distal pancreatectomy. Our aim was thus to extensively review the current literature of robot-assisted surgery for distal pancreatectomy and to evaluate advantages and possible limitations of the robotic approach.

  13. Melanoma miRNA trafficking controls tumour primary niche formation.

    PubMed

    Dror, Shani; Sander, Laureen; Schwartz, Hila; Sheinboim, Danna; Barzilai, Aviv; Dishon, Yuval; Apcher, Sebastien; Golan, Tamar; Greenberger, Shoshana; Barshack, Iris; Malcov, Hagar; Zilberberg, Alona; Levin, Lotan; Nessling, Michelle; Friedmann, Yael; Igras, Vivien; Barzilay, Ohad; Vaknine, Hananya; Brenner, Ronen; Zinger, Assaf; Schroeder, Avi; Gonen, Pinchas; Khaled, Mehdi; Erez, Neta; Hoheisel, Jörg D; Levy, Carmit

    2016-09-01

    Melanoma originates in the epidermis and becomes metastatic after invasion into the dermis. Prior interactions between melanoma cells and dermis are poorly studied. Here, we show that melanoma cells directly affect the formation of the dermal tumour niche by microRNA trafficking before invasion. Melanocytes, cells of melanoma origin, are specialized in releasing pigment vesicles, termed melanosomes. In melanoma in situ, we found melanosome markers in distal fibroblasts before melanoma invasion. The melanosomes carry microRNAs into primary fibroblasts triggering changes, including increased proliferation, migration and pro-inflammatory gene expression, all known features of cancer-associated fibroblasts (CAFs). Specifically, melanosomal microRNA-211 directly targets IGF2R and leads to MAPK signalling activation, which reciprocally encourages melanoma growth. Melanosome release inhibitor prevented CAF formation. Since the first interaction of melanoma cells with blood vessels occurs in the dermis, our data suggest an opportunity to block melanoma invasion by preventing the formation of the dermal tumour niche. PMID:27548915

  14. AMC: amyoplasia and distal arthrogryposis.

    PubMed

    Kimber, Eva

    2015-12-01

    Arthrogryposis multiplex congenita (AMC) is a heterogeneous condition defined as multiple congenital joint contractures in two or more body areas. The common pathogenesis is impaired fetal movements. Amyoplasia, the most frequent form, is a sporadically occurring condition with hypoplastic muscles and joint contractures. Distal arthrogryposis (DA) syndromes are often hereditary, and joint involvement is predominantly in the hands and feet. In a Swedish study, 131 patients with arthrogryposis were investigated. The most frequent diagnoses were amyoplasia and DA. In amyoplasia, muscle strength was found to be more important than joint range of motion (ROM) for motor function. In DA, muscle weakness was present in 44 % of investigated patients. The clinical findings were found to be highly variable between families and also within families with DA. Fetal myopathy due to sarcomeric protein dysfunction can cause DA. An early multidisciplinary team evaluation of the child with arthrogryposis for specific diagnosis and planning of treatment is recommended. Attention should be directed at the development of muscle strength with early stimulation of active movements. Immobilization should be minimized.

  15. Trafficking vesicles: pro or contra pathogens?

    PubMed

    Frei dit Frey, Nicolas; Robatzek, Silke

    2009-08-01

    Membrane compartmentalization and trafficking are pivotal for eukaryotic life and demand a higher order of coordination. Even in their resting state, most plant cells exhibit a polarized localization of membrane compartments, which is redirected when plant cells are attacked by microbes. Repositioning of organelles at pathogen penetration sites has been reported since more than a decade; however, only recently has targeted vesicle trafficking upon biotic stress emerged. It has become evident that vesicle secretion and endocytic pathways are engaged in the plant's immune system to actively defend against potential pathogens. By contrast, invasive pathogens have evolved means to utilize these trafficking pathways for the suppression of plant defenses and to the benefit of microbial proliferation. This review summarizes recent findings of host intracellular endomembrane adaptations in response to pathogens and how pathogens exploit them. PMID:19608452

  16. Vesicle trafficking and cell surface membrane patchiness.

    PubMed

    Tang, Q; Edidin, M

    2001-07-01

    Membrane proteins and lipids often appear to be distributed in patches on the cell surface. These patches are often assumed to be membrane domains, arising from specific molecular associations. However, a computer simulation (Gheber and Edidin, 1999) shows that membrane patchiness may result from a combination of vesicle trafficking and dynamic barriers to lateral mobility. The simulation predicts that the steady-state patches of proteins and lipids seen on the cell surface will decay if vesicle trafficking is inhibited. To test this prediction, we compared the apparent sizes and intensities of patches of class I HLA molecules, integral membrane proteins, before and after inhibiting endocytic vesicle traffic from the cell surface, either by incubation in hypertonic medium or by expression of a dominant-negative mutant dynamin. As predicted by the simulation, the apparent sizes of HLA patches increased, whereas their intensities decreased after endocytosis and vesicle trafficking were inhibited. PMID:11423406

  17. Purinergic Signaling During Immune Cell Trafficking.

    PubMed

    Ferrari, Davide; McNamee, Eóin N; Idzko, Marco; Gambari, Roberto; Eltzschig, Holger K

    2016-06-01

    Migration and positioning of immune cells is fundamental for their differentiation and recruitment at sites of infection. Besides the fundamental role played by chemokines and their receptors, recent studies demonstrate that a complex network of purinergic signaling events plays a key role in these trafficking events. This process includes the release of nucleotides (such as ATP and ADP) and subsequent autocrine and paracrine signaling events through nucleotide receptors. At the same time, surface-expressed ectoapyrases and nucleotidases convert extracellular nucleotides to adenosine, and adenosine signaling events play additional functional roles in leucocyte trafficking. In this review we revisit classical paradigms of inflammatory cell trafficking in the context of recent studies implicating purinergic signaling events in this process. PMID:27142306

  18. Trafficking in persons and development: towards greater policy coherence.

    PubMed

    Danailova-Trainor, Gergana; Laczko, Frank

    2010-01-01

    Poverty is often regarded as the "root cause" of trafficking, but the linkages between poverty, a lack of development and trafficking are complex. For example, there is some evidence to suggest that victims of cross-border trafficking are more likely to originate from middle-income rather than lower-income countries. Trafficking and development have tended to be treated as very separate policy areas and the assessment of the development impact of counter-trafficking programmes is still at an early stage. This paper outlines a possible framework for a more evidence-based approach to understanding the linkages between trafficking, trafficking policy and human development. The paper argues that the human development gains from greater mobility could be significantly enhanced if there was greater coherence between policies to combat trafficking and policies to promote development. PMID:20645470

  19. 31 CFR 536.312 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... designated narcotics trafficker means: (a) Persons listed in the annex to Executive Order 12978 (3 CFR, 1995... international narcotics trafficking centered in Colombia; or (2) Materially to assist in, or provide...

  20. Distal phalanges of Eosimias and Hoanghonius.

    PubMed

    Gebo, Daniel L; Beard, K Christopher; Ni, Xijun; Dagosto, Marian

    2015-09-01

    Seven primate distal phalanges have been identified from two middle Eocene fossil localities (Locality 1 and Nanbaotou) in the Yuanqu Basin, China, providing the first evidence of distal phalangeal morphology in Asian Eocene adapiform and eosimiid primates. The bones are best allocated to the basal anthropoid Eosimias centennicus and to hoanghoniine adapiforms. All distal phalangeal specimens display a morphology consistent with nail-bearing fingers and toes. The hallucal distal phalanx of the basal anthropoid Eosimias is more similar to that of primitive tarsiiforms than to crown group anthropoids. The adapiform distal phalanges from Locality 1 are allocated to Hoanghonius stehlini while those from Nanbaotou are tentatively assigned to an indeterminate hoanghoniine because dental remains of adapiforms have yet to be identified from this site. The distal phalangeal anatomy of hoanghoniines differs slightly from that documented for adapines and notharctines. One distal phalanx from Locality 1 shows a second pedal digit "grooming claw" morphology as noted for notharctines by Maiolino et al. (2012) and cercamoniines by Von Koenigswald et al. (2012).

  1. Human telomerase: biogenesis, trafficking, recruitment, and activation.

    PubMed

    Schmidt, Jens C; Cech, Thomas R

    2015-06-01

    Telomerase is the ribonucleoprotein enzyme that catalyzes the extension of telomeric DNA in eukaryotes. Recent work has begun to reveal key aspects of the assembly of the human telomerase complex, its intracellular trafficking involving Cajal bodies, and its recruitment to telomeres. Once telomerase has been recruited to the telomere, it appears to undergo a separate activation step, which may include an increase in its repeat addition processivity. This review covers human telomerase biogenesis, trafficking, and activation, comparing key aspects with the analogous events in other species.

  2. Homeostatic plasticity and NMDA receptor trafficking.

    PubMed

    Pérez-Otaño, Isabel; Ehlers, Michael D

    2005-05-01

    Learning, memory and brain development are associated with long-lasting modifications of synapses that are guided by specific patterns of neuronal activity. Such modifications include classical Hebbian plasticities (such as long-term potentiation and long-term depression), which are rapid and synapse-specific, and others, such as synaptic scaling and metaplasticity, that work over longer timescales and are crucial for maintaining and orchestrating neuronal network function. The cellular mechanisms underlying Hebbian plasticity have been well studied and involve rapid changes in the trafficking of highly mobile AMPA receptors. An emerging concept is that activity-dependent alterations in NMDA receptor trafficking contribute to homeostatic plasticity at central glutamatergic synapses.

  3. Nonbridging external fixation of distal radius fractures.

    PubMed

    Eichenbaum, Matthew D; Shin, Eon K

    2010-08-01

    Surgical management of distal radius fractures continues to evolve because of their high incidence in an increasingly active elderly population. Traditional radiocarpal external fixation relies on ligamentotaxis for fracture reduction but has several drawbacks. Nonbridging external fixation has evolved to provide early wrist mobility in the setting of anatomic fracture reduction. Several studies of the nonbridging technique have demonstrated satisfactory results in isolated nonbridging external fixation series and in comparison with traditional spanning external fixation. Nonbridging external fixation for surgical treatment of distal radius fractures can be technically demanding and requires at least 1 cm of intact volar cortex in the distal fracture fragment for successful implementation.

  4. Distal Peripheral Polyneuropathy in a Great Dane

    PubMed Central

    Henricks, Paul M.; Steiss, Jan; Petterson, Joanne D.

    1987-01-01

    A spayed female five year old Great Dane dog was diagnosed as having a chronic, progressive, symmetrical distal polyneuropathy and concurrent hypothyroidism. Axonal degeneration and segmental demyelination were evident in teased nerve fiber preparations. Clinical signs included hindlimb weakness and muscle atrophy of the head and distal limbs. Diagnosis was based on clinical, electrophysiological, and nerve and muscle biopsy findings. Thyroxine supplementation for one month was of no benefit. The etiology of the polyneuropathy was not established but several causes were considered. The extent of demyelination in our case was of greater magnitude than described in a previous report of a similar idiopathic distal symmetrical polyneuropathy in a Great Dane. PMID:17422753

  5. Child organ trafficking: global reality and inadequate international response.

    PubMed

    Bagheri, Alireza

    2016-06-01

    In organ transplantation, the demand for human organs has grown far faster than the supply of organs. This has opened the door for illegal organ trade and trafficking including from children. Organized crime groups and individual organ brokers exploit the situation and, as a result, black markets are becoming more numerous and organized organ trafficking is expanding worldwide. While underprivileged and vulnerable men and women in developing countries are a major source of trafficked organs, and may themselves be trafficked for the purpose of illegal organ removal and trade, children are at especial risk of exploitation. With the confirmed cases of children being trafficked for their organs, child organ trafficking, which once called a "modern urban legend", is a sad reality in today's world. By presenting a global picture of child organ trafficking, this paper emphasizes that child organ trafficking is no longer a myth but a reality which has to be addressed. It argues that the international efforts against organ trafficking and trafficking in human beings for organ removal have failed to address child organ trafficking adequately. This chapter suggests that more orchestrated international collaboration as well as development of preventive measure and legally binding documents are needed to fight child organ trafficking and to support its victims. PMID:26612382

  6. 78 FR 70571 - Advisory Council on Wildlife Trafficking; Rescheduled Meeting

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-11-26

    ... Fish and Wildlife Service Advisory Council on Wildlife Trafficking; Rescheduled Meeting AGENCY: Fish... Service (Service), announce a public meeting of the Advisory Council on Wildlife Trafficking (Council... announce that the Advisory Council on Wildlife Trafficking (Council) will hold a meeting to...

  7. 48 CFR 52.222-50 - Combating Trafficking in Persons.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 48 Federal Acquisition Regulations System 2 2011-10-01 2011-10-01 false Combating Trafficking in....222-50 Combating Trafficking in Persons. As prescribed in 22.1705(a), insert the following clause: Combating Trafficking in Persons (FEB 2009) (a) Definitions. As used in this clause— Coercion means—...

  8. Child organ trafficking: global reality and inadequate international response.

    PubMed

    Bagheri, Alireza

    2016-06-01

    In organ transplantation, the demand for human organs has grown far faster than the supply of organs. This has opened the door for illegal organ trade and trafficking including from children. Organized crime groups and individual organ brokers exploit the situation and, as a result, black markets are becoming more numerous and organized organ trafficking is expanding worldwide. While underprivileged and vulnerable men and women in developing countries are a major source of trafficked organs, and may themselves be trafficked for the purpose of illegal organ removal and trade, children are at especial risk of exploitation. With the confirmed cases of children being trafficked for their organs, child organ trafficking, which once called a "modern urban legend", is a sad reality in today's world. By presenting a global picture of child organ trafficking, this paper emphasizes that child organ trafficking is no longer a myth but a reality which has to be addressed. It argues that the international efforts against organ trafficking and trafficking in human beings for organ removal have failed to address child organ trafficking adequately. This chapter suggests that more orchestrated international collaboration as well as development of preventive measure and legally binding documents are needed to fight child organ trafficking and to support its victims.

  9. Human Trafficking: A Review for Mental Health Professionals

    ERIC Educational Resources Information Center

    Yakushko, Oksana

    2009-01-01

    This article provides a review of current research on human trafficking for mental health practitioners and scholars. In addition to an overview of definitions, causes and processes of trafficking, the article highlights mental health consequences of trafficking along with suggestions for treatment of survivors. Directions for counseling services,…

  10. Trafficking of Children in Albania: Patterns of Recruitment and Reintegration

    ERIC Educational Resources Information Center

    Gjermeni, Eglantina; Van Hook, Mary P.; Gjipali, Saemira; Xhillari, Lindita; Lungu, Fatjon; Hazizi, Anila

    2008-01-01

    Problem: Many children in Albania and other countries of Eastern Europe are being trafficked as part of the global business of human trafficking. Objectives: The study sought to identify the patterns of child trafficking involving Albanian children, and especially children's views of the role of family issues and the nature of the trafficking…

  11. Villous adenoma of the distal appendix.

    PubMed

    Taylor, J V; Thomas, M G; Kelly, S; Sutton, R

    1997-04-01

    Villous adenoma confined to the distal appendix has not been previously reported in conjunction with acute apendicitis. The presence of an adenoma indicates a need for further investigation due to an association with neoplasia elsewhere.

  12. Domestic minor sex trafficking: what the PNP needs to know.

    PubMed

    Hornor, Gail

    2015-01-01

    Human trafficking is a major global public health problem and represents a substantial human rights violation. Human trafficking has been receiving attention in both the lay media and professional literature. Human trafficking can include commercial sex, forced labor, child soldiers, and stealing of human organs. One form of human trafficking represents a significant American pediatric health problem: domestic minor sex trafficking (DMST). DMST is the commercial sexual abuse of children by selling, buying, or trading their sexual service. This continuing education article will define DMST and discuss it in terms of prevalence, risk factors, and practice implications for the pediatric nurse practitioner. PMID:25497135

  13. Domestic minor sex trafficking: what the PNP needs to know.

    PubMed

    Hornor, Gail

    2015-01-01

    Human trafficking is a major global public health problem and represents a substantial human rights violation. Human trafficking has been receiving attention in both the lay media and professional literature. Human trafficking can include commercial sex, forced labor, child soldiers, and stealing of human organs. One form of human trafficking represents a significant American pediatric health problem: domestic minor sex trafficking (DMST). DMST is the commercial sexual abuse of children by selling, buying, or trading their sexual service. This continuing education article will define DMST and discuss it in terms of prevalence, risk factors, and practice implications for the pediatric nurse practitioner.

  14. Cortical development of AMPA receptor trafficking proteins

    PubMed Central

    Murphy, Kathryn M.; Tcharnaia, Lilia; Beshara, Simon P.; Jones, David G.

    2012-01-01

    AMPA-receptor trafficking plays a central role in excitatory plasticity, especially during development. Changes in the number of AMPA receptors and time spent at the synaptic surface are important factors of plasticity that directly affect long-term potentiation (LTP), long-term depression (LTD), synaptic scaling, and the excitatory-inhibitory (E/I) balance in the developing cortex. Experience-dependent changes in synaptic strength in visual cortex (V1) use a molecularly distinct AMPA trafficking pathway that includes the GluA2 subunit. We studied developmental changes in AMPA receptor trafficking proteins by quantifying expression of GluA2, pGluA2 (GluA2serine880), GRIP1, and PICK1 in rat visual and frontal cortex. We used Western Blot analysis of synaptoneurosome preparations of rat visual and frontal cortex from animals ranging in age from P0 to P105. GluA2 and pGluA2 followed different developmental trajectories in visual and frontal cortex, with a brief period of over expression in frontal cortex. The over expression of GluA2 and pGluA2 in immature frontal cortex raises the possibility that there may be a period of GluA2-dependent vulnerability in frontal cortex that is not found in V1. In contrast, GRIP1 and PICK1 had the same developmental trajectories and were expressed very early in development of both cortical areas. This suggests that the AMPA-interacting proteins are available to begin trafficking receptors as soon as GluA2-containing receptors are expressed. Finally, we used all four proteins to analyze the surface-to-internalization balance and found that this balance was roughly equal across both cortical regions, and throughout development. Our finding of an exquisite surface-to-internalization balance highlights that these AMPA receptor trafficking proteins function as a tightly controlled system in the developing cortex. PMID:22623912

  15. Trafficking and contract migrant workers in the Middle East.

    PubMed

    Jureidini, Ray

    2010-01-01

    The paper addresses a number of issues regarding the extent to which trafficking may be applied to migrant domestic workers who enter under the kafala system of sponsorship in the Middle East. Migrant domestic workers are the most numerous of those mentioned in reports on trafficking for labour exploitation in the region. The discussion seeks to determine whether "trafficking" can be ex post facto, rather than ex ante? In other words, can the label of trafficking be attributed only after the worker has arrived in the receiving country and is victimized according to the principles of trafficking protocols? In addition, must there be a proven intent to traffic by agents, or can employers who harm and/or exploit them be considered as traffickers alone? Should the harm done to workers on arrival at their place of work be classified (and assisted) as victims of trafficking, or as exploited workers?

  16. Archaic and modern human distal humeral morphology.

    PubMed

    Yokley, Todd R; Churchill, Steven E

    2006-12-01

    The morphology of the proximal ulna has been shown to effectively differentiate archaic or premodern humans (such as Homo heidelbergensis and H. neanderthalensis) from modern humans (H. sapiens). Accordingly, the morphology of adjacent, articulating elements should be able to distinguish these two broad groups as well. Here we test the taxonomic utility of another portion of the elbow, the distal humerus, as a discriminator of archaic and modern humans. Principal components analysis was employed on a suite of log-raw and log-shape distal humeral measures to examine differences between Neandertal and modern human distal humeri. In addition, the morphological affinities of Broken Hill (Kabwe) E.898, an archaic human distal humeral fragment from the middle Pleistocene of Zambia, and five Pliocene and early Pleistocene australopith humeri were assessed. The morphometric analyses effectively differentiated the Neandertals from the other groups, while the Broken Hill humerus appears morphologically similar to modern human distal humeri. Thus, an archaic/modern human dichotomy-as previously reported for proximal ulnar morphology-is not supported with respect to distal humeral morphology. Relative to australopiths and modern humans, Neandertal humeri are characterized by large olecranon fossae and small distodorsal medial and lateral pillars. The seeming disparity in morphological affinities of proximal ulnae (in which all archaic human groups appear distinct from modern humans) and distal humeri (in which Neandertals appear distinct from modern humans, but other archaic humans do not) is probably indicative of a highly variable, possibly transitional population of which our knowledge is hampered by sample-size limitations imposed by the scarcity of middle-to-late Pleistocene premodern human fossils outside of Europe.

  17. Management of distal humeral coronal shear fractures

    PubMed Central

    Yari, Shahram S; Bowers, Nathan L; Craig, Miguel A; Reichel, Lee M

    2015-01-01

    Coronal shear fractures of the distal humerus are rare, complex fractures that can be technically challenging to manage. They usually result from a low-energy fall and direct compression of the distal humerus by the radial head in a hyper-extended or semi-flexed elbow or from spontaneous reduction of a posterolateral subluxation or dislocation. Due to the small number of soft tissue attachments at this site, almost all of these fractures are displaced. The incidence of distal humeral coronal shear fractures is higher among women because of the higher rate of osteoporosis in women and the difference in carrying angle between men and women. Distal humeral coronal shear fractures may occur in isolation, may be part of a complex elbow injury, or may be associated with injuries proximal or distal to the elbow. An associated lateral collateral ligament injury is seen in up to 40% and an associated radial head fracture is seen in up to 30% of these fractures. Given the complex nature of distal humeral coronal shear fractures, there is preference for operative management. Operative fixation leads to stable anatomic reduction, restores articular congruity, and allows initiation of early range-of-motion movements in the majority of cases. Several surgical exposure and fixation techniques are available to reconstruct the articular surface following distal humeral coronal shear fractures. The lateral extensile approach and fixation with countersunk headless compression screws placed in an anterior-to-posterior fashion are commonly used. We have found a two-incision approach (direct anterior and lateral) that results in less soft tissue dissection and better outcomes than the lateral extensile approach in our experience. Stiffness, pain, articular incongruity, arthritis, and ulnohumeral instability may result if reduction is non-anatomic or if fixation fails. PMID:25984515

  18. Physical health symptoms reported by trafficked women receiving post-trafficking support in Moldova: prevalence, severity and associated factors

    PubMed Central

    2012-01-01

    Background Many trafficked people suffer high levels of physical, sexual and psychological abuse. Yet, there has been limited research on the physical health problems associated with human trafficking or how the health needs of women in post-trafficking support settings vary according to socio-demographic or trafficking characteristics. Methods We analysed the prevalence and severity of 15 health symptoms reported by 120 trafficked women who had returned to Moldova between December 2007 and December 2008 and were registered with the International Organisation for Migration Assistance and Protection Programme. Women had returned to Moldova an average of 5.9 months prior to interview (range 2-12 months). Results Headaches (61.7%), stomach pain (60.9%), memory problems (44.2%), back pain (42.5%), loss of appetite (35%), and tooth pain (35%) were amongst the most commonly reported symptoms amongst both women trafficked for sexual exploitation and women trafficked for labour exploitation. The prevalence of headache and memory problems was strongly associated with duration of exploitation. Conclusions Trafficked women who register for post-trafficking support services after returning to their country of origin are likely to have long-term physical and dental health needs and should be provided with access to comprehensive medical services. Health problems among women who register for post-trafficking support services after returning to their country of origin are not limited to women trafficked for sexual exploitation but are also experienced by victims of labour exploitation. PMID:22834807

  19. Distal protection for treatment of complete cervical internal carotid occlusion.

    PubMed

    Hungerford, John P; Chaudry, Imran; Turner, Raymond; Turk, Aquilla S

    2012-01-01

    Distal protection devices (DPD) have been advocated for carotid artery stenting to reduce the risk of distal embolization. These devices were designed for deployment in the straight cervical segment of the internal carotid artery. We present a case of total cervical carotid occlusion recanalized with the aid of a distal protection device deployed 'distally' in the intracranial internal carotid artery.

  20. Sextant of Sapphires for Molar Distalization

    PubMed Central

    Palla, Yudistar Venkata; Ganugapanta, Vivek Reddy

    2016-01-01

    Introduction Space analysis quantifies the amount of crowding within the arches estimating the severity of space discrepancy. The space gaining procedures include extraction and non-extraction procedures like expansion, proximal stripping and molar distalization. Aim To identify features seen in molar distalization cases. Materials and Methods The sample size comprised 20 patients in whom molar distalization was decided as the treatment plan. The study models and lateral cephalograms of all the patients were taken. Occlusograms were obtained. Model analysis and cephalometric analysis were performed. Descriptive statistical analysis like mean, standard deviation, standard error and mode were done. Results The parameters in Question gave following results. The Bolton analysis showed anterior mandibular excess with mean value of 1.56mm±1.07. The first order discrepancy between maxillary central and lateral incisors was 5±1.95. The premolar rotation showed mean value of 16.58±5.12. The molar rotation showed the value of 7.66±2.26. The nasolabial angle showed the mean of 101.25±8.7 IMPA of 101.4±5.74. Conclusion The six features studied in molar distalization cases [First order discrepancy between upper central and lateral incisors; Rotation of premolars and molars; Bolton’s discrepancy in anterior dentition; Average to horizontal growth pattern; Proclined lower incisors and Obtuse nasolabial angle] can be taken as patterns seen in molar distalization cases and considered as a valid treatment plan. PMID:27656572

  1. Failure of distal biceps repair by gapping

    PubMed Central

    Copas, David; Watts, Adam C

    2016-01-01

    Background We describe the clinical, radiological and surgical findings of failed distal biceps repair by gapping and report the functional outcomes following revision repair. Methods A retrospective review of five consecutive patients was conducted. Patients presented with radial-sided forearm pain after their distal biceps fixation. All patients had less than 5 cm of retraction of the biceps muscle belly, a palpable tendon although the manoeuvre was painful with weakness on resisted supination. Flexed abducted supinated magnetic resonance imaging (FABS MRI) showed a gap between the distal end of the tendon and the footprint on the radial tuberosity. Results Mean FEA score at presentation was 44/100 (35 to 49). Mean time to re-operation was 18 months (range 4 months to 36 months). At revision, the distal end of the tendon was retracted and not making contact with the bone. All cases were revised to an in-bone endobutton repair. Mean postoperative Functional Elbow Assessment (FEA) scores undertaken at a mean of 14 months (range 5 months to 22 months) after revision improved to 95/100 (90 to 100). Conclusions Patients presenting with persistent radial sided forearm pain and weakness on provocative testing after distal biceps repair with a seemingly intact repair should be investigated with FABS MRI to look for evidence of failure of repair by gapping. Revision repair with an anatomic in-bone technique can lead to good results. PMID:27583018

  2. Sex Trafficking: Policies, Programs, and Services.

    PubMed

    Orme, Julie; Ross-Sheriff, Fariyal

    2015-10-01

    Sex trafficking (ST), a contemporary form of female slavery, is a human rights issue of critical concern to social work. The global response to ST has been substantial, and 166 countries have adopted anti-ST legislation. Despite considerable efforts to combat ST, the magnitude is increasing. To date, the majority of anti-ST efforts have focused on criminalization policies that target traffickers or purchasers of sexual services, who are predominantly male; prevention programming and services for predominantly female victims have received less support. Therapeutic services to assist pornography addicts and purchasers of sexual services are also necessary. In this article, authors examine current anti-ST policies, programs, and services, both domestically and globally, and present an innovative paradigm that addresses social inequities and emphasizes prevention programming. They conclude with a discussion of the paradigm's implications for social work policies, practices, and services. PMID:26489349

  3. Technosocial Predictive Analytics for Illicit Nuclear Trafficking

    SciTech Connect

    Sanfilippo, Antonio P.; Butner, R. Scott; Cowell, Andrew J.; Dalton, Angela C.; Haack, Jereme N.; Kreyling, Sean J.; Riensche, Roderick M.; White, Amanda M.; Whitney, Paul D.

    2011-03-29

    Illicit nuclear trafficking networks are a national security threat. These networks can directly lead to nuclear proliferation, as state or non-state actors attempt to identify and acquire nuclear weapons-related expertise, technologies, components, and materials. The ability to characterize and anticipate the key nodes, transit routes, and exchange mechanisms associated with these networks is essential to influence, disrupt, interdict or destroy the function of the networks and their processes. The complexities inherent to the characterization and anticipation of illicit nuclear trafficking networks requires that a variety of modeling and knowledge technologies be jointly harnessed to construct an effective analytical and decision making workflow in which specific case studies can be built in reasonable time and with realistic effort. In this paper, we explore a solution to this challenge that integrates evidentiary and dynamic modeling with knowledge management and analytical gaming, and demonstrate its application to a geopolitical region at risk.

  4. Maritime drug trafficking: an underrated problem.

    PubMed

    Aune, B R

    1990-01-01

    Seizure data indicate that a substantial proportion of the total quantity of drugs seized is confiscated from maritime modes of conveyance or has been transported by sea. The trafficking of narcotic drugs by sea has virtually become an industry comprised of many individual enterprises of varying size and organization. The maritime medium is one of the main ways by which drugs may enter some countries. In response to the problem, various sophisticated anti-trafficking offensives and strategies have been established or contemplated in certain geographical areas. The shipment of drugs to the primary consuming countries has not been curbed, however, and there is every indication that the overall movement of drugs is still unimpeded.

  5. Regulatory T-cell compartmentalization and trafficking

    PubMed Central

    Wei, Shuang; Kryczek, Ilona; Zou, Weiping

    2006-01-01

    CD4+CD25+FOXP3+ regulatory T cells (CD4+ Treg cells) are thought to differentiate in the thymus and immigrate from the thymus to the periphery. Treg cells can regulate both acquired and innate immunity through multiple modes of suppression. The cross-talk between Treg cells and targeted cells, such as antigen-presenting cells (APCs) and T cells, is crucial for ensuring suppression by Treg cells in the appropriate microenvironment. Emerging evidence suggests that Treg compartmentalization and trafficking may be tissue or/and organ specific and that distinct chemokine receptor and integrin expression may contribute to selective retention and trafficking of Treg cells at sites where regulation is required. In this review, the cellular and molecular signals that control specialized migration and retention of Treg cells are discussed. PMID:16537800

  6. Endocytic membrane trafficking and neurodegenerative disease.

    PubMed

    Schreij, Andrea M A; Fon, Edward A; McPherson, Peter S

    2016-04-01

    Neurodegenerative diseases are amongst the most devastating of human disorders. New technologies have led to a rapid increase in the identification of disease-related genes with an enhanced appreciation of the key roles played by genetics in the etiology of these disorders. Importantly, pinpointing the normal function of disease gene proteins leads to new understanding of the cellular machineries and pathways that are altered in the disease process. One such emerging pathway is membrane trafficking in the endosomal system. This key cellular process controls the localization and levels of a myriad of proteins and is thus critical for normal cell function. In this review we will focus on three neurodegenerative diseases; Parkinson disease, amyotrophic lateral sclerosis, and hereditary spastic paraplegias, for which a large number of newly discovered disease genes encode proteins that function in endosomal membrane trafficking. We will describe how alterations in these proteins affect endosomal function and speculate on the contributions of these disruptions to disease pathophysiology. PMID:26721251

  7. Sex Trafficking: Policies, Programs, and Services.

    PubMed

    Orme, Julie; Ross-Sheriff, Fariyal

    2015-10-01

    Sex trafficking (ST), a contemporary form of female slavery, is a human rights issue of critical concern to social work. The global response to ST has been substantial, and 166 countries have adopted anti-ST legislation. Despite considerable efforts to combat ST, the magnitude is increasing. To date, the majority of anti-ST efforts have focused on criminalization policies that target traffickers or purchasers of sexual services, who are predominantly male; prevention programming and services for predominantly female victims have received less support. Therapeutic services to assist pornography addicts and purchasers of sexual services are also necessary. In this article, authors examine current anti-ST policies, programs, and services, both domestically and globally, and present an innovative paradigm that addresses social inequities and emphasizes prevention programming. They conclude with a discussion of the paradigm's implications for social work policies, practices, and services.

