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Sample records for axles

  1. Axle Shaft Optical Inspection System

    NASA Astrophysics Data System (ADS)

    Freese, Fritz; Geise, Philip; George, Eugene; Singh, Tom

    1980-11-01

    An electro-optical instrument to gauge automotive rear axle shafts is described. A high contrast image of the axle lug flange is projected via a high quality photographic lens on two self-scanning linear photodiode arrays. In one three-second rotation, a dedicated digital processor measures bolt circle location, hole diameter and separation. The unit automatically: compares each measurement with preset tolerances, computes the average bolt circle diameter, computes the bolt circle runout, makes a pass/fail decision, provides a digital readout, marks the axle shaft with colored ink and provides the operator a pass/fail light.

  2. Axle efficiency test procedure. SAE standard

    SciTech Connect

    1995-04-01

    Data from this SAE Recommended Practice permit mapping axle efficiency and/or waste energy over the operating range of passenger cars, trucks, buses, and other highway vehicles. The procedure can be applied to single axles, tandem axles as a system, or other systems, by combining separate tests, such as tests of the front axle and power divider and rear axle of tandem or tri-drive type.

  3. 49 CFR 215.105 - Defective axle.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Suspension System § 215.105 Defective axle. A railroad may not place or continue in service a car, if— (a) An axle on the car has a crack or is broken; (b) An axle on the car has a gouge in the surface that is— (1)...

  4. 49 CFR 215.105 - Defective axle.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Suspension System § 215.105 Defective axle. A railroad may not place or continue in service a car, if— (a) An axle on the car has a crack or is broken; (b) An axle on the car has a gouge in the surface that is— (1)...

  5. 49 CFR 215.105 - Defective axle.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Suspension System § 215.105 Defective axle. A railroad may not place or continue in service a car, if— (a) An axle on the car has a crack or is broken; (b) An axle on the car has a gouge in the surface that is— (1)...

  6. AXL mediates resistance to cetuximab therapy

    PubMed Central

    Brand, Toni M.; Iida, Mari; Stein, Andrew P.; Corrigan, Kelsey L.; Braverman, Cara; Luthar, Neha; Toulany, Mahmoud; Gill, Parkash S.; Salgia, Ravi; Kimple, Randall J.; Wheeler, Deric L.

    2014-01-01

    The EGFR antibody cetuximab is used to treat numerous cancers, but intrinsic and acquired resistance to this agent is a common clinical problem. In this study we show that overexpression of the oncogenic receptor kinase AXL is sufficient to mediate acquired resistance to cetuximab in models of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where AXL was overexpressed, activated and tightly associated with EGFR expression in cells resistant to cetuximab (CtxR cells). Using RNAi methods and novel AXL targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation and MAPK signaling in CtxR cells. Notably, EGFR directly regulated the expression of AXL mRNA through MAPK signaling and the transcription factor c-Jun in CtxR cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable overexpression of AXL or stimulation with EGFR ligands, the latter of which increased AXL activity and association with the EGFR. In tumor xenograft assays, the development of resistance following prolonged treatment with cetuximab was associated with AXL hyperactivation and EGFR association. Furthermore, in an examination of patient-derived xenografts established from surgically resected HNSCCs, AXL was overexpressed and activated in tumors that displayed intrinsic resistance to cetuximab. Collectively, our results identify AXL as a key mediator of cetuximab resistance, providing a rationale for clinical evaluation of AXL targeting drugs to treat cetuximab-resistant cancers. PMID:25136066

  7. Generalised multi-axle vehicle handling

    NASA Astrophysics Data System (ADS)

    Williams, Daniel Eugene

    2012-01-01

    The familiar two-axle bicycle model and associated basic concepts of vehicle handling are reviewed and used to introduce minor changes in convention from the literature. The two-axle model is extended to a three-axle vehicle to illustrate the effectiveness of the notation combined with a simplifying mathematical identity found in the two-axle vehicle literature. A generalised model is then developed that produces dynamic equations of motion by inspection for a vehicle with an arbitrary number of steerable and non-steerable axles. Furthermore, the vehicle dynamic concepts of understeer and wheelbase are generalised and can be directly computed for various arbitrary vehicle configurations.

  8. An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis

    SciTech Connect

    Kariolis, Mihalis S.; Miao, Yu Rebecca; Jones, Douglas S.; Kapur, Shiven; Mathews, Irimpan I.; Giaccia, Amato J.; Cochran, Jennifer R.

    2014-09-21

    Aberrant signaling through the Axl receptor tyrosine kinase has been associated with a myriad of human diseases, most notably metastatic cancer, identifying Axl and its ligand Gas6 as important therapeutic targets. Using rational and combinatorial approaches, we engineered an Axl ‘decoy receptor’ that binds Gas6 with high affinity and inhibits its function, offering an alternative approach from drug discovery efforts that directly target Axl. Four mutations within this high affinity Axl variant caused structural alterations in side chains across the Gas6/Axl binding interface, stabilizing a conformational change on Gas6. When reformatted as an Fc-fusion, the engineered decoy receptor bound to Gas6 with femtomolar affinity, an 80-fold improvement compared to the wild-type Axl receptor, allowing effective sequestration of Gas6 and specific abrogation of Axl signaling. Additionally, increased Gas6 binding affinity was critical and correlative with the ability of decoy receptors to potently inhibit metastasis and disease progression in vivo.

  9. AXL mediates resistance to cetuximab therapy.

    PubMed

    Brand, Toni M; Iida, Mari; Stein, Andrew P; Corrigan, Kelsey L; Braverman, Cara M; Luthar, Neha; Toulany, Mahmoud; Gill, Parkash S; Salgia, Ravi; Kimple, Randall J; Wheeler, Deric L

    2014-09-15

    The EGFR antibody cetuximab is used to treat numerous cancers, but intrinsic and acquired resistance to this agent is a common clinical outcome. In this study, we show that overexpression of the oncogenic receptor tyrosine kinase AXL is sufficient to mediate acquired resistance to cetuximab in models of non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), where AXL was overexpressed, activated, and tightly associated with EGFR expression in cells resistant to cetuximab (Ctx(R) cells). Using RNAi methods and novel AXL-targeting agents, we found that AXL activation stimulated cell proliferation, EGFR activation, and MAPK signaling in Ctx(R) cells. Notably, EGFR directly regulated the expression of AXL mRNA through MAPK signaling and the transcription factor c-Jun in Ctx(R) cells, creating a positive feedback loop that maintained EGFR activation by AXL. Cetuximab-sensitive parental cells were rendered resistant to cetuximab by stable overexpression of AXL or stimulation with EGFR ligands, the latter of which increased AXL activity and association with the EGFR. In tumor xenograft models, the development of resistance following prolonged treatment with cetuximab was associated with AXL hyperactivation and EGFR association. Furthermore, in an examination of patient-derived xenografts established from surgically resected HNSCCs, AXL was overexpressed and activated in tumors that displayed intrinsic resistance to cetuximab. Collectively, our results identify AXL as a key mediator of cetuximab resistance, providing a rationale for clinical evaluation of AXL-targeting drugs to treat cetuximab-resistant cancers. Cancer Res; 74(18); 5152-64. ©2014 AACR. PMID:25136066

  10. 49 CFR 215.105 - Defective axle.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... conjunction with a plain bearing, has an end collar that is broken or cracked; (d) A journal on the car shows... plain bearing journal on the axle, or the fillet on the axle, has— (1) A ridge; (2) A depression; (3)...

  11. 49 CFR 215.105 - Defective axle.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... conjunction with a plain bearing, has an end collar that is broken or cracked; (d) A journal on the car shows... plain bearing journal on the axle, or the fillet on the axle, has— (1) A ridge; (2) A depression; (3)...

  12. Composite multi-axle suspension for vehicles

    SciTech Connect

    Sullivan, J.W.

    1986-09-30

    This patent describes a load dividing suspension system for vehicles comprising a chassis frame, a drive axle assembly supportively connected with the chassis frame, a fluid-pressure responsive spring means on the drive axle assembly and engaging the chassis frame and exerting a variable lifting force thereon. A tag axle assembly is attached to the chassis frame and includes a vertically swingable support structure for wheels of the tag axle assembly, a distribution valve means on the vehicle for pressurized fluid from an on-board supply of such fluid and having a connection with the supply, an outlet connection and a pressurized fluid line leading to and connected with the fluid-pressure responsive spring means, and an operating linkage for the valve means. The linkage is connected between a movable control element of the valve means and the vertically swingable support structure.

  13. An engineered Axl 'decoy receptor' effectively silences the Gas6-Axl signaling axis

    DOE PAGESBeta

    Kariolis, Mihalis S.; Miao, Yu Rebecca; Jones, Douglas S.; Kapur, Shiven; Mathews, Irimpan I.; Giaccia, Amato J.; Cochran, Jennifer R.

    2014-09-21

    Aberrant signaling through the Axl receptor tyrosine kinase has been associated with a myriad of human diseases, most notably metastatic cancer, identifying Axl and its ligand Gas6 as important therapeutic targets. Using rational and combinatorial approaches, we engineered an Axl ‘decoy receptor’ that binds Gas6 with high affinity and inhibits its function, offering an alternative approach from drug discovery efforts that directly target Axl. Four mutations within this high affinity Axl variant caused structural alterations in side chains across the Gas6/Axl binding interface, stabilizing a conformational change on Gas6. When reformatted as an Fc-fusion, the engineered decoy receptor bound tomore » Gas6 with femtomolar affinity, an 80-fold improvement compared to the wild-type Axl receptor, allowing effective sequestration of Gas6 and specific abrogation of Axl signaling. Additionally, increased Gas6 binding affinity was critical and correlative with the ability of decoy receptors to potently inhibit metastasis and disease progression in vivo.« less

  14. 2. DETAIL VIEW OF JOURNAL LATHE, AXLE FINISHING AREA. Grinding ...

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

    2. DETAIL VIEW OF JOURNAL LATHE, AXLE FINISHING AREA. Grinding bearing diameters on locomotive axle. Norton grinder, 1942 (dated). Melvin Grassmeyer, operator. - Juniata Shops, Machine Shop No. 1, East of Fourth Avenue at Third Street, Altoona, Blair County, PA

  15. 3. DETAIL VIEW OF JOURNAL LATHE, AXLE FINISHING AREA. Grinding ...

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

    3. DETAIL VIEW OF JOURNAL LATHE, AXLE FINISHING AREA. Grinding bearing diameters on locomotive axle. Norton grinder, 1942 (dated). Melvin Grassmeyer, operator. - Juniata Shops, Machine Shop No. 1, East of Fourth Avenue at Third Street, Altoona, Blair County, PA

  16. Imaging Axl expression in pancreatic and prostate cancer xenografts

    SciTech Connect

    Nimmagadda, Sridhar; Pullambhatla, Mrudula; Lisok, Ala; Hu, Chaoxin; Maitra, Anirban; Pomper, Martin G

    2014-01-10

    Highlights: •Axl is overexpressed in a variety of cancers. •Axl overexpression confers invasive phenotype. •Axl imaging would be useful for therapeutic guidance and monitoring. •Axl expression imaging is demonstrated in pancreatic and prostate cancer xenografts. •Graded levels of Axl expression imaging is feasible. -- Abstract: The receptor tyrosine kinase Axl is overexpressed in and leads to patient morbidity and mortality in a variety of cancers. Axl–Gas6 interactions are critical for tumor growth, angiogenesis and metastasis. The goal of this study was to investigate the feasibility of imaging graded levels of Axl expression in tumors using a radiolabeled antibody. We radiolabeled anti-human Axl (Axl mAb) and control IgG1 antibodies with {sup 125}I with high specific radioactivity and radiochemical purity, resulting in an immunoreactive fraction suitable for in vivo studies. Radiolabeled antibodies were investigated in severe combined immunodeficient mice harboring subcutaneous CFPAC (Axl{sup high}) and Panc1 (Axl{sup low}) pancreatic cancer xenografts by ex vivo biodistribution and imaging. Based on these results, the specificity of [{sup 125}I]Axl mAb was also validated in mice harboring orthotopic Panc1 or CFPAC tumors and in mice harboring subcutaneous 22Rv1 (Axl{sup low}) or DU145 (Axl{sup high}) prostate tumors by ex vivo biodistribution and imaging studies at 72 h post-injection of the antibody. Both imaging and biodistribution studies demonstrated specific and persistent accumulation of [{sup 125}I]Axl mAb in Axl{sup high} (CFPAC and DU145) expression tumors compared to the Axl{sup low} (Panc1 and 22Rv1) expression tumors. Axl expression in these tumors was further confirmed by immunohistochemical studies. No difference in the uptake of radioactivity was observed between the control [{sup 125}I]IgG1 antibody in the Axl{sup high} and Axl{sup low} expression tumors. These data demonstrate the feasibility of imaging Axl expression in pancreatic

  17. Targeting Axl and Mer kinases in cancer.

    PubMed

    Verma, Anupam; Warner, Steven L; Vankayalapati, Hariprasad; Bearss, David J; Sharma, Sunil

    2011-10-01

    Receptor tyrosine kinases (RTK) are cell-surface transmembrane receptors that contain regulated kinase activity within their cytoplasmic domain and play an important role in signal transduction in both normal and malignant cells. The mammalian TAM RTK family includes 3 closely related members: Tyro-3, Axl, and Mer. Overexpression or ectopic expression of the TAM receptors has been detected in a wide array of human cancers. Growth arrest-specific gene 6 has been identified as the major ligand for these TAM RTKs, and its binding to the receptors has been shown to promote proliferation and survival of cancer cells in vitro. Abnormal expression and activation of Axl or Mer can provide a survival advantage for certain cancer cells. Inhibition of Axl and Mer may enhance the sensitivity of cancer cells to cytotoxic agents and would potentially be a therapeutic strategy to target cancer cells. This review elucidates the role of Axl and Mer in normal cellular function and their role in oncogenesis. In addition, we review the potential to inhibit these RTKs for the development of therapeutic targets in treatment of cancer. PMID:21933973

  18. On the equivalent wheelbase of a three-axle vehicle

    NASA Astrophysics Data System (ADS)

    Williams, Daniel Eugene

    2011-09-01

    The steady-state handling properties of a rigid vehicle with a tandem rear axle configuration are developed. This work uses conventions resulting in a parsimonious characterisation of steady-state handling of such three-axle vehicles that is shown to be a simple extension of the well-known two-axle bicycle model. Specifically the concepts of understeer and wheelbase are developed for a three-axle vehicle, and shown to play the same role in characterising vehicle handling as they do in the well-known two-axle vehicle model. An equivalent wheelbase of a three-axle vehicle is expressed in terms of vehicle geometry and cornering stiffness of each axle. The model developed in this work is reconciled with previous models that make use of simplifying assumptions found in the literature.

  19. Structural basis for Gas6–Axl signalling

    PubMed Central

    Sasaki, Takako; Knyazev, Pjotr G; Clout, Naomi J; Cheburkin, Yuri; Göhring, Walter; Ullrich, Axel; Timpl, Rupert; Hohenester, Erhard

    2006-01-01

    Receptor tyrosine kinases of the Axl family are activated by the vitamin K-dependent protein Gas6. Axl signalling plays important roles in cancer, spermatogenesis, immunity, and platelet function. The crystal structure at 3.3 Å resolution of a minimal human Gas6/Axl complex reveals an assembly of 2:2 stoichiometry, in which the two immunoglobulin-like domains of the Axl ectodomain are crosslinked by the first laminin G-like domain of Gas6, with no direct Axl/Axl or Gas6/Gas6 contacts. There are two distinct Gas6/Axl contacts of very different size, both featuring interactions between edge β-strands. Structure-based mutagenesis, protein binding assays and receptor activation experiments demonstrate that both the major and minor Gas6 binding sites are required for productive transmembrane signalling. Gas6-mediated Axl dimerisation is likely to occur in two steps, with a high-affinity 1:1 Gas6/Axl complex forming first. Only the minor Gas6 binding site is highly conserved in the other Axl family receptors, Sky/Tyro3 and Mer. Specificity at the major contact is suggested to result from the segregation of charged and apolar residues to opposite faces of the newly formed β-sheet. PMID:16362042

  20. Rear axle designed in oriented FRP

    SciTech Connect

    Not Available

    1982-08-01

    Using techniques of both synthesis and analysis, together with carefully defined goals, a team of investigators devised a major suspension member using oriented fiber reinforced plastic. A weight saving of 57% resulted for an innovative rear axle design estimate to increase cost about /1.20 per kilogram of weight saved. Only durability fell short of expectations, a factor which should improve with further refinements.

  1. AXL kinase as a novel target for cancer therapy

    PubMed Central

    Lee, Chang Youl; Zhang, Zhenfeng; Halmos, Balazs

    2014-01-01

    The AXL receptor tyrosine kinase and its major ligand, GAS6 have been demonstrated to be overexpressed and activated in many human cancers (such as lung, breast, and pancreatic cancer) and have been correlated with poor prognosis, promotion of increased invasiveness/metastasis, the EMT phenotype and drug resistance. Targeting AXL in different model systems with specific small molecule kinase inhibitors or antibodies alone or in combination with other drugs can lead to inactivation of AXL-mediated signaling pathways and can lead to regained drug sensitivity and improved therapeutic efficacy, defining AXL as a promising novel target for cancer therapeutics. This review highlights the data supporting AXL as a novel treatment candidate in a variety of cancers as well as the current status of drug development targeting the AXL/GAS6 axis and future perspectives in this emerging field. PMID:25337673

  2. AXL is an oncotarget in human colorectal cancer.

    PubMed

    Martinelli, Erika; Martini, Giulia; Cardone, Claudia; Troiani, Teresa; Liguori, Giuseppina; Vitagliano, Donata; Napolitano, Stefania; Morgillo, Floriana; Rinaldi, Barbara; Melillo, Rosa Marina; Liotti, Federica; Nappi, Anna; Bianco, Roberto; Berrino, Liberato; Ciuffreda, Loreta Pia; Ciardiello, Davide; Iaffaioli, Vincenzo; Botti, Gerardo; Ferraiolo, Fiorella; Ciardiello, Fortunato

    2015-09-15

    AXL is a tyrosine kinase receptor activated by GAS6 and regulates cancer cell proliferation migration and angiogenesis. We studied AXL as new therapeutic target in colorectal cancer (CRC). Expression and activation of AXL and GAS6 were evaluated in a panel of human CRC cell lines. AXL gene silencing or pharmacologic inhibition with foretinib suppressed proliferation, migration and survival in CRC cells. In an orthotopic colon model of human HCT116 CRC cells overexpressing AXL, foretinib treatment caused significant inhibition of tumour growth and peritoneal metastatic spreading. AXL and GAS6 overexpression by immunohistochemistry (IHC) were found in 76,7% and 73.5%, respectively, of 223 human CRC specimens, correlating with less differentiated histological grading. GAS6 overexpression was associated with nodes involvement and tumour stage. AXL gene was found amplified by Fluorescence in situ hybridization (FISH) in 8/146 cases (5,4%) of CRC samples. Taken together, AXL inhibition could represent a novel therapeutic approach in CRC. PMID:25966280

  3. AXL is an oncotarget in human colorectal cancer

    PubMed Central

    Martinelli, Erika; Troiani, Teresa; Liguori, Giuseppina; Vitagliano, Donata; Napolitano, Stefania; Morgillo, Floriana; Rinaldi, Barbara; Melillo, Rosa Marina; Liotti, Federica; Nappi, Anna; Bianco, Roberto; Berrino, Liberato; Ciuffreda, Loreta Pia; Ciardiello, Davide; Iaffaioli, Vincenzo; Botti, Gerardo; Ferraiolo, Fiorella; Ciardiello, Fortunato

    2015-01-01

    AXL is a tyrosine kinase receptor activated by GAS6 and regulates cancer cell proliferation migration and angiogenesis. We studied AXL as new therapeutic target in colorectal cancer (CRC). Expression and activation of AXL and GAS6 were evaluated in a panel of human CRC cell lines. AXL gene silencing or pharmacologic inhibition with foretinib suppressed proliferation, migration and survival in CRC cells. In an orthotopic colon model of human HCT116 CRC cells overexpressing AXL, foretinib treatment caused significant inhibition of tumour growth and peritoneal metastatic spreading. AXL and GAS6 overexpression by immunohistochemistry (IHC) were found in 76,7% and 73.5%, respectively, of 223 human CRC specimens, correlating with less differentiated histological grading. GAS6 overexpression was associated with nodes involvement and tumour stage. AXL gene was found amplified by Fluorescence in situ hybridization (FISH) in 8/146 cases (5,4%) of CRC samples. Taken together, AXL inhibition could represent a novel therapeutic approach in CRC. PMID:25966280

  4. Axl receptor blockade protects from invasive pulmonary aspergillosis in mice.

    PubMed

    Shibata, Takehiko; Habiel, David M; Coelho, Ana Lucia; Hogaboam, Cory M

    2014-10-01

    Aspergillus fumigatus is a sporulating fungus found ubiquitously in the environment, which is quickly contained in the immunocompetent host but can cause lethal invasive aspergillosis in the immunocompromised host. We have recently demonstrated that Axl (one member of the Tyro3, Axl, Mertk receptor family) is a key regulator of antiviral immune responses in the lung. In this study, we investigated the role of Axl in antifungal immunity in a model of invasive pulmonary aspergillosis (IPA). In this model, Aspergillus fumigatus conidia were administered into the lungs of neutrophil-depleted mice, and the mice were monitored for survival, lung inflammatory response, and fungal clearance. The lethal effect of IPA was significantly reduced in anti-Axl mAb-treated mice compared with IgG control-treated mice. Targeting Axl significantly inhibited pulmonary inflammation, including the expression of IL-1β, IL-6, TNF-α, and chitinase-like proteins in whole lung. Further, anti-Axl mAb treatment significantly increased M1 macrophages that highly expressed inducible NO synthase and decreased M2 macrophages that expressed Arginase 1 and were found in inflammatory zone protein (Fizz1). More importantly, anti-Axl mAb treatment significantly increased the number of IFN-γ-producing T cells and NK cells compared with the IgG control group during IPA. Together, our results demonstrate that the Axl mAb treatment is protective during invasive aspergillosis in neutropenic mice. Collectively, these data suggest a potential deleterious role for Axl during primary immune responses directed against A. fumigatus and novel therapeutic strategy for IPA. PMID:25156363

  5. 13. DETAIL VIEW OF AXLE LATHE. Polishing journals on lathe. ...

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

    13. DETAIL VIEW OF AXLE LATHE. Polishing journals on lathe. Wilbur Johnston, operator. - Juniata Shops, Erecting Shop & Machine Shop, East of Fourth Avenue, between Fourth & Fifth Streets, Altoona, Blair County, PA

  6. 14. DETAIL VIEW OF AXLE LATHE. Polishing journals on lathe. ...

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

    14. DETAIL VIEW OF AXLE LATHE. Polishing journals on lathe. Wilbur Johnston, operator. - Juniata Shops, Erecting Shop & Machine Shop, East of Fourth Avenue, between Fourth & Fifth Streets, Altoona, Blair County, PA

  7. Lane-keeping benefits of practical rear axle steer

    NASA Astrophysics Data System (ADS)

    Williams, Daniel Eugene

    2014-04-01

    The classic two-degree-of-freedom yaw-plane or 'bicycle' vehicle model is augmented with two additional states to describe lane-keeping behaviour and further augmented with an additional control input to steer the rear axle. A simple driver model is hypothesised where the driver closes a loop on a projected lateral lane position. The driver can select the preview distance to compensate driver/vehicle dynamics, consistent with the 'cross-over' model found in the literature. A rear axle steer control law is found to be a function of the front axle steering input and vehicle speed that exhibits stability similar to a positive-real system, while at the same time improving the ability of the driver/vehicle system to track a complex curved lane and improving steady-state manoeuvrability. The theoretically derived control law bears similarity to practical embodiments allowing a deeper understanding of the functional value of steering a rear axle.

  8. [2]Pseudorotaxane composed of heteroditopic macrobicycle and pyridine N-oxide based axle: recognition site dependent axle orientation.

    PubMed

    Saha, Subrata; Santra, Saikat; Ghosh, Pradyut

    2015-04-17

    A strategy for threading an axle having a hydrogen bond acceptor unit in the cavity of a C3v symmetric amido-amine macrobicycle is investigated. The macrobicycle acts as a wheel in its neutral as well as triprotonated states to form threaded architectures with a pyridine N-oxide derivative. The negative oxygen dipole of the axle is capable of [2]pseudorotaxane formation in two different orientations with the wheel in its neutral and triprotonated states. PMID:25825821

  9. Axl, a receptor tyrosine kinase, mediates flow-induced vascular remodeling.

    PubMed

    Korshunov, Vyacheslav A; Mohan, Amy M; Georger, Mary A; Berk, Bradford C

    2006-06-01

    Intima-media thickening (IMT) in response to hemodynamic stress is a physiological process that requires coordinated signaling among endothelial, inflammatory, and vascular smooth muscle cells (VSMC). Axl, a receptor tyrosine kinase, whose ligand is Gas6, is highly induced in VSMC after carotid injury. Because Axl regulates cell migration, phagocytosis and apoptosis, we hypothesized that Axl would play a role in IMT. Vascular remodeling in mice deficient in Axl (Axl(-/-)) and wild-type littermates (Axl(+/+)) was induced by ligation of the left carotid artery (LCA) branches maintaining flow via the left occipital artery. Both genotypes had similar baseline hemodynamic parameters and carotid artery structure. Partial ligation altered blood flow equally in both genotypes: increased by 60% in the right carotid artery (RCA) and decreased by 80% in the LCA. There were no significant differences in RCA remodeling between genotypes. However, in the LCA Axl(-/-) developed significantly smaller intima+media compared with Axl(+/+) (31+/-4 versus 42+/-6x10(-6) microm3, respectively). Quantitative immunohistochemistry of Axl(-/-) LCA showed increased apoptosis compared with Axl(+/+) (5-fold). As expected, p-Akt was decreased in Axl(-/-), whereas there was no difference in Gas6 expression. Cell composition also changed significantly, with increases in CD45+ cells and decreases in VSMC, macrophages, and neutrophils in Axl(-/-) compared with Axl(+/+). These data demonstrate an important role for Axl in flow-dependent remodeling by regulating vascular apoptosis and vascular inflammation. PMID:16627783

  10. Vehicle dynamics control using an active third-axle system

    NASA Astrophysics Data System (ADS)

    Soltani, Amir; Goodarzi, Avesta; Hassan Shojaeefard, Mohammad; Khajepour, Amir

    2014-11-01

    This paper introduces the active third-axle system as an innovative vehicle dynamic control method. This method can be applicable for different kinds of three-axle vehicles such as buses, trucks, or even three-axle passenger cars. In this system, an actuator on the middle axle actively applies an independent force on the suspension to improve the handling characteristics, and hence, its technology is similar to slow-active suspension systems. This system can change the inherent vehicle dynamic characteristics, such as under/over steering behaviour, in the linear handling region, as well as vehicle stability in the nonlinear, limit handling region. In this paper, our main focus is to show the potential capabilities of this method in enhancing vehicle dynamic performance. For this purpose, as the first step, the proposed method in both linear and nonlinear vehicle handling regions is studied mathematically. Next, a comprehensive, nonlinear, 10 degrees of freedom vehicle model with a fuzzy control strategy is used to evaluate the effectiveness of this system. The dynamic behaviour of a vehicle, when either uncontrolled or equipped with the active third axle is then compared. Simulation results show that this active system can be considered as an innovative method for vehicle dynamic control.

  11. Modeling operating weight and axle weight distributions for highway vehicles

    SciTech Connect

    Greene, D.L.; Liang, J.C.

    1988-07-01

    The estimation of highway cost responsibility requires detailed information on vehicle operating weights and axle weights by type of vehicle. Typically, 10--20 vehicle types must be cross-classified by 10--20 registered weight classes and again by 20 or more operating weight categories, resulting in 100--400 relative frequencies to be determined for each vehicle type. For each of these, gross operating weight must be distributed to each axle or axle unit. Given the rarity of many of the heaviest vehicle types, direct estimation of these frequencies and axle weights from traffic classification count statistics and truck weight data may exceed the reliability of even the largest (e.g., 250,000 record) data sources. An alternative is to estimate statistical models of operating weight distributions as functions of registered weight, and models of axle weight shares as functions of operating weight. This paper describes the estimation of such functions using the multinomial logit model (a log-linear model) and the implementation of the modeling framework as a PC-based FORTRAN program. Areas for further research include the addition of highway class and region as explanatory variables in operating weight distribution models, and the development of theory for including registration costs and costs of operating overweight in the modeling framework. 14 refs., 45 figs., 5 tabs.

  12. Eddy current system for inspection of train hollow axles

    SciTech Connect

    Chady, Tomasz; Psuj, Grzegorz; Sikora, Ryszard; Kowalczyk, Jacek; Spychalski, Ireneusz

    2014-02-18

    The structural integrity of wheelsets used in rolling stock is of great importance to the safety. In this paper, electromagnetic system with an eddy current transducer suitable for the inspection of hollow axles have been presented. The transducer was developed to detect surface braking defects having depth not smaller than 0.5 mm. Ultrasound technique can be utilized to inspect the whole axle, but it is not sufficiently sensitive to shallow defects located close to the surface. Therefore, the electromagnetic technique is proposed to detect surface breaking cracks that cannot be detected by ultrasonic technique.

