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Sample records for cellular receptor car

  1. ADENOVIRUS INTERACTION WITH ITS CELLULAR RECEPTOR CAR.

    Energy Technology Data Exchange (ETDEWEB)

    HOWITT,J.; ANDERSON,C.W.; FREIMUTH,P.

    2001-08-01

    The mechanism of adenovirus attachment to the host cell plasma membrane has been revealed in detail by research over the past 10 years. It has long been known that receptor binding activity is associated with the viral fibers, trimeric spike proteins that protrude radially from the vertices of the icosahedral capsid (Philipson et al. 1968). In some adenovirus serotypes, fiber and other virus structural proteins are synthesized in excess and accumulate in the cell nucleus during late stages of infection. Fiber protein can be readily purified from lysates of cells infected with subgroup C viruses, for example Ad2 and Ad5 (Boulanger and Puvion 1973). Addition of purified fiber protein to virus suspensions during adsorption strongly inhibits infection, indicating that fiber and intact virus particles compete for binding sites on host cells (Philipson et al. 1968; Hautala et al. 1998). Cell binding studies using purified radiolabeled fiber demonstrated that fiber binds specifically and with high affinity to the cell plasma membrane, and that cell lines typically used for laboratory propagation of adenovirus have approximately 10{sup 4} high-affinity receptor sites per cell (Persson et al. 1985; Freimuth 1996). Similar numbers of high-affinity binding sites for radiolabeled intact virus particles also were observed (Seth et al. 1994).

  2. ADENOVIRUS INTERACTION WITH ITS CELLULAR RECEPTOR CAR

    International Nuclear Information System (INIS)

    The mechanism of adenovirus attachment to the host cell plasma membrane has been revealed in detail by research over the past 10 years. It has long been known that receptor binding activity is associated with the viral fibers, trimeric spike proteins that protrude radially from the vertices of the icosahedral capsid (Philipson et al. 1968). In some adenovirus serotypes, fiber and other virus structural proteins are synthesized in excess and accumulate in the cell nucleus during late stages of infection. Fiber protein can be readily purified from lysates of cells infected with subgroup C viruses, for example Ad2 and Ad5 (Boulanger and Puvion 1973). Addition of purified fiber protein to virus suspensions during adsorption strongly inhibits infection, indicating that fiber and intact virus particles compete for binding sites on host cells (Philipson et al. 1968; Hautala et al. 1998). Cell binding studies using purified radiolabeled fiber demonstrated that fiber binds specifically and with high affinity to the cell plasma membrane, and that cell lines typically used for laboratory propagation of adenovirus have approximately 10(sup 4) high-affinity receptor sites per cell (Persson et al. 1985; Freimuth 1996). Similar numbers of high-affinity binding sites for radiolabeled intact virus particles also were observed (Seth et al. 1994)

  3. Structure of adenovirus bound to cellular receptor car

    Science.gov (United States)

    Freimuth, Paul I.

    2007-01-02

    Disclosed is a mutant CAR-DI-binding adenovirus which has a genome comprising one or more mutations in sequences which encode the fiber protein knob domain wherein the mutation causes the encoded viral particle to have a significantly weakened binding affinity for CAR-DI relative to wild-type adenovirus. Such mutations may be in sequences which encode either the AB loop, or the HI loop of the fiber protein knob domain. Specific residues and mutations are described. Also disclosed is a method for generating a mutant adenovirus which is characterized by a receptor binding affinity or specificity which differs substantially from wild type.

  4. Car Deceleration Considering Its Own Velocity in Cellular Automata Model

    Institute of Scientific and Technical Information of China (English)

    LI Ke-Ping

    2006-01-01

    In this paper, we propose a new cellular automaton model, which is based on NaSch traffic model. In our method, when a car has a larger velocity, if the gap between the car and its leading car is not enough large, it will decrease. The aim is that the following car has a buffer space to decrease its velocity at the next time, and then avoid to decelerate too high. The simulation results show that using our model, the car deceleration is realistic, and is closer to thefield measure than that of NaSch model.

  5. Mode of Action and Human Relevance Analysis for Nuclear Receptor-Mediated Liver Toxicity: A Case Study with Phenobarbital as a Model Constitutive Androstane Receptor (CAR) Activator

    Science.gov (United States)

    The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are key nuclear receptors involved in the regulation of cellular responses. to exposure to many xenobiotics and various physiological processes. Phenobarbital (PB) is a non­ genotoxic i...

  6. The Use of the LanthaScreen TR-FRET CAR Coactivator Assay in the Characterization of Constitutive Androstane Receptor (CAR Inverse Agonists

    Directory of Open Access Journals (Sweden)

    Alejandro Carazo

    2015-04-01

    Full Text Available The constitutive androstane receptor (CAR is a critical nuclear receptor in the gene regulation of xenobiotic and endobiotic metabolism. The LanthaScreenTM TR-FRET CAR coactivator assay provides a simple and reliable method to analyze the affinity of a ligand to the human CAR ligand-binding domain (LBD with no need to use cellular models. This in silico assay thus enables the study of direct CAR ligands and the ability to distinguish them from the indirect CAR activators that affect the receptor via the cell signaling-dependent phosphorylation of CAR in cells. For the current paper we characterized the pharmacodynamic interactions of three known CAR inverse agonists/antagonists—PK11195, clotrimazole and androstenol—with the prototype agonist CITCO (6-(4-chlorophenylimidazo[2,1-b][1,3] thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyloxime using the TR-FRET LanthaScreenTM assay. We have confirmed that all three compounds are inverse agonists of human CAR, with IC50 0.51, 0.005, and 0.35 μM, respectively. All the compounds also antagonize the CITCO-mediated activation of CAR, but only clotrimazole was capable to completely reverse the effect of CITCO in the tested concentrations. Thus this method allows identifying not only agonists, but also antagonists and inverse agonists for human CAR as well as to investigate the nature of the pharmacodynamic interactions of CAR ligands.

  7. Cellular automata simulation of traffic including cars and bicycles

    Science.gov (United States)

    Vasic, Jelena; Ruskin, Heather J.

    2012-04-01

    As 'greening' of all aspects of human activity becomes mainstream, transportation science is also increasingly focused around sustainability. Modal co-existence between motorised and non-motorised traffic on urban networks is, in this context, of particular interest for traffic flow modelling. The main modelling problems here are posed by the heterogeneity of vehicles, including size and dynamics, and by the complex interactions at intersections. Herein we address these with a novel technique, based on one-dimensional cellular automata components, for modelling network infrastructure and its occupancy by vehicles. We use this modelling approach, together with a corresponding vehicle behaviour model, to simulate combined car and bicycle traffic for two elemental scenarios-examples of components that would be used in the building of an arbitrary network. Results of simulations performed on these scenarios, (i) a stretch of road and (ii) an intersection causing conflict between cars and bicycles sharing a lane, are presented and analysed.

  8. Antiproliferation of berberine is mediated by epigenetic modification of constitutive androstane receptor (CAR) metabolic pathway in hepatoma cells

    OpenAIRE

    Lei Zhang; Xiao-Jie Miao; Xin Wang; Hai-Hui Pan; Pu Li; Hong Ren; Yong-Rui Jia; Chuang Lu; Hong-Bing Wang; Lan Yuan; Guo-Liang Zhang

    2016-01-01

    Constitutive androstane receptor (CAR) regulates hepatic xenobiotic and energy metabolism, as well as promotes cell growth and hepatocarcinogenesis. Berberine is an ancient multipotent alkaloid drug which derived from Coptis chinensis plants. Here we report that berberine is able to be cellular uptake and accessible to chromatin in human hepatoma HepG2 cells. Berberine induces more apoptosis, cell cycle arrest, but less ROS production in CAR overexpressed mCAR-HepG2 cells. Moreover, berberine...

  9. Cellular Functions of Transient Receptor Potential channels

    OpenAIRE

    Dadon, Daniela; Minke, Baruch

    2010-01-01

    Transient Receptor Potential channels are polymodal cellular sensors involved in a wide variety of cellular processes, mainly by increasing cellular Ca2+. In this review we focus on the roles of these channels in: i) cell death ii) proliferation and differentiation and iii) synaptic vesicle release.

  10. RXRα, PXR and CAR xenobiotic receptors mediate the apoptotic and neurotoxic actions of nonylphenol in mouse hippocampal cells.

    Science.gov (United States)

    Litwa, E; Rzemieniec, J; Wnuk, A; Lason, W; Krzeptowski, W; Kajta, M

    2016-02-01

    In the present study, we investigated the role of the retinoid X receptor (RXR), the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR), in the apoptotic and toxic effects of nonylphenol in mouse primary neuronal cell cultures. Our study demonstrated that nonylphenol activated caspase-3 and induced lactate dehydrogenase (LDH) release in hippocampal cells, which was accompanied by an increase in the mRNA expression and protein levels of RXRα, PXR and CAR. Nonylphenol stimulated Rxra, Pxr, and Car mRNA expression. These effects were followed by increase in the protein levels of particular receptors. Immunofluorescence labeling revealed the cellular distribution of RXRα, PXR and CAR in hippocampal neurons in response to nonylphenol, shortening of neurites and cytoplasmic shrinking, as indicated by MAP2 staining. It also showed NP-induced translocation of receptor-specific immunofluorescence from cytoplasm to the nucleus. The use of specific siRNAs demonstrated that Rxra-, Pxr-, and Car-siRNA-transfected cells were less vulnerable to nonylphenol-induced activation of caspase-3 and LDH, thus confirming the key involvement of RXRα/PXR/CAR signaling pathways in the apoptotic and neurotoxic actions of nonylphenol. These new data give prospects for the targeting xenobiotic nuclear receptors to protect the developing nervous system against endocrine disrupting chemicals. PMID:26643981

  11. Androgen receptor drives cellular senescence.

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    Yelena Mirochnik

    Full Text Available The accepted androgen receptor (AR role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor.

  12. MODULATION OF ACETAMINOPHEN-INDUCED HEPATOTOXICITY BY THE XENOBIOTIC RECEPTOR CAR

    Science.gov (United States)

    We have identified the xenobiotic receptor CAR (constitutive androstane receptor) as a key regulator of acetaminophen metabolism and hepatotoxicity. Known CAR activators as well as high doses of acetaminophen induced expression of three acetaminophen-metabolizing enzymes in wild-type but not in CAR-...

  13. Ortho-aminoazotoluene activates mouse constitutive androstane receptor (mCAR) and increases expression of mCAR target genes

    International Nuclear Information System (INIS)

    2'-3-dimethyl-4-aminoazobenzene (ortho-aminoazotoluene, OAT) is an azo dye and a rodent carcinogen that has been evaluated by the International Agency for Research on Cancer (IARC) as a possible (class 2B) human carcinogen. Its mechanism of action remains unclear. We examined the role of the xenobiotic receptor Constitutive Androstane Receptor (CAR, NR1I3) as a mediator of the effects of OAT. We found that OAT increases mouse CAR (mCAR) transactivation in a dose-dependent manner. This effect is specific because another closely related azo dye, 3'-methyl-4-dimethyl-aminoazobenzene (3'MeDAB), did not activate mCAR. Real-time Q-PCR analysis in wild-type C57BL/6 mice revealed that OAT induces the hepatic mRNA expression of the following CAR target genes: Cyp2b10, Cyp2c29, Cyp3a11, Ugt1a1, Mrp4, Mrp2 and c-Myc. CAR-null (Car-/-) mice showed no increased expression of these genes following OAT treatment, demonstrating that CAR is required for their OAT dependent induction. The OAT-induced CAR-dependent increase of Cyp2b10 and c-Myc expression was confirmed by Western blotting. Immunohistochemistry analysis of wild-type and Car-/- livers showed that OAT did not acutely induce hepatocyte proliferation, but at much later time points showed an unexpected CAR-dependent proliferative response. These studies demonstrate that mCAR is an OAT xenosensor, and indicate that at least some of the biological effects of this compound are mediated by this nuclear receptor. - Highlights: → The azo dye and mouse carcinogen OAT is a very effective mCAR activator. → OAT increases mCAR transactivation in a dose-dependent manner. → OAT CAR-dependently increases the expression of a specific subset of CAR target genes. → OAT induces an unexpectedly deferred, but CAR-dependent hepatocyte proliferation.

  14. Performance-enhancing drugs: design and production of redirected chimeric antigen receptor (CAR) T cells.

    Science.gov (United States)

    Levine, B L

    2015-03-01

    Performance enhancement of the immune system can now be generated through ex vivo gene modification of T cells in order to redirect native specificity to target tumor antigens. This approach combines the specificity of antibody therapy, the expanded response of cellular therapy and the memory activity of vaccine therapy. Recent clinical trials of chimeric antigen receptor (CAR) T cells directed toward CD19 as a stand-alone therapy have shown sustained complete responses in patients with acute lymphoblastic leukemia and chronic lymphocytic leukemia. As these drug products are individually derived from a patient's own cells, a different manufacturing approach is required for this kind of personalized therapy compared with conventional drugs. Key steps in the CAR T-cell manufacturing process include the selection and activation of isolated T cells, transduction of T cells to express CARs, ex vivo expansion of modified T cells and cryopreservation in infusible media. In this review, the steps involved in isolating, genetically modifying and scaling-out the CAR T cells for use in a clinical setting are described in the context of in-process and release testing and regulatory standards. PMID:25675873

  15. Surface localization of the nuclear receptor CAR in influenza A virus-infected cells

    International Nuclear Information System (INIS)

    Constitutive active/androstane receptor CAR is a member of the nuclear receptors which regulate transcription of xenobiotic metabolism enzymes. CAR is usually localized in the cytosol and nucleus. Here, we found that CAR was localized at the cell surface of influenza A virus (IAV)-infected cells. Additionally, we demonstrated that expression of a viral envelope glycoprotein, either hemagglutinin (HA) or neuraminidase (NA), but not viral nucleoprotein (NP), was responsible for this localization. This report is the first demonstration of CAR at the surface of tissue culture cells, and suggests that CAR may exert the IAV infection mechanism

  16. Role of nuclear receptor CAR in carbon tetrachloride-induced hepatotoxicity

    Institute of Scientific and Technical Information of China (English)

    Yuichi Yamazaki; Satoru Kakizaki; Norio Horiguchi; Hitoshi Takagi; Masatomo Mori; Masahiko Negishi

    2005-01-01

    AIM: To investigate the precise roles of CAR in CCl4-induced acute hepatotoxicity.METHODS: To prepare an acute liver injury model, CCl4 was intraperitoneally injected in CAR+/+ and CAR-/- mice.RESULTS: Elevation of serum alanine aminotransferase and extension of centrilobular necrosis were slightly inhibited in CAR-/- mice compared to CAR+/+ mice without PB. Administration of a CAR inducer, PB, revealed that CCl4-induced liver toxicity was partially inhibited in CAR-/- mice compared with CAR+/+ mice. On the other hand,androstanol, an inverse agonist ligand, inhibited hepatotoxicity in CAR+/+ but not in CAR-/- mice. Thus, CAR activation caused CCl4 hepatotoxicity while CAR inhibition resulted in partial protection against CCl4-induced hepatotoxicity.There were no differences in the expression of CYP2E1, the main metabolizing enzyme for CCl4, between CAR+/+ and CAR-/- mice. However, the expression of other CCl4-metabolizing enzymes, such as CYP2B10 and 3A11, was induced by PB in CAR+/+ but not in CAR-/- mice. Although the main pathway of CCl4-induced acute liver injury is mediated by CYP2E1, CAR modulates its pathway via induction of CYP2B10 and 3A11 in the presence of activator or inhibitor.CONCLUSION: The nuclear receptor CAR modulates CCl4-induced liver injury via induction of CCl4-metabolizing enzymes in the presence of an activator. Our results suggest that drugs interacting with nuclear receptors such as PB might play critical roles in drug-induced liver injury or drugdrug interaction even though such drugs themselves are not hepatotoxic.

  17. Bioinformatic analysis of microRNA networks following the activation of the constitutive androstane receptor (CAR) in mouse liver.

    Science.gov (United States)

    Hao, Ruixin; Su, Shengzhong; Wan, Yinan; Shen, Frank; Niu, Ben; Coslo, Denise M; Albert, Istvan; Han, Xing; Omiecinski, Curtis J

    2016-09-01

    The constitutive androstane receptor (CAR; NR1I3) is a member of the nuclear receptor superfamily that functions as a xenosensor, serving to regulate xenobiotic detoxification, lipid homeostasis and energy metabolism. CAR activation is also a key contributor to the development of chemical hepatocarcinogenesis in mice. The underlying pathways affected by CAR in these processes are complex and not fully elucidated. MicroRNAs (miRNAs) have emerged as critical modulators of gene expression and appear to impact many cellular pathways, including those involved in chemical detoxification and liver tumor development. In this study, we used deep sequencing approaches with an Illumina HiSeq platform to differentially profile microRNA expression patterns in livers from wild type C57BL/6J mice following CAR activation with the mouse CAR-specific ligand activator, 1,4-bis-[2-(3,5,-dichloropyridyloxy)] benzene (TCPOBOP). Bioinformatic analyses and pathway evaluations were performed leading to the identification of 51 miRNAs whose expression levels were significantly altered by TCPOBOP treatment, including mmu-miR-802-5p and miR-485-3p. Ingenuity Pathway Analysis of the differentially expressed microRNAs revealed altered effector pathways, including those involved in liver cell growth and proliferation. A functional network among CAR targeted genes and the affected microRNAs was constructed to illustrate how CAR modulation of microRNA expression may potentially mediate its biological role in mouse hepatocyte proliferation. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. PMID:27080131

  18. Identification of chemical modulators of the constitutive activated receptor (CAR) in a gene expression compendium

    Science.gov (United States)

    Oshida, Keiyu; Vasani, Naresh; Jones, Carlton; Moore, Tanya; Hester, Susan; Nesnow, Stephen; Auerbach, Scott; Geter, David R.; Aleksunes, Lauren M.; Thomas, Russell S.; Applegate, Dawn; Klaassen, Curtis D.; Corton, J. Christopher

    2015-01-01

    The nuclear receptor family member constitutive activated receptor (CAR) is activated by structurally diverse drugs and environmentally-relevant chemicals leading to transcriptional regulation of genes involved in xenobiotic metabolism and transport. Chronic activation of CAR increases liver cancer incidence in rodents, whereas suppression of CAR can lead to steatosis and insulin insensitivity. Here, analytical methods were developed to screen for chemical treatments in a gene expression compendium that lead to alteration of CAR activity. A gene expression biomarker signature of 83 CAR-dependent genes was identified using microarray profiles from the livers of wild-type and CAR-null mice after exposure to three structurally-diverse CAR activators (CITCO, phenobarbital, TCPOBOP). A rank-based algorithm (Running Fisher’s algorithm (p-value ≤ 10-4)) was used to evaluate the similarity between the CAR biomarker signature and a test set of 28 and 32 comparisons positive or negative, respectively, for CAR activation; the test resulted in a balanced accuracy of 97%. The biomarker signature was used to identify chemicals that activate or suppress CAR in an annotated mouse liver/primary hepatocyte gene expression database of ~1850 comparisons. CAR was activated by 1) activators of the aryl hydrocarbon receptor (AhR) in wild-type but not AhR-null mice, 2) pregnane X receptor (PXR) activators in wild-type and to lesser extents in PXR-null mice, and 3) activators of PPARα in wild-type and PPARα-null mice. CAR was consistently activated by five conazole fungicides and four perfluorinated compounds. Comparison of effects in wild-type and CAR-null mice showed that the fungicide propiconazole increased liver weight and hepatocyte proliferation in a CAR-dependent manner, whereas the perfluorinated compound perfluorooctanoic acid (PFOA) increased these endpoints in a CAR-independent manner. A number of compounds suppressed CAR coincident with increases in markers of

  19. Chimeric antigen receptor (CAR-specific monoclonal antibody to detect CD19-specific T cells in clinical trials.

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    Bipulendu Jena

    Full Text Available Clinical trials targeting CD19 on B-cell malignancies are underway with encouraging anti-tumor responses. Most infuse T cells genetically modified to express a chimeric antigen receptor (CAR with specificity derived from the scFv region of a CD19-specific mouse monoclonal antibody (mAb, clone FMC63. We describe a novel anti-idiotype monoclonal antibody (mAb to detect CD19-specific CAR(+ T cells before and after their adoptive transfer. This mouse mAb was generated by immunizing with a cellular vaccine expressing the antigen-recognition domain of FMC63. The specificity of the mAb (clone no. 136.20.1 was confined to the scFv region of the CAR as validated by inhibiting CAR-dependent lysis of CD19(+ tumor targets. This clone can be used to detect CD19-specific CAR(+ T cells in peripheral blood mononuclear cells at a sensitivity of 1∶1,000. In clinical settings the mAb is used to inform on the immunophenotype and persistence of administered CD19-specific T cells. Thus, our CD19-specific CAR mAb (clone no. 136.20.1 will be useful to investigators implementing CD19-specific CAR(+ T cells to treat B-lineage malignancies. The methodology described to develop a CAR-specific anti-idiotypic mAb could be extended to other gene therapy trials targeting different tumor associated antigens in the context of CAR-based adoptive T-cell therapy.

  20. Antiproliferation of berberine is mediated by epigenetic modification of constitutive androstane receptor (CAR) metabolic pathway in hepatoma cells.

    Science.gov (United States)

    Zhang, Lei; Miao, Xiao-Jie; Wang, Xin; Pan, Hai-Hui; Li, Pu; Ren, Hong; Jia, Yong-Rui; Lu, Chuang; Wang, Hong-Bing; Yuan, Lan; Zhang, Guo-Liang

    2016-01-01

    Constitutive androstane receptor (CAR) regulates hepatic xenobiotic and energy metabolism, as well as promotes cell growth and hepatocarcinogenesis. Berberine is an ancient multipotent alkaloid drug which derived from Coptis chinensis plants. Here we report that berberine is able to be cellular uptake and accessible to chromatin in human hepatoma HepG2 cells. Berberine induces more apoptosis, cell cycle arrest, but less ROS production in CAR overexpressed mCAR-HepG2 cells. Moreover, berberine inhibits expressions of CAR and its target genes CYP2B6 and CYP3A4. Furthermore, berberine enhances DNA methylation level in whole genome but reduces that in promoter regions CpG sites of CYP2B6 and CYP3A4 genes under the presence of CAR condition. These results indicated that the antiproliferation of berberine might be mediated by the unique epigenetic modifying mechanism of CAR metabolic pathway, suggesting that berberine is a promising candidate in anticancer adjuvant chemotherapy, due to its distinct pharmacological properties in clinic. PMID:27311637

  1. Cars

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    The first car In 1885,German mechanical engineer,Karl Benz designed and built the world’s first practical automobile to be powered by an internal-combustion engine(内燃机).On January 29,1886,Benz received the first patent(专利)for a gas-fueled car.It was a three- wheeler;Benz built his first four-wheeled car in 1891.Benz & Company,the company started by the inventor,became the world’s largest manufacturer of automobiles by 1900.

  2. Analysis of cellular metals as energy-absorbing elements in car seats

    Energy Technology Data Exchange (ETDEWEB)

    Nesic, Srecko; Michels, Wilhelm; Krupp, Ulrich [Laboratory for Material Design and Structural Integrity, Faculty of Engineering and Computer Science, University of Applied Sciences Osnabrueck (Germany); Schaeffler, Peter [Alulight International GmbH, Ranshofen (Austria); Unruh, Klaus [Faurecia Autositze GmbH, Stadthagen (Germany)

    2011-11-15

    Due to the high energy-absorption potential of metal foams and their excellent weight-to-stiffness ratio, metal foams in car seats may contribute to both increasing passenger safety and also weight reduction. An overview and the first results of a research project to apply cellular metals as energy-absorbing components in car seats in case of a crash are discussed. The project aims are material optimization and the generation of standards and design criteria for a novel technical application of metal foams. The first results reveal the microstructure and mechanical behavior of different metal foams and metal-foam/metal-sheet sandwich structures. (Copyright copyright 2011 WILEY-VCH Verlag GmbH and Co. KGaA, Weinheim)

  3. Cellular Automation Model of Traffic Flow Based on the Car-Following Model

    Institute of Scientific and Technical Information of China (English)

    LI Ke-Ping; GAO Zi-You

    2004-01-01

    @@ We propose a new cellular automation (CA) traffic model that is based on the car-following model. A class of driving strategies is used in the car-following model instead of the acceleration in the NaSch traffic model. In our model, some realistic driver behaviour and detailed vehicle characteristics have been taken into account, such as distance-headway and safe distance, etc. The simulation results show that our model can exhibit some traffic flow states that have been observed in the real traffic, and both of the maximum flux and the critical density are very close to the real measurement. Moreover, it is easy to extend our method to multi-lane traffic.

  4. Protein arginine methyltransferase 5 (PRMT5) is a novel coactivator of constitutive androstane receptor (CAR)

    International Nuclear Information System (INIS)

    The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that protein arginine methyltransferase 5 (PRMT5) is a novel CAR-interacting protein. Furthermore, the PRMT-dependent induction of a CAR reporter gene, which was independent of methyltransferase activity, was enhanced in the presence of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) or DEAD box DNA/RNA helicase DP97. Using tetracycline inducible-hCAR system in HepG2 cells, we showed that knockdown of PRMT5 with small interfering RNA suppressed tetracycline -induced mRNA expression of CYP2B6 but not of CYP2C9 or CYP3A4. PRMT5 enhanced phenobarbital-mediated transactivation of a phenobarbital-responsive enhancer module (PBREM)-driven reporter gene in co-operation with PGC-1α in rat primary hepatocytes. Based on these findings, we suggest PRMT5 to be a gene (or promoter)-selective coactivator of CAR by mediating the formation of complexes between hCAR and appropriate coactivators. - Highlights: • Nuclear receptor CAR interact with PRMT5. • PRMT5 enhances transcriptional activity of CAR. • PRMT5 synergistically enhances transactivity of CAR by the co-expression of SRC-1, DP97 or PGC1α. • PRMT5 is a gene-selective co-activator for hCAR

  5. Protein arginine methyltransferase 5 (PRMT5) is a novel coactivator of constitutive androstane receptor (CAR)

    Energy Technology Data Exchange (ETDEWEB)

    Kanno, Yuichiro, E-mail: ykanno@phar.toho-u.ac.jp; Inajima, Jun; Kato, Sayaka; Matsumoto, Maika; Tokumoto, Chikako; Kure, Yuki; Inouye, Yoshio

    2015-03-27

    The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that protein arginine methyltransferase 5 (PRMT5) is a novel CAR-interacting protein. Furthermore, the PRMT-dependent induction of a CAR reporter gene, which was independent of methyltransferase activity, was enhanced in the presence of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) or DEAD box DNA/RNA helicase DP97. Using tetracycline inducible-hCAR system in HepG2 cells, we showed that knockdown of PRMT5 with small interfering RNA suppressed tetracycline -induced mRNA expression of CYP2B6 but not of CYP2C9 or CYP3A4. PRMT5 enhanced phenobarbital-mediated transactivation of a phenobarbital-responsive enhancer module (PBREM)-driven reporter gene in co-operation with PGC-1α in rat primary hepatocytes. Based on these findings, we suggest PRMT5 to be a gene (or promoter)-selective coactivator of CAR by mediating the formation of complexes between hCAR and appropriate coactivators. - Highlights: • Nuclear receptor CAR interact with PRMT5. • PRMT5 enhances transcriptional activity of CAR. • PRMT5 synergistically enhances transactivity of CAR by the co-expression of SRC-1, DP97 or PGC1α. • PRMT5 is a gene-selective co-activator for hCAR.

