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Sample records for axles

  1. Giving AXL the axe: targeting AXL in human malignancy.

    PubMed

    Gay, Carl M; Balaji, Kavitha; Byers, Lauren Averett

    2017-02-14

    The receptor tyrosine kinase AXL, activated by a complex interaction between its ligand growth arrest-specific protein 6 and phosphatidylserine, regulates various vital cellular processes, including proliferation, survival, motility, and immunologic response. Although not implicated as an oncogenic driver itself, AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is overexpressed in several haematologic and solid malignancies, including acute myeloid leukaemia, non-small cell lung cancer, gastric and colorectal adenocarcinomas, and breast and prostate cancers. In the context of malignancy, evidence suggests that AXL overexpression drives wide-ranging processes, including epithelial to mesenchymal transition, tumour angiogenesis, resistance to chemotherapeutic and targeted agents, and decreased antitumor immune response. As a result, AXL is an attractive candidate not only as a prognostic biomarker in malignancy but also as a target for anticancer therapies. Several AXL inhibitors are currently in preclinical and clinical development. This article reviews the structure, regulation, and function of AXL; the role of AXL in the tumour microenvironment; the development of AXL as a therapeutic target; and areas of ongoing and future investigation.

  2. Giving AXL the axe: targeting AXL in human malignancy

    PubMed Central

    Gay, Carl M; Balaji, Kavitha; Byers, Lauren Averett

    2017-01-01

    The receptor tyrosine kinase AXL, activated by a complex interaction between its ligand growth arrest-specific protein 6 and phosphatidylserine, regulates various vital cellular processes, including proliferation, survival, motility, and immunologic response. Although not implicated as an oncogenic driver itself, AXL, a member of the TYRO3, AXL, and MERTK family of receptor tyrosine kinases, is overexpressed in several haematologic and solid malignancies, including acute myeloid leukaemia, non-small cell lung cancer, gastric and colorectal adenocarcinomas, and breast and prostate cancers. In the context of malignancy, evidence suggests that AXL overexpression drives wide-ranging processes, including epithelial to mesenchymal transition, tumour angiogenesis, resistance to chemotherapeutic and targeted agents, and decreased antitumor immune response. As a result, AXL is an attractive candidate not only as a prognostic biomarker in malignancy but also as a target for anticancer therapies. Several AXL inhibitors are currently in preclinical and clinical development. This article reviews the structure, regulation, and function of AXL; the role of AXL in the tumour microenvironment; the development of AXL as a therapeutic target; and areas of ongoing and future investigation. PMID:28072762

  3. Two speed axle assembly

    SciTech Connect

    Heine, C.F.; Krisher, J.A.; Pifer, R.L.

    1988-10-04

    This patent describes a two speed axle assembly comprising an input sun gear, an output sun gear, a plant carrier mounted for rotation about the input and output sun gears, at least one compound planetary gear rotatably mounted on the planet carrier and drivingly connected to the input sun gear and the output sun gear, first clutch means for selectively locking the planet carrier relative to the input sun gear for rotation therewith including means normally loading the first clutch means whereby the planet carrier rotates the input sun gear, second clutch means for alternatively locking the planet carrier against rotation whereby the compound planet gear rotates on the planet carrier in response to rotation of the input sun gear, and inflatable bladder means adapted when selectively inflated to load the second clutch means and simultaneously unload the normally loaded first clutch means whereby the planet carrier is unlocked relative to the input sun gear and locked against rotation, including means selectively supplying hydraulic fluid under pressure to the bladder means, means supplying hydraulic fluid comprising accumulator means, pump means remote from the axle assembly for pressurizing the hydraulic fluid and maintaining a supply of the fluid under at least a minimum pressure in the accumulator means, and valve means for selectively admitting the pressurized fluid from the accumulator means to the bladder means to inflate the bladder means and relieving the pressure to deflate the bladder means.

  4. Drive axle for electric vehicle

    SciTech Connect

    Travis, J.M.

    1981-06-02

    An electric powered vehicle drive axle is disclosed. The axle of the present invention comprises a ring gear; a first pinion gear for rotating the ring gear; a differential carried by the ring gear; a pair of axle shafts driven by the differential for rotatably driving a pair of drive wheels; the device supported and enclosed by a housing. A second pinion gear is employed which rotatably engages the ring gear. A first electric motor rotatably connected to the first pinion gear is connected to a power source for rotatably driving the vehicle. A second electric motor/generator is connected to the second pinion gear and electrically connected to the power source. The second electric motor/generator selectively powers the differential or derives power from the differential to recharge the power source as dictated by the power needs of the electric vehicle. A plurality of bevel gears are deployed along the length of the axles. Each bevel gear is rotatably connected to a pair of opposed bevel gears, each opposed bevel gear is rotatably connected to an electric motor/generator. By selectively and electrically causing the plurality of motors/generators to either power the axle or be powered by the axle optimum efficiency and recharging of the battery over a range of vehicle operating conditions is obtained.

  5. 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

  6. 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.

  7. 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. ©2014 American Association for Cancer Research.

  8. 49 CFR 215.105 - Defective axle.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... conjunction with a plain bearing, has an end collar that is broken or cracked; (d) A journal on the car shows evidence of overheating, as evidenced by a pronounced blue black discoloration; or (e) The surface of the plain bearing journal on the axle, or the fillet on the axle, has— (1) A ridge; (2) A depression; (3) A...

  9. 49 CFR 215.105 - Defective axle.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... conjunction with a plain bearing, has an end collar that is broken or cracked; (d) A journal on the car shows evidence of overheating, as evidenced by a pronounced blue black discoloration; or (e) The surface of the plain bearing journal on the axle, or the fillet on the axle, has— (1) A ridge; (2) A depression; (3) A...

  10. 49 CFR 215.105 - Defective axle.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... conjunction with a plain bearing, has an end collar that is broken or cracked; (d) A journal on the car shows evidence of overheating, as evidenced by a pronounced blue black discoloration; or (e) The surface of the plain bearing journal on the axle, or the fillet on the axle, has— (1) A ridge; (2) A depression; (3) A...

  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. 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)...

  13. Non-differential drive axle

    SciTech Connect

    Hardt, J.G.; Shea, D.W.

    1987-02-17

    This patent describes a drive axle for a vehicle, the vehicle having a set of wheels spaced along a first axis of rotation of the wheels, the drive axle comprising: a housing adapted to extend generally along the first axis between the two wheels, the housing first and second axially spaced ends, a gear support rotatably journalled in the housing adjacent the first end of the housing, an intermediate shaft drivingly connected to the gear support and rotatably journalled in the housing adjacent the second end of the housing, a first output shaft rotatably journalled in the first end of the housing and the gear support, a second output shaft rotatably journalled in the second end of the housing and the intermediate shaft, and a first bi-directional overrunning clutch positioned adjacent the first end of the housing and operable to connect the first output shaft with the gear support for conjoint rotation. The first overrunning clutch includes a first non-circular surface on the gear support, a first drum connected to the first output shaft and overlying the first non-circular surface, and rollers disposed between the first drum and the first non-circular surface actuatable to connect the first drum and the first non-circular surface for conjoint rotation.

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

    DOE PAGES

    Kariolis, Mihalis S.; Miao, Yu Rebecca; Jones, Douglas S.; ...

    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

  15. The Receptor Tyrosine Kinase AXL in Cancer Progression

    PubMed Central

    Rankin, Erinn B.; Giaccia, Amato J.

    2016-01-01

    The AXL receptor tyrosine kinase (AXL) has emerged as a promising therapeutic target for cancer therapy. Recent studies have revealed a central role of AXL signaling in tumor proliferation, survival, stem cell phenotype, metastasis, and resistance to cancer therapy. Moreover, AXL is expressed within cellular components of the tumor microenvironment where AXL signaling contributes to the immunosuppressive and protumorigenic phenotypes. A variety of AXL inhibitors have been developed and are efficacious in preclinical studies. These agents offer new opportunities for therapeutic intervention in the prevention and treatment of advanced disease. Here we review the literature that has illuminated the cellular and molecular mechanisms by which AXL signaling promotes tumor progression and we will discuss the therapeutic potential of AXL inhibition for cancer therapy. PMID:27834845

  16. 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

  17. 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

  18. 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.

  19. 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

  20. Role of Axl in early kidney inflammation and progression of salt-dependent hypertension.

    PubMed

    Batchu, Sri N; Hughson, Angie; Gerloff, Janice; Fowell, Deborah J; Korshunov, Vyacheslav A

    2013-08-01

    The Gas6/Axl pathway regulates many cell functions and is implicated in hypertension. In this study, we aimed to investigate the role of Axl in immune cells on initiation and progression of salt-dependent hypertension. Deoxycorticosterone acetate (75 mg/60 days release)-salt hypertension was induced for 1 week or 6 weeks in Axl chimeras generated by bone marrow transplant to restrict Axl deficiency to hematopoietic or nonhematopoietic compartments. Depletion of Axl in hematopoietic cells (Axl(-/-) →Axl(+/+)) reduced (133 ± 2 mm Hg) increase in systolic blood pressure compared with other Axl chimeras (≈150 mm Hg) 1 week after deoxycorticosterone acetate-salt. Urine protein and renal oxidative stress were lowest in Axl(-/-) →Axl(+/+) at 1 week after deoxycorticosterone acetate-salt. Compensatory increase in Gas6 in kidneys of recipient Axl(-/-) may affect kidney function and blood pressure in early phase of hypertension. Flow cytometry on kidneys from Axl(-/-) →Axl(+/+) showed increase in total leukocytes, B, and dendritic cells and decrease in macrophages compared with Axl(+/+) →Axl(+/+). These immune changes were associated with decrease in proinflammatory gene expression, in particular interferon γ. Systolic blood pressure returned to baseline in Axl(-/-) →Axl(+/+) and Axl(-/-) →Axl(-/-) but remained increased in Axl(+/+) →Axl(+/+) and Axl(+/+) →Axl(-/-) chimeras after 6 weeks of deoxycorticosterone acetate-salt. Vascular apoptosis was increased in the global Axl(-/-) chimeras in the late phase of hypertension. In summary, we found that expression of Axl in hematopoietic cells is critical for kidney pathology in early phase of salt-dependent hypertension. However, Axl in both hematopoietic and nonhematopoietic lineages contributes to the late phase of hypertension.

  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. Laboratory Based Axle Lubricant Efficiency Evaluation

    DTIC Science & Technology

    2014-07-01

    UNCLASSIFIED UNCLASSIFIED LABORATORY BASED AXLE LUBRICANT EFFICIENCY EVALUATION INTERIM REPORT TFLRF No. 459 by Robert W. Warden...Edwin A. Frame Adam C. Brandt Scott J. Tedesco U.S. Army TARDEC Fuels and Lubricants Research Facility Southwest Research Institute® (SwRI... LUBRICANT EFFICIENCY EVALUATION INTERIM REPORT TFLRF No. 459 by Robert W. Warden Edwin A. Frame Adam C. Brandt Scott J. Tedesco U.S. Army

  3. Hypoxia stabilizes GAS6/AXl signaling in metastatic prostate cancer

    PubMed Central

    Mishra, Anjali; Wang, Jingcheng; Shiozawa, Yusuke; McGee, Samantha; Kim, Jinkoo; Jung, Younghun; Joseph, Jeena; Berry, Janice E.; Havens, Aaron; Pienta, Kenneth J.; Taichman, Russell S.

    2012-01-01

    The receptor tyrosine kinase Axl is over-expressed in a variety of cancers and is known to play a role in proliferation and invasion. Previous data from our lab indicates that Axl and its ligand GAS6 may play a role in establishing metastatic dormancy in the bone marrow microenvironment. In the current study, we found that Axl is highly expressed in metastatic prostate cancer (PCa) cell lines PC3 and DU145 and has negligible levels of expression in a non-metastatic cancer cell line LNCaP. Knockdown of Axl in PC3 and DU145 cells resulted in decreased expression of several mesenchymal markers including Snail, Slug, and N-cadherin, and enhanced expression of the epithelial marker E-cadherin, suggesting that Axl is involved in the epithelial to mesenchymal transition in PCa cells. The Axl-knockdown PC3 and DU145 cells also displayed decreased in vitro migration and invasion. Interestingly, when PC3 and DU145 cells were treated with GAS6, Axl protein levels were down-regulated. Moreover, CoCl2, a hypoxia mimicking agent, prevented GAS6 mediated down-regulation of Axl in these cell lines. Immunochemical staining of human PCa tissue microarrays demonstrated that Axl, GAS6 and Hif1-α (indicator of hypoxia) were all co-expressed in PCa and in bone metastases, compared to normal tissues. Together, our studies indicate that Axl plays a crucial role in PCa metastasis, and that GAS6 regulates the expression of Axl. Importantly, in a hypoxic tumor microenvironment Axl expression maintained leading to enhanced signaling. PMID:22516347

  4. Single-axle, double-axis solar tracker

    NASA Technical Reports Server (NTRS)

    Brantley, L. W.; Lawson, B. D.

    1979-01-01

    Solar concentrator tracking mechanism consisting of angular axle and two synchronized drive motors, follows seasonal as well as diurnal changes in earth's orientation with respect to incoming sunlight.

  5. A general model of the axle vibration in piezoelectric motors.

    PubMed

    Iula, Antonio; Pappalardo, Massimo

    2004-04-01

    In the present work a general model of the vibrational behavior of the axle of a piezoelectric motor is proposed. In this motor, a cylinder-shaped permanent magnet, which act as a rotor, is pressed in contact with an end of a steel axle by means of the magnetic forces. The other end of the axle is fitted at the center of a rotating traveling wave generator. A piezoelectric membrane, vibrating in a flexural anti-symmetrical mode, or a thick disk, vibrating in a radial anti-symmetrical mode, can be exploited as traveling wave generators. In the first case a bending moment, in the second case a transverse force is applied to the axle. In both cases, if the driving frequency coincides with a resonance frequency of the axle, the axle acts as a resonant displacement amplifier; a continuous slipping takes place between the axle and the rotor, and a torque is transmitted to the rotor. The proposed model is able to describe the axle vibrational behavior when it is excited by a bending moment, by a transverse force, and also when these two excitations are simultaneously applied. The axle is modeled as a four-port system and all its transfer functions, as well as the transversal displacement along the axle at each frequency can be easily computed. Computed results have been compared with experimental measurements carried out on two motor prototypes that exploit as traveling wave generators a membrane and a disk, respectively. A good agreement was obtained by properly taking into account the loading effect of the generator on the axle.

  6. 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

  7. The AXL Receptor is a Sensor of Ligand Spatial Heterogeneity

    PubMed Central

    Meyer, Aaron S.; Zweemer, Annelien J.M.; Lauffenburger, Douglas A.

    2015-01-01

    The AXL receptor is a TAM (Tyro3, AXL, MerTK) receptor tyrosine kinase (RTK) important in physiological inflammatory processes such as blood clotting, viral infection, and innate immune-mediated cell clearance. Overexpression of the receptor in a number of solid tumors is increasingly appreciated as a key drug resistance and tumor dissemination mechanism. Although the ligand-receptor (Gas6-AXL) complex structure is known, literature reports on ligand-mediated signaling have provided conflicting conclusions regarding the influence of other factors such as phosphatidylserine binding, and a detailed, mechanistic picture of AXL activation has not emerged. Integrating quantitative experiments with mathematical modeling, we show here that AXL operates to sense local spatial heterogeneity in ligand concentration, a feature consistent with its physiological role in inflammatory cell responses. This effect arises as a result of an intricate reaction-diffusion interaction. Our results demonstrate that AXL functions distinctly from other RTK families, a vital insight for envisioned design of AXL-targeted therapeutic intervention. PMID:26236777

  8. Inertial Stabilization Of Periscopic Sights Band Driven Three Axle Gimbal

    NASA Astrophysics Data System (ADS)

    Ellison, Bruce; Richi, James

    1983-10-01

    There are many applications for the use of optical instruments in vehicles, especially in the military. It is required that these instruments function while the vehicle is on the move, in rough terrain. Angular distrubances of the line-of-sight pointing vector can render these instruments useless as observation or pointing devices, due to image blurring. Instruments that must retain resolution in this environment are usually stabilized by means of gimbals. If the entire instrument (such as a large television camera) is to be stabilized, the problem becomes one of a simple stable platform, or, a single axle gimbal. If, however, the instrument is hard mounted to the vehicle and the image is instead to be stabilized by means of a compensating optical component, such as a periscope head mirror, the problem is a little more complex. In a periscopic sight the head mirror must be driven at half-speed to the line-of-sight disturbance to compensate for the angle doubling effect of the mirror. That is, in order to stabilize the line-of-sight, the mirror cannot be inertiallv stable, but must be coupled to a stable mass at a ratio of 1:2. In many applications it is necessary to transmit the elevation angle of the line-of-sight to a fire control system, or, to direct the lines-of-sight of other platforms. In order to do this, transducers are mounted on the "drive axle", (gyros, synchros, tachometers, potentiometers, motors), which detect and trasmit the angular position and rate of the elevation line-of-sight. This drive axle becomes the stable element and is coupled to the mirror axle, at a 2:1 ratio, by means of gears or metallic belts or bands. This is a double axle gimbal system. When subjected to a rotational disturbance such as boat or vehicle motion the inertias of the drive and mirror axles react with one-another to cause a displacement of the line-of-sight pointing vector. This disturbance is a dynamic coupling of inertias. It exists even in the absence of friction

  9. 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

  10. 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

  11. Influence of Initial Inclined Surface Crack on Estimated Residual Fatigue Lifetime of Railway Axle

    NASA Astrophysics Data System (ADS)

    Náhlík, Luboš; Pokorný, Pavel; Ševčík, Martin; Hutař, Pavel

    2016-11-01

    Railway axles are subjected to cyclic loading which can lead to fatigue failure. For safe operation of railway axles a damage tolerance approach taking into account a possible defect on railway axle surface is often required. The contribution deals with an estimation of residual fatigue lifetime of railway axle with initial inclined surface crack. 3D numerical model of inclined semi-elliptical surface crack in railway axle was developed and its curved propagation through the axle was simulated by finite element method. Presence of press-fitted wheel in the vicinity of initial crack was taken into account. A typical loading spectrum of railway axle was considered and residual fatigue lifetime was estimated by NASGRO approach. Material properties of typical axle steel EA4T were considered in numerical calculations and lifetime estimation.

  12. 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.

  13. The Application of Phased Array Ultrasonic Techniques for Inspection of Railway Axles from Their End Face

    NASA Astrophysics Data System (ADS)

    Liaptsis, D.; Cooper, I.; Boyle, K.; Nicholson, P. I.

    2011-06-01

    As part of the development of a non destructive testing (NDT) system combining complementary inspection techniques, an inspection system based on phased array ultrasonic testing (PAUT) for detection of transverse cracking in solid railway axles is being developed. This paper presents the initial study, which includes the PAUT experimental setup and the initial results obtained after testing the system on railway axle blocks. The inspection of solid axles from their axle end face is investigated.

  14. Better load-weight distribution is needed for tandem-axle logging trucks

    Treesearch

    John E. Baumgras

    1976-01-01

    To determine the GVW and axle weights of tandem-axle logging trucks hauling into two West Virginia sawmills, 543 truckloads of hardwood sawlogs were weighed. The results showed that less than 2 percent of the truckloads exceeded the 48,000 pound GVW limit. While 58 percent of the truckloads exceeded the 32,000 pound tandem-axle weight limit, the front-axle weights...

  15. A fluorophoric-axle-based, nonfluororescent, metallo anti-[3]pseudorotaxane: recovery of fluorescence by means of an axle substitution reaction.

    PubMed

    Saha, Subrata; Ravikumar, I; Ghosh, Pradyut

    2011-12-02

    A Cu(2+)-templated, multinuclear, nonfluorescent, anti-[3]pseudorotaxane was synthesized on a fluorophoric axle. The Cu(2+)-templated [3]pseudorotaxane was characterized by the electrospray ionization mass spectroscopy (ESI-MS), UV/Vis and EPR spectroscopy, and single-crystal X-ray data. The ESI-MS showed peaks that support the formation of [3]pseudorotaxane. The UV/Vis spectrum of [3]pseudorotaxane in CH(3)CN showed a characteristic d-d band of a Cu(2+) complex at 650 nm. Further, the X-band in the EPR spectrum of [3]pseudorotaxane suggested a distorted square-pyramidal geometry of Cu(2+). Importantly, formation of the [3]pseudorotaxane was confirmed by the single-crystal X-ray structural analysis, which showed that one fluorophoric axle was threaded into two Cu(2+) macrocyclic wheels (MC-Cu(2+)) with an anti conformation. The UV/Vis and fluorescence titration experiments were carried out to follow the solution-state formation of [3]pseudorotaxane by MC-Cu(2+) and fluorophoric axle in CH(3)CN. In both studies, the sigmoidal curve fit supported the formation of 1:2 complex of the fluorophoric axle and MC-Cu(2+) complex. Secondly, the release of the fluorophoric axle from the nonfluorescent [3]pseudorotaxane through the formation of a [2]pseudorotaxane was demonstrated by titrating a solution of the [3]pseudorotaxane with a stronger bidentate chelating ligand, such as 1,10-phenanthroline (Phen). Substitution of the fluorophoric axle from the [3]pseudorotaxane with about 100% efficiency was achieved by the addition of approximately two equivalents of Phen, and the formation of a Phen-threaded [2]pseudorotaxane was established by ESI-MS of the resulting solution and a single-crystal X-ray study. Axle substitution was also confirmed by a fluorescence titration experiment, which showed a step-wise recovery of the fluorescence intensity of the fluorophoric axle. The association constants for the formation of the [3]- and [2]pseudrotaxanes were calculated from the

  16. 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

  17. Gas6 - Axl receptor signaling is regulated by glucose in vascular smooth muscle cells

    PubMed Central

    Cavet, Megan E.; Smolock, Elaine M.; Ozturk, Oktay H.; World, Cameron; Pang, Jinjiang; Konishi, Atsushi; Berk, Bradford C.

    2009-01-01

    Objective The receptor tyrosine kinase Axl and its ligand Gas6 are involved in the development of renal diabetic disease. In vascular smooth muscle cells (VSMC) Axl is activated by reactive oxygen species and stimulates migration and cell survival, suggesting a role for Axl in the vascular complications of diabetes. Methods and Results We investigated the effect of varying glucose concentration on Axl signaling in VSMC. Glucose exerted powerful effects on Gas6-Axl signaling with greater activation of Akt and mTOR in low glucose, and greater activation of ERK1/2 in high glucose. Plasma membrane distribution and tyrosine phosphorylation of Axl were not affected by glucose. However, co-immunoprecipitation studies demonstrated that glucose changed the interaction of Axl with its binding partners. Specifically, binding of Axl to the p85 subunit of PI3-kinase was increased in low glucose, whereas binding to SHP-2 was increased in high glucose. Furthermore, Gas6-Axl induced migration was increased in high glucose, while Gas6-Axl mediated inhibition of apoptosis was greater in low glucose. Conclusion This study demonstrates a role for glucose in altering Axl signaling through coupling to binding partners, and suggests a mechanism by which Axl contributes to VSMC dysfunction in diabetes. PMID:18292389

  18. 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

  19. Mechanisms of AXL overexpression and function in Imatinib-resistant chronic myeloid leukemia cells

    PubMed Central

    Dufies, Maeva; Jacquel, Arnaud; Belhacene, Nathalie; Robert, Guillaume; Cluzeau, Thomas; Luciano, Fréderic; Cassuto, Jill Patrice; Raynaud, Sophie; Auberger, Patrick

    2011-01-01

    AXL is a receptor tyrosine kinase of the TAM family, the function of which is poorly understood. We previously identified AXL overexpression in Imatinib (IM)-resistant CML cell lines and patients. The present study was conducted to investigate the role of AXL and the mechanisms underlying AXL overexpression in Tyrosine Kinase Inhibitor (TKI)-resistant CML cells. We present evidence that high AXL expression level is a feature of TKI-resistant CML cells and knockdown of AXL sensitized TKI-resistant cells to IM. In addition, expression of wild-type AXL but not a dominant negative form of AXL confers IM-sensitive CML cells the capacity to resist IM effect. AXL overexpression required PKCα and β and constitutive activation of ERK1/2. Accordingly, GF109203X a PKC inhibitor, U0126 a MEK1 inhibitor and PKCα/β knockdown restore sensitivity to IM while PKCα or PKCβ overexpression in CML cells promotes protection against IM-induced cell death. Finally, using luciferase promoter activity assays we established that AXL is regulated transcriptionally through the AP1 transcription factor. Our findings reveal an unexpected role of AXL in resistance to TKI in CML cells, identify the molecular mechanisms involved in its overexpression and support the notion that AXL is a new marker of resistance to TKI in CML. PMID:22141136

  20. Reprogramming the immunological microenvironment through radiation and targeting Axl

    PubMed Central

    Aguilera, Todd A.; Rafat, Marjan; Castellini, Laura; Shehade, Hussein; Kariolis, Mihalis S.; Hui, Angela Bik-Yu; Stehr, Henning; von Eyben, Rie; Jiang, Dadi; Ellies, Lesley G.; Koong, Albert C.; Diehn, Maximilian; Rankin, Erinn B.; Graves, Edward E.; Giaccia, Amato J.

    2016-01-01

    Increasing evidence suggests that ionizing radiation therapy (RT) in combination with checkpoint immunotherapy is highly effective in treating a subset of cancers. To better understand the limited responses to this combination we analysed the genetic, microenvironmental, and immune factors in tumours derived from a transgenic breast cancer model. We identified two tumours with similar growth characteristics but different RT responses primarily due to an antitumour immune response. The combination of RT and checkpoint immunotherapy resulted in cures in the responsive but not the unresponsive tumours. Profiling the tumours revealed that the Axl receptor tyrosine kinase is overexpressed in the unresponsive tumours, and Axl knockout resulted in slower growth and increased radiosensitivity. These changes were associated with a CD8+ T-cell response, which was improved in combination with checkpoint immunotherapy. These results suggest a novel role for Axl in suppressing antigen presentation through MHCI, and enhancing cytokine release, which promotes a suppressive myeloid microenvironment. PMID:28008921

  1. Eddy current system for inspection of train hollow axles

    NASA Astrophysics Data System (ADS)

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

    2014-02-01

    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.

  2. 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.

  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 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

  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 modulates extracellular matrix protein expression and is essential for invasion and metastasis in endometrial cancer

    PubMed Central

    Meller, Eric; Desai, Riva A.; Arif, Batool; Rankin, Erinn B.; Bligard, Katherine H.; Meyerson, Cherise; Hagemann, Ian S.; Massad, Maria; Thaker, Premal H.; Hagemann, Andrea R.; McCourt, Carolyn K.; Powell, Matt A.; Mutch, David G.; Fuh, Katherine C.

    2016-01-01

    The receptor tyrosine kinase AXL promotes migration, invasion, and metastasis. Here, we evaluated the role of AXL in endometrial cancer. High immunohistochemical expression of AXL was found in 76% (63/83) of advanced-stage, and 77% (82/107) of high-grade specimens and correlated with worse survival in uterine serous cancer patients. In vitro, genetic silencing of AXL inhibited migration and invasion but had no effect on proliferation of ARK1 endometrial cancer cells. AXL-deficient cells showed significantly decreased expression of phospho-AKT as well as uPA, MMP-1, MMP-2, MMP-3, and MMP-9. In a xenograft model of human uterine serous carcinoma with AXL-deficient ARK1 cells, there was significantly less tumor burden than xenografts with control ARK1 cells. Together, these findings underscore the therapeutic potentials of AXL as a candidate target for treatment of metastatic endometrial cancer. PMID:27764792

  7. 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...

  8. 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

  9. 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…

  10. 49 CFR 230.99 - Tender truck axles.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 4 2013-10-01 2013-10-01 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 and...

  11. 49 CFR 230.99 - Tender truck axles.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... 49 Transportation 4 2012-10-01 2012-10-01 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 and...

  12. 49 CFR 230.99 - Tender truck axles.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 4 2011-10-01 2011-10-01 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 and...

  13. 49 CFR 230.99 - Tender truck axles.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 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 and...

  14. AXL and GAS6 co-expression in lung adenocarcinoma as a prognostic classifier.

    PubMed

    Seike, Masahiro; Kim, Cheol-Hong; Zou, Fenfei; Noro, Rintaro; Chiba, Mika; Ishikawa, Arimi; Κunugi, Shinobu; Kubota, Kaoru; Gemma, Akihiko

    2017-06-01

    AXL, a receptor tyrosine kinase implicated in cell survival, proliferation, and migration, is also associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor therapy. However, its prognostic significance in lung adenocarcinoma (AD) remains unclear. We therefore evaluated the prognostic significance of the expression of AXL and/or its ligand, growth arrest-specific 6 (GAS6), in completely resected lung AD. We evaluated the relationship between AXL, GAS6, and vimentin expression, as determined by immunohistochemistry (IHC) analysis, with overall survival and disease-free survival in 113 patients with stages I-III lung AD. Protein expression was also assayed using western blot analysis in 10 lung AD cell lines. AXL-positive (AXL+), GAS6-positive (GAS6+), or AXL+/GAS6+ staining was significantly associated with vimentin-positive (vimentin+) expression. AXL+/GAS6+ and vimentin+ showed a negative tendency toward an association with EGFR mutation. AXL+, GAS6+, or AXL+/GAS6+ status significantly correlated with poor overall survival. In stage I cases, AXL+/GAS6+ status significantly correlated with poor overall survival and disease-free survival, especially in cases with wild-type EGFR. In multivariate analysis, AXL/GAS6 classifications in stage I as well as in stages I-III lung AD were found to be independent factors for poor patient outcomes. Unlike lung AD cell lines with mutant EGFR, almost all cells with wild-type EGFR showed AXL and vimentin co-expression as determined by western blotting. AXL+ and GAS6+ expression is relevant to a poor prognosis in resected lung AD patients at stage I. AXL/GAS6 might serve as crucial predictive and prognostic biomarkers and targets to identify individuals at high risk of post-operative death.

  15. 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.

  16. 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.

  17. Soluble Axl Is Generated by ADAM10-Dependent Cleavage and Associates with Gas6 in Mouse Serum†

    PubMed Central

    Budagian, Vadim; Bulanova, Elena; Orinska, Zane; Duitman, Erwin; Brandt, Katja; Ludwig, Andreas; Hartmann, Dieter; Lemke, Greg; Saftig, Paul; Bulfone-Paus, Silvia

    2005-01-01

    Axl receptor tyrosine kinase exists as a transmembrane protein and as a soluble molecule. We show that constitutive and phorbol 12-myristate 13-acetate-induced generation of soluble Axl (sAxl) involves the activity of disintegrin-like metalloproteinase 10 (ADAM10). Spontaneous and inducible Axl cleavage was inhibited by the broad-spectrum metalloproteinase inhibitor GM6001 and by hydroxamate GW280264X, which is capable of blocking ADAM10 and ADAM17. Furthermore, murine fibroblasts deficient in ADAM10 expression exhibited a significant reduction in constitutive and inducible Axl shedding, whereas reconstitution of ADAM10 restored sAxl production, suggesting that ADAM10-mediated proteolysis constitutes a major mechanism for sAxl generation in mice. Partially overlapping 14-amino-acid stretch deletions in the membrane-proximal region of Axl dramatically affected sAxl generation, indicating that these regions are involved in regulating the access of the protease to the cleavage site. Importantly, relatively high circulating levels of sAxl are present in mouse sera in a heterocomplex with Axl ligand Gas6. Conversely, two other family members, Tyro3 and Mer, were not detected in mouse sera and conditioned medium. sAxl is constitutively released by murine primary cells such as dendritic and transformed cell lines. Upon immobilization, sAxl promoted cell migration and induced the phosphorylation of Axl and phosphatidylinositol 3-kinase. Thus, ADAM10-mediated generation of sAxl might play an important role in diverse biological processes. PMID:16227584

  18. Soluble Axl is generated by ADAM10-dependent cleavage and associates with Gas6 in mouse serum.

    PubMed

    Budagian, Vadim; Bulanova, Elena; Orinska, Zane; Duitman, Erwin; Brandt, Katja; Ludwig, Andreas; Hartmann, Dieter; Lemke, Greg; Saftig, Paul; Bulfone-Paus, Silvia

    2005-11-01

    Axl receptor tyrosine kinase exists as a transmembrane protein and as a soluble molecule. We show that constitutive and phorbol 12-myristate 13-acetate-induced generation of soluble Axl (sAxl) involves the activity of disintegrin-like metalloproteinase 10 (ADAM10). Spontaneous and inducible Axl cleavage was inhibited by the broad-spectrum metalloproteinase inhibitor GM6001 and by hydroxamate GW280264X, which is capable of blocking ADAM10 and ADAM17. Furthermore, murine fibroblasts deficient in ADAM10 expression exhibited a significant reduction in constitutive and inducible Axl shedding, whereas reconstitution of ADAM10 restored sAxl production, suggesting that ADAM10-mediated proteolysis constitutes a major mechanism for sAxl generation in mice. Partially overlapping 14-amino-acid stretch deletions in the membrane-proximal region of Axl dramatically affected sAxl generation, indicating that these regions are involved in regulating the access of the protease to the cleavage site. Importantly, relatively high circulating levels of sAxl are present in mouse sera in a heterocomplex with Axl ligand Gas6. Conversely, two other family members, Tyro3 and Mer, were not detected in mouse sera and conditioned medium. sAxl is constitutively released by murine primary cells such as dendritic and transformed cell lines. Upon immobilization, sAxl promoted cell migration and induced the phosphorylation of Axl and phosphatidylinositol 3-kinase. Thus, ADAM10-mediated generation of sAxl might play an important role in diverse biological processes.

  19. 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.

  20. Implication of the Receptor Tyrosine Kinase AXL in Head and Neck Cancer Progression

    PubMed Central

    von Mässenhausen, Anne; Brägelmann, Johannes; Billig, Hannah; Thewes, Britta; Queisser, Angela; Vogel, Wenzel; Kristiansen, Glen; Schröck, Andreas; Bootz, Friedrich; Brossart, Peter; Kirfel, Jutta; Perner, Sven

    2016-01-01

    Head and neck squamous cell carcinoma (HNSCC) remains a clinical challenge and identification of novel therapeutic targets is necessary. The receptor tyrosine kinase AXL has been implicated in several tumor entities and a selective AXL small molecule inhibitor (BGB324) is currently being tested in clinical trials for patients suffering from non-small cell lung cancer or acute myeloid leukemia. Our study investigates AXL expression during HNSCC progression and its use as a potential therapeutic target in HNSCC. AXL protein expression was determined in a HNSCC cohort (n = 364) using immunohistochemical staining. For functional validation, AXL was either overexpressed or inhibited with BGB324 in HNSCC cell lines to assess proliferation, migration and invasion. We found AXL protein expression increasing during tumor progression with highest expression levels in recurrent tumors. In HNSCC cell lines in vitro, AXL overexpression increased migration as well as invasion. Both properties could be reduced through treatment with BGB324. In contrast, proliferation was neither affected by AXL overexpression nor by inhibition with BGB324. Our patient-derived data and in vitro results show that, in HNSCC, AXL is important for the progression to more advanced tumor stages. Moreover, they suggest that AXL could be a target for precision medicine approaches in this dismal tumor entity. PMID:28025482

  1. AXL is a logical molecular target in head and neck squamous cell carcinoma

    PubMed Central

    Brand, Toni M.; Iida, Mari; Stein, Andrew P.; Corrigan, Kelsey L.; Braverman, Cara M.; Coan, John; Pearson, Hannah E.; Bahrar, Harsh; Fowler, Tyler L.; Bednarz, Bryan P.; Saha, Sandeep; Yang, David; Gill, Parkash S.; Lingen, Mark W.; Saloura, Vassiliki; Villaflor, Victoria M.; Salgia, Ravi; Kimple, Randall J.; Wheeler, Deric L.

    2016-01-01

    Purpose Head and neck squamous cell carcinoma (HNSCC) represents the eighth most common malignancy worldwide. Standard of care treatments for HNSCC patients include surgery, radiation and chemotherapy. Additionally, the anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab is often used in combination with these treatment modalities. Despite clinical success with these therapeutics, HNSCC remains a difficult to treat malignancy. Thus, identification of new molecular targets is critical. Experimental Design In the current study, the receptor tyrosine kinase AXL was investigated as a molecular target in HNSCC using established cell lines, HNSCC patient derived xenografts (PDXs), and human tumors. HNSCC dependency on AXL was evaluated with both anti-AXL siRNAs and the small molecule AXL inhibitor R428. Furthermore, AXL inhibition was evaluated with standard of care treatment regimes used in HNSCC. Results AXL was found to be highly overexpressed in several models of HNSCC, where AXL was significantly associated with higher pathologic grade, presence of distant metastases and shorter relapse free survival in patients with HNSCC. Further investigations indicated that HNSCC cells were reliant on AXL for cellular proliferation, migration, and invasion. Additionally, targeting AXL increased HNSCC cell line sensitivity to chemotherapy, cetuximab, and radiation. Moreover, radiation resistant HNSCC cell line xenografts and PDXs expressed elevated levels of both total and activated AXL, indicating a role for AXL in radiation resistance. Conclusion Collectively, this study provides evidence for the role of AXL in HNSCC pathogenesis and supports further pre-clinical and clinical evaluation of anti-AXL therapeutics for the treatment of patients with HNSCC. PMID:25767293

  2. Preclinical validation of AXL receptor as a target for antibody-based pancreatic cancer immunotherapy

    PubMed Central

    Leconet, Wilhem; Larbouret, Christel; Chardès, Thierry; Thomas, Gaëlle; Neiveyans, Madeline; Busson, Muriel; Jarlier, Marta; Radosevic-Robin, Nina; Pugnière, Martine; Bernex, Florence; Penault-Llorca, Frédérique; Pasquet, Jean-Max; Pèlegrin, André; Robert, Bruno

    2014-01-01

    AXL receptor tyrosine kinases is implicated in proliferation and invasion of many cancers, particularly in pancreatic ductal adenocarcinoma (PDAC), for which new therapeutic options are urgently required. We investigated whether inhibition of AXL activity by specific monoclonal antibodies (mAbs) is efficient in limiting proliferation and migration of pancreatic cancer cells. Expression of AXL was evaluated by immunohistochemistry in 42 PDAC. The AXL role in oncogenesis was studied using the short hairpin RNA approach in a pancreatic carcinoma cell line. We further generated anti-human AXL mAbs and evaluated their inhibitory effects and the AXL downstream signaling pathways first in vitro, in a panel of pancreatic cancer cell lines and then in vivo, using subcutaneous or orthotopic pancreatic tumor xenografts. AXL receptor was found expressed in 76% (32/42) of PDAC and was predominantly present in invasive cells. The AXL-knockdown Panc-1 cells decreased in vitro cell migration, survival and proliferation, and reduced in vivo tumor growth. Two selected anti-AXL mAbs (D9 and E8), which inhibited phosphorylation of AXL and of its downstream target AKT without affecting GAS6 binding, induced down-expression of AXL by internalization, leading to an inhibition of proliferation and migration in the four pancreatic cancer cell lines studied. In vivo, treatment by anti-AXL mAbs significantly reduced growth of both subcutaneous and orthotopic pancreatic tumor xenografts independently of their KRAS mutation status. Our in vitro and preclinical in vivo data demonstrate that anti-human AXL mAbs could represent a new approach to the pancreatic cancer immunotherapy. PMID:24240689

  3. Soluble AXL: a possible circulating biomarker for neurofibromatosis type 1 related tumor burden.

    PubMed

    Johansson, Gunnar; Peng, Po-Chun; Huang, Po-Yuan; Chien, Hsiung-Fei; Hua, Kuo-Tai; Kuo, Min-Liang; Chen, Chin-Tin; Lee, Ming-Jen

    2014-01-01

    Neurofibromatosis type 1 (NF1) is the most common tumor predisposition disorder affecting 1/3500 worldwide. Patients are at risk of developing benign (neurofibromas) and malignant peripheral nerve sheath tumors (MPNST). The AXL receptor tyrosine kinase has been implicated in several kinds of cancers, but so far no studies have investigated the role of AXL in NF1 related tumorigenesis. Recently, the soluble fraction from the extracellular domain of AXL (sAXL) has been found in human plasma, and its level was correlated to poor prognosis in patients with renal cancer. Compared to normal human Schwann cells, a significantly high expression level of AXL was found in three of the four MPNST cell lines and two of the three primary MPNST tissues. Similarly, the level of sAXL in conditioned media corresponded to the protein and mRNA levels of AXL in the MPNST cell lines. Furthermore, in two different human MPNST xenograft models, the human sAXL could be detected in the mouse plasma. Its level was proportionate to the size of the xenograft tumors, while no human sAXL was detect prior to the formation of the tumors. Treatment with a newly developed photodynamic therapy, prevented further tumor growth and resulted in drastically reduced the levels of sAXL compared to that of the control group. Finally, the level of sAXL was significantly increased in patients with plexiform tumors compared to patients with only dermal neurofibromas, further supporting the role of sAXL as a marker for NF1 related tumor burden.