  13. Clinical, Pathological, and Molecular Features of Lung Adenocarcinomas with AXL Expression.

    PubMed

    Sato, Katsuaki; Suda, Kenichi; Shimizu, Shigeki; Sakai, Kazuko; Mizuuchi, Hiroshi; Tomizawa, Kenji; Takemoto, Toshiki; Nishio, Kazuto; Mitsudomi, Tetsuya

    2016-01-01

    The receptor tyrosine kinase AXL is a member of the Tyro3-Axl-Mer receptor tyrosine kinase subfamily. AXL affects several cellular functions, including growth and migration. AXL aberration is reportedly a marker for poor prognosis and treatment resistance in various cancers. In this study, we analyzed clinical, pathological, and molecular features of AXL expression in lung adenocarcinomas (LADs). We examined 161 LAD specimens from patients who underwent pulmonary resections. When AXL protein expression was quantified (0, 1+, 2+, 3+) according to immunohistochemical staining intensity, results were 0: 35%; 1+: 20%; 2+: 37%; and 3+: 7% for the 161 samples. AXL expression status did not correlate with clinical features, including smoking status and pathological stage. However, patients whose specimens showed strong AXL expression (3+) had markedly poorer prognoses than other groups (P = 0.0033). Strong AXL expression was also significantly associated with downregulation of E-cadherin (P = 0.025) and CD44 (P = 0.0010). In addition, 9 of 12 specimens with strong AXL expression had driver gene mutations (6 with EGFR, 2 with KRAS, 1 with ALK). In conclusion, we found that strong AXL expression in surgically resected LADs was a predictor of poor prognosis. LADs with strong AXL expression were characterized by mesenchymal status, higher expression of stem-cell-like markers, and frequent driver gene mutations. PMID:27100677

  14. Clinical, Pathological, and Molecular Features of Lung Adenocarcinomas with AXL Expression

    PubMed Central

    Suda, Kenichi; Shimizu, Shigeki; Sakai, Kazuko; Mizuuchi, Hiroshi; Tomizawa, Kenji; Takemoto, Toshiki; Nishio, Kazuto; Mitsudomi, Tetsuya

    2016-01-01

    The receptor tyrosine kinase AXL is a member of the Tyro3-Axl-Mer receptor tyrosine kinase subfamily. AXL affects several cellular functions, including growth and migration. AXL aberration is reportedly a marker for poor prognosis and treatment resistance in various cancers. In this study, we analyzed clinical, pathological, and molecular features of AXL expression in lung adenocarcinomas (LADs). We examined 161 LAD specimens from patients who underwent pulmonary resections. When AXL protein expression was quantified (0, 1+, 2+, 3+) according to immunohistochemical staining intensity, results were 0: 35%; 1+: 20%; 2+: 37%; and 3+: 7% for the 161 samples. AXL expression status did not correlate with clinical features, including smoking status and pathological stage. However, patients whose specimens showed strong AXL expression (3+) had markedly poorer prognoses than other groups (P = 0.0033). Strong AXL expression was also significantly associated with downregulation of E-cadherin (P = 0.025) and CD44 (P = 0.0010). In addition, 9 of 12 specimens with strong AXL expression had driver gene mutations (6 with EGFR, 2 with KRAS, 1 with ALK). In conclusion, we found that strong AXL expression in surgically resected LADs was a predictor of poor prognosis. LADs with strong AXL expression were characterized by mesenchymal status, higher expression of stem-cell-like markers, and frequent driver gene mutations. PMID:27100677

  15. Axl Expression Stratifies Patients with Poor Prognosis after Hepatectomy for Hepatocellular Carcinoma

    PubMed Central

    Xia, Yong; Li, Jun; Shi, Lehua; Zou, Qifei; Wan, Xuying; Jiao, Binghua; Wang, Hongyang; Wu, Mengchao; Zhang, Yongjie; Shen, Feng

    2016-01-01

    Background Axl is a receptor tyrosine kinase which plays an important role in multiple human malignancies. Design The Axl expression was examined in several hepatocellular carcinoma(HCC) cell lines, paired tumor and nontumorous samples. Then, we examined cell growth curve, cell apoptosis and cell migration in SMMC-7721 cells over-expressed with Axl or siRNA against Axl, respectively. Finally, the prognostic value of Axl was investigated in a prospective cohort of 246 consecutive HCC patients undergoing curative hepatoectomy. Results We found Axl was positive in 22% of examined tumor tissues and all four cell lines. Over-expressing Axl in SMMC-7721 cells accelerated cell growth, cell migration and inhibited cell apoptosis, while knock-down of Axl exerted opposite effect. Axl expression was closely associated with serum AFP, multiple tumors, absence of encapsulation, microvascular invasion, and advanced BCLC or TNM stage. Patients with positive Axl staining had a higher 5-year recurrence rate (92% vs. 71%, P<0.001) and a lower 5-year survival rate (9% vs. 48%, P<0.001) than those with negative staining. The multivariate analyses showed that Axl expression was an independent factor for both tumor recurrence (HR: 1.725; 95% CI: 1.219–2.441) and survival (1.847; 1.291–2.642). Conclusion Axl expression suggests more aggressive tumor invasiveness and predicts worse prognosis for HCC patients undergoing resection. PMID:27182739

  16. Axl as a mediator of cellular growth and survival

    PubMed Central

    Axelrod, Haley; Pienta, Kenneth J.

    2014-01-01

    The control of cellular growth and proliferation is key to the maintenance of homeostasis. Survival, proliferation, and arrest are regulated, in part, by Growth Arrest Specific 6 (Gas6) through binding to members of the TAM receptor tyrosine kinase family. Activation of the TAM receptors leads to downstream signaling through common kinases, but the exact mechanism within each cellular context varies and remains to be completely elucidated. Deregulation of the TAM family, due to its central role in mediating cellular proliferation, has been implicated in multiple diseases. Axl was cloned as the first TAM receptor in a search for genes involved in the progression of chronic to acute-phase leukemia, and has since been established as playing a critical role in the progression of cancer. The oncogenic nature of Axl is demonstrated through its activation of signaling pathways involved in proliferation, migration, inhibition of apoptosis, and therapeutic resistance. Despite its recent discovery, significant progress has been made in the development of effective clinical therapeutics targeting Axl. In order to accurately define the role of Axl in normal and diseased processes, it must be analyzed in a cell type-specific context. PMID:25344858

  17. 49 CFR 230.99 - Tender truck axles.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Tender truck axles. 230.99 Section 230.99 Transportation Other Regulations Relating to Transportation (Continued) FEDERAL RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION STEAM LOCOMOTIVE INSPECTION AND MAINTENANCE STANDARDS Steam Locomotives...

  18. Manual Drivetrain and Axles Specialist. Teacher Edition. Automotive Service Series.

    ERIC Educational Resources Information Center

    Oklahoma State Dept. of Vocational and Technical Education, Stillwater. Curriculum and Instructional Materials Center.

    This instructor's guide contains materials for teaching the manual drive trains and axle specialist component of a competency-based instructional program for students preparing for employment in the automotive service trade. It is based on National Institute of Automotive Service Excellence task lists. Six instructional units contain materials…

  19. Sunitinib activates Axl signaling in renal cell cancer.

    PubMed

    van der Mijn, Johannes C; Broxterman, Henk J; Knol, Jaco C; Piersma, Sander R; De Haas, Richard R; Dekker, Henk; Pham, Thang V; Van Beusechem, Victor W; Halmos, Balazs; Mier, James W; Jiménez, Connie R; Verheul, Henk M W

    2016-06-15

    Mass spectrometry-based phosphoproteomics provides a unique unbiased approach to evaluate signaling network in cancer cells. The tyrosine kinase inhibitor sunitinib is registered as treatment for patients with renal cell cancer (RCC). We investigated the effect of sunitinib on tyrosine phosphorylation in RCC tumor cells to get more insight in its mechanism of action and thereby to find potential leads for combination treatment strategies. Sunitinib inhibitory concentrations of proliferation (IC50) of 786-O, 769-p and A498 RCC cells were determined by MTT-assays. Global tyrosine phosphorylation was measured by LC-MS/MS after immunoprecipitation with the antiphosphotyrosine antibody p-TYR-100. Phosphoproteomic profiling of 786-O cells yielded 1519 phosphopeptides, corresponding to 675 unique proteins including 57 different phosphorylated protein kinases. Compared to control, incubation with sunitinib at its IC50 of 2 µM resulted in downregulation of 86 phosphopeptides including CDK5, DYRK3, DYRK4, G6PD, PKM and LDH-A, while 94 phosphopeptides including Axl, FAK, EPHA2 and p38α were upregulated. Axl- (y702), FAK- (y576) and p38α (y182) upregulation was confirmed by Western Blot in 786-O and A498 cells. Subsequent proliferation assays revealed that inhibition of Axl with a small molecule inhibitor (R428) sensitized 786-O RCC cells and immortalized endothelial cells to sunitinib up to 3 fold. In conclusion, incubation with sunitinib of RCC cells causes significant upregulation of multiple phosphopeptides including Axl. Simultaneous inhibition of Axl improves the antitumor activity of sunitinib. We envision that evaluation of phosphoproteomic changes by TKI treatment enables identification of new targets for combination treatment strategies. PMID:26815723

  20. Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein

    PubMed Central

    Brindley, Melinda A.; Hunt, Catherine L.; Kondratowicz, Andrew S.; Bowman, Jill; Sinn, Patrick L.; McCray, Paul B.; Quinn, Kathrina; Weller, Melodie L.; Chiorini, John A.; Maury, Wendy

    2011-01-01

    In a bioinformatics-based screen for cellular genes that enhance Zaire ebolavirus (ZEBOV) transduction, AXL mRNA expression strongly correlated with ZEBOV infection. A series of cell lines and primary cells were identified that require Axl for optimal ZEBOV entry. Using one of these cell lines, we identified ZEBOV entry events that are Axl-dependent. Interactions between ZEBOV-GP and the Axl ectodomain were not detected in immunoprecipitations and reduction of surface expressed Axl by RNAi did not alter ZEBOV-GP binding, providing evidence that Axl does not serve as a receptor for the virus. However, RNAi knock down of Axl reduced ZEBOV pseudovirion internalization and α-Axl antisera inhibited pseudovirion fusion with cellular membranes. Consistent with the importance of Axl for ZEBOV transduction, Axl transiently co-localized on the surface of cells with ZEBOV virus particles and was internalized during virion transduction. In total, these findings indicate that endosomal uptake of filoviruses is facilitated by Axl. PMID:21529875

  1. Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy.

    PubMed

    Scaltriti, Maurizio; Elkabets, Moshe; Baselga, José

    2016-03-15

    AXL is a tyrosine kinase membrane receptor that signals via PI3K, MAPK, and protein kinase C (PKC), among other pathways. AXL has oncogenic potential and interacts with other membrane receptors, depending on their relative abundance and availability. The increased expression of AXL in cancer is often the result of pharmacologic selective pressure to a number of chemotherapies and targeted therapies and acts as a mechanism of acquired drug resistance. This resistance phenotype, frequently accompanied by epithelial-to-mesenchymal transition, can be reversed by AXL inhibition. In tumors with high levels of EGFR, including lung, head and neck, and triple-negative breast cancer, AXL dimerizes with this receptor and initiates signaling that circumvents the antitumor effects of anti-EGFR therapies. Likewise, AXL overexpression and dimerization with EGFR can overcome PI3K inhibition by activating the phospholipase C-γ-PKC cascade that, in turn, sustains mTORC1 activity. The causative role of AXL in inducing drug resistance is underscored by the fact that the suppression of AXL restores sensitivity to these agents. Hence, these observations indicate that AXL is selectively expressed in tumor cells refractory to therapy and that cotargeting AXL in this setting would potentially overcome drug resistance. The use of AXL inhibitors should be considered in the clinic. PMID:26763248

  2. Axl Phosphorylates Elmo Scaffold Proteins To Promote Rac Activation and Cell Invasion

    PubMed Central

    Abu-Thuraia, Afnan; Gauthier, Rosemarie; Chidiac, Rony; Fukui, Yoshinori; Screaton, Robert A.; Gratton, Jean-Philippe

    2014-01-01

    The receptor tyrosine kinase Axl contributes to cell migration and invasion. Expression of Axl correlates with metastatic progression in cancer patients, yet the specific signaling events promoting invasion downstream of Axl are poorly defined. Herein, we report Elmo scaffolds to be direct substrates and binding partners of Axl. Elmo proteins are established to interact with Dock family guanine nucleotide exchange factors to control Rac-mediated cytoskeletal dynamics. Proteomics and mutagenesis studies reveal that Axl phosphorylates Elmo1/2 on a conserved carboxyl-terminal tyrosine residue. Upon Gas6-dependent activation of Axl, endogenous Elmo2 becomes phosphorylated on Tyr-713 and enters into a physical complex with Axl in breast cancer cells. Interfering with Elmo2 expression prevented Gas6-induced Rac1 activation in breast cancer cells. Similarly to blocking of Axl, Elmo2 knockdown or pharmacological inhibition of Dock1 abolishes breast cancer cell invasion. Interestingly, Axl or Elmo2 knockdown diminishes breast cancer cell proliferation. Rescue of Elmo2 knockdown cells with the wild-type protein but not with Elmo2 harboring Tyr-713-Phe mutations restores cell invasion and cell proliferation. These results define a new mechanism by which Axl promotes cell proliferation and invasion and identifies inhibition of the Elmo-Dock pathway as a potential therapeutic target to stop Axl-induced metastases. PMID:25332238

  3. Molecular Pathways: AXL, a Membrane Receptor Mediator of Resistance to Therapy

    PubMed Central

    Scaltriti, Maurizio; Elkabets, Moshe; Baselga, José

    2016-01-01

    AXL is a tyrosine kinase membrane receptor that signals via PI3K, MAPK, and protein kinase C (PKC), among other pathways. AXL has oncogenic potential and interacts with other membrane receptors, depending on their relative abundance and availability. The increased expression of AXL in cancer is often the result of pharmacologic selective pressure to a number of chemotherapies and targeted therapies and acts as a mechanism of acquired drug resistance. This resistance phenotype, frequently accompanied by epithelial-to-mesenchymal transition, can be reversed by AXL inhibition. In tumors with high levels of EGFR, including lung, head and neck, and triple-negative breast cancer, AXL dimerizes with this receptor and initiates signaling that circumvents the antitumor effects of anti-EGFR therapies. Likewise, AXL overexpression and dimerization with EGFR can overcome PI3K inhibition by activating the phospholipase C-γ-PKC cascade that, in turn, sustains mTORC1 activity. The causative role of AXL in inducing drug resistance is underscored by the fact that the suppression of AXL restores sensitivity to these agents. Hence, these observations indicate that AXL is selectively expressed in tumor cells refractory to therapy and that cotargeting AXL in this setting would potentially overcome drug resistance. The use of AXL inhibitors should be considered in the clinic. PMID:26763248

  4. Axl phosphorylates Elmo scaffold proteins to promote Rac activation and cell invasion.

    PubMed

    Abu-Thuraia, Afnan; Gauthier, Rosemarie; Chidiac, Rony; Fukui, Yoshinori; Screaton, Robert A; Gratton, Jean-Philippe; Côté, Jean-François

    2015-01-01

    The receptor tyrosine kinase Axl contributes to cell migration and invasion. Expression of Axl correlates with metastatic progression in cancer patients, yet the specific signaling events promoting invasion downstream of Axl are poorly defined. Herein, we report Elmo scaffolds to be direct substrates and binding partners of Axl. Elmo proteins are established to interact with Dock family guanine nucleotide exchange factors to control Rac-mediated cytoskeletal dynamics. Proteomics and mutagenesis studies reveal that Axl phosphorylates Elmo1/2 on a conserved carboxyl-terminal tyrosine residue. Upon Gas6-dependent activation of Axl, endogenous Elmo2 becomes phosphorylated on Tyr-713 and enters into a physical complex with Axl in breast cancer cells. Interfering with Elmo2 expression prevented Gas6-induced Rac1 activation in breast cancer cells. Similarly to blocking of Axl, Elmo2 knockdown or pharmacological inhibition of Dock1 abolishes breast cancer cell invasion. Interestingly, Axl or Elmo2 knockdown diminishes breast cancer cell proliferation. Rescue of Elmo2 knockdown cells with the wild-type protein but not with Elmo2 harboring Tyr-713-Phe mutations restores cell invasion and cell proliferation. These results define a new mechanism by which Axl promotes cell proliferation and invasion and identifies inhibition of the Elmo-Dock pathway as a potential therapeutic target to stop Axl-induced metastases. PMID:25332238

  5. Tyrosine kinase receptor Axl enhances entry of Zaire ebolavirus without direct interactions with the viral glycoprotein

    SciTech Connect

    Brindley, Melinda A.; Hunt, Catherine L.; Kondratowicz, Andrew S.; Bowman, Jill; Sinn, Patrick L.; McCray, Paul B.; Quinn, Kathrina; Weller, Melodie L.; Chiorini, John A.; Maury, Wendy

    2011-07-05

    In a bioinformatics-based screen for cellular genes that enhance Zaire ebolavirus (ZEBOV) transduction, AXL mRNA expression strongly correlated with ZEBOV infection. A series of cell lines and primary cells were identified that require Axl for optimal ZEBOV entry. Using one of these cell lines, we identified ZEBOV entry events that are Axl-dependent. Interactions between ZEBOV-GP and the Axl ectodomain were not detected in immunoprecipitations and reduction of surface-expressed Axl by RNAi did not alter ZEBOV-GP binding, providing evidence that Axl does not serve as a receptor for the virus. However, RNAi knock down of Axl reduced ZEBOV pseudovirion internalization and {alpha}-Axl antisera inhibited pseudovirion fusion with cellular membranes. Consistent with the importance of Axl for ZEBOV transduction, Axl transiently co-localized on the surface of cells with ZEBOV virus particles and was internalized during virion transduction. In total, these findings indicate that endosomal uptake of filoviruses is facilitated by Axl.

  6. AXL receptor tyrosine kinase is required for T cell priming and antiviral immunity.

    PubMed

    Schmid, Edward T; Pang, Iris K; Carrera Silva, Eugenio A; Bosurgi, Lidia; Miner, Jonathan J; Diamond, Michael S; Iwasaki, Akiko; Rothlin, Carla V

    2016-01-01

    The receptor tyrosine kinase (RTK) AXL is induced in response to type I interferons (IFNs) and limits their production through a negative feedback loop. Enhanced production of type I IFNs in Axl(-/-) dendritic cells (DCs) in vitro have led to speculation that inhibition of AXL would promote antiviral responses. Notwithstanding, type I IFNs also exert potent immunosuppressive functions. Here we demonstrate that ablation of AXL enhances the susceptibility to infection by influenza A virus and West Nile virus. The increased type I IFN response in Axl(-/-) mice was associated with diminished DC maturation, reduced production of IL-1β, and defective antiviral T cell immunity. Blockade of type I IFN receptor or administration of IL-1β to Axl(-/-) mice restored the antiviral adaptive response and control of infection. Our results demonstrate that AXL is essential for limiting the immunosuppressive effects of type I IFNs and enabling the induction of protective antiviral adaptive immunity. PMID:27350258

  7. Inhibition of Axl improves the targeted therapy against ALK-mutated neuroblastoma

    SciTech Connect

    Xu, Fei; Li, Hongling; Sun, Yong

    2014-11-28

    Highlights: • First reported Axl is co-expressed with ALK in neuroblastoma tissues and cell lines. • Axl activation promotes cell growth and impairs the efficiency of ALK inhibitor. • Further found silence of Axl leads to increased sensitivity to ALK inhibitors. • Axl inhibitor promotes the efficiency of targeted therapy in vitro and in vivo. • Axl activation should be considered in the clinical application of ALK inhibitors. - Abstract: Neuroblastoma (NB) patients harboring mutated ALK can be expected to potentially benefit from targeted therapy based on ALK tyrosine kinase inhibitor (TKI), such as crizotinib and ceritinib. However, the effect of the treatment varies with different individuals, although with the same genic changes. Axl receptor tyrosine kinase is expressed in a variety of human cancers, but little data are reported in NB, particularly in which carrying mutated ALK. In this study, we focus on the roles of Axl in ALK-mutated NB for investigating rational therapeutic strategy. We found that Axl is expressed in ALK-positive NB tissues and cell lines, and could be effectively activated by its ligand GAS6. Ligand-dependent Axl activation obviously rescued crizotinib-mediated suppression of cell proliferation in ALK-mutated NB cells. Genetic inhibition of Axl with specific small interfering RNA markedly increased the sensitivity of cells to ALK-TKIs. Furthermore, a small-molecule inhibitor of Axl significantly enhanced ALK-targeted therapy, as an increased frequency of apoptosis was observed in NB cells co-expressing ALK and Axl. Taken together, our results demonstrated that activation of Axl could lead to insensitivity to ALK inhibitors, and dual inhibition of ALK and Axl might be a potential therapeutic strategy against ALK-mutated NB.

  8. Passivation and Corrosion Behavior of Modified Ferritic-Pearlitic Railway Axle Steels

    NASA Astrophysics Data System (ADS)

    Moon, A. P.; Sangal, S.; Srivastav, Simant; Gajbhiye, N. S.; Mondal, K.

    2015-01-01

    Electrochemical polarization behavior of two newly developed ferritic-pearlitic railway axle steels (MS3 and MS6) and the standard Indian conventional axle steel has been studied in sodium borate buffer solution of pH 8.4 with and without the presence of NaCl. The polarization behavior of both the new axle steels shows close resemblance, whereas, different polarization behavior has been observed for the conventional axle steel. Electrochemical impedance spectroscopy measurements have clearly reflected significantly improved passivation behavior for the newly developed steels compared to that of the conventional axle steel. NaCl salt fog exposure tests have also shown superior corrosion resistance of the newly developed axle steels as compared to the conventional axle steel. Higher surface roughness on the corroded conventional axle steel has also been observed compared to the smoother surface in case of the new axle steels. Higher corrosion resistance of the new axle steels has been attributed to their finer microstructure and strongly adherent protective rusts.

  9. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma.

    PubMed

    Zhou, L; Liu, X-D; Sun, M; Zhang, X; German, P; Bai, S; Ding, Z; Tannir, N; Wood, C G; Matin, S F; Karam, J A; Tamboli, P; Sircar, K; Rao, P; Rankin, E B; Laird, D A; Hoang, A G; Walker, C L; Giaccia, A J; Jonasch, E

    2016-05-01

    Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib-treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line 786-O was chronically treated with sunitinib and assayed for AXL, MET, epithelial-mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by short hairpin RNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets vascular endothelial growth factor receptor, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT-associated gene expression changes, including upregulation of Snail and β-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/human umbilical vein endothelial cell co-culture models. The suppression of AXL or MET expression and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and

  10. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma

    PubMed Central

    Zhou, Lijun; Liu, Xian-De; Sun, Mianen; Zhang, Xuesong; German, Peter; Bai, Shanshan; Ding, Zhiyong; Tannir, Nizar; Wood, Christopher G; Matin, Surena F; Karam, Jose A; Tamboli, Pheroze; Sircar, Kanishka; Rao, Priya; Rankin, Erinn B.; Laird, Douglas A; Hoang, Anh G; Walker, Cheryl L; Giaccia, Amato J; Jonasch, Eric

    2016-01-01

    Antiangiogenic therapy resistance occurs frequently in patients with metastatic renal cell carcinoma (RCC). The purpose of this study was to understand the mechanism of resistance to sunitinib, an antiangiogenic small molecule, and to exploit this mechanism therapeutically. We hypothesized that sunitinib-induced upregulation of the prometastatic MET and AXL receptors is associated with resistance to sunitinib and with more aggressive tumor behavior. In the present study, tissue microarrays containing sunitinib treated and untreated RCC tissues were stained with MET and AXL antibodies. The low malignant RCC cell line, 786-O, was chronically treated with sunitinib, and assayed for AXL, MET, epithelial mesenchymal transition (EMT) protein expression and activation. Co-culture experiments were used to examine the effect of sunitinib pretreatment on endothelial cell growth. The effects of AXL and MET were evaluated in various cell-based models by shRNA or inhibition by cabozantinib, the multi-tyrosine kinases inhibitor that targets VEGFR, MET and AXL. Xenograft mouse models tested the ability of cabozantinib to rescue sunitinib resistance. We demonstrated that increased AXL and MET expression was associated with inferior clinical outcome in patients. Chronic sunitinib treatment of RCC cell lines activated both AXL and MET, induced EMT associated gene expression changes including upregulation of Snail and β-catenin, and increased cell migration and invasion. Pretreatment with sunitinib enhanced angiogenesis in 786-0/HUVEC co-culture models. The suppression of AXL or MET expression, and the inhibition of AXL and MET activation using cabozantinib both impaired chronic sunitinib treatment-induced prometastatic behavior in cell culture, and rescued acquired resistance to sunitinib in xenograft models. In summary, chronic sunitinib treatment induces the activation of AXL and MET signaling and promotes pro-metastatic behavior and angiogenesis. The inhibition of AXL and MET

  11. Axl receptor tyrosine kinase is up-regulated in metformin resistant prostate cancer cells

    PubMed Central

    Bansal, Nitu; Mishra, Prasun J.; Stein, Mark; DiPaola, Robert S.; Bertino, Joseph R.

    2015-01-01

    Recent epidemiological studies showed that metformin, a widely used anti-diabetic drug might prevent certain cancers. Metformin also has an anti-proliferative effect in preclinical studies of both hematologic malignancies as well as solid cancers and clinical studies testing metformin as an anti-cancer drug are in progress. However, all cancer types do not respond to metformin with the same effectiveness or acquire resistance. To understand the mechanism of acquired resistance and possibly its mechanism of action as an anti-proliferative agent, we developed metformin resistant LNCaP prostate cancer cells. Metformin resistant LNCaP cells had an increased proliferation rate, increased migration and invasion ability as compared to the parental cells, and expressed markers of epithelial-mesenchymal transition (EMT). A detailed gene expression microarray comparing the resistant cells to the wild type cells revealed that Edil2, Ereg, Axl, Anax2, CD44 and Anax3 were the top up-regulated genes and calbindin 2 and TPTE (transmembrane phosphatase with tensin homology) and IGF1R were down regulated. We focused on Axl, a receptor tyrosine kinase that has been shown to be up regulated in several drug resistance cancers. Here, we show that the metformin resistant cell line as well as castrate resistant cell lines that over express Axl were more resistant to metformin, as well as to taxotere compared to androgen sensitive LNCaP and CWR22 cells that do not overexpress Axl. Forced overexpression of Axl in LNCaP cells decreased metformin and taxotere sensitivity and knockdown of Axl in resistant cells increased sensitivity to these drugs. Inhibition of Axl activity by R428, a small molecule Axl kinase inhibitor, sensitized metformin resistant cells that overexpressed Axl to metformin. Inhibitors of Axl may enhance tumor responses to metformin and other chemotherapy in cancers that over express Axl. PMID:26036314

  12. Impact of Surface Type, Wheelchair Weight, and Axle Position on Wheelchair Propulsion by Novice Older Adults

    PubMed Central

    Cowan, Rachel E.; Nash, Mark S.; Collinger, Jennifer L.; Koontz, Alicia M.; Boninger, Michael L.

    2009-01-01

    Objective To examine the impact of surface type, wheelchair weight, and rear axle position on older adult propulsion biomechanics. Design Crossover trial. Setting Biomechanics laboratory. Participants Convenience sample of 53 ambulatory older adults with minimal wheelchair experience (65−87y); men = 20, women = 33. Intervention Participants propelled 4 different wheelchair configurations over 4 surfaces; tile, low carpet, high carpet, and an 8% grade ramp (surface, chair order randomized). Chair configurations included: (1) unweighted chair with an anterior axle position, (2) 9.05kg weighted chair with an anterior axle position, (3) unweighted chair with a posterior axle position (Δ0.08m), and (4) 9.05kg weighted chair with a posterior axle position (Δ0.08m). Weight was added to a titanium folding chair, simulating the weight difference between very light and depot wheelchairs. Instrumented wheels measured propulsion kinetics. Main Outcome Measures Average self-selected velocity, push-frequency, stroke length, peak resultant and tangential force. Results Velocity decreased as surface rolling resistance or chair weight increased. Peak resultant and tangential forces increased as chair weight increased, surface resistance increased, and with a posterior axle position. The effect of a posterior axle position was greater on high carpet and the ramp. The effect of weight was constant, but more easily observed on high carpet and ramp. The effects of axle position and weight were independent of one another. Conclusion Increased surface resistance decreases self-selected velocity and increases peak forces. Increased weight decreases self-selected velocity and increases forces. Anterior axle positions decrease forces, more so on high carpet. Effects of weight and axle position are independent. Greatest reductions in peak forces occur in lighter chairs with anterior axle positions. PMID:19577019

  13. Direct regulation of GAS6/AXL signaling by HIF promotes renal metastasis through SRC and MET.

    PubMed

    Rankin, Erinn B; Fuh, Katherine C; Castellini, Laura; Viswanathan, Kartik; Finger, Elizabeth C; Diep, Anh N; LaGory, Edward L; Kariolis, Mihalis S; Chan, Andy; Lindgren, David; Axelson, Håkan; Miao, Yu R; Krieg, Adam J; Giaccia, Amato J

    2014-09-16

    Dysregulation of the von Hippel-Lindau/hypoxia-inducible transcription factor (HIF) signaling pathway promotes clear cell renal cell carcinoma (ccRCC) progression and metastasis. The protein kinase GAS6/AXL signaling pathway has recently been implicated as an essential mediator of metastasis and receptor tyrosine kinase crosstalk in cancer. Here we establish a molecular link between HIF stabilization and induction of AXL receptor expression in metastatic ccRCC. We found that HIF-1 and HIF-2 directly activate the expression of AXL by binding to the hypoxia-response element in the AXL proximal promoter. Importantly, genetic and therapeutic inactivation of AXL signaling in metastatic ccRCC cells reversed the invasive and metastatic phenotype in vivo. Furthermore, we define a pathway by which GAS6/AXL signaling uses lateral activation of the met proto-oncogene (MET) through SRC proto-oncogene nonreceptor tyrosine kinase to maximize cellular invasion. Clinically, AXL expression in primary tumors of ccRCC patients correlates with aggressive tumor behavior and patient lethality. These findings provide an alternative model for SRC and MET activation by growth arrest-specific 6 in ccRCC and identify AXL as a therapeutic target driving the aggressive phenotype in renal clear cell carcinoma. PMID:25187556

  14. 49 CFR 230.100 - Defects in tender truck axles and journals.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... Steam Locomotives and Tenders Running Gear § 230.100 Defects in tender truck axles and journals. (a... repaired : (1) Cut journals that cannot be made to run cool without turning; (2) Seams in axles causing journals to run hot; (3) Overheating, as evidenced by pronounced blue black discoloration; (4)...

  15. 49 CFR 230.100 - Defects in tender truck axles and journals.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... Steam Locomotives and Tenders Running Gear § 230.100 Defects in tender truck axles and journals. (a... repaired : (1) Cut journals that cannot be made to run cool without turning; (2) Seams in axles causing journals to run hot; (3) Overheating, as evidenced by pronounced blue black discoloration; (4)...

  16. 49 CFR 230.100 - Defects in tender truck axles and journals.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... Steam Locomotives and Tenders Running Gear § 230.100 Defects in tender truck axles and journals. (a... repaired : (1) Cut journals that cannot be made to run cool without turning; (2) Seams in axles causing journals to run hot; (3) Overheating, as evidenced by pronounced blue black discoloration; (4)...

  17. 49 CFR 230.100 - Defects in tender truck axles and journals.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... Steam Locomotives and Tenders Running Gear § 230.100 Defects in tender truck axles and journals. (a... repaired : (1) Cut journals that cannot be made to run cool without turning; (2) Seams in axles causing journals to run hot; (3) Overheating, as evidenced by pronounced blue black discoloration; (4)...

  18. 49 CFR 230.100 - Defects in tender truck axles and journals.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... Steam Locomotives and Tenders Running Gear § 230.100 Defects in tender truck axles and journals. (a... repaired : (1) Cut journals that cannot be made to run cool without turning; (2) Seams in axles causing journals to run hot; (3) Overheating, as evidenced by pronounced blue black discoloration; (4)...

  19. 49 CFR 230.98 - Driving, trailing, and engine truck axles.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 false Driving, trailing, and engine truck axles. 230.98... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION STEAM LOCOMOTIVE INSPECTION AND MAINTENANCE STANDARDS Steam Locomotives and Tenders Running Gear § 230.98 Driving, trailing, and engine truck axles. (a)...

  20. 49 CFR 230.98 - Driving, trailing, and engine truck axles.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... 49 Transportation 4 2014-10-01 2014-10-01 false Driving, trailing, and engine truck axles. 230.98... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION STEAM LOCOMOTIVE INSPECTION AND MAINTENANCE STANDARDS Steam Locomotives and Tenders Running Gear § 230.98 Driving, trailing, and engine truck axles. (a)...

  1. 49 CFR 230.98 - Driving, trailing, and engine truck axles.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Driving, trailing, and engine truck axles. 230.98... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION STEAM LOCOMOTIVE INSPECTION AND MAINTENANCE STANDARDS Steam Locomotives and Tenders Running Gear § 230.98 Driving, trailing, and engine truck axles. (a)...

  2. 49 CFR 230.98 - Driving, trailing, and engine truck axles.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 false Driving, trailing, and engine truck axles. 230.98... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION STEAM LOCOMOTIVE INSPECTION AND MAINTENANCE STANDARDS Steam Locomotives and Tenders Running Gear § 230.98 Driving, trailing, and engine truck axles. (a)...

  3. 49 CFR 230.98 - Driving, trailing, and engine truck axles.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 false Driving, trailing, and engine truck axles. 230.98... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION STEAM LOCOMOTIVE INSPECTION AND MAINTENANCE STANDARDS Steam Locomotives and Tenders Running Gear § 230.98 Driving, trailing, and engine truck axles. (a)...

