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Sample records for caveolin-1 drives estrogen-hypersensitivity

  1. Static pressure drives proliferation of vascular smooth muscle cells via caveolin-1/ERK1/2 pathway

    SciTech Connect

    Luo, Di-xian; Cheng, Jiming; Xiong, Yan; Li, Junmo; Xia, Chenglai; Xu, Canxin; Wang, Chun; Zhu, Bingyang; Hu, Zhuowei; Liao, Duan-fang

    2010-01-22

    Intimal hyperplasia plays an important role in various types of vascular remodeling. Mechanical forces derived from blood flow are associated with the proliferation of vascular smooth muscle cells (VSMC). This contributes to many vascular disorders such as hypertension, atherosclerosis and restenosis after percutaneous transluminal angioplasty (PTA). In this study, we show that static pressure induces the proliferation of VSMC and activates its related signal pathway. VSMC from a rat aorta were treated with different pressures (0, 60, 90, 120, 150 and 180 mm Hg) in a custom-made pressure incubator for 24 h. The most active proliferation of VSMC was detected at a pressure of 120 mm Hg. VSMC was also incubated under a static pressure of 120 mm Hg for different time intervals (0, 2, 4, 8, 12 and 24 h). We found that static pressure significantly stimulates VSMC proliferation. Extracellular signal-regulated kinases 1/2 (ERK1/2) activation showed a peak at the pressure of 120 mm Hg at 4-h time point. Moreover, caveolin-1 expression was significantly inhibited by rising static pressure. Downregulation of VSMC proliferation could be found after PD98059 (ERK1/2 phosphorylation inhibitor) treatment. Our data also showed that a siRNA-mediated caveolin-1 knock down increased ERK1/2 phosphorylation and VSMC proliferation. These results demonstrate that static pressure promotes VSMC proliferation via the Caveolin-1/ERK1/2 pathway.

  2. Caveolin-1 signaling in lung fibrosis.

    PubMed

    Tourkina, Elena; Hoffman, Stanley

    2012-01-01

    Caveolin-1 is a master regulator of several signaling cascades because it is able to bind to and thereby inhibit members of a variety of kinase families. While associated with caveolae and involved in their generation, caveolin-1 is also present at other sites. A variety of studies have suggested that caveolin-1 may be a useful therapeutic target in fibrotic diseases of the lung and other tissues because in these diseases a low level of caveolin-1 expression is associated with a high level of collagen expression and fibrosis. Reduced caveolin-1 expression is observed not only in the fibroblasts that secrete collagen, but also in epithelial cells and monocytes. This is intriguing because both epithelial cells and monocytes have been suggested to be precursors of fibroblasts. Likely downstream effects of loss of caveolin-1 in fibrosis include activation of TGF-β signaling and upregulation of CXCR4 in monocytes resulting in their enhanced migration into damaged tissue where its ligand CXCL12 is produced. Finally, it may be possible to target caveolin-1 in fibrotic diseases without the use of gene therapy. A caveolin-1 peptide (caveolin-1 scaffolding domain) has been identified that retains the function of the full-length molecule to inhibit kinases and that can be modified by addition of the Antennapedia internalization sequence to allow it to enter cells both in vitro and in vivo. PMID:22802909

  3. Caveolin-1 in sarcomas: friend or foe?

    PubMed Central

    Sáinz-Jaspeado, Miguel; Martin-Liberal, Juan; Lagares-Tena, Laura; Mateo-Lozano, Silvia; del Muro, Xavier Garcia; Tirado, Oscar M

    2011-01-01

    Sarcomas represent a heterogeneous group of tumors with a complex and difficult reproducible classification. Their pathogenesis is poorly understood and there are few effective treatment options for advanced disease. Caveolin-1 is a multifunctional scaffolding protein with multiple binding partners that regulates multiple cancer-associated processes including cellular transformation, tumor growth, cell death and survival, multidrug resistance, angiogenesis, cell migration and metastasis. However, ambiguous roles have been ascribed to caveolin-1 in signal transduction and cancer, including sarcomas. In particular, evidence indicating that caveolin-1 function is cell context dependent has been repeatedly reported. Caveolin-1 appears to act as a tumor suppressor protein at early stages of cancer progression. In contrast, a growing body of evidence indicates that caveolin-1 is up-regulated in several multidrug-resistant and metastatic cancer cell lines and human tumor specimens. This review is focused on the role of caveolin-1 in several soft tissue and bone sarcomas and discusses the use of this protein as a potential diagnostic and prognostic marker and as a therapeutic target. PMID:21471610

  4. Direct Regulation of TLR5 Expression by Caveolin-1

    PubMed Central

    Lim, Jae Sung; Nguyen, Kim Cuc Thi; Han, Jung Min; Jang, Ik-Soon; Fabian, Claire; Cho, Kyung A

    2015-01-01

    Toll-like receptor 5 (TLR5) is a specific receptor for microbial flagellin and is one of the most well-known receptors in the TLR family. We reported previously that TLR5 signaling is well maintained during aging and that caveolin-1 may be involved in TLR5 signaling in aged macrophages through direct interactions. Therefore, it is important to clarify whether caveolin-1/TLR5 interactions affect TLR5 expression during aging. To assess the effect of caveolin-1 on TLR5, we analyzed TLR5 expression in senescent fibroblasts and aged tissues expressing high levels of caveolin-1. As expected, TLR5 mRNA and protein expression was well maintained in senescent fibroblasts and aged tissues, whereas TLR4 mRNA and protein were diminished in those cells and tissues. To determine the mechanism of caveolin-1-dependent TLR5 expression, we examined TLR5 expression in caveolin-1 deficient mice. Interestingly, TLR5 mRNA and protein levels were decreased dramatically in tissues from caveolin-1 knockout mice. Moreover, overexpressed caveolin-1 in vitro enhanced TLR5 mRNA through the MAPK pathway and prolonged TLR5 protein half-life through direct interaction. These results suggest that caveolin-1 may play a crucial role in maintaining of TLR5 by regulating transcription systems and increasing protein half-life. PMID:26615831

  5. Direct Regulation of TLR5 Expression by Caveolin-1.

    PubMed

    Lim, Jae Sung; Nguyen, Kim Cuc Thi; Han, Jung Min; Jang, Ik-Soon; Fabian, Claire; Cho, Kyung A

    2015-12-01

    Toll-like receptor 5 (TLR5) is a specific receptor for microbial flagellin and is one of the most well-known receptors in the TLR family. We reported previously that TLR5 signaling is well maintained during aging and that caveolin-1 may be involved in TLR5 signaling in aged macrophages through direct interactions. Therefore, it is important to clarify whether caveolin-1/TLR5 interactions affect TLR5 expression during aging. To assess the effect of caveolin-1 on TLR5, we analyzed TLR5 expression in senescent fibroblasts and aged tissues expressing high levels of caveolin-1. As expected, TLR5 mRNA and protein expression was well maintained in senescent fibroblasts and aged tissues, whereas TLR4 mRNA and protein were diminished in those cells and tissues. To determine the mechanism of caveolin-1-dependent TLR5 expression, we examined TLR5 expression in caveolin-1 deficient mice. Interestingly, TLR5 mRNA and protein levels were decreased dramatically in tissues from caveolin-1 knockout mice. Moreover, overexpressed caveolin-1 in vitro enhanced TLR5 mRNA through the MAPK pathway and prolonged TLR5 protein half-life through direct interaction. These results suggest that caveolin-1 may play a crucial role in maintaining of TLR5 by regulating transcription systems and increasing protein half-life. PMID:26615831

  6. Calcium regulates caveolin-1 expression at the transcriptional level

    SciTech Connect

    Yang, Xiao-Yan; Huang, Cheng-Cheng; Kan, Qi-Ming; Li, Yan; Liu, Dan; Zhang, Xue-Cheng; Sato, Toshinori; Yamagata, Sadako; Yamagata, Tatsuya

    2012-09-28

    Highlights: Black-Right-Pointing-Pointer Caveolin-1 expression is regulated by calcium signaling at the transcriptional level. Black-Right-Pointing-Pointer An inhibitor of or siRNA to L-type calcium channel suppressed caveolin-1 expression. Black-Right-Pointing-Pointer Cyclosporine A or an NFAT inhibitor markedly reduced caveolin-1 expression. Black-Right-Pointing-Pointer Caveolin-1 regulation by calcium signaling is observed in several mouse cell lines. -- Abstract: Caveolin-1, an indispensable component of caveolae serving as a transformation suppressor protein, is highly expressed in poorly metastatic mouse osteosarcoma FBJ-S1 cells while highly metastatic FBJ-LL cells express low levels of caveolin-1. Calcium concentration is higher in FBJ-S1 cells than in FBJ-LL cells; therefore, we investigated the possibility that calcium signaling positively regulates caveolin-1 in mouse FBJ-S1 cells. When cells were treated with the calcium channel blocker nifedipine, cyclosporin A (a calcineurin inhibitor), or INCA-6 (a nuclear factor of activated T-cells [NFAT] inhibitor), caveolin-1 expression at the mRNA and protein levels decreased. RNA silencing of voltage-dependent L-type calcium channel subunit alpha-1C resulted in suppression of caveolin-1 expression. This novel caveolin-1 regulation pathway was also identified in mouse NIH 3T3 cells and Lewis lung carcinoma cells. These results indicate that caveolin-1 is positively regulated at the transcriptional level through a novel calcium signaling pathway mediated by L-type calcium channel/Ca{sup 2+}/calcineurin/NFAT.

  7. Quantitative Proteomics of Caveolin-1-regulated Proteins

    PubMed Central

    Dávalos, Alberto; Fernández-Hernando, Carlos; Sowa, Grzegorz; Derakhshan, Behrad; Lin, Michelle I.; Lee, Ji Y.; Zhao, Hongyu; Luo, Ruiyan; Colangelo, Christopher; Sessa, William C.

    2010-01-01

    Caveolae are organelles abundant in the plasma membrane of many specialized cells including endothelial cells (ECs), epithelial cells, and adipocytes, and in these cells, caveolin-1 (Cav-1) is the major coat protein essential for the formation of caveolae. To identify proteins that require Cav-1 for stable incorporation into membrane raft domains, a quantitative proteomics analysis using isobaric tagging for relative and absolute quantification was performed on rafts isolated from wild-type and Cav-1-deficient mice. In three independent experiments, 117 proteins were consistently identified in membrane rafts with the largest differences in the levels of Cav-2 and in the caveola regulatory proteins Cavin-1 and Cavin-2. Because the lung is highly enriched in ECs, we validated and characterized the role of the newly described protein Cavin-1 in several cardiovascular tissues and in ECs. Cavin-1 was highly expressed in ECs lining blood vessels and in cultured ECs. Knockdown of Cavin-1 reduced the levels of Cav-1 and -2 and weakly influenced the formation of high molecular weight oligomers containing Cav-1 and -2. Cavin-1 silencing enhanced basal nitric oxide release from ECs but blocked proangiogenic phenotypes such as EC proliferation, migration, and morphogenesis in vitro. Thus, these data support an important role of Cavin-1 as a regulator of caveola function in ECs. PMID:20585024

  8. Role of caveolin-1 in the regulation of lipoprotein metabolism

    PubMed Central

    Frank, Philippe G.; Pavlides, Stephanos; Cheung, Michelle W.-C.; Daumer, Kristin; Lisanti, Michael P.

    2008-01-01

    Lipoprotein metabolism plays an important role in the development of several human diseases, including coronary artery disease and the metabolic syndrome. A good comprehension of the factors that regulate the metabolism of the various lipoproteins is therefore key to better understanding the variables associated with the development of these diseases. Among the players identified are regulators such as caveolins and caveolae. Caveolae are small plasma membrane invaginations that are observed in terminally differentiated cells. Their most important protein marker, caveolin-1, has been shown to play a key role in the regulation of several cellular signaling pathways and in the regulation of plasma lipoprotein metabolism. In the present paper, we have examined the role of caveolin-1 in lipoprotein metabolism using caveolin-1-deficient (Cav-1−/−) mice. Our data show that, while Cav-1−/− mice show increased plasma triglyceride levels, they also display reduced hepatic very low-density lipoprotein (VLDL) secretion. Additionally, we also found that a caveolin-1 deficiency is associated with an increase in high-density lipoprotein (HDL), and these HDL particles are enriched in cholesteryl ester in Cav-1−/− mice when compared with HDL obtained from wild-type mice. Finally, our data suggest that a caveolin-1 deficiency prevents the transcytosis of LDL across endothelial cells, and therefore, that caveolin-1 may be implicated in the regulation of plasma LDL levels. Taken together, our studies suggest that caveolin-1 plays an important role in the regulation of lipoprotein metabolism by controlling their plasma levels as well as their lipid composition. Thus caveolin-1 may also play an important role in the development of atherosclerosis. PMID:18508910

  9. The caveolin-1 connection to cell death and survival.

    PubMed

    Quest, A F G; Lobos-González, L; Nuñez, S; Sanhueza, C; Fernández, J-G; Aguirre, A; Rodríguez, D; Leyton, L; Torres, V

    2013-02-01

    Caveolins are a family of membrane proteins required for the formation of small plasma membrane invaginations called caveolae that are implicated in cellular trafficking processes. In addition to this structural role, these scaffolding proteins modulate numerous intracellular signaling pathways; often via direct interaction with specific binding partners. Caveolin-1 is particularly well-studied in this respect and has been attributed a large variety of functions. Thus, Caveolin-1 also represents the best-characterized isoform of this family with respect to its participation in cancer. Rather strikingly, available evidence indicates that Caveolin-1 belongs to a select group of proteins that function, depending on the cellular settings, both as tumor suppressor and promoter of cellular traits commonly associated with enhanced malignant behavior, such as metastasis and multi-drug resistance. The mechanisms underlying such ambiguity in Caveolin-1 function constitute an area of great interest. Here, we will focus on discussing how Caveolin-1 modulates cell death and survival pathways and how this may contribute to a better understanding of the ambiguous role this protein plays in cancer. PMID:23228128

  10. Caveolin-1 Associated Adenovirus Entry into Human Corneal Cells

    PubMed Central

    Mukherjee, Santanu; Chintakuntlawar, Ashish V.; Lee, Jeong Yoon; Ramke, Mirja; Chodosh, James; Rajaiya, Jaya

    2013-01-01

    The cellular entry of viruses represents a critical area of study, not only for viral tropism, but also because viral entry dictates the nature of the immune response elicited upon infection. Epidemic keratoconjunctivitis (EKC), caused by viruses within human adenovirus species D (HAdV-D), is a severe, ocular surface infection associated with corneal inflammation. Clathrin-mediated endocytosis has previously been shown to play a critical role in entry of other HAdV species into many host cell types. However, HAdV-D endocytosis into corneal cells has not been extensively studied. Herein, we show an essential role for cholesterol rich, lipid raft microdomains and caveolin-1, in the entry of HAdV-D37 into primary human corneal fibroblasts. Cholesterol depletion using methyl-β-cyclodextrin (MβCD) profoundly reduced viral infection. When replenished with soluble cholesterol, the effect of MβCD was reversed, allowing productive viral infection. HAdV-D37 DNA was identified in caveolin-1 rich endosomal fractions after infection. Src kinase activity was also increased in caveolin-1 rich endosomal fractions after infection, and Src phosphorylation and CXCL1 induction were both decreased in caveolin-1-/- mice corneas compared to wild type mice. siRNA knock down of caveolin-1 in corneal cells reduced chemokine induction upon viral infection, and caveolin-1-/- mouse corneas showed reduced cellular entry of HAdV-D37. As a control, HAdV-C2, a non-corneal pathogen, appeared to utilize the caveolar pathway for entry into A549 cells, but failed to infect corneal cells entirely, indicating virus and cell specific tropism. Immuno-electron microscopy confirmed the presence of caveolin-1 in HAdV-D37-containing vesicles during the earliest stages of viral entry. Collectively, these experiments indicate for the first time that HAdV-D37 uses a lipid raft mediated caveolin-1 associated pathway for entry into corneal cells, and connects the processes of viral entry with downstream

  11. Caveolin-1 and -2 in the Exocytic Pathway of MDCK Cells

    PubMed Central

    Scheiffele, P.; Verkade, P.; Fra, A.M.; Virta, H.; Simons, K.; Ikonen, E.

    1998-01-01

    Abstract. We have studied the biosynthesis and transport of the endogenous caveolins in MDCK cells. We show that in addition to homooligomers of caveolin-1, heterooligomeric complexes of caveolin-1 and -2 are formed in the ER. The oligomers become larger, increasingly detergent insoluble, and phosphorylated on caveolin-2 during transport to the cell surface. In the TGN caveolin-1/-2 heterooligomers are sorted into basolateral vesicles, whereas larger caveolin-1 homooligomers are targeted to the apical side. Caveolin-1 is present on both the apical and basolateral plasma membrane, whereas caveolin-2 is enriched on the basolateral surface where caveolae are present. This suggests that caveolin-1 and -2 heterooligomers are involved in caveolar biogenesis in the basolateral plasma membrane. Anti–caveolin-1 antibodies inhibit the apical delivery of influenza virus hemagglutinin without affecting basolateral transport of vesicular stomatitis virus G protein. Thus, we suggest that caveolin-1 homooligomers play a role in apical transport. PMID:9472032

  12. Overexpression of caveolin-1 is sufficient to phenocopy the behavior of a disease-associated mutant

    PubMed Central

    Hanson, Caroline A.; Drake, Kimberly R.; Baird, Michelle A.; Han, Bing; Kraft, Lewis J.; Davidson, Michael W.; Kenworthy, Anne K.

    2013-01-01

    Mutations and alterations in caveolin-1 expression levels have been linked to a number of human diseases. How misregulation of caveolin-1 contributes to disease is not fully understood, but has been proposed to involve the intracellular accumulation of mutant forms of the protein. To better understand the molecular basis for trafficking defects that trap caveolin-1 intracellularly, we compared the properties of a GFP-tagged version of caveolin-1 P132L, a mutant form of caveolin-1 previously linked to breast cancer, with wild type caveolin-1. Unexpectedly, wild type caveolin-1-GFP also accumulated intracellularly, leading us to examine the mechanisms underlying the abnormal localization of the wild type and mutant protein in more detail. We show that both the nature of the tag and cellular context impact the subcellular distribution of caveolin-1, demonstrate that even the wild type form of caveolin-1 can function as a dominant negative under some conditions, and identify specific conformation changes associated with incorrectly targeted forms of the protein. In addition, we find intracellular caveolin-1 is phosphorylated on Tyr14, but phosphorylation is not required for mistrafficking of the protein. These findings identify novel properties of mistargeted forms of caveolin-1 and raise the possibility that common trafficking defects underlie diseases associated with overexpression and mutations in caveolin-1. PMID:23469926

  13. Caveolin-1: an ambiguous partner in cell signalling and cancer

    PubMed Central

    Quest, Andrew F G; Gutierrez-Pajares, Jorge L; Torres, Vicente A

    2008-01-01

    Caveolae are small plasma membrane invaginations that have been implicated in a variety of functions including transcytosis, potocytosis and cholesterol transport and signal transduction. The major protein component of this compartment is a family of proteins called caveolins. Experimental data obtained in knockout mice have provided unequivocal evidence for a requirement of caveolins to generate morphologically detectable caveolae structures. However, expression of caveolins is not sufficient per seto assure the presence of these structures. With respect to other roles attributed to caveolins in the regulation of cellular function, insights are even less clear. Here we will consider, more specifically, the data concerning the ambiguous roles ascribed to caveolin-1 in signal transduction and cancer. In particular, evidence indicating that caveolin-1 function is cell context dependent will be discussed. PMID:18400052

  14. MicroRNA 802 stimulates ROMK channels by suppressing caveolin-1.

    PubMed

    Lin, Dao-Hong; Yue, Peng; Pan, Chunyang; Sun, Peng; Wang, Wen-Hui

    2011-06-01

    Dietary potassium stimulates the surface expression of ROMK channels in the aldosterone-sensitive distal nephron, but the mechanism by which this occurs is incompletely understood. Here, a high-potassium diet increased the transcription of microRNA (miR) 802 in the cortical collecting duct in mice. In addition, high-potassium intake decreased the expression of caveolin-1, whose 3' untranslated region contains the seed sequence of miR-802. In vitro, expression of miR-802 suppressed the expression of caveolin-1, and conversely, downregulation of endogenous miR-802 increased the expression of caveolin-1. Sucrose-gradient centrifugation suggested that caveolin-1 closely associated with ROMK channels, and immunoprecipitation showed that caveolin-1 interacted with the N terminus of ROMK. Expression of caveolin-1 varied inversely with the expression of ROMK1 in the plasma membrane, and caveolin-1 inhibited ROMK1 channel activity. Removal of the clathrin-dependent endocytosis motif from ROMK1 failed to abolish the effect of caveolin-1 on ROMK1 channel activity. Last, expression of miR-802 increased ROMK1 channel activity, an effect blocked by coexpression of caveolin-1. Taken together, miR-802 mediates the stimulatory effect of a high-potassium diet on ROMK channel activity by suppressing caveolin-1 expression, which leads to increased surface expression of ROMK channels in the distal nephron. PMID:21566059

  15. Kainic acid induces expression of caveolin-1 in activated microglia in rat brain.

    PubMed

    Takeuchi, Shigeko; Matsuda, Wakoto; Tooyama, Ikuo; Yasuhara, Osamu

    2013-01-01

    Caveolin-1, a major constituent of caveolae, has been implicated in endocytosis, signal transduction and cholesterol transport in a wide variety of cells. In the present study, the expression of caveolin-1 was examined by immunohistochemistry in rat brain with or without systemic injection of kainic acid (KA). Caveolin-1 immunoreactivity was observed in capillary walls in brains of control rats. From one to seven days after KA injection, caveolin-1 immunoreactivity appeared in activated microglia in the cerebral cortex, hippocampus and other brain regions. The strongest immunoreactivity of microglia was seen after 3 days after KA administration. The expression of caveolin-1 was confirmed by RT-PCR and Western blot analysis, respectively. The induction of caveolin-1 expression in microglia activated in response to kainic acid administration suggests its possible role in a modulation of inflammation. PMID:23690214

  16. Palmitoylation of caveolin-1 in endothelial cells is post-translational but irreversible

    NASA Technical Reports Server (NTRS)

    Parat, M. O.; Fox, P. L.

    2001-01-01

    Caveolin-1 is a palmitoylated protein involved in assembly of signaling molecules in plasma membrane subdomains termed caveolae and in intracellular cholesterol transport. Three cysteine residues in the C terminus of caveolin-1 are subject to palmitoylation, which is not necessary for caveolar targeting of caveolin-1. Protein palmitoylation is a post-translational and reversible modification that may be regulated and that in turn may regulate conformation, membrane association, protein-protein interactions, and intracellular localization of the target protein. We have undertaken a detailed analysis of [(3)H]palmitate incorporation into caveolin-1 in aortic endothelial cells. The linkage of palmitate to caveolin-1 was hydroxylamine-sensitive and thus presumably a thioester bond. However, contrary to expectations, palmitate incorporation was blocked completely by the protein synthesis inhibitors cycloheximide and puromycin. In parallel experiments to show specificity, palmitoylation of aortic endothelial cell-specific nitric-oxide synthase was unaffected by these reagents. Inhibitors of protein trafficking, brefeldin A and monensin, blocked caveolin-1 palmitoylation, indicating that the modification was not cotranslational but rather required caveolin-1 transport from the endoplasmic reticulum and Golgi to the plasma membrane. In addition, immunophilin chaperones that form complexes with caveolin-1, i.e. FK506-binding protein 52, cyclophilin A, and cyclophilin 40, were not necessary for caveolin-1 palmitoylation because agents that bind immunophilins did not inhibit palmitoylation. Pulse-chase experiments showed that caveolin-1 palmitoylation is essentially irreversible because the release of [(3)H]palmitate was not significant even after 24 h. These results show that [(3)H]palmitate incorporation is limited to newly synthesized caveolin-1, not because incorporation only occurs during synthesis but because the continuous presence of palmitate on caveolin-1 prevents

  17. Regulation of Phagolysosomal Digestion by Caveolin-1 of the Retinal Pigment Epithelium Is Essential for Vision.

    PubMed

    Sethna, Saumil; Chamakkala, Tess; Gu, Xiaowu; Thompson, Timothy C; Cao, Guangwen; Elliott, Michael H; Finnemann, Silvia C

    2016-03-18

    Caveolin-1 associates with the endo/lysosomal machinery of cells in culture, suggesting that it functions at these organelles independently of its contribution to cell surface caveolae. Here we explored mice lacking caveolin-1 specifically in the retinal pigment epithelium (RPE). The RPE supports neighboring photoreceptors via diurnal phagocytosis of spent photoreceptor outer segment fragments. Like mice lacking caveolin-1 globally, (RPE)CAV1(-/-) mice developed a normal RPE and neural retina but showed reduced rod photoreceptor light responses, indicating that lack of caveolin-1 affects photoreceptor function in a non-cell-autonomous manner. (RPE)CAV1(-/-) RPE in situ showed normal particle engulfment but delayed phagosome clearance and reversed diurnal profiles of levels and activities of lysosomal enzymes. Therefore, eliminating caveolin-1 specifically impairs phagolysosomal degradation by the RPE in vivo. Endogenous caveolin-1 was recruited to maturing phagolysosomes in RPE cells in culture. Consistent with these in vivo data, a moderate increase (to ∼ 2.5-fold) or decrease (by half) of caveolin-1 protein levels in RPE cells in culture was sufficient to accelerate or impair phagolysosomal digestion, respectively. A mutant form of caveolin-1 that fails to reach the cell surface augmented degradation like wild-type caveolin-1. Acidic lysosomal pH and increased protease activity are essential for digestion. We show that halving caveolin-1 protein levels significantly alkalinized lysosomal pH and decreased lysosomal enzyme activities. Taken together, our results reveal a novel role for intracellular caveolin-1 in modulating phagolysosomal function. Moreover, they show, for the first time, that organellar caveolin-1 significantly affects tissue functionality in vivo. PMID:26814131

  18. Caveolin-1 overexpression in benign and malignant salivary gland tumors.

    PubMed

    Jaafari-Ashkavandi, Zohreh; Ashraf, Mohammad Javad; Nazhvani, Ali Dehghani; Azizi, Zahra

    2016-02-01

    Caveolin-1, a tyrosine-phosphorylated protein, is supposed to have different regulatory roles as promoter or suppressor in many human cancers. However, no published study concerned its expression in benign and malignant salivary gland tumors. The aim of this study was to evaluate and compare the expression of Cav-1 in the most common benign and malignant salivary gland tumors and evaluate its correlation with proliferation activity. In this cross-sectional retrospective study, immunohistochemical expression of caveolin-1 and Ki67 were evaluated in 49 samples, including 11 normal salivary glands, 15 cases of pleomorphic adenoma (PA), 13 adenoid cystic carcinomas (AdCC), and 10 mucoepidermoid carcinomas (MEC). The expression of Cav-1 was seen in 18 % of normal salivary glands and 85 % of tumors. The immunoreaction in the tumors was significantly higher than normal tissues (P = 0.001), but the difference between benign and malignant tumors was not significant (P = 0.07). Expression of Cav-1 was correlated with Ki67 labeling index in PAs, but not in malignant tumors. Cav-1 expression was not in association with tumor size and stage. Overexpression of Cav-1 was found in salivary gland tumors in comparison with normal tissues, but no significant difference was observed between benign and malignant tumors. Cav-1 was inversely correlated with proliferation in PA. Therefore, this marker may participate in tumorigenesis of salivary gland tumors and may be a potential biomarker for cancer treatments. PMID:26323261

  19. The membrane-spanning domains of caveolins-1 and -2 mediate the formation of caveolin hetero-oligomers. Implications for the assembly of caveolae membranes in vivo.

    PubMed

    Das, K; Lewis, R Y; Scherer, P E; Lisanti, M P

    1999-06-25

    The mammalian caveolin gene family consists of caveolins-1, -2, and -3. The expression of caveolin-3 is muscle-specific. In contrast, caveolins-1 and -2 are co-expressed, and they form a hetero-oligomeric complex in many cell types, with particularly high levels in adipocytes, endothelial cells, and fibroblasts. These caveolin hetero-oligomers are thought to represent the functional assembly units that drive caveolae formation in vivo. Here, we investigate the mechanism by which caveolins-1 and -2 form hetero-oligomers. We reconstituted this reciprocal interaction in vivo and in vitro using a variety of complementary approaches, including the generation of glutathione S-transferase fusion proteins and synthetic peptides. Taken together, our results indicate that the membrane-spanning domains of both caveolins-1 and -2 play a critical role in mediating their ability to interact with each other. This is the first demonstration that these unusual membrane-spanning regions found in the caveolin family play a specific role in protein-protein interactions. PMID:10373486

  20. Caveolae and Caveolin-1 Integrate Reverse Cholesterol Transport and Inflammation in Atherosclerosis

    PubMed Central

    Qin, Li; Zhu, Neng; Ao, Bao-Xue; Liu, Chan; Shi, Ya-Ning; Du, Ke; Chen, Jian-Xiong; Zheng, Xi-Long; Liao, Duan-Fang

    2016-01-01

    Lipid disorder and inflammation play critical roles in the development of atherosclerosis. Reverse cholesterol transport is a key event in lipid metabolism. Caveolae and caveolin-1 are in the center stage of cholesterol transportation and inflammation in macrophages. Here, we propose that reverse cholesterol transport and inflammation in atherosclerosis can be integrated by caveolae and caveolin-1. PMID:27011179

  1. Caveolin-1 as a Novel Indicator of Wound-Healing Capacity in Aged Human Corneal Epithelium

    PubMed Central

    Rhim, Ji Heon; Kim, Jae Hoon; Yeo, Eui-Ju; Kim, Jae Chan; Park, Sang Chul

    2010-01-01

    Excess caveolin-1 has been reported to play a role in age-dependent hyporesponsiveness to growth factors in vitro. Therefore, we hypothesized that caveolin-1–dependent hyporesponsiveness to growth factors in aged corneal epithelial cells might be responsible for delayed wound healing in vivo. To test this hypothesis, we evaluated corneal wound-healing time by vital staining using fluorescein after laser epithelial keratomileusis (LASEK). We compared wound-healing times in young, middle-aged and elderly patients. We also examined caveolin-1 levels and other aging markers, such as p53 and p21, in the corneal epithelium. Elderly patients generally had higher caveolin-1 levels in the corneal epithelia than young patients. There were, however, variations among individuals with increased caveolin-1 in some young patients and decreased levels in some elderly patients. Wound-healing time after LASEK correlated well with the corneal caveolin-1 status. Therefore, we suggest that caveolin-1 status might be responsible for delayed wound healing in elderly patients after LASEK. Caveolin-1 status might be a regulator for wound-healing capacity and a novel target for in vivo adjustment. PMID:20644900

  2. Caveolin-1 modulates the activity of the volume-regulated chloride channel

    PubMed Central

    Trouet, Dominique; Nilius, Bernd; Jacobs, Axel; Remacle, Claude; Droogmans, Guy; Eggermont, Jan

    1999-01-01

    Caveolae are small invaginations of the plasma membrane that have recently been implicated in signal transduction. In the present study, we have investigated whether caveolins, the principal protein of caveolae, also modulate volume-regulated anion channels (VRACs). ICl,swell, the cell swelling-induced chloride current through VRACs, was studied in three caveolin-1-deficient cell lines: Caco-2, MCF-7 and T47D. Electrophysiological measurements showed that ICl,swell was very small in these cells and that transient expression of caveolin-1 restored ICl,swell. The caveolin-1 effect was isoform specific: caveolin-1β but not caveolin-1α upregulated VRACs. This correlated with a different subcellular distribution of caveolin-1α (perinuclear location) from caveolin-1β (perinuclear and peripheral). To explain the modulation of ICl,swell by caveolin-1 we propose that caveolin increases the availability of VRACs in the plasma membrane or, alternatively, that it plays a crucial role in the signal transduction cascade of VRACs. PMID:10517805

  3. Spatiotemporal expression of caveolin-1 and EMMPRIN during mouse tooth development.

    PubMed

    Shi, Lu; Li, Lingyun; Wang, Ding; Li, Shu; Chen, Zhi; An, Zhengwen

    2016-06-01

    Caveolin-1 is a scaffolding protein involved in the formation of cholesterol-rich caveolae lipid rafts within the plasma membrane and is capable of collecting signaling molecules into the caveolae and regulating their activity, including extracellular matrix metalloproteinase inducer (EMMPRIN). However, detailed expression patterns of caveolin-1 and EMMPRIN in the developing dental germ are largely unknown. The present study investigated the expression patterns of caveolin-1 and EMMPRIN in the developing mouse tooth germ by immunohistochemistry and real-time polymerase chain reaction. At the bud stage, caveolin-1 expression was initiated in the epithelium bud and mesenchymal cells, while EMMPRIN was weakly expressed at this stage. At the cap stage, caveolin-1 protein was located in the lingual part of the tooth germ; however, EMMPRIN protein was located in the labial part. From the bell stage to 2 days postnatal, caveolin-1 expression was detected in the ameloblasts and cervical loop area; with EMMPRIN expression in the ameloblasts and odontoblasts. Real-time polymerase chain reaction results showed that both caveolin-1 and EMMPRIN mRNA levels increased gradually with progression of developmental stages, and peaked at day two postnatal. The current finding suggests that both caveolin-1 and EMMPRIN take part in mouse tooth development, especially in the differentiation and organization of odontogenic tissues. PMID:27075451

  4. Caveolin-1, a stress-related oncotarget, in drug resistance

    PubMed Central

    Wang, Zhiyu; Wang, Neng; Liu, Pengxi; Peng, Fu; Tang, Hailin; Chen, Qianjun; Xu, Rui; Dai, Yan; Lin, Yi; Xie, Xiaoming; Peng, Cheng; Situ, Honglin

    2015-01-01

    Caveolin-1 (Cav-1) is both a tumor suppressor and an oncoprotein. Cav-1 overexpression was frequently confirmed in advanced cancer stages and positively associated with ABC transporters, cancer stem cell populations, aerobic glycolysis activity and autophagy. Cav-1 was tied to various stresses including radiotherapy, fluid shear and oxidative stresses and ultraviolet exposure, and interacted with stress signals such as AMP-activated protein kinase. Finally, a Cav-1 fluctuation model during cancer development is provided and Cav-1 is suggested to be a stress signal and cytoprotective. Loss of Cav-1 may increase susceptibility to oncogenic events. However, research to explore the underlying molecular network between Cav-1 and stress signals is warranted. PMID:26431273

  5. Nanoscale Imaging of Caveolin-1 Membrane Domains In Vivo

    PubMed Central

    Gabor, Kristin A.; Kim, Dahan; Kim, Carol H.; Hess, Samuel T.

    2015-01-01

    Light microscopy enables noninvasive imaging of fluorescent species in biological specimens, but resolution is generally limited by diffraction to ~200–250 nm. Many biological processes occur on smaller length scales, highlighting the importance of techniques that can image below the diffraction limit and provide valuable single-molecule information. In recent years, imaging techniques have been developed which can achieve resolution below the diffraction limit. Utilizing one such technique, fluorescence photoactivation localization microscopy (FPALM), we demonstrated its ability to construct super-resolution images from single molecules in a living zebrafish embryo, expanding the realm of previous super-resolution imaging to a living vertebrate organism. We imaged caveolin-1 in vivo, in living zebrafish embryos. Our results demonstrate the successful image acquisition of super-resolution images in a living vertebrate organism, opening several opportunities to answer more dynamic biological questions in vivo at the previously inaccessible nanoscale. PMID:25646724

  6. Caveolin-1 is involved in reactive oxygen species-induced SHP-2 activation in astrocytes

    PubMed Central

    Yun, Ji Hee; Park, Soo Jung; Jo, Ara; Jou, Ilo; Park, Jung Soo

    2011-01-01

    Recent evidence supports a neuroprotective role of Src homology 2-containing protein tyrosine phosphatase 2 (SHP-2) against ischemic brain injury. However, the molecular mechanisms of SHP-2 activation and those governing how SHP-2 exerts its function under oxidative stress conditions are not well understood. Recently we have reported that reactive oxygen species (ROS)-mediated oxidative stress promotes the phosphorylation of endogenous SHP-2 through lipid rafts, and that this phosphorylation strongly occurs in astrocytes, but not in microglia. To investigate the molecules involved in events leading to phosphorylation of SHP-2, raft proteins were analyzed using astrocytes and microglia. Interestingly, caveolin-1 and -2 were detected only in astrocytes but not in microglia, whereas flotillin-1 was expressed in both cell types. To examine whether the H2O2-dependent phosphorylation of SHP-2 is mediated by caveolin-1, we used specific small interfering RNA (siRNA) to downregulate caveolin-1 expression. In the presence of caveolin-1 siRNA, the level of SHP-2 phosphorylation induced by H2O2 was significantly decreased, compared with in the presence of control siRNA. Overexpression of caveolin-1 effectively increased H2O2-induced SHP-2 phosphorylation in microglia. Lastly, H2O2 induced extracellular signal-regulated kinase (ERK) activation in astrocytes through caveolin-1. Our results suggest that caveolin-1 is involved in astrocyte-specific intracellular responses linked to the SHP-2-mediated signaling cascade following ROS-induced oxidative stress. PMID:21918362

  7. Divergent expression and roles for caveolin-1 in mouse hepatocarcinoma cell lines with varying invasive ability

    SciTech Connect

    Zhou Huimin; Jia Li; Wang Shujing; Wang Hongmei; Chu Haiying; Hu Yichuan; Cao Jun; Zhang Jianing . E-mail: jnzhang@dlmedu.edu.cn

    2006-06-23

    Caveolin-1 is the major component protein of caveolae and associated with a lot of cellular events such as endocytosis, cholesterol homeostasis, signal transduction, and tumorigenesis. The majority of results suggest that caveolin-1 might not only act as a tumor suppressor gene but also a promoting metastasis gene. In this study, the divergent expression and roles of caveolin-1 were investigated in mouse hepatocarcinoma cell lines Hca-F, Hca-P, and Hepa1-6, which have high, low, and no metastatic potential in the lymph nodes, as compared with normal mouse liver cell line IAR-20. The results showed that expression of caveolin-1 mRNA and protein along with the amount of caveolae number in Hca-F cells was higher than that in Hca-P cells, but was not detectable in Hepa1-6 cells. When caveolin-1 expression in Hca-F cells was down-regulated by RNAi approach, Hca-F cells proliferation rate in vitro declined and the expression of lymphangiogenic factor VEGFA in Hca-F decreased as well. Furthermore, in vivo implantation assay indicated that reduction of caveolin-1 expression in Hca-F prevented the lymphatic metastasis tumor burden of Hca-F cells in 615 mice. These results suggest that caveolin-1 facilities the lymphatic metastasis ability of mouse hepatocarcinoma cells via regulation tumor cell growth and VEGFA expression.

  8. Caveolin-1 regulates expression of junction-associated proteins in brain microvascular endothelial cells

    PubMed Central

    Song, Li; Ge, Shujun; Pachter, Joel S.

    2007-01-01

    Recent evidence from this laboratory indicated that reduced expression of caveolin-1 accompanied the diminished expression of tight junction (TJ)–associated proteins occludin and zonula occludens-1 (ZO-1) following stimulation of brain microvascular endothelial cells (BMECs) with the chemokine CCL2 (formerly called MCP-1). Because attenuated caveolin-1 levels have also been correlated with heightened permeability of other endothelia, the objective of this study was to test the hypothesis that reduced caveolin-1 expression is causally linked to the action of CCL2 on BMEC junctional protein expression and barrier integrity. This was achieved using adenovirus to nondestructively deliver caveolin-1 siRNA (Ad-siCav-1) to BMEC monolayers, which model the blood-brain barrier (BBB). Treatment with siRNA reduced the caveolin-1 protein level as well as occludin and ZO-1. Additionally, occludin exhibited dissociation from the cytoskeletal framework. These changes were attended by comparable alterations in adherens junction (AJ)–associated proteins, VE-cadherin and β-catenin, increased BMEC paracellular permeability, and facilitated the ability of CCL2 to stimulate monocytic transendothelial migration. Furthermore, treating BMECs with cavtratin, a synthetic cell-permeable peptide encoding the caveolin-1 scaffolding domain, antagonized effects of both Ad-siCav-1 and CCL2. These results collectively highlight caveolin-1 loss as a critical step in CCL2-induced modulation of BMEC junctional protein expression and integrity, and possibly serve a crucial role in regulating inflammation at the BBB. PMID:17023578

  9. Soy protein isolate down-regulates caveolin-1 expression to suppress osteoblastic cell senescence pathways.

    PubMed

    Zhang, Jian; Lazarenko, Oxana P; Blackburn, Michael L; Badger, Thomas M; Ronis, Martin J J; Chen, Jin-Ran

    2014-07-01

    It has been suggested that the beneficial effects of soy protein isolate (SPI) on bone quality are due to either stimulation of estrogenic signaling via isoflavones or through a novel and as yet uncharacterized nonestrogenic pathway. In our study, SPI-fed rat serum inhibited the osteoblastic cell senescence pathway. This effect was accompanied by stimulation of cell differentiation, proliferation, and significant restoration of replicative senescent bone marrow mesenchymal ST2 cells (passaged 30 times). These effects were reproduced in bone from 5-wk-old intact and 10-wk-old ovariectomized female rats fed SPI diets. Caveolin-1 and p53 expression was decreased in bone in SPI-fed, but not in 17β-estradiol (E2)-treated rats. In cell culture studies, membranous caveolin-1 and nuclear p53 expression was greater in replicative senescent ST2 cell cultures than in earlier passaged cells. SPI-fed rat serum significantly down-regulated both caveolin-1 and p53 in senescent and nonsenescent cells. Replicative senescent ST2 cells exhibited a strong association among caveolin-1, p53, and mouse double minute 2 homologue (mdm2), which was inhibited by SPI-fed rat serum. Overexpression of caveolin-1 in ST2 cells resulted in increased expression of p53 and p21, whereas, knockdown of caveolin-1 using shRNA led to increases in mdm2 and eliminated SPI-fed rat serum's effects on p53 and p21 expression. In contrast, manipulation of caveolin-1 expression did not affect the actions of E2 or isoflavones on p53 expression in either ST2 or OB6 cells. These results suggest that caveolin-1 is a mediator of nonestrogenic SPI effects on bone cells.-Zhang, J., Lazarenko, O. P., Blackburn, M. L., Badger, T. M., Ronis, M. J. J., Chen, J.-R. Soy protein isolate down-regulates caveolin-1 expression to suppress osteoblastic cell senescence pathways. PMID:24719353

  10. Oxidative stress inhibits caveolin-1 palmitoylation and trafficking in endothelial cells

    NASA Technical Reports Server (NTRS)

    Parat, Marie-Odile; Stachowicz, Rafal Z.; Fox, Paul L.

    2002-01-01

    During normal and pathological conditions, endothelial cells (ECs) are subjected to locally generated reactive oxygen species, produced by themselves or by other vessel wall cells. In excess these molecules cause oxidative injury to the cell but at moderate levels they might modulate intracellular signalling pathways. We have investigated the effect of oxidative stress on the palmitoylation and trafficking of caveolin-1 in bovine aortic ECs. Exogenous H2O2 did not alter the intracellular localization of caveolin-1 in ECs. However, metabolic labelling experiments showed that H2O2 inhibited the trafficking of newly synthesized caveolin-1 to membrane raft domains. Several mechanisms potentially responsible for this inhibition were examined. Impairment of caveolin-1 synthesis by H2O2 was not responsible for diminished trafficking. Similarly, the inhibition was independent of H2O2-induced caveolin-1 phosphorylation as shown by the markedly different concentration dependences. We tested the effect of H2O2 on palmitoylation of caveolin-1 by the incorporation of [3H]palmitic acid. Exposure of ECs to H2O2 markedly inhibited the palmitoylation of caveolin-1. Comparable inhibition was observed after treatment of cells with H2O2 delivered either as a bolus or by continuous delivery with glucose and glucose oxidase. Kinetic studies showed that H2O2 did not alter the rate of caveolin-1 depalmitoylation but instead decreased the 'on-rate' of palmitoylation. Together these results show for the first time the modulation of protein palmitoylation by oxidative stress, and suggest a cellular mechanism by which stress might influence caveolin-1-dependent cell activities such as the concentration of signalling proteins and cholesterol trafficking.

  11. Temozolomide Modifies Caveolin-1 Expression in Experimental Malignant Gliomas In Vitro and In Vivo1

    PubMed Central

    Bruyère, Céline; Abeloos, Laurence; Lamoral-Theys, Delphine; Senetta, Rebecca; Mathieu, Véronique; Le Mercier, Marie; Kast, Richard E; Cassoni, Paola; Vandenbussche, Guy; Kiss, Robert; Lefranc, Florence

    2011-01-01

    BACKGROUND: Caveolin-1 is a protein that displays promotive versus preventive roles in cancer progression according to circumstances. Temozolomide (TMZ) is the standard chemotherapeutic to treat glioma patients. The present work aims to characterizeTMZ-induced effects on caveolin-1 expression in glioma cells. METHODS: Human astroglioma (U373 and T98G) and oligodendroglioma (Hs683) cell lines were used in vitro as well as in vivo orthotopic xenografts (Hs683 and U373) into the brains of immunocompromisedmice. In vitro TMZ-induced effects on protein expression and cellular localization were determined by Western blot analysis and on the actin cytoskeleton organization by means of immunofluorescence approaches. In vivo TMZ-induced effects in caveolin-1 expression in human glioma xenografts were monitored by means of immunohistochemistry. RESULTS: TMZ modified caveolin-1 expression and localization in vitro and in vivo after an administration schedule that slightly, if at all, impaired cell growth characteristics in vitro. Caveolin-1 by itself (at a 100-ng/ml concentration) was able to significantly reduce invasiveness (Boyden chambers) of the three human glioma cell lines. The TMZ-inducedmodification in caveolin-1 expression in flotation/raft compartments was paralleled by altered Cyr61 and β1 integrin expression, two elements that have already been reported to collaborate with caveolin-1 in regulating glioma cell biology, and all these features led to profound reorganization of the actin cytoskeleton. An experimental Src kinase inhibitor, AZD0530, almost completely antagonized the TMZ-induced modulation in caveolin-1 expression. CONCLUSION: TMZ modifies caveolin-1 expression in vitro and in vivo in glioma cells, a feature that directly affects glioma cell migration properties. PMID:21461172

  12. siRNA-induced caveolin-1 knockdown in mice increases lung vascular permeability via the junctional pathway.

    PubMed

    Miyawaki-Shimizu, Kayo; Predescu, Dan; Shimizu, Jun; Broman, Michael; Predescu, Sanda; Malik, Asrar B

    2006-02-01

    Caveolin-1, the principal integral membrane protein of caveolae, has been implicated in regulating the structural integrity of caveolae, vesicular trafficking, and signal transduction. Although the functions of caveolin-1 are beginning to be explored in caveolin-1-/- mice, these results are confounded by unknown compensatory mechanisms and the development of pulmonary hypertension, cardiomyopathy, and lung fibrosis. To address the role of caveolin-1 in regulating lung vascular permeability, in the present study we used small interfering RNA (siRNA) to knock down caveolin-1 expression in mouse lung endothelia in vivo. Intravenous injection of siRNA against caveolin-1 mRNA incorporated in liposomes selectively reduced the expression of caveolin-1 by approximately 90% within 96 h of injection compared with wild-type mice. We observed the concomitant disappearance of caveolae in lung vessel endothelia and dilated interendothelial junctions (IEJs) as well as increased lung vascular permeability to albumin via IEJs. The reduced caveolin-1 expression also resulted in increased plasma nitric oxide concentration. The nitric oxide synthase inhibitor L-NAME, in part, blocked the increased vascular albumin permeability. These morphological and functional effects of caveolin-1 knockdown were reversible within 168 h after siRNA injection, corresponding to the restoration of caveolin-1 expression. Thus our results demonstrate the essential requirement of caveolin-1 in mediating the formation of caveolae in endothelial cells in vivo and in negatively regulating IEJ permeability. PMID:16183667

  13. Loss of Caveolin 1 is Associated With the Expression of Aquaporin 1 and Bladder Dysfunction in Mice

    PubMed Central

    Jung, Seheon; Kim, Sun-Ouck; Cho, Kyung-Aa; Song, Seung Hee; Kang, Teak Won; Park, Kwangsung; Kwon, Dongdeuk

    2015-01-01

    Purpose: It is suggested that caveolin and aquaporin might be closely associated with bladder signal activity. We investigated the effect of the deletion of caveolin 1, using caveolin 1 knockout mice, on the expression of aquaporin 1 in order to identify their relation in the urothelium of the urinary bladder. Methods: The cellular localization and expressions of aquaporin 1 and caveolin 1, in the wild type and caveolin 1 knockout mice urinary bladder, were examined by Western blot and immunofluorescence techniques. Results: Aquaporin 1 and caveolin 1 were coexpressed in the arterioles, venules, and capillaries of the suburothelial layer in the wild type controls. Aquaporin 1 protein expression was significantly higher in the caveolin 1 knockout mice than in the wild type controls (P <0.05). Conclusions: The results imply that aquaporin 1 and caveolin 1 may share a distinct relation with the bladder signal activity. This might play a specific role in bladder dysfunction. PMID:25833479

  14. Telmisartan regresses left ventricular hypertrophy in caveolin-1 deficient mice

    PubMed Central

    Kreiger, Marta H; Di Lorenzo, Annarita; Teutsch, Christine; Kauser, Katalin; Sessa, William C.

    2011-01-01

    The role of angiotensin II (Ang II) in promoting cardiac hypertrophy is well known, however the role of the Ang II in a spontaneous model of hypertrophy in mice lacking the protein caveolin-1 (Cav- KO) has not been explored. In this study, WT and Cav-1 KO mice were treated with angiotensin receptor blocker (ARB), telmisartan, and cardiac function assessed by echocardiography. Treatment of Cav-1 KO mice with telmisartan significantly improved cardiac function compared to age-matched, vehicle treated Cav-1 KO mice, while telmisartan did not affected cardiac function in WT mice. Both left ventricular (LV) weight to body weight ratios and LV to tibial length ratios were also reverted by telmisartan in Cav-1 KO but not WT mice. LV hypertrophy was associated with increased expression of natriuretic peptides-A and –B, β-myosin heavy chain and TGF-β and telmisartan treatment normalized the expression of these genes. Telmisartan reduced the expression of collagen genes (Col1A and Col3A) and associated perivascular fibrosis in intramyocardial vessels in Cav-1 KO mice. In conclusion, telmisartan treatment reduces indexes of cardiac hypertrophy in this unique genetic model of spontaneous LV hypertrophy. PMID:20585312

  15. Telmisartan regresses left ventricular hypertrophy in caveolin-1-deficient mice.

    PubMed

    Krieger, Marta H; Di Lorenzo, Annarita; Teutsch, Christine; Kauser, Katalin; Sessa, William C

    2010-11-01

    The role of angiotensin II (Ang II) in promoting cardiac hypertrophy is well known; however, its role in a spontaneous model of hypertrophy in mice lacking the protein caveolin-1 (Cav-1 KO) has not been explored. In this study, WT and Cav-1 KO mice were treated with angiotensin receptor blocker (ARB), telmisartan (Telm), and cardiac function was assessed by echocardiography. Treatment of Cav-1 KO mice with Telm significantly improved cardiac function compared with age-matched vehicle-treated Cav-1 KO mice, whereas Telm did not affect cardiac function in WT mice. Both left ventricular (LV) weight to body weight ratios and LV to tibial length ratios were also reverted by Telm in Cav-1 KO but not in WT mice. LV hypertrophy was associated with increased expression of natriuretic peptides A and B, β-myosin heavy chain and TGF-β, and Telm treatment normalized the expression of these genes. Telm reduced the expression of collagen genes (Col1A and Col3A) and associated perivascular fibrosis in intramyocardial vessels in Cav-1 KO mice. In conclusion, Telm treatment reduces indexes of cardiac hypertrophy in this unique genetic model of spontaneous LV hypertrophy. PMID:20585312

  16. Tagging Strategies Strongly Affect the Fate of Overexpressed Caveolin-1

    PubMed Central

    Han, Bing; Tiwari, Ajit; Kenworthy, Anne K

    2015-01-01

    Caveolin-1 (Cav1) is the primary scaffolding protein of caveolae, flask-shaped invaginations of the plasma membrane thought to function in endocytosis, mechanotransduction, signaling and lipid homeostasis. A significant amount of our current knowledge about caveolins and caveolae is derived from studies of transiently overexpressed, C-terminally tagged caveolin proteins. However, how different tags affect the behavior of ectopically expressed Cav1 is still largely unknown. To address this question, we performed a comparative analysis of the subcellular distribution, oligomerization state and detergent resistance of transiently overexpressed Cav1 labeled with three different C-terminal tags (EGFP, mCherry and myc). We show that addition of fluorescent protein tags enhances the aggregation and/or degradation of both wild-type Cav1 and an oligomerization defective P132L mutant. Strikingly, complexes formed by overexpressed Cav1 fusion proteins excluded endogenous Cav1 and Cav2, and the properties of native caveolins were largely preserved even when abnormal aggregates were present in cells. These findings suggest that differences in tagging strategies may be a source of variation in previously published studies of Cav1 and that overexpressed Cav1 may exert functional effects outside of caveolae. They also highlight the need for a critical re-evaluation of current knowledge based on transient overexpression of tagged Cav1. PMID:25639341

  17. HIV Infection Upregulates Caveolin 1 Expression To Restrict Virus Production▿

    PubMed Central

    Lin, Shanshan; Wang, Xiao Mei; Nadeau, Peter E.; Mergia, Ayalew

    2010-01-01

    Caveolin 1 (Cav-1) is a major protein of a specific membrane lipid raft known as caveolae. Cav-1 interacts with the gp41 of the human immunodeficiency virus (HIV) envelope, but the role of Cav-1 in HIV replication and pathogenesis is not known. In this report, we demonstrate that HIV infection in primary human monocyte-derived macrophages (MDMs), THP-1 macrophages, and U87-CD4 cells results in a dramatic upregulation of Cav-1 expression mediated by HIV Tat. The activity of p53 is essential for Tat-induced Cav-1 expression, as our findings show enhanced phosphorylation of serine residues at amino acid positions 15 and 46 in the presence of Tat with a resulting Cav-1 upregulation. Furthermore, inhibition of p38 mitogen-activated protein kinase (MAPK) blocked phosphorylation of p53 in the presence of Tat. Infection studies of Cav-1-overexpressing cells reveal a significant reduction of HIV production. Taken together, these results suggest that HIV infection enhances the expression of Cav-1, which subsequently causes virus reduction, suggesting that Cav-1 may contribute to persistent infection in macrophages. PMID:20610713

  18. Altered Arachidonate Distribution in Macrophages from Caveolin-1 Null Mice Leading to Reduced Eicosanoid Synthesis*

    PubMed Central

    Astudillo, Alma M.; Pérez-Chacón, Gema; Meana, Clara; Balgoma, David; Pol, Albert; del Pozo, Miguel A.; Balboa, María A.; Balsinde, Jesús

    2011-01-01

    In this work we have studied the effect of caveolin-1 deficiency on the mechanisms that regulate free arachidonic acid (AA) availability. The results presented here demonstrate that macrophages from caveolin-1-deficient mice exhibit elevated fatty acid incorporation and remodeling and a constitutively increased CoA-independent transacylase activity. Mass spectrometry-based lipidomic analyses reveal stable alterations in the profile of AA distribution among phospholipids, manifested by reduced levels of AA in choline glycerophospholipids but elevated levels in ethanolamine glycerophospholipids and phosphatidylinositol. Furthermore, macrophages from caveolin-1 null mice show decreased AA mobilization and prostaglandin E2 and LTB4 production upon cell stimulation. Collectively, these results provide insight into the role of caveolin-1 in AA homeostasis and suggest an important role for this protein in the eicosanoid biosynthetic response. PMID:21852231

  19. Interleukin-1β induces the upregulation of caveolin-1 expression in a rat brain tumor model

    PubMed Central

    QIN, LI-JUAN; JIA, YONG-SEN; ZHANG, YI-BING; WANG, YIN-HUAN

    2016-01-01

    The aim of the present study was to investigate the expression of caveolin-1 in rat brain glioma tissue, and to determine whether interleukin-1β (IL-1β) has a role in this process. Using glioma cells, a tumor-burdened rat model was established, and the expression of caveolin-1 protein in the tumor sites was significantly increased following intracarotid infusion of IL-1β (3.7 ng/kg/min), as indicated by western blot analysis. The maximum value of the caveolin-1 expression was observed in tumor-burdened rats after 60 min of IL-1β perfusion, and which was significantly enhanced by vascular endothelial growth factor (VEGF). In addition, VEGF also significantly increased IL-1β-induced blood tumor barrier (BTB) permeability. The results suggest that the IL-1β-induced BTB permeability increase may be associated with the expression of caveolin-1 protein, and VEGF may be involved in this process. PMID:27073627

  20. Caveolin-1 regulates shear stress-dependent activation of extracellular signal-regulated kinase

    NASA Technical Reports Server (NTRS)

    Park, H.; Go, Y. M.; Darji, R.; Choi, J. W.; Lisanti, M. P.; Maland, M. C.; Jo, H.

    2000-01-01

    Fluid shear stress activates a member of the mitogen-activated protein (MAP) kinase family, extracellular signal-regulated kinase (ERK), by mechanisms dependent on cholesterol in the plasma membrane in bovine aortic endothelial cells (BAEC). Caveolae are microdomains of the plasma membrane that are enriched with cholesterol, caveolin, and signaling molecules. We hypothesized that caveolin-1 regulates shear activation of ERK. Because caveolin-1 is not exposed to the outside, cells were minimally permeabilized by Triton X-100 (0.01%) to deliver a neutralizing, polyclonal caveolin-1 antibody (pCav-1) inside the cells. pCav-1 then bound to caveolin-1 and inhibited shear activation of ERK but not c-Jun NH(2)-terminal kinase. Epitope mapping studies showed that pCav-1 binds to caveolin-1 at two regions (residues 1-21 and 61-101). When the recombinant proteins containing the epitopes fused to glutathione-S-transferase (GST-Cav(1-21) or GST-Cav(61-101)) were preincubated with pCav-1, only GST-Cav(61-101) reversed the inhibitory effect of the antibody on shear activation of ERK. Other antibodies, including m2234, which binds to caveolin-1 residues 1-21, had no effect on shear activation of ERK. Caveolin-1 residues 61-101 contain the scaffolding and oligomerization domains, suggesting that binding of pCav-1 to these regions likely disrupts the clustering of caveolin-1 or its interaction with signaling molecules involved in the shear-sensitive ERK pathway. We suggest that caveolae-like domains play a critical role in the mechanosensing and/or mechanosignal transduction of the ERK pathway.

  1. Dexamethasone induces caveolin-1 in vascular endothelial cells: implications for attenuated responses to VEGF.

    PubMed

    Igarashi, Junsuke; Hashimoto, Takeshi; Shoji, Kazuyo; Yoneda, Kozo; Tsukamoto, Ikuko; Moriue, Tetsuya; Kubota, Yasuo; Kosaka, Hiroaki

    2013-04-15

    Steroids exert direct actions on cardiovascular cells, although underlying molecular mechanisms remain incompletely understood. We examined if steroids modulate abundance of caveolin-1, a regulatory protein of cell-surface receptor pathways that regulates the magnitudes of endothelial response to vascular endothelial growth factor (VEGF). Dexamethasone, a synthetic glucocorticoid, induces caveolin-1 at both levels of protein and mRNA in a time- and dose-dependent manner in pharmacologically relevant concentrations in cultured bovine aortic endothelial cells. Aldosterone, a mineralocorticoid, but not the sex steroids 17β-estradiol, testosterone, or progesterone, elicits similar caveolin-1 induction. Caveolin-1 induction by dexamethasone and that by aldosterone were abrogated by RU-486, an inhibitor of glucocorticoid receptor, and by spironolactone, a mineralocorticoid receptor inhibitor, respectively. Dexamethasone attenuates VEGF-induced responses at the levels of protein kinases Akt and ERK1/2, small-G protein Rac1, nitric oxide production, and migration. When induction of caveolin-1 by dexamethasone is attenuated either by genetically by transient transfection with small interfering RNA or pharmacologically by RU-486, kinase responses to VEGF are rescued. Dexamethasone also increases expression of caveolin-1 protein in cultured human umbilical vein endothelial cells, associated with attenuated tube formation responses of these cells when cocultured with normal fibroblasts. Immunohistochemical analyses revealed that intraperitoneal injection of dexamethasone induces endothelial caveolin-1 protein in thoracic aorta and in lung artery in healthy male rats. Thus steroids functionally attenuate endothelial responses to VEGF via caveolin-1 induction at the levels of signal transduction, migration, and tube formation, identifying a novel point of cross talk between nuclear and cell-surface receptor signaling pathways. PMID:23426970

  2. Caveolin-1 as a Prognostic Marker for Local Control After Preoperative Chemoradiation Therapy in Rectal Cancer

    SciTech Connect

    Roedel, Franz Capalbo, Gianni; Roedel, Claus; Weiss, Christian

    2009-03-01

    Purpose: Caveolin-1 is a protein marker for caveolae organelles and has an essential impact on cellular signal transduction pathways (e.g., receptor tyrosine kinases, adhesion molecules, and G-protein-coupled receptors). In the present study, we investigated the expression of caveolin-1 in patients with rectal adenocarcinoma and correlated its expression pattern with the risk for disease recurrences after preoperative chemoradiation therapy (CRT) and surgical resection. Methods and Materials: Caveolin-1 mRNA and protein expression were evaluated by Affymetrix microarray analysis (n = 20) and immunohistochemistry (n = 44) on pretreatment biopsy samples of patients with locally advanced adenocarcinoma of the rectum, and were correlated with clinical and histopathologic characteristics as well as with 5-year rates of local failure and overall survival. Results: A significantly decreased median caveolin-1 intracellular mRNA level was observed in tumor biopsy samples as compared with noncancerous mucosa. Individual mRNA levels and immunohistologic staining, however, revealed an overexpression in 7 of 20 patients (35%) and 17 of 44 patients (38.6%), respectively. Based on immunohistochemical evaluation, local control rates at 5 years for patients with tumors showing low caveolin-1 expression were significantly better than for patients with high caveolin-1-expressing carcinoma cells (p = 0.05; 92%, 95% confidence interval [95% CI] = 82-102% vs. 72%, 95% CI = 49-84%). A low caveolin-1 protein expression was also significantly related to an increased overall survival rate (p = 0.05; 45%, 95% CI 16-60% vs. 82%, 95% CI = 67-97%). Conclusion: Caveolin-1 may provide a novel prognostic marker for local control and survival after preoperative CRT and surgical resection in rectal cancer.

  3. Growth suppression of MCF-7 cancer cell-derived xenografts in nude mice by caveolin-1

    SciTech Connect

    Wu Ping; Wang Xiaohui; Li Fei; Qi Baoju; Zhu Hua; Liu Shuang; Cui Yeqing; Chen Jianwen

    2008-11-07

    Caveolin-1 is an essential structural constituent of caveolae membrane domains that has been implicated in mitogenic signaling and oncogenesis. However, the exact functional role of caveolin-1 still remains controversial. In this report, utilizing MCF-7 human breast adenocarcinoma cells stably transfected with caveolin-1 (MCF-7/cav-1 cells), we demonstrate that caveolin-1 expression dramatically inhibits invasion and migration of these cells. Importantly, in vivo experiments employing xenograft tumor models demonstrated that expression of caveolin-1 results in significant growth inhibition of breast tumors. Moreover, a dramatic delay in tumor progression was observed in MCF-7/cav-1 cells as compared with MCF-7 cells. Histological analysis of tumor sections demonstrated a marked decrease in the percentage of proliferating tumor cells (Ki-67 assay) along with an increase in apoptotic tumor cells (TUNEL assay) in MCF-7/cav-1-treated animals. Our current findings provide for the first time in vivo evidence that caveolin-1 can indeed function as a tumor suppressor in human breast adenocarcinoma derived from MCF-7 cells rather than as a tumor promoter.

  4. Potential role of caveolin-1 in acetaminophen-induced hepatotoxicity

    SciTech Connect

    Gardner, Carol R.; Gray, Joshua P.; Joseph, Laurie B.; Cervelli, Jessica; Bremer, Nicole; Kim, Yunjung; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2010-05-15

    Caveolin-1 (Cav-1) is a membrane scaffolding protein, which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1{sup -/-}) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild-type mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was correlated with decreased expression of Cav-1 in the liver. Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1{sup -/-} mice, an effect that was independent of acetaminophen metabolism. Acetaminophen administration resulted in increased hepatic expression of the oxidative stress marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and superoxide dismutase-1; no differences were noted between the genotypes suggesting that reduced toxicity in Cav-1{sup -/-} mice is not due to alterations in antioxidant defense. In wild-type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1beta, and monocyte chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in Cav-1{sup -/-} mice. Although expression of tumor necrosis factor-alpha, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1{sup -/-} mice after acetaminophen, expression of proliferating cell nuclear antigen and survivin, markers of cellular proliferation, were delayed, which may reflect the reduced need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a role in promoting inflammation and toxicity during the pathogenesis of acetaminophen-induced injury.

  5. Potential Role of Caveolin-1 in Acetaminophen-Induced Hepatotoxicity

    PubMed Central

    Gardner, Carol R.; Gray, Joshua P.; Joseph, Laurie B.; Cervelli, Jessica; Bremer, Nicole; Kim, Yunjung; Mishin, Vladimir; Laskin, Jeffrey D.; Laskin, Debra L.

    2010-01-01

    Caveolin-1 (Cav-1) is a membrane scaffolding protein which functions to regulate intracellular compartmentalization of various signaling molecules. In the present studies, transgenic mice with a targeted disruption of the Cav-1 gene (Cav-1−/−) were used to assess the role of Cav-1 in acetaminophen-induced hepatotoxicity. Treatment of wild type mice with acetaminophen (300 mg/kg) resulted in centrilobular hepatic necrosis and increases in serum transaminases. This was correlated with decreased expression of Cav-1 in the liver. Acetaminophen-induced hepatotoxicity was significantly attenuated in Cav-1−/− mice, an effect that was independent of acetaminophen metabolism. Acetaminophen administration resulted in increased hepatic expression of the oxidative stress marker, lipocalin 24p3, as well as hemeoxygenase-1, but decreased glutathione and superoxide dismutase-1; no differences were noted between the genotypes suggesting that reduced toxicity in Cav-1−/− mice is not due to alterations in anti-oxidant defense. In wild type mice, acetaminophen increased mRNA expression of the pro-inflammatory cytokines, interleukin-1β and monocyte chemoattractant protein-1 (MCP-1), as well as cyclooxygenase-2, while 15-lipoxygenase (15-LOX), which generates anti-inflammatory lipoxins, decreased. Acetaminophen-induced changes in MCP-1 and 15-LOX expression were greater in Cav-1−/− mice. Although expression of tumor necrosis factor-α, a potent hepatocyte mitogen, was up-regulated in the liver of Cav-1−/− mice after acetaminophen, expression of proliferating cell nuclear antigen and survivin, markers of cellular proliferation, were delayed which may reflect the reduced need for tissue repair. Taken together, these data demonstrate that Cav-1 plays a role in promoting inflammation and toxicity during the pathogenesis of acetaminophen-induced injury. PMID:20100502

  6. Caveolin-1 mediates chemoresistance in breast cancer stem cells via β-catenin/ABCG2 signaling pathway.

    PubMed

    Wang, Zhiyu; Wang, Neng; Li, Wenping; Liu, Pengxi; Chen, Qianjun; Situ, Honglin; Zhong, Shaowen; Guo, Li; Lin, Yi; Shen, Jiangang; Chen, Jianping

    2014-10-01

    Accumulating evidence has suggested that cancer stem cells (CSCs) are at the root of drug resistance, and recent studies have indicated that caveolin-1, a membrane transporter protein, is involved in the regulation of cancer chemoresistance and stem cell signaling. However, the current understanding of the role of caveolin-1 in breast cancer development remains controversial. Herein, we demonstrate that caveolin-1 expression was upregulated after breast cancer chemotherapy in vitro and in vivo, accompanied by co-overexpression of β-catenin and ATP-binding cassette subfamily G member 2 (ABCG2) signaling. Additionally, breast CSCs were enriched for caveolin-1 expression. Caveolin-1 silencing sensitized breast CSCs by limiting their self-renewal ability but promoting the differentiation process. β-catenin silencing prevented the enhanced chemoresistance of CSCs induced by caveolin-1 overexpression, indicating that β-catenin is an essential molecule responsible for caveolin-1-mediated action. Further mechanistic investigation revealed that caveolin-1 silencing could downregulate the β-catenin/ABCG2 pathway through glycogen synthase kinase 3 beta activation and Akt inhibition, resulting in increased β-catenin phosphorylation and proteasomal degradation. Clinical investigation also revealed a close correlation between caveolin-1 and β-catenin/ABCG2 signaling in breast cancer samples. Notably, caveolin-1 was highly elevated in triple-negative breast cancer, and caveolin-1 silencing significantly impaired the tumorigenicity and chemoresistance of breast CSCs in in vivo models. Overall, our study not only highlights the role of caveolin-1 in mediating the chemoresistance of breast CSCs via β-catenin/ABCG2 regulation but also provides novel approaches for future therapies targeting CSCs. PMID:25085904

  7. Profibrogenic phenotype in caveolin-1 deficiency via differential regulation of STAT-1/3 proteins.

    PubMed

    Ryter, Stefan W; Choi, Augustine M K; Kim, Hong Pyo

    2014-10-01

    Fibrosis underlies the pathogenesis of several human diseases, which can lead to severe injury of vital organs. We previously demonstrated that caveolin-1 expression is reduced in experimental fibrosis and that caveolin-1 exerts antiproliferative and antifibrotic effects in lung fibrosis models. The signal transducers and activators of transcription (STAT) proteins, STAT1 and STAT3, can be activated simultaneously. STAT1 can inhibit cell growth and promote apoptosis while STAT3 inhibits apoptosis. Here, we show that caveolin-1-deficient (cav-1(-/-)) lung fibroblasts display dramatically upregulated STAT3 activation in response to platelet-derived growth factor-BB and transforming growth factor-β stimuli, whereas STAT1 activation is undetectable. Downregulation of protein tyrosine phosphatase-1B played a role in the preferential activation of STAT3 in cav-1(-/-) fibroblasts. Genetic deletion of STAT3 by siRNA modulated the expression of genes involved in cell proliferation and fibrogenesis. Basal expression of α-smooth muscle actin was prominent in cav-1(-/-) liver and kidney, consistent with deposition of collagen in these organs. Collectively, we demonstrate that the antiproliferative and antifibrogenic properties of caveolin-1 in vitro are mediated by the balance between STAT1 and STAT3 activation. Deregulated STAT signaling associated with caveolin-1 deficiency may be relevant to proliferative disorders such as tissue fibrosis. PMID:25263949

  8. Hypoxia regulates global membrane protein endocytosis through caveolin-1 in cancer cells

    PubMed Central

    Bourseau-Guilmain, E.; Menard, J. A.; Lindqvist, E.; Indira Chandran, V.; Christianson, H. C.; Cerezo Magaña, M.; Lidfeldt, J.; Marko-Varga, G.; Welinder, C.; Belting, M.