  8. Regulation of ENaC trafficking in rat kidney

    PubMed Central

    Frindt, Gustavo; Gravotta, Diego

    2016-01-01

    The epithelial Na channel (ENaC) forms a pathway for Na+ reabsorption in the distal nephron, and regulation of these channels is essential for salt homeostasis. In the rat kidney, ENaC subunits reached the plasma membrane in both immature and fully processed forms, the latter defined by either endoglycosidase H–insensitive glycosylation or proteolytic cleavage. Animals adapted to a low-salt diet have increased ENaC surface expression that is specific for the mature forms of the subunit proteins and is similar (three- to fourfold) for α, β, and γENaC. Kidney membranes were fractionated using differential centrifugation, sucrose-gradient separation, and immunoabsorption. Endoplasmic reticulum membranes, isolated using an antibody against calnexin, expressed immature γENaC, and the content decreased with Na depletion. Golgi membranes, isolated with an antibody against the cis-Golgi protein GM130, expressed both immature and processed γENaC; Na depletion increased the content of processed γENaC in this fraction by 3.8-fold. An endosomal compartment isolated using an antibody against Rab11 contained both immature and processed γENaC; the content of processed subunit increased 2.4-fold with Na depletion. Finally, we assessed the content of γENaC in the late endocytic compartments indirectly using urinary exosomes. All of the γENaC in these exosomes was in the fully cleaved form, and its content increased by 4.5-fold with Na depletion. These results imply that stimulation of ENaC surface expression results at least in part from increased rates of formation of fully processed subunits in the Golgi and subsequent trafficking to the apical membrane. PMID:26880754

  9. Fabrication and Evaluation of a Noncompliant Molar Distalizing Appliance: Bonded Molar Distalizer

    PubMed Central

    Sodagar, A.; Ahmad Akhoundi, M. S.; Rafighii, A.; Arab, S.

    2011-01-01

    Objective Attempts to treat class II malocclusions without extraction in non-compliant patients have led to utilization of intraoral molar distalizing appliances. The purpose of this study was to investigate dental and skeletal effects of Bonded Molar Distalizer (BMD) which is a simple molar distalizing appliance. Materials and Methods Sixteen patients (12 girls, four boys) with bilateral half-cusp class II molar relationship, erupted permanent second molars and normal or vertical growth pattern were selected for bilateral distalization of maxillary molars via BMD. The screws were activated every other day, alternately. Lateral cephalograms and study models were obtained before treatment and after 11 weeks activation of the appliance. Results Significant amounts of molar distalization, molar distal tipping and anchorage loss were observed. The mean maxillary first molar distal movement was 1.22±0.936 mm with a distal tipping of 2.97±3.74 degrees in 11 weeks. The rate of distal movement was 0.48 mm per month. Reciprocal mesial movement of the first premolars was 2.26±1.12 mm with a mesial tipping of 4.25±3.12 degrees. Maxillary incisors moved 3.55±1.46 mm and tipped 9.87±5.03 degrees mesially. Lower anterior face height (LAFH) decreased 1.28±1.36 mm. Conclusion BMD is appropriate for distalizing maxillary molars, especially in patients with critical LAFH, although significant amounts of anchorage loss occur using this appliance. PMID:22457837

  10. Treatment Options for Distal Femur Fractures.

    PubMed

    von Keudell, Arvind; Shoji, Kristin; Nasr, Michael; Lucas, Robert; Dolan, Robert; Weaver, Michael J

    2016-08-01

    Despite advances in implant design, the management of distal femur fractures remains challenging. Fracture comminution and intra-articular extension can make it difficult to obtain an adequate reduction while preserving the soft tissue attachments to bone fragments to allow for bone healing. Many implant manufacturers have developed optimal anatomically contoured, distal femoral locking plates with percutaneous guides. This environment allows for the application of lateral locked plates in a biologically friendly manner. Although initial reports had high success rates, more recently a high rate of nonunion has been found, particularly in elderly patients. Limited literature is available for the treatment of patients with osteoporotic bone and associated ipsilateral total knee replacement and hip replacement. We present a patient with a distal femur fracture with significant comminution in the setting of an ipsilateral total hip replacement. PMID:27441931

  11. Protein trafficking during plant innate immunity.

    PubMed

    Wang, Wen-Ming; Liu, Peng-Qiang; Xu, Yong-Ju; Xiao, Shunyuan

    2016-04-01

    Plants have evolved a sophisticated immune system to fight against pathogenic microbes. Upon detection of pathogen invasion by immune receptors, the immune system is turned on, resulting in production of antimicrobial molecules including pathogenesis-related (PR) proteins. Conceivably, an efficient immune response depends on the capacity of the plant cell's protein/membrane trafficking network to deploy the right defense-associated molecules in the right place at the right time. Recent research in this area shows that while the abundance of cell surface immune receptors is regulated by endocytosis, many intracellular immune receptors, when activated, are partitioned between the cytoplasm and the nucleus for induction of defense genes and activation of programmed cell death, respectively. Vesicle transport is an essential process for secretion of PR proteins to the apoplastic space and targeting of defense-related proteins to the plasma membrane or other endomembrane compartments. In this review, we discuss the various aspects of protein trafficking during plant immunity, with a focus on the immunity proteins on the move and the major components of the trafficking machineries engaged. PMID:26345282

  12. Role of adaptor proteins and clathrin in the trafficking of human kidney anion exchanger 1 (kAE1) to the cell surface.

    PubMed

    Junking, Mutita; Sawasdee, Nunghathai; Duangtum, Natapol; Cheunsuchon, Boonyarit; Limjindaporn, Thawornchai; Yenchitsomanus, Pa-thai

    2014-07-01

    Kidney anion exchanger 1 (kAE1) plays an important role in acid-base homeostasis by mediating chloride/bicarbornate (Cl-/HCO3-) exchange at the basolateral membrane of α-intercalated cells in the distal nephron. Impaired intracellular trafficking of kAE1 caused by mutations of SLC4A1 encoding kAE1 results in kidney disease - distal renal tubular acidosis (dRTA). However, it is not known how the intracellular sorting and trafficking of kAE1 from trans-Golgi network (TGN) to the basolateral membrane occurs. Here, we studied the role of basolateral-related sorting proteins, including the mu1 subunit of adaptor protein (AP) complexes, clathrin and protein kinase D, on kAE1 trafficking in polarized and non-polarized kidney cells. By using RNA interference, co-immunoprecipitation, yellow fluorescent protein-based protein fragment complementation assays and immunofluorescence staining, we demonstrated that AP-1 mu1A, AP-3 mu1, AP-4 mu1 and clathrin (but not AP-1 mu1B, PKD1 or PKD2) play crucial roles in intracellular sorting and trafficking of kAE1. We also demonstrated colocalization of kAE1 and basolateral-related sorting proteins in human kidney tissues by double immunofluorescence staining. These findings indicate that AP-1 mu1A, AP-3 mu1, AP-4 mu1 and clathrin are required for kAE1 sorting and trafficking from TGN to the basolateral membrane of acid-secreting α-intercalated cells. PMID:24698155

  13. Role of adaptor proteins and clathrin in the trafficking of human kidney anion exchanger 1 (kAE1) to the cell surface.

    PubMed

    Junking, Mutita; Sawasdee, Nunghathai; Duangtum, Natapol; Cheunsuchon, Boonyarit; Limjindaporn, Thawornchai; Yenchitsomanus, Pa-thai

    2014-07-01

    Kidney anion exchanger 1 (kAE1) plays an important role in acid-base homeostasis by mediating chloride/bicarbornate (Cl-/HCO3-) exchange at the basolateral membrane of α-intercalated cells in the distal nephron. Impaired intracellular trafficking of kAE1 caused by mutations of SLC4A1 encoding kAE1 results in kidney disease - distal renal tubular acidosis (dRTA). However, it is not known how the intracellular sorting and trafficking of kAE1 from trans-Golgi network (TGN) to the basolateral membrane occurs. Here, we studied the role of basolateral-related sorting proteins, including the mu1 subunit of adaptor protein (AP) complexes, clathrin and protein kinase D, on kAE1 trafficking in polarized and non-polarized kidney cells. By using RNA interference, co-immunoprecipitation, yellow fluorescent protein-based protein fragment complementation assays and immunofluorescence staining, we demonstrated that AP-1 mu1A, AP-3 mu1, AP-4 mu1 and clathrin (but not AP-1 mu1B, PKD1 or PKD2) play crucial roles in intracellular sorting and trafficking of kAE1. We also demonstrated colocalization of kAE1 and basolateral-related sorting proteins in human kidney tissues by double immunofluorescence staining. These findings indicate that AP-1 mu1A, AP-3 mu1, AP-4 mu1 and clathrin are required for kAE1 sorting and trafficking from TGN to the basolateral membrane of acid-secreting α-intercalated cells.

  14. Distal Humerus Fractures: Open Reduction Internal Fixation.

    PubMed

    Mighell, Mark A; Stephens, Brent; Stone, Geoffrey P; Cottrell, Benjamin J

    2015-11-01

    Distal humerus fractures are challenging injuries for the upper extremity surgeon. However, recent techniques in open reduction internal fixation have been powerful tools in getting positive outcomes. To get such results, the surgeon must be aware of how to properly use these techniques in their respective practices. The method of fixation depends on the fracture, taking the degree of comminution and the restoration of the columns and articular surface into account. This article helps surgeons understand the concepts behind open reduction internal fixation of the distal humerus and makes them aware of pitfalls that may lead to negative results.

  15. Exposure of the forearm and distal radius.

    PubMed

    Klausmeyer, Melissa A; Mudgal, Chaitanya

    2014-11-01

    Approaches to the forearm use internervous planes to allow adequate bone exposure and prevent muscle denervation. The Henry approach utilizes the plane between muscles supplied by the median and radial nerves. The Thompson approach utilizes the plane between muscles supplied by the radial and posterior interosseous nerves. The distal radius may be approached volarly. The extended flexor carpi radialis approach is useful for intraarticular fractures, subacute fractures, and malunions. The distal radius can be approached dorsally by releasing the third dorsal compartment and continuing the dissection subperiosteally. Choice of approach depends on the injury pattern and the need for exposure. PMID:25440071

  16. A TRPV4 Channel C-terminal Folding Recognition Domain Critical for Trafficking and Function*

    PubMed Central

    Lei, Lei; Cao, Xu; Yang, Fan; Shi, Di-Jing; Tang, Yi-Quan; Zheng, Jie; Wang, KeWei

    2013-01-01

    The Ca2+-permeable transient receptor potential vanilloid subtype 4 (TRPV4) channel mediates crucial physiological functions, such as calcium signaling, temperature sensing, and maintaining cell volume and energy homeostasis. Noticeably, most disease-causing genetic mutations are concentrated in the cytoplasmic domains. In the present study, we focused on the role of the TRPV4 C terminus in modulating protein folding, trafficking, and activity. By examining a series of C-terminal deletions, we identified a 20-amino acid distal region covering residues 838–857 that is critical for channel folding, maturation, and trafficking. Surface biotinylation, confocal imaging, and fluorescence-based calcium influx assay demonstrated that mutant proteins missing this region were trapped in the endoplasmic reticulum and unglycosylated, leading to accelerated degradation and loss of channel activity. Rosetta de novo structural modeling indicated that residues 838–857 assume a defined conformation, with Gly849 and Pro851 located at critical positions. Patch clamp recordings confirmed that lowering the temperature from 37 to 30 °C rescued channel activity of folding-defective mutants. Moreover, biochemical tests demonstrated that, in addition to participating in C-C interaction, the C terminus also interacts with the N terminus. Taken together, our findings indicate that the C-terminal region of TRPV4 is critical for channel protein folding and maturation, and the short distal segment plays an essential role in this process. Therefore, selectively disrupting the folding-sensitive region may present therapeutic potential for treating overactive TRPV4-mediated diseases, such as pain and skeletal dysplasias. PMID:23457335

  17. Comparison of Maxillary Molar Distalization with an Implant-Supported Distal Jet and a Traditional Tooth-Supported Distal Jet Appliance

    PubMed Central

    Cozzani, Mauro; Pasini, Marco; Zallio, Francesco; Ritucci, Robert; Mutinelli, Sabrina; Mazzotta, Laura; Giuca, Maria Rita; Piras, Vincenzo

    2014-01-01

    Aim. To investigate and compare the efficiency of two appliances for molar distalization: the bone-anchored distal screw (DS) and the traditional tooth-supported distal jet (DJ) for molar distalization and anchorage loss. Methods. Tests (18 subjects) were treated with a DS and controls (18 subjects) were treated with a DJ. Lateral cephalograms were obtained before and at the end of molar distalization and were analysed. Shapiro Wilk test, unpaired t-test, and Wilcoxon rank-sum test were applied according to values distribution. The α level was fixed at 0.05. Results. Maxillary first molars were successfully distalized into a Class I relationship in all patients. The mean molar distalization and treatment time were similar in both groups. The DS group exhibited a spontaneous distalization (2.1 ± 0.9 mm) of the first premolar with control of anchorage loss, distal tipping, extrusion, and skeletal changes. Conclusions. The DS is an adequate compliance-free distalizing appliance that can be used safely for the correction of Class II malocclusions. In comparison to the traditional DJ, the DS enables not only a good rate of molar distalization, but also a spontaneous distalization of the first premolars. PMID:25018770

  18. Forensic medical examination of victims of trafficking in human beings.

    PubMed

    Alempijevic, Djordie; Jecmenica, Dragan; Pavlekic, Snezana; Savic, Slobodan; Aleksandric, Branimir

    2007-01-01

    Trafficking in human beigns (THB) is recognized as a global public health issue as well as a violation of human rights. Trafficking has been identified to be associated with several health risks including psychological trauma, injuries from violence, and substance misuse. Public and media reports suggest that the morbidity and mortality associated with trafficking are substantial. The need of medico-legal healthcare for THB victims is being neglected. Forensic medical examination, as specific intervention, is a highly desirable element of ermegency health care provided for victims of tracking. Acting in such a way, the investigation should establish the facts related to the allegatation of trafficking, thereby assisting in identifying those responsible, but also contributing to the procedures designed to obtain redress for the victims. Local anti-trafficking policies and interventions, however, have not acknowledged these needs. Therefore, the agenda of anti-trafficking policies needs to be redrawn to include forensic medical assessment of victims for legal purposes.

  19. Dynein light chain regulates axonal trafficking and synaptic levels of Bassoon.

    PubMed

    Fejtova, Anna; Davydova, Daria; Bischof, Ferdinand; Lazarevic, Vesna; Altrock, Wilko D; Romorini, Stefano; Schöne, Cornelia; Zuschratter, Werner; Kreutz, Michael R; Garner, Craig C; Ziv, Noam E; Gundelfinger, Eckart D

    2009-04-20

    Bassoon and the related protein Piccolo are core components of the presynaptic cytomatrix at the active zone of neurotransmitter release. They are transported on Golgi-derived membranous organelles, called Piccolo-Bassoon transport vesicles (PTVs), from the neuronal soma to distal axonal locations, where they participate in assembling new synapses. Despite their net anterograde transport, PTVs move in both directions within the axon. How PTVs are linked to retrograde motors and the functional significance of their bidirectional transport are unclear. In this study, we report the direct interaction of Bassoon with dynein light chains (DLCs) DLC1 and DLC2, which potentially link PTVs to dynein and myosin V motor complexes. We demonstrate that Bassoon functions as a cargo adapter for retrograde transport and that disruption of the Bassoon-DLC interactions leads to impaired trafficking of Bassoon in neurons and affects the distribution of Bassoon and Piccolo among synapses. These findings reveal a novel function for Bassoon in trafficking and synaptic delivery of active zone material.

  20. Comparative evaluation of molar distalization therapy using pendulum and distal screw appliances

    PubMed Central

    Cafagna, Alessandra; Fontana, Mattia; Cozzani, Mauro

    2015-01-01

    Objective To compare dentoalveolar and skeletal changes produced by the pendulum appliance (PA) and the distal screw appliance (DS) in Class II patients. Methods Forty-three patients (19 men, 24 women) with Class II malocclusion were retrospectively selected for the study. Twenty-four patients (mean age, 12.2 ± 1.5 years) were treated with the PA, and 19 patients (mean age, 11.3 ± 1.9 years) were treated with the DS. The mean distalization time was 7 months for the PA group and 9 months for the DS group. Lateral cephalograms were obtained at T1, before treatment, and at T2, the end of distalization. A Mann-Whitney U test was used for statistical comparisons of the two groups between T1 and T2. Results PA and DS were equally effective in distalizing maxillary molars (4.7 mm and 4.2 mm, respectively) between T1 and T2; however, the maxillary first molars showed less distal tipping in the DS group than in the PA group (3.2° vs. 9.0°, respectively). Moreover, significant premolar anchorage loss (2.7 mm) and incisor proclination (5.0°) were noted in the PA group, whereas premolar distal movement (1.9 mm) and no significant changes at the incisor (0.1°) were observed in the DS group. No significant sagittal or vertical skeletal changes were detected between the two groups during the distalization phase. Conclusions PA and DS seem to be equally effective in distalizing maxillary molars; however, greater distal molar tipping and premolar anchorage loss can be expected using PA. PMID:26258063

  1. A New Distal Radioulnar Joint Prosthesis

    PubMed Central

    Schuurman, Arnold H.

    2013-01-01

    Pain and instability of the distal radioulnar joint (DRUJ) are common sequelae following a fracture of the distal radius. Many soft tissue procedures have been described, not all of which are successful. Ulnar head replacement prostheses are available but do not always provide stability. We designed a two-part, easy to implant, distal radioulnar prosthesis and implanted it in 19 patients. The first prototype was inserted in 2002 and is still in place. During the study, the design was changed twice, resulting in three groups with four patients in group A, five in group B, and ten in group C. Unfortunately all five prostheses in group B had to be removed because of loosening, while only two prostheses in group C had to be removed, for nonprosthetic reasons. For the 12 patients who retained their prosthesis, forearm function increased while grip strength increased significantly. Pain scores decreased and the Disabilities of the Arm, Shoulder, and Hand (DASH) score improved but remained high. We conclude that the prosthesis offers a new treatment option for ulnar instability following distal ulnar resection. PMID:24436843

  2. Domestic minor sex trafficking in the United States.

    PubMed

    Kotrla, Kimberly

    2010-04-01

    By now, most social workers are familiar with the issue of human trafficking. However, many are likely unfamiliar with research indicating that youths constitute the most vulnerable group in the United States for becoming victims of sex trafficking and that most women in prostitution actually entered as minors. Some experts are now referring to the sex trafficking of U.S. children and youths as "domestic minor sex trafficking," or DMST. This article seeks to acquaint readers with what is currently known regarding the extent of DMST, who is at risk for becoming a victim, and implications for the social work profession in addressing this tragedy.

  3. Domestic minor sex trafficking in the United States.

    PubMed

    Kotrla, Kimberly

    2010-04-01

    By now, most social workers are familiar with the issue of human trafficking. However, many are likely unfamiliar with research indicating that youths constitute the most vulnerable group in the United States for becoming victims of sex trafficking and that most women in prostitution actually entered as minors. Some experts are now referring to the sex trafficking of U.S. children and youths as "domestic minor sex trafficking," or DMST. This article seeks to acquaint readers with what is currently known regarding the extent of DMST, who is at risk for becoming a victim, and implications for the social work profession in addressing this tragedy. PMID:20408359

  4. 3 CFR - Continuation of the National Emergency With Respect to Significant Narcotics Traffickers Centered...

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... to Significant Narcotics Traffickers Centered in Colombia Presidential Documents Other Presidential... Narcotics Traffickers Centered in Colombia On October 21, 1995, by Executive Order 12978, the President... economy of the United States constituted by the actions of significant narcotics traffickers centered...

  5. 3 CFR - Continuation of the National Emergency With Respect to Significant Narcotics Traffickers Centered...

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... to Significant Narcotics Traffickers Centered in Colombia Presidential Documents Other Presidential... Narcotics Traffickers Centered in Colombia On October 21, 1995, by Executive Order 12978, the President... economy of the United States constituted by the actions of significant narcotics traffickers centered...

  6. 3 CFR - Continuation of the National Emergency With Respect to Significant Narcotics Traffickers Centered...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... to Significant Narcotics Traffickers Centered in Colombia Presidential Documents Other Presidential... Narcotics Traffickers Centered in Colombia On October 21, 1995, by Executive Order 12978, the President declared a national emergency with respect to significant narcotics traffickers centered in...

  7. Assisting victims of human trafficking: strategies to facilitate identification, exit from trafficking, and the restoration of wellness.

    PubMed

    Hodge, David R

    2014-04-01

    Human trafficking is a pressing social justice concern. Social work is uniquely situated to address this problem. However, despite the profession's commitment to social justice, the scholarship to equip social workers to address this issue has been largely absent from professional discourse. To address this gap, this article helps social work practitioners to assist victims of human trafficking. After orienting readers to the scope and process of human trafficking, the topics of victim identification, exit from trafficking, and the restoration of psychological wellness are discussed. By equipping themselves in these three areas, practitioners can advance social justice on behalf of some of the most exploited people in the world. PMID:24855860

  8. Assisting victims of human trafficking: strategies to facilitate identification, exit from trafficking, and the restoration of wellness.

    PubMed

    Hodge, David R

    2014-04-01

    Human trafficking is a pressing social justice concern. Social work is uniquely situated to address this problem. However, despite the profession's commitment to social justice, the scholarship to equip social workers to address this issue has been largely absent from professional discourse. To address this gap, this article helps social work practitioners to assist victims of human trafficking. After orienting readers to the scope and process of human trafficking, the topics of victim identification, exit from trafficking, and the restoration of psychological wellness are discussed. By equipping themselves in these three areas, practitioners can advance social justice on behalf of some of the most exploited people in the world.

  9. Ganglioside Regulation of AMPA Receptor Trafficking

    PubMed Central

    Prendergast, Jillian; Umanah, George K.E.; Yoo, Seung-Wan; Lagerlöf, Olof; Motari, Mary G.; Cole, Robert N.; Huganir, Richard L.; Dawson, Ted M.; Dawson, Valina L.

    2014-01-01

    Gangliosides are major cell-surface determinants on all vertebrate neurons. Human congenital disorders of ganglioside biosynthesis invariably result in intellectual disability and are often associated with intractable seizures. To probe the mechanisms of ganglioside functions, affinity-captured ganglioside-binding proteins from rat cerebellar granule neurons were identified by quantitative proteomic mass spectrometry. Of the six proteins that bound selectively to the major brain ganglioside GT1b (GT1b:GM1 > 4; p < 10−4), three regulate neurotransmitter receptor trafficking: Thorase (ATPase family AAA domain-containing protein 1), soluble N-ethylmaleimide-sensitive factor (NSF) attachment protein (γ-SNAP), and the transmembrane protein Nicalin. Thorase facilitates endocytosis of GluR2 subunit-containing AMPA-type glutamate receptors (AMPARs) in an ATPase-dependent manner; its deletion in mice results in learning and memory deficits (J. Zhang et al., 2011b). GluR2-containing AMPARs did not bind GT1b, but bound specifically to another ganglioside, GM1. Addition of noncleavable ATP (ATPγS) significantly disrupted ganglioside binding, whereas it enhanced AMPAR association with Thorase, NSF, and Nicalin. Mutant mice lacking GT1b expressed markedly higher brain Thorase, whereas Thorase-null mice expressed higher GT1b. Treatment of cultured hippocampal neurons with sialidase, which cleaves GT1b (and other sialoglycans), resulted in a significant reduction in the size of surface GluR2 puncta. These data support a model in which GM1-bound GluR2-containing AMPARs are functionally segregated from GT1b-bound AMPAR-trafficking complexes. Release of ganglioside binding may enhance GluR2-containing AMPAR association with its trafficking complexes, increasing endocytosis. Disrupting ganglioside biosynthesis may result in reduced synaptic expression of GluR2-contianing AMPARs resulting in intellectual deficits and seizure susceptibility in mice and humans. PMID:25253868

  10. Autophagy and proteins involved in vesicular trafficking.

    PubMed

    Amaya, Celina; Fader, Claudio Marcelo; Colombo, María Isabel

    2015-11-14

    Autophagy is an intracellular degradation system that, as a basic mechanism it delivers cytoplasmic components to the lysosomes in order to maintain adequate energy levels and cellular homeostasis. This complex cellular process is activated by low cellular nutrient levels and other stress situations such as low ATP levels, the accumulation of damaged proteins or organelles, or pathogen invasion. Autophagy as a multistep process involves vesicular transport events leading to tethering and fusion of autophagic vesicles with several intracellular compartments. This review summarizes our current understanding of the autophagic pathway with emphasis in the trafficking machinery (i.e. Rabs GTPases and SNAP receptors (SNAREs)) involved in specific steps of the pathway.

  11. Plant vacuole morphology and vacuolar trafficking

    PubMed Central

    Zhang, Chunhua; Hicks, Glenn R.; Raikhel, Natasha V.

    2014-01-01

    Plant vacuoles are essential organelles for plant growth and development, and have multiple functions. Vacuoles are highly dynamic and pleiomorphic, and their size varies depending on the cell type and growth conditions. Vacuoles compartmentalize different cellular components such as proteins, sugars, ions and other secondary metabolites and play critical roles in plants response to different biotic/abiotic signaling pathways. In this review, we will summarize the patterns of changes in vacuole morphology in certain cell types, our understanding of the mechanisms of plant vacuole biogenesis, and the role of SNAREs and Rab GTPases in vacuolar trafficking. PMID:25309565

  12. Genetics Home Reference: distal hereditary motor neuropathy, type II

    MedlinePlus

    ... hereditary motor neuropathy, type II distal hereditary motor neuropathy, type II Enable Javascript to view the expand/ ... Open All Close All Description Distal hereditary motor neuropathy, type II is a progressive disorder that affects ...

  13. Genetics Home Reference: distal hereditary motor neuropathy, type V

    MedlinePlus

    ... hereditary motor neuropathy, type V distal hereditary motor neuropathy, type V Enable Javascript to view the expand/ ... Open All Close All Description Distal hereditary motor neuropathy, type V is a progressive disorder that affects ...

  14. 31 CFR 536.312 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... designated narcotics trafficker means: (a) Persons listed in the annex to Executive Order 12978 (3 CFR, 1995... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING...

  15. 31 CFR 536.312 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... designated narcotics trafficker means: (a) Persons listed in the annex to Executive Order 12978 (3 CFR, 1995... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING...

  16. 31 CFR 536.312 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... designated narcotics trafficker means: (a) Persons listed in the annex to Executive Order 12978 (3 CFR, 1995... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING...

  17. 31 CFR 536.312 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... designated narcotics trafficker means: (a) Persons listed in the annex to Executive Order 12978 (3 CFR, 1995... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY NARCOTICS TRAFFICKING...

  18. Adolescent Black Males' Drug Trafficking and Addiction: Three Theoretical Perspectives.

    ERIC Educational Resources Information Center

    Moore, Sharon E.

    1995-01-01

    Explains the incidence and nature of drug trafficking and chemical dependency among adolescent black males. The paper also discusses the social science theories of Emile Durkheim, Karl Marx, and Molefi Asante to better understand the behaviors, and the consequences of those behaviors, of young black males who participate in drug trafficking. (GR)

  19. 78 FR 59317 - Federal Acquisition Regulation; Ending Trafficking in Persons

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-26

    ... INFORMATION: I. Background The United States has long had a zero-tolerance policy regarding Government... subjection to involuntary servitude, peonage, debt bondage, or slavery, and sex trafficking. As the largest... (77 FR 60029, October 2, 2012), and Title XVII, entitled ``Ending Trafficking in...

  20. Protein kinesis: The dynamics of protein trafficking and stability

    SciTech Connect

    1995-12-31

    The purpose of this conference is to provide a multidisciplinary forum for exchange of state-of-the-art information on protein kinesis. This volume contains abstracts of papers in the following areas: protein folding and modification in the endoplasmic reticulum; protein trafficking; protein translocation and folding; protein degradation; polarity; nuclear trafficking; membrane dynamics; and protein import into organelles.

  1. Aggression in Sexually Abused Trafficked Girls and Efficacy of Intervention

    ERIC Educational Resources Information Center

    Deb, Sibnath; Mukherjee, Aparna; Mathews, Ben

    2011-01-01

    The broad objective of this study was to understand the incidence and severity of aggression among sexually abused girls who were trafficked and who were then further used for commercial sexual exploitation (referred to subsequently as sexually abused trafficked girls). In addition, the impact of counseling for minimizing aggression in these girls…

  2. Domestic Minor Sex Trafficking in the United States

    ERIC Educational Resources Information Center

    Kotrla, Kimberly

    2010-01-01

    By now, most social workers are familiar with the issue of human trafficking. However, many are likely unfamiliar with research indicating that youths constitute the most vulnerable group in the United States for becoming victims of sex trafficking and that most women in prostitution actually entered as minors. Some experts are now referring to…

  3. Teaching about Trafficking: Opportunities and Challenges for Critical Engagement

    ERIC Educational Resources Information Center

    Dragiewicz, Molly

    2008-01-01

    The author came to know about trafficking by accident, when she was hired as a research assistant at The Protection Project (TPP) in 1999. As a feminist teacher, the author was very aware of the divisions among feminists on the subject of trafficking, and was interested in communicating these differences to students who were not well versed in the…

  4. Extracorporeal shockwave lithotripsy of distal ureteral calculi.

    PubMed

    Miller, K; Bubeck, J R; Hautmann, R

    1986-01-01

    To date, the use of extracorporeal shockwave lithotripsy (ESWL) has been limited to renal calculi and ureteral calculi above the pelvic brim. Modifying the position of the patient on the support of the Dornier lithotripter HM3, we were able to localize and treat distal ureteral calculi. Until April 1986, 43 patients with stones in the lower ureter underwent contact-free lithotripsy. Treatment was successful in 39 patients (90%), 2 of these requiring 2 sessions. In 4 patients treatment failed and stone removal was accomplished using ureteroscopy or open surgery. No complications or adverse side effects were encountered in the whole series. ESWL is now the method of choice for the treatment of distal ureteral calculi in our department.

  5. [Fracture endoprosthesis of distal humerus fractures].