  4. Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival

    PubMed Central

    Vajkoczy, Peter; Knyazev, Pjotr; Kunkel, Andrea; Capelle, Hans-Holger; Behrndt, Sandra; von Tengg-Kobligk, Hendrik; Kiessling, Fabian; Eichelsbacher, Uta; Essig, Marco; Read, Tracy-Ann; Erber, Ralf; Ullrich, Axel

    2006-01-01

    Malignant gliomas remain incurable brain tumors because of their diffuse-invasive growth. So far, the genetic and molecular events underlying gliomagenesis are poorly understood. In this study, we have identified the receptor tyrosine kinase Axl as a mediator of glioma growth and invasion. We demonstrate that Axl and its ligand Gas6 are overexpressed in human glioma cell lines and that Axl is activated under baseline conditions. Furthermore, Axl is expressed at high levels in human malignant glioma. Inhibition of Axl signaling by overexpression of a dominant-negative receptor mutant (AXL-DN) suppressed experimental gliomagenesis (growth inhibition >85%, P < 0.05) and resulted in long-term survival of mice after intracerebral glioma cell implantation when compared with Axl wild-type (AXL-WT) transfected tumor cells (survival times: AXL-WT, 10 days; AXL-DN, >72 days). A detailed analysis of the distinct hallmarks of glioma pathology, such as cell proliferation, migration, and invasion and tumor angiogenesis, revealed that inhibition of Axl signaling interfered with cell proliferation (inhibition 30% versus AXL-WT), glioma cell migration (inhibition 90% versus mock and AXL-WT, P < 0.05), and invasion (inhibition 62% and 79% versus mock and AXL-WT, respectively; P < 0.05). This study describes the identification, functional manipulation, in vitro and in vivo validation, and preclinical therapeutic inhibition of a target receptor tyrosine kinase mediating glioma growth and invasion. Our findings implicate Axl in gliomagenesis and validate it as a promising target for the development of approaches toward a therapy of these highly aggressive but, as yet, therapy-refractory, tumors. PMID:16585512

  5. AXL receptor tyrosine kinase is required for T cell priming and antiviral immunity

    PubMed Central

    Schmid, Edward T; Pang, Iris K; Carrera Silva, Eugenio A; Bosurgi, Lidia; Miner, Jonathan J; Diamond, Michael S; Iwasaki, Akiko; Rothlin, Carla V

    2016-01-01

    The receptor tyrosine kinase (RTK) AXL is induced in response to type I interferons (IFNs) and limits their production through a negative feedback loop. Enhanced production of type I IFNs in Axl-/-dendritic cells (DCs) in vitro have led to speculation that inhibition of AXL would promote antiviral responses. Notwithstanding, type I IFNs also exert potent immunosuppressive functions. Here we demonstrate that ablation of AXL enhances the susceptibility to infection by influenza A virus and West Nile virus. The increased type I IFN response in Axl-/- mice was associated with diminished DC maturation, reduced production of IL-1β, and defective antiviral T cell immunity. Blockade of type I IFN receptor or administration of IL-1β to Axl-/- mice restored the antiviral adaptive response and control of infection. Our results demonstrate that AXL is essential for limiting the immunosuppressive effects of type I IFNs and enabling the induction of protective antiviral adaptive immunity. DOI: http://dx.doi.org/10.7554/eLife.12414.001 PMID:27350258

  6. Activation of HER3 Interferes with Antitumor Effects of Axl Receptor Tyrosine Kinase Inhibitors: Suggestion of Combination Therapy1

    PubMed Central

    Torka, Robert; Pénzes, Kinga; Gusenbauer, Simone; Baumann, Christine; Szabadkai, István; Őrfi, Lászlȯ; Kéri, György; Ullrich, Axel

    2014-01-01

    The Axl receptor tyrosine kinase (RTK) has been established as a strong candidate for targeted therapy of cancer. However, the benefits of targeted therapies are limited due to acquired resistance and activation of alternative RTKs. Therefore, we asked if cancer cells are able to overcome targeted Axl therapies. Here, we demonstrate that inhibition of Axl by short interfering RNA or the tyrosine kinase inhibitor (TKI) BMS777607 induces the expression of human epidermal growth factor receptor 3 (HER3) and the neuregulin 1(NRG1)–dependent phosphorylation of HER3 in MDA-MB231 and Ovcar8 cells. Moreover, analysis of 20 Axl-expressing cancer cell lines of different tissue origin indicates a low basal phosphorylation of RAC-α serine/threonine-protein kinase (AKT) as a general requirement for HER3 activation on Axl inhibition. Consequently, phosphorylation of AKT arises as an independent biomarker for Axl treatment. Additionally, we introduce phosphorylation of HER3 as an independent pharmacodynamic biomarker for monitoring of anti-Axl therapy response. Inhibition of cell viability by BMS777607 could be rescued by NRG1-dependent activation of HER3, suggesting an escape mechanism by tumor microenvironment. The Axl-TKI MPCD84111 simultaneously blocked Axl and HER2/3 signaling and thereby prohibited HER3 feedback activation. Furthermore, dual inhibition of Axl and HER2/3 using BMS777607 and lapatinib led to a significant inhibition of cell viability in Axl-expressing MDA-MB231 and Ovcar8 cells. Therefore, we conclude that, in patient cohorts with expression of Axl and low basal activity of AKT, a combined inhibition of Axl and HER2/3 kinase would be beneficial to overcome acquired resistance to Axl-targeted therapies. PMID:24862757

  7. CONOCOPHILLIPS FUEL EFFICIENT HIGH-PERFORMANCE(FEHP) SAE 75W90 REAR AXLE GEAR LUBRICANT

    EPA Science Inventory

    This report is on the Environmental Verification Test of a ConocoPhillips real axle gear lubricant to determine whether it could save vehicle fuel. It determined that a verifyable fuel savings could be measured.

  8. Anion recognition in water by a rotaxane containing a secondary rim functionalised cyclodextrin stoppered axle.

    PubMed

    Řezanka, Michal; Langton, Matthew J; Beer, Paul D

    2015-03-14

    The synthesis of a water soluble [2]rotaxane is reported using hydrophilic secondary rim functionalised permethylated β-cyclodextrin derivatives as the axle stopper groups. The rotaxane recognises halide anions in pure water with impressive selectivity over sulfate. PMID:25682747

  9. The role of AXL and the in vitro activity of the receptor tyrosine kinase inhibitor BGB324 in Ewing sarcoma

    PubMed Central

    Fleuren, Emmy D.G.; Hillebrandt-Roeffen, Melissa H.S.; Flucke, Uta E.; te Loo, D. Maroeska W.M.; Boerman, Otto C.; van der Graaf, Winette T.A.; Versleijen-Jonkers, Yvonne M.H.

    2014-01-01

    New targets for Ewing sarcoma (ES) patients are urgently needed. Therefore, we investigated the expression and genetic aberrations of the oncogenic receptor tyrosine kinase (RTK) AXL in ES and determined the efficacy of AXL targeting on cell viability and migration. First, AXL and Gas6 (ligand) mRNA expression was determined by RT-PCR on 29 ES samples. Low, medium and high AXL mRNA expression was observed in 31% (n = 9), 48% (n = 14) and 21% (n = 6) of samples. Gas6 was abundantly present in all specimens. We next tested AXL protein expression immunohistochemically in 36 tumors (primary, post-chemotherapy, metastasized and relapsed samples) from 25 ES patients. Low, medium and high AXL protein expression was observed in 17% (n = 6), 19% (n = 7) and 36% (n = 13) of samples. In primary tumors (n = 15), high AXL expression correlated significantly with a worse overall survival compared to patients with lower expression (61 vs. 194 months, p = 0.026). No genetic aberrations were detected in the AXL RTK domain (n = 29). The AXL-inhibitor BGB324 affected viability (IC50 0.79–2.13 μmol/L) and migratory potential of all tested ES cell lines in vitro (n = 5–6). BGB324 chemosensitized chemotherapy-resistant ES-4 cells to vincristine and doxorubicin. These data suggest that AXL is a potential novel, druggable therapeutic target in ES. PMID:25528764

  10. Opposing Roles of Tyrosine Kinase Receptors Mer and Axl Determine Clinical Outcomes in Experimental Immune-Mediated Nephritis.

    PubMed

    Zhen, Yuxuan; Priest, Stephen O; Shao, Wen-Hai

    2016-09-15

    Glomerulonephritis is one of the most severe manifestations of systemic lupus erythematosus, with considerable morbidity and mortality. There remains a major unmet need for successful management of lupus nephritis. TAM family receptor tyrosine kinases (Mer and Axl) play an important role in the maintenance of immune homeostasis in the kidney. Mer is constitutively expressed in the glomeruli; Axl expression is inducible in glomeruli under inflammatory conditions. To investigate the distinct functions of Axl and Mer in lupus nephritis, we compared the severity of nephrotoxic serum glomerulonephritis in wild-type (WT), Axl-knockout (KO), Mer-KO, and Axl/Mer-KO mice. Mer-KO mice developed severe glomerulonephritis, with significantly decreased survival and increased blood urea nitrogen levels compared with WT mice given the same treatment. However, nephrotoxic serum-treated Axl-KO mice had significantly increased survival rates and improved renal function compared with similarly treated WT, Mer-KO, and Axl/Mer-KO mice. Interestingly, mice lacking both Axl and Mer developed kidney inflammation comparable to WT mice. Western blot analysis revealed significantly increased Stat3 phosphorylation and caspase-1 activation in the kidneys of nephritic Mer-KO mice. In contrast, Axl-deficient nephrotoxic serum-injected mice showed decreased Akt phosphorylation and Bcl-xL upregulation. Thus, the reciprocal activation of Axl and Mer receptor tyrosine kinases has a major impact on the outcome of renal inflammation. PMID:27527599

  11. Deformation effect simulation and optimization for double front axle steering mechanism

    NASA Astrophysics Data System (ADS)

    Wu, Jungang; Zhang, Siqin; Yang, Qinglong

    2013-03-01

    This paper research on tire wear problem of heavy vehicles with Double Front Axle Steering Mechanism from the flexible effect of Steering Mechanism, and proposes a structural optimization method which use both traditional static structural theory and dynamic structure theory - Equivalent Static Load (ESL) method to optimize key parts. The good simulated and test results show this method has high engineering practice and reference value for tire wear problem of Double Front Axle Steering Mechanism design.

  12. Influence of polygonal wear of railway wheels on the wheel set axle stress

    NASA Astrophysics Data System (ADS)

    Wu, Xingwen; Chi, Maoru; Wu, Pingbo

    2015-11-01

    The coupled vehicle/track dynamic model with the flexible wheel set was developed to investigate the effects of polygonal wear on the dynamic stresses of the wheel set axle. In the model, the railway vehicle was modelled by the rigid multibody dynamics. The wheel set was established by the finite element method to analyse the high-frequency oscillation and dynamic stress of wheel set axle induced by the polygonal wear based on the modal stress recovery method. The slab track model was taken into account in which the rail was described by the Timoshenko beam and the three-dimensional solid finite element was employed to establish the concrete slab. Furthermore, the modal superposition method was adopted to calculate the dynamic response of the track. The wheel/rail normal forces and the tangent forces were, respectively, determined by the Hertz nonlinear contact theory and the Shen-Hedrick-Elkins model. Using the coupled vehicle/track dynamic model, the dynamic stresses of wheel set axle with consideration of the ideal polygonal wear and measured polygonal wear were investigated. The results show that the amplitude of wheel/rail normal forces and the dynamic stress of wheel set axle increase as the vehicle speeds rise. Moreover, the impact loads induced by the polygonal wear could excite the resonance of wheel set axle. In the resonance region, the amplitude of the dynamic stress for the wheel set axle would increase considerably comparing with the normal conditions.

  13. Two axles threaded using a single template site: active metal template macrobicyclic [3]rotaxanes.

    PubMed

    Goldup, Stephen M; Leigh, David A; McGonigal, Paul R; Ronaldson, Vicki E; Slawin, Alexandra M Z

    2010-01-13

    Template approaches to rotaxanes normally require at least n - 1 template sites to interlock n components. Here we describe the one-pot synthesis of [3]rotaxanes in which a single metal template site induces formation of axles through each cavity of a bicyclic macrocycle. Central to the approach is that a portion of the bicyclic molecule acts as a ligand for a transition metal ion that mediates covalent bond formation through one or other macrocyclic cavity, depending on the ligand's orientation, making a mechanical bond. The ligand can then rotate so that the transition metal can catalyze the formation of a second axle through the other macrocycle. Using this strategy with the Cu(I)-catalyzed azide-alkyne cycloaddition (the CuAAC reaction) generates a [3]rotaxane with two identical axles in up to 86% yield. [3]Rotaxanes with two different axles threaded through the macrobicyclic rings can also be created using a single template site, either by having copper(I) sequentially form both mechanical bonds (via the CuAAC reaction) using different sets of building blocks for each axle or by using two different reactions catalyzed by two different metal ions: a palladium(II)-mediated alkyne homocoupling to assemble the first thread through one cavity, followed by a copper(I)-mediated CuAAC reaction to form the second axle through the other ring. PMID:19968281

  14. Mice lacking Axl and Mer tyrosine kinase receptors are susceptible to experimental autoimmune orchitis induction.

    PubMed

    Li, Nan; Liu, Zhenghui; Zhang, Yue; Chen, Qiaoyuan; Liu, Peng; Cheng, C Yan; Lee, Will M; Chen, Yongmei; Han, Daishu

    2015-03-01

    The mammalian testis is an immunoprivileged organ where male germ cell autoantigens are immunologically ignored. Both systemic immune tolerance to autoantigens and local immunosuppressive milieu contribute to the testicular immune privilege. Testicular immunosuppression has been intensively studied, but information on systemic immune tolerance to autoantigens is lacking. In the present study, we aimed to determine the role of Axl and Mer receptor tyrosine kinases in maintaining the systemic tolerance to male germ cell antigens using the experimental autoimmune orchitis (EAO) model. Axl and Mer double-knockout (Axl(-/-)Mer(-/-)) mice developed evident EAO after a single immunization with germ cell homogenates emulsified with complete Freund's adjuvant. EAO was characterized by the accumulation of macrophages and T lymphocytes in the testis. Damage to the seminiferous epithelium was also observed. EAO induction was associated with pro-inflammatory cytokine upregulation in the testes, impaired permeability of the blood-testis barrier and generation of autoantibodies against germ cell antigens in Axl(-/-)Mer(-/-) mice. Immunization also induced mild EAO in Axl or Mer single-gene-knockout mice. By contrast, a single immunization failed to induce EAO in wild-type mice. The results indicate that Axl and Mer receptors cooperatively regulate the systemic immune tolerance to male germ cell antigens. PMID:25403570

  15. The Axl receptor tyrosine kinase is a discriminator of macrophage function in the inflamed lung

    PubMed Central

    Kaur, Manminder; Bell, Thomas J; Fujino, Naoya; Cook, Peter C; Svedberg, Freya R; MacDonald, Andrew S; Maciewicz, Rose A; Singh, Dave; Hussell, Tracy

    2014-01-01

    Much of the biology surrounding macrophage functional specificity has arisen through examining inflammation-induced polarising signals, but this also occurs in homeostasis, requiring tissue-specific environmental triggers that influence macrophage phenotype and function. The TAM receptor family of receptor tyrosine kinases (Tyro3, Axl and MerTK) mediates the non-inflammatory removal of apoptotic cells by phagocytes through the bridging phosphatidylserine-binding molecules Gas6 or Protein S. We show that one such TAM receptor (Axl) is exclusively expressed on mouse airway macrophages, but not interstitial macrophages and other lung leukocytes, under homeostatic conditions and is constitutively ligated to Gas6. Axl expression is potently induced by GM-CSF expressed in the healthy and inflamed airway, and by type I interferon or TLR3 stimulation on human and mouse macrophages, indicating potential involvement of Axl in apoptotic cell removal under inflammatory conditions. Indeed, an absence of Axl does not cause sterile inflammation in health, but leads to exaggerated lung inflammatory disease upon influenza infection. These data imply that Axl allows specific identification of airway macrophages, and that its expression is critical for macrophage functional compartmentalisation in the airspaces or lung interstitium. We propose that this may be a critical feature to prevent excessive inflammation due to secondary necrosis of apoptotic cells that have not been cleared by efferocytosis. PMID:25603826

  16. Metrological approach to the force exerted by the axle of a road vehicle in motion carrying liquid

    NASA Astrophysics Data System (ADS)

    Faruolo, Luciano Bruno; de Noronha Castro Pinto, Fernando Augusto

    2016-01-01

    Weigh-in-motion (WIM) systems are used for identifying the dynamic force exerted on the ground by axles of a vehicle. These systems are important for monitoring the gross vehicle weight and the vehicle axle load. Overweighted trucks on the roads increase pavement damage and traffic accidents. Knowing the accuracy of WIM systems is necessary. In the case of liquid transport the ‘sloshing effect’ affects this accuracy. This paper aims to analyze the dynamic measurement of the axle forces in vehicles carrying liquid during WIM up to 6 km h-1. Laboratory experiments using one vehicle with six axles and liquid loads on different levels in weighing instruments are presented. A non-linear computational multi-mass-springs model was developed and laboratory experiments were carried out to show the acceleration influences on axle forces of vehicles with six axles and with and without baffles to vary the ‘sloshing effect’.

  17. axl, a transforming gene isolated from primary human myeloid leukemia cells, encodes a novel receptor tyrosine kinase

    SciTech Connect

    O'Bryan, J.P.; Frye, R.A.; Cogswell, P.C.; Neubauer, A.; Kitch, B.; Prokop, C.; Earp, H.S.; Liu, E.T. ); Espinosa, R. III; Le Beau, M.M. )

    1991-10-01

    Using a sensitive transfection-tumorigenicity assay, the authors have isolated a novel transforming gene from the DNA of two patients with chronic myelogenous leukemia. Sequence analysis indicates that the product of this gene, axl, is a receptor tyrosine kinase. Overexpression of axl cDNA in NIH 3T3 cells induces neoplastic transformation with the concomitant appearance of a 140-kDa axl tyrosine-phosphorylated protein. Expression of axl cDNA in the baculovirus system results in the expression of the appropriate recombinant protein that is recognized by antophosphotyrosine antibodies, confirming that the axl protein is a tyrosine kinase. The juxtaposition of fibronectin type II and immunoglobulinlike repeats in the extracellular domain, as well as distinct amino acid sequences in the kinase domain, indicate that the axl protein represents a novel subclass of receptor tyrosine kinases.

  18. Reliability analysis of laser ultrasonics for train axle diagnostics based on model assisted POD curves

    NASA Astrophysics Data System (ADS)

    Malik, M. S.; Cavuto, A.; Martarelli, M.; Pandarese, G.; Revel, G. M.

    2014-05-01

    High speed train axles are integrated for a lifetime and it is time and resource consuming to conduct in service inspection with high accuracy. Laser ultrasonics is a proposed solution as a subset of non-contact measuring methods effective also for hard to reach areas and even recently proved to be effective using Laser Doppler Vibrometer (LDV) or air-coupled probes in reception. A reliability analysis of laser ultrasonics for this specific application is here performed. The research is mainly based on numerical study of the effect of high energy laser pulses on the surface of a steel axle and of the behavior of the ultrasonic waves in detecting possible defects. Probability of Detection (POD) concept is used as an estimated reliability of the inspection method. In particular Model Assisted Probability of Detection (MAPOD), a modified form of POD where models are used to infer results for making a decisive statistical approach of POD curve, is here adopted. This paper implements this approach by taking the inputs from limited experiments conducted on a high speed train axle using laser ultrasonics (source pulsed Nd:Yag, reception by high-frequency LDV) to calibrate a multiphysics FE model and by using the calibrated model to generate data samples statistically representative of damaged train axles. The simulated flaws are in accordance with the real defects present on the axle. A set of flaws of different depth has been modeled in order to assess the laser ultrasonics POD for this specific application.

  19. ALK inhibitor resistance in ALKF1174L-driven neuroblastoma is associated with AXL activation and induction of EMT

    PubMed Central

    Debruyne, D N; Bhatnagar, N; Sharma, B; Luther, W; Moore, N F; Cheung, N-K; Gray, N S; George, R E

    2016-01-01

    The crizotinib-resistant ALKF1174L mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALKF1174L. Here we demonstrate acquired resistance to TAE684 and LDK378 in ALKF1174L-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated extracellular signal-regulated kinase (ERK) signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, that also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALKF1174L-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance. PMID:26616860

  20. Heightened cleavage of Axl receptor tyrosine kinase by ADAM metalloproteases may contribute to disease pathogenesis in SLE.

    PubMed

    Orme, Jacob J; Du, Yong; Vanarsa, Kamala; Mayeux, Jessica; Li, Li; Mutwally, Azza; Arriens, Cristina; Min, Soyoun; Hutcheson, Jack; Davis, Laurie S; Chong, Benjamin F; Satterthwaite, Anne B; Wu, Tianfu; Mohan, Chandra

    2016-08-01

    Systemic lupus erythematosus (SLE) is characterized by antibody-mediated chronic inflammation in the kidney, lung, skin, and other organs to cause inflammation and damage. Several inflammatory pathways are dysregulated in SLE, and understanding these pathways may improve diagnosis and treatment. In one such pathway, Axl tyrosine kinase receptor responds to Gas6 ligand to block inflammation in leukocytes. A soluble form of the Axl receptor ectodomain (sAxl) is elevated in serum from patients with SLE and lupus-prone mice. We hypothesized that sAxl in SLE serum originates from the surface of leukocytes and that the loss of leukocyte Axl contributes to the disease. We determined that macrophages and B cells are a source of sAxl in SLE and in lupus-prone mice. Shedding of the Axl ectodomain from the leukocytes of lupus-prone mice is mediated by the matrix metalloproteases ADAM10 and TACE (ADAM17). Loss of Axl from lupus-prone macrophages renders them unresponsive to Gas6-induced anti-inflammatory signaling in vitro. This phenotype is rescued by combined ADAM10/TACE inhibition. Mice with Axl-deficient macrophages develop worse disease than controls when challenged with anti-glomerular basement membrane (anti-GBM) sera in an induced model of nephritis. ADAM10 and TACE also mediate human SLE PBMC Axl cleavage. Collectively, these studies indicate that increased metalloprotease-mediated cleavage of leukocyte Axl may contribute to end organ disease in lupus. They further suggest dual ADAM10/TACE inhibition as a potential therapeutic modality in SLE. PMID:27237127

  1. Rational Design for Rotaxane Synthesis through Intramolecular Slippage: Control of Activation Energy by Rigid Axle Length.

    PubMed

    Masai, Hiroshi; Terao, Jun; Fujihara, Tetsuaki; Tsuji, Yasushi

    2016-05-01

    We describe a new concept for rotaxane synthesis through intramolecular slippage using π-conjugated molecules as rigid axles linked with organic soluble and flexible permethylated α-cyclodextrins (PM α-CDs) as macrocycles. Through hydrophilic-hydrophobic interactions and flipping of PM α-CDs, successful quantitative conversion into rotaxanes was achieved without covalent bond formation. The rotaxanes had high activation barrier for their de-threading, so that they were kinetically isolated and derivatized even under conditions unfavorable for maintaining the rotaxane structures. (1) H NMR spectroscopy experiments clearly revealed that the restricted motion of the linked macrocycle with the rigid axle made it possible to control the kinetic stability by adjusting the length of the rigid axle in the precursor structure rather than the steric bulkiness of the stopper unit. PMID:27027800

  2. 76 FR 32327 - Regulatory Guidance on the Designation of Steerable Rear Axle Operators (Tillermen) as Drivers of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-06-06

    .... 383.3(a)). Current Regulatory Guidance Question 14 to Sec. 390.5 (62 FR 16370, 16407, April 4, 1997..., but walks alongside it to use a wired or wireless remote control to steer the rear axle; sometimes the...'s design. In the self-steering mode, the axle automatically steers itself within a range...

  3. Finite element simulation on thermal mechanical expansion of the automobile rear axle housing

    NASA Astrophysics Data System (ADS)

    Liu, Hua-min; Zhao, Yufeng; Zhi, Fuxin

    2013-05-01

    Mechanical thermal expansion is a new metal processing method, which improved not only the properties of materials and the production efficiency, but also achieves better processing surface quality and comprehensive mechanical properties. Axle housing mechanical thermal expansion is simulated by DEFORM-3D, then by metal flow analysis, explored the deformation characteristics through stress-strain distribution and velocity, predicted possible forming defects types and locations and propose appropriate solutions. Through analysis of the influence of different process parameters on the axle housing mechanical thermal expansion, theoretical guidance for actual production is provided.

  4. 4-Oxo-1,4-dihydroquinoline-3-carboxamide Derivatives as New Axl Kinase Inhibitors.

    PubMed

    Tan, Li; Zhang, Zhang; Gao, Donglin; Luo, Jinfeng; Tu, Zheng-Chao; Li, Zhengqiu; Peng, Lijie; Ren, Xiaomei; Ding, Ke

    2016-07-28

    Axl is a new potential target for anticancer drug discovery. A series of 4-oxo-1,4-dihydroquinoline-3-carboxamides were designed and synthesized as highly potent Axl kinase inhibitors. One of the most promising compounds, 9im, tightly bound with Axl protein and potently inhibited its kinase function with a Kd value of 2.7 nM and an IC50 value of 4.0 nM, respectively, while was obviously less potent against most of the 403 wild-type kinases evaluated at a relatively high concentration. The compound dose-dependently inhibited the TGF-β1-induced epithelial-mesenchymal transition (EMT) and suppressed the migration and invasion of MDA-MB-231 breast cancer cells. In addition, 9im also demonstrated reasonable pharmacokinetics properties in rats and exhibited in vivo therapeutic effect on hepatic metastasis in a xenograft model of highly metastatic 4T1 murine breast cancer cells. Compound 9im may serve as a lead compound for new anticancer drug discovery and a valuable research probe for further biological investigation on Axl. PMID:27379978

  5. Wheeled Vehicle Drive Lines, Axles, and Suspension Systems. Military Curriculum Materials for Vocational and Technical Education.

    ERIC Educational Resources Information Center

    Army Ordnance Center and School, Aberdeen Proving Ground, MD.

    This course is one of several subcourses that make up the entire Army correspondence course on wheeled vehicle maintenance. The subcourse is designed to provide the student with information about the operation, malfunction diagnosis, maintenance, and repair of wheeled vehicle drive lines, axles, and suspension systems. It provides the basic…

  6. In vitro and in vivo antiangiogenic activity of desacetylvinblastine monohydrazide through inhibition of VEGFR2 and Axl pathways

    PubMed Central

    Lei, Xueping; Chen, Minfeng; Nie, Qiulin; Hu, Jianyang; Zhuo, Zhenjian; Yiu, Anita; Chen, Heru; Xu, Nanhui; Huang, Maohua; Ye, Kaihe; Bai, Liangliang; Ye, Wencai; Zhang, Dongmei

    2016-01-01

    Tumor angiogenic process is regulated by multiple proangiogenic pathways, such as vascular endothelial growth factor receptor 2 (VEGFR2) and Axl receptor tyrosine kinase (Axl). Axl is one of many important factors involved in anti-VEGF resistance. Inhibition of VEGF/VEGFR2 signaling pathway alone fails to block tumor neovascularization. Therefore, discovery of novel agents targeting multiple angiogenesis pathways is in demand. Desacetylvinblastine monohydrazide (DAVLBH), a derivative of vinblastine (VLB), has been reported exhibit an anticancer activity via its cytotoxic effect. However, little attention has been paid to the antiangiogenic properties of DAVLBH. Here, we firstly reported that DAVLBH exerted a more potent antiangiogenic effect than VLB in vitro and in vivo, which was associated with inactivation of VEGF/VEGFR2 and Gas6/Axl signaling pathways. We found that DAVLBH inhibited VEGF- and Gas6-induced HUVECs proliferation, migration, tube formation and vessel sprouts formation in vitro and ex vivo. It significantly inhibited in vivo tumor angiogenesis and tumor growth in HeLa xenografts. It also inhibited Gas6-induced pericytes recruitment to endothelial tubes accompanied with a decrease in expression and activation of Axl. Besides, it could block the compensatory up-regulating expression and activation of Axl in response to bevacizumab treatment in HUVECs. Taken together, our results suggest that DAVLBH potently inhibits angiogenesis-mediated tumor growth through blockage of the activation of VEGF/VEGFR2 and Gas6/Axl pathways and it might serve as a promising antiangiogenic agent for the cancer therapy. PMID:27186435

  7. Effect of Understress on Fretting Fatigue Crack Initiation of Press-Fitted Axle

    NASA Astrophysics Data System (ADS)

    Kubota, Masanobu; Niho, Sotaro; Sakae, Chu; Kondo, Yoshiyuki

    Axles are one of the most important components in railway vehicles with regard to safety, since a fail-safe design is not available. The problems of fretting fatigue crack initiation in a press-fitted axle have not been completely solved even though up-to-date fatigue design methods are employed. The objective of the present study is to clarify the effect of understress on fretting fatigue crack initiation behavior in the press-fitted axle. Most of the stress amplitude given to the axle in service is smaller than the fretting fatigue limit based on the stress to initiate cracks under a constant load σwf1. Rotating bending fatigue tests were performed using a 40mm-diameter press-fitted axle assembly. Two-step variable stresses consisting of σwf1 and half or one-third of σwf1 were used in the experiment. Crack initiation life was defined as the number of cycles when a fretting fatigue crack, which is longer than 30µm, was found using a metallurgical microscope. Fretting fatigue cracks were initiated even when the variable stress did not contain the stress above the fretting fatigue crack initiation limit. The crack initiation life varied from 4.0×107 to 1.2×108 depending on the stress frequency ratio nL/nH. The sum of the number of cycles of higher stress at crack initiation NH was much smaller than the number of cycles to initiate cracks estimated from the modified Miner's rule. The value of the modified Miner's damage ranged from 0.013 to 0.185. To clarify the effect of variable amplitude on the fretting fatigue crack initiation, a comprehensive investigation related to relative slip, tangential force and fretting wear is necessary.

  8. Axl is a novel target of withaferin A in the induction of apoptosis and the suppression of invasion.

    PubMed

    Woo, Seon Min; Min, Kyoung-jin; Kim, Shin; Park, Jong-Wook; Kim, Dong Eun; Kim, Sang Hyun; Choi, Yung Hyun; Kwon, Taeg Kyu

    2014-08-29

    Withaferin A, a withanolide derived from the medicinal plant Withania somnifera, has been reported to exhibit anti-tumorigenic activity against various cancer cells. In this study, we show that withaferin A inhibits the constitutive and recombinant human growth-arrest-specific protein 6 (rhGas6)-induced phosphorylation of Axl and STAT3. In addition, withaferin A also induces the down-regulation of Axl protein expression in a lysosome-dependent manner and inhibits rhGas6-induced wound healing and cell migration. Furthermore, the overexpression of Axl attenuates withaferin A-induced apoptosis. Taken together, the data from the present study indicate that the withaferin A-mediated down-regulation of the Gas6/Axl signaling pathway mediates the inhibition of cell migration and the induction of apoptosis. PMID:25117439

  9. The novel receptor tyrosine kinase Axl is constitutively active in B-cell chronic lymphocytic leukemia and acts as a docking site of nonreceptor kinases: implications for therapy

    PubMed Central

    Secreto, Charla; Boysen, Justin; Sassoon, Traci; Shanafelt, Tait D.; Mukhopadhyay, Debabrata; Kay, Neil E.