    2016-01-01

    Hypoxia promotes tumour aggressiveness and resistance of cancers to oncological treatment. The identification of cancer cell internalizing antigens for drug targeting to the hypoxic tumour niche remains a challenge of high clinical relevance. Here we show that hypoxia down-regulates the surface proteome at the global level and, more specifically, membrane proteome internalization. We find that hypoxic down-regulation of constitutive endocytosis is HIF-independent, and involves caveolin-1-mediated inhibition of dynamin-dependent, membrane raft endocytosis. Caveolin-1 overexpression inhibits protein internalization, suggesting a general negative regulatory role of caveolin-1 in endocytosis. In contrast to this global inhibitory effect, we identify several proteins that can override caveolin-1 negative regulation, exhibiting increased internalization at hypoxia. We demonstrate antibody-mediated cytotoxin delivery and killing specifically of hypoxic cells through one of these proteins, carbonic anhydrase IX. Our data reveal that caveolin-1 modulates cell-surface proteome turnover at hypoxia with potential implications for specific targeting of the hypoxic tumour microenvironment. PMID:27094744

  9. Hypoxia regulates global membrane protein endocytosis through caveolin-1 in cancer cells.

    PubMed

    Bourseau-Guilmain, E; Menard, J A; Lindqvist, E; Indira Chandran, V; Christianson, H C; Cerezo Magaña, M; Lidfeldt, J; Marko-Varga, G; Welinder, C; Belting, M

    2016-01-01

    Hypoxia promotes tumour aggressiveness and resistance of cancers to oncological treatment. The identification of cancer cell internalizing antigens for drug targeting to the hypoxic tumour niche remains a challenge of high clinical relevance. Here we show that hypoxia down-regulates the surface proteome at the global level and, more specifically, membrane proteome internalization. We find that hypoxic down-regulation of constitutive endocytosis is HIF-independent, and involves caveolin-1-mediated inhibition of dynamin-dependent, membrane raft endocytosis. Caveolin-1 overexpression inhibits protein internalization, suggesting a general negative regulatory role of caveolin-1 in endocytosis. In contrast to this global inhibitory effect, we identify several proteins that can override caveolin-1 negative regulation, exhibiting increased internalization at hypoxia. We demonstrate antibody-mediated cytotoxin delivery and killing specifically of hypoxic cells through one of these proteins, carbonic anhydrase IX. Our data reveal that caveolin-1 modulates cell-surface proteome turnover at hypoxia with potential implications for specific targeting of the hypoxic tumour microenvironment. PMID:27094744

  10. Caveolin-1 Orchestrates TCR Synaptic Polarity, Signal Specificity, and Function in CD8 T Cells

    PubMed Central

    Tomassian, Tamar; Humphries, Lisa A.; Liu, Scot D.; Silva, Oscar; Brooks, David G.; Miceli, M. Carrie

    2013-01-01

    TCR engagement triggers the polarized recruitment of membrane, actin, and transducer assemblies within the T cell–APC contact that amplify and specify signaling cascades and Teffector activity. We report that caveolin-1, a scaffold that regulates polarity and signaling in nonlymphoid cells, is required for optimal TCR-induced actin polymerization, synaptic membrane raft polarity, and function in CD8, but not CD4, T cells. In CD8+ T cells, caveolin-1 ablation selectively impaired TCR-induced NFAT-dependent NFATc1 and cytokine gene expression, whereas caveolin-1 re-expression promoted NFATc1 gene expression. Alternatively, caveolin-1 ablation did not affect TCR-induced NF-κB–dependent Iκbα expression. Cav-1−/− mice did not efficiently promote CD8 immunity to lymphocytic choriomeningitis virus, nor did cav-1−/− OT-1+ CD8+ T cells efficiently respond to Listeria mono-cytogenes-OVA after transfer into wild-type hosts. Therefore, caveolin-1 is a T cell-intrinsic orchestrator of TCR-mediated membrane polarity and signal specificity selectively employed by CD8 T cells to customize TCR responsiveness. PMID:21849673

  11. Ciprofloxacin mediates cancer stem cell phenotypes in lung cancer cells through caveolin-1-dependent mechanism.

    PubMed

    Phiboonchaiyanan, Preeyaporn Plaimee; Kiratipaiboon, Chayanin; Chanvorachote, Pithi

    2016-04-25

    Cancer stem cells (CSCs), a subpopulation of cancer cells with high aggressive behaviors, have been identified in many types of cancer including lung cancer as one of the key mediators driving cancer progression and metastasis. Here, we have reported for the first time that ciprofloxacin (CIP), a widely used anti-microbial drug, has a potentiating effect on CSC-like features in human non-small cell lung cancer (NSCLC) cells. CIP treatment promoted CSC-like phenotypes, including enhanced anchorage-independent growth and spheroid formation. The known lung CSC markers: CD133, CD44, ABCG2 and ALDH1A1 were found to be significantly increased, while the factors involving in epithelial to mesenchymal transition (EMT): Slug and Snail, were depleted. Also, self-renewal transcription factors Oct-4 and Nanog were found to be up-regulated in CIP-treated cells. The treatment of CIP on CSC-rich populations obtained from secondary spheroids resulted in the further increase of CSC markers. In addition, we have proven that the mechanistic insight of the CIP induced stemness is through Caveolin-1 (Cav-1)-dependent mechanism. The specific suppression of Cav-1 by stably transfected Cav-1 shRNA plasmid dramatically reduced the effect of CIP on CSC markers as well as the CIP-induced spheroid formation ability. Cav-1 was shown to activate protein kinase B (Akt) and extracellular signal-regulated kinase (ERK) pathways in CSC-rich population; however, such an effect was rarely found in the main lung cancer cells population. These findings reveal a novel effect of CIP in positively regulating CSCs in lung cancer cells via the activation of Cav-1, Akt and ERK, and may provoke the awareness of appropriate therapeutic strategy in cancer patients. PMID:26947806

  12. Effect of quercetin and its metabolite on caveolin-1 expression induced by oxidized LDL and lysophosphatidylcholine in endothelial cells.

    PubMed

    Kamada, Chiemi; Mukai, Rie; Kondo, Akari; Sato, Shinya; Terao, Junji

    2016-05-01

    Oxidized low-density lipoprotein contributes to atherosclerotic plaque formation, and quercetin is expected to exert anti-atherosclerotic effects. We previously reported accumulation of conjugated quercetin metabolites in the aorta of rabbits fed high-cholesterol diets with quercetin glucosides, resulting in attenuation of lipid peroxidation and inhibition of lipid accumulation. Caveolin-1, a major structural protein of caveolae in vascular endothelial cells, plays a role in atherosclerosis development. Here we investigated effects of oxidized low-density lipoprotein, quercetin and its metabolite, quercetin 3-O-β-glucuronide, on caveolin-1 expression. Oxidized low-density lipoprotein significantly upregulated caveolin-1 mRNA expression. An oxidized low-density lipoprotein component, lysophosphatidylcholine, also induced expression of both caveolin-1 mRNA and protein. However, lysophosphatidylcholine did not affect the location of caveolin-1 proteins within caveolae structures. Co-treatment with quercetin or quercetin 3-O-β-glucuronide inhibited lysophosphatidylcholine-induced caveolin-1 expression. Quercetin and quercetin 3-O-β-glucuronide also suppressed expression of adhesion molecules induced by oxidized low-density lipoprotein and lysophosphatidylcholine. These results strongly suggest lysophosphatidylcholine derived from oxidized low-density lipoprotein contributes to atherosclerotic events by upregulating caveolin-1 expression, resulting in induction of adhesion molecules. Quercetin metabolites are likely to exert an anti-atherosclerotic effect by attenuating caveolin-1 expression in endothelial cells. PMID:27257344

  13. Effect of quercetin and its metabolite on caveolin-1 expression induced by oxidized LDL and lysophosphatidylcholine in endothelial cells

    PubMed Central

    Kamada, Chiemi; Mukai, Rie; Kondo, Akari; Sato, Shinya; Terao, Junji

    2016-01-01

    Oxidized low-density lipoprotein contributes to atherosclerotic plaque formation, and quercetin is expected to exert anti-atherosclerotic effects. We previously reported accumulation of conjugated quercetin metabolites in the aorta of rabbits fed high-cholesterol diets with quercetin glucosides, resulting in attenuation of lipid peroxidation and inhibition of lipid accumulation. Caveolin-1, a major structural protein of caveolae in vascular endothelial cells, plays a role in atherosclerosis development. Here we investigated effects of oxidized low-density lipoprotein, quercetin and its metabolite, quercetin 3-O-β-glucuronide, on caveolin-1 expression. Oxidized low-density lipoprotein significantly upregulated caveolin-1 mRNA expression. An oxidized low-density lipoprotein component, lysophosphatidylcholine, also induced expression of both caveolin-1 mRNA and protein. However, lysophosphatidylcholine did not affect the location of caveolin-1 proteins within caveolae structures. Co-treatment with quercetin or quercetin 3-O-β-glucuronide inhibited lysophosphatidylcholine-induced caveolin-1 expression. Quercetin and quercetin 3-O-β-glucuronide also suppressed expression of adhesion molecules induced by oxidized low-density lipoprotein and lysophosphatidylcholine. These results strongly suggest lysophosphatidylcholine derived from oxidized low-density lipoprotein contributes to atherosclerotic events by upregulating caveolin-1 expression, resulting in induction of adhesion molecules. Quercetin metabolites are likely to exert an anti-atherosclerotic effect by attenuating caveolin-1 expression in endothelial cells. PMID:27257344

  14. Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment

    PubMed Central

    2011-01-01

    Cancer cells show a broad spectrum of bioenergetic states, with some cells using aerobic glycolysis while others rely on oxidative phosphorylation as their main source of energy. In addition, there is mounting evidence that metabolic coupling occurs in aggressive tumors, between epithelial cancer cells and the stromal compartment, and between well-oxygenated and hypoxic compartments. We recently showed that oxidative stress in the tumor stroma, due to aerobic glycolysis and mitochondrial dysfunction, is important for cancer cell mutagenesis and tumor progression. More specifically , increased autophagy/mitophagy in the tumor stroma drives a form of parasitic epithelial-stromal metabolic coupling. These findings explain why it is effective to treat tumors with either inducers or inhibitors of autophagy, as both would disrupt this energetic coupling. We also discuss evidence that glutamine addiction in cancer cells produces ammonia via oxidative mitochondrial metabolism. Ammonia production in cancer cells, in turn, could then help maintain autophagy in the tumor stromal compartment. In this vicious cycle, the initial glutamine provided to cancer cells would be produced by autophagy in the tumor stroma. Thus, we believe that parasitic epithelial-stromal metabolic coupling has important implications for cancer diagnosis and therapy, for example, in designing novel metabolic imaging techniques and establishing new targeted therapies. In direct support of this notion, we identified a loss of stromal caveolin-1 as a marker of oxidative stress, hypoxia, and autophagy in the tumor microenvironment, explaining its powerful predictive value. Loss of stromal caveolin-1 in breast cancers is associated with early tumor recurrence, metastasis, and drug resistance, leading to poor clinical outcome. PMID:21867571

  15. Caveolin 1 Is Required for the Activation of Endothelial Nitric Oxide Synthase in Response to 17β-Estradiol

    PubMed Central

    Sud, Neetu; Wiseman, Dean A.; Black, Stephen M.

    2010-01-01

    Evidence suggests that estrogen mediates rapid endothelial nitric oxide synthase (eNOS) activation via estrogen receptor-a (ERα) within the plasma membrane of endothelial cells (EC). ERα is known to colocalize with caveolin 1, the major structural protein of caveolae, and caveolin 1 stimulates the translocation of ERα to the plasma membrane. However, the role played by caveolin 1 in regulating 17β-estradiol-mediated NO signaling in EC has not been adequately resolved. Thus, the purpose of this study was to explore how 17β-estradiol stimulates eNOS activity and the role of caveolin 1 in this process. Our data demonstrate that modulation of caveolin 1 expression using small interfering RNA or adenoviral gene delivery alters ERα localization to the plasma membrane in EC. Further, before estrogen stimulation ERα associates with caveolin 1, whereas stimulation promotes a pp60Src-mediated phosphorylation of caveolin 1 at tyrosine 14, increasing ERα-PI3 kinase interactions and disrupting caveolin 1-ERα interactions. Adenoviral mediated overexpression of a phosphorylation-deficient mutant of caveolin (Y14FCav) attenuated the ERα/PI3 kinase interaction and prevented Akt-mediated eNOS activation. Furthermore, Y14FCav overexpression reduced eNOS phosphorylation at serine1177 and decreased NO generation after estrogen exposure. Using a library of overlapping peptides we identified residues 62–73 of caveolin 1 as the ERα-binding site. Delivery of a synthetic peptide based on this sequence decreased ERα plasma membrane translocation and reduced estrogen-mediated activation of eNOS. In conclusion, caveolin 1 stimulates 17β-estradiol-induced NO production by promoting ERα to the plasma membrane, which facilitates the activation of the PI3 kinase pathway, leading to eNOS activation and NO generation. PMID:20610538

  16. Interaction with Caveolin-1 Modulates G Protein Coupling of Mouse β3-Adrenoceptor*

    PubMed Central

    Sato, Masaaki; Hutchinson, Dana S.; Halls, Michelle L.; Furness, Sebastian G. B.; Bengtsson, Tore; Evans, Bronwyn A.; Summers, Roger J.

    2012-01-01

    Caveolins act as scaffold proteins in multiprotein complexes and have been implicated in signaling by G protein-coupled receptors. Studies using knock-out mice suggest that β3-adrenoceptor (β3-AR) signaling is dependent on caveolin-1; however, it is not known whether caveolin-1 is associated with the β3-AR or solely with downstream signaling proteins. We have addressed this question by examining the impact of membrane rafts and caveolin-1 on the differential signaling of mouse β3a- and β3b-AR isoforms that diverge at the distal C terminus. Only the β3b-AR promotes pertussis toxin (PTX)-sensitive cAMP accumulation. When cells expressing the β3a-AR were treated with filipin III to disrupt membrane rafts or transfected with caveolin-1 siRNA, the cyclic AMP response to the β3-AR agonist CL316243 became PTX-sensitive, suggesting Gαi/o coupling. The β3a-AR C terminus, SP384PLNRF389DGY392EGARPF398PT, resembles a caveolin interaction motif. Mutant β3a-ARs (F389A/Y392A/F398A or P384S/F389A) promoted PTX-sensitive cAMP responses, and in situ proximity assays demonstrated an association between caveolin-1 and the wild type β3a-AR but not the mutant receptors. In membrane preparations, the β3b-AR activated Gαo and mediated PTX-sensitive cAMP responses, whereas the β3a-AR did not activate Gαi/o proteins. The endogenous β3a-AR displayed Gαi/o coupling in brown adipocytes from caveolin-1 knock-out mice or in wild type adipocytes treated with filipin III. Our studies indicate that interaction of the β3a-AR with caveolin inhibits coupling to Gαi/o proteins and suggest that signaling is modulated by a raft-enriched complex containing the β3a-AR, caveolin-1, Gαs, and adenylyl cyclase. PMID:22535965

  17. Oxidative Stress Induces Caveolin 1 Degradation and Impairs Caveolae Functions in Skeletal Muscle Cells

    PubMed Central

    Mougeolle, Alexis; Poussard, Sylvie; Decossas, Marion; Lamaze, Christophe

    2015-01-01

    Increased level of oxidative stress, a major actor of cellular aging, impairs the regenerative capacity of skeletal muscle and leads to the reduction in the number and size of muscle fibers causing sarcopenia. Caveolin 1 is the major component of caveolae, small membrane invaginations involved in signaling and endocytic trafficking. Their role has recently expanded to mechanosensing and to the regulation of oxidative stress-induced pathways. Here, we increased the amount of reactive oxidative species in myoblasts by addition of hydrogen peroxide (H2O2) at non-toxic concentrations. The expression level of caveolin 1 was significantly decreased as early as 10 min after 500 μM H2O2 treatment. This reduction was not observed in the presence of a proteasome inhibitor, suggesting that caveolin 1 was rapidly degraded by the proteasome. In spite of caveolin 1 decrease, caveolae were still able to assemble at the plasma membrane. Their functions however were significantly perturbed by oxidative stress. Endocytosis of a ceramide analog monitored by flow cytometry was significantly diminished after H2O2 treatment, indicating that oxidative stress impaired its selective internalization via caveolae. The contribution of caveolae to the plasma membrane reservoir has been monitored after osmotic cell swelling. H2O2 treatment increased membrane fragility revealing that treated cells were more sensitive to an acute mechanical stress. Altogether, our results indicate that H2O2 decreased caveolin 1 expression and impaired caveolae functions. These data give new insights on age-related deficiencies in skeletal muscle. PMID:25799323

  18. Caveolin-1 gene knockout impairs nitrergic function in mouse small intestine

    PubMed Central

    El-Yazbi, Ahmed F; Cho, Woo-Jung; Boddy, Geoffrey; Daniel, Edwin E

    2005-01-01

    Caveolin-1 is a plasma membrane-associated protein that is responsible for caveolae formation. It plays an important role in the regulation of the function of different signaling molecules, among which are the different isoforms of nitric oxide synthase (NOS). Nitric oxide (NO) is known to be an important inhibitory mediator in the mouse gut. Caveolin-1 knockout mice (Cav1−/−) were used to examine the effect of caveolin-1 absence on the NO function in the mouse small intestine (ileum and jejunum) compared to their genetic controls and BALB/c controls. Immunohistochemical staining showed loss of caveolin-1 and NOS in the jejunal smooth muscles and myenteric plexus interstitial cells of Cajal (ICC) of Cav1−/− mice; however, nNOS immunoreactive nerves were still present in myenteric ganglia. Under nonadrenergic noncholinergic (NANC) conditions, small intestinal tissues from Cav1−/− mice relaxed to electrical field stimulation (EFS), as did tissues from control mice. Relaxation of tissues from control mice was markedly reduced by N-omega-nitro-L-arginine (10−4 M), but relaxation of Cav1−/− animals was affected much less. Also, Cav1−/− mice tissues showed reduced relaxation responses to sodium nitroprusside (100 μM) compared to controls; yet there were no significant differences in the relaxation responses to 8-bromoguanosine-3′ : 5′-cyclic monophosphate (100 μM). Apamin (10−6 M) significantly reduced relaxations to EFS in NANC conditions in Cav1−/− mice, but not in controls. The data from this study suggest that caveolin-1 gene knockout causes alterations in the smooth muscles and the ICC, leading to an impaired NO function in the mouse small intestine that could possibly be compensated by apamin-sensitive inhibitory mediators. PMID:15937515

  19. Probing the caveolin-1 P132L mutant: Critical insights into its oligomeric behavior and structure

    PubMed Central

    Rieth, Monica D.; Lee, Jinwoo; Glover, Kerney Jebrell

    2012-01-01

    Caveolin-1 is the most important protein found in caveolae, which are cell surface invaginations of the plasma membrane that act as signaling platforms. A single point mutation in the transmembrane domain of caveolin-1 (proline 132 to leucine) has deleterious effects on caveolae formation in vivo, and has been implicated in various disease states, particularly aggressive breast cancers. Using a combination of gel filtration chromatography and analytical ultracentrifugation we found that a fully-functional construct of caveolin-1 (Cav162–178) was a monomer in dodecylphosphocholine micelles. In contrast, the P132L mutant of Cav162–178 was dimeric. To explore the dimerization of the P132L mutant further, various truncated constructs (Cav182–178, Cav196–178, Cav162–136, Cav182–136, Cav196–136) were prepared which revealed that oligomerization occurs in the transmembrane domain (residues 96–136) of caveolin-1. To characterize the mutant structurally, solution-state NMR experiments in lyso-myristoylphosphatidylglycerol were undertaken of the Cav196–136 P132L mutant. Chemical shift analysis revealed that compared to the wild type, helix 2 in the transmembrane domain was lengthened by four residues (wild type, residues 111 to 129; mutant, residues 111–133), which corresponds to an extra turn in helix 2 of the mutant. Lastly, point mutations at position 132 of Cav162–178 (P132A, P132I, P132V, P132G, P132W, P132F) revealed that no other hydrophobic amino acid can preserve the monomeric state of Cav162–178 which indicates that proline 132 is critical in supporting proper caveolin-1 behavior. PMID:22506673

  20. Caveolin-1 Induces Formation of Membrane Tubules That Sense Actomyosin Tension and Are Inhibited by Polymerase I and Transcript Release Factor/Cavin-1

    PubMed Central

    Verma, Prakhar; Ostermeyer-Fay, Anne G.

    2010-01-01

    Caveolin-1 and caveolae are often lost in cancer. We found that levels of caveolin-1 and polymerase I and transcript release factor (PTRF)/cavin-1 correlated closely in a panel of cancer and normal cells. Caveolin-1 reexpression in cancer cells lacking both proteins induced formation of long membrane tubules rarely seen in normal cells. PTRF/cavin-1 inhibited tubule formation when coexpressed with caveolin-1 in these cells, whereas suppression of PTRF/cavin-1 expression in cells that normally expressed both genes stimulated tubule formation by endogenous caveolin-1. Caveolin-1 tubules shared several features with previously described Rab8 tubules. Coexpressed Rab8 and caveolin-1 labeled the same tubules (as did EHD proteins), and synergized to promote tubule formation, whereas a dominant-interfering Rab8 mutant inhibited caveolin-1 tubule formation. Both overexpression and inhibition of dynamin-2 reduced the abundance of caveolin-1 tubules. Caveolin-1 reexpression in SK-BR-3 breast cancer cells also induced formation of short membrane tubules close to cortical actin filaments, which required actin filaments but not microtubules. Actomyosin-induced tension destabilized both long and short tubules; they often snapped and resolved to small vesicles. Actin filament depolymerization or myosin II inhibition reduced tension and stabilized tubules. These data demonstrate a new function for PTRF/cavin-1, a new functional interaction between caveolin-1 and Rab8 and that actomyosin interactions can induce tension on caveolin-1-containing membranes. PMID:20427576

  1. Phosphorylation of caveolin-1 on tyrosine-14 induced by ROS enhances palmitate-induced death of beta-pancreatic cells.

    PubMed

    Wehinger, Sergio; Ortiz, Rina; Díaz, María Inés; Aguirre, Adam; Valenzuela, Manuel; Llanos, Paola; Mc Master, Christopher; Leyton, Lisette; Quest, Andrew F G

    2015-05-01

    A considerable body of evidence exists implicating high levels of free saturated fatty acids in beta pancreatic cell death, although the molecular mechanisms and the signaling pathways involved have not been clearly defined. The membrane protein caveolin-1 has long been implicated in cell death, either by sensitizing to or directly inducing apoptosis and it is normally expressed in beta cells. Here, we tested whether the presence of caveolin-1 modulates free fatty acid-induced beta cell death by reexpressing this protein in MIN6 murine beta cells lacking caveolin-1. Incubation of MIN6 with palmitate, but not oleate, induced apoptotic cell death that was enhanced by the presence of caveolin-1. Moreover, palmitate induced de novo ceramide synthesis, loss of mitochondrial transmembrane potential and reactive oxygen species (ROS) formation in MIN6 cells. ROS generation promoted caveolin-1 phosphorylation on tyrosine-14 that was abrogated by the anti-oxidant N-acetylcysteine or the incubation with the Src-family kinase inhibitor, PP2 (4-amino-5-(4-chlorophenyl)-7(dimethylethyl)pyrazolo[3,4-d]pyrimidine). The expression of a non-phosphorylatable caveolin-1 tyrosine-14 to phenylalanine mutant failed to enhance palmitate-induced apoptosis while for MIN6 cells expressing the phospho-mimetic tyrosine-14 to glutamic acid mutant caveolin-1 palmitate sensitivity was comparable to that observed for MIN6 cells expressing wild type caveolin-1. Thus, caveolin-1 expression promotes palmitate-induced ROS-dependent apoptosis in MIN6 cells in a manner requiring Src family kinase mediated tyrosine-14 phosphorylation. PMID:25572853

  2. Identification of a novel domain at the N terminus of caveolin-1 that controls rear polarization of the protein and caveolae formation.

    PubMed

    Sun, Xing-Hui; Flynn, Daniel C; Castranova, Vincent; Millecchia, Lyndell L; Beardsley, Andrew R; Liu, Jun

    2007-03-01

    When cells are migrating, caveolin-1, the principal protein component of caveolae, is excluded from the leading edge and polarized at the cell rear. The dynamic feature depends on a specific sequence motif that directs intracellular trafficking of the protein. Deletion mutation analysis revealed a putative polarization domain at the N terminus of caveolin-1, between amino acids 32-60. Alanine substitution identified a minimal sequence of 10 residues ((46)TKEIDLVNRD(55)) necessary for caveolin-1 rear polarization. Interestingly, deletion of amino acids 1-60 did not prevent the polarization of caveolin-1 in human umbilical vein endothelial cells or wild-type mouse embryonic fibroblasts because of an interaction of Cav(61-178) mutant with endogenous caveolin-1. Surprisingly, expression of the depolarization mutant in caveolin-1 null cells dramatically impeded caveolae formation. Furthermore, knockdown of caveolae formation by methyl-beta-cyclodextrin failed to prevent wild-type caveolin-1 rear polarization. Importantly, genetic depletion of caveolin-1 led to disoriented migration, which can be rescued by full-length caveolin-1 but not the depolarization mutant, indicating a role of caveolin-1 polarity in chemotaxis. Thus, we have identified a sequence motif that is essential for caveolin-1 rear polarization and caveolae formation. PMID:17213184

  3. Flagellin-dependent TLR5/caveolin-1 as a promising immune activator in immunosenescence.

    PubMed

    Lim, Jae Sung; Nguyen, Kim Cuc Thi; Nguyen, Chung Truong; Jang, Ik-Soon; Han, Jung Min; Fabian, Claire; Lee, Shee Eun; Rhee, Joon Haeng; Cho, Kyung A

    2015-10-01

    The age-associated decline of immune responses causes high susceptibility to infections and reduced vaccine efficacy in the elderly. However, the mechanisms underlying age-related deficits are unclear. Here, we found that the expression and signaling of flagellin (FlaB)-dependent Toll-like receptor 5 (TLR5), unlike the other TLRs, were well maintained in old macrophages, similar to young macrophages. The expression and activation of TLR5/MyD88, but not TLR4, were sensitively regulated by the upregulation of caveolin-1 in old macrophages through direct interaction. This interaction was also confirmed using macrophages from caveolin-1 or MyD88 knockout mice. Because TLR5 and caveolin-1 were well expressed in major old tissues including lung, skin, intestine, and spleen, we analyzed in vivo immune responses via a vaccine platform with FlaB as a mucosal adjuvant for the pneumococcal surface protein A (PspA) against Streptococcus pneumoniae infection in young and aged mice. The FlaB-PspA fusion protein induced a significantly higher level of PspA-specific IgG and IgA responses and demonstrated a high protective efficacy against a lethal challenge with live S. pneumoniae in aged mice. These results suggest that caveolin-1/TLR5 signaling plays a key role in age-associated innate immune responses and that FlaB-PspA stimulation of TLR5 may be a new strategy for a mucosal vaccine adjuvant against pneumococcal infection in the elderly. PMID:26223660

  4. Rosiglitazone ameliorates diffuse axonal injury by reducing loss of tau and up-regulating caveolin-1 expression

    PubMed Central

    Zhao, Yong-lin; Song, Jin-ning; Ma, Xu-dong; Zhang, Bin-fei; Li, Dan-dong; Pang, Hong-gang

    2016-01-01

    Rosiglitazone up-regulates caveolin-1 levels and has neuroprotective effects in both chronic and acute brain injury. Therefore, we postulated that rosiglitazone may ameliorate diffuse axonal injury via its ability to up-regulate caveolin-1, inhibit expression of amyloid-beta precursor protein, and reduce the loss and abnormal phosphorylation of tau. In the present study, intraperitoneal injection of rosiglitazone significantly reduced the levels of amyloid-beta precursor protein and hyperphosphorylated tau (phosphorylated at Ser404(p-tau (S404)), and it increased the expression of total tau and caveolin-1 in the rat cortex. Our results show that rosiglitazone inhibits the expression of amyloid-beta precursor protein and lowers p-tau (S404) levels, and it reduces the loss of total tau, possibly by up-regulating caveolin-1. These actions of rosiglitazone may underlie its neuroprotective effects in the treatment of diffuse axonal injury. PMID:27482223

  5. Interphase adhesion geometry is transmitted to an internal regulator for spindle orientation via caveolin-1.

    PubMed

    Matsumura, Shigeru; Kojidani, Tomoko; Kamioka, Yuji; Uchida, Seiichi; Haraguchi, Tokuko; Kimura, Akatsuki; Toyoshima, Fumiko

    2016-01-01

    Despite theoretical and physical studies implying that cell-extracellular matrix adhesion geometry governs the orientation of the cell division axis, the molecular mechanisms that translate interphase adhesion geometry to the mitotic spindle orientation remain elusive. Here, we show that the cellular edge retraction during mitotic cell rounding correlates with the spindle axis. At the onset of mitotic cell rounding, caveolin-1 is targeted to the retracting cortical region at the proximal end of retraction fibres, where ganglioside GM1-enriched membrane domains with clusters of caveola-like structures are formed in an integrin and RhoA-dependent manner. Furthermore, Gαi1-LGN-NuMA, a well-known regulatory complex of spindle orientation, is targeted to the caveolin-1-enriched cortical region to guide the spindle axis towards the cellular edge retraction. We propose that retraction-induced cortical heterogeneity of caveolin-1 during mitotic cell rounding sets the spindle orientation in the context of adhesion geometry. PMID:27292265

  6. Interphase adhesion geometry is transmitted to an internal regulator for spindle orientation via caveolin-1

    PubMed Central

    Matsumura, Shigeru; Kojidani, Tomoko; Kamioka, Yuji; Uchida, Seiichi; Haraguchi, Tokuko; Kimura, Akatsuki; Toyoshima, Fumiko

    2016-01-01

    Despite theoretical and physical studies implying that cell-extracellular matrix adhesion geometry governs the orientation of the cell division axis, the molecular mechanisms that translate interphase adhesion geometry to the mitotic spindle orientation remain elusive. Here, we show that the cellular edge retraction during mitotic cell rounding correlates with the spindle axis. At the onset of mitotic cell rounding, caveolin-1 is targeted to the retracting cortical region at the proximal end of retraction fibres, where ganglioside GM1-enriched membrane domains with clusters of caveola-like structures are formed in an integrin and RhoA-dependent manner. Furthermore, Gαi1–LGN–NuMA, a well-known regulatory complex of spindle orientation, is targeted to the caveolin-1-enriched cortical region to guide the spindle axis towards the cellular edge retraction. We propose that retraction-induced cortical heterogeneity of caveolin-1 during mitotic cell rounding sets the spindle orientation in the context of adhesion geometry. PMID:27292265

  7. Endothelial caveolin-1 plays a major role in the development of atherosclerosis

    PubMed Central

    Pavlides, Stephanos; Gutierrez-Pajares, Jorge L.; Iturrieta, Jeannette; Lisanti, Michael P.

    2015-01-01

    Clinical studies have established the important impact of atherosclerotic disease in Western societies. This disease is characterized by the accumulation of lipids and the migration of various cell types in the sub-endothelial space of blood vessels. As demonstrated by many studies, endothelial cells play an essential role in the development of this disease. The endothelium acts as a gatekeeper of blood vessel integrity and cardiovascular health status. For instance, the transfer of lipids via the transport of lipoproteins in the arterial intima is believed to be mediated by endothelial cells through a process termed transcytosis. In addition, lipoproteins that accumulate in the sub-endothelial space may also be modified, in a process that can direct the activation of endothelial cells. These steps are essential for the initiation of an atherosclerotic plaque and may be mediated, at least in part, by caveolae and their associated protein caveolin-1. In the present study, we evaluate the role of caveolin-1/caveolae in the regulation of these two steps in endothelial cells. Our data clearly demonstrate that caveolin-1 is involved in the regulation of lipoprotein transcytosis across endothelial cells and in the regulation of vascular inflammation. PMID:24390341

  8. Inhibition of macrophage-derived foam cell formation by ezetimibe via the caveolin-1/MAPK pathway.

    PubMed

    Qin, Li; Yang, Yun-Bo; Yang, Yi-Xin; Zhu, Neng; Liu, Zheng; Ni, Ya-Guang; Li, Shun-Xiang; Zheng, Xi-Long; Liao, Duan-Fang

    2016-02-01

    Ezetimibe, a selective inhibitor of intestinal cholesterol absorption, effectively reduces plasma cholesterol, but its effect on atherosclerosis is unclear. Foam cell formation has been implicated as a key mediator during the development of atherosclerosis. The purpose of this study was to investigate the effects of ezetimibe on foam cell formation and explore the underlying mechanism. The results presented here show that ezetimibe reduces atherosclerotic lesions in apolipoprotein E deficient (apoE-/-) mice by lowering cholesterol levels. Treatment of macrophages with Chol:MβCD resulted in foam cell formation, which was concentration-dependently inhibited by the presence of ezetimibe. Mechanically, ezetimibe treatment downregulated the expression of CD36 and scavenger receptor class B1 (SR-B1), but upregulated the expression of apoE and caveolin-1 in macrophage-derived foam cells, which kept consistent with our microarray results. Moreover, treatment with ezetimibe abrogated the increase of phospho-extracellular signal regulated kinase (ERK) 1/2 and their nuclear accumulation in foam cells. Inhibition of the MAPK pathway by the MEK inhibitor PD98059 attenuated the inhibitory effect of ezetimibe on the expression of p-ERK1/2 and caveolin-1. Taken together, these results showed that ezetimibe suppressed foam cell formation via the caveolin-1/MAPK signalling pathway, suggesting that inhibition of foam cell formation might be a novel mechanism underlying the anti-atherosclerotic effect of ezetimibe. PMID:26666965

  9. Translocation of Endothelial Nitric-Oxide Synthase Involves a Ternary Complex with Caveolin-1 and NOSTRIN

    PubMed Central

    Schilling, Kirstin; Opitz, Nils; Wiesenthal, Anja; Oess, Stefanie; Tikkanen, Ritva; Icking, Ann

    2006-01-01

    Recently, we characterized a novel endothelial nitric-oxide synthase (eNOS)-interacting protein, NOSTRIN (for eNOS-trafficking inducer), which decreases eNOS activity upon overexpression and induces translocation of eNOS away from the plasma membrane. Here, we show that NOSTRIN directly binds to caveolin-1, a well-established inhibitor of eNOS. Because this interaction occurs between the N terminus of caveolin (positions 1–61) and the central domain of NOSTRIN (positions 323–434), it allows for independent binding of each of the two proteins to eNOS. Consistently, we were able to demonstrate the existence of a ternary complex of NOSTRIN, eNOS, and caveolin-1 in Chinese hamster ovary (CHO)-eNOS cells. In human umbilical vein endothelial cells (HUVECs), the ternary complex assembles at the plasma membrane upon confluence or thrombin stimulation. In CHO-eNOS cells, NOSTRIN-mediated translocation of eNOS involves caveolin in a process most likely representing caveolar trafficking. Accordingly, trafficking of NOSTRIN/eNOS/caveolin is affected by altering the state of actin filaments or cholesterol levels in the plasma membrane. During caveolar trafficking, NOSTRIN functions as an adaptor to recruit mediators such as dynamin-2 essential for membrane fission. We propose that a ternary complex between NOSTRIN, caveolin-1, and eNOS mediates translocation of eNOS, with important implications for the activity and availability of eNOS in the cell. PMID:16807357

  10. CAVEOLIN-1 expression in brain metastasis from lung cancer predicts worse outcome and radioresistance, irrespective of tumor histotype

    PubMed Central

    Pittaro, Alessandra; Verdun di Cantogno, Ludovica; Stella, Giulia; De Blasi, Pierpaolo; Zorzetto, Michele; Mantovani, Cristina; Papotti, Mauro; Cassoni, Paola

    2015-01-01

    Brain metastases develop in one-third of patients with non-small-cell lung cancer and are associated with a dismal prognosis, irrespective of surgery or chemo-radiotherapy. Pathological markers for predicting outcomes after surgical resection and radiotherapy responsiveness are still lacking. Caveolin 1 has been associated with chemo- and radioresistance in various tumors, including non-small-cell lung cancer. Here, caveolin 1 expression was assessed in a series of 69 brain metastases from non-small-cell lung cancer and matched primary tumors to determine its role in predicting survival and radiotherapy responsiveness. Only caveolin 1 expression in brain metastasis was associated with poor prognosis and an increased risk of death (log rank test, p = 0.015). Moreover, in the younger patients (median age of <54 years), caveolin 1 expression neutralized the favorable effect of young age on survival compared with the older patients. Among the radiotherapy-treated patients, an increased risk of death was detected in the group with caveolin 1-positive brain metastasis (14 out of 22 patients, HR=6.839, 95% CI 1.849 to 25.301, Wald test p = 0.004). Overall, caveolin 1 expression in brain metastasis from non-small-cell lung cancer is independently predictive of worse outcome and radioresistance and could become an additional tool for personalized therapy in the critical subset of brain-metastatic non-small-cell lung cancer patients. PMID:26315660

  11. Diet-induced hypercholesterolemia promotes androgen-independent prostate cancer metastasis via IQGAP1 and caveolin-1

    PubMed Central

    Moon, Hyeongsun; Ruelcke, Jayde E.; Choi, Eunju; Sharpe, Laura J.; Nassar, Zeyad D.; Bielefeldt-Ohmann, Helle; Parat, Marie-Odile; Shah, Anup; Francois, Mathias; Inder, Kerry L.; Brown, Andrew J.; Russell, Pamela J.; Parton, Robert G.; Hill, Michelle M.

    2015-01-01

    Obesity and metabolic syndrome are associated with several cancers, however, the molecular mechanisms remain to be fully elucidated. Recent studies suggest that hypercholesterolemia increases intratumoral androgen signaling in prostate cancer, but it is unclear whether androgen-independent mechanisms also exist. Since hypercholesterolemia is associated with advanced, castrate-resistant prostate cancer, in this study, we aimed to determine whether and how hypercholesterolemia affects prostate cancer progression in the absence of androgen signaling. We demonstrate that diet-induced hypercholesterolemia promotes orthotopic xenograft PC-3 cell metastasis, concomitant with elevated expression of caveolin-1 and IQGAP1 in xenograft tumor tissues. In vitro cholesterol treatment of PC-3 cells stimulated migration and increased IQGAP1 and caveolin-1 protein level and localization to a detergent-resistant fraction. Down-regulation of caveolin-1 or IQGAP1 in PC-3 cells reduced migration and invasion in vitro, and hypercholesterolemia-induced metastasis in vivo. Double knock-down of caveolin-1 and IQGAP1 showed no additive effect, suggesting that caveolin-1 and IQGAP1 act via the same pathway. Taken together, our data show that hypercholesterolemia promotes prostate cancer metastasis independent of the androgen pathway, in part by increasing IQGAP1 and caveolin-1. These results have broader implications for managing metastasis of cancers in general as IQGAP1 and hypercholesterolemia are implicated in the progression of several cancers. PMID:25924234

  12. Caveolin-1 mutants P132L and Y14F are dominant negative regulators of invasion, migration and aggregation in H1299 lung cancer cells

    SciTech Connect

    Shatz, Maria; Lustig, Gila; Reich, Reuven; Liscovitch, Mordechai

    2010-06-10

    Caveolin-1 is an essential protein constituent of caveolae. Accumulating evidence indicates that caveolin-1 may act as a positive regulator of cancer progression. In this study, we investigated the function of caveolin-1 in human lung cancer cells. Caveolin-1 knockdown inhibited cell proliferation and reduced focal adhesion kinase (Fak) phosphorylation. Matrix invasion and cell migration as well as expression and activity of matrix metalloproteases were attenuated following caveolin-1 RNAi-mediated knockdown or overexpression of Y14F and P132L mutants, demonstrating dominant-negative activity of these mutants. Time-lapse fluorescence microscopy revealed that caveolin-1 and its mutants P132L and Y14F are localized to the trailing edge of migrating cells during both random and directed cell movement, implying an active role of caveolin-1 in the migration process. Suppression of caveolin-1 function greatly elevated the percentage of H1299 cells exhibiting focal adhesions. In addition, cell aggregation was increased by wild type caveolin-1 and attenuated by both P132L and Y14F mutants. Overexpression of wild type caveolin-1 increased caveolae density, however, P132L and Y14F mutants did not affect caveolae formation, suggesting that in this respect that the mutants do not act in a dominant negative manner, and that effects of caveolin-1 on caveolae and cell invasion, migration, focal adhesion and aggregation, are separable. Our data provide novel mechanistic insights into the role of caveolin-1 in cell motility, invasiveness and aggregation, therefore, expanding our understanding of the tumor-promoting activities of caveolin-1 in advanced-stage cancer.

  13. Polychlorinated biphenyl-induced VCAM-1 expression is attenuated in aortic endothelial cells isolated from caveolin-1 deficient mice

    SciTech Connect

    Han, Sung Gu; Eum, Sung Yong; Toborek, Michal; Smart, Eric; Hennig, Bernhard

    2010-07-15

    Exposure to environmental contaminants, such as polychlorinated biphenyls (PCBs), is a risk factor for the development of cardiovascular diseases such as atherosclerosis. Vascular cell adhesion molecule-1 (VCAM-1) is a critical mediator for adhesion and uptake of monocytes across the endothelium in the early stages of atherosclerosis development. The upregulation of VCAM-1 by PCBs may be dependent on functional membrane domains called caveolae. Caveolae are particularly abundant in endothelial cell membranes and involved in trafficking and signal transduction. The objective of this study was to investigate the role of caveolae in PCB-induced endothelial cell dysfunction. Primary mouse aortic endothelial cells (MAECs) isolated from caveolin-1-deficient mice and background C57BL/6 mice were treated with coplanar PCBs, such as PCB77 and PCB126. In addition, siRNA gene silencing technique was used to knockdown caveolin-1 in porcine vascular endothelial cells. In MAECs with functional caveolae, VCAM-1 protein levels were increased after exposure to both coplanar PCBs, whereas expression levels of VCAM-1 were not significantly altered in cells deficient of caveolin-1. Furthermore, PCB-induced monocyte adhesion was attenuated in caveolin-1-deficient MAECs. Similarly, siRNA silencing of caveolin-1 in porcine endothelial cells confirmed the caveolin-1-dependent VCAM-1 expression. Treatment of cells with PCB77 and PCB126 resulted in phosphorylation of extracellular signal-regulated kinase-1/2 (ERK1/2), and pharmacological inhibition of ERK1/2 diminished the observed PCB-induced increase in monocyte adhesion. These findings suggest that coplanar PCBs induce adhesion molecule expression, such as VCAM-1, in endothelial cells, and that this response is regulated by caveolin-1 and functional caveolae. Our data demonstrate a critical role of functional caveolae in the activation and dysfunction of endothelial cells by coplanar PCBs.

  14. Elafin Reverses Pulmonary Hypertension via Caveolin-1–Dependent Bone Morphogenetic Protein Signaling

    PubMed Central

    Nickel, Nils P.; Spiekerkoetter, Edda; Gu, Mingxia; Li, Caiyun G.; Li, Hai; Kaschwich, Mark; Diebold, Isabel; Hennigs, Jan K.; Kim, Ki-Yoon; Miyagawa, Kazuya; Wang, Lingli; Cao, Aiqin; Sa, Silin; Jiang, Xinguo; Stockstill, Raymond W.; Nicolls, Mark R.; Zamanian, Roham T.; Bland, Richard D.

    2015-01-01

    Rationale: Pulmonary arterial hypertension is characterized by endothelial dysfunction, impaired bone morphogenetic protein receptor 2 (BMPR2) signaling, and increased elastase activity. Synthetic elastase inhibitors reverse experimental pulmonary hypertension but cause hepatotoxicity in clinical studies. The endogenous elastase inhibitor elafin attenuates hypoxic pulmonary hypertension in mice, but its potential to improve endothelial function and BMPR2 signaling, and to reverse severe experimental pulmonary hypertension or vascular pathology in the human disease was unknown. Objectives: To assess elafin-mediated regression of pulmonary vascular pathology in rats and in lung explants from patients with pulmonary hypertension. To determine if elafin amplifies BMPR2 signaling in pulmonary artery endothelial cells and to elucidate the underlying mechanism. Methods: Rats with pulmonary hypertension induced by vascular endothelial growth factor receptor blockade and hypoxia (Sugen/hypoxia) as well as lung organ cultures from patients with pulmonary hypertension were used to assess elafin-mediated reversibility of pulmonary vascular disease. Pulmonary arterial endothelial cells from patients and control subjects were used to determine the efficacy and mechanism of elafin-mediated BMPR2 signaling. Measurements and Main Results: In Sugen/hypoxia rats, elafin reduced elastase activity and reversed pulmonary hypertension, judged by regression of right ventricular systolic pressure and hypertrophy and pulmonary artery occlusive changes. Elafin improved endothelial function by increasing apelin, a BMPR2 target. Elafin induced apoptosis in human pulmonary arterial smooth muscle cells and decreased neointimal lesions in lung organ culture. In normal and patient pulmonary artery endothelial cells, elafin promoted angiogenesis by increasing pSMAD-dependent and -independent BMPR2 signaling. This was linked mechanistically to augmented interaction of BMPR2 with caveolin-1 via

  15. Blockade of CD26-mediated T cell costimulation with soluble caveolin-1-Ig fusion protein induces anergy in CD4{sup +}T cells

    SciTech Connect

    Ohnuma, Kei; Division of Clinical Immunology, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639 ; Uchiyama, Masahiko; Department of Computational Intelligence and System Science, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama, Kanagawa 226-8503 ; Hatano, Ryo; Takasawa, Wataru; Endo, Yuko; Dang, Nam H.; Morimoto, Chikao; Division of Clinical Immunology, The Advanced Clinical Research Center, The Institute of Medical Science, The University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639

    2009-08-21

    CD26 binds to caveolin-1 in antigen-presenting cells (APC), and that ligation of CD26 by caveolin-1 induces T cell proliferation in a TCR/CD3-dependent manner. We report herein the effects of CD26-caveolin-1 costimulatory blockade by fusion protein caveolin-1-Ig (Cav-Ig). Soluble Cav-Ig inhibits T cell proliferation and cytokine production in response to recall antigen, or allogeneic APC. Our data hence suggest that blocking of CD26-associated signaling by soluble Cav-Ig may be an effective approach as immunosuppressive therapy.

  16. Caveolin-1 expression and cavin stability regulate caveolae dynamics in adipocyte lipid store fluctuation.

    PubMed

    Briand, Nolwenn; Prado, Cécilia; Mabilleau, Guillaume; Lasnier, Françoise; Le Lièpvre, Xavier; Covington, Jeffrey D; Ravussin, Eric; Le Lay, Soazig; Dugail, Isabelle

    2014-12-01

    Adipocytes specialized in the storage of energy as fat are among the most caveolae-enriched cell types. Loss of caveolae produces lipodystrophic diabetes in humans, which cannot be reversed by endothelial rescue of caveolin expression in mice, indicating major importance of adipocyte caveolae. However, how caveolae participate in fat cell functions is poorly understood. We investigated dynamic conditions of lipid store fluctuations and demonstrate reciprocal regulation of caveolae density and fat cell lipid droplet storage. We identified caveolin-1 expression as a crucial step in adipose cell lines and in mice to raise the density of caveolae, to increase adipocyte ability to accommodate larger lipid droplets, and to promote cell expansion by increased glucose utilization. In human subjects enrolled in a trial of 8 weeks of overfeeding to promote fattening, adipocyte expansion response correlated with initial caveolin-1 expression. Conversely, lipid mobilization in cultured adipocytes to induce lipid droplet shrinkage led to biphasic response of cavin-1 with ultimate loss of expression of cavin-1 and -3 and EHD2 by protein degradation, coincident with caveolae disassembly. We have identified the key steps in cavin/caveolin interplay regulating adipocyte caveolae dynamics. Our data establish that caveolae participate in a unique cell response connected to lipid store fluctuation, suggesting lipid-induced mechanotension in adipocytes. PMID:24969108

  17. Caveolin-1 Expression and Cavin Stability Regulate Caveolae Dynamics in Adipocyte Lipid Store Fluctuation

    PubMed Central

    Briand, Nolwenn; Prado, Cécilia; Mabilleau, Guillaume; Lasnier, Françoise; Le Lièpvre, Xavier; Covington, Jeffrey D.; Ravussin, Eric; Le Lay, Soazig

    2014-01-01

    Adipocytes specialized in the storage of energy as fat are among the most caveolae-enriched cell types. Loss of caveolae produces lipodystrophic diabetes in humans, which cannot be reversed by endothelial rescue of caveolin expression in mice, indicating major importance of adipocyte caveolae. However, how caveolae participate in fat cell functions is poorly understood. We investigated dynamic conditions of lipid store fluctuations and demonstrate reciprocal regulation of caveolae density and fat cell lipid droplet storage. We identified caveolin-1 expression as a crucial step in adipose cell lines and in mice to raise the density of caveolae, to increase adipocyte ability to accommodate larger lipid droplets, and to promote cell expansion by increased glucose utilization. In human subjects enrolled in a trial of 8 weeks of overfeeding to promote fattening, adipocyte expansion response correlated with initial caveolin-1 expression. Conversely, lipid mobilization in cultured adipocytes to induce lipid droplet shrinkage led to biphasic response of cavin-1 with ultimate loss of expression of cavin-1 and -3 and EHD2 by protein degradation, coincident with caveolae disassembly. We have identified the key steps in cavin/caveolin interplay regulating adipocyte caveolae dynamics. Our data establish that caveolae participate in a unique cell response connected to lipid store fluctuation, suggesting lipid-induced mechanotension in adipocytes. PMID:24969108

  18. Registered report: Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis.

    PubMed

    Fiering, Steven; Ang, Lay-Hong; Lacoste, Judith; Smith, Tim D; Griner, Erin

    2015-01-01

    The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replicating selected results from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012 were selected on the basis of citations and Altimetric scores (Errington et al., 2014). This Registered report describes the proposed replication plan of key experiments from 'Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis' by Goetz and colleagues, published in Cell in 2011 (Goetz et al., 2011). The key experiments being replicated are those reported in Figures 7C (a-d), Supplemental Figure S2A, and Supplemental Figure S7C (a-c) (Goetz et al., 2011). In these experiments, which are a subset of all the experiments reported in the original publication, Goetz and colleagues show in a subcutaneous xenograft model that stromal caveolin-1 remodels the intratumoral microenvironment, which is correlated with increased metastasis formation. The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife. PMID:26179155

  19. Caveolin-1 regulates neural differentiation of rat bone mesenchymal stem cells into neurons by modulating Notch signaling.

    PubMed

    Wang, Shuyang; Kan, Quancheng; Sun, Yingpu; Han, Rui; Zhang, Guangyu; Peng, Tao; Jia, Yanjie

    2013-02-01

    Bone marrow mesenchymal stem cells (MSCs) are known to differentiate into neurons in vitro. However, the mechanism underlying MSC differentiation remains controversial. A recent analysis has shown that Notch signaling is involved in regulating the differentiation of MSCs. This study examines the potential mechanism of the differentiation of MSCs into neurons, and it considers the role of caveolin-1 in this process. We investigated neuron differentiation and Notch signaling by detecting the expression levels of microtubule-associated protein 2 (MAP-2), Neuron-specific Enolase (NSE), Notch-1, Notch intracellular domain (NICD) and hairy enhancer of split 5 (Hes5). We found that by down-regulating caveolin-1 during induction, MSCs were prone to neural differentiation and expressed high levels of neuronal markers. Meanwhile, the expression levels of Notch-1, NICD and Hes5 decreased. Our results indicate that down-regulation of caveolin-1 promotes the neuronal differentiation of MSCs by modulating the Notch signaling pathway. PMID:23031836

  20. Hypoxia induces cardiac fibroblast proliferation and phenotypic switch: a role for caveolae and caveolin-1/PTEN mediated pathway

    PubMed Central

    Gao, Yao; Chu, Ming; Hong, Jian; Shang, Jingping

    2014-01-01

    Background Cardiac fibrosis following myocardial infarction (MI) results in heart failure. Caveolin-1, the main structural protein of caveolae, regulates signal transduction pathways controlling cell proliferation and apoptosis. Meanwhile, low phosphatase and tensin homolog (PTEN) activity enhances the PI3K/Akt signal pathway to induce cell proliferation. But whether caveolin-1 and PTEN activation regulates cardiac fibroblast proliferation and contributes to cardiac fibrosis from ischemic injury is incompletely understood. This study investigates whether hypoxia inducing cardiac fibroblast proliferation and phenotypic switch is caveolin-dependent. Methods We used in vitro and in vivo models of ischemic injury, immunohistochemical staining, and cell proliferation assays to address this hypothesis. Results We found that MI induced collagen deposition and cardiac dysfunction. After MI, mice displayed reduced caveolin-1 and PTEN expression and increased α-smooth muscle actin (α-SMA) expression in the infarct zone. Qualitative and quantitative analyses indicated that caveolin-1 expression was lowest at 7 days after MI, accompanied by increased collagen deposition and attenuated cardiac function. We cultured cardiac fibroblasts of mice were in hypoxia or normoxia conditions for 12, 24 and 48 hours. At all the time points, caveolin-1 and PTEN expression were gradually reduced, whereas, α-SMA was gradually increased. We also observed that cell viability was increased at 12 and 24 h after hypoxia then lightly decreased at 48 h. Additionally, disruption of caveolae with methyl-β-cyclodextrin (MβCD) enhanced p-Akt and α-SMA expression and fibroblast proliferation and phenotypic switch. Conclusions These findings suggest a key role for caveolae, perhaps through the caveolin-1/PTEN signaling pathway, in cardiac fibroblast proliferation and phenotypic switch under hypoxia. PMID:25364523

  1. Caveolin-1 Dependent Endocytosis Enhances the Chemosensitivity of HER-2 Positive Breast Cancer Cells to Trastuzumab Emtansine (T-DM1)

    PubMed Central

    Chung, Yuan-Chiang; Kuo, Jang-Fang; Wei, Wan-Chen; Chang, King-Jen; Chao, Wei-Ting

    2015-01-01

    The humanized monoclonal antibody-drug conjugate trastuzumab emtansine (T-DM1, Kadcyla) has been approved by the U.S. FDA to treat human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. Despite its effectiveness in most patients, some are initially resistant or develop resistance. No biomarker of drug resistance to T-DM1 has been identified. Antibody-drug efficacy is associated with antibody internalization in the cell; therefore, cellular sensitivity of cells to the drug may be linked to cellular vesicle trafficking systems. Caveolin-1 is a 22 KD protein required for caveolae formation and endocytic membrane transport. In this study, the relationship between caveolin-1 expression and the chemosensitivity of HER-2-positive breast cancer cells to T-DM1 was investigated. Samples from 32 human breast cancer biopsy and normal tissue specimens were evaluated immunohistochemically for caveolin-1 expression. Caveolin-1 was shown to be expressed in 68% (22/32) of the breast cancer specimens. In addition, eight (72.7%, 8/11) HER-2 positive breast cancer specimens had a higher caveolin-1 expression than normal tissues. HER-2-positive BT-474 and SKBR-3 breast cancer cells that express low and moderate levels of caveolin-1, respectively, were treated with trastuzumab or its conjugate T-DM1. Cell viability and molecular localizations of caveolin-1, antibody and its conjugate were examined. Confocal microscopy showed that T-DM1 and caveolin-1 colocalized in SKBR-3 cells, which also were five times more sensitive to the conjugate in terms of cell survival than BT-474 cells, although T-DM1 also showed improved drug efficacy in BT-474 cells than trastuzumab treatment. Caveolin-1 expression in these lines was manipulated by transfection of GFP-tagged caveolin-1 or caveolin-1 siRNA. BT-474 cells overexpressing caveolin-1 were more sensitive to T-DM1 treatment than mock-transfected cells, whereas the siRNA-transfected SKBR-3 cells had decreased sensitivity

  2. Interplay between hepatic mitochondria-associated membranes, lipid metabolism and caveolin-1 in mice

    PubMed Central

    Sala-Vila, Aleix; Navarro-Lérida, Inmaculada; Sánchez-Alvarez, Miguel; Bosch, Marta; Calvo, Carlos; López, Juan Antonio; Calvo, Enrique; Ferguson, Charles; Giacomello, Marta; Serafini, Annalisa; Scorrano, Luca; Enriquez, José Antonio; Balsinde, Jesús; Parton, Robert G.; Vázquez, Jesús; Pol, Albert; Del Pozo, Miguel A.

    2016-01-01

    The mitochondria-associated membrane (MAM) is a specialized subdomain of the endoplasmic reticulum (ER) which acts as an intracellular signaling hub. MAM dysfunction has been related to liver disease. We report a high-throughput mass spectrometry-based proteomics characterization of MAMs from mouse liver, which portrays them as an extremely complex compartment involved in different metabolic processes, including steroid metabolism. Interestingly, we identified caveolin-1 (CAV1) as an integral component of hepatic MAMs, which determine the relative cholesterol content of these ER subdomains. Finally, a detailed comparative proteomics analysis between MAMs from wild type and CAV1-deficient mice suggests that functional CAV1 contributes to the recruitment and regulation of intracellular steroid and lipoprotein metabolism-related processes accrued at MAMs. The potential impact of these novel aspects of CAV1 biology on global cell homeostasis and disease is discussed. PMID:27272971

  3. Interplay between hepatic mitochondria-associated membranes, lipid metabolism and caveolin-1 in mice.

    PubMed

    Sala-Vila, Aleix; Navarro-Lérida, Inmaculada; Sánchez-Alvarez, Miguel; Bosch, Marta; Calvo, Carlos; López, Juan Antonio; Calvo, Enrique; Ferguson, Charles; Giacomello, Marta; Serafini, Annalisa; Scorrano, Luca; Enriquez, José Antonio; Balsinde, Jesús; Parton, Robert G; Vázquez, Jesús; Pol, Albert; Del Pozo, Miguel A

    2016-01-01

    The mitochondria-associated membrane (MAM) is a specialized subdomain of the endoplasmic reticulum (ER) which acts as an intracellular signaling hub. MAM dysfunction has been related to liver disease. We report a high-throughput mass spectrometry-based proteomics characterization of MAMs from mouse liver, which portrays them as an extremely complex compartment involved in different metabolic processes, including steroid metabolism. Interestingly, we identified caveolin-1 (CAV1) as an integral component of hepatic MAMs, which determine the relative cholesterol content of these ER subdomains. Finally, a detailed comparative proteomics analysis between MAMs from wild type and CAV1-deficient mice suggests that functional CAV1 contributes to the recruitment and regulation of intracellular steroid and lipoprotein metabolism-related processes accrued at MAMs. The potential impact of these novel aspects of CAV1 biology on global cell homeostasis and disease is discussed. PMID:27272971

  4. Caveolin-1/-3: therapeutic targets for myocardial ischemia/reperfusion injury.

    PubMed

    Yang, Yang; Ma, Zhiqiang; Hu, Wei; Wang, Dongjin; Jiang, Shuai; Fan, Chongxi; Di, Shouyin; Liu, Dong; Sun, Yang; Yi, Wei

    2016-07-01

    Myocardial ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality worldwide. Caveolae, caveolin-1 (Cav-1), and caveolin-3 (Cav-3) are essential for the protective effects of conditioning against myocardial I/R injury. Caveolins are membrane-bound scaffolding proteins that compartmentalize and modulate signal transduction. In this review, we introduce caveolae and caveolins and briefly describe the interactions of caveolins in the cardiovascular diseases. We also review the roles of Cav-1/-3 in protection against myocardial ischemia and I/R injury, and in conditioning. Finally, we suggest several potential research avenues that may be of interest to clinicians and basic scientists. The information included, herein, is potentially useful for the design of future studies and should advance the investigation of caveolins as therapeutic targets. PMID:27282376

  5. Identification of caveolin-1 as a potential causative factor in the generation of trastuzumab resistance in breast cancer cells.

    PubMed

    Sekhar, Sreeja C; Kasai, Tomonari; Satoh, Ayano; Shigehiro, Tsukasa; Mizutani, Akifumi; Murakami, Hiroshi; El-Aarag, Bishoy Ya; Salomon, David S; Massaguer, Anna; de Llorens, Rafael; Seno, Masaharu

    2013-01-01

    The oncogenic tyrosine kinase receptor ErbB2 is a prognostic factor and target for breast cancer therapeutics. In contrast with the other ErbB receptors, ErbB2 is hardly internalized by ligand induced mechanisms, indicating a prevalent surface expression. Elevated levels of ErbB2 in tumor cells are associated with its defective endocytosis and down regulation. Here we show that caveolin-1 expression in breast cancer derived SKBR-3 cells (SKBR-3/Cav-1) facilitates ligand induced ErbB2 endocytosis using an artificial peptide ligand EC-eGFP. Similarly, stimulation with humanized anti ErbB2 antibody Trastuzumab (Herceptin) was found to be internalized and co-localized with caveolin-1 in SKBR-3/Cav-1 cells. Internalized EC-eGFP and Trastuzumab in SKBR-3/Cav-1 cells were then delivered via caveolae to the caveolin-1 containing early endosomes. Consequently, attenuated Fc receptor mediated ADCC functions were observed when exposed to Trastuzumab and EC-Fc (EC-1 peptide conjugated to Fc part of human IgG). On the other hand, this caveolae dependent endocytic synergy was not observed in parental SKBR-3 cells. Therefore, caveolin-1 expression in breast cancer cells could be a predictive factor to estimate how cancer cells are likely to respond to Trastuzumab treatment. PMID:23833684

  6. ACTH-induced caveolin-1 tyrosine phosphorylation is related to podosome assembly in Y1 adrenal cells

    SciTech Connect

    Colonna, Cecilia . E-mail: ccolonna@fmed.uba.ar; Podesta, Ernesto J.

    2005-04-01

    Y1 adrenocortical cells respond to ACTH with a characteristic rounding-up that facilitates cAMP signaling, critical for transport of cholesterol to the mitochondria and increase in steroid secretion. We here demonstrate that caveolin-1 participates in coupling activation of protein kinase A (PKA) to the control of cell shape. ACTH/8-Br-cAMP induced reorganization of caveolin-1-positive structures in correlation with the cellular rounding-up. Concomitant with this change, there was an increase in the phosphorylation of caveolin-1 (Tyr-14) localized at focal adhesions (FA) with reorganization of FA to rounded, ringlike structures. Colocalization with phalloidin showed that phosphocaveolin is present at the edge of actin filaments and that after ACTH stimulation F-actin dots at the cell periphery become surrounded by phosphocaveolin-1. These observations along with electron microscopy studies revealed these structures as podosomes. Podosome assembly was dependent on both PKA and tyrosine kinase activities because their formation was impaired after treatment with specific inhibitors [myristoylated PKI (mPKI) or PP2, respectively] previous to ACTH/8-Br-cAMP stimulation. These results show for the first time that ACTH induces caveolin-1 phosphorylation and podosome assembly in Y1 cells and support the view that the morphological and functional responses to PKA activation in steroidogenic cells are related to cytoskeleton dynamics.

  7. Inter-domain tagging implicates caveolin-1 in insulin receptor trafficking and Erk signaling bias in pancreatic beta-cells

    PubMed Central

    Boothe, Tobias; Lim, Gareth E.; Cen, Haoning; Skovsø, Søs; Piske, Micah; Li, Shu Nan; Nabi, Ivan R.; Gilon, Patrick; Johnson, James D.

    2016-01-01

    Objective The role and mechanisms of insulin receptor internalization remain incompletely understood. Previous trafficking studies of insulin receptors involved fluorescent protein tagging at their termini, manipulations that may be expected to result in dysfunctional receptors. Our objective was to determine the trafficking route and molecular mechanisms of functional tagged insulin receptors and endogenous insulin receptors in pancreatic beta-cells. Methods We generated functional insulin receptors tagged with pH-resistant fluorescent proteins between domains. Confocal, TIRF and STED imaging revealed a trafficking pattern of inter-domain tagged insulin receptors and endogenous insulin receptors detected with antibodies. Results Surprisingly, interdomain-tagged and endogenous insulin receptors in beta-cells bypassed classical Rab5a- or Rab7-mediated endocytic routes. Instead, we found that removal of insulin receptors from the plasma membrane involved tyrosine-phosphorylated caveolin-1, prior to trafficking within flotillin-1-positive structures to lysosomes. Multiple methods of inhibiting caveolin-1 significantly reduced Erk activation in vitro or in vivo, while leaving Akt signaling mostly intact. Conclusions We conclude that phosphorylated caveolin-1 plays a role in insulin receptor internalization towards lysosomes through flotillin-1-positive structures and that caveolin-1 helps bias physiological beta-cell insulin signaling towards Erk activation. PMID:27110488

  8. Fatty acid-binding protein 7 regulates function of caveolae in astrocytes through expression of caveolin-1.

    PubMed

    Kagawa, Yoshiteru; Yasumoto, Yuki; Sharifi, Kazem; Ebrahimi, Majid; Islam, Ariful; Miyazaki, Hirofumi; Yamamoto, Yui; Sawada, Tomoo; Kishi, Hiroko; Kobayashi, Sei; Maekawa, Motoko; Yoshikawa, Takeo; Takaki, Eiichi; Nakai, Akira; Kogo, Hiroshi; Fujimoto, Toyoshi; Owada, Yuji

    2015-05-01

    Fatty acid-binding proteins (FABPs) bind and solubilize long-chain fatty acids, controlling intracellular lipid dynamics. FABP7 is expressed by astrocytes in the developing brain, and suggested to be involved in the control of astrocyte lipid homeostasis. In this study, we sought to examine the role of FABP7 in astrocytes, focusing on plasma membrane lipid raft function, which is important for receptor-mediated signal transduction in response to extracellular stimuli. In FABP7-knockout (KO) astrocytes, the ligand-dependent accumulation of Toll-like receptor 4 (TLR4) and glial cell-line-derived neurotrophic factor receptor alpha 1 into lipid raft was decreased, and the activation of mitogen-activated protein kinases and nuclear factor-κB was impaired after lipopolysaccharide (LPS) stimulation when compared with wild-type astrocytes. In addition, the expression of caveolin-1, not cavin-1, 2, 3, caveolin-2, and flotillin-1, was found to be decreased at the protein and transcriptional levels. FABP7 re-expression in FABP7-KO astrocytes rescued the decreased level of caveolin-1. Furthermore, caveolin-1-transfection into FABP7-KO astrocytes significantly increased TLR4 recruitment into lipid raft and tumor necrosis factor-α production after LPS stimulation. Taken together, these data suggest that FABP7 controls lipid raft function through the regulation of caveolin-1 expression and is involved in the response of astrocytes to the external stimuli. GLIA 2015;63:780-794. PMID:25601031

  9. Fyn is required for oxidative- and hyperosmotic-stress-induced tyrosine phosphorylation of caveolin-1.

    PubMed Central

    Sanguinetti, Amy R; Cao, Haiming; Corley Mastick, Cynthia

    2003-01-01

    Caveolin-1 is phosphorylated on Tyr(14) in response to both oxidative and hyperosmotic stress. In the present paper, we show that this phosphorylation requires activation of the Src family kinase Fyn. Stress-induced caveolin phosphorylation was abolished by three Src kinase inhibitors, SU6656, PP2 and PD180970, and was not observed in fibroblasts derived from a Src, Yes and Fyn triple-knockout mouse (SYF-/-). Using cell lines derived from single-kinase-knockout mice (Src-/-, Yes-/- and Fyn-/-), we show that expression of Fyn, but not Src or Yes, is required for stress-induced caveolin phosphorylation. Heterologous expression of Fyn in the SYF-/- and Fyn-/- cells was sufficient to reconstitute stress-induced caveolin phosphorylation, and overexpression of Fyn in wild-type cells induced hyperphosphorylation of caveolin. Fyn was autophosphorylated following oxidative stress, verifying activation of this kinase. Interestingly, there was a concomitant increase in the phosphorylation of Fyn on its Csk (C-terminal Src kinase) site, indicating feedback inhibition. Csk binds to phosphocaveolin [Cao, Courchesne and Mastick (2002) J. Biol. Chem. 277, 8771-8774] and should phosphorylate any co-localized Src-family kinases. Oxidative-stress-induced phosphorylation of caveolin-1 also requires expression of Abl [Sanguinetti and Mastick (2003) Cell Signal. 15, 289-298]. Using inhibitors and cells derived from knockout mice, we verified a requirement for both Abl and Fyn in stress-induced caveolin phosphorylation in a single cell type. Our data suggest a novel mechanism for attenuation of Src-kinase activity by Abl: stable tyrosine phosphorylation of a scaffolding protein, caveolin, and recruitment of Csk. Paxillin, a substrate of both Abl and Src, organizes a similar regulatory complex. PMID:12921535

  10. Caveolin-1 mediates tissue plasminogen activator-induced MMP-9 up-regulation in cultured brain microvascular endothelial cells.

    PubMed

    Jin, Xinchun; Sun, Yanyun; Xu, Ji; Liu, Wenlan

    2015-03-01

    Thrombolysis with tissue plasminogen activator (tPA) increases matrix metalloproteinase-9 (MMP-9) activity in the ischemic brain, which exacerbates blood-brain barrier injury and increases the risk of symptomatic cerebral hemorrhage. The mechanism through which tPA enhances MMP-9 activity is not well understood. Here we report an important role of caveolin-1 in mediating tPA-induced MMP-9 synthesis. Brain microvascular endothelial cell line bEnd3 cells were incubated with 5 or 20 μg/ml tPA for 24 hrs before analyzing MMP-9 levels in the conditioned media and cellular extracts by gelatin zymography. tPA at a dose of 20 μg/mL tPA, but not 5 μg/mL, significantly increased MMP-9 level in cultured media while decreasing it in cellular extracts. Concurrently, tPA treatment induced a 2.3-fold increase of caveolin-1 protein levels in endothelial cells. Interestingly, knockdown of Cav-1 with siRNA inhibited tPA-induced MMP-9 mRNA up-regulation and MMP-9 increase in the conditioned media, but did not affect MMP-9 decrease in cellular extracts. These results suggest that caveolin-1 critically contributes to tPA-mediated MMP-9 up-regulation, but may not facilitate MMP-9 secretion in endothelial cells. Thrombolysis with tissue plasminogen activator (tPA) increases matrix metalloproteinase-9 (MMP-9) activity in the ischemic brain, which exacerbates ischemic blood brain barrier (BBB) injury and increases the risk of symptomatic cerebral hemorrhage. Our results suggest a novel mechanism underlying this tPA-MMP 9 axis. In response to tPA treatment, caveolin-1 protein levels increased in endothelial cells, which mediate MMP-9 mRNA up-regulation and its secretion into extracellular space. Caveolin-1 may, however, not facilitate MMP-9 secretion in endothelial cells. Our data suggest caveolin-1 as a novel therapeutic target for protecting the BBB against ischemic damage. The schematic outlines tPA-induced MMP-9 upreguation. PMID:25683686

  11. Altered monocyte and fibrocyte phenotype and function in scleroderma interstitial lung disease: reversal by caveolin-1 scaffolding domain peptide.

    PubMed

    Tourkina, Elena; Bonner, Michael; Oates, James; Hofbauer, Ann; Richard, Mathieu; Znoyko, Sergei; Visconti, Richard P; Zhang, Jing; Hatfield, Corey M; Silver, Richard M; Hoffman, Stanley

    2011-01-01

    Interstitial lung disease (ILD) is a major cause of morbidity and mortality in scleroderma (systemic sclerosis, or SSc). Fibrocytes are a monocyte-derived cell population implicated in the pathogenesis of fibrosing disorders. Given the recently recognized importance of caveolin-1 in regulating function and signaling in SSc monocytes, in the present study we examined the role of caveolin-1 in the migration and/or trafficking and phenotype of monocytes and fibrocytes in fibrotic lung disease in human patients and an animal model. These studies fill a gap in our understanding of how monocytes and fibrocytes contribute to SSc-ILD pathology. We found that C-X-C chemokine receptor type 4-positive (CXCR4+)/collagen I-positive (ColI+), CD34+/ColI+ and CD45+/ColI+ cells are present in SSc-ILD lungs, but not in control lungs, with CXCR4+ cells being most prevalent. Expression of CXCR4 and its ligand, stromal cell-derived factor 1 (CXCL12), are also highly upregulated in SSc-ILD lung tissue. SSc monocytes, which lack caveolin-1 and therefore overexpress CXCR4, exhibit almost sevenfold increased migration toward CXCL12 compared to control monocytes. Restoration of caveolin-1 function by administering the caveolin scaffolding domain (CSD) peptide reverses this hypermigration. Similarly, transforming growth factor β-treated normal monocytes lose caveolin-1, overexpress CXCR4 and exhibit 15-fold increased monocyte migration that is CSD peptide-sensitive. SSc monocytes exhibit a different phenotype than normal monocytes, expressing high levels of ColI, CD14 and CD34. Because ColI+/CD14+ cells are prevalent in SSc blood, we looked for such cells in lung tissue and confirmed their presence in SSc-ILD lungs but not in normal lungs. Finally, in the bleomycin model of lung fibrosis, we show that CSD peptide diminishes fibrocyte accumulation in the lungs. Our results suggest that low caveolin-1 in SSc monocytes contributes to ILD via effects on cell migration and phenotype and that the

  12. Caveolin-1–dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo

    PubMed Central

    Marchiando, Amanda M.; Shen, Le; Graham, W. Vallen; Weber, Christopher R.; Schwarz, Brad T.; Austin, Jotham R.; Raleigh, David R.; Guan, Yanfang; Watson, Alastair J.M.; Montrose, Marshall H.