  4. Rotation of artificial rotor axles in rotary molecular motors

    PubMed Central

    Baba, Mihori; Iwamoto, Kousuke; Ueno, Hiroshi; Hara, Mayu; Nakanishi, Atsuko; Kishikawa, Jun-ichi; Noji, Hiroyuki; Yokoyama, Ken

    2016-01-01

    F1- and V1-ATPase are rotary molecular motors that convert chemical energy released upon ATP hydrolysis into torque to rotate a central rotor axle against the surrounding catalytic stator cylinder with high efficiency. How conformational change occurring in the stator is coupled to the rotary motion of the axle is the key unknown in the mechanism of rotary motors. Here, we generated chimeric motor proteins by inserting an exogenous rod protein, FliJ, into the stator ring of F1 or of V1 and tested the rotation properties of these chimeric motors. Both motors showed unidirectional and continuous rotation, despite no obvious homology in amino acid sequence between FliJ and the intrinsic rotor subunit of F1 or V1. These results showed that any residue-specific interactions between the stator and rotor are not a prerequisite for unidirectional rotation of both F1 and V1. The torque of chimeric motors estimated from viscous friction of the rotation probe against medium revealed that whereas the F1-FliJ chimera generates only 10% of WT F1, the V1-FliJ chimera generates torque comparable to that of V1 with the native axle protein that is structurally more similar to FliJ than the native rotor of F1. This suggests that the gross structural mismatch hinders smooth rotation of FliJ accompanied with the stator ring of F1. PMID:27647891

  5. Rotation of artificial rotor axles in rotary molecular motors.

    PubMed

    Baba, Mihori; Iwamoto, Kousuke; Iino, Ryota; Ueno, Hiroshi; Hara, Mayu; Nakanishi, Atsuko; Kishikawa, Jun-Ichi; Noji, Hiroyuki; Yokoyama, Ken

    2016-10-04

    F1- and V1-ATPase are rotary molecular motors that convert chemical energy released upon ATP hydrolysis into torque to rotate a central rotor axle against the surrounding catalytic stator cylinder with high efficiency. How conformational change occurring in the stator is coupled to the rotary motion of the axle is the key unknown in the mechanism of rotary motors. Here, we generated chimeric motor proteins by inserting an exogenous rod protein, FliJ, into the stator ring of F1 or of V1 and tested the rotation properties of these chimeric motors. Both motors showed unidirectional and continuous rotation, despite no obvious homology in amino acid sequence between FliJ and the intrinsic rotor subunit of F1 or V1 These results showed that any residue-specific interactions between the stator and rotor are not a prerequisite for unidirectional rotation of both F1 and V1 The torque of chimeric motors estimated from viscous friction of the rotation probe against medium revealed that whereas the F1-FliJ chimera generates only 10% of WT F1, the V1-FliJ chimera generates torque comparable to that of V1 with the native axle protein that is structurally more similar to FliJ than the native rotor of F1 This suggests that the gross structural mismatch hinders smooth rotation of FliJ accompanied with the stator ring of F1.

  6. 49 CFR 230.100 - Defects in tender truck axles and journals.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION STEAM LOCOMOTIVE INSPECTION AND MAINTENANCE STANDARDS Steam Locomotives and Tenders Running Gear § 230.100 Defects in tender truck axles and journals....

  7. Axl is not an indispensable factor for Zika virus infection in mice.

    PubMed

    Wang, Zhao-Yang; Wang, Zai; Zhen, Zi-Da; Feng, Kai-Hao; Guo, Jing; Gao, Na; Fan, Dong-Ying; Han, Dai-Shu; Wang, Pei-Gang; An, Jing

    2017-08-01

    Recently, Zika virus (ZIKV) outbreak has been associated with a sharp increase in cases of Guillain-Barré syndrome and severe fetal abnormalities. However, the mechanism underlying the interaction of ZIKV with host cells is not yet clear. Axl, a receptor tyrosine kinase, is postulated as a receptor for ZIKV entry; however, its in vivo role during ZIKV infection and its impact on the outcome of the disease have not been fully characterized and evaluated. Moreover, there are contradictory results on its involvement in ZIKV infection. Here we utilized Axl-deficient mice (Axl-/-) and their littermates (Axl+/-) to study the in vivo role of Axl in ZIKV infection. Our results showed that both Axl+/- and Axl-/- suckling mice supported the replication of ZIKV and presented clinical manifestations. No significant difference has been found between Axl-deficient mice and their littermates in terms of the survival rate, clinical manifestations, viral load, ZIKV distribution and histopathological changes in major organs. These results therefore indicate that Axl is not an indispensable factor for ZIKV infection in mice.

  8. A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control.

    PubMed

    Budagian, Vadim; Bulanova, Elena; Orinska, Zane; Thon, Lutz; Mamat, Uwe; Bellosta, Paola; Basilico, Claudio; Adam, Dieter; Paus, Ralf; Bulfone-Paus, Silvia

    2005-12-21

    Discrimination between cytokine receptor and receptor tyrosine kinase (RTK) signaling pathways is a central paradigm in signal transduction research. Here, we report a 'promiscuous liaison' between both receptors that enables interleukin (IL)-15 to transactivate the signaling pathway of a tyrosine kinase. IL-15 protects murine L929 fibroblasts from tumor necrosis factor alpha (TNFalpha)-induced cell death, but fails to rescue them upon targeted depletion of the RTK, Axl; however, Axl-overexpressing fibroblasts are TNFalpha-resistant. IL-15Ralpha and Axl colocalize on the cell membrane and co-immunoprecipitate even in the absence of IL-15, whereby the extracellular part of Axl proved to be essential for Axl/IL-15Ralpha interaction. Most strikingly, IL-15 treatment mimics stimulation by the Axl ligand, Gas6, resulting in a rapid tyrosine phosphorylation of both Axl and IL-15Ralpha, and activation of the phosphatidylinositol 3-kinase/Akt pathway. This is also seen in mouse embryonic fibroblasts from wild-type but not Axl-/- or IL-15Ralpha-/- mice. Thus, IL-15-induced protection from TNFalpha-mediated cell death involves a hitherto unknown IL-15 receptor complex, consisting of IL-15Ralpha and Axl RTK, and requires their reciprocal activation initiated by ligand-induced IL-15Ralpha.

  9. Axl receptor tyrosine kinase is a novel target of apigenin for the inhibition of cell proliferation.

    PubMed

    Kim, Kyung-Chan; Choi, Eun-Ha; Lee, Chuhee

    2014-08-01

    The Axl receptor tyrosine kinase (RTK), along with Tyro 3 and Mer, belongs to the TAM subfamily that promotes survival, stimulates proliferation and/or inhibits apoptosis. In various types of human cancer, including breast, lung and prostate cancer, Axl expression is increased and correlates with an advanced clinical stage. In this study, we examined whether apigenin has an effect on Axl expression, which in turn can affect cell proliferation. The treatment of the non‑small cell lung cancer (NSCLC) cells, A549 and H460, with apigenin decreased Axl mRNA and protein expression in a dose‑dependent manner. Axl promoter activity was also inhibited by apigenin, indicating that apigenin suppressed Axl expression at the transcriptional level. Upon treatment with apigenin, the viability of both the A549 and H460 cells was gradually decreased and the anti-proliferative effects were further confirmed by the dose‑dependent decrease in the clonogenic ability of the apigenin‑treated cells. Subsequently, we found that the viability and clonogenic ability of the cells treated with apigenin was less or more affected by transfection of the cells with a Axl-expressing plasmid or Axl targeting siRNA, compared to transfection with the empty vector or control siRNA, respectively. In addition, apigenin increased the expression of p21, a cyclin-dependent kinase inhibitor, but reduced the expression of X-linked inhibitor of apoptosis protein (XIAP). These cell cycle arrest and pro-apoptotic effects of apigenin were also attenuated or augmented by the up- or downregulation of Axl expression, respectively, which suggests that Axl is a novel target of apigenin through which it exerts its inhibitory effects on cell proliferation. Taken together, our data indicate that apigenin downregulates Axl expression, which subsequently results in the inhibition of NSCLC cell proliferation through the increase and decrease of p21 and XIAP expression, respectively.

  10. Cilostazol inhibits uremic toxin-induced vascular smooth muscle cell dysfunction: role of Axl signaling.

    PubMed

    Lee, Chien-Hsing; Hung, Yi-Jen; Shieh, Yi-Shing; Chien, Chu-Yen; Hsu, Yu-Juei; Lin, Chih-Yuan; Chiang, Chi-Fu; Huang, Chia-Luen; Hsieh, Chang-Hsun

    2017-03-01

    Chronic kidney disease (CKD) is associated with increased cardiovascular mortality, and vascular smooth muscle cell (VSMC) dysfunction plays a pivotal role in uremic atherosclerosis. Axl signaling is involved in vascular injury and is highly expressed in VSMCs. Recent reports have shown that cilostazol, a phosphodiesterase type 3 inhibitor (PDE3), can regulate various stages of the atherosclerotic process. However, the role of cilostazol in uremic vasculopathy remains unclear. This study aimed to identify the effect of cilostazol in VSMCs in the experimental CKD and to investigate whether the regulatory mechanism occurs through Axl signaling. We investigated the effect of P-cresol and cilostazol on Axl signaling in A7r5 rat VSMCs and the rat and human CKD models. From the in vivo CKD rats and patients, aortic tissue exhibited significantly decreased Axl expression after cilostazol treatment. P-cresol increased Axl, proliferating of cell nuclear antigen (PCNA), focal adhesion kinase (FAK), and matrix metalloproteinase-2 (MMP-2) expressions, decreased caspase-3 expression, and was accompanied by increased cell viability and migration. Cilostazol significantly reversed P-cresol-induced Axl, downstream gene expressions, and cell functions. Along with the increased Axl expression, P-cresol activated PLCγ, Akt, and ERK phosphorylation and cilostazol significantly suppressed the effect of P-cresol. Axl knockdown significantly reversed the expressions of P-cresol-induced Axl-related gene expression and cell functions. Cilostazol with Axl knockdown have additive changes in downstream gene expression and cell functions in P-cresol culture. Both in vitro and in vivo experimental CKD models elucidate a new signal transduction of cilostazol-mediated protection against uremic toxin-related VSMCs dysfunction and highlight the involvement of the Axl signaling and downstream pathways. Copyright © 2017 the American Physiological Society.

  11. 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

  12. Impact of surface type, wheelchair weight, and axle position on wheelchair propulsion by novice older adults.

    PubMed

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

    2009-07-01

    To examine the impact of surface type, wheelchair weight, and rear axle position on older adult propulsion biomechanics. Crossover trial. Biomechanics laboratory. Convenience sample of 53 ambulatory older adults with minimal wheelchair experience (65-87y); men, n=20; women, n=33. 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) 9.05 kg weighted chair with an anterior axle position, (3) unweighted chair with a posterior axle position (Delta0.08 m), and (4) 9.05 kg weighted chair with a posterior axle position (Delta0.08 m). Weight was added to a titanium folding chair, simulating the weight difference between very light and depot wheelchairs. Instrumented wheels measured propulsion kinetics. Average self-selected velocity, push frequency, stroke length, peak resultant and tangential force. Velocity decreased as surface rolling resistance or chair weight increased. Peak resultant and tangential forces increased as chair weight increased, as 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 was more easily observed on high carpet and ramp. The effects of axle position and weight were independent of one another. 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. The effects of weight and axle position are independent. The greatest reductions in peak forces occur in lighter chairs with anterior axle positions.

  13. 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)...

  14. 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)...

  15. 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)...

  16. Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies

    SciTech Connect

    Kariolis, Mihalis S.; Miao, Yu Rebecca; Diep, Anh; Nash, Shannon E.; Olcina, Monica M.; Jiang, Dadi; Jones, Douglas S.; Kapur, Shiven; Mathews, Irimpan I.; Koong, Albert C.; Rankin, Erinn B.; Cochran, Jennifer R.; Giaccia, Amato J.

    2016-11-28

    The AXL receptor and its activating ligand, growth arrest–specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. But, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. We have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6. Our decoy receptor, MYD1-72, profoundly inhibited disease progression in aggressive preclinical models of human cancers and induced cell killing in leukemia cells. When directly compared with the most advanced anti-AXL small molecules in the clinic, MYD1-72 achieved superior antitumor efficacy while displaying no toxicity. Furthermore, we uncovered a relationship between AXL and the cellular response to DNA damage whereby abrogation of AXL signaling leads to accumulation of the DNA-damage markers γH2AX, 53BP1, and RAD51. MYD1-72 exploited this relationship, leading to improvements upon the therapeutic index of current standard-of-care chemotherapies in preclinical models of advanced pancreatic and ovarian cancer.

  17. A promiscuous liaison between IL-15 receptor and Axl receptor tyrosine kinase in cell death control

    PubMed Central

    Budagian, Vadim; Bulanova, Elena; Orinska, Zane; Thon, Lutz; Mamat, Uwe; Bellosta, Paola; Basilico, Claudio; Adam, Dieter; Paus, Ralf; Bulfone-Paus, Silvia

    2005-01-01

    Discrimination between cytokine receptor and receptor tyrosine kinase (RTK) signaling pathways is a central paradigm in signal transduction research. Here, we report a ‘promiscuous liaison' between both receptors that enables interleukin (IL)-15 to transactivate the signaling pathway of a tyrosine kinase. IL-15 protects murine L929 fibroblasts from tumor necrosis factor α (TNFα)-induced cell death, but fails to rescue them upon targeted depletion of the RTK, Axl; however, Axl-overexpressing fibroblasts are TNFα-resistant. IL-15Rα and Axl colocalize on the cell membrane and co-immunoprecipitate even in the absence of IL-15, whereby the extracellular part of Axl proved to be essential for Axl/IL-15Rα interaction. Most strikingly, IL-15 treatment mimics stimulation by the Axl ligand, Gas6, resulting in a rapid tyrosine phosphorylation of both Axl and IL-15Rα, and activation of the phosphatidylinositol 3-kinase/Akt pathway. This is also seen in mouse embryonic fibroblasts from wild-type but not Axl−/− or IL-15Rα−/− mice. Thus, IL-15-induced protection from TNFα-mediated cell death involves a hitherto unknown IL-15 receptor complex, consisting of IL-15Rα and Axl RTK, and requires their reciprocal activation initiated by ligand-induced IL-15Rα. PMID:16308569

  18. Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors

    PubMed Central

    Linger, Rachel M.A.; Keating, Amy K.; Earp, H. Shelton

    2010-01-01

    Importance of the field Axl and/or Mer expression correlates with poor prognosis in several cancers. Until recently, the specific role of these receptor tyrosine kinases (RTKs) in the development and progression of cancer remained unexplained. Studies demonstrating that Axl and Mer contribute to mechanisms of cell survival, migration, invasion, metastasis, and chemosensitivity justify further investigation of Axl and Mer as novel therapeutic targets in cancer. Areas covered in this review Axl and Mer signaling pathways in cancer cells are summarized and evidence validating these RTKs as therapeutic targets in glioblastoma multiforme, non-small cell lung cancer, and breast cancer is examined. A comprehensive discussion of Axl and/or Mer inhibitors in development is also provided. What the reader will gain Potential toxicities associated with Axl or Mer inhibition are addressed. We hypothesize that the probable action of Mer and Axl inhibitors on cells within the tumor microenvironment will provide a unique therapeutic opportunity to target both tumor cells and the stromal components which facilitate disease progression. Take home message Axl and Mer mediate multiple oncogenic phenotypes and activation of these RTKs constitutes a mechanism of chemoresistance in a variety of solid tumors. Targeted inhibition of these RTKs may be effective as anti-tumor and/or anti-metastatic therapy, particularly if combined with standard cytotoxic therapies. PMID:20809868

  19. Axl Mediates ZIKA Virus Entry in Human Glial Cells and Modulates Innate Immune Responses.

    PubMed

    Meertens, Laurent; Labeau, Athena; Dejarnac, Ophelie; Cipriani, Sara; Sinigaglia, Laura; Bonnet-Madin, Lucie; Le Charpentier, Tifenn; Hafirassou, Mohamed Lamine; Zamborlini, Alessia; Cao-Lormeau, Van-Mai; Coulpier, Muriel; Missé, Dorothée; Jouvenet, Nolwenn; Tabibiazar, Ray; Gressens, Pierre; Schwartz, Olivier; Amara, Ali

    2017-01-10

    ZIKA virus (ZIKV) is an emerging pathogen responsible for neurological disorders and congenital microcephaly. However, the molecular basis for ZIKV neurotropism remains poorly understood. Here, we show that Axl is expressed in human microglia and astrocytes in the developing brain and that it mediates ZIKV infection of glial cells. Axl-mediated ZIKV entry requires the Axl ligand Gas6, which bridges ZIKV particles to glial cells. Following binding, ZIKV is internalized through clathrin-mediated endocytosis and traffics to Rab5+ endosomes to establish productive infection. During entry, the ZIKV/Gas6 complex activates Axl kinase activity, which downmodulates interferon signaling and facilitates infection. ZIKV infection of human glial cells is inhibited by MYD1, an engineered Axl decoy receptor, and by the Axl kinase inhibitor R428. Our results highlight the dual role of Axl during ZIKV infection of glial cells: promoting viral entry and modulating innate immune responses. Therefore, inhibiting Axl function may represent a potential target for future antiviral therapies. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  20. Expression of Axl and its prognostic significance in human breast cancer

    PubMed Central

    Jin, Gaoyuan; Wang, Zhenzhen; Wang, Jianguang; Zhang, Like; Chen, Yanbin; Yuan, Pengfei; Liu, Dechun

    2017-01-01

    Breast cancer is the most common malignant cancer and second leading cause of cancer-related death among women, and its prevalence continues to increase. Axl overexpression has been identified in the many types of human cancer, and it has been demonstrated to participate in signaling pathways related to carcinogenesis and cancer development. In the present study, Axl expression was examined by performing immunohistochemical staining in 60 breast cancer tumors and 40 benign breast lesions (25 mammary dysplasia and 15 breast fibroadenoma). In total, 34 (56.67%) cancer tissues and 13 (32.5%) benign breast lesions were classified as exhibiting high levels of Axl expression, indicating a significant association between malignancy and high Axl expression. High Axl expression was also associated with estrogen receptor (ER) positivity (P=0.028), progesterone receptor (PR) positivity (P=0.007), and poor tumor differentiation (P=0.033). No significant associations were observed between Axl expression and age, tumor size, lymph node metastasis, tumor node metastasis staging, human epidermal growth factor receptor 2 and Ki67 antigen. The Kaplan-Meier survival analysis and Cox proportional hazard model both demonstrated that there was no statistical difference between Axl expression and breast cancer prognosis. However, it remains unclear whether the expression of Axl is correlated with the prognosis of luminal type breast cancer patients. PMID:28356938

  1. 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)...

  2. 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)...

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

    PubMed Central

    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.

    2014-01-01

    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

  4. Inhibition of the GAS6/AXL pathway augments the efficacy of chemotherapies

    DOE PAGES

    Kariolis, Mihalis S.; Miao, Yu Rebecca; Diep, Anh; ...

    2016-11-28

    The AXL receptor and its activating ligand, growth arrest–specific 6 (GAS6), are important drivers of metastasis and therapeutic resistance in human cancers. Given the critical roles that GAS6 and AXL play in refractory disease, this signaling axis represents an attractive target for therapeutic intervention. But, the strong picomolar binding affinity between GAS6 and AXL and the promiscuity of small molecule inhibitors represent important challenges faced by current anti-AXL therapeutics. We have addressed these obstacles by engineering a second-generation, high-affinity AXL decoy receptor with an apparent affinity of 93 femtomolar to GAS6. Our decoy receptor, MYD1-72, profoundly inhibited disease progression inmore » aggressive preclinical models of human cancers and induced cell killing in leukemia cells. When directly compared with the most advanced anti-AXL small molecules in the clinic, MYD1-72 achieved superior antitumor efficacy while displaying no toxicity. Furthermore, we uncovered a relationship between AXL and the cellular response to DNA damage whereby abrogation of AXL signaling leads to accumulation of the DNA-damage markers γH2AX, 53BP1, and RAD51. MYD1-72 exploited this relationship, leading to improvements upon the therapeutic index of current standard-of-care chemotherapies in preclinical models of advanced pancreatic and ovarian cancer.« less

  5. Role of AXL expression in non-small cell lung cancer.

    PubMed

    Qu, Xiaohan; Liu, Jinlu; Zhong, Xinwen; Li, Xi; Zhang, Qigang

    2016-12-01

    The present study aimed to investigate the expression profile of AXL in non-small cell lung cancer (NSCLC) and its clinical significance. The current study included 257 NSCLC patients, tyrosine-protein kinase receptor UFO (AXL) expression in paired lung cancer and adjacent normal lung tissues of NSCLC patients were compared by immunohistochemistry, western blot analysis and quantitative polymerase chain reaction (qPCR). These methods were used to detect the expression of the AXL gene and protein in fresh tissues from 35 patients. Small interfering RNA (siRNA) was transfected into the H1299 lung cancer cell line to knock down AXL expression; the effects of AXL-siRNA on cell proliferation and migration were examined by MTT and Transwell migration assay, respectively. It was found that AXL staining density in lung cancer tissues was significantly increased compared with adjacent normal lung tissues (55.25 vs. 26.85%; P<0.01); and the expression level of AXL in NSCLC patients was significantly associated with the degree of tumor differentiation (P<0.01) and the clinical stage of disease (P<0.01). Western blotting and qPCR showed that AXL expression was significantly higher in cancer tissues compared with that in adjacent lung tissue (P<0.05). Additionally, the current study also showed that AXL-siRNA inhibited H1299 cell proliferation and migration in vitro. The present study demonstrates the association between increased expression of AXL in NSCLC and the low differentiation phenotype, and its effects on cell proliferation and migration, suggesting its potential clinical values for the prognosis of NSCLC.

  6. Role of AXL expression in non-small cell lung cancer

    PubMed Central

    Qu, Xiaohan; Liu, Jinlu; Zhong, Xinwen; Li, Xi; Zhang, Qigang

    2016-01-01

    The present study aimed to investigate the expression profile of AXL in non-small cell lung cancer (NSCLC) and its clinical significance. The current study included 257 NSCLC patients, tyrosine-protein kinase receptor UFO (AXL) expression in paired lung cancer and adjacent normal lung tissues of NSCLC patients were compared by immunohistochemistry, western blot analysis and quantitative polymerase chain reaction (qPCR). These methods were used to detect the expression of the AXL gene and protein in fresh tissues from 35 patients. Small interfering RNA (siRNA) was transfected into the H1299 lung cancer cell line to knock down AXL expression; the effects of AXL-siRNA on cell proliferation and migration were examined by MTT and Transwell migration assay, respectively. It was found that AXL staining density in lung cancer tissues was significantly increased compared with adjacent normal lung tissues (55.25 vs. 26.85%; P<0.01); and the expression level of AXL in NSCLC patients was significantly associated with the degree of tumor differentiation (P<0.01) and the clinical stage of disease (P<0.01). Western blotting and qPCR showed that AXL expression was significantly higher in cancer tissues compared with that in adjacent lung tissue (P<0.05). Additionally, the current study also showed that AXL-siRNA inhibited H1299 cell proliferation and migration in vitro. The present study demonstrates the association between increased expression of AXL in NSCLC and the low differentiation phenotype, and its effects on cell proliferation and migration, suggesting its potential clinical values for the prognosis of NSCLC. PMID:28105215

  7. Therapeutic Activity of Anti-AXL Antibody against Triple-Negative Breast Cancer Patient-Derived Xenografts and Metastasis.

    PubMed

    Leconet, Wilhem; Chentouf, Myriam; du Manoir, Stanislas; Chevalier, Clément; Sirvent, Audrey; Aït-Arsa, Imade; Busson, Muriel; Jarlier, Marta; Radosevic-Robin, Nina; Theillet, Charles; Chalbos, Dany; Pasquet, Jean-Max; Pèlegrin, André; Larbouret, Christel; Robert, Bruno

    2016-12-06

    Purpose: AXL receptor tyrosine kinase has been described as a relevant molecular marker and a key player in invasiveness, especially in triple-negative breast cancer (TNBC).Experimental Design: We evaluate the antitumor efficacy of the anti-AXL monoclonal antibody 20G7-D9 in several TNBC cell xenografts or patient-derived xenograft (PDX) models and decipher the underlying mechanisms. In a dataset of 254 basal-like breast cancer samples, genes correlated with AXL expression are enriched in EMT, migration, and invasion signaling pathways.Results: Treatment with 20G7-D9 inhibited tumor growth and bone metastasis formation in AXL-positive TNBC cell xenografts or PDX, but not in AXL-negative PDX, highlighting AXL role in cancer growth and invasion. In vitro stimulation of AXL-positive cancer cells by its ligand GAS6 induced the expression of several EMT-associated genes (SNAIL, SLUG, and VIM) through an intracellular signaling implicating the transcription factor FRA-1, important in cell invasion and plasticity, and increased their migration/invasion capacity. 20G7-D9 induced AXL degradation and inhibited all AXL/GAS6-dependent cell signaling implicated in EMT and in cell migration/invasion.Conclusions: The anti-AXL antibody 20G7-D9 represents a promising therapeutic strategy in TNBC with mesenchymal features by inhibiting AXL-dependent EMT, tumor growth, and metastasis formation. Clin Cancer Res; 1-11. ©2016 AACR.

  8. The receptor tyrosine kinase AXL promotes migration and invasion in colorectal cancer

    PubMed Central

    Uribe, Diana J.; Mandell, Edward K.; Watson, Adam; Martinez, Jesse D.; Leighton, Jonathan A.; Ghosh, Sourav

    2017-01-01

    The receptor tyrosine kinases (RTKs) TYRO3, AXL and MERTK (TAM) have well-described oncogenic functions in a number of cancers. Notwithstanding, TAM RTKs are also potent and indispensable inhibitors of inflammation. The combined deletion of Axl and Mertk in mice enhances chronic inflammation and autoimmunity, including increased inflammation in the gut and colitis-associated cancer. On the other hand, deletion of Tyro3 increases the risk of allergic responses. Therefore, the indiscriminate inhibition of these TAM RTKs could result in undesirable immunological diseases. Here we show that AXL, but not MERTK or TYRO3 expression is enhanced in late stage colorectal cancer (CRC) and AXL expression associates with a cell migration gene signature. Silencing AXL or the inhibition of AXL kinase activity significantly inhibits tumor cell migration and invasion. These results indicate that the selective inhibition of AXL alone might confer sufficient therapeutic benefit in CRC, while preserving at least some of the beneficial, anti-inflammatory effects of MERTK and TYRO3 RTKs. PMID:28727830

  9. Phenotypic screening identifies Axl kinase as a negative regulator of an alveolar epithelial cell phenotype.

    PubMed

    Fujino, Naoya; Kubo, Hiroshi; Maciewicz, Rose A

    2017-09-01

    Loss of epithelial barrier integrity is implicated in a number of human lung diseases. However, the molecular pathways underlying this process are poorly understood. In a phenotypic screen, we identified Axl kinase as a negative regulator of epithelial phenotype and function. Furthermore, suppression of Axl activity by a small molecule kinase inhibitor or downregulation of Axl expression by small interfering RNA led to: (1) the increase in epithelial surfactant protein expression; (2) a cell morphology transition from front-rear polarity to cuboidal shape; (3) the cytoskeletal re-organization resulting in decreased cell mobility; and (4) the acquisition of epithelial junctions. Loss of Axl activity reduced activation of the Axl canonical pathway members, Akt and extracellular signal-regulated kinase-1/2 and resulted in the loss of gene expression of a unique profile of epithelial-to-mesenchymal transition transcription factors including SNAI2, HOXA5, TBX2 or TBX3. Finally, we observed that Axl was activated in hyperplasia of epithelial cells in idiopathic pulmonary fibrosis where epithelial barrier integrity was lost. These results suggest that the Axl kinase signaling pathway is associated with the loss integrity of alveolar epithelium in pathological remodeling of human lung diseases.

  10. Feedback regulation of IFN-α/β signaling by Axl receptor tyrosine kinase modulates HBV immunity.

    PubMed

    Huang, Miao-Tzu; Liu, Wei-Liang; Lu, Chun-Wei; Huang, Jian-Jhih; Chuang, Hsiao-Li; Huang, Yen-Te; Horng, Jau-Haw; Liu, Peng; Han, Dai-Shu; Chiang, Bor-Luen; Shih, Chiaho; Chen, Pei-Jer; Chen, Ding-Shinn

    2015-06-01

    Hepatitis B virus (HBV) is known to cause age-dependent infection outcomes wherein most infections during young age result in chronicity. The mechanism underlying the differential outcome remains elusive. By using hydrodynamic injection of the replication-competent pAAV-HBV, we established a mouse model in which HBV persistence was generated in 4-5 w/o C57BL/6 young mice, but not in adult mice over 10 w/o. HBV-tolerant young mice expressed higher interferon (IFN)-α/β levels in hepatocytes and intrahepatic plasmacytoid DCs (pDCs) than adult mice after pAAV-HBV injection. Excessive IFN-α/β expression in young mice was associated with induction of the Axl regulatory pathway and expansion of intrahepatic Treg cells. In line with these findings, augmented IFN-β expression increased Axl expression in the liver and HBV persistence in adult mice, whereas IFN-α/β signaling blockage decreased Axl expression and HBV persistence in young mice. Accordingly, Axl overexpression decreased HBV clearance of adult mice whereas Axl silencing enhanced HBV clearance of young mice. In vitro, IFN-β priming of pDCs and Axl-overexpressing macrophages enhanced Treg-cell differentiation. These findings suggest that age-dependent HBV chronicity is attributed to IFN-β-Axl immune regulation, which is selectively induced in young mice by excessive IFN-α/β production at early stage of HBV infection.

  11. Split axle drive mechanism for part-time four-wheel drive vehicle

    SciTech Connect

    Onodera, T.

    1986-12-02

    A split axle drive mechanism is described for a part-time four-wheel drive vehicle equipped with a transfer device adapted to change the operating mode of the vehicle drive system to a two wheel drive mode and a four wheel drive mode, comprising: a differential housing; a differential case rotatably mounted within the housing. The differential case is provided thereon with a ring gear for rotation about a first axis and provided therein with pinion gears for rotation about a second axis perpendicular to the first axis and a pair of side gear for rotation about the first axis and in meshing engagement with each of the pinion gears; a first axle shaft disposed along the first axis and connected to one of the side gears for rotation therewith; a second axle shaft disposed along the first axis and axially slidably connected to the other side gear for rotation therewith; a first output member disposed along the first axis to be connected to the first axle shaft and having an outer end adapted for attachment to one split axle part for driving one of a pair of vehicle road wheels; and a second output member disposed along the first axis to be connected to the second axle shaft and having an outer end adapted for attachment to the other split axle part for driving the other road wheel.

  12. Numerical study for a new methodology of flaws detection in train axles.

    PubMed

    Mineo, C; Cerniglia, D; Pantano, A

    2014-03-01

    Train loads and travel speeds have increased over time, requiring more efficient non-destructive inspection methods. Railway axles are critical elements; despite being designed to last more than 20 years several cases of premature failure have been recorded. Train axles are inspected regularly, but the limits associated to the traditional inspection technologies create a growing interest towards new solutions. Here a novel non-destructive inspection method of in-service axles based on non-contact data collection is presented. The propagation of surface waves, generated by a thermo-elastic laser source, is investigated using a finite element method based on dynamic explicit integration. Coupled thermo-mechanical simulations allow visualization of the ultrasonic field guiding the definition of the optimal NDT setup. The geometry of the axle and of the elements mounted on it is accurately reproduced; moreover the press fit effect caused by the wheel and the bearing rings is implemented. The current NDT techniques for railway axles require removing wheels and other components from the axle. The presented scheme uses non-contact ultrasonic generation and detection allowing non-contact in-service inspection of railway axles at trackside station. The numerical results are promising and encourage us to test the new approach experimentally.

  13. Deficiency of AXL in Bone Marrow-Derived Cells Does Not Affect Advanced Atherosclerotic Lesion Progression.

    PubMed

    Subramanian, Manikandan; Proto, Jonathan D; Matsushima, Glenn K; Tabas, Ira

    2016-12-13

    AXL, a member of the TAM (Tyro3, Axl, MerTK) family of receptors, plays important roles in cell survival, clearance of dead cells (efferocytosis), and suppression of inflammation, which are processes that critically influence atherosclerosis progression. Whereas MerTK deficiency promotes defective efferocytosis, inflammation, and plaque necrosis in advanced murine atherosclerosis, the role of Axl in advanced atherosclerosis progression is not known. Towards this end, bone marrow cells from Axl(-/-) or wild-type mice were transplanted into lethally irradiated Ldlr(-/-) mice. These chimeric mice were then fed the Western-type diet (WD) for 17 weeks. We demonstrate that lesional macrophages in WT mice express Axl but that Axl deficiency in bone marrow-derived cells does not affect lesion size, cellularity, necrosis, or inflammatory parameters in advanced atherosclerotic plaques. Moreover, apoptosis of lesional cells was unaffected, and we found no evidence of defective lesional efferocytosis. In contrast to previously reported findings with MerTK deficiency, hematopoietic cell-Axl deficiency in WD-fed Ldlr(-/-) mice does not affect the progression of advanced atherosclerosis or lesional processes associated with TAM receptor signaling. These findings suggest a heretofore unappreciated TAM receptor hierarchy in advanced atherosclerosis.

  14. Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

    PubMed Central

    Bárcena, Cristina; Stefanovic, Milica; Tutusaus, Anna; Joannas, Leonel; Menéndez, Anghara; García-Ruiz, Carmen; Sancho-Bru, Pau; Marí, Montserrat; Caballeria, Joan; Rothlin, Carla V.; Fernández-Checa, José C.; de Frutos, Pablo García; Morales, Albert

    2015-01-01

    Background & Aims Liver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase, and its ligand Gas6 are involved in cell differentiation, immune response and carcinogenesis. Methods HSCs were obtained from wild type and Axl−/− mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated wild type and Axl−/− mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients. Results In primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl KO mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality. Conclusions: The Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management. PMID:25908269

  15. 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

  16. [2]pseudorotaxane formation with N-benzylanilinium axles and 24-crown-8 ether wheels.

    PubMed

    Loeb, Stephen J; Tiburcio, Jorge; Vella, Sarah J

    2005-10-27

    [reaction: see text] As a hybrid of the N,N-dibenzylammonium and 1,2-bis(pyridinium)ethane axles, various N-benzylanilinium cations were investigated as suitable axles for the formation of [2]pseudorotaxanes with the 24-membered crown ethers 24C8 and DB24C8. The effect of electron-donating OCH(3) and electron-withdrawing CF(3) groups on both the anilinium and benzyl aromatic rings was studied. Formation constants and structural details were compared to the [2]pseudorotaxanes formed by the two aforementioned dibenzylammonium and 1,2-bis(pyridinium)ethane axles.

  17. Regulated intramembrane proteolysis of the AXL receptor kinase generates an intracellular domain that localizes in the nucleus of cancer cells.

    PubMed

    Lu, Yinzhong; Wan, Jun; Yang, Zhifeng; Lei, Xiling; Niu, Qi; Jiang, Lanxin; Passtoors, Willemijn M; Zang, Aiping; Fraering, Patrick C; Wu, Fang

    2017-04-01

    Deregulation of the TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases (RTKs) has recently been demonstrated to predominately promote survival and chemoresistance of cancer cells. Intramembrane proteolysis mediated by presenilin/γ-secretase is known to regulate the homeostasis of some RTKs. In the present study, we demonstrate that AXL, but not TYRO3 or MERTK, is efficiently and sequentially cleaved by α- and γ-secretases in various types of cancer cell lines. Proteolytic processing of AXL redirected signaling toward a secretase-mediated pathway, away from the classic, well-known, ligand-dependent canonical RTK signaling pathway. The AXL intracellular domain cleavage product, but not full-length AXL, was further shown to translocate into the nucleus via a nuclear localization sequence that harbored a basic HRRKK motif. Of interest, we found that the γ-secretase-uncleavable AXL mutant caused an elevated chemoresistance in non-small-cell lung cancer cells. Altogether, our findings suggest that AXL can undergo sequential processing mediated by various proteases kept in a homeostatic balance. This newly discovered post-translational processing of AXL may provide an explanation for the diverse functions of AXL, especially in the context of drug resistance in cancer cells.-Lu, Y., Wan, J., Yang, Z., Lei, X., Niu, Q., Jiang, L., Passtoors, W. M., Zang, A., Fraering, P. C., Wu, F. Regulated intramembrane proteolysis of the AXL receptor kinase generates an intracellular domain that localizes in the nucleus of cancer cells. © The Author(s).

  18. The AXL receptor tyrosine kinase is associated with adverse prognosis and distant metastasis in esophageal squamous cell carcinoma

    PubMed Central

    Wong, Li-Fan; Lee, Jang-Ming

    2016-01-01

    Esophageal squamous cell carcinoma (ESCC) is a frequently recurrent deadly cancer for which no efficient targeted drug exists. AXL is an adverse prognostic factor in some cancers. Strong clinical evidence to support the prognostic role of AXL in ESCC is lacking. A total of 116 patients diagnosed with operable primary ESCC were enrolled. Both AXL and HER2 expression were detected by immunohistochemistry (IHC) in esophageal tissue and were correlated with the clinical outcome of patients. The efficacy of the AXL targeted drug foretinib was also evaluated in ESCC cells. Expression of AXL was found in about 80 % of ESCC tissue, and was significantly correlated with progression of tumor (P<0.001), increased risk of death (Hazard ratio HR [95 % CI=2.09[1.09-4.04], P=0.028], and distant metastasis (odds ratio OR [95 %CI]=3.96 (1.16-13.60), P=0.029). The adverse clinical impact of AXL was more evident when cumulatively expressed with HER2. In cell model, ESCC cells were more sensitive to AXL inhibitor foretinib than to the HER2 inhibitor lapatinib. Meanwhile, the AXL inhibitor foretinib showed a synergistic effect with HER2 inhibitors and the potential to overcome drug resistance to lapatinib. We thus concluded that AXL is a strong adverse prognostic factor for ESCC. Therapeutic agents targeting AXL have great potential to improve prognosis of ESCC patients. PMID:27172793

  19. Regulated intramembrane proteolysis of the AXL receptor kinase generates an intracellular domain that localizes in the nucleus of cancer cells

    PubMed Central

    Lu, Yinzhong; Wan, Jun; Yang, Zhifeng; Lei, Xiling; Niu, Qi; Jiang, Lanxin; Passtoors, Willemijn M.; Zang, Aiping; Fraering, Patrick C.; Wu, Fang

    2017-01-01

    Deregulation of the TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases (RTKs) has recently been demonstrated to predominately promote survival and chemoresistance of cancer cells. Intramembrane proteolysis mediated by presenilin/γ-secretase is known to regulate the homeostasis of some RTKs. In the present study, we demonstrate that AXL, but not TYRO3 or MERTK, is efficiently and sequentially cleaved by α- and γ-secretases in various types of cancer cell lines. Proteolytic processing of AXL redirected signaling toward a secretase-mediated pathway, away from the classic, well-known, ligand-dependent canonical RTK signaling pathway. The AXL intracellular domain cleavage product, but not full-length AXL, was further shown to translocate into the nucleus via a nuclear localization sequence that harbored a basic HRRKK motif. Of interest, we found that the γ-secretase–uncleavable AXL mutant caused an elevated chemoresistance in non–small-cell lung cancer cells. Altogether, our findings suggest that AXL can undergo sequential processing mediated by various proteases kept in a homeostatic balance. This newly discovered post-translational processing of AXL may provide an explanation for the diverse functions of AXL, especially in the context of drug resistance in cancer cells.—Lu, Y., Wan, J., Yang, Z., Lei, X., Niu, Q., Jiang, L., Passtoors, W. M., Zang, A., Fraering, P. C., Wu, F. Regulated intramembrane proteolysis of the AXL receptor kinase generates an intracellular domain that localizes in the nucleus of cancer cells. PMID:28034848

  20. 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.

  1. 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.

  2. 49 CFR 230.100 - Defects in tender truck axles and journals.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION STEAM LOCOMOTIVE INSPECTION AND MAINTENANCE STANDARDS Steam Locomotives and Tenders Running Gear § 230.100 Defects in tender truck axles and journals. (a...

  3. 49 CFR 230.100 - Defects in tender truck axles and journals.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... RAILROAD ADMINISTRATION, DEPARTMENT OF TRANSPORTATION STEAM LOCOMOTIVE INSPECTION AND MAINTENANCE STANDARDS Steam Locomotives and Tenders Running Gear § 230.100 Defects in tender truck axles and journals. (a...

  4. 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.

  5. Non-intrusive schemes for speed and axle identification in bridge-weigh-in-motion systems

    NASA Astrophysics Data System (ADS)

    Kalhori, Hamed; Makki Alamdari, Mehrisadat; Zhu, Xinqun; Samali, Bijan; Mustapha, Samir

    2017-02-01

    Bridge weigh-in-motion (BWIM) is an approach through which the axle and gross weight of trucks travelling at normal highway speed are identified using the response of an instrumented bridge. The vehicle speed, the number of axles, and the axle spacing are crucial parameters, and are required to be determined in the majority of BWIM algorithms. Nothing-on-the-road (NOR) strategy suggests using the strain signals measured at some particular positions underneath the deck or girders of a bridge to obtain this information. The objective of this research is to present a concise overview of the challenges of the current non-intrusive schemes for speed and axle determination through bending-strain and shear-strain based approaches. The problem associated with the global bending-strain responses measured at quarter points of span is discussed and a new sensor arrangement is proposed as an alternative. As for measurement of local responses rather than the global responses, the advantage of shear strains over bending strains is presented. However, it is illustrated that shear strains at quarter points of span can only provide accurate speed estimation but fail to detect the correct number of axles. As a remedy, it is demonstrated that, even for closely-spaced axles, the shear strain at the beginning of the bridge is capable of reliably identifying the number of axles. In order to provide a fully automated speed and axle identification system, appropriate signal processing including low-pass filtering and wavelet transforms are applied to the raw time signals. As case studies, the results of experimental testing in laboratory and on a real bridge are presented.