  6. Xenobiotic-sensing nuclear receptors CAR and PXR as drug targets in cholestatic liver disease.

    Science.gov (United States)

    Kakizaki, Satoru; Takizawa, Daichi; Tojima, Hiroki; Yamazaki, Yuichi; Mori, Masatomo

    2009-11-01

    Cholestasis results in the intrahepatic retention of cytotoxic bile acid and it can thus lead to liver injury and/or liver fibrosis. Cholestatic liver damage is counteracted by a variety of intrinsic hepatoprotective mechanisms including a complex network of drug metabolizing enzymes and transporters. During the last decade, much progress has been made in dissecting the mechanisms which regulate the hepatic xeno- and endobiotic metabolism by nuclear receptors. The xenobiotic receptors CAR and PXR are two important members of the NR1I nuclear receptor family. They function as sensors of toxic byproducts derived from the endogenous metabolism and of exogenous chemicals, in order to enhance their elimination. Ligands for both receptors, including phenobarbital, have already been used to treat cholestatic liver diseases before the mechanisms of these receptors were revealed. Furthermore, Yin Zhi Huang, a traditional Chinese herbal medicine, which has been used to prevent and treat neonatal jaundice, was identified to be a CAR ligand which also accelerates bilirubin clearance. Therefore, CAR and PXR have a protective effect on cholestasis by activating both detoxification enzymes and transporters. As a result, novel compounds targeting CAR and PXR with specific effects and fewer side effects will therefore be useful for the treatment of cholestatic liver diseases. This article will review the current knowledge on xenobiotic-sensing nuclear receptors CAR and PXR, while also discussing their potential role in the treatment of cholestatic liver diseases. PMID:19925451

  7. Cellular receptors for human enterovirus species A

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    Yorihiro eNishimura

    2012-03-01

    Full Text Available Human enterovirus species A (HEV-A is one of the four species of HEV in the genus Enterovirus in the family Picornaviridae. Among HEV-A, coxsackievirus A16 (CVA16 and enterovirus 71 (EV71 are the major causative agents of hand, foot, and mouth disease (HFMD. Some other types of HEV-A are commonly associated with herpangina. Although HFMD and herpangina due to HEV-A are common febrile diseases among infants and children, EV71 can cause various neurological diseases, such as aseptic meningitis and fatal encephalitis.Recently, two human transmembrane proteins, P-selectin glycoprotein ligand-1 (PSGL-1 and scavenger receptor class B, member 2 (SCARB2, were identified as functional receptors for EV71 and CVA16. In in vitro infection experiments using the prototype HEV-A strains, PSGL-1 and SCARB2 could be responsible for the specific receptors for EV71 and CVA16. However, the involvement of both receptors in the in vitro and in vivo infections of clinical isolates of HEV-A has not been clarified yet. To elucidate a diverse array of the clinical outcome of HEV-A-associated diseases, the identification and characterization of HEV-A receptors may provide useful information in understanding the HEV-A pathogenesis at a molecular level.

  8. Multiple phenotypes in adult mice following inactivation of the Coxsackievirus and Adenovirus Receptor (Car gene.

    Directory of Open Access Journals (Sweden)

    Ahmad Pazirandeh

    Full Text Available To determine the normal function of the Coxsackievirus and Adenovirus Receptor (CAR, a protein found in tight junctions and other intercellular complexes, we constructed a mouse line in which the CAR gene could be disrupted at any chosen time point in a broad spectrum of cell types and tissues. All knockouts examined displayed a dilated intestinal tract and atrophy of the exocrine pancreas with appearance of tubular complexes characteristic of acinar-to-ductal metaplasia. The mice also exhibited a complete atrio-ventricular block and abnormal thymopoiesis. These results demonstrate that CAR exerts important functions in the physiology of several organs in vivo.

  9. Protein arginine methyltransferase 5 (PRMT5) is a novel coactivator of constitutive androstane receptor (CAR).

    Science.gov (United States)

    Kanno, Yuichiro; Inajima, Jun; Kato, Sayaka; Matsumoto, Maika; Tokumoto, Chikako; Kure, Yuki; Inouye, Yoshio

    2015-03-27

    The constitutive androstane receptor (CAR) plays a key role in the expression of xenobiotic/steroid and drug metabolizing enzymes and their transporters. In this study, we demonstrated that protein arginine methyltransferase 5 (PRMT5) is a novel CAR-interacting protein. Furthermore, the PRMT-dependent induction of a CAR reporter gene, which was independent of methyltransferase activity, was enhanced in the presence of steroid receptor coactivator 1 (SRC1), peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1α) or DEAD box DNA/RNA helicase DP97. Using tetracycline inducible-hCAR system in HepG2 cells, we showed that knockdown of PRMT5 with small interfering RNA suppressed tetracycline -induced mRNA expression of CYP2B6 but not of CYP2C9 or CYP3A4. PRMT5 enhanced phenobarbital-mediated transactivation of a phenobarbital-responsive enhancer module (PBREM)-driven reporter gene in co-operation with PGC-1α in rat primary hepatocytes. Based on these findings, we suggest PRMT5 to be a gene (or promoter)-selective coactivator of CAR by mediating the formation of complexes between hCAR and appropriate coactivators. PMID:25721668

  10. The Coxsackievirus and Adenovirus Receptor (CAR undergoes ectodomain shedding and regulated intramembrane proteolysis (RIP.

    Directory of Open Access Journals (Sweden)

    Nadia Houri

    Full Text Available The Coxsackievirus and Adenovirus Receptor (CAR is a cell adhesion molecule originally characterized as a virus receptor but subsequently shown to be involved in physiological processes such as neuronal and heart development, epithelial tight junction integrity, and tumour suppression. Proteolysis of cell adhesion molecules and a wide variety of other cell surface proteins serves as a mechanism for protein turnover and, in some cases, cell signaling. Metalloproteases such as A Disintegrin and Metalloprotease (ADAM family members cleave cell surface receptors to release their substrates' ectodomains, while the presenilin/ɣ-secretase complex mediates regulated intramembrane proteolysis (RIP, releasing intracellular domain fragments from the plasma membrane. In the case of some substrates such as Notch and amyloid precursor protein (APP, the released intracellular domains enter the nucleus to modulate gene expression. We report that CAR ectodomain is constitutively shed from glioma cells and developing neurons, and is also shed when cells are treated with the phorbol ester phorbol 12-myristate 13-acetate (PMA and the calcium ionophore ionomycin. We identified ADAM10 as a sheddase of CAR using assays involving shRNA knockdown and rescue, overexpression of wild-type ADAM10 and inhibition of ADAM10 activity by addition of its prodomain. In vitro peptide cleavage, mass spectrometry and mutagenesis revealed the amino acids M224 to L227 of CAR as the site of ADAM10-mediated ectodomain cleavage. CAR also undergoes RIP by the presenilin/γ-secretase complex, and the intracellular domain of CAR enters the nucleus. Ectodomain shedding is a prerequisite for RIP of CAR. Thus, CAR belongs to the increasing list of cell surface molecules that undergo ectodomain shedding and that are substrates for ɣ-secretase-mediated RIP.

  11. Coxsackie- and adenovirus receptor (CAR) is expressed in lymphatic vessels in human skin and affects lymphatic endothelial cell function in vitro

    International Nuclear Information System (INIS)

    Lymphatic vessels play an important role in tissue fluid homeostasis, intestinal fat absorption and immunosurveillance. Furthermore, they are involved in pathologic conditions, such as tumor cell metastasis and chronic inflammation. In comparison to blood vessels, the molecular phenotype of lymphatic vessels is less well characterized. Performing comparative gene expression analysis we have recently found that coxsackie- and adenovirus receptor (CAR) is significantly more highly expressed in cultured human, skin-derived lymphatic endothelial cells (LECs), as compared to blood vascular endothelial cells. Here, we have confirmed these results at the protein level, using Western blot and FACS analysis. Immunofluorescence performed on human skin confirmed that CAR is expressed at detectable levels in lymphatic vessels, but not in blood vessels. To address the functional significance of CAR expression, we modulated CAR expression levels in cultured LECs in vitro by siRNA- and vector-based transfection approaches. Functional assays performed with the transfected cells revealed that CAR is involved in distinct cellular processes in LECs, such as cell adhesion, migration, tube formation and the control of vascular permeability. In contrast, no effect of CAR on LEC proliferation was observed. Overall, our data suggest that CAR stabilizes LEC-LEC interactions in the skin and may contribute to lymphatic vessel integrity

  12. Sexually dimorphic regulation and induction of P450s by the constitutive androstane receptor (CAR)

    International Nuclear Information System (INIS)

    The constitutive androstane receptor (CAR) is a xenosensing nuclear receptor and regulator of cytochrome P450s (CYPs). However, the role of CAR as a basal regulator of CYP expression nor its role in sexually dimorphic responses have been thoroughly studied. We investigated basal regulation and sexually dimorphic regulation and induction by the potent CAR activator TCPOBOP and the moderate CAR activator Nonylphenol (NP). NP is an environmental estrogen and one of the most commonly found environmental toxicants in Europe and the United States. Previous studies have demonstrated that NP induces several CYPs in a sexually dimorphic manner, however the role of CAR in regulating NP-mediated sexually dimorphic P450 expression and induction has not been elucidated. Therefore, wild-type and CAR-null male and female mice were treated with honey as a carrier, NP, or TCPOBOP and CYP expression monitored by QPCR and Western blotting. CAR basally regulates the expression of Cyp2c29, Cyp2b13, and potentially Cyp2b10 as demonstrated by QPCR. Furthermore, we observed a shift in the testosterone 6α/15α-hydroxylase ratio in untreated CAR-null female mice to the male pattern, which indicates an alteration in androgen status and suggests a role for androgens as CAR inverse agonists. Xenobiotic-treatments with NP and TCPOBOP induced Cyp2b10, Cyp2c29, and Cyp3a11 in a CAR-mediated fashion; however NP only induced these CYPs in females and TCPOBOP induced these CYPs in both males and females. Interestingly, Cyp2a4, was only induced in wild-type male mice by TCPOBOP suggesting Cyp2a4 induction is not sensitive to CAR-mediated induction in females. Overall, TCPOBOP and NP show similar CYP induction profiles in females, but widely different profiles in males potentially related to lower sensitivity of males to either indirect or moderate CAR activators such as NP. In summary, CAR regulates the basal and chemically inducible expression of several sexually dimorphic xenobiotic metabolizing P

  13. Essential Role of the Coxsackie - and Adenovirus Receptor (CAR) in Development of the Lymphatic System in Mice.

    OpenAIRE

    Mirza, Momina; Pang, Mei-Fong; Zaini, Mohamad Amr; Haiko, Paula Irmeli; Tammela, Tuomas; Fuxe, Jonas; Sollerbrant, Kerstin; Philipson, Lennart; Alitalo, Kari

    2012-01-01

    The coxsackie- and adenovirus receptor (CAR) is a cell adhesion molecule predominantly associated with epithelial tight junctions in adult tissues. CAR is also expressed in cardiomyocytes and essential for heart development up to embryonic day 11.5, but not thereafter. CAR is not expressed in vascular endothelial cells but was recently detected in neonatal lymphatic vessels, suggesting that CAR could play a role in the development of the lymphatic system. To address this, we generated mice ca...

  14. Regulation of Drug Disposition Gene Expression in Pregnant Mice with Car Receptor Activation

    Directory of Open Access Journals (Sweden)

    Amanda S. Bright

    2016-07-01

    Full Text Available More than half of pregnant women use prescription medications in order to maintain both maternal and fetal health. The constitutive androstane receptor (Car critically affects the disposition of chemicals by regulating the transcription of genes encoding metabolic enzymes and transporters. However, the effects of Car activation on chemical disposition during pregnancy are unclear. This study aims to determine the degree to which pregnancy alters the expression of drug metabolizing enzymes and transporters in response to the pharmacological activation of Car. To test this, pregnant C57BL/6 mice were administered IP doses of vehicle, or a potent Car agonist, TCPOBOP, on gestation days 14, 15 and 16. Hepatic mRNA and protein expression of Car target genes (phase I, II and transporters were quantified on gestation day 17. Pregnancy-related changes, such as induction of Cyp2b10, Ugt1a1 and Sult1a1 and repression of Ugt1a6, Gsta1, Gsta2 and Mrp6, were observed. Interestingly, the induction of Cyp2b10, Gsta1, Gsta2 and Mrp2–4 mRNAs by TCPOBOP was attenuated in maternal livers suggesting that Car activation is impeded by the biochemical and/or physiological changes that occur during gestation. Taken together, these findings suggest that pregnancy and pharmacological activation of Car can differentially regulate the expression of drug metabolism and transport genes.

  15. Therapeutic Potential of T Cell Chimeric Antigen Receptors (CARs) in Cancer Treatment: Counteracting Off-Tumor Toxicities for Safe CAR T Cell Therapy.

    Science.gov (United States)

    Gross, Gideon; Eshhar, Zelig

    2016-01-01

    A chimeric antigen receptor (CAR) is a recombinant fusion protein combining an antibody-derived targeting fragment with signaling domains capable of activating T cells. Recent early-phase clinical trials have demonstrated the remarkable ability of CAR-modified T cells to eliminate B cell malignancies. This review describes the choice of target antigens and CAR manipulations to maximize antitumor specificity. Benefits and current limitations of CAR-modified T cells are discussed, with a special focus on the distribution of tumor antigens on normal tissues and the risk of on-target, off-tumor toxicities in the clinical setting. We present current methodologies for pre-evaluating these risks and review the strategies for counteracting potential off-tumor effects. Successful implementation of these approaches will improve the safety and efficacy of CAR T cell therapy and extend the range of cancer patients who may be treated. PMID:26738472

  16. Cars, Cars, Cars

    Science.gov (United States)

    McIntosh, Phyllis

    2013-01-01

    Cars are the focus of this feature article, which explores such topics as the history of cars in the United States, the national highway system, safety and pollution concerns, mobility and freedom for women, classic car shows, and the road trip in American literature and film. Also included are links to the websites of Automobile in American Life…

  17. A receptor for infectious and cellular prion protein

    Directory of Open Access Journals (Sweden)

    V.R. Martins

    1999-07-01

    Full Text Available Prions are an unconventional form of infectious agents composed only of protein and involved in transmissible spongiform encephalopathies in humans and animals. The infectious particle is composed by PrPsc which is an isoform of a normal cellular glycosyl-phosphatidylinositol (GPI anchored protein, PrPc, of unknown function. The two proteins differ only in conformation, PrPc is composed of 40% a helix while PrPsc has 60% ß-sheet and 20% a helix structure. The infection mechanism is trigged by interaction of PrPsc with cellular prion protein causing conversion of the latter's conformation. Therefore, the infection spreads because new PrPsc molecules are generated exponentially from the normal PrPc. The accumulation of insoluble PrPsc is probably one of the events that lead to neuronal death. Conflicting data in the literature showed that PrPc internalization is mediated either by clathrin-coated pits or by caveolae-like membranous domains. However, both pathways seem to require a third protein (a receptor or a prion-binding protein either to make the connection between the GPI-anchored molecule to clathrin or to convert PrPc into PrPsc. We have recently characterized a 66-kDa membrane receptor which binds PrPc in vitro and in vivo and mediates the neurotoxicity of a human prion peptide. Therefore, the receptor should have a role in the pathogenesis of prion-related diseases and in the normal cellular process. Further work is necessary to clarify the events triggered by the association of PrPc/PrPsc with the receptor.

  18. Coxsackie and adenovirus receptor (CAR) is a modifier of cardiac conduction and arrhythmia vulnerability in the setting of myocardial ischemia

    Science.gov (United States)

    Marsman, Roos F.J.; Bezzina, Connie R.; Freiberg, Fabian; Verkerk, Arie O.; Adriaens, Michiel E.; Podliesna, Svitlana; Chen, Chen; Purfürst, Bettina; Spallek, Bastian; Koopmann, Tamara T.; Baczko, Istvan; dos Remedios, Cristobal G.; George, Alfred L.; Bishopric, Nanette H.; Lodder, Elisabeth M.; de Bakker, Jacques M.T.; Fischer, Robert; Coronel, Ruben; Wilde, Arthur A.M.; Gotthardt, Michael; Remme, Carol Ann

    2014-01-01

    Objectives To investigate the modulatory effect of the Coxsackie and adenovirus receptor (CAR) on ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Background A heritable component in risk for ventricular fibrillation (VF) during myocardial infarction (MI) has been well established. A recent genome-wide association study (GWAS) for VF during acute MI has led to the identification of a locus on chromosome 21q21 (rs2824292) in the vicinity of the CXADR gene. CXADR encodes the coxsackie and adenovirus receptor (CAR), a cell adhesion molecule predominantly located at intercalated discs of the cardiomyocyte. Methods The correlation between CAR transcript levels and rs2824292 genotype was investigated in human left ventricular samples. Electrophysiological studies and molecular analyses were performed CAR haploinsufficient mice (CAR+/−). Results In human left ventricular samples, the risk allele at the chr21q21 GWAS locus was associated with lower CXADR mRNA levels, suggesting that decreased cardiac levels of CAR predispose to ischemia-induced VF. Hearts from CAR+/− mice displayed ventricular conduction slowing in addition to an earlier onset of ventricular arrhythmias during the early phase of acute myocardial ischemia following LAD ligation. Connexin43 expression and distribution was unaffected, but CAR+/− hearts displayed increased arrhythmia susceptibility upon pharmacological electrical uncoupling. Patch-clamp analysis of isolated CAR+/− myocytes showed reduced sodium current magnitude specifically at the intercalated disc. Moreover, CAR co-precipitated with NaV1.5 in vitro, suggesting that CAR affects sodium channel function through a physical interaction with NaV1.5. Conclusion We identify CAR as a novel modifier of ventricular conduction and arrhythmia vulnerability in the setting of myocardial ischemia. Genetic determinants of arrhythmia susceptibility (such as CAR) may constitute future targets for risk

  19. Protein L: a novel reagent for the detection of Chimeric Antigen Receptor (CAR) expression by flow cytometry

    OpenAIRE

    Zheng Zhili; Chinnasamy Nachimuthu; Morgan Richard A

    2012-01-01

    Abstract Background There has been significant progress in the last two decades on the design of chimeric antigen receptors (CAR) for adoptive immunotherapy targeting tumor-associated antigens. Structurally CARs consist of a single chain antibody fragment directed against a tumor-associated antigen fused to an extracellular spacer and transmembrane domain followed by T cell cytoplasmic signaling moieties. Currently several clinical trials are underway using gene modified peripheral blood lymp...

  20. Protein L: a novel reagent for the detection of Chimeric Antigen Receptor (CAR expression by flow cytometry

    Directory of Open Access Journals (Sweden)

    Zheng Zhili

    2012-02-01

    Full Text Available Abstract Background There has been significant progress in the last two decades on the design of chimeric antigen receptors (CAR for adoptive immunotherapy targeting tumor-associated antigens. Structurally CARs consist of a single chain antibody fragment directed against a tumor-associated antigen fused to an extracellular spacer and transmembrane domain followed by T cell cytoplasmic signaling moieties. Currently several clinical trials are underway using gene modified peripheral blood lymphocytes (PBL with CARs directed against a variety of tumor associated antigens. Despite the improvements in the design of CARs and expansion of the number of target antigens, there is no universal flow cytometric method available to detect the expression of CARs on the surface of transduced lymphocytes. Methods Currently anti-fragment antigen binding (Fab conjugates are most widely used to determine the expression of CARs on gene-modified lymphocytes by flow cytometry. The limitations of these reagents are that many of them are not commercially available, generally they are polyclonal antibodies and often the results are inconsistent. In an effort to develop a simple universal flow cytometric method to detect the expression of CARs, we employed protein L to determine the expression of CARs on transduced lymphocytes. Protein L is an immunoglobulin (Ig-binding protein that binds to the variable light chains (kappa chain of Ig without interfering with antigen binding site. Protein L binds to most classes of Ig and also binds to single-chain antibody fragments (scFv and Fab fragments. Results We used CARs derived from both human and murine antibodies to validate this novel protein L based flow cytometric method and the results correlated well with other established methods. Activated human PBLs were transduced with retroviral vectors expressing two human antibody based CARs (anti-EGFRvIII, and anti-VEGFR2, two murine antibody derived CARs (anti-CSPG4, and anti

  1. Development of second generation peptides modulating cellular adiponectin receptor responses

    Science.gov (United States)

    Otvos, Laszlo; Knappe, Daniel; Hoffmann, Ralf; Kovalszky, Ilona; Olah, Julia; Hewitson, Tim; Stawikowska, Roma; Stawikowski, Maciej; Cudic, Predrag; Lin, Feng; Wade, John; Surmacz, Eva; Lovas, Sandor

    2014-10-01

    The adipose tissue participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active adipokines, including adiponectin. Recently we developed and characterized a first-in-class peptide-based adiponectin receptor agonist by using in vitro and in vivo models of glioblastoma and breast cancer (BC). In the current study, we further explored the effects of peptide ADP355 in additional cellular models and found that ADP355 inhibited chronic myeloid leukemia (CML) cell proliferation and renal myofibroblast differentiation with mid-nanomolar IC50 values. According to molecular modeling calculations, ADP355 was remarkably flexible in the global minimum with a turn present in the middle of the peptide. Considering these structural features of ADP355 and the fact that adiponectin normally circulates as multimeric complexes, we developed and tested the activity of a linear branched dimer (ADP399). The dimer exhibited approximately 20-fold improved cellular activity inhibiting K562 CML and MCF-7 cell growth with high pM - low nM relative IC50 values. Biodistribution studies suggested superior tissue dissemination of both peptides after subcutaneous administration relative to intraperitoneal inoculation. After screening of a 397-member adiponectin active site library, a novel octapeptide (ADP400) was designed that counteracted 10-1000 nM ADP355- and ADP399-mediated effects on CML and BC cell growth at nanomolar concentrations. ADP400 induced mitogenic effects in MCF-7 BC cells perhaps due to antagonizing endogenous adiponectin actions or acting as an inverse agonist. While the linear dimer agonist ADP399 meets pharmacological criteria of a contemporary peptide drug lead, the peptide showing antagonist activity (ADP400) at similar concentrations will be an important target validation tool to study adiponectin functions.

  2. Development of second generation peptides modulating cellular adiponectin receptor responses

    Directory of Open Access Journals (Sweden)

    Laszlo eOtvos

    2014-10-01

    Full Text Available The adipose tissue participates in the regulation of energy homeostasis as an important endocrine organ that secretes a number of biologically active adipokines, including adiponectin. Recently we developed and characterized a first-in-class peptide-based adiponectin receptor agonist by using in vitro and in vivo models of glioblastoma and breast cancer (BC. In the current study, we further explored the effects of peptide ADP355 in additional cellular models and found that ADP355 inhibited chronic myeloid leukemia (CML cell proliferation and renal myofibroblast differentiation with mid-nanomolar IC50 values. According to molecular modeling calculations, ADP355 was remarkably flexible in the global minimum with a turn present in the middle of the peptide. Considering these structural features of ADP355 and the fact that adiponectin normally circulates as multimeric complexes, we developed and tested the activity of a linear branched dimer (ADP399. The dimer exhibited approximately 20-fold improved cellular activity inhibiting K562 CML and MCF-7 cell growth with high pM - low nM relative IC50 values. Biodistribution studies suggested superior tissue dissemination of both peptides after subcutaneous administration relative to intraperitoneal inoculation. After screening of a 397-member adiponectin active site library, a novel octapeptide (ADP400 was designed that counteracted 10-1000 nM ADP355- and ADP399-mediated effects on CML and BC cell growth at nanomolar concentrations. ADP400 induced mitogenic effects in MCF-7 BC cells perhaps due to antagonizing endogenous adiponectin actions or acting as an inverse agonist. While the linear dimer agonist ADP399 meets pharmacological criteria of a contemporary peptide drug lead, the peptide showing antagonist activity (ADP400 at similar concentrations will be an important target validation tool to study adiponectin functions.

  3. Quantum dot multiplexing for the profiling of cellular receptors

    Science.gov (United States)

    Lee-Montiel, Felipe T.; Li, Peter; Imoukhuede, P. I.

    2015-11-01

    The profiling of cellular heterogeneity has wide-reaching importance for our understanding of how cells function and react to their environments in healthy and diseased states. Our ability to interpret and model cell behavior has been limited by the difficulties of measuring cell differences, for example, comparing tumor and non-tumor cells, particularly at the individual cell level. This demonstrates a clear need for a generalizable approach to profile fluorophore sites on cells or molecular assemblies on beads. Here, a multiplex immunoassay for simultaneous detection of five different angiogenic markers was developed. We targeted angiogenic receptors in the vascular endothelial growth factor family (VEGFR1, VEGFR2 and VEGFR3) and Neuropilin (NRP) family (NRP1 and NRP2), using multicolor quantum dots (Qdots). Copper-free click based chemistry was used to conjugate the monoclonal antibodies with 525, 565, 605, 655 and 705 nm CdSe/ZnS Qdots. We tested and performed colocalization analysis of our nanoprobes using the Pearson correlation coefficient statistical analysis. Human umbilical vein endothelial cells (HUVEC) were tested. The ability to easily monitor the molecular indicators of angiogenesis that are a precursor to cancer in a fast and cost effective system is an important step towards personalized nanomedicine.The profiling of cellular heterogeneity has wide-reaching importance for our understanding of how cells function and react to their environments in healthy and diseased states. Our ability to interpret and model cell behavior has been limited by the difficulties of measuring cell differences, for example, comparing tumor and non-tumor cells, particularly at the individual cell level. This demonstrates a clear need for a generalizable approach to profile fluorophore sites on cells or molecular assemblies on beads. Here, a multiplex immunoassay for simultaneous detection of five different angiogenic markers was developed. We targeted angiogenic receptors

  4. Planes, Trains, and Automobiles: Perspectives on CAR T Cells and Other Cellular Therapies for Hematologic Malignancies.