    2010-01-01

    Epithelial paracellular barrier function, determined primarily by tight junction permeability, is frequently disrupted in disease. In the intestine, barrier loss can be mediated by tumor necrosis factor (α) (TNF) signaling and epithelial myosin light chain kinase (MLCK) activation. However, TNF induces only limited alteration of tight junction morphology, and the events that couple structural reorganization to barrier regulation have not been defined. We have used in vivo imaging and transgenic mice expressing fluorescent-tagged occludin and ZO-1 fusion proteins to link occludin endocytosis to TNF-induced tight junction regulation. This endocytosis requires caveolin-1 and is essential for structural and functional tight junction regulation. These data demonstrate that MLCK activation triggers caveolin-1–dependent endocytosis of occludin to effect structural and functional tight junction regulation. PMID:20351069

  13. Caveolin-1 Expression Ameliorates Nephrotic Damage in a Rabbit Model of Cholesterol-Induced Hypercholesterolemia

    PubMed Central

    Chen, Ya-Hui; Lin, Wei-Wen; Liu, Chin-San; Hsu, Li-Sung; Lin, Yueh-Min; Su, Shih-Li

    2016-01-01

    Caveolin-1 (CAV-1) participates in regulating vesicular transport, signal transduction, tumor progression, and cholesterol homeostasis. In the present study, we tested the hypothesis that CAV-1 improves dyslipidemia, inhibits cyclophilin A (CypA)- mediated ROS production, prevents mitochondrial compensatory action and attenuates oxidative stress responses in cholesterol-induced hypercholesterolemia. To determine the role of CAV-1 in mediating oxidative and antioxidative as well as cholesterol homeostasis, hypercholesterolemic rabbits were intravenously administered antenapedia-CAV-1 (AP-CAV-1) peptide for 2 wk. AP-CAV-1 enhanced CAV-1 expression by ˃15%, inhibited CypA expression by ˃50% (P < 0.05) and significantly improved dyslipidemia, thus reducing neutral lipid peroxidation. Moreover, CAV-1 attenuated hypercholesterolemia-induced changes in mitochondrial morphology and biogenesis and preserved mitochondrial respiratory function. In addition, CAV-1 protected against hypercholesterol-induced oxidative stress responses by reducing the degree of oxidative damage and enhancing the expression of antioxidant enzymes. CAV-1 treatment significantly suppressed apoptotic cell death, as evidenced by the reduction in the number of terminal deoxynucleotidyl transferase dUTP nick end-labeling-positive cells. We concluded that CAV-1 plays a critical role in inhibiting CypA-mediated ROS production, improving dyslipidemia, maintaining mitochondrial function, and suppressing oxidative stress responses that are vital for cell survival in hypercholesterol-affected renal organs. PMID:27124120

  14. E-cadherin determines Caveolin-1 tumor suppression or metastasis enhancing function in melanoma cells

    PubMed Central

    Lobos-González, L; Aguilar, L; Diaz, J; Diaz, N; Urra, H; Torres, V; Silva, V; Fitzpatrick, C; Lladser, A; Hoek, K.S.; Leyton, L; Quest, AFG

    2013-01-01

    SUMMARY The role of caveolin-1 (CAV1) in cancer is highly controversial. CAV1 suppresses genes that favor tumor development, yet also promotes focal adhesion turnover and migration of metastatic cells. How these contrasting observations relate to CAV1 function in vivo is unclear. Our previous studies implicate E-cadherin in CAV1-dependent tumor suppression. Here we use murine melanoma B16F10 cells, with low levels of endogenous CAV1 and E-cadherin, to unravel how CAV1 affects tumor growth and metastasis, and to assess how co-expression of E-cadherin modulates CAV1 function in vivo in C57BL/6 mice. We find that overexpression of CAV1 in B16F10(cav-1) cells reduces subcutaneous tumor formation, but enhances metastasis relative to control cells. Furthermore, E-cadherin expression in B16F10(E-cad) cells reduces subcutaneous tumor formation, and lung metastasis when intravenously injected. Importantly, co-expression of CAV1 and E-cadherin in B16F10(cav1/E-cad) cells abolishes tumor formation, lung metastasis, increased Rac-1 activity and cell migration observed with B16F10(cav-1) cells. Finally, consistent with the notion that CAV1 participates in switching human melanomas to a more malignant phenotype, elevated levels of CAV1 expression correlated with enhanced migration and Rac-1 activation in these cells. PMID:23470013

  15. E-cadherin determines Caveolin-1 tumor suppression or metastasis enhancing function in melanoma cells.

    PubMed

    Lobos-González, Lorena; Aguilar, Lorena; Diaz, Jorge; Diaz, Natalia; Urra, Hery; Torres, Vicente A; Silva, Veronica; Fitzpatrick, Christopher; Lladser, Alvaro; Hoek, Keith S; Leyton, Lisette; Quest, Andrew F G

    2013-07-01

    The role of caveolin-1 (CAV1) in cancer is highly controversial. CAV1 suppresses genes that favor tumor development, yet also promotes focal adhesion turnover and migration of metastatic cells. How these contrasting observations relate to CAV1 function in vivo is unclear. Our previous studies implicate E-cadherin in CAV1-dependent tumor suppression. Here, we use murine melanoma B16F10 cells, with low levels of endogenous CAV1 and E-cadherin, to unravel how CAV1 affects tumor growth and metastasis and to assess how co-expression of E-cadherin modulates CAV1 function in vivo in C57BL/6 mice. We find that overexpression of CAV1 in B16F10 (cav-1) cells reduces subcutaneous tumor formation, but enhances metastasis relative to control cells. Furthermore, E-cadherin expression in B16F10 (E-cad) cells reduces subcutaneous tumor formation and lung metastasis when intravenously injected. Importantly, co-expression of CAV1 and E-cadherin in B16F10 (cav-1/E-cad) cells abolishes tumor formation, lung metastasis, increased Rac-1 activity, and cell migration observed with B16F10 (cav-1) cells. Finally, consistent with the notion that CAV1 participates in switching human melanomas to a more malignant phenotype, elevated levels of CAV1 expression correlated with enhanced migration and Rac-1 activation in these cells. PMID:23470013

  16. Significance of caveolin-1 and matrix metalloproteinase 14 gene expression in canine mammary tumours.

    PubMed

    Ebisawa, M; Iwano, H; Nishikawa, M; Tochigi, Y; Komatsu, T; Endou, Y; Hirayama, K; Taniyama, H; Kadosawa, T; Yokota, H

    2015-11-01

    Canine mammary tumours (CMTs) are the most common neoplasms affecting female dogs. There is an urgent need for molecular biomarkers that can detect early stages of the disease in order to improve accuracy of CMT diagnosis. The aim of this study was to examine whether caveolin-1 (Cav-1) and matrix metalloproteinase 14 (MMP14) are associated with CMT histological malignancy and invasion. Sixty-five benign and malignant CMT samples and six normal canine mammary glands were analysed using quantitative reverse transcription-polymerase chain reaction. Cav-1 and MMP14 genes were highly expressed in CMT tissues compared to normal tissues. Cav-1 especially was overexpressed in malignant and invasive CMT tissues. When a CMT cell line was cultured on fluorescent gelatin-coated coverslips, localisation of Cav-1 was observed at invadopodia-mediated degradation sites of the gelatin matrix. These findings suggest that Cav-1 may be involved in CMT invasion and that the markers may be useful for estimating CMT malignancy. PMID:26364240

  17. Identification of a novel prostate cancer biomarker, caveolin-1: Implications and potential clinical benefit

    PubMed Central

    Corn, Paul G; Thompson, Timothy C

    2010-01-01

    While prostate cancer is a common disease in men, it is uncommonly life-threatening. To better understand this phenomenon, tumor biologists have sought to elucidate the mechanisms that contribute to the development of virulent prostate cancer. The recent discovery that caveolin-1 (Cav-1) functions as an important oncogene involved in prostate cancer progression reflects the success of this effort. Cav-1 is a major structural coat protein of caveolae, specialized plasma membrane invaginations involved in multiple cellular functions, including molecular transport, cell adhesion, and signal transduction. Cav-1 is aberrantly overexpressed in human prostate cancer, with higher levels evident in metastatic versus primary sites. Intracellular Cav-1 promotes cell survival through activation of Akt and enhancement of additional growth factor pro-survival pathways. Cav-1 is also secreted as a biologically active molecule that promotes cell survival and angiogenesis within the tumor microenvironment. Secreted Cav-1 can be reproducibly detected in peripheral blood using a sensitive and specific immunoassay. Cav-1 levels distinguish men with prostate cancer from normal controls, and preoperative Cav-1 levels predict which patients are at highest risk for relapse following radical prostatectomy for localized disease. Thus, secreted Cav-1 is a promising biomarker in identifying clinically significant prostate cancer. PMID:21188102

  18. Pilus phase variation switches gonococcal adherence to invasion by caveolin-1-dependent host cell signaling.

    PubMed

    Faulstich, Michaela; Böttcher, Jan-Peter; Meyer, Thomas F; Fraunholz, Martin; Rudel, Thomas

    2013-01-01

    Many pathogenic bacteria cause local infections but occasionally invade into the blood stream, often with fatal outcome. Very little is known about the mechanism underlying the switch from local to invasive infection. In the case of Neisseria gonorrhoeae, phase variable type 4 pili (T4P) stabilize local infection by mediating microcolony formation and inducing anti-invasive signals. Outer membrane porin PorB(IA), in contrast, is associated with disseminated infection and facilitates the efficient invasion of gonococci into host cells. Here we demonstrate that loss of pili by natural pilus phase variation is a prerequisite for the transition from local to invasive infection. Unexpectedly, both T4P-mediated inhibition of invasion and PorB(IA)-triggered invasion utilize membrane rafts and signaling pathways that depend on caveolin-1-Y14 phosphorylation (Cav1-pY14). We identified p85 regulatory subunit of PI3 kinase (PI3K) and phospholipase Cγ1 as new, exclusive and essential interaction partners for Cav1-pY14 in the course of PorBIA-induced invasion. Active PI3K induces the uptake of gonococci via a new invasion pathway involving protein kinase D1. Our data describe a novel route of bacterial entry into epithelial cells and offer the first mechanistic insight into the switch from local to invasive gonococcal infection. PMID:23717204

  19. Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells.

    PubMed

    Schönle, Anne; Hartl, Frederike A; Mentzel, Jan; Nöltner, Theresa; Rauch, Katharina S; Prestipino, Alessandro; Wohlfeil, Sebastian A; Apostolova, Petya; Hechinger, Anne-Kathrin; Melchinger, Wolfgang; Fehrenbach, Kerstin; Guadamillas, Marta C; Follo, Marie; Prinz, Gabriele; Ruess, Ann-Katrin; Pfeifer, Dietmar; Angel Del Pozo, Miguel; Schmitt-Graeff, Annette; Duyster, Justus; Hippen, Keli I; Blazar, Bruce R; Schachtrup, Kristina; Minguet, Susana; Zeiser, Robert

    2016-04-14

    Caveolin-1 (Cav-1) is a key organizer of membrane specializations and a scaffold protein that regulates signaling in multiple cell types. We found increased Cav-1 expression in human and murine T cells after allogeneic hematopoietic cell transplantation. Indeed, Cav-1(-/-)donor T cells caused less severe acute graft-versus-host disease (GVHD) and yielded higher numbers of regulatory T cells (Tregs) compared with controls. Depletion of Tregs from the graft abrogated this protective effect. Correspondingly, Treg frequencies increased when Cav-1(-/-)T cells were exposed to transforming growth factor-β/T-cell receptor (TCR)/CD28 activation or alloantigen stimulation in vitro compared with wild-type T cells. Mechanistically, we found that the phosphorylation of Cav-1 is dispensable for the control of T-cell fate by using a nonphosphorylatable Cav-1 (Y14F/Y14F) point-mutation variant. Moreover, the close proximity of lymphocyte-specific protein tyrosine kinase (Lck) to the TCR induced by TCR-activation was reduced in Cav-1(-/-)T cells. Therefore, less TCR/Lck clustering results in suboptimal activation of the downstream signaling events, which correlates with the preferential development into a Treg phenotype. Overall, we report a novel role for Cav-1 in TCR/Lck spatial distribution upon TCR triggering, which controls T-cell fate toward a regulatory phenotype. This alteration translated into a significant increase in the frequency of Tregs and reduced GVHD in vivo. PMID:26837700

  20. ROR1 sustains caveolae and survival signalling as a scaffold of cavin-1 and caveolin-1.

    PubMed

    Yamaguchi, Tomoya; Lu, Can; Ida, Lisa; Yanagisawa, Kiyoshi; Usukura, Jiro; Cheng, Jinglei; Hotta, Naoe; Shimada, Yukako; Isomura, Hisanori; Suzuki, Motoshi; Fujimoto, Toyoshi; Takahashi, Takashi

    2016-01-01

    The receptor tyrosine kinase-like orphan receptor 1 (ROR1) sustains prosurvival signalling directly downstream of the lineage-survival oncogene NKX2-1/TTF-1 in lung adenocarcinoma. Here we report an unanticipated function of this receptor tyrosine kinase (RTK) as a scaffold of cavin-1 and caveolin-1 (CAV1), two essential structural components of caveolae. This kinase-independent function of ROR1 facilitates the interactions of cavin-1 and CAV1 at the plasma membrane, thereby preventing the lysosomal degradation of CAV1. Caveolae structures and prosurvival signalling towards AKT through multiple RTKs are consequently sustained. These findings provide mechanistic insight into how ROR1 inhibition can overcome EGFR-tyrosine kinase inhibitor (TKI) resistance due to bypass signalling via diverse RTKs such as MET and IGF-IR, which is currently a major clinical obstacle. Considering its onco-embryonic expression, inhibition of the scaffold function of ROR1 in patients with lung adenocarcinoma is an attractive approach for improved treatment of this devastating cancer. PMID:26725982

  1. Herpes Simplex Virus 1 Suppresses the Function of Lung Dendritic Cells via Caveolin-1

    PubMed Central

    Wu, Bing; Geng, Shuang; Bi, Yanmin; Liu, Hu; Hu, Yanxin; Li, Xinqiang; Zhang, Yizhi; Zhou, Xiaoyu; Zheng, Guoxing; He, Bin

    2015-01-01

    Caveolin-1 (Cav-1), the principal structural protein of caveolae, has been implicated as a regulator of virus-host interactions. Several viruses exploit caveolae to facilitate viral infections. However, the roles of Cav-1 in herpes simplex virus 1 (HSV-1) infection have not fully been elucidated. Here, we report that Cav-1 downregulates the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide (NO) in dendritic cells (DCs) during HSV-1 infection. As a result, Cav-1 deficiency led to an accelerated elimination of virus and less lung pathological change following HSV-1 infection. This protection was dependent on iNOS and NO production in DCs. Adoptive transfer of DCs with Cav-1 knockdown was sufficient to confer the protection to wild-type (WT) mice. In addition, Cav-1 knockout (KO) (Cav-1−/−) mice treated with an iNOS inhibitor exhibited significantly reduced survival compared to that of the nontreated controls. We found that Cav-1 colocalized with iNOS and HSV-1 in caveolae in HSV-1-infected DCs, suggesting their interaction. Taken together, our results identified Cav-1 as a novel regulator utilized by HSV-1 to evade the host antiviral response mediated by NO production. Therefore, Cav-1 might be a valuable target for therapeutic approaches against herpesvirus infections. PMID:26018534

  2. Perivascular Adipose Tissue Inhibits Endothelial Function of Rat Aortas via Caveolin-1

    PubMed Central

    Lee, Michelle Hui-Hsin; Chen, Shiu-Jen

    2014-01-01

    Perivascular adipose tissue (PVAT)-derived factors have been proposed to play an important role in the pathogenesis of atherosclerosis. Caveolin-1 (Cav-1), occupying the calcium/calmodulin binding site of endothelial NO synthase (eNOS) and then inhibiting nitric oxide (NO) production, is also involved in the development of atherosclerosis. Thus, we investigated whether PVAT regulated vascular tone via Cav-1 and/or endothelial NO pathways. Isometric tension studies were carried out in isolated thoracic aortas from Wistar rats in the presence and absence of PVAT. Concentration-response curves of phenylephrine, acetylcholine, and sodium nitroprusside were illustrated to examine the vascular reactivity and endothelial function. The protein expressions of eNOS and Cav-1 were also examined in aortic homogenates. Our results demonstrated that PVAT significantly enhanced vasoconstriction and inhibited vasodilatation via endothelium-dependent mechanism. The aortic NO production was diminished after PVAT treatment, whereas protein expression and activity of eNOS were not significantly affected. In addition, Cav-1 protein expression was significantly increased in aortas with PVAT transfer. Furthermore, a caveolae depleter methyl-β-cyclodextrin abolished the effect of PVAT on the enhancement of vasoconstriction, and reversed the impairment of aortic NO production. In conclusion, unknown factor(s) released from PVAT may inhibit endothelial NO production and induce vasocontraction via an increase of Cav-1 protein expression. PMID:24926683

  3. Lower Serum Caveolin-1 Is Associated with Cerebral Microbleeds in Patients with Acute Ischemic Stroke

    PubMed Central

    Zhang, Jun; Zhu, Wusheng; Xiao, Lulu; Cao, Qinqin; Zhang, Hao; Wang, Huaiming; Ye, Zusen; Hao, Yonggang; Dai, Qiliang; Sun, Wen; Liu, Xinfeng; Ye, Ruidong

    2016-01-01

    Caveolin-1 (Cav-1) plays pivotal roles in the endothelial damage following stroke. The present study aimed to investigate whether serum Cav-1 level is associated with the presence of cerebral small vessel disease (cSVD) in patients with acute ischemic stroke. To this end, 156 patients were consecutively enrolled. Cranial magnetic resonance imaging was analyzed to determine the surrogates of cSVD, including cerebral microbleeds (CMBs), silent lacunar infarcts (SLIs), and white matter hyperintensities (WMHs). After adjusting for potential confounders, patients with low Cav-1 level had a higher risk of CMBs than patients with high Cav-1 level (OR: 4.05, 95% CI: 1.77–9.30). However, there was no relationship between Cav-1 and the presence of SLIs or WMHs. When CMBs were stratified by location and number, a similar association was found in patients with deep or infratentorial CMBs (OR: 4.04, 95% CI: 1.59–10.25) and with multiple CMBs (OR: 3.18, 95% CI: 1.16–8.72). These results suggest lower serum Cav-1 levels may be associated with CMBs, especially those that are multiple and located in deep brain or infratentorial structures, in patients with acute ischemic stroke. Cav-1 may be involved in the pathophysiology of CMBs, and may act as a potential target for treating cSVD. PMID:27119011

  4. Oligomerization of Clostridium perfringens Epsilon Toxin Is Dependent upon Caveolins 1 and 2

    PubMed Central

    Fennessey, Christine M.; Sheng, Jinsong; Rubin, Donald H.; McClain, Mark S.

    2012-01-01

    Evidence from multiple studies suggests that Clostridium perfringens ε-toxin is a pore-forming toxin, assembling into oligomeric complexes in the plasma membrane of sensitive cells. In a previous study, we used gene-trap mutagenesis to identify mammalian factors contributing to toxin activity, including caveolin-2 (CAV2). In this study, we demonstrate the importance of caveolin-2 and its interaction partner, caveolin-1 (CAV1), in ε-toxin-induced cytotoxicity. Using CAV2-specific shRNA in a toxin-sensitive human kidney cell line, ACHN, we confirmed that cells deficient in CAV2 exhibit increased resistance to ε-toxin. Similarly, using CAV1-specific shRNA, we demonstrate that cells deficient in CAV1 also exhibit increased resistance to the toxin. Immunoprecipitation of CAV1 and CAV2 from ε-toxin-treated ACHN cells demonstrated interaction of both CAV1 and -2 with the toxin. Furthermore, blue-native PAGE indicated that the toxin and caveolins were components of a 670 kDa protein complex. Although ε-toxin binding was only slightly perturbed in caveolin-deficient cells, oligomerization of the toxin was dramatically reduced in both CAV1- and CAV2-deficient cells. These results indicate that CAV1 and -2 potentiate ε-toxin induced cytotoxicity by promoting toxin oligomerization – an event which is requisite for pore formation and, by extension, cell death. PMID:23056496

  5. Non-caveolar caveolin-1 expression in prostate cancer cells promotes lymphangiogenesis

    PubMed Central

    Nassar, Zeyad D.; Hill, Michelle M.; Parton, Robert G.; Francois, Mathias; Parat, Marie-Odile

    2015-01-01

    Lymphangiogenesis allows prostate cancer (PCa) lymphatic metastasis, which is associated with poor prognosis and short survival rates. Caveolin-1 (Cav-1) is a membrane protein localized in caveolae, but also exists in non-caveolar, cellular or extracellular forms. Cav-1 is overexpressed in PCa, promotes prostate tumour progression and metastasis. We investigated the effect of caveolar and non-caveolar Cav-1 on PCa lymphangiogenic potential. Cav-1 was down-regulated in PC3 and DU145, and ectopically expressed in LNCaP cells. The effect of PCa cell conditioned media on lymphatic endothelial cell (LEC) viability, chemotaxis, chemokinesis and differentiation was assessed. The effect of Cav-1 on PCa cell expression of lymphangiogenesis-modulators VEGF-A and VEGF-C was assessed using qPCR and ELISA of the conditioned medium. Non-caveolar Cav-1, whether exogenous or endogenous (in LNCaP and PC3 cells, respectively) enhanced LEC proliferation, migration and differentiation. In contrast, caveolar Cav-1 (in DU145 cells) did not significantly affect PCa cell lymphangiogenic potential. The effect of non-caveolar Cav-1 on LECs was mediated by increased expression of VEGF-A as demonstrated by neutralization by anti-VEGF-A antibody. This study unveils for the first time a crucial role for non-caveolar Cav-1 in modulating PCa cell expression of VEGF-A and subsequent LEC proliferation, migration and tube formation. PMID:26328273

  6. The influence of a caveolin-1 mutant on the function of P-glycoprotein

    PubMed Central

    Lee, Chih-Yuan; Lai, Ting-Yu; Tsai, Meng-Kun; Ou-Yang, Pu; Tsai, Ching-Yi; Wu, Shu-Wei; Hsu, Li-Chung; Chen, Jin-Shing

    2016-01-01

    The genetic heterogeneity in cancer cells has an increased chance in the acquisition of new mutant such as drug-resistant phenotype in cancer cells. The phenotype of drug resistance in cancer cells could be evaluated by the number or function of drug transporters on cell membranes, which would lead to decreased intracellular anti-cancer drugs concentration. Caveolae are flask-shaped invaginations on cell membrane that function in membrane trafficking, endocytosis, and as a compartment where receptors and signaling proteins are concentrated. Caveolin-1 (CAV1) is the principal structural protein of caveolae and closely correlates with multidrug resistance in cancer cells. In a systematic study of the ubiquitin-modified proteome, lysine 176 of CAV1 was identified as a potential post-translational modification site for ubiquitination. In this article, we identified a mutation at lysine 176 to arginine (K176R) on CAV1 would interfere with the biogenesis of caveolae and broke the interaction of CAV1 with P-glycoprotein. Functional assays further revealed that K176R mutant of CAV1 in cancer cells increased the transport activity of P-glycoprotein and decreased the killing ability of anti-cancer drugs in non-small-cell lung cancer cell lines. PMID:26843476

  7. Wogonin inhibits H2O2-induced vascular permeability through suppressing the phosphorylation of caveolin-1.

    PubMed

    Wang, Fei; Song, Xiuming; Zhou, Mi; Wei, Libin; Dai, Qinsheng; Li, Zhiyu; Lu, Na; Guo, Qinglong

    2013-03-01

    Wogonin, a naturally occurring monoflavonoid extracted from the root of Scutellaria baicalensis Georgi, has been reported for its anti-oxidant activity. However, it is still unclear whether wogonin can inhibit oxidant-induced vascular permeability. In this study, we evaluated the effects of wogonin on H2O2-induced vascular permeability in human umbilical vein endothelial cells (HUVECs). We found that wogonin can suppress the H2O2-stimulated actin remodeling and albumin uptake of HUVECs, as well as transendothelial cell migration of the human breast carcinoma cell MDA-MB-231. The mechanism revealed that wogonin inhibited H2O2-induced phosphorylation of caveolin-1 (cav-1) associating with the suppression of stabilization of VE-cadherin and β-catenin. Moreover, wogonin repressed anisomycin-induced phosphorylation of p38, cav-1 and vascular permeability. These results suggested that wogonin could inhibit H2O2-induced vascular permeability by downregulating the phosphorylation of cav-1, and that it might have a therapeutic potential for the diseases associated with the development of both oxidant and vascular permeability. PMID:23246481

  8. Caveolin-1 is ubiquitinated and targeted to intralumenal vesicles in endolysosomes for degradation

    PubMed Central

    Hayer, Arnold; Stoeber, Miriam; Ritz, Danilo; Engel, Sabrina; Meyer, Hemmo H.

    2010-01-01

    Caveolae are long-lived plasma membrane microdomains composed of caveolins, cavins, and a cholesterol-rich membrane. Little is known about how caveolae disassemble and how their coat components are degraded. We studied the degradation of caveolin-1 (CAV1), a major caveolar protein, in CV1 cells. CAV1 was degraded very slowly, but turnover could be accelerated by compromising caveolae assembly. Now, CAV1 became detectable in late endosomes (LE) and lysosomes where it was degraded. Targeting to the degradative pathway required ubiquitination and the endosomal sorting complex required for transport (ESCRT) machinery for inclusion into intralumenal vesicles in endosomes. A dual-tag strategy allowed us to monitor exposure of CAV1 to the acidic lumen of individual, maturing LE in living cells. Importantly, we found that “caveosomes,” previously described by our group as independent organelles distinct from endosomes, actually correspond to late endosomal compartments modified by the accumulation of overexpressed CAV1 awaiting degradation. The findings led us to a revised model for endocytic trafficking of CAV1. PMID:21041450

  9. Cardiopulmonary bypass increases pulmonary microvascular permeability through the Src kinase pathway: Involvement of caveolin-1 and vascular endothelial cadherin

    PubMed Central

    ZHANG, JUNWEN; JIANG, ZHAOLEI; BAO, CHUNRONG; MEI, JU; ZHU, JIAQUAN

    2016-01-01

    Changes in pulmonary microvascular permeability following cardiopulmonary bypass (CPB) and the underlying mechanisms have not yet been established. Therefore, the aim of the present study was to elucidate the alterations in pulmonary microvascular permeability following CPB and the underlying mechanism. The pulmonary microvascular permeability was measured using Evans Blue dye (EBD) exclusion, and the neutrophil infiltration and proinflammatory cytokine secretion was investigated. In addition, the activation of Src kinase and the phosphorylation of caveolin-1 and vascular endothelial cadherin (VE-cadherin) was examined. The results revealed that CPB increased pulmonary microvascular leakage, neutrophil count and proinflammatory cytokines in the bronchoalveolar lavage fluid, and activated Src kinase. The administration of PP2, an inhibitor of Src kinase, decreased the activation of Src kinase and attenuated the increase in pulmonary microvascular permeability observed following CPB. Two important proteins associated with vascular permeability, caveolin-1 and VE-cadherin, were significantly activated at 24 h in the lung tissues following CPB, which correlated with the alterations in pulmonary microvascular permeability and Src kinase. PP2 administration inhibited their activation, suggesting that they are downstream factors of Src kinase activation. The data indicated that the Src kinase pathway increased pulmonary microvascular permeability following CPB, and the activation of caveolin-1 and VE-cadherin may be involved. Inhibition of this pathway may provide a potential therapy for acute lung injury following cardiac surgery. PMID:26847917

  10. Escherichia coli K1 internalization via caveolae requires caveolin-1 and protein kinase Calpha interaction in human brain microvascular endothelial cells.

    PubMed

    Sukumaran, Sunil K; Quon, Michael J; Prasadarao, Nemani V

    2002-12-27

    The morbidity and mortality associated with Escherichia coli K1 meningitis during the neonatal period have remained significant over the last decade and are once again on the rise. Transcytosis of brain microvascular endothelial cells (BMEC) by E. coli within an endosome to avoid lysosomal fusion is crucial for dissemination into the central nervous system. Central to E. coli internalization of BMEC is the expression of OmpA (outer membrane protein A), which interacts with its receptor for the actin reorganization that leads to invasion. However, nothing is known about the nature of the signaling events for the formation of endosomes containing E. coli K1. We show here that E. coli K1 infection of human BMEC (HBMEC) results in activation of caveolin-1 for bacterial uptake via caveolae. The interaction of caveolin-1 with phosphorylated protein kinase Calpha (PKCalpha) at the E. coli attachment site is critical for the invasion of HBMEC. Optical sectioning of confocal images of infected HBMEC indicates continuing association of caveolin-1 with E. coli during transcytosis. Overexpression of a dominant-negative form of caveolin-1 containing mutations in the scaffolding domain blocked the interaction of phospho-PKCalpha with caveolin-1 and the E. coli invasion of HBMEC, but not actin cytoskeleton rearrangement or the phosphorylation of PKCalpha. The interaction of caveolin-1 with phospho-PKCalpha was completely abrogated in HBMEC overexpressing dominant-negative forms of either focal adhesion kinase or PKCalpha. Treatment of HBMEC with a cell-permeable peptide that represents the scaffolding domain, which was coupled to an antennapedia motif of a Drosophila transcription factor significantly blocked the interaction of caveolin-1 with phospho-PKCalpha and E. coli invasion. These results show that E. coli K1 internalizes HBMEC via caveolae and that the scaffolding domain of caveolin-1 plays a significant role in the formation of endosomes. PMID:12386163

  11. Caveolin-1-mediated suppression of cyclooxygenase-2 via a beta-catenin-Tcf/Lef-dependent transcriptional mechanism reduced prostaglandin E2 production and survivin expression.

    PubMed

    Rodriguez, Diego A; Tapia, Julio C; Fernandez, Jaime G; Torres, Vicente A; Muñoz, Nicolas; Galleguillos, Daniela; Leyton, Lisette; Quest, Andrew F G

    2009-04-01

    Augmented expression of cyclooxygenase-2 (COX-2) and enhanced production of prostaglandin E(2) (PGE(2)) are associated with increased tumor cell survival and malignancy. Caveolin-1 is a scaffold protein that has been proposed to function as a tumor suppressor in human cancer cells, although mechanisms underlying this ability remain controversial. Intriguingly, the possibility that caveolin-1 regulates the expression of COX-2 has not been explored. Here we show that augmented caveolin-1 expression in cells with low basal levels of this protein, such as human colon cancer (HT29, DLD-1), breast cancer (ZR75), and embryonic kidney (HEK293T) cells reduced COX-2 mRNA and protein levels and beta-catenin-Tcf/Lef and COX-2 gene reporter activity, as well as the production of PGE(2) and cell proliferation. Moreover, COX-2 overexpression or PGE(2) supplementation increased levels of the inhibitor of apoptosis protein survivin by a transcriptional mechanism, as determined by PCR analysis, survivin gene reporter assays and Western blotting. Furthermore, addition of PGE(2) to the medium prevented effects attributed to caveolin-1-mediated inhibition of beta-catenin-Tcf/Lef-dependent transcription. Finally, PGE(2) reduced the coimmunoprecipitation of caveolin-1 with beta-catenin and their colocalization at the plasma membrane. Thus, by reducing COX-2 expression, caveolin-1 interrupts a feedback amplification loop involving PGE(2)-induced signaling events linked to beta-catenin/Tcf/Lef-dependent transcription of tumor survival genes including cox-2 itself and survivin. PMID:19244345

  12. Methamphetamine reduces expression of caveolin-1 in the dorsal striatum: Implication for dysregulation of neuronal function.

    PubMed

    Somkuwar, Sucharita S; Fannon, McKenzie J; Head, Brian P; Mandyam, Chitra D

    2016-07-22

    Role of striatal dopamine D1 receptors (D1Rs) in methamphetamine (Meth) taking and seeking is recognized from contingent Meth self-administration studies. For example, Meth increases levels of D1Rs in the dorsal striatum in animal models of Meth addiction, and blockade of striatal D1Rs decreased responding for Meth and reduced Meth priming-induced drug seeking. However, the mechanism underlying enhanced expression of striatal D1Rs in animals self-administering Meth is unknown and is hypothesized to involve maladaptive intracellular signal transduction mechanism via hyperphosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2). D1Rs are predominantly localized to detergent-resistant membrane/lipid raft fractions (MLR fraction), and in vitro studies indicate that D1R signaling and recycling is regulated by the MLR-resident protein caveolin-1 (Cav-1), in an endocytotic-dependent manner. Notably, expression of Cav-1 is inversely regulated by ERK1/2 activation, suggesting a signaling interplay among D1Rs, ERK1/2 and Cav-1. We therefore evaluated the effects of extended access Meth self-administration on expression of striatal D1Rs, activated ERK1/2 and Cav-1. We first report that Cav-1 is heavily expressed in neurons located in the dorsal striatum. We also report that extended access Meth produces compulsive-like unregulated intake of the drug, and these behavioral outcomes are associated with enhanced expression of D1Rs, increased activity of ERK1/2, and reduced Cav-1 expression in the dorsal striatum. These data suggest a possible cellular mechanism that involves Cav-1 regulation of D1R expression in response to escalated Meth intake, and how this response of altered D1Rs and enhanced ERK1/2 activation to Meth self-administration contributes to contingent-related processes such as addiction. PMID:27138644

  13. Smooth muscle NOS, colocalized with caveolin-1, modulates contraction in mouse small intestine

    PubMed Central

    El-Yazbi, Ahmed F; Cho, Woo Jung; Cena, Jonathan; Schulz, Richard; Daniel, Edwin E

    2008-01-01

    Neuronal nitric oxide synthase (nNOS) in myenteric neurons is activated during peristalsis to produce nitric oxide which relaxes intestinal smooth muscle. A putative nNOS is also found in the membrane of intestinal smooth muscle cells in mouse and dog. In this study we studied the possible functions of this nNOS expressed in mouse small intestinal smooth muscle colocalized with caveolin-1(Cav-1). Cav-1 knockout mice lacked nNOS in smooth muscle and provided control tissues. 60 mM KCl was used to increase intracellular [Ca2+] through L-type Ca2+ channel opening and stimulate smooth muscle NOS activity in intestinal tissue segments. An additional contractile response to LNNA (100 μM, NOS inhibitor) was observed in KCl-contracted tissues from control mice and was almost absent in tissues from Cav-1 knockout mice. Disruption of caveolae with 40 mM methyl-β cyclodextrin in tissues from control mice led to the loss of Cav-1 and nNOS immunoreactivity from smooth muscle as shown by immunohistochemistry and a reduction in the response of these tissues to N-ω-nitro-L-arginine (LNNA). Reconstitution of membrane cholesterol using water soluble cholesterol in the depleted segments restored the immunoreactivity and the response to LNNA added after KCl. Nicardipine (1 μM) blocked the responses to KCl and LNNA confirming the role of L-type Ca2+ channels. ODQ (1 μM, soluble guanylate cyclase inhibitor) had the same effect as inhibition of NOS following KCl. We conclude that the activation of nNOS, localized in smooth muscle caveolae, by calcium entering through L-type calcium channels triggers nitric oxide production which modulates muscle contraction by a cGMP-dependent mechanism. PMID:18400048

  14. Caveolin-1 regulates P2X7 receptor signaling in osteoblasts

    PubMed Central

    Gangadharan, Vimal; Nohe, Anja; Caplan, Jeffrey; Czymmek, Kirk

    2014-01-01

    The synthesis of new bone in response to a novel applied mechanical load requires a complex series of cellular signaling events in osteoblasts and osteocytes. The activation of the purinergic receptor P2X7R is central to this mechanotransduction signaling cascade. Recently, P2X7R have been found to be associated with caveolae, a subset of lipid microdomains found in several cell types. Deletion of caveolin-1 (CAV1), the primary protein constituent of caveolae in osteoblasts, results in increased bone mass, leading us to hypothesize that the P2X7R is scaffolded to caveolae in osteoblasts. Thus, upon activation of the P2X7R, we postulate that caveolae are endocytosed, thereby modulating the downstream signal. Sucrose gradient fractionation of MC3T3-E1 preosteoblasts showed that CAV1 was translocated to the denser cytosolic fractions upon stimulation with ATP. Both ATP and the more specific P2X7R agonist 2′(3′)-O-(4-benzoylbenzoyl)ATP (BzATP) induced endocytosis of CAV1, which was inhibited when MC3T3-E1 cells were pretreated with the specific P2X7R antagonist A-839977. The P2X7R cofractionated with CAV1, but, using superresolution structured illumination microscopy, we found only a subpopulation of P2X7R in these lipid microdomains on the membrane of MC3T3-E1 cells. Suppression of CAV1 enhanced the intracellular Ca2+ response to BzATP, suggesting that caveolae regulate P2X7R signaling. This proposed mechanism is supported by increased mineralization in CAV1 knockdown MC3T3-E1 cells treated with BzATP. These data suggest that caveolae regulate P2X7R signaling upon activation by undergoing endocytosis and potentially carrying with it other signaling proteins, hence controlling the spatiotemporal signaling of P2X7R in osteoblasts. PMID:25318104

  15. Src-dependent phosphorylation of caveolin-1 Tyr-14 promotes swelling and release of caveolae.

    PubMed

    Zimnicka, Adriana M; Husain, Yawer S; Shajahan, Ayesha N; Sverdlov, Maria; Chaga, Oleg; Chen, Zhenlong; Toth, Peter T; Klomp, Jennifer; Karginov, Andrei V; Tiruppathi, Chinnaswamy; Malik, Asrar B; Minshall, Richard D

    2016-07-01

    Caveolin 1 (Cav1) is a required structural component of caveolae, and its phosphorylation by Src is associated with an increase in caveolae-mediated endocytosis. Here we demonstrate, using quantitative live-cell 4D, TIRF, and FRET imaging, that endocytosis and trafficking of caveolae are associated with a Cav1 Tyr-14 phosphorylation-dependent conformational change, which spatially separates, or loosens, Cav1 molecules within the oligomeric caveolar coat. When tracked by TIRF and spinning-disk microscopy, cells expressing phosphomimicking Cav1 (Y14D) mutant formed vesicles that were greater in number and volume than with Y14F-Cav1-GFP. Furthermore, we observed in HEK cells cotransfected with wild-type, Y14D, or Y14F Cav1-CFP and -YFP constructs that FRET efficiency was greater with Y14F pairs than with Y14D, indicating that pY14-Cav1 regulates the spatial organization of Cav1 molecules within the oligomer. In addition, albumin-induced Src activation or direct activation of Src using a rapamycin-inducible Src construct (RapR-Src) led to an increase in monomeric Cav1 in Western blots, as well as a simultaneous increase in vesicle number and decrease in FRET intensity, indicative of a Src-mediated conformational change in CFP/YFP-tagged WT-Cav1 pairs. We conclude that phosphorylation of Cav1 leads to separation or "spreading" of neighboring negatively charged N-terminal phosphotyrosine residues, promoting swelling of caveolae, followed by their release from the plasma membrane. PMID:27170175

  16. Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice.

    PubMed

    Shivshankar, Pooja; Brampton, Christopher; Miyasato, Shelley; Kasper, Michael; Thannickal, Victor J; Le Saux, Claude Jourdan

    2012-07-01

    Idiopathic pulmonary fibrosis is associated with a decreased expression of caveolin-1 (cav-1), yet its role remains unclear. To investigate the role of cav-1, we induced pulmonary fibrosis in wild-type (WT) and cav-1-deficient (cav-1(-/-)) mice using intratracheal instillation of bleomycin. Contrary to expectations, significantly less collagen deposition was measured in tissue from cav-1(-/-) mice than in their WT counterparts, consistent with reduced mRNA expression of procollagen1a2 and procollagen3a1. Moreover, cav-1(-/-) mice demonstrated 77% less α-smooth muscle actin staining, suggesting reduced mesenchymal cell activation. Levels of pulmonary injury, assessed by tenascin-C mRNA expression and CD44v10 detection, were significantly increased at Day 21 after injury in WT mice, an effect significantly attenuated in cav-1(-/-) mice. The apparent protective effect against bleomycin-induced fibrosis in cav-1(-/-) mice was attributed to reduce cellular senescence and apoptosis in cav-1(-/-) epithelial cells during the early phase of lung injury. Reduced matrix metalloproteinase (MMP)-2 and MMP-9 expressions indicated a low profile of senescence-associated secretory phenotype (SASP) in the bleomycin-injured cav-1(-/-) mice. However, IL-6 and macrophage inflammatory protein 2 were increased in WT and cav-1(-/-) mice after bleomycin challenge, suggesting that bleomycin-induced inflammatory response substantiated the SASP pool. Thus, loss of cav-1 attenuates early injury response to bleomycin by limiting stress-induced cellular senescence/apoptosis in epithelial cells. In contrast, decreased cav-1 expression promotes fibroblast activation and collagen deposition, effects that may be relevant in later stages of reparative response. Hence, therapeutic strategies to modulate the expression of cav-1 should take into account cell-specific effects in the regenerative responses of the lung epithelium to injury. PMID:22362388

  17. Vascular smooth muscle cell proliferation depends on caveolin-1-regulated polyamine uptake

    PubMed Central

    Grossi, Mario; Rippe, Catarina; Sathanoori, Ramasri; Swärd, Karl; Forte, Amalia; Erlinge, David; Persson, Lo; Hellstrand, Per; Nilsson, Bengt-Olof

    2014-01-01

    Much evidence highlights the importance of polyamines for VSMC (vascular smooth muscle cell) proliferation and migration. Cav-1 (caveolin-1) was recently reported to regulate polyamine uptake in intestinal epithelial cells. The aim of the present study was to assess the importance of Cav-1 for VSMC polyamine uptake and its impact on cell proliferation and migration. Cav-1 KO (knockout) mouse aortic cells showed increased polyamine uptake and elevated proliferation and migration compared with WT (wild-type) cells. Both Cav-1 KO and WT cells expressed the smooth muscle differentiation markers SM22 and calponin. Cell-cycle phase distribution analysis revealed a higher proportion of Cav-1 KO than WT cells in the S phase. Cav-1 KO cells were hyper-proliferative in the presence but not in the absence of extracellular polyamines, and, moreover, supplementation with exogenous polyamines promoted proliferation in Cav-1 KO but not in WT cells. Expression of the solute carrier transporters Slc7a1 and Slc43a1 was higher in Cav-1 KO than in WT cells. ODC (ornithine decarboxylase) protein and mRNA expression as well as ODC activity were similar in Cav-1 KO and WT cells showing unaltered synthesis of polyamines in Cav-1 KO cells. Cav-1 was reduced in migrating cells in vitro and in carotid lesions in vivo. Our data show that Cav-1 negatively regulates VSMC polyamine uptake and that the proliferative advantage of Cav-1 KO cells is critically dependent on polyamine uptake. We provide proof-of-principle for targeting Cav-1-regulated polyamine uptake as a strategy to fight unwanted VSMC proliferation as observed in restenosis. PMID:25301005

  18. Caveolin-1 protects against hepatic ischemia/reperfusion injury through ameliorating peroxynitrite-mediated cell death.

    PubMed

    Gao, Lei; Chen, Xingmiao; Peng, Tao; Yang, Dan; Wang, Qi; Lv, Zhiping; Shen, Jiangang

    2016-06-01

    Nitrative stress is considered as an important pathological process of hepatic ischemia and reperfusion injury but its regulating mechanisms are largely unknown. In this study, we tested the hypothesis that caveolin-1 (Cav-1), a plasma membrane scaffolding protein, could be an important cellular signaling against hepatic I/R injury through inhibiting peroxynitrite (ONOO(-))-induced cellular damage. Male wild-type mice and Cav-1 knockout (Cav-1(-/-)) were subjected to 1h hepatic ischemia following 1, 6 and 12h of reperfusion by clipping and releasing portal vessels respectively. Immortalized human hepatocyte cell line (L02) was subjected to 1h hypoxia and 6h reoxygenation and treated with Cav-1 scaffolding domain peptide. The major discoveries included: (1) the expression of Cav-1 in serum and liver tissues of wild-type mice was time-dependently elevated during hepatic ischemia-reperfusion injury. (2) Cav-1 scaffolding domain peptide treatment inhibited cleaved caspase-3 expression in the hypoxia-reoxygenated L02 cells; (3) Cav-1 knockout (Cav-1(-/-)) mice had significantly higher levels of serum transaminases (ALT&AST) and TNF-α, and higher rates of apoptotic cell death in liver tissues than wild-type mice after subjected to 1h hepatic ischemia and 6hour reperfusion; (4) Cav-1(-/-) mice revealed higher expression levels of iNOS, ONOO(-) and 3-nitrotyrosine (3-NT) in the liver than wild-type mice, and Fe-TMPyP, a representative peroxynitrite decomposition catalyst (PDC), remarkably reduced level of ONOO(-) and 3-NT and ameliorated the serum ALT, AST and TNF-α levels in both wild-type and Cav-1(-/-) mice. Taken together, we conclude that Cav-1 could play a critical role in preventing nitrative stress-induced liver damage during hepatic ischemia-reperfusion injury. PMID:27021966

  19. SorLA in glia: shared subcellular distribution patterns with caveolin-1.

    PubMed

    Salgado, Iris K; Serrano, Melissa; García, José O; Martínez, Namyr A; Maldonado, Héctor M; Báez-Pagán, Carlos A; Lasalde-Dominicci, José A; Silva, Walter I

    2012-04-01

    SorLA is an established sorting and trafficking protein in neurons with demonstrated relevance to Alzheimer's disease (AD). It shares these roles with the caveolins, markers of membrane rafts microdomains. To further our knowledge on sorLA's expression and traffic, we studied sorLA expression in various cultured glia and its relation to caveolin-1 (cav-1), a caveolar microdomain marker. RT-PCR and immunoblots demonstrated sorLA expression in rat C6 glioma, primary cultures of rat astrocytes (PCRA), and human astrocytoma 1321N1 cells. PCRA were determined to express the highest levels of sorLA's message. Induction of differentiation of C6 cells into an astrocyte-like phenotype led to a significant decrease in sorLA's mRNA and protein expression. A set of complementary experimental approaches establish that sorLA and cav-1 directly or indirectly interact in glia: (1) co-fractionation in light-density membrane raft fractions of rat C6 glioma, PCRA, and human 1321N1 astrocytoma cells; (2) a subcellular co-localization distribution pattern in vesicular perinuclear compartments seen via confocal imaging in C6 and PCRA; (3) additional confocal analysis in C6 cells suggesting that the perinuclear compartments correspond to their co-localization in early endosomes and the trans-Golgi; and; (4) co-immunoprecipitation data strongly supporting their direct or indirect physical interaction. These findings further establish that sorLA is expressed in glia and that it shares its subcellular distribution pattern with cav-1. A direct or indirect cav-1/sorLA interaction could modify the trafficking and sorting functions of sorLA in glia and its proposed neuroprotective role in AD. PMID:22127416

  20. Loss of caveolin-1 and gain of MCT4 expression in the tumor stroma

    PubMed Central

    Martins, Diana; Beça, Francisco F; Sousa, Bárbara; Baltazar, Fátima; Paredes, Joana; Schmitt, Fernando

    2013-01-01

    The progression from in situ to invasive breast carcinoma is still an event poorly understood. However, it has been suggested that interactions between the neoplastic cells and the tumor microenvironment may play an important role in this process. Thus, the determination of differential tumor-stromal metabolic interactions could be an important step in invasiveness. The expression of stromal Caveolin-1 (Cav-1) has already been implicated in the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Additionally, stromal Cav-1 expression has been associated with the expression of stromal monocarboxylate transporter 4 (MCT4) in invasive breast cancer. However, the role of stromal MCT4 in invasiveness has never been explored, neither the association between Cav-1 and MCT4 in the transition from breast DCIS to IDC. Therefore, our aim was to investigate in a series of breast cancer samples including matched in situ and invasive components, if there was a relationship between stromal Cav-1 and MCT4 in the progression from in situ to invasive carcinoma. We found loss of stromal Cav-1 in the progression to IDC in 75% of the cases. In contrast, MCT4 stromal expression was acquired in 87% of the IDCs. Interestingly, a concomitant loss of Cav-1 and gain of MCT4 was observed in the stroma of 75% of the cases, when matched in situ and invasive carcinomas were compared. These results suggest that alterations in Cav-1 and MCT4 may thus mark a critical point in the progression from in situ to invasive breast cancer. PMID:23907124

  1. A role for caveolin-1 in desmoglein binding and desmosome dynamics

    PubMed Central

    Brennan, Donna; Peltonen, Sirkku; Dowling, Alicia; Medhat, Walid; Green, Kathleen J.; Wahl, James K.; Del Galdo, Francesco; Mahoney, Mỹ G.

    2011-01-01

    Desmoglein 2 (Dsg2) is a desmosomal cadherin that is aberrantly expressed in human skin carcinomas. In addition to its well-known role in mediating intercellular desmosomal adhesion, Dsg2 regulates mitogenic signaling that may promote cancer development and progression. However, the mechanisms by which Dsg2 activates these signaling pathways and the relative contribution of its signaling and adhesion functions in tumor progression are poorly understood. In this study we show that Dsg2 associates with caveolin-1 (Cav-1), the major protein of specialized membrane microdomains called caveolae, which functions in both membrane protein turnover and intracellular signaling. Sequence analysis revealed that Dsg2 contains a putative Cav-1 binding motif. A permeable competing peptide resembling the Cav-1 scaffolding domain bound to Dsg2, disrupted normal Dsg2 staining and interfered with the integrity of epithelial sheets in vitro. Additionally, we observed that Dsg2 is proteolytically processed; resulting in a 95 kDa ectodomain shed product and a 65 kDa membrane-spanning fragment, the latter of which localizes to lipid rafts along with full-length Dsg2. Disruption of lipid rafts shifted Dsg2 to the non-raft fractions, leading to the accumulation of these proteins. Interestingly, Dsg2 proteolytic products are elevated in vivo in skin tumors from transgenic mice overexpressing Dsg2. Collectively, these data are consistent with the possibility that accumulation of truncated Dsg2 protein interferes with desmosome assembly and/or maintenance to disrupt cell-cell adhesion. Furthermore, the association of Dsg2 with Cav-1 may provide a mechanism for regulating mitogenic signaling and modulating the cell surface presentation of an important adhesion molecule, both of which could contribute to malignant transformation and tumor progression. PMID:21841821

  2. Expression of caveolin-1 is correlated with disease stage and survival in lung adenocarcinomas.

    PubMed

    Zhan, Ping; Shen, Xiao-Kun; Qian, Qian; Wang, Qin; Zhu, Ji-Ping; Zhang, Yu; Xie, Hai-Yan; Xu, Chuen-Hua; Hao, Ke-Ke; Hu, Wei; Xia, Ning; Lu, Guo-Jun; Yu, Li-Ke

    2012-04-01

    Caveolin-1 (cav-1) has been implicated in the development of human cancers. However, the distribution of cav-1 in non-small cell lung cancer (NSCLC) and its significance require further study. Real-time PCR and Western blot assays were performed to detect cav-1 mRNA and protein levels in tumor tissues (TT) and matched tumor-free tissues (TF). The protein expression in 115 paraffin-embedded blocks was examined by immunohistochemical staining (IHC). Correlations between cav-1 mRNA and protein expression by IHC and clinicopathological features were statistically evaluated. For the 136 patients examined, the levels of cav-1 mRNA and protein expression were significantly lower in lung TT compared to matched TF (P<0.05). High cav-1 expression was detected in 60 of 115 (52.2%) NSCLC tissues and this level was significantly lower than cav-1 expression in non-cancerous lung tissues (15 of 19, 78.9%, P<0.05). Up-regulation of cav-1 mRNA expression in lung adenocarcinoma (AC) (29.7%) was higher than that observed in lung squamous cell carcinoma (SCC) (15.8%). Statistical analysis of the correlation between cav-1 protein expression and clinical features showed a statistical association with poorer N-stage (P=0.032) and higher pathological TNM stage (P=0.012) in lung AC patients, that was not found in lung SCC patients. Moreover, lung AC patients with higher cav-1 expression showed significantly shorter life-spans than those with lower cav-1 expression (P=0.032, log-rank test). The levels of cav-1 mRNA and protein expression were significantly lower in lung cancers when compared to matched TF or non-cancerous lung tissues. The higher protein expression correlated with the advanced pathological stage and shorter survival rates in lung AC patients. PMID:22200856

  3. Prognostic value of caveolin-1 in genitourinary cancer: a meta-analysis

    PubMed Central

    Liu, Jia-Ming; Cheng, Si-Hang; Liu, Xiao-Xiao; Xia, Chao; Wang, Wei-Wen; Ma, Xue-Lei

    2015-01-01

    We aimed to obtain the most comprehensive picture to date of the prognostic value of caveolin-1 (Cav-1) in genitourinary carcinoma by meta-analyzing all eligible studies in PubMed and EMBASE. Data on patient clinical characteristics, cancer-specific survival (CSS) and recurrence-free survival (RFS) were extracted. The meta-analysis included 6 articles on prostate cancer, 5 on renal cancer, 1 on bladder cancer and 1 on transition cell carcinoma of the upper urinary tract. Two studies examining the association of ELISA-measured Cav-1 levels in serum with RFS in 621 patients with prostate cancer gave a combined hazard ratio (HR) of 1.25 (95% CI 0.36 to 4.36). The other 4 studies on prostate cancer examined the association of immunohistochemically determined Cav-1 levels in cancerous tissue with RFS and gave a combined HR of 1.83 (95% CI 1.36 to 2.47). Three studies on renal cancer examining the association of Cav-1 levels with CSS gave a multivariate HR of 1.98 (95% CI 1.35 to 2.90). The single studies on bladder carcinoma and upper urinary tract carcinoma gave, respectively, a multivariate HR of 2.28 (95% CI 1.09 to 4.74) for the relationship of Cav-1 levels to DFS, and a multivariate HR of 5.08 (95% CI 1.799 to 14.342) for the relationship of Cav-1 levels to CSS. This meta-analysis of available evidence suggests that elevated Cav-1 levels in serum can predict poor survival in patients with genitourinary cancer, which may help identify high-risk patients earlier and guide clinical decision-making. PMID:26884999

  4. Deletion of Caveolin-1 Protects against Oxidative Lung Injury via Up-Regulation of Heme Oxygenase-1

    PubMed Central

    Jin, Yang; Kim, Hong Pyo; Chi, Minli; Ifedigbo, Emeka; Ryter, Stefan W.; Choi, Augustine M. K.

    2008-01-01

    Acute lung injury (ALI) is a major cause of morbidity and mortality in critically ill patients. Hyperoxia causes lung injury in animals and humans, and is an established model of ALI. Caveolin-1, a major constituent of caveolae, regulates numerous biological processes, including cell death and proliferation. Here we demonstrate that caveolin-1–null mice (cav-1−/−) were resistant to hyperoxia-induced death and lung injury. Cav-1−/− mice sustained reduced lung injury after hyperoxia as determined by protein levels in bronchoalveolar lavage fluid and histologic analysis. Furthermore, cav-1−/− fibroblasts and endothelial cells and cav-1 knockdown epithelial cells resisted hyperoxia-induced cell death in vitro. Basal and inducible expression of the stress protein heme oxygenase-1 (HO-1) were markedly elevated in lung tissue or fibroblasts from cav-1−/− mice. Hyperoxia induced the physical interaction between cav-1 and HO-1 in fibroblasts assessed by co-immunoprecipitation studies, which resulted in attenuation of HO activity. Inhibition of HO activity with tin protoporphyrin-IX abolished the survival benefits of cav-1−/− cells and cav-1−/− mice exposed to hyperoxia. The cav-1−/− mice displayed elevated phospho-p38 mitogen-activated protein kinase (MAPK) and p38β expression in lung tissue/cells under basal conditions and during hyperoxia. Treatment with SB202190, an inhibitor of p38 MAPK, decreased hyperoxia-inducible HO-1 expression in wild-type and cav-1−/− fibroblasts. Taken together, our data demonstrated that cav-1 deletion protects against hyperoxia-induced lung injury, involving in part the modulation of the HO-1–cav-1 interaction, and the enhanced induction of HO-1 through a p38 MAPK–mediated pathway. These studies identify caveolin-1 as a novel component involved in hyperoxia-induced lung injury. PMID:18323531

  5. Up-regulation of endothelial monocyte chemoattractant protein-1 by coplanar PCB77 is caveolin-1-dependent

    SciTech Connect

    Majkova, Zuzana; Smart, Eric; Toborek, Michal; Hennig, Bernhard

    2009-05-15

    Atherosclerosis, the primary cause of heart disease and stroke is initiated in the vascular endothelium, and risk factors for its development include environmental exposure to persistent organic pollutants. Caveolae are membrane microdomains involved in regulation of many signaling pathways, and in particular in endothelial cells. We tested the hypothesis that intact caveolae are required for coplanar PCB77-induced up-regulation of monocyte chemoattractant protein-1 (MCP-1), an endothelium-derived chemokine that attracts monocytes into sub-endothelial space in early stages of the atherosclerosis development. Atherosclerosis-prone LDL-R{sup -/-} mice (control) or caveolin-1{sup -/-}/LDL-R{sup -/-} mice were treated with PCB77. PCB77 induced aortic mRNA expression and plasma protein levels of MCP-1 in control, but not caveolin-1{sup -/-}/LDL-R{sup -/-} mice. To study the mechanism of this effect, primary endothelial cells were used. PCB77 increased MCP-1 levels in endothelial cells in a time- and concentration-dependent manner. This effect was abolished by caveolin-1 silencing using siRNA. Also, MCP-1 up-regulation by PCB77 was prevented by inhibiting p38 and c-Jun N-terminal kinase (JNK), but not ERK1/2, suggesting regulatory functions via p38 and JNK MAPK pathways. Finally, pre-treatment of endothelial cells with the aryl hydrocarbon receptor (AhR) inhibitor {alpha}-naphthoflavone ({alpha}-NF) partially blocked MCP-1 up-regulation. Thus, our data demonstrate that coplanar PCB77 can induce MCP-1 expression by endothelial cells and that this effect is mediated by AhR, as well as p 38 and JNK MAPK pathways. Intact caveolae are required for these processes both in vivo and in vitro. This further supports a key role for caveolae in vascular inflammation induced by persistent organic pollutants.

  6. Caveolin-1 and CDC42 mediated endocytosis of silica-coated iron oxide nanoparticles in HeLa cells

    PubMed Central

    Jordan, Andreas

    2015-01-01

    Summary Nanomedicine is a rapidly growing field in nanotechnology, which has great potential in the development of new therapies for numerous diseases. For example iron oxide nanoparticles are in clinical use already in the thermotherapy of brain cancer. Although it has been shown, that tumor cells take up these particles in vitro, little is known about the internalization routes. Understanding of the underlying uptake mechanisms would be very useful for faster and precise development of nanoparticles for clinical applications. This study aims at the identification of key proteins, which are crucial for the active uptake of iron oxide nanoparticles by HeLa cells (human cervical cancer) as a model cell line. Cells were transfected with specific siRNAs against Caveolin-1, Dynamin 2, Flotillin-1, Clathrin, PIP5Kα and CDC42. Knockdown of Caveolin-1 reduces endocytosis of superparamagnetic iron oxide nanoparticles (SPIONs) and silica-coated iron oxide nanoparticles (SCIONs) between 23 and 41%, depending on the surface characteristics of the nanoparticles and the experimental design. Knockdown of CDC42 showed a 46% decrease of the internalization of PEGylated SPIONs within 24 h incubation time. Knockdown of Dynamin 2, Flotillin-1, Clathrin and PIP5Kα caused no or only minor effects. Hence endocytosis in HeLa cells of iron oxide nanoparticles, used in this study, is mainly mediated by Caveolin-1 and CDC42. It is shown here for the first time, which proteins of the endocytotic pathway mediate the endocytosis of silica-coated iron oxide nanoparticles in HeLa cells in vitro. In future studies more experiments should be carried out with different cell lines and other well-defined nanoparticle species to elucidate possible general principles. PMID:25671161

  7. Increased PEA3/E1AF and decreased Net/Elk-3, both ETS proteins, characterize human NSCLC progression and regulate caveolin-1 transcription in Calu-1 and NCI-H23 NSCLC cell lines.

    PubMed

    Sloan, Karin A; Marquez, Hector A; Li, Jun; Cao, Yuxia; Hinds, Anne; O'Hara, Carl J; Kathuria, Satinder; Ramirez, Maria I; Williams, Mary C; Kathuria, Hasmeena

    2009-08-01

    Caveolin-1 protein has been called a 'conditional tumor suppressor' because it can either suppress or enhance tumor progression depending on cellular context. Caveolin-1 levels are dynamic in non-small-cell lung cancer, with increased levels in metastatic tumor cells. We have shown previously that transactivation of an erythroblastosis virus-transforming sequence (ETS) cis-element enhances caveolin-1 expression in a murine lung epithelial cell line. Based on high sequence homology between the murine and human caveolin-1 promoters, we proposed that ETS proteins might regulate caveolin-1 expression in human lung tumorigenesis. We confirm that caveolin-1 is not detected in well-differentiated primary lung tumors. Polyoma virus enhancer activator 3 (PEA3), a pro-metastatic ETS protein in breast cancer, is expressed at low levels in well-differentiated tumors and high levels in poorly differentiated tumors. Conversely, Net, a known ETS repressor, is expressed at high levels in the nucleus of well-differentiated primary tumor cells. In tumor cells in metastatic lymph node sites, caveolin-1 and PEA3 are highly expressed, whereas Net is now expressed in the cytoplasm. We studied transcriptional regulation of caveolin-1 in two human lung cancer cell lines, Calu-1 (high caveolin-1 expressing) and NCI-H23 (low caveolin-1 expressing). Chromatin immunoprecipitation-binding assays and small interfering RNA experiments show that PEA3 is a transcriptional activator in Calu-1 cells and that Net is a transcriptional repressor in NCI-H23 cells. These results suggest that Net may suppress caveolin-1 transcription in primary lung tumors and that PEA3 may activate caveolin-1 transcription in metastatic lymph nodes. PMID:19483189

  8. Prolonged nitric oxide exposure enhances anoikis resistance and migration through epithelial-mesenchymal transition and caveolin-1 upregulation.

    PubMed

    Chanvorachote, Pithi; Pongrakhananon, Varisa; Chunhacha, Preedakorn

    2014-01-01

    Nitric oxide (NO) in tumor microenvironment may have a significant impact on metastatic behaviors of cancer. Noncytotoxic doses of NO enhanced anoikis resistance and migration in lung cancer H23 cells via an increase in lamellipodia, epithelial-mesenchymal transition (EMT) markers including vimentin and snail, and caveolin-1 (Cav-1). However, the induction of EMT was found in Cav-1-knock down cells treated with NO, suggesting that EMT was through Cav-1-independent pathway. These effects of NO were consistently observed in other lung cancer cells including H292 and H460 cells. These findings highlight the novel role of NO on EMT and metastatic behaviors of cancer cells. PMID:24967418

  9. Gene expression profiling of early intervertebral disc degeneration reveals a down-regulation of canonical Wnt signaling and caveolin-1 expression: implications for development of regenerative strategies

    PubMed Central

    2013-01-01

    Introduction Early degeneration of the intervertebral disc (IVD) involves a change in cellular differentiation from notochordal cells (NCs) in the nucleus pulposus (NP) to chondrocyte-like cells (CLCs). The purpose of this study was to investigate the gene expression profiles involved in this process using NP tissue from non-chondrodystrophic and chondrodystrophic dogs, a species with naturally occurring IVD degeneration. Methods Dual channel DNA microarrays were used to compare 1) healthy NP tissue containing only NCs (NC-rich), 2) NP tissue with a mixed population of NCs and CLCs (Mixed), and 3) NP tissue containing solely CLCs (CLC-rich) in both non-chondrodystrophic and chondrodystrophic dogs. Based on previous reports and the findings of the microarray analyses, canonical Wnt signaling was further evaluated using qPCR of relevant Wnt target genes. We hypothesized that caveolin-1, a regulator of Wnt signaling that showed significant changes in gene expression in the microarray analyses, played a significant role in early IVD degeneration. Caveolin-1 expression was investigated in IVD tissue sections and in cultured NCs. To investigate the significance of Caveolin-1 in IVD health and degeneration, the NP of 3-month-old Caveolin-1 knock-out mice was histopathologically evaluated and compared with the NP of wild-type mice of the same age. Results Early IVD degeneration involved significant changes in numerous pathways, including Wnt/β-catenin signaling. With regard to Wnt/β-catenin signaling, axin2 gene expression was significantly higher in chondrodystrophic dogs compared with non-chondrodystrophic dogs. IVD degeneration involved significant down-regulation of axin2 gene expression. IVD degeneration involved significant down-regulation in Caveolin-1 gene and protein expression. NCs showed abundant caveolin-1 expression in vivo and in vitro, whereas CLCs did not. The NP of wild-type mice was rich in viable NCs, whereas the NP of Caveolin-1 knock-out mice

  10. Caveolin-1 binding to endoplasmic reticulum membranes and entry into the regulated secretory pathway are regulated by serine phosphorylation. Protein sorting at the level of the endoplasmic reticulum.

    PubMed

    Schlegel, A; Arvan, P; Lisanti, M P

    2001-02-01

    Caveolin-1 serves as the main coat protein of caveolae membranes, as an intracellular cholesterol shuttle, and as a regulator of diverse signaling molecules. Of the 12 residues conserved across all caveolin isoforms from all species examined to date, only Ser(80) and Ser(168) could serve as phosphorylation sites. We show here that mimicking chronic phosphorylation of Ser(80) by mutation to Glu (i.e. Cav-1(S80E)), blocks phosphate incorporation. However, Cav-1(S168E) is phosphorylated to the same extent as wild-type caveolin-1. Cav-1(S80E) targets to the endoplasmic reticulum membrane, remains oligomeric, and maintains normal membrane topology. In contrast, Cav-1(S80A), which cannot be phosphorylated, targets to caveolae membranes. Some exocrine cells secrete caveolin-1 in a regulated manner. Cav-1(S80A) is not secreted by AR42J pancreatic adenocarcinoma cells even in the presence of dexamethasone, an agent that induces the secretory phenotype. Conversely, Cav-1(S80E) is secreted to a greater extent than wild-type caveolin-1 following dexamethasone treatment. We conclude that caveolin-1 phosphorylation on invariant serine residue 80 is required for endoplasmic reticulum retention and entry into the regulated secretory pathway. PMID:11078729

  11. Display of membrane proteins on the heterologous caveolae carved by caveolin-1 in the Escherichia coli cytoplasm.

    PubMed

    Shin, Jonghyeok; Jung, Young-Hun; Cho, Da-Hyeong; Park, Myungseo; Lee, Kyung Eun; Yang, Yoosoo; Jeong, Cherlhyun; Sung, Bong Hyun; Sohn, Jung-Hoon; Park, Jin-Byung; Kweon, Dae-Hyuk

    2015-11-01

    Caveolae are membrane-budding structures that exist in many vertebrate cells. One of the important functions of caveolae is to form membrane curvature and endocytic vesicles. Recently, it was shown that caveolae-like structures were formed in Escherichia coli through the expression of caveolin-1. This interesting structure seems to be versatile for a variety of biotechnological applications. Targeting of heterologous proteins in the caveolae-like structure should be the first question to be addressed for this purpose. Here we show that membrane proteins co-expressed with caveolin-1 are embedded into the heterologous caveolae (h-caveolae), the cavaolae-like structures formed inside the cell. Two transmembrane SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins, Syntaxin 1a and vesicle-associated membrane protein 2 (VAMP2), were displayed on the h-caveolae surface. The size of the h-caveolae harboring the transmembrane proteins was ∼100 nm in diameter. The proteins were functional and faced outward on the h-caveolae. Multi-spanning transmembrane proteins FtsH and FeoB could be included in the h-caveolae, too. Furthermore, the recombinant E. coli cells were shown to endocytose substrate supplemented in the medium. These results provide a basis for exploiting the h-caveolae formed inside E. coli cells for future biotechnological applications. PMID:26320715

  12. Oxidative Stress Induces Premature Senescence by Stimulating Caveolin-1 Gene Transcription through p38 Mitogen-Activated Protein Kinase/Sp1–Mediated Activation of Two GC-Rich Promoter Elements

    PubMed Central

    Dasari, Arvind; Bartholomew, Janine N.; Volonte, Daniela; Galbiati, Ferruccio

    2015-01-01

    Cellular senescence is believed to represent a natural tumor suppressor mechanism. We have previously shown that up-regulation of caveolin-1 was required for oxidative stress–induced premature senescence in fibroblasts. However, the molecular mechanisms underlying caveolin-1 up-regulation in senescent cells remain unknown. Here, we show that subcytotoxic oxidative stress generated by hydrogen peroxide application promotes premature senescence and stimulates the activity of a (−1,296) caveolin-1 promoter reporter gene construct in fibroblasts. Functional deletion analysis mapped the oxidative stress response elements of the mouse caveolin-1 promoter to the sequences −244/−222 and −124/−101. The hydrogen peroxide–mediated activation of both Cav-1 (−244/−222) and Cav-1 (−124/−101) was prevented by the antioxidant quercetin. Combination of electrophoretic mobility shift studies, chromatin immunoprecipitation analysis, Sp1 overexpression experiments, as well as promoter mutagenesis identifies enhanced Sp1 binding to two GC-boxes at −238/−231 and −118/−106 as the core mechanism of oxidative stress–triggered caveolin-1 transactivation. In addition, signaling studies show p38 mitogen-activated protein kinase (MAPK) as the upstream regulator of Sp1-mediated activation of the caveolin-1 promoter following oxidative stress. Inhibition of p38 MAPK prevents the oxidant-induced Sp1-mediated up-regulation of caveolin-1 protein expression and development of premature senescence. Finally, we show that oxidative stress induces p38-mediated up-regulation of caveolin-1 and premature senescence in normal human mammary epithelial cells but not in MCF-7 breast cancer cells, which do not express caveolin-1 and undergo apoptosis. This study delineates for the first time the molecular mechanisms that modulate caveolin-1 gene transcription upon oxidative stress and brings new insights into the redox control of cellular senescence in both normal and cancer

  13. Roxithromycin suppresses airway remodeling and modulates the expression of caveolin-1 and phospho-p42/p44MAPK in asthmatic rats.

    PubMed

    Wu, Li-Qin; Wang, Rui-Li; Dai, Yuan-Rong; Li, Feng-Qin; Wu, Hai-Ya; Yan, Sun-Shun; Wang, Liang-Rong; Jin, Li-da; Xia, Xiao-Dong

    2015-02-01

    Roxithromycin (RXM) expresses anti-asthmatic effects that are separate from its antibiotic activity, but its effects on airway remodeling are still unknown. Here, we evaluated the effects of RXM on airway remodeling and the expression of caveolin-1 and phospho-p42/p44mitogen-activated protein kinase (phospho-p42/p44MAPK) in chronic asthmatic rats. The chronic asthma was induced by ovalbumin/Al(OH)3 sensitization and ovalbumin challenge, RXM (30mg/kg) or dexamethasone (0.5mg/kg) was given before airway challenge initiation. We measured the thickness of bronchial wall and bronchial smooth muscle cell layer to indicate airway remodeling, and caveolin-1 and phospho-p42/p44MAPK expression in lung tissue and airway smooth muscle were detected by immunohistochemistry and western blot analysis, respectively. The results demonstrated that RXM treatment decreased the thickness of bronchial wall and bronchial smooth muscle cell layer, and also downregulated the phospho-p42/p44MAPK expression and upregulated the caveolin-1 expression. The above effects of RXM were similar to dexamethasone. Our results suggested that pretreatment with RXM could suppress airway remodeling and regulate the expression of caveolin-1 and phospho-p42/p44MAPK in chronic asthmatic rats. PMID:25479721

  14. Static pressure accelerates ox-LDL-induced cholesterol accumulation via SREBP-1-mediated caveolin-1 downregulation in cultured vascular smooth muscle cells

    SciTech Connect

    Luo, Di-xian; Xia, Cheng-lai; Li, Jun-mu; Xiong, Yan; Yuan, Hao-yu; TANG, Zhen-Wang; Zeng, Yixin; Liao, Duan-fang

    2010-12-03

    Research highlights: {yields} Vertical static pressure accelerates ox-LDL-induced cholesterol accumulation in cultured vascular smooth muscle cells. {yields} Static pressure induces SREBP-1 activation. {yields} Static pressure downregulates the expressions of caveolin-1 by activating SREBP-1. {yields} Static pressure also downregulates the transcription of ABCA1 by activating SREBP-1. {yields} Static pressure increases ox-LDL-induced cholesterol accumulation by SREBP-1-mediated caveolin-1 downregulation in vascular smooth muscle cells cultured in vitro. -- Abstract: Objective: To investigate the effect of static pressure on cholesterol accumulation in vascular smooth muscle cells (VSMCs) and its mechanism. Methods: Rat-derived VSMC cell line A10 treated with 50 mg/L ox-LDL and different static pressures (0, 60, 90, 120, 150, 180 mm Hg) in a custom-made pressure incubator for 48 h. Intracellular lipid droplets and lipid levels were assayed by oil red O staining and HPLC; The mRNA levels of caveolin-1 and ABCA1, the protein levels of caveolin-1 SREBP-1 and mature SREBP-1 were respectively detected by RT-PCR or western blot. ALLN, an inhibitor of SREBP metabolism, was used to elevate SREBP-1 protein level in VSMCs treated with static pressure. Results: Static pressures significantly not only increase intracellular lipid droplets in VSMCs, but also elevate cellular lipid content in a pressure-dependent manner. Intracellular free cholesterol (FC), cholesterol ester (CE), total cholesterol (TC) were respectively increased from 60.5 {+-} 2.8 mg/g, 31.8 {+-} 0.7 mg/g, 92.3 {+-} 2.1 mg/g at atmosphere pressure (ATM, 0 mm Hg) to 150.8 {+-} 9.4 mg/g, 235.9 {+-} 3.0 mg/g, 386.7 {+-} 6.4 mg/g at 180 mm Hg. At the same time, static pressures decrease the mRNA and protein levels of caveolin-1, and induce the activation and nuclear translocation of SREBP-1. ALLN increases the protein level of mature SREBP-1 and decreases caveolin-1 expression, so that cellular lipid levels were

  15. Reconstitution and spectroscopic analysis of caveolin-1 residues 62-178 reveals that proline 110 governs its structure and solvent exposure.