  6. Experimental investigation by laser ultrasonics for high speed train axle diagnostics.

    PubMed

    Cavuto, A; Martarelli, M; Pandarese, G; Revel, G M; Tomasini, E P

    2015-01-01

    The present paper demonstrates the applicability of a laser-ultrasonic procedure to improve the performances of train axle ultrasonic inspection. The method exploits an air-coupled ultrasonic probe that detects the ultrasonic waves generated by a high-power pulsed laser. As a result, the measurement chain is completely non-contact, from generation to detection, this making it possible to considerably speed up inspection time and make the set-up more flexible. The main advantage of the technique developed is that it works in thermo-elastic regime and it therefore can be considered as a non-destructive method. The laser-ultrasonic procedure investigated has been applied for the inspection of a real high speed train axle provided by the Italian railway company (Trenitalia), on which typical fatigue defects have been expressly created according to standard specifications. A dedicated test bench has been developed so as to rotate the axle with the angle control and to speed up the inspection of the axle surface. The laser-ultrasonic procedure proposed can be automated and is potentially suitable for regular inspection of train axles. The main achievements of the activity described in this paper are: – the study of the effective applicability of laser-ultrasonics for the diagnostic of train hollow axles with variable sections by means of a numerical FE model, – the carrying out of an automated experiment on a real train axle, – the analysis of the sensitivity to experimental parameters, like laser source – receiving probe distance and receiving probe angular position, – the demonstration that the technique is suitable for the detection of surface defects purposely created on the train axle.

  7. DEVELOPMENT OF AN ARMY STATIONARY AXLE TEST STAND FOR LUBRICANT EFFICIENCY EVALUATION-PART II

    DTIC Science & Technology

    2017-01-13

    Standard Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 UNCLASSIFIED UNCLASSIFIED v EXECUTIVE SUMMARY The U.S. Army Tank Automotive Research...Maddock, D., “Development of a Standardized Axle Efficiency Test Methodology,” 2nd CTI Symposium, Automotive Transmissions, North America, 2008 7...axle and oil temperature control loop. 4. REFERENCES, STANDARDS , and APPARATUS 4.1. References 4.1.1. SAE Standard J2360, Automotive Gear

  8. AXL.Net: Web-Enabled Case Method Instruction for Accelerating Tacit Knowledge Acquisition in Leaders

    DTIC Science & Technology

    2006-11-01

    King, Salvo Lavis , Scott Rocher USC Institute for Creative Technologies ABSTRACT AXL.Net is a prototype web-based immersive technology...needed to be invented for augmenting existing techniques or creating wholly new ones. Finally, theories about the acquisition of tacit knowledge... attention to the issues that they did not select. AXL.Net provides different points of view through a virtual (though currently non-animated

  9. 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.

  10. Deficiency of AXL in Bone Marrow-Derived Cells Does Not Affect Advanced Atherosclerotic Lesion Progression

    PubMed Central

    Subramanian, Manikandan; Proto, Jonathan D.; Matsushima, Glenn K.; Tabas, Ira

    2016-01-01

    AXL, a member of the TAM (Tyro3, Axl, MerTK) family of receptors, plays important roles in cell survival, clearance of dead cells (efferocytosis), and suppression of inflammation, which are processes that critically influence atherosclerosis progression. Whereas MerTK deficiency promotes defective efferocytosis, inflammation, and plaque necrosis in advanced murine atherosclerosis, the role of Axl in advanced atherosclerosis progression is not known. Towards this end, bone marrow cells from Axl−/− or wild-type mice were transplanted into lethally irradiated Ldlr−/− mice. These chimeric mice were then fed the Western-type diet (WD) for 17 weeks. We demonstrate that lesional macrophages in WT mice express Axl but that Axl deficiency in bone marrow-derived cells does not affect lesion size, cellularity, necrosis, or inflammatory parameters in advanced atherosclerotic plaques. Moreover, apoptosis of lesional cells was unaffected, and we found no evidence of defective lesional efferocytosis. In contrast to previously reported findings with MerTK deficiency, hematopoietic cell-Axl deficiency in WD-fed Ldlr−/− mice does not affect the progression of advanced atherosclerosis or lesional processes associated with TAM receptor signaling. These findings suggest a heretofore unappreciated TAM receptor hierarchy in advanced atherosclerosis. PMID:27958361

  11. Novel wavelet threshold denoising method in axle press-fit zone ultrasonic detection

    NASA Astrophysics Data System (ADS)

    Peng, Chaoyong; Gao, Xiaorong; Peng, Jianping; Wang, Ai

    2017-02-01

    Axles are important part of railway locomotives and vehicles. Periodic ultrasonic inspection of axles can effectively detect and monitor axle fatigue cracks. However, in the axle press-fit zone, the complex interface contact condition reduces the signal-noise ratio (SNR). Therefore, the probability of false positives and false negatives increases. In this work, a novel wavelet threshold function is created to remove noise and suppress press-fit interface echoes in axle ultrasonic defect detection. The novel wavelet threshold function with two variables is designed to ensure the precision of optimum searching process. Based on the positive correlation between the correlation coefficient and SNR and with the experiment phenomenon that the defect and the press-fit interface echo have different axle-circumferential correlation characteristics, a discrete optimum searching process for two undetermined variables in novel wavelet threshold function is conducted. The performance of the proposed method is assessed by comparing it with traditional threshold methods using real data. The statistic results of the amplitude and the peak SNR of defect echoes show that the proposed wavelet threshold denoising method not only maintains the amplitude of defect echoes but also has a higher peak SNR.

  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. 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’.

  14. Identification of Axl as a downstream effector of TGF-β1 during Langerhans cell differentiation and epidermal homeostasis

    PubMed Central

    Bauer, Thomas; Zagórska, Anna; Jurkin, Jennifer; Yasmin, Nighat; Köffel, René; Richter, Susanne; Gesslbauer, Bernhard; Lemke, Greg

    2012-01-01

    Transforming growth factor-β1 (TGF-β1) is a fundamental regulator of immune cell development and function. In this study, we investigated the effects of TGF-β1 on the differentiation of human Langerhans cells (LCs) and identified Axl as a key TGF-β1 effector. Axl belongs to the TAM (Tyro3, Axl, and Mer) receptor tyrosine kinase family, whose members function as inhibitors of innate inflammatory responses in dendritic cells and are essential to the prevention of lupus-like autoimmunity. We found that Axl expression is induced by TGF-β1 during LC differentiation and that LC precursors acquire Axl early during differentiation. We also describe prominent steady-state expression as well as inflammation-induced activation of Axl in human epidermal keratinocytes and LCs. TGF-β1–induced Axl enhances apoptotic cell (AC) uptake and blocks proinflammatory cytokine production. The antiinflammatory role of Axl in the skin is reflected in a marked impairment of the LC network preceding spontaneous skin inflammation in mutant mice that lack all three TAM receptors. Our findings highlight the importance of constitutive Axl expression to tolerogenic barrier immunity in the epidermis and define a mechanism by which TGF-β1 enables silent homeostatic clearing of ACs to maintain long-term self-tolerance. PMID:23071254

  15. Dynamic axle and wheel loads identification: laboratory studies

    NASA Astrophysics Data System (ADS)

    Zhu, X. Q.; Law, S. S.

    2003-12-01

    Two methods have been reported by Zhu and Law to identify moving loads on the top of a bridge deck. One is based on the exact solution (ESM) and the other is based on the finite element formulation (FEM). Simulation studies on the effect of different influencing factors have been reported previously. This paper comparatively studies the performances of these two methods with experimental measurements obtained from a bridge/vehicle system in the laboratory. The strains of the bridge deck are measured when a model car moves across the bridge deck along different paths. The moving loads on the bridge deck are identified from the measured strains using these two methods, and the responses are reconstructed from the identified loads for comparison with the measured responses to verify the performances of these methods. Studies on the identification accuracy due to the effect of the number of vibration mode used, the number of measuring points and eccentricities of travelling paths are performed. Results show that the ESM could identify the moving loads individually or as axle loads when they are travelling at an eccentricity with the sensors located close to the travelling path of the forces. And the accuracy of the FEM is dependent on the amount of measured information used in the identification.

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

    PubMed Central

    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

    2016-01-01

    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

  17. Low MITF/AXL ratio predicts early resistance to multiple targeted drugs in melanoma

    PubMed Central

    Müller, Judith; Krijgsman, Oscar; Tsoi, Jennifer; Robert, Lidia; Hugo, Willy; Song, Chunying; Kong, Xiangju; Possik, Patricia A.; Cornelissen-Steijger, Paulien D.M.; Foppen, Marnix H. Geukes; Kemper, Kristel; Goding, Colin R.; McDermott, Ultan; Blank, Christian; Haanen, John; Graeber, Thomas G.; Ribas, Antoni; Lo, Roger S.; Peeper, Daniel S.

    2015-01-01

    Increased expression of the Microphthalmia-associated transcription factor (MITF) contributes to melanoma progression and resistance to BRAF pathway inhibition. Here we show that the lack of MITF is associated with more severe resistance to a range of inhibitors, while its presence is required for robust drug responses. Both in primary and acquired resistance, MITF levels inversely correlate with the expression of several activated receptor tyrosine kinases, most frequently AXL. The MITF-low/AXL-high/drug-resistance phenotype is common among mutant BRAF and NRAS melanoma cell lines. The dichotomous behaviour of MITF in drug response is corroborated in vemurafenib-resistant biopsies, including MITF-high and -low clones in a relapsed patient. Furthermore, drug cocktails containing AXL inhibitor enhance melanoma cell elimination by BRAF or ERK inhibition. Our results demonstrate that a low MITF/AXL ratio predicts early resistance to multiple targeted drugs, and warrant clinical validation of AXL inhibitors to combat resistance of BRAF and NRAS mutant MITF-low melanomas. PMID:25502142

  18. AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses

    PubMed Central

    Richard, Audrey Stéphanie; Shim, Byoung-Shik; Kwon, Young-Chan; Zhang, Rong; Otsuka, Yuka; Schmitt, Kimberly; Berri, Fatma; Diamond, Michael S.; Choe, Hyeryun

    2017-01-01

    Although a causal relationship between Zika virus (ZIKV) and microcephaly has been established, it remains unclear why ZIKV, but not other pathogenic flaviviruses, causes congenital defects. Here we show that when viruses are produced in mammalian cells, ZIKV, but not the closely related dengue virus (DENV) or West Nile virus (WNV), can efficiently infect key placental barrier cells that directly contact the fetal bloodstream. We show that AXL, a receptor tyrosine kinase, is the primary ZIKV entry cofactor on human umbilical vein endothelial cells (HUVECs), and that ZIKV uses AXL with much greater efficiency than does DENV or WNV. Consistent with this observation, only ZIKV, but not WNV or DENV, bound the AXL ligand Gas6. In comparison, when DENV and WNV were produced in insect cells, they also infected HUVECs in an AXL-dependent manner. Our data suggest that ZIKV, when produced from mammalian cells, infects fetal endothelial cells much more efficiently than other pathogenic flaviviruses because it binds Gas6 more avidly, which in turn facilitates its interaction with AXL. PMID:28167751

  19. AXL-dependent infection of human fetal endothelial cells distinguishes Zika virus from other pathogenic flaviviruses.

    PubMed

    Richard, Audrey Stéphanie; Shim, Byoung-Shik; Kwon, Young-Chan; Zhang, Rong; Otsuka, Yuka; Schmitt, Kimberly; Berri, Fatma; Diamond, Michael S; Choe, Hyeryun

    2017-02-21

    Although a causal relationship between Zika virus (ZIKV) and microcephaly has been established, it remains unclear why ZIKV, but not other pathogenic flaviviruses, causes congenital defects. Here we show that when viruses are produced in mammalian cells, ZIKV, but not the closely related dengue virus (DENV) or West Nile virus (WNV), can efficiently infect key placental barrier cells that directly contact the fetal bloodstream. We show that AXL, a receptor tyrosine kinase, is the primary ZIKV entry cofactor on human umbilical vein endothelial cells (HUVECs), and that ZIKV uses AXL with much greater efficiency than does DENV or WNV. Consistent with this observation, only ZIKV, but not WNV or DENV, bound the AXL ligand Gas6. In comparison, when DENV and WNV were produced in insect cells, they also infected HUVECs in an AXL-dependent manner. Our data suggest that ZIKV, when produced from mammalian cells, infects fetal endothelial cells much more efficiently than other pathogenic flaviviruses because it binds Gas6 more avidly, which in turn facilitates its interaction with AXL.

  20. 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.

  1. Taurine restores Axl/Gas6 expression in vascular smooth muscle cell calcification model.

    PubMed

    Liao, Xiao-Bo; Peng, Yi-Qun; Zhou, Xin-Min; Yang, Bing; Zheng, Zhe; Liu, Li-Ming; Song, Feng-Lin; Li, Jian-Ming; Zhou, Kang; Meng, Ji-Cai; Yuan, Ling-Qing; Xie, Hui

    2010-07-01

    Our previous studies demonstrated that taurine inhibits osteoblastic differentiation of vascular smooth muscular cells (VSMCs) via the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, but the underlying mechanism is not elucidated. The tyrosine kinase receptor Axl and its ligand growth arrest-specific protein 6 (Gas6) are expressed in VSMCs. Axl/Gas6 signaling system is known to inhibit VSMCs calcification. We herein showed that taurine partially restored Axl and Gas6 expression in beta-glycerophosphate (beta-GP)-induced VSMC calcification model. Taurine also induced activation of ERK, but not other two MAPKs including c-jun N-terminal Kinase (JNK) and p38 in VSMCs. Either knockdown of the taurine transporter (TAUT) or treatment with the ERK-specific inhibitor PD98059 blocked the activation of ERK by taurine and abolished taurine-induced Axl/Gas6 expression and calcium deposition reduction in beta-GP-induced VSMC calcification model. These results demonstrate for the first time that taurine stimulates expression of Axl and Gas6 via TAUT/ERK signaling pathway in beta-GP-induced VSMC calcification model.

  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

    ..., but walks alongside it to use a wired or wireless remote control to steer the rear axle; sometimes the... relevance to the remote-control operation of a steerable rear axle on an oversized CMV. Therefore, FMCSA... maintained, equipped, loaded, and operated safely; (2) the responsibilities imposed on operators of CMVs do...

  3. 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

    2016-05-04

    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.

  4. Axl promotes the proliferation, invasion and migration of Wilms’ tumor and can be used as a prognostic factor

    PubMed Central

    Zhu, Shibo; Liu, Guochang; Fu, Wen; Hu, Jinhua; Fu, Kai; Jia, Wei

    2017-01-01

    Purpose Overexpression of Axl has been reported in many tumors, where it promotes tumorigenesis and progression, as well as correlates with the prognosis of different malignancies. However, Axl expression and its function have rarely been reported in Wilms’ tumor (WT). This study aimed to reveal the clinical significance of Axl expression in patients with WT and determine its mechanisms. Materials and methods We analyzed the expression of Axl and its correlations with various clinicopathological features in 72 WT tissues and 72 adjacent non-cancerous tissues by immunohistochemistry. Cox proportional hazards regression models were used to investigate the correlations between Axl expression and the prognosis of WT patients. Fresh frozen samples from 20 WT patients were examined using Western blotting (WB) and real-time quantitative polymerase chain reaction (RT-qPCR). In WT cell line, after Axl knockdown by sh-Axl and growth arrest-specific 6 (Gas6) stimulation, the cell proliferation, migration and invasion abilities were detected by methyl-thiazolyl-tetrazolium (MTT), clone-forming, wound-healing and transwell assays. Meanwhile, the tumor-forming ability was tested on nude mice xenograft models. Finally, the expression of several proteins in signal pathways was quantified by WB assays. Results Compared with the adjacent non-cancerous tissues, the expression of Axl was significantly higher in WT tissues (P<0.05). High expression of Axl was associated with tumor recurrence or lung metastasis of WT patients and was a prognostic factor for WT patients (P<0.05). In vitro assays, the proliferation, migration and invasion of WT cells decreased with Axl knockdown and significantly increased with Axl activation by Gas6 (P<0.05). In vivo assays, the ability of tumorigenicity in WT cells reduced dramatically after Axl knockout (P<0.05). Moreover, PI3K–Akt pathway proteins decreased with Axl knockdown. Conclusion Our results suggest that Axl is highly expressed in WT and

  5. Axl signaling induces development of natural killer cells in vitro and in vivo.

    PubMed

    Kim, Eun-Mi; Lee, Eun-Hee; Lee, Hwa-Yeon; Choi, Ha-Rim; Ji, Kon-Young; Kim, Su-Man; Kim, Kwang Dong; Kang, Hyung-Sik

    2017-03-01

    Natural killer (NK) cells have been well known to play a critical role in innate immunity, but they are also capable of regulating adaptive immunity through the induction of T cell-mediated memory response and B cell-mediated autoimmune response. NK cells are differentiated from hematopoietic stem cells (HSCs) in the bone marrow (BM), and a series of surface molecules are expressed on NK cells in a differentiation stage-specific manner. Axl receptor tyrosine kinase is originally identified as homeostatic regulators for antigen-presenting cells, and its ligand, growth-arrest-specific gene 6 (Gas6), has been reported to promote cell survival, proliferation, and migration, but their regulatory role in the development and effector function of NK cells is not yet fully understood. In this study, to investigate whether Axl is required for the regulation of NK cell development, the expression of mature NK (mNK) cell-specific receptors and NK cell-associated genes was analyzed in the differentiated HSCs-derived NK cells in vitro and the NK cells harvested from Axl(-/-) mice. We found that agonistic anti-Axl antibody or recombinant Gas6 specifically upregulated the expression of mNK cell-specific receptors, such as LY49A, Ly49G2, Ly49C/F/I, NKG2A/C/E (1.5- to 3.5-fold increase), and NK cell-associated genes, such as IL-2Rβ (2.3- or 2.4-fold increase), Perforin (4.1- or 2.1-fold increase), IL-15Rα (2.14- or 2.04-fold increase), and IFN-γ (3.3- or 2.8-fold increase) compared to each isotype control, whereas it was abrogated by treatment of Axl-Ig. Anti-Axl antibody or rGas6 also induced a 2.5- or 1.9-fold increase in the proliferation of developing NK cells compared to each control, respectively. mNK cell populations expressing mNK cell-specific receptors were reduced about twofold in NK cells differentiated from HSCs of Axl(-/-) mice compared with those of wild-type mice. Furthermore, the triggering of Axl signaling by agonistic anti-Axl antibody promoted the

  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. Axl is required for TGF-β2-induced dormancy of prostate cancer cells in the bone marrow

    PubMed Central

    Yumoto, Kenji; Eber, Matthew R.; Wang, Jingcheng; Cackowski, Frank C.; Decker, Ann M.; Lee, Eunsohl; Nobre, Ana Rita; Aguirre-Ghiso, Julio A.; Jung, Younghun; Taichman, Russell S.

    2016-01-01

    Disseminated prostate cancer (PCa) cells in the marrow survive for years without evidence of proliferation, while maintaining the capacity to develop into metastatic lesions. These dormant disseminated tumor cells (DTCs) may reside in close proximity to osteoblasts, while expressing high levels of Axl, one of the tyrosine kinase receptors for growth arrest specific 6 (Gas6). Yet how Axl regulates DTC proliferation in marrow remains undefined. Here, we explored the impact of the loss of Axl in PCa cells (PC3 and DU145) on the induction of their dormancy when they are co-cultured with a pre-osteoblastic cell line, MC3T3-E1. MC3T3-E1 cells dramatically decrease the proliferation of PCa cells, however this suppressive effect of osteoblasts is significantly reduced by the reduction of Axl expression in PCa cells. Interestingly, expression of both TGF-β and its receptors were regulated by Axl expression in PCa cells, while specific blockade of TGF-β signaling limited the ability of the osteoblasts to induce dormancy of PCa cells. Finally, we found that both Gas6 and Axl are required for TGF-β2-mediated cell growth suppression. Taken together, these data suggest that a loop between the Gas6/Axl axis and TGF-β2 signaling plays a significant role in the induction of PCa cell dormancy. PMID:27819283

  8. 75 FR 76036 - American Axle & Manufacturing Detroit Manufacturing Complex Holbrook Avenue and Saint Aubin...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-12-07

    ... Avenue and Saint Aubin Including On-Site Leased Workers From Paint Tech International Detroit, MI... from Paint Tech International were employed on-site at the Detroit, Michigan location of American Axle..., the Department is amending this certification to include workers leased from Paint Tech...

  9. 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…

  10. Influence of axle-wheel interface on ultrasonic testing of fatigue cracks in wheelset.

    PubMed

    Makino, Kazunari; Biwa, Shiro

    2013-01-01

    For the ultrasonic testing at the wheel seat of railway axles, quantitative investigation of the reflection and transmission phenomena at the axle-wheel interface is important. This paper describes the influence of the axle-wheel interface on the ultrasonic testing of a fatigue crack in a wheelset by applying the spring interface model. The normal and tangential stiffnesses were identified experimentally for an as-manufactured wheelset at the normal incidence, and the reflection coefficient for the shear-wave oblique incidence was calculated. A parametric study was performed to clarify the influence of these interfacial stiffnesses on the incident-angle dependence of the reflection coefficient. The calculated reflection coefficient at the incident angle of 45° qualitatively explained the relative echo-height decrease due to the presence of a wheel observed experimentally for a wheelset in fatigue loading by rotating bending. The quantitative difference between the experimental and calculated results was considered to be due to the reduction of the effective interference of shrink fit by the wear at the axle-wheel interface during the fatigue loading as well as by the applied bending moment. For the estimated relative echo-height decrease to agree with the experimental results, the interfacial stiffnesses were found to be smaller than the values identified for the as-manufactured wheelset by a factor of 0.5-0.7. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. 49 CFR 230.98 - Driving, trailing, and engine truck axles.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 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) Condemning... more in diameter below the original/new diameter. (b) Journal diameter stamped. For steam locomotives...

  12. 49 CFR 230.98 - Driving, trailing, and engine truck axles.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 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) Condemning... more in diameter below the original/new diameter. (b) Journal diameter stamped. For steam locomotives...

  13. AXL-Mediated Productive Infection of Human Endothelial Cells by Zika Virus.

    PubMed

    Liu, Shufeng; DeLalio, Leon J; Isakson, Brant E; Wang, Tony T

    2016-11-11

    The mosquito-borne Zika virus (ZIKV) is now recognized as a blood-borne pathogen, raising an important question about how the virus gets into human bloodstream. The imminent threat of the ZIKV epidemic to the global blood supply also demands novel therapeutics to stop virus transmission though transfusion. We intend to characterize ZIKV tropism for human endothelial cells (ECs) and provide potential targets for intervention. We conducted immunostaining, plaque assay, and quantitative reverse transcription-polymerase chain reaction of ZIKV RNA to evaluate the possible infection of ECs by ZIKV. Both the African and the South American ZIKV strains readily infect human umbilical vein endothelial cells and human ECs derived from aortic and coronary artery, as well as the saphenous vein. Infected ECs released infectious progeny virus. Compared with the African strains, South American ZIKV isolates replicate faster in ECs and are partially cytopathic, suggesting enhanced virulence of these isolates. Flow cytometric analyses showed that the susceptibility of ECs positively correlated with the cell surface levels of tyrosine-protein kinase receptor UFO (AXL) receptor tyrosine kinase. Gain- and loss-of-function studies further revealed that AXL is required for ZIKV entry at a postbinding step. Finally, small-molecule inhibitors of the AXL kinase significantly reduced ZIKA infection of ECs. We identified EC as a key cell type for ZIKV infection. These data support the view of hematogenous dissemination of ZIKV and implicate AXL as a new target for antiviral therapy. © 2016 American Heart Association, Inc.

  14. Plasma concentrations of Gas6 and sAxl correlate with disease activity in systemic lupus erythematosus

    PubMed Central

    Ekman, Carl; Jönsen, Andreas; Sturfelt, Gunnar; Bengtsson, Anders A.

    2011-01-01

    Objectives. SLE is a systemic autoimmune disease with an annual incidence of 3.8 per 100 000. Several pathogenic mechanisms are believed to be operating in SLE, including an impaired clearance of apoptotic cells, activation of the type I IFN pathway and generation of autoimmune leucocytes. Growth arrest-specific protein 6 (Gas6) and its receptor Axl are known to regulate inflammation and may be implicated in lupus pathogenesis. We have recently developed immunological methods to quantify the vitamin-K-dependent protein Gas6 and its soluble receptor sAxl in human plasma, which we have used to investigate the role of Gas6 and soluble Axl in SLE. Methods. We have investigated the relation between the plasma concentrations of Gas6 and sAxl and disease activity and specific symptoms in 96 SLE patients. Results. Gas6 and sAxl concentrations correlated with SLEDAI (r = 0.48, P < 0.001 and r = 0.39, P < 0.001, respectively). Furthermore, concentrations of Gas6 and sAxl correlated with ESR and CRP and inversely with haemoglobin levels. Gas6 and sAxl concentrations were significantly higher in patients with anti-DNA antibodies, leucopenia and GN. Conclusion. The plasma concentrations of Gas6 and sAxl vary with disease activity in SLE, in particular GN, and may have a role in lupus pathogenesis. Furthermore, Gas6 and sAxl may be of use as biomarkers of disease activity. PMID:21278074

  15. 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

  16. 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

    ... production of automotive axles a substantial portion of which are shipped to an affiliated plant where they are used in the assembly of automotive vehicles. New information shows that workers leased...

  17. n-Butylidenephthalide Regulated Tumor Stem Cell Genes EZH2/AXL and Reduced Its Migration and Invasion in Glioblastoma

    PubMed Central

    Yen, Ssu-Yin; Chuang, Hong-Meng; Huang, Mao-Hsuan; Lin, Shinn-Zong; Chiou, Tzyy-Wen; Harn, Horng-Jyh

    2017-01-01

    Glioblastoma (GBM) is one of the most common and aggressive types of brain tumor. Due to its highly recurrent rate and poor prognosis, the overall survival time with this type of tumor is only 20–21 months. Recent knowledge suggests that its recurrence is in part due to the presence of cancer stem cells (CSCs), which display radioresistant, chemoresistant, self-renewal and tumorigenic potential. Enhancers of Zeste 2 (EZH2) and AXL receptor tyrosine kinase (AXL) are both highly expressed in GBM. Additionally, they are an essential regulator involved in CSCs maintenance, migration, invasion, epithelial-to-mesenchymal transition (EMT), stemness, metastasis and patient survival. In this study, we used a small molecule, n-butylidenephthalide (BP), to assess the anti-GBM stem-like cells potential, and then tried to find out the associated genes involved with regulation in migration and invasion. We demonstrated that BP reduced the expression of AXL and stemness related genes in a dose-dependent manner. The migratory and invasive capabilities of GBM stem-like cells could be reduced by AXL/EZH2. Finally, in the overexpression of AXL, EZH2 and Sox2 by transfection in GBM stem-like cells, we found that AXL/EZH2/TGF-β1, but not Sox2, might be a key regulator in tumor invasion, migration and EMT. These results might help in the development of a new anticancer compound and can be a target for treating GBM. PMID:28208648

  18. Threading of an Inherently Directional Calixarene Wheel with Oriented Ammonium Axles.

    PubMed

    La Manna, Pellegrino; Talotta, Carmen; Gaeta, Carmine; Soriente, Annunziata; De Rosa, Margherita; Neri, Placido

    2017-09-01

    The threading of monostoppered alkylbenzylammonium axles 7(+) and 8(+) with the calix[6]-wheel 3 can occur by both routes of entering the macrocycle 3 in the cone conformation: passage through the upper rim and the through the lower rim. Thus, under thermodynamic conditions, with both the axles 7(+) and 8(+), the two possible orientations of calix[2]pseudorotaxane, namely, endo-benzyl and endo-alkyl, are formed by a stereoselectivity controlled by the endo-alkyl rule. Interestingly, by (1)H NMR monitoring of the threading process between 8(+) and 3, we revealed two calix[2]pseudorotaxane isomers in which the calix-wheel adopts 1,2,3-alternate and cone conformations, which represent the kinetic and thermodynamic species, respectively. Finally, the synthesis of ammonium-based oriented calix[2]rotaxane is here described.

  19. Factors affecting the threading of axle molecules through macrocycles: Binding constants for semirotaxane formation

    PubMed Central

    Clifford, Thomas; Abushamleh, Ahmad; Busch, Daryle H.

    2002-01-01

    The threading of more or less linear axle molecules through macrocyclic molecules, a fundamental process relating to the formation of interlocked molecular structures, has been investigated through the study in acetone of the equilibrium constants for the formation of pseudorotaxanes by NMR methods. The 30 new axle molecules have in common a secondary ammonium group, present as the thiocyanate salt, and an anthracen-9-ylmethyl group, but are rendered unique by the second amine substituent. All rotaxanes involve the well known polyether macrocycle, benzo[24]crown-8. The constants for the binding of axles having linear groups ranging from 2 to 18 carbon atoms show little variation in binding constant but are divided into two groups by their equilibration rates. Those with less than five methylene groups react rapidly on the NMR timescale, whereas those having more than five methylene groups are slow. Branching inhibits binding, but the effect decreases as the branch is moved away from the amine. Phenyl groups weaken binding when close to the amine but strengthen binding when more remote. Some functional groups decrease pseudorotaxane stability (alcohol functions), whereas others increase binding (carboxylic acid groups). PMID:11959934

  20. 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

  1. 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).

  2. In brain, Axl recruits Grb2 and the p85 regulatory subunit of Pl3 kinase; in vitro mutagenesis defines th requisite binding sites for downstream Akt activation

    PubMed Central

    Weinger, Jason G.; Gohari, Pouyan; Yan, Ying; Backer, Jonathan M.; Varnum, Brian; Shafit-Zagardo, Bridget

    2010-01-01

    Axl is a receptor tyrosine kinase implicated in cell survival following growth factor withdrawal and other stressors. The binding of Axl's ligand, growth arrest-specific protein 6 (Gas6), results in Axl autophosphorylation, recruitment of signaling molecules, and activation of downstream survival pathways. Pull-down assays and immunoprecipitations using wildtype and mutant Axl transfected cells determined that Axl directly binds growth factor receptor-bound protein 2 (Grb2) at pYVN and the p85 subunit of phosphatidylinositol-3 kinase (PI3 kinase) at two pYXXM sites (pY779 and pY821). Also, p85 can indirectly bind to Axl via an interaction between p85's second proline-rich region and the N-terminal SH3 domain of Grb2. Further, Grb2 and p85 can compete for binding at the pY821VNM site. Gas6-stimulation of Axl-transfected COS7 cells recruited activated PI3 kinase and phosphorylated Akt. An interaction between Axl, p85 and Grb2 was confirmed in brain homogenates, enriched populations of O4+ oligodendrocytes, and O4– flow-through prepared from day 10 mouse brain, indicating that cells with active Gas6/Axl signal through Grb2 and the PI3 kinase/Akt pathways. PMID:18346204

  3. 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

  4. The GAS6-AXL signaling network is a mesenchymal (Mes) molecular subtype-specific therapeutic target for ovarian cancer.

    PubMed

    Antony, Jane; Tan, Tuan Zea; Kelly, Zoe; Low, Jeffrey; Choolani, Mahesh; Recchi, Chiara; Gabra, Hani; Thiery, Jean Paul; Huang, Ruby Yun-Ju

    2016-10-04

    Ovarian cancer is a complex disease with heterogeneity among the gene expression molecular subtypes (GEMS) between patients. Patients with tumors of a mesenchymal ("Mes") subtype have a poorer prognosis than patients with tumors of an epithelial ("Epi") subtype. We evaluated GEMS of ovarian cancer patients for molecular signaling profiles and assessed how the differences in these profiles could be leveraged to improve patient clinical outcome. Kinome enrichment analysis identified AXL as a particularly abundant kinase in Mes-subtype tumor tissue and cell lines. In Mes cells, upon activation by its ligand GAS6, AXL coclustered with and transactivated the receptor tyrosine kinases (RTKs) cMET, EGFR, and HER2, producing sustained extracellular signal-regulated kinase (ERK) activation. In Epi-A cells, AXL was less abundant and induced a transient activation of ERK without evidence of RTK transactivation. AXL-RTK crosstalk also stimulated sustained activation of the transcription factor FRA1, which correlated with the induction of the epithelial-mesenchymal transition (EMT)-associated transcription factor SLUG and stimulation of motility exclusively in Mes-subtype cells. The AXL inhibitor R428 attenuated RTK and ERK activation and reduced cell motility in Mes cells in culture and reduced tumor growth in a chick chorioallantoic membrane model. A higher concentration of R428 was needed to inhibit ERK activation and cell motility in Epi-A cells. Silencing AXL in Mes-subtype cells reversed the mesenchymal phenotype in culture and abolished tumor formation in an orthotopic xenograft mouse model. Thus, AXL-targeted therapy may improve clinical outcome for patients with Mes-subtype ovarian cancer. Copyright © 2016, American Association for the Advancement of Science.

  5. Mer or Axl receptor tyrosine kinase inhibition promotes apoptosis, blocks growth and enhances chemosensitivity of human non-small cell lung cancer.

    PubMed

    Linger, R M A; Cohen, R A; Cummings, C T; Sather, S; Migdall-Wilson, J; Middleton, D H G; Lu, X; Barón, A E; Franklin, W A; Merrick, D T; Jedlicka, P; DeRyckere, D; Heasley, L E; Graham, D K

    2013-07-18

    Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon and pancreatic cancers combined. Current research suggests that standard chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway-involving AKT, CREB, Bcl-xL, survivin, and Bcl-2-downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that short hairpin RNA (shRNA) knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl have complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl.

  6. Mer or Axl Receptor Tyrosine Kinase Inhibition Promotes Apoptosis, Blocks Growth, and Enhances Chemosensitivity of Human Non-Small Cell Lung Cancer

    PubMed Central

    Linger, Rachel M.A.; Cohen, Rebecca A.; Cummings, Christopher T.; Sather, Susan; Migdall-Wilson, Justine; Middleton, Deryck H.G.; Lu, Xian; Barón, Anna E.; Franklin, Wilbur A.; Merrick, Daniel T.; Jedlicka, Paul; DeRyckere, Deborah; Heasley, Lynn E.; Graham, Douglas K.

    2012-01-01

    Non-small cell lung cancer (NSCLC) is a prevalent and devastating disease that claims more lives than breast, prostate, colon, and pancreatic cancers combined. Current research suggests that standard chemotherapy regimens have been optimized to maximal efficiency. Promising new treatment strategies involve novel agents targeting molecular aberrations present in subsets of NSCLC. We evaluated 88 human NSCLC tumors of diverse histology and identified Mer and Axl as receptor tyrosine kinases (RTKs) overexpressed in 69% and 93%, respectively, of tumors relative to surrounding normal lung tissue. Mer and Axl were also frequently overexpressed and activated in NSCLC cell lines. Ligand-dependent Mer or Axl activation stimulated MAPK, AKT, and FAK signaling pathways indicating roles for these RTKs in multiple oncogenic processes. In addition, we identified a novel pro-survival pathway—involving AKT, CREB, Bcl-xL, survivin, and Bcl-2—downstream of Mer, which is differentially modulated by Axl signaling. We demonstrated that shRNA knockdown of Mer or Axl significantly reduced NSCLC colony formation and growth of subcutaneous xenografts in nude mice. Mer or Axl knockdown also improved in vitro NSCLC sensitivity to chemotherapeutic agents by promoting apoptosis. When comparing the effects of Mer and Axl knockdown, Mer inhibition exhibited more complete blockade of tumor growth while Axl knockdown more robustly improved chemosensitivity. These results indicate that Mer and Axl play complementary and overlapping roles in NSCLC and suggest that treatment strategies targeting both RTKs may be more effective than singly-targeted agents. Our findings validate Mer and Axl as potential therapeutic targets in NSCLC and provide justification for development of novel therapeutic compounds that selectively inhibit Mer and/or Axl. PMID:22890323

  7. 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

  8. 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.

  9. Product Design and Production Practice of 700MPa High Strength Hot Rolled Strip for Auto Axle Tube

    NASA Astrophysics Data System (ADS)

    Hui, Pan; Zhao-dong, Wang; Ya-jun, Hui; Yang, Cui; Xiang-tao, Deng; Chun-lin, Bao

    According to the technical specifications of 700MPa high strength automotive axle tube steel, a low cost of 0.07%C+1.5%Mn+0.05%Nb+0.10%Ti was designed. The high strength mainly relies on grain refinement strengthening and precipitation strengthening. The recrystallization, precipitation, and CCT curves of the 700MPa grade axle tube steel were studied in order to determine a reasonable TMCP process. By controlling the low level segregation band, low level of C and N content, 700MPa grade high strength automotive axle tube steel is successfully developed with excellent mechanical property, welding property, flattening and flaring property, torsion fatigue property, static torsional property and surface quality.

  10. Role of AXL in invasion and drug resistance of colon and breast cancer cells and its association with p53 alterations.

    PubMed

    Abdel-Rahman, Wael M; Al-Khayyal, Noura A; Nair, Vidhya A; Aravind, S R; Saber-Ayad, Maha

    2017-05-21

    To characterize AXL receptor tyrosine kinase (AXL) expression in relationship to tumor protein P53 (TP53 gene, p53 protein) and its role in tumor invasion and response to therapy. We used 14 cell lines, including 3 isogenic pairs carrying mutant/knockout p53, to gain insight into the relationship between AXL and TP53. These included HCT116, HCT116.p53 mutant, RKO, and RKO.p53(-/-) lines (all from colon cancers) as well as breast cancer cell lines MCF7 and 1001 (MCF7-p53 mutant clone). HeLa cell line was used as a positive control for epithelial to mesenchymal transition (EMT). AXL expression was determined by Western blotting using rabbit monoclonal antibody clone C89E7. AXL siRNA silencing was performed and followed by collagen invasion assay. Cell viability analysis using the sulforhodamine B assay and the invasion assay were performed after exposure to chemotherapeutic agents (doxorubicin for breast cancer cells; 5FU or irinotecan for colon cancer cells). We showed that the introduction of p53 mutations or knockout increased expression levels of AXL in isogenic cells compared to the matching p53 wild-type parental cells. Overall, we found a trend for correlation between the potential EMT candidate AXL, p53 alterations, and EMT markers in colorectal and breast cancers. The expression of AXL in RKO cells, a rare colon cancer cell line with inactive Wnt signaling, suggests that the AXL oncogene might provide an alternative genetic pathway for colorectal carcinogenesis in the absence of Wnt signaling activation and TP53 mutation. AXL silencing in the TP53 mutant isogenic cell lines 1001, HCT116.p53 mutant and RKO.P53(-/-) was > 95% efficient and the silenced cells were less invasive compared to the parental TP53 wild-type cells. AXL silencing showed a subtle trend to restore colon cancer cell sensitivity to 5FU or irinotecan. Importantly, AXL expressing cells developed more invasive potential after exposure to chemotherapy compared to the AXL-silenced cells. AXL is

  11. Kinome-wide shRNA screen identifies the receptor tyrosine kinase AXL as a key regulator for mesenchymal glioblastoma stem-like cells.

    PubMed

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

    2015-05-12

    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.

  12. The TRAIL Receptor Agonist Drozitumab Targets Basal B Triple Negative Breast Cancer Cells that Express Vimentin and Axl

    PubMed Central

    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

    Purpose Previously, we found that GST-tagged tumor necrosis factor-related apoptosis inducing ligand (TRAIL) 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. Methods 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. Results and Conclusions 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

  13. Axl-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells

    PubMed Central

    Vouri, M; Croucher, D R; Kennedy, S P; An, Q; Pilkington, G J; Hafizi, S

    2016-01-01

    Acquired resistance to conventional and targeted therapies is becoming a major hindrance in cancer management. It is increasingly clear that cancer cells are able to evolve and rewire canonical signalling pathways to their advantage, thus evading cell death and promoting cell invasion. The Axl receptor tyrosine kinase (RTK) has been shown to modulate acquired resistance to EGFR-targeted therapies in both breast and lung cancers. Glioblastoma multiforme (GBM) is a highly infiltrative and invasive form of brain tumour with little response to therapy. Both Axl and EGFR have been identified as major players in gliomagenesis and invasiveness. However, the mechanisms underlying a potential signalling crosstalk between EGFR and Axl RTKs are unknown. The purpose of this study was to investigate this novel and unconventional interaction among RTKs of different families in human GBM cells. With the use of western blotting, in vitro kinase activity, co-immunoprecipitation and bimolecular fluorescence complementation assays, we show that EGF stimulates activation of Axl kinase and that there is a hetero-interaction between the two RTKs. Through small interfering RNA knockdown and quantitative PCR screening, we identified distinct gene expression patterns in GBM cells that were specifically regulated by signalling from EGFR-EGFR, Axl–Axl and EGFR-Axl RTK parings. These included genes that promote invasion, which were activated only via the EGFR-Axl axis (MMP9), while EGFR-EGFR distinctly regulated the cell cycle and Axl–Axl regulated invasion. Our findings provide critical insights into the role of EGFR-Axl hetero-dimerisation in cancer cells and reveal regulation of cell invasion via Axl as a novel function of EGFR signalling. PMID:27775700

  14. 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.

  15. 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. ©2016 American Association for Cancer Research.

  16. 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

  17. Halotriazolium axle functionalised [2]rotaxanes for anion recognition: investigating the effects of halogen-bond donor and preorganisation.