    Science.gov (United States)

    Gill, Saar

    2016-08-01

    Hematologic oncologists now have at their disposal (or a referral away) a myriad of new options to get from point A (a patient with relapsed or poor-risk disease) to point B (potential tumor eradication and long-term disease-free survival). In this perspective piece, we discuss the putative mechanisms of action and the relative strengths and weaknesses of currently available cellular therapy approaches. Notably, while many of these approaches have been published in high impact journals, with the exception of allogeneic stem cell transplantation and of checkpoint inhibitors (PD1/PDL1 or CTLA4 blockade), the published clinical trials have mostly been early phase, uncontrolled studies. Therefore, many of the new cellular therapy approaches have yet to demonstrate incontrovertible evidence of enhanced overall survival compared with controls. Nonetheless, the science behind these is sure to advance our understanding of cancer immunology and ultimately to bring us closer to our goal of curing cancer. PMID:27136938

  5. Potential cellular receptors involved in hepatitis C virus entry into cells

    Directory of Open Access Journals (Sweden)

    Muellhaupt Beat

    2005-04-01

    Full Text Available Abstract Hepatitis C virus (HCV infects hepatocytes and leads to permanent, severe liver damage. Since the genomic sequence of HCV was determined, progress has been made towards understanding the functions of the HCV-encoded proteins and identifying the cellular receptor(s responsible for adsorption and penetration of the virus particle into the target cells. Several cellular receptors for HCV have been proposed, all of which are associated with lipid and lipoprotein metabolism. This article reviews the cellular receptors for HCV and suggests a general model for HCV entry into cells, in which lipoproteins play a crucial role.

  6. Nuclear Translocation of Adenoviral-Enhanced Yellow Fluorescent Protein-Tagged-Human Constitutive Androstane Receptor (hCAR): A Novel Tool for Screening hCAR Activators in Human Primary HepatocytesS⃞

    OpenAIRE

    Li, Haishan; Tao CHEN; Cottrell, John; Wang, Hongbing

    2009-01-01

    The constitutive androstane receptor [(CAR) NR1I3] is a hepatic transcription factor that controls the expression of numerous drug-metabolizing enzymes and transporters in response to xenobiotic exposures. In primary hepatocytes and intact liver, CAR resides in the cytoplasm under basal condition and translocates to the nucleus upon exposure to inducers. However, CAR spontaneously accumulates in the nucleus of immortalized cell lines and exhibits constitutive activatio...

  7. Prospects for chimeric antigen receptor (CAR) γδ T cells: A potential game changer for adoptive T cell cancer immunotherapy.

    Science.gov (United States)

    Mirzaei, Hamid Reza; Mirzaei, Hamed; Lee, Sang Yun; Hadjati, Jamshid; Till, Brian G

    2016-10-01

    Excitement is growing for therapies that harness the power of patients' immune systems to combat their diseases. One approach to immunotherapy involves engineering patients' own T cells to express a chimeric antigen receptor (CAR) to treat advanced cancers, particularly those refractory to conventional therapeutic agents. Although these engineered immune cells have made remarkable strides in the treatment of patients with certain hematologic malignancies, success with solid tumors has been limited, probably due to immunosuppressive mechanisms in the tumor niche. In nearly all studies to date, T cells bearing αβ receptors have been used to generate CAR T cells. In this review, we highlight biological characteristics of γδ T cells that are distinct from those of αβ T cells, including homing to epithelial and mucosal tissues and unique functions such as direct antigen recognition, lack of alloreactivity, and ability to present antigens. We offer our perspective that these features make γδ T cells promising for use in cellular therapy against several types of solid tumors, including melanoma and gastrointestinal cancers. Engineered γδ T cells should be considered as a new platform for adoptive T cell cancer therapy for mucosal tumors. PMID:27392648

  8. In Vitro and In Vivo Comparison of Lymphocytes Transduced with a Human CD16 or with a Chimeric Antigen Receptor Reveals Potential Off-Target Interactions due to the IgG2 CH2-CH3 CAR-Spacer

    Directory of Open Access Journals (Sweden)

    Béatrice Clémenceau

    2015-01-01

    Full Text Available The present work was designed to compare two mechanisms of cellular recognition based on Ab specificity: firstly, when the anti-HER2 mAb trastuzumab bridges target cells and cytotoxic lymphocytes armed with a Fc receptor (ADCC and, secondly, when HER2 positive target cells are directly recognized by cytotoxic lymphocytes armed with a chimeric antigen receptor (CAR. To compare these two mechanisms, we used the same cellular effector (NK-92 and the same signaling domain (FcεRIγ. The NK-92 cytotoxic cell line was transfected with either a FcγRIIIa-FcεRIγ (NK-92CD16 or a trastuzumab-based scFv-FcεRIγ chimeric receptor (NK-92CAR. In vitro, the cytotoxic activity against HER2 positive target cells after indirect recognition by NK-92CD16 was always inferior to that observed after direct recognition by NK-92CAR. In contrast, and somehow unexpectedly, in vivo, adoptive transfer of NK-92CD16 + trastuzumab but not of NK-92CAR induced tumor regression. Analysis of the in vivo xenogeneic system suggested that the human CH2-CH3 IgG2 used as a spacer in our construct was able to interact with the FcR present at the cell surface of the few NSG-FcR+ remaining immune cells. This interaction, leading to blockage of the NK-92CAR in the periphery of the engrafted tumor cells, stresses the critical role of the composition of the spacer domain.

  9. A Global Genomic Screening Strategy Reveals Diverse Activators of Constitutive Activated Receptor (CAR)

    Science.gov (United States)

    A comprehensive survey of conditions that activate CAR in the mouse liver has not been carried out but would be useful in understanding their impact on CAR-dependent liver tumor induction. A gene signature dependent on CAR activation was identified by comparing the transcript pr...

  10. Morbilliviruses Use Signaling Lymphocyte Activation Molecules (CD150) as Cellular Receptors

    OpenAIRE

    Tatsuo, Hironobu; Ono, Nobuyuki; Yanagi, Yusuke

    2001-01-01

    Morbilliviruses comprise measles virus, canine distemper virus, rinderpest virus, and several other viruses that cause devastating human and animal diseases accompanied by severe immunosuppression and lymphopenia. Recently, we have shown that human signaling lymphocyte activation molecule (SLAM) is a cellular receptor for measles virus. In this study, we examined whether canine distemper and rinderpest viruses also use canine and bovine SLAMs, respectively, as cellular receptors. The Onderste...

  11. Nucleic acid sequences encoding D1 and D1/D2 domains of human coxsackievirus and adenovirus receptor (CAR)

    Science.gov (United States)

    Freimuth, Paul I.

    2010-04-06

    The invention provides recombinant human CAR (coxsackievirus and adenovirus receptor) polypeptides which bind adenovirus. Specifically, polypeptides corresponding to adenovirus binding domain D1 and the entire extracellular domain of human CAR protein comprising D1 and D2 are provided. In another aspect, the invention provides nucleic acid sequences encoding these domains and expression vectors for producing the domains and bacterial cells containing such vectors. The invention also includes an isolated fusion protein comprised of the D1 polypeptide fused to a polypeptide which facilitates folding of D1 when expressed in bacteria. The functional D1 domain finds application in a therapeutic method for treating a patient infected with a CAR D1-binding virus, and also in a method for identifying an antiviral compound which interferes with viral attachment. The invention also provides a method for specifically targeting a cell for infection by a virus which binds to D1.

  12. Chimeric antigen receptor (CAR)-engineered T cells redirected against hepatitis C virus (HCV) E2 glycoprotein

    Science.gov (United States)

    Sautto, Giuseppe A; Wisskirchen, Karin; Clementi, Nicola; Castelli, Matteo; Diotti, Roberta A; Graf, Julia; Clementi, Massimo; Burioni, Roberto; Protzer, Ulrike; Mancini, Nicasio

    2016-01-01

    Objective The recent availability of novel antiviral drugs has raised new hope for a more effective treatment of hepatitis C virus (HCV) infection and its severe sequelae. However, in the case of non-responding or relapsing patients, alternative strategies are needed. To this end we have used chimeric antigen receptors (CARs), a very promising approach recently used in several clinical trials to redirect primary human T cells against different tumours. In particular, we designed the first CARs against HCV targeting the HCV/E2 glycoprotein (HCV/E2). Design Anti-HCV/E2 CARs were composed of single-chain variable fragments (scFvs) obtained from a broadly cross-reactive and cross-neutralising human monoclonal antibody (mAb), e137, fused to the intracellular signalling motif of the costimulatory CD28 molecule and the CD3ζ domain. Activity of CAR-grafted T cells was evaluated in vitro against HCV/E2-transfected cells as well as hepatocytes infected with cell culture-derived HCV (HCVcc). Results In this proof-of-concept study, retrovirus-transduced human T cells expressing anti-HCV/E2 CARs were endowed with specific antigen recognition accompanied by degranulation and secretion of proinflammatory and antiviral cytokines, such as interferon γ, interleukin 2 and tumour necrosis factor α. Moreover, CAR-grafted T cells were capable of lysing target cells of both hepatic and non-hepatic origin expressing on their surface the HCV/E2 glycoproteins of the most clinically relevant genotypes, including 1a, 1b, 2a, 3a, 4 and 5. Finally, and more importantly, they were capable of lysing HCVcc-infected hepatocytes. Conclusions Clearance of HCV-infected cells is a major therapeutic goal in chronic HCV infection, and adoptive transfer of anti-HCV/E2 CARs-grafted T cells represents a promising new therapeutic tool. PMID:25661083

  13. Molecular and cellular designs of insect taste receptor system

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    Kunio Isono

    2010-06-01

    Full Text Available The insect gustatory receptors (GRs are members of a large G-protein coupled receptor family distantly related to the insect olfactory receptors. They are phylogenetically different from taste receptors of most other animals. GRs are often coexpressed with other GRs in single receptor neurons. Taste receptors other than GRs are also expressed in some neurons. Recent molecular studies in the fruitfly Drosophila revealed that the insect taste receptor system not only covers a wide ligand spectrum of sugars, bitter substances or salts that are common to mammals but also includes reception of pheromone and somatosensory stimulants. However, the central mechanism to perceive and discriminate taste information is not yet elucidated. Analysis of the primary projection of taste neurons to the brain shows that the projection profiles depend basically on the peripheral locations of the neurons as well as the GRs that they express. These results suggest that both peripheral and central design principles of insect taste perception are different from those of olfactory perception.

  14. Cellular Uptake of Cobalamin: Transcobalamin and the TCblR/CD320 Receptor

    OpenAIRE

    Quadros, Edward V; Sequeira, Jeffrey M.

    2013-01-01

    Cellular uptake of cobalamin is facilitated by a receptor mediated endocytosis process involving transcobalamin, a plasma protein that binds cobalamin and a cell surface receptor that specifically binds transcobalamin saturated with cobalamin. Intracellular Cbl concentration is maintained by modulating the expression of the receptor, which is cell cycle associated with highest expression in actively proliferating cells and an efflux system that shunts the excess cobalamin out of the cells for...

  15. Receptor Oligomerization as a Process Modulating Cellular Semiotics

    DEFF Research Database (Denmark)

    Giorgi, Franco; Bruni, Luis Emilio; Maggio, Roberto

    2010-01-01

    The majority of G protein-coupled receptors (GPCRs) self-assemble in the form dimeric/oligomeric complexes along the plasma membrane. Due to the molecular interactions they participate, GPCRs can potentially provide the framework for discriminating a wide variety of intercellular signals, as base...

  16. A mollusk VDR/PXR/CAR-like (NR1J) nuclear receptor provides insight into ancient detoxification mechanisms.

    Science.gov (United States)

    Cruzeiro, Catarina; Lopes-Marques, Mónica; Ruivo, Raquel; Rodrigues-Oliveira, Nádia; Santos, Miguel M; Rocha, Maria João; Rocha, Eduardo; Castro, L Filipe C

    2016-05-01

    The origin and diversification of the metazoan endocrine systems represents a fundamental research issue in biology. Nuclear receptors are critical components of these systems. A particular group named VDR/PXR/CAR (NR1I/J) is central in the mediation of detoxification responses. While orthologues have been thoroughly characterized in vertebrates, a sparse representation is currently available for invertebrates. Here, we provide the first isolation and characterization of a lophotrochozoan protostome VDR/PXR/CAR nuclear receptor (NR1J), in the estuarine bivalve the peppery furrow shell (Scrobicularia plana). Using a reporter gene assay, we evaluated the xenobiotic receptor plasticity comparing the human PXR with the S. plana NR1Jβ. Our results show that the molluscan receptor responds to a natural toxin (okadaic acid) in a similar fashion to that reported for other invertebrates. In contrast, the pesticide esfenvalerate displayed a unique response, since it down regulated transactivation at higher concentrations, while for triclosan no response was observed. Additionally, we uncovered lineage specific gene duplications and gene loss in the gene group encoding NRs in protostomes with likely impacts on the complexity of detoxification mechanisms across different phyla. Our findings pave the way for the development of multi-specific sensor tools to screen xenobiotic compounds acting via the NR1I/J group. PMID:26921727

  17. Techniques to Study Specific Cell-Surface Receptor-Mediated Cellular Vitamin A Uptake

    OpenAIRE

    KAWAGUCHI, RIKI; Sun, Hui

    2010-01-01

    STRA6 is a multitransmembrane domain protein that was recently identified as the cell-surface receptor for plasma retinol binding protein (RBP), the vitamin A carrier protein in the blood. STRA6 binds to RBP with high affinity and mediates cellular uptake of vitamin A from RBP. It is not homologous to any known receptors, transporters, and channels, and it represents a new class of membrane transport protein. Consistent with the diverse physiological functions of vitamin A, STRA6 is widely ex...

  18. Tumor Necrosis Factor Receptor 2: Its Contribution to Acute Cellular Rejection and Clear Cell Renal Carcinoma

    OpenAIRE

    Jun Wang; Al-Lamki, Rafia S.

    2013-01-01

    Tumor necrosis factor receptor 2 (TNFR2) is a type I transmembrane glycoprotein and one of the two receptors that orchestrate the complex biological functions of tumor necrosis factor (TNF, also designed TNF- α ). Accumulating experimental evidence suggests that TNFR2 plays an important role in renal disorders associated with acute cellular rejection and clear cell renal carcinoma but its exact role in these settings is still not completely understood. This papers reviews the factors that may...

  19. Characterization of the Interaction of Lassa Fever Virus with Its Cellular Receptor α-Dystroglycan

    OpenAIRE

    Kunz, Stefan; Rojek, Jillian M.; Perez, Mar; Spiropoulou, Christina F.; Oldstone, Michael B. A.

    2005-01-01

    The cellular receptor for the Old World arenaviruses Lassa fever virus (LFV) and lymphocytic choriomeningitis virus (LCMV) has recently been identified as α-dystroglycan (α-DG), a cell surface receptor that provides a molecular link between the extracellular matrix and the actin-based cytoskeleton. In the present study, we show that LFV binds to α-DG with high affinity in the low-nanomolar range. Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the recepto...

  20. Development of a Systems Computational Model to Investigate Early Biological Events in Hepatic Activation of Constitutive Androstane Receptor (CAR) by Phenobarbital

    Science.gov (United States)

    Activation of the nuclear receptor CAR (constitutive active/androstane receptor) is implicated in the control several key biological events such as metabolic pathways. Here, we combined data from literature with information obtained from in vitro assays in the US EPA ToxCast dat...

  1. New Functions for Oxysterols and Their Cellular Receptors

    Directory of Open Access Journals (Sweden)

    Vesa M. Olkkonen

    2008-01-01

    Full Text Available Oxysterols are naturally occurring oxidized derivatives of cholesterol, or by-products of cholesterol biosynthesis, with multiple biologic functions. These compounds display cytotoxic, pro-apoptotic, and pro-inflammatory activities and may play a role in the pathology of atherosclerosis. Their functions as intermediates in the synthesis of bile acids and steroid hormones, and as readily transportable forms of sterol are well established. During the past decade, however, novel physiologic activities of oxysterols have emerged. They are now thought to act as endogenous regulators of gene expression in lipid metabolism. Recently, new intracellular oxysterol receptors have been identified and novel functions of oxysterols in cell signaling discovered, evoking novel interest in these compounds in several branches of biomedical research.

  2. Regulation of urokinase by cellular receptors and inhibitors

    International Nuclear Information System (INIS)

    Several cell types display binding sites for 125I-urokinase which in certain cases are occupied with endogenous urokinase. These sites appear to focus urokinase at cell surfaces and hence may participate in tissue matrix destruction and cell invasion. Using immunofluorescence double labeling, the author shows that the receptor-bound urokinase present on human foreskin fibroblasts and HT1080 human fibrosarcoma cells is colocalized with vinculin, an intracellular actin-binding protein that is deposited at cell to substratum focal adhesion sites. Thus, this indicates linkage of the plasminogen/plasmin system both to sites of cell adhesion and to the cytoskeleton. He furthermore reports that neither EGF, TGFβ or PDGF significantly altered the shape or intensity of the receptor-bound urokinase clusters but that thrombin, at mitogenic doses, caused a disappearance of the urokinase strands and a loss or gross alteration of the underlying focal adhesion plaques, as indicated by immunofluorescence staining for vinculin and talin, and by interference reflection microscopy. These observations suggest that thrombin may be a unique effector of cell adhesion, shape and movement. He used a quantitative in vitro invasion assay to study the role of plasminogen activator inhibitors type 1 and 2 (PAI-1, PAI-2) and protease nexin (PN1) in basement membrane (BM) invasion by 125I-iododeoxyuridine-labeled HT 1080 cells. The results obtained showed that 5 μg/ml of PAI-1, PAI-2 and PN1 preadsorbed to the BM completely blocked HT1080 invasion. On the contrary an anti-PAI-1 monoclonal antibody induced an approximately two-fold increase in invasion. 125I-fibrinogen was polymerized on the amnion BM and the fibrinolytic activity of the cells was measured under the invasion assay conditions by measuring the radioactivity in the culture medium at different time points

  3. In vivo effects of chronic contamination with depleted uranium on CYP3A and associated nuclear receptors PXR and CAR in the rat

    International Nuclear Information System (INIS)

    In addition to its natural presence at high concentrations in some areas, uranium has several civilian and military applications that could cause contamination of human populations, mainly through chronic ingestion. Reports describe the accumulation of this radionuclide in some organs (including the bone, kidney, and liver) after acute or chronic contamination and show that it produces chemical or radiological toxicity or both. The literature is essentially devoid of information about uranium-related cellular and molecular effects on metabolic functions such as xenobiotic detoxification. The present study thus evaluated rats chronically exposed to depleted uranium in their drinking water (1 mg/(rat day)) for 9 months. Our specific aim was to evaluate the hepatic and extrahepatic mRNA expression of CYP3A1/A2, CYP2B1, and CYP1A1 as well as of the nuclear receptors PXR, CAR, and RXR in these rats. CYP3A1 mRNA expression was significantly higher in the brain (200%), liver (300%), and kidneys (900%) of exposed rats compared with control rats, while CYP3A2 mRNA levels were higher in the lungs (300%) and liver (200%), and CYP2B1 mRNA expression in the kidneys (300%). Expression of CYP1A1 mRNA did not change significantly during this study. PXR mRNA levels increased in the brain (200%), liver (150%), and kidneys (200%). Uranium caused CAR mRNA expression in the lungs to double. Expression of RXR mRNA did not change significantly in the course of this study, nor did the hepatic activity of CYP2C, CYP3A, CYP2A, or CYP2B. Uranium probably affects the expression of drug-metabolizing CYP enzymes through the PXR and CAR nuclear receptors. These results suggest that the stimulating effect of uranium on these enzymes might lead to hepatic or extrahepatic toxicity (or both) during drug treatment and then affect the entire organism

  4. Functional Proteomics Defines the Molecular Switch Underlying FGF Receptor Trafficking and Cellular Outputs

    DEFF Research Database (Denmark)

    Francavilla, Chiara; Rigbolt, Kristoffer T.G.; Emdal, Kristina B;

    2013-01-01

    The stimulation of fibroblast growth factor receptors (FGFRs) with distinct FGF ligands generates specific cellular responses. However, the mechanisms underlying this paradigm have remained elusive. Here, we show that FGF-7 stimulation leads to FGFR2b degradation and, ultimately, cell proliferati...

  5. Modeling mechanical restriction differences between car and heavy truck in two-lane cellular automata traffic flow model

    Science.gov (United States)

    Li, Xin; Li, Xingang; Xiao, Yao; Jia, Bin

    2016-06-01

    Real traffic is heterogeneous with car and truck. Due to mechanical restrictions, the car and the truck have different limited deceleration capabilities, which are important factors in safety driving. This paper extends the single lane safety driving (SD) model with limited deceleration capability to two-lane SD model, in which car-truck heterogeneous traffic is considered. A car has a larger limited deceleration capability while a heavy truck has a smaller limited deceleration capability as a result of loaded goods. Then the safety driving conditions are different as the types of the following and the leading vehicles vary. In order to eliminate the well-known plug in heterogeneous two-lane traffic, it is assumed that heavy truck has active deceleration behavior when the heavy truck perceives the forming plug. The lane-changing decisions are also determined by the safety driving conditions. The fundamental diagram, spatiotemporal diagram, and lane-changing frequency were investigated to show the effect of mechanical restriction on heterogeneous traffic flow. It was shown that there would be still three traffic phases in heterogeneous traffic condition; the active deceleration of the heavy truck could well eliminate the plug; the lane-changing frequency was low in synchronized flow; the flow and velocity would decrease as the proportion of heavy truck grows or the limited deceleration capability of heavy truck drops; and the flow could be improved with lane control measures.

  6. Antigen-specific T cell activation independently of the MHC: chimeric antigen receptor (CAR-redirected T cells.

    Directory of Open Access Journals (Sweden)

    Hinrich eAbken

    2013-11-01

    Full Text Available Adoptive T cell therapy has recently shown powerful in initiating a lasting anti-tumor response with spectacular therapeutic success in some cases. Specific T cell therapy, however, is limited since a number of cancer cells are not recognized by T cells due to various mechanisms including the limited availability of tumor-specific T cells and deficiencies in antigen processing or major histocompatibility complex (MHC expression of cancer cells. To make adoptive cell therapy applicable for the broad variety of cancer entities, patient's T cells are engineered ex vivo with pre-defined specificity by a recombinant chimeric antigen receptor (CAR which consists in the extracellular part of an antibody-derived domain for binding with a tumor-associated antigen and in the intracellular part of a TCR-derived signaling moiety for T cell activation. The specificity of CAR mediated T cell recognition is defined by the antibody domain, is independent of MHC presentation and can be extended to any target for which an antibody is available. We discuss the advantages and limitations of MHC-independent T cell targeting by an engineered CAR and review most significant progress recently made in early stage clinical trials to treat cancer.

  7. Toll-like receptors: cellular signal transducers for exogenous molecular patterns causing immune responses.

    Science.gov (United States)

    Kirschning, C J; Bauer, S

    2001-09-01

    Innate immunity initiates protection of the host organism against invasion and subsequent multiplication of microbes by specific recognition. Germ line-encoded receptors have been identified for microbial products such as mannan, lipopeptide, peptidoglycan (PGN), lipoteichoic acid (LTA), lipopolysaccharide (LPS), and CpG-DNA. The Drosophila Toll protein has been shown to be involved in innate immune response of the adult fruitfly. Members of the family of Toll-like receptors (TLRs) in vertebrates have been implicated as pattern recognition receptors (PRRs). Ten TLRs are known and six of these have been demonstrated to mediate cellular activation by distinct microbial products. TLR4 has been implicated as activator of adaptive immunity, and analysis of systemic LPS responses in mice led to the identification of LPS-resistant strains instrumental in its identification as a transmembrane LPS signal transducer. Structural similarities between TLRs and receptor molecules involved in immune responses such as CD14 and the IL-1 receptors (IL-1Rs), as well as functional analysis qualified TLR2 as candidate receptor for LPS and other microbial products. Targeted disruption of the TLR9 gene in mice led to identification of TLR9 as CpG-DNA signal transducer. Involvement of TLR5 in cell activation by bacterial flagellin has been demonstrated. Further understanding of recognition and cellular signaling activated through the ancient host defense system represented by Toll will eventually lead to means for its therapeutic modulation. PMID:11680785

  8. Flame retardant BDE-47 effectively activates nuclear receptor CAR in human primary hepatocytes

    Science.gov (United States)

    Polybrominated diphenyl ether BDE-47 (2,2’,4,4’-tetrabromodiphenyl ether) is a thyroid hormone disruptor in mice; hepatic induction of various metabolic enzymes and transporters has been suggested as the mechanism for this disruption. Utilizing Car-/- and Pxr-/- mice as well as h...

  9. An investigation of merging and diverging cars on a multi-lane road using a cellular automation model

    Institute of Scientific and Technical Information of China (English)

    K.Jetto; H.Ez-Zahraouy; A.Benyoussef

    2012-01-01

    In this paper,we have investigated two observed situations in a multi-lane road.The first one concerns a fast merging vehicle.The second situation is related to the case of a fast vehicle leaving the fastest lane back into the slowest lane and targeting a specific way out.We are interested in the relaxation time τ,i.e.,which is the time that the merging (diverging) vehicle spends before reaching the desired lane.Using analytical treatment and numerical simulations for the NaSch model,we have found two states,namely,the free state in which the merging (diverging) vehicle reaches the desired lane,and the trapped state in which τ diverges.We have established phase diagrams for several values of the braking probability.In the second situation,we have shown that diverging from the fast lane targeting a specific way out is not a simple task.Even if the diverging vehicle is in the free phase,two different states can be distinguished.One is the critical state,in which the diverging car can probably reach the desired way out.The other is the safe state,in which the diverging car can surely reach the desired way out.In order to be in the safe state,we have found that the driver of the diverging car must know the critical distance (below which the way out will be out of his reach) in each lane.Furthermore,this critical distance depends on the density of cars,and it follows an exponential law.

  10. Insulin receptors in isolated human adipocytes. Characterization by photoaffinity labeling and evidence for internalization and cellular processing.

    OpenAIRE

    Berhanu, P; Kolterman, O G; Baron, A; Tsai, P; Olefsky, J M; Brandenburg, D.

    1983-01-01

    We photolabeled and characterized insulin receptors in isolated adipocytes from normal human subjects and then studied the cellular fate of the labeled insulin-receptor complexes at physiologic temperatures. The biologically active photosensitive insulin derivative, B2(2-nitro-4-azidophenylacetyl)des-PheB1-insulin (NAPA-DP-insulin) was used to photoaffinity label the insulin receptors, and the specifically labeled cellular proteins were identified by sodium dodecyl sulfate-polyacrylamide gel ...

  11. The Molecular Interaction of CAR and JAML Recruits the Central Cell Signal Transducer PI3K

    Energy Technology Data Exchange (ETDEWEB)

    Verdino, Petra; Witherden, Deborah A.; Havran, Wendy L.; Wilson, Ian A. (Scripps)

    2010-11-15

    Coxsackie and adenovirus receptor (CAR) is the primary cellular receptor for group B coxsackieviruses and most adenovirus serotypes and plays a crucial role in adenoviral gene therapy. Recent discovery of the interaction between junctional adhesion molecule-like protein (JAML) and CAR uncovered important functional roles in immunity, inflammation, and tissue homeostasis. Crystal structures of JAML ectodomain (2.2 angstroms) and its complex with CAR (2.8 angstroms) reveal an unusual immunoglobulin-domain assembly for JAML and a charged interface that confers high specificity. Biochemical and mutagenesis studies illustrate how CAR-mediated clustering of JAML recruits phosphoinositide 3-kinase (P13K) to a JAML intracellular sequence motif as delineated for the {alpha}{beta} T cell costimulatory receptor CD28. Thus, CAR and JAML are cell signaling receptors of the immune system with implications for asthma, cancer, and chronic nonhealing wounds.