    PubMed

    Root, Kyle T; Glover, Kerney Jebrell

    2016-04-01

    Caveolin-1 is a membrane protein that possesses an unusual topology where both N- and C-termini are cytoplasmic as a result of a membrane-embedded turn. In particular, proline 110 has been postulated to be the linchpin of this unusual motif. Using a caveolin-1 construct (residues 62-178) reconstituted into dodecylphosphocholine micelles with and without a cholesterol mimic, the changes that occurred upon P110A mutation were probed. Using far UV circular dichroism spectroscopy it was shown that cholesterol attenuated the helicity of caveolin-1, and that mutation of P110 to alanine caused a significant increase in the α-helicity of the protein. Near UV circular dichroism spectroscopy showed significant changes in structure and/or environment upon mutation that again were modulated by the presence of cholesterol. Stern-Volmer quenching and λ(max) analysis of tryptophan residues showed that the proline mutation caused W85 to become more exposed, W98 and W115 to become less exposed, and W128 showed no change. This finding provided evidence that regions proximal and far away from the proline are buried differentially upon its mutation and therefore this residue is strongly tied to maintaining the hydrophobic coverage along the caveolin-1 sequence. In the presence of cholesterol, the accessibilities of the two tryptophan residues that proceeded position 110 were altered much more significantly upon P110A mutation than the two tryptophans aft P110. Overall, this work provides strong evidence that proline 110 is critical for maintaining both the structure and hydrophobic coverage of caveolin-1 and that cholesterol also plays a significant role in modulating these parameters. PMID:26775739

  16. Cholesterol and phytosterols differentially regulate the expression of caveolin 1 and a downstream prostate cell growth-suppressor gene

    PubMed Central

    Ifere, Godwin O.; Equan, Anita; Gordon, Kereen; Nagappan, Peri; Igietseme, Joseph U.; Ananaba, Godwin A.

    2010-01-01

    Background The purpose of our study was to show the distinction between the apoptotic and anti-proliferative signaling of phytosterols and cholesterol enrichment in prostate cancer cell lines, mediated by the differential transcription of caveolin-1, and N-myc downstream regulated gene1 (NDRG1), a pro-apoptotic androgen-regulated tumor suppressor. Methods PC-3 and DU145 cells were treated with sterols (cholesterol and phytosterols) for 72 h, followed by trypan blue dye exclusion measurement of necrosis and cell growth measured with a Coulter counter. Sterol induction of cell growth-suppressor gene expression was evaluated by mRNA transcription using RT-PCR, while cell cycle analysis was performed by FACS analysis. Altered expression of Ndrg1 protein was confirmed by Western blot analysis. Apoptosis was evaluated by real time RT-PCR amplification of P53, Bcl-2 gene and its related pro- and anti-apoptotic family members. Results Physiological doses (16 µM) of cholesterol and phytosterols were not cytotoxic in these cells. Cholesterol enrichment promoted cell growth (P<0.05), while phytosterols significantly induced growth-suppression (P<0.05) and apoptosis. Cell cycle analysis showed that contrary to cholesterol, phytosterols decreased mitotic subpopulations. We demonstrated for the first time that cholesterols concertedly attenuated the expression of caveolin-1(cav-1) and NDRG1 genes in both prostate cancer cell lines. Phytosterols had the opposite effect by inducing overexpression of cav-1, a known mediator of androgen-dependent signals that presumably control cell growth or apoptosis. Conclusions Cholesterol and phytosterol treatment differentially regulated the growth of prostate cancer cells and the expression of p53 and cav-1, a gene that regulates androgen-regulated signals. These sterols also differentially regulated cell cycle arrest, downstream pro-apoptotic androgen-regulated tumor-suppressor, NDRG1 suggesting that cav-1 may mediate pro-apoptotic NDRG1

  17. Caveolin-1-negative head and neck squamous cell carcinoma primary tumors display increased epithelial to mesenchymal transition and prometastatic properties

    PubMed Central

    Jung, Alain C.; Ray, Anne-Marie; Ramolu, Ludivine; Macabre, Christine; Simon, Florian; Noulet, Fanny; Blandin, Anne-Florence; Renner, Guillaume; Lehmann, Maxime; Choulier, Laurence; Kessler, Horst; Abecassis, Joseph; Dontenwill, Monique; Martin, Sophie

    2015-01-01

    Distant metastases arise in 20-30% of patients with squamous cell carcinoma of the head and neck (HNSCC) in the 2 years following treatment. Therapeutic options are limited and the outcome of the patients is poor. The identification of predictive biomarkers of patient at risk for distant metastasis and therapies are urgently needed. We previously identified a clinical subgroup, called “R1” characterized by high propensity for rapid distant metastasis. Here, we showed that “R1” patients do not or at very low level express caveolin-1 (Cav1). Low or no expression of Cav1 is of bad prognosis. Disappearance of Cav1 enables cells to undergo epithelial-mesenchymal transition (EMT). EMT is associated with enhanced migration and invasion. Our study uncovered a new target, α5β1 integrin. Targeting α5β1 integrins might not only prevent metastasis of HNSCC but also delay the development of the primary tumor by reducing tumor cell viability. Cav1 detection might be taken into consideration in the future in the clinic not only to identify patients at high risk of metastasis but also to select patient who might benefit from an anti-integrin therapy. PMID:26474461

  18. Caveolin-1 plays a critical role in host immunity against Klebsiella pneumoniae by regulating STAT5 and Akt activity.

    PubMed

    Guo, Qiang; Shen, Nan; Yuan, Kefei; Li, Jiaxin; Wu, Hong; Zeng, Yong; Fox, John; Bansal, Arvind K; Singh, Brij B; Gao, Hongwei; Wu, Min

    2012-06-01

    Caveolin-1 (Cav1) is a structural protein of caveolae. Although Cav1 is associated with certain bacterial infections, it is unknown whether Cav1 is involved in host immunity against Klebsiella pneumoniae, the third most commonly isolated microorganism from bacterial sepsis patients. Here, we showed that cav1 knockout mice succumbed to K. pneumoniae infection with markedly decreased survival rates, increased bacterial burdens, intensified tissue injury, hyperactive proinflammatory cytokines, and systemic bacterial dissemination as compared with WT mice. Knocking down Cav1 by a dominant negative approach in lung epithelial MLE-12 cells resulted in similar outcomes (decreased bacterial clearance and increased proinflammatory cytokine production). Furthermore, we revealed that STAT5 influences the GSK3β-β-catenin-Akt pathway, which contributes to the intensive inflammatory response and rapid infection dissemination seen in Cav1 deficiency. Collectively, our findings indicate that Cav1 may offer resistance to K. pneumoniae infection, by affecting both systemic and local production of proinflammatory cytokines via the actions of STAT5 and the GSK3β-β-catenin-Akt pathway. PMID:22678904

  19. Caveolin-1 regulates cell apoptosis and invasion ability in paclitaxel-induced multidrug-resistant A549 lung cancer cells

    PubMed Central

    Han, Fei; Zhang, Long; Zhou, Yongxin; Yi, Xianghua

    2015-01-01

    The aim of the study was to investigate the effect and potential mechanism of caveolin-1 (Cav1) knockdown in paclitaxel-resistant lung cancer A549/Taxol cells. The human paclitaxel-resistant lung cancer cell line A549/Taxol was transfected with a Cav1 shRNA lentiviral vector. Interference efficiency for Cav1 was detected by real-time PCR and Western blotting. A MTT assay was used to determine cell proliferation, and flow cytometry was used to detect the cell cycle stage and apoptosis. Cell migration and invasion capability were detected by a transwell assay. Protein levels of related signaling molecules were detected by Western blotting. We successfully constructed a stable A549/Taxol cell line expressing low levels of Cav1. Cav1 knockdown significantly inhibited cell proliferation and induced G0/G1 arrest and cell apoptosis in vitro and in vivo. In addition, these effects correlated significantly with a reduction in cyclin D1 expression and activation of the Bcl-2/Bax-mediated mitochondrial apoptosis pathway. Furthermore, knockdown of Cav1 inhibited cell migration and invasion, and this may be related to the inhibition of AKT and the subsequent decreased protein expression of MMP2, MMP7 and MMP9. PMID:26464635

  20. DJ-1 deficiency impairs glutamate uptake into astrocytes via the regulation of flotillin-1 and caveolin-1 expression

    PubMed Central

    Kim, Jin-Mo; Cha, Seon-Heui; Choi, Yu Ree; Jou, Ilo; Joe, Eun-Hye; Park, Sang Myun

    2016-01-01

    Parkinson’s disease (PD) is a common chronic and progressive neurodegenerative disorder. Although the cause of PD is still poorly understood, mutations in many genes including SNCA, parkin, PINK1, LRRK2, and DJ-1 have been identified in the familial forms of PD. It was recently proposed that alterations in lipid rafts may cause the neurodegeneration shown in PD. Here, we observe that DJ-1 deficiency decreased the expression of flotillin-1 (flot-1) and caveolin-1 (cav-1), the main protein components of lipid rafts, in primary astrocytes and MEF cells. As a mechanism, DJ-1 regulated flot-1 stability by direct interaction, however, decreased cav-1 expression may not be a direct effect of DJ-1, but rather as a result of decreased flot-1 expression. Dysregulation of flot-1 and cav-1 by DJ-1 deficiency caused an alteration in the cellular cholesterol level, membrane fluidity, and alteration in lipid rafts-dependent endocytosis. Moreover, DJ-1 deficiency impaired glutamate uptake into astrocytes, a major function of astrocytes in the maintenance of CNS homeostasis, by altering EAAT2 expression. This study will be helpful to understand the role of DJ-1 in the pathogenesis of PD, and the modulation of lipid rafts through the regulation of flot-1 or cav-1 may be a novel therapeutic target for PD. PMID:27346864

  1. Evidence for Dsg3 in regulating Src signaling by competing with it for binding to caveolin-1

    PubMed Central

    Wan, Hong; Lin, Kuang; Tsang, Siu Man; Uttagomol, Jutamas

    2015-01-01

    This data article contains extended, complementary analysis related to the research articles entitled “Desmoglein 3, via an interaction with E-cadherin, is associated with activation of Src” (Tsang et al., 2010) [1] and figures related to the review article entitled “Desmoglein 3: a help or a hindrance in cancer progression?” (Brown et al., 2014) [2]. We show here that both Src and caveolin-1 (Cav-1) associate with Dsg3 in a non-ionic detergent soluble pool and that modulation of Dsg3 levels inversely alters the expression of Src in the Cav-1 complex. Furthermore, immunofluorescence analysis revealed a reduced colocalization of Cav-1/total Src in cells with overexpression of Dsg3 compared to control cells. In support, the sequence analysis has identified a region within the carboxyl-terminus of human Dsg3 for a likelihood of binding to the scaffolding domain of Cav-1, the known Src binding site in Cav-1, and this region is highly conserved across most of 18 species as well as within desmoglein family members. Based on these findings, we propose a working model that Dsg3 activates Src through competing with its inactive form for binding to Cav-1, thus leading to release of Src followed by its auto-activation. PMID:26858977

  2. Role of NF-kappaB-dependent caveolin-1 expression in the mechanism of increased endothelial permeability induced by lipopolysaccharide.

    PubMed

    Tiruppathi, Chinnaswamy; Shimizu, Jun; Miyawaki-Shimizu, Kayo; Vogel, Stephen M; Bair, Angela M; Minshall, Richard D; Predescu, Dan; Malik, Asrar B

    2008-02-15

    We investigated the role of NF-kappaB activation by the bacterial product lipopolysaccharide (LPS) in inducing caveolin-1 (Cav-1) expression and its consequence in contributing to the leakiness of the endothelial barrier. We observed that LPS challenge of human lung microvascular endothelial cells induced concentration- and time-dependent increases in expression of Cav-1 mRNA and protein. The NEMO (NF-kappaB essential modifier binding domain)-binding domain peptide (IkB kinase (IKK)-NEMO-binding domain (NBD) peptide), which prevents NF-kappaB activation by inhibiting the interaction of IKKgamma with the IKK complex, blocked LPS-induced Cav-1 mRNA and protein expression. Knockdown of NF-kappaB subunit p65/RelA expression with small interfering RNA also prevented LPS-induced Cav-1 expression. Caveolae open to the apical and basal plasmalemma of endothelial cells increased 2-4-fold within 4 h of LPS exposure. IKK-NBD peptide markedly reduced the LPS-induced increase in the number of caveolae as well as transendothelial albumin permeability. These observations were recapitulated in mouse studies in which IKK-NBD peptide prevented Cav-1 expression and interfered with the increase in lung microvessel permeability induced by LPS. Thus, LPS mediates NF-kappaB-dependent Cav-1 expression that results in increased caveolae number and thereby contributes to the mechanism of increased transendothelial albumin permeability. PMID:18077459

  3. Tyrosine-Phosphorylated Caveolin-1 Blocks Bacterial Uptake by Inducing Vav2-RhoA-Mediated Cytoskeletal Rearrangements

    PubMed Central

    Kaushansky, Alexis; Pompaiah, Malvika; Thorn, Hans; Brinkmann, Volker; MacBeath, Gavin; Meyer, Thomas F.

    2010-01-01

    Certain bacterial adhesins appear to promote a pathogen's extracellular lifestyle rather than its entry into host cells. However, little is known about the stimuli elicited upon such pathogen host-cell interactions. Here, we report that type IV pili (Tfp)-producing Neisseria gonorrhoeae (P+GC) induces an immediate recruitment of caveolin-1 (Cav1) in the host cell, which subsequently prevents bacterial internalization by triggering cytoskeletal rearrangements via downstream phosphotyrosine signaling. A broad and unbiased analysis of potential interaction partners for tyrosine-phosphorylated Cav1 revealed a direct interaction with the Rho-family guanine nucleotide exchange factor Vav2. Both Vav2 and its substrate, the small GTPase RhoA, were found to play a direct role in the Cav1-mediated prevention of bacterial uptake. Our findings, which have been extended to enteropathogenic Escherichia coli, highlight how Tfp-producing bacteria avoid host cell uptake. Further, our data establish a mechanistic link between Cav1 phosphorylation and pathogen-induced cytoskeleton reorganization and advance our understanding of caveolin function. PMID:20808760

  4. Nitrosation-dependent caveolin 1 phosphorylation, ubiquitination, and degradation and its association with idiopathic pulmonary arterial hypertension.

    PubMed

    Bakhshi, Farnaz R; Mao, Mao; Shajahan, Ayesha N; Piegeler, Tobias; Chen, Zhenlong; Chernaya, Olga; Sharma, Tiffany; Elliott, W Mark; Szulcek, Robert; Bogaard, Harm Jan; Comhair, Suzy; Erzurum, Serpil; van Nieuw Amerongen, Geerten P; Bonini, Marcelo G; Minshall, Richard D

    2013-12-01

    In the present study, we tested the hypothesis that chronic inflammation and oxidative/nitrosative stress induce caveolin 1 (Cav-1) degradation, providing an underlying mechanism of endothelial cell activation/dysfunction and pulmonary vascular remodeling in patients with idiopathic pulmonary arterial hypertension (IPAH). We observed reduced Cav-1 protein despite increased Cav-1 messenger RNA expression and also endothelial nitric oxide synthase (eNOS) hyperphosphorylation in human pulmonary artery endothelial cells (PAECs) from patients with IPAH. In control human lung endothelial cell cultures, tumor necrosis factor α-induced nitric oxide (NO) production and S-nitrosation (SNO) of Cav-1 Cys-156 were associated with Src displacement and activation, Cav-1 Tyr-14 phosphorylation, and destabilization of Cav-1 oligomers within 5 minutes that could be blocked by eNOS or Src inhibition. Prolonged stimulation (72 hours) with NO donor DETANONOate reduced oligomerized and total Cav-1 levels by 40%-80%, similar to that observed in IPAH patient-derived PAECs. NO donor stimulation of endothelial cells for >72 hours, which was associated with sustained Src activation and Cav-1 phosphorylation, ubiquitination, and degradation, was blocked by NOS inhibitor L-NAME, Src inhibitor PP2, and proteosomal inhibitor MG132. Thus, chronic inflammation, sustained eNOS and Src signaling, and Cav-1 degradation may be important causal factors in the development of IPAH by promoting PAEC dysfunction/activation via sustained oxidative/nitrosative stress. PMID:25006397

  5. Distinct structural domains of caveolin-1 independently regulate Ca2+ release-activated Ca2+ channels and Ca2+ microdomain-dependent gene expression.

    PubMed

    Yeh, Yi-Chun; Parekh, Anant B

    2015-04-01

    In eukaryotic cells, calcium entry across the cell surface activates nuclear gene expression, a process critically important for cell growth and differentiation, learning, and memory and immune cell functions. In immune cells, calcium entry occurs through store-operated Ca(2+) release-activated Ca(2+) (CRAC) channels, comprised of STIM1 and Orai1 proteins. Local calcium entry through CRAC channels activates expression of c-fos- and nuclear factor of activated T cells (NFAT)-dependent genes. Although c-fos and NFAT often interact to activate gene expression synergistically, they can be activated independently of one another to regulate distinct genes. This raises the question of how one transcription factor can be activated and not the other when both are stimulated by the same trigger. Here, we show that the lipid raft scaffolding protein caveolin-1 interacts with the STIM1-Orai1 complex to increase channel activity. Phosphorylation of tyrosine 14 on caveolin-1 regulates CRAC channel-evoked c-fos activation without impacting the NFAT pathway or Orai1 activity. Our results reveal that structurally distinct domains of caveolin-1 selectively regulate the ability of local calcium to activate distinct transcription factors. More generally, our findings reveal that modular regulation by a scaffolding protein provides a simple, yet effective, mechanism to tunnel a local signal down a specific pathway. PMID:25645930

  6. Cellular Factor XIIIA Transglutaminase Localizes in Caveolae and Regulates Caveolin-1 Phosphorylation, Homo-oligomerization and c-Src Signaling in Osteoblasts.

    PubMed

    Wang, Shuai; Kaartinen, Mari T

    2015-11-01

    Transglutaminases (TGs) are a family of widely distributed enzymes that catalyze protein crosslinking by forming a covalent isopeptide bond between the substrate proteins. We have shown that MC3T3-E1 osteoblasts express Factor XIII-A (FXIII-A), and that the extracellular crosslinking activity of FXIII-A is involved in regulating matrix secretion and deposition. In this study, we have investigated the localization and potential role of intracellular FXIII-A. Conventional immunofluorescence microscopy and TIRF microscopy analyses showed that FXIII-A co-localizes with caveolin-1 in specialized membrane structures, caveolae, in differentiating osteoblasts. The caveolae-disrupting agent methyl-β-cyclodextrin abolished FXIII-A staining and co-localization with caveolin-1 from the osteoblast plasma membrane. The presence of FXIII-A in caveolae was confirmed by preparing caveolae-enriched cellular fractions using sucrose density gradient ultracentrifugation followed by western blotting. Despite this association of FXIII-A with caveolae, there was no detectable transglutaminase activity in caveolae, as measured by monodansylcadaverine incorporation. TG inhibitor NC9--which can alter TG enzyme conformation--localized to caveolae and displaced FXIII-A from these structures when added to the osteoblast cultures. The decreased FXIII-A levels in caveolae after NC9 treatment increased c-Src activation, which resulted in caveolin-1 phosphorylation, homo-oligomerization and Akt phosphorylation, suggesting cellular FXIII-A has a role in regulating c-Src signaling in osteoblasts. PMID:26231113

  7. Roles of Caveolin-1 in Angiotensin II-Induced Hypertrophy and Inward Remodeling of Cerebral Pial Arterioles.

    PubMed

    Umesalma, Shaikamjad; Houwen, Frederick Keith; Baumbach, Gary L; Chan, Siu-Lung

    2016-03-01

    Angiotensin II (Ang II) is a major determinant of inward remodeling and hypertrophy in pial arterioles that may have an important role in stroke during chronic hypertension. Previously, we found that epidermal growth factor receptor is critical in Ang II-mediated hypertrophy that may involve caveolin-1 (Cav-1). In this study, we examined the effects of Cav-1 and matrix metalloproteinase-9 (MMP9) on Ang II-mediated structural changes in pial arterioles. Cav-1-deficient (Cav-1(-/-)), MMP9-deficient (MMP9(-/-)), and wild-type mice were infused with either Ang II (1000 ng/kg per minute) or saline via osmotic minipumps for 28 days (n=6-8 per group). Systolic arterial pressure was measured by a tail-cuff method. Pressure and diameter of pial arterioles were measured through an open cranial window in anesthetized mice. Cross-sectional area of the wall was determined histologically in pressurized fixed pial arterioles. Expression of Cav-1, MMP9, phosphorylated epidermal growth factor receptor, and Akt was determined by Western blotting and immunohistochemistry. Deficiency of Cav-1 or MMP9 did not affect Ang II-induced hypertension. Ang II increased the expression of Cav-1, phosphorylated epidermal growth factor receptor, and Akt in wild-type mice, which was attenuated in Cav-1(-/-) mice. Ang II-induced hypertrophy, inward remodeling, and increased MMP9 expression in pial arterioles were prevented in Cav-1(-/-) mice. Ang II-mediated increases in MMP9 expression and inward remodeling, but not hypertrophy, were prevented in MMP9(-/-) mice. In conclusion, Cav-1 is essential in Ang II-mediated inward remodeling and hypertrophy in pial arterioles. Cav-1-induced MMP9 is exclusively involved in inward remodeling, not hypertrophy. Further studies are needed to determine the role of Akt in Ang II-mediated hypertrophy. PMID:26831194

  8. Integrin α1β1 Promotes Caveolin-1 Dephosphorylation by Activating T Cell Protein-tyrosine Phosphatase*

    PubMed Central

    Borza, Corina M.; Chen, Xiwu; Mathew, Sijo; Mont, Stacey; Sanders, Charles R.; Zent, Roy; Pozzi, Ambra

    2010-01-01

    Integrin α1β1 is a collagen receptor that down-regulates collagen and reactive oxygen species (ROS) production, and mice lacking this receptor show increased ROS levels and exacerbated glomerular sclerosis following injury. Caveolin-1 (Cav-1) is a multifunctional protein that is tyrosine-phosphorylated in response to injury and has been implicated in ROS-mediated injury. Cav-1 interacts with integrins, and integrin α1β1 binds/activates T cell protein-tyrosine phosphatase (TCPTP), which is homologous to the tyrosine phosphatase PTP1B known to dephosphorylate Cav-1. In this study, we analyzed whether phosphorylated Cav-1 (pCav-1) is a substrate of TCPTP and if integrin α1β1 is essential for promoting TCPTP-mediated Cav-1 dephosphorylation. We found that Cav-1 phosphorylation is significantly higher in cells lacking integrin α1β1 at base line and following oxidative stress. Overexpression of TCPTP leads to reduced pCav-1 levels only in cells expressing integrin α1β1. Using solid phase binding assays, we demonstrated that 1) purified Cav-1 directly interacts with TCPTP and the integrin α1 subunit, 2) pCav-1 is a substrate of TCPTP, and 3) TCPTP-mediated Cav-1 dephosphorylation is highly increased by the addition of purified integrin α1β1 or an integrin α1 cytoplasmic peptide to which TCPTP has been shown to bind. Thus, our results demonstrate that pCav-1 is a new substrate of TCPTP and that integrin α1β1 acts as a negative regulator of Cav-1 phosphorylation by activating TCPTP. This could explain the protective function of integrin α1β1 in oxidative stress-mediated damage and why integrin α1-null mice are more susceptible to fibrosis following injury. PMID:20940300

  9. Integrin {alpha}1{beta}1 promotes caveolin-1 dephosphorylation by activating T cell protein-tyrosine phosphatase.

    PubMed

    Borza, Corina M; Chen, Xiwu; Mathew, Sijo; Mont, Stacey; Sanders, Charles R; Zent, Roy; Pozzi, Ambra

    2010-12-17

    Integrin α1β1 is a collagen receptor that down-regulates collagen and reactive oxygen species (ROS) production, and mice lacking this receptor show increased ROS levels and exacerbated glomerular sclerosis following injury. Caveolin-1 (Cav-1) is a multifunctional protein that is tyrosine-phosphorylated in response to injury and has been implicated in ROS-mediated injury. Cav-1 interacts with integrins, and integrin α1β1 binds/activates T cell protein-tyrosine phosphatase (TCPTP), which is homologous to the tyrosine phosphatase PTP1B known to dephosphorylate Cav-1. In this study, we analyzed whether phosphorylated Cav-1 (pCav-1) is a substrate of TCPTP and if integrin α1β1 is essential for promoting TCPTP-mediated Cav-1 dephosphorylation. We found that Cav-1 phosphorylation is significantly higher in cells lacking integrin α1β1 at base line and following oxidative stress. Overexpression of TCPTP leads to reduced pCav-1 levels only in cells expressing integrin α1β1. Using solid phase binding assays, we demonstrated that 1) purified Cav-1 directly interacts with TCPTP and the integrin α1 subunit, 2) pCav-1 is a substrate of TCPTP, and 3) TCPTP-mediated Cav-1 dephosphorylation is highly increased by the addition of purified integrin α1β1 or an integrin α1 cytoplasmic peptide to which TCPTP has been shown to bind. Thus, our results demonstrate that pCav-1 is a new substrate of TCPTP and that integrin α1β1 acts as a negative regulator of Cav-1 phosphorylation by activating TCPTP. This could explain the protective function of integrin α1β1 in oxidative stress-mediated damage and why integrin α1-null mice are more susceptible to fibrosis following injury. PMID:20940300

  10. Caveolin 1 is critical for abdominal aortic aneurysm formation induced by angiotensin II and inhibition of lysyl oxidase.

    PubMed

    Takayanagi, Takehiko; Crawford, Kevin J; Kobayashi, Tomonori; Obama, Takashi; Tsuji, Toshiyuki; Elliott, Katherine J; Hashimoto, Tomoki; Rizzo, Victor; Eguchi, Satoru

    2014-06-01

    Although AngII (angiotensin II) and its receptor AT1R (AngII type 1 receptor) have been implicated in AAA (abdominal aortic aneurysm) formation, the proximal signalling events primarily responsible for AAA formation remain uncertain. Caveolae are cholesterol-rich membrane microdomains that serve as a signalling platform to facilitate the temporal and spatial localization of signal transduction events, including those stimulated by AngII. Cav1 (caveolin 1)-enriched caveolae in vascular smooth muscle cells mediate ADAM17 (a disintegrin and metalloproteinase 17)-dependent EGFR (epidermal growth factor receptor) transactivation, which is linked to vascular remodelling induced by AngII. In the present study, we have tested our hypothesis that Cav1 plays a critical role for the development of AAA at least in part via its specific alteration of AngII signalling within caveolae. Cav1-/- mice and the control wild-type mice were co-infused with AngII and β-aminopropionitrile to induce AAA. We found that Cav1-/- mice with the co-infusion did not develop AAA compared with control mice in spite of hypertension. We found an increased expression of ADAM17 and enhanced phosphorylation of EGFR in AAA. These events were markedly attenuated in Cav1-/- aortas with the co-infusion. Furthermore, aortas from Cav1-/- mice with the co-infusion showed less endoplasmic reticulum stress, oxidative stress and inflammatory responses compared with aortas from control mice. Cav1 silencing in cultured vascular smooth muscle cells prevented AngII-induced ADAM17 induction and activation. In conclusion, Cav1 appears to play a critical role in the formation of AAA and associated endoplasmic reticulum/oxidative stress, presumably through the regulation of caveolae compartmentalized signals induced by AngII. PMID:24329494

  11. Involvement of Caveolin-1 in Repair of DNA Damage through Both Homologous Recombination and Non-Homologous End Joining

    PubMed Central

    Zhu, Hua; Yue, Jingyin; Pan, Zui; Wu, Hao; Cheng, Yan; Lu, Huimei; Ren, Xingcong; Yao, Ming; Shen, Zhiyuan; Yang, Jin-Ming

    2010-01-01

    Background Caveolin-1 (Cav-1), the major component of caveolae, is a 21–24 kDa integral membrane protein that interacts with a number of signaling molecules. By acting as a scaffolding protein, Cav-1 plays crucial roles in the regulation of various physiologic and patho-physiologic processes including oncogenic transformation and tumorigenesis, and tumor invasion and metastasis. Methodology/Principal Findings In the present study we sought to explore the role of Cav-1 in response to DNA damage and the mechanism involved. We found that the level of Cav-1 was up-regulated rapidly in cells treated with ionizing radiation. The up-regulation of Cav-1 following DNA damage occurred only in cells expressing endogenous Cav-1, and was associated with the activation of DNA damage response pathways. Furthermore, we demonstrated that the expression of Cav-1 protected cells against DNA damage through modulating the activities of both the homologous recombination (HR) and non-homologous end joining (NHEJ) repair systems, as evidenced by the inhibitory effects of the Cav-1-targeted siRNA on cell survival, HR frequency, phosphorylation of DNA-dependent protein kinase (DNA-PK), and nuclear translocation of epidermal growth factor receptor (EGFR) following DNA damage, and by the stimulatory effect of the forced expression of Cav-1 on NHEJ frequency. Conclusion/Significance Our results indicate that Cav-1 may play a critical role in sensing genotoxic stress and in orchestrating the response of cells to DNA damage through regulating the important molecules involved in maintaining genomic integrity. PMID:20700465

  12. Antenatal glucocorticoids counteract LPS changes in TGF-β pathway and caveolin-1 in ovine fetal lung.

    PubMed

    Collins, Jennifer J P; Kunzmann, Steffen; Kuypers, Elke; Kemp, Matthew W; Speer, Christian P; Newnham, John P; Kallapur, Suhas G; Jobe, Alan H; Kramer, Boris W

    2013-03-15

    Inflammation and antenatal glucocorticoids, the latter given to mothers at risk for preterm birth, affect lung development and may contribute to the development of bronchopulmonary dysplasia (BPD). The effects of the combined exposures on inflammation and antenatal glucocorticoids on transforming growth factor (TGF)-β signaling are unknown. TGF-β and its downstream mediators are implicated in the etiology of BPD. Therefore, we asked whether glucocorticoids altered intra-amniotic lipopolysaccharide (LPS) effects on TGF-β expression, its signaling molecule phosphorylated sma and mothers against decapentaplegic homolog 2 (pSmad2), and the downstream mediators connective tissue growth factor (CTGF) and caveolin-1 (Cav-1). Ovine singleton fetuses were randomized to receive either an intra-amniotic injection of LPS and/or maternal betamethasone (BTM) intramuscularly 7 and/or 14 days before delivery at 120 days gestational age (GA; term = 150 days GA). Saline was used for controls. Protein levels of TGF-β1 and -β2 were measured by ELISA. Smad2 phosphorylation was assessed by immunohistochemistry and Western blot. CTGF and Cav-1 mRNA and protein levels were determined by RT-PCR and Western blot. Free TGF-β1 and -β2 and total TGF-β1 levels were unchanged after LPS and/or BTM exposure, although total TGF-β2 increased in animals exposed to BTM 7 days before LPS. pSmad2 immunostaining increased 7 days after LPS exposure although pSmad2 protein expression did not increase. Similarly, CTGF mRNA and protein levels increased 7 days after LPS exposure as Cav-1 mRNA and protein levels decreased. BTM exposure before LPS prevented CTGF induction and Cav-1 downregulation. This study demonstrated that the intrauterine inflammation-induced TGF-β signaling can be inhibited by antenatal glucocorticoids in fetal lungs. PMID:23333802

  13. Rab5 is required in metastatic cancer cells for Caveolin-1-enhanced Rac1 activation, migration and invasion.

    PubMed

    Díaz, Jorge; Mendoza, Pablo; Ortiz, Rina; Díaz, Natalia; Leyton, Lisette; Stupack, Dwayne; Quest, Andrew F G; Torres, Vicente A

    2014-06-01

    Rab5 is a small GTPase that regulates early endosome trafficking and other cellular processes, including cell adhesion and migration. Specifically, Rab5 promotes Rac1 activation and cancer cell migration, but little is known about the upstream regulators of Rab5. We have previously shown that the scaffolding protein Caveolin-1 (CAV1) promotes Rac1 activation and migration of cancer cells. Here, we hypothesized that CAV1 stimulates Rab5 activation, leading to increased Rac1 activity and cell migration. Expression of CAV1 in B16-F10 mouse melanoma and HT-29(US) human colon adenocarcinoma cells increased the GTP loading of Rab5, whereas shRNA-mediated targeting of endogenous CAV1 in MDA-MB-231 breast cancer cells decreased Rab5-GTP levels. Accordingly, shRNA-mediated downregulation of Rab5 decreased CAV1-mediated Rac1 activation, cell migration and invasion in B16-F10 and HT-29(US) cells. Expression of CAV1 was accompanied by increased recruitment of Tiam1, a Rac1 guanine nucleotide exchange factor (GEF), to Rab5-positive early endosomes. Using the inhibitor NSC23766, Tiam1 was shown to be required for Rac1 activation and cell migration induced by CAV1 and Rab5. Mechanistically, we provide evidence implicating p85α (also known as PIK3R1), a Rab5 GTPase-activating protein (GAP), in CAV1-dependent effects, by showing that CAV1 recruits p85α, precluding p85α-mediated Rab5 inactivation and increasing cell migration. In summary, these studies identify a novel CAV1-Rab5-Rac1 signaling axis, whereby CAV1 prevents Rab5 inactivation, leading to increased Rac1 activity and enhanced tumor cell migration and invasion. PMID:24659799

  14. Curcumin attenuates high glucose-induced podocyte apoptosis by regulating functional connections between caveolin-1 phosphorylation and ROS

    PubMed Central

    Sun, Li-na; Liu, Xiang-chun; Chen, Xiang-jun; Guan, Guang-ju; Liu, Gang

    2016-01-01

    Aim: Caveolin-1 (cav-1) is a major multifunctional scaffolding protein of caveolae. Cav-1 is primarily expressed in mesangial cells, renal proximal tubule cells and podocytes in kidneys. Recent evidence shows that the functional connections between cav-1 and ROS play a key role in many diseases. In this study we investigated whether regulating the functional connections between cav-1 and ROS in kidneys contributed to the beneficial effects of curcumin in treating diabetic nephropathy in vitro and in vivo. Methods: Cultured mouse podocytes (mpc5) were incubated in a high glucose (HG, 30 mmol/L) medium for 24, 48 or 72 h. Male rats were injected with STZ (60 mg/kg, ip) to induce diabetes. ROS generation, SOD activity, MDA content and caspase-3 activity in the cultured cells and kidney cortex homogenate were determined. Apoptotic proteins and cav-1 phosphorylation were analyzed using Western blot analyses. Results: Incubation in HG-containing medium time-dependently increased ROS production, oxidative stress, apoptosis, and cav-1 phosphorylation in podocytes. Pretreatment with curcumin (1, 5, and 10 μmol/L) dose-dependently attenuated these abnormalities in HG-treated podocytes. Furthermore, in HG-containing medium, the podocytes transfected with a recombinant plasmid GFP-cav-1 Y14F (mutation at a cav-1 phosphorylation site) exhibited significantly decreased ROS production and apoptosis compared with the cells transfected with empty vector. In diabetic rats, administration of curcumin (100 or 200 mg/kg body weight per day, ig, for 8 weeks) not only significantly improved the renal function, but also suppressed ROS levels, oxidative stress, apoptosis and cav-1 phosphorylation in the kidneys. Conclusion: Curcumin attenuates high glucose-induced podocyte apoptosis in vitro and diabetic nephropathy in vivo partly through regulating the functional connections between cav-1 phosphorylation and ROS. PMID:26838071

  15. Caveolin-1 regulates cancer cell metabolism via scavenging Nrf2 and suppressing MnSOD-driven glycolysis

    PubMed Central

    Hart, Peter C.; Ratti, Bianca A.; Mao, Mao; Ansenberger-Fricano, Kristine; Shajahan-Haq, Ayesha N.; Tyner, Angela L.; Minshall, Richard D.; Bonini, Marcelo G.

    2016-01-01

    Aerobic glycolysis is an indispensable component of aggressive cancer cell metabolism. It also distinguishes cancer cells from most healthy cell types in the body. Particularly for this reason, targeting the metabolism to improve treatment outcomes has long been perceived as a potentially valuable strategy. In practice, however, our limited knowledge of why and how metabolic reprogramming occurs has prevented progress towards therapeutic interventions that exploit the metabolic peculiarities of tumors. We recently described that in breast cancer, MnSOD upregulation is both necessary and sufficient to activate glycolysis. Here, we focused on determining the molecular mechanisms of MnSOD upregulation. We found that Caveolin-1 (Cav-1) is a central component of this mechanism due to its suppressive effects of NF-E2-related factor 2 (Nrf2), a transcription factor upstream of MnSOD. In transformed MCF10A(Er/Src) cells, Cav-1 loss preceded the activation of Nrf2 and its induction of MnSOD expression. Consistently, with previous observations, MnSOD expression secondary to Nrf2 activation led to an increase in the glycolytic rate dependent on mtH2O2 production and the activation of AMPK. Moreover, rescue of Cav-1 expression in a breast cancer cell line (MCF7) suppressed Nrf2 and reduced MnSOD expression. Experimental data were reinforced by epidemiologic nested case-control studies showing that Cav-1 and MnSOD are inversely expressed in cases of invasive ductal carcinoma, with low Cav-1 and high MnSOD expression being associated with lower 5-year survival rates and molecular subtypes with poorest prognosis. PMID:26543228

  16. Overexpression of Aquaporin-1 and Caveolin-1 in the Rat Urinary Bladder Urothelium Following Bladder Outlet Obstruction

    PubMed Central

    Song, Seung Hee; Park, Kwangsung; Kwon, Dongdeuk

    2013-01-01

    Purpose This study was designed to investigate the effect of detrusor overactivity induced by partial bladder outlet obstruction (BOO) on the expression of aquaporin 1 (AQP1) and caveolin 1 (CAV1) in the rat urinary bladder, and to determine the role of these molecules in detrusor overactivity. Methods Female Sprague-Dawley rats were divided into control (n=30) and experimental (n=30) groups. The BOO group underwent partial BOO, and the control group underwent a sham operation. After 4 weeks, an urodynamic study was performed to measure the contraction interval and contraction pressure. The expression and cellular localization of AQP1 and CAV1 were determined by western blot and immunofluorescence experiments in the rat urinary bladder. Results In cystometrograms, the contraction interval was significantly lower in the BOO group (2.9±1.5 minutes) than in the control group (6.7±1.0 minutes) (P<0.05). Conversely, the average contraction pressure was significantly higher in the BOO group (21.2±3.3 mmHg) than in the control group (13.0±2.5 mmHg) (P<0.05). AQP1 and CAV1 were coexpressed in the capillaries, arterioles, and venules of the suburothelial layer. AQP1 and CAV1 protein expression was significantly increased in the BOO rats compared to the control rats (P<0.05). Conclusions Detrusor overactivity induced by BOO causes a significant increase in the expression of AQP1 and CAV1, which were coexpressed in the suburothelial microvasculature. This finding suggests that AQP1 and CAV1 might be closely related to bladder signal activity and may have a functional role in BOO-associated detrusor overactivity. PMID:24466464

  17. Caveolin-1 prevents sustained angiotensin II-induced resistance artery constriction and obesity-induced high blood pressure

    PubMed Central

    Czikora, Istvan; Feher, Attila; Lucas, Rudolf; Fulton, David J. R.

    2014-01-01

    The type 1 angiotensin II (ANG II) receptor (AT1R) undergoes internalization following stimulation by ANG II. Internalization reduces cell surface AT1Rs, and it is required for AT1R resensitization. In this process AT1R may interact with caveolin-1 (Cav1), the main scaffolding protein of caveolae. We hypothesized that the interaction between Cav1 and AT1R delays AT1R resensitization and thereby prevents sustained ANG II-induced resistance artery (RA) constriction under normal conditions and in experimental obesity. In rat and mouse skeletal muscle RA (diameter: ∼90–120 μm) ANG II-induced constrictions were reduced upon repeated (30-min apart) administrations. Upon disruption of caveolae with methyl-β-cyclodextrin or in RA of Cav1 knockout mice, repeated ANG II applications resulted in essentially maintained constrictions. In vascular smooth muscle cells, AT1R interacted with Cav1, and the degree of cell surface interactions was reduced by long-term (15-min), but not short-term (2-min), exposure to ANG II. When Cav1 was silenced, the amount of membrane-associated AT1R was significantly reduced by a short-term ANG II exposure. Moreover, Cav1 knockout mice fed a high-fat diet exhibited augmented and sustained RA constriction to ANG II and had elevated systemic blood pressure, when compared with normal or high-fat fed wild-type mice. Thus, Cav1, through a direct interaction, delays internalization and subsequent resensitization of AT1R. We suggest that this mechanism prevents sustained ANG II-induced RA constriction and elevated systemic blood pressure in diet-induced obesity. PMID:25527780

  18. Caveolin-1 Deficiency Induces Spontaneous Endothelial-to-Mesenchymal Transition in Murine Pulmonary Endothelial Cells in Vitro

    PubMed Central

    Li, Zhaodong; Wermuth, Peter J.; Benn, Bryan S.; Lisanti, Michael P.; Jimenez, Sergio A.

    2014-01-01

    It was previously demonstrated that transforming growth factor β (TGF-β) induces endothelial-to-mesenchymal transition (EndoMT) in murine lung endothelial cells (ECs) in vitro. Owing to the important role of caveolin-1 (CAV1) in TGF-β receptor internalization and TGF-β signaling, the participation of CAV1 in the induction of EndoMT in murine lung ECs was investigated. Pulmonary ECs were isolated from wild-type and Cav1 knockout mice using immunomagnetic methods with sequential anti-CD31 and anti-CD102 antibody selection followed by in vitro culture and treatment with TGF-β1. EndoMT was assessed by semiquantitative RT-PCR for Acta2, Col1a1, Snai1, and Snai2; by immunofluorescence for α-smooth muscle actin; and by Western blot analysis for α-smooth muscle actin, SNAIL1, SNAIL2, and the α2 chain of type I collagen. The same studies were performed in Cav1−/− pulmonary ECs after restoration of functional CAV1 domains using a cell-permeable CAV1 scaffolding domain peptide. Pulmonary ECs from Cav1 knockout mice displayed high levels of spontaneous Acta2, Col1A, Snai1, and Snai2 expression, which increased after TGF-β treatment. Spontaneous and TGF-β1–stimulated EndoMT were abrogated by the restoration of functional CAV1 domains using a cell-permeable peptide. The findings suggest that CAV1 regulation of EndoMT may play a role in the development of fibroproliferative vasculopathies. PMID:23195429

  19. Loss of Stromal Caveolin-1 Expression: A Novel Tumor Microenvironment Biomarker That Can Predict Poor Clinical Outcomes for Pancreatic Cancer

    PubMed Central

    Shan, Tao; Lu, Hongwei; Ji, Hong; Li, Yiming; Guo, Jian; Chen, Xi; Wu, Tao

    2014-01-01

    Aims Cancer development and progression is not only associated with the tumor cell proliferation but also depends on the interaction between tumor cells and the stromal microenvironment. A new understanding of the role of the tumor microenvironment suggests that the loss of stromal caveolin-1 (Cav-1) as a key regulator may become a potential therapy target. This study aims to elucidate whether stromal Cav-1 expression in pancreatic cancer can be a strong prognosis biomarker. Methods Tissue samples from 45 pancreatic cancer patients were studied. Parenchyma and stroma were separated and purified using laser capture microdissection. Stromal Cav-1 expression was measured from pancreatic cancer, paraneoplastic, and normal tissue using immunohistochemistry. We analyzed the correlation of stromal Cav-1 expression with clinicopathologic features and prognostic indicators, such as tumor marker HER-2/neu gene. Results Specimens from six patients (13.3%) showed high levels of stromal Cav-1 staining, those from eight patients (17.8%) showed a lower, intermediate level of staining, whereas those from 31 patients (68.9%) showed an absence of staining. Cav-1 expression in cancer-associated fibroblasts was lower than that in paracancer-associated and in normal fibroblasts. Stromal Cav-1 loss was associated with TNM stage (P = 0.018), lymph node metastasis (P = 0.014), distant metastasis (P = 0.027), and HER-2/neu amplification (P = 0.007). The relationships of age, sex, histological grade, and tumor size with stromal Cav-1 expression were not significant (P>0.05). A negative correlation was found between circulating tumor cells and stromal Cav-1 expression (P<0.05). Conclusion The loss of stromal Cav-1 in pancreatic cancer was an independent prognostic indicator, thus suggesting that stromal Cav-1 may be an effective therapeutic target for patients with pancreatic cancer. PMID:24949874

  20. Interaction of caveolin-1, nitric oxide, and nitric oxide synthases in hypoxic human SK-N-MC neuroblastoma cells.

    PubMed

    Shen, Jiangang; Lee, Waisin; Li, Yue; Lau, Chi Fai; Ng, Kwong Man; Fung, Man Lung; Liu, Ke Jian

    2008-10-01

    Neuroblastoma cells are capable of hypoxic adaptation, but the mechanisms involved are not fully understood. We hypothesized that caveolin-1 (cav-1), a plasma membrane signal molecule, might play a role in protecting neuroblastoma cells from oxidative injury by modulating nitric oxide (NO) production. We investigated the alterations of cav-1, cav-2, nitric oxide synthases (NOS), and NO levels in human SK-N-MC neuroblastoma cells exposed to hypoxia with 2% [O2]. The major discoveries include: (i) cav-1 but not cav-2 was up-regulated in the cells exposed to 15 h of hypoxia; (ii) NO donor 1-[N, N-di-(2-aminoethyl) amino] diazen-1-ium-1, 2-diolate up-regulated the expression of cav-1, whereas the non-selective NOS inhibitor N(G)-nitro-L-arginine methyl ester and inducible NOS (iNOS) inhibitor 1400W each abolished the increase in cav-1 expression in the hypoxic SK-N-MC cells. These results suggest that iNOS-induced NO production contributes to the up-regulation of cav-1 in the hypoxic SK-N-MC cells. Furthermore, we studied the roles played by cav-1 in regulating NO, NOS, and apoptotic cell death in the SK-N-MC cells subjected to 15 h of hypoxic treatment. Both cav-1 transfection and cav-1 scaffolding domain peptide abolished the induction of iNOS, reduced the production of NO, and reduced the rates of apoptotic cell death in the hypoxic SK-N-MC cells. These results suggest that increased expression of cav-1 in response to hypoxic stimulation could prevent oxidative injury induced by reactive oxygen species. The interactions of cav-1, NO, and NOS could be an important signal pathway in protecting the neuroblastoma cells from oxidative injury, contributing to the hypoxic tolerance of neuroblastoma cells. PMID:18717816

  1. Caveolin-1 mediates endotoxin inhibition of endothelin-1-induced endothelial nitric oxide synthase activity in liver sinusoidal endothelial cells.

    PubMed

    Kwok, Willson; Lee, Sang Ho; Culberson, Cathy; Korneszczuk, Katarzyna; Clemens, Mark G

    2009-11-01

    Endothelin-1 (ET-1) plays a key role in the regulation of endothelial nitric oxide synthase (eNOS) activation in liver sinusoidal endothelial cells (LSECs). In the presence of endotoxin, an increase in caveolin-1 (Cav-1) expression impairs ET-1/eNOS signaling; however, the molecular mechanism is unknown. The objective of this study was to investigate the molecular mechanism of Cav-1 in the regulation of LPS suppression of ET-1-mediated eNOS activation in LSECs by examining the effect of caveolae disruption using methyl-beta-cyclodextrin (CD) and filipin. Treatment with 5 mM CD for 30 min increased eNOS activity (+255%, P < 0.05). A dose (0.25 microg/ml) of filipin for 30 min produced a similar effect (+111%, P < 0.05). CD induced the perinuclear localization of Cav-1 and eNOS and stimulated NO production in the same region. Readdition of 0.5 mM cholesterol to saturate CD reversed these effects. Both the combined treatment with CD and ET-1 (CD + ET-1) and with filipin and ET-1 stimulated eNOS activity; however, pretreatment with endotoxin (LPS) abrogated these effects. Following LPS pretreatment, CD + ET-1 failed to stimulate eNOS activity (+51%, P > 0.05), which contributed to the reduced levels of eNOS-Ser1177 phosphorylation and eNOS-Thr495 dephosphorylation, the LPS/CD-induced overexpression and translocation of Cav-1 in the perinuclear region, and the increased perinuclear colocalization of eNOS with Cav-1. These results supported the hypothesis that Cav-1 mediates the action of endotoxin in suppressing ET-1-mediated eNOS activation and demonstrated that the manipulation of caveolae produces significant effects on ET-1-mediated eNOS activity in LSECs. PMID:20501440

  2. Inhibition of CaV2.3 channels by NK1 receptors is sensitive to membrane cholesterol but insensitive to caveolin-1.

    PubMed

    Licon, Yamhilette; Leandro, Deniss; Romero-Mendez, Catalina; Rodriguez-Menchaca, Aldo A; Sanchez-Armass, Sergio; Meza, Ulises

    2015-08-01

    Voltage-gated, CaV2.3 calcium channels and neurokinin-1 (NK1) receptors are both present in nuclei of the central nervous system. When transiently coexpressed in human embryonic kidney (HEK) 293 cells, CaV2.3 is primarily inhibited during strong, agonist-dependent activation of NK1 receptors. NK1 receptors localize to plasma membrane rafts, and their modulation by Gq/11 protein-coupled signaling is sensitive to plasma membrane cholesterol. Here, we show that inhibition of CaV2.3 by NK1 receptors is attenuated following methyl-β-cyclodextrin (MBCD)-mediated depletion of membrane cholesterol. By contrast, inhibition of CaV2.3 was unaffected by intracellular diffusion of caveolin-1 scaffolding peptide or by overexpression of caveolin-1. Interestingly, MΒCD treatment had no effect on the macroscopic biophysical properties of CaV2.3, though it significantly decreased whole-cell membrane capacitance. Our data indicate that (1) cholesterol supports at least one component of the NK1 receptor-linked signaling pathway that inhibits CaV2.3 and (2) caveolin-1 is dispensable within this pathway. Our findings suggest that NK1 receptors reside within non-caveolar membrane rafts and that CaV2.3 resides nearby but outside the rafts. Raft-dependent modulation of CaV2.3 could be important in the physiological and pathophysiological processes in which these channels participate, including neuronal excitability, synaptic plasticity, epilepsy, and chronic pain. PMID:25204428

  3. Expression of Caveolin-1 in Periodontal Tissue and Its Role in Osteoblastic and Cementoblastic Differentiation In Vitro.

    PubMed

    Lee, So-Youn; Yi, Jin-Kyu; Yun, Hyung-Mun; Bae, Cheol-Hyeon; Cho, Eui-Sic; Lee, Kook-Sun; Kim, Eun-Cheol

    2016-05-01

    It has been previously reported that caveolin-1 (Cav-1) knockout mice exhibit increased bone size and stiffness. However, the expression and role of Cav-1 on periodontal tissue is poorly understood. The aim of this study was to investigate the immunohistochemical expression of Cav-1 in the mouse periodontium and explore the role of Cav-1 on osteoblastic and cementoblastic differentiation in human periodontal ligament cells (hPDLCs), cementoblasts, and osteoblasts. To reveal the molecular mechanisms of Cav-1 activity, associated signaling pathways were also examined. Immunolocalization of Cav-1 was studied in mice periodontal tissue. Differentiation was evaluated by ALP activity, alizarin red S staining, and RT-PCR for marker genes. Signal transduction was analyzed using Western blotting and confocal microscopy. Cav-1 expression was observed in hPDLCs, cementoblasts, and osteoblasts of the periodontium both in vivo and in vitro. Inhibition of Cav-1 expression by methyl-β-cyclodextrin (MβCD) and knockdown of Cav-1 by siRNA promoted osteoblastic and cementoblastic differentiation by increasing ALP activity, calcium nodule formation, and mRNA expression of differentiation markers in hPDLCs, cementoblasts, and osteoblasts. Osteogenic medium-induced BMP-2 and BMP-7 expression, and phosphorylation of Smad1/5/8 were enhanced by MβCD and siRNA knockdown of Cav-1, which was reversed by BMP inhibitor noggin. MβCD and Cav-1 siRNA knockdown increased OM-induced AMPK, Akt, GSK3β, and CREB phosphorylation, which were reversed by Ara-A, a specific AMPK inhibitor. Moreover, OM-induced activation of p38, ERK, JNK, and NF-κB was enhanced by Cav-1 inhibition. This study demonstrates, for the first time, that Cav-1 is expressed in developing periodontal tissue and in vitro in periodontal-related cells. Cav-1 inhibition positively regulates osteoblastic differentiation in hPDLCs, cementoblasts, and osteoblasts via BMP, AMPK, MAPK, and NF-κB pathway. Thus, Cav-1 inhibition may be

  4. Lipopolysaccharide-induced caveolin-1 phosphorylation-dependent increase in transcellular permeability precedes the increase in paracellular permeability

    PubMed Central

    Wang, Nan; Zhang, Dan; Sun, Gengyun; Zhang, Hong; You, Qinghai; Shao, Min; Yue, Yang

    2015-01-01

    Background Lipopolysaccharide (LPS) was shown to induce an increase in caveolin-1 (Cav-1) expression in endothelial cells; however, the mechanisms regarding this response and the consequences on caveolae-mediated transcellular transport have not been completely investigated. This study aims to investigate the role of LPS-induced Cav-1 phosphorylation in pulmonary microvascular permeability in pulmonary microvascular endothelial cells (PMVECs). Methods Rat PMVECs were isolated, cultured, and identified. Endocytosis experiments were employed to stain the nuclei by DAPI, and images were obtained with a fluorescence microscope. Permeability of endothelial cultures was measured to analyze the barrier function of endothelial monolayer. Western blot assay was used to examine the expression of Cav-1, pCav-1, triton-insoluble Cav-1, and triton-soluble Cav-1 protein. Results The LPS treatment induced phosphorylation of Cav-1, but did not alter the total Cav-1 level till 60 min in both rat and human PMVECs. LPS treatment also increased the triton-insoluble Cav-1 level, which peaked 15 min after LPS treatment in both rat and human PMVECs. LPS treatment increases the intercellular cell adhesion molecule-1 expression. Src inhibitors, including PP2, PP1, Saracatinib, and Quercetin, partially inhibited LPS-induced phosphorylation of Cav-1. In addition, both PP2 and caveolae disruptor MβCD inhibited LPS-induced increase of triton-insoluble Cav-1. LPS induces permeability by activating interleukin-8 and vascular endothelial growth factor and targeting other adhesion markers, such as ZO-1 and occludin. LPS treatment also significantly increased the endocytosis of albumin, which could be blocked by PP2 or MβCD. Furthermore, LPS treatment for 15 min significantly elevated Evans Blue-labeled BSA transport in advance of a decrease in transendothelial electrical resistance of PMVEC monolayer at this time point. After LPS treatment for 30 min, transendothelial electrical resistance

  5. Caveolin-1 Regulates the P2Y2 Receptor Signaling in Human 1321N1 Astrocytoma Cells.

    PubMed

    Martinez, Namyr A; Ayala, Alondra M; Martinez, Magdiel; Martinez-Rivera, Freddyson J; Miranda, Jorge D; Silva, Walter I

    2016-06-01

    Damage to the CNS can cause a differential spatio-temporal release of multiple factors, such as nucleotides, ATP and UTP. The latter interact with neuronal and glial nucleotide receptors. The P2Y2 nucleotide receptor (P2Y2R) has gained prominence as a modulator of gliotic responses after CNS injury. Still, the molecular mechanisms underlying these responses in glia are not fully understood. Membrane-raft microdomains, such as caveolae, and their constituent caveolins, modulate receptor signaling in astrocytes; yet, their role in P2Y2R signaling has not been adequately explored. Hence, this study evaluated the role of caveolin-1 (Cav-1) in modulating P2Y2R subcellular distribution and signaling in human 1321N1 astrocytoma cells. Recombinant hP2Y2R expressed in 1321N1 cells and Cav-1 were found to co-fractionate in light-density membrane-raft fractions, co-localize via confocal microscopy, and co-immunoprecipitate. Raft localization was dependent on ATP stimulation and Cav-1 expression. This hP2Y2R/Cav-1 distribution and interaction was confirmed with various cell model systems differing in the expression of both P2Y2R and Cav-1, and shRNA knockdown of Cav-1 expression. Furthermore, shRNA knockdown of Cav-1 expression decreased nucleotide-induced increases in the intracellular Ca(2+) concentration in 1321N1 and C6 glioma cells without altering TRAP-6 and carbachol Ca(2+) responses. In addition, Cav-1 shRNA knockdown also decreased AKT phosphorylation and altered the kinetics of ERK1/2 activation in 1321N1 cells. Our findings strongly suggest that P2Y2R interaction with Cav-1 in membrane-raft caveolae of 1321N1 cells modulates receptor coupling to its downstream signaling machinery. Thus, P2Y2R/Cav-1 interactions represent a novel target for controlling P2Y2R function after CNS injury. PMID:27129210

  6. Slightly modifying pseudoproline dipeptides incorporation strategy enables solid phase synthesis of a 54 AA fragment of caveolin-1 encompassing the intramembrane domain.

    PubMed

    Coïc, Yves-Marie; Lan, Charlotte Le; Neumann, Jean-Michel; Jamin, Nadège; Baleux, Françoise

    2010-02-01

    This work contributes to highlight the benefits of pseudoproline dipeptides introduction in difficult SPPS. We show how a slight modification in the positioning choice conditioned the synthesis achievement of a 54 amino acid long caveolin-1 peptide encompassing the intramembrane domain. Furthermore, we report a side reaction correlated with the coupling steps and generating truncated fragments with a mass deviation of + 42 Da. Considering the need of structural data for membrane proteins, most of which are considered as prevalent therapeutic targets, chemical synthesis provides an interesting alternative pathway to obtain hydrophobic domains by pushing back the frontiers of conventional RP methods of purification. PMID:20014324

  7. The Importance of Caveolin-1 as Key-Regulator of Three-Dimensional Growth in Thyroid Cancer Cells Cultured under Real and Simulated Microgravity Conditions

    PubMed Central

    Riwaldt, Stefan; Bauer, Johann; Pietsch, Jessica; Braun, Markus; Segerer, Jürgen; Schwarzwälder, Achim; Corydon, Thomas J.; Infanger, Manfred; Grimm, Daniela

    2015-01-01

    We recently demonstrated that the CAV1 gene was down-regulated, when poorly differentiated thyroid FTC-133 cancer cells formed spheroids under simulated microgravity conditions. Here, we present evidence that the caveolin-1 protein is involved in the inhibition of spheroid formation, when confluent monolayers are exposed to microgravity. The evidence is based on proteins detected in cells and their supernatants of the recent spaceflight experiment: “NanoRacks-CellBox-Thyroid Cancer”. The culture supernatant had been collected in a special container adjacent to the flight hardware incubation chamber and stored at low temperature until it was analyzed by Multi-Analyte Profiling (MAP) technology, while the cells remaining in the incubation chamber were fixed by RNAlater and examined by mass spectrometry. The soluble proteins identified by MAP were investigated in regard to their mutual interactions and their influence on proteins, which were associated with the cells secreting the soluble proteins and had been identified in a preceding study. A Pathway Studio v.11 analysis of the soluble and cell-associated proteins together with protein kinase C alpha (PRKCA) suggests that caveolin-1 is involved, when plasminogen enriched in the extracellular space is not activated and the vascular cellular adhesion molecule (VCAM-1) mediated cell–cell adhesion is simultaneously strengthened and activated PRKCA is recruited in caveolae, while the thyroid cancer cells do not form spheroids. PMID:26633361

  8. Xuezhikang, Extract of Red Yeast Rice, Improved Abnormal Hemorheology, Suppressed Caveolin-1 and Increased eNOS Expression in Atherosclerotic Rats

    PubMed Central

    Yang, Ya-Bing; Liu, Mei-Lin

    2013-01-01

    Background Xuezhikang is the extract of red yeast rice, which has been widely used for the management of atherosclerotic disease, but the molecular basis of its antiatherosclerotic effects has not yet been fully identified. Here we investigated the changes of eNOS in vascular endothelia and RBCs, eNOS regulatory factor Caveolin-1 in endothelia, and hemorheological parameters in atherosclerotic rats to explore the protective effects of Xuezhikang. Methodology/Principal Findings Wistar rats were divided into 4 groups (n = 12/group) group C, controls; group M, high-cholesterol diet (HCD) induced atherosclerotic models; group X, HCD+Xuezhikang; and group L, HCD +Lovastatin. In group X, Xuezhikang inhibited oxidative stress, down-regulated caveolin-1 in aorta wall (P<0.05), up-regulated eNOS expression in vascular endothelia and erythrocytes (P<0.05), increased NOx (nitrite and nitrate) in plasma and cGMP in erythrocyte plasma and aorta wall (P<0.05), increased erythrocyte deformation index (EDI), and decreased whole blood viscosity and plasma viscosity (P<0.05), with the improvement of arterial pathology. Conclusions/Significance Xuezhikang up-regulated eNOS expression in vascular endothelia and RBCs, increased plasma NOx and improved abnormal hemorheology in high cholesterol diet induced atherosclerotic rats. The elevated eNOS/NO and improved hemorheology may be beneficial to atherosclerotic disease. PMID:23675421

  9. The Importance of Caveolin-1 as Key-Regulator of Three-Dimensional Growth in Thyroid Cancer Cells Cultured under Real and Simulated Microgravity Conditions.

    PubMed

    Riwaldt, Stefan; Bauer, Johann; Pietsch, Jessica; Braun, Markus; Segerer, Jürgen; Schwarzwälder, Achim; Corydon, Thomas J; Infanger, Manfred; Grimm, Daniela

    2015-01-01

    We recently demonstrated that the CAV1 gene was down-regulated, when poorly differentiated thyroid FTC-133 cancer cells formed spheroids under simulated microgravity conditions. Here, we present evidence that the caveolin-1 protein is involved in the inhibition of spheroid formation, when confluent monolayers are exposed to microgravity. The evidence is based on proteins detected in cells and their supernatants of the recent spaceflight experiment: "NanoRacks-CellBox-Thyroid Cancer". The culture supernatant had been collected in a special container adjacent to the flight hardware incubation chamber and stored at low temperature until it was analyzed by Multi-Analyte Profiling (MAP) technology, while the cells remaining in the incubation chamber were fixed by RNAlater and examined by mass spectrometry. The soluble proteins identified by MAP were investigated in regard to their mutual interactions and their influence on proteins, which were associated with the cells secreting the soluble proteins and had been identified in a preceding study. A Pathway Studio v.11 analysis of the soluble and cell-associated proteins together with protein kinase C alpha (PRKCA) suggests that caveolin-1 is involved, when plasminogen enriched in the extracellular space is not activated and the vascular cellular adhesion molecule (VCAM-1) mediated cell-cell adhesion is simultaneously strengthened and activated PRKCA is recruited in caveolae, while the thyroid cancer cells do not form spheroids. PMID:26633361

  10. Conserved Molecular Underpinnings and Characterization of a Role for Caveolin-1 in the Tumor Microenvironment of Mature T-Cell Lymphomas

    PubMed Central

    Herek, Tyler A.; Shew, Timothy D.; Spurgin, Heather N.; Cutucache, Christine E.

    2015-01-01

    Neoplasms of extra-thymic T-cell origin represent a rare and difficult population characterized by poor clinical outcome, aggressive presentation, and poorly defined molecular characteristics. Much work has been done to gain greater insights into distinguishing features among malignant subtypes, but there also exists a need to identify unifying characteristics to assist in rapid diagnosis and subsequent potential treatment. Herein, we investigated gene expression data of five different mature T-cell lymphoma subtypes (n = 187) and found 21 genes to be up- and down-regulated across all malignancies in comparison to healthy CD4+ and CD8+ T-cell controls (n = 52). From these results, we sought to characterize a role for caveolin-1 (CAV1), a gene with previous description in the progression of both solid and hematological tumors. Caveolin-1 was upregulated, albeit with a heterogeneous nature, across all mature T-cell lymphoma subtypes, a finding confirmed using immunohistochemical staining on an independent sampling of mature T-cell lymphoma biopsies (n = 65 cases). Further, stratifying malignant samples in accordance with high and low CAV1 expression revealed that higher expression of CAV1 in mature T-cell lymphomas is analogous with an enhanced inflammatory and invasive gene expression profile. Taken together, these results demonstrate a role for CAV1 in the tumor microenvironment of mature T-cell malignancies and point toward potential prognostic implications. PMID:26566034

  11. Ovine caveolin-1: cDNA cloning, E. coli expression, and association with endothelial nitric oxide synthase.

    PubMed

    Chen, D; Zangl, A L; Zhao, Q; Markley, J L; Zheng, J; Bird, I M; Magness, R R

    2001-04-25

    Caveolin-1 (Cav-1), the principal coat protein of caveolae, plays an obligatory role in regulating the activity of endothelial nitric oxide (NO) synthase (eNOS). We propose that Cav-1 may be critical to eNOS-NO mediated uterine vasodilatation during pregnancy and estrogen replacement therapy. To test this hypothesis in the sheep model, we isolated the full-length cDNA of ovine Cav-1 (oCav-1) from a Lambda ZAP cDNA library of ovine placental artery endothelial cells. Thirty-two positive oCav-1 clones were recognized by a partial oCav-1 cDNA from this library, of which eight were sequenced. Restriction digestion of these clones revealed that the cDNAs of oCav-1 ranged from approximately 2.1 to 2.7 kb. Northern analysis of Cav-1 mRNAs in ovine uterine artery endothelial cells (UAEC) showed two transcripts of approximately 2.1 and 2.7 kb, respectively. Immunoreactive Cav-1 protein, but not caveolin-2 or caveolin-3, was detected in UAEC. Sequence analysis revealed that in addition to a 537-bp open reading frame encoding a 178 amino acid oCav-1 protein, full-length oCav-1 cDNAs apparently possess a approximately 1.6-2.1 kb 3'-untranslated region. Database searches with oCav-1 cDNA revealed that the coding region of mammalian Cav-1 genes is highly conserved. We prepared a recombinant full-length oCav-1 protein in which six consecutive histidine residues were tagged at the end of its COOH-terminus and developed a [His]6-tagged oCav-1 'pull-down assay' for studying the association of eNOS with Cav-1. Incubation of exogenous [His]6-tagged oCav-1 with resting UAEC extracts led to the formation of a [His]6-tagged oCav-1-eNOS complex. In the presence of a synthetic caveolin-scaffolding domain (CSD, aa 82-101) peptide, but not a mutated CSD peptide, [His]6-tagged oCav-1 associated eNOS was dose (0-10 microM)-dependently inhibited. eNOS association with Cav-1 in UAEC was further confirmed by the facts that eNOS co-immunoprecipitated with Cav-1 and vice versa, and that eNOS co

  12. Role of G(i/o)-Src kinase-PI3K/Akt pathway and caveolin-1 in β₂-adrenoceptor coupling to endothelial NO synthase in mouse pulmonary artery.

    PubMed

    Banquet, Sébastien; Delannoy, Estelle; Agouni, Abdelali; Dessy, Chantal; Lacomme, Sabrina; Hubert, Fabien; Richard, Vincent; Muller, Bernard; Leblais, Véronique

    2011-07-01

    Activation of the β₂-adrenoceptor (β₂-AR) elicits an endothelial nitric oxide synthase (eNOS)-dependent relaxation in mouse pulmonary artery, which, contrary to the muscarinic receptor-dependent relaxation, is preserved in hypoxic pulmonary arterial hypertension. We therefore characterized the signaling pathways underlying the β₂-AR-mediated eNOS activation, with special focus on G(i/o) proteins, protein kinases and caveolae. Functional studies (for evaluation of vasorelaxant response), Western blotting (for assessment of eNOS and caveolin-1 phosphorylation) and transmission electron microscopy (for visualization of caveolae) were conducted in pulmonary arteries from wild-type or caveolin-1 knockout mice. In wild-type isolated arteries, relaxation to the selective β₂-AR agonist procaterol was reduced by inhibitors of G(i/o) proteins (pertussis toxin, PTX), phosphatidylinositol 3-kinase (PI3K; wortmannin or LY 294002), Akt (Akt inhibitor X) and Src-kinase (PP2) and by cholesterol depletion (using methyl-β-cyclodextrin). Procaterol induced eNOS phosphorylation at Ser(1177), which was prevented by PTX, PP2 or Akt inhibitor. Procaterol also promoted caveolin-1 phosphorylation at Tyr(14), which was decreased by PTX or PP2. Caveolin-1 gene deletion resulted in endothelial caveolae disruption in mouse pulmonary artery and in potentiation of procaterol-induced relaxation. Unlike procaterol, acetylcholine-induced relaxation was unaffected by PTX, methyl-β-cyclodextrin or caveolin-1 gene deletion. To conclude, the mouse pulmonary endothelial β₂-AR is coupled to a G(i/o)-Src kinase-PI3K/Akt pathway to promote eNOS phosphorylation at Ser(1177) leading to a NO-dependent vasorelaxation. Caveolin-1 exerts a negative control on this response that is abrogated by its phosphorylation at Tyr(14), through a G(i/o)-Src kinase pathway. Since pulmonary β₂-AR- and muscarinic receptor-mediated relaxations differentiate in their respective signaling pathways leading to e

  13. Cavin-1 and Caveolin-1 are both required to support cell proliferation, migration and anchorage-independent cell growth in rhabdomyosarcoma.

    PubMed

    Faggi, Fiorella; Chiarelli, Nicola; Colombi, Marina; Mitola, Stefania; Ronca, Roberto; Madaro, Luca; Bouche, Marina; Poliani, Pietro L; Vezzoli, Marika; Longhena, Francesca; Monti, Eugenio; Salani, Barbara; Maggi, Davide; Keller, Charles; Fanzani, Alessandro

    2015-06-01

    Rhabdomyosarcoma (RMS) is a childhood soft tissue tumor with broad expression of markers that are typically found in skeletal muscle. Cavin-1 is a recently discovered protein actively cooperating with Caveolin-1 (Cav-1) in the morphogenesis of caveolae and whose role in cancer is drawing increasing attention. Using a combined in silico and in vitro analysis here we show that Cavin-1 is expressed in myogenic RMS tumors as well as in human and primary mouse RMS cultures, exhibiting a broad subcellular localization, ranging from nuclei and cytosol to plasma membrane. In particular, the coexpression and plasma membrane interaction between Cavin-1 and Cav-1 characterized the proliferation of human and mouse RMS cell cultures, while a downregulation of their expression levels was observed during the myogenic differentiation. Knockdown of Cavin-1 or Cav-1 in the human RD and RH30 cells led to impairment of cell proliferation and migration. Moreover, loss of Cavin-1 in RD cells impaired the anchorage-independent cell growth in soft agar. While the loss of Cavin-1 did not affect the Cav-1 protein levels in RMS cells, Cav-1 overexpression and knockdown triggered a rise or depletion of Cavin-1 protein levels in RD cells, respectively, in turn reflecting on increased or decreased cell proliferation, migration and anchorage-independent cell growth. Collectively, these data indicate that the interaction between Cavin-1 and Cav-1 underlies the cell growth and migration in myogenic tumors. PMID:25822667

  14. Critical role of CAV1/caveolin-1 in cell stress responses in human breast cancer cells via modulation of lysosomal function and autophagy

    PubMed Central

    Shi, Yin; Tan, Shi-Hao; Ng, Shukie; Zhou, Jing; Yang, Na-Di; Koo, Gi-Bang; McMahon, Kerrie-Ann; Parton, Robert G; Hill, Michelle M; del Pozo, Miguel A; Kim, You-Sun; Shen, Han-Ming

    2015-01-01

    CAV1 (caveolin 1, caveolae protein, 22kDa) is well known as a principal scaffolding protein of caveolae, a specialized plasma membrane structure. Relatively, the caveolae-independent function of CAV1 is less studied. Autophagy is a process known to involve various membrane structures, including autophagosomes, lysosomes, and autolysosomes for degradation of intracellular proteins and organelles. Currently, the function of CAV1 in autophagy remains largely elusive. In this study, we demonstrate for the first time that CAV1 deficiency promotes both basal and inducible autophagy. Interestingly, the promoting effect was found mainly in the late stage of autophagy via enhancing lysosomal function and autophagosome-lysosome fusion. Notably, the regulatory function of CAV1 in lysosome and autophagy was found to be caveolae-independent, and acts through lipid rafts. Furthermore, the elevated autophagy level induced by CAV1 deficiency serves as a cell survival mechanism under starvation. Importantly, downregulation of CAV1 and enhanced autophagy level were observed in human breast cancer cells and tissues. Taken together, our data reveal a novel function of CAV1 and lipid rafts in breast cancer development via modulation of lysosomal function and autophagy. PMID:25945613

  15. Role of NF-κB-dependent Caveolin-1 Expression in the Mechanism of Increased Endothelial Permeability Induced by Lipopolysaccharide*S

    PubMed Central

    Tiruppathi, Chinnaswamy; Shimizu, Jun; Miyawaki-Shimizu, Kayo; Vogel, Stephen M.; Bair, Angela M.; Minshall, Richard D.; Predescu, Dan; Malik, Asrar B.