    PubMed

    Mercurio, James M; Knighton, Richard C; Cookson, James; Beer, Paul D

    2014-09-08

    The anion-templated synthesis of three novel halogen-bonding 5-halo-1,2,3-triazolium axle containing [2]rotaxanes is described, and the effects of altering the nature of the halogen-bond donor atom together with the degree of inter-component preorganisation on the anion-recognition properties of the interlocked host investigated. The ability of the bromotriazolium motif to direct the halide-anion-templated assembly of interpenetrated [2]pseudorotaxanes was studied initially; bromide was found to be the most effective template. As a consequence, bromide anion templation was used to synthesise the first bromotriazolium axle containing [2]rotaxane, the anion-binding properties of which, determined by (1) H NMR spectroscopic titration experiments, revealed enhanced bromide and iodide recognition relative to a hydrogen-bonding protic triazolium rotaxane analogue. Two halogen-bonding [2]rotaxanes with bromo- and iodotriazolium motifs integrated into shortened axles designed to increase inter-component preorganisation were also synthesised. Anion (1) H NMR spectroscopic titration experiments demonstrated that these rotaxanes were able to bind halide anions even more strongly, with the iodotriazolium axle integrated rotaxane capable of recognising halides in aqueous solvent media. Importantly, these observations suggest that a halogen-bonding interlocked host binding domain, in combination with increased inter-component preorganisation, are requisite design features for a potent anion receptor.

  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. Phyllodes tumor of the breast: role of Axl and ST6GalNAcII in the development of mammary phyllodes tumors.

    PubMed

    Ren, Dongliang; Li, Yanyan; Gong, Yanxin; Xu, Jingchao; Miao, Xiaolong; Li, Xiangnan; Liu, Chen; Jia, Li; Zhao, Yongfu

    2014-10-01

    Phyllodes tumor exhibits an aggressive growth. The expression of many biological markers has been explored to discriminate between different grades of phyllodes tumor and to predict their behavior. The purpose of this study was to evaluate the implications of Axl and ST6GalNAcII in phyllodes tumors. Real-time PCR, Western blot, and immunohistochemical were used to analyze differential expression of ST6GalNAcII and Axl in phyllodes tumor (PT) cell lines and tissue specimens. RNAi assay, ECM invasion assay, and tumorigenicity assay were used to analyze the altered expression of ST6GalNAcII gene effects on the expression of Axl and invasive ability of phyllodes tumor cells in vitro and in vivo. Compared to benign tumors, borderline and malignant ones showed a remarkable increase in mRNA levels of Axl and ST6GalNAcII gene, and it was higher in malignant tumor cells than in borderline tumor cells. When ST6GalNAcII was silenced, compared to the control, the expression level of Axl was significantly reduced in malignant tumor cell transfectants and knockdown of ST6GalNAcII gene significantly inhibited invasive activity in malignant tumor cells. The high expression of ST6GalNAcII and Axl was significantly correlated with tumor grade and distance metastasis by immunohistochemical analysis. Axl and ST6GalNAcII expression increases with increasing tumor grade in mammary phyllodes tumors. ST6GalNAc II might be participated in the glycosylation of Axl, and this Axl glycosylation may mediate the tumorigenicity, invasion, and distant metastasis of PT cells.

  20. 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.

  1. 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

    2016-09-05

    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. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. 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.

  3. 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

  4. Effects of extracellular acid stimulation on rat vascular smooth muscle cell in Gas6/Axl or PI3K/Akt signaling pathway.

    PubMed

    Cui, Liwen; Bai, Yaling; Zhang, Junxia; Zhang, Shenglei; Xu, Jinsheng

    Recent studies have indicated that extracellular acid stimulation inhibited the calcification of vascular smooth muscle cells (VSMCs). Cell apoptosis played an important role in the occurrence and development of vascular calcification. We further explored the effects of Gas6/Axl or PI3K/Akt signaling pathway on the inhibition of rat VSMCs calcification in response to extracellular acid stimulation. Our study demonstrated that a high concentration of phosphorus induced apoptosis and calcification of VSMCs, decreased expression of Axl, and reduced phosphorylation of Akt. Stimulation of extracellular acid counteracted the effects as above by increasing the expression of Axl and Akt phosphorylation and decreasing the expression of activated Caspase3, which thereby decreased cell apoptosis and calcification. Moreover, the effects can be attenuated by PI3K inhibitor. Our study proved that extracellular acid stimulation played a vital role in the inhibition of rat VSMCs calcification and apoptosis in Gas6/Axl or PI3K/Akt signaling pathway.

  5. Research of 600C Grade Welding V-N Micro-Alloyed Steel Used on Truck Axle Housing After Thermal Forming

    NASA Astrophysics Data System (ADS)

    Quanli, Wang; Hui, Pan; Qingmei, Liu

    Automobile axle housing is the basic element to install the main reducing gear, differential mechanism, semi-axis, wheel hub and suspension. The main function of automobile axle housing is to support the automobile quality with driven axle, fix the driving wheel relative axial position and bear the driving wheel transmission force during the automobile running. Axle housing steel with the thickness of not less than 12mm is produced by the thermal forming method, which is to heat the plate to 830 degree and hold some time, then thermal forming, and cool to room temperature. The steel plate should maintain the original strength and good ductility and toughness requirements with thermal forming process.

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

    PubMed

    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

    2016-04-28

    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

  7. 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

  8. Suppression of the metastatic spread of breast cancer by DN10764 (AZD7762)-mediated inhibition of AXL signaling

    PubMed Central

    Kim, Dayea; Son, Jung Beom; Ko, Eunhwa; Cho, Joong-Heui; Kim, Nam-Doo; Nan, Hong-Yan; Kim, Choong-Yong; Yoon, Sukkyoon; Lee, Sun-Hwa; Choi, Hwan Geun

    2016-01-01

    Breast cancer is the most common malignant disease occurring in women and represents a substantial proportion of the global cancer burden. In these patients, metastasis but not the primary tumor is the main cause of breast cancer-related deaths. Here, we report the novel finding that DN10764 (AZD7762, a selective inhibitor of checkpoint kinases 1 and 2) can suppress breast cancer metastasis. In breast cancer cells, DN10764 inhibited cell proliferation and GAS6-mediated AXL signaling, consequently resulting in suppressed migration and invasion. In addition, DN10764 induced caspase 3/7-mediated apoptosis in breast cancer cells and inhibited tube formation of human umbilical vein endothelial cells. Finally, DN10764 significantly suppressed the tumor growth and metastasis of breast cancer cells in in vivo metastasis models. Taken together, these data suggest that therapeutic strategies targeting AXL in combination with systemic therapies could improve responses to anti-cancer therapies and reduce breast cancer recurrence and metastases. PMID:27829217

  9. 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.

  10. The comparative analysis of different computations methods of strength of materials by the example of calculations of the axle beam

    NASA Astrophysics Data System (ADS)

    Evtushenko, S. I.; Petrov, I. A.; Shutova, M. N.; Alekseeva, A. S.

    2017-02-01

    The paper presents data of calculation the main characteristics of resilience by different ways. The basic data for the article were the calculation of the guiding axle beam of the vehicle. The calculation was performed by the analytic method and it was necessary to re-check strength of materials by any other method for reliability of the carried-out work. The finite element method was chosen as the competing option.

  11. 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.

  12. 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

  13. 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.

  14. AP-2α regulates migration of GN-11 neurons via a specific genetic programme involving the Axl receptor tyrosine kinase

    PubMed Central

    Orso, Francesca; Jäger, Richard; Calogero, Raffaele Adolfo; Schorle, Hubert; Sismondi, Piero; De Bortoli, Michele; Taverna, Daniela

    2009-01-01

    Background Neuronal migration is a crucial process that allows neurons to reach their correct target location to allow the nervous system to function properly. AP-2α is a transcription factor essential for neural crest cell migration and its mutation results in apoptosis within this cell population, as demonstrated by genetic models. Results We down-modulated AP-2α expression in GN-11 neurons by RNA interference and observe reduced neuron migration following the activation of a specific genetic programme including the Adhesion Related Kinase (Axl) gene. We prove that Axl is able to coordinate migration per se and by ChIP and promoter analysis we observe that its transcription is directly driven by AP-2α via the binding to one or more functional AP-2α binding sites present in its regulatory region. Analysis of migration in AP-2α null mouse embryo fibroblasts also reveals an essential role for AP-2α in cell movement via the activation of a distinct genetic programme. Conclusion We show that AP-2α plays an essential role in cell movement via the activation of cell-specific genetic programmes. Moreover, we demonstrate that the AP-2α regulated gene Axl is an essential player in GN-11 neuron migration. PMID:19463168

  15. 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

  16. Wheel/rail contact geometry assessment to limit rolling contact fatigue initiation at high axle loads

    NASA Astrophysics Data System (ADS)

    Fröhling, Robert; Spangenberg, Ulrich; Hettasch, Georg

    2012-01-01

    Rolling contact fatigue on any railway system has a significant impact on the safety and efficiency of the operation. This is especially true for heavy haul railways where higher axle loads and demands for higher throughput have, over the years, challenged the limits within the wheel/rail interface. The objective of this paper is to present a methodology to manage this stress state using a detailed wheel/rail contact stress analysis. Based on the results of recent wheel profile and rail profile surveys, a kinematic wheel/rail contact analysis is performed to identify and eliminate profiles that cause high stresses. The results show that the current hollow wear criterion is effective, but that an alternative or additional criterion based on the gauge side false flange gradient or the calculated peak contact stress values can further reduce the stress state. Within the wheel and rail profile combinations investigated, the contact stresses were largely independent of the transverse profile of the high rail.

  17. A TNF-JNK-Axl-ERK signaling axis mediates primary resistance to EGFR inhibition in glioblastoma.

    PubMed

    Guo, Gao; Gong, Ke; Ali, Sonia; Ali, Neha; Shallwani, Shahzad; Hatanpaa, Kimmo J; Pan, Edward; Mickey, Bruce; Burma, Sandeep; Wang, David H; Kesari, Santosh; Sarkaria, Jann N; Zhao, Dawen; Habib, Amyn A

    2017-08-01

    Aberrant epidermal growth factor receptor (EGFR) signaling is widespread in cancer, making the EGFR an important target for therapy. EGFR gene amplification and mutation are common in glioblastoma (GBM), but EGFR inhibition has not been effective in treating this tumor. Here we propose that primary resistance to EGFR inhibition in glioma cells results from a rapid compensatory response to EGFR inhibition that mediates cell survival. We show that in glioma cells expressing either EGFR wild type or the mutant EGFRvIII, EGFR inhibition triggers a rapid adaptive response driven by increased tumor necrosis factor (TNF) secretion, which leads to activation in turn of c-Jun N-terminal kinase (JNK), the Axl receptor tyrosine kinase and extracellular signal-regulated kinases (ERK). Inhibition of this adaptive axis at multiple nodes rendered glioma cells with primary resistance sensitive to EGFR inhibition. Our findings provide a possible explanation for the failures of anti-EGFR therapy in GBM and suggest a new approach to the treatment of EGFR-expressing GBM using a combination of EGFR and TNF inhibition.

  18. Analysis and optimization of an innovative fatigue tests profile for three axle semi-trailers

    NASA Astrophysics Data System (ADS)

    Malon, H.; Tello, L.; Martin, C.

    2011-10-01

    Nowadays, a fundamental aspect in the design of any type of vehicle, in particular of semi-trailers, is the development and testing of prototypes that confirm the correct performance of the vehicles before their launch into the market. At present, fatigue tests exist for different structural components from large machines to small components in vehicles, but up to now, there is no knowledge about fatigue tests of complete vehicles of large dimensions, with the exception of the fatigue tests of semi-trailers that are carried out by the company LECITRAILER S.A., under the supervision of the Transportation Engineering Area of the University of Zaragoza, in particular the research group VEHIVIAL. The aim of this paper is to decribe the process developed for the analysis and optimization of an initial profile of fatigue testing for semitrailer. The result of this optimization process is an innovative profile of fatigue testing for three axle semi-trailers developed by the University of Zaragoza in collaboration with the company LECITRAILER S.A., which is applied to the process of optimization of all the prototypes made by the company.

  19. Thermal Property Analysis of Axle Load Sensors for Weighing Vehicles in Weigh-in-Motion System

    PubMed Central

    Burnos, Piotr; Gajda, Janusz

    2016-01-01

    Systems which permit the weighing of vehicles in motion are called dynamic Weigh-in-Motion scales. In such systems, axle load sensors are embedded in the pavement. Among the influencing factors that negatively affect weighing accuracy is the pavement temperature. This paper presents a detailed analysis of this phenomenon and describes the properties of polymer, quartz and bending plate load sensors. The studies were conducted in two ways: at roadside Weigh-in-Motion sites and at a laboratory using a climate chamber. For accuracy assessment of roadside systems, the reference vehicle method was used. The pavement temperature influence on the weighing error was experimentally investigated as well as a non-uniform temperature distribution along and across the Weigh-in-Motion site. Tests carried out in the climatic chamber allowed the influence of temperature on the sensor intrinsic error to be determined. The results presented clearly show that all kinds of sensors are temperature sensitive. This is a new finding, as up to now the quartz and bending plate sensors were considered insensitive to this factor. PMID:27983704

  20. 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.

  1. Thermal Property Analysis of Axle Load Sensors for Weighing Vehicles in Weigh-in-Motion System.

    PubMed

    Burnos, Piotr; Gajda, Janusz

    2016-12-15

    Systems which permit the weighing of vehicles in motion are called dynamic Weigh-in-Motion scales. In such systems, axle load sensors are embedded in the pavement. Among the influencing factors that negatively affect weighing accuracy is the pavement temperature. This paper presents a detailed analysis of this phenomenon and describes the properties of polymer, quartz and bending plate load sensors. The studies were conducted in two ways: at roadside Weigh-in-Motion sites and at a laboratory using a climate chamber. For accuracy assessment of roadside systems, the reference vehicle method was used. The pavement temperature influence on the weighing error was experimentally investigated as well as a non-uniform temperature distribution along and across the Weigh-in-Motion site. Tests carried out in the climatic chamber allowed the influence of temperature on the sensor intrinsic error to be determined. The results presented clearly show that all kinds of sensors are temperature sensitive. This is a new finding, as up to now the quartz and bending plate sensors were considered insensitive to this factor.

  2. 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.

  3. S49076 is a novel kinase inhibitor of MET, AXL, and FGFR with strong preclinical activity alone and in association with bevacizumab.

    PubMed

    Burbridge, Mike F; Bossard, Céline J; Saunier, Carine; Fejes, Imre; Bruno, Alain; Léonce, Stéphane; Ferry, Gilles; Da Violante, Georges; Bouzom, François; Cattan, Valérie; Jacquet-Bescond, Anne; Comoglio, Paolo M; Lockhart, Brian P; Boutin, Jean A; Cordi, Alex; Ortuno, Jean-Claude; Pierré, Alain; Hickman, John A; Cruzalegui, Francisco H; Depil, Stéphane

    2013-09-01

    Aberrant activity of the receptor tyrosine kinases MET, AXL, and FGFR1/2/3 has been associated with tumor progression in a wide variety of human malignancies, notably in instances of primary or acquired resistance to existing or emerging anticancer therapies. This study describes the preclinical characterization of S49076, a novel, potent inhibitor of MET, AXL/MER, and FGFR1/2/3. S49076 potently blocked cellular phosphorylation of MET, AXL, and FGFRs and inhibited downstream signaling in vitro and in vivo. In cell models, S49076 inhibited the proliferation of MET- and FGFR2-dependent gastric cancer cells, blocked MET-driven migration of lung carcinoma cells, and inhibited colony formation of hepatocarcinoma cells expressing FGFR1/2 and AXL. In tumor xenograft models, a good pharmacokinetic/pharmacodynamic relationship for MET and FGFR2 inhibition following oral administration of S49076 was established and correlated well with impact on tumor growth. MET, AXL, and the FGFRs have all been implicated in resistance to VEGF/VEGFR inhibitors such as bevacizumab. Accordingly, combination of S49076 with bevacizumab in colon carcinoma xenograft models led to near total inhibition of tumor growth. Moreover, S49076 alone caused tumor growth arrest in bevacizumab-resistant tumors. On the basis of these preclinical studies showing a favorable and novel pharmacologic profile of S49076, a phase I study is currently underway in patients with advanced solid tumors. Mol Cancer Ther; 12(9); 1749-62. ©2013 AACR.

  4. Development and characterization of K562 cell clones expressing BCL11A-XL: Decreased hemoglobin production with fetal hemoglobin inducers and its rescue with mithramycin

    PubMed Central

    Finotti, Alessia; Gasparello, Jessica; Breveglieri, Giulia; Cosenza, Lucia Carmela; Montagner, Giulia; Bresciani, Alberto; Altamura, Sergio; Bianchi, Nicoletta; Martini, Elisa; Gallerani, Eleonora; Borgatti, Monica; Gambari, Roberto

    2015-01-01

    Induction of fetal hemoglobin (HbF) is considered a promising strategy in the treatment of β-thalassemia, in which production of adult hemoglobin (HbA) is impaired by mutations affecting the β-globin gene. Recent results indicate that B-cell lymphoma/leukemia 11A (BCL11A) is a major repressor of γ-globin gene expression. Therefore, disrupting the binding of the BCL11A transcriptional repressor complex to the γ-globin gene promoter provides a novel approach for inducing expression of the γ-globin genes. To develop a cellular screening system for the identification of BCL11A inhibitors, we produced K562 cell clones with integrated copies of a BCL11A-XL expressing vector. We characterized 12 K562 clones expressing different levels of BCL11A-XL and found that a clear inverse relationship does exist between the levels of BCL11A-XL and the extent of hemoglobinization induced by a panel of HbF inducers. Using mithramycin as an inducer, we found that this molecule was the only HbF inducer efficient in rescuing the ability to differentiate along the erythroid program, even in K562 cell clones expressing high levels of BCL11A-XL, suggesting that BCL11A-XL activity is counteracted by mithramycin. PMID:26342260

  5. Differential expression of the ufo/axl oncogene in human leukemia-lymphoma cell lines.

    PubMed

    Challier, C; Uphoff, C C; Janssen, J W; Drexler, H G

    1996-05-01

    The ufo protein (also termed axl) is a member of a new family of receptor tyrosine kinases and is encoded by a transforming gene that was initially isolated from primary human myeloid leukemia cells by DNA-mediated transformation of NIH/3T3 cells. The ligand, Gas6, a protein S-related molecule lacking any known function yet, has recently been identified. We report the expression pattern of ufo mRNA in a panel of 76 human continuous leukemia-lymphoma cell lines. The gene was not expressed in cell lines derived from lymphoid malignancies (n=28), but transcription was seen in 3/11 myeloid, 0/6 monocytic, 9/13 erythroid and 11/18 megakaryocytic cell lines. Several cell lines were treated with phorbol ester leading to significant upregulation of the ufo message in constitutively positive cells. An apparent ufo mRNA overexpression was not found in any of the positive leukemia cell lines, but was identified in the drug-resistant subclones of the cervix carcinoma cell line HeLa. Southern blot analysis of restriction enzyme-digested genomic DNA did not provide evidence for gene amplification, but the HeLa subclones showed banding patterns suggestive of gene rearrangement. Two main ufo mRNA bands of 3.2 and 5.0 kb were identified; no differences in the half-lives (t1/2 = 2.5 h) of these two mRNA species could be identified. In summary, ufo, representing a novel type of receptor tyrosine kinase, is expressed solely in myeloid and erythro-megakaryocytic leukemias but not in lymphoid malignancies. These and previous data suggest an involvement of the ufo receptor tyrosine kinase in normal and malignant myelopoiesis; however, its exact role, if any, and mode of operation in leukemogenesis remains to be determined.

  6. 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.

  7. Therapeutic efficacy of Tyro3, Axl, and Mer tyrosine kinase agonists in collagen-induced arthritis.

    PubMed

    van den Brand, B T; Abdollahi-Roodsaz, S; Vermeij, E A; Bennink, M B; Arntz, O J; Rothlin, C V; van den Berg, W B; van de Loo, F A J

    2013-03-01

    Hyperactivation of innate immunity by Toll-like receptors (TLRs) can contribute to the development of autoinflammatory or autoimmune diseases. This study evaluated the activation of Tyro3, Axl, Mer (TAM) receptors, physiologic negative regulators of TLRs, by their agonists, growth arrest-specific protein 6 (GAS-6) and protein S, in the prevention of collagen-induced arthritis (CIA). Adenoviruses overexpressing GAS-6 and protein S were injected intravenously or intraarticularly into mice during CIA. Splenic T helper cell subsets from intravenously injected mice were studied by flow cytometry, and the knee joints of mice injected intravenously and intraarticularly were assessed histologically. Synovium from mice injected intraarticularly was evaluated for cytokine and suppressor of cytokine signaling (SOCS) expression. Protein S significantly reduced ankle joint swelling when overexpressed systemically. Further analysis of knee joints revealed a moderate reduction in pathologic changes in the joint and a significant reduction in the number of splenic Th1 cells when protein S was overexpressed systemically. Local overexpression of GAS-6 decreased joint inflammation and joint pathology. Protein S treatment showed a similar trend of protection. Consistently, GAS-6 and protein S reduced cytokine production in the synovium. Moreover, levels of messenger RNA for interleukin-12 (IL-12) and IL-23 were reduced by GAS-6 and protein S treatment, with a corresponding decrease in the production of interferon-γ and IL-17. TAM ligand overexpression was associated with an increase in SOCS-3 levels, which likely contributed to the amelioration of arthritis. This study provides the first evidence that TAM receptor stimulation by GAS-6 and protein S can be used to ameliorate arthritis when applied systemically or locally. TAM receptor stimulation limits proinflammatory signaling and adaptive immunity. This pathway provides a novel strategy by which to combat rheumatoid arthritis

  8. Gilteritinib, a FLT3/AXL inhibitor, shows antileukemic activity in mouse models of FLT3 mutated acute myeloid leukemia.

    PubMed

    Mori, Masamichi; Kaneko, Naoki; Ueno, Yoko; Yamada, Masaki; Tanaka, Ruriko; Saito, Rika; Shimada, Itsuro; Mori, Kenichi; Kuromitsu, Sadao

    2017-05-17

    Advances in the understanding of the molecular basis for acute myeloid leukemia (AML) have generated new potential targets for treatment. Fms-like tyrosine kinase 3 (FLT3) is one of the most frequently mutated genes in AML and mutations in this gene are associated with poor overall survival. AXL plays a role in the activation of FLT3 and has been implicated in the pathogenesis of AML. The studies reported here evaluated the ability of a novel FLT3/AXL inhibitor, gilteritinib, to block mutated FLT3 in cellular and animal models of AML. Initial kinase studies showed that gilteritinib, a type I tyrosine kinase inhibitor, was highly selective for both FLT3 and AXL while having weak activity against c-KIT. Gilteritinib demonstrated potent inhibitory activity against the internal tandem duplication (FLT3-ITD) and FLT3-D835Y point mutations in cellular assays using MV4-11 and MOLM-13 cells as well as Ba/F3 cells expressing mutated FLT3. Gilteritinib also inhibited FLT3-F691 mutations, although to a lesser degree, in these assays. Furthermore, gilteritinib decreased the phosphorylation levels of FLT3 and its downstream targets in both cellular and animal models. In vivo, gilteritinib was distributed at high levels in xenografted tumors after oral administration. The decreased FLT3 activity and high intratumor distribution of gilteritinib translated to tumor regression and improved survival in xenograft and intra-bone marrow transplantation models of FLT3-driven AML. No overt toxicity was seen in mouse models treated with gilteritinib. These results indicate that gilteritinib may be an important next-generation FLT3 inhibitor for use in the treatment of FLT3 mutation-positive AML.

  9. 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

  10. 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).

  11. Vehicle design influences whole body vibration exposures: effect of the location of the front axle relative to the cab.

    PubMed

    Blood, Ryan P; Rynell, Patrik W; Johnson, Peter W

    2011-06-01

    Using a repeated measure design, this study compared differences in whole body vibration (WBV) exposures among 13 drivers who drove a truck with the cab over the front axle (cab-over design) and a truck with the cab situated behind the front axle (non-cab-over design). The drivers drove both trucks over a standardized route that comprised three distinct segments: a freeway segment, a city street segment with stop-and-go driving (traffic lights), and a city street segment without traffic lights. A portable WBV data acquisition system collected tri-axial time-weighted and raw WBV data per ISO 2631-1 and 2631-5 standards. Simultaneous global positioning system (GPS) data were also collected to compare vehicle speeds. The GPS data indicated that there were no speed differences between the two vehicles. However, average and impulsive z-axis vibration levels were significantly higher for the cab-over design than for the non-cab-over design. In addition, significant WBV exposure differences between road types were found, with the freeway segments having the lowest exposures and the city street segments without traffic lights having the highest exposures. Vehicle type and the associated WBV exposures should be considered when purchasing vehicles to be used by full-time professional vehicle operators.

  12. Substituent effects on axle binding in amide pseudorotaxanes: comparison of NMR titration and ITC data with DFT calculations.

    PubMed

    Kaufmann, Lena; Dzyuba, Egor V; Malberg, Friedrich; Löw, Nora L; Groschke, Matthias; Brusilowskij, Boris; Huuskonen, Juhani; Rissanen, Kari; Kirchner, Barbara; Schalley, Christoph A

    2012-08-14

    The binding behaviour of differently substituted diamide axle molecules to Hunter/Vögtle tetralactam macrocycles was studied with a combination of NMR titration, isothermal titration calorimetry (ITC) experiments and calculations employing density functional theory (DFT), along with dispersion-corrected exchange-correlation functionals. Guests with alkyl or alkenyl chains attached to the diamide carbonyl groups have a significantly higher binding affinity to the macrocycle than guests with benzoyl amides and their substituted analogues. While the binding of the benzoyl and alkenyl substituted axles is enthalpically driven, the alkyl-substituted guest binds mainly because of a positive binding entropy. The electronic effects of para-substituents at the benzoyl moieties have an influence on the binding affinities. Electron donating substituents increase, while electron-withdrawing substituents decrease the binding energies. The binding affinities obtained from both NMR titration and ITC experiments correlate well with each other. The substituent effects observed in the experimental data are reflected in adiabatic interaction energies calculated with density functional methods. The calculated structures also agree well with pseudorotaxane crystal structures.

  13. Growth Arrest-Specific 6 Enhances the Suppressive Function of CD4+CD25+ Regulatory T Cells Mainly through Axl Receptor

    PubMed Central

    Zhao, Guang-ju; Zheng, Jia-yi; Bian, Jia-lan; Chen, Long-wang; Dong, Ning; Yu, Yan; Hong, Guang-liang; Chandoo, Arvine

    2017-01-01

    Background. Growth arrest-specific (Gas) 6 is one of the endogenous ligands of TAM receptors (Tyro3, Axl, and Mertk), and its role as an immune modulator has been recently emphasized. Naturally occurring CD4+CD25+ regulatory T cells (Tregs) are essential for the active suppression of autoimmunity. The present study was designed to investigate whether Tregs express TAM receptors and the potential role of Gas6-TAM signal in regulating the suppressive function of Tregs. Methods. The protein and mRNA levels of TAM receptors were determined by using Western blot, immunofluorescence, flow cytometry, and RT-PCR. Then, TAM receptors were silenced using targeted siRNA or blocked with specific antibody. The suppressive function of Tregs was assessed by using a CFSE-based T cell proliferation assay. Flow cytometry was used to determine the expression of Foxp3 and CTLA4 whereas cytokines secretion levels were measured by ELISA assay. Results. Tregs express both Axl and Mertk receptors. Gas6 increases the suppressive function of Tregs in vitro and in mice. Both Foxp3 and CTLA-4 expression on Tregs are enhanced after Gas6 stimulation. Gas6 enhances the suppressive activity of Tregs mainly through Axl receptor. Conclusion. Gas6 has a direct effect on the functions of CD4+CD25+Tregs mainly through its interaction with Axl receptor. PMID:28270700

  14. O-Glycosylation of Axl2/Bud10p by Pmt4p Is Required for Its Stability, Localization, and Function in Daughter Cells

    PubMed Central

    Sanders, Sylvia L.; Gentzsch, Martina; Tanner, Widmar; Herskowitz, Ira

    1999-01-01

    Cells of the yeast Saccharomyces cerevisiae choose bud sites in a manner that is dependent upon cell type: a and α cells select axial sites; a/α cells utilize bipolar sites. Mutants specifically defective in axial budding were isolated from an α strain using pseudohyphal growth as an assay. We found that a and α mutants defective in the previously identified PMT4 gene exhibit unipolar, rather than axial budding: mother cells choose axial bud sites, but daughter cells do not. PMT4 encodes a protein mannosyl transferase (pmt) required for O-linked glycosylation of some secretory and cell surface proteins (Immervoll, T., M. Gentzsch, and W. Tanner. 1995. Yeast. 11:1345–1351). We demonstrate that Axl2/Bud10p, which is required for the axial budding pattern, is an O-linked glycoprotein and is incompletely glycosylated, unstable, and mislocalized in cells lacking PMT4. Overexpression of AXL2 can partially restore proper bud-site selection to pmt4 mutants. These data indicate that Axl2/Bud10p is glycosylated by Pmt4p and that O-linked glycosylation increases Axl2/ Bud10p activity in daughter cells, apparently by enhancing its stability and promoting its localization to the plasma membrane. PMID:10366591

  15. Neither helix in the coiled coil region of the axle of F1-ATPase plays a significant role in torque production.

    PubMed

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

    2008-11-15

    F(1)-ATPase is an ATP-driven rotary molecular motor in which the central gamma-subunit rotates inside the cylinder made of alpha(3)beta(3) subunits. The amino and carboxy termini of the gamma-subunit form the axle, an alpha-helical coiled coil that deeply penetrates the stator cylinder. We previously truncated the axle step by step, starting with the longer carboxy terminus and then cutting both termini at the same levels, resulting in a slower yet considerably powerful rotation. Here we examine the role of each helix by truncating only the carboxy terminus by 25-40 amino-acid residues. Longer truncation impaired the stability of the motor complex severely: 40 deletions failed to yield rotating the complex. Up to 36 deletions, however, the mutants produced an apparent torque at nearly half of the wild-type torque, independent of truncation length. Time-averaged rotary speeds were low because of load-dependent stumbling at 120 degrees intervals, even with saturating ATP. Comparison with our previous work indicates that half the normal torque is produced at the orifice of the stator. The very tip of the carboxy terminus adds the other half, whereas neither helix in the middle of the axle contributes much to torque generation and the rapid progress of catalysis. None of the residues of the entire axle played a specific decisive role in rotation.

  16. Neither Helix in the Coiled Coil Region of the Axle of F1-ATPase Plays a Significant Role in Torque Production

    PubMed Central

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

    2008-01-01

    F1-ATPase is an ATP-driven rotary molecular motor in which the central γ-subunit rotates inside the cylinder made of α3β3 subunits. The amino and carboxy termini of the γ-subunit form the axle, an α-helical coiled coil that deeply penetrates the stator cylinder. We previously truncated the axle step by step, starting with the longer carboxy terminus and then cutting both termini at the same levels, resulting in a slower yet considerably powerful rotation. Here we examine the role of each helix by truncating only the carboxy terminus by 25–40 amino-acid residues. Longer truncation impaired the stability of the motor complex severely: 40 deletions failed to yield rotating the complex. Up to 36 deletions, however, the mutants produced an apparent torque at nearly half of the wild-type torque, independent of truncation length. Time-averaged rotary speeds were low because of load-dependent stumbling at 120° intervals, even with saturating ATP. Comparison with our previous work indicates that half the normal torque is produced at the orifice of the stator. The very tip of the carboxy terminus adds the other half, whereas neither helix in the middle of the axle contributes much to torque generation and the rapid progress of catalysis. None of the residues of the entire axle played a specific decisive role in rotation. PMID:18708468

  17. How can rotaxanes be modified by varying functional groups at the axle?--a combined theoretical and experimental analysis of thermochemistry and electronic effects.

    PubMed

    Spickermann, Christian; Felder, Thorsten; Schalley, Christoph A; Kirchner, Barbara

    2008-01-01

    We present theoretically as well as experimentally determined thermochemical data of the non-covalent interactions in different axle-substituted pseudorotaxanes. The overall interaction energy lies in the region of 35 kJ mol(-1), independent of the substitution pattern at the axle. Because rearrangement energies of 7 and 3 kJ mol(-1) are required for wheel and axle, respectively, the sum of the net interactions of individual non-covalent bonds must exceed 10 kJ mol(-1) to achieve a successful host-guest interaction. The geometrical analysis shows three hydrogen bonds, and the close inspection of the individual dipole moments as well as the individual hydrogen bonds reveals trends according to the different functional groups at the axle. The individual trends for the different hydrogen bonds almost lead to a cancellation of the substitution effects. From solvent-effect considerations it can be predicted that the pseudorotaxane is stable in CHCl(3) and CH(2)Cl(2), whereas it would dethread in water. Comparing experimentally and theoretically calculated Gibbs free enthalpies, we find reasonable agreement if an exchange reaction of one solvent molecule instead of the direct formation reaction is considered.

  18. The influence of axle position and the use of accessories on the activity of upper limb muscles during manual wheelchair propulsion.

    PubMed

    Bertolaccini, Guilherme da Silva; Carvalho Filho, Idinei Francisco Pires de; Christofoletti, Gustavo; Paschoarelli, Luis Carlos; Medola, Fausto Orsi

    2017-03-24

    Wheelchair configuration is an important factor influencing the ergonomics of the user-device interface and, from a biomechanical point of view, small changes in chair setup may have a positive influence on the demand on the upper limbs during manual propulsion. This study aimed to investigate the influence of the position of the rear wheels' axle and the use of accessories on the activity of upper limb muscles during manual wheelchair propulsion. Electromyography signals of the biceps, triceps, anterior deltoids and pectoralis major were collected for 11 able-bodied subjects in a wheelchair propulsion protocol with four different wheelchair configurations (differing in axle position and the use of accessories) on a straightforward sprint and a slalom course. With accessories, moving the axle forward led to a decrease in the activity of all muscles in both the straightforward sprint (significant differences in triceps, anterior deltoids and biceps) and the slalom course (significant difference in anterior deltoids and biceps). However, when propelling the chair without accessories, no difference was found related to axle position. Changes in wheelchair configuration can influence the ergonomics of manual wheelchair propulsion. Reducing the biomechanical loads may benefit users' mobility, independence and social participation.

  19. lncRNA DANCR promotes tumor progression and cancer stemness features in osteosarcoma by upregulating AXL via miR-33a-5p inhibition.

    PubMed

    Jiang, Nian; Wang, Xuedi; Xie, Xianbiao; Liao, Yan; Liu, Ni; Liu, Junfeng; Miao, Nabo; Shen, Jingnan; Peng, Tingsheng

    2017-10-01

    lncRNAs regulate the initiation and progression of osteosarcoma, although the mechanism by which this occurs remains unknown. The present study shows that over-expression of the lncRNA DANCR increased osteosarcoma cell proliferation, migration, and invasion in vitro, as well as promoted xenograft tumor growth and lung metastasis in vivo. Mechanistically, DANCR promoted osteosarcoma progression by mediating cancer stem cells (CSCs) features. Moreover, pull-down assays and luciferase reporter assays indicated that DANCR upregulated expression of the receptor tyrosine kinase AXL by competitively binding to miR-33a-5p. Furthermore, DANCR enhanced the expression of proteins downstream of the AXL-Akt pathway. DANCR was consistently significantly increased in osteosarcoma tissues, and its expression was positively correlated with tumor size and metastasis as an independent poor prognostic factor. Furthermore, both in patient tumors and xenograft tumors, DANCR expression was positively related to AXL and negatively related to miR-33a-5p. Taken together, our results suggest that DANCR is a crucial upregulator of osteosarcoma and an independent predictor of prognosis. DANCR increases CSCs function by upregulating AXL via competitively binding to miR-33a-5p, and this function is sequentially performed through the PI3K-Akt signaling pathway. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. 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),…

  1. An integrated control strategy for the composite braking system of an electric vehicle with independently driven axles

    NASA Astrophysics Data System (ADS)

    Sun, Fengchun; Liu, Wei; He, Hongwen; Guo, Hongqiang

    2016-08-01

    For an electric vehicle with independently driven axles, an integrated braking control strategy was proposed to coordinate the regenerative braking and the hydraulic braking. The integrated strategy includes three modes, namely the hybrid composite mode, the parallel composite mode and the pure hydraulic mode. For the hybrid composite mode and the parallel composite mode, the coefficients of distributing the braking force between the hydraulic braking and the two motors' regenerative braking were optimised offline, and the response surfaces related to the driving state parameters were established. Meanwhile, the six-sigma method was applied to deal with the uncertainty problems for reliability. Additionally, the pure hydraulic mode is activated to ensure the braking safety and stability when the predictive failure of the response surfaces occurs. Experimental results under given braking conditions showed that the braking requirements could be well met with high braking stability and energy regeneration rate, and the reliability of the braking strategy was guaranteed on general braking conditions.

  2. Influence of process parameters on the microstructural evolution of a rear axle tube during cross wedge rolling

    NASA Astrophysics Data System (ADS)

    Ma, Jia-wei; Yang, Cui-ping; Zheng, Zhen-hua; Zhang, Kang-sheng; Ma, Wen-yu

    2016-11-01

    In the shaping process of cross wedge rolling (CWR), metal undergoes a complex microstructural evolution, which affects the quality and mechanical properties of the product. Through secondary development of the DEFORM-3D software, we developed a rigid plastic finite element model for a CWR-processed rear axle tube, coupled with thermomechanical and microstructural aspects of workpieces. Using the developed model, we investigated the microstructural evolution of the CWR process. Also, the influence of numerous parameters, including the initial temperature of workpieces, the roll speed, the forming angle, and the spreading angle, on the grain size and the grain-size uniformity of the rolled workpieces was analyzed. The numerical simulation was verified through rolling and metallographic experiments. Good agreement was obtained between the calculated and experimental results, which demonstrated the reliability of the model constructed in this work.

  3. Multipurpose optic-electronic autocollimators for measuring deformations of the axle with a millimeter wave range radiotelescope

    NASA Astrophysics Data System (ADS)

    Konyakhin, Igor; Molev, Fedor; Konyakhin, Alexey; Li, Renpu

    2015-02-01

    The improved autocollimators for measuring angular deformations of the large constructions as support tube of mirror and elevation axle of the radio telescopes are analyzed. Two new types of the reflector for autocollimator are researched. The first type of the reflectors is the tetrahedral reflector with flat reflecting sides and invariant axis. The autocollimator with tetrahedral reflector is used for the measuring 3-D deformations as roll, pitch and yaw angular deviations. The second type of the reflector is the composition of the anamorphic wedge system and ordinary cube-corner retroreflector. This reflector generates the narrow beam, as result the work distance and the range of measurement of the roll angle increase. Technical characteristics of the experimental setups of new reflectors are presented. Features of the tetrahedral reflector and anamorphic system as the reflectors for multipurpose autocollimator are discussed.

  4. Influence on operator's health of hand-transmitted vibrations from handles of a single-axle tractor.

    PubMed

    Goglia, Vlado; Gospodaric, Zlatko; Filipovic, Dubravko; Djukic, Igor

    2006-01-01

    The operators of the single-axle tractors are especially exposed to hand-arm transmitted vibrations. These vibrations can cause the complex of vascular, neurological and musculoskeletal disorders, collectively named hand-arm vibration syndrome. Among these, the most common disorder is vibration-induced white finger (Raynaud's phenomenon). The vibration levels were measured in three tractor's working conditions, namely idling, transportation and soil tillage. The vibration level on the handles was measured and analysed and the frequency spectra for the chosen working conditions were obtained. The frequency-weighted acceleration, given in m/s2, was calculated and the obtained values are graphically presented. The measured vibration levels are then discussed with regard to the operator's daily exposure limits recommended by the ISO 5349. The vibration levels were much higher in the x and y directions than the z-direction in all working conditions. The vibration total values in idling, transportation and soil tillage were 3.37, 8.37 and 9.62 m/s2, respectively. Results showed that the 10% of workers are exposed to a risk of vibration-induced white finger disorder of the hands after relatively short periods (3-4 years), if the tractor is used 8 hour per day in soil tillage and transportation at full load. Considering the criteria of the ISO 5349, the daily working time with the single-axle tractor should be limited in order to protect the operator and work schedules should be arranged to include vibration-free periods.

  5. A phase I pilot study of the insulin-like growth factor 1 receptor pathway modulator AXL1717 in combination with gemcitabine HCl and carboplatin in previously untreated, locally advanced, or metastatic non-small cell lung cancer.

    PubMed

    Holgersson, Georg; Bergström, Stefan; Harmenberg, Johan; Ringbom, Magnus; Klockare, Maria; Jerling, Markus; Ekman, Simon; Lundström, Kristina Lamberg; Koyi, Hirsh; Brandén, Eva; Larsson, Olle; Bergqvist, Michael

    2015-04-01

    AXL1717 is an orally bioavailable IGF-1R pathway modulator that has been shown to have anti-tumoral effects. The objectives of the present study were to define maximum tolerated dose and the recommended phase II dose (RPTD) of AXL1717 in combination with gemcitabine HCl and carboplatin in non-small cell lung cancer (NSCLC). Patients with previously untreated, locally advanced, or metastatic NSCLC (squamous cell cancer or adenocarcinoma) in good performance status and with preserved major organ functions were enrolled in the study. The study was an open-label phase I study with planned cohorts of three patients per dose level of AXL1717 (215, 290, and 390 mg BID). In total, 12 patients were enrolled in the study, and of these, two were prematurely excluded. AXL1717 was administered at one dose level, 215 mg BID. A total number of 81 unique adverse events were reported. Bone marrow toxicity was reported in 10 out of 12 patients, and this organ class showed the largest number of related events. AXL1717 in combination with gemcitabine HCl and carboplatin is a possible treatment approach in previously untreated, locally advanced, or metastatic non-small cell lung cancer. However, due to the bone marrow toxicity profile shown in the present study, further dose increases of AXL1717 above 215 mg BID will probably not be feasible. Therefore, 215 mg BID constitutes maximum tolerated dose and RPTD.