    2011-01-01

    Recently, we detected that chronic lymphocytic leukemia (CLL) B-cell–derived microvesicles in CLL plasma carry a constitutively phosphorylated novel receptor tyrosine kinase (RTK), Axl, indicating that Axl was acquired from the leukemic B cells. To examine Axl status in CLL, we determined the expression of phosphorylated-Axl (P-Axl) in freshly isolated CLL B cells by Western blot analysis. We detected differential levels of P-Axl in CLL B cells, and further analysis showed that expression of P-Axl was correlated with the other constitutively phosphorylated kinases, including Lyn, phosphoinositide-3 kinase, SyK/ζ-associated protein of 70 kDa, phospholipase C γ2 in CLL B cells. We found that these intracellular signaling molecules were complexed with P-Axl in primary CLL B cells. When Axl and Src kinases were targeted by a Src/Abl kinase inhibitor, bosutinib (SKI-606), or a specific-inhibitor of Axl (R428), robust induction of CLL B-cell apoptosis was observed in both a dose- and time-dependent manner. Therefore, we have identified a novel RTK in CLL B cells which appears to work as a docking site for multiple non-RTKs and drives leukemic cell survival signals. These findings highlight a unique target for CLL treatment. PMID:21135257

  10. The tyrosine receptor kinase of Axl is an essential regulator of prostate cancer proliferation and tumor growth and represents a new therapeutic target

    PubMed Central

    Paccez, Juliano D; Vasques, Gabriela J; Correa, Ricardo G; Vasconcellos, Jaira F; Duncan, Kristal; Gu, Xuesong; Bhasin, Manoj; Libermann, Towia A; Zerbini, Luiz F

    2014-01-01

    Deregulation of the receptor tyrosine kinase Axl has been implicated in the progression of several human cancers. However, the role of Axl in prostate cancer remains poorly understood, and the therapeutic efficacy of Axl targeting remains untested. In this report we identified Axl as a new therapeutic target for prostate cancer. Axl is consistently overexpressed in prostate cancer cell lines and human prostate tumors. Interestingly, the blockage of Axl gene expression strongly inhibits proliferation, migration, invasion, and tumor growth. Furthermore, inhibition of Axl expression by small interfering RNA regulates a transcriptional program of genes involved in cell survival, strikingly all connected to the NF-κB pathway. Additionally, blockage of Axl expression leads to inhibition of Akt, IKKα and IκBα phosphorylation, increasing IκBα expression and stability. Furthermore, induction of Akt phosphorylation by IGF1 in Axl knockdown cells restores Akt activity and proliferation. Taken together our results establish an unambiguous role for Axl in prostate cancer tumorigenesis with implications for prostate cancer treatment. PMID:22410775

  11. Association between the expression levels of TAZ, AXL and CTGF and clinicopathological parameters in patients with colon cancer

    PubMed Central

    ZHANG, SHU-DONG; MCCRUDDEN, CIAN M.; YUEN, HIU-FUNG; LEUNG, KA LAI; HONG, WAN-JIN; KWOK, HANG FAI

    2016-01-01

    Colon cancer accounts for a large proportion of all the cancer-associated morbidities worldwide. Genetic analysis and stratification of patients based on survival may identify genetic signatures potentially useful for prognostic or treatment planning purposes. Previous studies have reported that the messenger (m)RNA expression levels of tafazzin (TAZ), AXL receptor tyrosine kinase (AXL) and connective tissue growth factor (CTGF) were able to predict the survival of patients with colon cancer in two independent colon cancer datasets. However, limited clinicopathological data were available from these two datasets. By contrast, a large colon cancer dataset comprising 566 patients has been recently published in the Gene Expression Omnibus database, which contains data regarding tumor stage and location, and genetic status of mismatch repair (MMR), Kirsten rat sarcoma viral oncogene homolog (KRAS), B-Raf proto-oncogene serine/threonine kinase (BRAF) and tumor protein p53 (TP53). In the present study, the mRNA expression levels of TAZ, AXL and CTGF were evaluated, and the TAZ-AXL-CTGF signature was correlated with the available pathological parameters and survival data. Overexpression of TAZ, AXL and CTGF was observed to be associated with severe pathological stage, deficiency in MMR, colon cancer subtype C4 and mutations in the BRAF gene. In addition, overexpression of TAZ-AXL-CTGF was associated with short overall survival in patients with mutations in the TP53 gene, colon cancer subtype C6, proficient MMR and wild-type status of the KRAS and BRAF genes. Furthermore, the prognostic value of TAZ-AXL-CTGF overexpression was observed to be independent of all the clinicopathological parameters and mutational statuses analyzed. The results of the present study confirm the previously reported findings, and suggest that the TAZ-AXL-CTGF mRNA signature is a potential prognostic indicator in colon cancer. PMID:26893723

  12. An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo

    PubMed Central

    Subramanian, Manikandan; Hayes, Crystal D.; Thome, Joseph J.; Thorp, Edward; Matsushima, Glenn K.; Herz, Joachim; Farber, Donna L.; Liu, Kang; Lakshmana, Madepalli; Tabas, Ira

    2014-01-01

    The phagocytosis of apoptotic cells (ACs), or efferocytosis, by DCs is critical for self-tolerance and host defense. Although many efferocytosis-associated receptors have been described in vitro, the functionality of these receptors in vivo has not been explored in depth. Using a spleen efferocytosis assay and targeted genetic deletion in mice, we identified a multiprotein complex — composed of the receptor tyrosine kinase AXL, LDL receptor–related protein–1 (LRP-1), and RAN-binding protein 9 (RANBP9) — that mediates DC efferocytosis and antigen cross-presentation. We found that AXL bound ACs, but required LRP-1 to trigger internalization, in murine CD8α+ DCs and human-derived DCs. AXL and LRP-1 did not interact directly, but relied on RANBP9, which bound both AXL and LRP-1, to form the complex. In a coculture model of antigen presentation, the AXL/LRP-1/RANBP9 complex was used by DCs to cross-present AC-associated antigens to T cells. Furthermore, in a murine model of herpes simplex virus–1 infection, mice lacking DC-specific LRP-1, AXL, or RANBP9 had increased AC accumulation, defective viral antigen-specific CD8+ T cell activation, enhanced viral load, and decreased survival. The discovery of this multiprotein complex that mediates functionally important DC efferocytosis in vivo may have implications for future studies related to host defense and DC-based vaccines. PMID:24509082

  13. CBL controls a tyrosine kinase network involving AXL, SYK and LYN in nilotinib-resistant chronic myeloid leukaemia.

    PubMed

    Gioia, Romain; Trégoat, Claire; Dumas, Pierre-Yves; Lagarde, Valérie; Prouzet-Mauléon, Valérie; Desplat, Vanessa; Sirvent, Audrey; Praloran, Vincent; Lippert, Eric; Villacreces, Arnaud; Leconet, Wilhem; Robert, Bruno; Vigon, Isabelle; Roche, Serge; Mahon, François-Xavier; Pasquet, Jean-Max

    2015-09-01

    A tyrosine kinase network composed of the TAM receptor AXL and the cytoplasmic kinases LYN and SYK is involved in nilotinib-resistance of chronic myeloid leukaemia (CML) cells. Here, we show that the E3-ubiquitin ligase CBL down-regulation occurring during prolonged drug treatment plays a critical role in this process. Depletion of CBL in K562 cells increases AXL and LYN protein levels, promoting cell resistance to nilotinib. Conversely, forced expression of CBL in nilotinib-resistant K562 cells (K562-rn) dramatically reduces AXL and LYN expression and resensitizes K562-rn cells to nilotinib. A similar mechanism was found to operate in primary CML CD34(+) cells. Mechanistically, the E3-ligase CBL counteracts AXL/SYK signalling, promoting LYN transcription by controlling AXL protein stability. Surprisingly, the role of AXL in resistance was independent of its ligand GAS6 binding and its TK activity, in accordance with a scaffold activity for this receptor being involved in this cellular process. Collectively, our results demonstrate a pivotal role for CBL in the control of a tyrosine kinase network mediating resistance to nilotinib treatment in CML cells. PMID:25965880

  14. Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells.

    PubMed

    Nowakowski, Tomasz J; Pollen, Alex A; Di Lullo, Elizabeth; Sandoval-Espinosa, Carmen; Bershteyn, Marina; Kriegstein, Arnold R

    2016-05-01

    The recent outbreak of Zika virus (ZIKV) in Brazil has been linked to substantial increases in fetal abnormalities and microcephaly. However, information about the underlying molecular and cellular mechanisms connecting viral infection to these defects remains limited. In this study we have examined the expression of receptors implicated in cell entry of several enveloped viruses including ZIKV across diverse cell types in the developing brain. Using single-cell RNA-seq and immunohistochemistry, we found that the candidate viral entry receptor AXL is highly expressed by human radial glial cells, astrocytes, endothelial cells, and microglia in developing human cortex and by progenitor cells in developing retina. We also show that AXL expression in radial glia is conserved in developing mouse and ferret cortex and in human stem cell-derived cerebral organoids, highlighting multiple experimental systems that could be applied to study mechanisms of ZIKV infectivity and effects on brain development. PMID:27038591

  15. Faults Diagnostics of Railway Axle Bearings Based on IMF's Confidence Index Algorithm for Ensemble EMD.

    PubMed

    Yi, Cai; Lin, Jianhui; Zhang, Weihua; Ding, Jianming

    2015-01-01

    As train loads and travel speeds have increased over time, railway axle bearings have become critical elements which require more efficient non-destructive inspection and fault diagnostics methods. This paper presents a novel and adaptive procedure based on ensemble empirical mode decomposition (EEMD) and Hilbert marginal spectrum for multi-fault diagnostics of axle bearings. EEMD overcomes the limitations that often hypothesize about data and computational efforts that restrict the application of signal processing techniques. The outputs of this adaptive approach are the intrinsic mode functions that are treated with the Hilbert transform in order to obtain the Hilbert instantaneous frequency spectrum and marginal spectrum. Anyhow, not all the IMFs obtained by the decomposition should be considered into Hilbert marginal spectrum. The IMFs' confidence index arithmetic proposed in this paper is fully autonomous, overcoming the major limit of selection by user with experience, and allows the development of on-line tools. The effectiveness of the improvement is proven by the successful diagnosis of an axle bearing with a single fault or multiple composite faults, e.g., outer ring fault, cage fault and pin roller fault. PMID:25970256

  16. A Flexible Arrayed Eddy Current Sensor for Inspection of Hollow Axle Inner Surfaces

    PubMed Central

    Sun, Zhenguo; Cai, Dong; Zou, Cheng; Zhang, Wenzeng; Chen, Qiang

    2016-01-01

    A reliable and accurate inspection of the hollow axle inner surface is important for the safe operation of high-speed trains. In order to improve the reliability of the inspection, a flexible arrayed eddy current sensor for non-destructive testing of the hollow axle inner surface was designed, fabricated and characterized. The sensor, consisting of two excitation traces and 28 sensing traces, was developed by using the flexible printed circuit board (FPCB) technique to conform the geometric features of the inner surfaces of the hollow axles. The main innovative aspect of the sensor was the new arrangement of excitation/sensing traces to achieve a differential configuration. Finite element model was established to analyze sensor responses and to determine the optimal excitation frequency. Experimental validations were conducted on a specimen with several artificial defects. Results from experiments and simulations were consistent with each other, with the maximum relative error less than 4%. Both results proved that the sensor was capable of detecting longitudinal and transverse defects with the depth of 0.5 mm under the optimal excitation frequency of 0.9 MHz. PMID:27347952

  17. A Flexible Arrayed Eddy Current Sensor for Inspection of Hollow Axle Inner Surfaces.

    PubMed

    Sun, Zhenguo; Cai, Dong; Zou, Cheng; Zhang, Wenzeng; Chen, Qiang

    2016-01-01

    A reliable and accurate inspection of the hollow axle inner surface is important for the safe operation of high-speed trains. In order to improve the reliability of the inspection, a flexible arrayed eddy current sensor for non-destructive testing of the hollow axle inner surface was designed, fabricated and characterized. The sensor, consisting of two excitation traces and 28 sensing traces, was developed by using the flexible printed circuit board (FPCB) technique to conform the geometric features of the inner surfaces of the hollow axles. The main innovative aspect of the sensor was the new arrangement of excitation/sensing traces to achieve a differential configuration. Finite element model was established to analyze sensor responses and to determine the optimal excitation frequency. Experimental validations were conducted on a specimen with several artificial defects. Results from experiments and simulations were consistent with each other, with the maximum relative error less than 4%. Both results proved that the sensor was capable of detecting longitudinal and transverse defects with the depth of 0.5 mm under the optimal excitation frequency of 0.9 MHz. PMID:27347952

  18. Static rear stability of conventional and lightweight variable-axle-position wheelchairs.

    PubMed

    Loane, T D; Kirby, R L

    1985-03-01

    Wheelchair users with high or posteriorly placed centers of mass often complain of rear tipping on inclines or when accelerating. In this study we compared the rear stability of occupied conventional and lightweight wheelchairs and determined the effect of various rear axle positions. Ten normal subjects were studied in both a conventional (22.6 kg) and a lightweight (12.3 kg) wheelchair. Twenty-one experienced wheelchair users were also studied in their own wheelchairs. Stability points were determined with brakes unlocked on a tilt platform. Inter- and intraobserver test-retest reliabilities were 0.97 and 0.974, respectively. For the normal subjects the mean (+/- 1SD) stability point in the conventional chair was 28.6 (+/- 2.7) degrees. In the lightweight chair their mean stability points ranged from 21.7 (+/- 2.6) degrees to 9.4 (+/- 2.9) degrees, depending upon axle position. The mean difference between the conventional chair and the lightweight chair in its most stable position was 6.9 (+/- 1.7) degrees (t = 13.04, p less than 0.0001) and in its least stable position 19.3 (+/- 2.4) degrees (t = 24.97, p less than 0.0001). Experienced wheelchair users in their own lightweight wheelchairs were less stable than users of conventional chairs (t = 2.16, p less than 0.05) or chairs with posteriorly offset axles (t = 3.64, p less than 0.01). PMID:3977572

  19. Heavy and Overweight Vehicle Brake Testing: Five-Axle Combination Tractor-Flatbed Final Report

    SciTech Connect

    Lascurain, Mary Beth; Capps, Gary J; Franzese, Oscar

    2013-10-01

    The Federal Motor Carrier Safety Administration, in coordination with the Federal Highway Administration, sponsored the Heavy and Overweight Vehicle Brake Testing (HOVBT) program in order to provide information about the effect of gross vehicle weight (GVW) on braking performance. Because the Federal Motor Carrier Safety Regulations limit the number of braking system defects that may exist for a vehicle to be allowed to operate on the roadways, the examination of the effect of brake defects on brake performance for increased loads is also relevant. The HOVBT program seeks to provide relevant information to policy makers responsible for establishing load limits, beginning with providing test data for a combination tractor/trailer. This testing was conducted on a five-axle combination vehicle with tractor brakes meeting the Reduced Stopping Distance requirement rulemaking. This report provides a summary of the testing activities, the results of various analyses of the data, and recommendations for future research. Following a complete brake rebuild, instrumentation, and brake burnish, stopping tests were performed from 20 and 40 mph with various brake application pressures (15 psi, 25 psi, 35 psi, 45 psi, 55 psi, and full system pressure). These tests were conducted for various brake conditions at the following GVWs: 60,000, 80,000, 91,000, 97,000, 106,000, and 116,000 lb. The 80,000-lb GVWs included both balanced and unbalanced loads. The condition of the braking system was also varied. To introduce these defects, brakes (none, forward drive axle, or rear trailer axle) were made inoperative. In addition to the stopping tests, performance-based brake tests were conducted for the various loading and brake conditions. Analysis of the stopping test data showed the stopping distance to increase with load (as expected) and also showed that more braking force was generated by the drive axle brakes than the trailer axle brakes. The constant-pressure stopping test data

  20. Sequential and Distinct Roles of the Cadherin Domain-containing Protein Axl2p in Cell Polarization in Yeast Cell Cycle

    PubMed Central

    Gao, Xiang-Dong; Sperber, Lauren M.; Kane, Steven A.; Tong, Zongtian; Tong, Amy Hin Yan; Boone, Charles

    2007-01-01

    Polarization of cell growth along a defined axis is essential for the generation of cell and tissue polarity. In the budding yeast Saccharomyces cerevisiae, Axl2p plays an essential role in polarity-axis determination, or more specifically, axial budding in MATa or α cells. Axl2p is a type I membrane glycoprotein containing four cadherin-like motifs in its extracellular domain. However, it is not known when and how Axl2p functions together with other components of the axial landmark, such as Bud3p and Bud4p, to direct axial budding. Here, we show that the recruitment of Axl2p to the bud neck after S/G2 phase of the cell cycle depends on Bud3p and Bud4p. This recruitment is mediated via an interaction between Bud4p and the central region of the Axl2p cytoplasmic tail. This region of Axl2p, together with its N-terminal region and its transmembrane domain, is sufficient for axial budding. In addition, our work demonstrates a previously unappreciated role for Axl2p. Axl2p interacts with Cdc42p and other polarity-establishment proteins, and it regulates septin organization in late G1 independently of its role in polarity-axis determination. Together, these results suggest that Axl2p plays sequential and distinct roles in the regulation of cellular morphogenesis in yeast cell cycle. PMID:17460121

  1. Combined inhibition of AXL, Lyn and p130Cas kinases block migration of triple negative breast cancer cells

    PubMed Central

    Pénzes, Kinga; Baumann, Christine; Szabadkai, István; Őrfi, László; Kéri, György; Ullrich, Axel; Torka, Robert

    2014-01-01

    Blocking the migration of metastatic cancer cells is a major goal in the therapy of cancer. The receptor tyrosine kinase AXL is one of the main triggers for cancer cell migration in neoplasia of breast, colon, skin, thyroid and prostate. In our study we analyzed the effect of AXL inhibition on cell motility and viability in triple negative breast cancer cell lines overexpressing AXL. Thereby we reveal that the compound BMS777607, exhibiting the lowest IC50 values for inhibition of AXL kinase activity in the studied cell lines, attenuates cell motility to a lower extent than the kinase inhibitors MPCD84111 and SKI606. By analyzing the target kinases of MPCD84111 and SKI606 with kinase profiling assays we identified Lyn, a Src family kinase, as a target of both compounds. Knockdown of Lyn and the migration-related CRK-associated substrate (p130Cas), had a significant inhibitory effect on cell migration. Taken together, our findings highlight the importance of combinatorial or multikinase inhibition of non-receptor tyrosine kinases and AXL receptor tyrosine kinase in the therapy of triple negative breast cancer. PMID:25482942

  2. Dethreading of a Photoactive Azobenzene-Containing Molecular Axle from a Crown Ether Ring: A Computational Investigation.

    PubMed

    Tabacchi, Gloria; Silvi, Serena; Venturi, Margherita; Credi, Alberto; Fois, Ettore

    2016-06-17

    Pseudorotaxanes formed by a dibenzo[24]crown-8 ring (R) and a dialkylammonium axle bearing either two E- or two Z-azobenzene units (EE-A or ZZ-A) revealed useful for the construction of light-powered molecular machines and motors, as they provide the opportunity of photocontrolling self-assembly/disassembly processes. The potential energies profiles for the dethreading of these complexes have been investigated by adopting a combination of first-principles molecular dynamics, metadynamics and quantum-chemical geometry optimization approaches. While the dethreading of the EE-A axle is associated with a monotonic energy increase, for that of the ZZ-A axle a transition state and an intermediate structure, in which the components are still threaded together, are found. The rate determining step for the dethreading of the ZZ axle has a higher energy barrier than that of the EE axle, in agreement with the experimental kinetic data. Moreover, the results suggest that the elliptic shape of the ring cavity is important for discriminating between the E and Z terminal azobenzene during dethreading. PMID:26918775

  3. The receptor AXL diversifies EGFR signaling and limits the response to EGFR-targeted inhibitors in triple-negative breast cancer cells.

    PubMed

    Meyer, Aaron S; Miller, Miles A; Gertler, Frank B; Lauffenburger, Douglas A

    2013-08-01

    The relationship between drug resistance, changes in signaling, and emergence of an invasive phenotype is well appreciated, but the underlying mechanisms are not well understood. Using machine learning analysis applied to the Cancer Cell Line Encyclopedia database, we identified expression of AXL, the gene that encodes the epithelial-to-mesenchymal transition (EMT)-associated receptor tyrosine kinase (RTK) AXL, as exceptionally predictive of lack of response to ErbB family receptor-targeted inhibitors. Activation of EGFR (epidermal growth factor receptor) transactivated AXL, and this ligand-independent AXL activity diversified EGFR-induced signaling into additional downstream pathways beyond those triggered by EGFR alone. AXL-mediated signaling diversification was required for EGF (epidermal growth factor)-elicited motility responses in AXL-positive TNBC (triple-negative breast cancer) cells. Using cross-linking coimmunoprecipitation assays, we determined that AXL associated with EGFR, other ErbB receptor family members, MET (hepatocyte growth factor receptor), and PDGFR (platelet-derived growth factor receptor) but not IGF1R (insulin-like growth factor 1 receptor) or INSR (insulin receptor). From these AXL interaction data, we predicted AXL-mediated signaling synergy for additional RTKs and validated these predictions in cells. This alternative mechanism of receptor activation limits the use of ligand-blocking therapies and indicates against therapy withdrawal after acquired resistance. Further, subadditive interaction between EGFR- and AXL-targeted inhibitors across all AXL-positive TNBC cell lines may indicate that increased abundance of EGFR is principally a means to transactivation-mediated signaling. PMID:23921085

  4. ALK inhibitor resistance in ALK(F1174L)-driven neuroblastoma is associated with AXL activation and induction of EMT.

    PubMed

    Debruyne, D N; Bhatnagar, N; Sharma, B; Luther, W; Moore, N F; Cheung, N-K; Gray, N S; George, R E

    2016-07-14

    The crizotinib-resistant ALK(F1174L) mutation arises de novo in neuroblastoma (NB) and is acquired in ALK translocation-driven cancers, lending impetus to the development of novel anaplastic lymphoma kinase (ALK) inhibitors with different modes of action. The diaminopyrimidine TAE684 and its derivative ceritinib (LDK378), which are structurally distinct from crizotinib, are active against NB cells expressing ALK(F1174L). Here we demonstrate acquired resistance to TAE684 and LDK378 in ALK(F1174L)-driven human NB cells that is linked to overexpression and activation of the AXL tyrosine kinase and epithelial-to-mesenchymal transition (EMT). AXL phosphorylation conferred TAE684 resistance to NB cells through upregulated extracellular signal-regulated kinase (ERK) signaling. Inhibition of AXL partly rescued TAE684 resistance, resensitizing these cells to this compound. AXL activation in resistant cells was mediated through increased expression of the active form of its ligand, GAS6, that also served to stabilize the AXL protein. Although ectopic expression of AXL and TWIST2 individually in TAE684-sensitive parental cells led to the elevated expression of mesenchymal markers and invasive capacity, only AXL overexpression induced resistance to TAE684 as well. TAE684-resistant cells showed greater sensitivity to HSP90 inhibition than did their parental counterparts, with downregulation of AXL and AXL-mediated ERK signaling. Our studies indicate that aberrant AXL signaling and development of an EMT phenotype underlie resistance of ALK(F1174L)-driven NB cells to TAE684 and its derivatives. We suggest that the combination of ALK and AXL or HSP90 inhibitors be considered to delay the emergence of such resistance. PMID:26616860

  5. MiR-34a suppresses ovarian cancer proliferation and motility by targeting AXL.

    PubMed

    Li, Rui; Shi, Xuejun; Ling, Fengyu; Wang, Chunguang; Liu, Junxia; Wang, Wei; Li, Ming

    2015-09-01

    Increasing evidence has suggested that dysregulation of microRNAs (miRNAs) could contribute to tumor progression. The miR-34 family is directly transactivated by tumor suppressor p53 which is frequently mutated in various cancers; however, the effect of miR-34a on the ovarian cancer cells remains unclear. The aim of the paper was to study the expression of miR-34a in ovarian cancer and miR-34a's relation to the cell proliferation and metastasis in ovarian cancer in vitro. miR-34a expression was determined by quantitative RT-PCR in a panel of 60 human ovarian cancer samples. Functional characterization of miR-34a was accomplished by reconstitution of miR-34a expression in ovarian cancer cells by determining changes in proliferation, migration, and invasion. Our results showed that miR-34a is downregulated in ovarian cancer tissues compared with the corresponding adjacent non-neoplastic tissues, and the expression level of miR-34a was significantly lower in ovarian cancer cell lines in comparison with normal human fallopian tube epithelial cell line. The 3-(4,5)-dimethylthiahiazo(-z-y1)-3,5-diphenytetrazoliumromide (MTT) assay revealed significant cell proliferation inhibition in miR-34a transfectant compared with the control from HO8910 and SKOV3 cells, which displayed lowest expressions of miR-34a. Furthermore, the transwell assay also showed significant cell migration inhibition in miR-34a transfectant, compared with cell lines transfected with NC. Overexpression of miR-34a led to the inhibition of AXL expression, indicating that AXL is a target gene for miR-34a. Our data suggest that miR-34a may function as a tumor suppressor through repression of oncogenic AXL in ovarian cancer. PMID:25895459

  6. Axle counter for high-speed railway based on fibre Bragg grating sensor and algorithm optimization for peak searching

    NASA Astrophysics Data System (ADS)

    Quan, Yu; He, Dawei; Wang, Yongsheng; Wang, Pengfei

    2014-08-01

    For the benefit of electrical isolation, corrosion resistance and quasi-distributed detecting, Fiber Bragg Grating Sensor has been studied for high-speed railway application progressively. Existing Axle counter system based on fiber Bragg grating sensor isn't appropriate for high-speed railway for the shortcoming of emplacement of fiber Bragg grating sensor, low Sampling rate and un-optimized algorithm for peak searching. We propose a new design for the Axle counter of high-speed railway based on high-speed fiber Bragg grating demodulating system. We also optimized algorithm for peak searching by synthesizing the three sensor data, bringing forward the time axle, Gaussian fitting and Finite Element Analysis. The feasibility was verified by field experiment.

  7. The TRAIL receptor agonist drozitumab targets basal B triple-negative breast cancer cells that express vimentin and Axl.

    PubMed

    Dine, Jennifer L; O'Sullivan, Ciara C; Voeller, Donna; Greer, Yoshimi E; Chavez, Kathryn J; Conway, Catherine M; Sinclair, Sarah; Stone, Brandon; Amiri-Kordestani, Laleh; Merchant, Anand S; Hewitt, Stephen M; Steinberg, Seth M; Swain, Sandra M; Lipkowitz, Stanley

    2016-01-01

    Previously, we found that GST-tagged tumor necrosis factor-related apoptosis inducing ligand preferentially killed triple-negative breast cancer (TNBC) cells with a mesenchymal phenotype by activating death receptor 5 (DR5). The purpose of this study was to explore the sensitivity of breast cancer cell lines to drozitumab, a clinically tested DR5-specific agonist; identify potential biomarkers of drozitumab-sensitive breast cancer cells; and determine if those biomarkers were present in tumors from patients with TNBC. We evaluated viability, caspase activity, and sub-G1 DNA content in drozitumab-treated breast cancer cell lines and we characterized expression of potential biomarkers by immunoblot. Expression levels of vimentin and Axl were then explored in 177 TNBC samples from a publically available cDNA microarray dataset and by immunohistochemistry (IHC) in tumor tissue samples obtained from 53 African-American women with TNBC. Drozitumab-induced apoptosis in mesenchymal TNBC cell lines but not in cell lines from other breast cancer subtypes. The drozitumab-sensitive TNBC cell lines expressed the mesenchymal markers vimentin and Axl. Vimentin and Axl mRNA and protein were expressed in a subset of human TNBC tumors. By IHC, ~15 % of TNBC tumors had vimentin and Axl expression in the top quartile for both. These findings indicate that drozitumab-sensitive mesenchymal TNBC cells express vimentin and Axl, which can be identified in a subset of human TNBC tumors. Thus, vimentin and Axl may be useful to identify TNBC patients who would be most likely to benefit from a DR5 agonist. PMID:26759246

  8. Axl mediates acquired resistance of head and neck cancer cells to the epidermal growth factor receptor inhibitor erlotinib.

    PubMed

    Giles, Keith M; Kalinowski, Felicity C; Candy, Patrick A; Epis, Michael R; Zhang, Priscilla M; Redfern, Andrew D; Stuart, Lisa M; Goodall, Gregory J; Leedman, Peter J

    2013-11-01

    Elevated expression and activity of the epidermal growth factor receptor (EGFR) is associated with development and progression of head and neck cancer (HNC) and a poor prognosis. Clinical trials with EGFR tyrosine kinase inhibitors (e.g., erlotinib) have been disappointing in HNC. To investigate the mechanisms mediating resistance to these agents, we developed an HNC cell line (HN5-ER) with acquired erlotinib resistance. In contrast to parental HN5 HNC cells, HN5-ER cells exhibited an epithelial-mesenchymal (EMT) phenotype with increased migratory potential, reduced E-cadherin and epithelial-associated microRNAs (miRNA), and elevated vimentin expression. Phosphorylated receptor tyrosine kinase profiling identified Axl activation in HN5-ER cells. Growth and migration of HN5-ER cells were blocked with a specific Axl inhibitor, R428, and R428 resensitized HN5-ER cells to erlotinib. Microarray analysis of HN5-ER cells confirmed the EMT phenotype associated with acquired erlotinib resistance, and identified activation of gene expression associated with cell migration and inflammation pathways. Moreover, increased expression and secretion of interleukin (IL)-6 and IL-8 in HN5-ER cells suggested a role for inflammatory cytokine signaling in EMT and erlotinib resistance. Expression of the tumor suppressor miR-34a was reduced in HN5-ER cells and increasing its expression abrogated Axl expression and reversed erlotinib resistance. Finally, analysis of 302 HNC patients revealed that high tumor Axl mRNA expression was associated with poorer survival (HR = 1.66, P = 0.007). In summary, our results identify Axl as a key mediator of acquired erlotinib resistance in HNC and suggest that therapeutic inhibition of Axl by small molecule drugs or specific miRNAs might overcome anti-EGFR therapy resistance. PMID:24026012

  9. POD curves for non-maximizable ultrasonic responses: Statistical derivation and application to solid freight axles

    NASA Astrophysics Data System (ADS)

    Carboni, Michele; Cantini, Stefano

    2016-02-01

    The most relevant standards on ultrasonic testing, and an effective inspection practice, require the maximization of echo responses due to indications before their evaluation in terms of amplitude and size. This is achieved effectively pointing the acoustic axis of the sound beam to the indication, in a way to get back the maximum possible sound energy. Considering some operative cases, however, such a response maximization is not always feasible, mainly due to geometrical constraints impeding the inspection of the whole control area with a constant sensitivity. The traditional end inspection of solid railway axles by a rotating probe mounting conventional sensors falls back into this kind of inspections. In particular, inspection angles are fixed and the probe holder cannot move along the axle allowing response maximization of in-service damages located, for example, along the cylindrical body. It follows some control areas cannot be inspected using the maximum sound pressure. The present research shows how the derivation of "Probability of Detection" curves for non-maximizable ultrasonic responses cannot be carried out by the traditional statistical approach and a novel one, of the "Model-Assisted Probability of Detection" kind, is consequently proposed based on experiments and numerical simulations.