    PubMed

    Müller, L P; Wegmann, K; Burkhart, K J

    2013-08-01

    The treatment of choice for fractures of the distal humerus is double plate osteosynthesis. Due to anatomical preshaped angle stable plates the primary stability and management of soft tissues has been improved. However, osteoporotic comminuted fractures in the elderly are often not amenable to stable osteosynthesis and total elbow arthroplasty has been established as an alternative therapy. Although complication rates have been reduced, complications of total elbow arthroplasty are still much more frequent than in total hip replacement. Furthermore, patients are advised not to exceed a weight bearing of 5 kg. Therefore, the indications for elbow arthroplasty must be evaluated very strictly and should be reserved for comminuted distal humeral fractures in the elderly with poor bone quality that are not amenable to stable osteosynthesis or for simple fractures in cases of preexisting symptomatic osteoarthritis. This article introduces and discusses modern concepts of elbow arthroplasty, such as modular convertible prosthesis systems, hemiarthroplasty and radial head replacement in total elbow arthroplasty.

  6. Fracture of distal end clavicle: A review

    PubMed Central

    Sambandam, Balaji; Gupta, Rajat; Kumar, Santosh; Maini, Lalit

    2014-01-01

    Management of fracture distal end clavicle has always puzzled the orthopaedic surgeons. Now-a-days with a relatively active lifestyle, patients want better results both cosmetically and functionally. Despite so much literature available for the management of this common fracture, there is no consensus regarding the gold standard treatment for this fracture. In this article, we reviewed the literature on various techniques of management for this fracture, both conservative as well as surgical, and their merits and demerits. PMID:25983473

  7. Fractures of Distal Radius: An Overview

    PubMed Central

    Meena, Sanjay; Sharma, Pankaj; Sambharia, Abhishek Kumar; Dawar, Ashok

    2014-01-01

    Fractures of distal radius account for up to 20% of all fractures treated in emergency department. Initial assessment includes a history of mechanism of injury, associated injury and appropriate radiological evaluation. Treatment options include conservative management, internal fixation with pins, bridging and non-bridging external fixation, dorsal or volar plating with/without arthroscopy assistance. However, many questions regarding these fractures remain unanswered and good prospective randomized trials are needed. PMID:25657938

  8. Vesicle trafficking in plant immune responses.

    PubMed

    Robatzek, Silke

    2007-01-01

    In plants, perception of pathogen-associated molecular patterns at the surface is the first line of defence in cellular immunity. This review summarizes recent evidence of the involvement of vesicle trafficking in the plant's immune response against pathogens. I first discuss aspects of ligand-stimulated receptor endocytosis. The best-characterized pattern-recognition receptor (PRR), FLS2, is a transmembrane leucine-rich repeat receptor kinase that recognizes bacterial flagellin. FLS2 was recently shown to undergo internalization upon activation with its cognate ligand. An animal PRR, TLR4 that mediates perception of bacterial-derived lipopolysaccharides, similarly exhibits ligand-stimulated endocytosis. The second focus is N-ethylmaleimide-sensitive factor adaptor protein receptor (SNARE)-mediated immunity involving syntaxins and their cognate partners. One of the genes involved in basal immunity in Arabidopsis, PEN1, encodes a syntaxin that focally accumulates at fungal penetration sites, raising the possibility that induced exocytosis is important for active defence. Pathogen-triggered endocytic and exocytic processes have to be balanced to ensure host cell homeostasis. Thus, understanding how phytopathogens have evolved strategies to exploit host cell vesicle trafficking to manipulate immune responses is currently an area of intense study. PMID:17081192

  9. Trafficking of Estrella lausannensis in human macrophages.

    PubMed

    Rusconi, Brigida; Kebbi-Beghdadi, Carole; Greub, Gilbert

    2015-07-01

    Estrella lausannensis is a new member of the Chlamydiales order. Like other Chlamydia-related bacteria, it is able to replicate in amoebae and in fish cell lines. A preliminary study investigating the pathogenic potential of Chlamydia-related bacteria found a correlation between antibody response to E. lausannensis and pneumonia in children. To further investigate the pathogenic potential of E. lausannensis, we determined its ability to grow in human macrophages and its intracellular trafficking. The replication in macrophages resulted in viable E. lausannensis; however, it caused a significant cytopathic effect. The intracellular trafficking of E. lausannensis was analyzed by determining the interaction of the Estrella-containing inclusions with various endocytic markers as well as host organelles. The E. lausannensis inclusion escaped the endocytic pathway rapidly avoiding maturation into phagolysosomes by preventing both EEA-1 and LAMP-1 accumulation. Compared to Waddlia chondrophila, another Chlamydia-related bacteria, the recruitment of mitochondria and endoplasmic reticulum was minimal for E. lausannensis inclusions. Estrella lausannensis appears to use a distinct source of nutrients and energy compared to other members of the Chlamydiales order. In conclusion, we hypothesize that E. lausannensis has a restricted growth in human macrophages, due to its reduced capacity to control programmed cell death. PMID:25857735

  10. Secretory protein trafficking in Giardia intestinalis.

    PubMed

    Hehl, Adrian B; Marti, Matthias

    2004-07-01

    Early diverged extant organisms, which may serve as convenient laboratory models to look for and study evolutionary ancient features of eukaryotic cell biology, are rare. The diplomonad Giardia intestinalis, a protozoan parasite known to cause diarrhoeal disease, has become an increasingly popular object of basic research in cell biology, not least because of a genome sequencing project nearing completion. Commensurate with its phylogenetic status, the Giardia trophozoite has a very basic secretory system and even lacks hallmark structures such as a morphologically identifiable Golgi apparatus. The cell's capacity for protein sorting is nevertheless unimpeded, exemplified by its ability to cope with massive amounts of newly synthesized cyst wall proteins and glycans, which are sorted to dedicated Golgi-like compartments termed encystation-specific vesicles (ESVs) generated from endoplasmic reticulum (ER)-derived transport intermediates. This soluble bulk cargo is kept strictly separate from constitutively transported variant surface proteins during export, a function that is dependent on the stage-specific recognition of trafficking signals. Encysting Giardia therefore provide a unique system for the study of unconventional, Golgi-independent protein trafficking mechanisms in the broader context of eukaryotic endomembrane organization and evolution. PMID:15225300

  11. Distal Embolic Protection for Renal Arterial Interventions

    SciTech Connect

    Dubel, Gregory J. Murphy, Timothy P.

    2008-01-15

    Distal or embolic protection has intuitive appeal for its potential to prevent embolization of materials generated during interventional procedures. Distal protection devices (DPDs) have been most widely used in the coronary and carotid vascular beds, where they have demonstrated the ability to trap embolic materials and, in some cases, to reduce complications. Given the frequency of chronic kidney disease in patients with renal artery stenosis undergoing stent placement, it is reasonable to propose that these devices may play an important role in limiting distal embolization in the renal vasculature. Careful review of the literature reveals that atheroembolization does occur during renal arterial interventions, although it often goes undetected. Early experience with DPDs in the renal arteries in patients with suitable anatomy suggests retrieval of embolic materials in approximately 71% of cases and renal functional improvement/stabilization in 98% of cases. The combination of platelet inhibition and a DPD may provide even greater benefit. Given the critical importance of renal functional preservation, it follows that everything that can be done to prevent atheroembolism should be undertaken including the use of DPDs when anatomically feasible. The data available at this time support a beneficial role for these devices.

  12. Distal nerve entrapment following nerve repair.

    PubMed

    Schoeller, T; Otto, A; Wechselberger, G; Pommer, B; Papp, C

    1998-04-01

    Failure of nerve repair or poor functional outcome after reconstruction can be influenced by various causes. Besides improper microsurgical technique, fascicular malalignment and unphysiologic tension, we found in our clinical series that a subclinical nerve compression distal to the repair site can seriously impair regeneration. We concluded that the injured nerve, whether from trauma or microsurgical intervention, could be more susceptible to distal entrapment in the regenerative stage because of its disturbed microcirculation, swelling and the increase of regenerating axons followed by increased nerve volume. In two cases we found the regenerating nerve entrapped at pre-existing anatomical sites of narrowing resulting in impaired functional recovery. In both cases the surgical therapy was decompression of the distal entrapped nerve and this was followed by continued regeneration. Thorough clinical and electrophysiologic follow-up is necessary to detect such adverse compression effects and to distinguish between the various causes of failed regeneration. Under certain circumstances primary preventive decompression may be beneficial if performed at the time of nerve coaptation.

  13. Mirrored visual feedback limits distal effect anticipation.

    PubMed

    Sutter, Christine; Ladwig, Stefan

    2012-04-01

    Modern tools in technological environments are often characterized by a spatial separation of hand actions (operating a remote control) and their intended action effects (displayed movements of an unmanned vehicle, a robot, or an avatar on a screen). Often non-corresponding proximal and distal movement effects put high demands on the human information processing system. The present study aimed to investigate how modern technological environments influence processes of planning and controlling actions. Participants performed ipsi- or contralateral movements in response to colored stimuli, while the stimulus location had to be ignored. They did not see the stimuli and hands directly, but received visual feedback (with retained or reversed spatial relations) on a projection screen in front of them. Visual feedback retaining spatial relations led to the usual Simon effect. However, visual feedback reversing spatial relations inverted the Simon effect in ipsilateral responses, and eliminated it in contralateral responses (Exp. 1). Impairing the proximal movement-effect loop so that proprioceptive/tactile information from the moving hand was no longer a reliable source for planning and controlling actions attenuated compatibility effects (Exp. 2). Moreover, distal action effects predominated action control even for opposing body-related effects. It seemed that action control of transformed movements depended on the reliability of proprioceptive/tactile and visual information. When the amount of feature overlap between proprioception and vision was low and proprioceptive (visual) information was no longer reliable, then distal (proximal) action effects stepped forward and became crucial in controlling transformed actions.

  14. Entrapment and Enmeshment Schemes Used by Sex Traffickers.

    PubMed

    Reid, Joan A

    2016-09-01

    Emerging research suggests that sex traffickers/pimps control the majority of trafficked girls in the United States. The youthfulness of these victims and their lack of psychosocial maturity severely diminish their ability to detect exploitative motives or withstand manipulation of traffickers. A review of 43 cases of sexually exploited girls involving non-relative traffickers and 10 semi-structured interviews with social service providers revealed numerous scripts and schemes used by sex traffickers to entrap and entangle victims including boyfriend/lover scripts, ruses involving debt bondage, friendship or faux-family scripts, threats of forced abortion or to take away children, and coerced co-offending. These findings inform potential prevention efforts and highlight the need for multi-systemic, victim-centered approaches to intervention. PMID:25079777

  15. Entrapment and Enmeshment Schemes Used by Sex Traffickers.

    PubMed

    Reid, Joan A

    2016-09-01

    Emerging research suggests that sex traffickers/pimps control the majority of trafficked girls in the United States. The youthfulness of these victims and their lack of psychosocial maturity severely diminish their ability to detect exploitative motives or withstand manipulation of traffickers. A review of 43 cases of sexually exploited girls involving non-relative traffickers and 10 semi-structured interviews with social service providers revealed numerous scripts and schemes used by sex traffickers to entrap and entangle victims including boyfriend/lover scripts, ruses involving debt bondage, friendship or faux-family scripts, threats of forced abortion or to take away children, and coerced co-offending. These findings inform potential prevention efforts and highlight the need for multi-systemic, victim-centered approaches to intervention.

  16. The role of the nurse in combating human trafficking.

    PubMed

    Sabella, Donna

    2011-02-01

    Human trafficking, also called modern slavery, happens worldwide--and the United States is no exception. Within our borders, thousands of foreign nationals and U.S. citizens, many of them children, are forced or coerced into sex work or various forms of labor every year. Nurses and other health care providers who encounter victims of trafficking often don't realize it, and opportunities to intervene are lost. Although no one sign can demonstrate with certainty when someone is being trafficked, there are several indicators that clinicians should know. This article provides an overview of human trafficking, describes how to recognize signs that a person is being trafficked and how to safely intervene, and offers an extensive resource list.

  17. The role of the nurse in combating human trafficking.

    PubMed

    Sabella, Donna

    2011-02-01

    Human trafficking, also called modern slavery, happens worldwide--and the United States is no exception. Within our borders, thousands of foreign nationals and U.S. citizens, many of them children, are forced or coerced into sex work or various forms of labor every year. Nurses and other health care providers who encounter victims of trafficking often don't realize it, and opportunities to intervene are lost. Although no one sign can demonstrate with certainty when someone is being trafficked, there are several indicators that clinicians should know. This article provides an overview of human trafficking, describes how to recognize signs that a person is being trafficked and how to safely intervene, and offers an extensive resource list. PMID:21270581

  18. Human trafficking: the role of the health care provider.

    PubMed

    Dovydaitis, Tiffany

    2010-01-01

    Human trafficking is a major public health problem, both domestically and internationally. Health care providers are often the only professionals to interact with trafficking victims who are still in captivity. The expert assessment and interview skills of providers contribute to their readiness to identify victims of trafficking. The purpose of this article is to provide clinicians with knowledge on trafficking and give specific tools that they may use to assist victims in the clinical setting. Definitions, statistics, and common health care problems of trafficking victims are reviewed. The role of the health care provider is outlined through a case study and clinical practice tools are provided. Suggestions for future research are also briefly addressed. PMID:20732668

  19. Psychological Coercion in Human Trafficking: An Application of Biderman's Framework.

    PubMed

    Baldwin, Susie B; Fehrenbacher, Anne E; Eisenman, David P

    2015-09-01

    This study examined coercive conditions experienced by trafficked persons in the context of Biderman's theory of coercion. We conducted semi-structured interviews with 12 adult women trafficked into Los Angeles County, from 10 countries, for domestic work and/or sex work. Participants described health problems they experienced in relation to their trafficking experience and their perceptions of conditions that caused health problems. Utilizing a framework analysis approach, we analyzed themes using Biderman's framework. Participants reported experiencing the range of nonphysical coercive tactics outlined by Biderman, including isolation, monopolization of perception, induced debility or exhaustion, threats, occasional indulgences, demonstration of omnipotence, degradation, and enforcement of trivial demands. Our analysis demonstrates how these coercion tactics reinforced the submission of trafficked persons to their traffickers even in the absence of physical force or restraints. Such psychological abuse creates extreme stress that can lead to acute and chronic, physical and mental health problems. PMID:25371382

  20. Human Trafficking: The Role of the Health Care Provider

    PubMed Central

    Dovydaitis, Tiffany

    2011-01-01

    Human trafficking is a major public health problem, both domestically and internationally. Health care providers are often the only professionals to interact with trafficking victims who are still in captivity. The expert assessment and interview skills of providers contribute to their readiness to identify victims of trafficking. The purpose of this article is to provide clinicians with knowledge on trafficking and give specific tools that they may use to assist victims in the clinical setting. Definitions, statistics, and common health care problems of trafficking victims are reviewed. The role of the health care provider is outlined through a case study and clinical practice tools are provided. Suggestions for future research are also briefly addressed. PMID:20732668

  1. New Insights into How Trafficking Regulates T Cell Receptor Signaling

    PubMed Central

    Lou, Jieqiong; Rossy, Jérémie; Deng, Qiji; Pageon, Sophie V.; Gaus, Katharina

    2016-01-01

    There is emerging evidence that exocytosis plays an important role in regulating T cell receptor (TCR) signaling. The trafficking molecules involved in lytic granule (LG) secretion in cytotoxic T lymphocytes (CTL) have been well-studied due to the immune disorder known as familial hemophagocytic lymphohistiocytosis (FHLH). However, the knowledge of trafficking machineries regulating the exocytosis of receptors and signaling molecules remains quite limited. In this review, we summarize the reported trafficking molecules involved in the transport of the TCR and downstream signaling molecules to the cell surface. By combining this information with the known knowledge of LG exocytosis and general exocytic trafficking machinery, we attempt to draw a more complete picture of how the TCR signaling network and exocytic trafficking matrix are interconnected to facilitate T cell activation. This also highlights how membrane compartmentalization facilitates the spatiotemporal organization of cellular responses that are essential for immune functions. PMID:27508206

  2. SLC6A3 coding variant Ala559Val found in two autism probands alters dopamine transporter function and trafficking.

    PubMed

    Bowton, E; Saunders, C; Reddy, I A; Campbell, N G; Hamilton, P J; Henry, L K; Coon, H; Sakrikar, D; Veenstra-VanderWeele, J M; Blakely, R D; Sutcliffe, J; Matthies, H J G; Erreger, K; Galli, A

    2014-10-14

    Emerging evidence associates dysfunction in the dopamine (DA) transporter (DAT) with the pathophysiology of autism spectrum disorder (ASD). The human DAT (hDAT; SLC6A3) rare variant with an Ala to Val substitution at amino acid 559 (hDAT A559V) was previously reported in individuals with bipolar disorder or attention-deficit hyperactivity disorder (ADHD). We have demonstrated that this variant is hyper-phosphorylated at the amino (N)-terminal serine (Ser) residues and promotes an anomalous DA efflux phenotype. Here, we report the novel identification of hDAT A559V in two unrelated ASD subjects and provide the first mechanistic description of its impaired trafficking phenotype. DAT surface expression is dynamically regulated by DAT substrates including the psychostimulant amphetamine (AMPH), which causes hDAT trafficking away from the plasma membrane. The integrity of DAT trafficking directly impacts DA transport capacity and therefore dopaminergic neurotransmission. Here, we show that hDAT A559V is resistant to AMPH-induced cell surface redistribution. This unique trafficking phenotype is conferred by altered protein kinase C β (PKCβ) activity. Cells expressing hDAT A559V exhibit constitutively elevated PKCβ activity, inhibition of which restores the AMPH-induced hDAT A559V membrane redistribution. Mechanistically, we link the inability of hDAT A559V to traffic in response to AMPH to the phosphorylation of the five most distal DAT N-terminal Ser. Mutation of these N-terminal Ser to Ala restores AMPH-induced trafficking. Furthermore, hDAT A559V has a diminished ability to transport AMPH, and therefore lacks AMPH-induced DA efflux. Pharmacological inhibition of PKCβ or Ser to Ala substitution in the hDAT A559V background restores AMPH-induced DA efflux while promoting intracellular AMPH accumulation. Although hDAT A559V is a rare variant, it has been found in multiple probands with neuropsychiatric disorders associated with imbalances in DA neurotransmission

  3. Illicit trafficking of radiological & nuclear materials : modeling and analysis of trafficking trends and risks.

    SciTech Connect

    York, David L.; Love, Tracia L.; Rochau, Gary Eugene

    2005-01-01

    Concerns over the illicit trafficking of radiological and nuclear materials were focused originally on the lack of security and accountability of such material throughout the former Soviet states. This is primarily attributed to the frequency of events that have occurred involving the theft and trafficking of critical material components that could be used to construct a Radiological Dispersal Device (RDD) or even a rudimentary nuclear device. However, with the continued expansion of nuclear technology and the deployment of a global nuclear fuel cycle these materials have become increasingly prevalent, affording a more diverse inventory of dangerous materials and dual-use items. To further complicate the matter, the list of nuclear consumers has grown to include: (1) Nation-states that have gone beyond the IAEA agreed framework and additional protocols concerning multiple nuclear fuel cycles and processes that reuse the fuel through reprocessing to exploit technologies previously confined to the more industrialized world; (2) Terrorist organizations seeking to acquire nuclear and radiological material due to the potential devastation and psychological effect of their use; (3) Organized crime, which has discovered a lucrative market in trafficking of illicit material to international actors and/or countries; and (4) Amateur smugglers trying to feed their families in a post-Soviet era. An initial look at trafficking trends of this type seems scattered and erratic, localized primarily to a select group of countries. This is not necessarily the case. The success with which other contraband has been smuggled throughout the world suggests that nuclear trafficking may be carried out with relative ease along the same routes by the same criminals or criminal organizations. Because of the inordinately high threat posed by terrorist or extremist groups acquiring the ingredients for unconventional weapons, it is necessary that illicit trafficking of these materials be better

  4. Robotic distal pancreatectomy versus conventional laparoscopic distal pancreatectomy: a comparative study for short-term outcomes.

    PubMed

    Lai, Eric C H; Tang, Chung Ngai

    2015-09-01

    Robotic system has been increasingly used in pancreatectomy. However, the effectiveness of this method remains uncertain. This study compared the surgical outcomes between robot-assisted laparoscopic distal pancreatectomy and conventional laparoscopic distal pancreatectomy. During a 15-year period, 35 patients underwent minimally invasive approach of distal pancreatectomy in our center. Seventeen of these patients had robot-assisted laparoscopic approach, and the remaining 18 had conventional laparoscopic approach. Their operative parameters and perioperative outcomes were analyzed retrospectively in a prospective database. The mean operating time in the robotic group (221.4 min) was significantly longer than that in the laparoscopic group (173.6 min) (P = 0.026). Both robotic and conventional laparoscopic groups presented no significant difference in spleen-preservation rate (52.9% vs. 38.9%) (P = 0.505), operative blood loss (100.3 ml vs. 268.3 ml) (P = 0.29), overall morbidity rate (47.1% vs. 38.9%) (P = 0.73), and post-operative hospital stay (11.4 days vs. 14.2 days) (P = 0.46). Both groups also showed no perioperative mortality. Similar outcomes were observed in robotic distal pancreatectomy and conventional laparoscopic approach. However, robotic approach tended to have the advantages of less blood loss and shorter hospital stay. Further studies are necessary to determine the clinical position of robotic distal pancreatectomy.

  5. Human anion exchanger1 mutations and distal renal tubular acidosis.

    PubMed

    Yenchitsomanus, Pa-thai

    2003-09-01

    The human anion exchanger 1 (AE1 or SLC4A1) gene encodes anion exchanger 1 (or band 3) protein in erythrocytes and in alpha-intercalated cells of the kidney. Thus, AE1 mutations show pleiotrophic effects resulting in two distinct and seemingly unrelated defects, an erythrocyte abnormality and distal renal tubular acidosis (dRTA). Southeast Asian ovalocytosis (SAO), a well-known red blood cell (RBC) defect, which is widespread in Southeast Asian regions, is caused by AE1 mutation due to a deletion of 27 base pairs in codons 400-408 (delta400-408) leading to an in-frame 9 amino-acid loss in the protein. Co-existence of SAO and dRTA is usually not seen in the same individual. However, the two conditions can co-exist as the result of compound heterozygosities between delta400-408 and other mutations. The reported genotypes include delta400-408/G701D, delta400-408/R602H, delta400-408/deltaV850, and delta400-408/A858D. The presence of dRTA, with or without RBC abnormalities, may occur from homozygous or compound heterozygous conditions of recessive AE1 mutations (eg G701D/G701D, V488M/V488M, deltaV850/deltaV850, deltaV850/A858D, G701D/S773P) or heterozygous dominant AE1 mutations (eg R598H, R589C, R589S, S613F, R901X). Codon 589 of this gene seems to be a 'mutational hot-spot' since repeated mutations at this codon occurring in different ethnic groups and at least two de novo (R589H and R589C) mutations have been observed. Therefore, AE1 mutations can result in both recessive and dominant dRTA, possibly depending on the position of the amino acid change in the protein. As several mutant AE1 proteins still maintain a significant anion transport function but are defective in targeting to the cell surface, impaired intracellular trafficking of the mutant AE1 is an important molecular mechanism involved in the pathogenesis of dRTA associated with AE1 mutations. PMID:15115146

  6. Discrete control of TRPV4 channel function in the distal nephron by protein kinases A and C.

    PubMed

    Mamenko, Mykola; Zaika, Oleg L; Boukelmoune, Nabila; Berrout, Jonathan; O'Neil, Roger G; Pochynyuk, Oleh

    2013-07-12

    We have recently documented that the Ca(2+)-permeable TRPV4 channel, which is abundantly expressed in distal nephron cells, mediates cellular Ca(2+) responses to elevated luminal flow. In this study, we combined Fura-2-based [Ca(2+)]i imaging with immunofluorescence microscopy in isolated split-opened distal nephrons of C57BL/6 mice to probe the molecular determinants of TRPV4 activity and subcellular distribution. We found that activation of the PKC pathway with phorbol 12-myristate 13-acetate significantly increased [Ca(2+)]i responses to flow without affecting the subcellular distribution of TRPV4. Inhibition of PKC with bisindolylmaleimide I diminished cellular responses to elevated flow. In contrast, activation of the PKA pathway with forskolin did not affect TRPV4-mediated [Ca(2+)]i responses to flow but markedly shifted the subcellular distribution of the channel toward the apical membrane. These actions were blocked with the specific PKA inhibitor H-89. Concomitant activation of the PKA and PKC cascades additively enhanced the amplitude of flow-induced [Ca(2+)]i responses and greatly increased basal [Ca(2+)]i levels, indicating constitutive TRPV4 activation. This effect was precluded by the selective TRPV4 antagonist HC-067047. Therefore, the functional status of the TRPV4 channel in the distal nephron is regulated by two distinct signaling pathways. Although the PKA-dependent cascade promotes TRPV4 trafficking and translocation to the apical membrane, the PKC-dependent pathway increases the activity of the channel on the plasma membrane. PMID:23709216

  7. Hyperinsulinemia and skeletal muscle fatty acid trafficking.

    PubMed

    Kanaley, Jill A; Shadid, Samyah; Sheehan, Michael T; Guo, ZengKui; Jensen, Michael D

    2013-08-15

    We hypothesized that insulin alters plasma free fatty acid (FFA) trafficking into intramyocellular (im) long-chain acylcarnitines (imLCAC) and triglycerides (imTG). Overnight-fasted adults (n = 41) received intravenous infusions of [U-¹³C]palmitate (0400-0900 h) and [U-¹³C]oleate (0800-1400 h) to label imTG and imLCAC. A euglycemic-hyperinsulinemic (1.0 mU·kg fat-free mass⁻¹·min⁻¹) clamp (0800-1400 h) and two muscle biopsies (0900 h, 1400 h) were performed. The patterns of [U-¹³C]palmitate incorporation into imTG-palmitate and palmitoylcarnitine were similar to those we reported in overnight postabsorptive adults (saline control); the intramyocellular palmitoylcarnitine enrichment was not different from and correlated with imTG-palmitate enrichment for both the morning (r = 0.38, P = 0.02) and afternoon (r = 0.44, P = 0.006) biopsy samples. Plasma FFA concentrations, flux, and the incorporation of plasma oleate into imTG-oleate during hyperinsulinemia were ~1/10th of that observed in the previous saline control studies (P < 0.001). At the time of the second biopsy, the enrichment in oleoylcarnitine was <25% of that in imTG-oleate and was not correlated with imTG-oleate enrichment. The intramyocellular nonesterified fatty acid-palmitate-to-imTG-palmitate enrichment ratio was greater (P < 0.05) in women than men, suggesting that sex differences in intramyocellular palmitate trafficking may occur under hyperinsulinemic conditions. We conclude that plasma FFA trafficking into imTG during hyperinsulinemia is markedly suppressed, and these newly incorporated FFA fatty acids do not readily enter the LCAC preoxidative pools. Hyperinsulinemia does not seem to inhibit the entry of fatty acids from imTG pools that were labeled under fasting conditions, possibly reflecting the presence of two distinct imTG pools that are differentially regulated by insulin. PMID:23820622

  8. Plant Vascular Biology 2013: vascular trafficking.

    PubMed

    Ursache, Robertas; Heo, Jung-Ok; Helariutta, Ykä

    2014-04-01

    About 200 researchers from around the world attended the Third International Conference on Plant Vascular Biology (PVB 2013) held in July 2013 at the Rantapuisto Conference Center, in Helsinki, Finland (http://www.pvb2013.org). The plant vascular system, which connects every organ in the mature plant, continues to attract the interest of researchers representing a wide range of disciplines, including development, physiology, systems biology, and computational biology. At the meeting, participants discussed the latest research advances in vascular development, long- and short-distance vascular transport and long-distance signalling in plant defence, in addition to providing a context for how these studies intersect with each other. The meeting provided an opportunity for researchers working across a broad range of fields to share ideas and to discuss future directions in the expanding field of vascular biology. In this report, the latest advances in understanding the mechanism of vascular trafficking presented at the meeting have been summarized.

  9. Glycobiology of leukocyte trafficking in inflammation.

    PubMed

    Wright, Rachael D; Cooper, Dianne

    2014-12-01

    To fulfill their potential, leukocytes must be able to exit the vasculature and reach the site of inflammation within the tissue. This process of leukocyte extravasation is a tightly regulated sequence of events that is governed by a host of cell adhesion molecules, cytokines, chemokines and lipid mediators. Of major importance to this process and the function of many of the proteins and lipids involved is the posttranslational modification of these moieties by glycosylation. The glycosylation process is coordinated by multiple enzymes that add and remove saccharides to/from glycan structures on proteins and lipids, resulting in a unique molecular signature that affords specificity to the molecules involved in leukocyte recruitment. This review will discuss how glycosylation impacts the function of these key molecules involved in the recruitment of leukocytes during inflammation and the function of specific lectins (carbohydrate-binding proteins) that have a role in leukocyte trafficking.

  10. Transnational criminal organizations and drug trafficking.

    PubMed

    Williams, P; Florez, C

    1994-01-01

    Transnational criminal organizations, particularly drug-trafficking organizations, operate unrestricted across international borders. They are very similar in kind to legitimate transnational corporations in structure, strength, size, geographical range and scope of their operations. Above all other features they engage in unregulated forms of capitalist enterprise. To fully understand transnational criminal organizations it is necessary to examine them as organizations responding to economic opportunities and focus on the factors that influence their emergence. Those factors can be understood as a result of the confluence of opportunities, pressures, incentives and resources at the global and national level. The present article identifies the key environmental factors relevant to the emergence of transnational criminal organizations, and explores the intrinsic relationship between those organizations, their home States and host States. It is those conditions which not only give rise to transnational criminal organizations, but also help to sustain them.

  11. Endocytic pathways and endosomal trafficking: a primer.

    PubMed

    Elkin, Sarah R; Lakoduk, Ashley M; Schmid, Sandra L

    2016-05-01

    This brief overview of endocytic trafficking is written in honor of Renate Fuchs, who retires this year. In the mid-1980s, Renate pioneered studies on the ion-conducting properties of the recently discovered early and late endosomes and the mechanisms governing endosomal acidification. As described in this review, after uptake through one of many mechanistically distinct endocytic pathways, internalized proteins merge into a common early/sorting endosome. From there they again diverge along distinct sorting pathways, back to the cell surface, on to the trans-Golgi network or across polarized cells. Other transmembrane receptors are packaged into intraluminal vesicles of late endosomes/multivesicular bodies that eventually fuse with and deliver their content to lysosomes for degradation. Endosomal acidification, in part, determines sorting along this pathway. We describe other sorting machinery and mechanisms, as well as the rab proteins and phosphatidylinositol lipids that serve to dynamically define membrane compartments along the endocytic pathway. PMID:26861668

  12. Chinese narcotics trafficking: a preliminary report.

    PubMed

    Huang, Kaicheng; Liu, Jianhong; Zhao, Ruohui; Zhao, Guoling; Friday, Paul C

    2012-02-01

    Questions of existence of the "China Route" for drug smuggling and trafficking have been important in the literature. The profile of the offenders, particularly whether they are primarily members of traditional criminal organization, is a hotly debated issue. Much qualitative evidence has been collected and it provides important insights into these questions. However, little quantitative data has ever been collected and analyzed to provide a broader picture of these issues. The present study involves the systematical collection of data from court sentencing files from seven high courts whose jurisdictions cover the China Route. The findings provide valuable information that sheds light on the debated questions. Some evidence consistent with the China Route arguments is found. No evidence supports the idea that traditional organized criminal syndicates are behind most offenses. Logistic regression results reveal interesting associations between offender characteristics and types of offenses.