  6. A receptor tyrosine kinase, UFO/Axl, and other genes isolated by a modified differential display PCR are overexpressed in metastatic prostatic carcinoma cell line DU145.

    PubMed

    Jacob, A N; Kalapurakal, J; Davidson, W R; Kandpal, G; Dunson, N; Prashar, Y; Kandpal, R P

    1999-01-01

    We have used a modified differential display PCR protocol for isolating 3' restriction fragments of cDNAs specifically expressed or overexpressed in metastatic prostate carcinoma cell line DU145. Several cDNA fragments were identified that matched to milk fat globule protein, UFO/Axl, a receptor tyrosine kinase, human homologue of a Xenopus maternal transcript, laminin and laminin receptor, human carcinoma-associated antigen, and some expressed sequence tags. The transcript for milk fat globule protein, a marker protein shown to be overexpressed in breast tumors, was elevated in DU145 cells. The expression of UFO/Axl, a receptor tyrosine kinase, was considerably higher in DU145 cells as compared to normal prostate cells and prostatic carcinoma cell line PC-3. The overexpression of UFO oncogene in DU145 cells is discussed in the context of prostate cancer metastasis.

  7. Expression level of CRKL and AXL combined with exon 19 deletion in EGFR and ALK status confer differential prognosis of lung adenocarcinoma subtypes

    PubMed Central

    Cai, Yi-Ran; Dong, Yu-Jie; Wu, Hong-Bo; Yu, Da-Ping; Zhou, Li-Juan; Su, Dan; Zhang, Li; Chen, Xue-Jing

    2016-01-01

    Non-small cell lung cancer (NSCLC) is a lethal cancer-related disease in population. Adenocarcinoma (AC) is subclassified into several subtypes based on the new classification by the International Association for the Study of Lung Cancer, American Thoracic Society and European Respiratory Society in 2011. Correlation between original expression of Crk-like (CRKL) and anaplastic lymphoma receptor tyrosine kinase in diverse histological components of AC and epidermal growth factor receptor (EGFR) or ALK status was evaluated by immunohistochemistry and sequencing in present study. A total of 106 cases, including 83 patients (78.3%) with mixed-type ACs, were assessed in the present study using eligible follow-up data. The ACs consisted of 32 acinar, 12 papillary, 5 mucinous, 11 micropapillary and 46 solid-predominant ACs. In total, 69.8% samples were composed of 2 or 3 histological components, with different expression levels of CRKL and AXL. ACs with EGFR mutation had a higher level of AXL expression compared with ACs without mutation (P=0.019). Multivariate survival analysis showed that AC subtypes and EGFR mutation subtypes were significantly associated with the progression-free survival (PFS) time. Acinar AC was the subtype with the most notable PFS time (30.6 months), which was significantly different from the PFS time of papillary, mucinous, micropapillary and solid-predominant ACs (hazard ratio, 0.4; 95% CI, 0.21–0.75; P=0.005). Among the ACs with exon 19 mutation, the median PFS time (28.8 months) of patients with a lower level of AXL protein expression was increased compared with the PFS time of patients with the L858R mutation and wild-type EGFR (9.1 months and 11 months, respectively; P=0.03), whereas no significant difference in ACs with an increased level of AXL expression. However, AC patients with higher level of CRKL expression had better PFS (28.8 months) than patients with the L858R mutation and wild-type EGFR (9.1 months and 11.3 months

  8. Vitamin K2 inhibits rat vascular smooth muscle cell calcification by restoring the Gas6/Axl/Akt anti-apoptotic pathway.

    PubMed

    Qiu, Cuiting; Zheng, Haijun; Tao, Huiren; Yu, Wenjun; Jiang, Xiaoyu; Li, Aiqin; Jin, Hui; Lv, Anlin; Li, Huan

    2017-04-06

    Vascular calcification is associated with cardiovascular disease as a complication of hypertension, hyperlipidemia, diabetes mellitus, and chronic kidney disease. Vitamin K2 (VK2) delays vascular calcification by an unclear mechanism. Moreover, apoptosis modulates vascular smooth muscle cell (VSMC) calcification. This paper aimed to study VK2-modified VSMC calcification and survival cell signaling mediated by growth arrest-specific gene 6 (Gas6) and its tyrosine kinase receptor Axl. Primary-cultured VSMCs were dose-dependently treated with VK2 in the presence of calcification medium for 8 days, or pre-treated for 1 h with/without the Axl inhibitor R428 (2 μmol/L) or the caspase inhibitor Z-VAD-fmk (20 μmol/L) followed by treatment with VK2 (10 μmol/L) or rmGas6 (200 nmol/L) in calcification medium for 8 days. Calcium deposition was determined by the o-cresolphthalein complexone assay and Alizarin Red S staining. Apoptosis was determined by TUNEL and flow cytometry using Annexin V-FITC and propidium iodide staining. Western blotting detected the expressions of Axl, Gas6, p-Akt, Akt, and Bcl2. VK2 significantly inhibited CaCl2- and β-sodium glycerophosphate (β-GP)-induced VSMC calcification and apoptosis, which was dependent on restored Gas6 expression and activated downstream signaling by Axl, p-Akt, and Bcl2. Z-VAD-fmk significantly inhibited CaCl2- and β-GP-induced VSMC calcification and apoptosis. Augmented recombinant mouse Gas6 protein (rmGas6) expression significantly reduced VSMC calcification and apoptosis. Furthermore, the Gas6/Axl interaction was inhibited by R428, which abolished the preventive effect of VK2 on CaCl2- and β-GP-induced apoptosis and calcification. These results suggest that Gas6 is critical in VK2-mediated functions that attenuate CaCl2- and β-GP-induced VSMC calcification by blocking apoptosis.

  9. The Effect of Flexible Pavement Mechanics on the Accuracy of Axle Load Sensors in Vehicle Weigh-in-Motion Systems.

    PubMed

    Burnos, Piotr; Rys, Dawid

    2017-09-07

    Weigh-in-Motion systems are tools to prevent road pavements from the adverse phenomena of vehicle overloading. However, the effectiveness of these systems can be significantly increased by improving weighing accuracy, which is now insufficient for direct enforcement of overloaded vehicles. Field tests show that the accuracy of Weigh-in-Motion axle load sensors installed in the flexible (asphalt) pavements depends on pavement temperature and vehicle speeds. Although this is a known phenomenon, it has not been explained yet. The aim of our study is to fill this gap in the knowledge. The explanation of this phenomena which is presented in the paper is based on pavement/sensors mechanics and the application of the multilayer elastic half-space theory. We show that differences in the distribution of vertical and horizontal stresses in the pavement structure are the cause of vehicle weight measurement errors. These studies are important in terms of Weigh-in-Motion systems for direct enforcement and will help to improve the weighing results accuracy.

  10. The Effect of Flexible Pavement Mechanics on the Accuracy of Axle Load Sensors in Vehicle Weigh-in-Motion Systems

    PubMed Central

    Rys, Dawid

    2017-01-01

    Weigh-in-Motion systems are tools to prevent road pavements from the adverse phenomena of vehicle overloading. However, the effectiveness of these systems can be significantly increased by improving weighing accuracy, which is now insufficient for direct enforcement of overloaded vehicles. Field tests show that the accuracy of Weigh-in-Motion axle load sensors installed in the flexible (asphalt) pavements depends on pavement temperature and vehicle speeds. Although this is a known phenomenon, it has not been explained yet. The aim of our study is to fill this gap in the knowledge. The explanation of this phenomena which is presented in the paper is based on pavement/sensors mechanics and the application of the multilayer elastic half-space theory. We show that differences in the distribution of vertical and horizontal stresses in the pavement structure are the cause of vehicle weight measurement errors. These studies are important in terms of Weigh-in-Motion systems for direct enforcement and will help to improve the weighing results accuracy. PMID:28880215

  11. 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.

  12. 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.

  13. The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy.

    PubMed

    Clémenson, Céline; Chargari, Cyrus; Liu, Winchygn; Mondini, Michele; Ferté, Charles; Burbridge, Mike F; Cattan, Valérie; Jacquet-Bescond, Anne; Deutsch, Eric

    2017-10-01

    Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107-19. ©2017 AACR. ©2017 American Association for Cancer Research.

  14. Serial analysis of gene expression reveals differential expression between endometriosis and normal endometrium. Possible roles for AXL and SHC1 in the pathogenesis of endometriosis

    PubMed Central

    Honda, Hiroshi; Barrueto, Fermin F; Gogusev, Jean; Im, Dwight D; Morin, Patrice J

    2008-01-01

    Background Endometriosis is a clinical condition that affects up to 10% of the women of reproductive age. Endometriosis is characterized by the presence of endometrial tissues outside the uterine cavity and can lead to chronic pelvic pain, infertility and, in some cases, to ovarian cancer. Methods In order to better understand the pathogenesis of endometriosis, we have used Serial Analysis of Gene Expression (SAGE) to identify genes differentially in this disease by studying three endometriotic tissues and a normal endometrium sample. Promising candidates (AXL, SHC1, ACTN4, PI3KCA, p-AKT, p-mTOR, and p-ERK) were independently validated by immunohistochemistry in additional normal and endometriotic tissues. Results We identified several genes differentially expressed between endometriosis and normal endometrium. IGF2, ACTN4, AXL, and SHC1 were among the most upregulated genes. Comparison of the endometriosis gene expression profiles with the gene expression patterns observed in normal human tissues allowed the identification of endometriosis-specific genes, which included several members of the MMP family (MMP1,2,3,10,11,14). Immunohistochemical analysis of several candidates confirmed the SAGE findings, and suggested the involvement of the PI3K-Akt and MAPK signaling pathways in endometriosis. Conclusion In human endometriosis, the PI3K-Akt and MAPK signaling pathways may be activated via overexpression of AXL and SHC1, respectively. These genes, as well as others identified as differentially expressed in this study, may be useful for the development of novel strategies for the detection and/or therapy of endometriosis. PMID:19055724

  15. Intracellular signaling of the Ufo/Axl receptor tyrosine kinase is mediated mainly by a multi-substrate docking-site.

    PubMed

    Braunger, J; Schleithoff, L; Schulz, A S; Kessler, H; Lammers, R; Ullrich, A; Bartram, C R; Janssen, J W

    1997-06-05

    Ufo/Axl belongs to a new family of receptor tyrosine kinases with an extracellular structure similar to that of neural cell adhesion molecules. In order to elucidate intracellular signaling, the cytoplasmic moiety of Ufo/Axl was used to screen an expression library according to the CORT (cloning of receptor targets) method. Three putative Ufo substrates were identified: phospholipase Cgamma1 (PLCgamma), as well as p85alpha and p85beta subunits of phosphatidylinositol 3'-kinase (PI3-kinase). Subsequently, chimeric EGFR/Ufo receptors consisting of the extracellular domains of the epidermal growth factor receptor (EGFR) and the transmembrane and intracellular moiety of Ufo were engineered. Using different far-Western blot analyses and coimmunoprecipitation assays, receptor binding of PLCgamma and p85 proteins as well as GRB2, c-src and lck was examined in vitro and in vivo. Competitive inhibition of substrate binding and mutagenesis experiments with EGFR/Ufo constructs revealed C-terminal tyrosine 821 (EILpYVNMDEG) as a docking site for multiple effectors, namely PLCgamma, p85 proteins, GRB2, c-src and lck. Tyrosine 779 (DGLpYALMSRC) demonstrated an additional, but lower binding affinity for the p85 proteins in vitro. In addition, binding of PLCgamma occurred through tyrosine 866 (AGRpYVLCPST). Moreover, our in vivo data indicate that further direct or indirect binding sites for PLCgamma, GRB2, c-src and lck on the human Ufo receptor may exist.

  16. Screening and identification of novel compounds with potential anti-proliferative effects on gallium-resistant lung cancer through an AXL kinase pathway.

    PubMed

    Oyewumi, Moses O; Alazizi, Adnan; Liva, Sophia; Lin, Li; Geldenhuys, Werner J

    2014-09-15

    The clinical application of gallium compounds as anticancer agents is hampered by development of resistance. As a potential strategy to overcome the limitation, eight series of compounds were identified through virtual screening of AXL kinase homology model. Anti-proliferative studies were carried using gallium-sensitive (S) and gallium-resistant (R) human lung adenocarcinoma (A549) cells. Compounds 5476423 and 7919469 were identified as leads. The IC50 values from treating R-cells showed compounds 5476423 and 7919469 had 80 fold and 13 fold increased potency, respectively, compared to gallium acetylacetonate (GaAcAc). The efficacy of GaAcAc against R-cells was increased 2 fold and 1.2 fold when combined with compounds 5476423 and 7919469, respectively. Compared with S-cells, R-cells showed elevated expression of AXL protein, which was significantly suppressed through treatments with the lead compounds. It is anticipated that the lead compounds could be applied in virtual screening programs to identify novel scaffolds for new therapeutic agents as well as combinatorial therapy agents in gallium resistant lung cancer. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. 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.

  18. ORNL-GM: Development of Ionic Liquid-Additized, GF-5/6 Compatible Low-Viscosity Oils for Automotive Engine and Rear Axle Lubrication for 4% Improved Fuel Economy

    SciTech Connect

    Qu, Jun; Zhou, Yan; Luo, Huimin; Toops, Todd J.; Brookshear, Daniel W.; Stump, Benjamin C.; Viola, Michael B.; Zreik, Khaled; Ahmed, Tasfia

    2017-01-01

    The overall objective of this project are as follows: Further develop ionic liquid (IL)-additized lowviscosity engine oils meeting the GF-5/6 specifications and possessing superior lubricating characteristics; Expand the IL additive technology to rear axle lubricants; and Seek a combined improvement in the vehicle fuel economy

  19. Axle Lubricant Efficiency

    DTIC Science & Technology

    2014-05-09

    have identical fluids CAN Controller Area Network CAT Caterpillar C.I. Confidence Interval cSt CentiStoke CTIS Central Tire Inflation System ECM...Information Caterpillar Inc. C7 ACERT – 330 hp @ 2400 RPM, 860 ft-lbs @ 1440 RPM, Meets 2006 EPA Emissions Standards under National Security

  20. Extended-Kalman-filter-based regenerative and friction blended braking control for electric vehicle equipped with axle motor considering damping and elastic properties of electric powertrain

    NASA Astrophysics Data System (ADS)

    Lv, Chen; Zhang, Junzhi; Li, Yutong

    2014-11-01

    Because of the damping and elastic properties of an electrified powertrain, the regenerative brake of an electric vehicle (EV) is very different from a conventional friction brake with respect to the system dynamics. The flexibility of an electric drivetrain would have a negative effect on the blended brake control performance. In this study, models of the powertrain system of an electric car equipped with an axle motor are developed. Based on these models, the transfer characteristics of the motor torque in the driveline and its effect on blended braking control performance are analysed. To further enhance a vehicle's brake performance and energy efficiency, blended braking control algorithms with compensation for the powertrain flexibility are proposed using an extended Kalman filter. These algorithms are simulated under normal deceleration braking. The results show that the brake performance and blended braking control accuracy of the vehicle are significantly enhanced by the newly proposed algorithms.

  1. First-in-human phase I study of oral S49076, a unique MET/AXL/FGFR inhibitor, in advanced solid tumours.

    PubMed

    Rodon, Jordi; Postel-Vinay, Sophie; Hollebecque, Antoine; Nuciforo, Paolo; Azaro, Analia; Cattan, Valérie; Marfai, Lucie; Sudey, Isabelle; Brendel, Karl; Delmas, Audrey; Malasse, Stéphanie; Soria, Jean-Charles

    2017-08-01

    S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD. Pharmacokinetic (PK) parameters were assessed and pharmacodynamic end-points were evaluated in pre- and post-treatment tumour biopsies. Preliminary anti-tumour activity was evaluated as per the Response Evaluation Criteria In Solid Tumours 1.1 criteria. A total of 103 patients were treated: 79 in the dose-escalation and 24 in the expansion. Doses from 15 to 900 mg were evaluated. Dose-limiting toxicities were reported in 9 patients and occurred at 30, 760 and 900 mg in the qd arm and at 180, 225 and 285 mg in the bid arm. The RD was defined at 600 mg qd. Adverse events (AEs) occurred with similar frequency in both regimens at an equivalent total daily dose. Overall, 83 patients (81.4%) had drug-related AEs, the majority (93%) of which were grade I-II (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) and only 3% led to drug discontinuation. Intratumoural PK analysis at the RD suggested hitting of MET, AXL and FGFR. S49076 demonstrated a tolerable safety profile with limited single-agent activity. PK/pharmacodynamic readouts of S49076 are encouraging for further investigation of S49076 in combination therapies. ISRCTN00759419. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. α-Lipoic acid attenuates vascular calcification via reversal of mitochondrial function and restoration of Gas6/Axl/Akt survival pathway

    PubMed Central

    Kim, Hyunsoo; Kim, Han-Jong; Lee, Kyunghee; Kim, Jin-Man; Kim, Hee Sun; Kim, Jae-Ryong; Ha, Chae-Myeong; Choi, Young-Keun; Lee, Sun Joo; Kim, Joon-Young; Harris, Robert A; Jeong, Daewon; Lee, In-Kyu

    2012-01-01

    Abstract Vascular calcification is prevalent in patients with chronic kidney disease and leads to increased cardiovascular morbidity and mortality. Although several reports have implicated mitochondrial dysfunction in cardiovascular disease and chronic kidney disease, little is known about the potential role of mitochondrial dysfunction in the process of vascular calcification. This study investigated the effect of α-lipoic acid (ALA), a naturally occurring antioxidant that improves mitochondrial function, on vascular calcification in vitro and in vivo. Calcifying vascular smooth muscle cells (VSMCs) treated with inorganic phosphate (Pi) exhibited mitochondrial dysfunction, as demonstrated by decreased mitochondrial membrane potential and ATP production, the disruption of mitochondrial structural integrity and concurrently increased production of reactive oxygen species. These Pi-induced functional and structural mitochondrial defects were accompanied by mitochondria-dependent apoptotic events, including release of cytochrome c from the mitochondria into the cytosol, subsequent activation of caspase-9 and -3, and chromosomal DNA fragmentation. Intriguingly, ALA blocked the Pi-induced VSMC apoptosis and calcification by recovery of mitochondrial function and intracellular redox status. Moreover, ALA inhibited Pi-induced down-regulation of cell survival signals through the binding of growth arrest-specific gene 6 (Gas6) to its cognate receptor Axl and subsequent Akt activation, resulting in increased survival and decreased apoptosis. Finally, ALA significantly ameliorated vitamin D3-induced aortic calcification and mitochondrial damage in mice. Collectively, the findings suggest ALA attenuates vascular calcification by inhibiting VSMC apoptosis through two distinct mechanisms; preservation of mitochondrial function via its antioxidant potential and restoration of the Gas6/Axl/Akt survival pathway. PMID:21362131

  3. Characterization of Gas6, a member of the superfamily of G domain-containing proteins, as a ligand for Rse and Axl.

    PubMed

    Mark, M R; Chen, J; Hammonds, R G; Sadick, M; Godowsk, P J

    1996-04-19

    Rse, Ax1, and c-Mer comprise a family of cell adhesion molecule-related tyrosine kinase receptors. Human Gas6 was recently shown to act as a ligand for both human Rse (Godowski et al., 1995) and human Ax1 (Varnum et al., 1995). Gas6 contains an NH2-terminal Gla domain followed by four epidermal growth factor-like repeats and tandem globular (G) domains. The G domains are related to those found in sex hormone-binding globulin and to those utilized by laminin and agrin for binding to the dystroglycan complex. A series of Gas6 variants were tested for their ability to bind to Rse and Ax1. The Gla domain and epidermal growth factor-like repeats were not required for receptor binding, as deletion variants of Gas6 which lacked these domains bound to the extracellular domains of both Rse and Axl. A deletion variant of Gas6 containing just the G domain region was shown to activate Rse phosphorylation. These results provide evidence that G domains can act as signaling molecules by activating transmembrane receptor tyrosine kinases. Furthermore, they provide a structural link between the activation of cell adhesion related receptors and the control of cell growth and differentiation by the G domain-containing superfamily of proteins.

  4. rse, a novel receptor-type tyrosine kinase with homology to Axl/Ufo, is expressed at high levels in the brain.

    PubMed

    Mark, M R; Scadden, D T; Wang, Z; Gu, Q; Goddard, A; Godowski, P J

    1994-04-08

    We have isolated cDNA clones that encode the human and murine forms of a novel receptor-type tyrosine kinase termed Rse. Sequence analysis indicates that human Rse contains 890 amino acids, with an extracellular region composed of two immunoglobulin-like domains followed by two fibronectin type III domains. Murine Rse contains 880 amino acids and shares 90% amino acid identity with its human counterpart. Rse is structurally similar to the receptor-type tyrosine kinase Axl/Ufo, and the two proteins have 35 and 63% sequence identity in their extracellular and intracellular domains, respectively. To study the synthesis and activation of this putative receptor-type tyrosine kinase, we constructed a version of Rse (termed gD-Rse, where gD represents glycoprotein D) that contains an NH2-terminal epitope tag. NIH3T3 cells were engineered to express gD-Rse, which could be detected at the cell surface by fluorescence-activated cell sorting. Moreover, gD-Rse was rapidly phosphorylated on tyrosine residues upon incubation of the cells with an antibody directed against the epitope tag, suggesting that rse encodes an active tyrosine kinase. In the human tissues we examined, the highest level of expression of rse mRNA was observed in the brain; rse mRNA was also detected in the premegakaryocytopoietic cell lines CMK11-5 and Dami. The gene for rse was localized to human chromosome 15.

  5. A Performance Evaluation of a Long Load Steering Tri-Axle Dolly on the Alaska Highway, 1981 (Evaluation du Rendement d’un Chariot a Tubes a Trois Essieux, Dont un Essieu Directeur Asservi, sur l’Autoroute de l’Alaska en 1981)

    DTIC Science & Technology

    1981-07-01

    emergency braking or excessive cornering speeds. The British Unit System has been chosen for this report because it is the system that much of the trucking ...Specifications Tractor Manufacturer Freightliner Manufactured May 1980 Model FLT 9664T Type Cab over Wheelbase 174 inches, as measured from the front axle to...by the trucking industry to denote a tractor trailer assembly. 3 The 5th wheel is the coupling assembly on the tractor about which a semi-traler pivots

  6. qPCR in gastrointestinal stromal tumors: Evaluation of reference genes and expression analysis of KIT and the alternative receptor tyrosine kinases FLT3, CSF1-R, PDGFRB, MET and AXL

    PubMed Central

    2010-01-01

    Background Gastrointestinal stromal tumors (GIST) represent the most common mesenchymal tumors of the gastrointestinal tract. About 85% carry an activating mutation in the KIT or PDGFRA gene. Approximately 10% of GIST are so-called wild type GIST (wt-GIST) without mutations in the hot spots. In the present study we evaluated appropriate reference genes for the expression analysis of formalin-fixed, paraffin-embedded and fresh frozen samples from gastrointestinal stromal tumors. We evaluated the gene expression of KIT as well as of the alternative receptor tyrosine kinase genes FLT3, CSF1-R, PDGFRB, AXL and MET by qPCR. wt-GIST were compared to samples with mutations in KIT exon 9 and 11 and PDGFRA exon 18 in order to evaluate whether overexpression of these alternative RTK might contribute to the pathogenesis of wt-GIST. Results Gene expression variability of the pooled cDNA samples is much lower than the single reverse transcription cDNA synthesis. By combining the lowest variability values of fixed and fresh tissue, the genes POLR2A, PPIA, RPLPO and TFRC were chosen for further analysis of the GIST samples. Overexpression of KIT compared to the corresponding normal tissue was detected in each GIST subgroup except in GIST with PDGFRA exon 18 mutation. Comparing our sample groups, no significant differences in the gene expression levels of FLT3, CSF1R and AXL were determined. An exception was the sample group with KIT exon 9 mutation. A significantly reduced expression of CSF1R, FLT3 and PDGFRB compared to the normal tissue was detected. GIST with mutations in KIT exon 9 and 11 and in PDGFRA exon 18 showed a significant PDGFRB downregulation. Conclusions As the variability of expression levels for the reference genes is very high comparing fresh frozen and formalin-fixed tissue there is a strong need for validation in each tissue type. None of the alternative receptor tyrosine kinases analyzed is associated with the pathogenesis of wild-type or mutated GIST. It

  7. 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.

  8. Transfer case for multiple drive axle vehicle

    SciTech Connect

    Batchelor, R.B.

    1987-07-07

    This patent describes a transfer case for a vehicle drive train having a transmission comprising: a housing; input means for receiving the torque output from the vehicle transmission; a first output shaft and first means for rotatably supporting the first output shaft in the housing; a second output shaft and second means for rotatably supporting the second output shaft in the housing; and means for selectively driving the first and second output shafts in response to actuation of the input means. The means for selectively driving comprises a planetary gear set having an annulus, a first set of first planet gears a second set of second planet gears, engaged with one of the first planet gear. A sun gear engages with the second planet gears, third means for rotatably mounting the sun gear in the housing and a planet carrier having means for rotatably supporting the first and second planet gears and co-axially secured to the first output shaft for rotation. A clutch means for selectively engages the sun gear with the planet carrier and the second output shaft, and the input means comprises means for rotatably driving the annulus.

  9. 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.

  10. 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.

  11. 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

  12. 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 Central

    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

  13. Management of Transportation Equipment.

    DTIC Science & Technology

    1982-11-01

    SEMITRAILER , STAKE, 1- AXLE 03 15 0811 SEMITRAILER , VAN, 1- AXLE 03 15 0812 SEMITRAILER , STAKE, 1 OR 2- AXLE 03 15 0813 SEMITRAILER , VAN, 1 OR 2... AXLE 03 15 0814 SEMITRAILER , STAKE, 1 OR 2- AXLE 03 15 0815 SEMITRAILER , VAN, 2- AXLE 03 15 0816 SEMITRAILER , STAKE, 2- AXLE 03 15 0817 SEMITRAILER , VAN...2- AXLE 03 15 0818 SEMITRAILER , STAKE, 2- AXLE 03 15 0819 SEMITRAILER , VAN,

  14. 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)…

  15. Plugging a Bipyridinium Axle into Multichromophoric Calix[6]arene Wheels Bearing Naphthyl Units at Different Rims

    PubMed Central

    Orlandini, Guido; Ragazzon, Giulio; Zanichelli, Valeria; Degli Esposti, Lorenzo; Baroncini, Massimo; Silvi, Serena; Venturi, Margherita; Arduini, Arturo

    2017-01-01

    Abstract Tris‐(N‐phenylureido)‐calix[6]arene derivatives are heteroditopic non‐symmetric molecular hosts that can form pseudorotaxane complexes with 4,4′‐bipyridinium‐type guests. Owing to the unique structural features and recognition properties of the calix[6]arene wheel, these systems are of interest for the design and synthesis of novel molecular devices and machines. We envisaged that the incorporation of photoactive units in the calixarene skeleton could lead to the development of systems the working modes of which can be governed and monitored by means of light‐activated processes. Here, we report on the synthesis, structural characterization, and spectroscopic, photophysical, and electrochemical investigation of two calix[6]arene wheels decorated with three naphthyl groups anchored to either the upper or lower rim of the phenylureido calixarene platform. We found that the naphthyl units interact mutually and with the calixarene skeleton in a different fashion in the two compounds, which thus exhibit a markedly distinct photophysical behavior. For both hosts, the inclusion of a 4,4′‐bipyridinium guest activates energy‐ and/or electron‐transfer processes that lead to non‐trivial luminescence changes. PMID:28168152

  16. 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)…

  17. Army Excellence in Leadership (AXL): Educating Army Leaders with the Tripwire Film

    DTIC Science & Technology

    2007-03-01

    reading intentions, building trust, converting opinions, and managing perceptions, all tasks that demand an exceptional ability to understand people, their...between two team members, one individual and the entire team, several team members, and between different teams ( Schermerhorn , Hunt, & Osborn, 2000...the team, but interferes with the person’s ability to perform ( Schermerhorn et al.). There are also task conflicts, which involve disputes over how a

  18. Development of an Army Stationary Axle Efficiency Test Stand - Interim Report TFLRF No. 471

    DTIC Science & Technology

    2015-09-01

    other yellow metal parts within heavy -duty components  OEM warranty approvals SAE 75W-90 AND FE 75W-90 FULL SYNTHETIC GEAR LUBRICANT COMPONENT...driving cycle for the tactical wheeled vehicles representing light, medium, and heavy duty equipment. Preliminary repeatability data has been...medium, and heavy tactical wheeled vehicles. The test stand was constructed and installed at the TARDEC Fuels and Lubricants Research Facility located

  19. Army Excellence in Leadership (AXL): A Multimedia Approach to Building Tacit Knowledge and Cultural Reasoning

    DTIC Science & Technology

    2007-01-01

    Commander-Excellence in Leadership (TLAC-XL). These individuals include Andrew Gordon, Salvo Lavis , Sudeep Gandhe, David Traum, Stewart King, Reid Swanson...the current operating environment places many demands on junior leaders, the United States Army has devoted substantial attention to the challenge of...information each system can process individually, cognitive load as a whole can be reduced by presenting information in multiple modalities so that

  20. 23 CFR 658.13 - Length.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... axle(s)), including “low boys,” or less than 75 feet on stinger-steered automobile transporters... traditional boat transporters (fifth wheel located on tractor frame over rear axle(s), including “low boys...

  1. 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.

  2. Defense Transportation Regulation, Part III: Mobility.

    DTIC Science & Technology

    1997-04-11

    cargo, passenger and personal property transportation services (including rail, highway, air, sea, pipeline, inland waterway, coastal, intercostal ...vehicle. Center of Balance Formula W1 -- Front axle weight. W2 -- Rear axle weight. D1 -- Distance from RDL to front axle or center of articulated ...tandem axle D2 -- Distance from RDL to rear axle or center of articulated tandem axle. (Wl X D1) + (W2 X D2) Gross Weight = CB b. The vehicle CB is

  3. MX Transporter Emplacer Guidance and Control,

    DTIC Science & Technology

    1980-06-01

    on each of the two unsteerable axles , the drive axles and the tag axle . Brakes are applied to all wheels on all axles . The tractors are identical...represented by the following equation at slow speeds 2L1 GTR2 - GTR1 - 0.7 radian/radian 2 where L distance between the fixed and steered axles on each tractor ...and L the distance between the fixed axles of one tractor to the fixed axles of ihe other. The filter constant, AFLT, was adjusted to give a small

  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. Calculation of Manpower Requirements for Vehicle Maintenance at U.S. Army Installation Directorates of Engineering and Housing, Based on Air Force, Navy and Army Reserves Staffing Techniques

    DTIC Science & Technology

    1988-10-01

    Alpha Abbreviated *Payload Code Code Description NAVFAC Expanded Long Description lbs 0810 P SEMI 10-T STAKE SEMITRAILER , STAKE, 1- AXLE * 20,000...0811 P SEMI 10-T VAN SEMITRAILER , VAN, 1- AXLE * 20,000 0812 P SEMI 14-T STAKE SEMITRAILER , STAKE, 1 OR 2- AXLE * 22,000/ 28,000 0813 P SEMI 12-T VAN... SEMITRAILER , VAN, 1 OR 2- AXLE * 24,000 0814 P SEMI 19-T STAKE SEMITRAILER , STAKE, 1 OR 2- AXLE * 38,000 0815 P SEMI 19-T VAN SEMITRAILER , VAN, 2- AXLE

  6. 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... requirements of this chapter, and the Act, unless, at a minimum, the trailer running gear assembly...

  7. 49 CFR 571.7 - Applicability.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... engine, transmission, and drive axle(s) (as a minimum) of the assembled vehicle are not new, and at least...), wheels, braking and suspension) is not new, and was taken from an existing trailer— (1) Whose identity is...

  8. 49 CFR 568.4 - Requirements for incomplete vehicle manufacturers.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... single value, with the label indicating to which axles the ratings apply. Examples of combined ratings... exceed any of the gross axle weight ratings, if the center of gravity at GVWR is not higher than...

  9. 49 CFR 568.4 - Requirements for incomplete vehicle manufacturers.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... single value, with the label indicating to which axles the ratings apply. Examples of combined ratings... exceed any of the gross axle weight ratings, if the center of gravity at GVWR is not higher than...

  10. 49 CFR 568.4 - Requirements for incomplete vehicle manufacturers.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... single value, with the label indicating to which axles the ratings apply. Examples of combined ratings... exceed any of the gross axle weight ratings, if the center of gravity at GVWR is not higher than...

  11. 49 CFR 568.4 - Requirements for incomplete vehicle manufacturers.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... single value, with the label indicating to which axles the ratings apply. Examples of combined ratings... exceed any of the gross axle weight ratings, if the center of gravity at GVWR is not higher than...

  12. 49 CFR 568.4 - Requirements for incomplete vehicle manufacturers.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... single value, with the label indicating to which axles the ratings apply. Examples of combined ratings... exceed any of the gross axle weight ratings, if the center of gravity at GVWR is not higher than...

  13. 36 CFR 7.71 - Delaware Water Gap National Recreation Area.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... at such facility; (iii) On a first come-first served basis, up to 125 northbound and up to 125...-axle vehicle $13 (vi) Five or more-axle vehicle $18 The fees charged are for one trip, one way....

  14. 36 CFR 7.71 - Delaware Water Gap National Recreation Area.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... at such facility; (iii) On a first come-first served basis, up to 125 northbound and up to 125...-axle vehicle $13 (vi) Five or more-axle vehicle $18 The fees charged are for one trip, one way....

  15. High-Mobility Multipurpose Wheeled Vehicle/High-Mobility Trailer (HMMWV/ HMT) Brake Analysis.

    DTIC Science & Technology

    1990-10-01

    motor vehicle shall be (c) Trucks and truck tractors having equipped with brakes acting on all three or more axles need not have wheels, except: brakes...the case of a three - system when movement in the line is axle truck or truck tractor manufac- anticipated. Brake tubing is intended tured before March...this section, a full service brake appli- hi aing orore axles cation is considered to be made when hicles having three or more axles . the service brake

  16. 49 CFR 575.103 - Truck-camper loading.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... scale and weigh on the front and on the rear wheels separately to determine axle loads. The load on an... scale and weigh on the front and on the rear wheels separately to determine axle loads. Individual axle... steering and braking. (c) Application. This section applies to slide-in campers and to trucks that are...

  17. 78 FR 9623 - Federal Motor Vehicle Safety Standards; Air Brake Systems

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-02-11

    ... conclusion that modifications needed for ``typical three-axle tractors'' to meet the improved requirements... the new requirements. These typical three-axle tractors comprise approximately 82 percent of the total... manner in which NHTSA characterized the typical three-axle tractor, and the fuel tank fill level...

  18. 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

  19. 75 FR 59060 - Airworthiness Directives; Turboméca S.A. ARRIEL 2B Turboshaft Engines

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-09-27

    ...-mechanical unit (HMU) acceleration controller axle except on engines that incorporate modification TU 132... stuck controller axles in the metering valve body. We are issuing this AD to prevent loss of control of... for proper operation of the HMU acceleration controller axle on engines that incorporate modification...

  20. FLOYDS Classification of MASTER OT J161308.18+260953.3 as a Type II Supernova and ASASSN-17cq/AT 2017axl as a Type Ia Supernova Near Peak

    NASA Astrophysics Data System (ADS)

    Hosseinzadeh, G.; Arcavi, I.; Howell, D. A.; McCully, C.; Valenti, S.

    2017-02-01

    We obtained a spectrum of MASTER OT J161308.18+260953.3 (ATel #10099) on 2017 February 21.5 UT with the robotic FLOYDS instrument mounted on the Las Cumbres Observatory (LCO) 2-meter telescope on Haleakala, Hawai'i.

  1. Real-Time Driving Simulation of Magneto-Rheological Active Damper Stryker Suspension

    DTIC Science & Technology

    2011-10-24

    front and two in the rear (Figure 2). All axles are driven and consist of Macpherson Strut suspensions with the front two axles as steering axles...Magneto-Rheological Active Damper Stryker Suspension Michael G. Megiveron, Amandeep Singh US Army, Tank Automotive Research, Development and...real-time driving experiment has been developed for Stryker to compare the ride and handling performance of a baseline passive suspension to that of a

  2. Field study on moving force identification

    NASA Astrophysics Data System (ADS)

    Chan, Hung-tin Tommy; Yung, Tak H.; Law, S. S.

    2001-08-01

    A field measurement to validate a moving force identification method was carried out on an existing prestressed concrete highway bridge with a span length of 28 m. The test bridge is located at Ma Tau Wai, Kowloon, Hong Kong. A heavy 2-axle truck with known axle loads was used as a control vehicle. Besides the control vehicle, axle load data of in-service vehicles were also collected. The bridge responses acquired for the identification were indirectly measured using strain gauges. Results show that dynamic axle loads induced from both control and in-service vehicles can be identified indicating the method is valid for identification of moving forces.

  3. 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... light-duty vehicle as defined in subpart A of this part. (7) Test Vehicle means a vehicle in a test...

  4. 49 CFR 393.207 - Suspension systems.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... 49 Transportation 5 2010-10-01 2010-10-01 false Suspension systems. 393.207 Section 393.207... NECESSARY FOR SAFE OPERATION Frames, Cab and Body Components, Wheels, Steering, and Suspension Systems § 393.207 Suspension systems. (a) Axles. No axle positioning part shall be cracked, broken, loose or missing...

  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. 76 FR 27865 - Airworthiness Directives; Cessna Aircraft Company Models 150, 152, 170, 172, 175, 177, 180, 182...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-13

    ... seat rail holes; seat pin engagement; seat rollers, washers, and axle bolts or bushings; wall thickness... seat rail and seat rail holes; seat pin engagement; seat rollers, washers, and axle bolts or bushings... for inspecting seat track hole wear and for inspecting proper seat lock pin engagement depth....

  7. 75 FR 68543 - Airworthiness Directives; Cessna Aircraft Company Models 150, 152, 170, 172, 175, 177, 180, 182...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-08

    ... rail holes; seat pin engagement; seat rollers, washers, and axle bolts or bushings; wall thickness of...; seat pin engagement; seat rollers, washers, and axle bolts or bushings; wall thickness of roller... engagement of the seat locking pins. Before further flight, after any inspection where dirt or debris...

  8. 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 of...

  9. 14 CFR 27.497 - Ground loading conditions: landing gear with tail wheels.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ....471 through 27.475; (2) The vertical load at each axle must be combined with a drag load at that axle... be resisted by angular inertia forces. (c) Level landing attitude with all wheels contacting the... specified in paragraphs (b)(1) and (2) of this section must be determined and applied, using a rational...

  10. 14 CFR 29.497 - Ground loading conditions: landing gear with tail wheels.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ....471 through 29.475; (2) The vertical load at each axle must be combined with a drag load at that axle... be resisted by angular inertia forces. (c) Level landing attitude with all wheels contacting the... specified in paragraph (b)(1) and (2) of this section must be determined and applied, using a rational...

  11. 14 CFR 27.497 - Ground loading conditions: landing gear with tail wheels.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ....471 through 27.475; (2) The vertical load at each axle must be combined with a drag load at that axle... be resisted by angular inertia forces. (c) Level landing attitude with all wheels contacting the... specified in paragraphs (b)(1) and (2) of this section must be determined and applied, using a rational...

  12. 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... be resisted by angular inertia forces. (c) Level landing attitude with all wheels contacting the... specified in paragraph (b)(1) and (2) of this section must be determined and applied, using a rational...

  13. 14 CFR 27.497 - Ground loading conditions: landing gear with tail wheels.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ....471 through 27.475; (2) The vertical load at each axle must be combined with a drag load at that axle... be resisted by angular inertia forces. (c) Level landing attitude with all wheels contacting the... specified in paragraphs (b)(1) and (2) of this section must be determined and applied, using a rational...

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

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ....471 through 29.475; (2) The vertical load at each axle must be combined with a drag load at that axle... be resisted by angular inertia forces. (c) Level landing attitude with all wheels contacting the... specified in paragraph (b)(1) and (2) of this section must be determined and applied, using a rational...

  15. 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... be resisted by angular inertia forces. (c) Level landing attitude with all wheels contacting the... specified in paragraphs (b)(1) and (2) of this section must be determined and applied, using a rational...

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

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ....471 through 29.475; (2) The vertical load at each axle must be combined with a drag load at that axle... be resisted by angular inertia forces. (c) Level landing attitude with all wheels contacting the... specified in paragraph (b)(1) and (2) of this section must be determined and applied, using a rational...

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

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ....471 through 27.475; (2) The vertical load at each axle must be combined with a drag load at that axle... be resisted by angular inertia forces. (c) Level landing attitude with all wheels contacting the... specified in paragraphs (b)(1) and (2) of this section must be determined and applied, using a rational...

  18. 14 CFR 29.497 - Ground loading conditions: landing gear with tail wheels.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ....471 through 29.475; (2) The vertical load at each axle must be combined with a drag load at that axle... be resisted by angular inertia forces. (c) Level landing attitude with all wheels contacting the... specified in paragraph (b)(1) and (2) of this section must be determined and applied, using a rational...