  10. Dicer Elicits Paclitaxel Chemosensitization and Suppresses Cancer Stemness in Breast Cancer by Repressing AXL.

    PubMed

    Chang, Ting-Yu; Chen, Hsin-An; Chiu, Ching-Feng; Chang, Yi-Wen; Kuo, Tsang-Chih; Tseng, Po-Chun; Wang, Weu; Hung, Mien-Chie; Su, Jen-Liang

    2016-07-01

    Paclitaxel is a standard-of-care chemotherapy for breast cancer, despite the increasing recognition of its poor effectiveness in the treatment of patients with advanced disease. Here, we report that adenovirus-type 5 E1A-mediated elevation of the miRNA-processing enzyme Dicer is sufficient to enhance paclitaxel sensitization and reduce cancer stem-like cell properties in this setting. Elevating Dicer expression increased levels of the AXL kinase targeting miRNA miR-494, thereby repressing AXL expression to increase paclitaxel sensitivity. We found that Dicer expression was regulated at the transcription level by E1A, through activation of an MAPK14/CEBPα pathway. Our findings define a mechanism of E1A-mediated chemosensitization for paclitaxel, which is based upon the suppression of breast cancer stem-like cells, with potential implications for the diagnosis and treatment of breast cancer patients. Cancer Res; 76(13); 3916-28. ©2016 AACR. PMID:27216190

  11. Novel Axl-driven signaling pathway and molecular signature characterize high-grade ovarian cancer patients with poor clinical outcome

    PubMed Central

    Rea, Katia; Pinciroli, Patrizia; Sensi, Marialuisa; Alciato, Federica; Bisaro, Brigitte; Lozneanu, Ludmila; Raspagliesi, Francesco; Centritto, Floriana; Cabodi, Sara; Defilippi, Paola; Avanzi, Gian Carlo; Canevari, Silvana; Tomassetti, Antonella

    2015-01-01

    High-grade epithelial ovarian cancer (HGEOC) is a clinically diverse and molecularly heterogeneous disease comprising subtypes with distinct biological features and outcomes. The receptor tyrosine kinases, expressed by EOC cells, and their ligands, present in the microenvironment, activate signaling pathways, which promote EOC cells dissemination. Herein, we established a molecular link between the presence of Gas6 ligand in the ascites of HGEOCs, the expression and activation of its receptor Axl in ovarian cancer cell lines and biopsies, and the progression of these tumors. We demonstrated that Gas6/Axl signalling converges on the integrin β3 pathway in the presence of the adaptor protein p130Cas, thus inducing tumor cell adhesion to the extracellular matrix and invasion. Accordingly, Axl and p130Cas were significantly co-expressed in HGEOC samples. Clinically, we identified an Axl-associated signature of 62 genes able to portray the HGEOCs with the shortest overall survival. These data biologically characterize a group of HGEOCs and could help guide a more effective therapeutic approach to be taken for these patients. PMID:26356564

  12. Gas6/Axl is the sensor of arginine-auxotrophic response in targeted chemotherapy with arginine-depleting agents.

    PubMed

    Tsai, W-B; Long, Y; Park, J-R; Chang, J T; Liu, H; Rodriguez-Canales, J; Savaraj, N; Feun, L G; Davies, M A; Wistuba, I I; Kuo, M T

    2016-03-31

    Many human malignancies lack de novo biosynthesis of arginine (Arg) as the key enzyme argininosuccinate synthetase 1 (ASS1) is silenced. These tumors acquire ectopic Arg for survival, and depleting this source by Arg-depleting recombinant enzyme ADI-PEG20 results in cell death. Mechanisms underlying Arg auxotrophy in these tumors and how they respond to Arg-auxotrophic stress are poorly understood. Here, we report that an immediate-early event of Arg-auxotrophic response involves reactive oxygen species-mediated secretion of Gas6, which interacts with its receptor Axl and activates the downstream Ras/PI3K/Akt growth signal leading to accumulation of c-Myc by protein stabilization. Arg-auxotrophic challenge also transcriptionally upregulates c-Myc expression, which provides a feedback mechanism to enhance Axl expression. c-Myc is a positive regulator of ASS1, but elevated ASS1 provides a feedback mechanism to suppress c-Myc and Axl. Our results revealed multiple inter-regulatory pathways in Arg-auxotrophic response, consisting of Axl, c-Myc and ASS1, which regulate Arg homeostasis and ADI-PEG20 sensitivity. These pathways provide potential targets for improving the efficacy of treating Arg-auxotrophic tumors using Arg-deprivation strategies. PMID:26096933

  13. Protein kinase C α is involved in the regulation of AXL receptor tyrosine kinase expression in triple-negative breast cancer cells.

    PubMed

    Yue, Chia-Herng; Liu, Liang-Chih; Kao, Erl-Shyh; Lin, Ho; Hsu, Li-Sung; Hsu, Chih-Wei; Lin, Yu-Yu; Lin, Yi-Syuan; Liu, Jer-Yuh; Lee, Chia-Jen

    2016-08-01

    AXL receptor tyrosine kinase is overexpressed in triple-negative breast cancer (TNBC), and has a function in cancer progression and metastases. However, the mechanism underlying AXL gene regulation in TNBC remains unknown. In this study, the involvement of protein kinase C α (PKCα) in the expression of AXL was investigated in human TNBC cells. The microarray data from other studies showed that PKCα is significantly correlated with AXL expression in TNBC cell lines. Tissue array analysis also confirmed their correlation in TNBC. The PKCα inhibitor Go6976 was used to treat MDA‑MB‑231 and Hs578T TNBC cells, which resulted in decreased expression of AXL and epithelia-mesenchymal transition-related gene vimentin, and decreased cell proliferation. An MZF‑1 acidic domain fragment (MZF-1 peptide), which was designed to downregulate PKCα expression, was transfected into the cells and resulted in inhibition of AXL expression. This effect was reversed by co‑treatment with the constitutive form of PKCα. Moreover, the downregulation of PKCα was also confirmed by treatment with TAT‑fused MZF‑1 peptide. Thus, the current study proposes that AXL may be correlated with PKCα‑dependent TNBC cells, and could be modulated by MZF‑1 peptides. PMID:27357025

  14. Gas6/Axl Axis Contributes to Chemoresistance and Metastasis in Breast Cancer through Akt/GSK-3β/β-catenin Signaling

    PubMed Central

    Wang, Cun; Jin, Haojie; Wang, Ning; Fan, Shaohua; Wang, Yanyan; Zhang, Yurong; Wei, Lin; Tao, Xuemei; Gu, Dishui; Zhao, Fangyu; Fang, Jingyuan; Yao, Ming; Qin, Wenxin

    2016-01-01

    Chemoresistance in breast cancer has been of great interest in past studies. However, the development of rational therapeutic strategies targeting chemoresistant cells is still a challenge in clinical oncology. By integrating data from global differences of gene expression and phospho-receptor tyrosine kinases between sensitive parental cells (MCF-7) and doxorubicin-resistant cells (MCF-7/ADR), we identified Axl as a potential target for chemoresistance and metastasis in multidrug resistant breast cancer cells. We analyzed Axl expression in 57 breast cancer cell lines and detected a dramatic increase in its expression level in mesenchymal breast cancer cell lines. Axl silencing suppressed invasive and metastatic potentials of chemoresistant breast cancer cells as well as increased elimination of cancer cells when combined with doxorubicin. Furthermore, in preclinical assays, an Axl inhibitor R428 showed increased cell death upon doxorubicin treatment. Additionally, using phospho-kinase array based proteomic analysis, we identified that Akt/GSK-3β/β-catenin cascade was responsible for Axl-induced cell invasion. Nuclear translocation of β-catenin then induced transcriptional upregulation of ZEB1, which in turn regulated DNA damage repair and doxorubicin-resistance in breast cancer cells. Most importantly, Axl was correlated with its downstream targets in tumor samples and was associated with poor prognosis in breast cancer patients. These results demonstrate that Gas6/Axl axis confers aggressiveness in breast cancer and may represent a therapeutic target for chemoresistance and metastasis. PMID:27279912

  15. Up-Regulation of Soluble Axl and Mer Receptor Tyrosine Kinases Negatively Correlates with Gas6 in Established Multiple Sclerosis Lesions

    PubMed Central

    Weinger, Jason G.; Omari, Kakuri M.; Marsden, Kurt; Raine, Cedric S.; Shafit-Zagardo, Bridget

    2009-01-01

    Multiple sclerosis is a disease that is characterized by inflammation, demyelination, and axonal damage; it ultimately forms gliotic scars and lesions that severely compromise the function of the central nervous system. Evidence has shown previously that altered growth factor receptor signaling contributes to lesion formation, impedes recovery, and plays a role in disease progression. Growth arrest-specific protein 6 (Gas6), the ligand for the TAM receptor tyrosine kinase family, consisting of Tyro3, Axl, and Mer, is important for cell growth, survival, and clearance of debris. In this study, we show that levels of membrane-bound Mer (205 kd), soluble Mer (∼150 kd), and soluble Axl (80 kd) were all significantly elevated in homogenates from established multiple sclerosis lesions comprised of both chronic active and chronic silent lesions. Whereas in normal tissue Gas6 positively correlated with soluble Axl and Mer, there was a negative correlation between Gas6 and soluble Axl and Mer in established multiple sclerosis lesions. In addition, increased levels of soluble Axl and Mer were associated with increased levels of mature ADAM17, mature ADAM10, and Furin, proteins that are associated with Axl and Mer solubilization. Soluble Axl and Mer are both known to act as decoy receptors and block Gas6 binding to membrane-bound receptors. These data suggest that in multiple sclerosis lesions, dysregulation of protective Gas6 receptor signaling may prolong lesion activity. PMID:19541935

  16. Vitamin K2 regression aortic calcification induced by warfarin via Gas6/Axl survival pathway in rats.

    PubMed

    Jiang, Xiaoyu; Tao, Huiren; Qiu, Cuiting; Ma, Xiaolei; Li, Shan; Guo, Xian; Lv, Anlin; Li, Huan

    2016-09-01

    The aim of this study was to investigate the effect of vitamin K2 on aortic calcification induced by warfarin via Gas6/Axl survival pathway in rats. A calcification model was established by administering 3mg/g warfarin to rats. Rats were divided into 9 groups: control group (0W, 4W, 6W and 12W groups), 4W calcification group, 6W calcification group, 12W calcification group, 6W calcification+6W normal group and 6W calcification+6W vitamin K2 group. Alizarin red S staining measured aortic calcium depositions; alkaline phosphatase activity in serum was measured by a kit; apoptosis was evaluated by TUNEL assay; protein expression levels of Gas6, Axl, phosphorylated Akt (p-Akt), and Bcl-2 were determined by western blotting. The calcium content, calcium depositions, ALP activity and apoptosis were significantly higher in the calcification groups than control group. Gas6, Axl, p-Akt and Bcl-2 expression was lower in the calcification group than control group. 100μg/g vitamin K2 treatment decreased calcium depositions, ALP activity and apoptosis significantly, but increased Gas6, Axl, p-Akt and Bcl-2 expression. 100μg/g vitamin K2 reversed 44% calcification. Pearson correlation analysis showed a positive correlation between formation calcification and apoptosis (R(2)=0.8853, P<0.0001). In conclusion, we established a warfarin-induced calcification model and showed vitamin K2 can inhibit warfarin-induced aortic calcification and apoptosis. The regression of aortic calcification by vitamin K2 involved the Gas6/Axl axis. This data may provide a theoretical basis for future clinical treatments for aortic calcification. PMID:27212383

  17. Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway.

    PubMed

    Chen, Yan-Qing; Zhao, Jing; Jin, Cheng-Wei; Li, Yi-Hui; Tang, Meng-Xiong; Wang, Zhi-Hao; Zhang, Wei; Zhang, Yun; Li, Li; Zhong, Ming

    2016-06-01

    Testosterone deficiency is associated with a higher incidence of cardiovascular diseases in men. However, its effect on cell senescence, which plays a causal role in vascular aging, remains unclear. Here, we tested the hypothesis that testosterone alleviated vascular smooth muscle cell (VSMC) senescence and collagen synthesis via growth arrest-specific protein 6 (Gas6)/Axl- and Akt/FoxO1a-dependent pathways. Testosterone significantly ameliorated angiotensin II-induced VSMC senescence and collagen overexpression. In addition, testosterone inhibited angiotensin II-induced matrix metalloproteinase-2 (MMP-2) activity, which played a pivotal role in facilitating age-related collagen deposition. Testosterone increased the expression of tissue inhibitor of metalloproteinase-2 but decreased the expression of MMP-2 and membrane type-1 metalloproteinase which contributed to increase MMP-2 activity. The effects on VSMCs senescence and collagen synthesis were mediated by restoration of angiotensin II-induced downregulation of Gas6 and Axl expression and a subsequent reduction of Akt and FoxO1a phosphorylation. The effects of testosterone were reversed by a Gas6 blocker, Axl-Fc, and a specific inhibitor of Axl, R428. Treatment of VSMCs with PI3K inhibitor LY294002 abrogated the downregulating effect of testosterone on MMP-2 activity. Furthermore, when FoxO1a expression was silenced by using a specific siRNA, the inhibitory effect of testosterone on MMP-2 activity was revered as well, that indicated this process was Akt/FoxO1a dependence. Taken together, Gas6/Axl and Akt/FoxO1a were involved in protective effects of testosterone on VSMCs senescence and collagen synthesis. Our results provide a novel mechanism underlying the protective effect of testosterone on vascular aging and may serve as a theoretical basis for testosterone replacement therapy. PMID:27206970

  18. Inhibiting receptor tyrosine kinase AXL with small molecule inhibitor BMS-777607 reduces glioblastoma growth, migration, and invasion in vitro and in vivo

    PubMed Central

    Onken, Julia; Torka, Robert; Korsing, Sören; Radke, Josefine; Krementeskaia, Irina; Nieminen, Melina; Bai, Xi; Ullrich, Axel; Heppner, Frank; Vajkoczy, Peter

    2016-01-01

    Purpose Receptor tyrosine kinase AXL (RTK-AXL) is regarded as suitable target in glioma therapy. Here we evaluate the anti-tumoral effect of small molecule inhibitor BMS-777607 targeting RTK-AXL in a preclinical glioma model and provide evidence that RTK-AXL is expressed and phosphorylated in primary and recurrent glioblastoma multiforme (GBM). Experimental design We studied the impact of BMS-777607 targeting RTK-AXL in GBM models in vitro and in vivo utilizing glioma cells SF126 and U118MG. Impact on proliferation, apoptosis and angiogenesis was investigated by immunohistochemistry (IHC) and functional assays in vitro and in vivo. Tumor growth was assessed with MRI. Human GBM tissue was analyzed in terms of RTK-AXL phosphorylation by immunoprecipitation and immunohistochemistry. Results BMS-777607 displayed various anti-cancer effects dependent on increased apoptosis, decreased proliferation and migration in vitro and ex vivo in SF126 and U118 GBM cells. In vivo we observed a 56% tumor volume reduction in SF126 xenografts and remission in U118MG xenografts of more than 91%. The tube formation assay confirmed the anti-angiogenic effect of BMS-777607, which became also apparent in tumor xenografts. IHC of human GBM tissue localized phosphorylated RTK-AXL in hypercellular tumor regions, the migratory front of tumor cells in pseudo-palisades, and in vascular proliferates within the tumor. We further proved RTK-AXL phosphorylation in primary and recurrent disease state. Conclusion Collectively, these data strongly suggest that targeting RTK-AXL with BMS-777607 could represent a novel and potent regimen for the treatment of primary and recurrent GBM. PMID:26848524

  19. Axle-less F1-ATPase rotates in the correct direction.

    PubMed

    Furuike, Shou; Hossain, Mohammad Delawar; Maki, Yasushi; Adachi, Kengo; Suzuki, Toshiharu; Kohori, Ayako; Itoh, Hiroyasu; Yoshida, Masasuke; Kinosita, Kazuhiko

    2008-02-15

    F1-adenosine triphosphatase (ATPase) is an ATP-driven rotary molecular motor in which the central gamma subunit rotates inside a cylinder made of three alpha and three beta subunits alternately arranged. The rotor shaft, an antiparallel alpha-helical coiled coil of the amino and carboxyl termini of the gamma subunit, deeply penetrates the central cavity of the stator cylinder. We truncated the shaft step by step until the remaining rotor head would be outside the cavity and simply sat on the concave entrance of the stator orifice. All truncation mutants rotated in the correct direction, implying torque generation, although the average rotary speeds were low and short mutants exhibited moments of irregular motion. Neither a fixed pivot nor a rigid axle was needed for rotation of F1-ATPase. PMID:18276891

  20. A new optical axle measuring instrument for wheel alignment in assembly-line production

    SciTech Connect

    Bruhn, H.; Felske, A.

    1985-01-01

    The newly developed optical measuring system allows adjustment of front and rear wheel angularities - toe, camber, caster - in assembly-line production. There is no need to align the car, since the measuring base for the angle alignment is formed by the car itself. Defined spring compression values and direct caster angle determination lead to higher accuracy. Adjustment is carried out directly on the assembly line. Measuring pits are not required. The working time for each car and the working area required, which are important cost factors, are markedly lower than with conventional instruments. The axle measuring system was developed for the VW Vanagon, but can also be used for passenger car chassis. The measuring principle, the optical and mechanical design of the device, and a statistical analysis of over 100 cars aligned by means of this system are described in comparison with conventional measuring instruments.

  1. Development of a new time domain-based algorithm for train detection and axle counting

    NASA Astrophysics Data System (ADS)

    Allotta, B.; D'Adamio, P.; Meli, E.; Pugi, L.

    2015-12-01

    This paper presents an innovative train detection algorithm, able to perform the train localisation and, at the same time, to estimate its speed, the crossing times on a fixed point of the track and the axle number. The proposed solution uses the same approach to evaluate all these quantities, starting from the knowledge of generic track inputs directly measured on the track (for example, the vertical forces on the sleepers, the rail deformation and the rail stress). More particularly, all the inputs are processed through cross-correlation operations to extract the required information in terms of speed, crossing time instants and axle counter. This approach has the advantage to be simple and less invasive than the standard ones (it requires less equipment) and represents a more reliable and robust solution against numerical noise because it exploits the whole shape of the input signal and not only the peak values. A suitable and accurate multibody model of railway vehicle and flexible track has also been developed by the authors to test the algorithm when experimental data are not available and in general, under any operating conditions (fundamental to verify the algorithm accuracy and robustness). The railway vehicle chosen as benchmark is the Manchester Wagon, modelled in the Adams VI-Rail environment. The physical model of the flexible track has been implemented in the Matlab and Comsol Multiphysics environments. A simulation campaign has been performed to verify the performance and the robustness of the proposed algorithm, and the results are quite promising. The research has been carried out in cooperation with Ansaldo STS and ECM Spa.

  2. The Gas6-Axl Protein Interaction Mediates Endothelial Uptake of Platelet Microparticles.

    PubMed

    Happonen, Kaisa E; Tran, Sinh; Mörgelin, Matthias; Prince, Raja; Calzavarini, Sara; Angelillo-Scherrer, Anne; Dahlbäck, Björn

    2016-05-13

    Upon activation, platelets release plasma membrane-derived microparticles (PMPs) exposing phosphatidylserine on their surface. The functions and clearance mechanism of these microparticles are incompletely understood. As they are pro-coagulant and potentially pro-inflammatory, rapid clearance from the circulation is essential for prevention of thrombotic diseases. The tyrosine kinase receptors Tyro3, Axl, and Mer (TAMs) and their ligands protein S and Gas6 are involved in the uptake of phosphatidylserine-exposing apoptotic cells in macrophages and dendritic cells. Both TAMs and their ligands are expressed in the vasculature, the functional significance of which is poorly understood. In this study, we investigated how vascular TAMs and their ligands may mediate endothelial uptake of PMPs. PMPs, generated from purified human platelets, were isolated by ultracentrifugation and labeled with biotin or PKH67. The uptake of labeled microparticles in the presence of protein S and Gas6 in human aortic endothelial cells and human umbilical vein endothelial cells was monitored by flow cytometry, Western blotting, and confocal/electron microscopy. We found that both endothelial cell types can phagocytose PMPs, and by using TAM-blocking antibodies or siRNA knockdown of individual TAMs, we show that the uptake is mediated by endothelial Axl and Gas6. As circulating PMP levels were not altered in Gas6(-/-) mice compared with Gas6(+/+) mice, we hypothesize that the Gas6-mediated uptake is not a means to clear the bulk of circulating PMPs but may serve to locally phagocytose PMPs generated at sites of platelet activation and as a way to effect endothelial responses. PMID:27006397

  3. AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas.

    PubMed

    Elkabets, Moshe; Pazarentzos, Evangelos; Juric, Dejan; Sheng, Qing; Pelossof, Raphael A; Brook, Samuel; Benzaken, Ana Oaknin; Rodon, Jordi; Morse, Natasha; Yan, Jenny Jiacheng; Liu, Manway; Das, Rita; Chen, Yan; Tam, Angela; Wang, Huiqin; Liang, Jinsheng; Gurski, Joseph M; Kerr, Darcy A; Rosell, Rafael; Teixidó, Cristina; Huang, Alan; Ghossein, Ronald A; Rosen, Neal; Bivona, Trever G; Scaltriti, Maurizio; Baselga, José

    2015-04-13

    Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous cell carcinomas (SCCs) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance, we have observed that SCC cells that become refractory to PI3Kα inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)-protein kinase C (PKC), which, in turn, activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance. PMID:25873175

  4. AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR axis in head and neck and esophageal squamous cell carcinomas

    PubMed Central

    Elkabets, Moshe; Pazarentzos, Evangelos; Juric, Dejan; Sheng, Qing; Pelossof, Raphael A.; Brook, Samuel; Benzaken, Ana Oaknin; Rodon, Jordi; Morse, Natasha; Yan, Jenny Jiacheng; Liu, Manway; Das, Rita; Chen, Yan; Tam, Angela; Wang, Huiqin; Liang, Jinsheng; Gurski, Joseph M.; Kerr, Darcy A.; Rosell, Rafael; Teixidó, Cristina; Huang, Alan; Ghossein, Ronald A.; Rosen, Neal; Bivona, Trever G.; Scaltriti, Maurizio; Baselga, José

    2015-01-01

    Summary Phosphoinositide-3-kinase (PI3K)-α inhibitors have shown clinical activity in squamous carcinoma (SCC) of head and neck (H&N) bearing PIK3CA mutations or amplification. Studying models of therapeutic resistance we have observed that SCCs cells that become refractory to PI3Kα inhibition maintain PI3K-independent activation of the mammalian target of rapamycin (mTOR). This persistent mTOR activation is mediated by the tyrosine kinase receptor AXL. AXL is overexpressed in resistant tumors from both laboratory models and patients treated with the PI3Kα inhibitor BYL719. AXL dimerizes with and phosphorylates epidermal growth factor receptor (EGFR), resulting in activation of phospholipase Cγ (PLCγ)- protein kinase C (PKC), which in turn activates mTOR. Combined treatment with PI3Kα and either EGFR, AXL, or PKC inhibitors reverts this resistance. PMID:25873175

  5. Biodegradable interstitial release polymer loading a novel small molecule targeting Axl receptor tyrosine kinase and reducing brain tumour migration and invasion

    PubMed Central

    Yen, S-Y; Chen, S-R; Hsieh, J; Li, Y-S; Chuang, S-E; Chuang, H-M; Huang, M-H; Lin, S-Z; Harn, H-J; Chiou, T-W

    2016-01-01

    Glioblastoma multiforme (GBM) is the most common and aggressive brain tumour. The neoplasms are difficult to resect entirely because of their highly infiltration property and leading to the tumour edge is unclear. Gliadel wafer has been used as an intracerebral drug delivery system to eliminate the residual tumour. However, because of its local low concentration and short diffusion distance, patient survival improves non-significantly. Axl is an essential regulator in cancer metastasis and patient survival. In this study, we developed a controlled-release polyanhydride polymer loading a novel small molecule, n-butylidenephthalide (BP), which is not only increasing local drug concentration and extending its diffusion distance but also reducing tumour invasion, mediated by reducing Axl expression. First, we determined that BP inhibited the expression of Axl in a dose- and time-dependent manner and reduced the migratory and invasive capabilities of GBM cells. In addition, BP downregulated matrix metalloproteinase activity, which is involved in cancer cell invasion. Furthermore, we demonstrated that BP regulated Axl via the extracellular signal-regulated kinases pathway. Epithelial-to-mesenchymal transition (EMT) is related to epithelial cells in the invasive migratory mesenchymal cells that underlie cancer progression; we demonstrated that BP reduced the expression of EMT-related genes. Furthermore, we used the overexpression of Axl in GBM cells to prove that Axl is a crucial target in the inhibition of GBM EMT, migration and invasion. In an in vivo study, we demonstrated that BP inhibited tumour growth and suppressed Axl expression in a dose-dependent manner according to a subcutaneous tumour model. Most importantly, in an intracranial tumour model with BP wafer in situ treatment, we demonstrated that the BP wafer not only significantly increased the survival rate but also decreased Axl expression, and inhibited tumour invasion. These results contribute to the

  6. Reversible photoswitching of rotaxane character and interplay of thermodynamic stability and kinetic lability in a self-assembling ring-axle molecular system.

    PubMed

    Baroncini, Massimo; Silvi, Serena; Venturi, Margherita; Credi, Alberto

    2010-10-11

    We have designed, synthesized, and investigated a self-assembling system that can be reversibly interconverted between thermodynamically stable (pseudorotaxane) and kinetically inert (rotaxane) forms by light irradiation. The system is composed of a dibenzo[24]crown-8 ring and an axle comprised of a dibenzylammonium recognition site and two azobenzene end groups. The isomeric form of the azobenzene units of the axle has a little influence on the stability constants of the respective pseudorotaxanes but greatly affects the threading-dethreading rate constants. In fact, equilibration of the ring and the axle in its EE isomeric form occurs within seconds in acetonitrile at room temperature, whereas the ZZ axle threads-dethreads the ring at least four orders of magnitude slower. Moreover, we show that a change in the stability of the complex, achieved by deprotonating the dibenzylammonium recognition site on the axle, affects its kinetic behavior. We compare the results of these experiments with those observed upon dethreading the (pseudo)rotaxane by using a competitive guest for the ring, an approach which does not inherently destabilize the ring-axle interaction. This study outlines a general strategy for the reversible photochemical control of motion kinetics in threaded and interlocked compounds and constitutes a starting point for the construction of multicomponent structures that can behave as photochemically driven nanomachines. PMID:20842670

  7. Optic-electronic systems for measurement the three-dimension angular deformation of axles at the millimeter wave range radiotelescope

    NASA Astrophysics Data System (ADS)

    Konyakhin, Igor A.; Kopylova, Tatyana V.; Konyakhin, Alexsey I.; Smekhov, Andrey A.

    2013-01-01

    Researches in the millimetre wave range require the high accuracy for position of the mirror components of the radiotelescope. A mirror weight is the cause of the three-dimension angular deformation of the elevation axle and azimuth axle relatively bearings. At result the elevation angle and azimuth angle of a parabolic mirror axis orientation is not equal to the set values. For the measuring roll, pitch and yaw angular deformations the autocollimation system with new type of the reflector are used. Reflector for autocollimation measurements as compositions of the anamorphic prism and special tetrahedral reflector is described. New methods for roll, pitch, yaw angles measuring are discussed. Optical scheme for the measurement system, structure the anamorphic prism and tetrahedral reflector are proposed. Equations for the static characteristic of the measuring system are shown.

  8. Track train dynamics analysis and test program: Methodology development for the derailment safety analysis of six-axle locomotives

    NASA Technical Reports Server (NTRS)

    Marcotte, P. P.; Mathewson, K. J. R.

    1982-01-01

    The operational safety of six axle locomotives is analyzed. A locomotive model with corresponding data on suspension characteristics, a method of track defect characterization, and a method of characterizing operational safety are used. A user oriented software package was developed as part of the methodology and was used to study the effect (on operational safety) of various locomotive parameters and operational conditions such as speed, tractive effort, and track curvature. The operational safety of three different locomotive designs was investigated.

  9. Faults Diagnostics of Railway Axle Bearings Based on IMF’s Confidence Index Algorithm for Ensemble EMD

    PubMed Central

    Yi, Cai; Lin, Jianhui; Zhang, Weihua; Ding, Jianming

    2015-01-01

    As train loads and travel speeds have increased over time, railway axle bearings have become critical elements which require more efficient non-destructive inspection and fault diagnostics methods. This paper presents a novel and adaptive procedure based on ensemble empirical mode decomposition (EEMD) and Hilbert marginal spectrum for multi-fault diagnostics of axle bearings. EEMD overcomes the limitations that often hypothesize about data and computational efforts that restrict the application of signal processing techniques. The outputs of this adaptive approach are the intrinsic mode functions that are treated with the Hilbert transform in order to obtain the Hilbert instantaneous frequency spectrum and marginal spectrum. Anyhow, not all the IMFs obtained by the decomposition should be considered into Hilbert marginal spectrum. The IMFs’ confidence index arithmetic proposed in this paper is fully autonomous, overcoming the major limit of selection by user with experience, and allows the development of on-line tools. The effectiveness of the improvement is proven by the successful diagnosis of an axle bearing with a single fault or multiple composite faults, e.g., outer ring fault, cage fault and pin roller fault. PMID:25970256

  10. Effect of Quenching Rate on Distortion and Residual Stresses During Induction Hardening of a Full-Float Truck Axle Shaft

    NASA Astrophysics Data System (ADS)

    Li, Zhichao; Ferguson, B. Lynn; Nemkov, Valentin; Goldstein, Robert; Jackowski, John; Fett, Greg

    2014-12-01

    Computer simulation is used to predict the residual stresses and distortion of a full-float truck axle shaft that has been induction scan hardened. Flux2D® is used to model the electromagnetic behavior and the power distributions inside the axle shaft in terms of time. The power distributions are imported and mapped into DANTE® model for thermal, phase transformation, and stress analysis. The truck axle shaft has three main geometrical regions: the flange/filet, the shaft, and the spline. Both induction heating and spray quenching processes have significant effect on the quenching results: distortion and residual stress distributions. In this study, the effects of spray quenching severity on residual stresses and distortion are investigated using modeling. The spray quenching rate can be adjusted by spray nozzle design, ratio of polymer solution, and quenchant flow rate. Different quenching rates are modeled by assigning different heat transfer coefficients as thermal boundary conditions during spray quenching. In this paper, three heat transfer coefficients, 5, 12, and 25 kW/(m2 °C), are applied while keeping all other conditions constant. With the understanding of effects of heating and quenching on residual stresses and distortion of induction hardened parts, the induction hardening process can be optimized for improved part performance.

  11. Fault Prognosis and Diagnosis of an Automotive Rear Axle Gear Using a RBF-BP Neural Network

    NASA Astrophysics Data System (ADS)

    Shao, Yimin; Liang, Jie; Gu, Fengshou; Chen, Zaigang; Ball, Andrew

    2011-07-01

    The rear axle gear is one of the key parts of transmission system for automobiles. Its healthy state directly influences the security and reliability of the automotives. However, non-stationary and nonlinear characteristics of gear vibration due to load and speed fluctuations, makes it difficult to detect and diagnosis the faults from the transmission gear. To solve this problem a fault prognosis and diagnosis method based on a combination of radial basis function(RBF) and back-propagation (BP) neural networks is proposed in this paper. Firstly, a moving average pretreatment is used to suppress the time series fluctuation of vibration characteristic parameter tie series and reduce the interference of random noise. Then, the RBF network is applied to the pretreated parameter sequences for fault prognosis. Furthermore, based on self-learning ability of neural networks, characteristic parameters for different common faults are learned by a BP network. Then the trained BP neural network is utilized for fault diagnosis of the rear axle gear. The results show that the proposed method has a good performance in prognosing and diagnosing different faults from the rear axle gear.

  12. Modelling and characteristic analysis of tri-axle trucks with hydraulically interconnected suspensions

    NASA Astrophysics Data System (ADS)

    Ding, Fei; Han, Xu; Luo, Zhen; Zhang, Nong

    2012-12-01

    In this paper, a new hydraulically interconnected suspension (HIS) system is proposed for the implementation of a resistance control for the pitch and bounce modes of tri-axle heavy trucks. A lumped-mass half-truck model is established using the free-body diagram method. The equations of motion of a mechanical and hydraulic coupled system are developed by incorporating the hydraulic strut forces into the mechanical subsystem as externally applied forces. The transfer matrix method (TMM) is used to evaluate the impedance matrix of the hydraulic subsystem consisting of models of fluid pipes, damper valves, accumulators, and three-way junctions. The TMM is further applied to find the quantitative relationships between the hydraulic strut forces and boundary flow of the mechanical-fluid interactive subsystem. The modal analysis method is employed to perform the vibration analysis between the trucks with the conventional suspension and the proposed HIS. Comparison analysis focuses on free vibration with identified eigenvalues and eigenvectors, isolation vibration capacity, and force vibration in terms of the power spectrum density responses. The obtained results show the effectiveness of the proposed HIS system in reducing the pitch motion of sprung mass and simultaneously maintaining the ride comfort. The pitch stiffness is increased while the bounce stiffness is slightly softened. The peak values of sprung mass and wheel hop motions are greatly reduced, and the vibration decay rate of sprung mass is also significantly increased.