  13. Superresolution imaging of viral protein trafficking

    PubMed Central

    Salka, Kyle; Bhuvanendran, Shivaprasad; Yang, David

    2015-01-01

    The endoplasmic reticulum (ER) membrane is closely apposed to the outer mitochondrial membrane (OMM), which facilitates communication between these organelles. These contacts, known as mitochondria-associated membranes (MAM), facilitate calcium signaling, lipid transfer, as well as antiviral and stress responses. How cellular proteins traffic to the MAM, are distributed therein, and interact with ER and mitochondrial proteins are subject of great interest. The human cytomegalovirus UL37 exon 1 protein or viral mitochondria-localized inhibitor of apoptosis (vMIA) is crucial for viral growth. Upon synthesis at the ER, vMIA traffics to the MAM and OMM, where it reprograms the organization and function of these compartments. vMIA significantly changes the abundance of cellular proteins at the MAM and OMM, including proteins that regulate calcium homeostasis and cell death. Through the use of superresolution imaging, we have shown that vMIA is distributed at the OMM in nanometer scale clusters. This is similar to the clusters reported for the mitochondrial calcium channel, VDAC, as well as electron transport chain, translocase of the OMM complex, and mitochondrial inner membrane organizing system components. Thus, aside from addressing how vMIA targets the MAM and regulates survival of infected cells, biochemical studies and superresolution imaging of vMIA offer insights into the formation, organization, and functioning of MAM. Here, we discuss these insights into trafficking, function, and organization of vMIA at the MAM and OMM and discuss how the use of superresolution imaging is contributing to the study of the formation and trafficking of viruses. PMID:25724304

  14. Ubiquitination of CXCR7 Controls Receptor Trafficking

    PubMed Central

    de Munnik, Sabrina; Han, Mitchell K. L.; Smit, Martine J.; Leurs, Rob

    2012-01-01

    The chemokine receptor CXCR7 binds CXCL11 and CXCL12 with high affinity, chemokines that were previously thought to bind exclusively to CXCR4 and CXCR3, respectively. Expression of CXCR7 has been associated with cardiac development as well as with tumor growth and progression. Despite having all the canonical features of G protein-coupled receptors (GPCRs), the signalling pathways following CXCR7 activation remain controversial, since unlike typical chemokine receptors, CXCR7 fails to activate Gαi-proteins. CXCR7 has recently been shown to interact with β-arrestins and such interaction has been suggested to be responsible for G protein-independent signals through ERK-1/2 phosphorylation. Signal transduction by CXCR7 is controlled at the membrane by the process of GPCR trafficking. In the present study we investigated the regulatory processes triggered by CXCR7 activation as well as the molecular interactions that participate in such processes. We show that, CXCR7 internalizes and recycles back to the cell surface after agonist exposure, and that internalization is not only β-arrestin-mediated but also dependent on the Serine/Threonine residues at the C-terminus of the receptor. Furthermore we describe, for the first time, the constitutive ubiquitination of CXCR7. Such ubiquitination is a key modification responsible for the correct trafficking of CXCR7 from and to the plasma membrane. Moreover, we found that CXCR7 is reversibly de-ubiquitinated upon treatment with CXCL12. Finally, we have also identified the Lysine residues at the C-terminus of CXCR7 to be essential for receptor cell surface delivery. Together these data demonstrate the differential regulation of CXCR7 compared to the related CXCR3 and CXCR4 receptors, and highlight the importance of understanding the molecular determinants responsible for this process. PMID:22457824

  15. Ligand-directed trafficking of receptor stimulus.

    PubMed

    Chilmonczyk, Zdzisław; Bojarski, Andrzej J; Sylte, Ingebrigt

    2014-12-01

    GPCRs are seven transmembrane-spanning receptors that convey specific extracellular stimuli to intracellular signalling. They represent the largest family of cell surface proteins that are therapeutically targeted. According to the traditional two-state model of receptor theory, GPCRs were considered as operating in equilibrium between two functional conformations, an active (R*) and inactive (R) state. Thus, it was assumed that a GPCR can exist either in an "off" or "on" conformation causing either no activation or equal activation of all its signalling pathways. Over the past several years it has become evident that this model is too simple and that GPCR signalling is far more complex. Different studies have presented a multistate model of receptor activation in which ligand-specific receptor conformations are able to differentiate between distinct signalling partners. Recent data show that beside G proteins numerous other proteins, such as β-arrestins and kinases, may interact with GPCRs and activate intracellular signalling pathways. GPCR activation may therefore involve receptor desensitization, coupling to multiple G proteins, Gα or Gβγ signalling, and pathway activation that is independent of G proteins. This latter effect leads to agonist "functional selectivity" (also called ligand-directed receptor trafficking, stimulus trafficking, biased agonism, biased signalling), and agonist intervention with functional selectivity may improve the therapy. Many commercially available drugs with beneficial efficacy also show various undesirable side effects. Further studies of biased signalling might facilitate our understanding of the side effects of current drugs and take us to new avenues to efficiently design pathway-specific medications.

  16. Complications of Distal Biceps Tendon Repair

    PubMed Central

    Amin, Nirav H.; Volpi, Alex; Lynch, T. Sean; Patel, Ronak M.; Cerynik, Douglas L.; Schickendantz, Mark S.; Jones, Morgan H.

    2016-01-01

    Background: Anatomic reinsertion of the distal biceps is critical for restoring flexion and supination strength. Single- and double-incision surgical techniques have been reported, analyzing complications and outcomes measures. Which technique results in superior clinical outcomes and the lowest associated complications remains unclear. Hypothesis: We hypothesized that rerupture rates would be similar between the 2 techniques, while nerve complications would be higher for the single-incision technique and heterotopic ossification would be more frequent with the double-incision technique. Study Design: Systematic review and meta-analysis; Level of evidence, 4. Methods: A systematic review was conducted using the PubMed, MEDLINE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), SPORTSDiscus, and the Cochrane Central Register of Controlled Trials databases to identify articles reporting distal biceps ruptures up to August 2013. We included English-language articles on adult patients with a minimum of 3 cases reporting single- and double-incision techniques. Frequencies of each complication as a percentage of total cases were calculated. Fisher exact tests were used to test the association between frequencies for each repair method, with P < .05 considered statistically significant. Odds ratios with 95% CIs were also computed. Results: A total of 87 articles met the inclusion criteria. Lateral antebrachial cutaneous nerve neurapraxia was the most common complication in the single-incision group, occurring in 77 of 785 cases (9.8%). Heterotopic ossification was the most common complication in the double-incision group, occurring in 36 of 498 cases (7.2%). Conclusion: The overall frequency of reported complications is higher for single-incision distal biceps repair than for double-incision repair. The frequencies of rerupture and nerve complications are both higher for single-incision repairs while the frequency of heterotopic ossification is higher for

  17. Distal Renal Tubular Acidosis and Calcium Nephrolithiasis

    NASA Astrophysics Data System (ADS)

    Moe, Orson W.; Fuster, Daniel G.; Xie, Xiao-Song

    2008-09-01

    Calcium stones are commonly encountered in patients with congenital distal renal tubular acidosis, a disease of renal acidification caused by mutations in either the vacuolar H+-ATPase (B1 or a4 subunit), anion exchanger-1, or carbonic anhydrase II. Based on the existing database, we present two hypotheses. First, heterozygotes with mutations in B1 subunit of H+-ATPase are not normal but may harbor biochemical abnormalities such as renal acidification defects, hypercalciuria, and hypocitraturia which can predispose them to kidney stone formation. Second, we propose at least two mechanisms by which mutant B1 subunit can impair H+-ATPase: defective pump assembly and defective pump activity.

  18. Human Trafficking of Children in the United States: A Fact Sheet for Schools

    ERIC Educational Resources Information Center

    Office of Safe and Healthy Students, US Department of Education, 2013

    2013-01-01

    Human trafficking is a serious federal crime with penalties of up to imprisonment for life. Federal law defines "severe forms of trafficking in persons." In short, human trafficking is a form of modern slavery. Those who recruit minors into commercial sexual exploitation (or prostitution) violate federal anti-trafficking laws, even if there is no…

  19. Human Trafficking of Children in the United States: A Fact Sheet

    ERIC Educational Resources Information Center

    US Department of Education, 2007

    2007-01-01

    This fact sheet presents questions and answers related to the human trafficking of children in the United States. It describes human trafficking and its extent in the United States, how human traffickers target children for coerced labor and sex exploitation, how to identify victims of human trafficking, how to report a suspected incidence of…

  20. Aqueous outflow: Segmental and distal flow

    PubMed Central

    Swaminathan, Swarup S.; Oh, Dong-Jin; Kang, Min Hyung; Rhee, Douglas J.

    2014-01-01

    A prominent risk factor of primary open-angle glaucoma is ocular hypertension, a pathologic state caused by impaired outflow of aqueous humor through the trabecular meshwork within the iridocorneal angle. The juxtacanalicular region of the trabecular meshwork and the inner wall of Schlemm canal have been identified as the main contributors to aqueous outflow resistance, and both extracellular matrix within the trabecular meshwork and trabecular meshwork cell shape have been shown to affect outflow. Overexpression of multiple ECM proteins in perfused cadaveric human eyes has led to increased outflow resistance and elevated IOP. Pharmacologic agents targeting trabecular meshwork cytoskeletal arrangements have been developed after multiple studies demonstrated the importance of cell shape on outflow. Several groups have shown that aqueous outflow occurs only at certain segments of the trabecular meshwork circumferentially, a concept known as segmental flow. This is based on the theory that aqueous outflow is dependent on the presence of discrete pores within the Schlemm canal. Segmental flow has been described in the eyes of multiple species, including primate, bovine, mouse, and human samples. While the trabecular meshwork appears to be the major source of resistance, trabecular meshwork bypass procedures have been unable to achieve the degree of IOP reduction observed with trabeculectomy, reflecting the potential impact of distal flow, or flow through Schlemm canal and collector channels, on outflow. Multiple studies have demonstrated that outflow occurs preferentially near collector channels, suggesting that these distal structures may be more important to aqueous outflow than previously believed. PMID:25088623

  1. Maxillary molar distalization with first class appliance

    PubMed Central

    Ramesh, Namitha; Palukunnu, Biswas; Ravindran, Nidhi; Nair, Preeti P

    2014-01-01

    Non-extraction treatment has gained popularity for corrections of mild-to-moderate class II malocclusion over the past few decades. The distalization of maxillary molars is of significant value for treatment of cases with minimal arch discrepancy and mild class II molar relation associated with a normal mandibular arch and acceptable profile. This paper describes our experience with a 16-year-old female patient who reported with irregularly placed upper front teeth and unpleasant smile. The patient was diagnosed to have angles class II malocclusion with moderate maxillary anterior crowding, deep bite of 4 mm on a skeletal class II base with an orthognathic maxilla and retrognathic mandible and normal growth pattern. She presented an ideal profile and so molar distalization was planned with the first-class appliance. Molars were distalised by 8 mm on the right and left quadrants and class I molar relation achieved within 4 months. The space gained was utilised effectively to align the arch and establish a class I molar and canine relation. PMID:24577171

  2. Distal metatarsal coalition: A rare case report

    PubMed Central

    Vun, Shen Hwa; Drampalos, Efstathios; Shareef, Sajan; Sinha, Satyajit; Bramley, Diane

    2015-01-01

    Introduction Metatarsal coalition is an extremely rare condition. We report the second documented case of 4th and 5th distal metatarsal coalition in the literature. Presentation of case An eight-year-old girl was referred to an orthopaedic clinic with a four-month history of forefoot pain and swelling on the plantar aspect of the right little toe. Radiograph and clinical examination confirmed distal metatarsal coalition between the 4th and 5th metatarsals. Following a period of conservative treatment, excision was eventually performed due to worsening symptoms. Patient re-attended two years later with a recurrence of the coalition confirmed by computed tomography (CT) scan. The case was discussed at a tertiary paediatric orthopaedic insititution. Decision was made to manage patient conservatively with insole and physiotherapy until skeletal maturity. A year later, patient’s symptoms did not worsen, and her foot displayed no evidence of change in the arch and shape. Discussion The timing of ossification of coalition varies from one anatomical site to another. Surgery when performed before ossification is complete runs the risk of recurrence. Conclusion Our case report illustrates the importance of restoring normal weight bearing dynamics and pain relief when managing metatarsal coalition, or synostosis in skeletally immature patients. We recommend persevering with conservative treatment, with operative treatment reserved only as a later option, and ideally, until skeletal maturity is achieved. PMID:25670408

  3. Distal vacuolar myopathy in nephropathic cystinosis.

    PubMed

    Charnas, L R; Luciano, C A; Dalakas, M; Gilliatt, R W; Bernardini, I; Ishak, K; Cwik, V A; Fraker, D; Brushart, T A; Gahl, W A

    1994-02-01

    Nephropathic cystinosis is a lysosomal storage disorder leading to renal failure by age 10 years. Prolonged patient survival following renal transplantation has allowed the development of previously unknown long-term complications. Muscle involvement has been reported in a single posttransplant cystinosis patient, but the range of clinical, electrophysiologic, and histologic features has not been fully described. Thirteen of 54 post-renal-transplant patients that we examined developed weakness and wasting in the small hand muscles, with or without facial weakness and dysphagia. Tendon reflexes were preserved and sensory examinations were normal. Electrophysiologic studies in 11 affected patients showed normal nerve conduction velocities and preserved sensory action potentials. The voluntary motor units in the affected distal muscles had reduced amplitude and brief duration, confirmed with quantitative electromyography in 4 patients. Biopsy of the severely affected abductor digiti minimi or extensor carpi radialis brevis muscles in 2 patients revealed marked fiber size variability, prominent acid phosphatase-positive vacuoles, and absence of fiber type grouping or inflammatory cells. Crystals of cystine were detected in perimysial cells but not within the muscle cell vacuoles. The muscle cystine content of clinically affected muscles was markedly elevated. We conclude that a distal vacuolar myopathy is a common late complication of untreated nephropathic cystinosis. Although the cause is unclear, the general lysosomal defect in this disease may also affect the lysosomes within muscle fibers.

  4. Human trafficking and health: a cross-sectional survey of NHS professionals’ contact with victims of human trafficking

    PubMed Central

    Ross, Claire; Dimitrova, Stoyanka; Howard, Louise M; Dewey, Michael; Zimmerman, Cathy; Oram, Siân

    2015-01-01

    Objectives (1) To estimate the proportion of National Health Service (NHS) professionals who have come into contact with trafficked people and (2) to measure NHS professionals’ knowledge and confidence to respond to human trafficking. Design A cross-sectional survey. Setting Face-to-face mandatory child protection and/or vulnerable adults training sessions at 10 secondary healthcare provider organisations in England, and meetings of the UK College of Emergency Medicine. Participants 782/892 (84.4%) NHS professionals participated, including from emergency medicine, maternity, mental health, paediatrics and other clinical disciplines. Measures Self-completed questionnaire developed by an expert panel. Questionnaire asks about prior training and contact with potential victims of trafficking, perceived and actual human trafficking knowledge, confidence in responding to human trafficking, and interest in future human trafficking training. Results 13% participants reported previous contact with a patient they knew or suspected of having been trafficked; among maternity services professionals this was 20.4%. However, 86.8% (n=679) reported lacking knowledge of what questions to ask to identify potential victims and 78.3% (n=613) reported that they had insufficient training to assist trafficked people. 71% (n=556), 67.5% (n=528) and 53.4% (n=418) lacked confidence in making appropriate referrals for men, women and children, respectively, who had been trafficked. 95.3% (n=746) of respondents were unaware of the scale of human trafficking in the UK, and 76.5% (n=598) were unaware that calling the police could put patients in more danger. Psychometric analysis showed that subscales measuring perceived knowledge, actual knowledge and confidence to respond to human trafficking demonstrated good internal consistency (Cronbach's αs 0.93, 0.63 and 0.64, respectively) and internal correlations. Conclusions NHS professionals working in secondary care are in contact with potential

  5. The Medical Response to Sex Trafficking of Minors in Wisconsin.

    PubMed

    Rabbitt, Angela

    2015-04-01

    Medical professionals are in a unique position to identify and assist pediatric victims of sex trafficking, who experience a high prevalence of physical, mental, and sexual health problems. However, providers report a need for education and guidelines for medical care of this population. A literature review was conducted on the nature and scope of pediatric sex trafficking in Wisconsin, the medical and mental health needs of victims, and existing guidelines for medical management. Few existing medical guidelines for the care of trafficking victims are specific to pediatrics or include specific recommendations for the forensic medical evaluation. Because of legislation and resources specific to Wisconsin, national guidelines may not apply locally. Based on the literature review, as well as input from community partners and medical professionals who frequently provide services to victims, guidelines for the medical care of pediatric sex trafficking victims in Wisconsin were developed. Additional community barriers that may prevent an effective medical response also are discussed. PMID:26756057

  6. Recognizing victims of human trafficking in the pediatric emergency department.

    PubMed

    Becker, Heather J; Bechtel, Kirsten

    2015-02-01

    Human trafficking is a form of modern-day slavery that is rapidly expanding in the United States and throughout the world. It is a crime under both the United States and international law. The child and adult victims of human trafficking are denied their basic human rights and subjected to unspeakable physical and emotional harm. Traffickers exert complete control over their victims and are proficient at hiding their condition from authorities. Healthcare practitioners may be the only professionals who come into contact with victims if they present for medical care. This article will describe human trafficking and its potential victims, as well as guide medical management and access to services that will ensure their safety and restore their freedom.

  7. Endocytosis and Intracellular Trafficking of Human Natural Killer Cell Receptors

    PubMed Central

    Masilamani, Madhan; Peruzzi, Giovanna; Borrego, Francisco; Coligan, John E.

    2009-01-01

    Natural killer (NK) cells play a vital role in the defense against viral infections and tumor development. NK cell function is primarily regulated by the sum of signals from a broad array of activation and inhibitory receptors. Key to generating the input level of either activating or inhibitory signals is the maintenance of receptor expression levels on the cell surface. Although the mechanisms of endocytosis and trafficking for some cell surface receptors, such as transferrin receptor, and certain immune receptors, are very well known, that is not the situation for receptors expressed by NK cells. Recent studies have uncovered that endocytosis and trafficking routes characteristic for specific activation and inhibitory receptors can regulate the functional responses of NK cells. In this review, we summarize the current knowledge of receptor endocytosis and trafficking, and integrate this with our current understanding of NK cell receptor trafficking. PMID:19719476

  8. Recognizing victims of human trafficking in the pediatric emergency department.

    PubMed

    Becker, Heather J; Bechtel, Kirsten

    2015-02-01

    Human trafficking is a form of modern-day slavery that is rapidly expanding in the United States and throughout the world. It is a crime under both the United States and international law. The child and adult victims of human trafficking are denied their basic human rights and subjected to unspeakable physical and emotional harm. Traffickers exert complete control over their victims and are proficient at hiding their condition from authorities. Healthcare practitioners may be the only professionals who come into contact with victims if they present for medical care. This article will describe human trafficking and its potential victims, as well as guide medical management and access to services that will ensure their safety and restore their freedom. PMID:25651385

  9. Regulation of nucleocytoplasmic trafficking of transcription factor OREBP/TonEBP/NFAT5.

    PubMed

    Tong, Edith H Y; Guo, Jin-Jun; Huang, Ai-Long; Liu, Han; Hu, Chang-Deng; Chung, Stephen S M; Ko, Ben C B

    2006-08-18

    The osmotic response element-binding protein (OREBP), also known as tonicity enhancer-binding protein (TonEBP) or NFAT5, regulates the hypertonicity-induced expression of a battery of genes crucial for the adaptation of mammalian cells to extracellular hypertonic stress. The activity of OREBP/TonEBP is regulated at multiple levels, including nucleocytoplasmic trafficking. OREBP/TonEBP protein can be detected in both the cytoplasm and nucleus under isotonic conditions, although it accumulates exclusively in the nucleus or cytoplasm when subjected to hypertonic or hypotonic challenges, respectively. Using immunocytochemistry and green fluorescent protein fusions, the protein domains that determine its subcellular localization were identified and characterized. We found that OREBP/TonEBP nuclear import is regulated by a nuclear localization signal. However, under isotonic conditions, nuclear export of OREBP/TonEBP is mediated by a CRM1-dependent, leucine-rich canonical nuclear export sequence (NES) located in the N terminus. Disruption of NES by site-directed mutagenesis yielded a mutant OREBP/TonEBP protein that accumulated in the nucleus under isotonic conditions but remained a target for hypotonicity-induced nuclear export. More importantly, a putative auxiliary export domain distal to the NES was identified. Disruption of the auxiliary export domain alone is sufficient to abolish the nuclear export of OREBP/TonEBP induced by hypotonicity. By using bimolecular fluorescence complementation assay, we showed that CRM1 interacts with OREBP/TonEBP, but not with a mutant protein deficient in NES. Our findings provide insight into how nucleocytoplasmic trafficking of OREBP/TonEBP is regulated by changes in extracellular tonicity. PMID:16782704

  10. Drug Trafficking Organizations and Local Economic Activity in Mexico.

    PubMed

    González, Felipe

    2015-01-01

    Little is known about the relationship between illegal firms and local economic activity. In this paper I study changes in satellite night lights across Mexican municipalities after the arrival of large drug trafficking organizations in the period 2000-2010. After accounting for state trends and differences in political regimes, results indicate no significant change in night lights after the arrival of these illegal firms. Estimated coefficients are precise, robust, and similar across different drug trafficking organizations.

  11. Drug Trafficking Organizations and Local Economic Activity in Mexico.

    PubMed

    González, Felipe

    2015-01-01

    Little is known about the relationship between illegal firms and local economic activity. In this paper I study changes in satellite night lights across Mexican municipalities after the arrival of large drug trafficking organizations in the period 2000-2010. After accounting for state trends and differences in political regimes, results indicate no significant change in night lights after the arrival of these illegal firms. Estimated coefficients are precise, robust, and similar across different drug trafficking organizations. PMID:26348041

  12. Drug Trafficking Organizations and Local Economic Activity in Mexico

    PubMed Central

    González, Felipe

    2015-01-01

    Little is known about the relationship between illegal firms and local economic activity. In this paper I study changes in satellite night lights across Mexican municipalities after the arrival of large drug trafficking organizations in the period 2000–2010. After accounting for state trends and differences in political regimes, results indicate no significant change in night lights after the arrival of these illegal firms. Estimated coefficients are precise, robust, and similar across different drug trafficking organizations. PMID:26348041

  13. Sex trafficking of minors in metropolitan, micropolitan, and rural communities.

    PubMed

    Cole, Jennifer; Sprang, Ginny

    2015-02-01

    The purpose of the study was to examine professionals' awareness, knowledge, and experiences working with youth victims of sex trafficking in metropolitan and non-metropolitan communities. Professionals who worked with at-risk youth and/or crime victims were recruited from all counties in a southern, rural state in the U.S. to complete a telephone survey. Surveys included closed and open-ended questions, which were theme coded. Professionals' (n=289) were classified into one of four categories based on the counties in which they worked: metropolitan, micropolitan, rural, and all three community types. Although there were many similarities found in trafficking situations across the different types of communities, some expected differences were found. First, as expected, more professionals in metropolitan communities perceived CSEC as being a fairly or very serious problem in the state overall. Consistent with other studies, more professionals in metropolitan communities had received training on human trafficking and reported they were familiar with the state and federal laws on human trafficking (Newton et al., 2008). Significantly more professionals in metropolitan (54.7%) communities reported they had worked with a suspected or definite victim of STM compared to professionals in micropolitan communities (29.8%). There were few differences in victim characteristics, vulnerability factors, and trafficking situations (e.g., relationship to trafficker, traffickers' techniques for controlling victims, transportation, and Internet-facilitation of trafficking) across the community types. There is a continued need for awareness building of STM and training, particularly in non-metropolitan communities, as well as adoption of screening tools, integration of trauma-informed care, and identification of best practices. PMID:25151302

  14. Sex trafficking of minors in metropolitan, micropolitan, and rural communities.

    PubMed

    Cole, Jennifer; Sprang, Ginny

    2015-02-01

    The purpose of the study was to examine professionals' awareness, knowledge, and experiences working with youth victims of sex trafficking in metropolitan and non-metropolitan communities. Professionals who worked with at-risk youth and/or crime victims were recruited from all counties in a southern, rural state in the U.S. to complete a telephone survey. Surveys included closed and open-ended questions, which were theme coded. Professionals' (n=289) were classified into one of four categories based on the counties in which they worked: metropolitan, micropolitan, rural, and all three community types. Although there were many similarities found in trafficking situations across the different types of communities, some expected differences were found. First, as expected, more professionals in metropolitan communities perceived CSEC as being a fairly or very serious problem in the state overall. Consistent with other studies, more professionals in metropolitan communities had received training on human trafficking and reported they were familiar with the state and federal laws on human trafficking (Newton et al., 2008). Significantly more professionals in metropolitan (54.7%) communities reported they had worked with a suspected or definite victim of STM compared to professionals in micropolitan communities (29.8%). There were few differences in victim characteristics, vulnerability factors, and trafficking situations (e.g., relationship to trafficker, traffickers' techniques for controlling victims, transportation, and Internet-facilitation of trafficking) across the community types. There is a continued need for awareness building of STM and training, particularly in non-metropolitan communities, as well as adoption of screening tools, integration of trauma-informed care, and identification of best practices.

  15. Distal Communication by Chimpanzees (Pan troglodytes): Evidence for Common Ground?

    PubMed

    Leavens, David A; Reamer, Lisa A; Mareno, Mary Catherine; Russell, Jamie L; Wilson, Daniel; Schapiro, Steven J; Hopkins, William D

    2015-01-01

    van der Goot et al. (2014) proposed that distal, deictic communication indexed the appreciation of the psychological state of a common ground between a signaler and a receiver. In their study, great apes did not signal distally, which they construed as evidence for the human uniqueness of a sense of common ground. This study exposed 166 chimpanzees to food and an experimenter, at an angular displacement, to ask, "Do chimpanzees display distal communication?" Apes were categorized as (a) proximal or (b) distal signalers on each of four trials. The number of chimpanzees who communicated proximally did not statistically differ from the number who signaled distally. Therefore, contrary to the claim by van der Goot et al., apes do communicate distally.

  16. PHILOS humerus plate for a distal tibial fracture.

    PubMed

    Twaij, Haider; Damany, Dev

    2013-01-04

    This report discusses the use of an alternative implant in the emergency fixation of a distal tibial fracture. We planned to fix the shear-type medial malleolar fracture in a closed, tri-malleolar fracture with a locking distal tibial plate. Intra-operatively, it was noted that the required plate was unavailable. A PHILOS humeral plate seemed to fit the contours of the distal tibia. The broad end of the PHILOS, when placed distally, gave options to place locking screws in the medial malleolar fragment. The fracture was stable after fixation. The patient made a full post-operative recovery and follow-up at 4 months was satisfactory. Despite adequate planning, there will be instances where one has to improvise. An understanding of the principles of fracture management can aid in finding solutions. PHILOS humeral plate may be used to stabilize a distal tibial fracture if an appropriate distal tibial locking plate is not available.