  19. 49 CFR 571.3 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... than three designated seating positions, unless the seat design or vehicle design is such that the... pole trailer, that is equipped with two or more axles that support the entire weight of the trailer. Gross axle weight rating or GAWR means the value specified by the vehicle manufacturer as the...

  20. 75 FR 65514 - Sypris Technologies, Sypris Solutions Division, Kenton, OH; Notice of Affirmative Determination...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-10-25

    ... Employment and Training Administration Sypris Technologies, Sypris Solutions Division, Kenton, OH; Notice of... period, there was no increase in imports of articles like or directly competitive with the trailer axles... articles like or directly competitive with trailer axles. The investigation also revealed that the subject...

  1. String and Sticky Tape Experiments: Simple Self-Lubricated Electric Motor for Elementary Physics Lab.

    ERIC Educational Resources Information Center

    Entrikin, Jerry; Griffiths, David

    1983-01-01

    The main problem in constructing functioning electric motors from simple parts is the mounting of the axle (which is too flimsy to maintain good electrical contacts or too tight, imposing excessive friction at the supports). This problem is solved by using a pencil sharpened at both ends as the axle. (JN)

  2. 78 FR 23105 - Airworthiness Directives; Airbus Airplanes

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-04-18

    ... machined with a radius as small as 0.4 millimeters. This AD requires replacing the wheel axle of the MLG... have been machined with a radius as small as 0.4 mm. This condition, if not corrected, has a... prompted by a report that revealed the wheel axles were machined with a radius as small as 0.4...

  3. 77 FR 51729 - Airworthiness Directives; Airbus Airplanes

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-08-27

    ... wheel axles of the main landing gear (MLG) were machined with a radius as small as 0.4 millimeters. This... machined with a radius as small as 0.4 mm. This condition, if not corrected, has a detrimental effect on... prompted by a report that revealed the wheel axles were machined with a radius as small as 0.4...

  4. Characterizing and Targeting Replication Stress Response Defects in Breast Cancer

    DTIC Science & Technology

    2015-08-01

    AXL, AZD6244, SCH772984, hallow gold nanoparticle (HAuNS) 16. SECURITY CLASSIFICATION OF: 17. LIMITATION OF ABSTRACT 18. NUMBER OF PAGES 19a. NAME...developing antibody-conjugated hallow gold nanoparticle (HAuNS) to bind RSRD cells in vitro. We conjugated HAuNS with the antibodies against AXL and

  5. 23 CFR 658.17 - Weight.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    .... States may not limit tire loads to less than 500 pounds per inch of tire or tread width, except that such limits may not be applied to tires on the steering axle. States may not limit steering axle weights to... utilizes an auxiliary power or idle reduction technology unit in order to promote reduction of fuel use and...

  6. String and Sticky Tape Experiments: Simple Self-Lubricated Electric Motor for Elementary Physics Lab.

    ERIC Educational Resources Information Center

    Entrikin, Jerry; Griffiths, David

    1983-01-01

    The main problem in constructing functioning electric motors from simple parts is the mounting of the axle (which is too flimsy to maintain good electrical contacts or too tight, imposing excessive friction at the supports). This problem is solved by using a pencil sharpened at both ends as the axle. (JN)

  7. 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.

  8. Single gear-pair vehicle differential

    SciTech Connect

    Holan, R.J.; Lindsey, K.D.

    1987-01-20

    An apparatus is described for transforming rotary power conveyable into the apparatus by a drive shaft to rotary power to at least two wheels of a vehicle comprising: (a) a driving gear coupleable to an input power drive shaft, (b) a driven gear meshing with the driving gear, (c) a first half axle rigidly coupled to the driven gear, (d) a second half axle colinear with the first half axle, (e) means for rotatably supporting the driving gear and intermediate longitudinal portions of the first and second half axles, (f) means for rotatably supporting inner facing portions of the first and second half axles in coaxial alignment. The means comprises a coaxial, cylindrical cavity extending perpendicularly inward from an inner face of one of the first and second half axles, and a constricted diameter inner end of the other half axle adapted to fit insertably and rotatably within the cavity, and (g) means for slippably connecting the inner facing ends of the first and second half axles.

  9. Data Quality and Reliability Analysis of U.S. Marine Corps Ground Vehicle Maintenance Records

    DTIC Science & Technology

    2015-06-01

    E AXLE AXLE SYSTEM 3 CARB CARBURETION SYSTEM E04 AXLE N 95 E AXLE AXLE SYSTEM 4 CARR CARRIAGE AND MOUNT MECHANISM E06 AXLE N 111 E AXLE AXLE SYSTEM 6...MODIFICATION APPLICATION I71 ARMT N 207 I ARMT ARMAMENT 71 RPR REPAIR I ARMT N 124 I ARMT ARMAMENT NOT GIVEN J03 COOL N 1 J COOL COOLING SYSTEM 3 CARB ...N02 AIR N 3541 N AIR AIR SYSTEM 2 BRK BRAKE SYSTEMS AND COMPONENTS N03 AIR N 23 N AIR AIR SYSTEM 3 CARB CARBURETION SYSTEM N05 AIR N 113 N AIR AIR

  10. A novel application of E1A in combination therapy with EGFR-TKI treatment in breast cancer

    PubMed Central

    Su, Chih-Ming; Chang, Ting-Yu; Hsu, Hui-Ping; Lai, Hui-Huang; Li, Jie-Ning; Lyu, Yu-Jhen; Kuo, Kuang-Tai; Huang, Ming-Te; Su, Jen-Liang; Chen, Pai-Sheng

    2016-01-01

    Epidermal growth factor receptor (EGFR) is commonly overexpressed in breast cancer and is associated with poor clinical outcomes; however, an increasing number of patients have shown a poor effective response to EGFR tyrosine kinase inhibitors (EGFR-TKI). Here, we found that AXL expression was positively correlated with poor progression in breast cancer patients. Suppression of AXL by an anti-tumor protein, E1A, enhanced EGFR-TKI (gefitinib, erlotinib and lapatinib) sensitization, resulting in significant inhibition of tumor growth in breast cancer cells. Additionally, AXL overexpression dramatically impaired E1A-mediated EGFR-TKI sensitization. These findings show that downregulation of AXL expression by E1A contributes to sensitization to EGFR-TKI in breast cancer, suggesting that combinatorial therapy of AXL inhibitors or E1A gene therapy with EGFR-TKI may be a potential therapeutic strategy for treatment of breast cancer patients. PMID:27590506

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

    PubMed

    Sevick, Edith M; Williams, David R M

    2013-10-30

    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.

  12. 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.

  13. 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)

  14. 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)

  15. 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)

  16. 49 CFR 587.6 - General description.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ...) The specifications for the research axle assembly are provided in drawings shown in DSL-1287, dated... surface, supporting structure, and carriage, weighs 3,015 pounds, has a track width of 74 inches, and has...

  17. 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...

  18. 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...

  19. 14 CFR 25.509 - Towing loads.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 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...

  20. 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...

  1. 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...

  2. 40 CFR 86.602-98 - Definitions.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... subclassification of an engine-system combination on the basis of engine code, inertia weight class, transmission type and gear ratios, axle ratio, and other parameters which may be designated by the...

  3. 49 CFR 238.419 - Truck-to-car-body and truck component attachment.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... on the truck, along with the resulting vertical reaction to this load. (b) Each component of a truck (which include axles, wheels, bearings, the truck-mounted brake system, suspension system components,...

  4. 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.

  5. 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.

  6. GAS6 Receptor Status Is Associated with Dormancy and Bone Metastatic Tumor Formation

    PubMed Central

    Taichman, Russell S.; Patel, Lalit R.; Bedenis, Rachel; Wang, Jingcheng; Weidner, Savannah; Schumann, Taibriana; Yumoto, Kenji; Berry, Janice E.; Shiozawa, Yusuke; Pienta, Kenneth J.

    2013-01-01

    Disseminated tumor cells (DTCs) are believed to lie dormant in the marrow before they can be activated to form metastases. How DTCs become dormant in the marrow and how dormant DTCs escape dormancy remains unclear. Recent work has shown that prostate cancer (PCa) cell lines express the growth-arrest specific 6 (GAS6) receptors Axl, Tyro3, and Mer, and become growth arrested in response to GAS6. We therefore hypothesized that GAS6 signaling regulates the proliferative activity of DTCs in the marrow. To explore this possibility, in vivo studies were performed where it was observed that when Tyro3 expression levels exceed Axl expression, the PCa cells exhibit rapid growth. When when Axl levels predominate, PCa cells remain largely quiescent. These findings suggest that a balance between the expression of Axl and Tyro3 is associated with a molecular switch between a dormant and a proliferative phenotype in PCa metastases. PMID:23637920

  7. 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.

  8. Joint Light Tactical Vehicle Power Requirements

    DTIC Science & Technology

    2007-04-24

    Power & Thermal Management Engine Drivetrain Diesel Turbine Gasoline Stratified Charge Diesel Fuel Cell Turbine Battery Generators Driveline Components...continuous ■ 7 speed hydrokinetic automatic transmission MSV Companion Trailer (CT) Commonality with MSV ■ Axles, suspension, wheels, tires, brakes

  9. A Methodology for Quantitative Comparison of Experimental to Predicted Chemical Deposition Data

    DTIC Science & Technology

    1990-07-01

    INTRODUCTION ..................................................................................... 1 II. BACKGROUN D...Ed Kerhn ANL\\SY-J (J Bloomquist) Dr Ni Charrn ANC -S’i -GD (R Mezan) 1801 N Beauregard Street ANIXS’ (Chandler) Alexandria. %A 22311 AXL\\SY (Chris

  10. 40 CFR 86.097-9 - Emission standards for 1997 and later model year light-duty trucks.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... (ii) Are equipped with a unique, high-altitude axle ratio (rear-wheel drive vehicles) or a unique, high-altitude drivetrain (front-wheel drive vehicles) with a higher N/V ratio than other configurations...

  11. 40 CFR 86.097-9 - Emission standards for 1997 and later model year light-duty trucks.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... (ii) Are equipped with a unique, high-altitude axle ratio (rear-wheel drive vehicles) or a unique, high-altitude drivetrain (front-wheel drive vehicles) with a higher N/V ratio than other configurations...

  12. Electronic differential for tramcar bogies: system development and performance evaluation by means of numerical simulation

    NASA Astrophysics Data System (ADS)

    Barbera, Andrea N.; Bucca, Giuseppe; Corradi, Roberto; Facchinetti, Alan; Mapelli, Ferdinando

    2014-05-01

    The dynamic behaviour of railway vehicles depends on the wheelset configuration, i.e. solid axle wheelset or independently rotating wheels (IRWs). The self-centring behaviour, peculiar of the solid axle wheelset, makes this kind of wheelset very suitable for tangent track running at low speed: the absence of the self-centring mechanism in the IRWs may lead to anomalous wheel/rail wear, reduced vehicle safety and passengers' discomfort. On the contrary, during negotiation of the sharp curves typical of urban tramways, solid axle wheelsets produce lateral contact forces higher than those of IRWs. This paper illustrates an electronic differential system to be applied to tramcar bogies equipped with wheel-hub motors which allows switching from solid axle in tangent track to IRWs in sharp curve (and vice versa). An electro-mechanical vehicle model is adopted for the design of the control system and for the evaluation of the vehicle dynamic performances.

  13. Steel - Structural, reinforcing; Pressure vessel, railway

    SciTech Connect

    Not Available

    1986-01-01

    This book contains specifications for structural steel used in various constructions; concrete reinforcement; plate and forgings for boilers and pressure vesseles; rails, axles, wheels and other accessories for railway service.

  14. 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)

  15. 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)

  16. 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)

  17. 49 CFR 238.419 - Truck-to-car-body and truck component attachment.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... on the truck, along with the resulting vertical reaction to this load. (b) Each component of a truck (which include axles, wheels, bearings, the truck-mounted brake system, suspension system components, and...

  18. 49 CFR 238.419 - Truck-to-car-body and truck component attachment.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... on the truck, along with the resulting vertical reaction to this load. (b) Each component of a truck (which include axles, wheels, bearings, the truck-mounted brake system, suspension system components, and...

  19. 49 CFR 238.419 - Truck-to-car-body and truck component attachment.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... on the truck, along with the resulting vertical reaction to this load. (b) Each component of a truck (which include axles, wheels, bearings, the truck-mounted brake system, suspension system components, and...

  20. 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.

  1. 40 CFR 205.51 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... contains the operator/passenger compartment is directly above the engine and front axle and the entire cab... or cause the reduction of noise emitted from a vehicle. (19) Noise emission test means a...

  2. 40 CFR 205.51 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... contains the operator/passenger compartment is directly above the engine and front axle and the entire cab... or cause the reduction of noise emitted from a vehicle. (19) Noise emission test means a...

  3. 49 CFR 393.201 - Frames.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ..., broken, or missing. (c) The frame rail flanges between the axles shall not be bent, cut or notched... recommendations. (e) No holes shall be drilled in the top or bottom rail flanges, except as specified by the...

  4. 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.

  5. Anticancer effect of luteolin is mediated by downregulation of TAM receptor tyrosine kinases, but not interleukin-8, in non-small cell lung cancer cells.

    PubMed

    Lee, Youn Ju; Lim, Taeho; Han, Min Su; Lee, Sun-Hwa; Baek, Suk-Hwan; Nan, Hong-Yan; Lee, Chuhee

    2017-02-01

    TAM receptor tyrosine kinases (RTKs), Tyro3, Axl and MerTK, transduce diverse signals responsible for cell survival, growth, proliferation and anti-apoptosis. In the present study, we demonstrated the effect of luteolin, a flavonoid with antioxidant, anti-inflammatory and anticancer activities, on the expression and activation of TAM RTKs and the association with its cytotoxicity in non-small cell lung cancer (NSCLC) cells. We observed the cytotoxic effect of luteolin in parental A549 and H460 cells as well as in cisplatin-resistant A549/CisR and H460/CisR cells. Exposure of these cells to luteolin also resulted in a dose‑dependent decrease in clonogenic ability. Next, luteolin was found to decrease the protein levels of all three TAM RTKs in the A549 and A549/CisR cells in a dose‑dependent manner. In a similar manner, in H460 and H460/CisR cells, the protein levels of Axl and Tyro3 were decreased following luteolin treatment. In addition, Axl promoter activity was decreased by luteolin, indicating that luteolin suppresses Axl expression at the transcriptional level. We next found that luteolin abrogated Axl phosphorylation in response to growth arrest-specific 6 (Gas6), its ligand, implying the inhibitory effect of luteolin on Gas6-induced Axl activation. Ectopic expression of Axl was observed to attenuate the antiproliferative effect of luteolin, while knockdown of the Axl protein level using a gold nanoparticle-assisted gene delivery system increased its cytotoxicity. In contrast to the inhibitory effect of luteolin on the expression of TAM RTKs, interleukin-8 (IL-8) production was not decreased by luteolin in H460 and H460/CisR cells, while IL-8 production/cell was increased. Collectively, our data suggest that TAM RTKs, but not IL-8, are promising therapeutic targets of luteolin to abrogate cell proliferation and to overcome chemoresistance in NSCLC cells.

  6. 76 FR 68306 - Airworthiness Directives; Bombardier, Inc. Airplanes

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-11-04

    ... 49263-3, we want to avoid the possibility of an operator overlooking the intent of this final rule... to include new Note 2 to inform operators that MLG piston axles having P/N 49203-3 or 49203-5 that... cases of failure of the MLG [main landing gear] piston axle, P/N 49203-3 or 49203-5, resulting...

  7. 49 CFR 393.47 - Brake actuators, slack adjusters, linings/pads and drums/rotors.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... steering axle of a truck, truck-tractor or bus shall not be less than 4.8 mm (3/16 inch) at the shoe center....6 mm (1/16 inch) or less for hydraulic disc, drum and electric brakes. (2) Non-steering axle brakes... for drum brakes); or less than 3.2 mm (1/8 inch) for disc brakes. Hydraulic or electric braked...

  8. Joint Recovery and Distribution System (JRaDS) Joint Capability Technology Demonstration (JCTD), Technical Manager’s Report

    DTIC Science & Technology

    2013-09-01

    the longer gooseneck required for HET compatibility. The three - axle , hydraulic, independent suspension was designed for operations over rough terrain...scenario three Recover 6x6 MRAP Buffalo (vehicle shell, only body and axles ) from Mire III positioned laterally in mud pit 4. Recovery scenario four...PROGRAM BACKGROUND This document serves as the TM’s final report for the JRaDS JCTD. The JRaDS JCTD was comprised of three trailer variants: the 34T

  9. Transportability

    DTIC Science & Technology

    2013-04-25

    psi). (g) Maximum axle load (pneumatic tires) - 2,268 kg (5,000 lb). (h) Maximum wheel load (pneumatic tires) - 1,134 kg (2,500 lb). (i...survivability following the shock or vibration environment induced. Vehicles not typically transported with payload such as wreckers, truck tractors ...combination weight rating (GCWR) means the value specified by the manufacturer as the loaded weight of the combination vehicle. (d) Gross axle weight

  10. The Coast Artillery Journal. Volume 80, Number 4, July-August 1937

    DTIC Science & Technology

    1937-08-01

    with low bodies, one each for searchlight, power plant, and sound locator. Nfethod No. 5, Three short-coupled commercial trucks with semitrailers , each...Wheels. Universal Joints, Drive Shafts, and Differentials. ga Valves and Valve Operating Mechanisms. Rear Axles , Frames, Springs, and Shock Absorbers...na Valve Timing. Brakes. n .. Crankcase Lubrication. Front Axles and Steering... !1 Engine Cooling Systems .. Tires, Rims and \\Vheels. :: ~ Fl’ 0 h

  11. Ground Transportation for Polar Operations - 16 Wheel Low-Ground- Pressure Vehicle (LGPB-16)

    DTIC Science & Technology

    1976-01-01

    Polar transportation equipment - six by six truck tractor and 20-ton semitrailer with high-flotation tire, by W. H. Beard and G. E...transportation, polar regions, tires, high flotation, wobbly- axle , walking beam suspension. 20 ABSln^AC T (Conllnu* on tovtt» aidm II n*c*«*«rv...the vehicle. Each group of eight wheels would be subgrouped into four wheels connected by a wobbly- axle , walking-beam assembly to provide

  12. Mountain Braking Test Venue Study

    DTIC Science & Technology

    2013-12-12

    absorbed by tire rolling resistance is shown in Figure 2 for an 80,000 lb four axle tractor -trailer. Fitting this data and recognizing that rolling...aerodynamic drag is shown in Figure 2 for an 80,000 lb four axle tractor -trailer. Fitting this data and recognizing that aerodynamic drag is...the optimum mountain braking strategy to reduce the range of brake temperatures among the brakes of a tractor - semitrailer combination weighing nearly

  13. Proceedings of the International Conference on The Performance of Off-Road Vehicles and Machines (8th). Volume 2. Held at Cambridge England, on August 5-11, 1984.

    DTIC Science & Technology

    1984-08-01

    of the electronics. 2. They were costly to install owing to the skilled labor required to install the sensors. 3. The system would not completely...rejected owing to excessive installation cost and cost of replacement or repair. Highly skilled labor was required. 2. Weldable strain gages directly...tractor ront axle Or rar axle of omie harv estr ; 4. stearablity and stabLity of tracte and Implain ts during operation an skcpe: 5. w eral drive

  14. Soviet Union, Military Affairs.

    DTIC Science & Technology

    1987-07-08

    hydraulic brake linkage is connected separately to the actuating brakes of the front and rear axles . In case of hermetic-seal failure in one of the...safety. Designers had this in mind when they used polypropylene to fabricate the steering wheel and used a joint to connect the steering wheel shaft...good lubrication of the bearing needles. The casing lever of the front- axle rotary cam has been reinforced. The well-known, multi-purpose GAZ-66

  15. Apparatus and Method for Generating Electric Energy in a Fluid Environment

    DTIC Science & Technology

    2005-03-14

    IONISTATEIENT A Filing Date 14 March 2005 Approved for Public Release Distribution Unlimited Inventor Donald H. Steinbrecher If you have any questions...member, a gear system disposed 6 in the housing, and an axle interconnects each of the crank 7 members and the gear system. An electrical generator is...fixed to an axle extending into the housing 25 and connected to the gear system, and an electrical generator is 3 1 disposed in the housing and driven

  16. Support structure of differential gear unit

    SciTech Connect

    Yasui, Y.; Suganuma, T.

    1989-04-18

    A support structure is described of a differential gear unit assembled in a trans-axle casing having a pair of axially spaced carrier portions and an open end closed by a removable cover member secured thereto, an outer case of the gear unit having a pair of side journals rotatable supported by a pair of tapered roller bearings which are removably coupled within respective cylindrical bores in the carrier portions of the trans-axle casing.

  17. Dual trailing arm vehicle suspension system

    SciTech Connect

    Weitzenhof, D.A.; Sayre, C.F.

    1986-11-18

    This patent describes a vehicle suspension system adapted to be interposed between a vehicle frame and at least two wheels arranged one in advance of the other on a side of the vehicle frame; the suspension system including: (a) at least two axles on a side of the vehicle frame for independently rotatably mounting each of the wheels; (b) at least two trailing arms, each of the arms being attached at one end to a respective axle and extending forwardly from the axle wherein the number of the trailing arms does not exceed the number of axles; (c) at least two pivot means mounted on the vehicle frame and connected to the other end of the trailing arms for pivotally mounting the vehicle frame wherein the number of the pivot means, does not exceed the number of axles; (d) lever means attached to and extending outwardly from each of the pivot means for pivotal movement with the pivot means means in relationship to movement of the trailing arms, with the length of the lever means being independent of the spacing between the axles; and (e) elastomer spring means extending between and pivotally mounted on the lever means for absorbing and balancing the forces exerted on the wheels particularly during braking and when encountering variations in the road surface.

  18. 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.

  19. 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. © Georg Thieme Verlag KG Stuttgart · New York.

  20. TAZ Expression as a Prognostic Indicator in Colorectal Cancer

    PubMed Central

    Tham, Jill M.; Zhang, Xiaoqian; Zeng, Qi; Zhang, Shu-Dong; Hong, WanJin

    2013-01-01

    The Hippo pathway restricts the activity of transcriptional coactivators TAZ (WWTR1) and YAP. TAZ and YAP are reported to be overexpressed in various cancers, however, their prognostic significance in colorectal cancers remains unstudied. The expression levels of TAZ and YAP, and their downstream transcriptional targets, AXL and CTGF, were extracted from two independent colon cancer patient datasets available in the Gene Expression Omnibus database, totaling 522 patients. We found that mRNA expressions of both TAZ and YAP were positively correlated with those of AXL and CTGF (p<0.05). High level mRNA expression of TAZ, AXL or CTGF significantly correlated with shorter survival. Importantly, patients co-overexpressing all 3 genes had a significantly shorter survival time, and combinatorial expression of these 3 genes was an independent predictor for survival. The downstream target genes for TAZ-AXL-CTGF overexpression were identified by Java application MyStats. Interestingly, genes that are associated with colon cancer progression (ANTXR1, EFEMP2, SULF1, TAGLN, VCAN, ZEB1 and ZEB2) were upregulated in patients co-overexpressing TAZ-AXL-CTGF. This TAZ-AXL-CTGF gene expression signature (GES) was then applied to Connectivity Map to identify small molecules that could potentially be utilized to reverse this GES. Of the top 20 small molecules identified by connectivity map, amiloride (a potassium sparing diuretic,) and tretinoin (all-trans retinoic acid) have shown therapeutic promise in inhibition of colon cancer cell growth. Using MyStats, we found that low level expression of either ANO1 or SQLE were associated with a better prognosis in patients who co-overexpressed TAZ-AXL-CTGF, and that ANO1 was an independent predictor of survival together with TAZ-AXL-CTGF. Finally, we confirmed that TAZ regulates Axl, and plays an important role in clonogenicity and non-adherent growth in vitro and tumor formation in vivo. These data suggest that TAZ could be a therapeutic

  1. 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

  2. Choroidal thickness profile in healthy Indian children.

    PubMed

    Chhablani, Jay Kumar; Deshpande, Riddhima; Sachdeva, Virender; Vidya, Sagar; Rao, P Srinivasa; Panigati, Anand; Mahat, Birendra; Pappuru, Rajeev Reddy; Pehere, Niranjan; Pathengay, Avinash

    2015-06-01

    The purpose was to study choroidal thickness and its profile based on location in healthy Indian children using enhanced depth spectral-domain-optical coherence tomography (SD-OCT). In this cross-sectional observational study 255 eyes of 136 children with no retinal or choroidal disease were consecutively scanned using enhanced depth SD-OCT. Eyes with any ocular disease or axial length (AXL) >25 mm or < 20 mm were excluded. A single observer measured choroidal thickness from the posterior edge of the retinal pigment epithelium to the choroid/sclera junction at 500-microns intervals up to 2500 microns temporal and nasal to the fovea. Generalized estimating equations were used to evaluate the correlation between choroidal thickness at various locations and age, AXL, gender and spherical equivalent (SEq). Mean age of the subjects was 11.9 ± 3.4 years (range: 5-18 years). There were 62 Females and 74 males. The mean AXL was 23.55 ± 0.74 mm. Mean subfoveal choroidal thickness was 312.1 ± 45.40 μm. Choroid was found to be thickest subfoveally, then temporally. Age, AXL and SEq showed a significant correlation with choroidal thickness, whereas gender did not affect choroidal thickness. Our study provides a valid normative database of choroidal thickness in healthy Indian children. This database could be useful for further studies evaluating choroidal changes in various chorioretinal disorders. Age and AXL are critical factors, which negatively correlated with choroidal thickness.

  3. Small molecule inhibitors block Gas6-inducible TAM activation and tumorigenicity

    PubMed Central

    Kimani, Stanley G.; Kumar, Sushil; Bansal, Nitu; Singh, Kamalendra; Kholodovych, Vladyslav; Comollo, Thomas; Peng, Youyi; Kotenko, Sergei V.; Sarafianos, Stefan G.; Bertino, Joseph R.; Welsh, William J.; Birge, Raymond B.

    2017-01-01

    TAM receptors (Tyro-3, Axl, and Mertk) are a family of three homologous type I receptor tyrosine kinases that are implicated in several human malignancies. Overexpression of TAMs and their major ligand Growth arrest-specific factor 6 (Gas6) is associated with more aggressive staging of cancers, poorer predicted patient survival, acquired drug resistance and metastasis. Here we describe small molecule inhibitors (RU-301 and RU-302) that target the extracellular domain of Axl at the interface of the Ig-1 ectodomain of Axl and the Lg-1 of Gas6. These inhibitors effectively block Gas6-inducible Axl receptor activation with low micromolar IC50s in cell-based reporter assays, inhibit Gas6-inducible motility in Axl-expressing cell lines, and suppress H1299 lung cancer tumor growth in a mouse xenograft NOD-SCIDγ model. Furthermore, using homology models and biochemical verifications, we show that RU301 and 302 also inhibit Gas6 inducible activation of Mertk and Tyro3 suggesting they can act as pan-TAM inhibitors that block the interface between the TAM Ig1 ectodomain and the Gas6 Lg domain. Together, these observations establish that small molecules that bind to the interface between TAM Ig1 domain and Gas6 Lg1 domain can inhibit TAM activation, and support the further development of small molecule Gas6-TAM interaction inhibitors as a novel class of cancer therapeutics. PMID:28272423

  4. 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.

  5. Torque Generation in F1-ATPase Devoid of the Entire Amino-Terminal Helix of the Rotor That Fills Half of the Stator Orifice

    PubMed Central

    Kohori, Ayako; Chiwata, Ryohei; Hossain, Mohammad Delawar; Furuike, Shou; Shiroguchi, Katsuyuki; Adachi, Kengo; Yoshida, Masasuke; Kinosita, Kazuhiko

    2011-01-01

    F1-ATPase is an ATP-driven rotary molecular motor in which the central γ-subunit rotates inside a cylinder made of α3β3 subunits. The amino and carboxyl termini of the γ rotor form a coiled coil of α-helices that penetrates the stator cylinder to serve as an axle. Crystal structures indicate that the axle is supported by the stator at two positions, at the orifice and by the hydrophobic sleeve surrounding the axle tip. The sleeve contacts are almost exclusively to the longer carboxyl-terminal helix, whereas nearly half the orifice contacts are to the amino-terminal helix. Here, we truncated the amino-terminal helix stepwise up to 50 residues, removing one half of the axle all the way up and far beyond the orifice. The half-sliced axle still rotated with an unloaded speed a quarter of the wild-type speed, with torque nearly half the wild-type torque. The truncations were made in a construct where the rotor tip was connected to a β-subunit via a short peptide linker. Linking alone did not change the rotational characteristics significantly. These and previous results show that nearly half the normal torque is generated if rotor-stator interactions either at the orifice or at the sleeve are preserved, suggesting that the make of the motor is quite robust. PMID:21723829

  6. Torque generation in F1-ATPase devoid of the entire amino-terminal helix of the rotor that fills half of the stator orifice.

    PubMed

    Kohori, Ayako; Chiwata, Ryohei; Hossain, Mohammad Delawar; Furuike, Shou; Shiroguchi, Katsuyuki; Adachi, Kengo; Yoshida, Masasuke; Kinosita, Kazuhiko

    2011-07-06

    F(1)-ATPase is an ATP-driven rotary molecular motor in which the central γ-subunit rotates inside a cylinder made of α(3)β(3) subunits. The amino and carboxyl termini of the γ rotor form a coiled coil of α-helices that penetrates the stator cylinder to serve as an axle. Crystal structures indicate that the axle is supported by the stator at two positions, at the orifice and by the hydrophobic sleeve surrounding the axle tip. The sleeve contacts are almost exclusively to the longer carboxyl-terminal helix, whereas nearly half the orifice contacts are to the amino-terminal helix. Here, we truncated the amino-terminal helix stepwise up to 50 residues, removing one half of the axle all the way up and far beyond the orifice. The half-sliced axle still rotated with an unloaded speed a quarter of the wild-type speed, with torque nearly half the wild-type torque. The truncations were made in a construct where the rotor tip was connected to a β-subunit via a short peptide linker. Linking alone did not change the rotational characteristics significantly. These and previous results show that nearly half the normal torque is generated if rotor-stator interactions either at the orifice or at the sleeve are preserved, suggesting that the make of the motor is quite robust. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  7. A self-threaded "molecular 8".

    PubMed

    Reuter, C; Wienand, W; Schmuck, C; Vögtle, F

    2001-04-17

    A new type of [1]rotaxanes containing two aliphatic bridges between axle and wheel is obtained in 39% yield in a one-step synthesis starting from a [2]rotaxane which contained one sulfonamide group each in both the wheel and the axle. Temperature controlled chemoselective substitution reactions first at these sulfonamide nitrogens and then subsequently at the various other carboxamide nitrogens in the wheel and axle give rise to the formation of an isomeric mixture of three double-bridged [1]rotaxanes which could be separated by HPLC. Structure determination of the main product 3a was possible by NMR experiments supported by molecular modeling calculations. Using different reaction conditions, a double-substituted but not yet bridged [2]rotaxane 4 could be isolated as an intermediate giving further evidence for the assigned structure of 3a and the way of its formation. The shape of this double-bridged [1]rotaxane 3a reminds of a self-intertwining chiral "molecular 8", in which any possible racemization due to deslipping is hindered by the two stoppers originating from the former rotaxane axle. Hence, to the best of our knowledge this is the first example of a molecule in which both concepts, cycloenantiomerism and helical chirality, are realised in one structure. Enantiomer separation of the main product was possible by further HPLC using chiral stationary phases. The Cotton effects of the circular dichrograms are different to those of the already synthesized [1]rotaxanes bearing just one aliphatic bridge between axle and wheel.

  8. Amuvatinib has cytotoxic effects against NRAS-mutant melanoma but not BRAF-mutant melanoma.

    PubMed

    Fedorenko, Inna V; Fang, Bin; Koomen, John M; Gibney, Geoffrey T; Smalley, Keiran S M

    2014-10-01

    Effective targeted therapy strategies are still lacking for the 15-20% of melanoma patients whose melanomas are driven by oncogenic NRAS. Here, we report on the NRAS-specific behavior of amuvatinib, a kinase inhibitor with activity against c-KIT, Axl, PDGFRα, and Rad51. An analysis of BRAF-mutant and NRAS-mutant melanoma cell lines showed the NRAS-mutant cohort to be enriched for targets of amuvatinib, including Axl, c-KIT, and the Axl ligand Gas6. Increasing concentrations of amuvatinib selectively inhibited the growth of NRAS-mutant, but not BRAF-mutant melanoma cell lines, an effect associated with induction of S-phase and G2/M-phase cell cycle arrest and induction of apoptosis. Mechanistically, amuvatinib was noted to either inhibit Axl, AKT, and MAPK signaling or Axl and AKT signaling and to induce a DNA damage response. In three-dimensional cell culture experiments, amuvatinib was cytotoxic against NRAS-mutant melanoma cell lines. Thus, we show for the first time that amuvatinib has proapoptotic activity against melanoma cell lines, with selectivity observed for those harboring oncogenic NRAS.

  9. A double-stranded DNA rotaxane.

    PubMed

    Ackermann, Damian; Schmidt, Thorsten L; Hannam, Jeffrey S; Purohit, Chandra S; Heckel, Alexander; Famulok, Michael

    2010-06-01

    Mechanically interlocked molecules such as rotaxanes and catenanes have potential as components of molecular machinery. Rotaxanes consist of a dumb-bell-shaped molecule encircled by a macrocycle that can move unhindered along the axle, trapped by bulky stoppers. Previously, rotaxanes have been made from a variety of molecules, but not from DNA. Here, we report the design, assembly and characterization of rotaxanes in which both the dumb-bell-shaped molecule and the macrocycle are made of double-stranded DNA, and in which the axle of the dumb-bell is threaded through the macrocycle by base pairing. The assembly involves the formation of pseudorotaxanes, in which the macrocycle and the axle are locked together by hybridization. Ligation of stopper modules to the axle leads to the characteristic dumb-bell topology. When an oligonucleotide is added to release the macrocycle from the axle, the pseudorotaxanes are either converted to mechanically stable rotaxanes, or they disassemble by means of a slippage mechanism to yield a dumb-bell and a free macrocycle. Our DNA rotaxanes allow the fields of mechanically interlocked molecules and DNA nanotechnology to be combined, thus opening new possibilities for research into molecular machines and synthetic biology.

  10. A double-stranded DNA rotaxane

    NASA Astrophysics Data System (ADS)

    Ackermann, Damian; Schmidt, Thorsten L.; Hannam, Jeffrey S.; Purohit, Chandra S.; Heckel, Alexander; Famulok, Michael

    2010-06-01

    Mechanically interlocked molecules such as rotaxanes and catenanes have potential as components of molecular machinery. Rotaxanes consist of a dumb-bell-shaped molecule encircled by a macrocycle that can move unhindered along the axle, trapped by bulky stoppers. Previously, rotaxanes have been made from a variety of molecules, but not from DNA. Here, we report the design, assembly and characterization of rotaxanes in which both the dumb-bell-shaped molecule and the macrocycle are made of double-stranded DNA, and in which the axle of the dumb-bell is threaded through the macrocycle by base pairing. The assembly involves the formation of pseudorotaxanes, in which the macrocycle and the axle are locked together by hybridization. Ligation of stopper modules to the axle leads to the characteristic dumb-bell topology. When an oligonucleotide is added to release the macrocycle from the axle, the pseudorotaxanes are either converted to mechanically stable rotaxanes, or they disassemble by means of a slippage mechanism to yield a dumb-bell and a free macrocycle. Our DNA rotaxanes allow the fields of mechanically interlocked molecules and DNA nanotechnology to be combined, thus opening new possibilities for research into molecular machines and synthetic biology.

  11. Amuvatinib has cytotoxic effects against NRAS- but not BRAF-mutant melanoma

    PubMed Central

    Fedorenko, Inna V.; Fang, Bin; Koomen, John M; Gibney, Geoffrey T.; Smalley, Keiran S.M.

    2015-01-01

    Effective targeted therapy strategies are still lacking for the 15–20% of melanoma patients whose melanomas are driven by oncogenic NRAS. We here report on the NRAS-specific behavior of amuvatinib, a kinase inhibitor with activity against c-KIT, Axl, PDGFRα and Rad51. An analysis of BRAF- and NRAS-mutant melanoma cell lines showed the NRAS-mutant cohort to be enriched for targets of amuvatinib, including Axl, c-KIT and the Axl ligand Gas6. Increasing concentrations of amuvatinib selectively inhibited the growth of NRAS- but not BRAF-mutant melanoma cell lines, an effect associated with induction of S- and G2/M-phase cell cycle arrest and induction of apoptosis. Mechanistically, amuvatinib was noted to either inhibit Axl, AKT and MAPK signaling or Axl and AKT signaling and to induce a DNA damage response. In 3D cell culture experiments, amuvatinib was cytotoxic against NRAS-mutant melanoma cell lines. Thus we show for the first time that amuvatinib has pro-apoptotic activity against melanoma cell lines, with selectivity observed for those harboring oncogenic NRAS. PMID:24950457

  12. 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.

  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. Identification of cell surface molecules involved in dystroglycan-independent Lassa virus cell entry.

    PubMed

    Shimojima, Masayuki; Ströher, Ute; Ebihara, Hideki; Feldmann, Heinz; Kawaoka, Yoshihiro

    2012-02-01

    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.

  15. Hierarchical Control Strategy for the Cooperative Braking System of Electric Vehicle.

    PubMed

    Peng, Jiankun; He, Hongwen; Liu, Wei; Guo, Hongqiang

    2015-01-01

    This paper provides a hierarchical control strategy for cooperative braking system of an electric vehicle with separated driven axles. Two layers are defined: the top layer is used to optimize the braking stability based on two sliding mode control strategies, namely, the interaxle control mode and signal-axle control strategies; the interaxle control strategy generates the ideal braking force distribution in general braking condition, and the single-axle control strategy can ensure braking safety in emergency braking condition; the bottom layer is used to maximize the regenerative braking energy recovery efficiency with a reallocated braking torque strategy; the reallocated braking torque strategy can recovery braking energy as much as possible in the premise of meeting battery charging power. The simulation results show that the proposed hierarchical control strategy is reasonable and can adapt to different typical road surfaces and load cases; the vehicle braking stability and safety can be guaranteed; furthermore, the regenerative braking energy recovery efficiency can be improved.

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

    PubMed

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

    2014-02-12

    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.

  18. Time-resolved fluorescence resonance energy transfer as a versatile tool in the development of homogeneous cellular kinase assays.

    PubMed

    Saville, Lisa; Spais, Chrysanthe; Mason, Jennifer L; Albom, Mark S; Murthy, Seetha; Meyer, Sheryl L; Ator, Mark A; Angeles, Thelma S; Husten, Jean

    2012-12-01

    Homogeneous cellular assays can streamline product detection in the drug discovery process. One commercially available assay employing time-resolved fluorescence resonance energy transfer (TR-FRET) that detects phosphorylated products was used to evaluate inhibitors of the receptor tyrosine kinase AXL in a cell line expressing an AXL-green fluorescent protein fusion protein. This TR-FRET assay was modified to evaluate the phosphorylation state of the AXL family member MER in a cell line expressing MER with a V5 tag by adding a fluorescein-labeled anti-V5 antibody. This homogeneous cellular assay was further modified to evaluate the nonreceptor tyrosine kinase focal adhesion kinase (FAK) in cell lines that expressed an untagged kinase by the inclusion of a commercially available anti-FAK antibody conjugated with an acceptor dye. The methods described here can be further adapted for TR-FRET detection of other cellular kinase activities.

  19. 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.

  20. Caring for Residents of Eldercare Facilities: A Concept Analysis.

    PubMed

    Hwang, Huei-Lih

    2017-01-01

    To report the results of an evolutionary concept analysis of caring in facilities that provide care for elders. Cumulative indices for CINAHL, ERIC, Academic Search Complete, PsychINFO, Medline, and CEPTS. Caring is an interactive process characterized by seeing, helping, and communicating, which are analogous to two wheels with one axle. Caring is preceded by individuality and followed by well-being. The findings explicate the core components of caring in facilities that provide care for elders. The metaphor of an axle and wheel can guide caregivers in delivering effective care as the demand for improved well-being of residents of eldercare facilities increases. © 2015 NANDA International, Inc.

  1. Powered Wheels in the Turned Mode Operating on Yielding Soils

    DTIC Science & Technology

    1976-09-01

    after Schuring , 1966) ... ........ 6 2.2. Conditions of a Wheel on Yielding Soil ..... ........... 7 2.3. Development of Trail Moment SF.C from An...forces and moments applied to the axle and at the interface area. Figure 2.1 (after Schuring , 1966) illustrates the possible combination of torque and...Horizontal Axle Pull P of a Free-Bodied Wheel (after Schuring , 1966). il ll l !ili l I m I U I 1 I II li i~ l6I TORQUE M o PULL P NEGA TI VE SLIP POS1TI

  2. JPRS Report, Soviet Union, Foreign Military Review, No. 8, August 1987

    DTIC Science & Technology

    2007-11-02

    pulse of a nuclear explosion, thunderstorm discharges and electromagnetic interference. The hut is mounted on a two- axle semitrailer transported by...vehicle (M819 truck- tractor with hoisting crane and M269A1 semitrailer with four trans- port-launch canisters); —Mobile maintenance point (on M814...United States developed a three - axle gyroscope 25.4x25.4x25.4 mm in size. The FRG has tested a prototype of a gyroscope with optical fiber length

  3. Simplified Input for Certain Aerodynamic Nose Configurations to the Grumman Quick-Geometry System (A KWIKNOSE User’s Manual)

    DTIC Science & Technology

    1978-02-01

    slanted line. Discontinuities in the surface slope 10 AE DC-T R -77-89 would occur at this line in moving along a body llne. In the math model...results from two conditions: (I) QUICK assembles cross sections in planes normal to the geometric axis; (2) as modeled in Fig. 3, the slanted llne... slanted llne. Note, however, that the geometric axls might pene- trate the skin and require bending of the map axls to keep QUICK’s radius vector

  4. Traction Boot for Tires

    DTIC Science & Technology

    1992-04-08

    34AD-D0 15 390 IN THE UNITED STATES PATENT AND TRADEMARK OFFICE Patent Application NAME Or INVENTOR : Joseph G. Warner DLECTI TITLE Of INVENTION...this nature include tiro chains or a loop of track connecting fore and aft wh#ls of a tandem axle assembly. There are disadvqstages with these known...vehicles with tandeo axles . o ed imfd pubr𔃾fl1a 99214-255191 92 9 14 085 SUNMARX My invention ii a boot or temporary recap for a tire that can be

  5. 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.