    2008-01-01

    We investigated the role of NF-κB activation by the bacterial product lipopolysaccharide (LPS) in inducing caveolin-1 (Cav-1) expression and its consequence in contributing to the leakiness of the endothelial barrier. We observed that LPS challenge of human lung microvascular endothelial cells induced concentration- and time-dependent increases in expression of Cav-1 mRNA and protein. The NEMO (NF-κB essential modifier binding domain)-binding domain peptide (IkB kinase (IKK)-NEMO-binding domain (NBD) peptide), which prevents NF-κB activation by inhibiting the interaction of IKKγ with the IKK complex, blocked LPS-induced Cav-1 mRNA and protein expression. Knockdown of NF-κB subunit p65/RelA expression with small interfering RNA also prevented LPS-induced Cav-1 expression. Caveolae open to the apical and basal plasmalemma of endothelial cells increased 2–4-fold within 4 h of LPS exposure. IKK-NBD peptide markedly reduced the LPS-induced increase in the number of caveolae as well as transendothelial albumin permeability. These observations were recapitulated in mouse studies in which IKK-NBD peptide prevented Cav-1 expression and interfered with the increase in lung microvessel permeability induced by LPS. Thus, LPS mediates NF-κB-dependent Cav-1 expression that results in increased caveolae number and thereby contributes to the mechanism of increased transendothelial albumin permeability. PMID:18077459

  16. Ubiquitination of the N-terminal Region of Caveolin-1 Regulates Endosomal Sorting by the VCP/p97 AAA-ATPase*

    PubMed Central

    Kirchner, Philipp; Bug, Monika; Meyer, Hemmo

    2013-01-01

    Caveolin-1 (CAV1) is the defining constituent of caveolae at the plasma membrane of many mammalian cells. For turnover, CAV1 is ubiquitinated and sorted to late endosomes and lysosomes. Sorting of CAV1 requires the AAA+-type ATPase VCP and its cofactor UBXD1. However, it is unclear in which region CAV1 is ubiquitinated and how ubiquitination is linked to sorting of CAV1 by VCP-UBXD1. Here, we show through site-directed mutagenesis that ubiquitination of CAV1 occurs at any of the six lysine residues, 5, 26, 30, 39, 47, and 57, that are clustered in the N-terminal region but not at lysines in the oligomerization, intramembrane, or C-terminal domains. Mutation of Lys-5–57 to arginines prevented binding of the VCP-UBXD1 complex and, importantly, strongly reduced recruitment of VCP-UBXD1 to endocytic compartments. Moreover, the Lys-5–57Arg mutation specifically interfered with trafficking of CAV1 from early to late endosomes. Conversely and consistently, depletion of VCP or UBXD1 led to accumulation of ubiquitinated CAV1, suggesting that VCP acts downstream of ubiquitination and is required for transport of the ubiquitinated form of CAV1 to late endosomes. These results define the N-terminal region of CAV1 as the critical ubiquitin conjugation site and, together with previous data, demonstrate the significance of this ubiquitination for binding to the VCP-UBXD1 complex and for sorting into lysosomes. PMID:23335559

  17. Exercise-Induced Changes in Caveolin-1, Depletion of Mitochondrial Cholesterol, and the Inhibition of Mitochondrial Swelling in Rat Skeletal Muscle but Not in the Liver.

    PubMed

    Flis, Damian Jozef; Olek, Robert Antoni; Kaczor, Jan Jacek; Rodziewicz, Ewa; Halon, Malgorzata; Antosiewicz, Jedrzej; Wozniak, Michal; Gabbianelli, Rosita; Ziolkowski, Wieslaw

    2016-01-01

    The reduction in cholesterol in mitochondria, observed after exercise, is related to the inhibition of mitochondrial swelling. Caveolin-1 (Cav-1) plays an essential role in the regulation of cellular cholesterol metabolism and is required by various signalling pathways. Therefore, the aim of this study was to investigate the effect of prolonged swimming on the mitochondrial Cav-1 concentration; additionally, we identified the results of these changes as they relate to the induction of changes in the mitochondrial swelling and cholesterol in rat skeletal muscle and liver. Male Wistar rats were divided into a sedentary control group and an exercise group. The exercised rats swam for 3 hours and were burdened with an additional 3% of their body weight. After the cessation of exercise, their quadriceps femoris muscles and livers were immediately removed for experimentation. The exercise protocol caused an increase in the Cav-1 concentration in crude muscle mitochondria; this was related to a reduction in the cholesterol level and an inhibition of mitochondrial swelling. There were no changes in rat livers, with the exception of increased markers of oxidative stress in mitochondria. These data indicate the possible role of Cav-1 in the adaptive change in the rat muscle mitochondria following exercise. PMID:26839631

  18. Release of Matrix Metalloproteinases-2 and 9 by S-Nitrosylated Caveolin-1 Contributes to Degradation of Extracellular Matrix in tPA-Treated Hypoxic Endothelial Cells

    PubMed Central

    Bi, Gang; Zhu, Yihui; Jun, Wei; Ma, Wenlin; Wu, Huimin

    2016-01-01

    Intracranial hemorrhage remains the most feared complication in tissue plasminogen activator (tPA) thrombolysis for ischemic stroke. However, the underlying molecular mechanisms are still poorly elucidated. In this study, we reported an important role of caveolin-1 (Cav-1) s-nitrosylation in matrix metalloproteinase (MMP)-2 and 9 secretion from tPA-treated ischemic endothelial cells. Brain vascular endothelial cells (bEND3) were exposed to oxygen-glucose deprivation (OGD) for 2 h before adding recombinant human tPA for 6 h. This treatment induced a significant increase of MMP2 and 9 in the media of bEND3 cells and a simultaneous degradation of fibronectin and laminin β-1, the two main components of extracellular matrix (ECM). Inhibition of MMP2 and 9 with SB-3CT completely blocked the degradation of fibronectin and laminin β-1. ODG+tPA treatment led to Cav-1 shedding from bEND3 cells into the media. Notably, OGD triggered nitric oxide (NO) production and S-nitrosylationof Cav-1 (SNCav-1). Meanwhile tPA induced activation of ERK signal pathway and stimulates the secretion of SNCav-1. Pretreatment of bEND3 cells with C-PTIO (a NO scavenger) or U0126 (a specific ERK inhibitor) significantly reduced OGD-induced S-nitrosylation of Cav-1 in cells and blocked the secretion of Cav-1 and MMP2 and 9 into the media as well as the degradation of fibronectin and laminin β-1 in OGD and tPA-treated cells. These data indicate that OGD-triggered Cav-1 S-nitrosylation interacts with tPA-induced ERK activation to augment MMP2 and 9 secretion and subsequent ECM degradation, which may account for the exacerbation of ischemic blood brain barrier damage following tPA thrombolysis for ischemic stroke. PMID:26881424

  19. Matrix metalloproteinase-2-mediated occludin degradation and caveolin-1-mediated claudin-5 redistribution contribute to blood-brain barrier damage in early ischemic stroke stage.

    PubMed

    Liu, Jie; Jin, Xinchun; Liu, Ke J; Liu, Wenlan

    2012-02-29

    Blood-brain barrier (BBB) disruption occurs early enough to be within the thrombolytic time window, and this early ischemic BBB damage is closely associated with hemorrhagic transformation and thus emerging as a promising target for reducing the hemorrhagic complications of thrombolytic stroke therapy. However, the mechanisms underlying early ischemic BBB damage remain poorly understood. Here, we investigated the early molecular events of ischemic BBB damage using in vitro oxygen-glucose deprivation (OGD) and in vivo rat middle cerebral artery occlusion (MCAO) models. Exposure of bEND3 monolayer to OGD for 2 h significantly increased its permeability to FITC-labeled dextran and promoted the secretion of metalloproteinase-2 and -9 (MMP-2/9) and cytosolic translocation of caveolin-1 (Cav-1). This same OGD treatment also led to rapid degradation of tight junction protein occludin and dissociation of claudin-5 from the cytoskeleton, which contributed to OGD-induced endothelial barrier disruption. Using selective MMP-2/9 inhibitor SB-3CT (2-[[(4-phenoxyphenyl)sulfonyl]methyl]-thiirane) or their neutralizing antibodies or Cav-1 siRNA, we found that MMP-2 was the major enzyme mediating OGD-induced occludin degradation, while Cav-1 was responsible for claudin-5 redistribution. The interaction between Cav-1 and claudin-5 was further confirmed by coimmunoprecipitation. Consistent with these in vitro findings, we observed fluorescence tracer extravasation, increased gelatinolytic activity, and elevated interstitial MMP-2 levels in ischemic subcortical tissue after 2 h MCAO. Moreover, occludin protein loss and claudin-5 redistribution were detected in ischemic cerebromicrovessels. These data indicate that cerebral ischemia initiates two rapid parallel processes, MMP-2-mediated occludin degradation and Cav-1-mediated claudin-5 redistribution, to cause BBB disruption at early stroke stages relevant to acute thrombolysis. PMID:22378877

  20. Release of Matrix Metalloproteinases-2 and 9 by S-Nitrosylated Caveolin-1 Contributes to Degradation of Extracellular Matrix in tPA-Treated Hypoxic Endothelial Cells.

    PubMed

    Song, Haoming; Cheng, Youjun; Bi, Gang; Zhu, Yihui; Jun, Wei; Ma, Wenlin; Wu, Huimin

    2016-01-01

    Intracranial hemorrhage remains the most feared complication in tissue plasminogen activator (tPA) thrombolysis for ischemic stroke. However, the underlying molecular mechanisms are still poorly elucidated. In this study, we reported an important role of caveolin-1 (Cav-1) s-nitrosylation in matrix metalloproteinase (MMP)-2 and 9 secretion from tPA-treated ischemic endothelial cells. Brain vascular endothelial cells (bEND3) were exposed to oxygen-glucose deprivation (OGD) for 2 h before adding recombinant human tPA for 6 h. This treatment induced a significant increase of MMP2 and 9 in the media of bEND3 cells and a simultaneous degradation of fibronectin and laminin β-1, the two main components of extracellular matrix (ECM). Inhibition of MMP2 and 9 with SB-3CT completely blocked the degradation of fibronectin and laminin β-1. ODG+tPA treatment led to Cav-1 shedding from bEND3 cells into the media. Notably, OGD triggered nitric oxide (NO) production and S-nitrosylationof Cav-1 (SNCav-1). Meanwhile tPA induced activation of ERK signal pathway and stimulates the secretion of SNCav-1. Pretreatment of bEND3 cells with C-PTIO (a NO scavenger) or U0126 (a specific ERK inhibitor) significantly reduced OGD-induced S-nitrosylation of Cav-1 in cells and blocked the secretion of Cav-1 and MMP2 and 9 into the media as well as the degradation of fibronectin and laminin β-1 in OGD and tPA-treated cells. These data indicate that OGD-triggered Cav-1 S-nitrosylation interacts with tPA-induced ERK activation to augment MMP2 and 9 secretion and subsequent ECM degradation, which may account for the exacerbation of ischemic blood brain barrier damage following tPA thrombolysis for ischemic stroke. PMID:26881424

  1. Integrin alpha1beta1 regulates epidermal growth factor receptor activation by controlling peroxisome proliferator-activated receptor gamma-dependent caveolin-1 expression.

    PubMed

    Chen, Xiwu; Whiting, Carrie; Borza, Corina; Hu, Wen; Mont, Stacey; Bulus, Nada; Zhang, Ming-Zhi; Harris, Raymond C; Zent, Roy; Pozzi, Ambra

    2010-06-01

    Integrin alpha1beta1 negatively regulates the generation of profibrotic reactive oxygen species (ROS) by inhibiting epidermal growth factor receptor (EGFR) activation; however, the mechanism by which it does this is unknown. In this study, we show that caveolin-1 (Cav-1), a scaffolding protein that binds integrins and controls growth factor receptor signaling, participates in integrin alpha1beta1-mediated EGFR activation. Integrin alpha1-null mesangial cells (MCs) have reduced Cav-1 levels, and reexpression of the integrin alpha1 subunit increases Cav-1 levels, decreases EGFR activation, and reduces ROS production. Downregulation of Cav-1 in wild-type MCs increases EGFR phosphorylation and ROS synthesis, while overexpression of Cav-1 in the integrin alpha1-null MCs decreases EGFR-mediated ROS production. We further show that integrin alpha1-null MCs have increased levels of activated extracellular signal-regulated kinase (ERK), which leads to reduced activation of peroxisome proliferator-activated receptor gamma (PPARgamma), a transcription factor that positively regulates Cav-1 expression. Moreover, activation of PPARgamma or inhibition of ERK increases Cav-1 levels in the integrin alpha1-null MCs. Finally, we show that glomeruli of integrin alpha1-null mice have reduced levels of Cav-1 and activated PPARgamma but increased levels of phosphorylated EGFR both at baseline and following injury. Thus, integrin alpha1beta1 negatively regulates EGFR activation by positively controlling Cav-1 levels, and the ERK/PPARgamma axis plays a key role in regulating integrin alpha1beta1-dependent Cav-1 expression and consequent EGFR-mediated ROS production. PMID:20368353

  2. Integrin α1β1 Regulates Epidermal Growth Factor Receptor Activation by Controlling Peroxisome Proliferator-Activated Receptor γ-Dependent Caveolin-1 Expression ▿ # ‖

    PubMed Central

    Chen, Xiwu; Whiting, Carrie; Borza, Corina; Hu, Wen; Mont, Stacey; Bulus, Nada; Zhang, Ming-Zhi; Harris, Raymond C.; Zent, Roy; Pozzi, Ambra

    2010-01-01

    Integrin α1β1 negatively regulates the generation of profibrotic reactive oxygen species (ROS) by inhibiting epidermal growth factor receptor (EGFR) activation; however, the mechanism by which it does this is unknown. In this study, we show that caveolin-1 (Cav-1), a scaffolding protein that binds integrins and controls growth factor receptor signaling, participates in integrin α1β1-mediated EGFR activation. Integrin α1-null mesangial cells (MCs) have reduced Cav-1 levels, and reexpression of the integrin α1 subunit increases Cav-1 levels, decreases EGFR activation, and reduces ROS production. Downregulation of Cav-1 in wild-type MCs increases EGFR phosphorylation and ROS synthesis, while overexpression of Cav-1 in the integrin α1-null MCs decreases EGFR-mediated ROS production. We further show that integrin α1-null MCs have increased levels of activated extracellular signal-regulated kinase (ERK), which leads to reduced activation of peroxisome proliferator-activated receptor γ (PPARγ), a transcription factor that positively regulates Cav-1 expression. Moreover, activation of PPARγ or inhibition of ERK increases Cav-1 levels in the integrin α1-null MCs. Finally, we show that glomeruli of integrin α1-null mice have reduced levels of Cav-1 and activated PPARγ but increased levels of phosphorylated EGFR both at baseline and following injury. Thus, integrin α1β1 negatively regulates EGFR activation by positively controlling Cav-1 levels, and the ERK/PPARγ axis plays a key role in regulating integrin α1β1-dependent Cav-1 expression and consequent EGFR-mediated ROS production. PMID:20368353

  3. Mechanosensitive caveolin-1 activation-induced PI3K/Akt/mTOR signaling pathway promotes breast cancer motility, invadopodia formation and metastasis in vivo.

    PubMed

    Yang, Hong; Guan, Liuyuan; Li, Shun; Jiang, Ying; Xiong, Niya; Li, Li; Wu, Chunhui; Zeng, Hongjuan; Liu, Yiyao

    2016-03-29

    Cancer cells are subjected to fluid shear stress during passage through the venous and lymphatic system. Caveolin-1 (Cav-1), a principal structural component of caveolar membrane domains, contributes to cancer development but its mechanobiological roles under low shear stress (LSS) conditions remain largely unknown. Here, we identified Cav-1 is mechanosensitive to LSS exposure, and its activation-induced PI3K/Akt/mTOR signaling promotes motility, invadopodia formation and metastasis of breast carcinoma MDA-MB-231 cells. Application of LSS (1.8 and 4.0 dynes/cm2) to MDA-MB-231 cells significantly increased the cell motility, invadopodia formation, MT1-MMP expression, ECM degradation, and also induced a sustained activation of Cav-1 and PI3K/Akt/mTOR signaling cascades. Methyl-β-cyclodextrin-caused caveolae destruction markedly decreased LSS-induced activation of both Cav-1 and PI3K/Akt/mTOR, leading to suppress MT1-MMP expression, inhibit invadopodia formation and ECM degradation, suggesting that caveolae integrity also involved in metastasis. Immunocytochemical assay showed that LSS induces the Cav-1 clustering in lipid rafts and co-localization of Cav-1 and MT1-MMP on invadopodia. Immunofluorescence confocal analysis demonstrated that Cav-1 activation were required for the acquisition of a polarized phenotype in MDA-MB-231 cells. Finally, Cav-1 knockdown significantly suppressed tumor colonization in the lungs and distant metastases in animal models. Our findings highlight the importance of Cav-1 in hematogenous metastasis, and provide new insights into the underlying mechanisms of mechanotransduction induced by LSS. PMID:26919102

  4. Downregulation of caveolin-1 upregulates the expression of growth factors and regulators in co-culture of fibroblasts with cancer cells

    PubMed Central

    SHI, XIAO-YU; XIONG, LI-XIA; XIAO, LIANG; MENG, CHUANG; QI, GUAN-YUN; LI, WEN-LIN

    2016-01-01

    Reduced expression levels of caveolin-1 (Cav-1) in tumor stromal fibroblasts influences the occurrence and progression of tumors, particularly in breast cancer, but the relevant molecular mechanism is unclear. The present study aimed to clarify the potential mechanism underlying the promotion of tumor growth by reduced Cav-1 expression levels, by investigating Cav-1-targeted molecules in fibroblasts and breast cancer cells. The expression of growth factors in the ESF fibroblast cell line transfected with Cav-1 small interfering RNA (siRNA) was examined. The expression of apoptotic regulators in the BT474 breast cancer cell line that was co-cultured with the fibroblasts, was also investigated. The transfection of Cav-1-targeting siRNA in ESF cells resulted in efficient and specific inhibition of Cav-1 expression. The downregulation of Cav-1 increased the expression and secretion of stromal cell-derived factor-1 (SDF-1), epidermal growth factor (EGF) and fibroblast-specific protein-1 (FSP-1) in ESF cells. This resulted in the accelerated proliferation of the breast cancer cells. Tumor protein 53-induced glycolysis and apoptosis regulator (TIGAR) was upregulated in the BT474 cells under the condition of co-culture with Cav-1 siRNA fibroblasts, while levels of reactive oxygen species (ROS) were decreased, resulting in apoptosis inhibition in the breast cancer cells. These results demonstrated that the downregulation of Cav-1 promoted the growth of breast cancer cells through increasing SDF-1, EGF and FSP-1 in tumor stromal fibroblasts, and TIGAR levels in breast cancer cells. To the best of our knowledge, the present study supports the hypothesis that Cav-1 possesses tumor-suppressor properties, with the mechanism of Cav-1-dependent signaling involving the regulation of SDF-1, EGF, FSP-1 and TIGAR. PMID:26647977

  5. Protective Effect of Ginsenoside Rg1 on Bleomycin-Induced Pulmonary Fibrosis in Rats: Involvement of Caveolin-1 and TGF-β1 Signal Pathway.

    PubMed

    Zhan, Heqin; Huang, Feng; Ma, Wenzhuo; Zhao, Zhenghang; Zhang, Haifang; Zhang, Chong

    2016-01-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis and high mortality rate. Panax Notoginseng Saponins (PNS), extracted from Panax Notoginseng as a traditional Asian medicine, displayed a significant anti-fibrosis effect in liver and lung. However, whether Ginsenoside Rg1 (Rg1), an important and active ingredient of PNS, exerts anti-fibrotic activity on IPF still remain unclear. In this study, we investigated the effect of Rg1 on bleomycin-induced pulmonary fibrosis in rats. Bleomycin (5 mg/kg body weight) was intratracheally administrated to male rats. Rg1 (18, 36 and 72 mg/kg) was orally administered on the next day after bleomycin. Lungs were harvested at day 7 and 28 for the further experiments. Histological analysis revealed that bleomycin successfully induced pulmonary fibrosis, and that Rg1 restored the histological alteration of bleomycin-induced pulmonary fibrosis (PF), significantly decreased lung coefficient, scores of alveolitis, scores of PF as well as contents of alpha smooth muscle actin (α-SMA) and hydroxyproline (Hyp) in a dose-dependent manner in PF rats. Moreover, Rg1 increased the expression levels of Caveolin-1 (Cav-1) mRNA and protein, lowered the expression of transforming growth factor-β1 (TGF-β1) mRNA and protein in the lung tissues of PF rats. These data suggest that Rg1 exhibits protective effect against bleomycin-induced PF in rats, which is potentially associated with the down-regulation of TGF-β1 and up-regulation of Cav-1. PMID:27476938

  6. Cross-talk between Dopachrome Tautomerase and Caveolin-1 Is Melanoma Cell Phenotype-specific and Potentially Involved in Tumor Progression.

    PubMed

    Popa, Ioana L; Milac, Adina L; Sima, Livia E; Alexandru, Petruta R; Pastrama, Florin; Munteanu, Cristian V A; Negroiu, Gabriela

    2016-06-10

    l-Dopachrome tautomerase (l-DCT), also called tyrosinase-related protein-2 (TRP-2), is a melanoma antigen overexpressed in most chemo-/radiotherapeutic stress-resistant tumor clones, and caveolin-1 (CAV1) is a main regulator of numerous signaling processes. A structural and functional relationship between DCT and CAV1 is first presented here in two human amelanotic melanoma cell lines, derived from vertical growth phase (MelJuSo) and metastatic (SKMel28) melanomas. DCT co-localizes at the plasma membrane with CAV1 and Cavin-1, another molecular marker for caveolae in both cell phenotypes. Our novel structural model proposed for the DCT-CAV1 complex, in addition to co-immunoprecipitation and mass spectrometry data, indicates a possible direct interaction between DCT and CAV1. The CAV1 control on DCT gene expression, DCT post-translational processing, and subcellular distribution is cell phenotype-dependent. DCT is a modulator of CAV1 stability and supramolecular assembly in both cell phenotypes. During autocrine stimulation, the expressions of DCT and CAV1 are oppositely regulated; DCT increases while CAV1 decreases. Sub-confluent MelJuSo clones DCT(high)/CAV1(low) are proliferating and acquire fibroblast-like morphology, forming massive, confluent clusters as demonstrated by immunofluorescent staining and TissueFAXS quantitative image cytometry analysis. CAV1 down-regulation directly contributes to the expansion of MelJuSo DCT(high) subtype. CAV1 involved in the perpetuation of cell phenotype-overexpressing anti-stress DCT molecule supports the concept that CAV1 functions as a tumor suppressor in early stages of melanoma. DCT is a regulator of the CAV1-associated structures and is possibly a new molecular player in CAV1-mediated processes in melanoma. PMID:27053106

  7. Mechanosensitive caveolin-1 activation-induced PI3K/Akt/mTOR signaling pathway promotes breast cancer motility, invadopodia formation and metastasis in vivo

    PubMed Central

    Jiang, Ying; Xiong, Niya; Li, Li; Wu, Chunhui; Zeng, Hongjuan; Liu, Yiyao

    2016-01-01

    Cancer cells are subjected to fluid shear stress during passage through the venous and lymphatic system. Caveolin-1 (Cav-1), a principal structural component of caveolar membrane domains, contributes to cancer development but its mechanobiological roles under low shear stress (LSS) conditions remain largely unknown. Here, we identified Cav-1 is mechanosensitive to LSS exposure, and its activation-induced PI3K/Akt/mTOR signaling promotes motility, invadopodia formation and metastasis of breast carcinoma MDA-MB-231 cells. Application of LSS (1.8 and 4.0 dynes/cm2) to MDA-MB-231 cells significantly increased the cell motility, invadopodia formation, MT1-MMP expression, ECM degradation, and also induced a sustained activation of Cav-1 and PI3K/Akt/mTOR signaling cascades. Methyl-β-cyclodextrin-caused caveolae destruction markedly decreased LSS-induced activation of both Cav-1 and PI3K/Akt/mTOR, leading to suppress MT1-MMP expression, inhibit invadopodia formation and ECM degradation, suggesting that caveolae integrity also involved in metastasis. Immunocytochemical assay showed that LSS induces the Cav-1 clustering in lipid rafts and co-localization of Cav-1 and MT1-MMP on invadopodia. Immunofluorescence confocal analysis demonstrated that Cav-1 activation were required for the acquisition of a polarized phenotype in MDA-MB-231 cells. Finally, Cav-1 knockdown significantly suppressed tumor colonization in the lungs and distant metastases in animal models. Our findings highlight the importance of Cav-1 in hematogenous metastasis, and provide new insights into the underlying mechanisms of mechanotransduction induced by LSS. PMID:26919102

  8. Increase in caveolae and caveolin-1 expression modulates agonist-induced contraction and store- and receptor-operated Ca(2+) entry in pulmonary arteries of pulmonary hypertensive rats.

    PubMed

    Jiao, Hai-Xia; Mu, Yun-Ping; Gui, Long-Xin; Yan, Fu-Rong; Lin, Da-Cen; Sham, James S K; Lin, Mo-Jun

    2016-09-01

    Caveolin-1 (Cav-1) is a major component protein associated with caveolae in the plasma membrane and has been identified as a regulator of store-operated Ca(2+) entry (SOCE) and receptor-operated Ca(2+) entry (ROCE). However, the contributions of caveolae/Cav-1 of pulmonary arterial smooth muscle cells (PASMCs) to the altered Ca(2+) signaling pathways in pulmonary arteries (PAs) during pulmonary hypertension (PH) have not been fully characterized. The present study quantified caveolae number and Cav-1 expression, and determined the effects of caveolae disruption on ET-1, cyclopiazonic acid (CPA) and 1-Oleoyl-2-acetyl-glycerol (OAG)-induced contraction in PAs and Ca(2+) influx in PASMCs of chronic hypoxia (CH)- and monocrotaline (MCT)-induced PH rats. We found that the number of caveolae, and the Cav-1 mRNA and protein levels were increased significantly in PASMCs in both PH models. Disruption of caveolae by cholesterol depletion with methyl-β-cyclodextrin (MβCD) significantly inhibited the contractile response to ET-1, CPA and OAG in PAs of control rats. ET-1, SOCE and ROCE-mediated contractile responses were enhanced, and their susceptibility to MβCD suppression was potentiated in the two PH models. MβCD-induced inhibition was reversed by cholesterol repletion. Introduction of Cav-1 scaffolding domain peptide to mimic Cav-1 upregulation caused significant increase in CPA- and OAG-induced Ca(2+) entry in PASMCs of control, CH and MCT-treated groups. Our results suggest that the increase in caveolae and Cav-1 expression in PH contributes to the enhanced agonist-induced contraction of PA via modulation of SOCE and ROCE; and targeting caveolae/Cav-1 in PASMCs may provide a novel therapeutic strategy for the treatment of PH. PMID:27311393

  9. Caveolin-1 Facilitates the Direct Coupling between Large Conductance Ca2+-activated K+ (BKCa) and Cav1.2 Ca2+ Channels and Their Clustering to Regulate Membrane Excitability in Vascular Myocytes*

    PubMed Central

    Suzuki, Yoshiaki; Yamamura, Hisao; Ohya, Susumu; Imaizumi, Yuji

    2013-01-01

    L-type voltage-dependent Ca2+ channels (LVDCC) and large conductance Ca2+-activated K+ channels (BKCa) are the major factors defining membrane excitability in vascular smooth muscle cells (VSMCs). The Ca2+ release from sarcoplasmic reticulum through ryanodine receptor significantly contributes to BKCa activation in VSMCs. In this study direct coupling between LVDCC (Cav1.2) and BKCa and the role of caveoline-1 on their interaction in mouse mesenteric artery SMCs were examined. The direct activation of BKCa by Ca2+ influx through coupling LVDCC was demonstrated by patch clamp recordings in freshly isolated VSMCs. Using total internal reflection fluorescence microscopy, it was found that a large part of yellow fluorescent protein-tagged BKCa co-localized with the cyan fluorescent protein-tagged Cav1.2 expressed in the plasma membrane of primary cultured mouse VSMCs and that the two molecules often exhibited FRET. It is notable that each BKα subunit of a tetramer in BKCa can directly interact with Cav1.2 and promotes Cav1.2 cluster in the molecular complex. Furthermore, caveolin-1 deficiency in knock-out (KO) mice significantly reduced not only the direct coupling between BKCa and Cav1.2 but also the functional coupling between BKCa and ryanodine receptor in VSMCs. The measurement of single cell shortening by 40 mm K+ revealed enhanced contractility in VSMCs from KO mice than wild type. Taken together, caveolin-1 facilitates the accumulation/clustering of BKCa-LVDCC complex in caveolae, which effectively regulates spatiotemporal Ca2+ dynamics including the negative feedback, to control the arterial excitability and contractility. PMID:24202214

  10. Impact of the loss of caveolin-1 on lung mass and cholesterol metabolism in mice with and without the lysosomal cholesterol transporter, Niemann-Pick type C1

    PubMed Central

    Mundy, Dorothy I.; Lopez, Adam M.; Posey, Kenneth S.; Chuang, Jen-Chieh; Ramirez, Charina M.; Scherer, Philipp E.; Turley, Stephen D.

    2014-01-01

    Caveolin-1 (Cav-1) is a major structural protein in caveolae in the plasma membranes of many cell types, particularly endothelial cells and adipocytes. Loss of Cav-1 function has been implicated in multiple diseases affecting the cardiopulmonary and central nervous systems, as well as in specific aspects of sterol and lipid metabolism in the liver and intestine. Lungs contain an exceptionally high level of Cav-1. Parameters of cholesterol metabolism in the lung were measured, initially in Cav-1-deficient mice (Cav-1−/−), and subsequently in Cav-1−/− mice that also lacked the lysosomal cholesterol transporter Niemann-Pick C1 (Npc1) was also absent (Cav-1−/−:Npc1−/−). In 50-day-old Cav-1−/− mice fed a low- or high-cholesterol chow diet, the total cholesterol concentration (mg/g) in the lungs was marginally lower than in the Cav-1+/+ controls, but due to an expansion in their lung mass exceeding 30%, whole-lung cholesterol content (mg/organ) was moderately elevated. Lung mass (g) in the Cav-1−/−:Npc1−/− mice (0.356 ± 0.022) markedly exceeded that in their Cav-1+/+:Npc1+/+ controls (0.137 ± 0.009), as well as in their Cav-1−/−:Npc1+/+ (0.191 ± 0.013) and Cav-1+/+:Npc1−/− (0.213 ± 0.022) littermates. The corresponding lung total cholesterol content (mg/organ) in mice of these genotypes was 6.74 ± 0.17, 0.71 ± 0.05, 0.96 ± 0.05 and 3.12 ± 0.43, respectively, with the extra cholesterol in the Cav-1−/−:Npc1−/− and Cav-1+/+:Npc1−/− mice being nearly all unesterified (UC). The exacerbation of the Npc1 lung phenotype and increase in the UC level in the Cav-1−/−:Npc1−/− mice imply a regulatory role of Cav-1 in pulmonary cholesterol metabolism when lysosomal sterol transport is disrupted. PMID:24747682

  11. Cooperative Role of Mineralocorticoid Receptor and Caveolin-1 in Regulating the Vascular Response to Low Nitric Oxide-High Angiotensin II-Induced Cardiovascular Injury.

    PubMed

    Pojoga, Luminita H; Yao, Tham M; Opsasnick, Lauren A; Siddiqui, Waleed T; Reslan, Ossama M; Adler, Gail K; Williams, Gordon H; Khalil, Raouf A

    2015-10-01

    Aldosterone interacts with mineralocorticoid receptor (MR) to stimulate sodium reabsorption in renal tubules and may also affect the vasculature. Caveolin-1 (cav-1), an anchoring protein in plasmalemmal caveolae, binds steroid receptors and also endothelial nitric oxide synthase, thus limiting its translocation and activation. To test for potential MR/cav-1 interaction in the vasculature, we investigated if MR blockade in cav-1-replete or -deficient states would alter vascular function in a mouse model of low nitric oxide (NO)-high angiotensin II (AngII)-induced cardiovascular injury. Wild-type (WT) and cav-1 knockout mice (cav-1(-/-)) consuming a high salt diet (4% NaCl) received Nω-nitro-l-arginine methyl ester (L-NAME) (0.1-0.2 mg/ml in drinking water at days 1-11) plus AngII (0.7-2.8 mg/kg per day via an osmotic minipump at days 8-11) ± MR antagonist eplerenone (EPL) 100 mg/kg per day in food. In both genotypes, blood pressure increased with L-NAME + AngII. EPL minimally changed blood pressure, although its dose was sufficient to block MR and reverse cardiac expression of the injury markers cluster of differentiation 68 and plasminogen activator inhibitor-1 in L-NAME+AngII treated mice. In aortic rings, phenylephrine and KCl contraction was enhanced with EPL in L-NAME+AngII treated WT mice, but not cav-1(-/-) mice. AngII-induced contraction was not different, and angiotensin type 1 receptor expression was reduced in L-NAME + AngII treated WT and cav-1(-/-) mice. In WT mice, acetylcholine-induced relaxation was enhanced with L-NAME + AngII treatment and reversed with EPL. Acetylcholine relaxation in cav-1(-/-) mice was greater than in WT mice, not modified by L-NAME + AngII or EPL, and blocked by ex vivo L-NAME, 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), or endothelium removal, suggesting the role of NO-cGMP. Cardiac endothelial NO synthase was increased in cav-1(-/-) versus WT mice, further increased with L-NAME + AngII, and not affected by EPL

  12. Syndecan-2 Exerts Antifibrotic Effects by Promoting Caveolin-1–mediated Transforming Growth Factor-β Receptor I Internalization and Inhibiting Transforming Growth Factor-β1 Signaling

    PubMed Central

    Shi, Yuanyuan; Gochuico, Bernadette R.; Yu, Guoying; Tang, Xiaomeng; Osorio, Juan C.; Fernandez, Isis E.; Risquez, Cristobal F.; Patel, Avignat S.; Shi, Ying; Wathelet, Marc G.; Goodwin, Andrew J.; Haspel, Jeffrey A.; Ryter, Stefan W.; Billings, Eric M.; Kaminski, Naftali; Morse, Danielle

    2013-01-01

    Rationale: Alveolar transforming growth factor (TGF)-β1 signaling and expression of TGF-β1 target genes are increased in patients with idiopathic pulmonary fibrosis (IPF) and in animal models of pulmonary fibrosis. Internalization and degradation of TGF-β receptor TβRI inhibits TGF-β signaling and could attenuate development of experimental lung fibrosis. Objectives: To demonstrate that after experimental lung injury, human syndecan-2 confers antifibrotic effects by inhibiting TGF-β1 signaling in alveolar epithelial cells. Methods: Microarray assays were performed to identify genes differentially expressed in alveolar macrophages of patients with IPF versus control subjects. Transgenic mice that constitutively overexpress human syndecan-2 in macrophages were developed to test the antifibrotic properties of syndecan-2. In vitro assays were performed to determine syndecan-2–dependent changes in epithelial cell TGF-β1 signaling, TGF-β1, and TβRI internalization and apoptosis. Wild-type mice were treated with recombinant human syndecan-2 during the fibrotic phase of bleomycin-induced lung injury. Measurements and Main Results: We observed significant increases in alveolar macrophage syndecan-2 levels in patients with IPF. Macrophage-specific overexpression of human syndecan-2 in transgenic mice conferred antifibrotic effects after lung injury by inhibiting TGF-β1 signaling and downstream expression of TGF-β1 target genes, reducing extracellular matrix production and alveolar epithelial cell apoptosis. In vitro, syndecan-2 promoted caveolin-1–dependent internalization of TGF-β1 and TβRI in alveolar epithelial cells, which inhibited TGF-β1 signaling and epithelial cell apoptosis. Therapeutic administration of human syndecan-2 abrogated lung fibrosis in mice. Conclusions: Alveolar macrophage syndecan-2 exerts antifibrotic effects by promoting caveolin-1–dependent TGF-β1 and TβRI internalization and inhibiting TGF-β1 signaling in alveolar epithelial

  13. Expression of Caveolin-1 reduces cellular responses to TGF-{beta}1 through down-regulating the expression of TGF-{beta} type II receptor gene in NIH3T3 fibroblast cells

    SciTech Connect

    Lee, Eun Kyung; Lee, Youn Sook; Han, In-Oc; Park, Seok Hee . E-mail: parks@skku.edu

    2007-07-27

    Transcriptional repression of Transforming Growth Factor-{beta} type II receptor (T{beta}RII) gene has been proposed to be one of the major mechanisms leading to TGF-{beta} resistance. In this study, we demonstrate that expression of Caveolin-1 (Cav-1) gene in NIH3T3 fibroblast cells down-regulates the expression of T{beta}RII gene in the transcriptional level, eventually resulting in the decreased responses to TGF-{beta}. The reduced expression of T{beta}RII gene by Cav-1 appeared to be due to the changes of the sequence-specific DNA binding proteins to either Positive Regulatory Element 1 (PRE1) or PRE2 of the T{beta}RII promoter. In addition, Cav-1 expression inhibited TGF-{beta}-mediated cellular proliferation and Plasminogen Activator Inhibitor (PAI)-1 gene expression as well as TGF-{beta}-induced luciferase activity. Furthermore, the inhibition of endogeneous Cav-1 by small interfering RNA increased the expression of T{beta}RII gene. These findings strongly suggest that expression of Cav-1 leads to the decreased cellular responsiveness to TGF-{beta} through down-regulating T{beta}RII gene expression.

  14. The Ras Inhibitors Caveolin-1 and Docking Protein 1 Activate Peroxisome Proliferator-Activated Receptor γ through Spatial Relocalization at Helix 7 of Its Ligand-Binding Domain ▿

    PubMed Central

    Burgermeister, Elke; Friedrich, Teresa; Hitkova, Ivana; Regel, Ivonne; Einwächter, Henrik; Zimmermann, Wolfgang; Röcken, Christoph; Perren, Aurel; Wright, Matthew B.; Schmid, Roland M.; Seger, Rony; Ebert, Matthias P. A.

    2011-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a transcription factor that promotes differentiation and cell survival in the stomach. PPARγ upregulates and interacts with caveolin-1 (Cav1), a scaffold protein of Ras/mitogen-activated protein kinases (MAPKs). The cytoplasmic-to-nuclear localization of PPARγ is altered in gastric cancer (GC) patients, suggesting a so-far-unknown role for Cav1 in spatial regulation of PPARγ signaling. We show here that loss of Cav1 accelerated proliferation of normal stomach and GC cells in vitro and in vivo. Downregulation of Cav1 increased Ras/MAPK-dependent phosphorylation of serine 84 in PPARγ and enhanced nuclear translocation and ligand-independent transcription of PPARγ target genes. In contrast, Cav1 overexpression sequestered PPARγ in the cytosol through interaction of the Cav1 scaffolding domain (CSD) with a conserved hydrophobic motif in helix 7 of PPARγ's ligand-binding domain. Cav1 cooperated with the endogenous Ras/MAPK inhibitor docking protein 1 (Dok1) to promote the ligand-dependent transcriptional activity of PPARγ and to inhibit cell proliferation. Ligand-activated PPARγ also reduced tumor growth and upregulated the Ras/MAPK inhibitors Cav1 and Dok1 in a murine model of GC. These results suggest a novel mechanism of PPARγ regulation by which Ras/MAPK inhibitors act as scaffold proteins that sequester and sensitize PPARγ to ligands, limiting proliferation of gastric epithelial cells. PMID:21690289

  15. miR-199a-5p Is Upregulated during Fibrogenic Response to Tissue Injury and Mediates TGFbeta-Induced Lung Fibroblast Activation by Targeting Caveolin-1

    PubMed Central

    Courcot, Elisabeth; Roderburg, Christoph; Cauffiez, Christelle; Aubert, Sébastien; Copin, Marie-Christine; Wallaert, Benoit; Glowacki, François; Dewaeles, Edmone; Milosevic, Jadranka; Maurizio, Julien; Tedrow, John; Marcet, Brice; Lo-Guidice, Jean-Marc; Kaminski, Naftali; Barbry, Pascal; Luedde, Tom; Perrais, Michael

    2013-01-01

    As miRNAs are associated with normal cellular processes, deregulation of miRNAs is thought to play a causative role in many complex diseases. Nevertheless, the precise contribution of miRNAs in fibrotic lung diseases, especially the idiopathic form (IPF), remains poorly understood. Given the poor response rate of IPF patients to current therapy, new insights into the pathogenic mechanisms controlling lung fibroblasts activation, the key cell type driving the fibrogenic process, are essential to develop new therapeutic strategies for this devastating disease. To identify miRNAs with potential roles in lung fibrogenesis, we performed a genome-wide assessment of miRNA expression in lungs from two different mouse strains known for their distinct susceptibility to develop lung fibrosis after bleomycin exposure. This led to the identification of miR-199a-5p as the best miRNA candidate associated with bleomycin response. Importantly, miR-199a-5p pulmonary expression was also significantly increased in IPF patients (94 IPF versus 83 controls). In particular, levels of miR-199a-5p were selectively increased in myofibroblasts from injured mouse lungs and fibroblastic foci, a histologic feature associated with IPF. Therefore, miR-199a-5p profibrotic effects were further investigated in cultured lung fibroblasts: miR-199a-5p expression was induced upon TGFβ exposure, and ectopic expression of miR-199a-5p was sufficient to promote the pathogenic activation of pulmonary fibroblasts including proliferation, migration, invasion, and differentiation into myofibroblasts. In addition, we demonstrated that miR-199a-5p is a key effector of TGFβ signaling in lung fibroblasts by regulating CAV1, a critical mediator of pulmonary fibrosis. Remarkably, aberrant expression of miR-199a-5p was also found in unilateral ureteral obstruction mouse model of kidney fibrosis, as well as in both bile duct ligation and CCl4-induced mouse models of liver fibrosis, suggesting that dysregulation of mi

  16. Caveolin 1 (Cav-1) and actin-related protein 2/3 complex, subunit 1B (ARPC1B) expressions as prognostic indicators for oral squamous cell carcinoma (OSCC).

    PubMed

    Auzair, Lukman Bin Md; Vincent-Chong, Vui King; Ghani, Wan Maria Nabillah; Kallarakkal, Thomas George; Ramanathan, Anand; Lee, Chia Ee; Rahman, Zainal Ariff Abdul; Ismail, Siti Mazlipah; Abraham, Mannil Thomas; Zain, Rosnah Binti

    2016-07-01

    Caveolin-1 (Cav-1) and Actin-Related Protein 2/3 Complex, Subunit 1B (ARPC1B) have been implicated in various human cancers, yet its role in tumorigenesis remains controversial. Therefore, this study aims to determine the protein expression of these two genes in oral squamous cell carcinomas (OSCCs) and to evaluate the clinical and prognostic impact of these genes in OSCC. Protein expressions of these two genes were determined by immunohistochemistry technique. The association between Cav-1 and ARPC1B with clinico-pathological parameters was evaluated by Chi-square test (or Fisher exact test where appropriate). Correlation between the protein expressions of these 2 genes with survival was analyzed using Kaplan-Meier and Cox regression models. Cav-1 and ARPC1B were found to be significantly over-expressed in OSCC compared to normal oral mucosa (p = 0.002 and p = 0.033, respectively). Low level of ARPC1B protein expression showed a significant correlation with lymph node metastasis (LNM) (p = 0.010) and advanced tumor staging (p = 0.003). Kaplan-Meier survival analyses demonstrated that patients with over-expression of Cav-1 protein were associated with poor prognosis (p = 0.030). Adjusted multivariate Cox regression model revealed that over-expression of Cav-1 remained as an independent significant prognostic factor for OSCC (HRR = 2.700, 95 % CI 1.013-7.198, p = 0.047). This study demonstrated that low-expression of ARPC1B is significantly associated with LNM and advanced tumor staging whereas high expression of Cav-1 can be a prognostic indicator for poor prognosis in OSCC patients. PMID:26138391

  17. QRFP-43 inhibits lipolysis by preventing ligand-induced complex formation between perilipin A, caveolin-1, the catalytic subunit of protein kinase and hormone-sensitive lipase in 3T3-L1 adipocytes.

    PubMed

    Mulumba, Mukandila; Granata, Riccarda; Marleau, Sylvie; Ong, Huy

    2015-05-01

    QRFP (RFamide) peptides are neuropeptides involved in food intake and adiposity regulation in rodents. We have previously shown that QRFP-43 (43RFa) and QRFP-26 (26RFa) inhibited isoproterenol (ISO)-induced lipolysis in adipocytes. However, the antilipolytic signaling pathways activated by QRFP peptides have not been investigated. In the present study, 3T3-L1 adipocytes were used to identify the main pathways involved in QRFP-43 decreasing ISO-induced lipolysis. Our results show that QRFP-43 reduced ISO-induced phosphorylation of perilipin A (PLIN) and hormone-sensitive lipase (HSL) on Ser660 by 43 and 25%, respectively, but increased Akt phosphorylation by 44%. However, the inhibition of phosphodiesterase 3B (PDE3B), a regulator of lipolysis activated by Akt, did not reverse the antilipolytic effect of QRFP-43. PDE3B inhibition reversed the decrease of Ser660 HSL phosphorylation associated with QRFP-43 antilipolytic effect. QRFP-43 also prevented PKC activation and ISO-induced Src kinases activation leading to the inhibition of the caveolin-1 (CAV-1) translocation on lipid droplets. Indeed, QRFP-43 attenuated phorbol 12-myristate 13-acetate-induced lipolysis and ISO-induced extracellular signal-regulated and Src kinases by 28, 37 and 48%, respectively. The attenuation of ISO-induced lipolysis by QRFP-43 was associated with a decrease of phosphorylated Ser660 HSL, PKA-catalytic (PKA-c) subunit and CAV-1 translocation on lipid droplets by 37, 50 and 46%, respectively. The decrease in ISO-induced CAV-1 and PKA-c translocation was associated with a reduction of PLIN phosphorylation by 44% in QRFP-43-treated adipocytes. These results suggest that QRFP-43 attenuated ISO-induced lipolysis by preventing the formation of an active complex on lipid droplets and the activation of Src kinases and PKC. PMID:25677823

  18. Epithelial membrane protein 2 regulates sphingosylphosphorylcholine-induced keratin 8 phosphorylation and reorganization: Changes of PP2A expression by interaction with alpha4 and caveolin-1 in lung cancer cells.

    PubMed

    Lee, Eun Ji; Park, Mi Kyung; Kim, Hyun Ji; Kim, Eun Ji; Kang, Gyeoung-Jin; Byun, Hyun Jung; Lee, Chang Hoon

    2016-06-01

    Sphingosylphosphorylcholine (SPC) is found at increased in the malignant ascites of tumor patients and induces perinuclear reorganization of keratin 8 (K8) filaments that contribute to the viscoelasticity of metastatic cancer cells. However, the detailed mechanism of SPC-induced K8 phosphorylation and reorganization is not clear. We observed that SPC dose-dependently reduced the expression of epithelial membrane protein 2 (EMP2) in lung cancer cells. Then, we examined the role of EMP2 in SPC-induced phosphorylation and reorganization of K8 in lung cancer cells. We found that SPC concentration-dependently reduced EMP2 in A549, H1299, and other lung cancer cells. This was verified at the mRNA level by RT-PCR and real-time PCR (qPCR), and intracellular variation through confocal microscopy. EMP2 gene silencing and stable lung cancer cell lines established using EMP2 lentiviral shRNA induced K8 phosphorylation and reorganization. EMP2 overexpression reduced K8 phosphorylation and reorganization. We also observed that SPC-induced loss of EMP2 induces phosphorylation of JNK and ERK via reduced expression of protein phosphatase 2A (PP2A). Loss of EMP2 induces ubiquitination of protein phosphatase 2A (PP2A). SPC induced caveolin-1 (cav-1) expression and EEA1 endosome marker protein but not cav-2. SPC treatment enhanced the binding of cav-1 and PP2A and lowered binding of PP2A and alpha4. Gene silencing of EMP2 increased and gene silencing of cav-1 reduced migration of A549 lung cancer cells. Overall, these results suggest that SPC induces EMP2 down-regulation which reduces the PP2A via ubiquitination induced by cav-1, which sequestered alpha4, leading to the activation of ERK and JNK. PMID:26876307

  19. iDriving (Intelligent Driving)

    Energy Science and Technology Software Center (ESTSC)

    2012-09-17

    iDriving identifies the driving style factors that have a major impact on fuel economy. An optimization framework is used with the aim of optimizing a driving style with respect to these driving factors. A set of polynomial metamodels is constructed to reflect the responses produced in fuel economy by changing the driving factors. The optimization framework is used to develop a real-time feedback system, including visual instructions, to enable drivers to alter their driving stylesmore » in responses to actual driving conditions to improve fuel efficiency.« less

  20. iDriving (Intelligent Driving)

    SciTech Connect

    Malikopoulos, Andreas

    2012-09-17

    iDriving identifies the driving style factors that have a major impact on fuel economy. An optimization framework is used with the aim of optimizing a driving style with respect to these driving factors. A set of polynomial metamodels is constructed to reflect the responses produced in fuel economy by changing the driving factors. The optimization framework is used to develop a real-time feedback system, including visual instructions, to enable drivers to alter their driving styles in responses to actual driving conditions to improve fuel efficiency.

  1. Impaired Driving

    MedlinePlus

    ... Risk Factors BAC Effects Prevention Additional Resources How big is the problem? In 2014, 9,967 people ... Driving: A Threat to Everyone (October 2011) Additional Data Drunk Driving State Data and Maps Motor Vehicle ...

  2. Drugged Driving

    MedlinePlus

    ... Infographics » Drugged Driving Drugged Driving Email Facebook Twitter Text Description of Infographic Top Right Figure : In 2009, ... crash than those who don't smoke. Bottom Text: Develop Social Strategies Offer to be a designated ...

  3. Pile Driving

    NASA Technical Reports Server (NTRS)

    1987-01-01

    Machine-oriented structural engineering firm TERA, Inc. is engaged in a project to evaluate the reliability of offshore pile driving prediction methods to eventually predict the best pile driving technique for each new offshore oil platform. Phase I Pile driving records of 48 offshore platforms including such information as blow counts, soil composition and pertinent construction details were digitized. In Phase II, pile driving records were statistically compared with current methods of prediction. Result was development of modular software, the CRIPS80 Software Design Analyzer System, that companies can use to evaluate other prediction procedures or other data bases.

  4. Distracted Driving

    MedlinePlus

    ... combines all three types of distraction. 3 How big is the problem? Deaths In 2013, 3,154 ... European countries. More A CDC study analyzed 2011 data on distracted driving, including talking on a cell ...

  5. Distracted driving

    MedlinePlus

    ... stay safe with a cell phone in the car. ... for Disease Control and Prevention Injury Prevention & Control. Motor Vehicle Safety. www.cdc.gov/motorvehiclesafety/distracted_driving . Accessed May ...

  6. Driving Safely

    MedlinePlus

    ... drivers’ flexibility and coordination, and reduced driving errors. S l Hand grip strengthening to help you hold on to the steering wheel l Shoulder and upper arm flexibility exercises to make ...

  7. Myocardin Family Members Drive Formation of Caveolae

    PubMed Central

    Krawczyk, Katarzyna K.; Yao Mattisson, Ingrid; Ekman, Mari; Oskolkov, Nikolay; Grantinge, Rebecka; Kotowska, Dorota; Olde, Björn; Hansson, Ola; Albinsson, Sebastian; Miano, Joseph M.; Rippe, Catarina; Swärd, Karl

    2015-01-01

    Caveolae are membrane organelles that play roles in glucose and lipid metabolism and in vascular function. Formation of caveolae requires caveolins and cavins. The make-up of caveolae and their density is considered to reflect cell-specific transcriptional control mechanisms for caveolins and cavins, but knowledge regarding regulation of caveolae genes is incomplete. Myocardin (MYOCD) and its relative MRTF-A (MKL1) are transcriptional coactivators that control genes which promote smooth muscle differentiation. MRTF-A communicates changes in actin polymerization to nuclear gene transcription. Here we tested if myocardin family proteins control biogenesis of caveolae via activation of caveolin and cavin transcription. Using human coronary artery smooth muscle cells we found that jasplakinolide and latrunculin B (LatB), substances that promote and inhibit actin polymerization, increased and decreased protein levels of caveolins and cavins, respectively. The effect of LatB was associated with reduced mRNA levels for these genes and this was replicated by the MRTF inhibitor CCG-1423 which was non-additive with LatB. Overexpression of myocardin and MRTF-A caused 5-10-fold induction of caveolins whereas cavin-1 and cavin-2 were induced 2-3-fold. PACSIN2 also increased, establishing positive regulation of caveolae genes from three families. Full regulation of CAV1 was retained in its proximal promoter. Knock down of the serum response factor (SRF), which mediates many of the effects of myocardin, decreased cavin-1 but increased caveolin-1 and -2 mRNAs. Viral transduction of myocardin increased the density of caveolae 5-fold in vitro. A decrease of CAV1 was observed concomitant with a decrease of the smooth muscle marker calponin in aortic aneurysms from mice (C57Bl/6) infused with angiotensin II. Human expression data disclosed correlations of MYOCD with CAV1 in a majority of human tissues and in the heart, correlation with MKL2 (MRTF-B) was observed. The myocardin family

  8. Dementia and driving

    MedlinePlus

    ... not drive at times of the day when traffic is heaviest. Do not drive when the weather is bad. Do not drive long distances. Drive only on roads the person is used to. Caregivers should try to lessen ...

  9. Extended Driving Impairs Nocturnal Driving Performances

    PubMed Central

    Sagaspe, Patricia; Taillard, Jacques; Åkerstedt, Torbjorn; Bayon, Virginie; Espié, Stéphane; Chaumet, Guillaume; Bioulac, Bernard; Philip, Pierre

    2008-01-01

    Though fatigue and sleepiness at the wheel are well-known risk factors for traffic accidents, many drivers combine extended driving and sleep deprivation. Fatigue-related accidents occur mainly at night but there is no experimental data available to determine if the duration of prior driving affects driving performance at night. Participants drove in 3 nocturnal driving sessions (3–5am, 1–5am and 9pm–5am) on open highway. Fourteen young healthy men (mean age [±SD] = 23.4 [±1.7] years) participated Inappropriate line crossings (ILC) in the last hour of driving of each session, sleep variables, self-perceived fatigue and sleepiness were measured. Compared to the short (3–5am) driving session, the incidence rate ratio of inappropriate line crossings increased by 2.6 (95% CI, 1.1 to 6.0; P<.05) for the intermediate (1–5am) driving session and by 4.0 (CI, 1.7 to 9.4; P<.001) for the long (9pm–5am) driving session. Compared to the reference session (9–10pm), the incidence rate ratio of inappropriate line crossings were 6.0 (95% CI, 2.3 to 15.5; P<.001), 15.4 (CI, 4.6 to 51.5; P<.001) and 24.3 (CI, 7.4 to 79.5; P<.001), respectively, for the three different durations of driving. Self-rated fatigue and sleepiness scores were both positively correlated to driving impairment in the intermediate and long duration sessions (P<.05) and increased significantly during the nocturnal driving sessions compared to the reference session (P<.01). At night, extended driving impairs driving performances and therefore should be limited. PMID:18941525

  10. Electrical drive for automobile

    SciTech Connect

    Fobbs, H.

    1980-09-16

    Electrical apparatus for driving an automobile is described that is comprised of a dc motor operationally connected to the rear axle through a drive shaft with the motor energized from storage batteries and recharged from alternators coupled to the drive shaft adjacent a clutch at the rear end of the automobile through an auxiliary drive shaft.

  11. Coaxial Redundant Drives

    NASA Technical Reports Server (NTRS)

    Brissette, R.

    1983-01-01

    Harmonic drives allow redundancy and high out put torque in small package. If main drive fails, standby drive takes over and produces torque along same axis as main drive. Uses include power units in robot for internal pipeline inspection, manipulators in deep submersible probes or other applications in which redundancy protects against costly failures.

  12. Solar array drive system

    NASA Technical Reports Server (NTRS)

    Berkopec, F. D.; Sturman, J. C.; Stanhouse, R. W.

    1976-01-01

    A solar array drive system consisting of a solar array drive mechanism and the corresponding solar array drive electronics is being developed. The principal feature of the solar array drive mechanism is its bidirectional capability which enables its use in mechanical redundancy. The solar array drive system is of a widely applicable design. This configuration will be tested to determine its acceptability for generic mission sets. Foremost of the testing to be performed is the testing for extended duration.

  13. Driving and neurodegenerative diseases.

    PubMed

    Uc, Ergun Y; Rizzo, Matthew

    2008-09-01

    The proportion of elderly people in the general population is rising, resulting in greater numbers of drivers with neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. These neurodegenerative disorders impair cognition, visual perception, and motor function, leading to reduced driver fitness and greater crash risk. Yet neither medical diagnosis nor age alone is reliable enough to predict driver safety or crashes or to revoke the driving privileges of these individuals. Driving research utilizes tools such as questionnaires about driving habits and history, driving simulators, standardized road tests utilizing instrumented vehicles, and state driving records. Research challenges include outlining the evolution of driving safety, understanding the mechanisms of driving impairment, and developing a reliable and efficient standardized test battery for prediction of driver safety in neurodegenerative disorders. This information will enable healthcare providers to advise their patients with neurodegenerative disorders with more certainty, affect policy, and help develop rehabilitative measures for driving. PMID:18713573

  14. Gear bearing drive

    NASA Technical Reports Server (NTRS)

    Weinberg, Brian (Inventor); Mavroidis, Constantinos (Inventor); Vranish, John M. (Inventor)

    2011-01-01

    A gear bearing drive provides a compact mechanism that operates as an actuator providing torque and as a joint providing support. The drive includes a gear arrangement integrating an external rotor DC motor within a sun gear. Locking surfaces maintain the components of the drive in alignment and provide support for axial loads and moments. The gear bearing drive has a variety of applications, including as a joint in robotic arms and prosthetic limbs.

  15. Magnetic drive coupling

    NASA Technical Reports Server (NTRS)

    Carter, Edward L. (Inventor)

    1987-01-01

    The driving and driven members of a magnetic drive are separated by en enlarged gap to provide clearance for a conduit or other member. Flux pins in the gap maintain the torque transmitting capability of the drive. The spacing between two of the flux pins is increased to provide space for the conduit.

  16. Magnetic drive coupling

    NASA Technical Reports Server (NTRS)

    Carter, Edward L. (Inventor)

    1989-01-01

    The driving (30) and driven (32) members of a magnetic drive (20) are separated by an enlarged gap (35) to provide clearance for a conduit (23) or other member. Flux pins (40) in the gap (35) maintain the torque transmitting capability of the drive (20). The spacing between two of the flux pins is increased to provide space for the conduit (23).

  17. Sequential Dependencies in Driving

    ERIC Educational Resources Information Center

    Doshi, Anup; Tran, Cuong; Wilder, Matthew H.; Mozer, Michael C.; Trivedi, Mohan M.

    2012-01-01

    The effect of recent experience on current behavior has been studied extensively in simple laboratory tasks. We explore the nature of sequential effects in the more naturalistic setting of automobile driving. Driving is a safety-critical task in which delayed response times may have severe consequences. Using a realistic driving simulator, we find…

  18. Grieving while Driving

    ERIC Educational Resources Information Center

    Rosenblatt, Paul C.

    2004-01-01

    Secondary analysis of data from 84 people in 2 interview studies shows that some bereaved people grieve actively while driving. The grief can be intense, even years after a death. Grief while driving may erupt spontaneously or be set off by a wide range of reminders. Some bereaved people seem to save their grieving for times when they drive,…

  19. Electric versus hydraulic drives

    SciTech Connect

    Not Available

    1983-01-01

    This volume records the proceedings of a conference organised by the Engineering Manufacturing Industries Division of the Institution of Mechanical Engineers. Topics considered include high performance position control - a review of the current state of developments; hydrostatic drives - present and future; electric drives - present and future trends; electrical and hydraulic drives for heavy industrial robots; the development of an electro-mechanical tilt system for the advanced passenger train; industrial hydraulic ring mains - effective or efficient. the comparison of performance of servo feed-drive systems; overhead crane drives; the future of d.c. servodrives; the choice of actuator for military systems; linear electro-hydraulic actuators; and actuation for industrial robots.

  20. Drill drive mechanism

    DOEpatents

    Dressel, Michael O.

    1979-01-01

    A drill drive mechanism is especially adapted to provide both rotational drive and axial feed for a drill of substantial diameter such as may be used for drilling holes for roof bolts in mine shafts. The drill shaft is made with a helical pattern of scroll-like projections on its surface for removal of cuttings. The drill drive mechanism includes a plurality of sprockets carrying two chains of drive links which are arranged to interlock around the drill shaft with each drive link having depressions which mate with the scroll-like projections. As the chain links move upwardly or downwardly the surfaces of the depressions in the links mate with the scroll projections to move the shaft axially. Tangs on the drive links mate with notch surfaces between scroll projections to provide a means for rotating the shaft. Projections on the drive links mate together at the center to hold the drive links tightly around the drill shaft. The entire chain drive mechanism is rotated around the drill shaft axis by means of a hydraulic motor and gear drive to cause rotation of the drill shaft. This gear drive also connects with a differential gearset which is interconnected with a second gear. A second motor is connected to the spider shaft of the differential gearset to produce differential movement (speeds) at the output gears of the differential gearset. This differential in speed is utilized to drive said second gear at a speed different from the speed of said gear drive, this speed differential being utilized to drive said sprockets for axial movement of said drill shaft.

  1. Magnetostrictive roller drive motor

    NASA Astrophysics Data System (ADS)

    Vranish, John M.

    1992-01-01

    A magnetostrictive drive motor is disclosed which has a rotary drive shaft in the form of a drum which is encircled by a plurality of substantially equally spaced roller members in the form of two sets of cones which are in contact with the respective cam surfaces on the inside surface of an outer drive ring. The drive ring is attached to sets of opposing pairs of magnetostrictive rods. Each rod in a pair is mutually positioned end to end within respective energizing coils. When one of the coils in an opposing pair is energized, the energized rod expands while the other rod is caused to contract, causing the drive ring to rock, i.e., rotate slightly in either the clockwise or counterclockwise direction, depending upon which rod in a pair is energized. As the drive ring is activated in repetitive cycles in either direction, one set of drive cones attempts to roll up their respective cam surface but are pinned between the drive shaft drum and the drive ring. As the frictional force preventing sliding builds up, the cones become locked, setting up reaction forces including a tangential component which is imparted to the drive shaft drum to provide a source of motor torque. Simultaneously the other set of cones are disengaged from the drive shaft drum. Upon deactivation of the magnetostrictive rod coils, the force on the drive cones is released, causing the system to return to an initial rest position. By repetitively cycling the energization of the magnetostrictive rods, the drive shaft drum indexes in microradian rotational steps.

  2. Superluminal warp drive

    NASA Astrophysics Data System (ADS)

    González-Díaz, Pedro F.

    2007-09-01

    In this Letter we consider a warp drive spacetime resulting from that suggested by Alcubierre when the spaceship can only travel faster than light. Restricting to the two dimensions that retains most of the physics, we derive the thermodynamic properties of the warp drive and show that the temperature of the spaceship rises up as its apparent velocity increases. We also find that the warp drive spacetime can be exhibited in a manifestly cosmological form.

  3. Diabetes and driving.

    PubMed

    Inkster, B; Frier, B M

    2013-09-01

    The principal safety concern for driving for people treated with insulin or insulin secretagogues is hypoglycaemia, which impairs driving performance. Other complications, such as those causing visual impairment and peripheral neuropathy, are also relevant to medical fitness to drive. Case control studies have suggested that drivers with diabetes pose a modestly increased but acceptable and measurable risk of motor vehicle accidents compared to non-diabetic drivers, but many studies are limited and of poor quality. Factors which have been shown to increase driving risk include previous episodes of severe hypoglycaemia, previous hypoglycaemia while driving, strict glycaemic control (lower HbA1c) and absence of blood glucose monitoring before driving. Impaired awareness of hypoglycaemia may be counteracted by frequent blood glucose testing. The European Union Third directive on driving (2006) has necessitated changes in statutory regulations for driving licences for people with diabetes in all European States, including the UK. Stricter criteria have been introduced for Group 1 vehicle licences while those for Group 2 licences have been relaxed. Insulin-treated drivers can now apply to drive Group 2 vehicles, but in the UK must meet very strict criteria and be assessed by an independent specialist to be issued with a 1-year licence. PMID:23350766

  4. Reading Text While Driving

    PubMed Central

    Horrey, William J.; Hoffman, Joshua D.

    2015-01-01

    Objective In this study, we investigated how drivers adapt secondary-task initiation and time-sharing behavior when faced with fluctuating driving demands. Background Reading text while driving is particularly detrimental; however, in real-world driving, drivers actively decide when to perform the task. Method In a test track experiment, participants were free to decide when to read messages while driving along a straight road consisting of an area with increased driving demands (demand zone) followed by an area with low demands. A message was made available shortly before the vehicle entered the demand zone. We manipulated the type of driving demands (baseline, narrow lane, pace clock, combined), message format (no message, paragraph, parsed), and the distance from the demand zone when the message was available (near, far). Results In all conditions, drivers started reading messages (drivers’ first glance to the display) before entering or before leaving the demand zone but tended to wait longer when faced with increased driving demands. While reading messages, drivers looked more or less off road, depending on types of driving demands. Conclusions For task initiation, drivers avoid transitions from low to high demands; however, they are not discouraged when driving demands are already elevated. Drivers adjust time-sharing behavior according to driving demands while performing secondary tasks. Nonetheless, such adjustment may be less effective when total demands are high. Application This study helps us to understand a driver’s role as an active controller in the context of distracted driving and provides insights for developing distraction interventions. PMID:25850162

  5. Piezoelectric drive circuit

    DOEpatents

    Treu, C.A. Jr.

    1999-08-31

    A piezoelectric motor drive circuit is provided which utilizes the piezoelectric elements as oscillators and a Meacham half-bridge approach to develop feedback from the motor ground circuit to produce a signal to drive amplifiers to power the motor. The circuit automatically compensates for shifts in harmonic frequency of the piezoelectric elements due to pressure and temperature changes. 7 figs.

  6. Piezoelectric drive circuit

    DOEpatents

    Treu, Jr., Charles A.

    1999-08-31

    A piezoelectric motor drive circuit is provided which utilizes the piezoelectric elements as oscillators and a Meacham half-bridge approach to develop feedback from the motor ground circuit to produce a signal to drive amplifiers to power the motor. The circuit automatically compensates for shifts in harmonic frequency of the piezoelectric elements due to pressure and temperature changes.

  7. Dual drive actuators

    NASA Technical Reports Server (NTRS)

    Packard, D. T.

    1982-01-01

    A new class of electromechanical actuators is described. These dual drive actuators were developed for the NASA-JPL Galileo Spacecraft. The dual drive actuators are fully redundant and therefore have high inherent reliability. They can be used for a variety of tasks, and they can be fabricated quickly and economically.

  8. Design of traction drives

    NASA Technical Reports Server (NTRS)

    Loewenthal, S. H.; Zaretsky, E. V.

    1985-01-01

    Traction drives are among the simplest of all speed-changing mechanisms. Because of their simplicity and their ability to smoothly and continuously adjust speed, they are excellent choices for many drive system applications. They have been used in industrial service for more than 100 years. Today's traction drives have power capacities which rival the best gear and belt drives due to modern traction fluids and highly fatigue-resistant bearing steels. This report summarizes methods to analyze and size traction drives. Lubrication principles, contact kinematics, stress, fatigue life, and performance prediction methods are presented. The effects of the lubricant's traction characteristics on life and power loss are discussed. An example problem is given which illustrates the effects of spin on power loss. Loading mechanism design and the design of nonlubricated friction wheels and rings are also treated.

  9. Vision and Driving

    PubMed Central

    Owsley, Cynthia; McGwin, Gerald

    2010-01-01

    Driving is the primary means of personal travel in many countries and is relies heavily on vision for its successful execution. Research over the past few decades has addressed the role of vision in driver safety (motor vehicle collision involvement) and in driver performance (both on-road and using interactive simulators in the laboratory). Here we critically review what is currently known about the role of various aspects of visual function in driving. We also discuss translational research issues on vision screening for licensure and re-licensure and rehabilitation of visually impaired persons who want to drive. PMID:20580907

  10. Redundant motor drive system

    NASA Technical Reports Server (NTRS)

    Calvert, J. A. (Inventor)

    1980-01-01

    A drive system characterized by a base supporting a pair of pillars arranged in spaced parallelism, a shaft extended between and supported by the pillars for rotation about the longitudinal axis thereof, a worm gear affixed to the shaft and supported in coaxial relation therewith is described. A bearing housing of a sleeve like configuration is concentrically related to the shaft and is supported thereby for free rotation. A first and a second quiescent drive train, alternatively activatable, is provided for imparting rotation into said bearing housing. Each of the drive trains is characterized by a selectively energizable motor connected to a spur gear.

  11. The Test Drive

    NASA Technical Reports Server (NTRS)

    2004-01-01

    This image taken at NASA's Jet Propulsion Laboratory shows engineers rehearsing the sol 133 (June 8, 2004) drive into 'Endurance' crater by NASA's Mars Exploration Rover Opportunity. Engineers and scientists have recreated the martian surface and slope the rover will encounter using a combination of bare and thinly sand-coated rocks, simulated martian 'blueberries' and a platform tilted at a 25-degree angle. The results of this test convinced engineers that the rover was capable of driving up and down a straight slope before it attempted the actual drive on Mars.

  12. Dementia and driving

    MedlinePlus

    ... getting more dangerous include: Getting lost on familiar roads Reacting more slowly in traffic Driving too slowly ... attention to traffic signs Taking chances on the road Drifting into other lanes Getting more agitated in ...

  13. Control rod drive

    SciTech Connect

    Hawke, Basil C.

    1986-01-01

    A control rod drive uses gravitational forces to insert one or more control rods upwardly into a reactor core from beneath the reactor core under emergency conditions. The preferred control rod drive includes a vertically movable weight and a mechanism operatively associating the weight with the control rod so that downward movement of the weight is translated into upward movement of the control rod. The preferred control rod drive further includes an electric motor for driving the control rods under normal conditions, an electrically actuated clutch which automatically disengages the motor during a power failure and a decelerator for bringing the control rod to a controlled stop when it is inserted under emergency conditions into a reactor core.

  14. Drive program documentation

    NASA Technical Reports Server (NTRS)

    Graham, S.

    1979-01-01

    The program description and user's guide for the Downlist Requirement Integrated Verification and Evaluation (DRIVE) program is provided. The program is used to compare existing telemetry downlist files with updated downlist requirements.

  15. Safe driving for teens

    MedlinePlus

    ... drivers. Do not use cell phones for talking, texting, or email when you are driving. Mobile phones ... pull off of the road before answering or texting. Other tips include: Avoid putting on makeup while ...

  16. Direct drive wind turbine

    DOEpatents

    Bywaters, Garrett Lee; Danforth, William; Bevington, Christopher; Stowell, Jesse; Costin, Daniel

    2006-09-19

    A wind turbine is provided that minimizes the size of the drive train and nacelle while maintaining the power electronics and transformer at the top of the tower. The turbine includes a direct drive generator having an integrated disk brake positioned radially inside the stator while minimizing the potential for contamination. The turbine further includes a means for mounting a transformer below the nacelle within the tower.

  17. Direct drive wind turbine

    DOEpatents

    Bywaters, Garrett; Danforth, William; Bevington, Christopher; Jesse, Stowell; Costin, Daniel

    2007-02-27

    A wind turbine is provided that minimizes the size of the drive train and nacelle while maintaining the power electronics and transformer at the top of the tower. The turbine includes a direct drive generator having an integrated disk brake positioned radially inside the stator while minimizing the potential for contamination. The turbine further includes a means for mounting a transformer below the nacelle within the tower.

  18. Direct drive wind turbine

    DOEpatents

    Bywaters, Garrett; Danforth, William; Bevington, Christopher; Stowell, Jesse; Costin, Daniel

    2006-07-11

    A wind turbine is provided that minimizes the size of the drive train and nacelle while maintaining the power electronics and transformer at the top of the tower. The turbine includes a direct drive generator having an integrated disk brake positioned radially inside the stator while minimizing the potential for contamination. The turbine further includes a means for mounting a transformer below the nacelle within the tower.

  19. Direct drive wind turbine

    DOEpatents

    Bywaters, Garrett; Danforth, William; Bevington, Christopher; Jesse, Stowell; Costin, Daniel

    2006-10-10

    A wind turbine is provided that minimizes the size of the drive train and nacelle while maintaining the power electronics and transformer at the top of the tower. The turbine includes a direct drive generator having an integrated disk brake positioned radially inside the stator while minimizing the potential for contamination. The turbine further includes a means for mounting a transformer below the nacelle within the tower.

  20. CONTROL ROD DRIVE

    DOEpatents

    Chapellier, R.A.