  13. Tyro3, Axl, and Mertk Receptor Signaling in Inflammatory Bowel Disease and Colitis-associated Cancer

    PubMed Central

    Rothlin, Carla V.; Leighton, Jonathan A.; Ghosh, Sourav

    2015-01-01

    Three receptor tyrosine kinases, Tyro3, Axl, and Mertk (TAM) and their ligands Gas6 and Protein S, have emerged as potent negative regulators of innate immune responses. A number of studies using genetic ablation of TAM loci in mice have elucidated the mechanism of TAM engagement and function during the immune response and removal of apoptotic cells. Following phagocytosis of apoptotic cells or the induction of T-cell dependent adaptive immune responses, ligand-induced TAM signaling dampens proinflammatory cytokine production and thus prevents exaggerated or prolonged inflammation. It is believed that the TAM pathway may play an important role in the pathogenesis of inflammatory bowel disease. Suppression of inflammation and removal of apoptotic cells followed by tissue repair are essential processes for disease remission and the successful management of inflammatory bowel disease. In light of the key role of TAMs in controlling inflammatory responses, here, we review the recent advances on TAM research vis-à-vis the resolution of intestinal inflammation. Targeted activation of TAM receptor tyrosine kinases may represent a potent therapeutic opportunity in inflammatory bowel disease. PMID:24846720

  14. The Design and Performance Evaluation of Hydroformed Tubular Torsion Beam Axle

    NASA Astrophysics Data System (ADS)

    Kim, Jaehyun; Oh, Jinho; Choi, Hanho

    2010-06-01

    Suspensions for vehicles are structural devices used for suspending a vehicle body and absorbing shocks from the road. Thus, the suspensions must be designed such that they can attenuate shocks from a road and make passengers feel comfortable despite the shocks, and improve steering stability, determined by the ground contact force of tires during running of vehicles. Another important factor to be considered while designing suspensions is that the suspensions must maintain desired stiffness and desired durability despite the repeated application of shocks from roads thereto. The present relates, in general, to a tubular torsion beam for rear suspensions of vehicles and a manufacturing method thereof and, more particularly, to the provision of tubular torsion beams having excellent roll stiffness and excellent roll strength, produced through hydroforming. The hydroforming technology has a lot of benefit which is shape accuracy, good durability caused by compressive pressure, and good forming quality. In this study, the performance evaluation of the hydroformed tubular torsion beam axle is evaluated.

  15. Axl Inhibition Primes Chronic Lymphocytic Leukemia B-Cells to Apoptosis and Show Synergistic/Additive Effects in Combination with BTK inhibitors

    PubMed Central

    Sinha, Sutapa; Boysen, Justin; Nelson, Michael; Secreto, Charla; Warner, Steven L.; Bearss, David J.; Lesnick, Connie; Shanafelt, Tait D.; Kay, Neil E.; Ghosh, Asish K.

    2015-01-01

    Purpose B-cell chronic lymphocytic leukemia (CLL) is an incurable disease despite aggressive therapeutic approaches. We previously found that Axl receptor tyrosine kinase (RTK) plays a critical role in CLL B-cell survival. Here, we explored the possibility of using a high-affinity Axl inhibitor as a single agent or in combination with Bruton’s tyrosine kinase (BTK) inhibitors for future clinical trial to treat CLL patients. Experimental Design Expression/activation status of other members of the TAM (Tyro3, Axl, MER) family of RTKs in CLL B-cells was evaluated. Cells were treated with a high-affinity orally bioavailable Axl inhibitor TP-0903 with or without presence of CLL bone marrow stromal cells (BMSCs). Inhibitory effects of TP-0903 on Axl signaling pathway was also evaluated in CLL B-cells. Finally, cells were exposed to TP-0903 in combination with BTK inhibitors to determine any synergistic/additive effects of the combination. Results CLL B-cells overexpress Tyro3, but not MER. Of interest, Tyro3 remains as constitutively phosphorylated and form a complex with Axl in CLL B-cells. TP-0903 induces massive apoptosis in CLL B-cells with LD50 values of nanomolar ranges. Importantly, CLL BMSCs could not protect the leukemic B-cells from TP-0903 induced apoptosis. A marked reduction of the anti-apoptotic proteins Mcl-1, Bcl-2, XIAP and upregulation of the pro-apoptotic protein BIM in CLL B-cells were detected as a result of Axl inhibition. Finally, combination of TP-0903 with BTK inhibitors augments CLL B-cell apoptosis. Conclusion Administration of TP-0903 either as a single agent or in combination with BTK inhibitors may be effective in treating CLL patients. PMID:25673699

  16. Control of A Five-axle, Three-steering Coupled-vehicle System

    NASA Astrophysics Data System (ADS)

    Yamaguchi, Hiroaki; Mori, Masato; Kawakami, Atsushi

    This paper presents a new type of coupled-vehicle system: a five-axle, three-steering coupled-vehicle system and its path following feedback control law. The coupled-vehicle system consists of two car-like mobile robots, two carriers and a steering system. One of the two car-like mobile robots is coupled by one of the two carriers via a revolute joint passively rotating and the other car-like mobile robot is also coupled by one remaining carrier via a passive revolute joint, and the two carriers are coupled via another passive revolute joint. The steering system is attached to one of the carriers and its steering axis is located at the same position of the rotating axis of the passive revolute joint coupling the two carriers. We first show that, by assuming virtual mechanical elements, it is possible to convert the kinematical equation of the coupled-vehicle system into three-chain, single-generator chained form in a coordinate system in which a path two times differentiable is an axis and a straight line perpendicular to the tangent of the path is another axis. Based on chained form, we secondly derive the path following feedback control law which enables the orientations of the two carriers relative to the tangent of the path to be controllable. By the feedback control law, it is possible to cause the two carriers to form a line-shaped composed carrier or a V-shaped composed carrier and to cause them to keep such shapes while performing a path following behavior, which means that the coupled-vehicle system is able to adapt the shape of the composed carrier to the shape of a transported object. The validity of the mechanical design of the coupled-vehicle system and its path following feedback control law has been verified experimentally.

  17. Vibration control of bridge subjected to multi-axle vehicle using multiple tuned mass friction dampers

    NASA Astrophysics Data System (ADS)

    Pisal, Alka Y.; Jangid, R. S.

    2016-06-01

    The effectiveness of tuned mass friction damper (TMFD) in reducing undesirable resonant response of the bridge subjected to multi-axle vehicular load is investigated. A Taiwan high-speed railway (THSR) bridge subjected to Japanese SKS (Salkesa) train load is considered. The bridge is idealized as a simply supported Euler-Bernoulli beam with uniform properties throughout the length of the bridge, and the train's vehicular load is modeled as a series of moving forces. Simplified model of vehicle, bridge and TMFD system has been considered to derive coupled differential equations of motion which is solved numerically using the Newmark's linear acceleration method. The critical train velocities at which the bridge undergoes resonant vibration are investigated. Response of the bridge is studied for three different arrangements of TMFD systems, namely, TMFD attached at mid-span of the bridge, multiple tuned mass friction dampers (MTMFD) system concentrated at mid-span of the bridge and MTMFD system with distributed TMFD units along the length of the bridge. The optimum parameters of each TMFD system are found out. It has been demonstrated that an optimized MTMFD system concentrated at mid-span of the bridge is more effective than an optimized TMFD at the same place with the same total mass and an optimized MTMFD system having TMFD units distributed along the length of the bridge. However, the distributed MTMFD system is more effective than an optimized TMFD system, provided that TMFD units of MTMFD system are distributed within certain limiting interval and the frequency of TMFD units is appropriately distributed.

  18. Kinome-wide shRNA Screen Identifies the Receptor Tyrosine Kinase AXL as a Key Regulator for Mesenchymal Glioblastoma Stem-like Cells

    PubMed Central

    Cheng, Peng; Phillips, Emma; Kim, Sung-Hak; Taylor, David; Hielscher, Thomas; Puccio, Laura; Hjelmeland, Anita B.; Lichter, Peter; Nakano, Ichiro; Goidts, Violaine

    2015-01-01

    Summary Glioblastoma is a highly lethal cancer for which novel therapeutics are urgently needed. Two distinct subtypes of glioblastoma stem-like cells (GSCs) were recently identified: mesenchymal (MES) and proneural (PN). To identify mechanisms to target the more aggressive MES GSCs, we combined transcriptomic expression analysis and kinome-wide short hairpin RNA screening of MES and PN GSCs. In comparison to PN GSCs, we found significant upregulation and phosphorylation of the receptor tyrosine kinase AXL in MES GSCs. Knockdown of AXL significantly decreased MES GSC self-renewal capacity in vitro and inhibited the growth of glioblastoma patient-derived xenografts. Moreover, inhibition of AXL with shRNA or pharmacologic inhibitors also increased cell death significantly more in MES GSCs. Clinically, AXL expression was elevated in the MES GBM subtype and significantly correlated with poor prognosis in multiple cancers. In conclusion, we identified AXL as a potential molecular target for novel approaches to treat glioblastoma and other solid cancers. PMID:25921812

  19. Prostaglandin E₂ induces oncostatin M expression in human chronic wound macrophages through Axl receptor tyrosine kinase pathway.

    PubMed

    Ganesh, Kasturi; Das, Amitava; Dickerson, Ryan; Khanna, Savita; Parinandi, Narasimham L; Gordillo, Gayle M; Sen, Chandan K; Roy, Sashwati

    2012-09-01

    Monocytes and macrophages (m) are plastic cells whose functions are governed by microenvironmental cues. Wound fluid bathing the wound tissue reflects the wound microenvironment. Current literature on wound inflammation is primarily based on the study of blood monocyte-derived macrophages, cells that have never been exposed to the wound microenvironment. We sought to compare pair-matched monocyte-derived macrophages with m isolated from chronic wounds of patients. Oncostatin M (OSM) was differentially overexpressed in pair-matched wound m. Both PGE₂ and its metabolite 13,14-dihydro-15-keto-PGE₂ (PGE-M) were abundant in wound fluid and induced OSM in wound-site m. Consistently, induction of OSM mRNA was observed in m isolated from PGE₂-enriched polyvinyl alcohol sponges implanted in murine wounds. Treatment of human THP-1 cell-derived m with PGE₂ or PGE-M caused dose-dependent induction of OSM. Characterization of the signal transduction pathways demonstrated the involvement of EP4 receptor and cAMP signaling. In human m, PGE₂ phosphorylated Axl, a receptor tyrosine kinase (RTK). Axl phosphorylation was also induced by a cAMP analogue demonstrating interplay between the cAMP and RTK pathways. PGE₂-dependent Axl phosphorylation led to AP-1 transactivation, which is directly implicated in inducible expression of OSM. Treatment of human m or mice excisional wounds with recombinant OSM resulted in an anti-inflammatory response as manifested by attenuated expression of endotoxin-induced TNF-α and IL-1β. OSM treatment also improved wound closure during the early inflammatory phase of healing. In summary, this work recognizes PGE₂ in the wound fluid as a potent inducer of m OSM, a cytokine with an anti-inflammatory role in cutaneous wound healing. PMID:22844123

  20. Comparative analysis into the tractor-trailer braking dynamics: tractor with single axle brakes, tractor with all wheel brakes

    NASA Astrophysics Data System (ADS)

    Nastasoiu, Mircea; Ispas, Nicolae

    2014-06-01

    The paper elaborates a mathematical model in order to conduct a study into the dynamics of tractor-trailer systems during braking. The braking dynamics is analyzed by considering two versions for the braking system: 1) braking applied on the rear axle and 2) braking applied on all four wheels. In both versions the trailer is braked on all wheels. The mathematical model enables us to determine and graphically illustrate the evolution of the following parameters: braking deceleration, braking speed and the distance traveled by the tractor during braking. The mathematical model elaborated is applied on a tractor-trailer system completing transportation works.

  1. Identification of the receptor tyrosine kinase AXL in breast cancer as a target for the human miR-34a microRNA

    PubMed Central

    Mackiewicz, Mark; Huppi, Konrad; Pitt, Jason J.; Dorsey, Tiffany H.; Ambs, Stefan

    2012-01-01

    The identification of molecular features that contribute to the progression of breast cancer can provide valuable insight into the pathogenesis of this disease. Deregulated microRNA expression represents one type of molecular event that has been associated with many different human cancers. In order to identify a miRNA/mRNA regulatory interaction that is biologically relevant to the triple-negative breast cancer genotype/phenotype, we initially conducted a miRNA profiling experiment to detect differentially expressed miRNAs in cell line models representing triple-negative (MDA-MB-231), ER+ (MCF7), and HER-2 over expressed (SK-BR-3) histotypes. We identified human miR-34a expression as being >3-fold down (from its median expression value across all cell lines) in MDA-MB-231 cells, and identified AXL as a putative mRNA target using multiple miRNA/target prediction algorithms. The miR-34a/AXL interaction was functionally characterized through ectopic over expression experiments with a miR-34a mimic in two independent triple-negative breast cancer cell lines. In reporter assays, miR-34a binds to its putative target site within the AXL 3′UTR to inhibit luciferase expression. We also observed degradation of AXL mRNA and decreased AXL protein levels, as well as cell signaling effects on AKT phosphorylation and phenotypic effects on cell migration. Finally, we present an inverse correlative trend in miR-34a and AXL expression for both cell line and patient tumor samples. PMID:21814748

  2. On "impact of surface type, wheelchair weight, and axle position on wheelchair propulsion by novice older adults".

    PubMed

    Sprigle, Stephen

    2009-07-01

    The mechanical efficiency of propelling manual wheelchairs is a very important topic. Wheelchair users, clinicians, manufacturers and payers would all benefit from better understanding of mechanical efficiency. However, the measurement of the mechanical efficiency is a nontrivial challenge. Cowan et al deserve a lot of credit for tackling such a difficult problem in their article "Impact of surface type, wheelchair weight, and axle position on wheelchair propulsion by novice older adults." The study demonstrated good internal validity in detecting a 4% difference in peak propulsion forces in wheelchairs that differed in mass by 9.1 kg. However, the instrumentation used to measure forces altered both the mass and inertia of the wheelchair-occupant system--2 factors that directly affect system energy. This approach, therefore, affects external validity, and the results cannot be extended to infer differences across wheelchair codes. That said, this study adds important information to the body of work into mechanical efficiency of wheelchairs. We now have evidence to suggest that addition of 9 kg and an 8 cm posterior displacement of axle position adversely affects propulsion biomechanics in an elderly cohort. Improved methodology can lead to mechanical efficiency measurement of different wheelchair models and different wheelchair options. PMID:19577018

  3. Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation*

    PubMed Central

    Tsou, Wen-I; Nguyen, Khanh-Quynh N.; Calarese, Daniel A.; Garforth, Scott J.; Antes, Anita L.; Smirnov, Sergey V.; Almo, Steve C.; Birge, Raymond B.; Kotenko, Sergei V.

    2014-01-01

    TYRO3, AXL, and MER receptors (TAMs) are three homologous type I receptor-tyrosine kinases that are activated by endogenous ligands, protein S (PROS1) and growth arrest-specific gene 6 (GAS6). These ligands can either activate TAMs as soluble factors, or, in turn, opsonize phosphatidylserine (PS) on apoptotic cells (ACs) and serve as bridging molecules between ACs and TAMs. Abnormal expression and activation of TAMs have been implicated in promoting proliferation and survival of cancer cells, as well as in suppressing anti-tumor immunity. Despite the fact that TAM receptors share significant similarity, little is known about the specificity of interaction between TAM receptors and their ligands, particularly in the context of ACs, and about the functional diversity of TAM receptors. To study ligand-mediated activation of TAMs, we generated a series of reporter cell lines expressing chimeric TAM receptors. Using this system, we found that each TAM receptor has a unique pattern of interaction with and activation by GAS6 and PROS1, which is also differentially affected by the presence of ACs, PS-containing lipid vesicles and enveloped virus. We also demonstrated that γ-carboxylation of ligands is essential for the full activation of TAMs and that soluble immunoglobulin-like TAM domains act as specific ligand antagonists. These studies demonstrate that, despite their similarity, TYRO3, AXL, and MER are likely to perform distinct functions in both immunoregulation and the recognition and removal of ACs. PMID:25074926

  4. Evaluation of pitch up of two-axle solid waste collection compactor trucks in the static condition.

    PubMed

    Souza, Rosilene Viana de Freitas; Pinto, João Mário Andrade; Cimini, Carlos Alberto; Pereira, Sérgio Luiz de Souza

    2011-03-01

    The study of pitch up limit for solid waste collection compactor trucks in tilted public roads is of great relevance both for the planning of waste collection, mainly in cities with very uneven street gradient, or for use as a design parameter in projects involving public roads. Considering the typical construction and use of rear loader waste compactor equipment, the centre of gravity moves towards the rear of the vehicle as it is loaded, resulting in overload in the rear axle at the end of the waste collection period. In the city of Belo Horizonte (Brazil), several cases of pitch up have been reported for this type of vehicle, in streets with different inclinations and with loading situations in which the load box was not completely full. The present study investigated the variation of the imminence pitch up angles of the two-axle, rear-loading, solid waste collection compactor truck in a static condition, determined by the variation of its centre of gravity coordinates, which were obtained experimentally by means of a testing programme for different loading situations. The critical inclination angle was 0.347 rad (19.89°), which corresponds to a ramp inclination of 36.17%, for the condition of total weight of 157.06 kN (16 027 kgf) with payload of 63.42 kN (6472 kgf). PMID:20406754

  5. AUTOMOTIVE DIESEL MAINTENANCE 1. UNIT XIX, I--ENGINE TUNE-UP--CUMMINS DIESEL ENGINE, II--FRONT END SUSPENSION AND AXLES.

    ERIC Educational Resources Information Center

    Minnesota State Dept. of Education, St. Paul. Div. of Vocational and Technical Education.

    THIS MODULE OF A 30-MODULE COURSE IS DESIGNED TO DEVELOP AN UNDERSTANDING OF DIESEL ENGINE TUNE-UP PROCEDURES AND THE DESIGN OF FRONT END SUSPENSION AND AXLES USED ON DIESEL ENGINE EQUIPMENT. TOPICS ARE (1) PRE-TUNE-UP CHECKS, (2) TIMING THE ENGINE, (3) INJECTOR PLUNGER AND VALVE ADJUSTMENTS, (4) FUEL PUMP ADJUSTMENTS ON THE ENGINE (PTR AND PTG),…

  6. Non-contacting fluid ring seal systems for railcar axle bearing systems: Quarterly progress report No. 1, June 15 to September 15, 1987

    SciTech Connect

    Not Available

    1987-01-01

    The main objectives of this DOE contract is the technical development of a practical, cost effective Fluid Ring seal system capable of: Drastically reducing locomotive drawbar traction power requirements by lowering seal friction losses prevalent in present railcar axle bearing systems; increasing reliability and safety of railroad cars by minimizing bearing lubricant leakage and minimizing bearing ''hot boxes''; and improving the productivity of the railway transportation systems by reducing rolling stock ''outages'' due to long seal life. 14 refs.

  7. Potential of Active-Steering Bogie for Reducing Lateral Axle Load Caused at Worn Welded Joints of Outer Rail in Curved Track

    NASA Astrophysics Data System (ADS)

    Iizuka, Tatsuya; Tanifuji, Katsuya; Soma, Hitoshi

    This paper deals with the potential of an active-steering bogie to reduce the large lateral axle load that arises at worn welded joints of the outer rail in a curved track when high-speed trains pass. The shape of the worn joint, called lateral ‘angular bent’, is modeled on the basis of the measured irregularity shape of actual joints. Then, numerical simulation of running on a curved track is carried out for a two-axle bogie vehicle to compare an active-steering bogie and a conventional nonsteering bogie. The behavior of the vehicle negotiating the curve is evaluated from the viewpoints of decreasing the peak value of lateral axle load within the allowance limit and maintaining the running stability. To satisfy the requirements, wheelset-supporting parameters and feedback gains for active-steering are optimized on a curved section of 400 m radius by the Genetic Algorithm. On the basis of the optimized wheelset-supporting parameter values, additional sets of feedback gains, which are adjusted for the curves of different radii, are proposed. The numerical simulation shows that the operation speed of a vehicle with active-steering bogies having the optimized parameter values has the potential to be raised to the possible speed for tilting trains while satisfying the criterion of riding comfort.

  8. Chemical bonding and dynamic fluxionality of a B15(+) cluster: a nanoscale double-axle tank tread.

    PubMed

    Wang, Ying-Jin; You, Xue-Rui; Chen, Qiang; Feng, Lin-Yan; Wang, Kang; Ou, Ting; Zhao, Xiao-Yun; Zhai, Hua-Jin; Li, Si-Dian

    2016-06-21

    A planar, elongated B15(+) cationic cluster is shown to be structurally fluxional and functions as a nanoscale tank tread on the basis of electronic structure calculations, bonding analyses, and molecular dynamics simulations. The outer B11 peripheral ring behaves like a flexible chain gliding around an inner B4 rhombus core, almost freely at the temperature of 500 K. The rotational energy barrier is only 1.37 kcal mol(-1) (0.06 eV) at the PBE0/6-311+G* level, further refined to 1.66 kcal mol(-1) (0.07 eV) at the single-point CCSD(T)/6-311G*//CCSD/6-311G* level. Two soft vibrational modes of 166.3 and 258.3 cm(-1) are associated with the rotation, serving as double engines for the system. Bonding analysis suggests that the "island" electron clouds, both σ and π, between the peripheral ring and inner core flow and shift continuously during the intramolecular rotation, facilitating the dynamic fluxionality of the system with a small rotational barrier. The B15(+) cluster, roughly 0.6 nm in dimension, is the first double-axle nanoscale tank tread equipped with two engines, which expands the concepts of molecular wheels, Wankel motors, and molecular tanks. PMID:27229290

  9. In-service parametric modelling a rail vehicle's axle-box hydraulic damper for high-speed transit problems

    NASA Astrophysics Data System (ADS)

    Wang, W. L.; Yu, D. S.; Zhou, Z.

    2015-10-01

    Due to the high-speed operation of modern rail vehicles and severe in-service environment of their hydraulic dampers, it has become important to establish more practical and accurate damper models and apply those models in high-speed transit problem studies. An improved full parametric model with actual in-service parameters, such as variable viscous damping, comprehensive stiffness and small mounting clearance was established for a rail vehicle's axle-box hydraulic damper. A subtle variable oil property model was built and coupled to the modelling process, which included modelling of the dynamic flow losses and the relief-valve system dynamics. The experiments validated the accuracy and robustness of the established full in-service parametric model and simulation which captured the damping characteristics over an extremely wide range of excitation speeds. Further simulations were performed using the model to uncover the effects of key in-service parameter variations on the nominal damping characteristics of the damper. The obtained in-service parametric model coupled all of the main factors that had significant impacts on the damping characteristics, so that the model could be useful in more extensive parameter effects analysis, optimal specification and product design optimisation of hydraulic dampers for track-friendliness, ride comfort and other high-speed transit problems.

  10. GAS6/AXL Axis Regulates Prostate Cancer Invasion, Proliferation, and Survival in the Bone Marrow Niche12

    PubMed Central

    Shiozawa, Yusuke; Pedersen, Elisabeth A; Patel, Lalit R; Ziegler, Anne M; Havens, Aaron M; Jung, Younghun; Wang, Jingcheng; Zalucha, Stephanie; Loberg, Robert D; Pienta, Kenneth J; Taichman, Russell S

    2010-01-01

    Our recent studies have shown that annexin II, expressed on the cell surface of osteoblasts, plays an important role in the adhesion of hematopoietic stem cells (HSCs) to the endosteal niche. Similarly, prostate cancer (PCa) cells express the annexin II receptor and seem to use the stem cell niche for homing to the bone marrow. The role of the niche is thought to be the induction and sustenance of HSC dormancy. If metastatic PCa cells occupy a similar or the same ecological niche as HSCs, then it is likely that the initial role of the HSC niche will be to induce dormancy in metastatic cells. In this study, we demonstrate that the binding of PCa to annexin II induces the expression of the growth arrest-specific 6 (GAS6) receptors AXL, Sky, and Mer, which, in the hematopoietic system, induce dormancy. In addition, GAS6 produced by osteoblasts prevents PCa proliferation and protects PCa from chemotherapy-induced apoptosis. Our results suggest that the activation of GAS6 receptors on PCa in the bone marrow environment may play a critical role as a molecular switch, establishing metastatic tumor cell dormancy. PMID:20126470

  11. Nonlinearity-induced time-varying harmonic dynamic axle load and its impact on dynamic stability of car-trailer combinations

    NASA Astrophysics Data System (ADS)

    Zhang, Ning; Xiao, Hong; Winner, Hermann

    2016-06-01

    A nonlinearity-induced time-varying harmonic dynamic axle load is found in the road test of a car-trailer combination. To understand its influence on system dynamic stability, a corresponding linear single-track model (STM) is proposed. System dynamic stability is described and sensitivity analysis for the system parameters is achieved. The contribution of the harmonic force is quantified by a derived effective axle load. Because the harmonic effect might be time varying in practice, a time-frequency analysis-based parameter identification method is introduced. Experimental study shows that a time-varying harmonic effect really exists. A yaw-rate-based simulation method is designed to simulate this behaviour. The sensitivity analysis of the influence of the harmonic amplitude or phase on dynamic stability is performed with a simulation study. With appropriate modification of the harmonic amplitude and phase shift applied in selected time windows, the time-varying system characteristics in the road test can be simulated very well.

  12. MicroRNA-432 functions as a tumor suppressor gene through targeting E2F3 and AXL in lung adenocarcinoma

    PubMed Central

    Chen, Ling; Kong, Guangming; Zhang, Chuantao; Dong, Hongyan; Yang, Cuicui; Song, Guanhua; Guo, Chengye; Wang, Lin; Yu, Hongsheng

    2016-01-01

    Abnormal proliferation and drug resistance are the hallmarks of lung adenocarcinoma (LAD). Dispite the advances in diagnosis and therapy, the 5-year survival remains low. Increasing studies regarding its pathological mechanism have been focused on microRNA (miRNA) due to its nodal regulatory properties. This study aims to characterize the expression of miR-432 in LAD and investigate its effects on the proliferation and sensitivity of lung cancer cells to cisplatin. Here, we report that downregulation of miR-432 in LAD tissues was correlated with a higher clinical stage (p = 0.03) and poor prognosis (p = 0.036). Additionally, miR-432 expression was negative correlated with high Ki67 labeling index (p = 0.016) in our cohorts. Functionally, over-expression of miR-432 inhibits cell proliferation through arresting cell cycle and sensitizes tumor cells to cisplatin. Mechanistically, miR-432 functions by directly targeting E2F3 and AXL, and they, in turn, mediate the regulation of miR-432 towards cell proliferation and cisplatin sensitivity. Importantly, miR-432 levels are negatively correlated with the levels of E2F3 and AXL in human LAD tissues. These results demonstrated that miR-432 functions as a tumor-suppressive miRNA and may represent a prognostic parameter and therapeutic target for LAD. PMID:26942465

  13. Structural studies on inclusion compounds and solvent sorption behavior of gradually elongated wheel-and-axle-type diol hosts featuring lateral benzo[b]thiophene units

    NASA Astrophysics Data System (ADS)

    Katzsch, Felix; Gruber, Tobias; Weber, Edwin

    2016-06-01

    Based on the wheel-and-axle design strategy, a series of six new clathrate hosts featuring two di(benzo[b]thien-2-yl)hydroxymethyl units attached to both ends of a central linear building element of varying length have been synthesized and their capability to form crystalline inclusion compounds with a fixed range of organic solvents are reported. X-ray crystal structures of relevant inclusion compounds have been determined and are comparatively discussed involving structural modification of the host molecules. Organic vapor sorption behavior of the host compounds coated as solid films on the quartz crystal of a QCM device has been studied. Significant differences in the affinities towards solvent vapors dependent both on structural and polarity properties of host and solvent are observed, indicating potential application as mass sensitive materials.

  14. Improved Apparatus for Measuring Distance Between Axles

    NASA Technical Reports Server (NTRS)

    Willard, Douglas E.; Townsend, Ivan I., III

    2003-01-01

    An improved version of an optoelectronic apparatus for measuring distances of the order of tens of feet with an error no larger than a small fraction of an inch (a few millimeters) has been built. Like the previous version, the present improved version of the apparatus is designed to measure the distance approximately equal to 66 ft (approximately equal to 20 m) between the axes of rotation of the front and rear tires of the space shuttle orbiter as it rests in a ground-based processing facility. Like the previous version, the present version could also be adapted for similar purposes in other settings: Examples include measuring perpendicular distance from a wall in a building, placement of architectural foundations, and general alignment and measurement operations.

  15. Evaluation of the 30 Ton CHA Crane Wheel Axle Modification

    SciTech Connect

    RICH, J.W.

    2002-06-04

    An existing design for eccentric bushings was utilized and updated as necessary to accommodate minor adjustment as required to correct wheel alignment on the North West Idler wheel. The design is revised to install eccentric bushings on only one end.

  16. Transfer case with inter-axle dual-planetary differential

    SciTech Connect

    Eastman, R.E.; Williams, R.C.

    1987-07-07

    A transfer case apparatus is described adapted for driving a four wheel drive motor vehicle having front and rear ground engaging wheels. The apparatus includes a housing, an input shaft adapted for connection to a transmission of the motor vehicle, a pair of first and second output shafts supported for rotation in the housing, the first output shaft adapted for driving connection to the rear ground engaging wheels and the second output shaft adapted for driving connection to the front ground engaging wheels. A dual helical planetary differential gear assembly is arranged in a compact manner for proportioning torque between the first and second output shafts. The dual planetary differential helical gear assembly comprises a dual planetary carrier including first and second longitudinally spaced carrier rings rotatable about the central axis of the first output shaft. The first carrier ring has a central opening formed with internal splines concentrically disposed about the first output shaft. First and second juxtaposed toothed helical gun gears are concentrically disposed about the first output shaft. The first sun gear is fixed to the first output shaft and has its teeth at a first uniform radius. The second sun gear is journalled on the first output shaft and has its teeth at a second uniform radius a predetermined distance less than the first sun gear teeth radius.

  17. Will the Requirement by the US FDA to Simultaneously Co-Develop Companion Diagnostics (CDx) Delay the Approval of Receptor Tyrosine Kinase Inhibitors for RTK-Rearranged (ROS1-, RET-, AXL-, PDGFR-α-, NTRK1-) Non-Small Cell Lung Cancer Globally?