  17. Cellular membrane trafficking of mesoporous silica nanoparticles

    SciTech Connect

    Fang, I-Ju

    2012-01-01

    This dissertation mainly focuses on the investigation of the cellular membrane trafficking of mesoporous silica nanoparticles. We are interested in the study of endocytosis and exocytosis behaviors of mesoporous silica nanoparticles with desired surface functionality. The relationship between mesoporous silica nanoparticles and membrane trafficking of cells, either cancerous cells or normal cells was examined. Since mesoporous silica nanoparticles were applied in many drug delivery cases, the endocytotic efficiency of mesoporous silica nanoparticles needs to be investigated in more details in order to design the cellular drug delivery system in the controlled way. It is well known that cells can engulf some molecules outside of the cells through a receptor-ligand associated endocytosis. We are interested to determine if those biomolecules binding to cell surface receptors can be utilized on mesoporous silica nanoparticle materials to improve the uptake efficiency or govern the mechanism of endocytosis of mesoporous silica nanoparticles. Arginine-glycine-aspartate (RGD) is a small peptide recognized by cell integrin receptors and it was reported that avidin internalization was highly promoted by tumor lectin. Both RGD and avidin were linked to the surface of mesoporous silica nanoparticle materials to investigate the effect of receptor-associated biomolecule on cellular endocytosis efficiency. The effect of ligand types, ligand conformation and ligand density were discussed in Chapter 2 and 3. Furthermore, the exocytosis of mesoporous silica nanoparticles is very attractive for biological applications. The cellular protein sequestration study of mesoporous silica nanoparticles was examined for further information of the intracellular pathway of endocytosed mesoporous silica nanoparticle materials. The surface functionality of mesoporous silica nanoparticle materials demonstrated selectivity among the materials and cancer and normal cell lines. We aimed to determine

  18. UNC-108/Rab2 Regulates Postendocytic Trafficking in Caenorhabditis elegans

    PubMed Central

    Chun, Denise K.; McEwen, Jason M.; Burbea, Michelle

    2008-01-01

    After endocytosis, membrane proteins are often sorted between two alternative pathways: a recycling pathway and a degradation pathway. Relatively little is known about how trafficking through these alternative pathways is differentially regulated. Here, we identify UNC-108/Rab2 as a regulator of postendocytic trafficking in both neurons and coelomocytes. Mutations in the Caenorhabditis elegans Rab2 gene unc-108, caused the green fluorescent protein (GFP)-tagged glutamate receptor GLR-1 (GLR-1::GFP) to accumulate in the ventral cord and in neuronal cell bodies. In neuronal cell bodies of unc-108/Rab2 mutants, GLR-1::GFP was found in tubulovesicular structures that colocalized with markers for early and recycling endosomes, including Syntaxin-13 and Rab8. GFP-tagged Syntaxin-13 also accumulated in the ventral cord of unc-108/Rab2 mutants. UNC-108/Rab2 was not required for ubiquitin-mediated sorting of GLR-1::GFP into the multivesicular body (MVB) degradation pathway. Mutations disrupting the MVB pathway and unc-108/Rab2 mutations had additive effects on GLR-1::GFP levels in the ventral cord. In coelomocytes, postendocytic trafficking of the marker Texas Red-bovine serum albumin was delayed. These results demonstrate that UNC-108/Rab2 regulates postendocytic trafficking, most likely at the level of early or recycling endosomes, and that UNC-108/Rab2 and the MVB pathway define alternative postendocytic trafficking mechanisms that operate in parallel. These results define a new function for Rab2 in protein trafficking. PMID:18434599

  19. Ultrasound-Assisted Distal Radius Fracture Reduction

    PubMed Central

    Socransky, Steve; Skinner, Andrew; Bromley, Mark; Smith, Andrew; Anawati, Alexandre; Middaugh, Jeff; Ross, Peter

    2016-01-01

    Introduction Closed reduction of distal radius fractures (CRDRF) is a commonly performed emergency department (ED) procedure. The use of point-of-care ultrasound (PoCUS) to diagnose fractures and guide reduction has previously been described. The primary objective of this study was to determine if the addition of PoCUS to CRDRF changed the perception of successful initial reduction. This was measured by the rate of further reduction attempts based on PoCUS following the initial clinical determination of achievement of best possible reduction. Methods  We performed a multicenter prospective cohort study, using a convenience sample of adult ED patients presenting with a distal radius fracture to five Canadian EDs. All study physicians underwent standardized PoCUS training for fractures. Standard clinically-guided best possible fracture reduction was initially performed. PoCUS was then used to assess the reduction adequacy. Repeat reduction was performed if deemed indicated. A post-reduction radiograph was then performed. Clinician impression of reduction adequacy was scored on a 5 point Likert scale following the initial clinically-guided reduction and following each PoCUS scan and the post-reduction radiograph. Results  There were 131 patients with 132 distal radius fractures. Twelve cases were excluded prior to analysis. There was no significant difference in the assessment of the initial reduction status by PoCUS as compared to the clinical exam (mean score: 3.8 vs. 3.9; p = 0.370; OR 0.89; 95% CI 0.46 to 1.72; p = 0.87). Significantly fewer cases fell into the uncertain category with PoCUS than with clinical assessment (2 vs 12; p = 0.008). Repeat reduction was performed in 49 patients (41.2%). Repeat reduction led to a significant improvement (p < 0.001) in the PoCUS determined adequacy of reduction (mean score: 4.3 vs 3.1; p < 0.001). In this group, the odds ratio for adequate vs. uncertain or inadequate reduction assessment using PoCUS was 12.5 (95% CI 3

  20. Ultrasound-Assisted Distal Radius Fracture Reduction.

    PubMed

    Socransky, Steve; Skinner, Andrew; Bromley, Mark; Smith, Andrew; Anawati, Alexandre; Middaugh, Jeff; Ross, Peter; Atkinson, Paul

    2016-01-01

    Introduction Closed reduction of distal radius fractures (CRDRF) is a commonly performed emergency department (ED) procedure. The use of point-of-care ultrasound (PoCUS) to diagnose fractures and guide reduction has previously been described. The primary objective of this study was to determine if the addition of PoCUS to CRDRF changed the perception of successful initial reduction. This was measured by the rate of further reduction attempts based on PoCUS following the initial clinical determination of achievement of best possible reduction. Methods  We performed a multicenter prospective cohort study, using a convenience sample of adult ED patients presenting with a distal radius fracture to five Canadian EDs. All study physicians underwent standardized PoCUS training for fractures. Standard clinically-guided best possible fracture reduction was initially performed. PoCUS was then used to assess the reduction adequacy. Repeat reduction was performed if deemed indicated. A post-reduction radiograph was then performed. Clinician impression of reduction adequacy was scored on a 5 point Likert scale following the initial clinically-guided reduction and following each PoCUS scan and the post-reduction radiograph. Results  There were 131 patients with 132 distal radius fractures. Twelve cases were excluded prior to analysis. There was no significant difference in the assessment of the initial reduction status by PoCUS as compared to the clinical exam (mean score: 3.8 vs. 3.9; p = 0.370; OR 0.89; 95% CI 0.46 to 1.72; p = 0.87). Significantly fewer cases fell into the uncertain category with PoCUS than with clinical assessment (2 vs 12; p = 0.008). Repeat reduction was performed in 49 patients (41.2%). Repeat reduction led to a significant improvement (p < 0.001) in the PoCUS determined adequacy of reduction (mean score: 4.3 vs 3.1; p < 0.001). In this group, the odds ratio for adequate vs. uncertain or inadequate reduction assessment using PoCUS was 12.5 (95% CI 3

  1. Distal Xq duplication and functional Xq disomy

    PubMed Central

    Sanlaville, Damien; Schluth-Bolard, Caroline; Turleau, Catherine

    2009-01-01

    Distal Xq duplications refer to chromosomal disorders resulting from involvement of the long arm of the X chromosome (Xq). Clinical manifestations widely vary depending on the gender of the patient and on the gene content of the duplicated segment. Prevalence of Xq duplications remains unknown. About 40 cases of Xq28 functional disomy due to cytogenetically visible rearrangements, and about 50 cases of cryptic duplications encompassing the MECP2 gene have been reported. The most frequently reported distal duplications involve the Xq28 segment and yield a recognisable phenotype including distinctive facial features (premature closure of the fontanels or ridged metopic suture, broad face with full cheeks, epicanthal folds, large ears, small and open mouth, ear anomalies, pointed nose, abnormal palate and facial hypotonia), major axial hypotonia, severe developmental delay, severe feeding difficulties, abnormal genitalia and proneness to infections. Xq duplications may be caused either by an intrachromosomal duplication or an unbalanced X/Y or X/autosome translocation. In XY males, structural X disomy always results in functional disomy. In females, failure of X chromosome dosage compensation could result from a variety of mechanisms, including an unfavourable pattern of inactivation, a breakpoint separating an X segment from the X-inactivation centre in cis, or a small ring chromosome. The MECP2 gene in Xq28 is the most important dosage-sensitive gene responsible for the abnormal phenotype in duplications of distal Xq. Diagnosis is based on clinical features and is confirmed by CGH array techniques. Differential diagnoses include Prader-Willi syndrome and Alpha thalassaemia-mental retardation, X linked (ATR-X). The recurrence risk is significant if a structural rearrangement is present in one of the parent, the most frequent situation being that of an intrachromosomal duplication inherited from the mother. Prenatal diagnosis is performed by cytogenetic testing

  2. Analysis of Occludin Trafficking, Demonstrating Continuous Endocytosis, Degradation, Recycling and Biosynthetic Secretory Trafficking

    PubMed Central

    Fletcher, Sarah J.; Iqbal, Mudassar; Jabbari, Sara; Stekel, Dov; Rappoport, Joshua Z.

    2014-01-01

    Tight junctions (TJs) link adjacent cells and are critical for maintenance of apical-basolateral polarity in epithelial monolayers. The TJ protein occludin functions in disparate processes, including wound healing and Hepatitis C Virus infection. Little is known about steady-state occludin trafficking into and out of the plasma membrane. Therefore, we determined the mechanisms responsible for occludin turnover in confluent Madin-Darby canine kidney (MDCK) epithelial monolayers. Using various biotin-based trafficking assays we observed continuous and rapid endocytosis of plasma membrane localised occludin (the majority internalised within 30 minutes). By 120 minutes a significant reduction in internalised occludin was observed. Inhibition of lysosomal function attenuated the reduction in occludin signal post-endocytosis and promoted co-localisation with the late endocytic system. Using a similar method we demonstrated that ∼20% of internalised occludin was transported back to the cell surface. Consistent with these findings, significant co-localisation between internalised occludin and recycling endosomal compartments was observed. We then quantified the extent to which occludin synthesis and transport to the plasma membrane contributes to plasma membrane occludin homeostasis, identifying inhibition of protein synthesis led to decreased plasma membrane localised occludin. Significant co-localisation between occludin and the biosynthetic secretory pathway was demonstrated. Thus, under steady-state conditions occludin undergoes turnover via a continuous cycle of endocytosis, recycling and degradation, with degradation compensated for by biosynthetic exocytic trafficking. We developed a mathematical model to describe the endocytosis, recycling and degradation of occludin, utilising experimental data to provide quantitative estimates for the rates of these processes. PMID:25422932

  3. Improved radiographic visualization of calculus in distal ureter.

    PubMed

    Amar, A D

    1979-10-01

    Roentgenographic visualization of a calculus in the distal ureter is often made difficult by gas or bowel contents in the region of the pelvis. Filling the bladder with sterile water raises the bladder dome and displaces the bowel upward. Any calculus in the lower 4 to 5 cm. of the distal ureter is then clearly demonstrated on roentgenograms taken against the water-filled bladder instead of against the bowel filled with gas and feces. This maneuver also aids in differentiation of a calculus in the distal ureter from a phlebolith in the bladder wall, and has improved visualization of distal ureteral calculus in 50 patients during the last six years. PMID:494477

  4. Distal myopathy with rimmed vacuoles and cerebellar atrophy.

    PubMed

    Merkli, Hajnalka; Pál, Endre; Gáti, István; Czopf, József

    2006-01-01

    Distal myopathies constitute a clinically and pathologically heterogeneous group of genetically determined neuromuscular disorders, where the distal muscles of the upper or lower limbs are affected. The disease of a 41-year-old male patient started with gait disturbances, when he was 25. The progression was slow, but after 16 years he became seriously disabled. Neurological examination showed moderate to severe weakness in distal muscles of all extremities, marked cerebellar sign and steppage gait. Muscle biopsy resulted in myopathic changes with rimmed vacuoles. Brain MRI scan showed cerebellar atrophy. This case demonstrates a rare association of distal myopathy and cerebellar atrophy.

  5. Genome-wide analysis of the rat colon reveals proximal-distal differences in histone modifications and proto-oncogene expression.

    PubMed

    Triff, Karen; Konganti, Kranti; Gaddis, Sally; Zhou, Beiyan; Ivanov, Ivan; Chapkin, Robert S

    2013-12-15

    Since disease susceptibility of the intestine exhibits an anatomical bias, we propose that the chromatin landscape, especially the site-specific epigenetic differences in histone modification patterns throughout the colonic longitudinal axis, contributes to the differential incidence of site-specific pathology. To test this hypothesis, we assessed the chromatin structure associated with gene expression profiles in the rat proximal and distal colon by globally correlating chromatin immunoprecipitation next-generation sequencing analysis (ChIP-Seq) with mRNA transcription (RNA-Seq) data. Crypts were isolated from the proximal and distal colonic regions from rats maintained on a semipurified diet, and mRNA gene expression profiles were generated by RNA-Seq. The remaining isolated crypts were formaldehyde-cross-linked and chromatin immunoprecipitated with antibodies against H3K4me3, H3K9me3, and RNA polymerase II. Globally, RNA-Seq results indicate that 9,866 genes were actively expressed, of which 540 genes were differentially expressed between the proximal and distal colon. Gene ontology analysis indicates that crypt location significantly affected both chromatin and transcriptional regulation of genes involved in enterocyte movement, lipid metabolism, lymphatic development, and immune cell trafficking. Gene function analysis indicates that the PI3-kinase signaling pathway was regulated in a site-specific manner, e.g., proto-oncogenes, JUN, FOS, and ATF, were upregulated in the distal colon. Middle and long noncoding RNAs (lncRNAs) were also detected in the colon, including select lncRNAs formerly only detected in the rat nervous system. In summary, distinct combinatorial patterns of histone modifications exist in the proximal versus distal colon. These site-specific differences may explain the differential effects of chemoprotective agents on cell transformation in the ascending (proximal) and descending (distal) colon.

  6. Genome-wide analysis of the rat colon reveals proximal-distal differences in histone modifications and proto-oncogene expression

    PubMed Central

    Triff, Karen; Konganti, Kranti; Gaddis, Sally; Zhou, Beiyan; Ivanov, Ivan

    2013-01-01

    Since disease susceptibility of the intestine exhibits an anatomical bias, we propose that the chromatin landscape, especially the site-specific epigenetic differences in histone modification patterns throughout the colonic longitudinal axis, contributes to the differential incidence of site-specific pathology. To test this hypothesis, we assessed the chromatin structure associated with gene expression profiles in the rat proximal and distal colon by globally correlating chromatin immunoprecipitation next-generation sequencing analysis (ChIP-Seq) with mRNA transcription (RNA-Seq) data. Crypts were isolated from the proximal and distal colonic regions from rats maintained on a semipurified diet, and mRNA gene expression profiles were generated by RNA-Seq. The remaining isolated crypts were formaldehyde-cross-linked and chromatin immunoprecipitated with antibodies against H3K4me3, H3K9me3, and RNA polymerase II. Globally, RNA-Seq results indicate that 9,866 genes were actively expressed, of which 540 genes were differentially expressed between the proximal and distal colon. Gene ontology analysis indicates that crypt location significantly affected both chromatin and transcriptional regulation of genes involved in enterocyte movement, lipid metabolism, lymphatic development, and immune cell trafficking. Gene function analysis indicates that the PI3-kinase signaling pathway was regulated in a site-specific manner, e.g., proto-oncogenes, JUN, FOS, and ATF, were upregulated in the distal colon. Middle and long noncoding RNAs (lncRNAs) were also detected in the colon, including select lncRNAs formerly only detected in the rat nervous system. In summary, distinct combinatorial patterns of histone modifications exist in the proximal versus distal colon. These site-specific differences may explain the differential effects of chemoprotective agents on cell transformation in the ascending (proximal) and descending (distal) colon. PMID:24151245

  7. Implant arthroplasty for the distal radioulnar joint.

    PubMed

    Scheker, Luis R

    2008-11-01

    The distal radioulnar joint (DRUJ) is a weight-bearing joint; the ulnar head is frequently excised either totally or partially and in some cases is fused because of degenerative, rheumatoid, or posttraumatic arthritis and treated with a "salvage procedure." The result of these procedures is the inability of those patients to lift even minor weight. Articles about these procedures report the ability to pronate and supinate, but they rarely discuss grip strength or lifting capacity. We present an alternative to the salvage procedures that allows full range of motions as well as the ability to grip and lift weights encountered in daily living, such as a gallon of milk. The Aptis total DRUJ replacement prosthesis (Aptis Medical, Louisville, KY), a bipolar self-stabilizing DRUJ endoprosthesis, restores the forearm function. The technique of implantation is presented here.

  8. [Distal radius fractures: conservative or surgical treatment?].

    PubMed

    Mark, G; Ryf, C

    1993-07-01

    The "classical" Colles fracture of the distal radius is the most common fracture in the adult. In order to reduce the still rather high rate of permanent disability, this fracture involving a functionally important joint requires accurate reduction. The AO-fracture classification introduced by Müller not only defines the severity of an injury, but also allows for decision-making as to the most adequate treatment. Besides the purely conservative management by closed reduction and plaster cast for the type-A fractures, we have a number of other treatment modalities for the more complex-B and C-type fractures, such as closed reduction and percutaneous K-wire application or the use of the small external fixator as well as open reduction and internal fixation by plates and screws for a few selected indications. PMID:8211844

  9. The Anatomy of Human Trafficking: Learning About the Blues: A Healthcare Provider's Guide.

    PubMed

    Stevens, Meriam; Berishaj, Kelly

    2016-01-01

    Human trafficking is a major global public health concern. It is a grave crime that violates human rights. Contrary to healthcare providers' perceptions, victims of human trafficking come in contact with the healthcare system while being trafficked, with the emergency department being the most frequented setting for medical treatment. In this article, we explore the anatomy of human trafficking, including the scope of the problem, definitions, and types and elements of human trafficking. The roles of clinicians, particularly emergency department nurses and advanced practice nurses, in screening and identifying those at risk are examined. Clinical practice tools and guidelines that may be used by clinicians to guide the treatment of human trafficking victims are reviewed. Finally, current strategies and resources that address human trafficking are presented. For the purpose of this article, the terms "human trafficking" or "trafficking" will be used throughout.

  10. Human trafficking and health: a conceptual model to inform policy, intervention and research.

    PubMed

    Zimmerman, Cathy; Hossain, Mazeda; Watts, Charlotte

    2011-07-01

    Human trafficking is an international crime renowned for extreme forms of violence against women, men and children. Although trafficking-related violence has been well-documented, the health of trafficked persons has been a largely neglected topic. For people who are trafficked, health risks and consequences may begin before they are recruited into the trafficking process, continue throughout the period of exploitation and persist even after individuals are released. Policy-making, service provision and research often focus narrowly on criminal violations that occur during the period of exploitation, regularly overlooking the health implications of trafficking. Similarly, the public health sector has not yet incorporated human trafficking as a health concern. We present a conceptual model that highlights the migratory and exploitative nature of a multi-staged trafficking process, which includes: 'recruitment', travel-transit', 'exploitation' and 'integration' or 'reintegration', and for some trafficked persons, 'detention' and 're-trafficking' stages. Trafficked persons may suffer from physical, sexual and psychological harm, occupational hazards, legal restrictions and difficulties associated with being marginalised or stigmatised. Researchers and decision-makers will benefit from a theoretical approach that conceptualizes trafficking and health as a multi-staged process of cumulative harm. To address a health risk such as trafficking, which spans geographical boundaries and involves multiple sectors, including immigration and law enforcement, labour, social and health services, interventions must be coordinated between nations and across sectors to promote the protection and recovery of people who are trafficked.

  11. Human trafficking: Role of oral health care providers.

    PubMed

    Nuzzolese, E

    2014-11-01

    Trafficking in human beings is a modern form of slavery and is a well-known phenomenon throughout the European Union and beyond. After drug dealing and the weapons industry, human trafficking is the second largest criminal activity in the world today and it is a growing crime. The aim of governmental and non-governmental agencies, which are either directly or indirectly involved in combating trafficking in human beings, is the identification and referral of victims of trafficking and also to encourage self-referrals. Identification is the most important step to provide protection and assistance to victims of trafficking. Victims often have a variety of physical and mental health needs, including psychological trauma, injuries from violence, head and neck trauma, sexually transmitted infections and other gynaecological problems, dental/oral problems and have poor nutrition. The author's experience in the field of community dentistry in presented within. Volunteer dental services are offered to non-European Union patients held in a centre for asylum seekers in Bari (Italy). Dental professionals can, in fact, contribute to the identification, assistance and protection of trafficked persons, as well as offering forensic services to assist the police investigation in order to identify crimes and find the criminal organizations behind them. As for domestic violence and child abuse cases, there are ethical concerns involved in the identification and protection of the trafficked persons, as well as the need for interdisciplinary work and awareness. Adequate training in behavioural science and intercultural learning is paramount in order to avoid misunderstandings and increase sensitivity. PMID:25557409

  12. Human trafficking: Role of oral health care providers.

    PubMed

    Nuzzolese, E

    2014-11-30

    Trafficking in human beings is a modern form of slavery and is a well-known phenomenon throughout the European Union and beyond. After drug dealing and the weapons industry, human trafficking is the second largest criminal activity in the world today and it is a growing crime. The aim of governmental and non-governmental agencies, which are either directly or indirectly involved in combating trafficking in human beings, is the identification and referral of victims of trafficking and also to encourage self-referrals. Identification is the most important step to provide protection and assistance to victims of trafficking. Victims often have a variety of physical and mental health needs, including psychological trauma, injuries from violence, head and neck trauma, sexually transmitted infections and other gynaecological problems, dental/oral problems and have poor nutrition. The author's experience in the field of community dentistry in presented within. Volunteer dental services are offered to non-European Union patients held in a centre for asylum seekers in Bari (Italy). Dental professionals can, in fact, contribute to the identification, assistance and protection of trafficked persons, as well as offering forensic services to assist the police investigation in order to identify crimes and find the criminal organizations behind them. As for domestic violence and child abuse cases, there are ethical concerns involved in the identification and protection of the trafficked persons, as well as the need for interdisciplinary work and awareness. Adequate training in behavioural science and intercultural learning is paramount in order to avoid misunderstandings and increase sensitivity.

  13. Young Children's Sibling Relationship Quality: Distal and Proximal Correlates

    ERIC Educational Resources Information Center

    Kretschmer, Tina; Pike, Alison

    2009-01-01

    Background: Relationships within families are interdependent and related to distal environmental factors. Low socioeconomic status (SES) and high household chaos (distal factors) have been linked to less positive marital and parent-child relationships, but have not yet been examined with regard to young children's sibling relationships. The…

  14. Educating Health Care Professionals on Human Trafficking

    PubMed Central

    Grace, Aimee M.; Lippert, Suzanne; Collins, Kristin; Pineda, Noelle; Tolani, Alisha; Walker, Rebecca; Jeong, Monica; Trounce, Milana Boukhman; Graham-Lamberts, Caroline; Bersamin, Melina; Martinez, Det. Jeremy; Dotzler, Det. Jennifer; Vanek, Lt John; Storfer-Isser, Amy; Chamberlain, Lisa J.; Horwitz, Sarah M.

    2015-01-01

    Background The US Department of State estimates that there are between 4 and 27 million individuals worldwide in some form of modern slavery. Recent studies have demonstrated that 28% to 50% of trafficking victims in the United States encountered health care professionals while in captivity, but were not identified and recognized. This study aimed to determine whether an educational presentation increased emergency department (ED) providers' recognition of human trafficking (HT) victims and knowledge of resources to manage cases of HT. Methods The 20 largest San Francisco Bay Area EDs were randomized into intervention (10 EDs) or delayed intervention comparison groups (10 EDs) to receive a standardized educational presentation containing the following: background about HT, relevance of HT to health care, clinical signs in potential victims, and referral options for potential victims. Participants in the delayed intervention group completed a pretest in the period the immediate intervention group received the educational presentation, and all participants were assessed immediately before (pretest) and after (posttest) the intervention. The intervention effect was tested by comparing the pre–post change in the intervention group to the change in 2 pretests in the delayed intervention group adjusted for the effect of clustering within EDs. The 4 primary outcomes were importance of knowledge of HT to the participant's profession (5-point Likert scale), self-rated knowledge of HT (5-point Likert scale), knowledge of who to call for potential HT victims (yes/no), and suspecting that a patient was a victim of HT (yes/no). Findings There were 258 study participants from 14 EDs; 141 from 8 EDs in the intervention group and 117 from 7 EDs in the delayed intervention comparison group, of which 20 served as the delayed intervention comparison group. Participants in the intervention group reported greater increases in their level of knowledge about HT versus those in the

  15. Conservative Treatment Is Sufficient for Acute Distal Radioulnar Joint Instability With Distal Radius Fracture.

    PubMed

    Lee, Sang Ki; Kim, Kap Jung; Cha, Yong Han; Choy, Won Sik

    2016-09-01

    Treatments for acute distal radioulnar joint (DRUJ) instability with distal radius fracture vary from conservative to operative treatment, although it seems to be no consensus regarding which treatment is optimal. This prospective randomized study was designed to compare the clinical outcomes for operative and conservative treatment of acute DRUJ instability with distal radius fracture, according to the presence or absence and type of ulnar styloid process fracture and the degree of its displacement. Between July 2008 and February 2013, we enrolled 157 patients who exhibited an unstable DRUJ during intraoperative manual stress testing (via the ballottement test) after fixation of the distal radius. Patients were classified according to the type of the ulnar styloid process fracture, using preoperative wrist radiography, and each group was divided into subgroups, according to their treatment method. We then compared the clinical outcomes between the conservative and operative treatments, using their range of motion; Disabilities of the Arm, Shoulder, and Hand score; modified Mayo wrist score; and grip strength. At 3 months after surgery, among patients without ulnar styloid process fracture, the flexion-extension range was 79 ± 15° after supination sugar-tong splinting (group A-1), 91 ± 14° after DRUJ transfixation (group A-2), and 89 ± 10° after arthroscopic triangular fibrocartilage complex repair (group A-3); the operative treatments provided greater joint motion ranges than conservative treatment. The groups with ulnar styloid process fractures at the tip (group B) or base (group C) also exhibited better clinical outcomes after the operative treatments, compared with after the conservative treatment. However, at the final follow-up, groups A-1, A-2, and A-3 exhibited similar flexion-extension ranges (122 ± 25°, 119° ± 18°, and 120° ± 16°, respectively) and modified Mayo wrist scores (87 ± 7, 89 ± 8, and 85 ± 9). Thus, the conservative and

  16. Osteoarticular Allograft Reconstruction for an Angiosarcoma of the Distal Radius.

    PubMed

    Mavrogenis, Andreas F; Galanopoulos, John; Vottis, Christos; Megaloikonomos, Panayiotis D; Palmerini, Emanuela; Kokkalis, Zinon T

    2016-01-01

    Angiosarcoma of bone is a rare high-grade malignant vascular tumor accounting for <1% of malignant bone tumors. Tumor location in the distal radius is very rare. Complete surgical resection with limb salvage surgery or amputation is essential for the outcome of the patient. However, the literature is vague regarding the best surgical approach for resection of the distal radius and the optimal reconstruction option after a bone tumor resection. Several reconstruction techniques have been described, varying from arthrodesis to arthroplasties. In this article, we present a report of a patient with angiosarcoma of the distal radius treated with complete resection and reconstruction with a distal radius osteoarticular allograft. We discuss the advantages and the limitations of this surgical technique for the distal radius. PMID:27649764

  17. Giant serpentine aneurysm of the distal anterior cerebral artery.

    PubMed

    Senbokuya, Nobuo; Kanemaru, Kazuya; Kinouchi, Hiroyuki; Horikoshi, Toru

    2012-11-01

    We report a case of a 38-year-old man with a giant serpentine aneurysm arising from the distal anterior cerebral artery. This aneurysm grew from a fusiform aneurysm to a huge aneurysm within 5 months before manifesting as a mass lesion. The aneurysm was largely filled with thrombus, and 4 distal branches arose from the aneurysm dome. Selective balloon test occlusion of the distal anterior cerebral artery using an intravascular technique was performed to confirm the tolerance of the brain tissue. The balloon test occlusion elicited adequate leptomeningeal collateral circulation and no neurologic symptoms; thus, the aneurysm was treated with trapping and resection. The patient had no ischemic complications after the surgery and returned to his job 1 month later. No ischemia developed in the 2 years after surgery. Selective balloon test occlusion of the distal cerebral artery using an intravascular technique can be a very useful tool in planning the therapeutic strategy for a complicated distal cerebral aneurysm.

  18. National Human Trafficking Initiatives: Dimensions of Policy Diffusion1

    PubMed Central

    Yoo, Eun-hye; Boyle, Elizabeth Heger

    2014-01-01

    The implementation of criminal law involves formal law enforcement, education and public outreach aimed at preventing criminal activity, and providing services for victims. Historically, quantitative research on global trends has tended to focus on a single policy dimension, potentially masking the unique factors that affect the diffusion of each policy dimension independently. Using an ordered-probit model to analyze new human trafficking policy data on national prosecution, prevention, and victim-protection efforts, we find that global ties and domestic interest groups matter more in areas where international law is less defined. While prosecution, officially mandated by the Trafficking Protocol, was relatively impervious to global ties and domestic interest groups, both trafficking prevention and victim protection were associated with these factors. Our findings also suggest that fear of repercussions is not a major driver of state actions to combat trafficking—neither ratification of the Trafficking Protocol nor levels of United States aid were associated with greater implementation of anti-trafficking measures. PMID:26538806

  19. Regulation of GPCR Anterograde Trafficking by Molecular Chaperones and Motifs.

    PubMed

    Young, Brent; Wertman, Jaime; Dupré, Denis J

    2015-01-01

    G protein-coupled receptors (GPCRs) make up a superfamily of integral membrane proteins that respond to a wide variety of extracellular stimuli, giving them an important role in cell function and survival. They have also proven to be valuable targets in the fight against various diseases. As such, GPCR signal regulation has received considerable attention over the last few decades. With the amplitude of signaling being determined in large part by receptor density at the plasma membrane, several endogenous mechanisms for modulating GPCR expression at the cell surface have come to light. It has been shown that cell surface expression is determined by both exocytic and endocytic processes. However, the body of knowledge surrounding GPCR trafficking from the endoplasmic reticulum to the plasma membrane, commonly known as anterograde trafficking, has considerable room for growth. We focus here on the current paradigms of anterograde GPCR trafficking. We will discuss the regulatory role of both the general and "nonclassical private" chaperone systems in GPCR trafficking as well as conserved motifs that serve as modulators of GPCR export from the endoplasmic reticulum and Golgi apparatus. Together, these topics summarize some of the known mechanisms by which the cell regulates anterograde GPCR trafficking. PMID:26055064

  20. A 3-Dimensional Anatomic Study of the Distal Biceps Tendon

    PubMed Central

    Walton, Christine; Li, Zhi; Pennings, Amanda; Agur, Anne; Elmaraghy, Amr

    2015-01-01

    Background Complete rupture of the distal biceps tendon from its osseous attachment is most often treated with operative intervention. Knowledge of the overall tendon morphology as well as the orientation of the collagenous fibers throughout the musculotendinous junction are key to intraoperative decision making and surgical technique in both the acute and chronic setting. Unfortunately, there is little information available in the literature. Purpose To comprehensively describe the morphology of the distal biceps tendon. Study Design Descriptive laboratory study. Methods The distal biceps terminal musculature, musculotendinous junction, and tendon were digitized in 10 cadaveric specimens and data reconstructed using 3-dimensional modeling. Results The average length, width, and thickness of the external distal biceps tendon were found to be 63.0, 6.0, and 3.0 mm, respectively. A unique expansion of the tendon fibers within the distal muscle was characterized, creating a thick collagenous network along the central component between the long and short heads. Conclusion This study documents the morphologic parameters of the native distal biceps tendon. Reconstruction may be necessary, especially in chronic distal biceps tendon ruptures, if the remaining tendon morphology is significantly compromised compared with the native distal biceps tendon. Knowledge of normal anatomical distal biceps tendon parameters may also guide the selection of a substitute graft with similar morphological characteristics. Clinical Relevance A thorough description of distal biceps tendon morphology is important to guide intraoperative decision making between primary repair and reconstruction and to better select the most appropriate graft. The detailed description of the tendinous expansion into the muscle may provide insight into better graft-weaving and suture-grasping techniques to maximize proximal graft incorporation. PMID:26665092

  1. Effect of coffee on distal colon function.

    PubMed Central

    Brown, S R; Cann, P A; Read, N W

    1990-01-01

    Ninety nine healthy young volunteers (58 men, 34 women, aged 17-27 years) answered a questionnaire concerning their bowel habit with particular reference to the effects of beverages. Twenty nine per cent (63% women) claimed that coffee induced a desire to defecate. The rectosigmoid motor responses to black, unsweetened coffee were then investigated by multiport manometry in 14 healthy-subjects (12 men, two women, eight of whom claimed coffee caused a desire to defecate (responders). Results revealed an increase in motility index within four minutes after ingestion of both regular and decaffeinated coffee (p less than 0.05) in the eight responders, but not in the six non-responders. The increase in rectosigmoid motility induced by coffee lasted at least 30 minutes. There was no increase in the motility index in any subject after a drink of hot water. These results suggest that drinking coffee can stimulate a motor response of the distal colon in some normal people. PMID:2338272

  2. Distal Stressors and Depression among Homeless Men.

    PubMed

    Coohey, Carol; Easton, Scott D

    2016-05-01

    Depression is a common problem among homeless men that may interfere with functional tasks, such as securing stable housing, obtaining employment, and accessing health services. Previous research on depression among homeless men has largely focused on current psychosocial resources, substance abuse, and past victimization. Guided by Ensel and Lin's life course stress process model, the authors examined whether distal stressors, including victimization and exposure to parent problems in childhood, contributed to men's depression above and beyond current (or proximal) stressors, such as substance abuse and health problems, and social resources. The sample consisted of 309 homeless men who had entered a federally funded emergency shelter. Using the Burns Depression Checklist, the authors found that one out of three men met the threshold for moderate to severe depression during the past week. The logistic regression showed that past exposure to parent problems was related to depression after accounting for current stressors and social resources (number of close adult relationships and whether their emotional support needs were met). Past victimization was not related to depression. To address men's depression, workers should concurrently provide services that meet men's basic needs (for example, housing) and address their relationship needs, including their need for emotional support. PMID:27263201

  3. Increased risk of distal ventriculoperitoneal shunt obstruction associated with slit valves or distal slits in the peritoneal catheter.