    1960-05-24

    BS>A drive mechanism was invented for the control rod of a nuclear reactor. Power is provided by an electric motor and an outside source of fluid pressure is utilized in conjunction with the fluid pressure within the reactor to balance the loadings on the motor. The force exerted on the drive mechanism in the direction of scramming the rod is derived from the reactor fluid pressure so that failure of the outside pressure source will cause prompt scramming of the rod.

  1. Common drive unit

    NASA Technical Reports Server (NTRS)

    Ellis, R. C.; Fink, R. A.; Moore, E. A.

    1987-01-01

    The Common Drive Unit (CDU) is a high reliability rotary actuator with many versatile applications in mechanism designs. The CDU incorporates a set of redundant motor-brake assemblies driving a single output shaft through differential. Tachometers provide speed information in the AC version. Operation of both motors, as compared to the operation of one motor, will yield the same output torque with twice the output speed.

  2. Self-driving carsickness.

    PubMed

    Diels, Cyriel; Bos, Jelte E

    2016-03-01

    This paper discusses the predicted increase in the occurrence and severity of motion sickness in self-driving cars. Self-driving cars have the potential to lead to significant benefits. From the driver's perspective, the direct benefits of this technology are considered increased comfort and productivity. However, we here show that the envisaged scenarios all lead to an increased risk of motion sickness. As such, the benefits this technology is assumed to bring may not be capitalised on, in particular by those already susceptible to motion sickness. This can negatively affect user acceptance and uptake and, in turn, limit the potential socioeconomic benefits that this emerging technology may provide. Following a discussion on the causes of motion sickness in the context of self-driving cars, we present guidelines to steer the design and development of automated vehicle technologies. The aim is to limit or avoid the impact of motion sickness and ultimately promote the uptake of self-driving cars. Attention is also given to less well known consequences of motion sickness, in particular negative aftereffects such as postural instability, and detrimental effects on task performance and how this may impact the use and design of self-driving cars. We conclude that basic perceptual mechanisms need to be considered in the design process whereby self-driving cars cannot simply be thought of as living rooms, offices, or entertainment venues on wheels. PMID:26446454

  3. Parkinson disease and driving

    PubMed Central

    Classen, Sherrilene; Uc, Ergun Y.

    2012-01-01

    ABSTRACT The growing literature on driving in Parkinson disease (PD) has shown that driving is impaired in PD compared to healthy comparison drivers. PD is a complex neurodegenerative disorder leading to motor, cognitive, and visual impairments, all of which can affect fitness to drive. In this review, we examined studies of driving performance (on-road tests and simulators) in PD for outcome measures and their predictors. We searched through various databases and found 25 (of 99) primary studies, all published in English. Using the American Academy of Neurology criteria, a study class of evidence was assigned (I–IV, I indicating the highest level of evidence) and recommendations were made (Level A: predictive or not; B: probably predictive or not; C: possibly predictive or not; U: no recommendations). From available Class II and III studies, we identified various cognitive, visual, and motor measures that met different levels of evidence (usually Level B or C) with respect to predicting on-road and simulated driving performance. Class I studies reporting Level A recommendations for definitive predictors of driving performance in drivers with PD are needed by policy makers and clinicians to develop evidence-based guidelines. PMID:23150533

  4. Hydraulic drive system prevents backlash

    NASA Technical Reports Server (NTRS)

    Acord, J. D.

    1965-01-01

    Hydraulic drive system uses a second drive motor operating at reduced torque. This exerts a relative braking action which eliminates the normal gear train backlash that is intolerable when driving certain heavy loads.

  5. Family Influences and Unconscious Drives.

    ERIC Educational Resources Information Center

    English, Fanita

    2001-01-01

    Drives for survival, expression, and quiescence influence early human development and continue to influence career development throughout life. Turmoil may arise when a drive conflicts with others or is suppressed by other drives. (SK)

  6. Mental workload and driving

    PubMed Central

    Paxion, Julie; Galy, Edith; Berthelon, Catherine

    2014-01-01

    The aim of this review is to identify the most representative measures of subjective and objective mental workload in driving, and to understand how the subjective and objective levels of mental workload influence the performance as a function of situation complexity and driving experience, i.e., to verify whether the increase of situation complexity and the lack of experience increase the subjective and physiological levels of mental workload and lead to driving performance impairments. This review will be useful to both researchers designing an experimental study of mental workload and to designers of drivers’ training content. In the first part, we will broach the theoretical approach with two factors of mental workload and performance, i.e., situation complexity and driving experience. Indeed, a low complex situation (e.g., highways), or conversely a high complex situation (e.g., town) can provoke an overload. Additionally, performing the driving tasks implies producing a high effort for novice drivers who have not totally automated the driving activity. In the second part, we will focus on subjective measures of mental workload. A comparison of questionnaires usually used in driving will allow identifying the most appropriate ones as a function of different criteria. Moreover, we will review the empirical studies to verify if the subjective level of mental workload is high in simple and very complex situations, especially for novice drivers compared to the experienced ones. In the third part, we will focus on physiological measures. A comparison of physiological indicators will be realized in order to identify the most correlated to mental workload. An empirical review will also take the effect of situation complexity and experience on these physiological indicators into consideration. Finally, a more nuanced comparison between subjective and physiological measures will be established from the impact on situation complexity and experience. PMID:25520678

  7. Driving Anger and Driving Behavior in Adults with ADHD

    ERIC Educational Resources Information Center

    Richards, Tracy L.; Deffenbacher, Jerry L.; Rosen, Lee A.; Barkley, Russell A.; Rodricks, Trisha

    2006-01-01

    Objective: This study assesses whether anger in the context of driving is associated with the negative driving outcomes experienced by individuals with ADHD. Method: ADHD adults (n = 56) complete measures of driving anger, driving anger expression, angry thoughts behind the wheel, and aggressive, risky, and crash-related behavior. Results are…

  8. Driving anger in Malaysia.

    PubMed

    Sullman, Mark J M; Stephens, Amanda N; Yong, Michelle

    2014-10-01

    The present study examined the types of situations that cause Malaysian drivers to become angry. The 33-item version of the driver anger scale (Deffenbacher et al., 1994) was used to investigate driver anger amongst a sample of 339 drivers. Confirmatory factor analysis showed that the fit of the original six-factor model (discourtesy, traffic obstructions, hostile gestures, slow driving, illegal driving and police presence), after removing one item and allowing three error pairs to covary, was satisfactory. Female drivers reported more anger, than males, caused by traffic obstruction and hostile gestures. Age was also negatively related to five (discourtesy, traffic obstructions, hostile gestures, slow driving and police presence) of the six factors and also to the total DAS score. Furthermore, although they were not directly related to crash involvement, several of the six forms of driving anger were significantly related to the crash-related conditions of: near misses, loss of concentration, having lost control of a vehicle and being ticketed. Overall the pattern of findings made in the present research were broadly similar to those from Western countries, indicating that the DAS is a valid measure of driving anger even among non-European based cultures. PMID:24863369

  9. [Drug use and driving].

    PubMed

    Lemaire-Hurtel, Anne-Sophie; Goullé, Jean-Pierre; Alvarez, Jean-Claude; Mura, Patrick; Verstraete, Alain G

    2015-10-01

    Some drugs are known to impair driving because they can change the vision or hearing, and/or disrupt the intellectual or motor abilities: impaired vigilance, sedation, disinhibition effect, the coordination of movement disorders and the balance. The doctor during prescribing and the pharmacist during deliverance of drug treatment should inform their patients of the potential risks of drugs on driving or operating machinery. The driver has direct responsibility, who hired him and him alone, to follow the medical advice received. The pictograms on the outer packaging of medicinal products intended to classify substances according to their risk driving: The driver can whether to observe simple precautions (level one "be prudent"), or follow the advice of a health professional (level two "be very careful"), or if it is totally not drive (level three "danger caution: do not drive"). This classification only evaluates the intrinsic danger of drugs but not the individual variability. Medicines should be taken into account also the conditions for which the medication is prescribed. It is important to inform the patient on several points. PMID:25956300

  10. Ceramic vane drive joint

    DOEpatents

    Smale, Charles H.

    1981-01-01

    A variable geometry gas turbine has an array of ceramic composition vanes positioned by an actuating ring coupled through a plurality of circumferentially spaced turbine vane levers to the outer end of a metallic vane drive shaft at each of the ceramic vanes. Each of the ceramic vanes has an end slot of bow tie configuration including flared end segments and a center slot therebetween. Each of the vane drive shafts has a cross head with ends thereof spaced with respect to the sides of the end slot to define clearance for free expansion of the cross head with respect to the vane and the cross head being configured to uniformly distribute drive loads across bearing surfaces of the vane slot.

  11. U.S. DRIVE

    SciTech Connect

    2012-03-16

    U.S. DRIVE, which stands for United States Driving Research and Innovation for Vehicle efficiency and Energy sustainability, is an expanded government-industry partnership among the U.S. Department of Energy; USCAR, representing Chrysler Group LLC, Ford Motor Company and General Motors; Tesla Motors; five energy companies – BP America, Chevron Corporation, ConocoPhillips, ExxonMobil Corporation, and Shell Oil Products US; two utilities – Southern California Edison and Michigan-based DTE Energy; and the Electric Power Research Institute (EPRI). The U.S. DRIVE mission is to accelerate the development of pre-competitive and innovative technologies to enable a full range of affordable and clean advanced light-duty vehicles, as well as related energy infrastructure.

  12. LCLS Injector Drive Laser

    SciTech Connect

    Dowell, D.H.; Castro, J.; Emma, P.; Frisch, J.; Gilevich, A.; Hays, G.; Hering, P.; Limborg-Deprey, C.; Loos, H.; Miahnahri, A.; White, W.; /SLAC

    2007-11-02

    Requirements for the LCLS injector drive laser present significant challenges to the design of the system. While progress has been demonstrated in spatial shape, temporal shape, UV generation and rep-rate, a laser that meets all of the LCLS specifications simultaneously has yet to be demonstrated. These challenges are compounded by the stability and reliability requirements. The drive laser and transport system has been installed and tested. We will report on the current operational state of the laser and plans for future improvements.

  13. Optotech 5984 Drive Overview

    NASA Astrophysics Data System (ADS)

    Lee, Tzuo-Chang; Chen, Di

    1987-01-01

    We present in this paper an overview of Optotech's 5984 Optical Disk Drive. Key features such as the modulation code, the disk format, defect mapping scheme and the optical head and servo subsystem will be singled out for discussion. Description of Optotech's 5984 disk drive The Optotech 5984 optical disk drive is a write-once-read-mostly (WORM) rotating optical memory with 200 Megabyte capacity on each side of the disk. It has a 5 1/4 inch form factor that will fit into any personal computer full-height slot. The drive specification highlights are given in Table 1. A perspective view of the drive mechanical assembly is shown in Figure 1. The spindle that rotates the disk has a runout of less than 10 um. The rotational speed at 1200 revolutions per minute (rpm) is held to an accuracy of 10-3. The total angular tolerance from perfect perpendicular alignment between the rotating disk and the incident optical beam axis is held to less than 17 milliradians. The coarse seek is accomplished through a stepping motor driving the optical head with 1.3 milliseconds per step or 32 tracks per step. The analog channels including read/write, the phase lock loop and the servo loops for focus and track control are contained on one surface mount pc board while the digital circuitry that interfaces with the drive and the controller is on a separate pc board. A microprocessor 8039 is used to control the handshake and the sequence of R/W commands. A separate power board is used to provide power to the spindle and the stepping motors. In the following we will discuss some of the salient features in the drive and leave the details to three accompanying Optotech papers. These salient features are derived from a design that is driven by three major considerations. One is precise control of the one micron diameter laser spot to any desired location on the disk. The second consideration is effective management of media defects. Given the state of the art of the Te-based disk technology with

  14. CONTROL ROD DRIVE

    DOEpatents

    Chapellier, R.A.; Rogers, I.

    1961-06-27

    Accurate and controlled drive for the control rod is from an electric motor. A hydraulic arrangement is provided to balance a piston against which a control rod is urged by the application of fluid pressure. The electric motor drive of the control rod for normal operation is made through the aforementioned piston. In the event scramming is required, the fluid pressure urging the control rod against the piston is relieved and an opposite fluid pressure is applied. The lack of mechanical connection between the electric motor and control rod facilitates the scramming operation.

  15. CSI: Hard Drive

    ERIC Educational Resources Information Center

    Sturgeon, Julie

    2008-01-01

    Acting on information from students who reported seeing a classmate looking at inappropriate material on a school computer, school officials used forensics software to plunge the depths of the PC's hard drive, searching for evidence of improper activity. Images were found in a deleted Internet Explorer cache as well as deleted file space.…

  16. DrivePy

    Energy Science and Technology Software Center (ESTSC)

    2014-08-30

    DrivePy is physics-based drivetrain model that sizes drivetrain components based on aerodynamic and operational loads for use in a systems engineering model. It also calculates costs based on empirical data collected by NREL's National Wind Technology Center.

  17. No Pass, No Drive?

    ERIC Educational Resources Information Center

    Zirkel, Perry A.

    2001-01-01

    Discusses basis for Kentucky appellate court decision that state's no-pass, no-drive statute did not violate due-process and equal-protection clauses of the Kentucky and federal constitutions, but did violate the federal Family Education Rights and Privacy Act, but nevertheless did not invalidate the statute. Explains why the decision is…

  18. Teachers with Drive

    ERIC Educational Resources Information Center

    Coggins, Celine; Diffenbaugh, P. K.

    2013-01-01

    For students in U.S. classrooms today, the odds of being assigned to an inexperienced teacher are higher than they have ever been because so many teachers, some in the top 20 percent of effectiveness are leaving the classroom in their first five years. Coggins and Diffenbaugh turn to Daniel Pink's work on drive to determine how to motivate…

  19. [Epilepsy and driving].

    PubMed

    Adam, Claude

    2015-10-01

    Epilepsy contributes little to road traffic accidents (0.25% of accidents) compared, for instance, to alcohol abuse (at least 30 times higher). Current factors, such as age and sex, or other chronic medical conditions also increase the risk of road traffic accidents but do not carry driving restrictions. So, the European Commission fairly established rules permitting individuals having experienced one or more epileptic seizures to drive if their road accident risk is low. Road accident risk related to epileptic seizures in various clinical situations is evaluated by the driving license commission, mainly with the aid of criteria based on seizure-free periods. A person who has had an epileptic seizure should notify the authorities. He should be advised by treating physician not to drive before. In case of an authorisation, any new relevant event should be notified to the authorities in the course of legal follow-up. Improvements of the current regulations by European data registries are under way. PMID:26482490

  20. COMMENT: No warp drive

    NASA Astrophysics Data System (ADS)

    Coule, D. H.

    1998-08-01

    The warp drive spacetime of Alcubierre is impossible to set up without first being able to distribute matter at tachyonic speed, put roughly, you need one to make one! However, over small distances, where the energy conditions possibly can be violated, one can envision opening the light-cones to increase the apparent speed of light.

  1. Drive-Through Training

    ERIC Educational Resources Information Center

    Carter, Margie

    2010-01-01

    In this article, the author discusses how the early childhood field's approach to staff training reflects the drive-through, fast-food culture. Year after year directors send their teachers to workshops to get some quick refresher techniques. The author suggests that rather than focusing professional development on topics, focus on observing…

  2. Driving skills after whiplash.

    PubMed

    Gimse, R; Bjørgen, I A; Straume, A

    1997-09-01

    Previous studies have shown that some persons with longlasting problems after whiplash have changed eye movements. These changes have been related to disturbance of the posture control system. The question raised in the present study is whether such disturbances can influence daily life functions connected with balance, position and external movements, such as car driving. A group of 23 persons with disturbed eye movements due to whiplash injury, was tested in a driving simulator, together with a closely matched control group. The results revealed significant differences between the two groups with respect to response times to the traffic signs presented, identification of type of sign, as well as steering precision while the subjects' attention was directed to the process of identifying the signs. Alternative explanations such as driving experience, pain, medication or malingering are at least partly controlled for, but cannot completely be ruled out. A distorted posture control system leading to disturbance of eye movements seems to be the most likely primary causative factor, but these disturbances are most certainly complexly determined. Reduced attention capacity is considered to be a mediating secondary factor. Registration of eye movements may be a useful diagnostic tool to evaluate driving skill after whiplash. PMID:9309948

  3. Driving While Intoxicated.

    ERIC Educational Resources Information Center

    Brick, John

    Alcohol intoxication increases the risk of highway accidents, the relative risk of crash probability increasing as a function of blood alcohol content (BAC). Because alcohol use is more prevalent than use of other drugs, more is known about the relationship between alcohol use and driving. Most states presume a BAC of .10% to be evidence of drunk…

  4. [Driving ability with multiple sclerosis].

    PubMed

    Küst, J; Dettmers, C

    2014-07-01

    Driving is an important issue for young patients, especially for those whose walking capacity is impaired. Driving might support the patient's social and vocational participation. The question as to whether a patient with multiple sclerosis (MS) is restricted in the ability to drive a car depends on neurological and neuropsychological deficits, self-awareness, insight into deficits and ability to compensate for loss of function. Because of the enormous variability of symptoms in MS the question is highly individualized. A practical driving test under supervision of a driving instructor (possibly accompanied by a neuropsychologist) might be helpful in providing both patient and relatives adequate feedback on driving abilities. PMID:24906536

  5. Drive-by-Downloads

    SciTech Connect

    Narvaez, Julia; Endicott-Popovsky, Barbara E.; Seifert, Christian; Aval, Chiraag U.; Frincke, Deborah A.

    2010-02-01

    Abstract: Drive-by-downloads are malware that push, and then execute, malicious code on a client system without the user's consent. The purpose of this paper is to introduce a discussion of the usefulness of antivirus software for detecting the installation of such malware, providing groundwork for future studies. Client honeypots collected drive-by malware which was then evaluated using common antivirus products. Initial analysis showed that most of such antivirus products identified less than 70% of these highly polymorphic malware programs. Also, it was observed that the antivirus products tested, even when successfully detecting this malware, often failed to classify it, leading to the conclusion that further work could involve not only developing new behavioral detection technologies, but also empirical studies that improve general understanding of these threats. Toward that end, one example of malicious code was analyzed behaviorally to provide insight into next steps for the future direction of this research.

  6. Magnetostrictive direct drive motors

    NASA Technical Reports Server (NTRS)

    Naik, Dipak; Dehoff, P. H.

    1990-01-01

    Developing magnetostrictive direct drive research motors to power robot joints is discussed. These type motors are expected to produce extraordinary torque density, to be able to perform microradian incremental steps and to be self-braking and safe with the power off. Several types of motor designs have been attempted using magnetostrictive materials. One of the candidate approaches (the magnetostrictive roller drive) is described. The method in which the design will function is described as is the reason why this approach is inherently superior to the other approaches. Following this, the design will be modelled and its expected performance predicted. This particular candidate design is currently undergoing detailed engineering with prototype construction and testing scheduled for mid 1991.

  7. Variable speed drive

    NASA Technical Reports Server (NTRS)

    Obler, H. D. (Inventor)

    1983-01-01

    A variable speed drive wherein a first embodiment is comprised of a pivotally mounted prime mover coupled to a rotary fluid output device, such as a fan or pump, through a variable and fixed pulley drive arrangement is described. The pivotal position of the prime mover and accordingly the pitch diameter of variable pulley means is controlled in accordance with fluid motor means coupled to the prime mover. This is actuated in response to a fluid feedback control signal derived from a sensed output of the rotary fluid output device. The pivotal motion of the prime mover imparts an arcuate motion to the variable pulley means which effects a speed variation of the rotary fluid output device in accordance with the variation of the pitch diameter ratio of opposing variable and fixed pulley means.

  8. Sex chromosome drive.

    PubMed

    Helleu, Quentin; Gérard, Pierre R; Montchamp-Moreau, Catherine

    2015-02-01

    Sex chromosome drivers are selfish elements that subvert Mendel's first law of segregation and therefore are overrepresented among the products of meiosis. The sex-biased progeny produced then fuels an extended genetic conflict between the driver and the rest of the genome. Many examples of sex chromosome drive are known, but the occurrence of this phenomenon is probably largely underestimated because of the difficulty to detect it. Remarkably, nearly all sex chromosome drivers are found in two clades, Rodentia and Diptera. Although very little is known about the molecular and cellular mechanisms of drive, epigenetic processes such as chromatin regulation could be involved in many instances. Yet, its evolutionary consequences are far-reaching, from the evolution of mating systems and sex determination to the emergence of new species. PMID:25524548

  9. Forces Driving Chaperone Action.

    PubMed

    Koldewey, Philipp; Stull, Frederick; Horowitz, Scott; Martin, Raoul; Bardwell, James C A

    2016-07-14

    It is still unclear what molecular forces drive chaperone-mediated protein folding. Here, we obtain a detailed mechanistic understanding of the forces that dictate the four key steps of chaperone-client interaction: initial binding, complex stabilization, folding, and release. Contrary to the common belief that chaperones recognize unfolding intermediates by their hydrophobic nature, we discover that the model chaperone Spy uses long-range electrostatic interactions to rapidly bind to its unfolded client protein Im7. Short-range hydrophobic interactions follow, which serve to stabilize the complex. Hydrophobic collapse of the client protein then drives its folding. By burying hydrophobic residues in its core, the client's affinity to Spy decreases, which causes client release. By allowing the client to fold itself, Spy circumvents the need for client-specific folding instructions. This mechanism might help explain how chaperones can facilitate the folding of various unrelated proteins. PMID:27293188

  10. Advanced Motor Drives Studies

    NASA Technical Reports Server (NTRS)

    Ehsani, M.; Tchamdjou, A.

    1997-01-01

    This report presents an evaluation of advanced motor drive systems as a replacement for the hydrazine fueled APU units. The replacement technology must meet several requirements which are particular to the space applications and the Orbiter in general. Some of these requirements are high efficiency, small size, high power density. In the first part of the study several motors are compared, based on their characteristics and in light of the Orbiter requirements. The best candidate, the brushless DC is chosen because of its particularly good performance with regards to efficiency. Several power electronics drive technologies including the conventional three-phase hard switched and several soft-switched inverters are then presented. In the last part of the study, a soft-switched inverter is analyzed and compared to its conventional hard-switched counterpart. Optimal efficiency is a basic requirement for space applications and the soft-switched technology represents an unavoidable trend for the future.

  11. Gear Drive Testing

    NASA Technical Reports Server (NTRS)

    1982-01-01

    Philadelphia Gear Corporation used two COSMIC computer programs; one dealing with shrink fit analysis and the other with rotor dynamics problems in computerized design and test work. The programs were used to verify existing in-house programs to insure design accuracy by checking its company-developed computer methods against procedures developed by other organizations. Its specialty is in custom units for unique applications, such as Coast Guard ice breaking ships, steel mill drives, coal crusher, sewage treatment equipment and electricity.

  12. Driving on the Descartes

    NASA Technical Reports Server (NTRS)

    1972-01-01

    Astronaut John W. Young, Apollo 16 mission commander, drives the 'Rover', Lunar Roving Vehicle (LRV) to its final parking place near the end of the third extravehicular activity (EVA-3) at the Descartes landing site. Astronaut Charles M. Duke Jr., Lunar Module pilot, took this photograph looking southward. The flank of Stone Mountain can be seen on the horizon at left. The shadow of the Lunar Module 'Orion' is visible in the foreground.

  13. Variable reluctance drive system

    SciTech Connect

    Lipo, T.A.; Liang, F.

    1995-10-17

    A variable reluctance drive system including a motor and corresponding converter for improved current commutation is described. The motor incorporates a salient pole rotor and a salient pole stator having one or more full pitch windings which operate by mutual inductance to transfer the current from the active short pitch winding following phase alignment. This increases output torque and/or speed and permits a number of simple and economical converter circuits. 17 figs.

  14. [Automobile driving capacity in dementia].

    PubMed

    Seeger, Rolf

    2015-04-01

    Dementia influences at an early stage the driving aptitude of motor vehicle steering persons. Every year in Switzerland, around 16'000 driving permit holders suffer newly from dementia; therefore the driving aptitude is questioned, especially because of possibly limited executive functions. Individuals with early-stage dementia often may show a dangerous driving stile. However, a mild dementia does not a priori exclude the driving aptitude, and less than half of these drivers can continue driving for another 1 - 3 years. In contrast, there is no further driving aptitude in presence of moderate dementia. In the assessment of driving aptitude, the underlying cause of dementia is always taken into account. Cognitive short tests such as the Mini-Mental Status Exam, Clock Drawing Test and Trail-Making Test are not suitable to make reliable statements about the aptitude to drive, but these tests are very important for the initial diagnosis of dementia in primary care practice and can lead the way for further examination concerning driving aptitude. The legally prescribed regular check-up for motorists aged over 70 years in Switzerland provides an ideal opportunity for early detection of incipient dementia. The practical procedure for the assessment of aptitude to drive in the primary care practice is presented. The physician-guided on-road driving test represents a meaningful, practical and relatively cost-effective tool for the evaluation of driving aptitude in cases of doubt. PMID:25791047

  15. Who's Driving Home?: Assessing Adolescent Drinking and Driving.

    ERIC Educational Resources Information Center

    Swisher, John D.; Bibeau, Daniel

    1987-01-01

    Data from 13,998 students revealed that high percentages of students drank often and that many of these students reported being drunk often. While most students indicated they would prefer not to drive home after drinking, approximately one-third of driving age students indicated they would drive under the influence of alcohol or would ride with…

  16. Drive alignment pays maintenance dividends

    SciTech Connect

    Fedder, R.

    2008-12-15

    Proper alignment of the motor and gear drive on conveying and processing equipment will result in longer bearing and coupling life, along with lower maintenance costs. Selecting an alignment free drive package instead of a traditional foot mounted drive and motor is a major advancement toward these goals. 4 photos.

  17. Drive Diagnostic Filter Wheel Control

    Energy Science and Technology Software Center (ESTSC)

    2007-07-17

    DrD Filter Wheel Control is National Instrument's Labview software that drives a Drive Diagnostic filter wheel. The software can drive the filter wheel between each end limit, detect the positive and negative limit and each home position and post the stepper motot values to an Excel spreadsheet. The software can also be used to cycle the assembly between the end limits.

  18. Offset Compound Gear Drive

    NASA Technical Reports Server (NTRS)

    Stevens, Mark A.; Handschuh, Robert F.; Lewicki, David G.

    2010-01-01

    The Offset Compound Gear Drive is an in-line, discrete, two-speed device utilizing a special offset compound gear that has both an internal tooth configuration on the input end and external tooth configuration on the output end, thus allowing it to mesh in series, simultaneously, with both a smaller external tooth input gear and a larger internal tooth output gear. This unique geometry and offset axis permits the compound gear to mesh with the smaller diameter input gear and the larger diameter output gear, both of which are on the same central, or primary, centerline. This configuration results in a compact in-line reduction gear set consisting of fewer gears and bearings than a conventional planetary gear train. Switching between the two output ratios is accomplished through a main control clutch and sprag. Power flow to the above is transmitted through concentric power paths. Low-speed operation is accomplished in two meshes. For the purpose of illustrating the low-speed output operation, the following example pitch diameters are given. A 5.0 pitch diameter (PD) input gear to 7.50 PD (internal tooth) intermediate gear (0.667 reduction mesh), and a 7.50 PD (external tooth) intermediate gear to a 10.00 PD output gear (0.750 reduction mesh). Note that it is not required that the intermediate gears on the offset axis be of the same diameter. For this example, the resultant low-speed ratio is 2:1 (output speed = 0.500; product of stage one 0.667 reduction and stage two 0.750 stage reduction). The design is not restricted to the example pitch diameters, or output ratio. From the output gear, power is transmitted through a hollow drive shaft, which, in turn, drives a sprag during which time the main clutch is disengaged.

  19. Base drive circuit

    DOEpatents

    Lange, A.C.

    1995-04-04

    An improved base drive circuit having a level shifter for providing bistable input signals to a pair of non-linear delays. The non-linear delays provide gate control to a corresponding pair of field effect transistors through a corresponding pair of buffer components. The non-linear delays provide delayed turn-on for each of the field effect transistors while an associated pair of transistors shunt the non-linear delays during turn-off of the associated field effect transistor. 2 figures.

  20. Modular droplet actuator drive

    NASA Technical Reports Server (NTRS)

    Pollack, Michael G. (Inventor); Paik, Philip (Inventor)

    2011-01-01

    A droplet actuator drive including a detection apparatus for sensing a property of a droplet on a droplet actuator; circuitry for controlling the detection apparatus electronically coupled to the detection apparatus; a droplet actuator cartridge connector arranged so that when a droplet actuator cartridge electronically is coupled thereto: the droplet actuator cartridge is aligned with the detection apparatus; and the detection apparatus can sense the property of the droplet on a droplet actuator; circuitry for controlling a droplet actuator coupled to the droplet actuator connector; and the droplet actuator circuitry may be coupled to a processor.

  1. Base drive circuit

    DOEpatents

    Lange, Arnold C.

    1995-01-01

    An improved base drive circuit (10) having a level shifter (24) for providing bistable input signals to a pair of non-linear delays (30, 32). The non-linear delays (30, 32) provide gate control to a corresponding pair of field effect transistors (100, 106) through a corresponding pair of buffer components (88, 94). The non-linear delays (30, 32) provide delayed turn-on for each of the field effect transistors (100, 106) while an associated pair of transistors (72, 80) shunt the non-linear delays (30, 32) during turn-off of the associated field effect transistor (100, 106).

  2. Advances in traction drive technology

    NASA Technical Reports Server (NTRS)

    Loewenthal, S. H.; Anderson, N. E.; Rohn, D. A.

    1983-01-01

    Traction drives are traced from early uses as main transmissions in automobiles at the turn of the century to modern, high-powered traction drives capable of transmitting hundreds of horsepower. Recent advances in technology are described which enable today's traction drive to be a serious candidate for off-highway vehicles and helicopter applications. Improvements in materials, traction fluids, design techniques, power loss and life prediction methods will be highlighted. Performance characteristics of the Nasvytis fixed-ratio drive are given. Promising future drive applications, such as helicopter main transmissions and servo-control positioning mechanisms are also addressed.

  3. Glaucoma and Driving: On-Road Driving Characteristics

    PubMed Central

    Wood, Joanne M.; Black, Alex A.; Mallon, Kerry; Thomas, Ravi; Owsley, Cynthia

    2016-01-01

    Purpose To comprehensively investigate the types of driving errors and locations that are most problematic for older drivers with glaucoma compared to those without glaucoma using a standardized on-road assessment. Methods Participants included 75 drivers with glaucoma (mean = 73.2±6.0 years) with mild to moderate field loss (better-eye MD = -1.21 dB; worse-eye MD = -7.75 dB) and 70 age-matched controls without glaucoma (mean = 72.6 ± 5.0 years). On-road driving performance was assessed in a dual-brake vehicle by an occupational therapist using a standardized scoring system which assessed the types of driving errors and the locations where they were made and the number of critical errors that required an instructor intervention. Driving safety was rated on a 10-point scale. Self-reported driving ability and difficulties were recorded using the Driving Habits Questionnaire. Results Drivers with glaucoma were rated as significantly less safe, made more driving errors, and had almost double the rate of critical errors than those without glaucoma. Driving errors involved lane positioning and planning/approach, and were significantly more likely to occur at traffic lights and yield/give-way intersections. There were few between group differences in self-reported driving ability. Conclusions Older drivers with glaucoma with even mild to moderate field loss exhibit impairments in driving ability, particularly during complex driving situations that involve tactical problems with lane-position, planning ahead and observation. These results, together with the fact that these drivers self-report their driving to be relatively good, reinforce the need for evidence-based on-road assessments for evaluating driving fitness. PMID:27472221

  4. Soy protein isolate down-regulates caveolin-1 expression to suppress osteoblastic cell senescence pathways

    Technology Transfer Automated Retrieval System (TEKTRAN)

    It has been suggested that the beneficial effects of soy protein isolate (SPI) on bone quality might be due to either stimulation of estrogenic signaling via isoflavones or through a novel and as yet characterized non-estrogenic pathway. We report here that SPI-fed rat serum inhibited osteoblastic c...

  5. Experiment study on friction drive

    NASA Astrophysics Data System (ADS)

    Wang, Guomin; Ma, Lisheng; Yao, Zhengqiu; Li, Guoping

    2004-09-01

    In the past years, friction drive was developed to overcome the inherent deficiencies in both worm drive and gear drive. No periodical error and free of backlash are the main advantages of friction drive. With the trend towards bigger and bigger aperture of the optical telescopes, there are some reports about friction drive employed to drive the telescopes. However friction drive has its own deficiencies, such as slippage and creepage. This report here describes the study on the friction drive finished in an experiment arranged by LAMOST project. It comprises three main parts. First, it introduces the experiment apparatus and proposes a new kind of measurement and adjustment mechanisms. Secondly, the report gives the analysis of friction drive characteristics theoretically, such as slippage, creepage and gives the results of corresponding experiments. The experiment shows that the lowest stable speed reaches 0.05″/s with precision of 0.009″(RMS), the preload has little influence on the drive precision in the case of constant velocity and the variable velocity when the angle acceleration is less than 5″/s2 with close loop control and the creepage velocity of this experiment system is 1.47″/s. Lastly, the analysis in the second section lists some measures to improve the precision and stability further. These measures have been actually conducted in the testing system and proved to be reliable.

  6. Magnetostrictive direct drive motors

    NASA Technical Reports Server (NTRS)

    Naik, Dipak; Dehoff, P. H.

    1992-01-01

    A new rare earth alloy, Terfenol-D, combines low frequency operation and extremely high energy density with high magnetostriction. Its material properties make it suitable as a drive element for actuators requiring high output torque. The high strains, the high forces and the high controllability of Terfenol alloys provide a powerful and challenging basis for new ways to generate motion in actuators. Two prototypes of motors using Terfenol-D rods were developed at NASA Goddard. The basic principles of operation are provided of the motor along with other relevant details. A conceptual design of a torque limiting safety clutch/brake under development is illustrated. Also, preliminary design drawings of a linear actuator using Terfenol-D is shown.

  7. Automatism and driving offences.

    PubMed

    Rumbold, John

    2013-10-01

    Automatism is a rarely used defence, but it is particularly used for driving offences because many are strict liability offences. Medical evidence is almost always crucial to argue the defence, and it is important to understand the bars that limit the use of automatism so that the important medical issues can be identified. The issue of prior fault is an important public safeguard to ensure that reasonable precautions are taken to prevent accidents. The total loss of control definition is more problematic, especially with disorders of more gradual onset like hypoglycaemic episodes. In these cases the alternative of 'effective loss of control' would be fairer. This article explores several cases, how the criteria were applied to each, and the types of medical assessment required. PMID:24112330

  8. QUICK RELEASABLE DRIVE

    DOEpatents

    Dickson, J.J.

    1958-07-01

    A quick releasable mechanical drive system suitable for use in a nuclear reactor is described. A small reversible motor positions a control rod by means of a worm and gear speed reducer, a magnetic torque clutch, and a bell crank. As the control rod is raised to the operating position, a heavy coil spring is compressed. In the event of an emergency indicated by either a''scram'' signal or a power failure, the current to the magnetic clutch is cut off, thereby freeing the coil spring and the bell crank positioner from the motor and speed reduction gearing. The coil spring will immediately act upon the bell crank to cause the insertion of the control rod. This arrangement will allow the slow, accurate positioning of the control rod during reactor operation, while providing an independent force to rapidly insert the rod in the event of an emergency.

  9. Head tilt during driving.

    PubMed

    Zikovitz, D C; Harris, L R

    1999-05-01

    In order to distinguish between the use of visual and gravito-inertial force reference frames, the head tilt of drivers and passengers were measured as they went around corners at various speeds. The visual curvature of the corners were thus dissociated from the magnitude of the centripetal forces (0.30-0.77 g). Drivers' head tilts were highly correlated with the visually-available estimate of the curvature of the road (r2=0.86) but not with the centripetal force (r2<0.1). Passengers' head tilts were inversely correlated with the lateral forces (r2=0.3-0.7) and seem to reflect a passive sway. The strong correlation of the tilt of drivers' heads with a visual aspect of the road ahead, supports the use of a predominantly visual reference frame for the driving task. PMID:10722313

  10. All wheel drive vehicle

    SciTech Connect

    Watanabe, M.; Yagasaki, A.; Kawashima, Y.

    1986-07-15

    An all-wheel-drive vehicle is described which consists of: (a) a body; (b) an engine mounted on the body and having an output shaft; (c) front and rear pairs of wheels drivable by power from the engine, the front and rear wheels being vertically movably suspended from the body; (d) axles coupled to the front and rear wheels; (e) first power transmitting means for transmitting power from the output shaft of the engine to one of the axles of the front and rear wheels; (f) a power output unit mounted on the one axle; and (g) second power transmitting means for transmitting power from the power output unit to the other of the axles of the front and rear wheels.

  11. Rotary drive mechanism

    DOEpatents

    Kenderdine, Eugene W.

    1991-01-01

    A rotary drive mechanism includes a rotary solenoid having a stator and multi-poled rotor. A moving member rotates with the rotor and is biased by a biasing device. The biasing device causes a further rotational movement after rotation by the rotary solenoid. Thus, energization of the rotary solenoid moves the member in one direction to one position and biases the biasing device against the member. Subsequently, de-energization of the rotary solenoid causes the biasing device to move the member in the same direction to another position from where the moving member is again movable by energization and de-energization of the rotary solenoid. Preferably, the moving member is a multi-lobed cam having the same number of lobes as the rotor has poles. An anti-overdrive device is also preferably provided for preventing overdrive in the forward direction or a reverse rotation of the moving member and for precisely aligning the moving member.

  12. Hyperactive children as young adults: driving abilities, safe driving behavior, and adverse driving outcomes.

    PubMed

    Fischer, Mariellen; Barkley, Russell A; Smallish, Lori; Fletcher, Kenneth

    2007-01-01

    ADHD has been linked to poorer driving abilities and greater adverse outcomes (crashes, citations) in clinic-referred cases of teens and adults with ADHD. No study, however, has focused systematically on ADHD children followed into adulthood. The present paper does so while measuring driving-related cognitive abilities, driving behavior, and history of adverse driving outcomes. A multi-method, multi-source battery of driving measures was collected at the young adult follow-up on hyperactive (H; N=147; mean age=21.1) and community control children (CC; N=71; mean age=20.5) followed for more than 13 years. More of the H than CC groups had been ticketed for reckless driving, driving without a license, hit-and-run crashes, and had their licenses suspended or revoked. Official driving records found more of the H group having received traffic citations and a greater frequency of license suspensions. The cost of damage in their initial crashes was also significantly greater in the H than CC group. Both self-report and other ratings of actual driving behavior revealed less safe driving practices being used by the H group. Observations by driving instructors during a behind-the-wheel road test indicated significantly more impulsive errors. Performance on a simulator further revealed slower and more variable reaction times, greater errors of impulsiveness (false alarms, poor rule following), more steering variability, and more scrapes and crashes of the simulated vehicle against road boundaries in the H than in the CC group. These findings suggest that children growing up with ADHD may either have fewer driving risks or possibly under-report those risks relative to clinic-referred adults with this disorder. Deficits in simulator performance and safe driving behavior, however, are consistent with clinic-referred adults with ADHD suggesting ongoing risks for such adverse driving outcomes in children growing up with ADHD. PMID:16919226

  13. Dimensions of driving anger and their relationships with aberrant driving.

    PubMed

    Zhang, Tingru; Chan, Alan H S; Zhang, Wei

    2015-08-01

    The purpose of this study was to investigate the relationship between driving anger and aberrant driving behaviours. An internet-based questionnaire survey was administered to a sample of Chinese drivers, with driving anger measured by a 14-item short Driving Anger Scale (DAS) and the aberrant driving behaviours measured by a 23-item Driver Behaviour Questionnaire (DBQ). The results of Confirmatory Factor Analysis demonstrated that the three-factor model (hostile gesture, arrival-blocking and safety-blocking) of the DAS fitted the driving anger data well. The Exploratory Factor Analysis on DBQ data differentiated four types of aberrant driving, viz. emotional violation, error, deliberate violation and maintaining progress violation. For the anger-aberration relation, it was found that only "arrival-blocking" anger was a significant positive predictor for all four types of aberrant driving behaviours. The "safety-blocking" anger revealed a negative impact on deliberate violations, a finding different from previously established positive anger-aberration relation. These results suggest that drivers with different patterns of driving anger would show different behavioural tendencies and as a result intervention strategies may be differentially effective for drivers of different profiles. PMID:25984643

  14. Sequenced drive for rotary valves

    DOEpatents

    Mittell, Larry C.

    1981-01-01

    A sequenced drive for rotary valves which provides the benefits of applying rotary and linear motions to the movable sealing element of the valve. The sequenced drive provides a close approximation of linear motion while engaging or disengaging the movable element with the seat minimizing wear and damage due to scrubbing action. The rotary motion of the drive swings the movable element out of the flowpath thus eliminating obstruction to flow through the valve.

  15. Sizing criterial for traction drives

    NASA Technical Reports Server (NTRS)

    Rohn, D. A.; Loewenthal, S. H.; Coy, J. J.

    1983-01-01

    A simplified traction drive fatigue analysis which was derived from the Lundberg-Palmgren theory is measured and the effects of rotational speed, multiplicity of contacts, and variation in the available traction coefficient on traction drive system life, size, and power capacity was investigated. Simplified equations are provided for determining the 90% survival life rating of steel traction drive contacts of arbitrary geometry. References to life modifying factors for material, lubrication, and traction will be made.

  16. The drive-wise project: driving simulator training increases real driving performance in healthy older drivers

    PubMed Central

    Casutt, Gianclaudio; Theill, Nathan; Martin, Mike; Keller, Martin; Jäncke, Lutz

    2014-01-01

    Background: Age-related cognitive decline is often associated with unsafe driving behavior. We hypothesized that 10 active training sessions in a driving simulator increase cognitive and on-road driving performance. In addition, driving simulator training should outperform cognitive training. Methods: Ninety-one healthy active drivers (62–87 years) were randomly assigned to one of three groups: (1) a driving simulator training group, (2) an attention training group (vigilance and selective attention), or (3) a control group. The main outcome variables were on-road driving and cognitive performance. Seventy-seven participants (85%) completed the training and were included in the analyses. Training gains were analyzed using a multiple regression analysis with planned orthogonal comparisons. Results: The driving simulator-training group showed an improvement in on-road driving performance compared to the attention-training group. In addition, both training groups increased cognitive performance compared to the control group. Conclusion: Driving simulator training offers the potential to enhance driving skills in older drivers. Compared to the attention training, the simulator training seems to be a more powerful program for increasing older drivers' safety on the road. PMID:24860497

  17. Driving anger in Ukraine: Appraisals, not trait driving anger, predict anger intensity while driving.

    PubMed

    Stephens, A N; Hill, T; Sullman, M J M

    2016-03-01

    Trait driving anger is often, but not always, found to predict both the intensity of anger while driving and subsequent crash-related behaviours. However, a number of studies have not found support for a direct relationship between one's tendency to become angry and anger reported while driving, suggesting that other factors may mediate this relationship. The present self-report study investigated whether, in anger provoking driving situations, the appraisals made by drivers influence the relationship between trait and state anger. A sample of 339 drivers from Ukraine completed the 33-item version of the Driver Anger Scale (DAS; Deffenbacher et al., 1994) and eight questions about their most recent experience of driving anger. A structural equation model found that the intensity of anger experienced was predicted by the negative evaluations of the situation, which was in turn predicted by trait driving anger. However, trait driving anger itself did not predict anger intensity; supporting the hypothesis that evaluations of the driving situation mediate the relationship between trait and state anger. Further, the unique structure of the DAS required to fit the data from the Ukrainian sample, may indicate that the anger inducing situations in Ukraine are different to those of a more developed country. Future research is needed to investigate driving anger in Ukraine in a broader sample and also to confirm the role of the appraisal process in the development of driving anger in both developed and undeveloped countries. PMID:26710267

  18. 26. CAN CONVEYOR DRIVE MECHANISM Empty can conveyor driving mechanism, ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    26. CAN CONVEYOR DRIVE MECHANISM Empty can conveyor driving mechanism, second floor above canning area. The belt has been removed from the conveyor, but sections of can conveyor tracks are visible on the floor. - Hovden Cannery, 886 Cannery Row, Monterey, Monterey County, CA

  19. VIEW OF BEND IN CEDAR DRIVE WITH 603 CEDAR DRIVE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    VIEW OF BEND IN CEDAR DRIVE WITH 603 CEDAR DRIVE ON RIGHT. VIEW FACING NORTHEAST - Camp H.M. Smith and Navy Public Works Center Manana Title VII (Capehart) Housing, Intersection of Acacia Road and Brich Circle, Pearl City, Honolulu County, HI

  20. Handbook for Driving Knowledge Testing.

    ERIC Educational Resources Information Center

    Pollock, William T.; McDole, Thomas L.

    Materials intended for driving knowledge test development for use by operational licensing and education agencies are presented. A pool of 1,313 multiple choice test items is included, consisting of sets of specially developed and tested items covering principles of safe driving, legal regulations, and traffic control device knowledge pertinent to…

  1. Bidirectional drive and brake mechanism

    NASA Technical Reports Server (NTRS)

    Swan, Scott A. (Inventor)

    1991-01-01

    A space transport vehicle is disclosed as including a body which is arranged to be movably mounted on an elongated guide member disposed in outer space and driven therealong. A drive wheel is mounted on a drive shaft and arranged to be positioned in rolling engagement with the elongated guide carrying the vehicle. A brake member is arranged on the drive shaft for movement into and out of engagement with an adjacent surface of the drive wheel. An actuator is mounted on the body to be manually moved back and forth between spaced positions in an arc of movement. A ratchet-and-pawl mechanism is arranged to operate upon movements of the actuator in one direction between first and second positions for coupling the actuator to the drive wheel to incrementally rotate the wheel in one rotational direction and to operate upon movements of the actuator in the opposite direction for uncoupling the actuator from the wheel. The brake member is threadedly coupled to the drive shaft in order that the brake member will be operated only when the actuator is moved on beyond its first and second positions for shifting the brake member along the drive shaft and into frictional engagement with the adjacent surface on the drive wheel.

  2. Students: You... Alcohol and Driving.

    ERIC Educational Resources Information Center

    Department of Transportation, Washington, DC.

    The purpose of this manual is to provide accurate information about alcohol and about drinking and driving, so that the student may make responsible decisions about both. It covers youth drinking, drinking and driving, and the individual's responsibility to others in drinking situations. The booklet consists of eight readings, as well as…

  3. Driving difficulties in Parkinson's disease

    PubMed Central

    Rizzo, Matthew; Uc, Ergun Y; Dawson, Jeffrey; Anderson, Steven; Rodnitzky, Robert

    2011-01-01

    Safe driving requires the coordination of attention, perception, memory, motor and executive functions (including decision-making) and self-awareness. PD and other disorders may impair these abilities. Because age or medical diagnosis alone is often an unreliable criterion for licensure, decisions on fitness to drive should be based on empirical observations of performance. Linkages between cognitive abilities measured by neuropsychological tasks, and driving behavior assessed using driving simulators, and natural and naturalistic observations in instrumented vehicles, can help standardize the assessment of fitness-to-drive. By understanding the patterns of driver safety errors that cause crashes, it may be possible to design interventions to reduce these errors and injuries and increase mobility. This includes driver performance monitoring devices, collision alerting and warning systems, road design, and graded licensure strategies. PMID:20187237

  4. [Driving and health at work].

    PubMed

    Giorgio, Marie-Thérèse

    2015-09-01

    The role of the occupational physician is to prevent occupational accidents and diseases. Therefore, he is the one to decide if a worker is fit to drive in the context of his professional activity, including in cases where no specific driving license is required (e.g. forklift truck, mobile crane). This decision is an important one, as two thirds of fatal occupational accidents occur on the road. The decision is made on the basis of both a medical examination and the regulation, which indicates all contraindications to driving. The physician's responsibility is involved, as is the employer's, as he must ensure that his employee is fit to drive and possesses a valid driving license at all times. PMID:25960440

  5. Quantum gates by periodic driving

    PubMed Central

    Shi, Z. C.; Wang, W.; Yi, X. X.

    2016-01-01

    Topological quantum computation has been extensively studied in the past decades due to its robustness against decoherence. One way to realize the topological quantum computation is by adiabatic evolutions—it requires relatively long time to complete a gate, so the speed of quantum computation slows down. In this work, we present a method to realize single qubit quantum gates by periodic driving. Compared to adiabatic evolution, the single qubit gates can be realized at a fixed time much shorter than that by adiabatic evolution. The driving fields can be sinusoidal or square-well field. With the sinusoidal driving field, we derive an expression for the total operation time in the high-frequency limit, and an exact analytical expression for the evolution operator without any approximations is given for the square well driving. This study suggests that the period driving could provide us with a new direction in regulations of the operation time in topological quantum computation. PMID:26911900

  6. Driving the Landscape

    NASA Astrophysics Data System (ADS)

    Haff, P. K.

    2012-12-01

    Technological modification of the earth's surface (e.g., agriculture, urbanization) is an old story in human history, but what about the future? The future of landscape in an accelerating technological world, beyond a relatively short time horizon, lies hidden behind an impenetrable veil of complexity. Sufficiently complex dynamics generates not only the trajectory of a variable of interest (e.g., vegetation cover) but also the environment in which that variable evolves (e.g., background climate). There is no way to anticipate what variables will define that environment—the dynamics creates its own variables. We are always open to surprise by a change of conditions we thought or assumed were fixed or by the appearance of new phenomena of whose possible existence we had been unaware or thought unlikely. This is especially true under the influence of technology, where novelty is the rule. Lack of direct long-term predictability of landscape change does not, however, mean we cannot say anything about its future. The presence of persistence (finite time scales) in a system means that prediction by a calibrated numerical model should be good for a limited period of time barring bad luck or faulty implementation. Short-term prediction, despite its limitations, provides an option for dealing with the longer-term future. If a computer-controlled car tries to drive itself from New York to Los Angeles, no conceivable (or possible) stand-alone software can be constructed to predict a priori the space-time trajectory of the vehicle. Yet the drive is normally completed easily by most drivers. The trip is successfully completed because each in a series of very short (linear) steps can be "corrected" on the fly by the driver, who takes her cues from the environment to keep the car on the road and headed toward its destination. This metaphor differs in a fundamental way from the usual notion of predicting geomorphic change, because it involves a goal—to reach a desired

  7. Electric vehicle drive systems

    NASA Astrophysics Data System (ADS)

    Appleyard, M.

    1992-01-01

    New legislation in the State of California requires that 2% of vehicles sold there from 1998 will be 'zero-emitting'. This provides a unique market opportunity for developers of electric vehicles but substantial improvements in the technology are probably required if it is to be successfully exploited. There are around a dozen types of battery that are potentially relevant to road vehicles but, at the present, lead/acid and sodium—sulphur come closest to combining acceptable performance, life and cost. To develop an efficient, lightweight electric motor system requires up-to-date techniques of magnetics design, and the latest power-electronic and microprocessor control methods. Brushless machines, coupled with solid-state inverters, offer the most economical solution for mass production, even though their development costs are higher than for direct-current commutator machines. Fitted to a small car, even the highest energy-density batteries will only provide around 200 km average range before recharging. Therefore, some form of supplementary on-board power generation will probably be needed to secure widespread acceptance by the driving public. Engine-driven generators of quite low power can achieve useful increases in urban range but will fail to qualify as 'zero-emitting'. On the other hand, if the same function could be economically performed by a small fuel-cell using hydrogen derived from a methanol reformer, then most of the flexibility provided by conventional vehicles would be retained. The market prospects for electric cars would then be greatly enhanced and their dependence on very advanced battery technology would be reduced.

  8. Linear Back-Drive Differentials

    NASA Technical Reports Server (NTRS)

    Waydo, Peter

    2003-01-01

    Linear back-drive differentials have been proposed as alternatives to conventional gear differentials for applications in which there is only limited rotational motion (e.g., oscillation). The finite nature of the rotation makes it possible to optimize a linear back-drive differential in ways that would not be possible for gear differentials or other differentials that are required to be capable of unlimited rotation. As a result, relative to gear differentials, linear back-drive differentials could be more compact and less massive, could contain fewer complex parts, and could be less sensitive to variations in the viscosities of lubricants. Linear back-drive differentials would operate according to established principles of power ball screws and linear-motion drives, but would utilize these principles in an innovative way. One major characteristic of such mechanisms that would be exploited in linear back-drive differentials is the possibility of designing them to drive or back-drive with similar efficiency and energy input: in other words, such a mechanism can be designed so that a rotating screw can drive a nut linearly or the linear motion of the nut can cause the screw to rotate. A linear back-drive differential (see figure) would include two collinear shafts connected to two parts that are intended to engage in limited opposing rotations. The linear back-drive differential would also include a nut that would be free to translate along its axis but not to rotate. The inner surface of the nut would be right-hand threaded at one end and left-hand threaded at the opposite end to engage corresponding right- and left-handed threads on the shafts. A rotation and torque introduced into the system via one shaft would drive the nut in linear motion. The nut, in turn, would back-drive the other shaft, creating a reaction torque. Balls would reduce friction, making it possible for the shaft/nut coupling on each side to operate with 90 percent efficiency.

  9. Oil well pump driving unit

    SciTech Connect

    Gilbertson, T. A.

    1984-11-06

    An oil well pumping apparatus which includes a submerged reciprocating pump mounted in a tubing arrangement communicating with the wellhead, a sucker rod string extending through the tubing arrangement and connected in driving relation with the pump, and a pumping tee and stuffing box arrangement mounted on the casing of the well at the wellhead and including a sealed drive rod arrangement in the stuffing box connected in driving relation to said sucker rod string, and a pump driving unit. The pump driving unit includes a hydraulic cylinder and support means including a gimbal arrangement for supporting the hydraulic cylinder over the stuffing box with the axis of the cylinder rod aligned with the axis of said stuffing box. A coupling means is provided for coupling the cylinder rod to the sealed drive rod arrangement. A hydraulic drive/control unit is coupled to said in/out fluid line for operating cycle consisting of a hydraulic power upstroke and a gravity power downstroke. An assist cylinder and accumulator combination are provided to counteract part of the weight of the rod string and thus reduce the workload on t

  10. Driving Performance Under Alcohol in Simulated Representative Driving Tasks

    PubMed Central

    Kenntner-Mabiala, Ramona; Kaussner, Yvonne; Jagiellowicz-Kaufmann, Monika; Hoffmann, Sonja; Krüger, Hans-Peter

    2015-01-01

    Abstract Comparing drug-induced driving impairments with the effects of benchmark blood alcohol concentrations (BACs) is an approved approach to determine the clinical relevance of findings for traffic safety. The present study aimed to collect alcohol calibration data to validate findings of clinical trials that were derived from a representative test course in a dynamic driving simulator. The driving performance of 24 healthy volunteers under placebo and with 0.05% and 0.08% BACs was measured in a double-blind, randomized, crossover design. Trained investigators assessed the subjects’ driving performance and registered their driving errors. Various driving parameters that were recorded during the simulation were also analyzed. Generally, the participants performed worse on the test course (P < 0.05 for the investigators’ assessment) under the influence of alcohol. Consistent with the relevant literature, lane-keeping performance parameters were sensitive to the investigated BACs. There were significant differences between the alcohol and placebo conditions in most of the parameters analyzed. However, the total number of errors was the only parameter discriminating significantly between all three BAC conditions. In conclusion, data show that the present experimental setup is suitable for future psychopharmacological research. Thereby, for each drug to be investigated, we recommend to assess a profile of various parameters that address different levels of driving. On the basis of this performance profile, the total number of driving errors is recommended as the primary endpoint. However, this overall endpoint should be completed by a specifically sensitive parameter that is chosen depending on the effect known to be induced by the tested drug. PMID:25689289

  11. Magnetic compression laser driving circuit

    DOEpatents

    Ball, D.G.; Birx, D.; Cook, E.G.

    1993-01-05

    A magnetic compression laser driving circuit is disclosed. The magnetic compression laser driving circuit compresses voltage pulses in the range of 1.5 microseconds at 20 kilovolts of amplitude to pulses in the range of 40 nanoseconds and 60 kilovolts of amplitude. The magnetic compression laser driving circuit includes a multi-stage magnetic switch where the last stage includes a switch having at least two turns which has larger saturated inductance with less core material so that the efficiency of the circuit and hence the laser is increased.

  12. Magnetic compression laser driving circuit

    DOEpatents

    Ball, Don G.; Birx, Dan; Cook, Edward G.

    1993-01-01

    A magnetic compression laser driving circuit is disclosed. The magnetic compression laser driving circuit compresses voltage pulses in the range of 1.5 microseconds at 20 Kilovolts of amplitude to pulses in the range of 40 nanoseconds and 60 Kilovolts of amplitude. The magnetic compression laser driving circuit includes a multi-stage magnetic switch where the last stage includes a switch having at least two turns which has larger saturated inductance with less core material so that the efficiency of the circuit and hence the laser is increased.

  13. Driving Speed vs Fuel Efficiency.

    ERIC Educational Resources Information Center

    Vest, Floyd

    1980-01-01

    A mathematical treatment of the relationship between driving speed and fuel efficiency is presented. The material involves applications of exponentials, logarithms, and elementary calculus, and is intended to be enrichment material for secondary and lower college mathematics classes. (MP)

  14. Apparatus for forming drive belts

    NASA Technical Reports Server (NTRS)

    Topits, A., Jr. (Inventor)

    1974-01-01

    An apparatus for manufacturing belts, such as seamless belts, is provided, the apparatus has relatively movable rollers that are mounted in an oven. A belt blank, for example, of a thin polyester film, is rotated on the rollers as heat is applied. Four rollers, each mounted on a separate roller assembly, are movable along appropriate tracks while a fifth centrally located roller is stationary. A pair of dc motors are operatively connected to a speed reduction gear assembly to provide a pair of rotating drive shafts that extend into the oven. One rotating shaft drives all of the rollers through a rotational gear assembly while the other drive shaft is capable of positioning the movable rollers through respective rotating threaded shafts. Control devices are provided for controlling the motors while measuring devices are operatively connected to the positional drive shaft to indicate the position of the rollers.

  15. Novel driving scheme for FLCD

    NASA Astrophysics Data System (ADS)

    Wu, Jiin-chuan; Wang, Chi-Chang

    1996-03-01

    A frame change data driving scheme (FCDDS) for ferroelectric LCD(FLCD) of matrix- addressing is developed which uses only positive voltages for the row and column waveforms to achieve bipolar driving waveforms on the FLCD pixels. Thus the required supply voltage for the driver chips is half that of the conventional driving scheme. Each scan line is addressed in only twice the switching time (tau) (minimum response time of FLC) so that this scheme is suitable for high duty ratio panels. In order to meet this bistable electro-optic effect of FLCD and zero net dc voltage across each pixel of the liquid crystal, turning on and turning off pixels are done at different time slots and frame slots. This driving scheme can be easily implemented using commercially available STN LCD drivers plus a small external circuit or by making an ASIC which is a slight modification of the STN driver. Both methods are discussed.

  16. Distracted Driving Raises Crash Risk

    MedlinePlus

    ... Raises Crash Risk Video technology and in-vehicle sensors showed that distracted driving, especially among new drivers, ... whenever the cars were moving. A suite of sensors recorded acceleration, sudden braking or swerving, and other ...

  17. Dopaminergic Circuitry Underlying Mating Drive.

    PubMed

    Zhang, Stephen X; Rogulja, Dragana; Crickmore, Michael A

    2016-07-01

    We develop a new system for studying how innate drives are tuned to reflect current physiological needs and capacities, and how they affect sensory-motor processing. We demonstrate the existence of male mating drive in Drosophila, which is transiently and cumulatively reduced as reproductive capacity is depleted by copulations. Dopaminergic activity in the anterior of the superior medial protocerebrum (SMPa) is also transiently and cumulatively reduced in response to matings and serves as a functional neuronal correlate of mating drive. The dopamine signal is transmitted through the D1-like DopR2 receptor to P1 neurons, which also integrate sensory information relevant to the perception of females, and which project to courtship motor centers that initiate and maintain courtship behavior. Mating drive therefore converges with sensory information from the female at the point of transition to motor output, controlling the propensity of a sensory percept to trigger goal-directed behavior. PMID:27292538

  18. [Driving licenses and medical fitness].

    PubMed

    Sénéchal, Antoine; Manaouil, Cécile

    2015-09-01

    The Highway Code requires that any vehicle driver is constantly in a state and in position of performing easily and without delay all the maneuvers required of them. What about a vehicle driver suffering from a medical condition that does not allow it to meet the requirements of the Highway Code? While it may seem obvious that some diseases irrefutably presumed inability to drive, the regulatory authority had to answer a number of questions. What people should be subject to medical control of driving ability? What constitutes control? Who may be responsible for this control? The government, through a decree dated 17 July 2012 relating to medical control of driving ability, came to ask a new legal framework in this area meets all of these issues. In addition, a decree of 31 July 2012 came to specify the implementation rules for monitoring medical fitness to drive. PMID:25900083

  19. Dangers of Texting While Driving

    MedlinePlus

    ... laws Currently there is no national ban on texting or using a wireless phone while driving, but a number of states have passed laws banning texting or wireless phones or requiring hands-free use ...

  20. Direct drive field actuator motors

    DOEpatents

    Grahn, A.R.

    1998-03-10

    A positive-drive field actuator motor is described which includes a stator carrying at least one field actuator which changes in dimension responsive to application of an energy field, and at least one drive shoe movable by the dimensional changes of the field actuator to contact and move a rotor element with respect to the stator. Various embodiments of the motor are disclosed, and the rotor element may be moved linearly or arcuately. 62 figs.

  1. Mechanical drive for blood pump

    DOEpatents

    Bifano, N.J.; Pouchot, W.D.

    1975-07-29

    This patent relates to a highly efficient blood pump to be used as a replacement for a ventricle of the human heart to restore people disabled by heart disease. The mechanical drive of the present invention is designed to operate in conjunction with a thermoelectric converter power source. The mechanical drive system essentially converts the output of a rotary power into pulsatile motion so that the power demand from the thermoelectric converter remains essentially constant while the blood pump output is pulsed. (auth)

  2. Warp drive with zero expansion

    NASA Astrophysics Data System (ADS)

    Natário, José

    2002-03-01

    It is commonly believed that Alcubierre's warp drive works by contracting space in front of the warp bubble and expanding the space behind it. We show that this contraction/expansion is but a marginal consequence of the choice made by Alcubierre and explicitly construct a similar spacetime where no contraction/expansion occurs. Global and optical properties of warp-drive spacetimes are also discussed.

  3. Direct drive field actuator motors

    DOEpatents

    Grahn, Allen R.

    1998-01-01

    A positive-drive field actuator motor including a stator carrying at least one field actuator which changes in dimension responsive to application of an energy field, and at least one drive shoe movable by the dimensional changes of the field actuator to contact and move a rotor element with respect to the stator. Various embodiments of the motor are disclosed, and the rotor element may be moved linearly or arcuately.

  4. Low backlash direct drive actuator

    DOEpatents

    Kuklo, T.C.

    1994-10-25

    A low backlash direct drive actuator is described which comprises a motor such as a stepper motor having at least 200 steps per revolution; a two part hub assembly comprising a drive hub coaxially attached to the shaft of the motor and having a plurality of drive pins; a driven hub having a plurality of bores in one end thereof in alignment with the drive pins in the drive hub and a threaded shaft coaxially mounted in an opposite end of the driven hub; and a housing having a central bore therein into which are fitted the drive hub and driven hub, the housing having a motor mount on one end thereof to which is mounted the stepper motor, and a closed end portion with a threaded opening therein coaxial with the central bore in the housing and receiving therein the threaded shaft attached to the driven hub. Limit switches mounted to the housing cooperate with an enlarged lip on the driven hub to limit the lateral travel of the driven hub in the housing, which also acts to limit the lateral travel of the threaded shaft which functions as a lead screw. 10 figs.

  5. Low backlash direct drive actuator

    DOEpatents

    Kuklo, Thomas C.

    1994-01-01

    A low backlash direct drive actuator is described which comprises a motor such as a stepper motor having at least 200 steps per revolution; a two part hub assembly comprising a drive hub coaxially attached to the shaft of the motor and having a plurality of drive pins; a driven hub having a plurality of bores in one end thereof in alignment with the drive pins in the drive hub and a threaded shaft coaxially mounted in an opposite end of the driven hub; and a housing having a central bore therein into which are fitted the drive hub and driven hub, the housing having a motor mount on one end thereof to which is mounted the stepper motor, and a closed end portion with a threaded opening therein coaxial with the central bore in the housing and receiving therein the threaded shaft attached to the driven hub. Limit switches mounted to the housing cooperate with an enlarged lip on the driven hub to limit the lateral travel of the driven hub in the housing, which also acts to limit the lateral travel of the threaded shaft which functions as a lead screw.

  6. [Driving license and mellitus diabetes].

    PubMed

    Cimino, Luc; Deneufgermain, Alain; Lalau, Jean-Daniel

    2015-10-01

    For the "light group" as for the "heavy group" driving license cannot be issued or renewed to the applicant or drivers suffering from a condition that may constitute or lead to functional disability jeopardize road safety when driving a motor vehicle. The decision to issue or renew the license by the prefectural authority is taken on the advice of the departmental medical commission or a licensed physician. The decree of August 31, 2010 establishes the list of medical conditions incompatible with obtaining or maintaining the driving license or which may give rise to the issue of driving license limited validity. "Diabetes mellitus treated with medications that can cause hypoglycemia" belongs to this list. If the medical control of driving ability comes at the initiative of the user, the treating physician should firstly ensure the understanding of prescribed treatments that can cause hypoglycaemic episodes and other by informing diabetic person she must pass a medical examination of fitness to drive in a licensed physician. PMID:25956301

  7. Efficient Driving of Piezoelectric Transducers Using a Biaxial Driving Technique

    PubMed Central

    2015-01-01

    Efficient driving of piezoelectric materials is desirable when operating transducers for biomedical applications such as high intensity focused ultrasound (HIFU) or ultrasound imaging. More efficient operation reduces the electric power required to produce the desired bioeffect or contrast. Our preliminary work [Cole et al. Journal of Physics: Condensed Matter. 2014;26(13):135901.] suggested that driving transducers by applying orthogonal electric fields can significantly reduce the coercivity that opposes ferroelectric switching. We present here the experimental validation of this biaxial driving technique using piezoelectric ceramics typically used in HIFU. A set of narrow-band transducers was fabricated with two sets of electrodes placed in an orthogonal configuration (following the propagation and the lateral mode). The geometry of the ceramic was chosen to have a resonance frequency similar for the propagation and the lateral mode. The average (± s.d.) resonance frequency of the samples was 465.1 (± 1.5) kHz. Experiments were conducted in which each pair of electrodes was driven independently and measurements of effective acoustic power were obtained using the radiation force method. The efficiency (acoustic/electric power) of the biaxial driving method was compared to the results obtained when driving the ceramic using electrodes placed only in the pole direction. Our results indicate that the biaxial method increases efficiency from 50% to 125% relative to the using a single electric field. PMID:26418550

  8. Efficient Driving of Piezoelectric Transducers Using a Biaxial Driving Technique.

    PubMed

    Pichardo, Samuel; Silva, Rafael R C; Rubel, Oleg; Curiel, Laura

    2015-01-01

    Efficient driving of piezoelectric materials is desirable when operating transducers for biomedical applications such as high intensity focused ultrasound (HIFU) or ultrasound imaging. More efficient operation reduces the electric power required to produce the desired bioeffect or contrast. Our preliminary work [Cole et al. Journal of Physics: Condensed Matter. 2014;26(13):135901.] suggested that driving transducers by applying orthogonal electric fields can significantly reduce the coercivity that opposes ferroelectric switching. We present here the experimental validation of this biaxial driving technique using piezoelectric ceramics typically used in HIFU. A set of narrow-band transducers was fabricated with two sets of electrodes placed in an orthogonal configuration (following the propagation and the lateral mode). The geometry of the ceramic was chosen to have a resonance frequency similar for the propagation and the lateral mode. The average (± s.d.) resonance frequency of the samples was 465.1 (± 1.5) kHz. Experiments were conducted in which each pair of electrodes was driven independently and measurements of effective acoustic power were obtained using the radiation force method. The efficiency (acoustic/electric power) of the biaxial driving method was compared to the results obtained when driving the ceramic using electrodes placed only in the pole direction. Our results indicate that the biaxial method increases efficiency from 50% to 125% relative to the using a single electric field. PMID:26418550

  9. Driving performance and driver discomfort in an elevated and standard driving position during a driving simulation.

    PubMed

    Smith, Jordan; Mansfield, Neil; Gyi, Diane; Pagett, Mark; Bateman, Bob

    2015-07-01

    The primary purposes of a vehicle driver's seat, is to allow them to complete the driving task comfortably and safely. Within each class of vehicle (e.g. passenger, commercial, industrial, agricultural), there is an expected driving position to which a vehicle cabin is designed. This paper reports a study that compares two driving positions, in relation to Light Commercial Vehicles (LCVs), in terms of driver performance and driver discomfort. In the 'elevated' driving position, the seat is higher than usually used in road vehicles; this is compared to a standard driving position replicating the layout for a commercially available vehicle. It is shown that for a sample of 12 drivers, the elevated position did not, in general, show more discomfort than the standard position over a 60 min driving simulation, although discomfort increased with duration. There were no adverse effects shown for emergency stop reaction time or for driver headway for the elevated posture compared to the standard posture. The only body part that showed greater discomfort for the elevated posture compared to the standard posture was the right ankle. A second experiment confirmed that for 12 subjects, a higher pedal stiffness eliminated the ankle discomfort problem. PMID:25766419

  10. Optimized Direct-Drive Uniformity

    NASA Astrophysics Data System (ADS)

    Marshall, F. J.; McKenty, P. W.; Kessler, T. J.; Forties, R.; Kelly, J. A.; Waxer, L. J.

    2002-11-01

    The means of optimizing direct-drive illumination uniformity in laser fusion implosions will be discussed. To provide the most-uniform drive, the target must be illuminated by smooth single beams, symmetrically placed on target, with the optimum beam shape. On the 60-beam OMEGA laser system these near-optimum, direct-drive illumination conditions have been achieved by smoothing each beam with 1-THz smoothing by spectral dispersion (SSD), which incorporates distributed phase plates (DPP's) and polarization smoothing (PS), and by the modified soccer-ball orientation of the beams. The current beam smoothing provides for unprecedented levels of direct-drive uniformity, approaching σ_rms ˜ 2% up to ℓ = 200 after ˜300 ps. The sensitivity of the illumination to beam shape has been studied, and a new set of DPP's have been designed and are being built to further optimize the uniformity on OMEGA. Also, the sensitivity of the drive to beam balance, beam pointing, and target positioning has been studied both by calculation and by performing target implosions allowing quantitative limits to be placed on all contributors. This work was supported by the U.S. Department of Energy Office of Inertial Confinement Fusion under Cooperative Agreement No. DE-FC03-92SF19460.

  11. Virtual Rover Drives Toward Rock

    NASA Technical Reports Server (NTRS)

    2004-01-01

    This image shows a screenshot from the software used by engineers to test and drive the Mars Exploration Rover Spirit. The software simulates the rover's movements across the martian terrain, helping to plot a safe course. Here, engineers simulated Spirit's first post-egress drive on Mars Sunday. The 3-meter (10-foot) drive totaled approximately 30 minutes, including time to stop and take images. The rover drove toward its first rock target, a mountain-shaped rock called Adirondack. The blue line denotes the path of the rover's 'belly button,' as engineers like to call it, as the rover drove toward Adirondack. The virtual 3-D world around the rover was built from images taken by Spirit's stereo navigation cameras. Regions for which the rover has not yet acquired 3-D data are represented in beige.

  12. Drive: Theory and Construct Validation

    PubMed Central

    Petrides, K. V.

    2016-01-01

    This article explicates the theory of drive and describes the development and validation of two measures. A representative set of drive facets was derived from an extensive corpus of human attributes (Study 1). Operationalised using an International Personality Item Pool version (the Drive:IPIP), a three-factor model was extracted from the facets in two samples and confirmed on a third sample (Study 2). The multi-item IPIP measure showed congruence with a short form, based on single-item ratings of the facets, and both demonstrated cross-informant reliability. Evidence also supported the measures’ convergent, discriminant, concurrent, and incremental validity (Study 3). Based on very promising findings, the authors hope to initiate a stream of research in what is argued to be a rather neglected niche of individual differences and non-cognitive assessment. PMID:27409773

  13. Drive: Theory and Construct Validation.

    PubMed

    Siegling, Alex B; Petrides, K V

    2016-01-01

    This article explicates the theory of drive and describes the development and validation of two measures. A representative set of drive facets was derived from an extensive corpus of human attributes (Study 1). Operationalised using an International Personality Item Pool version (the Drive:IPIP), a three-factor model was extracted from the facets in two samples and confirmed on a third sample (Study 2). The multi-item IPIP measure showed congruence with a short form, based on single-item ratings of the facets, and both demonstrated cross-informant reliability. Evidence also supported the measures' convergent, discriminant, concurrent, and incremental validity (Study 3). Based on very promising findings, the authors hope to initiate a stream of research in what is argued to be a rather neglected niche of individual differences and non-cognitive assessment. PMID:27409773

  14. MULTIPLE DIFFERENTIAL ROTARY MECHANICAL DRIVE

    DOEpatents

    Smits, R.G.