    PubMed

    Ou, Sai-Hong Ignatius; Soo, Ross A; Kubo, Akihito; Kawaguchi, Tomoya; Ahn, Myung-Ju

    2014-01-01

    The discovery of anaplastic lymphoma kinase (ALK) rearrangement in non-small cell lung cancer (NSCLC) in 2007 and the approval of crizotinib for the treatment of advanced ALK-rearranged NSCLC in 2011 represents a landmark in the development of targeted oncology therapy. The approval of crizotinib was accompanied simultaneously by the approval of the Vysis (Abbott Molecular) break-apart fluorescence in situ hybridization (FISH) test as the companion diagnostic (CDx) test to detect ALK rearrangement. Pfizer, the manufacturer of crizotinib, sponsored the screening of thousands of patients and the standardization of the ALK FISH test as part of the approval process for crizotinib, a first in class ALK inhibitor. Many pharmaceutical companies are now using the Food and Drug Administration (FDA)-approved ALK FISH assay to enroll patients onto trials for their own respective ALK inhibitors. In essence they are "piggybacking" on the FDA-approved ALK FISH assay without having to pay for the development of a CDx, nor screening for ALK-rearranged NSCLC patients in the protocols because screening for ALK rearrangement is now the standard of care in NSCLC after the approval of crizotinib. Since 2007, rearrangement in more receptor tyrosine kinases (RTKs) such as ROS1, RET, AXL, PDGFR-α, and NTRK1 have been discovered in NSCLC but the incidence of each subtype of RTK-rearranged NSCLC is quite rare. Crizotinib has now demonstrated significant clinical activity in ROS1-rearranged NSCLC patients. Whether crizotinib will gain official FDA approval for use in ROS1-rearranged NSCLC, on the other hand, remains unclear as there is no test for ROS1-rearrangement currently being developed to support US FDA approval as a CDx. This may be due in part to the fact that the full cost associated with the development of a pre-market approved-approved CDx must be borne by the company seeking the first drug approval in a new indication. Given the low incidence of ROS1-rearrangement in NSCLC, and

  18. Manual Drive Train and Axles. Auto Mechanics Curriculum Guide Module 7. Instructor's Guide.

    ERIC Educational Resources Information Center

    Colesworthy, Robert; Donovan, Roger

    This document is one of a series of modules in the Missouri Auto Mechanics Curriculum Guide, which is based on 144 basic auto mechanics competencies identified on the Missouri Auto Mechanics Competency Profile. The instructor's materials in this document are for a 13-unit secondary education course. The following units are included: (1)…

  19. 75 FR 76036 - American Axle & Manufacturing Detroit Manufacturing Complex Holbrook Avenue and Saint Aubin...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-07

    ... December 10, 2008 (73 FR 75137). The Department's Notice was amended on January 8, 2009 to clarify that the... (subject firm). The Department's Notice was published in the Federal Register on January 15, 2009 (74 FR... Avenue and Saint Aubin Including On-Site Leased Workers From Paint Tech International Detroit,...

  20. Algorithm of orthogonal bi-axle for auto-separating of watermelon seeds

    NASA Astrophysics Data System (ADS)

    Sun, Yong; Guan, Miao; Yu, Daoqin; Wang, Jing

    2007-11-01

    During the process of watermelon seeds characteristic extraction as well as separation, watermelon seeds' major and minor axes, the length and width ratio have played a very important role in appearance regulating degree evaluation. It is quite difficult to find the answer of orthogonal bi-axes because the watermelon seeds are flat and irregular in shape and what's more there is no rule to follow. After a lot of experiments and research, the author proposed the algorithm of orthogonal bi-axes algorithm for granulated object. It has been put into practice and proved in the application of auto-separation system for watermelon seeds. This algorithm has the advantage of lower time complexity and higher precision compared with other algorithms. The algorithm can be used in the solution of other similar granulated objects, and has the widespread application value.

  1. 75 FR 11914 - Chrysler, LLC, Detroit Axle Plant, Including On-Site Leased Workers From Caravan Knight...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-03-12

    ... the Federal Register on February 2, 2009 (74 FR 5870). At the request of the State agency, the... From Caravan Knight Facilities Management LLC; Detroit, MI; Amended Certification Regarding Eligibility... Caravan Knight Facilities Management LLC were employed on-site at the Detroit, Michigan location...

  2. 75 FR 52981 - Chrysler, LLC, Detroit Axle Plant, Including On-Site Leased Workers from Caravan Knight...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-08-30

    ... from Caravan Knight Facilities Management LLC, and Syncreon, Detroit, MI; Amended Certification... was published in the Federal Register on February 2, 2009 (74 FR 5870). The notice was amended on March 4, 2010 to include on-site leased workers from Caravan Knight Facilities Management LLC....

  3. Influence of wheel and rail profile shape on the initiation of rolling contact fatigue cracks at high axle loads

    NASA Astrophysics Data System (ADS)

    Spangenberg, Ulrich; Desmond Fröhling, Robert; Schalk Els, Pieter

    2016-05-01

    The influence of wheel and rail profile shape features on the initiation of rolling contact fatigue (RCF) cracks is evaluated based on the results of multi-body vehicle dynamics simulations. The damage index and surface fatigue index are used as two damage parameters to assess the influence of the different features. The damage parameters showed good agreement to one another and to in-field observations. The wheel and rail profile shape features showed a correlation to the predicted RCF damage. The RCF damage proved to be most sensitive to the position of hollow wear and thus bogie tracking. RCF initiation and crack growth can be reduced by eliminating unwanted shape features through maintenance and design and by improving bogie tracking.

  4. AUTOMOTIVE DIESEL MAINTENANCE 1. UNIT XVIII, I--UNDERSTAND ENGINE GEARS AND GEARING PRINCIPLES, II--MACK INTER-AXLE POWER DIVIDER.

    ERIC Educational Resources Information Center

    Minnesota State Dept. of Education, St. Paul. Div. of Vocational and Technical Education.

    THIS MODULE OF A 30-MODULE COURSE IS DESIGNED TO DEVELOP AN UNDERSTANDING OF DIESEL ENGINE GEARS AND GEARING PRINCIPLES AND THE OPERATING PRINCIPLES AND MAINTENANCE OF POWER DIVIDERS (GEAR BOXES) USED IN DIESEL ENGINE POWER TRANSMISSION. TOPICS ARE (1) THE PURPOSE OF THE ENGINE GEARS, (2) INSPECTING FOR GEAR FAILURES, (3) INSPECTING FOR SHAFT…

  5. Increased roll stability suspension system

    SciTech Connect

    Giese, L.

    1987-05-26

    A suspension system is described for suspending an elongated chassis of a vehicle, such as a heavy duty truck, above the front axle and rear axle of a transversely extending tandem axle combination. The suspension system comprises: means for locating the roll center of the vehicle at an elevation below the elevation of the axles; and a stabilizer unit for providing roll stability to the vehicle. The stabilizer unit is mounted to the vehicle chassis at a pivot point longitudinally intermediate the front axle and the rear axle of the tandem axle combination for rotation in a generally horizontal plane. The stabilizer unit includes a pair of linkage members, each linkage member extending generally longitudinally outward from the pivot point in a direction opposite from the other linkage member and toward a corresponding axle.

  6. Axial length in unilateral idiopathic central serous chorioretinopathy

    PubMed Central

    Moon, Hoseok; Lee, Dae Yeong; Nam, Dong Heun

    2016-01-01

    AIM To evaluate the axial length (AXL) in unilateral idiopathic central serous chorioretinopathy (CSC). METHODS This retrospective case-control study was comprised of a consecutive case series of 35 patients with acute unilateral idiopathic CSC, and age- and sex-matched 50 control eyes. AXL of both eyes of unilateral CSC patients and the control eyes were investigated. AXL was measured by ultrasonic biometry, and the adjusted AXL was calculated for CSC eyes as measured AXL plus differences of foveal thickness between CSC and normal fellow eyes in millimeters. The main outcome measures were comparison of AXL between CSC, fellow and control eyes. RESULTS The mean age of 35 CSC patients was 45.5y, and 31 males were included. The adjusted AXL of CSC eyes was 23.52 mm, and the AXL of fellow eyes was 23.46 mm, and of control eyes 23.94 mm. The AXL of both CSC and fellow eyes were significantly shorter than control eyes (CSC vs control, P=0.044; fellow vs control, P=0.026). There was no statistically significant difference in AXL between CSC and fellow eyes. CONCLUSION In unilateral idiopathic CSC, the AXL of CSC and fellow eyes are shorter than that of control eyes. Short AXL may be related with choroidal circulation abnormality in CSC. PMID:27275428

  7. A Molecular Rotor Possessing an H-M-H "Spoke" on a P-M-P "Axle": A Platinum(II) trans-Dihydride Spins Rapidly Even at 75 K.

    PubMed

    Prack, Ernest; O'Keefe, Christopher A; Moore, Jeremy K; Lai, Angel; Lough, Alan J; Macdonald, Peter M; Conradi, Mark S; Schurko, Robert W; Fekl, Ulrich

    2015-10-28

    A new class of low-barrier molecular rotors, metal trans-dihydrides, is suggested here. To test whether rapid rotation can be achieved, the known complex trans-H2Pt(P(t)Bu3)2 was experimentally studied by (2)H and (195)Pt solid-state NMR spectroscopy (powder pattern changes with temperature) and computationally modeled as a (t)Bu3P-Pt-P(t)Bu3 stator with a spinning H-Pt-H rotator. Whereas the related chloro-hydride complex, trans-H(Cl)Pt(P(t)Bu3)2, does not show rotational behavior at room temperature, the dihydride trans-H2Pt(P(t)Bu3)2 rotates fast on the NMR time scale, even at low temperatures down to at least 75 K. The highest barrier to rotation is estimated to be ∼3 kcal mol(-1), for the roughly 3 Å long rotator in trans-H2Pt(P(t)Bu3)2. PMID:26448538

  8. Effect of Component Mobility on the Properties of Macromolecular [2]Rotaxanes.

    PubMed

    Chen, Zhen; Aoki, Daisuke; Uchida, Satoshi; Marubayashi, Hironori; Nojima, Shuichi; Takata, Toshikazu

    2016-02-18

    Macromolecular [2]rotaxanes comprising a polymer axle and crown ether wheel were synthesized to evaluate the effect of component mobility on the properties of the axle polymer, especially its crystallinity. Living ring-opening polymerization of δ-valerolactone with a pseudorotaxane initiator with a hydroxy group at the axle terminus was followed by end-capping with a bulky isocyanate. This yielded macromolecular [2]rotaxanes (M2Rs) possessing polyester axles of varying molecular weights. The crystallinity of the axle polymers of two series of M2Rs, with either fixed and movable components, was evaluated by differential scanning calorimetry. The results revealed that the effect of component mobility was significant in the fixed and movable M2Rs with a certain axle length, thus suggesting that the properties of the axle polymer depend on the mobility of the polyrotaxane components. PMID:26806916

  9. 49 CFR 537.7 - Pre-model year and mid-model year reports.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... resulting data to the Environmental Protection Agency under 40 CFR 600.509. (c) Model type and configuration... accordance with subpart D of 40 CFR part 600, (2) Body style, (3) Beginning model year 2010, base tire as defined in 49 CFR 523.2, (4) Beginning model year 2010, front axle, rear axle and average track width...

  10. 49 CFR 537.7 - Pre-model year and mid-model year reports.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... CFR 523.2, (B) Beginning model year 2013, front axle, rear axle and average track width as defined in 49 CFR 523.2, (C) Beginning model year 2013, wheelbase as defined in 49 CFR 523.2, and (D) Beginning model year 2013, footprint as defined in 49 CFR 523.2. (E) Optionally, beginning model year 2013,...

  11. 49 CFR 537.7 - Pre-model year and mid-model year reports.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... resulting data to the Environmental Protection Agency under 40 CFR 600.509. (c) Model type and configuration... accordance with subpart D of 40 CFR part 600, (2) Body style, (3) Beginning model year 2010, base tire as defined in 49 CFR 523.2, (4) Beginning model year 2010, front axle, rear axle and average track width...

  12. 49 CFR 537.7 - Pre-model year and mid-model year reports.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... CFR 523.2, (B) Beginning model year 2013, front axle, rear axle and average track width as defined in 49 CFR 523.2, (C) Beginning model year 2013, wheelbase as defined in 49 CFR 523.2, and (D) Beginning model year 2013, footprint as defined in 49 CFR 523.2. (E) Optionally, beginning model year 2013,...

  13. 49 CFR 393.48 - Brakes to be operative.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... motor vehicles provided the speed at which the combination of vehicles will be operated does not exceed... within 12.2 meters (40 feet) from the speed at which the vehicle is being operated or 32 km/hour (20 mph), whichever is less. (6) Raised lift axles. Brakes on lift axles need not be capable of being operated...

  14. 40 CFR 86.602-84 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... defined herein have the meaning given them in the Act. (1) Acceptable Quality Level (AQL) means the... satisfactory as a process average. (2) Axle Ratio means all ratios within ±3% of the axle ratio specified in the configuration in the test order. (3) Configuration means a subclassification of an...

  15. 40 CFR 86.602-84 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... defined herein have the meaning given them in the Act. (1) Acceptable Quality Level (AQL) means the... satisfactory as a process average. (2) Axle Ratio means all ratios within ±3% of the axle ratio specified in the configuration in the test order. (3) Configuration means a subclassification of an...

  16. 14 CFR 29.497 - Ground loading conditions: landing gear with tail wheels.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ....471 through 29.475; (2) The vertical load at each axle must be combined with a drag load at that axle... drag load must be applied, at the ground contact point, of not less than the lesser of— (i) 0.8...

  17. 14 CFR 27.497 - Ground loading conditions: landing gear with tail wheels.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ....471 through 27.475; (2) The vertical load at each axle must be combined with a drag load at that axle... drag load must be applied, at the ground contact point, of not less than the lesser of— (i) 0.8...

  18. 49 CFR 229.63 - Lateral motion.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Lateral motion. 229.63 Section 229.63....63 Lateral motion. (a) Except as provided in paragraph (b), the total uncontrolled lateral motion... powered axles. (b) The total uncontrolled lateral motion may not exceed 11/4 inches on the center axle...

  19. 49 CFR 571.7 - Applicability.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... engine, transmission, and drive axle(s) (as a minimum) of the assembled vehicle are not new, and at least..., DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR VEHICLE SAFETY STANDARDS General § 571.7 Applicability. (a... B of this part applies according to its terms to all motor vehicles or items of motor...

  20. 49 CFR 571.7 - Applicability.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... engine, transmission, and drive axle(s) (as a minimum) of the assembled vehicle are not new, and at least..., DEPARTMENT OF TRANSPORTATION FEDERAL MOTOR VEHICLE SAFETY STANDARDS General § 571.7 Applicability. (a... B of this part applies according to its terms to all motor vehicles or items of motor...

  1. Mode Orientation Control For Sapphire Dielectric Ring Resonator

    NASA Technical Reports Server (NTRS)

    Santiago, David G.; Dick, G. John; Prata, Aluizio

    1996-01-01

    Small sapphire tuning wedge used in technique for solving mode-purity problem associated with sapphire dielectric-ring resonator part of cryogenic microwave frequency discriminator. Breaks quasi-degeneracy of two modes and allows selective coupling to just one mode. Wedge mounted on axle entering resonator cavity and rotated while resonator cryogenically operating in vacuum. Furthermore, axle moved vertically to tune resonant frequency.

  2. 23 CFR Appendix B to Part 658 - Grandfathered Semitrailer Lengths

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... a kingpin-to-rearmost axle distance of 38 feet. Semitrailers that are consistent with 23 CFR 658.13... 23 CFR 658.13(g) may operate without a permit provided the distance from the kingpin to the center of the rear axle is 46 feet or less. 3 Semitrailers up to 53 feet in length may operate without a...

  3. 23 CFR Appendix B to Part 658 - Grandfathered Semitrailer Lengths

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... a kingpin-to-rearmost axle distance of 38 feet. Semitrailers that are consistent with 23 CFR 658.13... 23 CFR 658.13(g) may operate without a permit provided the distance from the kingpin to the center of the rear axle is 46 feet or less. 3 Semitrailers up to 53 feet in length may operate without a...

  4. 23 CFR Appendix B to Part 658 - Grandfathered Semitrailer Lengths

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... a kingpin-to-rearmost axle distance of 38 feet. Semitrailers that are consistent with 23 CFR 658.13... 23 CFR 658.13(g) may operate without a permit provided the distance from the kingpin to the center of the rear axle is 46 feet or less. 3 Semitrailers up to 53 feet in length may operate without a...

  5. All-terrain vehicle

    SciTech Connect

    Somerton-Rayner, M.

    1986-12-16

    This patent describes an all-terrain vehicle comprising: a chassis; four road wheel axles equally spaced along the chassis; suspension means mounting the axles on the chassis; wheels mounted adjacent both ends of each of the axles, the wheels on the foremost and the rearmost axles being steerably mounted; propulsion and driving means including a single internal combustion engine and gearbox, and first and second transfer boxes both coupled to be driven by the engine through the gearbox; the first transfer box driving the first and third axles and the second transfer box driving the second and fourth axles; means for driving in the alternative all four wheels and only the center two wheels; power-assisted steering gear means operatively connected to the steerably-mounted wheels of the foremost axle; and steering coupling means extending between the steerably-mounted wheels on the foremost and rearmost axles so dimensioned that upon steering of the front wheels, the rear wheels perform castoring constrained to a smaller turning angle and a lower rate of angular movement than the front wheels.

  6. Mount for continuously orienting a collector dish in a system adapted to perform both diurnal and seasonal solar tracking

    NASA Technical Reports Server (NTRS)

    Brantley, L. W., Jr.; Lawson, B. D. (Inventor)

    1977-01-01

    A collector dish is continuously oriented toward the sun in a system adapted to perform both diurnal and seasonal solar tracking. The mount is characterized by a rigid, angulated axle having a linear midportion supporting a collector dish, and oppositely extended end portions normally related to the midportion of the axle and received in spaced journals. The longitudinal axis of symmetry for the midportion of the axle is coincident with a seasonal axis while the axes of the journals are coincident with a diurnal axis paralleling the earth's polar axis. Drive means are provided for periodically displacing the axle about the diurnal axis at a substantially constant rate, while other drive means are provided for periodically indexing the dish through 1 deg about the seasonal axis whereby the position of the dish relative to the axle is varied for accommodating seasonal tracking as changes in the angle of inclination of the polar axis occurs.

  7. A piston-rotaxane with two potential stripes: force transitions and yield stresses.

    PubMed

    Sevick, Edith M; Williams, David R M

    2013-01-01

    We examine a rod piston-rotaxane system, where the positions of several mobile rings on the axle are controlled by an external force acting on one of the rings. This allows us to access the translational entropy of the rings. For a simple rotaxane molecule with an axle that has uniform ring-axle interactions along its length, the molecule behaves like a miniature piston filled with a one-dimensional ideal gas. We then examine the effect of two stripes on the axle, having different ring-axle interactions with the mobile rings, so that one section is of high energy (repulsive) for the rings and another section is of lower energy (or attractive). This kind of rotaxane can exhibit rapid changes in displacement or force, and in particular, this molecule can exhibit a yield stress in which the piston suddenly compresses under a small increase in the applied force. PMID:24177696

  8. Rear wheel suspension and steering system

    SciTech Connect

    Ewen, J.G.

    1990-07-17

    This patent describes an improvement in a rear wheel support and driving system. The system comprises a rack-type dead axle adapted to support a vehicle body thereupon through suitable spring means, a pair of wheels rotatably supported upon the dead axle, a differential drive mechanism adapted to be supported upon the vehicle body movable with the body relative to the dead axle, the differential mechanism including a power input shaft and power output shafts, a pair of live axles drivingly connecting the output shafts with the wheels. The dead axle being generally rectilinear in shape and having a first pair of longitudinal beams respectively transversely spaced outboard of the differential mechanism, a second pair of cross beams respectively spaced fore and aft of the differential mechanism and secured to the first pair of beams.

  9. Frame structure for a four-wheel drive vehicle

    SciTech Connect

    Yamanaka, I.

    1986-09-30

    A frame is described for a four-wheel drive vehicle of the type where the rider straddles the vehicle, comprising a front axle support structure extending transversely of the vehicle; an upper frame structure including two downtubes extending upwardly, rearwardly and inwardly from the axle support structure and two main body tubes extending rearwardly from the downtubes; a lower frame structure extending rearwardly from the axle support structure, the lower frame structure including two lower frame tubes mutually spaced and extending rearwardly from the axle support structure. The lower frame structure is laterally inward of the downtubes at the axle support structure and laterally outward of the main body tubes; and each of the downtubes, main body tubes and lower frame tubes being formed from a continuous tube, the main body tube and the lower frame tube forming a continuous U-bend at the rear of the vehicle.

  10. A deformable spherical planet exploration robot

    NASA Astrophysics Data System (ADS)

    Liang, Yi-shan; Zhang, Xiu-li; Huang, Hao; Yang, Yan-feng; Jin, Wen-tao; Sang, Zhong-xun

    2013-03-01

    In this paper, a deformable spherical planet exploration robot has been introduced to achieve the task of environmental detection in outer space or extreme conditions. The robot imitates the morphology structure and motion mechanism of tumbleweeds. The robot is wind-driven. It consists of an axle, a spherical steel skeleton and twelve airbags. The axle is designed as two parts. The robot contracts by contracting the two-part axle. The spherical robot installs solar panels to provide energy for its control system.

  11. Chassis stabilization system

    DOEpatents

    Claxton, Gerald L.

    1999-01-01

    A stabilizing suspension system is provided for vehicles carrying telescopic booms or aerial work platforms having a fixed axle and a oscillating axle. Hydraulic cylinders are connected to each end of the oscillating axle, each cylinder being capable of extending and retracting. An off level sensor senses the angle of tilt of the chassis in both left and right directions and, when a predetermined threshold of tilt has been detected, the hydraulic cylinder on the downhill side of the chassis is locked against retracting, but is free to move in the downhill direction to allow the downhill wheel to remain in contact with the ground.

  12. 14 CFR 25.509 - Towing loads.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... towing fittings and must act parallel to the ground. In addition— (1) A vertical load factor equal to 1.0...) A reaction with a maximum value equal to the vertical reaction must be applied at the axle of...

  13. 14 CFR 25.509 - Towing loads.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... towing fittings and must act parallel to the ground. In addition— (1) A vertical load factor equal to 1.0...) A reaction with a maximum value equal to the vertical reaction must be applied at the axle of...

  14. 14 CFR 25.509 - Towing loads.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... towing fittings and must act parallel to the ground. In addition— (1) A vertical load factor equal to 1.0...) A reaction with a maximum value equal to the vertical reaction must be applied at the axle of...

  15. 14 CFR 25.509 - Towing loads.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... towing fittings and must act parallel to the ground. In addition— (1) A vertical load factor equal to 1.0...) A reaction with a maximum value equal to the vertical reaction must be applied at the axle of...

  16. In-line drivetrain and four wheel drive work machine using same

    DOEpatents

    Hoff, Brian

    2008-08-05

    A four wheel drive articulated mine loader is powered by a fuel cell and propelled by a single electric motor. The drivetrain has the first axle, second axle, and motor arranged in series on the work machine chassis. Torque is carried from the electric motor to the back differential via a pinion meshed with the ring gear of the back differential. A second pinion oriented in an opposite direction away from the ring gear is coupled to a drive shaft to transfer torque from the ring gear to the differential of the front axle. Thus, the ring gear of the back differential acts both to receive torque from the motor and to transfer torque to the forward axle. The in-line drive configuration includes a single electric motor and a single reduction gear to power the four wheel drive mine loader.

  17. Daisy Chain Rotaxanes Made from Interlocked DNA Nanostructures.

    PubMed

    Weigandt, Johannes; Chung, Chia-Ling; Jester, Stefan-S; Famulok, Michael

    2016-04-25

    We report the stepwise assembly of supramolecular daisy chain rotaxanes (DCR) made of double-stranded DNA: Small dsDNA macrocycles bearing an axle assemble into a pseudo-DCR precursor that was connected to rigid DNA stoppers to form DCR with the macrocycles hybridized to the axles. In presence of release oligodeoxynucleotides (rODNs), the macrocycles are released from their respective hybridization sites on the axles, leading to stable mechanically interlocked DCRs. Besides the expected threaded DCRs, certain amounts of externally hybridized structures were observed, which dissociate into dumbbell structures in presence of rODNs. We show that the genuine DCRs have significantly higher degrees of freedom in their movement along the thread axle than the hybridized DCR precursors. Interlocking of DNA in DCRs might serve as a versatile principle for constructing functional DNA nanostructures where the movement of the subunits is restricted within precisely confined tolerance ranges. PMID:27010370

  18. Educational Materials Development in Primary Science: Simple Machines

    ERIC Educational Resources Information Center

    Franks, Frank L.; Butterfield, Lawrence H., Jr.

    1977-01-01

    Evaluated was the ability of 27 legally blind elementary students to identify and manipulate the parts of the following adapted simple machines: lever, inclined plane, wheel and axle, and pulley. (SBH)

  19. Cart Wheels

    ERIC Educational Resources Information Center

    Peck, Edson R.

    1978-01-01

    This paper draws attention to cart wheels, two wheels rotating freely about a common axle and rolling on an inclined plane, both as a demonstration and as a satisfying application of dynamical analysis. (BB)

  20. Simple Machines Simply Put.

    ERIC Educational Resources Information Center

    Kirkwood, James J.

    1994-01-01

    Students explore the workings of the lever, wheel and axle, and the inclined plane as they build simple toys--a bulldozer and a road grader. The project takes four weeks. Diagrams and procedures are included. (PR)

  1. Instability of Vibration of a Moving-Train Coupling System

    NASA Astrophysics Data System (ADS)

    Zheng, D. Y.; Fan, S. C.

    2002-08-01

    This paper presents the derivation of the governing equations for the stability of vibration of an integrated system comprising a moving train and the railway track. The train consists of a convoy of articulated two-axle wagons. The equations are applicable to any arbitrary number of axles at arbitrary spacing. Each axle is modelled as a mass-spring-damper vibration unit. The railway track is an infinitely long Euler beam subjected to an axial compressive force and rests on a visco-elastic foundation. The governing equations for the integrated system are coupled differential equations, which can be transformed to algebraic equations by Fourier and Laplace transforms. Subsequent inverse Fourier transform and contour integration yield the instability equation. Critical parameter is identified. It follows by parametric studies on the instability of vibration due to different train configurations. Illustrative examples for trains having up to 20 wagons or 40 axles are given.

  2. Surface-micromachined rotatable member having a low-contact-area hub

    DOEpatents

    Rodgers, M. Steven; Sniegowski, Jeffry J.; Krygowski, Thomas W.

    2003-11-18

    A surface-micromachined rotatable member formed on a substrate and a method for manufacturing thereof are disclosed. The surface-micromachined rotatable member, which can be a gear or a rotary stage, has a central hub, and an annulus connected to the central hub by an overarching bridge. The hub includes a stationary axle support attached to the substrate and surrounding an axle. The axle is retained within the axle support with an air-gap spacing therebetween of generally 0.3 .mu.m or less. The rotatable member can be formed by alternately depositing and patterning layers of a semiconductor (e.g. polysilicon or a silicon-germanium alloy) and a sacrificial material and then removing the sacrificial material, at least in part. The present invention has applications for forming micromechanical or microelectromechanical devices requiring lower actuation forces, and providing improved reliability.

  3. Method and appartus for converting static in-ground vehicle scales into weigh-in-motion systems

    DOEpatents

    Muhs, Jeffrey D.; Scudiere, Matthew B.; Jordan, John K.

    2002-01-01

    An apparatus and method for converting in-ground static weighing scales for vehicles to weigh-in-motion systems. The apparatus upon conversion includes the existing in-ground static scale, peripheral switches and an electronic module for automatic computation of the weight. By monitoring the velocity, tire position, axle spacing, and real time output from existing static scales as a vehicle drives over the scales, the system determines when an axle of a vehicle is on the scale at a given time, monitors the combined weight output from any given axle combination on the scale(s) at any given time, and from these measurements automatically computes the weight of each individual axle and gross vehicle weight by an integration, integration approximation, and/or signal averaging technique.

  4. Surface--micromachined rotatable member having a low-contact-area hub

    DOEpatents

    Rodgers, M. Steven; Sniegowski, Jeffry J.

    2002-01-01

    A surface-micromachined rotatable member formed on a substrate and a method for manufacturing thereof are disclosed. The surface-micromachined rotatable member, which can be a gear or a rotary stage, has a central hub, and an annulus connected to the central hub by an overarching bridge. The hub includes a stationary axle support attached to the substrate and surrounding an axle. The axle is retained within the axle support with an air-gap spacing therebetween of generally 0.3 .mu.m or less. The rotatable member can be formed by alternately depositing and patterning layers of a semiconductor (e.g. polysilicon or a silicon-germanium alloy) and a sacrificial material and then removing the sacrificial material, at least in part. The present invention has applications for forming micromechanical or microelectromechanical devices requiring lower actuation forces, and providing improved reliability.

  5. 49 CFR 393.48 - Brakes to be operative.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... a three-axle truck or truck tractor manufactured before March 1, 1975, a device to remove the front... braking effort may only be used on buses, trucks, and truck tractors manufactured before March 1,...

  6. Daisy Chain Rotaxanes Made from Interlocked DNA Nanostructures

    PubMed Central

    Weigandt, Johannes; Chung, Chia‐Ling; Jester, Stefan‐S.

    2016-01-01

    Abstract We report the stepwise assembly of supramolecular daisy chain rotaxanes (DCR) made of double‐stranded DNA: Small dsDNA macrocycles bearing an axle assemble into a pseudo‐DCR precursor that was connected to rigid DNA stoppers to form DCR with the macrocycles hybridized to the axles. In presence of release oligodeoxynucleotides (rODNs), the macrocycles are released from their respective hybridization sites on the axles, leading to stable mechanically interlocked DCRs. Besides the expected threaded DCRs, certain amounts of externally hybridized structures were observed, which dissociate into dumbbell structures in presence of rODNs. We show that the genuine DCRs have significantly higher degrees of freedom in their movement along the thread axle than the hybridized DCR precursors. Interlocking of DNA in DCRs might serve as a versatile principle for constructing functional DNA nanostructures where the movement of the subunits is restricted within precisely confined tolerance ranges. PMID:27010370

  7. 49 CFR 393.42 - Brakes required on all wheels.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... axles and manufactured before July 25, 1980, are not required to have brakes on the front wheels... driveaway-towaway operation (including the last truck of triple saddle-mount combinations (see §...

  8. 49 CFR 393.42 - Brakes required on all wheels.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... axles and manufactured before July 25, 1980, are not required to have brakes on the front wheels... driveaway-towaway operation (including the last truck of triple saddle-mount combinations (see §...

  9. 49 CFR 393.42 - Brakes required on all wheels.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... axles and manufactured before July 25, 1980, are not required to have brakes on the front wheels... driveaway-towaway operation (including the last truck of triple saddle-mount combinations (see §...

  10. 49 CFR 587.6 - General description.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... the ballast installation and details concerning the ballast plate are provided in drawings shown in... center of gravity: X=44.2 inches rear of front axle Y=0.3 inches left of longitudinal center line...

  11. 49 CFR 587.6 - General description.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... the ballast installation and details concerning the ballast plate are provided in drawings shown in... center of gravity: X=44.2 inches rear of front axle Y=0.3 inches left of longitudinal center line...

  12. 49 CFR 587.6 - General description.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... the ballast installation and details concerning the ballast plate are provided in drawings shown in... center of gravity: X=44.2 inches rear of front axle Y=0.3 inches left of longitudinal center line...

  13. Planning Torque Distribution Control of Rolling Stock for Fine Anti-slip/skid Re-adhesion Control

    NASA Astrophysics Data System (ADS)

    Imai, Kazutomi; Ohishi, Kiyoshi; Sano, Takashi; Makishima, Shingo; Yasukawa, Shinobu

    Generally, under a wet railway track condition, the axle adhesion coefficient of a train gradually increases from the head of a rolling stock. The improvement of adhesion characteristics is important in an electric motor coach. In order to suppress the slip/skid phenomenon, we have already proposed an anti-slip/skid re-adhesion control system based on a disturbance observer and sensor-less vector control. Moreover, we have confirmed that this system drives the train with the high adhesion force utilization ratio. This paper discusses the theoretical characteristic of the axle adhesion coefficient distribution of a rolling stock, which is based on the axle adhesion coefficient data of Shinkansen. In order to maintain the desired driving force performance, this paper proposes a new planning torque distribution control based on the axle adhesion coefficient distribution. This paper points out that the proposed method well maintains the desired driving force performance by the numerical simulation results.

  14. 75 FR 38081 - Notice of Scope Rulings

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-07-01

    ... Scope Rulings, 75 FR 14138 (March 24, 2010). This current notice covers all scope rulings and... from the People's Republic of China Requestor: Northern Tool & Equipment Co.; whether a high-axle...