  12. Development of novel cellular model for affinity studies of histamine H(4) receptor ligands.

    Science.gov (United States)

    Karcz, Tadeusz; Kieć-Kononowicz, Katarzyna

    2013-01-01

    The G protein-coupled histamine H4 receptor (H4R) is the last member of histamine receptors family discovered so far. Its expression pattern, together with postulated involvement in a wide variety of immunological and inflammatory processes make histamine H4 receptor an interesting target for drug development. Potential H4R ligands may provide an innovative therapies for different immuno-based diseases, including allergy, asthma, pruritus associated with allergy or autoimmune skin conditions, rheumatoid arthritis and pain. However, none of successfully developed selective and potent histamine H4 receptor ligands have been introduced to the market up to date. For that reason there is still a strong demand for pharmacological models to be used in studies on potent H4R ligands. In current work we present the development of novel mammalian cell line, stably expressing human histamine H4 receptor, with use of retroviral transduction approach. Obtained cell line was pharmacologically characterized in radioligand binding studies and its utility for affinity testing of potent receptor ligands was confirmed in comparative studies with the use of relevant insect cells expression model. Obtained results allow for statement that developed cellular model may be successfully employed in search for new compounds active at histamine H4 receptor. PMID:24432340

  13. Posttranslational Modification of α-Dystroglycan, the Cellular Receptor for Arenaviruses, by the Glycosyltransferase LARGE Is Critical for Virus Binding

    OpenAIRE

    Kunz, Stefan; Rojek, Jillian M.; Kanagawa, Motoi; Spiropoulou, Christina F.; Barresi, Rita; Campbell, Kevin P.; Oldstone, Michael B A

    2005-01-01

    The receptor for lymphocytic choriomeningitis virus (LCMV), the human pathogenic Lassa fever virus (LFV), and clade C New World arenaviruses is α-dystroglycan (α-DG), a cell surface receptor for proteins of the extracellular matrix (ECM). Specific posttranslational modification of α-DG by the glycosyltransferase LARGE is critical for its function as an ECM receptor. In the present study, we show that LARGE-dependent modification is also crucial for α-DG's function as a cellular receptor for a...

  14. Characterization of the Interaction of Lassa Fever Virus with Its Cellular Receptor α-Dystroglycan

    Science.gov (United States)

    Kunz, Stefan; Rojek, Jillian M.; Perez, Mar; Spiropoulou, Christina F.; Oldstone, Michael B. A.

    2005-01-01

    The cellular receptor for the Old World arenaviruses Lassa fever virus (LFV) and lymphocytic choriomeningitis virus (LCMV) has recently been identified as α-dystroglycan (α-DG), a cell surface receptor that provides a molecular link between the extracellular matrix and the actin-based cytoskeleton. In the present study, we show that LFV binds to α-DG with high affinity in the low-nanomolar range. Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on α-DG for infection of cells. Mapping of the binding site of LFV on α-DG revealed that LFV binding required the same domains of α-DG that are involved in the binding of LCMV. Further, LFV was found to efficiently compete with laminin α1 and α2 chains for α-DG binding. Together with our previous studies on receptor binding of the prototypic immunosuppressive LCMV isolate LCMV clone 13, these findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates. PMID:15857984

  15. Characterization of the interaction of lassa fever virus with its cellular receptor alpha-dystroglycan.

    Science.gov (United States)

    Kunz, Stefan; Rojek, Jillian M; Perez, Mar; Spiropoulou, Christina F; Oldstone, Michael B A

    2005-05-01

    The cellular receptor for the Old World arenaviruses Lassa fever virus (LFV) and lymphocytic choriomeningitis virus (LCMV) has recently been identified as alpha-dystroglycan (alpha-DG), a cell surface receptor that provides a molecular link between the extracellular matrix and the actin-based cytoskeleton. In the present study, we show that LFV binds to alpha-DG with high affinity in the low-nanomolar range. Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on alpha-DG for infection of cells. Mapping of the binding site of LFV on alpha-DG revealed that LFV binding required the same domains of alpha-DG that are involved in the binding of LCMV. Further, LFV was found to efficiently compete with laminin alpha1 and alpha2 chains for alpha-DG binding. Together with our previous studies on receptor binding of the prototypic immunosuppressive LCMV isolate LCMV clone 13, these findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates. PMID:15857984

  16. Cholecystokinin receptor-1 mediates the inhibitory effects of exogenous cholecystokinin octapeptide on cellular morphine dependence

    Directory of Open Access Journals (Sweden)

    Wen Di

    2012-06-01

    Full Text Available Abstract Background Cholecystokinin octapeptide (CCK-8, the most potent endogenous anti-opioid peptide, has been shown to regulate the processes of morphine dependence. In our previous study, we found that exogenous CCK-8 attenuated naloxone induced withdrawal symptoms. To investigate the precise effect of exogenous CCK-8 and the role of cholecystokinin (CCK 1 and/or 2 receptors in morphine dependence, a SH-SY5Y cell model was employed, in which the μ-opioid receptor, CCK1/2 receptors, and endogenous CCK are co-expressed. Results Forty-eight hours after treating SH-SY5Y cells with morphine (10 μM, naloxone (10 μM induced a cAMP overshoot, indicating that cellular morphine dependence had been induced. The CCK receptor and endogenous CCK were up-regulated after chronic morphine exposure. The CCK2 receptor antagonist (LY-288,513 at 1–10 μM inhibited the naloxone-precipitated cAMP overshoot, but the CCK1 receptor antagonist (L-364,718 did not. Interestingly, CCK-8 (0.1-1 μM, a strong CCK receptor agonist, dose-dependently inhibited the naloxone-precipitated cAMP overshoot in SH-SY5Y cells when co-pretreated with morphine. The L-364,718 significantly blocked the inhibitory effect of exogenous CCK-8 on the cAMP overshoot at 1–10 μM, while the LY-288,513 did not. Therefore, the CCK2 receptor appears to be necessary for low concentrations of endogenous CCK to potentiate morphine dependence in SH-SY5Y cells. An additional inhibitory effect of CCK-8 at higher concentrations appears to involve the CCK1 receptor. Conclusions This study reveals the difference between exogenous CCK-8 and endogenous CCK effects on the development of morphine dependence, and provides the first evidence for the participation of the CCK1 receptor in the inhibitory effects of exogenous CCK-8 on morphine dependence.

  17. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXRα

    OpenAIRE

    Venkateswaran, Asha; Laffitte, Bryan A.; Joseph, Sean B.; Mak, Puiying A.; Wilpitz, Damien C.; Edwards, Peter A.; Tontonoz, Peter

    2000-01-01

    LXRα is a nuclear receptor that has previously been shown to regulate the metabolic conversion of cholesterol to bile acids. Here we define a role for this transcription factor in the control of cellular cholesterol efflux. We demonstrate that retroviral expression of LXRα in NIH 3T3 fibroblasts or RAW264.7 macrophages and/or treatment of these cells with oxysterol ligands of LXR results in 7- to 30-fold induction of the mRNA encoding the putative cholesterol/phospholi...

  18. A Single Residue in Ebola Virus Receptor NPC1 Influences Cellular Host Range in Reptiles.

    Science.gov (United States)

    Ndungo, Esther; Herbert, Andrew S; Raaben, Matthijs; Obernosterer, Gregor; Biswas, Rohan; Miller, Emily Happy; Wirchnianski, Ariel S; Carette, Jan E; Brummelkamp, Thijn R; Whelan, Sean P; Dye, John M; Chandran, Kartik

    2016-01-01

    Filoviruses are the causative agents of an increasing number of disease outbreaks in human populations, including the current unprecedented Ebola virus disease (EVD) outbreak in western Africa. One obstacle to controlling these epidemics is our poor understanding of the host range of filoviruses and their natural reservoirs. Here, we investigated the role of the intracellular filovirus receptor, Niemann-Pick C1 (NPC1) as a molecular determinant of Ebola virus (EBOV) host range at the cellular level. Whereas human cells can be infected by EBOV, a cell line derived from a Russell's viper (Daboia russellii) (VH-2) is resistant to infection in an NPC1-dependent manner. We found that VH-2 cells are resistant to EBOV infection because the Russell's viper NPC1 ortholog bound poorly to the EBOV spike glycoprotein (GP). Analysis of panels of viper-human NPC1 chimeras and point mutants allowed us to identify a single amino acid residue in NPC1, at position 503, that bidirectionally influenced both its binding to EBOV GP and its viral receptor activity in cells. Significantly, this single residue change perturbed neither NPC1's endosomal localization nor its housekeeping role in cellular cholesterol trafficking. Together with other recent work, these findings identify sequences in NPC1 that are important for viral receptor activity by virtue of their direct interaction with EBOV GP and suggest that they may influence filovirus host range in nature. Broader surveys of NPC1 orthologs from vertebrates may delineate additional sequence polymorphisms in this gene that control susceptibility to filovirus infection. IMPORTANCE Identifying cellular factors that determine susceptibility to infection can help us understand how Ebola virus is transmitted. We asked if the EBOV receptor Niemann-Pick C1 (NPC1) could explain why reptiles are resistant to EBOV infection. We demonstrate that cells derived from the Russell's viper are not susceptible to infection because EBOV cannot bind to

  19. A Single Residue in Ebola Virus Receptor NPC1 Influences Cellular Host Range in Reptiles

    Science.gov (United States)

    Ndungo, Esther; Herbert, Andrew S.; Raaben, Matthijs; Obernosterer, Gregor; Biswas, Rohan; Miller, Emily Happy; Wirchnianski, Ariel S.; Carette, Jan E.; Brummelkamp, Thijn R.; Whelan, Sean P.

    2016-01-01

    ABSTRACT Filoviruses are the causative agents of an increasing number of disease outbreaks in human populations, including the current unprecedented Ebola virus disease (EVD) outbreak in western Africa. One obstacle to controlling these epidemics is our poor understanding of the host range of filoviruses and their natural reservoirs. Here, we investigated the role of the intracellular filovirus receptor, Niemann-Pick C1 (NPC1) as a molecular determinant of Ebola virus (EBOV) host range at the cellular level. Whereas human cells can be infected by EBOV, a cell line derived from a Russell’s viper (Daboia russellii) (VH-2) is resistant to infection in an NPC1-dependent manner. We found that VH-2 cells are resistant to EBOV infection because the Russell’s viper NPC1 ortholog bound poorly to the EBOV spike glycoprotein (GP). Analysis of panels of viper-human NPC1 chimeras and point mutants allowed us to identify a single amino acid residue in NPC1, at position 503, that bidirectionally influenced both its binding to EBOV GP and its viral receptor activity in cells. Significantly, this single residue change perturbed neither NPC1’s endosomal localization nor its housekeeping role in cellular cholesterol trafficking. Together with other recent work, these findings identify sequences in NPC1 that are important for viral receptor activity by virtue of their direct interaction with EBOV GP and suggest that they may influence filovirus host range in nature. Broader surveys of NPC1 orthologs from vertebrates may delineate additional sequence polymorphisms in this gene that control susceptibility to filovirus infection. IMPORTANCE Identifying cellular factors that determine susceptibility to infection can help us understand how Ebola virus is transmitted. We asked if the EBOV receptor Niemann-Pick C1 (NPC1) could explain why reptiles are resistant to EBOV infection. We demonstrate that cells derived from the Russell’s viper are not susceptible to infection because EBOV

  20. Young T cells age during a redirected anti-tumour attack: chimeric antigen receptor (CAR-provided dual costimulation is half the battle.

    Directory of Open Access Journals (Sweden)

    Andreas A Hombach

    2013-06-01

    Full Text Available Adoptive therapy with chimeric antigen receptor (CAR-redirected T cells showed spectacular efficacy in the treatment of leukaemia in recent early phase trials. Patient's T cells were ex vivo genetically engineered with a CAR, amplified and re-administered to the patient. While T cells mediating the primary response were predominantly of young effector and central memory phenotype, repetitive antigen engagement irreversible triggers T cell maturation leaving late memory cells with the KLRG-1+ CD57+ CD7- CCR7- phenotype in the long-term. These cells preferentially accumulate in the periphery, are hypo-responsive upon TCR engagement and prone to activation-induced cell death. A recent report indicates that those T cells can be rescued by CAR provided CD28 and OX40 (CD134 stimulation. We discuss the strategy with respect to prolong the anti-tumour response and to improve the over-all efficacy of adoptive cell therapy.

  1. Cellular Recognition and Trafficking of Amorphous Silica Nanoparticles by Macrophage Scavenger Receptor A

    Energy Technology Data Exchange (ETDEWEB)

    Orr, Galya; Chrisler, William B.; Cassens, Kaylyn J.; Tan, Ruimin; Tarasevich, Barbara J.; Markillie, Lye Meng; Zangar, Richard C.; Thrall, Brian D.

    2011-09-01

    The internalization of engineered nanoparticles (ENPs) into cells is known to involve active transport mechanisms, yet the precise biological molecules involved are poorly understood. We demonstrate that the uptake of amorphous silica ENPs (92 nm) by macrophage cells is strongly inhibited by silencing expression of scavenger receptor A (SR-A). In addition, ENP uptake is augmented by introducing SR-A expression into human cells that are normally non-phagocytic. Confocal fluorescent microscopy analyses show that the majority of single or small clusters of silica ENPs co-localize intracellularly with SR-A and are internalized through a pathway characteristic of clathrin-dependent endocytosis. In contrast, larger silica NP agglomerates (>500 nm) are poorly co-localized with the receptor, suggesting independent trafficking or internalization pathways are involved. SR-A silencing also caused decreased cellular secretion of pro-inflammatory cytokines in response to silica ENPs. As SR-A is expressed in macrophages throughout the reticulo-endothelial system, this pathway is likely an important determinant of the biodistribution of, and cellular response to ENPs.

  2. A truncated progesterone receptor (PR-M) localizes to the mitochondrion and controls cellular respiration.

    Science.gov (United States)

    Dai, Qunsheng; Shah, Anish A; Garde, Rachana V; Yonish, Bryan A; Zhang, Li; Medvitz, Neil A; Miller, Sara E; Hansen, Elizabeth L; Dunn, Carrie N; Price, Thomas M

    2013-05-01

    The cDNA for a novel truncated progesterone receptor (PR-M) was previously cloned from human adipose and aortic cDNA libraries. The predicted protein sequence contains 16 unique N-terminal amino acids, encoded by a sequence in the distal third intron of the progesterone receptor PR gene, followed by the same amino acid sequence encoded by exons 4 through 8 of the nuclear PR. Thus, PR-M lacks the N terminus A/B domains and the C domain for DNA binding, whereas containing the hinge and hormone-binding domains. In this report, we have localized PR-M to mitochondria using immunofluorescent localization of a PR-M-green fluorescent protein (GFP) fusion protein and in Western blot analyses of purified human heart mitochondrial protein. Removal of the putative N-terminal mitochondrial localization signal obviated association of PR-M with mitochondria, whereas addition of the mitochondrial localization signal to green fluorescent protein resulted in mitochondrial localization. Immunoelectron microscopy and Western blot analysis after mitochondrial fractionation identified PR-M in the outer mitochondrial membrane. Antibody specificity was shown by mass spectrometry identification of a PR peptide in a mitochondrial membrane protein isolation. Cell models of overexpression and gene silencing of PR-M demonstrated a progestin-induced increase in mitochondrial membrane potential and an increase in oxygen consumption consistent with an increase in cellular respiration. This is the first example of a truncated steroid receptor, lacking a DNA-binding domain that localizes to the mitochondrion and initiates direct non-nuclear progesterone action. We hypothesize that progesterone may directly affect cellular energy production to meet the increased metabolic demands of pregnancy. PMID:23518922

  3. The Cellular Prion Protein Prevents Copper-Induced Inhibition of P2X4 Receptors

    Directory of Open Access Journals (Sweden)

    Ramón A. Lorca

    2011-01-01

    Full Text Available Although the physiological function of the cellular prion protein (PrPC remains unknown, several evidences support the notion of its role in copper homeostasis. PrPC binds Cu2+ through a domain composed by four to five repeats of eight amino acids. Previously, we have shown that the perfusion of this domain prevents and reverses the inhibition by Cu2+ of the adenosine triphosphate (ATP-evoked currents in the P2X4 receptor subtype, highlighting a modulatory role for PrPC in synaptic transmission through regulation of Cu2+ levels. Here, we study the effect of full-length PrPC in Cu2+ inhibition of P2X4 receptor when both are coexpressed. PrPC expression does not significantly change the ATP concentration-response curve in oocytes expressing P2X4 receptors. However, the presence of PrPC reduces the inhibition by Cu2+ of the ATP-elicited currents in these oocytes, confirming our previous observations with the Cu2+ binding domain. Thus, our observations suggest a role for PrPC in modulating synaptic activity through binding of extracellular Cu2+.

  4. Restriction of Receptor Movement Alters Cellular Response: Physical Force Sensing by EphA2

    Energy Technology Data Exchange (ETDEWEB)

    Salaita, Khalid; Nair, Pradeep M; Petit, Rebecca S; Neve, Richard M; Das, Debopriya; Gray, Joe W; Groves, Jay T

    2009-09-09

    Activation of the EphA2 receptor tyrosine kinase by ephrin-A1 ligands presented on apposed cell surfaces plays important roles in development and exhibits poorly understood functional alterations in cancer. We reconstituted this intermembrane signaling geometry between live EphA2-expressing human breast cancer cells and supported membranes displaying laterally mobile ephrin-A1. Receptor-ligand binding, clustering, and subsequent lateral transport within this junction were observed. EphA2 transport can be blocked by physical barriers nanofabricated onto the underlying substrate. This physical reorganization of EphA2 alters the cellular response to ephrin-A1, as observed by changes in cytoskeleton morphology and recruitment of a disintegrin and metalloprotease 10. Quantitative analysis of receptor-ligand spatial organization across a library of 26 mammary epithelial cell lines reveals characteristic differences that strongly correlate with invasion potential. These observations reveal a mechanism for spatio-mechanical regulation of EphA2 signaling pathways.

  5. Advantages and Applications of CAR-Expressing Natural Killer Cells

    Directory of Open Access Journals (Sweden)

    Wolfgang eGlienke

    2015-02-01

    Full Text Available In contrast to donor T cells, natural killer (NK cells are known to mediate anti-cancer effects without the risk of inducing graft-versus-host disease (GvHD. In order to improve cytotoxicity against resistant cancer cells, auspicious efforts have been made with chimeric antigen receptor (CAR expressing T- and NK cells. These CAR-modified cells express antigen receptors against tumor-associated surface antigens, thus redirecting the effector cells and enhancing tumor-specific immunosurveillance. However, many cancer antigens are also expressed on healthy tissues, potentially leading to off tumor/ on target toxicity by CAR-engineered cells. In order to control such potentially severe side effects, the insertion of suicide genes into CAR-modified effectors can provide a means for efficient depletion of these cells. While CAR-expressing T cells have entered successfully clinical trials, experience with CAR-engineered NK cells is mainly restricted to pre-clinical investigations and predominantly to NK cell lines. In this review we summarize the data on CAR expressing NK cells focusing on the possible advantage using these short-lived effector cells and discuss the necessity of suicide switches. Furthermore, we address the compliance of such modified NK cells with regulatory requirements as a new field in cellular immunotherapy.

  6. Car Art.

    Science.gov (United States)

    Meilach, Dona Z.

    2002-01-01

    Discusses car art and its appeal to boys and girls. Describes the popularity of customizing cars, focusing on this as a future career for students. Includes a list of project ideas that focuses on car art. (CMK)

  7. Enhanced thyroid hormone breakdown in hepatocytes by mutual induction of the constitutive androstane receptor (CAR, NR1I3) and arylhydrocarbon receptor by benzo[a]pyrene and phenobarbital

    International Nuclear Information System (INIS)

    Xenobiotics may interfere with the hypothalamic-pituitary-thyroid endocrine axis by inducing enzymes that inactivate thyroid hormones and thereby reduce the metabolic rate. This induction results from an activation of xeno-sensing nuclear receptors. The current study shows that benzo[a]pyrene, a frequent contaminant of processed food and activator of the arylhydrocarbon receptor (AhR) activated the promoter and induced the transcription of the nuclear receptor constitutive androstane receptor (CAR, NR1I3) in rat hepatocytes. Likewise, phenobarbital induced the AhR transcription. This mutual induction of the nuclear receptors enhanced the phenobarbital-dependent induction of the prototypic CAR target gene Cyp2b1 as well as the AhR-dependent induction of UDP-glucuronosyltransferases. In both cases, the induction by the combination of both xenobiotics was more than the sum of the induction by either substance alone. By inducing the AhR, phenobarbital enhanced the benzo[a]pyrene-dependent reduction of thyroid hormone half-life and the benzo[a]pyrene-dependent increase in the rate of thyroid hormone glucuronide formation in hepatocyte cultures. CAR ligands might thus augment the endocrine disrupting potential of AhR activators by an induction of the AhR

  8. TNF and TNF Receptor Superfamily Members in HIV infection: New Cellular Targets for Therapy?

    Directory of Open Access Journals (Sweden)

    Amit Kumar

    2013-01-01

    Full Text Available Tumor necrosis factor (TNF and TNF receptors (TNFR superfamily members are engaged in diverse cellular phenomena such as cellular proliferation, morphogenesis, apoptosis, inflammation, and immune regulation. Their role in regulating viral infections has been well documented. Viruses have evolved with numerous strategies to interfere with TNF-mediated signaling indicating the importance of TNF and TNFR superfamily in viral pathogenesis. Recent research reports suggest that TNF and TNFRs play an important role in the pathogenesis of HIV. TNFR signaling modulates HIV replication and HIV proteins interfere with TNF/TNFR pathways. Since immune activation and inflammation are the hallmark of HIV infection, the use of TNF inhibitors can have significant impact on HIV disease progression. In this review, we will describe how HIV infection is modulated by signaling mediated through members of TNF and TNFR superfamily and in turn how these latter could be targeted by HIV proteins. Finally, we will discuss the emerging therapeutics options based on modulation of TNF activity that could ultimately lead to the cure of HIV-infected patients.

  9. Role of the nuclear xenobiotic receptors CAR and PXR in induction of cytochromes P450 by non-dioxinlike polychlorinated biphenyls in cultured rat hepatocytes

    International Nuclear Information System (INIS)

    Polychlorinated biphenyls (PCBs) are among the most ubiquitously detectable ‘persistent organic pollutants’. In contrast to ‘dioxinlike’ (DL) PCBs, less is known about the molecular mode of action of the larger group of the ‘non-dioxinlike’ (NDL) PCBs. Owing to the life-long exposure of the human population, a carcinogenic, i.e., tumor-promoting potency of NDL-PCBs has to be considered in human risk assessment. A major problem in risk assessment of NDL-PCBs is dioxin-like impurities that can occur in commercially available NDL-PCB standards. In the present study, we analyzed the induction of CYP2B1 and CYP3A1 in primary rat hepatocytes using a number of highly purified NDL-PCBs with various degrees of chlorination and substitution patterns. Induction of these enzymes is mediated by the nuclear xenobiotic receptors CAR (Constitutive androstane receptor) and PXR (Pregnane X receptor). For CYP2B1 induction, concentration–response analysis revealed a very narrow window of EC50 estimates, being in the range of 1–4 μM for PCBs 28 and 52, and between 0.4 and 1 μM for PCBs 101, 138, 153 and 180. CYP3A1 induction was less sensitive to NDL-PCBs, the most pronounced induction being achieved at 100 μM with the higher chlorinated congeners. Using okadaic acid and small interfering RNAs targeting CAR and PXR, we could demonstrate that CAR plays a major role and PXR a minor role in NDL-PCB-driven induction of CYPs, both effects showing no stringent structure–activity relationship. As the only obvious relevant determinant, the degree of chlorination was found to be positively correlated with the inducing potency of the congeners. - Highlights: • We analyzed six highly purified NDL-PCBs for CYP2B1 and CYP3A1 expression. • CAR plays a major, PXR a minor role in NDL-PCB-driven induction of CYPs. • The degree of chlorination seems to be the major parameter for the inducing potency. • There exists a competition between CAR and PXR. • Activated PXR may

  10. Role of the nuclear xenobiotic receptors CAR and PXR in induction of cytochromes P450 by non-dioxinlike polychlorinated biphenyls in cultured rat hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Gährs, Maike; Roos, Robert [University of Kaiserslautern, Food Chemistry and Toxicology, Erwin-Schroedinger-Str. 52, D-67663 Kaiserslautern (Germany); Andersson, Patrik L. [Umeå University, Department of Chemistry, Linnaeus väg 6, SE-901 87 Umeå (Sweden); Schrenk, Dieter, E-mail: schrenk@rhrk.uni-kl.de [University of Kaiserslautern, Food Chemistry and Toxicology, Erwin-Schroedinger-Str. 52, D-67663 Kaiserslautern (Germany)

    2013-10-01

    Polychlorinated biphenyls (PCBs) are among the most ubiquitously detectable ‘persistent organic pollutants’. In contrast to ‘dioxinlike’ (DL) PCBs, less is known about the molecular mode of action of the larger group of the ‘non-dioxinlike’ (NDL) PCBs. Owing to the life-long exposure of the human population, a carcinogenic, i.e., tumor-promoting potency of NDL-PCBs has to be considered in human risk assessment. A major problem in risk assessment of NDL-PCBs is dioxin-like impurities that can occur in commercially available NDL-PCB standards. In the present study, we analyzed the induction of CYP2B1 and CYP3A1 in primary rat hepatocytes using a number of highly purified NDL-PCBs with various degrees of chlorination and substitution patterns. Induction of these enzymes is mediated by the nuclear xenobiotic receptors CAR (Constitutive androstane receptor) and PXR (Pregnane X receptor). For CYP2B1 induction, concentration–response analysis revealed a very narrow window of EC{sub 50} estimates, being in the range of 1–4 μM for PCBs 28 and 52, and between 0.4 and 1 μM for PCBs 101, 138, 153 and 180. CYP3A1 induction was less sensitive to NDL-PCBs, the most pronounced induction being achieved at 100 μM with the higher chlorinated congeners. Using okadaic acid and small interfering RNAs targeting CAR and PXR, we could demonstrate that CAR plays a major role and PXR a minor role in NDL-PCB-driven induction of CYPs, both effects showing no stringent structure–activity relationship. As the only obvious relevant determinant, the degree of chlorination was found to be positively correlated with the inducing potency of the congeners. - Highlights: • We analyzed six highly purified NDL-PCBs for CYP2B1 and CYP3A1 expression. • CAR plays a major, PXR a minor role in NDL-PCB-driven induction of CYPs. • The degree of chlorination seems to be the major parameter for the inducing potency. • There exists a competition between CAR and PXR. • Activated PXR

  11. Improved localization of cellular membrane receptors using combined fluorescence microscopy and simultaneous topography and recognition imaging

    Energy Technology Data Exchange (ETDEWEB)

    Duman, M; Pfleger, M; Chtcheglova, L A; Neundlinger, I; Bozna, B L; Ebner, A; Schuetz, G J; Hinterdorfer, P [Institute for Biophysics, University of Linz, Altenbergerstrasse 69, A-4040 Linz (Austria); Zhu, R; Mayer, B [Christian Doppler Laboratory for Nanoscopic Methods in Biophysics, Institute for Biophysics, University of Linz, Altenbergerstrasse 69, A-4040 Linz (Austria); Rankl, C; Moertelmaier, M; Kada, G; Kienberger, F [Agilent Technologies Austria GmbH, Aubrunnerweg 11, A-4040 Linz (Austria); Salio, M; Shepherd, D; Polzella, P; Cerundolo, V [Cancer Research UK Tumor Immunology Group, Weatherall Institute of Molecular Medicine, Nuffield Department of Medicine, University of Oxford, Oxford OX3 9DS (United Kingdom); Dieudonne, M, E-mail: ferry_kienberger@agilent.com [Agilent Technologies Belgium, Wingepark 51, Rotselaar, AN B-3110 (Belgium)

    2010-03-19

    The combination of fluorescence microscopy and atomic force microscopy has a great potential in single-molecule-detection applications, overcoming many of the limitations coming from each individual technique. Here we present a new platform of combined fluorescence and simultaneous topography and recognition imaging (TREC) for improved localization of cellular receptors. Green fluorescent protein (GFP) labeled human sodium-glucose cotransporter (hSGLT1) expressed Chinese Hamster Ovary (CHO) cells and endothelial cells (MyEnd) from mouse myocardium stained with phalloidin-rhodamine were used as cell systems to study AFM topography and fluorescence microscopy on the same surface area. Topographical AFM images revealed membrane features such as lamellipodia, cytoskeleton fibers, F-actin filaments and small globular structures with heights ranging from 20 to 30 nm. Combined fluorescence and TREC imaging was applied to detect density, distribution and localization of YFP-labeled CD1d molecules on {alpha}-galactosylceramide ({alpha}GalCer)-loaded THP1 cells. While the expression level, distribution and localization of CD1d molecules on THP1 cells were detected with fluorescence microscopy, the nanoscale distribution of binding sites was investigated with molecular recognition imaging by using a chemically modified AFM tip. Using TREC on the inverted light microscope, the recognition sites of cell receptors were detected in recognition images with domain sizes ranging from {approx} 25 to {approx} 160 nm, with the smaller domains corresponding to a single CD1d molecule.