    1964-01-28

    This patent relates to a mechanism suitable for such applications as driving two spaced-apart spools which carry a roll film strip under conditions where the film movement must be rapidly started, stopped, and reversed while maintaining a constant tension on the film. The basic drive is provided by a variable speed, reversible rnotor coupled to both spools through a first differential mechanism and driving both spools in the same direction. A second motor, providing a constant torque, is connected to the two spools through a second differential mechanism and is coupled to impart torque to one spool in a first direction anid to the other spool in the reverse direction thus applying a constant tension to the film passing over the two spools irrespective of the speed or direction of rotation thereof. (AEC)

  15. Rover Takes a Sunday Drive

    NASA Technical Reports Server (NTRS)

    2004-01-01

    This animation, made with images from the Mars Exploration Rover Spirit hazard-identification camera, shows the rover's perspective of its first post-egress drive on Mars Sunday. Engineers drove Spirit approximately 3 meters (10 feet) toward its first rock target, a football-sized, mountain-shaped rock called Adirondack. The drive took approximately 30 minutes to complete, including time stopped to take images. Spirit first made a series of arcing turns totaling approximately 1 meter (3 feet). It then turned in place and made a series of short, straightforward movements totaling approximately 2 meters (6.5 feet).

  16. Future hard disk drive systems

    NASA Astrophysics Data System (ADS)

    Wood, Roger

    2009-03-01

    This paper briefly reviews the evolution of today's hard disk drive with the additional intention of orienting the reader to the overall mechanical and electrical architecture. The modern hard disk drive is a miracle of storage capacity and function together with remarkable economy of design. This paper presents a personal view of future customer requirements and the anticipated design evolution of the components. There are critical decisions and great challenges ahead for the key technologies of heads, media, head-disk interface, mechanics, and electronics.

  17. The onset of driving phobias.

    PubMed

    Munjack, D J

    1984-12-01

    Thirty driving phobics who called the Psychiatry Outpatient Phobia Clinic (25 females and five males) were given a 20-min semi-standardized telephone interview during which they were asked about the circumstances of the onset of their driving fears. Twelve (40%) reported that their fears were precipitated by a panic attack on the freeway; six (20%) by a collision; and three (10%) by other frightening experiences in automobiles. Four (13.3%) related the onset to family stress or upheaval. Other modes of onset also occurred. The implications of these findings are discussed in terms of existing theories of fear acquisition and treatment approaches. PMID:6526942

  18. Driving and Age-Related Macular Degeneration

    ERIC Educational Resources Information Center

    Owsley, Cynthia; McGwin, Gerald, Jr.

    2008-01-01

    This article reviews the research literature on driving and age-related macular degeneration, which is motivated by the link between driving and the quality of life of older adults and their increased collision rate. It addresses the risk of crashes, driving performance, driving difficulty, self-regulation, and interventions to enhance, safety,…

  19. Basic principles of variable speed drives

    NASA Technical Reports Server (NTRS)

    Loewenthal, S. H.

    1973-01-01

    An understanding of the principles which govern variable speed drive operation is discussed for successful drive application. The fundamental factors of torque, speed ratio, and power as they relate to drive selection are discussed. The basic types of variable speed drives, their operating characteristics and their applications are also presented.

  20. Driving and Age-Related Macular Degeneration

    PubMed Central

    Owsley, Cynthia; McGwin, Gerald

    2009-01-01

    This article reviews the research literature on driving and age-related macular degeneration, which is motivated by the link between driving and the quality of life of older adults and their increased collision rate. It addresses the risk of crashes, driving performance, driving difficulty, self-regulation, and interventions to enhance, safety, and considers directions for future research. PMID:20046818

  1. Electronic 4-wheel drive control device

    NASA Technical Reports Server (NTRS)

    Hayato, S.; Takanori, S.; Shigeru, H.; Tatsunori, S.

    1984-01-01

    The internal rotation torque generated during operation of a 4-wheel drive vehicle is reduced using a control device whose clutch is attached to one part of the rear-wheel drive shaft. One torque sensor senses the drive torque associated with the rear wheel drive shaft. A second sensor senses the drive torque associated with the front wheel drive shaft. Revolution count sensors sense the revolutions of each drive shaft. By means of a microcomputer, the engagement of the clutch is changed to insure that the ratio of the torque sensors remains constant.

  2. Drive reconfiguration mechanism for tracked robotic vehicle

    DOEpatents

    Willis, W. David

    2000-01-01

    Drive reconfiguration apparatus for changing the configuration of a drive unit with respect to a vehicle body may comprise a guide system associated with the vehicle body and the drive unit which allows the drive unit to rotate about a center of rotation that is located at about a point where the drive unit contacts the surface being traversed. An actuator mounted to the vehicle body and connected to the drive unit rotates the drive unit about the center of rotation between a first position and a second position.

  3. Promising Electric Aircraft Drive Systems

    NASA Technical Reports Server (NTRS)

    Dudley, Michael R.

    2010-01-01

    An overview of electric aircraft propulsion technology performance thresholds for key power system components is presented. A weight comparison of electric drive systems with equivalent total delivered energy is made to help identify component performance requirements, and promising research and development opportunities.

  4. Virtual Rewards for Driving Green

    ERIC Educational Resources Information Center

    Pritchard, Josh

    2010-01-01

    Carbon dioxide from automobiles is a major contributor to global climate change. In "Virtual Rewards for Driving Green," Josh Pritchard proposes a computer application that will enable fuel-efficient drivers to earn "green" dollars with which to buy digital merchandise on the Web. Can getting items that exist only in cyberspace actually change a…

  5. Anomalous-viscosity current drive

    DOEpatents

    Stix, T.H.; Ono, M.

    1986-04-25

    The present invention relates to a method and apparatus for maintaining a steady-state current for magnetically confining the plasma in a toroidal magnetic confinement device using anomalous viscosity current drive. A second aspect of this invention relates to an apparatus and method for the start-up of a magnetically confined toroidal plasma.

  6. Test-Driving Their Passions

    ERIC Educational Resources Information Center

    Davis, Noah

    2007-01-01

    This article describes how the Watson fellowships give recipients an opportunity to test-drive their passions and see if they could lead to a career path. Over the last 40 years, the Thomas J. Watson Foundation has awarded $29 million in fellowships to seniors graduating from 50 mostly top-tier colleges with fewer than 3,000 students. In 2007, 50…

  7. Driving and working with syncope.

    PubMed

    Barbic, Franca; Casazza, Giovanni; Zamunér, Antonio Roberto; Costantino, Giorgio; Orlandi, Mauro; Dipaola, Franca; Capitanio, Chiara; Achenza, Sara; Sheldon, Robert; Furlan, Raffaello

    2014-09-01

    Syncope is usually addressed in the Emergency Department (ED) by the doctor in charge of the clinical picture, i.e. the patient's risk is stratified, a diagnostic work-up is done and a prognosis is set. Patients are ultimately admitted to hospital or discharged. However, other aspects related to syncope may deeply affect their daily lives. These include how and when to return to work and to driving, the feelings about a recent loss of consciousness, and the potential relapse of syncope. This is particularly significant if the work setting is intrinsically hazardous. These patients need adequate clinical and psychological support. For patients with syncope, two main parameters should be considered regarding returning to work and to driving. The first is to evaluate the risk of syncope recurrence and the second is to consider the expected harm if syncope does indeed occur during these activities. In the present paper we detail the problem of driving (including professional driving) and work after syncope. We propose a new quantitative model that will guide the physician in stratifying the risk for patients who have had a previous syncope event. The new model considers the syncope recurrence risk, the job task duration, and features that facilitate a syncope during work. On the basis of these variables, the global risk index for a worker is calculated. Following appropriate validation, this method might help ED and occupational physicians in their decision-making process with the goal of safely readmitting syncope patients to the workplace. PMID:24881013

  8. Driving Competencies for the Elderly.

    ERIC Educational Resources Information Center

    New York State Education Dept., Albany. Bureau of Continuing Education Curriculum Development.

    Designed for use by directors of senior citizen groups, continuing education directors, and driver education instructors, this manual suggests a course outline, subject content, and instructional materials for effectively teaching a refresher driving course. The first seven topics represent the basic content and none should be omitted: orientation…

  9. Hydromechanical transmission with hydrodynamic drive

    DOEpatents

    Orshansky, Jr., deceased, Elias; Weseloh, William E.

    1979-01-01

    This transmission has a first planetary gear assembly having first input means connected to an input shaft, first output means, and first reaction means, and a second planetary gear assembly having second input means connected to the first input means, second output means, and second reaction means connected directly to the first reaction means by a reaction shaft. First clutch means, when engaged, connect the first output means to an output shaft in a high driving range. A hydrodynamic drive is used; for example, a torque converter, which may or may not have a stationary case, has a pump connected to the second output means, a stator grounded by an overrunning clutch to the case, and a turbine connected to an output member, and may be used in a starting phase. Alternatively, a fluid coupling or other type of hydrodynamic drive may be used. Second clutch means, when engaged, for connecting the output member to the output shaft in a low driving range. A variable-displacement hydraulic unit is mechanically connected to the input shaft, and a fixed-displacement hydraulic unit is mechanically connected to the reaction shaft. The hydraulic units are hydraulically connected together so that when one operates as a pump the other acts as a motor, and vice versa. Both clutch means are connected to the output shaft through a forward-reverse shift arrangement. It is possible to lock out the torque converter after the starting phase is over.

  10. Cannabis Effects on Driving Skills

    PubMed Central

    Hartman, Rebecca L.; Huestis, Marilyn A.

    2013-01-01

    BACKGROUND Cannabis is the most prevalent illicit drug identified in impaired drivers. The effects of cannabis on driving continue to be debated, making prosecution and legislation difficult. Historically, delays in sample collection, evaluating the inactive Δ9-tetrahydrocannabinol (THC) metabolite 11-nor-9-carboxy-THC, and polydrug use have complicated epidemiologic evaluations of driver impairment after cannabis use. CONTENT We review and evaluate the current literature on cannabis’ effects on driving, highlighting the epidemiologic and experimental data. Epidemiologic data show that the risk of involvement in a motor vehicle accident (MVA) increases approximately 2-fold after cannabis smoking. The adjusted risk of driver culpability also increases substantially, particularly with increased blood THC concentrations. Studies that have used urine as the biological matrix have not shown an association between cannabis and crash risk. Experimental data show that drivers attempt to compensate by driving more slowly after smoking cannabis, but control deteriorates with increasing task complexity. Cannabis smoking increases lane weaving and impaired cognitive function. Critical-tracking tests, reaction times, divided-attention tasks, and lane-position variability all show cannabis-induced impairment. Despite purported tolerance in frequent smokers, complex tasks still show impairment. Combining cannabis with alcohol enhances impairment, especially lane weaving. SUMMARY Differences in study designs frequently account for inconsistencies in results between studies. Participant-selection bias and confounding factors attenuate ostensible cannabis effects, but the association with MVA often retains significance. Evidence suggests recent smoking and/or blood THC concentrations 2–5 ng/mL are associated with substantial driving impairment, particularly in occasional smokers. Future cannabis-and-driving research should emphasize challenging tasks, such as divided attention

  11. Neural substrates of driving behaviour

    PubMed Central

    Spiers, Hugo J.; Maguire, Eleanor A.

    2007-01-01

    Driving a vehicle is an indispensable daily behaviour for many people, yet we know little about how it is supported by the brain. Given that driving in the real world involves the engagement of many cognitive systems that rapidly change to meet varying environmental demands, identifying its neural basis presents substantial problems. By employing a unique combination of functional magnetic resonance imaging (fMRI), an accurate interactive virtual simulation of a bustling central London (UK) and a retrospective verbal report protocol, we surmounted these difficulties. We identified different events that characterise the driving process on a second by second basis and the brain regions that underlie them. Prepared actions such as starting, turning, reversing and stopping were associated with a common network comprised of premotor, parietal and cerebellar regions. Each prepared action also recruited additional brain areas. We also observed unexpected hazardous events such as swerving and avoiding collisions that were associated with activation of lateral occipital and parietal regions, insula, as well as a more posterior region in the medial premotor cortex than prepared actions. By contrast, planning future actions and monitoring fellow road users were associated with activity in superior parietal, lateral occipital cortices and the cerebellum. The anterior pre-SMA was also recruited during action planning. The right lateral prefrontal cortex was specifically engaged during the processing of road traffic rules. By systematically characterising the brain dynamics underlying naturalistic driving behaviour in a real city, our findings may have implications for how driving competence is considered in the context of neurological damage. PMID:17412611

  12. Driving with Hemianopia, I: Detection Performance in a Driving Simulator

    PubMed Central

    Bowers, Alex R.; Mandel, Aaron J.; Goldstein, Robert B.; Peli, Eli

    2009-01-01

    Purpose This study was designed to examine the effect of homonymous hemianopia (HH) on detection of pedestrian figures in multiple realistic and hazardous situations within the controlled environment of a driving simulator. Methods Twelve people with complete HH and without visual neglect or cognitive decline and 12 matched (age, sex, and years of driving experience) normally sighted (NV) drivers participated. They drove predetermined city and rural highway routes (total, 120 minutes) during which pedestrian figures appeared at random intervals along the roadway (R-Peds; n = 144) and at intersections (I-Peds; n = 10). Detection rates and response times were derived from participant horn presses. Results Drivers with HH exhibited significantly (P < 0.001) lower R-Ped detection rates on the blind side than did NV drivers (range, 6%–100%). Detection of I-Peds on the blind side was also poor (8%–55%). Age and blind-side detection rates correlated negatively (Spearman r = −0.71, P = 0.009). Although blind-side response times of drivers with HH were significantly (P < 0.001) longer than those of NV drivers, most were within a commonly used 2.5-second guideline. Conclusions Most participants with HH had blind-side detection rates that seem incompatible with safe driving; however, the relationship of our simulator detection performance measures to on-road performance has yet to be established. In determining fitness to drive for people with HH, the results underscore the importance of individualized assessments including evaluations of blind-side hazard detection. PMID:19608541

  13. [Driving fitness/driving capacity of patients treated with methadone].

    PubMed

    Hauri-Bionda, R; Bär, W; Friedrich-Koch, A

    1998-10-10

    To answer the question whether or not therapeutic methadone doses significantly reduce traffic-related performance of drivers on medically supervised methadone programmes, 34 methadone substitution patients, all of them volunteers, were subjected to a test series: the focus of the study was a psychophysical test battery consisting of 10 individual performance tests to assess essential functions with regard to driving ability, such as concentration, attention, reaction capability, memory, perception and sensorimotor coordination. In evaluating the results of the psychophysical tests, multiple drug use and subjective methadone influence at the time of the examination were taken into consideration but current methadone blood level was neglected. The results were compared to those of a control group. The methadone group (n = 34) consisted of 25 men and 9 women aged between 18 and 38. At the time of the study, the majority of the test persons (29) were on low dosage methadone maintenance (up to 60 mg/day). In the urine samples of approximately 2/3 of the test persons, evidence was found for multiple drug use together with other psychotropic substances, the most frequent (14) being cannabis metabolites. Referring to their driving practices, a mere 4 out of 29 drivers had not committed any driving offences. A comparison of the psychophysical performance of the whole methadone group (n = 34) with a control group demonstrated that the methadone substitution patients achieved rather lower results in almost all variables. These performance deficits were particularly conspicuous in sustained attention, sensorimotor coordination and reaction capability. 12 "methadone only" participants, i.e. methadone probands without any additional consumption of psychotropic substances showed-partly considerably-better performance than the methadone group as a whole and also achieved normal results in relation to the test norm. Nevertheless, once again, results tended to be of lower level in

  14. Magnetically Coupled Adjustable Speed Drive Systems

    SciTech Connect

    Chvala, William D.; Winiarski, David W.

    2002-08-18

    Adjustable speed drive (ASD) technologies have the ability to precisely control motor sytems output and produce a numbr of benefits including energy and demand savings. This report examines the performance and cost effectiveness of a specific class of ASDs called magnetically-coupled adjustable speed drives (MC-ASD) which use the strength of a magnetic field to control the amount of torque transferred between motor and drive shaft. The MagnaDrive Adjustable Speed Coupling System uses fixed rare-earth magnets and varies the distance between rotating plates in the assembly. the PAYBACK Variable Speed Drive uses an electromagnet to control the speed of the drive

  15. Warp Drive - A New Approach

    NASA Astrophysics Data System (ADS)

    Obousy, R. K.; Cleaver, G.

    Certain classes of higher dimensional models suggest that the Casimir Effect is a candidate for the cosmological constant. In this paper we demonstrate that a sufficiently advanced civilization could, in principal, manipulate the radius of the extra dimension to locally adjust the value of the cosmological constant. This adjustment could be tuned to generate an expansion/ contraction of spacetime around a spacecraft creating an exotic form of field-propulsion. Due to the fact that spacetime expansion itself is not restricted by relativity, a faster-than-light `warp drive' could be created. Calculations of the energy requirements of such a drive are performed and an `ultimate' speed limit, based on the Planckian limits on the size of the extra dimensions is found.

  16. Conditional dynamics driving financial markets

    NASA Astrophysics Data System (ADS)

    Boguñá, M.; Masoliver, J.

    2004-08-01

    We revisit the problem of daily correlations in speculative prices and report empirical evidences on the existence of what we term a conditional or dual dynamics driving the evolution of financial assets. This dynamics is detected in several markets around the world and for different historical periods. In particular, we have analyzed the DJIA database from 1900 to 2002 as well as 65 companies trading in the LIFFE market of futures and 12 of the major European and American treasury bonds. In all cases, we find a twofold dynamics driving the financial evolution depending on whether the previous price went up or down. We conjecture that this effect is universal and intrinsic to all markets.

  17. [Daytime sleepiness and driving behaviour].

    PubMed

    Mathis, Johannes; Schreier, David

    2014-11-01

    Daytime sleepiness is reported by 10-15 % within the general population of industrialised countries. According to federal statistics in Switzerland, only ~1.5 % of motor vehicle crashes are caused by excessive daytime sleepiness, which is in sharp contrast to the scientific literature, indicating a figure of 10 to 30 %. This is most likely related to the difficulty to detect the underlying sleepiness by police officers and their low awareness of this cause in case of car accidents. As a consequence of this massively reduced figure, the real problem is underestimated and countermeasures as well as examinations of drivers at fault are inadequately realised in our country. The risk factors for sleepiness induced accidents are young age, male sex, driving at night or long distances and a number of diseases or sedative drugs. The most prevalent cause of sleepiness related accidents is the behaviourally induced sleep insufficiency syndrome or irregular sleep-wake rhythm in otherwise healthy subjects. Disease related sleepiness which may also cause motor vehicle accidents must be managed by physicians. In the diagnostic work-up sedative drugs, medical causes of sleepiness or tiredness as well as primary sleep-wake disorders must be considered. The most important duty of the treating physician, in addition to correct diagnosis and treatment, is to inform the affected patient of his or her responsibility not to drive while sleepy, about the theoretical legal consequences in case of an accident and about efficient countermeasures such as stopping in a rest area, drinking coffee, and taking a nap. For legal reasons, this information must be written in the patient's notes. Professional drivers suffering from sleep apnoea syndrome or other disorders with excessive daytime sleepiness, or private drivers who have already experienced a sleepiness induced accident, should be referred to a sleep-wake-centre for objective assessment of their sleepiness in the maintenance of

  18. Electric vehicle drive train components

    SciTech Connect

    Silver, F.

    1994-12-31

    Power Control Systems has developed a family of electric vehicle drive systems that range from 65 horsepower through 300 horse power. These propulsion systems support vehicle applications ranging from light cars and pickups to buses and trucks weighing as much as 40,000 lbs (18,400 kg). These robust systems are designed specifically for automotive applications including safety, electromagnetic emissions, and environment ruggedness. Dolphin Drive Systems are very flexible. Their inverter controllers are programmable and can be provided as stand alone components matched to customer specified motors. A selection of pre-calibrated systems including motor and inverter/controller can be provided. Accessory tools are also available for customer self programming. Dolphin Drive Systems provide precision control of AC induction motors providing excellent torque-speed performance usually eliminating the need for multistage transmissions. In addition, they are very efficient over a wide speed/torque range. This provides for excellent power management over a variety of continuous speed and stop and go applications.

  19. Warp drive space-time

    NASA Astrophysics Data System (ADS)

    González-Díaz, Pedro F.

    2000-08-01

    In this paper the problem of the quantum stability of the two-dimensional warp drive spacetime moving with an apparent faster than light velocity is considered. We regard as a maximum extension beyond the event horizon of that spacetime its embedding in a three-dimensional Minkowskian space with the topology of the corresponding Misner space. It is obtained that the interior of the spaceship bubble becomes then a multiply connected nonchronal region with closed spacelike curves and that the most natural vacuum allows quantum fluctuations which do not induce any divergent behavior of the renormalized stress-energy tensor, even on the event (Cauchy) chronology horizon. In such a case, the horizon encloses closed timelike curves only at scales close to the Planck length, so that the warp drive satisfies Ford's negative energy-time inequality. Also found is a connection between the superluminal two-dimensional warp drive space and two-dimensional gravitational kinks. This connection allows us to generalize the considered Alcubierre metric to a standard, nonstatic metric which is only describable on two different coordinate patches.

  20. 30 CFR 75.1727 - Drive belts.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Drive belts. 75.1727 Section 75.1727 Mineral... SAFETY STANDARDS-UNDERGROUND COAL MINES Miscellaneous § 75.1727 Drive belts. (a) Drive belts shall not be shifted while in motion unless the machines are provided with mechanical shifters. (b) Belt dressing...

  1. 30 CFR 75.1727 - Drive belts.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Drive belts. 75.1727 Section 75.1727 Mineral... SAFETY STANDARDS-UNDERGROUND COAL MINES Miscellaneous § 75.1727 Drive belts. (a) Drive belts shall not be shifted while in motion unless the machines are provided with mechanical shifters. (b) Belt dressing...

  2. 30 CFR 77.406 - Drive belts.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Drive belts. 77.406 Section 77.406 Mineral... Mechanical Equipment § 77.406 Drive belts. (a) Drive belts shall not be shifted while in motion unless the machines are provided with mechanical shifters. (b) Belt dressing shall not be applied while belts are...

  3. 30 CFR 77.406 - Drive belts.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 30 Mineral Resources 1 2012-07-01 2012-07-01 false Drive belts. 77.406 Section 77.406 Mineral... Mechanical Equipment § 77.406 Drive belts. (a) Drive belts shall not be shifted while in motion unless the machines are provided with mechanical shifters. (b) Belt dressing shall not be applied while belts are...

  4. 30 CFR 77.406 - Drive belts.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Drive belts. 77.406 Section 77.406 Mineral... Mechanical Equipment § 77.406 Drive belts. (a) Drive belts shall not be shifted while in motion unless the machines are provided with mechanical shifters. (b) Belt dressing shall not be applied while belts are...

  5. 30 CFR 75.1727 - Drive belts.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Drive belts. 75.1727 Section 75.1727 Mineral... SAFETY STANDARDS-UNDERGROUND COAL MINES Miscellaneous § 75.1727 Drive belts. (a) Drive belts shall not be shifted while in motion unless the machines are provided with mechanical shifters. (b) Belt dressing...

  6. 30 CFR 77.406 - Drive belts.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 30 Mineral Resources 1 2011-07-01 2011-07-01 false Drive belts. 77.406 Section 77.406 Mineral... Mechanical Equipment § 77.406 Drive belts. (a) Drive belts shall not be shifted while in motion unless the machines are provided with mechanical shifters. (b) Belt dressing shall not be applied while belts are...

  7. 30 CFR 75.1727 - Drive belts.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 30 Mineral Resources 1 2013-07-01 2013-07-01 false Drive belts. 75.1727 Section 75.1727 Mineral... SAFETY STANDARDS-UNDERGROUND COAL MINES Miscellaneous § 75.1727 Drive belts. (a) Drive belts shall not be shifted while in motion unless the machines are provided with mechanical shifters. (b) Belt dressing...

  8. 30 CFR 75.1727 - Drive belts.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 30 Mineral Resources 1 2014-07-01 2014-07-01 false Drive belts. 75.1727 Section 75.1727 Mineral... SAFETY STANDARDS-UNDERGROUND COAL MINES Miscellaneous § 75.1727 Drive belts. (a) Drive belts shall not be shifted while in motion unless the machines are provided with mechanical shifters. (b) Belt dressing...

  9. 30 CFR 77.406 - Drive belts.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Drive belts. 77.406 Section 77.406 Mineral... Mechanical Equipment § 77.406 Drive belts. (a) Drive belts shall not be shifted while in motion unless the machines are provided with mechanical shifters. (b) Belt dressing shall not be applied while belts are...

  10. Driving trajectories in chaotic scattering.

    PubMed

    Macau, Elbert E N; Caldas, Iberê L

    2002-02-01

    In this work we introduce a general approach for targeting in chaotic scattering that can be used to find a transfer trajectory between any two points located inside the scattering region. We show that this method can be used in association with a control of chaos strategy to drive around and keep a particle inside the scattering region. As an illustration of how powerful this approach is, we use it in a case of practical interest in celestial mechanics in which it is desired to control the evolution of two satellites that evolve around a large central body. PMID:11863640

  11. Computer-Aided Remote Driving

    NASA Technical Reports Server (NTRS)

    Wilcox, Brian H.

    1994-01-01

    System for remote control of robotic land vehicle requires only small radio-communication bandwidth. Twin video cameras on vehicle create stereoscopic images. Operator views cross-polarized images on two cathode-ray tubes through correspondingly polarized spectacles. By use of cursor on frozen image, remote operator designates path. Vehicle proceeds to follow path, by use of limited degree of autonomous control to cope with unexpected conditions. System concept, called "computer-aided remote driving" (CARD), potentially useful in exploration of other planets, military surveillance, firefighting, and clean-up of hazardous materials.

  12. Fluid cooled vehicle drive module

    DOEpatents

    Beihoff, Bruce C.; Radosevich, Lawrence D.; Meyer, Andreas A.; Gollhardt, Neil; Kannenberg, Daniel G.

    2005-11-15

    An electric vehicle drive includes a support may receive one or more power electronic circuits. The support may aid in removing heat from the circuits through fluid circulating through the support. The support, in conjunction with other packaging features may form a shield from both external EM/RFI and from interference generated by operation of the power electronic circuits. Features may be provided to permit and enhance connection of the circuitry to external circuitry, such as improved terminal configurations. Modular units may be assembled that may be coupled to electronic circuitry via plug-in arrangements or through interface with a backplane or similar mounting and interconnecting structures.

  13. Efficient alternatives for electric drives

    SciTech Connect

    Comnes, G.A.; Barnes, R.W.

    1987-11-01

    This analysis of industrial electric motors describes the current motor stock, its energy use and operating characteristics, and innovations that could change current use patterns. It provides calculations characterizing the economic attractiveness of several existing and potential options. One attractive option given particular attention is the adjustable-speed drive which can replace throttles or valves for many pumping operations. A major conclusion is that, throughout industry, options that are both energy-saving and economically attractive appear to penetrate markets more slowly than would be socially optimal. The final section examines characteristics of industry that may contribute to slow market penetration. 29 refs., 14 figs., 14 tabs.

  14. Voight variable speed drive. [for windpowered generator

    NASA Technical Reports Server (NTRS)

    Tompkin, J.

    1973-01-01

    The variable speed drive transmission is mounted within the gondola and connected with the wind turbine blades and the hub. This unit is designed for the production of ac power. The turbine turns by means of the variable speed drive and a set of synchronous three phase generators. This motion is controlled automatically by two wind rosettes in such a way that the wind turbine always opposes the wind direction. The Voight variable speed drive is a mechanical variable positive drive gear transmission. It has an unlimited power and torque transmission, a constant ratio with high degree of accuracy, a speed variation over a wide range, and a nonslip drive.

  15. Perceptual and Cognitive Impairments and Driving

    PubMed Central

    Korner-Bitensky, Nicol; Coopersmith, Henry; Mayo, Nancy; Leblanc, Ginette; Kaizer, Franceen

    1990-01-01

    Perceptual and cognitive disorders that frequently accompany stroke and head injury influence an individual's ability to drive a motor vehicle. Canadian physicians are legally responsible for identifying patients who are potentially unsafe to drive and, if they fail to do so, may be held liable in a civil action suit. The authors review the guidelines for physicians evaluating a patient's fitness to drive after brain injury. They also examine the actions a physician should take when a patient with perceptual and cognitive problems wants to drive. Ultimately, by taking these actions, physicians will help to prevent driving accidents. PMID:21234047

  16. 32 CFR 634.14 - Restoration of driving privileges upon acquittal of intoxicated driving.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... 32 National Defense 4 2012-07-01 2011-07-01 true Restoration of driving privileges upon acquittal of intoxicated driving. 634.14 Section 634.14 National Defense Department of Defense (Continued... SUPERVISION Driving Privileges § 634.14 Restoration of driving privileges upon acquittal of...

  17. 32 CFR 634.14 - Restoration of driving privileges upon acquittal of intoxicated driving.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... 32 National Defense 4 2010-07-01 2010-07-01 true Restoration of driving privileges upon acquittal of intoxicated driving. 634.14 Section 634.14 National Defense Department of Defense (Continued... SUPERVISION Driving Privileges § 634.14 Restoration of driving privileges upon acquittal of...

  18. 32 CFR 634.14 - Restoration of driving privileges upon acquittal of intoxicated driving.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 32 National Defense 4 2013-07-01 2013-07-01 false Restoration of driving privileges upon acquittal of intoxicated driving. 634.14 Section 634.14 National Defense Department of Defense (Continued... SUPERVISION Driving Privileges § 634.14 Restoration of driving privileges upon acquittal of...

  19. 32 CFR 634.14 - Restoration of driving privileges upon acquittal of intoxicated driving.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... 32 National Defense 4 2011-07-01 2011-07-01 false Restoration of driving privileges upon acquittal of intoxicated driving. 634.14 Section 634.14 National Defense Department of Defense (Continued... SUPERVISION Driving Privileges § 634.14 Restoration of driving privileges upon acquittal of...

  20. 32 CFR 634.14 - Restoration of driving privileges upon acquittal of intoxicated driving.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... 32 National Defense 4 2014-07-01 2013-07-01 true Restoration of driving privileges upon acquittal of intoxicated driving. 634.14 Section 634.14 National Defense Department of Defense (Continued... SUPERVISION Driving Privileges § 634.14 Restoration of driving privileges upon acquittal of...

  1. Four-wheel drive car

    SciTech Connect

    Ashikawa, N.

    1986-03-25

    A drive train in a four-wheel drive vehicle is described having an engine mounted on one end with a crankshaft oriented transverse to the direction of vehicle travel which consists of: a transmission having an output gear driven by the crankshaft and rotatable around an axis parallel to the axis of the crankshaft; a reduction gear operatively engaged with the output gear; a first differential gear having a gear and being concentrically engaged with the reduction gear to transmit the output of the reduction gear in a divided manner; a second differential gear transmitting power from one output of the differential gear to left and right wheels of the one end of the vehicle; a transmission gear meshing with the gear of the first differential gear for transmitting power from another output of the first differential gear in a direction generally perpendicular to the crankshaft through a propeller shaft to the other end of the vehicle, opposite the one end; a third differential gear receiving power from the propeller shaft for transmitting power to left and right wheels on the other end; and wherein a mesh portion where the transmission gear meshes with the gear of the first differential gear is closer to the crankshaft axis of engine than is the axis of the reduction gear.

  2. Current drive by helicon waves

    SciTech Connect

    Paul, Manash Kumar; Bora, Dhiraj

    2009-01-01

    Helicity in the dynamo field components of helicon wave is examined during the novel study of wave induced helicity current drive. Strong poloidal asymmetry in the wave magnetic field components is observed during helicon discharges formed in a toroidal vacuum chamber of small aspect ratio. High frequency regime is chosen to increase the phase velocity of helicon waves which in turn minimizes the resonant wave-particle interactions and enhances the contribution of the nonresonant current drive mechanisms. Owing to the strong poloidal asymmetry in the wave magnetic field structures, plasma current is driven mostly by the dynamo-electric-field, which arise due to the wave helicity injection by helicon waves. Small, yet finite contribution from the suppressed wave-particle resonance cannot be ruled out in the operational regime examined. A brief discussion on the parametric dependence of plasma current along with numerical estimations of nonresonant components is presented. A close agreement between the numerical estimation and measured plasma current magnitude is obtained during the present investigation.

  3. Driving Extreme Efficiency to Market

    NASA Astrophysics Data System (ADS)

    Garbesi, Karina

    2014-03-01

    The rapid development of extremely energy efficient appliances and equipment is essential to curtail catastrophic climate disruption. This will require the on-going development of products that apply all best-practices and that take advantage of the synergies of hybridization and building integration. Beyond that, it requires the development of new disruptive technologies and concepts. To facilitate these goals, in 2011 the Lawrence Berkeley National Laboratory and the U.S. Department of Energy launched the Max Tech and Beyond Design Competition for Ultra-Low-Energy-Use Appliances and Equipment. Now in its third year, the competition supports faculty-lead student design teams at U.S. universities to develop and test new technology prototypes. This talk describes what the competition and the Max Tech Program are doing to drive such rapid technology progress and to facilitate the entry to the market of successful Max Tech prototypes. The talk also initiates a discussion of physicists' unique role in driving that technology progress faster and farther. Emerging Technologies, Building Technologies Office, U.S. Department of Energy.

  4. Exposure to Movie Reckless Driving in Early Adolescence Predicts Reckless, but Not Inattentive Driving

    PubMed Central

    Kostermans, Evelien; Stoolmiller, Mike; de Leeuw, Rebecca N. H.; Engels, Rutger C. M. E.; Sargent, James D.

    2014-01-01

    Objective We examine the association between exposure to depictions of reckless driving in movies and unsafe driving, modeling inattentive and reckless driving as separate outcomes. Methods Data were obtained by telephone from 1,630 US adolescents aged 10 to 14 years at baseline who were drivers at a survey 6 years later. Exposure to movie reckless driving was measured based on movies seen from a randomly selected list of 50 movie titles that had been content coded for reckless driving among characters. Associations were tested with inattentive and reckless driving behaviors in the subsequent survey–controlling for baseline age, sex, socioeconomic status, parental education, school performance, extracurricular activities, daily television and video/computer game exposure, number of movies watched per week, self-regulation and sensation seeking. Results Exposure to movie reckless driving was common, with approximately 10% of movie characters having driven recklessly. Confirmatory factor analysis revealed a significant distinction between items tapping reckless and inattentive driving at the 6th wave. Age and exposure to movie reckless driving at baseline were directly associated with wave-6 reckless (but not inattentive) driving. Additionally, growth in sensation seeking mediated a prospective relation between the total number of movies watched per week at baseline and reckless driving, independent of exposure to movie reckless driving. Males and high sensation seekers reported lower seatbelt usage and more reckless driving, whereas lower self-regulation predicted inattentive driving. Discussion In this study, exposure to movie reckless driving during early adolescence predicted adolescents’ reckless driving, suggesting a direct modeling effect. Other aspects of movies were also associated with reckless driving, with that association mediated through growth in sensation seeking. Predictors of reckless driving were different from predictors of inattentive driving

  5. Circuit for Driving Piezoelectric Transducers

    NASA Technical Reports Server (NTRS)

    Randall, David P.; Chapsky, Jacob

    2009-01-01

    The figure schematically depicts an oscillator circuit for driving a piezoelectric transducer to excite vibrations in a mechanical structure. The circuit was designed and built to satisfy application-specific requirements to drive a selected one of 16 such transducers at a regulated amplitude and frequency chosen to optimize the amount of work performed by the transducer and to compensate for both (1) temporal variations of the resonance frequency and damping time of each transducer and (2) initially unknown differences among the resonance frequencies and damping times of different transducers. In other words, the circuit is designed to adjust itself to optimize the performance of whichever transducer is selected at any given time. The basic design concept may be adaptable to other applications that involve the use of piezoelectric transducers in ultrasonic cleaners and other apparatuses in which high-frequency mechanical drives are utilized. This circuit includes three resistor-capacitor networks that, together with the selected piezoelectric transducer, constitute a band-pass filter having a peak response at a frequency of about 2 kHz, which is approximately the resonance frequency of the piezoelectric transducers. Gain for generating oscillations is provided by a power hybrid operational amplifier (U1). A junction field-effect transistor (Q1) in combination with a resistor (R4) is used as a voltage-variable resistor to control the magnitude of the oscillation. The voltage-variable resistor is part of a feedback control loop: Part of the output of the oscillator is rectified and filtered for use as a slow negative feedback to the gate of Q1 to keep the output amplitude constant. The response of this control loop is much slower than 2 kHz and, therefore, does not introduce significant distortion of the oscillator output, which is a fairly clean sine wave. The positive AC feedback needed to sustain oscillations is derived from sampling the current through the

  6. Optimizing digital 8mm drive performance

    NASA Technical Reports Server (NTRS)

    Schadegg, Gerry

    1993-01-01

    The experience of attaching over 350,000 digital 8mm drives to 85-plus system platforms has uncovered many factors which can reduce cartridge capacity or drive throughput, reduce reliability, affect cartridge archivability and actually shorten drive life. Some are unique to an installation. Others result from how the system is set up to talk to the drive. Many stem from how applications use the drive, the work load that's present, the kind of media used and, very important, the kind of cleaning program in place. Digital 8mm drives record data at densities that rival those of disk technology. Even with technology this advanced, they are extremely robust and, given proper usage, care and media, should reward the user with a long productive life. The 8mm drive will give its best performance using high-quality 'data grade' media. Even though it costs more, good 'data grade' media can sustain the reliability and rigorous needs of a data storage environment and, with proper care, give users an archival life of 30 years or more. Various factors, taken individually, may not necessarily produce performance or reliability problems. Taken in combination, their effects can compound, resulting in rapid reductions in a drive's serviceable life, cartridge capacity, or drive performance. The key to managing media is determining the importance one places upon their recorded data and, subsequently, setting media usage guidelines that can deliver data reliability. Various options one can implement to optimize digital 8mm drive performance are explored.

  7. [Useful assessment for identifying unsafe driving].

    PubMed

    Gonthier, Régis; Fabrigoule, Colette; Domont, Alain

    2005-03-01

    Ability to drive safely is the resultant of interactions between the individual (the driver), the vector (the car) and the environment (the state of the road). For some aged drivers, an important decline of visual, musculosquelettic and cognitive performances, may affect the ability to drive and increase the rate of crashes per vehicle-kilometer-driven, and the morbidity and mortality related to crash. Therefore, each holder of a driving licence should be medically suited to control his driving ability. In case of transitory or lasting driving incapacity, drivers must, of their own initiative, stop driving according to the Highway code and the contractual obligations appearing in their vehicle insurance contract. A medical examination for aptitude to driving requires a standardized, reliable, reproducible procedure based on consensual assessment tools to avoid arbitrary decisions for driving cessation. We propose a multidisciplinary approach to detect important decline of visuospatial and motor skills, paroxystic drops of attention and vigilance, and decreased cognitive capacity to anticipate and adapt driving at every moment. This assessment is based on a semi-directed interview and simple diagnostic tests. According to the present French law, only twelve medical conditions or functional deficits are inconsistent with the retain of the driving licence for a light vehicle. PMID:15814324

  8. Driving, brain injury and assistive technology.

    PubMed

    Lane, Amy K; Benoit, Dana

    2011-01-01

    Individuals with brain injury often present with cognitive, physical and emotional impairments which impact their ability to resume independence in activities of daily living. Of those activities, the resumption of driving privileges is cited as one of the greatest concerns by survivors of brain injury. The integration of driving fundamentals within the hierarchical model proposed by Keskinen represents the complexity of skills and behaviors necessary for driving. This paper provides a brief review of specific considerations concerning the driver with TBI and highlights current vehicle technology which has been developed by the automotive industry and by manufacturers of adaptive driving equipment that may facilitate the driving task. Adaptive equipment technology allows for compensation of a variety of operational deficits, whereas technological advances within the automotive industry provide drivers with improved safety and information systems. However, research has not yet supported the use of such intelligent transportation systems or advanced driving systems for drivers with brain injury. Although technologies are intended to improve the safety of drivers within the general population, the potential of negative consequences for drivers with brain injury must be considered. Ultimately, a comprehensive driving evaluation and training by a driving rehabilitation specialist is recommended for individuals with brain injury. An understanding of the potential impact of TBI on driving-related skills and knowledge of current adaptive equipment and technology is imperative to determine whether return-to-driving is a realistic and achievable goal for the individual with TBI. PMID:21558628

  9. Alertness maintaining tasks (AMTs) while driving.

    PubMed

    Oron-Gilad, Tal; Ronen, Adi; Shinar, David

    2008-05-01

    We evaluated the effectiveness of alertness maintaining tasks (AMTs) on driver performance, subjective feelings, and psychophysiological state in monotonous simulated driving in two experiments. In the first experiment, 12 professional truck drivers participated in five sessions of simulated driving: driving only, driving with one of three AMTs (counterbalanced), and driving while listening to music. AMTs were not equally effective in maintaining alertness. The trivia AMT prevented driving performance deterioration, and increased alertness (measured by standardized HRV). The choice reaction time AMT was least demanding but also increased subjective sleepiness and reduced arousal (measured by alpha/beta ratio). The working memory AMT caused a significant decrement in driving speed, increased subjective fatigue, and was regarded by the participants as detrimental to driving. Trivia was preferred by the majority of the drivers over the other two AMTs. Experiment 2 further examined the utility of the trivia AMT. When the drivers engaged in the trivia AMT they maintained better driving performance and perceived the driving duration as shorter than the control condition. The two experiments demonstrated that AMTs can have a positive effect on alertness. The effect is localized in the sense that it does not persist beyond the period of the AMT activation. PMID:18460351

  10. Labs drive the arms race

    SciTech Connect

    DeWitt, H.E.

    1984-11-01

    The conviction of laboratory managers that high technology can provide safety and national security in a dangerous world and that technological solutions are paramount over political solutions has been a major driving force in perpetuating the nuclear arms race. The credo in the laboratories appears to be that there are never enough designs of nuclear weapons for deterrence so that there is always a need to develop such new ideas as the nuclear-pumped X-ray laser as a defense against energy missiles. The author outlines several alternative steps, including the ratification and reaffirmation of arms control treaties, negotiations, and a halt to the Star Wars program. A central point is to stop nuclear weapons testing. 7 references.

  11. Incentives required to drive change.

    PubMed

    Corbett, Stephen

    2012-01-01

    The authors of "Chartbook: Shining a Light on the Quality of Healthcare in Canada," focus on building a Canadian healthcare performance baseline, highlighting opportunities to improve the system and then raising policy questions. This is a thoughtful approach to gaining awareness of the relative performance across the Canadian healthcare system. In essence, it is necessary to first establish a felt need, identify areas to improve and then ensure the system will implement the necessary changes to improve. The authors build a reasonable case for why improvements are necessary, and they identify key barriers that must be removed to actually realize improvements and offer a wide range of policy recommendations. However, not all of these recommendations are focused on the key point of ensuring that there are incentives in place to drive participants to implement changes. PMID:22543330

  12. Current Drive in Recombining Plasma

    SciTech Connect

    P.F. Schmit and N.J. Fisch

    2012-05-15

    The Langevin equations describing the average collisional dynamics of suprathermal particles in nonstationary plasma remarkably admit an exact analytical solution in the case of recombining plasma. The current density produced by arbitrary particle fluxes is derived including the effect of charge recombination. Since recombination has the effect of lowering the charge density of the plasma, thus reducing the charged particle collisional frequencies, the evolution of the current density can be modified substantially compared to plasma with fixed charge density. The current drive efficiency is derived and optimized for discrete and continuous pulses of current, leading to the discovery of a nonzero "residual" current density that persists indefinitely under certain conditions, a feature not present in stationary plasmas.

  13. [Stress of driving: general overview].

    PubMed

    Costa, G

    2012-01-01

    Driving is a stressful task that requires high levels of attention and vigilance to cope properly with job demands, mainly related to working hours and timetables, weather and traffic conditions, passengers and goods safety, responsibility in case of error and/or accident. Scientific literature shows a higher prevalence of cardiovascular, gastrointestinal, neuropsychic and musculoskeletal disorders, and consequent sick leaves, in professional bus/lorry and train drivers. Several studies have emphasized that stress, fatigue and excessive sleepiness give a significant contribution to occupational road and rail accidents. There are noteworthy, interindividual differences concerning alertness/sleepiness and tolerance to fatigue, related to psychophysiological and behavioural characteristics and health status, in particular: age, ability to overcome drowsiness, morningness/eveningness, diet and intake of psychotropic substances (alcohol, drugs, medicaments), primary and secondary sleep disorders (insomnia, ipersomnias, parasomnias). PMID:23213814

  14. Unsafe driving behaviors and hospitalization.

    PubMed

    Van Tuinen, M

    1994-04-01

    The medical costs associated with motor vehicle crashes are difficult to measure. Most attempts have used crash data and cost data that are only indirectly related to each other or have followed patients in a few hospitals or trauma centers. These studies produce localized estimates or rough national estimates of limited use to policy makers. The result has been a dependence on more readily available mortality data, such as the Fatal Accident Reporting System, to guide automotive safety efforts. The limitations of mortality data and the increasing sophistication of medical care data bases have resulted in a strong interest in obtaining crash-linked morbidity data. Hence, in 1993, the National Highway Traffic Safety Administration (NHTSA) awarded the Missouri Department of Health and six other applicants grants to link automotive crash records to statewide ambulance trip, outpatient care, hospitalization and mortality records. By identifying an individual across multiple data sets, states would be able to determine directly the relationship of driver behaviors and crash characteristics to hospitalization rates and other medical outcomes. Examination of hospital pay source information would expose the toll of automotive crashes on public tax dollars. Having recently completed the record linkage phase of this project, Missouri Department of Health staff are beginning to analyze the impact of automotive crashes on health care costs in Missouri. In this report, three unsafe driving behaviors, failure to use a safety device (seatbelts and motorcycle helmets), driving under the influence of alcohol, and speeding, are related to the risk of hospitalization or death, hospital costs, and expected pay source. PMID:8202067

  15. Error analysis of friction drive elements

    NASA Astrophysics Data System (ADS)

    Wang, Guomin; Yang, Shihai; Wang, Daxing

    2008-07-01

    Friction drive is used in some large astronomical telescopes in recent years. Comparing to the direct drive, friction drive train consists of more buildup parts. Usually, the friction drive train consists of motor-tachometer unit, coupling, reducer, driving roller, big wheel, encoder and encoder coupling. Normally, these buildup parts will introduce somewhat errors to the drive system. Some of them are random error and some of them are systematic error. For the random error, the effective way is to estimate their contributions and try to find proper way to decrease its influence. For the systematic error, the useful way is to analyse and test them quantitively, and then feedback the error to the control system to correct them. The main task of this paper is to analyse these error sources and find out their characteristics, such as random error, systematic error and contributions. The methods or equations used in the analysis will be also presented detail in this paper.

  16. Electric vehicle drive train with contactor protection

    DOEpatents

    Konrad, C.E.; Benson, R.A.

    1994-11-29

    A drive train for an electric vehicle includes a traction battery, a power drive circuit, a main contactor for connecting and disconnecting the traction battery and the power drive circuit, a voltage detector across contacts of the main contactor, and a controller for controlling the main contactor to prevent movement of its contacts to the closed position when the voltage across the contacts exceeds a predetermined threshold, to thereby protect the contacts of the contactor. The power drive circuit includes an electric traction motor and a DC-to-AC inverter with a capacitive input filter. The controller also inhibits the power drive circuit from driving the motor and thereby discharging the input capacitor if the contacts are inadvertently opened during motoring. A precharging contactor is controlled to charge the input filter capacitor prior to closing the main contactor to further protect the contacts of the main contactor. 3 figures.

  17. Electric vehicle drive train with contactor protection

    DOEpatents

    Konrad, Charles E.; Benson, Ralph A.

    1994-01-01

    A drive train for an electric vehicle includes a traction battery, a power drive circuit, a main contactor for connecting and disconnecting the traction battery and the power drive circuit, a voltage detector across contacts of the main contactor, and a controller for controlling the main contactor to prevent movement of its contacts to the closed position when the voltage across the contacts exceeds a predetermined threshold, to thereby protect the contacts of the contactor. The power drive circuit includes an electric traction motor and a DC-to-AC inverter with a capacitive input filter. The controller also inhibits the power drive circuit from driving the motor and thereby discharging the input capacitor if the contacts are inadvertently opened during motoring. A precharging contactor is controlled to charge the input filter capacitor prior to closing the main contactor to further protect the contacts of the main contactor.

  18. Application of traction drives as servo mechanisms

    NASA Technical Reports Server (NTRS)

    Loewenthal, S. H.; Rohn, D. A.; Steinetz, B. M.

    1985-01-01

    The suitability of traction drives for a wide class of aerospace control mechanisms is examined. Potential applications include antenna or solar array drive positioners, robotic joints, control moment gyro (CMG) actuators and propeller pitch change mechanisms. In these and similar applications the zero backlash, high torsional stiffness, low hysteresis and torque ripple characteristics of traction drives are of particular interest, as is the ability to run without liquid lubrication in certain cases. Wear and fatigue considerations for wet and dry operation are examined along with the tribological performance of several promising self lubricating polymers for traction contracts. The speed regulation capabilities of variable ratio traction drives are reviewed. A torsional stiffness analysis described suggests that traction contacts are relatively stiff compared to gears and are significantly stiffer than the other structural elements in the prototype CMG traction drive analyzed. Discussion is also given of an advanced turboprop propeller pitch change mechanism that incorporates a traction drive.

  19. ATP13A3 and caveolin-1 as potential biomarkers for difluoromethylornithine-based therapies in pancreatic cancers

    PubMed Central

    Madan, Meenu; Patel, Arjun; Skruber, Kristen; Geerts, Dirk; Altomare, Deborah A; IV, Otto Phanstiel

    2016-01-01

    The purpose of this paper was to better understand the role of polyamine transport in pancreatic cancers.This paper identifies potential biomarkers for assessing the relative tumor commitment to polyamine biosynthesis or transport. Cell lines with low polyamine import activity and low ATP13A3 protein levels appear committed to polyamine biosynthesis and required high concentrations of the polyamine biosynthesis inhibitor, difluoromethylornithine (DFMO) to inhibit their growth (e.g., AsPC-1 and Capan 1). In contrast, cell lines with high polyamine import activity and high ATP13A3 protein expression (e.g., L3.6pl) demonstrated a commitment to polyamine transport and required lower DFMO concentrations to inhibit their growth. Pancreatic cancer cell lines which were most sensitive to DFMO also gave the highest EC50 values for the polyamine transport inhibitors (PTIs) tested indicating that more PTI was needed to inhibit the active polyamine transport systems of these cell lines. Most significant is that the combination therapy of DFMO+PTI was efficacious against both cell types with the PTI showing low efficacy in cell lines with low polyamine transport activity and high efficacy in cell lines with high polyamine transport activity. High ATP13A3 protein expression and moderate to low Cav-1 protein expression was shown to be predictive of tumors which effectively escape DFMO via polyamine import. In summary, this report demonstrates for the first time the role of ATP13A3 in polyamine transport and its use as a potential biomarker along with Cav-1 to select tumors most susceptible to DFMO. These findings may help stratify patients in the ongoing clinical trials with DFMO-based therapies and help predict tumor response. PMID:27429841

  20. High Mobility Group Box Protein 1 Boosts Endothelial Albumin Transcytosis through the RAGE/Src/Caveolin-1 Pathway.

    PubMed

    Shang, Dan; Peng, Tao; Gou, Shanmiao; Li, Yiqing; Wu, Heshui; Wang, Chunyou; Yang, Zhiyong

    2016-01-01

    High-mobility group box protein 1 (HMGB1), an inflammatory mediator, has been reported to destroy cell-cell junctions, resulting in vascular endothelial hyperpermeability. Here, we report that HMGB1 increases the endothelial transcytosis of albumin. In mouse lung vascular endothelial cells (MLVECs), HMGB1 at a concentration of 500 ng/ml or less did not harm cell-cell junctions but rapidly induced endothelial hyperpermeability to (125)I-albumin. HMGB1 induced an increase in (125)I-albumin and AlexaFluor 488-labeled albumin internalization in endocytosis assays. Depletion of receptor for advanced glycation end products (RAGE), but not TLR2 or TLR4, suppressed HMGB1-induced albumin transcytosis and endocytosis. Genetic and pharmacological destruction of lipid rafts significantly inhibited HMGB1-induced albumin endocytosis and transcytosis. HMGB1 induced the rapid phosphorylation of caveolin (Cav)-1 and Src. Either RAGE gene silencing or soluble RAGE suppressed Cav-1 Tyr14 phosphorylation and Src Tyr418 phosphorylation. The Src inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d] pyrimidine (PP2) blocked HMGB1-induced Cav-1 Tyr14 phosphorylation. PP2 and overexpression of Cav-1 with a T14F mutation significantly inhibited HMGB1-induced transcytosis and albumin endocytosis. Our findings suggest that HMGB1 induces the transcytosis of albumin via RAGE-dependent Src phosphorylation and Cav-1 phosphorylation. These studies revealed a new mechanism of HMGB1-induced endothelial hyperpermeability. PMID:27572515

  1. Association Between Upstream Purine Complexes of Human Caveolin-1 Gene and Schizophrenia in Qazvin Province of Iran

    PubMed Central

    Najafipour, Reza; Heidari, Abolfazl; Alizadeh, Safar Ali; Ghafelebashi, Hannaneh; Rashvand, Zahra; Javadi, Amir; Moradi, Mohammad; Afshar, Hosein

    2014-01-01

    Background: Caveolin is a multifunctional and scaffolding membrane protein, which involves cholesterol trafficking to plasma lipid microdomain. It organizes and targets synaptic parts of the neurotransmitter and neurotrophic receptor signaling pathways. Caveolins are encoded by CAV-1, 2 and 3 genes. Disruption of the CAV1 would likely ruin the neuronal signaling, which leads to symptoms of schizophrenia in predisposed individuals. Objectives: The upper area of CAV-1 gene is highly conserved and can have a regulatory role in neurodegenerative diseases. This study was designed to find out the possible association of polymorphisms of this area and schizophrenia. Patients and Methods: In a case-control study, 254 blood samples were obtained from 127 patients with schizophrenia and 127 well matched controls referred to 22 Bahman Hospital of Qazvin University of Medical Sciences (QUMS) in Qazvin province, Iran, using simple random sampling method. After extracting DNA, the upper region of the human CAV1- gene was amplified by PCR in all collected samples. The products were visualized by silver staining in 10% polyacrylamide gel and then sequenced. Results: We detected nine homozygotes in patients and 15 in control subjects. Homozygosity was 7.08% and 11.8% in cases and control, respectively. Nine types homozygote haplotype were detected in upper region of the CAV1 gene in cases and controls. Three haplotypes were common in cases and controls; four haplotypes were seen in controls only and two in cases. Conclusions: Our findings implied a significant correlation between some haplotypes of upper region of CAV1 gene and schizophrenia. Existence of some haplotypes and lack of another in CAV1 upstream can suggest a significant correlation between schizophrenia and some haplotypes. PMID:25763243

  2. Caveolin-1 is critical in the proliferative effect of leptin on osteoblasts through the activation of Akt.

    PubMed

    Zou, Lin; Zhang, Guichun; Liu, Lifeng; Chen, Chen; Cao, Xuecheng; Cai, Jinfang

    2016-09-01

    Osteoblasts are critical in bone remodeling and the repair of bone fractures. Leptin is involved in bone metabolism and osteoblast survival through the downstream signaling pathway, however, the exact mechanism of the effect of leptin on osteoblasts remains to be fully elucidated. In the present study, hFOB 1.19 cells were used to observe the effects of leptin on cell proliferation and apoptosis, and to investigate the underlying mechanism. The results confirmed that treatment of hFOB 1.19 cells with leptin significantly induced cell proliferation. Western blot analysis showed that the expression of caveolin‑1 and the activation of Akt in the cells treated with leptin were significantly increased, compared with the control cells. Additionally, inhibiting Akt activation eliminated the effects on cell proliferation induced by leptin. The rates of cell apoptosis and cell cycle distribution were examined using flow cytometry, which revealed a decrease in the apoptotic rate and an increase in the proportion of cells in the S phase. This indicated that leptin was capable of inducing cell proliferation by inhibiting apoptosis and stimulating cell progression to the S phase. Transfection of the cells with caveolin‑1 small interfering RNA showed that the activation of Akt induced by leptin was significantly inhibited. Furthermore, caveolin‑1 knockdown and inhibiting Akt activation eliminated the increased proliferation, increased proportion of cells in the S phase and increased anti‑apoptotic effects induced by leptin. Taken together, the data obtained in the present study demonstrated that caveolin‑1 was critical in the proliferative effect of leptin on osteoblasts via the activation of Akt. PMID:27430651

  3. High Mobility Group Box Protein 1 Boosts Endothelial Albumin Transcytosis through the RAGE/Src/Caveolin-1 Pathway

    PubMed Central

    Shang, Dan; Peng, Tao; Gou, Shanmiao; Li, Yiqing; Wu, Heshui; Wang, Chunyou; Yang, Zhiyong

    2016-01-01

    High-mobility group box protein 1 (HMGB1), an inflammatory mediator, has been reported to destroy cell-cell junctions, resulting in vascular endothelial hyperpermeability. Here, we report that HMGB1 increases the endothelial transcytosis of albumin. In mouse lung vascular endothelial cells (MLVECs), HMGB1 at a concentration of 500 ng/ml or less did not harm cell-cell junctions but rapidly induced endothelial hyperpermeability to 125I-albumin. HMGB1 induced an increase in 125I-albumin and AlexaFluor 488-labeled albumin internalization in endocytosis assays. Depletion of receptor for advanced glycation end products (RAGE), but not TLR2 or TLR4, suppressed HMGB1-induced albumin transcytosis and endocytosis. Genetic and pharmacological destruction of lipid rafts significantly inhibited HMGB1-induced albumin endocytosis and transcytosis. HMGB1 induced the rapid phosphorylation of caveolin (Cav)-1 and Src. Either RAGE gene silencing or soluble RAGE suppressed Cav-1 Tyr14 phosphorylation and Src Tyr418 phosphorylation. The Src inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d] pyrimidine (PP2) blocked HMGB1-induced Cav-1 Tyr14 phosphorylation. PP2 and overexpression of Cav-1 with a T14F mutation significantly inhibited HMGB1-induced transcytosis and albumin endocytosis. Our findings suggest that HMGB1 induces the transcytosis of albumin via RAGE-dependent Src phosphorylation and Cav-1 phosphorylation. These studies revealed a new mechanism of HMGB1-induced endothelial hyperpermeability. PMID:27572515

  4. An analysis of traction drive torsional stiffness

    NASA Technical Reports Server (NTRS)

    Rohn, D. A.; Loewenthal, S. H.

    1983-01-01

    The tangential compliance of elastic bodies in concentrated contact applied to traction drive elements to determine their torsional stiffness was analyzed. Static loading and rotating conditions are considered. The effects of several design variables are shown. The theoretical torsional stiffness of a fixed ratio multiroller drive is computed and compared to experimental values. It is shown that the torsional compliance of the traction contacts themselves is a relatively small portion of the overall drive system compliance.

  5. Driving Miss Bradley: performance measurement to support thermal driving

    NASA Astrophysics Data System (ADS)

    Piccione, Dino; Ferrett, Donald A.

    1998-07-01

    The Driver's Vision Enhancer (DVE) program is providing a system to enlarge the driving envelope for the community of military wheeled and tracked vehicles. The DVE, an IR device, provides the driver with images of the forward scene under night and adverse day conditions. During the DVE development program, several questions emerged requiring performance-based data to resolve. A comprehensive program to provide the Project Manager, Night Vision/Reconnaissance, Surveillance and Target Acquisition with driver performance data that will aid in the decision-making process is described in this paper. The program involves several linked efforts including: the relative merits of the DVE and night vision goggles (NVG); drivers' ability to detect the presence of drop-offs when using the DVE and NVG; the effect on performance of various levels of nonuniformity and nonresponsiveness in the display/sensor system; the analysis of drivers' vision using an eye-tracker in a vehicle; and the evaluation of candidate symbology to enhance the DVE's utility in the M2 Bradley. The data collected will aid in making decisions on how to write a system specification to reduce cost without sacrificing driver performance, gain an understanding of how drivers use the DVE in operational settings, and determine where training is needed to enhance safety and reduce risk on the battlefield.

  6. Women drive better if not stereotyped.

    PubMed

    Moè, Angelica; Cadinu, Mara; Maass, Anne

    2015-12-01

    A commonly held stereotype is that women are poor drivers. This stereotype is recognized and endorsed by women and girls very early on, long before taking their driving licence, nevertheless they are less involved in accidents and drive safer and less fast than men. In line with the stereotype threat theory, the present study tests the hypothesis that making the driving stereotype salient will lead women to underperform in a driving simulation task. In Experiment 1women in the stereotype threat condition were told that the aim of the study was to detect gender differences in driving whereas in a control condition no study aim was provided. In Experiment 2, two conditions were compared: stereotype threat (same instructions as in Experiment 1), and stereotype boost (the alleged goal was to compare driving ability of young vs. old people). As predicted, the results of both experiments showed that women under stereotype threat, as compared to either control or stereotype boost participants, doubled the number of mistakes. Nevertheless, they overall expected/self-reported to drive/have driven poorly. Importantly, their level of expectation was a significant predictor of their actual driving performance only in the stereotype threat condition. Implications of these effects of stereotype threat on women's driving performance and self-assessment are discussed. PMID:26457739

  7. Camshaft driving device for internal combustion engine

    SciTech Connect

    Ebesu, H.

    1988-06-14

    A camshaft driving device for use in a double overhead cam type internal combustion engine having a cylinder block, an upper deck formed at an upper portion of the cylinder block, a cylinder head disposed on the cylinder block, a driving shaft rotatably mounted at a lower portion of the cylinder block, and a pair of camshafts rotatably mounted at an upper portion of the cylinder head, is described comprising: driving force transmitting endless chain members engaging in the reduction gear means for transmitting a driving force from the driving shaft to the pair of camshaft through the reduction gear means. The camshaft driving device further including chain tensioners for tightening the chain, a nozzle means for supplying a lubricating oil to the driving force chain members on the side of the drive shaft and an oil guide wall formed immediately above the sprocket of the transmitting portion of the reduction gear means at a lower end portion of the journal boss and lapping thereover both in the radial direction and in the axial direction of the driving shaft. A mounting boss for mounting the reduction gear means thereon is formed on the upper deck of the cylinder block.

  8. Configuring NIF for direct drive experiments

    SciTech Connect

    Eimerl, D.; Rothenberg, J.; Key, M.

    1995-07-11

    The National Ignition Facility (NIF) is a proposed 1.8 MJ laser facility for carrying out experiments in inertial confinement fusion, currently designed for indirect drive experiments. The direct drive approach is being pursued at the 30 kJ Omega facility at the University of Rochester. In this paper we discuss the modifications to the NIF laser that would be required for both indirect and direct drive experiments. A primary concern is the additional cost of adding direct drive capability to the facility.

  9. Metal band drives in spacecraft mechanisms

    NASA Technical Reports Server (NTRS)

    Maus, Daryl

    1993-01-01

    Transmitting and changing the characteristics of force and stroke is a requirement in nearly all mechanisms. Examples include changing linear to rotary motion, providing a 90 deg change in direction, and amplifying stroke or force. Requirements for size, weight, efficiency and reliability create unique problems in spacecraft mechanisms. Flexible metal band and cam drive systems provide powerful solutions to these problems. Band drives, rack and pinion gears, and bell cranks are compared for effectiveness. Band drive issues are discussed including materials, bend radius, fabrication, attachment and reliability. Numerous mechanisms are shown which illustrate practical applications of band drives.

  10. Warp Drive - From Imagination to Reality

    NASA Astrophysics Data System (ADS)

    Gardiner, J.

    The realisation of warp drive is far beyond current science and technology; nevertheless, setting out a timetable for the realisation of warp drive is instructive as this will set expectations for the progress of future research. It is proposed that a time scale for the realisation of warp drive can be estimated by historical analogy with the development of manned space travel to the Moon, using conventional project estimation techniques. A timeline for space travel to the Moon begins with Cyrano de Bergerac's Voyage dans la Lune in 1657 and culminates with the Apollo 11 Moon landing in 1969, a little over 300 years later. A similar timeline for warp drive begins with John W. Campbell's novel Islands of Space in 1930. Fictional conjecture on the warp drive has given way to serious scientific speculation following publication of Alcubierre's seminal warp drive paper in 1994. It is concluded that the realisation of warp drive might be achieved around the year 2180. A projected timetable for the realisation of warp drive through phases of conjecture , speculation , science , technology and application suggests that the warp drive proposal should enter the science phase around the year 2030.

  11. Analysis of cache for streaming tape drive

    NASA Technical Reports Server (NTRS)

    Chinnaswamy, V.

    1993-01-01

    A tape subsystem consists of a controller and a tape drive. Tapes are used for backup, data interchange, and software distribution. The backup operation is addressed. During a backup operation, data is read from disk, processed in CPU, and then sent to tape. The processing speeds of a disk subsystem, CPU, and a tape subsystem are likely to be different. A powerful CPU can read data from a fast disk, process it, and supply the data to the tape subsystem at a faster rate than the tape subsystem can handle. On the other hand, a slow disk drive and a slow CPU may not be able to supply data fast enough to keep a tape drive busy all the time. The backup process may supply data to tape drive in bursts. Each burst may be followed by an idle period. Depending on the nature of the file distribution in the disk, the input stream to the tape subsystem may vary significantly during backup. To compensate for these differences and optimize the utilization of a tape subsystem, a cache or buffer is introduced in the tape controller. Most of the tape drives today are streaming tape drives. A streaming tape drive goes into reposition when there is no data from the controller. Once the drive goes into reposition, the controller can receive data, but it cannot supply data to the tape drive until the drive completes its reposition. A controller can also receive data from the host and send data to the tape drive at the same time. The relationship of cache size, host transfer rate, drive transfer rate, reposition, and ramp up times for optimal performance of the tape subsystem are investigated. Formulas developed will also show the advantages of cache watermarks to increase the streaming time of the tape drive, maximum loss due to insufficient cache, tradeoffs between cache and reposition times and the effectiveness of cache on a streaming tape drive due to idle times or interruptions due in host transfers. Several mathematical formulas are developed to predict the performance of the tape

  12. Driving DSA into volume manufacturing

    NASA Astrophysics Data System (ADS)

    Somervell, Mark; Yamauchi, Takashi; Okada, Soichiro; Tomita, Tadatoshi; Nishi, Takanori; Kawakami, Shinichiro; Muramatsu, Makoto; Iijima, Etsuo; Rastogi, Vinayak; Nakano, Takeo; Iwao, Fumiko; Nagahara, Seiji; Iwaki, Hiroyuki; Dojun, Makiko; Yatsuda, Koichi; Tobana, Toshikatsu; Romo Negreira, Ainhoa; Parnell, Doni; Rathsack, Benjamen; Nafus, Kathleen; Peyre, Jean-Luc; Kitano, Takahiro

    2015-03-01

    Directed Self-Assembly (DSA) is being extensively evaluated for application in semiconductor process integration.1-7 Since 2011, the number of publications on DSA at SPIE has exploded from roughly 26 to well over 80, indicating the groundswell of interest in the technology. Driving this interest are a number of attractive aspects of DSA including the ability to form both line/space and hole patterns at dimensions below 15 nm, the ability to achieve pitch multiplication to extend optical lithography, and the relatively low cost of the processes when compared with EUV or multiple patterning options. Tokyo Electron Limited has focused its efforts in scaling many laboratory demonstrations to 300 mm wafers. Additionally, we have recognized that the use of DSA requires specific design considerations to create robust layouts. To this end, we have discussed the development of a DSA ecosystem that will make DSA a viable technology for our industry, and we have partnered with numerous companies to aid in the development of the ecosystem. This presentation will focus on our continuing role in developing the equipment required for DSA implementation specifically discussing defectivity reduction on flows for making line-space and hole patterns, etch transfer of DSA patterns into substrates of interest, and integration of DSA processes into larger patterning schemes.

  13. Redundant arrays of IDE drives

    SciTech Connect

    D.A. Sanders et al.

    2002-01-02

    The authors report tests of redundant arrays of IDE disk drives for use in offline high energy physics data analysis. Parts costs of total systems using commodity EIDE disks are now at the $4000 per Terabyte level. Disk storage prices have now decreased to the point where they equal the cost per Terabyte of Storage Technology tape silos. The disks, however, offer far better granularity; even small institutions can afford to deploy systems. The tests include reports on software RAID-5 systems running under Linux 2.4 using Promise Ultra 100{trademark} disk controllers. RAID-5 protects data in case of a single disk failure by providing parity bits. Tape backup is not required. Journaling file systems are used to allow rapid recovery from crashes. The data analysis strategy is to encapsulate data and CPU processing power. Analysis for a particular part of a data set takes place on the PC where the data resides. The network is only used to put results together. They explore three methods of moving data between sites; internet transfers, not pluggable IDE disks in FireWire cases, and DVD-R disks.

  14. Empathic concern drives costly altruism

    PubMed Central

    FeldmanHall, Oriel; Dalgleish, Tim; Evans, Davy; Mobbs, Dean

    2015-01-01

    Why do we self-sacrifice to help others in distress? Two competing theories have emerged, one suggesting that prosocial behavior is primarily motivated by feelings of empathic other-oriented concern, the other that we help mainly because we are egoistically focused on reducing our own discomfort. Here we explore the relationship between costly altruism and these two sub-processes of empathy, specifically drawing on the caregiving model to test the theory that trait empathic concern (e.g. general tendency to have sympathy for another) and trait personal distress (e.g. predisposition to experiencing aversive arousal states) may differentially drive altruistic behavior. We find that trait empathic concern – and not trait personal distress – motivates costly altruism, and this relationship is supported by activity in the ventral tegmental area, caudate and subgenual anterior cingulate, key regions for promoting social attachment and caregiving. Together, this data helps identify the behavioral and neural mechanisms motivating costly altruism, while demonstrating that individual differences in empathic concern-related brain responses can predict real prosocial choice. PMID:25462694

  15. The Thermodynamics of Drunk Driving

    NASA Astrophysics Data System (ADS)

    Thompson, Robert Q.

    1997-05-01

    Chemical and instrumental tests for driving under the influence of alcohol (DUI) measure the concentration of ethanol in the breath (BrAC), while state DUI laws are described in terms of blood alcohol concentration (BAC). Consequently, accurate and fair conversion from BrAC to BAC is crucial to the judicial process. Theoretical treatment of the water-air-ethanol equilibrium system and the related blood-breath-ethanol system, based on principles from general chemistry and biology, yields an equation relating the ratio of BAC to BrAC to the absolute temperature of the breath, the fraction of water in the blood, and the enthalpy and entropy of vaporization of ethanol from aqueous solution. The model equation predicts an average value for the ratio of 2350+100, not significantly different from reported experimental values. An exponential temperature dependence is predicted and has been confirmed experimentally as well. Biological, chemical, and instrumental variables are described along with their contributions to the overall uncertainty in the value of BrAC/BAC. While the forensic science community uses, and debates, a fixed ratio of 2100, the theoretical model suggests that a value of 1880 should be used to reduce the fraction of false positives to <1%.

  16. Kinesin 1 Drives Autolysosome Tubulation.

    PubMed

    Du, Wanqing; Su, Qian Peter; Chen, Yang; Zhu, Yueyao; Jiang, Dong; Rong, Yueguang; Zhang, Senyan; Zhang, Yixiao; Ren, He; Zhang, Chuanmao; Wang, Xinquan; Gao, Ning; Wang, Yanfeng; Sun, Lingfei; Sun, Yujie; Yu, Li

    2016-05-23

    Autophagic lysosome reformation (ALR) plays an important role in maintaining lysosome homeostasis. During ALR, lysosomes are reformed by recycling lysosomal components from autolysosomes. The most noticeable step of ALR is autolysosome tubulation, but it is currently unknown how the process is regulated. Here, using an approach combining in vivo studies and in vitro reconstitution, we found that the kinesin motor protein KIF5B is required for autolysosome tubulation and that KIF5B drives autolysosome tubulation by pulling on the autolysosomal membrane. Furthermore, we show that KIF5B directly interacts with PtdIns(4,5)P2. Kinesin motors are recruited and clustered on autolysosomes via interaction with PtdIns(4,5)P2 in a clathrin-dependent manner. Finally, we demonstrate that clathrin promotes formation of PtdIns(4,5)P2-enriched microdomains, which are required for clustering of KIF5B. Our study reveals a mechanism by which autolysosome tubulation was generated. PMID:27219061

  17. What drives polymer glasses ductile?

    NASA Astrophysics Data System (ADS)

    Wang, Shi-Qing; Cheng, Shiwang; Li, Xiaoxiao; Lin, Panpan; Liu, Jianning

    2015-03-01

    The presentation aims to explore an important question in polymer physics: what makes polymer glasses of high molecular weight ductile? Upon deformation, load-bearing strands (LBS) emerge along the direction of the stress. Chain tension builds up in LBS due to the displacement of LBS. Segments that do not belong to LBS sequentially get activated by the LBS in the order of their proximity to LBS. If the chain network breaks down before driving the glass into a state of global plasticity, crazing and brittle fracture takes place instead of yielding and macroscopic plastic deformation. Fast deformation assures that chain pullout does not have time to materialize. Global plasticity also takes time to develop. Thus, the outcome is dictated by which process takes place first. In light of the recently proposed molecular model for yielding and brittle-ductile transition of polymer glasses, we present different examples from experiment to illustrate the importance to understand the interplay between short-ranged intersegmental interactions and long-ranged intrachain networking. NSF-DMR (EAGER- 1444859)

  18. Variable frequency drive applications guide

    SciTech Connect

    Laloudakis, D.J.