  6. 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.

  7. 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.

  8. Driveline Fundamentals and Lubrication

    NASA Astrophysics Data System (ADS)

    Joseph, I.

    The various gear types and automotive transmissions in drive trains are described. The need for automotive differential axle gears is demonstrated. SAE gear lubricant classifications are related to performance specifications. Automatic transmission fluids, ATFs, are described together with agricultural and off-highway fluids. Generic formulations of driveline fluids are discussed in terms of their tribology and performance and also the contribution of various additive classes to that performance. The main functions of manual gearbox, automatic transmission and axle lubricants are described. General trends and emerging technologies in drive train components are discussed in terms of the requirements placed on the lubricant, evolution in transmission technologies and relative market penetration.

  9. Wheel-rail profile matching based on finite element method for Beijing metro

    NASA Astrophysics Data System (ADS)

    Liu, Jia-huan; Zhang, Jun; Liu, Xiao-dong; Zhu, Huang-shi; Zhang, Lin; Shang, Weipeng

    2017-09-01

    An instrument that measures wheel-rail appearance is used to measure the size of the wheel and rail in the section of the Baishiqiao South Station of Beijing Metro Line 6 to develop a finite element entity. Different working conditions such as axle load and traction are considered. The results show that: Under axle load, the matching performance of wheel I/rail II is improved, its contact area is the largest, and its equivalent stress and contact force are minimal; Under traction force, the matching performance of wheel I/rail II is improved, and the shear stress and equivalent stress are minimal, and thus is ideal.

  10. Snowmobile Repair. Teacher Edition.

    ERIC Educational Resources Information Center

    Hennessy, Stephen S.; Conrad, Rex

    This teacher's guide contains 14 units on snowmobile repair: (1) introduction to snowmobile repair; (2) skis, front suspension, and steering; (3) drive clutch; (4) drive belts; (5) driven clutch; (6) chain drives; (7) jackshafts and axles; (8) rear suspension; (9) tracks; (10) shock absorbers; (11) brakes; (12) engines; (13) ignition and…

  11. Learning Activity Packets for Auto Mechanics II. Section C--Drive Train.

    ERIC Educational Resources Information Center

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

    Five learning activity packets (LAPs) are provided for the instructional area of drive train in the auto mechanics II program. They accompany an instructor's guide available separately. The LAPs outline the study activities and performance tasks for these five units: (1) clutch assembly, (2) standard transmission, (3) drive lines, (4) rear axle,…

  12. Teaching Simple Machines.

    ERIC Educational Resources Information Center

    Atwater, Mary M.

    1988-01-01

    Presents several fun activities and teacher demonstrations which simplify terms and condense science concepts for teaching about the lever, wedge, wheel and axle, screw, pulley, and the inclined plane. Includes objectives, materials, procedures, suggested follow-up assignments, and diagrams. (RT)

  13. Simple Machines Made Simple.

    ERIC Educational Resources Information Center

    St. Andre, Ralph E.

    Simple machines have become a lost point of study in elementary schools as teachers continue to have more material to cover. This manual provides hands-on, cooperative learning activities for grades three through eight concerning the six simple machines: wheel and axle, inclined plane, screw, pulley, wedge, and lever. Most activities can be…

  14. Fun with Physics in the Elementary School.

    ERIC Educational Resources Information Center

    Ediger, Marlow

    Primary grade pupils can become fascinated with simple machines. This paper suggests that teachers have simple machines in the classroom for a unit of study. It proposes some guidelines to create a unit of study for six simple machines that include the fulcrum, inclined plane, pulley, wheel and axle, wedge, and screw. Friction, gravity, force, and…

  15. Basic Machines. Navy Training Course.

    ERIC Educational Resources Information Center

    Bureau of Naval Personnel, Washington, DC.

    This document is a reference for the enlisted men in the Navy whose duties require knowledge of the fundamentals of machinery. Beginning with the simplest of machines--the lever--the book proceeds with the discussion of block and tackle, wheel and axle, inclined plane, screw and gears. It explains the concepts of work and power, and differentiates…

  16. Verge and Foliot Clock Escapement: A Simple Dynamical System

    ERIC Educational Resources Information Center

    Denny, Mark

    2010-01-01

    The earliest mechanical clocks appeared in Europe in the 13th century. From about 1250 CE to 1670 CE, these simple clocks consisted of a weight suspended from a rope or chain that was wrapped around a horizontal axle. To tell time, the weight must fall with a slow uniform speed, but, under the action of gravity alone, such a suspended weight would…

  17. 14 CFR 23.509 - Towing loads.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    .... In addition: (1) A vertical load factor equal to 1.0 must be considered acting at the center of... main gear must be reacted as follows: (i) A reaction with a maximum value equal to the vertical reaction must be applied at the axle of the wheel to which the load is applied. Enough airplane inertia...

  18. 14 CFR 23.509 - Towing loads.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    .... In addition: (1) A vertical load factor equal to 1.0 must be considered acting at the center of... main gear must be reacted as follows: (i) A reaction with a maximum value equal to the vertical reaction must be applied at the axle of the wheel to which the load is applied. Enough airplane inertia...

  19. 14 CFR 23.509 - Towing loads.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    .... In addition: (1) A vertical load factor equal to 1.0 must be considered acting at the center of... main gear must be reacted as follows: (i) A reaction with a maximum value equal to the vertical reaction must be applied at the axle of the wheel to which the load is applied. Enough airplane inertia...

  20. 14 CFR 23.509 - Towing loads.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    .... In addition: (1) A vertical load factor equal to 1.0 must be considered acting at the center of... main gear must be reacted as follows: (i) A reaction with a maximum value equal to the vertical reaction must be applied at the axle of the wheel to which the load is applied. Enough airplane inertia...

  1. 14 CFR 23.509 - Towing loads.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    .... In addition: (1) A vertical load factor equal to 1.0 must be considered acting at the center of... main gear must be reacted as follows: (i) A reaction with a maximum value equal to the vertical reaction must be applied at the axle of the wheel to which the load is applied. Enough airplane inertia...

  2. Vehicle Sprung Mass Estimation for Rough Terrain

    DTIC Science & Technology

    2011-03-01

    corner) Hub Assembly 2.3 kg Hub Assembly 2.4 kg ½ of Front Axle 4.2 kg Knuckle 6.4 kg Steering Knuckle 3.7 kg Strut Assembly 4.8 kg Strut...terrains are listed in order from smoothest to roughest: smooth pavement, dirt/gravel terrain, and rough pavement with potholes and cracks . Figure

  3. 40 CFR 1066.210 - Dynamometers.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... to recreate the mechanical inertia and frictional forces that a vehicle exerts on road surfaces... drive axles may share a single drive roll. Use good engineering judgment to ensure that the dynamometer... engineering judgment. (3) The load applied by the dynamometer simulates forces acting on the vehicle during...

  4. The Effect of Friction in Pulleys on the Tension in Cables and Strings

    ERIC Educational Resources Information Center

    Martell, Eric C.; Martell, Verda Beth

    2013-01-01

    Atwood's machine is used in countless introductory physics classes as an illustration of Newton's second law. Initially, the analysis is performed assuming the pulley and string are massless and the axle is frictionless. Although the mass of the pulley is often included when the problem is revisited later in the context of rotational dynamics, the…

  5. Gear box assembly

    SciTech Connect

    Harrod, L.R.; Siebern, M.R.

    1989-04-25

    This patent describes a gearbox assembly for a vehicle which includes a driven axle shaft extending transversely of the vehicle having wheels secured thereto: a drive gear concentric with the axle shaft nonrotatably connected to the shaft, the drive gear having an integral hub on each of opposite sides thereof, a pinion gear shiftably mounted above the drive gear having one position engaging the drive gear and shiftable laterally to disengage from the drive gear, a shift lever mounted in a position projecting upwardly from the pinion gear actuatable to shift the pinion gear, an electric motor with output shaft mounted with the output shaft paralleling the axle shaft and having a driving gear mounted thereon, a multiple gear gear train mounted so as to establish a driving connection between the driving gear and the pinion gear, and a transmission housing enclosing the driving gar, gear train, pinion gear and drive gear, the housing including sleeve portions rotatably receiving the hubs of the drive gear and thus rotatably mounting the drive gear and the axle shaft connected to the drive gear.

  6. Simple Machine Junk Cars

    ERIC Educational Resources Information Center

    Herald, Christine

    2010-01-01

    During the month of May, the author's eighth-grade physical science students study the six simple machines through hands-on activities, reading assignments, videos, and notes. At the end of the month, they can easily identify the six types of simple machine: inclined plane, wheel and axle, pulley, screw, wedge, and lever. To conclude this unit,…

  7. Every Day a New 3D Printing Material

    ERIC Educational Resources Information Center

    Hughes, Bill; Mona, Lynn; Wilson, Greg; Seamans, Jeff; McAninch, Steve; Stout, Heath

    2017-01-01

    A handful of technological episodes: fire, wheel and axle, Industrial Revolution, Faraday's discovery of electromagnetic induction, the transistor, and the digital age, have historically altered humanity. We are now witnessing/participating in the next transformational technology: 3D printing. Although dating back nearly 30 years, the technology…

  8. 16 CFR 20.0 - Scope and purpose of the guides.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ..., fan clutches, fuel injectors, fuel pumps, front wheel drive axles, generators, master cylinders, oil pumps, power brake units, power steering gears, power steering pumps, power window motors, rack and pinion steering units, rotors, starter drives, speedometers, solenoids, smog pumps, starters, stators...

  9. 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... 49 Transportation 5 2012-10-01 2012-10-01 false Brakes required on all wheels. 393.42 Section 393... ACCESSORIES NECESSARY FOR SAFE OPERATION Brakes § 393.42 Brakes required on all wheels. (a) Every commercial...

  10. 16 CFR 20.0 - Scope and purpose of the guides.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ..., fan clutches, fuel injectors, fuel pumps, front wheel drive axles, generators, master cylinders, oil pumps, power brake units, power steering gears, power steering pumps, power window motors, rack and pinion steering units, rotors, starter drives, speedometers, solenoids, smog pumps, starters, stators...

  11. 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... 49 Transportation 5 2013-10-01 2013-10-01 false Brakes required on all wheels. 393.42 Section 393... ACCESSORIES NECESSARY FOR SAFE OPERATION Brakes § 393.42 Brakes required on all wheels. (a) Every commercial...

  12. 49 CFR 570.60 - Steering system.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... value shown in Table 3, there is excessive steering linkage play. Table 3. Front Wheel Steering Linkage... steering axle wheels in the straight ahead position, turn the steering wheel in one direction until there is a perceptible movement of the wheel. If a point on the steering wheel rim moves more than the...

  13. 49 CFR 570.60 - Steering system.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... value shown in Table 3, there is excessive steering linkage play. Table 3. Front Wheel Steering Linkage... steering axle wheels in the straight ahead position, turn the steering wheel in one direction until there is a perceptible movement of the wheel. If a point on the steering wheel rim moves more than the...

  14. 49 CFR 570.60 - Steering system.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... value shown in Table 3, there is excessive steering linkage play. Table 3. Front Wheel Steering Linkage... steering axle wheels in the straight ahead position, turn the steering wheel in one direction until there is a perceptible movement of the wheel. If a point on the steering wheel rim moves more than the...

  15. 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... 49 Transportation 5 2014-10-01 2014-10-01 false Brakes required on all wheels. 393.42 Section 393... ACCESSORIES NECESSARY FOR SAFE OPERATION Brakes § 393.42 Brakes required on all wheels. (a) Every commercial...

  16. 16 CFR 20.0 - Scope and purpose of the guides.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ..., fan clutches, fuel injectors, fuel pumps, front wheel drive axles, generators, master cylinders, oil pumps, power brake units, power steering gears, power steering pumps, power window motors, rack and pinion steering units, rotors, starter drives, speedometers, solenoids, smog pumps, starters, stators...

  17. 49 CFR 665.5 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... vehicles manufactured on a third-party chassis, a change in frame structure, material or configuration, or a change in chassis suspension type. Major change in components means: (1) For those vehicles that... vehicles whose chassis structure has been modified to include: a tandem or tag axle; a drop or...

  18. 49 CFR 665.5 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... vehicles manufactured on a third-party chassis, a change in frame structure, material or configuration, or a change in chassis suspension type. Major change in components means: (1) For those vehicles that... vehicles whose chassis structure has been modified to include: a tandem or tag axle; a drop or...

  19. 49 CFR 571.121 - Standard No. 121; Air brake systems.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... emergency conditions. S3. Application. This standard applies to trucks, buses, and trailers equipped with... axle weight rating (GAWR) of 29,000 pounds or more; (c) Any truck or bus that has a speed attainable in..., 2013. S5.1Required equipment for trucks and buses. Each truck and bus shall have the following...

  20. Better Seals for Vacuum Bags

    NASA Technical Reports Server (NTRS)

    Penn, B.; Clemons, J. M.

    1983-01-01

    Roller tool spreads even layer of adhesive. Tool easily constructed from metal, plastic, or wood. Sewing-thread spool serves as roller, nail as axle, and jigsawed block of wood as handle. Tool rolled and pressed against plastic film to assure even layer of adhesive around periphery.

  1. The Fluid Foil: The Seventh Simple Machine

    ERIC Educational Resources Information Center

    Mitts, Charles R.

    2012-01-01

    A simple machine does one of two things: create a mechanical advantage (lever) or change the direction of an applied force (pulley). Fluid foils are unique among simple machines because they not only change the direction of an applied force (wheel and axle); they convert fluid energy into mechanical energy (wind and Kaplan turbines) or vice versa,…

  2. Every Day a New 3D Printing Material

    ERIC Educational Resources Information Center

    Hughes, Bill; Mona, Lynn; Wilson, Greg; Seamans, Jeff; McAninch, Steve; Stout, Heath

    2017-01-01

    A handful of technological episodes: fire, wheel and axle, Industrial Revolution, Faraday's discovery of electromagnetic induction, the transistor, and the digital age, have historically altered humanity. We are now witnessing/participating in the next transformational technology: 3D printing. Although dating back nearly 30 years, the technology…

  3. Tyro3 Family-Mediated Cell Entry of Ebola and Marburg Viruses

    PubMed Central

    Shimojima, Masayuki; Takada, Ayato; Ebihara, Hideki; Neumann, Gabriele; Fujioka, Kouki; Irimura, Tatsuro; Jones, Steven; Feldmann, Heinz; Kawaoka, Yoshihiro

    2006-01-01

    Filoviruses, represented by the genera Ebolavirus and Marburgvirus, cause a lethal hemorrhagic fever in humans and in nonhuman primates. Although filovirus can replicate in various tissues or cell types in these animals, the molecular mechanisms of its broad tropism remain poorly understood. Here we show the involvement of members of the Tyro3 receptor tyrosine kinase family—Axl, Dtk, and Mer—in cell entry of filoviruses. Ectopic expression of these family members in lymphoid cells, which otherwise are highly resistant to filovirus infection, enhanced infection by pseudotype viruses carrying filovirus glycoproteins on their envelopes. This enhancement was reduced by antibodies to Tyro3 family members, Gas6 ligand, or soluble ectodomains of the members. Live Ebola viruses infected both Axl- and Dtk-expressing cells more efficiently than control cells. Antibody to Axl inhibited infection of pseudotype viruses in a number of Axl-positive cell lines. These results implicate each Tyro3 family member as a cell entry factor in filovirus infection. PMID:17005688

  4. Simple Machines Made Simple.

    ERIC Educational Resources Information Center

    St. Andre, Ralph E.

    Simple machines have become a lost point of study in elementary schools as teachers continue to have more material to cover. This manual provides hands-on, cooperative learning activities for grades three through eight concerning the six simple machines: wheel and axle, inclined plane, screw, pulley, wedge, and lever. Most activities can be…

  5. Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury

    PubMed Central

    Brosius Lutz, Amanda; Sloan, Steven A.; Carson, Glenn A.; Zhou, Lu; Lovelett, Emilie; Posada, Sean; Zuchero, J. Bradley; Barres, Ben A.

    2017-01-01

    Ineffective myelin debris clearance is a major factor contributing to the poor regenerative ability of the central nervous system. In stark contrast, rapid clearance of myelin debris from the injured peripheral nervous system (PNS) is one of the keys to this system’s remarkable regenerative capacity, but the molecular mechanisms driving PNS myelin clearance are incompletely understood. We set out to discover new pathways of PNS myelin clearance to identify novel strategies for activating myelin clearance in the injured central nervous system, where myelin debris is not cleared efficiently. Here we show that Schwann cells, the myelinating glia of the PNS, collaborate with hematogenous macrophages to clear myelin debris using TAM (Tyro3, Axl, Mer) receptor-mediated phagocytosis as well as autophagy. In a mouse model of PNS nerve crush injury, Schwann cells up-regulate TAM phagocytic receptors Axl and Mertk following PNS injury, and Schwann cells lacking both of these phagocytic receptors exhibit significantly impaired myelin phagocytosis both in vitro and in vivo. Autophagy-deficient Schwann cells also display reductions in myelin clearance after mouse nerve crush injury, as has been recently shown following nerve transection. These findings add a mechanism, Axl/Mertk-mediated myelin clearance, to the repertoire of cellular machinery used to clear myelin in the injured PNS. Given recent evidence that astrocytes express Axl and Mertk and have previously unrecognized phagocytic potential, this pathway may be a promising avenue for activating myelin clearance after CNS injury. PMID:28874532

  6. Teaching Tips: For What Purpose?

    ERIC Educational Resources Information Center

    Hedges, Lowell E.; And Others

    1985-01-01

    Suggestions for teachers are presented, involving audiovisual materials, magazines, worksheets, safety reports, computers, bulletin boards, storage, problem solving, computer-assisted job searches, visual aids, motivating techniques, visual communications, engine valve display, computer printouts for stencils, wheel alignment for tractor axles,…

  7. 49 CFR 573.6 - Defect and noncompliance information report.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... vehicle equipment, the identification shall be by the generic name of the component (tires, child seating systems, axles, etc.), part number (for tires, a range of tire identification numbers, as required by 49... case of a remedy program involving the replacement of tires, the manufacturer's program for remedying...

  8. 40 CFR 86.602-98 - Definitions.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...) CONTROL OF EMISSIONS FROM NEW AND IN-USE HIGHWAY VEHICLES AND ENGINES (CONTINUED) Selective Enforcement... subclassification of an engine-system combination on the basis of engine code, inertia weight class, transmission type and gear ratios, axle ratio, and other parameters which may be designated by the Administrator...

  9. 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.

  10. 40 CFR 86.096-8 - Emission standards for 1996 and later model year light-duty vehicles.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ..., high-altitude axle ratio (rear-wheel drive vehicles) or a unique, high-altitude drivetrain (front-wheel drive vehicles) with a higher N/V ratio than other configurations of that model type which are certified... Drive, Warrendale, PA, 15096-0001. Copies may be inspected at U.S. EPA, OAR, 401 M St., SW., Washington...

  11. 40 CFR 86.096-8 - Emission standards for 1996 and later model year light-duty vehicles.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ..., high-altitude axle ratio (rear-wheel drive vehicles) or a unique, high-altitude drivetrain (front-wheel drive vehicles) with a higher N/V ratio than other configurations of that model type which are certified... Drive, Warrendale, PA, 15096-0001. Copies may be inspected at U.S. EPA, OAR, 401 M St., SW., Washington...

  12. 49 CFR 570.60 - Steering system.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... steering axle wheels in the straight ahead position, turn the steering wheel in one direction until there is a perceptible movement of the wheel. If a point on the steering wheel rim moves more than the value shown in Table 1 before perceptible return movement of the wheel under observation, there is...

  13. 49 CFR 571.138 - Standard No. 138; Tire pressure monitoring systems.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... those vehicles with dual wheels on an axle, according to the phase-in schedule specified in S7 of this... should stop and check your tires as soon as possible, and inflate them to the proper pressure. Driving on... or alternate tires or wheels on the vehicle that prevent the TPMS from functioning properly. Always...

  14. 49 CFR 571.110 - Tire selection and rims and motor home/recreation vehicle trailer load carrying capacity...

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ... battery, and special trim. Rim is used as defined in § 571.109. Rim diameter means nominal diameter of the bead seat. Rim size designation means rim diameter and width. Rim type designation means the industry... than the GAWR corresponding to the size designation of the tires fitted to the axle. S4.2.2.2When...

  15. 76 FR 23286 - New Pneumatic Off-the-Road Tires From the People's Republic of China: Final Results of...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-04-26

    ...,\\4\\ log-skidders,\\5\\ agricultural implements, highway-towed implements, agricultural logging, and... trucks, straddle carriers,\\10\\ graders,\\11\\ mobile cranes,\\12\\ compactors; and (3) industrial vehicles... fields. \\4\\ Industrial tractors are dual-axle vehicles that typically are designed to pull...

  16. The Fluid Foil: The Seventh Simple Machine

    ERIC Educational Resources Information Center

    Mitts, Charles R.

    2012-01-01

    A simple machine does one of two things: create a mechanical advantage (lever) or change the direction of an applied force (pulley). Fluid foils are unique among simple machines because they not only change the direction of an applied force (wheel and axle); they convert fluid energy into mechanical energy (wind and Kaplan turbines) or vice versa,…

  17. Talking Technology: Language and Literacy in the Primary School Examined through Children's Encounters with Mechanisms.

    ERIC Educational Resources Information Center

    Parkinson, Eric

    1999-01-01

    Technical terminology such as shaft and axle has a range of meanings in instructional support materials. Studies of children show that they use their own terms to describe unfamiliar components. Although appropriate vocabulary is desirable in technology education, teachers should find ways to incorporate children's own vocabulary to help them…

  18. 76 FR 44829 - Federal Motor Vehicle Safety Standards; Air Brake Systems

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-07-27

    ... system (ABS) resulting in slightly longer stopping distance. Bendix also stated that differing opinions... axle application timing (average of 0.43 seconds). Third, deep cycling of the ABS system was not...; Air Brake Systems AGENCY: National Highway Traffic Safety Administration (NHTSA), Department of...

  19. Accurate and portable weigh-in-motion system for manifesting air cargo

    SciTech Connect

    Nodine, R.N.; Scudiere, M.B.; Jordan, J.K.

    1995-12-01

    An automated and portable weigh-in-motion system has been developed at Oak Ridge National Laboratory for the purpose of manifesting cargo onto aircraft. The system has an accuracv range of {plus_minus} 3.0% to {plus_minus} 6.0% measuring gross vehicle weight and locating the center of balance of moving vehicles at speeds of 1 to 5 mph. This paper reviews the control/user interface system and weight determination algorithm developed to acquire, process, and interpret multiple sensor inputs. The development effort resulted in a self-zeroing, user-friendly system capable of weighing a wide range of vehicles in any random order. The control system is based on the STANDARD (STD) bus and incorporates custom-designed data acquisition and sensor fusion hardware controlled by a personal computer (PC) based single-board computer. The user interface is written in the ``C`` language to display number of axles, axle weight, axle spacing, gross weight, and center of balance. The weighing algorithm developed will function with any linear weight sensor and a set of four axle switches per sensor.

  20. Accurate and portable weigh-in-motion system for manifesting air cargo

    NASA Astrophysics Data System (ADS)

    Nodine, Robert N.; Scudiere, Matthew B.; Jordan, John K.

    1995-12-01

    An automated and portable weigh-in-motion system has been developed at Oak Ridge National Laboratory for the purpose of manifesting cargo onto aircraft. The system has an accuracy range of plus or minus 3.0% to plus or minus 6.0% measuring gross vehicle weight and locating the center of balance of moving vehicles at speeds of 1 to 5 mph. This paper reviews the control/user interface system and weight determination algorithm developed to acquire, process, and interpret multiple sensor inputs. The development effort resulted in a self- zeroing, user-friendly system capable of weighing a wide range of vehicles in any random order. The control system is based on the STANDARD (STD) bus and incorporates custom- designed data acquisition and sensor fusion hardware controlled by a personal computer (PC) based single-board computer. The user interface is written in the 'C' language to display number of axles, axle weight, axle spacing, gross weight, and center of balance. The weighing algorithm developed functions with any linear weight sensor and a set of four axle switches per sensor.

  1. Rolling Friction on a Wheeled Laboratory Cart

    ERIC Educational Resources Information Center

    Mungan, Carl E.

    2012-01-01

    A simple model is developed that predicts the coefficient of rolling friction for an undriven laboratory cart on a track that is approximately independent of the mass loaded onto the cart and of the angle of inclination of the track. The model includes both deformation of the wheels/track and frictional torque at the axles/bearings. The concept of…

  2. Fault detection method for railway wheel flat using an adaptive multiscale morphological filter

    NASA Astrophysics Data System (ADS)

    Li, Yifan; Zuo, Ming J.; Lin, Jianhui; Liu, Jianxin

    2017-02-01

    This study explores the capacity of the morphology analysis for railway wheel flat fault detection. A dynamic model of vehicle systems with 56 degrees of freedom was set up along with a wheel flat model to calculate the dynamic responses of axle box. The vehicle axle box vibration signal is complicated because it not only contains the information of wheel defect, but also includes track condition information. Thus, how to extract the influential features of wheels from strong background noise effectively is a typical key issue for railway wheel fault detection. In this paper, an algorithm for adaptive multiscale morphological filtering (AMMF) was proposed, and its effect was evaluated by a simulated signal. And then this algorithm was employed to study the axle box vibration caused by wheel flats, as well as the influence of track irregularity and vehicle running speed on diagnosis results. Finally, the effectiveness of the proposed method was verified by bench testing. Research results demonstrate that the AMMF extracts the influential characteristic of axle box vibration signals effectively and can diagnose wheel flat faults in real time.

  3. Automotive Power Flow System; Auto Mechanics I: 9043.04.

    ERIC Educational Resources Information Center

    Dade County Public Schools, Miami, FL.

    This automotive power flow system course sets the foundation in the theory of operation of the standard and automatic transmission, clutch assemblies, drive-line and rear axle assemblies. This is a one or two quinmester credit course covering 45 clock hours. In the fourth quinmester course in the tenth year, instruction consists of lectures,…

  4. Environmental and Other Criteria and Methods for Pavement Design.

    DTIC Science & Technology

    1979-02-01

    Default: 15 years LIFINC: granular road life increment Default: 1 year AM -AP AC IW I X ASmin ASmax ASincI MINLIF I KFC AM: asphalt modulus AP: asphalt...Default: 5 years KFC : fatigue law code 1. Shell 2. HRA 3. DBM (100 pen) 4. DBM (200 pen) NSD Grate TDL FP JDF Drate NSD: number of standard axles per day

  5. 49 CFR 229.73 - Wheel sets.

    Code of Federal Regulations, 2010 CFR

    2010-10-01

    ...) The variation in the circumference of wheels on the same axle may not exceed 1/4 inch (two tape sizes) when applied or turned. (b) The maximum variation in the diameter between any two wheel sets in a three... compensate for wheel diameter variation, the maximum variation may not exceed 11/4 inch. The maximum...

  6. The Effect of Friction in Pulleys on the Tension in Cables and Strings

    ERIC Educational Resources Information Center

    Martell, Eric C.; Martell, Verda Beth

    2013-01-01

    Atwood's machine is used in countless introductory physics classes as an illustration of Newton's second law. Initially, the analysis is performed assuming the pulley and string are massless and the axle is frictionless. Although the mass of the pulley is often included when the problem is revisited later in the context of rotational dynamics, the…

  7. Teaching Simple Machines.

    ERIC Educational Resources Information Center

    Atwater, Mary M.

    1988-01-01

    Presents several fun activities and teacher demonstrations which simplify terms and condense science concepts for teaching about the lever, wedge, wheel and axle, screw, pulley, and the inclined plane. Includes objectives, materials, procedures, suggested follow-up assignments, and diagrams. (RT)

  8. 14 CFR 25.481 - Tail-down landing conditions.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... components considered to be acting at the main wheel axle centerline. (b) For the tail-down landing condition for airplanes with tail wheels, the main and tail wheels are assumed to contact the ground simultaneously, in accordance with figure 3 of appendix A. Ground reaction conditions on the tail wheel are...

  9. 14 CFR 25.481 - Tail-down landing conditions.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... components considered to be acting at the main wheel axle centerline. (b) For the tail-down landing condition for airplanes with tail wheels, the main and tail wheels are assumed to contact the ground simultaneously, in accordance with figure 3 of appendix A. Ground reaction conditions on the tail wheel are...

  10. 14 CFR 25.481 - Tail-down landing conditions.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... components considered to be acting at the main wheel axle centerline. (b) For the tail-down landing condition for airplanes with tail wheels, the main and tail wheels are assumed to contact the ground simultaneously, in accordance with figure 3 of appendix A. Ground reaction conditions on the tail wheel are...

  11. 14 CFR 25.481 - Tail-down landing conditions.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... components considered to be acting at the main wheel axle centerline. (b) For the tail-down landing condition for airplanes with tail wheels, the main and tail wheels are assumed to contact the ground simultaneously, in accordance with figure 3 of appendix A. Ground reaction conditions on the tail wheel are...

  12. 14 CFR 25.481 - Tail-down landing conditions.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... components considered to be acting at the main wheel axle centerline. (b) For the tail-down landing condition for airplanes with tail wheels, the main and tail wheels are assumed to contact the ground simultaneously, in accordance with figure 3 of appendix A. Ground reaction conditions on the tail wheel are...

  13. 49 CFR 571.135 - Standard No. 135; Light vehicle brake systems.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... power source failure. Brake factor means the slope of the linear least squares regression equation best... temperature or IBT means the average temperature of the service brakes on the hottest axle of the vehicle 0.32... less than 95 percent at the beginning of the run. Objective brake factor means the arithmetic average...

  14. Evaluating the Effects of Restraint Systems on 4WD Testing Methodologies: A Collaborative Effort between the NVFEL and ANL

    EPA Science Inventory

    Testing vehicles for emissions and fuel economy has traditionally been conducted with a single-axle chassis dynamometer. The 2006 SAE All Wheel Drive Symposium cited four wheel drive (4WD) and all wheel drive (AWD) sales as climbing from 20% toward 30% of a motor vehicle mar...

  15. Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer's disease.

    PubMed

    Savage, Julie C; Jay, Taylor; Goduni, Elanda; Quigley, Caitlin; Mariani, Monica M; Malm, Tarja; Ransohoff, Richard M; Lamb, Bruce T; Landreth, Gary E

    2015-04-22

    Alzheimer's disease (AD) is characterized by a robust inflammatory response elicited by the accumulation and subsequent deposition of amyloid (Aβ) within the brain. The brain's immune cells migrate to and invest their processes within Aβ plaques but are unable to efficiently phagocytose and clear plaques from the brain. Previous studies have shown that treatment of myeloid cells with nuclear receptor agonists increases expression of phagocytosis-related genes. In this study, we elucidate a novel mechanism by which nuclear receptors act to enhance phagocytosis in the AD brain. Treatment of murine models of AD with agonists of the nuclear receptors PPARγ, PPARδ, LXR, and RXR stimulated microglial phagocytosis in vitro and rapidly induced the expression of the phagocytic receptors Axl and MerTK. In murine models of AD, we found that plaque-associated macrophages expressed Axl and MerTK and treatment of the cells with an RXR agonist further induced their expression, coincident with the rapid reduction in plaque burden. Further characterization of MerTK(+)/Axl(+) macrophages revealed that they also expressed the phagocytic receptor TREM2 and high levels of CD45, consistent with a peripheral origin of these cells. Importantly, in an ex vivo slice assay, nuclear receptor agonist treatment reversed the AD-related suppression of phagocytosis through a MerTK-dependent mechanism. Thus, nuclear receptor agonists increase MerTK and Axl expression on plaque-associated immune cells, consequently licensing their phagocytic activity and promoting plaque clearance.

  16. Dynamic Loads Affecting Artillery Launcher Crew

    DTIC Science & Technology

    2004-10-01

    limiters) front and rear wheel axles, the cabin, driving block, the launcher (or an open load-carrying body) as well as flexible- suppressing tyre ...Driver’s seat suspension change included the replacement of mechanical suspension with the pneumatic one, which can be characterized by a lower

  17. Neutral [2]rotaxane host systems that recognise halide anions in aqueous solvent mixtures.

    PubMed

    Mercurio, James M; Tyrrell, Fergus; Cookson, James; Beer, Paul D

    2013-11-28

    Four pyridine N-oxide axle containing [2]rotaxanes have been synthesised via an anion templated threading-followed-by-stoppering strategy and shown to be the first examples of neutral interlocked host systems capable of recognising halide anions in aqueous solvent mixtures.

  18. Soil structural changes caused by agricultural machinery

    USDA-ARS?s Scientific Manuscript database

    Effects of tractor traffic with high axle load on the aggregate size distribution, the total soil porosity, and the aggregate porosity were studied in a field experiment on a silty clay loam Greyzem soil. One and three tractors passes were made at pre-irrigated and non-irrigated 10x10 m plots. The v...

  19. Artificial Intelligence Applications for Nuclear Survivability Validation

    DTIC Science & Technology

    1992-11-01

    Speech recognition USAF: Flight simulator support General Devices: Engine Problem Diagnosis Eaton: Multi-axle truck brake control BC Hydro : Power...ENGRG ATTN: SLCHD-TL- WRF ATTN: LTC P J ENGSTROM ATTN: SLCHD-TN DEPUTY UNDER SECRETARY OF DEFENSE ATTN: SLC’S-;M-TL RESEARCH & ADVANCED TECHNOLOGY

  20. 75 FR 73132 - Sypris Technologies, Sypris Solutions Division, Kenton, OH; Notice of Revised Determination on...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-11-29

    ... administrative reconsideration filed by the United Steel Workers, Local 1-109, on behalf of workers and former... contribute importantly to worker separations at the subject firm and no shift in production to a foreign... related to the production of trailer axle beams, meet the worker group certification criteria...

  1. Can a String's Tension Exert a Torque on a Pulley?

    ERIC Educational Resources Information Center

    Krause, Dennis E.; Sun, Yifei

    2011-01-01

    A typical textbook problem in rotational dynamics involves calculating the angular acceleration of a massive pulley due to a string, such as in the example shown in Fig. 1. The string is assumed to be massless and to move without slipping over the pulley, which is mounted on a frictionless axle. If T[subscript L] and T[subscript R] are the…

  2. Can a String's Tension Exert a Torque on a Pulley?

    ERIC Educational Resources Information Center

    Krause, Dennis E.; Sun, Yifei

    2011-01-01

    A typical textbook problem in rotational dynamics involves calculating the angular acceleration of a massive pulley due to a string, such as in the example shown in Fig. 1. The string is assumed to be massless and to move without slipping over the pulley, which is mounted on a frictionless axle. If T[subscript L] and T[subscript R] are the…

  3. Rolling Friction on a Wheeled Laboratory Cart

    ERIC Educational Resources Information Center

    Mungan, Carl E.

    2012-01-01

    A simple model is developed that predicts the coefficient of rolling friction for an undriven laboratory cart on a track that is approximately independent of the mass loaded onto the cart and of the angle of inclination of the track. The model includes both deformation of the wheels/track and frictional torque at the axles/bearings. The concept of…

  4. Verge and Foliot Clock Escapement: A Simple Dynamical System

    ERIC Educational Resources Information Center

    Denny, Mark

    2010-01-01

    The earliest mechanical clocks appeared in Europe in the 13th century. From about 1250 CE to 1670 CE, these simple clocks consisted of a weight suspended from a rope or chain that was wrapped around a horizontal axle. To tell time, the weight must fall with a slow uniform speed, but, under the action of gravity alone, such a suspended weight would…

  5. Quantifying the effects of conservation practice implementation on predicted runoff and chemical losses under climate change

    USDA-ARS?s Scientific Manuscript database

    The Soil and Water Assessment Tool with downscaled weather data generated using the MarkSim weather file generator was used to evaluate the impact of long-term conservation practice implementation on runoff, sediment, atrazine, nitrogen (N) and phosphorus (P) losses in the AXL Watershed located in n...

  6. Performance of a logging truck with a central tire inflation system.

    Treesearch

    John A. Sturos; Douglas B. Brumm; Andrew Lehto

    1995-01-01

    Describes the performance of an 11-axle logging truck with a central tire inflation system. Results included reduced damages to roads, improved ride of the truck, improved drawbar pull, and reduced rolling resistance. Road construction costs were reduced 62%, primarily due to using 33% less gravel.

  7. Metal tube used as solar engine

    NASA Technical Reports Server (NTRS)

    Jedlicka, J. R.; Guist, L. R.; Beam, R. M.

    1973-01-01

    Ends of metal tube are fastened to axles which are supported on bearings so tube can rotate about its long axis while subjected to invariant bending moment that stresses it along longitudinal axis of rotation. Heat absorbed leads to expansion of metal, which unbalances internal forces and generates rotational moment in tube.

  8. Why Wheels Work.

    ERIC Educational Resources Information Center

    Stepp, Richard D.

    1982-01-01

    Discusses how the wheel works. The inherent mechanical advantage of wheel-and-axle system is that it reduced the distance the load-bearing surfaces have to slip relative to one another when the whole apparatus advances some given distance reducing (with leverage) the force needed to propel the system. (Author/JN)

  9. Why Does the Motorbike Feather?

    ERIC Educational Resources Information Center

    Ruocco, A.; De Luca, R.

    2007-01-01

    The problem of motorbike feathering has been analysed by writing the angular momentum theorem for non-inertial reference systems. The acceleration, for which the ideal line joining the median points of the axles of the two wheels makes an angle [theta] with the horizontal, has been calculated neglecting air friction and considering that the…

  10. Analysis of Rail Vehicle Suspension Spring with Special Emphasis on Curving, Tracking and Tractive Efforts

    NASA Astrophysics Data System (ADS)

    Kumbhalkar, M. A.; Bhope, D. V.; Vanalkar, A. V.

    2016-09-01

    The dynamics of the rail vehicle represents a balance between the forces acting between wheel and rail, the inertia forces and the forces exerted by suspension and articulation. Axial loading on helical spring causes vertical deflection at straight track but failures calls to investigate for lateral and longitudinal loading at horizontal and vertical curves respectively. Goods carrying vehicle has the frequent failures of middle axle inner suspension spring calls for investigation. The springs are analyzed for effect of stress concentration due to centripetal force and due to tractive and breaking effort. This paper also discusses shear failure analysis of spring at curvature and at uphill at various speeds for different loading condition analytically and by finite element analysis. Two mass rail vehicle suspension systems have been analyzed for vibration responses analytically using mathematical tool Matlab Simulink and the same will be evaluated using FFT vibration analyzer to find peak resonance in vertical, lateral and longitudinal direction. The results prove that the suspension acquires high repeated load in vertical and lateral direction due to tracking and curving causes maximum stress concentration on middle axle suspension spring as height of this spring is larger than end axle spring in primary suspension system and responsible for failure of middle axle suspension spring due to high stress acquisition.

  11. 6. VIEW OF BORING MILL. Chuck action of locomotive wheel ...

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

    6. VIEW OF BORING MILL. Chuck action of locomotive wheel Wheel weight 1200 pounds, 3'-0' diameter. Table 53' in diameter Wheel is 48'. Largest hole that can be bored is 9-1/2' plus (GE axle is 10'). - Juniata Shops, Erecting Shop & Machine Shop, East of Fourth Avenue, between Fourth & Fifth Streets, Altoona, Blair County, PA

  12. Evaluating the Effects of Restraint Systems on 4WD Testing Methodologies: A Collaborative Effort between the NVFEL and ANL

    EPA Science Inventory

    Testing vehicles for emissions and fuel economy has traditionally been conducted with a single-axle chassis dynamometer. The 2006 SAE All Wheel Drive Symposium cited four wheel drive (4WD) and all wheel drive (AWD) sales as climbing from 20% toward 30% of a motor vehicle mar...

  13. 40 CFR 1036.140 - Primary intended service class.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... POLLUTION CONTROLS CONTROL OF EMISSIONS FROM NEW AND IN-USE HEAVY-DUTY HIGHWAY ENGINES Emission Standards... axles, city tractors, and a variety of special purpose vehicles such as small dump trucks, and refuse trucks. Typical applications would include commercial short haul and intra-city delivery and...

  14. 40 CFR 1036.140 - Primary intended service class.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... POLLUTION CONTROLS CONTROL OF EMISSIONS FROM NEW AND IN-USE HEAVY-DUTY HIGHWAY ENGINES Emission Standards... axles, city tractors, and a variety of special purpose vehicles such as small dump trucks, and refuse trucks. Typical applications would include commercial short haul and intra-city delivery and...