  12. Scavenger receptor B1 facilitates macrophage uptake of silver nanoparticles and cellular activation

    Energy Technology Data Exchange (ETDEWEB)

    Aldossari, Abdullah A.; Shannahan, Jonathan H. [The University of Colorado Anschutz Medical Campus, Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences (United States); Podila, Ramakrishna [Clemson University, Department of Physics and Astronomy (United States); Brown, Jared M., E-mail: jared.brown@ucdenver.edu [The University of Colorado Anschutz Medical Campus, Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences (United States)

    2015-07-15

    Due to increased use of silver nanoparticles (AgNPs) for their antimicrobial activity, concerns have risen regarding potential adverse human health effects. Scavenger receptor B1 (SR-B1), a major receptor for high-density lipoprotein (HDL), is expressed by macrophages and has also been reported to play a role in recognition of negatively charged particles. We, therefore, hypothesized that SR-B1 mediates macrophage uptake of AgNPs and inflammatory activation. To test this hypothesis, we exposed a mouse macrophage cell line RAW264.7 (RAW) and bone marrow-derived macrophages (BMDM) to 20 nm citrate-suspended AgNPs. To verify the role of the SR-B1 receptor, we utilized a SR-B1 inhibitor (Blt2). In vitro studies demonstrated uptake of AgNPs and HDL-coated AgNPs by macrophages which were significantly reduced following pretreatment with Blt2. Inflammatory cytokine arrays revealed that macrophages exposed to AgNPs up-regulated expression of Tnf-α, Oncostatin m (OSM), Ccl4, Il17f, Ccl7, and Ccl2, whereas Il16 was found to be down-regulated. Macrophage activation was observed following AgNP and HDL-coated AgNP exposure as measured by OSM protein production and increased surface expression of CD86. These markers of activation were reduced with Blt2 pretreatment. The in vitro findings were confirmed in vivo through pulmonary instillation of AgNPs in mice. Pulmonary instillation of AgNPs resulted in a recruitment of inflammatory cells that were reduced in SR-B1-deficient mice or following Blt2 pretreatment. This study suggests that SR-B1 plays a major role in cellular recognition of AgNPs and the induction of cell responses that could contribute to inflammation caused by AgNP exposure.

  13. Scavenger receptor B1 facilitates macrophage uptake of silver nanoparticles and cellular activation

    International Nuclear Information System (INIS)

    Due to increased use of silver nanoparticles (AgNPs) for their antimicrobial activity, concerns have risen regarding potential adverse human health effects. Scavenger receptor B1 (SR-B1), a major receptor for high-density lipoprotein (HDL), is expressed by macrophages and has also been reported to play a role in recognition of negatively charged particles. We, therefore, hypothesized that SR-B1 mediates macrophage uptake of AgNPs and inflammatory activation. To test this hypothesis, we exposed a mouse macrophage cell line RAW264.7 (RAW) and bone marrow-derived macrophages (BMDM) to 20 nm citrate-suspended AgNPs. To verify the role of the SR-B1 receptor, we utilized a SR-B1 inhibitor (Blt2). In vitro studies demonstrated uptake of AgNPs and HDL-coated AgNPs by macrophages which were significantly reduced following pretreatment with Blt2. Inflammatory cytokine arrays revealed that macrophages exposed to AgNPs up-regulated expression of Tnf-α, Oncostatin m (OSM), Ccl4, Il17f, Ccl7, and Ccl2, whereas Il16 was found to be down-regulated. Macrophage activation was observed following AgNP and HDL-coated AgNP exposure as measured by OSM protein production and increased surface expression of CD86. These markers of activation were reduced with Blt2 pretreatment. The in vitro findings were confirmed in vivo through pulmonary instillation of AgNPs in mice. Pulmonary instillation of AgNPs resulted in a recruitment of inflammatory cells that were reduced in SR-B1-deficient mice or following Blt2 pretreatment. This study suggests that SR-B1 plays a major role in cellular recognition of AgNPs and the induction of cell responses that could contribute to inflammation caused by AgNP exposure

  14. Cellular receptor for urokinase plasminogen activator. Carboxyl-terminal processing and membrane anchoring by glycosyl-phosphatidylinositol

    DEFF Research Database (Denmark)

    Ploug, M; Rønne, E; Behrendt, N;

    1991-01-01

    The cellular receptor for human urokinase-type plasminogen activator (u-PAR) is shown by several independent criteria to be a true member of a family of integral membrane proteins, anchored to the plasma membrane exclusively by a COOH-terminal glycosyl-phosphatidylinositol moiety. 1) Amino acid a...

  15. Appearance and cellular distribution of lectin-like receptors for alpha 1-acid glycoprotein in the developing rat testis

    DEFF Research Database (Denmark)

    Andersen, U O; Bøg-Hansen, T C; Kirkeby, S

    1996-01-01

    A histochemical avidin-biotin technique with three different alpha 1-acid glycoprotein glycoforms showed pronounced alterations in the cellular localization of two alpha 1-acid glycoprotein lectin-like receptors during cell differentiation in the developing rat testis. The binding of alpha 1-acid...

  16. The relations of “go and stop” wave to car accidents in a cellular automaton with velocity-dependent randomization

    Science.gov (United States)

    Yang, Xian-Qing; Zhang, Wei; Qiu, Kang; Xu, Wen-tao; Tang, Gang; Ren, Lin

    2007-10-01

    In this paper we numerically study the probability Pac of the occurrence of traffic accidents in the Nagel-Schreckenberg (NS) model with velocity-dependent randomization (VDR). Numerical results show that there is a critical density over which car accidents occur, but below which no car accidents happen. Different from the accident probability in the NS model, the accident probability in the VDR model monotonously decreases with increase of car density above the critical density. The value of the accident probability is only determined by the stochastic noise and the number of cars on road. In the stochastic VDR model with the speed limit vmax=1, no critical density exists and car accidents happen in the whole density region. The braking probabilities of standing cars and moving cars have different influences on the accident probability. A mean-field theory reveals that the accident probability is proportional to the mean density of “go and stop” wave per time step. Theoretical analyses give excellent agreement with numerical results in the VDR model.

  17. Lysophosphatidic acid receptor-5 negatively regulates cellular responses in mouse fibroblast 3T3 cells

    International Nuclear Information System (INIS)

    Highlights: • LPA5 inhibits the cell growth and motile activities of 3T3 cells. • LPA5 suppresses the cell motile activities stimulated by hydrogen peroxide in 3T3 cells. • Enhancement of LPA5 on the cell motile activities inhibited by LPA1 in 3T3 cells. • The expression and activation of Mmp-9 were inhibited by LPA5 in 3T3 cells. • LPA signaling via LPA5 acts as a negative regulator of cellular responses in 3T3 cells. - Abstract: Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors (LPA1–LPA6) mediates a variety of biological functions, including cell migration. Recently, we have reported that LPA1 inhibited the cell motile activities of mouse fibroblast 3T3 cells. In the present study, to evaluate a role of LPA5 in cellular responses, Lpar5 knockdown (3T3-L5) cells were generated from 3T3 cells. In cell proliferation assays, LPA markedly stimulated the cell proliferation activities of 3T3-L5 cells, compared with control cells. In cell motility assays with Cell Culture Inserts, the cell motile activities of 3T3-L5 cells were significantly higher than those of control cells. The activity levels of matrix metalloproteinases (MMPs) were measured by gelatin zymography. 3T3-L5 cells stimulated the activation of Mmp-2, correlating with the expression levels of Mmp-2 gene. Moreover, to assess the co-effects of LPA1 and LPA5 on cell motile activities, Lpar5 knockdown (3T3a1-L5) cells were also established from Lpar1 over-expressing (3T3a1) cells. 3T3a1-L5 cells increased the cell motile activities of 3T3a1 cells, while the cell motile activities of 3T3a1 cells were significantly lower than those of control cells. These results suggest that LPA5 may act as a negative regulator of cellular responses in mouse fibroblast 3T3 cells, similar to the case for LPA1

  18. Lysophosphatidic acid receptor-5 negatively regulates cellular responses in mouse fibroblast 3T3 cells

    Energy Technology Data Exchange (ETDEWEB)

    Dong, Yan; Hirane, Miku; Araki, Mutsumi [Division of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Fukushima, Nobuyuki [Division of Molecular Neurobiology, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan); Tsujiuchi, Toshifumi, E-mail: ttujiuch@life.kindai.ac.jp [Division of Cancer Biology and Bioinformatics, Department of Life Science, Faculty of Science and Engineering, Kinki University, 3-4-1, Kowakae, Higashiosaka, Osaka 577-8502 (Japan)

    2014-04-04

    Highlights: • LPA{sub 5} inhibits the cell growth and motile activities of 3T3 cells. • LPA{sub 5} suppresses the cell motile activities stimulated by hydrogen peroxide in 3T3 cells. • Enhancement of LPA{sub 5} on the cell motile activities inhibited by LPA{sub 1} in 3T3 cells. • The expression and activation of Mmp-9 were inhibited by LPA{sub 5} in 3T3 cells. • LPA signaling via LPA{sub 5} acts as a negative regulator of cellular responses in 3T3 cells. - Abstract: Lysophosphatidic acid (LPA) signaling via G protein-coupled LPA receptors (LPA{sub 1}–LPA{sub 6}) mediates a variety of biological functions, including cell migration. Recently, we have reported that LPA{sub 1} inhibited the cell motile activities of mouse fibroblast 3T3 cells. In the present study, to evaluate a role of LPA{sub 5} in cellular responses, Lpar5 knockdown (3T3-L5) cells were generated from 3T3 cells. In cell proliferation assays, LPA markedly stimulated the cell proliferation activities of 3T3-L5 cells, compared with control cells. In cell motility assays with Cell Culture Inserts, the cell motile activities of 3T3-L5 cells were significantly higher than those of control cells. The activity levels of matrix metalloproteinases (MMPs) were measured by gelatin zymography. 3T3-L5 cells stimulated the activation of Mmp-2, correlating with the expression levels of Mmp-2 gene. Moreover, to assess the co-effects of LPA{sub 1} and LPA{sub 5} on cell motile activities, Lpar5 knockdown (3T3a1-L5) cells were also established from Lpar1 over-expressing (3T3a1) cells. 3T3a1-L5 cells increased the cell motile activities of 3T3a1 cells, while the cell motile activities of 3T3a1 cells were significantly lower than those of control cells. These results suggest that LPA{sub 5} may act as a negative regulator of cellular responses in mouse fibroblast 3T3 cells, similar to the case for LPA{sub 1}.

  19. Potentiation of nerve growth factor-induced neurite outgrowth by fluvoxamine: role of sigma-1 receptors, IP3 receptors and cellular signaling pathways.

    Directory of Open Access Journals (Sweden)

    Tomoko Nishimura

    Full Text Available BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs have been widely used and are a major therapeutic advance in psychopharmacology. However, their pharmacology is quite heterogeneous. The SSRI fluvoxamine, with sigma-1 receptor agonism, is shown to potentiate nerve-growth factor (NGF-induced neurite outgrowth in PC 12 cells. However, the precise cellular and molecular mechanisms underlying potentiation by fluvoxamine are not fully understood. In this study, we examined the roles of cellular signaling pathways in the potentiation of NGF-induced neurite outgrowth by fluvoxamine and sigma-1 receptor agonists. METHODS AND FINDINGS: The effects of three SSRIs (fluvoxamine, sertraline, paroxetine and three sigma-1 receptor agonists (SA4503, 4-phenyl-1-(4-phenylbutyl piperidine (PPBP, and dehydroepiandrosterone (DHEA-sulfate on NGF-induced neurite outgrowth in PC12 cells were examined. Also examined were the effects of the sigma-1 receptor antagonist NE-100, inositol 1,4,5-triphosphate (IP(3 receptor antagonist, and specific inhibitors of signaling pathways in the potentiation of NGF-induced neurite outgrowth by selective sigma-1 receptor agonist SA4503. Fluvoxamine (but not sertraline or paroxetine and the sigma-1 receptor agonists SA4503, PPBP, and DHEA-sulfate significantly potentiated NGF-induced neurite outgrowth in PC12 cells in a concentration-dependent manner. The potentiation by fluvoxamine and the three sigma-1 receptor agonists was blocked by co-administration of the selective sigma-1 receptor antagonist NE-100, suggesting that sigma-1 receptors play a role in blocking the enhancement of NGF-induced neurite outgrowth. Moreover, the potentiation by SA4503 was blocked by co-administration of the IP(3 receptor antagonist xestospongin C. In addition, the specific inhibitors of phospholipase C (PLC-gamma, phosphatidylinositol 3-kinase (PI3K, p38MAPK, c-Jun N-terminal kinase (JNK, and the Ras/Raf/mitogen-activated protein kinase (MAPK

  20. Chapter Three - Ubiquitination and Protein Turnover of G-Protein-Coupled Receptor Kinases in GPCR Signaling and Cellular Regulation.

    Science.gov (United States)

    Penela, P

    2016-01-01

    G-protein-coupled receptors (GPCRs) are responsible for regulating a wide variety of physiological processes, and distinct mechanisms for GPCR inactivation exist to guarantee correct receptor functionality. One of the widely used mechanisms is receptor phosphorylation by specific G-protein-coupled receptor kinases (GRKs), leading to uncoupling from G proteins (desensitization) and receptor internalization. GRKs and β-arrestins also participate in the assembly of receptor-associated multimolecular complexes, thus initiating alternative G-protein-independent signaling events. In addition, the abundant GRK2 kinase has diverse "effector" functions in cellular migration, proliferation, and metabolism homeostasis by means of the phosphorylation or interaction with non-GPCR partners. Altered expression of GRKs (particularly of GRK2 and GRK5) occurs during pathological conditions characterized by impaired GPCR signaling including inflammatory syndromes, cardiovascular disease, and tumor contexts. It is increasingly appreciated that different pathways governing GRK protein stability play a role in the modulation of kinase levels in normal and pathological conditions. Thus, enhanced GRK2 degradation by the proteasome pathway occurs upon GPCR stimulation, what allows cellular adaptation to chronic stimulation in a physiological setting. β-arrestins participate in this process by facilitating GRK2 phosphorylation by different kinases and by recruiting diverse E3 ubiquitin ligase to the receptor complex. Different proteolytic systems (ubiquitin-proteasome, calpains), chaperone activities and signaling pathways influence the stability of GRKs in different ways, thus endowing specificity to GPCR regulation as protein turnover of GRKs can be differentially affected. Therefore, modulation of protein stability of GRKs emerges as a versatile mechanism for feedback regulation of GPCR signaling and basic cellular processes. PMID:27378756

  1. Activation of arylhydrocarbon receptor (AhR) in T lineage cells inhibits cellular growth

    Energy Technology Data Exchange (ETDEWEB)

    Nohara, K.; Tomohiro, I.; Chiharu, T. [National Institute for Environmental Studies, Tsukuba (Japan)

    2004-09-15

    Dioxins, including the most toxic congener, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), exert their toxic effects by binding and activating the arylhydrocarbon receptor (AhR), a liganddependent transcription factor. Upon binding dioxins, the AhR in the cytoplasm is activated and translocated to the nucleus, where it heterodimerizes with another transcription factor, ARNT. The AhR/ARNT heterodimer modulates expressions of various genes by binding xenobiotic responsive elements (XREs) in their enhancer regions or modifies cellular functions through protein-protein interactions. The AhR activation by TCDD exposure induces various immunotoxic reactions including thymus involution and suppression of T cell-dependent antibody production. We have investigated the roles of AhR activation in T lineage cells and their underlying mechanisms by generating transgenic (Tg) mice expressing a constitutively active AhR (CA-AhR) mutant specifically in T cells and by transiently expressing the CA-AhR mutant in Jurkat T cells.

  2. Cellular, Molecular Consequences of Peroxisome Proliferator- Activated Receptor-δ Activation in Ovarian Cancer Cells

    Directory of Open Access Journals (Sweden)

    Sara Vignati

    2006-10-01

    Full Text Available Peroxisome proliferator-activated receptor-δ (PPAR-δ is a ligand-activated transcription factor. In addition to its canonical role in lipid, glucose metabolism, PPAR-δ controls cell proliferation, death, differentiation in several tissues. Here we have examined the expression of PPAR-δ in ovarian tumors, the cellular, molecular consequences of its activation in ovarian cancer cells. PPAR-δ was expressed in a large number of epithelial ovarian tumors, cell lines. The PPAR-δ lig, ciglitazone inhibited the growth, clonogenic survival of ovarian cancer cells, inducing cell cycle arrest, cell death. Growth inhibition by ciglitazone was reversed by the PPAR-δ antagonist GW9662, indicating the involvement of PPAR-δ- dependent mechanisms. Microarray-based gene profiling revealed complex changes in the transcriptional program of ovarian cancer cells on treatment with ciglitazone, identified multiple pathways that may contribute to PPAR-δ ligands' antitumor activity. Genes upregulated by ciglitazone were predominantly associated with metabolic, differentiation, tumorsuppressor pathways, whereas downregulated genes were involved in cell proliferation, cell cycle, cell organization, steroid biosynthesis. Collectively, our data indicate that PPAR-δ activation by selective agonists is a valid strategy for ovarian cancer therapy, prevention, should be tested alone, in combination with other anticancer drugs.

  3. Car Sickness

    Science.gov (United States)

    ... in Action Medical Editor & Editorial Advisory Board Sponsors Sponsorship Opporunities Spread the Word Shop AAP Find a ... Share Car Sickness Page Content Article Body My child gets sick in the car quite often. How ...

  4. Etude du rôle du récepteur nucléaire CAR, Constitutive Androstane Receptor, dans le métabolisme des lipides et la susceptibilité à l'athérosclérose

    OpenAIRE

    Sberna, Anne-Laure

    2011-01-01

    Le récepteur CAR, Constitutive Androstane Receptor, appartient à la-famille NR1 des récepteurs nucléaires. Initialement décrit comme un récepteur orphelin, CAR est en fait activé par un grand nombre de molécules exogènes et une des fonctions principales de CAR est celle de xénosenseur. L'activation CAR par ses différents ligands stimule la transcription des enzymes de phase I, II et III nécessaires à la détoxification et à l'élimination des xénobiotiques. Parallèlement, CAR a fait l'objet de ...

  5. Comparison of Cellular Uptake and Inflammatory Response via Toll-Like Receptor 4 to Lipopolysaccharide and Titanium Dioxide Nanoparticles

    OpenAIRE

    Akiyoshi Taniguchi; Koki Kanehira; Sharmy Saimon Mano

    2013-01-01

    The innate immune response is the earliest cellular response to infectious agents and mediates the interactions between microbes and cells. Toll-like receptors (TLRs) play an important role in these interactions. We have already shown that TLRs are involved with the uptake of titanium dioxide nanoparticles (TiO2 NPs) and promote inflammatory responses. In this paper, we compared role of cellular uptake and inflammatory response via TLR 4 to lipopolysaccharide (LPS) and TiO2 NPs. In the case o...

  6. New advances in leukaemia immunotherapy by the use of Chimeric Artificial Antigen Receptors (CARs: state of the art and perspectives for the near future

    Directory of Open Access Journals (Sweden)

    Cribioli Elisabetta

    2011-09-01

    Full Text Available Abstract Leukaemia immunotherapy represents a fascinating and promising field of translational research, particularly as an integrative approach of bone marrow transplantation. Adoptive immunotherapy by the use of donor-derived expanded leukaemia-specific T cells has showed some kind of clinical response, but the major advance is nowadays represented by gene manipulation of donor immune cells, so that they acquire strict specificity towards the tumour target and potent lytic activity, followed by significant proliferation, increased survival and possibly anti-tumour memory state. This is achieved by gene insertion of Chimeric T-cell Antigen Receptors (CARs, which are artificial molecules containing antibody-derived fragments (to bind the specific target, joined with potent signalling T-Cell Receptor (TCR-derived domains that activate the manipulated cells. This review will discuss the main application of this approach particularly focusing on the paediatric setting, raising advantages and disadvantages and discussing relevant perspectives of use in the nearest future.

  7. The anticancer plant triterpenoid, avicin D, regulates glucocorticoid receptor signaling: implications for cellular metabolism.

    Science.gov (United States)

    Haridas, Valsala; Xu, Zhi-Xiang; Kitchen, Doug; Jiang, Anna; Michels, Peter; Gutterman, Jordan U

    2011-01-01

    Avicins, a family of apoptotic triterpene electrophiles, are known to regulate cellular metabolism and energy homeostasis, by targeting the mitochondria. Having evolved from "ancient hopanoids," avicins bear a structural resemblance with glucocorticoids (GCs), which are the endogenous regulators of metabolism and energy balance. These structural and functional similarities prompted us to compare the mode of action of avicin D with dexamethasone (Dex), a prototypical GC. Using cold competition assay, we show that Avicin D competes with Dex for binding to the GC receptor (GR), leading to its nuclear translocation. In contrast to Dex, avicin-induced nuclear translocation of GR does not result in transcriptional activation of GC-dependent genes. Instead we observe a decrease in the expression of GC-dependent metabolic proteins such as PEPCK and FASN. However, like Dex, avicin D treatment does induce a transrepressive effect on the pro-inflammatory transcription factor NF-κB. While avicin's ability to inhibit NF-κB and its downstream targets appear to be GR-dependent, its pro-apoptotic effects were independent of GR expression. Using various deletion mutants of GR, we demonstrate the requirement of both the DNA and ligand binding domains of GR in mediating avicin D's transrepressive effects. Modeling of avicin-GR interaction revealed that avicin molecule binds only to the antagonist confirmation of GR. These findings suggest that avicin D has properties of being a selective GR modulator that separates transactivation from transrepression. Since the gene-activating properties of GR are mainly linked to its metabolic effects, and the negative interference with the activity of transcription factors to its anti-inflammatory and immune suppressive effects, the identification of such a dissociated GR ligand could have great potential for therapeutic use. PMID:22132201

  8. The anticancer plant triterpenoid, avicin D, regulates glucocorticoid receptor signaling: implications for cellular metabolism.

    Directory of Open Access Journals (Sweden)

    Valsala Haridas

    Full Text Available Avicins, a family of apoptotic triterpene electrophiles, are known to regulate cellular metabolism and energy homeostasis, by targeting the mitochondria. Having evolved from "ancient hopanoids," avicins bear a structural resemblance with glucocorticoids (GCs, which are the endogenous regulators of metabolism and energy balance. These structural and functional similarities prompted us to compare the mode of action of avicin D with dexamethasone (Dex, a prototypical GC. Using cold competition assay, we show that Avicin D competes with Dex for binding to the GC receptor (GR, leading to its nuclear translocation. In contrast to Dex, avicin-induced nuclear translocation of GR does not result in transcriptional activation of GC-dependent genes. Instead we observe a decrease in the expression of GC-dependent metabolic proteins such as PEPCK and FASN. However, like Dex, avicin D treatment does induce a transrepressive effect on the pro-inflammatory transcription factor NF-κB. While avicin's ability to inhibit NF-κB and its downstream targets appear to be GR-dependent, its pro-apoptotic effects were independent of GR expression. Using various deletion mutants of GR, we demonstrate the requirement of both the DNA and ligand binding domains of GR in mediating avicin D's transrepressive effects. Modeling of avicin-GR interaction revealed that avicin molecule binds only to the antagonist confirmation of GR. These findings suggest that avicin D has properties of being a selective GR modulator that separates transactivation from transrepression. Since the gene-activating properties of GR are mainly linked to its metabolic effects, and the negative interference with the activity of transcription factors to its anti-inflammatory and immune suppressive effects, the identification of such a dissociated GR ligand could have great potential for therapeutic use.

  9. Role of toll-like receptors 3, 4 and 7 in cellular uptake and response to titanium dioxide nanoparticles

    Science.gov (United States)

    Chen, Peng; Kanehira, Koki; Taniguchi, Akiyoshi

    2013-02-01

    Innate immune response is believed to be among the earliest provisional cellular responses, and mediates the interactions between microbes and cells. Toll-like receptors (TLRs) are critical to these interactions. We hypothesize that TLRs also play an important role in interactions between nanoparticles (NPs) and cells, although little information has been reported concerning such an interaction. In this study, we investigated the role of TLR3, TLR4 and TLR7 in cellular uptake of titanium dioxide NP (TiO2 NP) agglomerates and the resulting inflammatory responses to these NPs. Our data indicate that TLR4 is involved in the uptake of TiO2 NPs and promotes the associated inflammatory responses. The data also suggest that TLR3, which has a subcellular location distinct from that of TLR4, inhibits the denaturation of cellular protein caused by TiO2 NPs. In contrast, the unique cellular localization of TLR7 has middle-ground functional roles in cellular response after TiO2 NP exposure. These findings are important for understanding the molecular interaction mechanisms between NPs and cells.