    PubMed

    Cozzens, J W; Chandler, J P

    1997-11-01

    The authors describe a relationship between the presence of distal shunt catheter side-wall slits and distal catheter obstruction in a single-surgeon series of ventriculoperitoneal (VP) shunt revisions. Between 1985 and 1996, 168 operations for VP shunt revision were performed by the senior author (J.W.C.) in 71 patients. Indications for shunt revision included obstruction in 140 operations; overdrainage or underdrainage requiring a change of valve in 17 operations; inadequate length of distal shunt tubing resulting in the distal end no longer reaching the peritoneum in five operations; the ventricular catheter in the wrong ventricle or space, requiring repositioning in five operations; and a disconnected or broken shunt in one operation. Of the 140 instances of shunt obstruction, the blockage occurred at the ventricular end in 108 instances (77.1%), the peritoneal end in 17 (12.1%), the ventricular and the peritoneal end in 14 (10%), and in the valve mechanism (not including distal slit valves) in one (0.8%). Thus, the peritoneal end was obstructed in 31 (22.1%) of 140 cases of shunt malfunction. In every case in which the peritoneal end was obstructed, some form of distal slit was found: either a distal slit valve in an otherwise closed catheter or slits in the side of an open catheter. No instances were found of distal peritoneal catheter obstruction when the peritoneal catheter was a simple open-ended tube with no accompanying side slits (0 of 55). It is concluded that side slits in the distal peritoneal catheters of VP shunts are associated with a greater incidence of distal shunt obstruction.

  4. Polysialylation controls dendritic cell trafficking by regulating chemokine recognition.

    PubMed

    Kiermaier, Eva; Moussion, Christine; Veldkamp, Christopher T; Gerardy-Schahn, Rita; de Vries, Ingrid; Williams, Larry G; Chaffee, Gary R; Phillips, Andrew J; Freiberger, Friedrich; Imre, Richard; Taleski, Deni; Payne, Richard J; Braun, Asolina; Förster, Reinhold; Mechtler, Karl; Mühlenhoff, Martina; Volkman, Brian F; Sixt, Michael

    2016-01-01

    The addition of polysialic acid to N- and/or O-linked glycans, referred to as polysialylation, is a rare posttranslational modification that is mainly known to control the developmental plasticity of the nervous system. Here we show that CCR7, the central chemokine receptor controlling immune cell trafficking to secondary lymphatic organs, carries polysialic acid. This modification is essential for the recognition of the CCR7 ligand CCL21. As a consequence, dendritic cell trafficking is abrogated in polysialyltransferase-deficient mice, manifesting as disturbed lymph node homeostasis and unresponsiveness to inflammatory stimuli. Structure-function analysis of chemokine-receptor interactions reveals that CCL21 adopts an autoinhibited conformation, which is released upon interaction with polysialic acid. Thus, we describe a glycosylation-mediated immune cell trafficking disorder and its mechanistic basis. PMID:26657283

  5. Effects of Membrane Trafficking on Signaling by Receptor Tyrosine Kinases

    PubMed Central

    Miaczynska, Marta

    2013-01-01

    The intracellular trafficking machinery contributes to the spatial and temporal control of signaling by receptor tyrosine kinases (RTKs). The primary role in this process is played by endocytic trafficking, which regulates the localization of RTKs and their downstream effectors, as well as the duration and the extent of their activity. The key regulatory points along the endocytic pathway are internalization of RTKs from the plasma membrane, their sorting to degradation or recycling, and their residence in various endosomal compartments. Here I will review factors and mechanisms that modulate RTK signaling by (1) affecting receptor internalization, (2) regulating the balance between degradation and recycling of RTK, and (3) compartmentalization of signals in endosomes and other organelles. Cumulatively, these mechanisms illustrate a multilayered control of RTK signaling exerted by the trafficking machinery. PMID:24186066

  6. Monitoring receptor trafficking following retromer and WASH deregulation.

    PubMed

    Osborne, Douglas G; Phillips-Krawczak, Christine A; Billadeau, Daniel D

    2015-01-01

    Cell surface receptors that have been internalized and enter the endocytic pathway have multiple fates including entrance into the multivesicular body pathway on their way to lysosomal degradation, recycling back to the cell surface, or retrograde trafficking out of the endolysosomal system back to the Golgi apparatus. Two ubiquitously expressed protein complexes, WASH and the endosomal coat complex retromer, function together to play a central role in directing the fate of receptors into the latter two pathways. In this chapter, we describe fluorescent- and flow cytometry-based methods for analyzing the recycling and retrograde trafficking of two receptors, α5β1 and CI-M6PR, whose intracellular fates are regulated by WASH and retromer activity. The guidelines presented in this chapter can be applied to the analysis of any cell surface or intracellular membrane protein to determine the impact of WASH or retromer deregulation on its intracellular trafficking route. PMID:26360036

  7. Roles of membrane trafficking in plant cell wall dynamics

    PubMed Central

    Ebine, Kazuo; Ueda, Takashi

    2015-01-01

    The cell wall is one of the characteristic components of plant cells. The cell wall composition differs among cell types and is modified in response to various environmental conditions. To properly generate and modify the cell wall, many proteins are transported to the plasma membrane or extracellular space through membrane trafficking, which is one of the key protein transport mechanisms in eukaryotic cells. Given the diverse composition and functions of the cell wall in plants, the transport of the cell wall components and proteins that are involved in cell wall-related events could be specialized for each cell type, i.e., the machinery for cell wall biogenesis, modification, and maintenance could be transported via different trafficking pathways. In this review, we summarize the recent progress in the current understanding of the roles and mechanisms of membrane trafficking in plant cells and focus on the biogenesis and regulation of the cell wall. PMID:26539200

  8. Subversion of Retrograde Trafficking by Translocated Pathogen Effectors.

    PubMed

    Personnic, Nicolas; Bärlocher, Kevin; Finsel, Ivo; Hilbi, Hubert

    2016-06-01

    Intracellular bacterial pathogens subvert the endocytic bactericidal pathway to form specific replication-permissive compartments termed pathogen vacuoles or inclusions. To this end, the pathogens employ type III or type IV secretion systems, which translocate dozens, if not hundreds, of different effector proteins into their host cells, where they manipulate vesicle trafficking and signaling pathways in favor of the intruders. While the distinct cocktail of effectors defines the specific processes by which a pathogen vacuole is formed, the different pathogens commonly target certain vesicle trafficking routes, including the endocytic or secretory pathway. Recently, the retrograde transport pathway from endosomal compartments to the trans-Golgi network emerged as an important route affecting pathogen vacuole formation. Here, we review current insight into the host cell's retrograde trafficking pathway and how vacuolar pathogens of the genera Legionella, Coxiella, Salmonella, Chlamydia, and Simkania employ mechanistically distinct strategies to subvert this pathway, thus promoting intracellular survival and replication. PMID:26924068

  9. Social world of organ transplantation, trafficking, and policies.

    PubMed

    Yousaf, Farhan Navid; Purkayastha, Bandana

    2016-05-01

    Although success of organ transplants reflects advances in medical procedures, the success has generated debates about the ethical standards and policies that govern transplants, especially the acquisition of organs for transplants. We focus on laws, policies, and organ trafficking to highlight the interdisciplinary perspectives that can shape our understanding of transplantation as a social phenomenon. We discuss international policies and country-specific legislation from Pakistan to point to gaps and their implications for protecting vulnerable people who are exploited for organ removal. International collaboration and the legal framework need to be strengthened to fight the menace globally and to deal with the cases of organ trafficking within the legal ambit of human trafficking so that the rights of victims are upheld by states, justice systems, and ultimately medical establishments and practitioners. PMID:26841906

  10. Genetics Home Reference: SLC4A1-associated distal renal tubular acidosis

    MedlinePlus

    ... mutations of kidney anion exchanger 1 induce distinct trafficking defects in MDCK cells. Traffic. 2006 Feb;7( ... Khoprasert S, Li J, Reithmeier RA, Yenchitsomanus PT. Impaired trafficking and intracellular retention of mutant kidney anion exchanger ...

  11. Biodistribution and Trafficking of Hydrogel Nanoparticles in Adult Mosquitoes

    PubMed Central

    Paquette, Cynthia C. H.; Phanse, Yashdeep; Perry, Jillian L.; Sanchez-Vargas, Irma; Airs, Paul M.; Dunphy, Brendan M.; Xu, Jing; Carlson, Jonathan O.; Luft, J. Christopher; DeSimone, Joseph M.; Bartholomay, Lyric C.; Beaty, Barry J.

    2015-01-01

    Background Nanotechnology offers great potential for molecular genetic investigations and potential control of medically important arthropods. Major advances have been made in mammalian systems to define nanoparticle (NP) characteristics that condition trafficking and biodistribution of NPs in the host. Such information is critical for effective delivery of therapeutics and molecules to cells and organs, but little is known about biodistribution of NPs in mosquitoes. Methodology/Principal Findings PRINT technology was used to construct a library of fluorescently labeled hydrogel NPs of defined size, shape, and surface charge. The biodistribution (organ, tissue, and cell tropisms and trafficking kinetics) of positively and negatively charged 200 nm x 200 nm, 80 nm x 320 nm, and 80 nm x 5000 nm NPs was determined in adult Anopheles gambiae mosquitoes as a function of the route of challenge (ingestion, injection or contact) using whole body imaging and fluorescence microscopy. Mosquitoes readily ingested NPs in sugar solution. Whole body fluorescence imaging revealed substantial NP accumulation (load) in the alimentary tracts of the adult mosquitoes, with the greatest loads in the diverticula, cardia and foregut. Positively and negatively charged NPs differed in their biodistribution and trafficking. Following oral challenge, negatively charged NPs transited the alimentary tract more rapidly than positively charged NPs. Following contact challenge, negatively charged NPs trafficked more efficiently in alimentary tract tissues. Following parenteral challenge, positively and negatively charged NPs differed in tissue tropisms and trafficking in the hemocoel. Injected NPs were also detected in cardia/foregut, suggesting trafficking of NPs from the hemocoel into the alimentary tract. Conclusions/Significance Herein we have developed a tool box of NPs with the biodistribution and tissue tropism characteristics for gene structure/function studies and for delivery of vector

  12. 3 CFR 9074 - Proclamation 9074 of December 31, 2013. National Slavery and Human Trafficking Prevention Month...

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... down on traffickers, charging a record number of perpetrators. We are deploying new technology in the... leaders from every sector of society. Together, we came up with new ideas to fight trafficking at...

  13. Attitudes About Human Trafficking: Individual Differences Related to Belief and Victim Blame.

    PubMed

    Cunningham, Katherine C; Cromer, Lisa DeMarni

    2016-01-01

    Human trafficking is believed to oppress millions of people worldwide. Despite increased media attention and public awareness campaigns in recent years, no empirical research has examined public attitudes about human trafficking. The present study examined gender, sexual trauma history, and attitudes about human trafficking as they related to belief of a sex-trafficking scenario and willingness to blame the victim for the situation. Undergraduate students (N = 409) at a large private university in the Northeastern United States completed measures in which they responded to a vignette portraying sex trafficking in the United States. Participants also reported their personal trauma history and completed a Human Trafficking Myths Scale. Results indicated that gender and human trafficking myth acceptance, but not sexual trauma history, were significantly related to participants' belief of the sex-trafficking scenario and their perception of the victim's responsibility. Potential implications and directions for future research are discussed. PMID:25389189

  14. A model for assessing the risk of human trafficking on a local level

    NASA Astrophysics Data System (ADS)

    Colegrove, Amanda

    Human trafficking is a human rights violation that is difficult to quantify. Models for estimating the number of victims of trafficking presented by previous researchers depend on inconsistent, poor quality data. As an intermediate step to help current efforts by nonprofits to combat human trafficking, this project presents a model that is not dependent on quantitative data specific to human trafficking, but rather profiles the risk of human trafficking at the local level through causative factors. Businesses, indicated by the literature, were weighted based on the presence of characteristics that increase the likelihood of trafficking in persons. The mean risk was calculated by census tract to reveal the multiplicity of risk levels in both rural and urban settings. Results indicate that labor trafficking may be a more diffuse problem in Missouri than sex trafficking. Additionally, spatial patterns of risk remained largely the same regardless of adjustments made to the model.

  15. Attitudes About Human Trafficking: Individual Differences Related to Belief and Victim Blame.

    PubMed

    Cunningham, Katherine C; Cromer, Lisa DeMarni

    2016-01-01

    Human trafficking is believed to oppress millions of people worldwide. Despite increased media attention and public awareness campaigns in recent years, no empirical research has examined public attitudes about human trafficking. The present study examined gender, sexual trauma history, and attitudes about human trafficking as they related to belief of a sex-trafficking scenario and willingness to blame the victim for the situation. Undergraduate students (N = 409) at a large private university in the Northeastern United States completed measures in which they responded to a vignette portraying sex trafficking in the United States. Participants also reported their personal trauma history and completed a Human Trafficking Myths Scale. Results indicated that gender and human trafficking myth acceptance, but not sexual trauma history, were significantly related to participants' belief of the sex-trafficking scenario and their perception of the victim's responsibility. Potential implications and directions for future research are discussed.

  16. Distal anastomotic intimal hyperplasia: histopathologic character and biogenesis.

    PubMed

    Sottiurai, V S; Yao, J S; Batson, R C; Sue, S L; Jones, R; Nakamura, Y A

    1989-01-01

    Although thrombogenicity of the prosthetic graft, progression of the atherosclerotic disease and distal anastomotic intimal hyperplasia are known etiologic factors of late graft failure, its occurrence is frequently encountered in the late graft occlusion. Forth-two canine PTFE iliofemoral grafts (all with end-to-side distal anastomosis) were studied. Computer digitization revealed that distal anastomotic intimal hyperplasia occurred exclusively at the heel and the toe of the graft and the floor of the host artery. The distal anastomotic intimal hyperplasia was 80-130 cells thick. Light microscopy and transmission electron microscopy revealed a similar architecture of interlamination of cellular elements and extracellular matrix in the hyperplastic cells. Transmission electron microscopy further defined a gradual cell transformation and orientation from the graft to the lumen. The cells near the graft were characterized by a gradual reduction of rough endoplasmic reticulum with a concomitant acquisition of myofilaments, transforming ovoid mesenchymoid cells to slender myofibroblasts. The orientation of cells in distal anastomotic intimal hyperplasia was embodied by random cell distribution at the periphery to a well-organized interlamination of myofibroblasts and extracellular matrix near the lumen. Distal anastomotic intimal hyperplasia is a biologic entity with active cellular and subcellular events. Its biogenesis appears to be influenced by the hemodynamics of blood flow at the distal anastomosis. PMID:2713229

  17. The distal radioulnar joint. Anatomic and functional considerations.

    PubMed

    Kauer, J M

    1992-02-01

    The distal radioulnar joint is functionally coupled with the proximal radioulnar joint, thus forming a mechanism for the longitudinal rotation of the hand. Distal radioulnar mobility is derived from the geometry of the joint, joint surfaces, and radioulnar connections. There is a structural and functional separation between the distal radioulnar and carpal joints, giving the possibility of pronation and supination in every position of the hand to the forearm. As for the stability of the joints involved, the ulnar articular disk plays an essential role. Being part of both distal radioulnar and carpal joints, the disk has very specific morphologic features that not only are individualized to the function of both joints but also stabilize the joints in their independent movements. Developmental data give the strong impression of an architectural scheme, of which the distal radioulnar joint is only a part. Traumatic lesions at the distal radioulnar joint and disturbances in normal distal radioulnar alignment have to be viewed, therefore, in a wider context. PMID:1735231

  18. Multisite tyrosine phosphorylation of the N-terminus of Mint1/X11α by Src kinase regulates the trafficking of amyloid precursor protein.

    PubMed

    Dunning, Christopher J R; Black, Hannah L; Andrews, Katie L; Davenport, Elizabeth C; Conboy, Michael; Chawla, Sangeeta; Dowle, Adam A; Ashford, David; Thomas, Jerry R; Evans, Gareth J O

    2016-05-01

    Mint/X11 is one of the four neuronal trafficking adaptors that interact with amyloid precursor protein (APP) and are linked with its cleavage to generate β-amyloid peptide, a key player in the pathology of Alzheimer's disease. How APP switches between adaptors at different stages of the secretory pathway is poorly understood. Here, we show that tyrosine phosphorylation of Mint1 regulates the destination of APP. A canonical SH2-binding motif ((202) YEEI) was identified in the N-terminus of Mint1 that is phosphorylated on tyrosine by C-Src and recruits the active kinase for sequential phosphorylation of further tyrosines (Y191 and Y187). A single Y202F mutation in the Mint1 N-terminus inhibits C-Src binding and tyrosine phosphorylation. Previous studies observed that co-expression of wild-type Mint1 and APP causes accumulation of APP in the trans-Golgi. Unphosphorylatable Mint1 (Y202F) or pharmacological inhibition of Src reduced the accumulation of APP in the trans-Golgi of heterologous cells. A similar result was observed in cultured rat hippocampal neurons where Mint1(Y202F) permitted the trafficking of APP to more distal neurites than the wild-type protein. These data underline the importance of the tyrosine phosphorylation of Mint1 as a critical switch for determining the destination of APP. The regulation of amyloid precursor protein (APP) trafficking is poorly understood. We have discovered that the APP adapter, Mint1, is phosphorylated by C-Src kinase. Mint1 causes APP accumulation in the trans-Golgi network, whereas inhibition of Src or mutation of Mint1-Y202 permits APP recycling. The phosphorylation status of Mint1 could impact on the pathological trafficking of APP in Alzheimer's disease. PMID:26865271

  19. Trafficking in persons and victim health in Australia.

    PubMed

    Schloenhardt, Andreas; Klug, Benjamin

    2011-12-01

    This article explores the health problems experienced by victims of trafficking in persons in Australia and analyses the domestic support schemes established to assist these victims. It focuses specifically on the health of adult, female victims who constitute the majority of identified victims, and who are the principal recipients of government support services. Domestic experiences and support schemes are reviewed in the light of international law and best practice guidelines. Recommendations are made to improve the health services available to victims of trafficking in persons in Australia. PMID:22320010

  20. Organ economy: organ trafficking in Moldova and Israel.

    PubMed

    Lundin, Susanne

    2012-02-01

    Organ trafficking is an illegal means of meeting the shortage of transplants. The activity flourishes for several interacting reasons, such as medical needs, poverty and criminality. Other factors are fundamental conceptual structures such as the dream of the regenerative body as well as the view of the body as an object of utility and an object of value. The article aims to go behind the normative discussions that usually surround organ trafficking. Why this is happening, and what the societal consequences are, is examined through ethnographic fieldwork. The focus is on the shadow economies that govern existence and in which people, goods, weapons, money, bodies, etc. constitute components of the global market.

  1. Trafficking regulation of proteins in Alzheimer’s disease

    PubMed Central

    2014-01-01

    The β-amyloid (Aβ) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer’s disease (AD). Aβ is produced through sequential cleavage of the β-amyloid precursor protein (APP) by β- and γ-secretases. APP and relevant secretases are transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion. Perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering Aβ generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD. PMID:24410826

  2. A human rights approach to human trafficking for organ removal.

    PubMed

    Budiani-Saberi, Debra; Columb, Seán

    2013-11-01

    Human trafficking for organ removal (HTOR) should not be reduced to a problem of supply and demand of organs for transplantation, a problem of organized crime and criminal justice, or a problem of voiceless, abandoned victims. Rather, HTOR is at once an egregious human rights abuse and a form of human trafficking. As such, it demands a human-rights based approach in analysis and response to this problem, placing the victim at the center of initiatives to combat this phenomenon. Such an approach requires us to consider how various measures impact or disregard victims/potential victims of HTOR and gives us tools to better advocate their interests, rights and freedoms.

  3. Distal Insertions of the Biceps Femoris

    PubMed Central

    Branch, Eric A.; Anz, Adam W.

    2015-01-01

    Background: Avulsion of the biceps femoris from the fibula and proximal tibia is encountered in clinical practice. While the anatomy of the primary posterolateral corner structures has been qualitatively and quantitatively described, a quantitative analysis regarding the insertions of the biceps femoris on the fibula and proximal tibia is lacking. Purpose: To quantitatively assess the insertions of the biceps femoris, fibular collateral ligament (FCL), and anterolateral ligament (ALL) on the fibula and proximal tibia as well as establish relationships among these structures and to pertinent surgical anatomy. Study Design: Descriptive laboratory study. Methods: Dissections were performed on 12 nonpaired, fresh-frozen cadaveric specimens identifying the biceps femoris, FCL, and ALL, and their insertions on the proximal tibia and fibula. The footprint areas, orientations, and distances from relevant osseous landmarks were measured using a 3-dimensional coordinate measurement device. Results: Dissection produced 6 easily identifiable and reproducible anatomic footprints. Tibial footprints included the insertion of the ALL and an insertion of the biceps femoris (TBF). Fibular footprints included the insertion of the FCL, a distal insertion of the biceps femoris (DBF), a medial footprint of the biceps femoris (MBF), and a proximal footprint of the biceps femoris (PBF). The mean area of these footprints (95% CI) was as follows: ALL, 53.0 mm2 (38.4-67.6); TBF, 93.9 mm2 (72.0-115.8); FCL, 86.8 mm2 (72.3-101.2); DBF, 119 mm2 (91.1-146.9); MBF, 46.8 mm2 (29.0-64.5); and PBF, 215 mm2 (192.4-237.5). The mean distance (95% CI) from the Gerdy tubercle to the center of the ALL footprint was 24.3 mm (21.6-27.0) and to the center of the TBF was 22.5 mm (21.0-24.0). The center of the DBF was 8.68 mm (7.0-10.3) from the anterior border of the fibula, the center of the FCL was 14.6 mm (12.5-16.7) from the anterior border of the fibula and 20.7 mm (19.0-22.4) from the tip of the fibular

  4. The learning curve in robotic distal pancreatectomy.

    PubMed

    Napoli, Niccolò; Kauffmann, Emanuele F; Perrone, Vittorio Grazio; Miccoli, Mario; Brozzetti, Stefania; Boggi, Ugo

    2015-09-01

    No data are available on the learning curve in robotic distal pancreatectomy (RADP). The learning curve in RADP was assessed in 55 consecutive patients using the cumulative sum method, based on operative time. Data were extracted from a prospectively maintained database and analyzed retrospectively considering all events occurring within 90 days of surgery. No operation was converted to laparoscopic or open surgery and no patient died. Post-operative complications occurred in 34 patients (61.8%), being of Clavien-Dindo grade I-II in 32 patients (58.1%), including pancreatic fistula in 29 patients (52.7%). No grade C pancreatic fistula occurred. Four patients received blood transfusions (7.2%), three were readmitted (5.4%) and one required repeat surgery (1.8%). Based on the reduction of operative times (421.1 ± 20.5 vs 248.9 ± 9.3 min; p < 0.0001), completion of the learning curve was achieved after ten operations. Operative time of the first 10 operations was associated with a positive slope (0.47 + 1.78* case number; R (2) 0.97; p < 0.0001*), while that of the following 45 procedures showed a negative slope (23.52 - 0.39* case number; R (2) 0.97; p < 0.0001*). After completion of the learning curve, more patients had a malignant histology (0 vs 35.6%; p = 0.002), accounting for both higher lymph node yields (11.1 ± 12.2 vs 20.9 ± 18.5) (p = 0.04) and lower rate of spleen preservation (90 vs 55.6%) (p = 0.04). RADP was safely feasible in selected patients and the learning curve was completed after ten operations. Improvement in clinical outcome was not demonstrated, probably because of the limited occurrence of outcome comparators.

  5. The learning curve in robotic distal pancreatectomy.

    PubMed

    Napoli, Niccolò; Kauffmann, Emanuele F; Perrone, Vittorio Grazio; Miccoli, Mario; Brozzetti, Stefania; Boggi, Ugo

    2015-09-01

    No data are available on the learning curve in robotic distal pancreatectomy (RADP). The learning curve in RADP was assessed in 55 consecutive patients using the cumulative sum method, based on operative time. Data were extracted from a prospectively maintained database and analyzed retrospectively considering all events occurring within 90 days of surgery. No operation was converted to laparoscopic or open surgery and no patient died. Post-operative complications occurred in 34 patients (61.8%), being of Clavien-Dindo grade I-II in 32 patients (58.1%), including pancreatic fistula in 29 patients (52.7%). No grade C pancreatic fistula occurred. Four patients received blood transfusions (7.2%), three were readmitted (5.4%) and one required repeat surgery (1.8%). Based on the reduction of operative times (421.1 ± 20.5 vs 248.9 ± 9.3 min; p < 0.0001), completion of the learning curve was achieved after ten operations. Operative time of the first 10 operations was associated with a positive slope (0.47 + 1.78* case number; R (2) 0.97; p < 0.0001*), while that of the following 45 procedures showed a negative slope (23.52 - 0.39* case number; R (2) 0.97; p < 0.0001*). After completion of the learning curve, more patients had a malignant histology (0 vs 35.6%; p = 0.002), accounting for both higher lymph node yields (11.1 ± 12.2 vs 20.9 ± 18.5) (p = 0.04) and lower rate of spleen preservation (90 vs 55.6%) (p = 0.04). RADP was safely feasible in selected patients and the learning curve was completed after ten operations. Improvement in clinical outcome was not demonstrated, probably because of the limited occurrence of outcome comparators. PMID:25990666

  6. Quantitative shape measurements of distal volcanic ash

    NASA Astrophysics Data System (ADS)

    Riley, Colleen M.; Rose, William I.; Bluth, Gregg J. S.

    2003-10-01

    Large-scale volcanic eruptions produce fine ash (<200 μm) which has a long atmospheric residence time (1 hour or more) and can be transported great distances from the volcanic source, thus, becoming a hazard to aircraft and public health. Ash particles have irregular shapes, so data on particle shape, size, and terminal velocities are needed to understand how the irregular-shaped particles affect transport processes and radiative transfer measurements. In this study, a methodology was developed to characterize particle shapes, sizes, and terminal velocities for three ash samples of different compositions. The shape and size of 2500 particles from (1) distal fallout (˜100 km) of the 14 October 1974 Fuego eruption (basaltic), (2) the secondary maxima (˜250 km) of the 18 August 1992 Spurr eruption (andesitic), and (3) the Miocene Ash Hollow member, Nebraska (rhyolitic) were measured using image analysis techniques. Samples were sorted into 10 to 19 terminal velocity groups (0.6-59.0 cm/s) using an air elutriation device. Grain-size distributions for the samples were measured using laser diffraction. Aspect ratio, feret diameter, and perimeter measurements were found to be the most useful descriptors of how particle shape affects terminal velocity. These measurement values show particle shape differs greatly from a sphere (commonly used in models and algorithms). The diameters of ash particles were 10-120% larger than ideal spheres at the same terminal velocity, indicating that irregular particle shape greatly increases drag. Gas-adsorption derived surface areas are 1 to 2 orders of magnitude higher than calculated surface areas based on measured dimensions and simple geometry, indicating that particle shapes are highly irregular. Correction factors for surface area were derived from the ash sample measurements so that surface areas calculated by assuming spherical particle shapes can be corrected to reflect more realistic values.

  7. Sex trafficking in Nepal: a review of intervention and prevention programs.

    PubMed

    Kaufman, Michelle R; Crawford, Mary

    2011-05-01

    Trafficking of girls and women for the purpose of sexual exploitation is a problem worldwide, particularly in South Asia. This review focuses on Nepal-to-India sex trafficking with an examination of current anti-trafficking intervention and prevention programs. The activities of both governmental agencies and nongovernment organizations are described and critically analyzed. Suggestions for evaluating and improving interventions, and thereby reducing the trafficking of girls and women, are discussed. PMID:21502114

  8. An alternative method of osteosynthesis for distal humeral shaft fractures.

    PubMed

    Levy, Jonathan C; Kalandiak, Steven P; Hutson, James J; Zych, Gregory

    2005-01-01

    Treatment of extra-articular distal humerus shaft fractures with plating techniques is often difficult, as traditional centrally located posterior plates often encroach on the olecranon fossa, limiting distal osseous fixation. The use of a modified Synthes Lateral Tibial Head Buttress Plate (Synthes, Paoli, PA) allows for a centrally placed posterior plating of the humeral shaft that angles anatomically along the lateral column to treat far distal humeral shaft fractures. Fifteen patients treated in this manner were followed to radiographic and clinical union. There were no cases of instrumentation failure or loss of reduction.

  9. Two-wave propagation in in vitro swine distal ulna

    NASA Astrophysics Data System (ADS)

    Mano, Isao; Horii, Kaoru; Matsukawa, Mami; Otani, Takahiko

    2015-07-01

    Ultrasonic transmitted waves were obtained in an in vitro swine distal ulna specimen, which mimics a human distal radius, that consists of interconnected cortical bone and cancellous bone. The transmitted waveforms appeared similar to the fast waves, slow waves, and overlapping fast and slow waves measured in the specimen after removing the surface cortical bone (only cancellous bone). In addition, the circumferential waves in the cortical bone and water did not affect the fast and slow waves. This suggests that the fast-and-slow-wave phenomenon can be observed in an in vivo human distal radius.

  10. Hyperammonaemia in a child with distal renal tubular acidosis.

    PubMed

    Seracini, D; Poggi, G M; Pela, I

    2005-11-01

    A 5-month-old girl with distal renal tubular acidosis (RTA) and hyperammonaemia that had lasted for 12 days, despite metabolic acidosis correction, is presented in this report. The patient showed failure to thrive, poor feeding, hypotonia and vomiting crisis in absence of inborn errors of metabolism. Probably, hyperammonaemia was the result of an imbalance between the increased ammonia synthesis, in response to metabolic acidosis, and the impaired ammonia excretion, typical of distal RTA. Our case confirms that hyperammonaemia may be observed in distal RTA, mimicking an inborn error of metabolism, and it underlines that hyperammonaemia may persist several days after metabolic acidosis correction. PMID:16133056

  11. An Asian Perspective on the Management of Distal Radius Fractures

    PubMed Central

    Sebastin, Sandeep J.; Chung, Kevin C.

    2012-01-01

    Synopsis There is little data with regards to the epidemiology, pathology, or management of distal radius fractures from centers in Asia. Asia includes five advanced economies, namely Hong Kong SAR, Japan, Korea, Singapore, and Taiwan and a number of emerging economies prominent among which are China, India, Malaysia, Philippines, and Thailand. This article examines the available epidemiological data from Asia, and compares the management of distal radius fractures in the advanced and emerging Asian economies and how they match up to the current management in the west. It concludes by offering solutions for improving outcomes of distal radius fractures in both the advanced and emerging economies of Asia. PMID:22554658

  12. An Asian perspective on the management of distal radius fractures.

    PubMed

    Sebastin, Sandeep J; Chung, Kevin C

    2012-05-01

    There is limited data regarding the epidemiology, pathology, and management of distal radius fractures from centers in Asia. The advanced economies in Asia include Hong Kong, Japan, Korea, Singapore, and Taiwan, whereas the prominent emerging economies are China, India, Malaysia, Philippines, and Thailand. This article examines the available epidemiological data from Asia, compares the management of distal radius fractures in the advanced and emerging Asian economies and how they compare with the current management in the west. It concludes by offering solutions for improving outcomes of distal radius fractures in Asia.