  15. 49 CFR 537.4 - Definitions.

    Code of Federal Regulations, 2014 CFR

    2014-10-01

    ... weight is used as defined in subpart A of 40 CFR part 86. (2) The terms axle ratio, base level, body style, car line, combined fuel economy, engine code, equivalent test weight, gross vehicle weight, inertia weight, transmission class, and vehicle configuration are used as defined in subpart A of 40 CFR...

  16. 49 CFR 537.4 - Definitions.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... weight is used as defined in subpart A of 40 CFR part 86. (2) The terms axle ratio, base level, body style, car line, combined fuel economy, engine code, equivalent test weight, gross vehicle weight, inertia weight, transmission class, and vehicle configuration are used as defined in subpart A of 40 CFR...

  17. 49 CFR 537.4 - Definitions.

    Code of Federal Regulations, 2012 CFR

    2012-10-01

    ... weight is used as defined in subpart A of 40 CFR part 86. (2) The terms axle ratio, base level, body style, car line, combined fuel economy, engine code, equivalent test weight, gross vehicle weight, inertia weight, transmission class, and vehicle configuration are used as defined in subpart A of 40 CFR...

  18. 77 FR 36125 - Airworthiness Directives; SOCATA Airplanes

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-06-18

    ... serviceable bolt P/N 5101301111. (ii) Mark the landing gear with a green varnish line. (5) For the NLG P/Ns... actuator hinge axle of the NLG with a serviceable bolt P/N 5101301111 and; (ii) Mark the landing gear with.../ibr_locations.html . Issued in Kansas City, Missouri, on May 17, 2012. Earl Lawrence, Manager, Small...

  19. AUTOMOTIVE DIESEL MAINTENANCE 1. UNIT XXI, I--MAINTAINING THE AIR SYSTEM--CATERPILLAR DIESEL ENGINE, II--UNDERSTANDING REAR END SUSPENSION.

    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 THE OPERATION AND MAINTENANCE OF THE DIESEL ENGINE AIR SYSTEM AND REAR AXLE SUSPENSION USED ON DIESEL POWERED VEHICLES. TOPICS ARE (1) AIR INDUCTION AND EXHAUST SYSTEM, (2) VALVE MECHANISM, (3) TROUBLESHOOTING THE AIR SYSTEM, (4) PURPOSE OF VEHICLE SUSPENSION, (5) TANDEM…

  20. 49 CFR 396.3 - Inspection, repair, and maintenance.

    Code of Federal Regulations, 2013 CFR

    2013-10-01

    ... 49 Transportation 5 2013-10-01 2013-10-01 false Inspection, repair, and maintenance. 396.3 Section..., axles and attaching parts, wheels and rims, and steering systems. (2) Pushout windows, emergency doors... indicating their date and nature; and (4) A record of tests conducted on pushout windows, emergency...

  1. 49 CFR 396.3 - Inspection, repair, and maintenance.

    Code of Federal Regulations, 2011 CFR

    2011-10-01

    ... 49 Transportation 5 2011-10-01 2011-10-01 false Inspection, repair, and maintenance. 396.3 Section..., axles and attaching parts, wheels and rims, and steering systems. (2) Pushout windows, emergency doors... indicating their date and nature; and (4) A record of tests conducted on pushout windows, emergency...

  2. 10. 22'X34' original blueprint, VariableAngle Launcher, 'SIDE VIEW CAMERA CARSTEEL ...

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

    10. 22'X34' original blueprint, Variable-Angle Launcher, 'SIDE VIEW CAMERA CAR-STEEL FRAME AND AXLES' drawn at 1/2'=1'-0'. (BOURD Sketch # 209124). - Variable Angle Launcher Complex, Camera Car & Track, CA State Highway 39 at Morris Reservior, Azusa, Los Angeles County, CA

  3. Simple Machine Junk Cars

    ERIC Educational Resources Information Center

    Herald, Christine

    2010-01-01

    During the month of May, the author's eighth-grade physical science students study the six simple machines through hands-on activities, reading assignments, videos, and notes. At the end of the month, they can easily identify the six types of simple machine: inclined plane, wheel and axle, pulley, screw, wedge, and lever. To conclude this unit,…

  4. 77 FR 25647 - Airworthiness Directives; The Boeing Company Airplanes

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-01

    ... Model 777 airplanes. This proposed AD was prompted by heat damage and cracks at the pivot joint location... lubrication of the MLG pivot joints; repetitive detailed inspections of the outer diameter chrome on the... cracking in the MLG center axle and shock strut inner cylinder lugs (pivot joint), which could result...

  5. Why Does the Motorbike Feather?

    ERIC Educational Resources Information Center

    Ruocco, A.; De Luca, R.

    2007-01-01

    The problem of motorbike feathering has been analysed by writing the angular momentum theorem for non-inertial reference systems. The acceleration, for which the ideal line joining the median points of the axles of the two wheels makes an angle [theta] with the horizontal, has been calculated neglecting air friction and considering that the…

  6. Preliminary Assessment of Overweight Mainline Vehicles

    SciTech Connect

    Siekmann, Adam; Capps, Gary J; Lascurain, Mary Beth

    2011-11-01

    The Federal Motor Carrier Safety Administration requested information regarding overweight and oversized vehicle traffic entering inspection stations (ISs) in order to develop strategies for future research efforts and possibly help guide regulatory issues involving overweight commercial motor vehicles (CMVs). For a period of one month, inspection stations in Knox County and Greene County, Tennessee, recorded overweight and oversized vehicles that entered these ISs. During this period, 435 CMVs were recorded using an electronic form filled out by enforcement personnel at the IS. Of the 435 CMVs recorded, 381 had weight information documented with them. The majority (52.2%) of the vehicles recorded were five-axle combination vehicles, and 50.6% of all the vehicles were permitted to operate above the legal weight limit in Tennessee, which is 80,000 lb for vehicles with five or more axles. Only 16.8% of the CMVs recorded were overweight gross (11.5% of permitted vehicles) and 54.1% were overweight on an axle group. The low percentage of overweight gross CMVs was because only 45 of the vehicles over 80,000 lb. were not permitted. On average, axles that were overweight were 2,000 lb. over the legal limit for an axle or group of axles. Of the vehicles recorded, 172 vehicles were given a North American Standard (NAS) inspection during the assessment. Of those, 69% of the inspections were driver-only inspections (Level III) and only 25% of the inspections had a vehicle component (such as a Level I or Level II). The remaining 6% of inspections did not have valid Aspen numbers; the type of was inspection unknown. Data collected on the types of trailers of each vehicle showed that about half of the recorded CMVs could realistically be given a Level I (full vehicle and driver) inspection; this estimate was solely based on trailer type. Enforcement personnel at ISs without an inspection pit have difficulty fully inspecting certain vehicles due to low clearance below the trailer

  7. Controlling the rate of shuttling motions in [2]rotaxanes by electrostatic interactions: a cation as solvent-tunable brake.

    PubMed

    Ghosh, Pradyut; Federwisch, Guido; Kogej, Michael; Schalley, Christoph A; Haase, Detlev; Saak, Wolfgang; Lützen, Arne; Gschwind, Ruth M

    2005-08-07

    A series of rotaxanes, with phenolic axle centerpieces and tetralactam macrocycles as the wheels, has been prepared in good yields. The threaded rotaxane structure is confirmed in the gas phase by tandem mass spectrometric experiments through a detailed fragmentation pattern analysis, in solution by NMR spectroscopy, and in the solid state through X-ray crystallography. A close inspection of the 1H,1H NOESY and 1H,1H ROESY NMR data reveals the wheel to travel along the axle between two degenerate diamide "stations" close to the two stoppers. By deprotonation of a phenolic OH group in the axle centerpiece with Schwesinger's P1 base, surprisingly no additional shuttling station is generated at the axle center, although the wheel could form rather strong hydrogen bonds with the phenolate. Instead, the wheel continues to travel between the two diamide stations. Experimental data from 1H,1H NOESY spectra, together with theoretical calculations, show that strong electrostatic interactions between the phenolate moiety and the P1 cation displace the wheel from the "phenolate station". The cation acts as a "brake" for the shuttling movement. Instead of suppressing the shuttling motion completely, as observed in other rotaxanes, our rotaxane is the first system in which electrostatic interactions modulate the speed of the mechanical motion between a fast and a slow motion state as a response to a reversible external stimulus. By tuning these electrostatic interactions through solvent effects, the rate of movement can be influenced significantly, when for example different amounts of DMSO are added to dichloromethane. Besides the shuttling motion, circumrotation of the wheel around the axle is observed and analyzed by variable temperature NMR spectroscopy. Force field and AM1 calculations are in good agreement with the experimental findings.

  8. Choroidal thickness profile in healthy Indian children

    PubMed Central

    Chhablani, Jay Kumar; Deshpande, Riddhima; Sachdeva, Virender; Vidya, Sagar; Rao, P Srinivasa; Panigati, Anand; Mahat, Birendra; Pappuru, Rajeev Reddy; Pehere, Niranjan; Pathengay, Avinash

    2015-01-01

    Purpose: The purpose was to study choroidal thickness and its profile based on location in healthy Indian children using enhanced depth spectral-domain-optical coherence tomography (SD-OCT). Methods: In this cross-sectional observational study 255 eyes of 136 children with no retinal or choroidal disease were consecutively scanned using enhanced depth SD-OCT. Eyes with any ocular disease or axial length (AXL) >25 mm or < 20 mm were excluded. A single observer measured choroidal thickness from the posterior edge of the retinal pigment epithelium to the choroid/sclera junction at 500-microns intervals up to 2500 microns temporal and nasal to the fovea. Generalized estimating equations were used to evaluate the correlation between choroidal thickness at various locations and age, AXL, gender and spherical equivalent (SEq). Results: Mean age of the subjects was 11.9 ± 3.4 years (range: 5–18 years). There were 62 Females and 74 males. The mean AXL was 23.55 ± 0.74 mm. Mean subfoveal choroidal thickness was 312.1 ± 45.40 μm. Choroid was found to be thickest subfoveally, then temporally. Age, AXL and SEq showed a significant correlation with choroidal thickness, whereas gender did not affect choroidal thickness. Conclusion: Our study provides a valid normative database of choroidal thickness in healthy Indian children. This database could be useful for further studies evaluating choroidal changes in various chorioretinal disorders. Age and AXL are critical factors, which negatively correlated with choroidal thickness. PMID:26265634

  9. Molecular dynamics study of 2rotaxanes: influence of solvation and cation on co-conformation.

    PubMed

    Fradera, Xavier; Márquez, Manuel; Smith, Bradley D; Orozco, Modesto; Luque, F Javier

    2003-06-13

    The conformational preference of a [2]rotaxane system has been examined by molecular dynamics simulations. The rotaxane wheel consists of two bridged binding components: a cis-dibenzo-18-crown-6 ether and a 1,3-phenyldicarboxamide, and the penetrating axle consists of a central isophthaloyl unit with phenyltrityl capping groups. The influence of solvation on the co-conformation of the [2]rotaxane was evaluated by comparing the conformational flexibility in two solvents: chloroform and dimethyl sulfoxide. Attention was also paid to the effect of cation binding on the dynamical properties of the [2]rotaxane. The conformational stability of the [2]rotaxane was calculated using a MM/PB-SA strategy, and the occurrence of specific motions was examined by essential dynamics analysis. The changes in the co-conformational properties in the two solvents and upon cation binding are discussed in light of the available NMR data. The results indicate that in chloroform solution the [2]rotaxane system exists as a mixture of co-conformational states including some that have hydrogen bonds between axle C=O and wheel NH groups. Analysis of the simulations allow us to hypothesize that the [2]rotaxane's circumrotation motion can occur as the result of a dynamic process that combines a preliminary axle sliding step that breaks these hydrogen bonds and a conformational change in the ester group more distant from the wheel. In contrast, no hydrogen-bonded co-conformation was found in dimethyl sulfoxide, which appears to be due to the preferential formation of hydrogen bonds between the wheel NH groups with solvent molecules. Moreover, the axle experiences notable changes in anisotropic shielding, which would explain why the NMR signals are broadened in this solvent. Insertion of a sodium cation into the crown ether reduces co-conformational flexibility due to an interaction of the axle with the cation. Overall, the results reveal how both solvent and ionic atmosphere can influence the co

  10. A novel oral insulin-like growth factor-1 receptor pathway modulator and its implications for patients with non-small cell lung carcinoma: A phase I clinical trial.

    PubMed

    Ekman, Simon; Harmenberg, Johan; Frödin, Jan-Erik; Bergström, Stefan; Wassberg, Cecilia; Eksborg, Staffan; Larsson, Olle; Axelson, Magnus; Jerling, Markus; Abrahmsen, Lars; Hedlund, Åsa; Alvfors, Carina; Ståhl, Birgitta; Bergqvist, Michael

    2016-01-01

    A phase Ia/b dose-escalation study was performed to characterize the safety, efficacy and pharmacokinetic properties of the oral small molecule insulin-like growth factor-1-receptor pathway modulator AXL1717 in patients with advanced solid tumors. This was a prospective, single-armed, open label, dose-finding phase Ia/b study with the aim of single day dosing (phase Ia) to define the starting dose for multi-day dosing (phase Ib), and phase Ib to define and confirm recommended phase II dose (RP2D) and if possible maximum tolerated dose (MTD) for repeated dosing. Phase Ia enrolled 16 patients and dose escalations up to 2900 mg BID were successfully performed without any dose limiting toxicity (DLT). A total of 39 patients were treated in phase Ib. AXL1717 was well tolerated with neutropenia as the only dose-related, reversible, DLT. RP2D dose was found to be 390 mg BID for four weeks. Some patients, mainly with NSCLC, demonstrated signs of clinical benefit, including four partial tumor responses (one according to RECIST and three according to PET). The 15 patients with NSCLC with treatment duration longer than two weeks with single agent AXL1717 in third or fourth line of therapy showed a median progression-free survival of 31 weeks and overall survival of 60 weeks. Down-regulation of IGF-1R on granulocytes and increases of free serum levels of IGF-1 were seen in patients treated with AXL1717. AXL1717 had an acceptable safety profile and demonstrated promising efficacy in this heavily pretreated patient cohort, especially in patients with NSCLC. RP2D was concluded to be 390 mg BID for four weeks. Trial number is NCT01062620.

  11. A novel serrated columnar phased array ultrasonic transducer

    NASA Astrophysics Data System (ADS)

    Zou, Cheng; Sun, Zhenguo; Cai, Dong; Song, Hongwei; Chen, Qiang

    2016-02-01

    Traditionally, wedges are required to generate transverse waves in a solid specimen and mechanical rotation device is needed for interrogation of a specimen with a hollow bore, such as high speed railway locomotive axles, turbine rotors, etc. In order to eliminate the mechanical rotation process, a novel array pattern of phased array ultrasonic transducers named as serrated columnar phased array ultrasonic transducer (SCPAUT) is designed. The elementary transducers are planar rectangular, located on the outside surface of a cylinder. This layout is aimed to generate electrically rotating transverse waveforms so as to inspect the longitudinal cracks on the outside surface of a specimen which has a hollow bore at the center, such as the high speed railway locomotive axles. The general geometry of the SCPAUT and the inspection system are illustrated. A FEM model and mockup experiment has been carried out. The experiment results are in good agreement with the FEM simulation results.

  12. Fast tracking using edge histograms

    NASA Astrophysics Data System (ADS)

    Rokita, Przemyslaw

    1997-04-01

    This paper proposes a new algorithm for tracking objects and objects boundaries. This algorithm was developed and applied in a system used for compositing computer generated images and real world video sequences, but can be applied in general in all tracking systems where accuracy and high processing speed are required. The algorithm is based on analysis of histograms obtained by summing along chosen axles pixels of edge segmented images. Edge segmentation is done by spatial convolution using gradient operator. The advantage of such an approach is that it can be performed in real-time using available on the market hardware convolution filters. After edge extraction and histograms computation, respective positions of maximums in edge intensity histograms, in current and previous frame, are compared and matched. Obtained this way information about displacement of histograms maximums, can be directly converted into information about changes of target boundaries positions along chosen axles.

  13. Apparatus for raising or tilting a micromechanical structure

    DOEpatents

    Allen, James J.

    2008-09-09

    An active hinge apparatus is disclosed which can be used to raise a micromechanical structure (e.g. a plate or micromirror) on a substrate. The active hinge apparatus utilizes one or more of teeth protruding outward from an axle which also supports the micromechanical structure on one end thereof. A rack is used to engage the teeth and rotate the axle to raise the micromechanical structure and tilt the structure at an angle to the substrate. Motion of the rack is provided by an actuator which can be a mechanically-powered actuator, or alternately an electrostatic comb actuator or a thermal actuator. A latch can be optionally provided in the active hinge apparatus to lock the micromechanical structure in an "erected" position.

  14. On the way to rotaxane-based molecular motors: studies in molecular mobility and topological chirality.

    PubMed

    Schalley, C A; Beizai, K; Vögtle, F

    2001-06-01

    ATP synthase represents a machine at the molecular level which couples the rotation of an axle in a wheel with the endergonic production of ATP, the general source of chemical energy in the cell. The natural system prototypically bears all features of a macroscopic motor: a rotor within a stator held by a membrane and fueled by a difference in chemical potential in the form of a proton gradient combined with a machine for ATP production. The assembly of axle and wheel to a rotor device reminds one very much of a rotaxane. In this Account, we discuss some important features of motors and their (potential) realization in simpler artificial model systems, that is, the molecular mobility of mechanically bound molecules, the importance of chirality for unidirectional motion, the sources of energy for driving the rotation, and the potential of using membranes and surfaces for ordering a large number of devices to achieve macroscopic effects.

  15. Triply Threaded [4]Rotaxanes.

    PubMed

    Danon, Jonathan J; Leigh, David A; McGonigal, Paul R; Ward, John W; Wu, Jhenyi

    2016-09-28

    [4]Rotaxanes featuring three axles threaded through a single ring have been prepared through active metal template synthesis. Nickel-catalyzed sp(3)-sp(3) homocouplings of alkyl bromide "half-threads" through 37- and 38-membered 2,2':6',2″-terpyridyl macrocycles generate triply threaded [4]rotaxanes in up to 11% yield. An analogous 39-membered macrocycle produced no rotaxane products under similar conditions. The constitutions of the [4]rotaxanes were determined by NMR spectroscopy and mass spectrometry. Doubly threaded [3]rotaxanes were also obtained from the reactions but no [2]rotaxanes were isolated, suggesting that upon demetalation the axle of a singly threaded rotaxane can slip through a macrocycle that is sufficiently large to accommodate three threads.

  16. Traction drive automatic transmission for gas turbine engine driveline

    DOEpatents

    Carriere, Donald L.

    1984-01-01

    A transaxle driveline for a wheeled vehicle has a high speed turbine engine and a torque splitting gearset that includes a traction drive unit and a torque converter on a common axis transversely arranged with respect to the longitudinal centerline of the vehicle. The drive wheels of the vehicle are mounted on a shaft parallel to the turbine shaft and carry a final drive gearset for driving the axle shafts. A second embodiment of the final drive gearing produces an overdrive ratio between the output of the first gearset and the axle shafts. A continuously variable range of speed ratios is produced by varying the position of the drive rollers of the traction unit. After starting the vehicle from rest, the transmission is set for operation in the high speed range by engaging a first lockup clutch that joins the torque converter impeller to the turbine for operation as a hydraulic coupling.

  17. Long-range movement of large mechanically interlocked DNA nanostructures

    PubMed Central

    List, Jonathan; Falgenhauer, Elisabeth; Kopperger, Enzo; Pardatscher, Günther; Simmel, Friedrich C.

    2016-01-01

    Interlocked molecules such as catenanes and rotaxanes, connected only via mechanical bonds have the ability to perform large-scale sliding and rotational movements, making them attractive components for the construction of artificial molecular machines and motors. We here demonstrate the realization of large, rigid rotaxane structures composed of DNA origami subunits. The structures can be easily modified to carry a molecular cargo or nanoparticles. By using multiple axle modules, rotaxane constructs are realized with axle lengths of up to 355 nm and a fuel/anti-fuel mechanism is employed to switch the rotaxanes between a mobile and a fixed state. We also create extended pseudo-rotaxanes, in which origami rings can slide along supramolecular DNA filaments over several hundreds of nanometres. The rings can be actively moved and tracked using atomic force microscopy. PMID:27492061

  18. Role of Gas6 receptors in platelet signaling during thrombus stabilization and implications for antithrombotic therapy

    PubMed Central

    Angelillo-Scherrer, Anne; Burnier, Laurent; Flores, Nathalie; Savi, Pierre; DeMol, Maria; Schaeffer, Paul; Herbert, Jean-Marc; Lemke, Greg; Goff, Stephen P.; Matsushima, Glenn K.; Earp, H. Shelton; Vesin, Christian; Hoylaerts, Marc F.; Plaisance, Stéphane; Collen, Désiré; Conway, Edward M.; Wehrle-Haller, Bernhard; Carmeliet, Peter

    2005-01-01

    Mechanisms regulating thrombus stabilization remain largely unknown. Here, we report that loss of any 1 of the Gas6 receptors (Gas6-Rs), i.e., Tyro3, Axl, or Mer, or delivery of a soluble extracellular domain of Axl that traps Gas6 protects mice against life-threatening thrombosis. Loss of a Gas6-R does not prevent initial platelet aggregation but impairs subsequent stabilization of platelet aggregates, at least in part by reducing “outside-in” signaling and platelet granule secretion. Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the β3 integrin, thereby amplifying outside-in signaling via αIIbβ3. Blocking the Gas6-R–αIIbβ3 integrin cross-talk might be a novel approach to the reduction of thrombosis. PMID:15650770

  19. Structural elucidation of the DFG-Asp in and DFG-Asp out states of TAM kinases and insight into the selectivity of their inhibitors.

    PubMed

    Messoussi, Abdellah; Peyronnet, Lucile; Feneyrolles, Clémence; Chevé, Gwénaël; Bougrin, Khalid; Yasri, Aziz

    2014-10-10

    Structural elucidation of the active (DFG-Asp in) and inactive (DFG-Asp out) states of the TAM family of receptor tyrosine kinases is required for future development of TAM inhibitors as drugs. Herein we report a computational study on each of the three TAM members Tyro-3, Axl and Mer. DFG-Asp in and DFG-Asp out homology models of each one were built based on the X-ray structure of c-Met kinase, an enzyme with a closely related sequence. Structural validation and in silico screening enabled identification of critical amino acids for ligand binding within the active site of each DFG-Asp in and DFG-Asp out model. The position and nature of amino acids that differ among Tyro-3, Axl and Mer, and the potential role of these residues in the design of selective TAM ligands, are discussed.

  20. Helical screw viscometer

    NASA Astrophysics Data System (ADS)

    Aubert, J. H.; Chapman, R. N.; Kraynik, A. M.

    1983-06-01

    A helical screw viscometer for the measurement of the viscosity of Newtonian and nonNewtonian fluids is comprised of an elongated cylindrical container closed by end caps defining a circular cylindrical cavity within the container, a cylindrical rotor member having a helical screw or ribbon flight carried by the other periphery thereof rotatably carried within the cavity. The fluid to be measured is confined in the cavity filling the space between the rotor and the container wall. The rotor member is supported by axle members journaled in the end caps, one axle extending through one end cap and connectable to a drive source. A pair of longitudinally spaced ports are provided through the wall of the container in communication with the cavity and a differential pressure meter is connected between the ports for measuring the pressure drop caused by the rotation of the helical screw rotor acting on the confined fluid for computing viscosity.

  1. Noncircular rolling joints for vibrational reduction in slewing maneuvers

    NASA Technical Reports Server (NTRS)

    Chew, Meng-Sang (Inventor); Juang, Jer-Nan (Inventor); Yang, Li-Farn (Inventor)

    1992-01-01

    A rolling joint is provided for obtaining slewing maneuvers for various apparatus including space structures, space vehicles, robotic manipulators, and simulators. Two noncircular cylinders, namely a drive and a driven cylinder, are provided in driving contact with one another. This contact is maintained by two pairs of generally S-shaped bands, each pair forming a generally 8-shaped coupling tightly about the circumferential periphery of the noncircular drive and driven cylinders. A stationarily fixed arm extends between and is rotatably journalled with a drive axle and a spindle axle respectively extending through selected rotational points of the drive cylinder and of the driven cylinder. The noncircular cylinders are profiled to obtain the desired varying gear ratio. The novelty of the present invention resides in using specifically profiled noncircular cylinders to obtain a desired varying gear ratio.

  2. Anion recognition and cation-induced molecular motion in a heteroditopic [2]rotaxane.

    PubMed

    Leontiev, Alexandre V; Jemmett, Charlotte A; Beer, Paul D

    2011-01-17

    A heteroditopic [2]rotaxane consisting of a calix[4]diquinone-isophthalamide macrocycle and 3,5-bis-amide pyridinium axle components with the capability of switching between two positional isomers in response to barium cation recognition is synthesised. The anion binding properties of the rotaxane's interlocked cavity together with Na(+) , K(+) , NH(4) (+) and Ba(2+) cation recognition capabilities are elucidated by (1) H NMR and UV-visible spectroscopic titration experiments. Upon binding of Ba(2+) , molecular displacement of the axle's positively charged pyridinium group from the rotaxane's macrocyclic cavity occurs, whereas the monovalent cations Na(+) , K(+) and NH(4) (+) are bound without causing significant co-conformational change. The barium cation induced shuttling motion can be reversed on addition of tetrabutylammonium sulfate.

  3. Screening bioactives reveals nanchangmycin as a broad spectrum antiviral active against Zika virus

    PubMed Central

    Rausch, Keiko; Hackett, Brent; Weinbren, Nathan; Reeder, Sophia; Sadovsky, Yoel; Hunter, Christopher; Schultz, David C.; Coyne, Carolyn; Cherry, Sara

    2017-01-01

    Zika virus is an emerging arthropod-borne flavivirus for which there are no vaccines or specific therapeutics. We screened a library of 2000 ‘bioactive’ compounds for their ability to block Zika virus infection in three distinct cell-types with two different strains of Zika virus. Using a microscopy-based assay, we validated 38 drugs that inhibited Zika virus infection, including FDA approved nucleoside analogs. Cells expressing high levels of the attachment factor AXL can be protected from infection with receptor tyrosine kinase inhibitors, while placental-derived cells that lack AXL expression are insensitive to this inhibition. Importantly, we identified nanchangmycin as a potent inhibitor of Zika virus entry across all cell types tested including physiologically relevant primary cells. Nanchanmycin was also active against other medically relevant viruses including West Nile, dengue, and chikungunya virus that use a similar route of entry. This study provides a resource of small molecules to study Zika virus pathogenesis. PMID:28099856

  4. Cyclic host liquids for facile and high-yield synthesis of [2]rotaxanes.

    PubMed

    Ogoshi, Tomoki; Aoki, Takamichi; Shiga, Ryohei; Iizuka, Ryo; Ueda, Seita; Demachi, Kazuki; Yamafuji, Daiki; Kayama, Hitoshi; Yamagishi, Tada-aki

    2012-12-19

    We developed "cyclic host liquids (CHLs)" as a new type of solvent. The CHLs are a nonvolatile liquid over a wide temperature range, are biocompatible and recyclable, have high thermal stability, and are miscible with many organic solvents. Compared with typical complexation systems, the CHL system is extremely efficient for maintaining host-guest complexation because an additional solvent is not required. Based on the efficient host-guest complexation in the CHL system, we demonstrated synthesis of [2]rotaxanes in pillar[5]arene-based CHL. High yields were obtained for [2]rotaxanes capped by cationization (yield 91%) and Huisgen reaction (yield 88%) between the axle and the stopper components in the CHL system, while the association constants between the axles and wheels were quite low (10-15 M(-1)) in CDCl(3). The CHL system provides a new powerful approach for synthesis of mechanically interlocked molecules (MIMs) even with unfavorable statistical combinations of host-guest complexes.

  5. Long-range movement of large mechanically interlocked DNA nanostructures

    NASA Astrophysics Data System (ADS)

    List, Jonathan; Falgenhauer, Elisabeth; Kopperger, Enzo; Pardatscher, Günther; Simmel, Friedrich C.

    2016-08-01

    Interlocked molecules such as catenanes and rotaxanes, connected only via mechanical bonds have the ability to perform large-scale sliding and rotational movements, making them attractive components for the construction of artificial molecular machines and motors. We here demonstrate the realization of large, rigid rotaxane structures composed of DNA origami subunits. The structures can be easily modified to carry a molecular cargo or nanoparticles. By using multiple axle modules, rotaxane constructs are realized with axle lengths of up to 355 nm and a fuel/anti-fuel mechanism is employed to switch the rotaxanes between a mobile and a fixed state. We also create extended pseudo-rotaxanes, in which origami rings can slide along supramolecular DNA filaments over several hundreds of nanometres. The rings can be actively moved and tracked using atomic force microscopy.

  6. The Effect of Friction in Pulleys on the Tension in Cables and Strings

    NASA Astrophysics Data System (ADS)

    Martell, Eric C.; Martell, Verda Beth

    2013-02-01

    Atwood's machine is used in countless introductory physics classes as an illustration of Newton's second law. Initially, the analysis is performed assuming the pulley and string are massless and the axle is frictionless. Although the mass of the pulley is often included when the problem is revisited later in the context of rotational dynamics, the mass of the string and the friction associated with the axle are less frequently discussed. Two questions then arise: 1) If we are ignoring these effects, how realistic is our model? and 2) How can we determine when or if we need to incorporate these effects in order to make our model match up with reality? These questions are connected to fundamental issues faced by physics teachers, namely the frustration students sometimes feel when they do not see how they can use the results of the problems they have been working on and how we can help our students develop effective models for physical systems.

  7. Side gear mounting for differential assembly

    SciTech Connect

    Pederson, H.

    1989-02-21

    A differential gear assembly is described of the type which includes a differential gear housing having means for receiving a pair of axle ends together with a pair of substantially axially aligned side gears coupled to the pair of axle ends for rotation therewith, the side gears having helix angles inclined in the same direction with respect to the axes of rotation thereof, characterized in that the gear assembly includes means for preventing axial thrust forces developed by one of the side gears from loading the other of the side gears. The preventing means includes means for separating the side gears such that there is no direct or indirect engagement between confronting end faces of the side gears when thrust forces of one of the side gears are directed toward the other of the side gears; and the means for axially separating the side gears includes a pair of overlapping elements associated with one of the side gears of the gear housing.

  8. Battery powererd electric motor vehicle

    SciTech Connect

    Muhlbacker, K.

    1984-02-28

    A battery powered vehicle is provided with a vehicle frame and an electric motor whose main shaft is connected to a differential gear by means of a gear train with a variable transmission ratio, the motor shaft and all gear shafts being parallel to the axle of the driving wheels. In order to achieve a compact design and to avoid power-consuming drive elements the electric motor and the variable transmission gear as well as a potential reducing gear mounted between the latter and the differential gear, are positioned on a subframe which is connected to the housing of the driving wheel axle on the one side whereas the other side carrying the electric motor is attached to the vehicle frame by means of a cardanic suspension.

  9. Motor vehicle differential gear housing

    SciTech Connect

    Bitcon, L.L.

    1990-06-12

    This patent describes a motor vehicle differential gear housing. It comprises: a substantially box shaped casing having an interior and exterior defined by front, rear, top, bottom and two side panels, the front and rear panels each having an aperture, the apertures being at least partially in axial alignment; first bearing means cooperating with the apertures and demountably secured to each of the front and rear panels. The first bearing means is aligned coaxially with the aligned portions of the apertures; the side panels each having an opening, the openings being at least partially in axial alignment; axle support bearing housings aligned coaxially with the aligned portions of the openings on the side panels and threadedly mounted therein and adapted to have driving axles journaled in second bearing means in the bearing housings; and at least the front and rear panels being removably attached to the side panels.

  10. System and method for weighing and characterizing moving or stationary vehicles and cargo

    DOEpatents

    Beshears, David L [Knoxville, TN; Scudiere, Matthew B [Oak Ridge, TN; White, Clifford P [Seymour, TN

    2008-05-20

    A weigh-in-motion device and method having at least one transducer pad, each transducer pad having at least one transducer group with transducers positioned essentially perpendicular to the direction of travel. At least one pad microcomputer is provided on each transducer pad having a means for calculating first output signal indicative of weight, second output signal indicative of time, and third output signal indicative of speed. At least one host microcomputer is in electronic communication with each pad microcomputer, and having a means for calculating at least one unknown selected from the group consisting of individual tire weight, individual axle weight, axle spacing, speed profile, longitudinal center of balance, and transverse center of balance.

  11. Dynamic Measurement for the Diameter of A Train Wheel Based on Structured-Light Vision

    PubMed Central

    Gong, Zheng; Sun, Junhua; Zhang, Guangjun

    2016-01-01

    Wheels are very important for the safety of a train. The diameter of the wheel is a significant parameter that needs regular inspection. Traditional methods only use the contact points of the wheel tread to fit the rolling round. However, the wheel tread is easily influenced by peeling or scraping. Meanwhile, the circle fitting algorithm is sensitive to noise when only three points are used. This paper proposes a dynamic measurement method based on structured-light vision. The axle of the wheelset and the tread are both employed. The center of the rolling round is determined by the axle rather than the tread only. Then, the diameter is calculated using the center and the contact points together. Simulations are performed to help design the layout of the sensors, and the influences of different noise sources are also analyzed. Static and field experiments are both performed, and the results show it to be quite stable and accurate. PMID:27104543

  12. Predicting pavement distress in oil field areas

    SciTech Connect

    Mason, J.M.; Scullion, T.; Stampley, B.E.

    1983-05-01

    A study on oil field traffic characteristics was performed and a procedure was developed for assessing current and future effects of oil field truck traffic on surface-treated (stage construction type) pavements. A computer program calculates several types of pavement distress and serviceability parameters to evaluate pavement performance under various axle load repetitions. Stepwise regression analysis of 132 surface-treated pavement sections led to the development of individual distress equations for rutting, raveling, flushing, alligator cracking, patching, longitudinal and transverse cracking, and failures (potholes). The versatility of the program provides a means of anticipating early pavement failures due to increased axle load repetitions. The program also provides the basic framework for computing the effects of other ''special-use'' truck traffic demands.

  13. Predicting pavement distress in oil field areas

    SciTech Connect

    Mason, J.M.; Scullion, T.; Stampley, B.E.

    1984-05-01

    A study on oil field traffic characteristics was performed and a procedure was developed for assessing current and future effects of oil field truck traffic on surface-treated (stage construction type) pavements. A computer program calculates several types of pavement distress and serviceability parameters to evaluate pavement performance under various axle load repetitions. Stepwise regression analysis of 132 surface-treated pavement sections led to the development of individual distress equations for rutting, raveling, flushing, alligator cracking, patching, longitudinal and transverse cracking, and failures (potholes). The versatility of the program provides a means of anticipating early pavement failures due to increased axle load repetitions. The program also provides the basic framework for computing the effects of other ''special-use'' truck traffic demands.

  14. A pH-sensitive peptide-containing lasso molecular switch.

    PubMed

    Clavel, Caroline; Fournel-Marotte, Karine; Coutrot, Frédéric

    2013-09-17

    The synthesis of a peptide-containing lasso molecular switch by a self-entanglement strategy is described. The interlocked rotaxane molecular machine consists of a benzometaphenylene[25]crown-8 (BMP25C8) macrocycle surrounding a molecular axle. This molecular axle contains a tripeptidic sequence and two molecular stations: a N-benzyltriazolium and a pH-sensitive anilinium station. The tripeptide is located between the macrocycle and the triazolium station, so that its conformation can be tailored depending on the shuttling of the macrocycle from one station to the other. At acidic pH, the macrocycle resides around the anilinium moiety, whereas it shuttles around the triazolium station after deprotonation. This molecular machinery thus forces the lasso to adopt a tightened or a loosened conformation.

  15. Selective Nitrate Recognition by a Halogen-Bonding Four-Station [3]Rotaxane Molecular Shuttle.

    PubMed

    Barendt, Timothy A; Docker, Andrew; Marques, Igor; Félix, Vítor; Beer, Paul D

    2016-09-05

    The synthesis of the first halogen bonding [3]rotaxane host system containing a bis-iodo triazolium-bis-naphthalene diimide four station axle component is reported. Proton NMR anion binding titration experiments revealed the halogen bonding rotaxane is selective for nitrate over the more basic acetate, hydrogen carbonate and dihydrogen phosphate oxoanions and chloride, and exhibits enhanced recognition of anions relative to a hydrogen bonding analogue. This elaborate interlocked anion receptor functions via a novel dynamic pincer mechanism where upon nitrate anion binding, both macrocycles shuttle from the naphthalene diimide stations at the periphery of the axle to the central halogen bonding iodo-triazolium station anion recognition sites to form a unique 1:1 stoichiometric nitrate anion-rotaxane sandwich complex. Molecular dynamics simulations carried out on the nitrate and chloride halogen bonding [3]rotaxane complexes corroborate the (1) H NMR anion binding results.

  16. Selective Nitrate Recognition by a Halogen‐Bonding Four‐Station [3]Rotaxane Molecular Shuttle

    PubMed Central

    Barendt, Timothy A.; Docker, Andrew; Marques, Igor; Félix, Vítor

    2016-01-01

    Abstract The synthesis of the first halogen bonding [3]rotaxane host system containing a bis‐iodo triazolium‐bis‐naphthalene diimide four station axle component is reported. Proton NMR anion binding titration experiments revealed the halogen bonding rotaxane is selective for nitrate over the more basic acetate, hydrogen carbonate and dihydrogen phosphate oxoanions and chloride, and exhibits enhanced recognition of anions relative to a hydrogen bonding analogue. This elaborate interlocked anion receptor functions via a novel dynamic pincer mechanism where upon nitrate anion binding, both macrocycles shuttle from the naphthalene diimide stations at the periphery of the axle to the central halogen bonding iodo‐triazolium station anion recognition sites to form a unique 1:1 stoichiometric nitrate anion–rotaxane sandwich complex. Molecular dynamics simulations carried out on the nitrate and chloride halogen bonding [3]rotaxane complexes corroborate the 1H NMR anion binding results. PMID:27436297

  17. Some further pitfalls of prosaic precession

    NASA Astrophysics Data System (ADS)

    Hey, J. D.; Horsfield, E. C.

    2005-09-01

    We again consider the analysis of a cyclist on a bicycle in motion around a circular track. An expression derived earlier (Horsfield 1998 Eur. J. Phys. 19 347-50) for the motion is corrected, by inclusion of two neglected features of a more complete description: (1) the distinction between the velocity of the axles of the wheels, and that of the centre of mass of the system, which is usually located at some height above the axles; (2) the application of the parallel-axes theorem to the 'spin term'. The corresponding two correction terms turn out to be significant, being of the same order in the relevant parameters as the correction term introduced in Horsfield (1998) with respect to the 'lowest-order' formula.

  18. Vehicle systems: coupled and interactive dynamics analysis

    NASA Astrophysics Data System (ADS)

    Vantsevich, Vladimir V.

    2014-11-01

    This article formulates a new direction in vehicle dynamics, described as coupled and interactive vehicle system dynamics. Formalised procedures and analysis of case studies are presented. An analytical consideration, which explains the physics of coupled system dynamics and its consequences for dynamics of a vehicle, is given for several sets of systems including: (i) driveline and suspension of a 6×6 truck, (ii) a brake mechanism and a limited slip differential of a drive axle and (iii) a 4×4 vehicle steering system and driveline system. The article introduces a formal procedure to turn coupled system dynamics into interactive dynamics of systems. A new research direction in interactive dynamics of an active steering and a hybrid-electric power transmitting unit is presented and analysed to control power distribution between the drive axles of a 4×4 vehicle. A control strategy integrates energy efficiency and lateral dynamics by decoupling dynamics of the two systems thus forming their interactive dynamics.

  19. Flywheel energy accumlator

    SciTech Connect

    Keyes, J.H.

    1980-06-24

    Radial and axial bearings support an axle shaft attached to a flywheel apparatus to provide rotational support and limit axial movement during rotation of the flywheel. A cage generally surrounding the flywheel and receiving the flywheel within its hollow interior includes a cylindrically shaped side wall positioned adjacent to and concentric with the outside surface of the flywheel to rapidly absorb energy should distortion or shattering of the flywheel occur due to centrifugal force. Means for connecting the flywheel cage to a source of vacuum such as the intake manifold of a thermal engine is utilized to at least partially evacuate the interior of the flywheel cage and thereby increase the ability of the rotating flywheel to store and maintain kinetic energy. A plurality of lubricant passages and reservoirs supply lubricant to the bearings associated with the axle shaft of the flywheel.

  20. Dynamic Measurement for the Diameter of A Train Wheel Based on Structured-Light Vision.

    PubMed

    Gong, Zheng; Sun, Junhua; Zhang, Guangjun

    2016-04-20

    Wheels are very important for the safety of a train. The diameter of the wheel is a significant parameter that needs regular inspection. Traditional methods only use the contact points of the wheel tread to fit the rolling round. However, the wheel tread is easily influenced by peeling or scraping. Meanwhile, the circle fitting algorithm is sensitive to noise when only three points are used. This paper proposes a dynamic measurement method based on structured-light vision. The axle of the wheelset and the tread are both employed. The center of the rolling round is determined by the axle rather than the tread only. Then, the diameter is calculated using the center and the contact points together. Simulations are performed to help design the layout of the sensors, and the influences of different noise sources are also analyzed. Static and field experiments are both performed, and the results show it to be quite stable and accurate.