  10. Role of toll-like receptors 3, 4 and 7 in cellular uptake and response to titanium dioxide nanoparticles

    Directory of Open Access Journals (Sweden)

    Peng Chen, Koki Kanehira and Akiyoshi Taniguchi

    2013-01-01

    Full Text Available Innate immune response is believed to be among the earliest provisional cellular responses, and mediates the interactions between microbes and cells. Toll-like receptors (TLRs are critical to these interactions. We hypothesize that TLRs also play an important role in interactions between nanoparticles (NPs and cells, although little information has been reported concerning such an interaction. In this study, we investigated the role of TLR3, TLR4 and TLR7 in cellular uptake of titanium dioxide NP (TiO2 NP agglomerates and the resulting inflammatory responses to these NPs. Our data indicate that TLR4 is involved in the uptake of TiO2 NPs and promotes the associated inflammatory responses. The data also suggest that TLR3, which has a subcellular location distinct from that of TLR4, inhibits the denaturation of cellular protein caused by TiO2 NPs. In contrast, the unique cellular localization of TLR7 has middle-ground functional roles in cellular response after TiO2 NP exposure. These findings are important for understanding the molecular interaction mechanisms between NPs and cells.

  11. Robert Feulgen Prize Lecture 1993. The journey of the insulin receptor into the cell: from cellular biology to pathophysiology.

    Science.gov (United States)

    Carpentier, J L

    1993-09-01

    The data that we have reviewed indicate that insulin binds to a specific cell-surface receptor. The complex then becomes involved in a series of steps which lead the insulin-receptor complex to be internalized and rapidly delivered to endosomes. From this sorting station, the hormone is targeted to lysosomes to be degraded while the receptor is recycled back to the cell surface. This sequence of events presents two degrees of ligand specificity: (a) The first step is ligand-dependent and requires insulin-induced receptor phosphorylation of specific tyrosine residues. It consists in the surface redistribution of the receptor from microvilli where it preferentially localizes in its unoccupied form. (b) The second step is more general and consists in the association with clathrin-coated pits which represents the internalization gate common to many receptors. This sequence of events participates in the regulation of the biological action of the hormone and can thus be implicated in the pathophysiology of diabetes mellitus and various extreme insulin resistance syndromes, including type A extreme insulin resistance, leprechaunism, and Rabson-Mendehall syndrome. Alterations of the internalization process can result either from intrinsic abnormalities of the receptor or from more general alteration of the plasma membrane or of the cell metabolism. Type I diabetes is an example of the latter possibility, since general impairment of endocytosis could contribute to extracellular matrix accumulation and to an increase in blood cholesterol. Thus, better characterization of the molecular and cellular biology of the insulin receptor and of its journey inside the cell definitely leads to better understanding of disease states, including diabetes. PMID:8244769

  12. DIFFERENTIAL BINDING OF HUMAN INTERLEUKIN-1 (IL-1) RECEPTOR ANTAGONIST TO NATURAL AND RECOMBINANT SOLUBLE AND CELLULAR IL-1 TYPE-I RECEPTORS

    DEFF Research Database (Denmark)

    Svenson, Morten; Nedergaard, Susanne; Heegaard, Peter M. H.;

    1995-01-01

    A recently described factor, interleukin-1 receptor antagonist binding factor (IL-1raBF), in serum of normal individuals is immunologically related to the interleukin-1 receptor type I (IL-1RI). It is presumably a soluble form of the receptor that binds exclusively to interleukin-1 receptor...... antagonist (IL-1ra). Recombinant soluble human IL-1RI expressed in COS cells (sIL-1RI) consists of the extracellular part of the receptor and binds all three known IL-1 species but preferentially to IL-1ra. We further characterized the sizes and binding of IL-1raBF and sIL-1RI to IL-1ra by polyacrylamide gel...... electrophoresis in the presence of sodium dodecylsulfate, ligand binding interference analyses, N-glycosidase treatment, concanavalin A affinity chromatography, and with the use of monoclonal antibodies (mAb) to human recombinant IL-1ra. We also evaluated the binding of IL-1ra to cellular IL-1RI on MRC5...

  13. Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action

    International Nuclear Information System (INIS)

    Toxicogenomics (TGx) is employed frequently to investigate underlying molecular mechanisms of the compound of interest and, thus, has become an aid to mode of action determination. However, the results and interpretation of a TGx dataset are influenced by the experimental design and methods of analysis employed. This article describes an evaluation and reanalysis, by two independent laboratories, of previously published TGx mouse liver microarray data for a triazole fungicide, propiconazole (PPZ), and the anticonvulsant drug phenobarbital (PB). Propiconazole produced an increase incidence of liver tumors in male CD-1 mice only at a dose that exceeded the maximum tolerated dose (2500 ppm). Firstly, we illustrate how experimental design differences between two in vivo studies with PPZ and PB may impact the comparisons of TGx results. Secondly, we demonstrate that different researchers using different pathway analysis tools can come to different conclusions on specific mechanistic pathways, even when using the same datasets. Finally, despite these differences the results across three different analyses also show a striking degree of similarity observed for PPZ and PB treated livers when the expression data are viewed as major signaling pathways and cell processes affected. Additional studies described here show that the postulated key event of hepatocellular proliferation was observed in CD-1 mice for both PPZ and PB, and that PPZ is also a potent activator of the mouse CAR nuclear receptor. Thus, with regard to the events which are hallmarks of CAR-induced effects that are key events in the mode of action (MOA) of mouse liver carcinogenesis with PB, PPZ-induced tumors can be viewed as being promoted by a similar PB-like CAR-dependent MOA

  14. Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy

    Directory of Open Access Journals (Sweden)

    Vita Golubovskaya

    2016-03-01

    Full Text Available This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy––a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4+ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh and CD8+ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc.; intracellular markers (FOXP3; epigenetic and genetic programs; and metabolic pathways (catabolic or anabolic; and these differences can be modulated to improve CAR-T therapy. In addition, CD4+ Treg cells suppress the efficacy of CAR-T cell therapy, and different approaches to overcome this suppression are discussed in this review. Thus, next-generation CAR-T immunotherapy can be improved, based on our knowledge of T cell subsets functions, differentiation, proliferation, and signaling pathways to generate more active CAR-T cells against tumors.

  15. Different Subsets of T Cells, Memory, Effector Functions, and CAR-T Immunotherapy

    Science.gov (United States)

    Golubovskaya, Vita; Wu, Lijun

    2016-01-01

    This review is focused on different subsets of T cells: CD4 and CD8, memory and effector functions, and their role in CAR-T therapy––a cellular adoptive immunotherapy with T cells expressing chimeric antigen receptor. The CAR-T cells recognize tumor antigens and induce cytotoxic activities against tumor cells. Recently, differences in T cell functions and the role of memory and effector T cells were shown to be important in CAR-T cell immunotherapy. The CD4+ subsets (Th1, Th2, Th9, Th17, Th22, Treg, and Tfh) and CD8+ memory and effector subsets differ in extra-cellular (CD25, CD45RO, CD45RA, CCR-7, L-Selectin [CD62L], etc.); intracellular markers (FOXP3); epigenetic and genetic programs; and metabolic pathways (catabolic or anabolic); and these differences can be modulated to improve CAR-T therapy. In addition, CD4+ Treg cells suppress the efficacy of CAR-T cell therapy, and different approaches to overcome this suppression are discussed in this review. Thus, next-generation CAR-T immunotherapy can be improved, based on our knowledge of T cell subsets functions, differentiation, proliferation, and signaling pathways to generate more active CAR-T cells against tumors. PMID:26999211

  16. Revealing the sequence and resulting cellular morphology of receptor-ligand interactions during Plasmodium falciparum invasion of erythrocytes.

    Directory of Open Access Journals (Sweden)

    Greta E Weiss

    2015-02-01

    Full Text Available During blood stage Plasmodium falciparum infection, merozoites invade uninfected erythrocytes via a complex, multistep process involving a series of distinct receptor-ligand binding events. Understanding each element in this process increases the potential to block the parasite's life cycle via drugs or vaccines. To investigate specific receptor-ligand interactions, they were systematically blocked using a combination of genetic deletion, enzymatic receptor cleavage and inhibition of binding via antibodies, peptides and small molecules, and the resulting temporal changes in invasion and morphological effects on erythrocytes were filmed using live cell imaging. Analysis of the videos have shown receptor-ligand interactions occur in the following sequence with the following cellular morphologies; 1 an early heparin-blockable interaction which weakly deforms the erythrocyte, 2 EBA and PfRh ligands which strongly deform the erythrocyte, a process dependant on the merozoite's actin-myosin motor, 3 a PfRh5-basigin binding step which results in a pore or opening between parasite and host through which it appears small molecules and possibly invasion components can flow and 4 an AMA1-RON2 interaction that mediates tight junction formation, which acts as an anchor point for internalization. In addition to enhancing general knowledge of apicomplexan biology, this work provides a rational basis to combine sequentially acting merozoite vaccine candidates in a single multi-receptor-blocking vaccine.

  17. Comparison of Cellular Uptake and Inflammatory Response via Toll-Like Receptor 4 to Lipopolysaccharide and Titanium Dioxide Nanoparticles

    Directory of Open Access Journals (Sweden)

    Akiyoshi Taniguchi

    2013-06-01

    Full Text Available The innate immune response is the earliest cellular response to infectious agents and mediates the interactions between microbes and cells. Toll-like receptors (TLRs play an important role in these interactions. We have already shown that TLRs are involved with the uptake of titanium dioxide nanoparticles (TiO2 NPs and promote inflammatory responses. In this paper, we compared role of cellular uptake and inflammatory response via TLR 4 to lipopolysaccharide (LPS and TiO2 NPs. In the case of LPS, LPS binds to LPS binding protein (LBP and CD 14, and then this complex binds to TLR 4. In the case of TiO2 NPs, the necessity of LBP and CD 14 to induce the inflammatory response and for uptake by cells was investigated using over-expression, antibody blocking, and siRNA knockdown experiments. Our results suggested that for cellular uptake of TiO2 NPs, TLR 4 did not form a complex with LBP and CD 14. In the TiO2 NP-mediated inflammatory response, TLR 4 acted as the signaling receptor without protein complex of LPS, LBP and CD 14. The results suggested that character of TiO2 NPs might be similar to the complex of LPS, LBP and CD 14. These results are important for development of safer nanomaterials.

  18. Cellular analysis of the histamine H4 receptor in human myeloid cells.

    Science.gov (United States)

    Capelo, Ricardo; Lehmann, Christoph; Ahmad, Khalil; Snodgrass, Ryan; Diehl, Olaf; Ringleb, Julia; Flamand, Nicolas; Weigert, Andreas; Stark, Holger; Steinhilber, Dieter; Kahnt, Astrid S

    2016-03-01

    The human histamine H4 receptor (H4R) is a Gαi/o-coupled receptor which is mainly expressed on hematopoietic cells. Accordingly, the receptor is implicated in the pathology of various diseases such as autoimmune disorders, bronchial asthma and pruritus. Due to complicated receptor pharmacology, the lack of a reliable antibody and limited availability of primary cells expressing the receptor the physiology of this receptor is still poorly understood. Therefore, we aimed to assess absolute receptor mRNA expression and functionality (intracellular Ca(2+) release) in various human myeloid cell types such as granulocytes, monocytes, macrophages and dendritic cells (DCs). This was put into context with the expression of the H1R and H2R. In addition, the influence of various inflammatory stimuli on H4R expression was investigated in macrophages and monocyte-derived DCs. We found that classically activated macrophages treated with pro-inflammatory stimuli down-regulated histamine receptor mRNA expression as did LPS and zymosan A matured monocyte-derived DCs. In contrast, alternatively activated macrophages (IL-4 or IL-13) upregulated H2R and H4R expression compared to controls. Consistent with existing literature, we found eosinophils to be the major source of the H4R. Since availability of primary eosinophils is limited, we developed a cell model based on the differentiated eosinophilic cell line EOL-1, in which H4R pharmacology and physiology may be studied. PMID:26774453

  19. Antibody penetration into living cells. V. Interference between two fc gamma receptor-mediated functions: antibody penetration and antibody-dependent cellular cytotoxicity.

    Science.gov (United States)

    Llerena, J M; Ruíz-Argüelles, A; Alarcón-Segovia, D; Llorente, L; Díaz-Jouanen, E

    1981-01-01

    The same Fc gamma receptor appears to be shared for two important phenomena: antibody-dependent cellular cytotoxicity (ADCC) and antibody penetration into living cells. ADCC is inhibited through interaction with the Fc gamma receptor during the antibody penetration process, indicating that both mechanisms may modulate each other in vitro. PMID:6972908

  20. Cellular and Molecular Consequences of Peroxisome Proliferator-Activated Receptor-γ Activation in Ovarian Cancer Cells1*

    OpenAIRE

    Vignati, Sara; Albertini, Veronica; Rinaldi, Andrea; Kwee, Ivo; RIVA Cristina; Oldrini, Rita; Capella, Carlo; Bertoni, Francesco; Carbone, Giuseppina M; Catapano, Carlo V.

    2006-01-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-activated transcription factor. In addition to its canonical role in lipid and glucose metabolism, PPAR-γ controls cell proliferation, death, and differentiation in several tissues. Here we have examined the expression of PPAR-γ in ovarian tumors and the cellular and molecular consequences of its activation in ovarian cancer cells. PPAR-γ was expressed in a large number of epithelial ovarian tumors and cell lines. The PPAR-γ li...

  1. Effects of toxic cellular stresses and divalent cations on the human P2X7 cell death receptor

    OpenAIRE

    Dutot, Mélody; Liang, Hong; Pauloin, Thierry; Brignole-Baudouin, Françoise; Baudouin, Christophe; Warnet, Jean-Michel; Rat, Patrice

    2008-01-01

    Purpose The purpose of this study was to investigate responses to toxic cellular stresses in different human ocular epithelia. Methods Reactivity with a specific anti-P2X7 antibody was studied using confocal fluorescence microscopy on conjunctival, corneal, lens, and retinal cell lines as well as using impression cytology on human ocular cells. Activation of the P2X7 receptor by selective agonists (ATP and benzoylbenzoyl-ATP) and inhibition by antagonists (oATP, KN-62, and PPADS) were evaluat...

  2. Direct Channeling of Retinoic Acid between Cellular Retinoic Acid-Binding Protein II and Retinoic Acid Receptor Sensitizes Mammary Carcinoma Cells to Retinoic Acid-Induced Growth Arrest

    OpenAIRE

    Budhu, Anuradha S.; Noy, Noa

    2002-01-01

    Cellular retinoic acid-binding protein II (CRABP-II) is an intracellular lipid-binding protein that associates with retinoic acid with a subnanomolar affinity. We previously showed that CRABP-II enhances the transcriptional activity of the nuclear receptor with which it shares a common ligand, namely, the retinoic acid receptor (RAR), and we suggested that it may act by delivering retinoic acid to this receptor. Here, the mechanisms underlying the effects of CRABP-II on the transcriptional ac...

  3. The human angiotensin AT(1) receptor supports G protein-independent extracellular signal-regulated kinase 1/2 activation and cellular proliferation

    DEFF Research Database (Denmark)

    Hansen, Jakob Lerche; Aplin, Mark; Hansen, Jonas Tind; Christensen, Gitte Lund; Bonde, Marie Mi; Schneider, Mikael; Haunsø, Stig; Schiffer, Hans H; Burstein, Ethan S; Weiner, David M; Sheikh, Søren P

    AT(1) receptor signalling is illustrated by the common use of angiotensin AT(1) receptor-inverse agonists in clinical practice. It is well established that rodent orthologues of the angiotensin AT(1) receptor can selectively signal through G protein-dependent and -independent mechanisms in......(1) receptor actions. However, it is currently unknown whether the human angiotensin AT(1) receptor can signal through G protein-independent mechanisms - and if so, what the physiological impact of such signalling is. We have performed a detailed pharmacological analysis of the human angiotensin AT(1......) receptor using a battery of angiotensin analogues and registered drugs targeting this receptor. We show that the human angiotensin AT(1) receptor signals directly through G protein-independent pathways and supports NIH3T3 cellular proliferation. The realization of G protein-independent signalling by the...

  4. Microsatellite instability, KRAS mutations and cellular distribution of TRAIL-receptors in early stage colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Lydia Kriegl

    Full Text Available BACKGROUND: The fact that the receptors for the TNF-related apoptosis inducing ligand (TRAIL are almost invariably expressed in colorectal cancer (CRC represents the rationale for the employment of TRAIL-receptors targeting compounds for the therapy of patients affected by this tumor. Yet, first reports on the use of these bioactive agents provided disappointing results. We therefore hypothesized that loss of membrane-bound TRAIL-R might be a feature of some CRC and that the evaluation of membrane staining rather than that of the overall expression of TRAIL-R might predict the response to TRAIL-R targeting compounds in this tumor. AIM AND METHODS: Thus, we evaluated the immunofluorescence pattern of TRAIL-receptors and E-cadherin to assess the fraction of membrane-bound TRAIL-receptors in 231 selected patients with early-stage CRC undergoing surgical treatment only. Moreover, we investigated whether membrane staining for TRAIL-receptors as well as the presence of KRAS mutations or of microsatellite instability (MSI had an effect on survival and thus a prognostic effect. RESULTS: As expected, almost all CRC samples stained positive for TRAIL-R1 and 2. Instead, membrane staining for these receptors was positive in only 71% and 16% of samples respectively. No correlation between KRAS mutation status or MSI-phenotype and prognosis could be detected. TRAIL-R1 staining intensity correlated with survival in univariate analysis, but only membranous staining of TRAIL-R1 and TRAIL-R2 on cell membranes was an independent predictor of survival (cox multivariate analysis: TRAIL-R1: p = 0.019, RR 2.06[1.12-3.77]; TRAIL-R2: p = 0.033, RR 3.63[1.11-11.84]. CONCLUSIONS: In contrast to the current assumptions, loss of membrane staining for TRAIL-receptors is a common feature of early stage CRC which supersedes the prognostic significance of their staining intensity. Failure to achieve therapeutic effects in recent clinical trials using TRAIL-receptors targeting

  5. Receptor-independent, vacuolar ATPase-mediated cellular uptake of histamine receptor-1 ligands: Possible origin of pharmacological distortions and side effects

    International Nuclear Information System (INIS)

    The aims of this study were to investigate whether several histamine receptor agonists and antagonists are subjected to receptor-independent ion trapping into acidic organelles, and whether this sequestration influences their pharmacological or toxicological properties. Vacuolar (V)-ATPase-dependent intracellular sequestration of agonists was recognized as morphological alterations (large fluid-filled vacuoles for betahistine and 1-methylhistamine, granular uptake for fluorescent BODIPY FL histamine) prevented by the specific V-ATPase inhibitor bafilomycin A1 in rabbit vascular smooth muscle cells. Lipophilicity was the major determinant of these cellular effects (order of potency: BODIPY FL histamine > betahistine > 1-methylhistamine > histamine) that occurred at high concentrations. This ranking was dissociable from the potency order for H1 receptor-mediated contraction of the rabbit aorta, a response uninfluenced by bafilomycin. Antihistamines are inherently more lipophilic and caused vacuolization of a proportion of cells at 5-500 μM. Agonist or antagonist-induced vacuoles were of macroautophagic nature (labeled with GFP-conjugated LC3, Rab7 and CD63; detection of LC3 II). Further, the 2 most lipophilic antihistamines tested, astemizole and terfenadine, were potentiated by V-ATPase blockade in the aortic contractility assay (13- and 3.6-fold more potent, respectively, pA2 scale), suggesting that V-ATPase-mediated cation trapping sequesters these antagonists from the vicinity of H1 receptors in the therapeutic concentration range. This potentiation did not apply to less lipophilic antagonists (pyrilamine, diphenhydramine). While some agonists and all tested antagonists of the histamine H1 receptors induce the V-ATPase-dependent vacuolar and autophagic cytopathology, sequestration affects the pharmacology of only the most lipophilic antagonists, the ones prone to off-target arrhythmogenic side effects

  6. Ligand-induced Coupling versus Receptor Pre-association: Cellular automaton simulations of FGF-2 binding

    OpenAIRE

    Gopalakrishnan, Manoj; Forsten-Williams, Kimberly; Tauber, Uwe C.

    2003-01-01

    The binding of basic fibroblast growth factor (FGF-2) to its cell surface receptor (CSR) and subsequent signal transduction is known to be enhanced by Heparan Sulfate Proteoglycans (HSPGs). HSPGs bind FGF-2 with low affinity and likely impact CSR-mediated signaling via stabilization of FGF-2-CSR complexes via association with both the ligand and the receptor. What is unknown is whether HSPG associates with CSR in the absence of FGF-2. In this paper, we determine conditions by which pre-associ...

  7. A Truncated Progesterone Receptor (PR-M) Localizes to the Mitochondrion and Controls Cellular Respiration

    OpenAIRE

    Dai, Qunsheng; Shah, Anish A.; Garde, Rachana V.; Yonish, Bryan A.; Zhang, Li; Medvitz, Neil A.; Miller, Sara E.; Hansen, Elizabeth L.; Dunn, Carrie N.; Price, Thomas M.

    2013-01-01

    The cDNA for a novel truncated progesterone receptor (PR-M) was previously cloned from human adipose and aortic cDNA libraries. The predicted protein sequence contains 16 unique N-terminal amino acids, encoded by a sequence in the distal third intron of the progesterone receptor PR gene, followed by the same amino acid sequence encoded by exons 4 through 8 of the nuclear PR. Thus, PR-M lacks the N terminus A/B domains and the C domain for DNA binding, whereas containing the hinge and hormone-...

  8. The binding of NCAM to FGFR1 induces a specific cellular response mediated by receptor trafficking

    DEFF Research Database (Denmark)

    Francavilla, Chiara; Cattaneo, Paola; Berezin, Vladimir;

    2009-01-01

    effectors. Furthermore, NCAM, but not FGF-2, promotes cell migration, and this response depends on FGFR1 recycling and sustained Src activation. Our results implicate NCAM as a nonconventional ligand for FGFR1 that exerts a peculiar control on the intracellular trafficking of the receptor, resulting in a...

  9. Car-to-Car Communication

    OpenAIRE

    Eichler, Stephan; Schroth, Christoph; Eberspächer, Jörg

    2006-01-01

    Car-to-car communication aims at increased driving comfort and safety. Moreover, it changes the role of vehicles from mere transportation means to "smart objects". Despite many R&D activities in the last years, this technology still poses multiple challenges on the wireless transmission and network protocols. Aspects like efficient message dissemination, network scalability, and information security mechanisms are still major research areas in the area of vehicular ad hoc networks. In this pa...

  10. Chimeric antigen receptor engineering: a right step in the evolution of adoptive cellular immunotherapy.

    Science.gov (United States)

    Figueroa, Jose A; Reidy, Adair; Mirandola, Leonardo; Trotter, Kayley; Suvorava, Natallia; Figueroa, Alejandro; Konala, Venu; Aulakh, Amardeep; Littlefield, Lauren; Grizzi, Fabio; Rahman, Rakhshanda Layeequr; Jenkins, Marjorie R; Musgrove, Breeanna; Radhi, Saba; D'Cunha, Nicholas; D'Cunha, Luke N; Hermonat, Paul L; Cobos, Everardo; Chiriva-Internati, Maurizio

    2015-03-01

    Cancer immunotherapy comprises different therapeutic strategies that exploit the use of distinct components of the immune system, with the common goal of specifically targeting and eradicating neoplastic cells. These varied approaches include the use of specific monoclonal antibodies, checkpoint inhibitors, cytokines, therapeutic cancer vaccines and cellular anticancer strategies such as activated dendritic cell (DC) vaccines, tumor-infiltrating lymphocytes (TILs) and, more recently, genetically engineered T cells. Each one of these approaches has demonstrated promise, but their generalized success has been hindered by the paucity of specific tumor targets resulting in suboptimal tumor responses and unpredictable toxicities. This review will concentrate on recent advances on the use of engineered T cells for adoptive cellular immunotherapy (ACI) in cancer. PMID:25901860

  11. Lack of CAR impacts neuronal function and cerebrovascular integrity in vivo.

    Science.gov (United States)

    Boussadia, Baddreddine; Gangarossa, Giuseppe; Mselli-Lakhal, Laila; Rousset, Marie-Claude; de Bock, Frederic; Lassere, Frederic; Ghosh, Chaitali; Pascussi, Jean-Marc; Janigro, Damir; Marchi, Nicola

    2016-09-01

    Nuclear receptors (NRs) are a group of transcription factors emerging as players in normal and pathological CNS development. Clinically, an association between the constitutive androstane NR (CAR) and cognitive impairment was proposed, however never experimentally investigated. We wished to test the hypothesis that the impact of CAR on neurophysiology and behavior is underlined by cerebrovascular-neuronal modifications. We have used CAR(-/-) C57BL/6 and wild type mice and performed a battery of behavioral tests (recognition, memory, motor coordination, learning and anxiety) as well as longitudinal video-electroencephalographic recordings (EEG). Brain cell morphology was assessed using 2-photon or electron microscopy and fluorescent immunohistochemistry. We observed recognition memory impairment and increased anxiety-like behavior in CAR(-/-) mice, while locomotor activity was not affected. Concomitantly to memory deficits, EEG monitoring revealed a decrease in 3.5-7Hz waves during the awake/exploration and sleep periods. Behavioral and EEG abnormalities in CAR(-/-) mice mirrored structural changes, including tortuous fronto-parietal penetrating vessels. At the cellular level we found reduced ZO-1, but not CLDN5, tight junction protein expression in cortical and hippocampal isolated microvessel preparations. Interestingly, the neurotoxin kainic acid, when injected peripherally, provoked a rapid onset of generalized convulsions in CAR(-/-) as compared to WT mice, supporting the hypothesis of vascular permeability. The morphological phenotype of CAR(-/-) mice also included some modifications of GFAP/IBA1 glial cells in the parenchymal or adjacent to collagen-IV(+) or FITC(+) microvessels. Neuronal defects were also observed including increased cortical NEUN(+) cell density, hippocampal granule cell dispersion and increased NPY immunoreactivity in the CA1 region in CAR(-/-) mice. The latter may contribute to the in vivo phenotype. Our results indicate that behavioral

  12. Adenovirus type 5 (Ad5) is sequestered and inactivated by binding to coxsackievirus and adenovirus receptor (CAR) and complement receptor 1 (CR1) on human erythrocytes

    Czech Academy of Sciences Publication Activity Database

    Carlisle, R. C.; Di, Y.; Cerny, A.; Sonnen, A.; Sim, R.; Green, N.; Šubr, Vladimír; Ulbrich, Karel; Gilbert, R.; Fisher, K.; Finberg, R.; Seymour, L.