  15. Improvement of the directional stability of passenger car trailer couplings with actively controlled steering

    NASA Astrophysics Data System (ADS)

    Desens, Jens

    The stabilization of pendulum oscillations of passenger car trailer couplings, using active steering, was examined. A linear model of the couplings was presented. Each axle was provided with a controller. The controllers were optimized, with regard to necessary sensors, in order to minimize costs. The rear and the front axles were provided with a control unit in order to compute the potential prevailing in the active steering of several axles. It was shown that the passenger car rear axle was the most suitable for coupling stabilization. The experiment was simulated, using a complex coupling model. The developed controller allowed the passenger car trailer to be driven at a speed higher than 150 km per hour.

  16. 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.

  17. Track train dynamics analysis and test program: Locomotive dynamic characterization summary

    NASA Technical Reports Server (NTRS)

    Berry, R. L.

    1982-01-01

    Locomotive mechanical characteristics, track perturbations, and operational characteristics involving experimentally determined suspension system parameters are analyzed. Suspension bearings, shock absorbers, pads, and two- and three- axle trucks are comparatively evaluated with respect to locomotive design.

  18. 14 CFR 23.509 - Towing loads.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... reaction must be applied at the axle of the wheel to which the load is applied. Enough airplane inertia to achieve equilibrium must be applied. (ii) The loads must be reacted by airplane inertia. (d)...

  19. Facile and efficient formation and dissociation of a pseudo[2]rotaxane by a slippage approach using pillar[5]arene-based cyclic host liquid and solvent.

    PubMed

    Ogoshi, Tomoki; Tamura, Yuko; Yamafuji, Daiki; Aoki, Takamichi; Yamagishi, Tada-Aki

    2016-08-11

    A pillar[5]arene-based pseudo[2]rotaxane was synthesized using a slippage method by only heating an axle with bulky valine derivative ends in a cyclic host liquid (CHL), which is liquid at room temperature. The pseudo[2]rotaxane synthesized in a CHL can be converted back to the starting components, i.e., the pillar[5]arene wheel and the axle, by heating in a solvent. PMID:27471989

  20. Fatal car fires from rear-end crashes: the effects of fuel tank placement before and after regulation.

    PubMed

    Robertson, L S

    1993-08-01

    A federal standard for fuel tank integrity in cars was applied to 1977 and subsequent models. National data indicate that fatalities per 10,000 occupants in rear-end crashes of small cars, where fire was the most harmful event, were reduced by approximately 57% if the fuel tank was located behind the rear axle and 77% if the tank was situated directly above or in front of the rear axle. PMID:8342730

  1. Fatal car fires from rear-end crashes: the effects of fuel tank placement before and after regulation.

    PubMed Central

    Robertson, L S

    1993-01-01

    A federal standard for fuel tank integrity in cars was applied to 1977 and subsequent models. National data indicate that fatalities per 10,000 occupants in rear-end crashes of small cars, where fire was the most harmful event, were reduced by approximately 57% if the fuel tank was located behind the rear axle and 77% if the tank was situated directly above or in front of the rear axle. PMID:8342730

  2. Global phosphotyrosine survey in triple-negative breast cancer reveals activation of multiple tyrosine kinase signaling pathways

    PubMed Central

    Ma, Binyun; Liu, Ren; Renuse, Santosh; Sahasrabuddhe, Nandini A.; Chen, Lily; Chaerkady, Raghothama; Kim, Min-Sik; Zhong, Jun; Jelinek, Christine; Barbhuiya, Mustafa A.; Leal-Rojas, Pamela; Yang, Yi; Kashyap, Manoj Kumar; Marimuthu, Arivusudar; Ling, Min; Fackler, Mary Jo; Merino, Vanessa; Zhang, Zhen; Zahnow, Cynthia A.; Gabrielson, Edward; Stearns, Vered; Roa, Juan Carlos; Sukumar, Saraswati; Gill, Parkash S.; Pandey, Akhilesh

    2015-01-01

    Breast cancer is the most prevalent cancer in women worldwide. About 15–20% of all breast cancers are triple negative breast cancer (TNBC) and are often highly aggressive when compared to other subtypes of breast cancers. To better characterize the biology that underlies the TNBC phenotype, we profiled the phosphotyrosine proteome of a panel of twenty-six TNBC cell lines using quantitative high resolution Fourier transform mass spectrometry. A heterogeneous pattern of tyrosine kinase activation was observed based on 1,789 tyrosine-phosphorylated peptides identified from 969 proteins. One of the tyrosine kinases, AXL, was found to be activated in a majority of aggressive TNBC cell lines and was accompanied by a higher level of AXL expression. High levels of AXL expression are correlated with a significant decrease in patient survival. Treatment of cells bearing activated AXL with a humanized AXL antibody inhibited cell proliferation and migration in vitro, and tumor growth in mice. Overall, our global phosphoproteomic analysis provided new insights into the heterogeneity in the activation status of tyrosine kinase pathways in TNBCs. Our approach presents an effective means of identifying important novel biomarkers and targets for therapy such as AXL in TNBC. PMID:26356563

  3. Shaft-driven motor vehicle

    SciTech Connect

    Imaizumi, M.; Akai, H.; Irie, T.; Inagaki, T.

    1987-03-03

    A motor vehicle is described comprising: a frame; a rear fork composed of first and second rear fork members having front ends pivotally mounted on the fame and rear ends supporting rear wheels, respectively; an axle housing having first and second axial ends, the first axial end having an attachment flange joined to the rear end of the first rear fork member; a rear axle rotatably supported in the axle housing; a gear case coupled between the rear end of the second rear fork member and the second axial end of the axial housing and accommodating a gear mechanism for driving the rear axle; at least one cross member extending between and joined to the first and second rear fork members; the rear end of the first rear fork member having a first joining surface having at least one attachment hole defined therein and directed transversely of the frame; the attachment flange of the axle housing having a second joining surface having at least one attachment hole defined therein and facing the first joining surface; at least one of the attachment holes in the first and second joining surfaces being elongate; and fastener means for joining the first rear fork member and the axle housing through the attachment holes.

  4. Off-the-road four-wheel drive vehicle

    SciTech Connect

    Foote, D.C.; Grinde, J.E.

    1987-03-17

    An off-road recreational vehicle is described comprising, in combination: (a) a frame; (b) front and rear pairs of wheels, each having relatively wide, ultra-low pressure tires mounted thereon, each of the wheel being secured to an axle member; (c) a limited slip differential means including a drive input disposed between the axle members of the front pair of wheels; (d) driving means drivenly connected to the axle members of the rear pair of wheels; (e) means for independently suspending the frame relative to the axle members of the front pair of wheels and for resiliently securing the frame to the driving means connected to the axle members of the rear pair of wheels; (f) an engine supported on the frame between the front and rear pairs of wheels, the engine having an output shaft directly coupled to the drive means connected to the rear axle member; and (g) over-running clutch means operatively coupled to the output shaft of the engine and interposed between the output shaft of the engine and the drive input of the limited slip differential for applying a driving force to the front pair of wheels only when slipage exists between the rear pair of wheels and the ground.

  5. Efficacy and Safety of Ambroxol Lozenges in the Treatment of Acute Uncomplicated Sore Throat - a Pooled Analysis.

    PubMed

    de Mey, C; Koelsch, S; Richter, E; Pohlmann, T; Sousa, R

    2016-07-01

    A pooled analysis is presented of 7 placebo-controlled RCT that investigated lozenges containing ambroxol for pain relief in acute sore throat.2 242 patients were treated with different ambroxol doses or control treatments, 2 183 were evaluable for efficacy. The present analysis is focused on the recommended dose of 20 mg (AXL20): 856 patients were treated with AXL20, 847 with matched placebo lozenges (PL).The average reduction in pain intensity over the first 3 h after the first AXL20 ranged from 38% to 52% of the maximum achievable effect (MAE). The overall treatment difference between AXL20 and PL was 11% (95% CI: 8-13%) of the MAE (post-hoc meta-analysis). The corresponding NNT was 6.0 (CI: 4.7-8.4) for an average pain reduction from baseline of 33% of the MAE over the first 3 h.71.9, 79.0, and 85.3% of the AXL20-patients scored the efficacy as "very good or good" at the end of the 1(st), 2(nd) and 3(rd) day, respectively, vs. 57.5, 64.4, and 70.4% of the PL-patients resulting in odds ratios of 1.9 (CI: 1.5-2.3) for the 1(st), 2.1 (CI: 1.7-2.6) for the 2(nd) and 2.43 (CI: 1.8-3.3) for the 3(rd) day.At the end of treatment 'no redness' or 'slightly red' was scored on pharyngeal inspection in 84.4% and 77.3% of AXL20- and PL-patients (OR: 1.6, CI: 1.3-1.9).AXL20-treatment was well tolerated and is safe and efficacious for acute uncomplicated sore throat of recent onset in adolescent and adult patients. PMID:27281448

  6. Space allowance during commercial long distance transport of cattle in North America.

    PubMed

    González, L A; Schwartzkopf-Genswein, K S; Bryan, M; Silasi, R; Brown, F

    2012-10-01

    The objective of the present work was to study space allowance in cattle during commercial long haul transport (≥400 km; n = 6,152 journeys). Surveys, delivered to livestock transport carriers, gathered information on the number, BW, and distribution of cattle by trailer compartment as well as the characteristics of the transport vehicles used. Space allowance (SA; m(2)/animal), allometric coefficient (k = SA / BW(0.6667)), and the percentage of deviation from recommended SA (DRSA; %) in the Canadian Codes of Practice were calculated for each compartment of the trailers. All quad-axle (77%) and tri-axle (23%) cattle trailers were reported with 5 compartments (nose, deck, belly, back, and doghouse). Sixty percent of all animals were carried in the middle compartments (deck and belly), 30% in the rear (back and doghouse), and 10% in the front or nose. Approximately 30% of the journeys required that the cattle be redistributed at the Canada-USA border to comply with different axle weight regulations, and most journeys moved them between the deck and the doghouse. Total loaded weight increased and the number of animals decreased with increasing BW of the animals. space allowance, k-value, and DRSA were least for calves and feeders compared with fat and cull cattle (p < 0.01). Both total loaded weight and number of animals increased with the number of axles in the trailer, being greatest in quad-axle trailers pulled by push tractors, which were most frequently used. Space allowance (k-value) was least in vehicles with greater number of axles and transporting the lightest cattle (i.e., quad-axles trailers transporting calves and feeders). Space allowance, k-value, and variability among journeys were least in the middle compartments (belly and deck), followed by the back, then doghouse and nose compartments of the trailers showing the largest values (p < 0.05). Many factors contributed to the variability in SA such as body size (smaller animals are placed more densely

  7. Analysis of Semi-Active and Passive Suspensions System for Off-Road Vehicles

    NASA Astrophysics Data System (ADS)

    BenLahcene, Zohir; Faris, Waleed F.; Khan, M. D. Raisuddin

    2009-03-01

    The speed of off-road vehicles over rough terrain is generally determined by the ride quality not by the engine power. For this reason, researches are currently being undertaking to improve the ride dynamics of these vehicles using an advanced suspension system. This study intends to provide a preliminary evaluation of whether semi-active suspensions are beneficial to improving ride and handling in off-road vehicles. One of the greatest challenges in designing off-road vehicle suspension system is maintaining a good balance between vehicle ride and handling. Three configurations of these vehicles; 2-axle, 3-xle and 4-axles have been studied and their performances are compared. The application of several control policies of semi-active suspension system, namely skyhook; ground-hook and hybrid controls have been analyzed and compared with passive systems. The results show that the hybrid control policy yields better comfort than a passive suspension, without reducing the road-holding quality or increasing the suspension displacement. The hybrid control policy is also shown to be a better compromise between comfort, road-holding and suspension displacement than the skyhook and ground-hook control policies. Results show an improvement in ride comfort and vehicle handling using 4-axle over 3-axle and 2-axle when emphasis is placed on the response of the vehicle body acceleration, suspension and tyre deflection.

  8. Kinetic Study of [2]Pseudorotaxane Formation with an Asymmetrical Thread.

    PubMed

    Quiroga, Miguel; Parajó, Mercedes; Rodríguez-Dafonte, Pedro; García-Río, Luis

    2016-06-28

    Kinetic and thermodynamic studies on cyclodextrin (CD)-based [2]pseudorotaxane formation have been carried out by a combination of NMR and calorimetric techniques using bolaform surfactants as axles. Experimental evidence of the formation of an external complex between the trimethylammonium head groups of the axle and the external hydrogen atoms of α-cyclodextrin (α-CD) is reported. Inclusion of this external complex in the reaction pathway allows us to explain the kinetic behavior as well as the nonlinear dependence of the observed rate constant on CD concentrations. The equilibrium constant for [2]pseudorotaxane formation is strongly affected by the spacer length of the axle. This effect is a consequence of increasing rotaxane stability because the threading rate constant is almost independent of the spacer length, but dethreading strongly decreases on increasing the axle size. Using a nonsymmetrical axle with tripropyl and trimethylammonium cations precludes CD threading by the large head side. CDs will thread this asymmetrical bolaform by both their wide and narrow sides, yielding two isomeric [2]pseudorotaxanes. Threading by the wide side of the CD is 60% more favorable than that by the narrow one, but dethreading rate constants are the same for both isomers. PMID:27232769

  9. Differential TAM receptor–ligand–phospholipid interactions delimit differential TAM bioactivities

    PubMed Central

    Lew, Erin D; Oh, Jennifer; Burrola, Patrick G; Lax, Irit; Zagórska, Anna; Través, Paqui G; Schlessinger, Joseph; Lemke, Greg

    2014-01-01

    The TAM receptor tyrosine kinases Tyro3, Axl, and Mer regulate key features of cellular physiology, yet the differential activities of the TAM ligands Gas6 and Protein S are poorly understood. We have used biochemical and genetic analyses to delineate the rules for TAM receptor–ligand engagement and find that the TAMs segregate into two groups based on ligand specificity, regulation by phosphatidylserine, and function. Tyro3 and Mer are activated by both ligands but only Gas6 activates Axl. Optimal TAM signaling requires coincident TAM ligand engagement of both its receptor and the phospholipid phosphatidylserine (PtdSer): Gas6 lacking its PtdSer-binding ‘Gla domain’ is significantly weakened as a Tyro3/Mer agonist and is inert as an Axl agonist, even though it binds to Axl with wild-type affinity. In two settings of TAM-dependent homeostatic phagocytosis, Mer plays a predominant role while Axl is dispensable, and activation of Mer by Protein S is sufficient to drive phagocytosis. DOI: http://dx.doi.org/10.7554/eLife.03385.001 PMID:25265470

  10. Gas6 induces cancer cell migration and epithelial–mesenchymal transition through upregulation of MAPK and Slug

    SciTech Connect

    Lee, Yunhee; Lee, Mira; Kim, Semi

    2013-04-26

    Highlights: •We investigated the molecular mechanisms underlying Gas6-mediated cancer cell migration. •Gas6 treatment and subsequent Axl activation induce cell migration and EMT via upregulation of Slug. •Slug expression mediated by Gas6 is mainly through c-Jun and ATF-2 in an ERK1/2 and JNK-dependent manner. •The Gas6/Axl-Slug axis may be exploited as a target for anti-cancer metastasis therapy. -- Abstract: Binding of Gas6 to Axl (Gas6/Axl axis) alters cellular functions, including migration, invasion, proliferation, and survival. However, the molecular mechanisms underlying Gas6-mediated cell migration remain poorly understood. In this study, we found that Gas6 induced the activation of JNK and ERK1/2 signaling in cancer cells expressing Axl, resulting in the phosphorylation of activator protein-1 (AP-1) transcription factors c-Jun and ATF-2, and induction of Slug. Depletion of c-Jun or ATF-2 by siRNA attenuated the Gas6-induced expression of Slug. Slug expression was required for cell migration and E-cadherin reduction/vimentin induction induced by Gas6. These results suggest that Gas6 induced cell migration via Slug upregulation in JNK- and ERK1/2-dependent mechanisms. These data provide an important insight into the molecular mechanisms mediating Gas6-induced cell migration.

  11. Combination vehicle assembly

    SciTech Connect

    Silverman, M.J. Sr.

    1987-03-17

    A combination recreational vehicle assembly is described comprising: two vehicles of a different type, the vehicles comprising a first, leading vehicle having a steering mechanism for maneuvering the assembly and a drivable axle mechanism for propelling the assembly; an independently drivable second vehicle trailing the first vehicle comprising a standard road vehicle having a motor, and an axle mechanism for connecting the motor to the wheels of the second vehicle for providing power to the wheels of the vehicle. A gear means for selectively disconnecting the motor from the axle mechanism to place the vehicle in neutral, and a steering means for maneuvering the second vehicle when driven independently of the first vehicle are included; and a releasable mechanical drive connection between the second vehicle motor and the first vehicle axle mechanism to provide power for driving the assembly. The drive connection comprises a drive pinion projecting from the second vehicle motor to the front of the second vehicle, and a drive shaft projecting from the first vehicle axle mechanism to the rear of the first vehicle.

  12. Dual roadside seismic sensor for moving road vehicle detection and characterization.

    PubMed

    Wang, Hua; Quan, Wei; Wang, Yinhai; Miller, Gregory R

    2014-01-01

    This paper presents a method for using a dual roadside seismic sensor to detect moving vehicles on roadway by installing them on a road shoulder. Seismic signals are split into fixed time intervals in recording. In each interval, the time delay of arrival (TDOA) is estimated using a generalized cross-correlation approach with phase transform (GCC-PHAT). Various kinds of vehicle characterization information, including vehicle speed, axle spacing, detection of both vehicle axles and moving direction, can also be extracted from the collected seismic signals as demonstrated in this paper. The error of both vehicle speed and axle spacing detected by this approach has been shown to be less than 20% through the field tests conducted on an urban street in Seattle. Compared to most existing sensors, this new design of dual seismic sensor is cost effective, easy to install, and effective in gathering information for various traffic management applications. PMID:24526304

  13. Dual Roadside Seismic Sensor for Moving Road Vehicle Detection and Characterization

    PubMed Central

    Wang, Hua; Quan, Wei; Wang, Yinhai; Miller, Gregory R.

    2014-01-01

    This paper presents a method for using a dual roadside seismic sensor to detect moving vehicles on roadway by installing them on a road shoulder. Seismic signals are split into fixed time intervals in recording. In each interval, the time delay of arrival (TDOA) is estimated using a generalized cross-correlation approach with phase transform (GCC-PHAT). Various kinds of vehicle characterization information, including vehicle speed, axle spacing, detection of both vehicle axles and moving direction, can also be extracted from the collected seismic signals as demonstrated in this paper. The error of both vehicle speed and axle spacing detected by this approach has been shown to be less than 20% through the field tests conducted on an urban street in Seattle. Compared to most existing sensors, this new design of dual seismic sensor is cost effective, easy to install, and effective in gathering information for various traffic management applications. PMID:24526304

  14. Driving device for a mining machine

    SciTech Connect

    Blazewicz, A.; Cyrulo, J.; Krutki, M.; Sedlaczek, J.; Wozniak, T.

    1980-11-18

    The invention solves a problem of transferring the combined weight onto a conveyor through a railing, instead of through a link chain. For the aforesaid purpose a slide skid is provided, at both sides, with riding wheels. During operation of the combine the riding wheels roll on a railing; the riding wheels are mounted in a slide skid on a cranked axle. The cranked axle is protected against turning by means of a cover provided with a splined hole fixed on a splined pin of the cranked axle. The cover is fixed to the slide skid by means of screws. The design of the present device prevents deformation and tightening of vertical links of a chain between a rack and a slide skid in case of fouling of the rack with fine coal.

  15. Identification of Cell Surface Molecules Involved in Dystroglycan-Independent Lassa Virus Cell Entry

    PubMed Central

    Ströher, Ute; Ebihara, Hideki; Feldmann, Heinz

    2012-01-01

    Although O-mannosylated dystroglycan is a receptor for Lassa virus, a causative agent of Lassa fever, recent findings suggest the existence of an alternative receptor(s). Here we identified four molecules as receptors for Lassa virus: Axl and Tyro3, from the TAM family, and dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) and liver and lymph node sinusoidal endothelial calcium-dependent lectin (LSECtin), from the C-type lectin family. These molecules enhanced the binding of Lassa virus to cells and mediated infection independently of dystroglycan. Axl- or Tyro3-mediated infection required intracellular signaling via the tyrosine kinase activity of Axl or Tyro3, whereas DC-SIGN- or LSECtin-mediated infection and binding were dependent on a specific carbohydrate and on ions. The identification of these four molecules as Lassa virus receptors advances our understanding of Lassa virus cell entry. PMID:22156524

  16. Synthesis of multivalent host and guest molecules for the construction of multithreaded diamide pseudorotaxanes

    PubMed Central

    Kaufmann, Lena; Franzmann, Elisa; Maison, Wolfgang; Brandt, Emily; Aicher, Daniel; Wiehe, Arno

    2012-01-01

    Summary A series of di-, tri- and tetravalent axles and wheels for the synthesis of pseudorotaxanes bearing the tetralactam macrocycle/diamide axle binding motif was prepared. Starting from iodinated monovalent precursors, Sonogashira cross-coupling reactions were utilized to couple the binding sites to appropriate spacer groups. Through this “Lego” or “toolbox” approach, the convergent synthesis of host and guests with a well-defined number of the binding sites is possible. In addition, the spatial arrangement of the binding sites can be controlled through the quite rigid connections between linker and binding sites. Although a quantitative assessment of binding strengths was not possible by NMR titration experiments, typical and significant shifts of the signals of the diamide moiety indicate qualitatively the formation of pseudorotaxanes from the axle and wheel precursors. PMID:22423290

  17. Antibody-mediated neutralization of autocrine Gas6 inhibits the growth of pancreatic ductal adenocarcinoma tumors in vivo.

    PubMed

    Moody, Gordon; Belmontes, Brian; Masterman, Stephanie; Wang, Wei; King, Chadwick; Murawsky, Chris; Tsuruda, Trace; Liu, Shuying; Radinsky, Robert; Beltran, Pedro J

    2016-09-15

    Gas6 and its receptors Axl, Mer and Tyro-3 (TAM) are highly expressed in human malignancy suggesting that signaling through this axis may be tumor-promoting. In pancreatic ductal adenocarcinoma (PDAC), Gas6 and the TAM receptor Axl are frequently co-expressed and their co-expression correlates with poor survival. A strategy was devised to generate fully human neutralizing antibodies against Gas6 using XenoMouse® technology. Hybridoma supernatants were selected based on their ability to inhibit Gas6 binding to the receptor Axl and block Gas6-induced Axl phosphorylation in human cells. Two purified antibodies isolated from the screened hybridomas, GMAB1 and GMAB2, displayed optimal cellular potency which was comparable to that of the soluble extracellular domain of the receptor Axl (Axl-Fc). In vivo characterization of GMAB1 was conducted using a pharmacodynamic assay that measured inhibition of Gas6-induced Akt activation in the mouse spleen. Treatment of mice with a single dose (100-1000 µg) of GMAB1 led to greater than 90% inhibition of Gas6-induced phosphorylated Akt (pAkt) for up to 72 hr. Based on the target coverage observed in the PD assay, the efficacy of GMAB1 was tested against human pancreatic adenocarcinoma xenografts. At doses of 50 µg and 150 µg, twice weekly, GMAB1 was able to inhibit 55% and 76% of tumor growth, respectively (p < 0.001 for both treatments vs. control Ig). When combined with gemcitabine, GMAB1 significantly inhibited tumor growth compared to either agent alone (p < 0.001). Together, the data suggest that Gas6 neutralization may be important as a potential strategy for the treatment of PDAC. PMID:27170265

  18. Adhesion-related kinase induction of migration requires phosphatidylinositol-3-kinase and ras stimulation of rac activity in immortalized gonadotropin-releasing hormone neuronal cells.

    PubMed

    Nielsen-Preiss, Sheila M; Allen, Melissa P; Xu, Mei; Linseman, Daniel A; Pawlowski, John E; Bouchard, R J; Varnum, Brian C; Heidenreich, Kim A; Wierman, Margaret E

    2007-06-01

    GnRH neurons migrate into the hypothalamus during development. Although migratory defects may result in disordered activation of the reproductive axis and lead to delayed or absent sexual maturation, specific factors regulating GnRH neuronal migration remain largely unknown. The receptor tyrosine kinase, adhesion-related kinase (Ark) (also known as Axl, UFO, and Tyro7), has been implicated in the migration of GnRH neuronal cells. Binding of its ligand, growth arrest-specific gene 6 (Gas6), promotes cytoskeletal remodeling and migration of NLT GnRH neuronal cells via Rac and p38 MAPK. Here, we examined the Axl effectors proximal to Rac in the signaling pathway. Gas6/Axl-induced lamellipodia formation and migration were blocked after phosphatidylinositol-3-kinase (PI3K) inhibition in GnRH neuronal cells. The p85 subunit of PI3K coimmunoprecipitated with Axl and was phosphorylated in a Gas6-sensitive manner. In addition, PI3K inhibition in GnRH neuronal cells diminished Gas6-induced Rac activation. Exogenous expression of a dominant-negative form of Ras also decreased GnRH neuronal lamellipodia formation, migration, and Rac activation. PI3K inhibition blocked Ras in addition to Rac activation and migration. In contrast, pharmacological blockade of the phospholipase C gamma effectors, protein kinase C or calcium/calmodulin protein kinase II, had no effect on Gas6/Axl signaling to promote Rac activation or stimulate cytoskeletal reorganization and migration. Together, these data show that the PI3K-Ras pathway is a major mediator of Axl actions upstream of Rac to induce GnRH neuronal cell migration. PMID:17332061

  19. Side mounted V-type 4-cycle engine

    SciTech Connect

    Asano, A.; Kato, K.

    1987-06-09

    This patent describes a V-type four-cycle engine having overhead camshafts and a crankshaft, comprising: idle gear trains, the idle gear tram extending between the crankshaft and a camshaft and including idle gears; a gear retainer having first and second axles for rotatably mounting the idle gears; the first axle including a journal portion having a cylindrical surface about a first axial centerline and mounting portions having a cylindrical surface about a second axial centerline displaced from the first axial centerline; the mounting portions being supported by the gear retainer; and means for retaining the journal portion in selectable angular orientation with respect to the gear retainer.

  20. Vision-based industrial automatic vehicle classifier

    NASA Astrophysics Data System (ADS)

    Khanipov, Timur; Koptelov, Ivan; Grigoryev, Anton; Kuznetsova, Elena; Nikolaev, Dmitry

    2015-02-01

    The paper describes the automatic motor vehicle video stream based classification system. The system determines vehicle type at payment collection plazas on toll roads. Classification is performed in accordance with a preconfigured set of rules which determine type by number of wheel axles, vehicle length, height over the first axle and full height. These characteristics are calculated using various computer vision algorithms: contour detectors, correlational analysis, fast Hough transform, Viola-Jones detectors, connected components analysis, elliptic shapes detectors and others. Input data contains video streams and induction loop signals. Output signals are vehicle enter and exit events, vehicle type, motion direction, speed and the above mentioned features.

  1. Timing mechanism for wind motors

    SciTech Connect

    White, H.O.

    1980-09-23

    A plate is carried by the blade support shaft journalled within the frame of a wind motor. The axle shaft of the blade is securable to the plate at variable distances relative the support shaft to selectively vary the offset of the blade. A primary drive element, gear or sprocket, coaxial with the axle shaft and rotatable in response to rotation of the blade, drivingly engages a driven idler element, gear or sprocket, respectively, carried by an idler shaft journalled within the plate. A planetary gear rotatable in response to the driven idler element, drivingly engages a sun gear fixed to the frame coaxial with the support shaft.

  2. Method of measurement and analysis of the extent of wear of rope wheel bearings in Bogdanka coal mine

    SciTech Connect

    Mazurkiewicz, D.; Galinski, M.

    2007-03-15

    This paper presents the method of assessing rope wheel bearing wear, developed for the special case of a shaft hoist in the Bogdanka coal mine. The diagnosis method presented here may also be used for inspecting the bearings of direction rope wheels with movable axles and bearings placed outside the axle in bodies, of the type that prevail in Polish coal mining. The superiority of this method in comparison to those used so far consists in limiting the testing time, as well as in the fact that no extra workers are needed. Nor does it require special availability of the shaft equipment for performing the test.

  3. Molecular machinery: synthesis of a "nanodragster".

    PubMed

    Vives, Guillaume; Kang, Jungho; Kelly, Kevin F; Tour, James M

    2009-12-17

    The synthesis and imaging by scanning tunneling microscopy of a mixed wheeled nanovehicle composed of a p-carborane small-wheeled short front axle and a C(60) large-wheeled long rear axle that has been termed a nanodragster due to the structural relation to a dragster are reported. This nanodragster is expected to exhibit motion at a lower temperature than pure C(60)-wheeled nanocars and should allow the investigation of the role played by p-carborane wheels in directional motion. PMID:20000442

  4. 78 FR 49290 - Oshkosh Defense, a Division of Oshkosh Corporation, Including On-Site Leased Workers From...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-08-13

    ... IT Services, LLC, Landmark Staffing Resources, Inc., Larsen and Toubro Limited, MRI Network/Manta..., S-Series Front Discharge Cement Mixers and AARF axles), including component parts. The workers are... Services, LLC, Landmark Staffing Resources, Inc., Larsen and Toubro Limited, MRI Network/Manta...

  5. Vibration reduction on automotive shafts using piezoceramics

    NASA Astrophysics Data System (ADS)

    Kunze, Holger; Riedel, Mathias; Schmidt, Knut; Bianchini, Emanuele

    2003-08-01

    This paper reports an experimental study on active vibration reduction for automotive shafts with the use of piezoelectric material. The work focuses on an axle of an Audi A2. The demand in the automobile sector for higher comfort in the vehicle is of a great importance alongside the requirements of lighter weight and low fuel consumption. These requirements are typically in conflict with each other. One solution is the use of intelligent materials instead of viscoelastic materials and proof mass absorbers. These solutions are quite heavy especially at low frequencies. Active vibration control and piezoelectric devices are advantageous in this application due to their low mass to performance ratio. Our research study explores the use of such piezoelectric devices for an axle. In conjunction with electronics it will reduce vibrations in the first natural bending mode of the axle. Laboratory tests simulated the condition present in the road. At first a stationary set up was used, then a simulated disturbance was input at the attachment points of the shaft. Finally, a test with rotating shaft was performed. Piezoelectric devices (custom QuickPacks from ACX, a Division of Cymer) were used as sensors and as actuators to properly control the axle during the different operating conditions. The power consumption of each actuator pair was less than 20W. The work described here details the test setup, the control strategy, the hardware implementation as well as the test results obtained.

  6. 49 CFR 585.61 - Scope.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...,536 kilograms (10,000 pounds) or less, except those vehicles with dual wheels on an axle, to submit a report, and maintain records related to the report, concerning the number of such vehicles that meet the requirements of Standard No. 138, Tire pressure monitoring systems (49 CFR 571.138)....

  7. 49 CFR 585.61 - Scope.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...,536 kilograms (10,000 pounds) or less, except those vehicles with dual wheels on an axle, to submit a report, and maintain records related to the report, concerning the number of such vehicles that meet the requirements of Standard No. 138, Tire pressure monitoring systems (49 CFR 571.138)....

  8. 49 CFR 585.61 - Scope.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ...,536 kilograms (10,000 pounds) or less, except those vehicles with dual wheels on an axle, to submit a report, and maintain records related to the report, concerning the number of such vehicles that meet the requirements of Standard No. 138, Tire pressure monitoring systems (49 CFR 571.138)....

  9. 49 CFR 585.61 - Scope.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ...,536 kilograms (10,000 pounds) or less, except those vehicles with dual wheels on an axle, to submit a report, and maintain records related to the report, concerning the number of such vehicles that meet the requirements of Standard No. 138, Tire pressure monitoring systems (49 CFR 571.138)....

  10. 49 CFR 585.61 - Scope.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ...,536 kilograms (10,000 pounds) or less, except those vehicles with dual wheels on an axle, to submit a report, and maintain records related to the report, concerning the number of such vehicles that meet the requirements of Standard No. 138, Tire pressure monitoring systems (49 CFR 571.138)....