    1991-10-01

    Traditionally, fans and pumps have been designed to be capable of handling the maximum demand of the system in which they are installed. However, quite often the actual demand can vary and it can be much lower than the original design capacity. These situations have been corrected in the past through additions of outlet dampers to fans or throttling valves to pumps. While these can be effective and simple controls they severely affect the efficiency of the system. Variable frequency (speed) is the most efficient means of capacity control. The most cost effective method of achieving variable speed capacity control is using AC adjustable frequency drives. AC adjustable frequency controls convert any fixed speed AC motor into an adjustable speed device. Adjusting the speed of a motor, by controlling the frequency of the AC power to that motor, reduces its horsepower requirements. According to pump and fan laws, capacity is proportional to speed while horsepower is proportional to the cube of the speed. Therefore, by reducing the speed of an AC motor by 20 percent the horsepower requirement is reduced by nearly 50 percent. Reduced speed through variable frequency control allows for flexibility of meeting changing weather and comfort requirements without operating costly equipment at full capacity.

  19. Control rod drive hydraulic system

    DOEpatents

    Ose, Richard A.

    1992-01-01

    A hydraulic system for a control rod drive (CRD) includes a variable output-pressure CR pump operable in a charging mode for providing pressurized fluid at a charging pressure, and in a normal mode for providing the pressurized fluid at a purge pressure, less than the charging pressure. Charging and purge lines are disposed in parallel flow between the CRD pump and the CRD. A hydraulic control unit is disposed in flow communication in the charging line and includes a scram accumulator. An isolation valve is provided in the charging line between the CRD pump and the scram accumulator. A controller is operatively connected to the CRD pump and the isolation valve and is effective for opening the isolation valve and operating the CRD pump in a charging mode for charging the scram accumulator, and closing the isolation valve and operating the CRD pump in a normal mode for providing to the CRD through the purge line the pressurized fluid at a purge pressure lower than the charging pressure.

  20. 77 FR 61048 - Distracted Driving Grant Program

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-05

    ... grant program, 77 FR 51610 (Aug. 24, 2012), which established an application deadline of October 9, 2012... National Highway Traffic Safety Administration Distracted Driving Grant Program AGENCY: National Highway... Transportation (DOT) announced the availability of funding authorized for distracted driving grants on August...

  1. Mechanical vs electric drive: which to choose

    SciTech Connect

    Smiley, C.H.

    1983-03-01

    In the highly competitive 85 to 120 ton haul truck market, mechanical drive units have become increasingly popular because of their lower initial investment costs. But when total ownership costs over the life of the vehicle are considered, electric drive remains highly competitive.

  2. Steady State Tokamak Equilibria without Current Drive

    SciTech Connect

    Shaing, K.C.; Aydemir, A.Y.; Lin-Liu, Y.R.; Miller, R.L.

    1997-11-01

    Steady state tokamak equilibria without current drive are found. This is made possible by including the potato bootstrap current close to the magnetic axis. Tokamaks with this class of equilibria do not need seed current or current drive, and are intrinsically steady state. {copyright} {ital 1997} {ital The American Physical Society}

  3. Determining the focus of driving fears.

    PubMed

    Taylor, J E; Deane, F P; Podd, J V

    2000-01-01

    Fear of driving has been recognized as a complex diagnostic entity. Studies on flying phobia have drawn similar conclusions, although increasing clarity has been gained through research that indicates that there may be subtypes of flying phobia based on the focus of fear. However, it is unclear if similar subtypes exist for fear of driving. The aim of the present study was to conduct a preliminary investigation of driving fear subtypes and to clarify further whether there were differences between driving-fearful respondents who had been in a motor vehicle accident (MVA) and those who had not. Eighty-five driving-fearful, media-recruited respondents completed a questionnaire that assessed anxiety, avoidance, and concerns related to their driving fears. The sample had high expectations of negative events while driving. There were no significant differences between those who had experienced an MVA and those who had not on various measures of fear severity. Cluster analysis revealed two main foci of fear, one characterized by danger expectancies and the other based on anxiety expectancies and unpleasant driving situations. This emphasizes the importance of assessing both internal and external foci of fear. Although this finding is consistent with the results obtained for flying phobia, more research is required to replicate and extend these results and to develop and evaluate differential treatment programs. PMID:11095540

  4. Responsibility for Drinking and Driving in Adolescents.

    ERIC Educational Resources Information Center

    McKinney, J. P.; And Others

    An attempt to measure responsibility for the effects of careful or careless driving involved the development of a scale for driving locus of control (DLOC). An early version of the DLOC was given to 43 college students. Preliminary results indicated that test-retest reliability and internal consistency were high enough to warrant further…

  5. Dynamics and control of instrumented harmonic drives

    NASA Technical Reports Server (NTRS)

    Kazerooni, H.; Ellis, S. R. (Principal Investigator)

    1995-01-01

    Since torque in harmonic drives is transmitted by a pure couple, harmonic drives do not generate radial forces and therefore can be instrumented with torque sensors without interference from radial forces. The installation of torque sensors on the stationary component of harmonic drives (the Flexipline cup in this research work) produce backdrivability needed for robotic and telerobotic compliant maneuvers. Backdrivability of a harmonic drive, when used as torque increaser, means that the output shaft can be rotated via finite amount of torque. A high ratio harmonic drive is non-backdrivable because its output shaft cannot be turned by applying a torque on it. This article first develops the dynamic behavior of a harmonic drive, in particular the non-backdrivability, in terms of a sensitivity transfer function. The instrumentation of the harmonic drive with torque sensor is then described. This leads to a description of the control architecture which allows modulation of the sensitivity transfer function within the limits established by the closed-loop stability. A set of experiments on an active hand controller, powered by a DC motor coupled to an instrumented harmonic drive, is given to exhibit this method's limitations.

  6. Drive integration in perpendicular recording (invited)

    NASA Astrophysics Data System (ADS)

    Guarisco, Davide; Li, Zhaohui; Higgins, Bill E.; Saito, Kaz; Wu, Yan; Lefebvre, Andrew

    2006-04-01

    This paper reports on the progress in perpendicular drive integration. In the first part, an experiment comparing the effect of magnetic spacing variation between longitudinal and perpendicular recordings is discussed. First, it is shown that the Wallace equation applies to perpendicular recording provided that the density of the recorded signal is sufficiently high. Using a thermal actuator, the effect of separately changing the read and write magnetic spacings of longitudinal and perpendicular head and media is compared. It is shown that the bit error rate is more sensitive to write space variations versus read space variations. However, the dependence is similar between longitudinal and perpendicular components. In the second part, two types of single-head, 95 mm, 7200 rpm desktop perpendicular drives (40 and 80 Gbyte capacity) are presented. They both achieve good bit error rate and off-track capability in all zones. The thermal decay rate of the 40 Gbyte drive was measured and compared to a similar longitudinal drive. It was found that the decay rate is much smaller in the case of the perpendicular drive in the range of -6-+80 °C. The thermal decay rate of the two perpendicular drives was compared at ambient temperature and found to be equally small. Finally, a measurement of the bit error rate of the 40 Gbyte perpendicular drive over the same temperature range demonstrates that the drive operates well in this temperature range.

  7. 32 CFR 634.43 - Driving records.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Driving Records and the Traffic Point System § 634.43 Driving records. Each Service and DLA will use its own form to record vehicle traffic accidents, moving violations, suspension or revocation actions, and traffic point assessments involving military and DOD civilian...

  8. 32 CFR 634.43 - Driving records.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... INVESTIGATIONS MOTOR VEHICLE TRAFFIC SUPERVISION Driving Records and the Traffic Point System § 634.43 Driving records. Each Service and DLA will use its own form to record vehicle traffic accidents, moving violations, suspension or revocation actions, and traffic point assessments involving military and DOD civilian...

  9. DRIVE Analysis Tool Generates Custom Vehicle Drive Cycles Based on Real-World Data (Fact Sheet)

    SciTech Connect

    Not Available

    2013-04-01

    This fact sheet from the National Renewable Energy Laboratory describes the Drive-Cycle Rapid Investigation, Visualization, and Evaluation (DRIVE) analysis tool, which uses GPS and controller area network data to characterize vehicle operation and produce custom vehicle drive cycles, analyzing thousands of hours of data in a matter of minutes.

  10. DriveWise: An Interdisciplinary Hospital-Based Driving Assessment Program

    ERIC Educational Resources Information Center

    O'Connor, Margaret G.; Kapust, Lissa R.; Hollis, Ann M.

    2008-01-01

    Health care professionals working with the elderly have opportunities through research and clinical practice to shape public policy affecting the older driver. This article describes DriveWise, an interdisciplinary hospital-based driving assessment program developed in response to clinical concerns about the driving safety of individuals with…

  11. Adjustable Speed Drive Study, Part 2.

    SciTech Connect

    Wallace, Alan K.; Oregon State University. Dept. of Electrical and Computer Engineering.

    1989-08-01

    Advances in speed control for motors in recent years, notably those in power electronics, have widened the range of application for several adjustable speed drive (ASD) types to include the smaller horsepower sizes. The DC motor drive, formerly in almost universal use for speed control, is being challenged by the high efficiency induction motor/pulse width modulation (PWM) drive; and for special small horsepower size applications, by the permanent magnet motor/PWM inverter drive or by the switched reluctance motor drive. The main characteristics of the several ASD types suitable for small horsepower size applications are discussed, as well as their unwanted side effects: poor power factor, harmonic distortion of the supply, acoustic noise, and electromagnetic interference. A procedure is recommended for determining which, if any, ASD to use.

  12. Deep brain stimulation to reduce sexual drive

    PubMed Central

    Fuss, Johannes; Auer, Matthias K.; Biedermann, Sarah V.; Briken, Peer; Hacke, Werner

    2015-01-01

    To date there are few treatment options to reduce high sexual drive or sexual urges in paraphilic patients with a risk for sexual offending. Pharmacological therapy aims to reduce sexual drive by lowering testosterone at the cost of severe side effects. We hypothesize that high sexual drive could also be reduced with deep brain stimulation (DBS) of circuits that generate sexual drive. This approach would help to avoid systemic side effects of antiandrogenic drug therapies. So far the best investigated target to reduce sexual drive is the ventromedial hypothalamus, which was lesioned unilaterally and bilaterally by stereotaxic interventions in paraphilic patients in the 1970s. Here, we discuss DBS as a treatment strategy in patients with severe paraphilic disorders with a serious risk of sexual offending. There are profound ethical and practical issues associated with DBS treatment of paraphilic patients that must be solved before considering such a treatment approach. PMID:26057198

  13. Special considerations in distracted driving with teens.

    PubMed

    Durbin, Dennis R; McGehee, Daniel V; Fisher, Donald; McCartt, Anne

    2014-01-01

    Novice teen drivers have long been known to have an increased risk of crashing, as well as increased tendencies toward unsafe and risky driving behaviors. Teens are unique as drivers for several reasons, many of which have implications specifically in the area of distracted driving. This paper reviews several of these features, including the widespread prevalence of mobile device use by teens, their lack of driving experience, the influence of peer passengers as a source of distraction, the role of parents in influencing teens' attitudes and behaviors relevant to distracted driving and the impact of laws designed to prevent mobile device use by teen drivers. Recommendations for future research include understanding how engagement in a variety of secondary tasks by teen drivers affects their driving performance or crash risk; understanding the respective roles of parents, peers and technology in influencing teen driver behavior; and evaluating the impact of public policy on mitigating teen crash risk related to driver distraction. PMID:24776228

  14. DriveID: safety innovation through individuation.

    PubMed

    Sawyer, Ben; Teo, Grace; Mouloua, Mustapha

    2012-01-01

    The driving task is highly complex and places considerable perceptual, physical and cognitive demands on the driver. As driving is fundamentally an information processing activity, distracted or impaired drivers have diminished safety margins compared with non- distracted drivers (Hancock and Parasuraman, 1992; TRB 1998 a & b). This competition for sensory and decision making capacities can lead to failures that cost lives. Some groups, teens and elderly drivers for example, have patterns of systematically poor perceptual, physical and cognitive performance while driving. Although there are technologies developed to aid these different drivers, these systems are often misused and underutilized. The DriveID project aims to design and develop a passive, automated face identification system capable of robustly identifying the driver of the vehicle, retrieve a stored profile, and intelligently prescribing specific accident prevention systems and driving environment customizations. PMID:22317376

  15. Special Considerations in Distracted Driving with Teens

    PubMed Central

    Durbin, Dennis R; McGehee, Daniel V; Fisher, Donald; McCartt, Anne

    2014-01-01

    Novice teen drivers have long been known to have an increased risk of crashing, as well as increased tendencies toward unsafe and risky driving behaviors. Teens are unique as drivers for several reasons, many of which have implications specifically in the area of distracted driving. This paper reviews several of these features, including the widespread prevalence of mobile device use by teens, their lack of driving experience, the influence of peer passengers as a source of distraction, the role of parents in influencing teens’ attitudes and behaviors relevant to distracted driving and the impact of laws designed to prevent mobile device use by teen drivers. Recommendations for future research include understanding how engagement in a variety of secondary tasks by teen drivers affects their driving performance or crash risk; understanding the respective roles of parents, peers and technology in influencing teen driver behavior; and evaluating the impact of public policy on mitigating teen crash risk related to driver distraction. PMID:24776228

  16. Novel method for driving the ultrasonic motor.

    PubMed

    Kim, Hyeoung woo; Dong, Shuxiang; Laoratanakul, Pitak; Uchino, Kenji; Park, Tae gone

    2002-10-01

    This paper reports a novel driving method for an annular plate-type ultrasonic motor. Instead of the direct current/alternating current (DC/AC) converter type driver using conventional electromagnetic transformer, a compact disc-type piezoelectric transformer is used to obtain high voltage output for driving the ultrasonic motor. The piezoelectric transformer is operated in the radial vibration mode at resonance frequency close to the resonance frequency of the ultrasonic motor. Later, it was found that the piezoelectric transformer could drive the ultrasonic motor, even if their resonance frequencies are not exactly the same by incorporating the matching network in the circuit. The maximum speed of the ultrasonic motor obtained by using this driving method is over 300 rpm. It is believed that the results of this study will have impact on the integration and miniaturization of the ultrasonic motor and its driving circuit. PMID:12403137

  17. Exhaust powered drive shaft torque enhancer

    SciTech Connect

    Koch, A.B.

    1986-09-30

    This patent describes a power producing combination including an internal combustion engine and a mounting frame therefor, and power transmission means including rotating drive shaft means connected to the engine. The improvement described here is a drive shaft torque enhancing device, the device comprising: a multiplicity of blades secured to the drive shaft, equally spaced therearound, each generally lying in a plane containing the axis of the drive shaft; torque enhancer feed duct means for selectively directing a stream of exhaust gases from the engine to impact against the blades to impart torque to the drive shaft; and wherein the power producing combination is used in a vehicle, the vehicle having braking means including a brake pedal; and the power producing combination further comprising torque enhancer disengagement means responsive to motion of the brake pedal.

  18. Constant four wheel drive vehicle transaxle

    SciTech Connect

    Weismann, P.H.; Cameron, D.

    1986-04-15

    A dual differential four-wheel drive assembly is described adapted for a two-wheel drive front transaxle vehicle having an internal combustion engine with a transverse oriented crankshaft for driving the vehicle with front and rear pairs of road wheels, a transmission gear unit for the transaxle including transverse input and output shafts, and right and left laterally extending front axle drive shafts, each drive shaft having front wheel mounting means on its outboard end. The dual differential assembly consists of: housing means having a laterally extending passage therethrough aligned on a transverse axis, the housing means having first and second differential casings for associated first and second bevel gear differentials, the casings supported in laterally spaced alignment for rotation about the transverse axis, each first and second differential casing enclosing inboard and outboard side gears in meshing relation with planetary pinion gears, each casing having opposed inboard and outboard axial extensions thereon.

  19. Adolescence, Attention Allocation, and Driving Safety

    PubMed Central

    Romer, Daniel; Lee, Yi-Ching; McDonald, Catherine C.; Winston, Flaura K.

    2014-01-01

    Motor vehicle crashes are the leading source of morbidity and mortality in adolescents in the United States and the developed world. Inadequate allocation of attention to the driving task and to driving hazards are important sources of adolescent crashes. We review major explanations for these attention failures with particular focus on the roles that brain immaturity and lack of driving experience play in causing attention problems. The review suggests that the potential for overcoming inexperience and immaturity with training to improve attention to both the driving task and hazards is substantial. Nevertheless, there are large individual differences in both attentional abilities and risky driving tendencies that pose challenges to novice driver policies. Research that can provide evidence-based direction for such policies is urgently needed. PMID:24759442

  20. Bootstrapped tokamak with oscillating field current drive

    SciTech Connect

    Weening, R.H. )

    1993-07-01

    A magnetic helicity conserving mean-field Ohm's law is used to study bootstrapped tokamaks with oscillating field current drive. The Ohm's law leads to the conclusion that the tokamak bootstrap effect can convert the largely alternating current of oscillating field current drive into a direct toroidal plasma current. This plasma current rectification is due to the intrinsically nonlinear nature of the tokamak bootstrap effect, and suggests that it may be possible to maintain the toroidal current of a tokamak reactor by supplementing the bootstrap current with oscillating field current drive. Steady-state tokamak fusion reactors operating with oscillating field current drive could provide an alternative to tokamak reactors operating with external current drive.

  1. Adjustable speed drive study, part 1

    NASA Astrophysics Data System (ADS)

    Wallace, A.

    1989-08-01

    Advances in speed control for motors in recent years, notably those in power electronics, have widened the range of application for several adjustable speed drive (ASD) types to include the smaller horsepower sizes. The dc motor drive, formerly in almost universal use for speed control, is being challenged by the high efficiency induction motor/pulse width modulation (PWM) drive; and for special small horsepower size applications, by the permanent magnet motor/PWM inverter drive or by the switched reluctance motor drive. The main characteristics of the several ASD types suitable for small horsepower size applications are discussed, as well as their unwanted side effects: poor power factor, harmonic distortion of the supply, acoustic noise, and electromagnetic interference. A procedure is recommended for determining which, if any, ASD to use.

  2. Executive control functions in simulated driving.

    PubMed

    Mäntylä, Timo; Karlsson, Martin J; Marklund, Markus

    2009-01-01

    Teenage novice drivers have elevated crash rates compared with more experienced drivers. This study examined the hypothesis that driving accidents in young adults are associated with individual and developmental differences in prefrontally-mediated executive control functions. High-school students completed a simulated driving task and six experimental tasks that tapped three basic components of executive functioning (response inhibition, working memory updating, and mental shifting). Individual differences in executive functioning were related to simulated driving performance, and these effects were selective in that the updating component of executive functioning was the primary predictor of driving performance. Furthermore, the observed effects were accentuated in participants with minimal experience of computer games, suggesting that computer game skills compensated for inefficient working memory functions. The results of this study suggest that individual and developmental differences in executive functions contribute to driving accidents in young adults. PMID:19205943

  3. Adjustable Speed Drive Study, Part 1.

    SciTech Connect

    Wallace, Alan K.; Oregon State University. Dept. of Electrical and Computer Engineering.

    1989-08-01

    Advances in speed control for motors in recent years, notably those in power electronics, have widened the range of application for several adjustable speed drive (ASD) types to include the smaller horsepower sizes. The dc motor drive, formerly in almost universal use for speed control, is being challenged by the high efficiency induction motor/pulse width modulation (PWM) drive; and for special small horsepower size applications, by the permanent magnet motor/PWM inverter drive or by the switched reluctance motor drive. The main characteristics of the several ASD types suitable for small horsepower size applications are discussed, as well as their unwanted side effects: poor power factor, harmonic distortion of the supply, acoustic noise, and electromagnetic interference. A procedure is recommended for determining which, if any, ASD to use. 31 figs., 6 tabs.

  4. Inbreeding drives maize centromere evolution

    PubMed Central

    Schneider, Kevin L.; Xie, Zidian; Wolfgruber, Thomas K.; Presting, Gernot G.

    2016-01-01

    Functional centromeres, the chromosomal sites of spindle attachment during cell division, are marked epigenetically by the centromere-specific histone H3 variant cenH3 and typically contain long stretches of centromere-specific tandem DNA repeats (∼1.8 Mb in maize). In 23 inbreds of domesticated maize chosen to represent the genetic diversity of maize germplasm, partial or nearly complete loss of the tandem DNA repeat CentC precedes 57 independent cenH3 relocation events that result in neocentromere formation. Chromosomal regions with newly acquired cenH3 are colonized by the centromere-specific retrotransposon CR2 at a rate that would result in centromere-sized CR2 clusters in 20,000–95,000 y. Three lines of evidence indicate that CentC loss is linked to inbreeding, including (i) CEN10 of temperate lineages, presumed to have experienced a genetic bottleneck, contain less CentC than their tropical relatives; (ii) strong selection for centromere-linked genes in domesticated maize reduced diversity at seven of the ten maize centromeres to only one or two postdomestication haplotypes; and (iii) the centromere with the largest number of haplotypes in domesticated maize (CEN7) has the highest CentC levels in nearly all domesticated lines. Rare recombinations introduced one (CEN2) or more (CEN5) alternate CEN haplotypes while retaining a single haplotype at domestication loci linked to these centromeres. Taken together, this evidence strongly suggests that inbreeding, favored by postdomestication selection for centromere-linked genes affecting key domestication or agricultural traits, drives replacement of the tandem centromere repeats in maize and other crop plants. Similar forces may act during speciation in natural systems. PMID:26858403

  5. Recombination Drives Vertebrate Genome Contraction

    PubMed Central

    Nam, Kiwoong; Ellegren, Hans

    2012-01-01

    Selective and/or neutral processes may govern variation in DNA content and, ultimately, genome size. The observation in several organisms of a negative correlation between recombination rate and intron size could be compatible with a neutral model in which recombination is mutagenic for length changes. We used whole-genome data on small insertions and deletions within transposable elements from chicken and zebra finch to demonstrate clear links between recombination rate and a number of attributes of reduced DNA content. Recombination rate was negatively correlated with the length of introns, transposable elements, and intergenic spacer and with the rate of short insertions. Importantly, it was positively correlated with gene density, the rate of short deletions, the deletion bias, and the net change in sequence length. All these observations point at a pattern of more condensed genome structure in regions of high recombination. Based on the observed rates of small insertions and deletions and assuming that these rates are representative for the whole genome, we estimate that the genome of the most recent common ancestor of birds and lizards has lost nearly 20% of its DNA content up until the present. Expansion of transposable elements can counteract the effect of deletions in an equilibrium mutation model; however, since the activity of transposable elements has been low in the avian lineage, the deletion bias is likely to have had a significant effect on genome size evolution in dinosaurs and birds, contributing to the maintenance of a small genome. We also demonstrate that most of the observed correlations between recombination rate and genome contraction parameters are seen in the human genome, including for segregating indel polymorphisms. Our data are compatible with a neutral model in which recombination drives vertebrate genome size evolution and gives no direct support for a role of natural selection in this process. PMID:22570634

  6. Inbreeding drives maize centromere evolution.

    PubMed

    Schneider, Kevin L; Xie, Zidian; Wolfgruber, Thomas K; Presting, Gernot G

    2016-02-23

    Functional centromeres, the chromosomal sites of spindle attachment during cell division, are marked epigenetically by the centromere-specific histone H3 variant cenH3 and typically contain long stretches of centromere-specific tandem DNA repeats (∼1.8 Mb in maize). In 23 inbreds of domesticated maize chosen to represent the genetic diversity of maize germplasm, partial or nearly complete loss of the tandem DNA repeat CentC precedes 57 independent cenH3 relocation events that result in neocentromere formation. Chromosomal regions with newly acquired cenH3 are colonized by the centromere-specific retrotransposon CR2 at a rate that would result in centromere-sized CR2 clusters in 20,000-95,000 y. Three lines of evidence indicate that CentC loss is linked to inbreeding, including (i) CEN10 of temperate lineages, presumed to have experienced a genetic bottleneck, contain less CentC than their tropical relatives; (ii) strong selection for centromere-linked genes in domesticated maize reduced diversity at seven of the ten maize centromeres to only one or two postdomestication haplotypes; and (iii) the centromere with the largest number of haplotypes in domesticated maize (CEN7) has the highest CentC levels in nearly all domesticated lines. Rare recombinations introduced one (CEN2) or more (CEN5) alternate CEN haplotypes while retaining a single haplotype at domestication loci linked to these centromeres. Taken together, this evidence strongly suggests that inbreeding, favored by postdomestication selection for centromere-linked genes affecting key domestication or agricultural traits, drives replacement of the tandem centromere repeats in maize and other crop plants. Similar forces may act during speciation in natural systems. PMID:26858403

  7. Chapter 18: Variable Frequency Drive Evaluation Protocol

    SciTech Connect

    Romberger, J.

    2014-11-01

    An adjustable-speed drive (ASD) includes all devices that vary the speed of a rotating load, including those that vary the motor speed and linkage devices that allow constant motor speed while varying the load speed. The Variable Frequency Drive Evaluation Protocol presented here addresses evaluation issues for variable-frequency drives (VFDs) installed on commercial and industrial motor-driven centrifugal fans and pumps for which torque varies with speed. Constant torque load applications, such as those for positive displacement pumps, are not covered by this protocol. Other ASD devices, such as magnetic drive, eddy current drives, variable belt sheave drives, or direct current motor variable voltage drives, are also not addressed. The VFD is by far the most common type of ASD hardware. With VFD speed control on a centrifugal fan or pump motor, energy use follows the affinity laws, which state that the motor electricity demand is a cubic relationship to speed under ideal conditions. Therefore, if the motor runs at 75% speed, the motor demand will ideally be reduced to 42% of full load power; however, with other losses it is about 49% of full load power.

  8. [Car driving, cognitive aging and Alzheimer disease].

    PubMed

    Fabrigoule, Colette; Lafont, Sylviane

    2015-10-01

    Older drivers are more numerous on the roads. They are expert drivers, but with increasing age certain physiological changes can interfere with driving, which is a complex activity of daily living. Older drivers are involved in fewer accidents than younger drivers, but they have a higher accident rate per kilometer driven. The elderly are heavily represented in the balance sheet of road deaths, being motorists or pedestrians. This high mortality is largely explained by their physical frailty. In the presence of deficits, self-regulation of driving habits, changes/reductions or stopping in driving activity occur in the elderly. But cognitive deficits are associated with an increased risk of accidents. Among drivers with Alzheimer's disease, there is a heterogeneity of driving ability, making difficult the advisory role of a physician for driving. A protocol for physicians was developed to assess cognitive impairments that may affect driving in an elderly patient. The car plays an important role in the autonomy of the elderly and patient advice on stopping driving should take into account the risk/benefit ratio. PMID:26009241

  9. A high-fidelity harmonic drive model.

    SciTech Connect

    Preissner, C.; Royston, T. J.; Shu, D.

    2012-01-01

    In this paper, a new model of the harmonic drive transmission is presented. The purpose of this work is to better understand the transmission hysteresis behavior while constructing a new type of comprehensive harmonic drive model. The four dominant aspects of harmonic drive behavior - nonlinear viscous friction, nonlinear stiffness, hysteresis, and kinematic error - are all included in the model. The harmonic drive is taken to be a black box, and a dynamometer is used to observe the input/output relations of the transmission. This phenomenological approach does not require any specific knowledge of the internal kinematics. In a novel application, the Maxwell resistive-capacitor hysteresis model is applied to the harmonic drive. In this model, sets of linear stiffness elements in series with Coulomb friction elements are arranged in parallel to capture the hysteresis behavior of the transmission. The causal hysteresis model is combined with nonlinear viscous friction and spectral kinematic error models to accurately represent the harmonic drive behavior. Empirical measurements are presented to quantify all four aspects of the transmission behavior. These measurements motivate the formulation of the complete model. Simulation results are then compared to additional measurements of the harmonic drive performance.

  10. Fitness to Drive of Psychiatric Patients

    PubMed Central

    De las Cuevas, Carlos; Sanz, Emilio J.

    2008-01-01

    Background: Driving a motor vehicle could be central to the functional autonomy of patients with psychiatric illnesses. For patients, a driver's license could mean independence, the ability to care for themselves, and the freedom to travel when they wish. However, both psychiatric disorders and psychiatric drug treatments can produce changes in perception, information processing and integration, and psychomotor activity that can disturb and/or interfere with the ability to drive safely. Objective: To assess the fitness to drive of psychiatric outpatients in a sample representative of current clinical practice. Method: Cognitive functioning and psychomotor performance of 208 consecutive psychiatric outpatients treated in a community mental health center in the Canary Islands (Spain) were assessed in different clinical situations. The LNDETER 100 battery, an electronic assessment unit–based measurement that consists of 5 screenbased tests, was used to assess concentrated attention and resistance to monotony, multiple discriminative reactions and their correctness, anticipation of speed, bimanual coordination, and the decision making process and tendency to assume risk. The study was conducted from July 2007 to September 2007. Results: Of 208 patients, only 33 had scores compatible with the requirements of a driver's license, and 84% failed at least 1 of the required tests. Of patients with a driver's license who drive almost every day, 79.5% registered scores that would not allow obtaining or renewal of the license. None of the driving patients studied notified the traffic authorities that they had a psychiatric condition that may affect safe driving. No patient stopped driving, although 10% of them recognized that their ability to drive was somehow damaged. Conclusion: Guidance on how best to formulate and deliver recommendations on driving fitness in stable psychiatric patients is lacking and much needed. PMID:19158977

  11. Wind turbine ring/shroud drive system

    DOEpatents

    Blakemore, Ralph W.

    2005-10-04

    A wind turbine capable of driving multiple electric generators having a ring or shroud structure for reducing blade root bending moments, hub loads, blade fastener loads and pitch bearing loads. The shroud may further incorporate a ring gear for driving an electric generator. In one embodiment, the electric generator may be cantilevered from the nacelle such that the gear on the generator drive shaft is contacted by the ring gear of the shroud. The shroud also provides protection for the gearing and aids in preventing gear lubricant contamination.

  12. Landau-Zener interference at bichromatic driving

    NASA Astrophysics Data System (ADS)

    Forster, Florian; Mühlbacher, Max; Blattmann, Ralf; Schuh, Dieter; Wegscheider, Werner; Ludwig, Stefan; Kohler, Sigmund

    2015-12-01

    We investigate experimentally and theoretically the interference at avoided crossings which are repeatedly traversed as a consequence of an applied ac field. Our model system is a charge qubit in a serial double quantum dot connected to two leads. Our focus lies on effects caused by simultaneous driving with two different frequencies. We work out how the commensurability of the driving frequencies affects the symmetry of the interference patterns both in real space and in Fourier space. For commensurable frequencies, the symmetry depends sensitively on the relative phase between the two modes, whereas for incommensurable frequencies the symmetry of monochromatic driving is always recovered.

  13. Magnetostrictive Roller-Drive Stepping Motor

    NASA Technical Reports Server (NTRS)

    Vranish, John M.

    1993-01-01

    Proposed motor based on magnetostrictive effect provides stepped angular motion with angular increments of order of 100 microradians. Driven to repeat stepping cycle rapidly enough to achieve maximum speed of about 20 rpm, provides torque an order of magnitude greater than electric motors, and brakes itself when power turned off. Magnetostrictive rods in electromagnet coils push against drive plate, causing it to rotate slightly. This slight rotation jams conical rollers between cam surfaces on outer drive ring and split drum, so rollers transmit rotation to drum. Suitable for precise, high-torque, fail-safe-braking, direct drive of robot joint, without bulk and weight of additional brake mechanism and gear train.

  14. Bidirectional Drive-And-Brake Mechanism

    NASA Technical Reports Server (NTRS)

    Swan, Scott A.

    1991-01-01

    Vehicle that crawls along monorail combines features of both bicycle and railroad handcar. Bidirectional drive-and-brake mechanism includes selectable-pawl-and-ratchet overrunning clutch (drive mechanism) and mating stationary and rotating conical surfaces pressing against each other (brake mechanism). Operates similarly to bicycle drive-and-brake mechanism except limits rotation of sprocket in both directions and brakes at both limits. Conceived for use by astronaut traveling along structure in outer space, concept also applied on Earth to make very small railraod handcars or crawling vehicles for use on large structures, in pipelines under construction, or underwater.

  15. Microwave heating and current drive in tokamaks

    SciTech Connect

    Cohen, B.I.; Cohen, R.H.; Kerbel, G.D.; Logan, B.G.; Matsuda, Y.; McCoy, M.G.; Nevins, W.M.; Rognlien, T.D.; Smith, G.R.; Harvey, R.W.; Kritz, A.H.; Bonoli, P.T.; Porkolab, M.

    1988-08-23

    The use of powerful microwave sources provide unique opportunities for novel and efficient heating and current-drive schemes in the electron-cyclotron and lower-hybrid ranges of frequencies. Free- electron lasers and relativistic klystrons are new sources that have a number of technical advantages over conventional, lower-intensity sources; their use can lead to improved current-drive efficiencies and better penetration into a reactor-grade plasma in specific cases. This paper reports on modeling of absorption and current drive, in intense-pulse and quasilinear regimes, and on analysis of parametric instabilities and self-focusing. 16 refs., 2 figs.

  16. Control rod drive for reactor shutdown

    DOEpatents

    McKeehan, Ernest R.; Shawver, Bruce M.; Schiro, Donald J.; Taft, William E.

    1976-01-20

    A means for rapidly shutting down or scramming a nuclear reactor, such as a liquid metal-cooled fast breeder reactor, and serves as a backup to the primary shutdown system. The control rod drive consists basically of an in-core assembly, a drive shaft and seal assembly, and a control drive mechanism. The control rod is driven into the core region of the reactor by gravity and hydraulic pressure forces supplied by the reactor coolant, thus assuring that common mode failures will not interfere with or prohibit scramming the reactor when necessary.

  17. The Technique of Changing the Drive Method of Micro Step Drive and Sensorless Drive for Hybrid Stepping Motor

    NASA Astrophysics Data System (ADS)

    Yoneda, Makoto; Dohmeki, Hideo

    The position control system with the advantage large torque, low vibration, and high resolution can be obtained by the constant current micro step drive applied to hybrid stepping motor. However loss is large, in order not to be concerned with load torque but to control current uniformly. As the one technique of a position control system in which high efficiency is realizable, the same sensorless control as a permanent magnet motor is effective. But, it was the purpose that the control method proposed until now controls speed. Then, this paper proposed changing the drive method of micro step drive and sensorless drive. The change of the drive method was verified from the simulation and the experiment. On no load, it was checked not producing change of a large speed at the time of a change by making electrical angle and carrying out zero reset of the integrator. On load, it was checked that a large speed change arose. The proposed system could change drive method by setting up the initial value of an integrator using the estimated result, without producing speed change. With this technique, the low loss position control system, which employed the advantage of the hybrid stepping motor, has been built.

  18. Test-retest reliability of the driving habits questionnaire in older self-driving adults

    PubMed Central

    Song, Chiang-Soon; Chun, Byung-Yoon; Chung, Hyun-Sook

    2015-01-01

    [Purpose] The purpose of this study was to investigate the test-retest reliability of the Driving Habits Questionnaire in community-dwelling older self-drivers. [Subjects and Methods] Seventy-four participants were recruited by convenience sampling from local rehabilitation centers. This was a cross-sectional study design that used two clinical measures: the Driving Habits Questionnaire and Mini-mental State Examination. To examine the test-retest reliability of the Driving Habits Questionnaire, the clinical tool was measured twice, five days apart. [Results] The Driving Habits Questionnaire showed good reliability for older community-dwelling self-drivers. The Cronbach’s alpha coefficients for the four domains of dependence (0.572), difficulty (0.871), crashes and citations (0.689), and driving space (0.961) of the Driving Habits Questionnaire indicated good or high internal consistency. Driving difficulty correlated significantly with self-reported crashes and citations and driving space. [Conclusion] The results of this study suggest that the Driving Habits Questionnaire is a reliable measure of self-reported interview-based driving behavior in the community-dwelling elderly. PMID:26696745

  19. Test-retest reliability of the driving habits questionnaire in older self-driving adults.

    PubMed

    Song, Chiang-Soon; Chun, Byung-Yoon; Chung, Hyun-Sook

    2015-11-01

    [Purpose] The purpose of this study was to investigate the test-retest reliability of the Driving Habits Questionnaire in community-dwelling older self-drivers. [Subjects and Methods] Seventy-four participants were recruited by convenience sampling from local rehabilitation centers. This was a cross-sectional study design that used two clinical measures: the Driving Habits Questionnaire and Mini-mental State Examination. To examine the test-retest reliability of the Driving Habits Questionnaire, the clinical tool was measured twice, five days apart. [Results] The Driving Habits Questionnaire showed good reliability for older community-dwelling self-drivers. The Cronbach's alpha coefficients for the four domains of dependence (0.572), difficulty (0.871), crashes and citations (0.689), and driving space (0.961) of the Driving Habits Questionnaire indicated good or high internal consistency. Driving difficulty correlated significantly with self-reported crashes and citations and driving space. [Conclusion] The results of this study suggest that the Driving Habits Questionnaire is a reliable measure of self-reported interview-based driving behavior in the community-dwelling elderly. PMID:26696745

  20. Gear drive automatically indexes rotary table

    NASA Technical Reports Server (NTRS)

    Johns, M. F.

    1966-01-01

    Combination indexer and drive unit drills equally spaced circular hole patterns on rotary tables. It automatically rotates the table a distance exactly equal to one hole spacing for each revolution of a special idler gear.

  1. Cannabis and driving: a new perspective.

    PubMed

    O'Kane, Carl J; Tutt, Douglas C; Bauer, Lyndon A

    2002-09-01

    Cannabis and driving is an emerging injury-prevention concern. The incidence of driving while affected by cannabis is rising in parallel with increased cannabis use in the community. Younger drivers are at particular risk. Improvements in research methodology, technology and laboratory testing methods have occurred in the last 10 years. These cast doubt on earlier results and conclusions. Studies now show that cannabis has a significant impairing effect on driving when used alone and that this effect is exaggerated when combined with alcohol. Of particular concern is the presence of cannabis as the sole psychoactive drug in an increasing number of road fatalities and the lack of any structural response to this problem. A review of testing methods, laboratory and real driving studies, and recent epidemiological studies is presented. Suggestions for methods of further data collection and future public policy are made. PMID:12487047

  2. Chain friction system gives positive, reversible drive

    NASA Technical Reports Server (NTRS)

    Davidsen, J. S.

    1964-01-01

    By cementing a strip of an elastomer to the smooth metal rim of the pulley and neoprene covered idlers providing suitable tension to the chain around the pulley, a positive reversible drive is accomplished more quietly and with less vibration.

  3. Mechanical vs electric drive: which to choose

    SciTech Connect

    Smiley, C.H.

    1983-03-01

    One of the more basic decisions in haul truck selection is whether to buy a mechanical drive unit with transmission, torque converter, and propeller shaft or a unit with alternator, rectifier, and wheel drive motors. Both drives offer advantages and disadvantages for 85- to 120-ton trucks. The amount of horsepower actually available to the wheel via the 2 drive modes is discussed. It is suggested that an accurate comparison of life and cost of maintenance should be based on the number of tons of material moved as well as hours of service. Mechanical systems do have an advantage on very sharp grades (16% or more) at very low speeds and on gentle grades of 6% or less at speeds in excess of 30 mph. Between those 2 extremes, performance is nearly equal.

  4. Some Sleep Drugs Can Impair Driving

    MedlinePlus

    ... For Consumers Home For Consumers Consumer Updates Some Sleep Drugs Can Impair Driving Share Tweet Linkedin Pin ... OTC) drugs. back to top Most Widely Used Sleep Drug Zolpidem—which has been on the market ...

  5. How mantle slabs drive plate tectonics.

    PubMed

    Conrad, Clinton P; Lithgow-Bertelloni, Carolina

    2002-10-01

    The gravitational pull of subducted slabs is thought to drive the motions of Earth's tectonic plates, but the coupling between slabs and plates is not well established. If a slab is mechanically attached to a subducting plate, it can exert a direct pull on the plate. Alternatively, a detached slab may drive a plate by exciting flow in the mantle that exerts a shear traction on the base of the plate. From the geologic history of subduction, we estimated the relative importance of "pull" versus "suction" for the present-day plates. Observed plate motions are best predicted if slabs in the upper mantle are attached to plates and generate slab pull forces that account for about half of the total driving force on plates. Slabs in the lower mantle are supported by viscous mantle forces and drive plates through slab suction. PMID:12364804

  6. Distracted driving: prevalence, problems, and prevention.

    PubMed

    Overton, Tiffany L; Rives, Terry E; Hecht, Carrie; Shafi, Shahid; Gandhi, Rajesh R

    2015-01-01

    While the number of motor vehicle crashes has declined over the years, crashes resulting from distracted driving are increasing in the United States resulting in significant morbidity and mortality. The national public seems to be aware of the dangers associated with using technology while driving, but continues to engage in this dangerous behaviour, and may be unaware of or underestimate the impact of cell phone use on their own driving performance. Problems associated with distracted driving are not limited to novice or teenage drivers; multifaceted universal prevention efforts aimed at impacting large segments of the population may have the greatest impact. Legislation limiting drivers' cell phone use has had little impact, possibly due to low regulation and enforcement. Behaviour change programmes, improved vehicle safety, and public awareness campaigns have been developed as potential preventive efforts to reduce accidents caused by distracted drivers. PMID:24499372

  7. Drinking and driving among high school students.

    PubMed

    Williams, A F; Lund, A K; Preusser, D F

    1986-06-01

    A questionnaire survey of high school students conducted in 1983 provided information on their self-reported drinking and driving practices. By age 15 the majority reported drinking alcoholic beverages. By age 17 half or more of the males and one-third of the females reported driving after drinking at least once in the past month. About one-quarter of the students estimated that six or more cans of beer would be required to make someone an unsafe driver. Reported frequency of driving after drinking was associated with less time spent on homework and poorer academic performance, working part time, greater participation in social activities, less perceived parental influence regarding their travel, owning a car, driving high mileage, speeding, and having crashes and violations. PMID:3744616

  8. Driving and insulin-dependent diabetes.

    PubMed

    Frier, B M; Matthews, D M; Steel, J M; Duncan, L J

    1980-06-01

    A survey of 250 patients with insulin-dependent diabetes (IDD) holding a full motor vehicle driving licence revealed that 107 (42.8%) had not declared IDD on their application for a driving licence. 70 of these (28% of entire group) claimed that they were unaware of the statutory requirements. There was no difference in the declaration-rate between men and women. 159 patients (66%) declared IDD for their motor insurance. 86 patients (34.4%) had had severe or frequent hypoglycaemia in the preceding six months, during which they had been driving regularly. 34 patients (13.6%) admitted involvement in a driving accident since commencing treatment with insulin, and 13 of these patients were aware that hypoglycaemia had been an important causal factor. The prevalence of diabetic retinopathy and cataracts was considerable, but few patients (2.4%) had severe impairment of vision in both eyes. PMID:6104046

  9. Driving-related fear: a review.

    PubMed

    Taylor, Joanne; Deane, Frank; Podd, John

    2002-06-01

    This article reviews the research on driving-related fear (DRF). Until recently, research has concentrated almost exclusively on the effect of motor vehicle accidents (MVAs) on subsequent levels of DRF. However, recent findings have suggested that MVAs are not solely responsible for this fear reaction, and that non-MVA driving fear can be just as strong. Studies of the broader driving-fearful population have encountered difficulty with diagnostic conceptualisation of DRF, although some have investigated a possible typology of DRF. Driving skill has been a neglected issue in the DRF research, and may prove to be a useful part of assessment and remediation of this potentially debilitating problem. Issues of definitional inconsistency are highlighted, and suggestions are made for several directions that future research might profitably take. PMID:12113199

  10. The National Cancer Program: Driving Discovery

    Cancer.gov

    An overview of NCI’s role in driving cancer research discoveries: conducting and funding research in challenging areas and providing resources and leadership to national infrastructures for cancer research.

  11. 25 CFR 11.445 - Driving violations.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... ORDER CODE Criminal Offenses § 11.445 Driving violations. (a) A person who shall operate any vehicle in....450 depending on the nature of the traffic code violation, and may be deprived of the right to...

  12. Universal power transistor base drive control unit

    DOEpatents

    Gale, A.R.; Gritter, D.J.

    1988-06-07

    A saturation condition regulator system for a power transistor is disclosed which achieves the regulation objectives of a Baker clamp but without dumping excess base drive current into the transistor output circuit. The base drive current of the transistor is sensed and used through an active feedback circuit to produce an error signal which modulates the base drive current through a linearly operating FET. The collector base voltage of the power transistor is independently monitored to develop a second error signal which is also used to regulate base drive current. The current-sensitive circuit operates as a limiter. In addition, a fail-safe timing circuit is disclosed which automatically resets to a turn OFF condition in the event the transistor does not turn ON within a predetermined time after the input signal transition. 2 figs.

  13. Universal power transistor base drive control unit

    DOEpatents

    Gale, Allan R.; Gritter, David J.

    1988-01-01

    A saturation condition regulator system for a power transistor which achieves the regulation objectives of a Baker clamp but without dumping excess base drive current into the transistor output circuit. The base drive current of the transistor is sensed and used through an active feedback circuit to produce an error signal which modulates the base drive current through a linearly operating FET. The collector base voltage of the power transistor is independently monitored to develop a second error signal which is also used to regulate base drive current. The current-sensitive circuit operates as a limiter. In addition, a fail-safe timing circuit is disclosed which automatically resets to a turn OFF condition in the event the transistor does not turn ON within a predetermined time after the input signal transition.

  14. Opioids by Injection May Drive HIV Outbreaks

    MedlinePlus

    ... fullstory_159978.html Opioids by Injection May Drive HIV Outbreaks Indiana case offers a lesson for other ... drug abuse epidemic has increased the risk of HIV outbreaks in rural and suburban communities, where up ...

  15. Impediment to Spirit Drive on Sol 1806

    NASA Technical Reports Server (NTRS)

    2009-01-01

    The hazard avoidance camera on the front of NASA's Mars Exploration Rover Spirit took this image after a drive by Spirit on the 1,806th Martian day, or sol, (January 31, 2009) of Spirit's mission on the surface of Mars.

    The wheel at the bottom right of the image is Spirit's right-front wheel. Because that wheel no longer turns, Spirit drives backwards dragging that wheel. The drive on Sol 1806 covered about 30 centimeters (1 foot). The rover team had planned a longer drive, but Spirit stopped short, apparently from the right front wheel encountering the partially buried rock visible next to that wheel.

    The hazard avoidance cameras on the front and back of the rover provide wide-angle views. The hill on the horizon in the right half of this image is Husband Hill. Spirit reached the summit of Husband Hill in 2005.

  16. Automatic fluid separator supplies own driving power

    NASA Technical Reports Server (NTRS)

    Decker, M. S.; Majneri, L. A.; Spulgis, I. S.

    1966-01-01

    Centrifugal separator suspended in the fuel tank of a space vehicle selects and vents gas vapor at zero gravity. Escaping vapor is used to drive an expander turbine that is magnetically coupled to the separator.

  17. Rotating Drive for Electrical-Arc Machining

    NASA Technical Reports Server (NTRS)

    Fransen, C. D.

    1986-01-01

    Rotating drive improves quality of holes made by electrical-arc machining. Mechanism (Uni-tek, rotary head, or equivalent) attached to electrical-arc system. Drive rotates electrode as though it were mechanical drill, while an arc disintegrates metal in workpiece, thereby creating hole. Rotating electrode method often used in electric-discharge machining. NASA innovation is application of technique to electrical-arc machining.

  18. Additional Drive Circuitry for Piezoelectric Screw Motors

    NASA Technical Reports Server (NTRS)

    Smythe, Robert; Palmer, Dean; Gursel, Yekta; Reder, Leonard; Savedra, Raymond

    2004-01-01

    Modules of additional drive circuitry have been developed to enhance the functionality of a family of commercially available positioning motors (Picomotor . or equivalent) that provide linear motion controllable, in principle, to within increments .30 nm. A motor of this type includes a piezoelectric actuator that turns a screw. Unlike traditional piezoelectrically actuated mechanisms, a motor of this type does not rely on the piezoelectric transducer to hold position: the screw does not turn except when the drive signal is applied to the actuator.

  19. Camshaft driving system for internal combustion engine

    SciTech Connect

    Hiroshima, K.A.

    1987-06-23

    This patent describes camshaft driving system for a double overhead camshaft engine cylinder rows extend parallel to the crankshaft of the engine. The second cylinder row is rearwardly displaced from the first cylinder row in the axial direction of the crankshaft so that vacant spaces are formed respectively behind the first cylinder row and in front of the second cylinder row. All the pistons in the cylinders of the first and second cylinder rows are connected to the crankshaft and a pair of camshafts for driving the intake and exhaust valves are provided in the cylinder head of each cylinder row to extend in the direction of the crankshaft. The camshaft driving system comprises a timing pulley provided on one of the intake and exhaust camshafts of each cylinder row to rotate together with the camshaft; A crank pulley is driven by the crankshaft; A first driving force transmission means transmits rotation of the crank pulley to the timing pulleys of the first and second cylinder rows; a second driving force transmission means transmits rotation of the timing pulley of the first cylinder row to the other of the camshafts of the first cylinder row; and a third driving force transmission means transmits rotation of the timing pulley of the second cylinder row to the other of the camshafts of the second cylinder row. The second driving force transmission means is disposed in the vacant space behind the first cylinder row and the third driving force transmission means is disposed in the vacant space in front of the second cylinder row.

  20. Frequency modulation drive for a piezoelectric motor

    DOEpatents

    Mittas, Anthony

    2001-01-01

    A piezoelectric motor has peak performance at a specific frequency f.sub.1 that may vary over a range of frequencies. A drive system is disclosed for operating such a motor at peak performance without feedback. The drive system consists of the motor and an ac source connected to power the motor, the ac source repeatedly generating a frequency over a range from f.sub.1 -.DELTA.x to f.sub.1 +.DELTA.y.

  1. Direct-drive field actuator motors

    DOEpatents

    Grahn, Allen R.

    1995-01-01

    A high-torque, low speed, positive-drive field actuator motor including a stator carrying at least one field actuator which changes in dimension responsive to application of an energy field, and at least one drive shoe movable by the dimensional changes of the field actuator to contact and move a rotor element with respect to the stator. Various embodiments of the motor are disclosed, and the rotor element may be moved linearly or arcuately.

  2. Direct-drive field actuator motors

    DOEpatents

    Grahn, A.R.

    1995-07-11

    A high-torque, low speed, positive-drive field actuator motor is disclosed including a stator carrying at least one field actuator which changes in dimension responsive to application of an energy field, and at least one drive shoe movable by the dimensional changes of the field actuator to contact and move a rotor element with respect to the stator. Various embodiments of the motor are disclosed, and the rotor element may be moved linearly or arcuately. 37 figs.

  3. New Lower Bounds for Warp Drive Energy

    NASA Astrophysics Data System (ADS)

    Gauthier, C.; Gravel, P.; Melanson, J.

    The introduction of the warp drive metric by Alcubierre1 has aroused great interest over the past few years. Using an uncertainty-type principle, Ford and Pfenning2 proved that the warp drive transport of a spaceship in a regular bubble having a radius of 100 m is unrealistic. However, Van Den Broeck3 has shown that the situation largely improves when one uses a warp drive bubble with a small surface area and large spatial volume. Putting aside many physics problems related to the realization of the warp drive concept, we show in this paper4 how to modify Van Den Broeck's idea to improve his results. We find new lower bounds for the warp drive energy by working on parameters whose latitude has never been considered before. We also consider micro warp drive bubbles which can be treated as physical entities of their own and could possibly be used to transmit information faster than the speed of light. The conditions prevailing just after the Big Bang allow the spontaneous formation of such micro bubbles which could still be present in our period of time.

  4. 24. CARRIAGE DRIVE, CARRIAGE, HEAD RIG LOOKING WEST FROM INTERIOR ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    24. CARRIAGE DRIVE, CARRIAGE, HEAD RIG LOOKING WEST FROM INTERIOR OF MAIN BUILDING. NOTE CABLE DRIVE DRUM AND FLY WHEELS OF CARRIAGE DRIVE STEAM ENGINE IN FOREGROUND. - Hull-Oakes Lumber Company, 23837 Dawson Road, Monroe, Benton County, OR

  5. Commercial Truck Driver Health and Safety: Exploring Distracted Driving Performance and Self-Reported Driving Skill.

    PubMed

    Stavrinos, Despina; Heaton, Karen; Welburn, Sharon C; McManus, Benjamin; Griffin, Russell; Fine, Philip R

    2016-08-01

    Reducing distracters detrimental to commercial truck driving is a critical component of improving the safety performance of commercial drivers, and makes the highways safer for all drivers. This study used a driving simulator to examine effects of cell phone, texting, and email distractions as well as self-reported driver optimism bias on the driving performance of commercial truck drivers. Results revealed that more visually demanding tasks were related to poorer driving performance. However, the cell phone task resulted in less off-the-road eye glances. Drivers reporting being "very skilled" displayed poorer driving performance than those reporting being "skilled." Onboard communication devices provide a practical, yet visually and manually demanding, solution for connecting drivers and dispatchers. Trucking company policies should minimize interaction between dispatchers and drivers when the truck is in motion. Training facilities should integrate driving simulators into the instruction of commercial drivers, targeting over-confident drivers. PMID:26809775

  6. Driving Competence in Mild Dementia with Lewy Bodies: In Search of Cognitive Predictors Using Driving Simulation

    PubMed Central

    Yamin, Stephanie; Stinchcombe, Arne; Gagnon, Sylvain

    2015-01-01

    Driving is a multifactorial behaviour drawing on multiple cognitive, sensory, and physical systems. Dementia is a progressive and degenerative neurological condition that impacts the cognitive processes necessary for safe driving. While a number of studies have examined driving among individuals with Alzheimer's disease, less is known about the impact of Dementia with Lewy Bodies (DLB) on driving safety. The present study compared simulated driving performance of 15 older drivers with mild DLB with that of 21 neurologically healthy control drivers. DLB drivers showed poorer performance on all indicators of simulated driving including an increased number of collisions in the simulator and poorer composite indicators of overall driving performance. A measure of global cognitive function (i.e., the Mini Mental State Exam) was found to be related to the overall driving performance. In addition, measures of attention (i.e., Useful Field of View, UFOV) and space processing (Visual Object and Space Perception, VOSP, Test) correlated significantly with a rater's assessment of driving performance. PMID:26713169

  7. Acceptance of drinking and driving and alcohol-involved driving crashes in California

    PubMed Central

    Karriker-Jaffe, Katherine J.; Ragland, David R.; Satariano, William A.; Kelley-Baker, Tara; Lacey, John H.

    2016-01-01

    Background Alcohol-impaired driving accounts for substantial proportion of traffic-related fatalities in the U.S. Risk perceptions for drinking and driving have been associated with various measures of drinking and driving behavior. In an effort to understand how to intervene and to better understand how risk perceptions may be shaped, this study explored whether an objective environmental-level measure (proportion of alcohol-involved driving crashes in one's residential city) were related to individual-level perceptions and behavior. Methods Using data from a 2012 cross-sectional roadside survey of 1,147 weekend nighttime drivers in California, individual-level self-reported acceptance of drinking and driving and past-year drinking and driving were merged with traffic crash data using respondent ZIP codes. Population average logistic regression modeling was conducted for the odds of acceptance of drinking and driving and self-reported, past-year drinking and driving. Results A non-linear relationship between city-level alcohol-involved traffic crashes and individual-level acceptance of drinking and driving was found. Acceptance of drinking and driving did not mediate the relationship between the proportion of alcohol-involved traffic crashes and self-reported drinking and driving behavior. However, it was directly related to behavior among those most likely to drink outside the home. Discussion The present study surveys a particularly relevant population and is one of few drinking and driving studies to evaluate the relationship between an objective environmental-level crash risk measure and individual-level risk perceptions. In communities with both low and high proportions of alcohol-involved traffic crashes there was low acceptance of drinking and driving. This may mean that in communities with low proportions of crashes, citizens have less permissive norms around drinking and driving, whereas in communities with a high proportion of crashes, the incidence of

  8. Predictors of Driving Outcomes in Advancing Age

    PubMed Central

    Emerson, Jamie L.; Johnson, Amy M.; Dawson, Jeffrey D.; Uc, Ergun Y.; Anderson, Steven W.

    2012-01-01

    This study aimed to develop predictive models for real-life driving outcomes in older drivers. Demographics, driving history, on-road driving errors, and performance on visual, motor, and neuropsychological test scores at baseline were assessed in 100 older drivers (ages 65–89 years [72.7]). These variables were used to predict time to driving cessation, first moving violation, or crash. Using Cox proportional hazards regression models, significant individual predictors for driving cessation were greater age and poorer scores on Near Visual Acuity, Contrast Sensitivity, Useful Field of View, Judgment of Line Orientation, Trail Making Test-Part A, Benton Visual Retention Test, Grooved Pegboard, and a composite index of overall cognitive ability. Greater weekly mileage, higher education, and “serious” on-road errors predicted moving violations. Poorer scores from Trail Making Test-Part B or Trail Making Test (B-A) and serious on-road errors predicted crashes. Multivariate models using “off-road” predictors revealed (1) age and Contrast Sensitivity as best predictors for driving cessation; (2) education, weekly mileage, and Auditory Verbal Learning Task-Recall for moving violations; and (3) education, number of crashes over the past year, Auditory Verbal Learning Task-Recall, and Trail Making Test (B-A) for crashes. Diminished visual, motor, and cognitive abilities in older drivers can be easily and noninvasively monitored with standardized off-road tests, and performances on these measures predict involvement in motor vehicle crashes and driving cessation, even in the absence of a neurological disorder. PMID:22182364

  9. Cylindrical Implosion Experiments using Laser Direct Drive

    NASA Astrophysics Data System (ADS)

    Tubbs, David

    1998-11-01

    Development of high-gain targets for the National Ignition Facility relies considerably on computational modeling, and it is important that our codes are validated against relevant experimental data in convergent geometry.(W. J. Krauser et al., Phys. Plasmas 3, 2084 (1996); D. C. Wilson et al., Phys. Plasmas 5, 1953 (1998)) In collaboration with the University of Rochester, we have begun a campaign of hydrodynamic instability experiments in cylindrical geometry using direct drive,(D. L. Tubbs et al., submitted to Laser and Particle Beams (1998); C. W. Barnes et al., submitted to Rev. Sci. Instrm. (1998)) building on our success in indirect drive.( W. W. Hsing et al., Phys. Plasmas 5, 1832 (1997); W. W. Hsing and N. M. Hoffman, Phys. Rev. Lett., 3876 (1997)) Cylindrical targets facilitate direct diagnostic access to the convergent, hydrodynamic flow. The energy advantage of direct drive and its excellent target-illumination symmetry (achieved at OMEGA through use of Distributed Phase Plates and SSD) permit more energetic implosions, larger target scale (hence greater diagnostic resolution), longer acceleration timescales, and higher convergence than were possible using indirect drive. We estimate that specific laser energy delivered to the target for direct drive at OMEGA is roughly 4 times that achieved for indirect drive at Nova. Our first experiments (January 1998) yield excellent data for the first highly symmetrical direct-drive implosions, with which we benchmark zeroth-order hydrodynamic simulations. Two-dimensional (2-D) LASNEX calculations, using as-shot laser power histories and no further physics adjustments, match measured target-implosion data within theoretical and experimental errors. In addition, 2-D LASNEX simulations of single-mode (m=28, azimuthally symmetric) perturbation growth agree well with data obtained during our first week of experiments. For 1.5-micron initial perturbation amplitude, we observe Rayleigh-Taylor growth factors of order 10

  10. Fundamental limitations on 'warp drive' spacetimes

    NASA Astrophysics Data System (ADS)

    Lobo, Francisco S. N.; Visser, Matt

    2004-12-01

    'Warp drive' spacetimes are useful as 'gedanken-experiments' that force us to confront the foundations of general relativity, and among other things, to precisely formulate the notion of 'superluminal' communication. After carefully formulating the Alcubierre and Natário warp drive spacetimes, and verifying their non-perturbative violation of the classical energy conditions, we consider a more modest question and apply linearized gravity to the weak-field warp drive, testing the energy conditions to first and second orders of the warp-bubble velocity, v. Since we take the warp-bubble velocity to be non-relativistic, v Lt c, we are not primarily interested in the 'superluminal' features of the warp drive. Instead we focus on a secondary feature of the warp drive that has not previously been remarked upon—the warp drive (if it could be built) would be an example of a 'reaction-less drive'. For both the Alcubierre and Natário warp drives we find that the occurrence of significant energy condition violations is not just a high-speed effect, but that the violations persist even at arbitrarily low speeds. A particularly interesting feature of this construction is that it is now meaningful to think of placing a finite mass spaceship at the centre of the warp bubble, and then see how the energy in the warp field compares with the mass energy of the spaceship. There is no hope of doing this in Alcubierre's original version of the warp field, since by definition the point at the centre of the warp bubble moves on a geodesic and is 'massless'. That is, in Alcubierre's original formalism and in the Natário formalism the spaceship is always treated as a test particle, while in the linearized theory we can treat the spaceship as a finite mass object. For both the Alcubierre and Natário warp drives we find that even at low speeds the net (negative) energy stored in the warp fields must be a significant fraction of the mass of the spaceship.

  11. Energy Considerations of Hypothetical Space Drives

    NASA Technical Reports Server (NTRS)

    Millis, Marc G.

    2007-01-01

    The energy requirements of hypothetical, propellant-less space drives are compared to rockets. This serves to provide introductory estimates for potential benefits and to suggest analytical approaches for further study. A "space drive" is defined as an idealized form of propulsion that converts stored potential energy directly into kinetic energy using only the interactions between the spacecraft and its surrounding space. For Earth-to-orbit, the space drive uses 3.7 times less energy. For deep space travel, energy is proportional to the square of delta-v, whereas rocket energy scales exponentially. This has the effect of rendering a space drive 150-orders-of-magnitude better than a 17,000-s Specific Impulse rocket for sending a modest 5000 kg probe to traverse 5 ly in 50 years. Indefinite levitation, which is impossible for a rocket, could conceivably require 62 MJ/kg for a space drive. Assumption sensitivities and further analysis options are offered to guide further inquires.

  12. Space Drive Physics: Introduction and Next Steps

    NASA Astrophysics Data System (ADS)

    Millis, M. G.

    Research toward the visionary goal of propellantless ``space drives'' is introduced, covering key physics issues and a listing of roughly 2-dozen approaches. The targeted advantage of a space drive is to circumvent the propellant constraints of rockets and the maneuvering limits of light sails by using the interactions between the spacecraft and its surrounding space for propulsion. At present, the scientific foundations from which to engineer a space drive have not been discovered and, objectively, might be impossible. Although no propulsion breakthroughs appear imminent, the subject has matured to where the relevant questions have been broached and are beginning to be answered. The critical make-break issues include; conservation of momentum, uncertain sources of reaction mass, and the net-external thrusting requirement. Note: space drives are not necessarily faster- than-light devices. Speed limits are a separate, unanswered issue. Relevant unsolved physics includes; the sources and mechanisms of inertial frames, coupling of gravitation and electromagnetism, and the nature of the quantum vacuum. The propulsion approaches span mostly stages 1 through 3 of the scientific method (defining the problem, collecting data, and articulating hypotheses), while some have matured to stage 4 (testing hypotheses). Nonviable approaches include `stiction drives,' `gyroscopic antigravity,' and `lifters.' No attempt is made to gauge the prospects of the remaining approaches. Instead, a list of next-step research questions is derived from the examination of these goals, unknowns, and concepts.

  13. Portable top drive cuts horizontal drilling costs

    SciTech Connect

    Jackson, B.; Yager, D.

    1993-11-01

    Economic analysis of a seven-well, long-reach horizontal drilling program into an unconsolidated, heavy-oil-bearing reservoir in Winter field near the Alberta/Saskatchewan border in Canada reveals that -- in the right application -- renting a portable top drive drilling system can reduce total drilling costs. Use of the portable top drive combined with other cost-saving measures enabled Saskoil, one of Canada`s larger independents, to drill more cheaply, on a cost-per-meter basis, in 1993 than in 1992. This was despite significant rental rates for drilling rigs and directional drilling services caused by increased demand in Western Canada. Total cost savings of 10% on wells that would otherwise cost in the (C) $500,000 range are believed realistic. Based on this year`s performance, Saskoil recommends top drive for the company`s future horizontal wells in this area. This article describes the operator`s horizontal well program, advantages of top drive in that program and how it was installed and applied. Estimated time savings for six wells, plus other ways top drive can cut costs and improve operations are discussed.

  14. Single-crystal disk drive miniactuators

    NASA Astrophysics Data System (ADS)

    Giovanardi, Marco; McKenney, Kevin B.; Rule, John A.; Yoshikawa, Shoko

    2001-08-01

    As hard disk drive areal densities increase at a compound annual growth rate (CAGR) of 60%, disk drives must position the head over increasingly small areas while moving more rapidly to reach the desired position. This results in an increase in vibration disturbance. To meet this demand, many hard disk drive manufactures have created prototype dual-stage actuators employing piezoelectric ceramics for the second stage. These are an attractive means of obtaining higher-bandwidth control due to the low inertia and size of the actuator element. As the technology improves, the next limiting factor will be the amount of displacement obtainable with traditional piezoceramic elements. Under the AXIS (Advanced Crystal Integrated System) Consortium program funded by DARPA, the application of PZN-PT single crystal piezoceramic as a second stage disk drive actuator was studied, based on the fact that the single crystal material provides larger stroke than its traditional PZT counterparts. The transverse (d31) strain of PZN-PT single crystal was measured to be about two times larger than that of PZT-5H ceramic. Both materials were integrated into a disk drive system and compared as second stage actuators. The methodologies used and the servo control techniques applied are also discussed in the paper.

  15. DriveSafe and DriveAware Assessment Tools Are a Measure of Driving-Related Function and Predicts Self-Reported Restriction for Older Drivers.

    PubMed

    Allan, Claire; Coxon, Kristy; Bundy, Anita; Peattie, Laura; Keay, Lisa

    2016-06-01

    Safety concerns together with aging of the driving population has prompted research into clinic-based driving assessments. This study investigates the relationship between the DriveSafe and DriveAware assessments and restriction of driving. Community-dwelling adults aged more than 75 (n = 380) were recruited in New South Wales, Australia. Questionnaires were administered to assess driving habits and functional assessments to assess driving-related function. Self-reported restriction was prevalent in this cross-sectional sample (62%) and was related to DriveSafe scores and personal circumstances but not DriveAware scores. DriveSafe scores were correlated with better performance on the Trail-Making Test (TMT; β = -2.94, p < .0001) and better contrast sensitivity (β = 48.70, p < .0001). Awareness was associated with better performance on the TMT (β = 0.08, p < .0001). Our data suggest that DriveSafe and DriveAware are sensitive to deficits in vision and cognition, and drivers with worse DriveSafe scores self-report restricting their driving. PMID:25724948

  16. Association Between Alcohol-Impaired Driving Enforcement-Related Strategies and Alcohol-Impaired Driving

    PubMed Central

    Sanem, Julia R.; Erickson, Darin J.; Rutledge, Patricia C.; Lenk, Kathleen M.; Nelson, Toben F.; Jones-Webb, Rhonda; Toomey, Traci L.

    2015-01-01

    All states in the U.S. prohibit alcohol-impaired driving but active law enforcement is necessary for effectively reducing this behavior. Sobriety checkpoints, saturation patrols, open container laws, and media campaigns related to enforcement efforts are all enforcement-related strategies for reducing alcohol-impaired driving. We conducted surveys of all state patrol agencies and a representative sample of local law enforcement agencies to assess their use of alcohol-impaired driving enforcement-related strategies and to determine the relationship between these enforcement-related strategies and self-reported alcohol-impaired driving behavior obtained from the Behavioral Risk Factor Surveillance System. We found that sobriety checkpoints, saturation patrols, and enforcement of open container laws were associated with a lower prevalence of alcohol-impaired driving but, more importantly, a combination of enforcement-related strategies was associated with a greater decrease in alcohol-impaired driving than any individual enforcement-related activity. In addition, alcohol-impaired driving enforcement-related strategies were associated with decreased alcohol-impaired driving above and beyond their association with decreased binge drinking. Results suggest law enforcement agencies should give greater priority to using a combination of strategies rather than relying on any one individual enforcement activity. PMID:25756846

  17. A friction regulation hybrid driving method for backward motion restraint of the smooth impact drive mechanism

    NASA Astrophysics Data System (ADS)

    Wang, Liang; Chen, Dong; Cheng, Tinghai; He, Pu; Lu, Xiaohui; Zhao, Hongwei

    2016-08-01

    The smooth impact drive mechanism (SIDM) is a type of piezoelectric actuator that has been developed for several decades. As a kind of driving method for the SIDM, the traditional sawtooth (TS) wave is always employed. The kinetic friction force during the rapid contraction stage usually results in the generation of a backward motion. A friction regulation hybrid (FRH) driving method realized by a composite waveform for the backward motion restraint of the SIDM is proposed in this paper. The composite waveform is composed of a sawtooth driving (SD) wave and a sinusoidal friction regulation (SFR) wave which is applied to the rapid deformation stage of the SD wave. A prototype of the SIDM was fabricated and its output performance under the excitation of the FRH driving method and the TS wave driving method was tested. The results indicate that the backward motion can be restrained obviously using the FRH driving method. Compared with the driving effect of the TS wave, the backward rates of the prototype in forward and reverse motions are decreased by 83% and 85%, respectively.

  18. Association between alcohol-impaired driving enforcement-related strategies and alcohol-impaired driving.

    PubMed

    Sanem, Julia R; Erickson, Darin J; Rutledge, Patricia C; Lenk, Kathleen M; Nelson, Toben F; Jones-Webb, Rhonda; Toomey, Traci L

    2015-05-01

    All states in the U.S. prohibit alcohol-impaired driving but active law enforcement is necessary for effectively reducing this behavior. Sobriety checkpoints, saturation patrols, open container laws, and media campaigns related to enforcement efforts are all enforcement-related strategies for reducing alcohol-impaired driving. We conducted surveys of all state patrol agencies and a representative sample of local law enforcement agencies to assess their use of alcohol-impaired driving enforcement-related strategies and to determine the relationship between these enforcement-related strategies and self-reported alcohol-impaired driving behavior obtained from the Behavioral Risk Factor Surveillance System. We found that sobriety checkpoints, saturation patrols, and enforcement of open container laws were associated with a lower prevalence of alcohol-impaired driving but, more importantly, a combination of enforcement-related strategies was associated with a greater decrease in alcohol-impaired driving than any individual enforcement-related activity. In addition, alcohol-impaired driving enforcement-related strategies were associated with decreased alcohol-impaired driving above and beyond their association with decreased binge drinking. Results suggest law enforcement agencies should give greater priority to using a combination of strategies rather than relying on any one individual enforcement activity. PMID:25756846

  19. Continued Driving and Time to Transition to Nondriver Status through Error-Specific Driving Restrictions

    ERIC Educational Resources Information Center

    Freund, Barbara; Petrakos, Davithoula

    2008-01-01

    We developed driving restrictions that are linked to specific driving errors, allowing cognitively impaired individuals to continue to independently meet mobility needs while minimizing risk to themselves and others. The purpose of this project was to evaluate the efficacy and duration expectancy of these restrictions in promoting safe continued…

  20. After Opportunity's First Drive in Six Weeks

    NASA Technical Reports Server (NTRS)

    2007-01-01

    NASA's Mars Exploration Rover Opportunity used its front hazard-identification camera to obtain this image at the end of a drive on the rover's 1,271st sol, or Martian day (Aug. 21, 2007).

    Due to sun-obscuring dust storms limiting the rover's supply of solar energy, Opportunity had not driven since sol 1,232 (July 12, 2007). On sol 1,271, after the sky above Opportunity had been gradually clearing for more than two weeks, the rover rolled 13.38 meters (44 feet). Wheel tracks are visible in front of the rover because the drive ended with a short test of driving backwards.

    Opportunity's turret of four tools at the end of the robotic arm fills the center of the image. Victoria Crater, site of the rover's next science targets, lies ahead.