    New Rochelle: Mary Ann Liebert Inc, 2008, s. 1191-1192. ISSN 1043-0342. [Annual Congress of the European Society of Gene and Cell Therapy /16./. Brugge (BE), 13.11.2008-16.11.2008] EU Projects: European Commission(XE) 512087 - GIANT Institutional research plan: CEZ:AV0Z40500505 Keywords : adenovirus * Coxsackie receptor * gene delivery Subject RIV: CD - Macromolecular Chemistry

  13. Optical control of endogenous receptors and cellular excitability using targeted covalent photoswitches.

    Science.gov (United States)

    Izquierdo-Serra, Mercè; Bautista-Barrufet, Antoni; Trapero, Ana; Garrido-Charles, Aida; Díaz-Tahoces, Ariadna; Camarero, Nuria; Pittolo, Silvia; Valbuena, Sergio; Pérez-Jiménez, Ariadna; Gay, Marina; García-Moll, Alejandro; Rodríguez-Escrich, Carles; Lerma, Juan; de la Villa, Pedro; Fernández, Eduardo; Pericàs, Miquel À; Llebaria, Amadeu; Gorostiza, Pau

    2016-01-01

    Light-regulated drugs allow remotely photoswitching biological activity and enable plausible therapies based on small molecules. However, only freely diffusible photochromic ligands have been shown to work directly in endogenous receptors and methods for covalent attachment depend on genetic manipulation. Here we introduce a chemical strategy to covalently conjugate and photoswitch the activity of endogenous proteins and demonstrate its application to the kainate receptor channel GluK1. The approach is based on photoswitchable ligands containing a short-lived, highly reactive anchoring group that is targeted at the protein of interest by ligand affinity. These targeted covalent photoswitches (TCPs) constitute a new class of light-regulated drugs and act as prosthetic molecules that photocontrol the activity of GluK1-expressing neurons, and restore photoresponses in degenerated retina. The modularity of TCPs enables the application to different ligands and opens the way to new therapeutic opportunities. PMID:27436051

  14. Extracellular calcium-sensing-receptor (CaR)-mediated opening of an outward K(+) channel in murine MC3T3-E1 osteoblastic cells: evidence for expression of a functional CaR

    Science.gov (United States)

    Ye, C. P.; Yamaguchi, T.; Chattopadhyay, N.; Sanders, J. L.; Vassilev, P. M.; Brown, E. M.; O'Malley, B. W. (Principal Investigator)

    2000-01-01

    The existence in osteoblasts of the G-protein-coupled extracellular calcium (Ca(o)(2+))-sensing receptor (CaR) that was originally cloned from parathyroid and kidney remains controversial. In our recent studies, we utilized multiple detection methods to demonstrate the expression of CaR transcripts and protein in several osteoblastic cell lines, including murine MC3T3-E1 cells. Although we and others have shown that high Ca(o)(2+) and other polycationic CaR agonists modulate the function of MC3T3-E1 cells, none of these actions has been unequivocally shown to be mediated by the CaR. Previous investigations using neurons and lens epithelial cells have shown that activation of the CaR stimulates Ca(2+)-activated K(+) channels. Because osteoblastic cells express a similar type of channel, we have examined the effects of specific "calcimimetic" CaR activators on the activity of a Ca(2+)-activated K(+) channel in MC3T3-E1 cells as a way of showing that the CaR is not only expressed in those cells but is functionally active. Patch-clamp analysis in the cell-attached mode showed that raising Ca(o)(2+) from 0.75 to 2.75 mmol/L elicited about a fourfold increase in the open state probability (P(o)) of an outward K(+) channel with a conductance of approximately 92 pS. The selective calcimimetic CaR activator, NPS R-467 (0.5 micromol/L), evoked a similar activation of the channel, while its less active stereoisomer, NPSS-467 (0.5 micromol/L), did not. Thus, the CaR is not only expressed in MC3T3-E1 cells, but is also functionally coupled to the activity of a Ca(2+)-activated K(+) channel. This receptor, therefore, could transduce local or systemic changes in Ca(o)(2+) into changes in the activity of this ion channel and related physiological processes in these and perhaps other osteoblastic cells.

  15. Ghrelin and cannabinoids require the ghrelin receptor to affect cellular energy metabolism

    OpenAIRE

    Lim, Chung Thong; Kola, Blerina; Feltrin, Daniel; Perez-Tilve, Diego; Tschöp, Matthias H.; Grossman, Ashley B; Korbonits, Márta

    2013-01-01

    Introduction Ghrelin is a potent orexigenic brain-gut peptide with lipogenic and diabetogenic effects, possibly mediated by growth hormone secretagogue receptor (GHS-R1a). Cannabinoids also have orexigenic and lipogenic effects. AMPK is a regulator of energy homeostasis and we have previously shown that ghrelin and cannabinoids stimulate hypothalamic AMPK activity while inhibiting it in the liver and adipose tissue, suggesting that AMPK mediates both the central appetite-inducing and peripher...

  16. Chitinase 3-like 1 Regulates Cellular and Tissue Responses via IL-13 Receptor α2

    Directory of Open Access Journals (Sweden)

    Chuan Hua He

    2013-08-01

    Full Text Available Members of the 18 glycosyl hydrolase (GH 18 gene family have been conserved over species and time and are dysregulated in inflammatory, infectious, remodeling, and neoplastic disorders. This is particularly striking for the prototypic chitinase-like protein chitinase 3-like 1 (Chi3l1, which plays a critical role in antipathogen responses where it augments bacterial killing while stimulating disease tolerance by controlling cell death, inflammation, and remodeling. However, receptors that mediate the effects of GH 18 moieties have not been defined. Here, we demonstrate that Chi3l1 binds to interleukin-13 receptor α2 (IL-13Rα2 and that Chi3l1, IL-13Rα2, and IL-13 are in a multimeric complex. We also demonstrate that Chi3l1 activates macrophage mitogen-activated protein kinase, protein kinase B/AKT, and Wnt/β-catenin signaling and regulates oxidant injury, apoptosis, pyroptosis, inflammasome activation, antibacterial responses, melanoma metastasis, and TGF-β1 production via IL-13Rα2-dependent mechanisms. Thus, IL-13Rα2 is a GH 18 receptor that plays a critical role in Chi3l1 effector responses.

  17. Membrane cofactor protein (MCP or CD46) is a cellular pilus receptor for pathogenic Neisseria.

    Science.gov (United States)

    Källström, H; Liszewski, M K; Atkinson, J P; Jonsson, A B

    1997-08-01

    Pili of Neisseria gonorrhoeae and Neisseria meningitidis mediate binding of the bacteria to human cell-surface receptors. We found that purified pili bound to a 55- to 60-kDa doublet band on SDS-PAGE of separated human epithelial cell extracts. This is a migration pattern typical of membrane cofactor protein (MCP or CD46). MCP is a widely distributed human complement regulatory protein. Attachment of the bacteria to epithelial cells was blocked by polyclonal and monoclonal antibodies directed against MCP, suggesting that this complement regulator is a receptor for piliated Neisseria. We proved this hypothesis by demonstrating that piliated, but not non-piliated, gonococci bound to CHO cells transfected with human MCP-cDNA. We also demonstrated a direct interaction between purified recombinant MCP and piliated Neisseria. Finally, recombinant MCP protein produced in E. coli inhibited attachment of the bacteria to target cells. Taken together, our data show that MCP is a human cell-surface receptor for piliated pathogenic Neisseria. PMID:9379894

  18. Neu1 desialylation of sialyl alpha-2,3-linked beta-galactosyl residues of TOLL-like receptor 4 is essential for receptor activation and cellular signaling.

    Science.gov (United States)

    Amith, Schammim Ray; Jayanth, Preethi; Franchuk, Susan; Finlay, Trisha; Seyrantepe, Volkan; Beyaert, Rudi; Pshezhetsky, Alexey V; Szewczuk, Myron R

    2010-02-01

    The ectodomain of TOLL-like receptors (TLR) is highly glycosylated with several N-linked gylcosylation sites located in the inner concave surface. The precise role of these sugar N-glycans in TLR receptor activation is unknown. Recently, we have shown that Neu1 sialidase and not Neu2, -3 and -4 forms a complex with TLR-2, -3 and -4 receptors on the cell-surface membrane of naïve and activated macrophage cells (Glycoconj J DOI 10.1007/s10719-009-9239-8). Activation of Neu1 is induced by TLR ligands binding to their respective receptors. Here, we show that endotoxin lipopolysaccharide (LPS)-induced MyD88/TLR4 complex formation and subsequent NFkappaB activation is dependent on the removal of alpha-2,3-sialyl residue linked to beta-galactoside of TLR4 by the Neu1 activity associated with LPS-stimulated live primary macrophage cells, macrophage and dendritic cell lines but not with primary Neu1-deficient macrophage cells. Exogenous alpha-2,3 sialyl specific neuraminidase (Streptoccocus pneumoniae) and wild-type T. cruzi trans-sialidase (TS) but not the catalytically inactive mutant TSAsp98-Glu mediate TLR4 dimerization to facilitate MyD88/TLR4 complex formation and NFkappaB activation similar to those responses seen with LPS. These same TLR ligand-induced NFkappaB responses are not observed in TLR deficient HEK293 cells, but are re-established in HEK293 cells stably transfected with TLR4/MD2, and are significantly inhibited by alpha-2,3-sialyl specific Maackia amurensis (MAL-2) lectin, alpha-2,3-sialyl specific galectin-1 and neuraminidase inhibitor Tamiflu but not by alpha-2,6-sialyl specific Sambucus nigra lectin (SNA). Taken together, the findings suggest that Neu1 desialylation of alpha-2,3-sialyl residues of TLR receptors enables in removing a steric hinderance to receptor association for TLR activation and cellular signaling. PMID:19796680

  19. Car Shoe

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    历史悠久的意大利制鞋商Car Shoe为日本爱知世界博览会意大利展团迎宾小姐设计的两款皮鞋,轻松休闲又不失高雅,完美再现Car Shoe的设计理念,其中一款舒适大方“Driving”软底鞋,白1963年上市至今,始终风靡全球,成为一代经典。布满黑色胶皮钉的鞋底,是Car Shoe鞋子的标志性特点,另有一款3.5厘米的矮跟 鞋,尽显女性独特魅力。

  20. Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition.

    Science.gov (United States)

    Shi, Xiarong; Sousa, Leiliane P; Mandel-Bausch, Elizabeth M; Tome, Francisco; Reshetnyak, Andrey V; Hadari, Yaron; Schlessinger, Joseph; Lax, Irit

    2016-08-16

    Large genomic sequencing analysis as part of precision medicine efforts revealed numerous activating mutations in receptor tyrosine kinases, including KIT. Unfortunately, a single approach is not effective for inhibiting cancer cells or treating cancers driven by all known oncogenic KIT mutants. Here, we show that each of the six major KIT oncogenic mutants exhibits different enzymatic, cellular, and dynamic properties and responds distinctly to different KIT inhibitors. One class of KIT mutants responded well to anti-KIT antibody treatment alone or in combination with a low dose of tyrosine kinase inhibitors (TKIs). A second class of KIT mutants, including a mutant resistant to imatinib treatment, responded well to a combination of TKI with anti-KIT antibodies or to anti-KIT toxin conjugates, respectively. We conclude that the preferred choice of precision medicine treatments for cancers driven by activated KIT and other RTKs may rely on clear understanding of the dynamic properties of oncogenic mutants. PMID:27482095

  1. PTH1 receptor is involved in mediating cellular response to long-chain polyunsaturated fatty acids.

    Directory of Open Access Journals (Sweden)

    Jose Candelario

    Full Text Available The molecular pathways by which long chain polyunsaturated fatty acids (LCPUFA influence skeletal health remain elusive. Both LCPUFA and parathyroid hormone type 1 receptor (PTH1R are known to be involved in bone metabolism while any direct link between the two is yet to be established. Here we report that LCPUFA are capable of direct, PTH1R dependent activation of extracellular ligand-regulated kinases (ERK. From a wide range of fatty acids studied, varying in chain length, saturation, and position of double bonds, eicosapentaenoic (EPA and docosahexaenoic fatty acids (DHA caused the highest ERK phosphorylation. Moreover, EPA potentiated the effect of parathyroid hormone (PTH(1-34 in a superagonistic manner. EPA or DHA dependent ERK phosphorylation was inhibited by the PTH1R antagonist and by knockdown of PTH1R. Inhibition of PTH1R downstream signaling molecules, protein kinases A (PKA and C (PKC, reduced EPA and DHA dependent ERK phosphorylation indicating that fatty acids predominantly activate G-protein pathway and not the β-arrestin pathway. Using picosecond time-resolved fluorescence microscopy and a genetically engineered PTH1R sensor (PTH-CC, we detected conformational responses to EPA similar to those caused by PTH(1-34. PTH1R antagonist blocked the EPA induced conformational response of the PTH-CC. Competitive binding studies using fluorescence anisotropy technique showed that EPA and DHA competitively bind to and alter the affinity of PTH1 receptor to PTH(1-34 leading to a superagonistic response. Finally, we showed that EPA stimulates protein kinase B (Akt phosphorylation in a PTH1R-dependent manner and affects the osteoblast survival pathway, by inhibiting glucocorticoid-induced cell death. Our findings demonstrate for the first time that LCPUFAs, EPA and DHA, can activate PTH1R receptor at nanomolar concentrations and consequently provide a putative molecular mechanism for the action of fatty acids in bone.

  2. Identification and cellular distribution of distinct proteins forming human GM-CSF receptor.

    OpenAIRE

    Chiba, S; Shibuya, K.; Piao, Y F; Tojo, A.; Sasaki, N; Matsuki, S.; Miyagawa, K; Miyazono, K; Takaku, F

    1990-01-01

    Two proteins forming the receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF)1 were identified and characterized. One with apparent Mr of about 80,000 was defined as alpha-chain and has Kd of 0.7-2.8 nM. The other binding molecule with apparent Mr of about 135,000 was defined as beta-chain and is related to the high-affinity binding with Kd of 10-40 pM. The binding kinetic studies confirmed that the 125I-GM-CSF associated slower to and dissociated more rapidly from the...

  3. Ethanol regulation of adenosine receptor-stimulated cAMP levels in a clonal neural cell line: an in vitro model of cellular tolerance to ethanol.

    OpenAIRE

    Gordon, A S; Collier, K; Diamond, I.

    1986-01-01

    The acute and chronic neurologic effects of ethanol appear to be due to its interaction with neural cell membranes. Chronic exposure to ethanol induces changes in the membrane that lead to tolerance to the effects of ethanol. However, the actual membrane changes that account for tolerance to ethanol are not understood. We have developed a model cell culture system, using NG108-15 neuroblastoma-glioma hybrid cells, to study cellular tolerance to ethanol. We have found that adenosine receptor-s...

  4. Molecular and cellular dynamics of the Toll-like receptor 4 pathway.

    Directory of Open Access Journals (Sweden)

    Nick eGay

    2014-10-01

    Full Text Available As well as being the primary signaling receptor for bacterial endotoxin or lipopolysaccharide Toll-like receptor 4 function is modulated by numerous factors not only in the context of microbial pathogenesis but also autoimmune and allergic diseases. TLR4 is subject to multiple levels of endogenous control and regulation from biosynthesis and trafficking to signal transduction and degradation. On the other hand regulation of TLR4 activity breaks down during Gram –ve sepsis leading to systemic damage, multi organ failure and death. In this article we review how TLR4 traffics from the early secretory pathway, the cis/trans Golgi to the cell surface and endolysosomal compartments. We will present evidence about how these processes influence signaling and can potentially lead to ligand independent constitutive activation that may contribute to pathogenesis in sepsis. We will also discuss how sustained signaling may be coupled to endocytosis and consider the potential molecular mechanisms of immuno-modulators that modify TLR4 signalling function including the cat allergen FelD1 and endogenous protein ligands such as the extracellular matrix protein tenascin C and calprotectin (MRP8/14.

  5. The expression level of the transcription factor Aryl hydrocarbon receptor nuclear translocator (ARNT) determines cellular survival after radiation treatment

    International Nuclear Information System (INIS)

    Tumour hypoxia promotes radioresistance and is associated with poor prognosis. The transcription factor Aryl hydrocarbon receptor nuclear translocator (ARNT), also designated as Hypoxia-inducible factor (HIF)-1β, is part of the HIF pathway which mediates cellular adaptations to oxygen deprivation and facilitates tumour progression. The subunits HIF-1α and ARNT are key players within this pathway. HIF-1α is regulated in an oxygen-dependent manner whereas ARNT is considered to be constitutively expressed. However, there is mounting evidence that certain tumour cells are capable to elevate ARNT in hypoxia which suggests a survival benefit. Therefore the objective of this study was to elucidate effects of an altered ARNT expression level on the cellular response to radiation. Different human cell lines (Hep3B, MCF-7, 786-Owt, 786-Ovhl, RCC4wt and RCC4vhl) originating from various tumour entities (Hepatocellular carcinoma, breast cancer and renal cell carcinoma respectively) were X-irradiated using a conventional linear accelerator. Knockdown of ARNT expression was achieved by transient siRNA transfection. Complementary experiments were performed by forced ARNT overexpression using appropriate plasmids. Presence/absence of ARNT protein was confirmed by Western blot analysis. Clonogenic survival assays were performed in order to determine cellular survival post irradiation. Statistical comparison of two groups was achieved by the unpaired t-test. The results of this study indicate that ARNT depletion renders tumour cells susceptible to radiation whereas overexpression of this transcription factor confers radioresistance. These findings provide evidence to consider ARNT as a drug target and as a predictive marker in clinical applications concerning the response to radiation. The online version of this article (doi:10.1186/s13014-015-0539-9) contains supplementary material, which is available to authorized users

  6. Human reporter gene assays: Transcriptional activity of the androgen receptor is modulated by the cellular environment and promoter context

    International Nuclear Information System (INIS)

    The androgen receptor (AR) is a member of the nuclear receptor superfamily and mediates the physiological effects of androgens. Androgens are essential for male development and disruption of androgen signaling may cause androgen-dependent developmental defects and/or tumors. Here we present a comparative analysis of various model systems for the investigation of endocrine active compounds in human cell lines. We generated reporter plasmids containing androgen response elements derived from the human secretory component or the rat probasin genes as well as the glucocorticoid consensus response element and compared their activities to that of the mouse mammary tumor virus promotor. Additionally, we generated an expression plasmid containing the AR cDNA derived from LNCaP cells. In 22Rv1 cells transiently transfected with human AR, all reporters displayed a dose-dependent, high activity when treated with androgens. Interestingly, the potency of testosterone and its metabolite dihydrotestosterone was very low in HepG2 but not in 22Rv1 cells, independent of the reporter used. The efficacies of the androgens tested were comparable in both cell lines but highly dependent on the reporter used. Based on these results, 22Rv1 cells provide a highly sensitive in vitro test system to analyze endocrine activities of xenobiotics. Furthermore, this study highlights the need to investigate the (anti-) androgenic activity of compounds in dependence of the cellular and promoter context

  7. Nuclear epidermal growth factor receptor modulates cellular radio-sensitivity by regulation of chromatin access

    International Nuclear Information System (INIS)

    Purpose: Nuclear EGFR is involved in cellular stress management and regulation of cellular radio-sensitivity. The aim of this study was to elucidate the molecular mode of nuclear EGFR action. Methods: Radiation induced nuclear EGFR-shuttling and EGFR-foci formation was analyzed with immunohistochemistry and confocal microscopy. Composition of γH2AX-protein complexes was analyzed by western-blotting after immuno-precipitation. Functional relevance of nuclear EGFR was analyzed after siRNA mediated depletion of EGFR with respect to activation of ATM, histone H3 acetylation, residual DNA-damage and cell survival after irradiation. Results: Following radiation nuclear EGFR was localized in foci similar to γH2AX. EGFR co-localized in a sub-fraction of γH2AX-foci. Analysis of composition of γH2AX-complexes revealed presence of EGFR, ATM, promyelocytic leukemia protein (PML), histone H3 and hetero-chromatin binding protein (HP1) in response to radiation. Depletion of EGFR protein inhibited ATM activation due to inhibition of acetylase TIP60 activity following irradiation. Consequently, histone H3 acetylation and phosphorylation was blocked and chromatin could not be opened for repair. Thus, residual DNA-damage was increased 24 h after irradiation and cells were radio-sensitized. Comparable results were obtained when cells were treated with EGFR-NLS-peptide, which blocks EGFR nuclear shuttling specifically. Conclusions: Nuclear EGFR is part of DNA-damage repair complex and is involved in regulation of TIP60-acetylase activity. TIP60 is essential for ATM activation and chromatin relaxation which is a prerequisite for DNA-repair in heterochromatic DNA. Thus interventional EGFR strategies during tumor treatment may also interact with DNA-repair by blocking access to damaged DNA.

  8. Roles for glycosylation of cell surface receptors involved in cellular immune recognition.

    Science.gov (United States)

    Rudd, P M; Wormald, M R; Stanfield, R L; Huang, M; Mattsson, N; Speir, J A; DiGennaro, J A; Fetrow, J S; Dwek, R A; Wilson, I A

    1999-10-22

    The majority of cell surface receptors involved in antigen recognition by T cells and in the orchestration of the subsequent cell signalling events are glycoproteins. The length of a typical N-linked sugar is comparable with that of an immunoglobulin domain (30 A). Thus, by virtue of their size alone, oligosaccharides may be expected to play a significant role in the functions and properties of the cell surface proteins to which they are attached. A databank of oligosaccharide structures has been constructed from NMR and crystallographic data to aid in the interpretation of crystal structures of glycoproteins. As unambiguous electron density can usually only be assigned to the glycan cores, the remainder of the sugar is then modelled into the crystal lattice by superimposing the appropriate oligosaccharide from the database. This approach provides insights into the roles that glycosylation might play in cell surface receptors, by providing models that delineate potential close packing interactions on the cell surface. It has been proposed that the specific recognition of antigen by T cells results in the formation of an immunological synapse between the T cell and the antigen-presenting cell. The cell adhesion glycoproteins, such as CD2 and CD48, help to form a cell junction, providing a molecular spacer between opposing cells. The oligosaccharides located on the membrane proximal domains of CD2 and CD48 provide a scaffold to orient the binding faces, which leads to increased affinity. In the next step, recruitment of the peptide major histocompatibility complex (pMHC) by the T-cell receptors (TCRs) requires mobility on the membrane surface. The TCR sugars are located such that they could prevent non-specific aggregation. Importantly, the sugars limit the possible geometry and spacing of TCR/MHC clusters which precede cell signalling. We postulate that, in the final stage, the sugars could play a general role in controlling the assembly and stabilisation of the

  9. The mannose receptor LY75 (DEC205/CD205) modulates cellular phenotype and metastatic potential of ovarian cancer cells.

    Science.gov (United States)

    Faddaoui, Adnen; Bachvarova, Magdalena; Plante, Marie; Gregoire, Jean; Renaud, Marie-Claude; Sebastianelli, Alexandra; Gobeil, Stephane; Morin, Chantale; Macdonald, Elizabeth; Vanderhyden, Barbara; Bachvarov, Dimcho

    2016-03-22

    The molecular basis of epithelial ovarian cancer (EOC) dissemination is still poorly understood. Previously, we identified the mannose receptor LY75 gene as hypomethylated in high-grade (HG) serous EOC tumors, compared to normal ovarian tissues. LY75 represents endocytic receptor expressed on dendritic cells and so far, has been primarily studied for its role in antigen processing and presentation. Here we demonstrate that LY75 is overexpressed in advanced EOC and that LY75 suppression induces mesenchymal-to-epithelial transition (MET) in EOC cell lines with mesenchymal morphology (SKOV3 and TOV112), accompanied by reduction of their migratory and invasive capacity in vitro and enhanced tumor cell colonization and metastatic growth in vivo. LY75 knockdown in SKOV3 cells also resulted in predominant upregulation of functional pathways implicated in cell proliferation and metabolism, while pathways associated with cell signaling and adhesion, complement activation and immune response were mostly suppressed. Moreover, LY75 suppression had an opposite effect on EOC cell lines with epithelial phenotype (A2780s and OV2008), by directing epithelial-to-mesenchymal transition (EMT) associated with reduced capacity for in vivo EOC cell colonization, as similar/identical signaling pathways were reversely regulated, when compared to mesenchymal LY75 knockdown EOC cells.To our knowledge, this is the first report of a gene displaying such pleiotropic effects in sustaining the cellular phenotype of EOC cells and points to novel functions of this receptor in modulating EOC dissemination. Our data also support previous findings regarding the superior capacity of epithelial cancer cells in metastatic colonization of distant sites, compared to cancer cells with mesenchymal-like morphology. PMID:26871602

  10. iNR-Drug: Predicting the Interaction of Drugs with Nuclear Receptors in Cellular Networking

    Directory of Open Access Journals (Sweden)

    Yue-Nong Fan

    2014-03-01

    Full Text Available Nuclear receptors (NRs are closely associated with various major diseases such as cancer, diabetes, inflammatory disease, and osteoporosis. Therefore, NRs have become a frequent target for drug development. During the process of developing drugs against these diseases by targeting NRs, we are often facing a problem: Given a NR and chemical compound, can we identify whether they are really in interaction with each other in a cell? To address this problem, a predictor called “iNR-Drug” was developed. In the predictor, the drug compound concerned was formulated by a 256-D (dimensional vector derived from its molecular fingerprint, and the NR by a 500-D vector formed by incorporating its sequential evolution information and physicochemical features into the general form of pseudo amino acid composition, and the prediction engine was operated by the SVM (support vector machine algorithm. Compared with the existing prediction methods in this area, iNR-Drug not only can yield a higher success rate, but is also featured by a user-friendly web-server established at http://www.jci-bioinfo.cn/iNR-Drug/, which is particularly useful for most experimental scientists to obtain their desired data in a timely manner. It is anticipated that the iNR-Drug server may become a useful high throughput tool for both basic research and drug development, and that the current approach may be easily extended to study the interactions of drug with other targets as well.