  13. The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons.

    PubMed

    Gervasi, Noreen M; Scott, Shane S; Aschrafi, Armaz; Gale, Jenna; Vohra, Sanah N; MacGibeny, Margaret A; Kar, Amar N; Gioio, Anthony E; Kaplan, Barry B

    2016-06-01

    Synthesis and regulation of catecholamine neurotransmitters in the central nervous system are implicated in the pathogenesis of a number of neuropsychiatric disorders. To identify factors that regulate the presynaptic synthesis of catecholamines, we tested the hypothesis that the rate-limiting enzyme of the catecholamine biosynthetic pathway, tyrosine hydroxylase (TH), is locally synthesized in axons and presynaptic nerve terminals of noradrenergic neurons. To isolate pure axonal mRNA and protein, rat superior cervical ganglion sympathetic neurons were cultured in compartmentalized Campenot chambers. qRT-PCR and RNA in situ hybridization analyses showed that TH mRNA is present in distal axons. Colocalization experiments with nerve terminal marker proteins suggested that both TH mRNA and protein localize in regions of the axon that resemble nerve terminals (i.e., synaptic boutons). Analysis of polysome-bound RNA showed that TH mRNA is present in polysomes isolated from distal axons. Metabolic labeling of axonally synthesized proteins labeled with the methionine analog, L-azidohomoalanine, showed that TH is locally synthesized in axons. Moreover, the local transfection and translation of exogenous TH mRNA into distal axons facilitated axonal dopamine synthesis. Finally, using chimeric td-Tomato-tagged constructs, we identified a sequence element within the TH 3'UTR that is required for the axonal localization of the reporter mRNA. Taken together, our results provide the first direct evidence that TH mRNA is trafficked to the axon and that the mRNA is locally translated. These findings raise the interesting possibility that the biosynthesis of the catecholamine neurotransmitters is locally regulated in the axon and/or presynaptic nerve terminal. PMID:27095027

  14. 78 FR 76183 - Request for Information for the 2014; Trafficking in Persons Report

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-12-16

    ... trafficking. (2) For the knowing commission of any act of sex trafficking involving force, fraud, coercion, or in which the victim of sex trafficking is a child incapable of giving meaningful consent, or of... made serious and sustained efforts to reduce the demand for (A) commercial sex acts; and...

  15. 76 FR 1660 - Request for Information for the 2011 Trafficking in Persons Report

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-11

    ... and punish acts of such trafficking. (2) For the knowing commission of any act of sex trafficking involving force, fraud, coercion, or in which the victim of sex trafficking is a child incapable of giving... government of the country has made serious and sustained efforts to reduce the demand for (A) commercial...

  16. 22 CFR 104.2 - Sharing of information regarding international trafficking in persons.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... trafficking in persons. 104.2 Section 104.2 Foreign Relations DEPARTMENT OF STATE ECONOMIC AND OTHER FUNCTIONS INTERNATIONAL TRAFFICKING IN PERSONS: INTERAGENCY COORDINATION OF ACTIVITIES AND SHARING OF INFORMATION § 104.2 Sharing of information regarding international trafficking in persons. Each Federal Department or...

  17. 76 FR 71830 - Defense Federal Acquisition Regulation Supplement: Administering Trafficking in Persons...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-18

    ... Regulation Supplement: Administering Trafficking in Persons Regulations (DFARS Case 2011-D051) AGENCY... compliance with duties and responsibilities pertaining to trafficking in persons when they are incorporated... Trafficking in Persons, in all solicitations and contracts. When the contract will be performed outside...

  18. Combating trafficking in persons: a call to action for global health professionals.

    PubMed

    CdeBaca, Luis; Sigmon, Jane Nady

    2014-08-01

    Health care professionals can help identify victims of human trafficking, who commonly come into contact with providers during captivity. Providers can also help restore the physical and mental health of trafficking survivors. Training should focus on recognizing trafficking signs, interviewing techniques, and recommended responses when a victim is identified.

  19. Combating trafficking in persons: a call to action for global health professionals.

    PubMed

    CdeBaca, Luis; Sigmon, Jane Nady

    2014-08-01

    Health care professionals can help identify victims of human trafficking, who commonly come into contact with providers during captivity. Providers can also help restore the physical and mental health of trafficking survivors. Training should focus on recognizing trafficking signs, interviewing techniques, and recommended responses when a victim is identified. PMID:25276585

  20. Distal Triceps Knotless Anatomic Footprint Repair: A New Technique

    PubMed Central

    Paci, James M.; Clark, Jonathan; Rizzi, Angelo

    2014-01-01

    Distal triceps rupture is a rare injury causing significant disability. Several techniques for treating distal triceps ruptures have been described using bone tunnels or suture anchors. More recent techniques have focused on re-creating the anatomic footprint of the distal triceps tendon. However, the increasing numbers of anchors used increase the risk to the articular surface, and all earlier techniques require knot tying and bulky knots beneath the thin posterior elbow soft-tissue envelope. We describe a technique combining the use of bone tunnels and a single suture anchor to create a knotless anatomic footprint repair of the distal triceps. By using this technique, we are able to create a tension-band construct that self-reinforces the anatomic repair and is very low profile while significantly decreasing risk to the articular surface. PMID:25473618

  1. Distal Renal Tubular Acidosis in Infancy: A Bicarbonate Wasting State

    ERIC Educational Resources Information Center

    Rodriguez-Soriano, J.; And Others

    1975-01-01

    Studied were three unrelated infants with distal renal tubular acidosis (a condition characterized by an inability to acidify the urine to minimal pH levels resulting in the loss of bicarbonates). (DB)

  2. A distal airway foreign body removed with electromagnetic navigation bronchoscopy.

    PubMed

    Karpman, Craig; Midthun, David E; Mullon, John J

    2014-04-01

    Distal airway foreign bodies can be challenging to remove with a flexible bronchoscope because of angulation or deep impaction. Thoracic surgery may be required if bronchoscopy is not successful. The use of electromagnetic navigation for pulmonary nodule localization and characterization is well established; however, its use to localize and remove distal foreign bodies has not been described. We report the initial case of electromagnetic navigation-assisted foreign body removal.

  3. Comparison of Chevron and Distal Oblique Osteotomy for Bunion Correction.

    PubMed

    Scharer, Brandon M; DeVries, J George

    2016-01-01

    The chevron osteotomy is a standard procedure by which bunions are corrected. One of us routinely performs a distal oblique osteotomy, which, to the best of our knowledge, has not been described for the correction of bunion deformities. The purpose of the present study was to compare the short- and medium-term results of the distal oblique and chevron osteotomies for bunion correction. We performed a retrospective clinical and radiographic comparison of patients who had undergone a distal oblique or chevron osteotomy for the correction of bunion deformity. In addition, a prospective patient satisfaction survey was undertaken. A total of 55 patients were included in the present study and were treated from January 2012 to November 2014. Of the 55 patients, 27 (49.2%) were in the chevron group and 28 (50.8%) in the distal oblique group. Radiographically, no statistically significant difference was found between the 2 groups with respect to postoperative first intermetatarsal angle (p < .0001) and hallux valgus angle (p < .0001), but a greater change was found in the intermetatarsal angle in the distal oblique group (p = .467). Prospective patient satisfaction scores were available for 33 patients (60%), 16 (29%) in the chevron group and 17 (31%) in the distal oblique group. When converting the satisfaction score to a numerical score, the chevron group scored 3.3 ± 1.1 and the distal oblique group scored 3.2 ± 0.8 (p = .812). We found that the distal oblique osteotomy used in the present study is simple and reliable and showed radiographic correction and patient satisfaction equivalent to those in the chevron osteotomy. PMID:26972755

  4. 31 CFR 598.313 - Significant foreign narcotics trafficker.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Significant foreign narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.313 Significant foreign narcotics trafficker. The term...

  5. 31 CFR 598.314 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 31 Money and Finance:Treasury 3 2011-07-01 2011-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.314 Specially designated narcotics trafficker. The term...

  6. 31 CFR 598.313 - Significant foreign narcotics trafficker.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Significant foreign narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.313 Significant foreign narcotics trafficker. The term...

  7. 31 CFR 598.313 - Significant foreign narcotics trafficker.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false Significant foreign narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.313 Significant foreign narcotics trafficker. The term...

  8. 31 CFR 598.314 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 31 Money and Finance:Treasury 3 2013-07-01 2013-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.314 Specially designated narcotics trafficker. The term...

  9. 31 CFR 598.313 - Significant foreign narcotics trafficker.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Significant foreign narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.313 Significant foreign narcotics trafficker. The term...

  10. 31 CFR 598.314 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 31 Money and Finance:Treasury 3 2012-07-01 2012-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.314 Specially designated narcotics trafficker. The term...

  11. 31 CFR 598.313 - Significant foreign narcotics trafficker.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 31 Money and Finance: Treasury 3 2010-07-01 2010-07-01 false Significant foreign narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.313 Significant foreign narcotics trafficker. The term...

  12. 31 CFR 598.314 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 31 Money and Finance:Treasury 3 2014-07-01 2014-07-01 false Specially designated narcotics... (Continued) OFFICE OF FOREIGN ASSETS CONTROL, DEPARTMENT OF THE TREASURY FOREIGN NARCOTICS KINGPIN SANCTIONS REGULATIONS General Definitions § 598.314 Specially designated narcotics trafficker. The term...

  13. Child Trafficking in West Africa: Policy Responses. Innocenti Insight.

    ERIC Educational Resources Information Center

    United Nations Children's Fund, Florence (Italy). Innocenti Research Centre.

    This report examines policy responses and programming trends to combat the growing specter of child trafficking, focusing on the region of west and central Africa where strenuous advocacy efforts by UNICEF and its partners have helped to bring this problem to national and international attention. The report focuses on policy trends on child…

  14. Human Trafficking: A Call for Counselor Awareness and Action

    ERIC Educational Resources Information Center

    Stotts, Edward L., Jr.; Ramey, Luellen

    2009-01-01

    The counseling profession has given little attention to human trafficking, a form of modern slavery that is one of the most damaging forms of social injustice that exists today. Focusing on victims within the United States, the authors provide advocacy suggestions, treatment recommendations, and directions for research for this population.

  15. 48 CFR 52.222-50 - Combating Trafficking in Persons.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... bondage, or slavery. Sex trafficking means the recruitment, harboring, transportation, provision, or obtaining of a person for the purpose of a commercial sex act. (b) Policy. The United States Government has...) Notify its employees of— (i) The United States Government's zero tolerance policy described in...

  16. Regulation of intracellular heme trafficking revealed by subcellular reporters.

    PubMed

    Yuan, Xiaojing; Rietzschel, Nicole; Kwon, Hanna; Walter Nuno, Ana Beatriz; Hanna, David A; Phillips, John D; Raven, Emma L; Reddi, Amit R; Hamza, Iqbal

    2016-08-30

    Heme is an essential prosthetic group in proteins that reside in virtually every subcellular compartment performing diverse biological functions. Irrespective of whether heme is synthesized in the mitochondria or imported from the environment, this hydrophobic and potentially toxic metalloporphyrin has to be trafficked across membrane barriers, a concept heretofore poorly understood. Here we show, using subcellular-targeted, genetically encoded hemoprotein peroxidase reporters, that both extracellular and endogenous heme contribute to cellular labile heme and that extracellular heme can be transported and used in toto by hemoproteins in all six subcellular compartments examined. The reporters are robust, show large signal-to-background ratio, and provide sufficient range to detect changes in intracellular labile heme. Restoration of reporter activity by heme is organelle-specific, with the Golgi and endoplasmic reticulum being important sites for both exogenous and endogenous heme trafficking. Expression of peroxidase reporters in Caenorhabditis elegans shows that environmental heme influences labile heme in a tissue-dependent manner; reporter activity in the intestine shows a linear increase compared with muscle or hypodermis, with the lowest heme threshold in neurons. Our results demonstrate that the trafficking pathways for exogenous and endogenous heme are distinct, with intrinsic preference for specific subcellular compartments. We anticipate our results will serve as a heuristic paradigm for more sophisticated studies on heme trafficking in cellular and whole-animal models.

  17. Regulation of intracellular heme trafficking revealed by subcellular reporters.

    PubMed

    Yuan, Xiaojing; Rietzschel, Nicole; Kwon, Hanna; Walter Nuno, Ana Beatriz; Hanna, David A; Phillips, John D; Raven, Emma L; Reddi, Amit R; Hamza, Iqbal

    2016-08-30

    Heme is an essential prosthetic group in proteins that reside in virtually every subcellular compartment performing diverse biological functions. Irrespective of whether heme is synthesized in the mitochondria or imported from the environment, this hydrophobic and potentially toxic metalloporphyrin has to be trafficked across membrane barriers, a concept heretofore poorly understood. Here we show, using subcellular-targeted, genetically encoded hemoprotein peroxidase reporters, that both extracellular and endogenous heme contribute to cellular labile heme and that extracellular heme can be transported and used in toto by hemoproteins in all six subcellular compartments examined. The reporters are robust, show large signal-to-background ratio, and provide sufficient range to detect changes in intracellular labile heme. Restoration of reporter activity by heme is organelle-specific, with the Golgi and endoplasmic reticulum being important sites for both exogenous and endogenous heme trafficking. Expression of peroxidase reporters in Caenorhabditis elegans shows that environmental heme influences labile heme in a tissue-dependent manner; reporter activity in the intestine shows a linear increase compared with muscle or hypodermis, with the lowest heme threshold in neurons. Our results demonstrate that the trafficking pathways for exogenous and endogenous heme are distinct, with intrinsic preference for specific subcellular compartments. We anticipate our results will serve as a heuristic paradigm for more sophisticated studies on heme trafficking in cellular and whole-animal models. PMID:27528661

  18. 31 CFR 598.314 - Specially designated narcotics trafficker.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... REGULATIONS General Definitions § 598.314 Specially designated narcotics trafficker. The term specially... Central Intelligence, the Director of the Federal Bureau of Investigation, the Administrator of the Drug... persons determined to fall within this definition who have been designated pursuant to this part....

  19. Analysis of Lipolytic Protein Trafficking and Interactions in Adipocytes

    Technology Transfer Automated Retrieval System (TEKTRAN)

    This work examined the colocalization, trafficking, and interactions of key proteins involved in lipolysis during brief cAMP-dependent protein kinase A (PKA) activation. Double label immunofluorescence analysis of 3T3-L1 adipocytes indicated that PKA activation increases the translocation of hormon...

  20. Plant vacuolar trafficking occurs through distinctly regulated pathways.

    PubMed

    Ebine, Kazuo; Inoue, Takeshi; Ito, Jun; Ito, Emi; Uemura, Tomohiro; Goh, Tatsuaki; Abe, Hiroshi; Sato, Ken; Nakano, Akihiko; Ueda, Takashi

    2014-06-16

    The multifunctional vacuole is the largest organelle in plant cells, and many proteins are transported to and stored in this organelle; thus, the vacuole has great physiological and agronomical importance. However, the molecular mechanism and regulation of plant vacuolar traffic remain largely unknown. In this study, we demonstrate that multiple vacuolar trafficking pathways operate in plants. RAB5 and RAB7 are evolutionarily conserved subfamilies of Rab GTPase, whose animal and yeast counterparts regulate vacuolar/endosomal trafficking in a sequential manner. Functional analyses of a putative activating complex for RAB7 indicated that this complex is responsible for maturation from RAB5- to RAB7-positive endosomes in plant cells. Moreover, these machinery components are recruited to a more complex trafficking network. Mutations in RAB5 and RAB7 conferred counteracting effects on the vti11 mutant. Furthermore, impairment of RAB5- and RAB7-dependent pathways differentially affected the transport of distinctive cargos. These results indicate that plants have developed a complex vacuolar transport system distinct from that of nonplant systems by assigning evolutionarily conserved machinery to unique trafficking pathways. These pathways provide a fundamental basis for plant development at the cellular and higher-ordered levels.

  1. Leukocyte trafficking: Can we bring the fight to the tumor?

    PubMed

    Pachynski, Russell; Nazha, Jonathon; Kohrt, Holbrook

    2016-03-01

    Control of leukocyte trafficking plays a critical role in the establishment of effective immune responses. It is now well established that the number or ratio of effector to suppressor immune cells within the tumor microenvironment can significantly impact tumor growth and clinical outcomes. Recently approved immunotherapies by the FDA, and those in development, aim to stimulate effector immune cell function. For example, many checkpoint inhibitors seek to stimulate an immune response to tumors by reversing T-cell exhaustion. However, activation of the immune response outside the tumor microenvironment can lead to sometimes fatal immune-mediated adverse events -- the result of "on-target, off-tumor" effects. Thus, control of localization of these activated effector cells remains a critical component of optimizing tumor response while minimizing immune-mediated adverse events. Chemokines and chemoattractants, along with their receptors on immune cells, govern leukocyte trafficking; thus, understanding their expression pattern in the context of the tumor microenvironment and developing approaches to favorably alter those should lead to improved efficacy of current immunotherapeutics. This review highlights the background of cancer immunotherapy, leukocyte trafficking, and some novel approaches being utilized to optimize recruitment of effector immune cells into the tumor microenvironment. Future combinatorial immunotherapy should incorporate therapeutics aimed at 1) favorably altering the tumor microenvironment, 2) activating effector immune cells, and 3) optimizing effector cell trafficking into tumors.

  2. Trafficking of ciliary G protein-coupled receptors.

    PubMed

    McIntyre, Jeremy C; Hege, Mellisa M; Berbari, Nicolas F

    2016-01-01

    In the last decade highly conserved cellular appendages called cilia have enjoyed a renewed interest from basic, biomedical scientists, and clinicians alike. This interest has grown upon the elucidation that cilia throughout the body serve as important sensory and signaling centers in both development and adult homeostasis. Furthermore, the identification of several rare genetic disorders associated with cilia dysfunction has broadened the field. However, even though their potential role in human health and disease is now recognized many basic questions about their functions remain. This chapter seeks to explore the trafficking of cilia-specific G protein-coupled receptors (GPCRs) and discusses several model systems in which this has been explored. We open the chapter by briefly discussing cilia and GPCRs then begin discussing some aspects of rhodopsin trafficking, arguably the most well studied of cilia GPCRs. We continue with sections on neuronal cilia and olfactory cilia receptor trafficking. Finally, we conclude with the emerging area of dynamic ciliary GPCR trafficking and speculate about future directions and some of the questions that remain for ciliary GPCRs. PMID:26928538

  3. 78 FR 59950 - Advisory Council on Wildlife Trafficking

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-09-30

    ... Fish and Wildlife Service Advisory Council on Wildlife Trafficking AGENCY: Fish and Wildlife Service, Interior. ACTION: Notice of meeting. SUMMARY: We, the U.S. Fish and Wildlife Service (Service), announce a... strategies to reduce illicit trade and consumer demand for illegally traded wildlife, including...

  4. Distal Locking Screws for Intramedullary Nailing of Tibial Fractures.

    PubMed

    Agathangelidis, Filon; Petsatodis, Georgios; Kirkos, John; Papadopoulos, Pericles; Karataglis, Dimitrios; Christodoulou, Anastasios

    2016-01-01

    Recently introduced tibial intramedullary nails allow a number of distal screws to be used to reduce the incidence of malalignment and loss of fixation of distal metaphyseal fractures. However, the number of screws and the type of screw configuration to be used remains obscure. This biomechanical study was performed to address this question. Thirty-six Expert tibial nails (Synthes, Oberdorf, Switzerland) were introduced in composite bone models. The models were divided into 4 groups with different distal locking configurations ranging from 2 to 4 screws. A 7-mm gap osteotomy was performed 72 mm from the tibial plafond to simulate a 42-C3 unstable distal tibial fracture. Each group was divided in 3 subgroups and underwent nondestructive biomechanical testing in axial compression, coronal bending, and axial torsion. The passive construct stiffness was measured and statistically analyzed with one-way analysis of variance. Although some differences were noted between the stiffness of each group, these were not statistically significant in compression (P=.105), bending (P=.801), external rotation (P=.246), and internal rotation (P=.370). This in vitro study showed that, when using the Expert tibial nail for unstable distal tibial fractures, the classic configuration of 2 parallel distal screws could provide the necessary stability under partial weight-bearing conditions. PMID:26840700

  5. [Epidemiology and management of isolated distal deep venous thrombosis].

    PubMed

    Galanaud, J-P; Kahn, S R; Khau Van Kien, A; Laroche, J-P; Quéré, I

    2012-12-01

    Isolated distal deep-vein thromboses (DVT) are infra-popliteal DVT without involvement of proximal veins or pulmonary embolism (PE). They can affect deep calf (tibial anterior, tibial posterior, or peroneal) or muscular (gastrocnemius or soleal) veins. They represent half of all lower limbs DVT. Proximal and distal DVTs differ in terms of risk factor profile, proximal DVT being more frequently associated with chronic risk factors and distal DVT with transient ones. Their natural history (rate of spontaneous proximal extension) is debated leading to uncertainties on the need to diagnose and treat them with anticoagulant drugs. In the long term, the risk of venous thromboembolic recurrence is lower than that of proximal DVT and their absolute risk of post-thrombotic syndrome is unknown. French national guidelines suggest treating with anticoagulants for 6 weeks a first episode of isolated distal DVT provoked by a transient risk factor and treating for at least 3 months unprovoked or recurrent or active cancer-related distal DVT. The use of compression stockings use is suggested in case of deep calf vein thrombosis. Ongoing therapeutic trials should provide important data necessary to establish an evidence-based mode of care, especially about the need to treat distal DVT at low risk of extension with anticoagulants.

  6. Neutrophil elastase and proteinase 3 trafficking routes in myelomonocytic cells

    SciTech Connect

    Kaellquist, Linda; Rosen, Hanna; Nordenfelt, Pontus; Calafat, Jero; Janssen, Hans; Persson, Ann-Maj; Hansson, Markus; Olsson, Inge

    2010-11-15

    Neutrophil elastase (NE) and proteinase 3 (PR3) differ in intracellular localization, which may reflect different trafficking mechanisms of the precursor forms when synthesized at immature stages of neutrophils. To shed further light on these mechanisms, we compared the trafficking of precursor NE (proNE) and precursor PR3 (proPR3). Like proNE [1], proPR3 interacted with CD63 upon heterologous co-expression in COS cells but endogenous interaction was not detected although cell surface proNE/proPR3/CD63 were co-endocytosed in myelomonocytic cells. Cell surface proNE/proPR3 turned over more rapidly than cell surface CD63 consistent with processing/degradation of the pro-proteases but recycling of CD63. Colocalization of proNE/proPR3/CD63 with clathrin and Rab 7 suggested trafficking through coated vesicles and late endosomes. Partial caveolar trafficking of proNE/CD63 but not proPR3 was suggested by colocalization with caveolin-1. Blocking the C-terminus of proNE/proPR3 by creating a fusion with FK506 binding protein inhibited endosomal re-uptake of proNE but not proPR3 indicating 'pro{sub C}'-peptide-dependent structural/conformational requirements for proNE but not for proPR3 endocytosis. The NE aminoacid residue Y199 of a proposed NE sorting motif that interacts with AP-3 [2] was not required for proNE processing, sorting or endocytosis in rat basophilic leukemia (RBL) cells expressing heterologous Y199-deleted proNE; this suggests operation of another AP-3-link for proNE targeting. Our results show intracellular multi-step trafficking to be different between proNE and proPR3 consistent with their differential subcellular NE/PR3 localization in neutrophils.

  7. Rab GTPase mediated procollagen trafficking in ascorbic acid stimulated osteoblasts.

    PubMed

    Nabavi, Noushin; Pustylnik, Sofia; Harrison, Rene E

    2012-01-01

    Despite advances in investigating functional aspects of osteoblast (OB) differentiation, especially studies on how bone proteins are deposited and mineralized, there has been little research on the intracellular trafficking of bone proteins during OB differentiation. Collagen synthesis and secretion is the major function of OBs and is markedly up-regulated upon ascorbic acid (AA) stimulation, significantly more so than in fibroblast cells. Understanding the mechanism by which collagen is mobilized in specialized OB cells is important for both basic cell biology and diseases involving defects in bone protein secretion and deposition. Protein trafficking along the exocytic and endocytic pathways is aided by many molecules, with Rab GTPases being master regulators of vesicle targeting. In this study, we used microarray analysis to identify the Rab GTPases that are up-regulated during a 5-day AA differentiation of OBs, namely Rab1, Rab3d, and Rab27b. Further, we investigated the role of identified Rabs in regulating the trafficking of collagen from the site of synthesis in the ER to the Golgi and ultimately to the plasma membrane utilizing Rab dominant negative (DN) expression. We also observed that experimental halting of biosynthetic trafficking by these mutant Rabs initiated proteasome-mediated degradation of procollagen and ceased global protein translation. Acute expression of Rab1 and Rab3d DN constructs partially alleviated this negative feedback mechanism and resulted in impaired ER to Golgi trafficking of procollagen. Similar expression of Rab27b DN constructs resulted in dispersed collagen vesicles which may represent failed secretory vesicles sequestered in the cytosol. A significant and strong reduction in extracellular collagen levels was also observed implicating the functional importance of Rab1, Rab3d and Rab27b in these major collagen-producing cells.

  8. Microtubule and Actin Interplay Drive Intracellular c-Src Trafficking.

    PubMed

    Arnette, Christopher; Frye, Keyada; Kaverina, Irina

    2016-01-01

    The proto-oncogene c-Src is involved in a variety of signaling processes. Therefore, c-Src spatiotemporal localization is critical for interaction with downstream targets. However, the mechanisms regulating this localization have remained elusive. Previous studies have shown that c-Src trafficking is a microtubule-dependent process that facilitates c-Src turnover in neuronal growth cones. As such, microtubule depolymerization lead to the inhibition of c-Src recycling. Alternatively, c-Src trafficking was also shown to be regulated by RhoB-dependent actin polymerization. Our results show that c-Src vesicles primarily exhibit microtubule-dependent trafficking; however, microtubule depolymerization does not inhibit vesicle movement. Instead, vesicular movement becomes both faster and less directional. This movement was associated with actin polymerization directly at c-Src vesicle membranes. Interestingly, it has been shown previously that c-Src delivery is an actin polymerization-dependent process that relies on small GTPase RhoB at c-Src vesicles. In agreement with this finding, microtubule depolymerization induced significant activation of RhoB, together with actin comet tail formation. These effects occurred downstream of GTP-exchange factor, GEF-H1, which was released from depolymerizing MTs. Accordingly, GEF-H1 activity was necessary for actin comet tail formation at the Src vesicles. Our results indicate that regulation of c-Src trafficking requires both microtubules and actin polymerization, and that GEF-H1 coordinates c-Src trafficking, acting as a molecular switch between these two mechanisms. PMID:26866809

  9. Narco-scapes: Cocaine Trafficking and Deforestation in Central America

    NASA Astrophysics Data System (ADS)

    Wrathall, D.; McSweeney, K.; Nielsen, E.; Pearson, Z.

    2015-12-01

    Narcotics trafficking and drug interdiction efforts have resulted in a well-documented social crisis in Central America, but more recently, has been tightly linked to environmental catastrophe and accelerated deforestation in transit zones. This talk will outline synthesis findings from multi-country, interdisciplinary research on cocaine trafficking as an engine of forest loss in Central America. During the "narco-boom" of the mid-2000s, we observed a geographical evolution of cocaine flows into Central America, and the transit of cocaine through new spaces, accompanied by specific patterns of social and environmental change in new nodes of transit. We coarsely estimated that the total amount of cocaine flowing through Central America increased from 70 metric tons in 2000 to 350 mt in 2012, implying that total cocaine trafficking revenue in the region increased from roughly 600 million dollars to 3.5 billion in that time. We describe the mechanism by which these locally captured cocaine rents resulted in a rapid conversion of forest into cattle pasture. Narco-traffickers are drawn to invest in the cattle economy, as a direct means of laundering and formalizing proceeds. Ranching is a land intensive activity, and new narco-enriched cattle pastures can be isolated from other forms forest loss solely by their spatial and temporal change characteristics. A preliminary forest change study in Honduras, for example, indicated that areas of accelerated deforestation were in close proximity to known narcotics trafficking routes and were thirteen times more extensive on average than other forest clearings. Deforested areas commonly appeared in isolated and biodiverse lowland tropical rainforest regions that often intersected with protected areas and indigenous reserves. We find that narco-deforestation is a readily identifiable signal of the extent and health of the cocaine economy. This talk will feature summaries of both ethnographic and land cover change we have observed

  10. Microtubule and Actin Interplay Drive Intracellular c-Src Trafficking

    PubMed Central

    Arnette, Christopher; Frye, Keyada; Kaverina, Irina

    2016-01-01

    The proto-oncogene c-Src is involved in a variety of signaling processes. Therefore, c-Src spatiotemporal localization is critical for interaction with downstream targets. However, the mechanisms regulating this localization have remained elusive. Previous studies have shown that c-Src trafficking is a microtubule-dependent process that facilitates c-Src turnover in neuronal growth cones. As such, microtubule depolymerization lead to the inhibition of c-Src recycling. Alternatively, c-Src trafficking was also shown to be regulated by RhoB-dependent actin polymerization. Our results show that c-Src vesicles primarily exhibit microtubule-dependent trafficking; however, microtubule depolymerization does not inhibit vesicle movement. Instead, vesicular movement becomes both faster and less directional. This movement was associated with actin polymerization directly at c-Src vesicle membranes. Interestingly, it has been shown previously that c-Src delivery is an actin polymerization-dependent process that relies on small GTPase RhoB at c-Src vesicles. In agreement with this finding, microtubule depolymerization induced significant activation of RhoB, together with actin comet tail formation. These effects occurred downstream of GTP-exchange factor, GEF-H1, which was released from depolymerizing MTs. Accordingly, GEF-H1 activity was necessary for actin comet tail formation at the Src vesicles. Our results indicate that regulation of c-Src trafficking requires both microtubules and actin polymerization, and that GEF-H1 coordinates c-Src trafficking, acting as a molecular switch between these two mechanisms. PMID:26866809

  11. Preventing trafficking in women and children in Asia: issues and options.

    PubMed

    Bennett, T

    1999-09-01

    This article discusses the issues and options in the prevention of trafficking of women and children in Asia. Studies revealed a higher prevalence of trafficking in Asian countries such as Nepal, India, Bangladesh, Philippines, Cambodia, and Thailand. This is due to a huge population, growing urbanization, and poverty. Several programs by the government and nongovernmental organizations have been developed to address the trafficking problem. In Nepal, the Maiti program was organized to help trafficking victims return to their home country, while occupational alternatives and awareness campaigns were organized for young women vulnerable to trafficking. In Thailand, greater penalties were imposed to customers as compared to the sellers so as to discourage the continuance and decrease the prevalence of trafficking. Other strategies have also been identified, such as prosecution of procurers, community awareness through campaigns, poverty alleviation, and gender equalization to address the trafficking problem. PMID:12322333

  12. Distal antenna and distal antenna related encode nuclear proteins containing pipsqueak motifs involved in antenna development in Drosophila.

    PubMed

    Emerald, B Starling; Curtiss, Jennifer; Mlodzik, Marek; Cohen, Stephen M

    2003-03-01

    Legs and antennae are considered to be homologous appendages. The fundamental patterning mechanisms that organize spatial pattern are conserved, yet appendages with very different morphology develop. A genetic hierarchy for specification of antennal identity has been partly elucidated. We report identification of a novel family of genes with roles in antennal development. The distal antenna (dan) and distal antenna-related (danr) genes encode novel nuclear proteins that are expressed in the presumptive distal antenna, but not in the leg imaginal disc. Ectopic expression of dan or danr causes partial transformation of distal leg structure toward antennal identity. Mutants that remove dan and danr activity cause partial transformation of antenna toward leg identity. Therefore we suggest that dan and danr contribute to differentiation of antenna-specific characteristics. Antenna-specific expression of dan and danr depends on a regulatory hierarchy involving homothorax and Distal-less, as well as cut and spineless. We propose that dan and danr are effector genes that act downstream of these genes to control differentiation of distal antennal structures.

  13. Autoxidation of oxymyoglobin with the distal (E7) glutamine.

    PubMed

    Suzuki, T

    1987-08-01

    We reported previously that the distal(E7) histidine is replaced by glutamine in myoglobin from the shark, Galeorhinus japonicus. The amino-acid sequence of myoglobin from another shark, Heterodontus japonicus, has been determined. The myoglobin is composed of 148 residues, is acetylated at the N-terminus, and contains the distal(E7) histidine at position 59. Although the sequence homologies between G. japonicus, H. japonicus, and sperm-whale myoglobins were about 40-55%, their hydropathy profiles were very similar, indicating that they have a similar geometry in their globin folding. The autoxidation rates of the two shark oxymyoglobins were examined in 0.1 M buffer at 25 degrees C over pH range 4.5-11.5. The pH dependence for the autoxidation of H. japonicus myoglobin was very similar to that of sperm-whale myoglobin, although the rate was about 10-times higher over the pH range examined. In both myoglobins, autoxidation was largely accelerated by H+. On the other hand, the pH dependence of G. japonicus myoglobin, which has the distal glutamine in the place of histidine, was quite different from those of sperm-whale and H. japonicus myoglobins. One of the most remarkable features is the fact that the autoxidation rate is not enhanced with an increase in the concentration of H+ in the acidic range of pH, where the autoxidation of sperm-whale and H. japonicus myoglobins is most accelerated. This finding suggests that the distal(E7) histidine participates in the autoxidation reaction as a catalytic residue facilitating the movement of a catalytic proton.

  14. PPARy and GLUT-4 expression as developmental regulators/markers for preadipocyte differentiation into an adipocyte

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In this document, we have integrated knowledge about two major cellular markers found in cells of the adipocyte lineage. The first factor is PPARy, which has been identified as an important adipogenic regulator. PPARy plays an important role in converting adipofibroblasts, fibroblasts or preadipocyt...

  15. Differential cycling rates of Kv4.2 channels in proximal and distal dendrites of hippocampal CA1 pyramidal neurons

    PubMed Central

    Nestor, Michael W.; Hoffman, Dax A.

    2010-01-01

    The heterogeneous expression of voltage-gated channels in dendrites suggests that neurons perform local microdomain computations at different regions. It has been shown that A-type K+ channels have a non-uniform distribution along the primary apical dendrite in CA1 pyramidal neurons, increasing with distance from the soma. Kv4.2 channels, which are responsible for the somatodendritic A-type K+ current in CA1 pyramidal neurons, shape local synaptic input and regulate the back-propagation of APs into dendrites. Experiments were performed to test the hypothesis that Kv4.2 channels are differentially trafficked at different regions along the apical dendrite during basal activity and upon stimulation in CA1 neurons. Proximal (50–150 µm from the soma, primary and oblique) and distal (>200 µm) apical dendrites were selected. The fluorescence recovery after photobleaching (FRAP) technique was used to measure basal cycling rates of EGFP-tagged Kv4.2 (Kv4.2g). We found that the cycling rate of Kv4.2 channels was one order of magnitude slower at both primary and oblique dendrites between 50–150 µm from the soma. Kv4.2 channel cycling increased significantly at 200–250 µm from the soma. Expression of a Kv4.2 mutant lacking a phosphorylation site for protein kinase-A (Kv4.2gS552A) abolished this distance-dependent change in channel cycling; demonstrating that phosphorylation by PKA underlies the increased mobility in distal dendrites. Neuronal stimulation by α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) treatment increased cycling of Kv4.2 channels significantly at distal sites only. This activity-dependent increase in Kv4.2 cycling at distal dendrites was blocked by expression of Kv4.2gS552A. These results indicate that distance-dependent Kv4.2 mobility is regulated by activity-dependent phosphorylation of Kv4.2 by PKA. PMID:21472817

  16. Whole bone geometry and bone quality in distal forearm fracture.

    PubMed

    Parkinson, Ian H; Fazzalari, Nicola L

    2008-09-01

    Fracture of the distal radius is a sentinel for future increased risk of other "osteoporotic" fractures, in which the peak age for incidence of distal radius fracture is 5 to 10 years before that for spine and hip fractures. Mean bone mineral density (BMD) of the distal radius was lower in patients with osteoporosis compared with age- and sex-matched normal subjects. However, it has been shown that to predict the strength of the distal radius at the site where fractures occur requires more than measurement of bone mineral content (BMC) or BMD. Only moderate correlations have been found between forearm sites, which may be a result of differences in bone composition between sites. Different forearm sites may be used interchangeably for diagnostic purposes, but the prognostic value is not known. Using the distal radius as a screening tool for identifying individuals at risk of "osteoporotic" fracture shows that forearm site selection and accuracy of measurement can be important confounders in group studies.Improving resolution of computed tomography (CT) scanners has enabled quantitation of cortical bone density and cortical thickness. These measurements have enabled the mechanism of bone loss in the distal radius to be elucidated and show that, after menopause, bone loss is primarily through thinning of the cortex. CT imaging allows the precise localization of bone changes in individuals and should be of value in the assessment of the severity of osteoporosis. It also shows that this technology has the potential to determine the efficacy of therapeutic interventions. A concerted effort has been made to elucidate the interrelationships between the amount of bone and the geometry and that clinical imaging of BMC and/or cross-sectional area in the radius would provide improved prediction of an individual's risk of fracture.The technological tools are available, in the clinic, to accurately measure the 3-dimensional (3D) geometry of the distal radius and the amount of

  17. An intrinsic timer specifies distal structures of the vertebrate limb

    PubMed Central

    Saiz-Lopez, Patricia; Chinnaiya, Kavitha; Campa, Victor M.; Delgado, Irene; Ros, Maria A.; Towers, Matthew

    2015-01-01

    How the positional values along the proximo-distal axis (stylopod-zeugopod-autopod) of the limb are specified is intensely debated. Early work suggested that cells intrinsically change their proximo-distal positional values by measuring time. Recently, however, it is suggested that instructive extrinsic signals from the trunk and apical ectodermal ridge specify the stylopod and zeugopod/autopod, respectively. Here, we show that the zeugopod and autopod are specified by an intrinsic timing mechanism. By grafting green fluorescent protein-expressing cells from early to late chick wing buds, we demonstrate that distal mesenchyme cells intrinsically time Hoxa13 expression, cell cycle parameters and the duration of the overlying apical ectodermal ridge. In addition, we reveal that cell affinities intrinsically change in the distal mesenchyme, which we suggest results in a gradient of positional values along the proximo-distal axis. We propose a complete model in which a switch from extrinsic signalling to intrinsic timing patterns the vertebrate limb. PMID:26381580

  18. Distal Radius Radiographic Indices and Perilunate Fracture Dislocation

    PubMed Central

    Bagherifard, Abolfazl; Jafari, Davod; Keihan Shokouh, Hassan; Motavallian, Ebrahim; Najd Mazhar, Farid

    2016-01-01

    Background Distal radius radiographic indices may play a role as risk factors in pathogenesis of Kienbock’s disease, scaphoid fracture and nonunion. Perilunate fracture dislocations are devastating wrist injuries, and their relationship and distal radius indices have not been addressed in the literature. Objectives The aim of this study was to evaluate the possible role of distal radius radiographic indices including radial height, radial inclination, ulnar variance and volar tilt as risk factors in the perilunate fracture dislocation injury of the wrist. Patients and Methods We studied distal radius radiographic indices including radial height, radial inclination, ulnar variance and volar tilt in 43 patients with perilunate fracture dislocations and compared them with 44 wrists in the control group. Results The mean values of the radial height, radial inclination, ulnar variance and volar tilt were 12.74 (5 - 18), 24.20 (7 - 35), -0.73 (-5 - 4) and 12.28 (2 - 20) in the patient group. These values were 12.68 (9 - 22), 23.22 (17 - 30), -0.11 (-4 - 3) and 11.05 (-3 - 20), respectively in the control group. There was no statistically significant difference between the two groups. Conclusions This study did not show that distal radius anatomical indices including the radial height, radial inclination, ulnar variance and volar tilt influence perilunate fracture dislocation as risk factors.

  19. Implant Size Availability Affects Reproduction of Distal Femoral Anatomy.

    PubMed

    Morris, William Z; Gebhart, Jeremy J; Goldberg, Victor M; Wera, Glenn D

    2016-07-01

    A total knee arthroplasty system offers more distal femoral implant anterior-posterior (AP) sizes than its predecessor. The purpose of this study is to investigate the impact of increased size availability on an implant system's ability to reproduce the AP dimension of the native distal femur. We measured 200 cadaveric femora with the AP-sizing guides of Zimmer (Warsaw, IN) NexGen (8 sizes) and Zimmer Persona (12 sizes) total knee arthroplasty systems. We defined "size deviation" as the difference in the AP dimension between the anatomic size of the native femur and the closest implant size. We defined satisfactory reproduction of distal femoral dimensions as < 1 mm difference between the implant and native femur size. The NexGen system was associated with a mean 0.46 mm greater implant size deviation than Persona (p < 0.001). When using a 1 mm size deviation as a cutoff for satisfactory replication of the native distal femoral anatomy, 85/200 specimens (42.5%) were a poor fit by NexGen, but a satisfactory fit by Persona. Only 1/200 specimens (0.5%) was a poor fit by Persona, but a satisfactory fit by NexGen (p < 0.001). The novel knee system with 12 versus 8 sizes reproduces the AP dimension of the native distal femur more closely than its predecessor. Further study is needed to determine the clinical impact of these differences.

  20. A New Orthodontic Appliance with a Mini Screw for Upper Molar Distalization

    PubMed Central

    2016-01-01

    The aim of this study is to present a new upper molar distalization appliance called Cise distalizer designed as intraoral device supported with orthodontic mini screw for upper permanent molar distalization. The new appliance consists of eight main components. In order to understand the optimum force level, the appliance under static loading is tested by using strain gage measurement techniques. Results show that one of the open coils produces approximately 300 gr distalization force. Cise distalizer can provide totally 600 gr distalization force. This range of force level is enough for distalization of upper first and second molar teeth. PMID:27528796

  1. Ejecta emplacement: from distal to proximal

    NASA Astrophysics Data System (ADS)

    Artemieva, N.

    2008-09-01

    Introduction Most part of impact ejecta is deposited ballistically at some distance from a crater, defined by ejection velocity V and ejection angle α: d=v2sinα/g. In case of giant impacts, planetary curvature should be taken into account [1]. Combined with ejecta scaling [2], these relations allow to define ejecta thickness as a function of distance. Ejecta from large craters are deposited at velocity high enough to mobilize substrate material and to thicken ejecta deposits [3]. Ballistic approximation is valid for airless bodies (if impact vaporization is not vast) or for proximal ejecta of large impact craters, where ejecta mass per unit area is substantially greater than the mass of involved vapor/atmosphere (M-ratio). Deposition of distal ejecta, in which ejecta mass is negligible compared to the atmosphere, may be also treated in a simplified manner, i.e. as 1) passive motion of ejected particles within an impact plume and 2) later, as sedimentation of particles in undisturbed atmosphere (equilibrium between gravity and drag). In all intermediate M-ratio values, impact ejecta move like a surge, i.e. dilute suspension current in which particles are carried in turbulent flows under the influence of gravity. Surges are well-known for near-surface explosive tests, described in detail for volcanic explosions (Plinian column collapse, phreato-magmatic eruption, lateral blast), and found in ejecta from the Chicxulub [4] and the Ries [5]. Important aspects of surge transport include its ability to deposit ejecta over a larger area than that typical of continuous ballistic ejecta and to create multiple ejecta layers. Numerical model Two-phase hydrodynamics. Surges should be modeled in the frame of two-phase hydrodynamics, i.e. interaction between solid/molten particles and atmospheric gas/impact vapor should be taken into account. There are two techniques of solving equations for dust particle motion in a gas flow. The first one describes solid/molten particles as a

  2. Sexual slavery without borders: trafficking for commercial sexual exploitation in India

    PubMed Central

    Joffres, Christine; Mills, Edward; Joffres, Michel; Khanna, Tinku; Walia, Harleen; Grund, Darrin

    2008-01-01

    Trafficking in women and children is a gross violation of human rights. However, this does not prevent an estimated 800 000 women and children to be trafficked each year across international borders. Eighty per cent of trafficked persons end in forced sex work. India has been identified as one of the Asian countries where trafficking for commercial sexual exploitation has reached alarming levels. While there is a considerable amount of internal trafficking from one state to another or within states, India has also emerged as a international supplier of trafficked women and children to the Gulf States and South East Asia, as well as a destination country for women and girls trafficked for commercial sexual exploitation from Nepal and Bangladesh. Trafficking for commercial sexual exploitation is a highly profitable and low risk business that preys on particularly vulnerable populations. This paper presents an overview of the trafficking of women and girls for sexual exploitation (CSE) in India; identifies the health impacts of CSE; and suggest strategies to respond to trafficking and related issues. PMID:18817576

  3. Sexual slavery without borders: trafficking for commercial sexual exploitation in India.

    PubMed

    Joffres, Christine; Mills, Edward; Joffres, Michel; Khanna, Tinku; Walia, Harleen; Grund, Darrin

    2008-09-25

    Trafficking in women and children is a gross violation of human rights. However, this does not prevent an estimated 800 000 women and children to be trafficked each year across international borders. Eighty per cent of trafficked persons end in forced sex work. India has been identified as one of the Asian countries where trafficking for commercial sexual exploitation has reached alarming levels. While there is a considerable amount of internal trafficking from one state to another or within states, India has also emerged as a international supplier of trafficked women and children to the Gulf States and South East Asia, as well as a destination country for women and girls trafficked for commercial sexual exploitation from Nepal and Bangladesh. Trafficking for commercial sexual exploitation is a highly profitable and low risk business that preys on particularly vulnerable populations. This paper presents an overview of the trafficking of women and girls for sexual exploitation (CSE) in India; identifies the health impacts of CSE; and suggest strategies to respond to trafficking and related issues.

  4. Cytoplasmic sulfur trafficking in sulfur-oxidizing prokaryotes.

    PubMed

    Dahl, Christiane

    2015-04-01

    Persulfide groups are chemically versatile and participate in a wide array of biochemical pathways. Although it is well documented that persulfurated proteins supply a number of important and elaborate biosynthetic pathways with sulfane sulfur, it is far less acknowledged that the enzymatic generation of persulfidic sulfur, the successive transfer of sulfur as a persulfide between multiple proteins, and the oxidation of sulfane sulfur in protein-bound form are also essential steps during dissimilatory sulfur oxidation in bacteria and archaea. Here, the currently available information on sulfur trafficking in sulfur oxidizing prokaryotes is reviewed, and the idea is discussed that sulfur is always presented to cytoplasmic oxidizing enzymes in a protein-bound form, thus preventing the occurrence of free sulfide inside of the prokaryotic cell. Thus, sulfur trafficking emerges as a central element in sulfur-oxidizing pathways, and TusA homologous proteins appear to be central and common elements in these processes.

  5. Women and citizenship post‐trafficking: the case of Nepal

    PubMed Central

    Richardson, Diane; Laurie, Nina; Poudel, Meena; Townsend, Janet

    2016-01-01

    Abstract This article analyses the relationship between gender, sexuality and citizenship embedded in models of citizenship in the Global South, specifically in South Asia, and the meanings associated with having – or not having – citizenship. It does this through an examination of women's access to citizenship in Nepal in the context of the construction of the emergent nation state in the ‘new’ Nepal ‘post‐conflict’. Our analysis explores gendered and sexualized constructions of citizenship in this context through a specific focus on women who have experienced trafficking, and are beginning to organize around rights to sustainable livelihoods and actively lobby for changes in citizenship rules which discriminate against women. Building from this, in the final section we consider important implications of this analysis of post‐trafficking experiences for debates about gender, sexuality and citizenship more broadly.

  6. Organ economy: organ trafficking in Moldova and Israel.

    PubMed

    Lundin, Susanne

    2012-02-01

    Organ trafficking is an illegal means of meeting the shortage of transplants. The activity flourishes for several interacting reasons, such as medical needs, poverty and criminality. Other factors are fundamental conceptual structures such as the dream of the regenerative body as well as the view of the body as an object of utility and an object of value. The article aims to go behind the normative discussions that usually surround organ trafficking. Why this is happening, and what the societal consequences are, is examined through ethnographic fieldwork. The focus is on the shadow economies that govern existence and in which people, goods, weapons, money, bodies, etc. constitute components of the global market. PMID:22586847

  7. Women and citizenship post‐trafficking: the case of Nepal

    PubMed Central

    Richardson, Diane; Laurie, Nina; Poudel, Meena; Townsend, Janet

    2016-01-01

    Abstract This article analyses the relationship between gender, sexuality and citizenship embedded in models of citizenship in the Global South, specifically in South Asia, and the meanings associated with having – or not having – citizenship. It does this through an examination of women's access to citizenship in Nepal in the context of the construction of the emergent nation state in the ‘new’ Nepal ‘post‐conflict’. Our analysis explores gendered and sexualized constructions of citizenship in this context through a specific focus on women who have experienced trafficking, and are beginning to organize around rights to sustainable livelihoods and actively lobby for changes in citizenship rules which discriminate against women. Building from this, in the final section we consider important implications of this analysis of post‐trafficking experiences for debates about gender, sexuality and citizenship more broadly. PMID:27642193

  8. A human rights approach to human trafficking for organ removal.

    PubMed

    Budiani-Saberi, Debra; Columb, Seán

    2013-11-01

    Human trafficking for organ removal (HTOR) should not be reduced to a problem of supply and demand of organs for transplantation, a problem of organized crime and criminal justice, or a problem of voiceless, abandoned victims. Rather, HTOR is at once an egregious human rights abuse and a form of human trafficking. As such, it demands a human-rights based approach in analysis and response to this problem, placing the victim at the center of initiatives to combat this phenomenon. Such an approach requires us to consider how various measures impact or disregard victims/potential victims of HTOR and gives us tools to better advocate their interests, rights and freedoms. PMID:23743564

  9. Retrograde trafficking of AB₅ toxins: mechanisms to therapeutics.

    PubMed

    Mukhopadhyay, Somshuvra; Linstedt, Adam D

    2013-10-01

    Bacterial AB5 toxins are a clinically relevant class of exotoxins that include several well-known members such as Shiga, cholera, and pertussis toxins. Infections with toxin-producing bacteria cause devastating human diseases that affect millions of individuals each year and have no definitive medical treatment. The molecular targets of AB5 toxins reside in the cytosol of infected cells, and the toxins reach the cytosol by trafficking through the retrograde membrane transport pathway that avoids degradative late endosomes and lysosomes. Focusing on Shiga toxin as the archetype member, we review recent advances in understanding the molecular mechanisms involved in the retrograde trafficking of AB5 toxins and highlight how these basic science advances are leading to the development of a promising new therapeutic approach based on inhibiting toxin transport.

  10. Retroviral env glycoprotein trafficking and incorporation into virions.

    PubMed

    Murakami, Tsutomu

    2012-01-01

    Together with the Gag protein, the Env glycoprotein is a major retroviral structural protein and is essential for forming infectious virus particles. Env is synthesized, processed, and transported to certain microdomains at the plasma membrane and takes advantage of the same host machinery for its trafficking as that used by cellular glycoproteins. Incorporation of Env into progeny virions is probably mediated by the interaction between Env and Gag, in some cases with the additional involvement of certain host factors. Although several general models have been proposed to explain the incorporation of retroviral Env glycoproteins into virions, the actual mechanism for this process is still unclear, partly because structural data on the Env protein cytoplasmic tail is lacking. This paper presents the current understanding of the synthesis, trafficking, and virion incorporation of retroviral Env proteins.

  11. International Technical Working Group Cooperation to Counter Illicit Nuclear Trafficking

    SciTech Connect

    Smith, D K; Niemeyer, S

    2004-09-18

    The Nuclear Smuggling International Technical Working Group (ITWG) is an international body of nuclear forensic experts that cooperate to deter the illicit trafficking of nuclear materials. The objective of the ITWG is to provide a common approach and effective technical solutions to governments who request assistance in nuclear forensics. The ITWG was chartered in 1996 and since that time more than 28 nations and organizations have participated in 9 international meetings and 2 analytical round-robin trials. Soon after its founding the ITWG adopted a general framework to guide nuclear forensics investigations that includes recommendations for nuclear crime scene security and analysis, the best application of radioanalytical methods, the conduct of traditional forensic analysis of contaminated materials, and effective data analysis to interpret the history of seized nuclear materials. This approach has been adopted by many nations as they respond to incidents of illicit nuclear trafficking.

  12. Force dependence of phagosome trafficking in retinal pigment epithelial cells

    NASA Astrophysics Data System (ADS)

    Daniel, Rebekah; Koll, Andrew T.; Altman, David

    2014-09-01

    Retinal pigment epithelial (RPE) cells play an integral role in the renewal of photoreceptor disk membranes. As rod and cone cells shed their outer segments, they are phagocytosed and degraded by the RPE, and a failure in this process can result in retinal degeneration. We have studied the role of myosin VI in nonspecific phagocytosis in a human RPE primary cell line (ARPE-19), testing the hypothesis that this motor generates the forces required to traffic phagosomes in these cells. Experiments were conducted in the presence of forces through the use of in vivo optical trapping. Our results support a role for myosin VI in phagosome trafficking and demonstrate that applied forces modulate rates of phagosome trafficking.

  13. Creating an interdisciplinary medical home for survivors of human trafficking.

    PubMed

    McNiel, Melinda; Held, Theodore; Busch-Armendariz, Noël

    2014-09-01

    Health care providers play an important role in identifying victims of human trafficking and addressing their unique medical needs. In response to a recently published call to action in Obstetrics & Gynecology, an interdisciplinary medical home has been created in central Texas to serve as a model for delivery of care to survivors of human trafficking that is sensitive to their history of trauma, or "trauma-informed." An overview of the topic is provided along with a description of the stakeholders involved and the steps that were taken to create the clinic. This information is presented with the intention of educating health care providers on the long-term medical needs of survivors and on how they can establish a similar clinic in other parts of the country.

  14. Transferrin Receptor Controls AMPA Receptor Trafficking Efficiency and Synaptic Plasticity

    PubMed Central

    Liu, Ke; Lei, Run; Li, Qiong; Wang, Xin-Xin; Wu, Qian; An, Peng; Zhang, Jianchao; Zhu, Minyan; Xu, Zhiheng; Hong, Yang; Wang, Fudi; Shen, Ying; Li, Hongchang; Li, Huashun

    2016-01-01

    Transferrin receptor (TFR) is an important iron transporter regulating iron homeostasis and has long been used as a marker for clathrin mediated endocytosis. However, little is known about its additional function other than iron transport in the development of central nervous system (CNS). Here we demonstrate that TFR functions as a regulator to control AMPA receptor trafficking efficiency and synaptic plasticity. The conditional knockout (KO) of TFR in neural progenitor cells causes mice to develop progressive epileptic seizure, and dramatically reduces basal synaptic transmission and long-term potentiation (LTP). We further demonstrate that TFR KO remarkably reduces the binding efficiency of GluR2 to AP2 and subsequently decreases AMPA receptor endocytosis and recycling. Thus, our study reveals that TFR functions as a novel regulator to control AMPA trafficking efficiency and synaptic plasticity. PMID:26880306

  15. The trafficking of women and the role of the midwife.

    PubMed

    Tizard, Hannah

    2016-04-01

    Health can be contextualised in relation to globalisation. Economic and societal influences, increasing gaps between middle income and impoverished groups, mass media, culture sexualisation, consumerism, psychological control and criminal activities, such as the drugs and sex trades, amplify challenges to maintaining the health and wellbeing of populations (Lee 2004). UK policy makers develop tools to determine care pathways, in theory allowing those working in public health roles to support individuals to better long-term health. The health needs of trafficked women and the role of the midwife require particular consideration so that this group is not further exposed and unprotected. It requires partnership with a great number of agencies within healthcare itself, but also with charities, government bodies, external organisations and the police. This article explores the health problems associated with the trafficking of women and the clinical implications in the identification and treatment of these victims for the midwife in a public health capacity.

  16. The trafficking of women and the role of the midwife.

    PubMed

    Tizard, Hannah

    2016-04-01

    Health can be contextualised in relation to globalisation. Economic and societal influences, increasing gaps between middle income and impoverished groups, mass media, culture sexualisation, consumerism, psychological control and criminal activities, such as the drugs and sex trades, amplify challenges to maintaining the health and wellbeing of populations (Lee 2004). UK policy makers develop tools to determine care pathways, in theory allowing those working in public health roles to support individuals to better long-term health. The health needs of trafficked women and the role of the midwife require particular consideration so that this group is not further exposed and unprotected. It requires partnership with a great number of agencies within healthcare itself, but also with charities, government bodies, external organisations and the police. This article explores the health problems associated with the trafficking of women and the clinical implications in the identification and treatment of these victims for the midwife in a public health capacity. PMID:27172676

  17. Understanding the link between trafficking in persons and HIV and AIDS risk in Tanzania.

    PubMed

    Kamazima, Switbert R; Ezekiel, Mangi J; Kazaura, Method R; Fimbo, Benett

    2012-01-01

    The magnitude of trafficking in persons in Tanzania is unknown. Consequently, available information on health risks of persons trafficked for different forms of exploitation is extremely scanty. We conducted a baseline study in eight administrative regions of Tanzania using both qualitative and quantitative methods to generate data on the health conditions of trafficked persons to inform trafficking in persons control measures through HIV and AIDS interventions. Study participants included the national, regional and district community development officers, district medical officers, local government leaders, managers or representatives of non-governmental organizations involved in anti-trafficking in persons activities, members of the community and victims. Findings indicated that common forms of labour into which persons are trafficked include domestic services, agriculture (farming), construction, mining/quarrying, fishing, lumbering and manufacturing. Trafficked persons are reported to be exposed to risks like overcrowding, long working hours, psychological problems, physical injuries, impotence, breathing problems and sexually transmitted infections including HIV. It is concluded that the reported occupational hazards in industries where trafficked persons are forced into are not specific to trafficked persons as they affect all labourers. However, the underground nature of the trafficking in persons process increases health problems and risks, including the vulnerability to HIV infection. More tailored research is needed, especially to find means of how to reach out and provide services to this particular vulnerable population, validate labour forms of exploitation into which persons are trafficked to enable the integration or mainstreaming of HIV and AIDS and trafficking in persons at the policy and programmatic levels. In addition, findings would facilitate the understanding of the link between increased risk of IRV and trafficking in persons. PMID:26591750

  18. Understanding the link between trafficking in persons and HIV and AIDS risk in Tanzania.

    PubMed

    Kamazima, Switbert R; Ezekiel, Mangi J; Kazaura, Method R; Fimbo, Benett

    2012-01-01

    The magnitude of trafficking in persons in Tanzania is unknown. Consequently, available information on health risks of persons trafficked for different forms of exploitation is extremely scanty. We conducted a baseline study in eight administrative regions of Tanzania using both qualitative and quantitative methods to generate data on the health conditions of trafficked persons to inform trafficking in persons control measures through HIV and AIDS interventions. Study participants included the national, regional and district community development officers, district medical officers, local government leaders, managers or representatives of non-governmental organizations involved in anti-trafficking in persons activities, members of the community and victims. Findings indicated that common forms of labour into which persons are trafficked include domestic services, agriculture (farming), construction, mining/quarrying, fishing, lumbering and manufacturing. Trafficked persons are reported to be exposed to risks like overcrowding, long working hours, psychological problems, physical injuries, impotence, breathing problems and sexually transmitted infections including HIV. It is concluded that the reported occupational hazards in industries where trafficked persons are forced into are not specific to trafficked persons as they affect all labourers. However, the underground nature of the trafficking in persons process increases health problems and risks, including the vulnerability to HIV infection. More tailored research is needed, especially to find means of how to reach out and provide services to this particular vulnerable population, validate labour forms of exploitation into which persons are trafficked to enable the integration or mainstreaming of HIV and AIDS and trafficking in persons at the policy and programmatic levels. In addition, findings would facilitate the understanding of the link between increased risk of IRV and trafficking in persons.

  19. Septic arthritis of the distal interphalangeal joint in 12 horses.

    PubMed

    Honnas, C M; Welch, R D; Ford, T S; Vacek, J R; Watkins, J P

    1992-01-01

    The medical records of 12 horses with septic arthritis of a distal interphalangeal joint were reviewed to determine clinical features and response to treatment. Sepsis was caused by trauma or an injection that resulted in an open or contaminated distal interphalangeal joint. All horses were severely lame. Treatment included broad-spectrum parenterally administered antimicrobial drugs (ten horses), percutaneous through-and-through joint lavage (eight horses), indwelling drains (three horses), immobilization of the limb in a cast (three horses), intraarticular injection of sodium hyaluronate (one horse), intraarticular injection of antimicrobial drugs (five horses), curettage of the distal phalanx (one horse), and cancellous bone grafting to promote fusion (one horse). Five horses were euthanatized. Ankylosis of the affected joint developed in five horses, four of which are pasture sound. Two horses treated medically are sound although one underwent subsequent palmar digital neurectomy for treatment of navicular syndrome.

  20. Molar distalization with the assistance of Temporary Anchorage Devices.

    PubMed

    Palencar, Adrian J

    2015-01-01

    This article describes efficient techniques for distalization of maxillary and mandibular molars with the assistance of Temporary Anchorage Devices (TADs). There are numerous occasions where the distalization of molars is required in lieu of the odontectomy of bicuspids. In the past, extra-oral force has been used, (i.e. Cervical or Combination Head Gear, or intra-oral force, i.e. Posterior Sagittal Appliance, Modified Greenfield Appliance, Williams DMJ 20001, CD Distalizer, Magill Sagittal, Pendulum Appliance, etc.). All the intra-oral appliances have a common denominator the orthodontic clinician has to deal with, the undesirable expression of the Third Law of Newton. The utilization of TADs allows us to circumvent this shortcoming, establishing an absolute anchorage, and thus completely negate the expression of the Third Law of Newton. PMID:25881377