  11. Human RON receptor tyrosine kinase induces complete epithelial-to-mesenchymal transition but causes cellular senescence

    International Nuclear Information System (INIS)

    The RON receptor tyrosine kinase is a member of the MET proto-oncogene family and is important for cell proliferation, differentiation, and cancer development. Here, we created a series of Madin-Darby canine kidney (MDCK) epithelial cell clones that express different levels of RON, and have investigated their biological properties. While low levels of RON correlated with little morphological change in MDCK cells, high levels of RON expression constitutively led to morphological scattering or complete and stabilized epithelial-to-mesenchymal transition (EMT). Unexpectedly, MDCK clones expressing higher levels of RON exhibited retarded proliferation and senescence, despite increased motility and invasiveness. RON was constitutively tyrosine-phosphorylated in MDCK cells expressing high levels of RON and undergoing EMT, and the MAPK signaling pathway was activated. This study reveals for the first time that RON alone is sufficient to induce complete and stabilized EMT in MDCK cells, and overexpression of RON does not cause cell transformation but rather induces cell cycle arrest and senescence, leading to impaired cell proliferation

  12. Molecular recognition of antibody (IgG) by cellular Fc receptor (FcRI).

    Science.gov (United States)

    Burton, D R; Jefferis, R; Partridge, L J; Woof, J M

    1988-11-01

    Earlier studies from this and other laboratories have provided indirect evidence for the involvement of the C gamma 2 domain of human IgG in the binding of IgG to the high affinity monocyte Fc receptor (FcRI). Two approaches have been used to extend these studies and to further localize the site of interaction on human IgG. Firstly, monoclonal antibodies (MAbs) directed against different epitopes on IgG were assayed for their capacity to inhibit the binding of radiolabelled IgG to human monocytes or U937 cells. The capacity of the MAbs to interact with their respective epitopes on FcR-bound IgG was also studied using indirect radiobinding and immunofluorescence assays. Secondly, a number of IgGs from several different species and fragments of human IgGs were assayed for their ability to inhibit the binding of radiolabelled IgG to human monocytes. The amino acid sequences of those IgGs exhibiting relatively tight, intermediate or weak binding to monocyte FcRs were compared. On the basis of these studies a possible monocyte FcR-binding site on human IgG is postulated, involving the lower hinge region of IgG (residues Leu 234-Ser 239) with possible involvement of the nearby N-proximal bend and two beta-strands (Gly 316-Lys 338). PMID:2975762

  13. Dream Car

    Institute of Scientific and Technical Information of China (English)

    庄雅婷

    2010-01-01

    也许你需要一辆天马行空完全按自己心中所设计的车,无论是有太空感还是充满设计性,无论你希望它可以升空还是可以下水,那才是一辆真正的Dream Car!

  14. Non-genomic estrogen/estrogen receptor α promotes cellular malignancy of immature ovarian teratoma in vitro.

    Science.gov (United States)

    Hung, Yao-Ching; Chang, Wei-Chun; Chen, Lu-Min; Chang, Ying-Yi; Wu, Ling-Yu; Chung, Wei-Min; Lin, Tze-Yi; Chen, Liang-Chi; Ma, Wen-Lung

    2014-06-01

    Malignant immature ovarian teratomas (IOTs) most often occur in women of reproductive age. It is unclear, however, what roles estrogenic signaling plays in the development of IOT. In this study, we examined whether estrogen receptors (ERα and β) promote the cellular malignancy of IOT. Estradiol (E2), PPT (propylpyrazole), and DPN (diarylpropionitrile) (ERα- and β-specific agonists, respectively), as well as ERα- or ERβ-specific short hairpin (sh)RNA were applied to PA-1 cells, a well-characterized IOT cell line. Cellular tumorigenic characteristics, for example, cell migration/invasion, expression of the cancer stem/progenitor cell marker CD133, and evidence for epithelial-mesenchymal transition (EMT) were examined. In PA-1 cells that expressed ERα and ERβ, we found that ERα promoted cell migration and invasion. We also found that E2/ERα signaling altered cell behavior through non-classical transactivation function. Our data show non-genomic E2/ERα activations of focal adhesion kinase-Ras homolog gene family member A (FAK-RhoA) and ERK governed cell mobility capacity. Moreover, E2/ERα signaling induces EMT and overexpression of CD133 through upregulation micro-RNA 21 (miR21; IOT stem/progenitor promoter), and ERK phosphorylations. Furthermore, E2/ERα signaling triggers a positive feedback regulatory loop within miR21 and ERK. At last, expression levels of ERα, CD133, and EMT markers in IOT tissue samples were examined by immunohistochemistry. We found that cytosolic ERα was co-expressed with CD133 and mesenchymal cell markers but not epithelial cell markers. In conclusion, estrogenic signals exert malignant transformation capacity of cancer cells, exclusively through non-genomic regulation in female germ cell tumors. PMID:24142535

  15. Clinical manufacturing of CAR T cells: foundation of a promising therapy.

    Science.gov (United States)

    Wang, Xiuyan; Rivière, Isabelle

    2016-01-01

    The treatment of cancer patients with autologous T cells expressing a chimeric antigen receptor (CAR) is one of the most promising adoptive cellular therapy approaches. Reproducible manufacturing of high-quality, clinical-grade CAR-T cell products is a prerequisite for the wide application of this technology. Product quality needs to be built-in within every step of the manufacturing process. We summarize herein the requirements and logistics to be considered, as well as the state of the art manufacturing platforms available. CAR-T cell therapy may be on the verge of becoming standard of care for a few clinical indications. Yet, many challenges pertaining to manufacturing standardization and product characterization remain to be overcome in order to achieve broad usage and eventual commercialization of this therapeutic modality. PMID:27347557

  16. Expression of Human CAR Splicing Variants in BAC-Transgenic Mice

    OpenAIRE

    Zhang, Yu-Kun Jennifer; LU, Hong; Klaassen, Curtis D.

    2012-01-01

    The nuclear receptor constitutive androstane receptor (CAR) is a key regulator for drug metabolism in liver. Human CAR (hCAR) transcripts are subjected to alternative splicing. Some hCAR splicing variants (SVs) have been shown to encode functional proteins by reporter assays. However, in vivo research on the activity of these hCAR SVs has been impeded by the absence of a valid model. This study engineered an hCAR-BAC-transgenic (hCAR-TG) mouse model by integrating the 8.5-kbp hCAR gene as wel...

  17. Development of a recombinant CHO cell model for the investigation of CAR and DAF role during early steps of echovirus 6 infection.

    Science.gov (United States)

    Renois, Fanny; Hong, Saw-See; Le Naour, Richard; Gafa, Valérie; Talmud, Déborah; Andréoletti, Laurent; Lévêque, Nicolas

    2011-06-01

    The early steps of echovirus 6 (E6) infection remain poorly understood and the only described receptor for haemagglutinating E6 strains is the decay accelerating factor (DAF). There is, however, accumulating evidence suggesting that E6 interaction with DAF is necessary but not sufficient for infection. In this report, we investigated the role of the coxsackie-adenovirus-receptor (CAR) as a potential DAF co-receptor during E6 infection. Using stably transfected Chinese Hamster Ovary (CHO) cells expressing CAR and DAF receptors, we found that DAF expression allowed attachment of both haemagglutinating and non-haemagglutinating E6 strains but was not sufficient for promoting E6 cell entry. Interestingly, the co-expression of DAF and CAR rendered 0.1-0.2% of cells permissive to some E6 strains' infection. Although our results did not show a major role of the CAR/DAF cooperation for E6 infection, it nevertheless indicated the use of CAR in the cell entry step of some minor E6 quasispecies. Moreover, the present report validates the use of recombinant CHO cells as valuable cellular model for the further characterisation of E6 receptors. PMID:21420451

  18. CD19 chimeric antigen receptor (CD19 CAR)-redirected adoptive T-cell immunotherapy for the treatment of relapsed or refractory B-cell Non-Hodgkin’s Lymphomas

    Science.gov (United States)

    Onea, Alexandra S; Jazirehi, Ali R

    2016-01-01

    Recovery rates for B-cell Non-Hodgkin’s Lymphoma (NHL) are up to 70% with current standard-of-care treatments including rituximab (chimeric anti-CD20 monoclonal antibody) in combination with chemotherapy (R-CHOP). However, patients who do not respond to first-line treatment or develop resistance have a very poor prognosis. This signifies the need for the development of an optimal treatment approach for relapsed/refractory B-NHL. Novel CD19- chimeric antigen receptor (CAR) T-cell redirected immunotherapy is an attractive option for this subset of patients. Anti-CD19 CAR T-cell therapy has already had remarkable efficacy in various leukemias as well as encouraging outcomes in phase I clinical trials of relapsed/refractory NHL. In going forward with additional clinical trials, complementary treatments that may circumvent potential resistance mechanisms should be used alongside anti-CD19 T-cells in order to prevent relapse with resistant strains of disease. Some such supplementary tactics include conditioning with lymphodepletion agents, sensitizing with kinase inhibitors and Bcl-2 inhibitors, enhancing function with multispecific CAR T-cells and CD40 ligand-expressing CAR T-cells, and safeguarding with lymphoma stem cell-targeted treatments. A therapy regimen involving anti-CD19 CAR T-cells and one or more auxiliary treatments could dramatically improve prognoses for patients with relapsed/refractory B-cell NHL. This approach has the potential to revolutionize B-NHL salvage therapy in much the same way rituximab did for first-line treatments. PMID:27186412

  19. Shifting the Evolving CAR T Cell Platform into Higher Gear.

    Science.gov (United States)

    Holohan, Daniel R; Lee, James C; Bluestone, Jeffrey A

    2015-10-12

    In this issue of Cancer Cell, Zhao and colleagues test various chimeric antigen receptor (CAR) T cells to show that CD28-CD3ζ CAR T cells that constitutively express 4-1BBL promote T cell expansion and tumor eradication while reducing exhaustion. The results have important implications for the development of effective CAR T cell therapies in cancer patients. PMID:26461084

  20. New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer

    Directory of Open Access Journals (Sweden)

    Stroncek David F

    2012-03-01

    Full Text Available Abstract A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL, are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs, chimeric antibody-T cell receptors (CARs and cytokines. T cell subsets with more naïve and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies.

  1. Androgen Receptor Expression and Cellular Proliferation During Transition from Androgen-Dependent to Recurrent Growth after Castration in the CWR22 Prostate Cancer Xenograft

    OpenAIRE

    Kim, Desok; Gregory, Christopher W.; French, Frank S.; Smith, Gary J.; Mohler, James L.

    2002-01-01

    Androgen receptor expression was analyzed in the CWR22 human prostate cancer xenograft model to better understand its role in prostate cancer recurrence after castration. In androgen-dependent tumors, 98.5% of tumor cell nuclei expressed androgen receptor with a mean optical density of 0.26 ± 0.01. On day 2 after castration androgen deprivation decreased immunostained cells to 2% that stained weakly (mean optical density, 0.16 ± 0.08). Cellular proliferation measured using Ki-67 revealed

  2. Driving CAR T-cells forward.

    Science.gov (United States)

    Jackson, Hollie J; Rafiq, Sarwish; Brentjens, Renier J

    2016-06-01

    The engineered expression of chimeric antigen receptors (CARs) on the surface of T cells enables the redirection of T-cell specificity. Early clinical trials using CAR T cells for the treatment of patients with cancer showed modest results, but the impressive outcomes of several trials of CD19-targeted CAR T cells in the treatment of patients with B-cell malignancies have generated an increased enthusiasm for this approach. Important lessons have been derived from clinical trials of CD19-specific CAR T cells, and ongoing clinical trials are testing CAR designs directed at novel targets involved in haematological and solid malignancies. In this Review, we discuss these trials and present strategies that can increase the antitumour efficacy and safety of CAR T-cell therapy. Given the fast-moving nature of this field, we only discuss studies with direct translational application currently or soon-to-be tested in the clinical setting. PMID:27000958

  3. CAR STICKERS

    CERN Multimedia

    Access and Control Service

    2004-01-01

    Following to the operational circular No2 title III. Conditions of access, paragraph 21 . Except in the case of exemptions authorized by the Director-General, all drivers must facilitate the identification of their vehicle. For CERN car stickers to be valid in 2004, they must have the numbers 04 printed on them. As of Monday, March 15th, the security agents on duty at the various access points will have no alternative but to refuse entry to vehicles which do not have a valid sticker. Anyone in this situation is requested to follow the regularization procedure either by logging on to the web site, or by going in person to the registration service in bldg. 55, first floor, between 07h30 et 16h30, Monday through Friday. Access and Control Service - FM Group, TS Department

  4. Complete sequence of the human tissue factor gene, a highly regulated cellular receptor that initiates the coagulation protease cascade

    International Nuclear Information System (INIS)

    Tissue factor (TF) is the high-affinity receptor for plasma factors VII and VIIa. TF plays a role in normal hemostasis by initiating the cell-surface assembly and propagation of the coagulation protease cascade. outside the vasculature, TF expression is highly dependent upon cell type. TF can also be induced by inflammatory mediators to appear on monocytes and vascular endothelial cells as a component of cellular immune responses. As an initial step toward elucidating the regulatory regions involved in control of TF gene expression, we have established the organization of the 12.4 kbp human TF gene and its complete DNA sequence. There are six exons separated by five introns. Within intron 5, we have mapped the single nucleotide difference which leads to the previously described MspI polymorphism; the same intron also contains an apparently polymorphic PstI site. The TF gene also contains three full-length Alu repeats and one partial Alu repeat. A single major transcription start site was identified 26 bp downstream from a TATA consensus promoter element. The putative promoter and first exon are located within a 1.2 kbp region of very high G + C content which fits the criteria of an HTF island. A cluster of predicted binding sites for a number of known transcription factors was found to coincide with this putative promoter region. These factors included AP-1 and AP-2 which can mediate the effects of phorbol esters, agonists known to induce TF expression in monocytes and vascular endothelial cells

  5. Quantitative High-Throughput Luciferase Screening in Identifying CAR Modulators.

    Science.gov (United States)

    Lynch, Caitlin; Zhao, Jinghua; Wang, Hongbing; Xia, Menghang

    2016-01-01

    The constitutive androstane receptor (CAR, NR1I3) is responsible for the transcription of multiple drug metabolizing enzymes and transporters. There are two possible methods of activation for CAR, direct ligand binding and a ligand-independent method, which makes this a unique nuclear receptor. Both of these mechanisms require translocation of CAR from the cytoplasm into the nucleus. Interestingly, CAR is constitutively active in immortalized cell lines due to the basal nuclear location of this receptor. This creates an important challenge in most in vitro assay models because immortalized cells cannot be used without inhibiting the high basal activity. In this book chapter, we go into detail of how to perform quantitative high-throughput screens to identify hCAR1 modulators through the employment of a double stable cell line. Using this line, we are able to identify activators, as well as deactivators, of the challenging nuclear receptor, CAR. PMID:27518621

  6. Car Club

    CERN Multimedia

    Automobile Club

    2012-01-01

    The Car Club wishes all its members Good road and Happy New Year 2012. It is time to think about renewing your subscription for this year, at a cost of 50 CHF, unchanged since several years. For those of you who are regular users of our equipment and who know all the advantages that the club is in a position to offer, it seems pointless to going to more details, as we are sure that many of you have made use of them and are satisfied. Therefore don’t forget to fill in the payment slip to continue to be a part of our large family. We remind you that everyone who works on the CERN site can be members of our club, this includes industrial support personnel and the personnel of companies which have a contract with CERN. If you are not yet a member, come and visit us! We will be happy to welcome you and show you the installations, alternatively you can visit our web site: http://club-acc.web.cern.ch/club-acc/ The use of the club’s installations is strictly reserved for members. Pour t...

  7. Seatbelts in CAR therapy: How Safe Are CARS?

    OpenAIRE

    Kentaro Minagawa; Xiaoou Zhou; Shin Mineishi; Antonio Di Stasi

    2015-01-01

    T-cells genetically redirected with a chimeric antigen receptor (CAR) to recognize tumor antigens and kill tumor cells have been infused in several phase 1 clinical trials with success. Due to safety concerns related to on-target/off-tumor effects or cytokine release syndrome, however, strategies to prevent or abate serious adverse events are required. Pharmacologic therapies; suicide genes; or novel strategies to limit the cytotoxic effect only to malignant cells are under active investigati...

  8. CAR models: next-generation CAR modifications for enhanced T-cell function.

    Science.gov (United States)

    Abate-Daga, Daniel; Davila, Marco L

    2016-01-01

    T cells genetically targeted with a chimeric antigen receptor (CAR) to B-cell malignancies have demonstrated tremendous clinical outcomes. With the proof in principle for CAR T cells as a therapy for B-cell malignancies being established, current and future research is being focused on adapting CAR technology to other cancers, as well as enhancing its efficacy and/or safety. The modular nature of the CAR, extracellular antigen-binding domain fused to a transmembrane domain and intracellular T-cell signaling domains, allows for optimization by replacement of the various components. These modifications are creating a whole new class of therapeutic CARs. In this review, we discuss the recent major advances in CAR design and how these modifications will impact its clinical application. PMID:27231717

  9. Time-course comparison of xenobiotic activators of CAR and PPARα in mouse liver

    International Nuclear Information System (INIS)

    Constitutive androstane receptor (CAR) and peroxisome proliferator activated receptor (PPAR)α are transcription factors known to be primary mediators of liver effects, including carcinogenesis, by phenobarbital-like compounds and peroxisome proliferators, respectively, in rodents. Many similarities exist in the phenotypes elicited by these two classes of agents in rodent liver, and we hypothesized that the initial transcriptional responses to the xenobiotic activators of CAR and PPARα will exhibit distinct patterns, but at later time-points these biological pathways will converge. In order to capture the global transcriptional changes that result from activation of these nuclear receptors over a time-course in the mouse liver, microarray technology was used. First, differences in basal expression of liver genes between C57Bl/6J wild-type and Car-null mice were examined and 14 significantly differentially expressed genes were identified. Next, mice were treated with phenobarbital (100 mg/kg by gavage for 24 h, or 0.085% w/w diet for 7 or 28 days), and liver gene expression changes with regards to both time and treatment were identified. While several pathways related to cellular proliferation and metabolism were affected by phenobarbital in wild-type mice, no significant changes in gene expression were found over time in the Car-nulls. Next, we determined commonalities and differences in the temporal response to phenobarbital and WY-14,643, a prototypical activator of PPAR α. Gene expression signatures from livers of wild-type mice C57Bl6/J mice treated with PB or WY-14,643 were compared. Similar pathways were affected by both compounds; however, considerable time-related differences were present. This study establishes common gene expression fingerprints of exposure to activators of CAR and PPARα in rodent liver and demonstrates that despite similar phenotypic changes, molecular pathways differ between classes of chemical carcinogens

  10. Testin, a novel binding partner of the calcium-sensing receptor, enhances receptor-mediated Rho-kinase signalling

    International Nuclear Information System (INIS)

    Highlights: → A yeast two-hybrid screen revealed testin bound to the calcium-sensing receptor. → The second zinc finger of LIM domain 1 of testin is critical for interaction. → Testin bound to a region of the receptor tail important for cell signalling. → Testin and receptor interaction was confirmed in mammalian (HEK293) cells. → Overexpression of testin enhanced receptor-mediated Rho signalling in HEK293 cells. -- Abstract: The calcium-sensing receptor (CaR) plays an integral role in calcium homeostasis and the regulation of other cellular functions including cell proliferation and cytoskeletal organisation. The multifunctional nature of the CaR is manifested through ligand-dependent stimulation of different signalling pathways that are also regulated by partner binding proteins. Following a yeast two-hybrid library screen using the intracellular tail of the CaR as bait, we identified several novel binding partners including the focal adhesion protein, testin. Testin has not previously been shown to interact with cell surface receptors. The sites of interaction between the CaR and testin were mapped to the membrane proximal region of the receptor tail and the second zinc-finger of LIM domain 1 of testin, the integrity of which was found to be critical for the CaR-testin interaction. The CaR-testin association was confirmed in HEK293 cells by coimmunoprecipitation and confocal microscopy studies. Ectopic expression of testin in HEK293 cells stably expressing the CaR enhanced CaR-stimulated Rho activity but had no effect on CaR-stimulated ERK signalling. These results suggest an interplay between the CaR and testin in the regulation of CaR-mediated Rho signalling with possible effects on the cytoskeleton.

  11. Regulation of N-methyl-D-aspartate receptor expression and N-methyl-D-aspartate-induced cellular response during chronic hypoxia in differentiated rat PC12 cells.

    Science.gov (United States)

    Kobayashi, S; Millhorn, D E

    2000-01-01

    The purpose of the present study was to examine the effect of chronic hypoxia on N-methyl-D-aspartate-mediated cellular responses in differentiated PC12 cells. PC12 cells were differentiated by treatment with nerve growth factor. Patch-clamp analysis in differentiated PC12 cells showed that extracellularly applied N-methyl-D-aspartate induced an inward current that was abolished by the presence of the N-methyl-D-aspartate receptor antagonist MK-801. Results from Ca(2+) imaging experiments showed that N-methyl-D-aspartate induced an elevation in intracellular free Ca(2+) which was also abolished by MK-801. We also examined the effect of hypoxia on the N-methyl-D-aspartate-induced current in nerve growth factor-treated cells. We found that the N-methyl-D-aspartate-induced inward current and the N-methyl-D-aspartate-induced elevation in intracellular free Ca(2+) were markedly attenuated by chronic hypoxia. We next examined the possibility that the reduced N-methyl-D-aspartate responsiveness was due to down-regulation of N-methyl-D-aspartate receptor levels. Northern blot and immunoblot analyses showed that both messenger RNA and protein levels for N-methyl-D-aspartate receptor subunit 1 were markedly decreased during hypoxia. However, the messenger RNA for N-methyl-D-aspartate receptor subunit 2C was increased, whereas the protein level for subunit 2C did not change. Our results indicate that differentiated PC12 cells express functional N-methyl-D-aspartate receptors and that chronic exposure to hypoxia attenuates the N-methyl-D-aspartate-induced Ca(2+) accumulation in these cells via down-regulation of N-methyl-D-aspartate receptor subunit 1. This mechanism may play an important role in protecting PC12 cells against hypoxic stress. PMID:11113364

  12. 犬瘟热病毒细胞受体研究进展%Research Advance in Cellular Receptor of Canine Distemper Virus

    Institute of Scientific and Technical Information of China (English)

    苏建青; 褚秀玲

    2011-01-01

    Canine distemper,being a viral infectious disease,can cause multisystem infection on caninity, fur animals, wildlires and partial marine mammalians. The host specificity and tissue tropism of canine distemper virus is determined by the cellular receptor of infected animal. Currently, the viral receptor of canine distemper virus that has been determined has signalling lymphocyte activation molecule. To further study on receptor of canine distemper virus, the progress on viral receptor are reviewed in the article.%犬瘟热病毒是一种引起犬类、毛皮动物、野生动物和部分海洋哺乳动物发生多系统感染的病毒性传染病.犬瘟热的宿主范围和组织嗜性主要由其感染动物的细胞表面受体决定.目前,已经确认的犬瘟热受体有信号淋巴细胞激活因子.为了更好地对犬瘟热病毒的受体进行研究,就当前犬瘟热病毒的受体研究进行综述.

  13. Driving an improved CAR for cancer immunotherapy.

    Science.gov (United States)

    Huang, Xiaopei; Yang, Yiping

    2016-08-01

    The recent clinical success of chimeric antigen receptor (CAR) T cell therapy for B cell malignancies represents a paradigm shift in cancer immunotherapy. Unfortunately, application of CAR T cell-mediated therapy for solid tumors has so far been disappointing, and the reasons for this poor response in solid tumors remain unknown. In this issue of the JCI, Cherkassky and colleagues report on their use of a murine model of human pleural mesothelioma to explore potential factors that limit CAR T cell efficacy. Their studies have uncovered the importance of the tumor microenvironment in the inhibition of CAR T cell functions, revealed a critical role for the programmed death-1 (PD-1) pathway in CAR T cell exhaustion within the tumor microenvironment, and demonstrated improved antitumor effects with a CAR T cell-intrinsic PD-1 blockade strategy using a dominant negative form of PD-1. Together, the results of this study lay the groundwork for further evaluation of mechanisms underlying CAR T cell immune evasion within the tumor microenvironment for the improvement of CAR T cell-mediated therapy for solid tumors. PMID:27454296

  14. Transduction of brain dopamine neurons by adenoviral vectors is modulated by CAR expression: rationale for tropism modified vectors in PD gene therapy.

    Directory of Open Access Journals (Sweden)

    Travis B Lewis

    Full Text Available BACKGROUND: Gene-based therapy is a new paradigm for the treatment of Parkinson disease (PD and offers considerable promise for precise targeting and flexibility to impact multiple pathobiological processes for which small molecule agents are not available. Some success has been achieved utilizing adeno-associated virus for this approach, but it is likely that the characteristics of this vector system will ultimately create barriers to progress in clinical therapy. Adenovirus (Ad vector overcomes limitations in payload size and targeting. The cellular tropism of Ad serotype 5 (Ad5-based vectors is regulated by the Ad attachment protein binding to its primary cellular receptor, the coxsackie and adenovirus receptor (CAR. Many clinically relevant tissues are refractory to Ad5 infection due to negligible CAR levels but can be targeted by tropism-modified, CAR-independent forms of Ad. Our objective was to evaluate the role of CAR protein in transduction of dopamine (DA neurons in vivo. METHODOLOGY/PRINCIPAL FINDINGS: Ad5 was delivered to the substantia nigra (SN in wild type (wt and CAR transgenic animals. Cellular tropism was assessed by immunohistochemistry (IHC in the SN and striatal terminals. CAR expression was assessed by western blot and IHC. We found in wt animals, Ad5 results in robust transgene expression in astrocytes and other non-neuronal cells but poor infection of DA neurons. In contrast, in transgenic animals, Ad5 infects SNc neurons resulting in expression of transduced protein in their striatal terminals. Western blot showed low CAR expression in the ventral midbrain of wt animals compared to transgenic animals. Interestingly, hCAR protein localizes with markers of post-synaptic structures, suggesting synapses are the point of entry into dopaminergic neurons in transgenic animals. CONCLUSIONS/SIGNIFICANCE: These findings demonstrate that CAR deficiency limits infection of wild type DA neurons by Ad5 and provide a rationale for the

  15. The Socialist Car

    DEFF Research Database (Denmark)

    Christensen, Lars K.

    2013-01-01

    Review of L.H. Siegelbaum (ed.) The Socialist Car. Automobility in the Eastern Block. Cornell University Press, 2011.......Review of L.H. Siegelbaum (ed.) The Socialist Car. Automobility in the Eastern Block. Cornell University Press, 2011....

  16. Receptor complementation and mutagenesis reveal SR-BI as an essential HCV entry factor and functionally imply its intra- and extra-cellular domains.

    Directory of Open Access Journals (Sweden)

    Marlène Dreux

    2009-02-01

    Full Text Available HCV entry into cells is a multi-step and slow process. It is believed that the initial capture of HCV particles by glycosaminoglycans and/or lipoprotein receptors is followed by coordinated interactions with the scavenger receptor class B type I (SR-BI, a major receptor of high-density lipoprotein (HDL, the CD81 tetraspanin, and the tight junction protein Claudin-1, ultimately leading to uptake and cellular penetration of HCV via low-pH endosomes. Several reports have indicated that HDL promotes HCV entry through interaction with SR-BI. This pathway remains largely elusive, although it was shown that HDL neither associates with HCV particles nor modulates HCV binding to SR-BI. In contrast to CD81 and Claudin-1, the importance of SR-BI has only been addressed indirectly because of lack of cells in which functional complementation assays with mutant receptors could be performed. Here we identified for the first time two cell types that supported HCVpp and HCVcc entry upon ectopic SR-BI expression. Remarkably, the undetectable expression of SR-BI in rat hepatoma cells allowed unambiguous investigation of human SR-BI functions during HCV entry. By expressing different SR-BI mutants in either cell line, our results revealed features of SR-BI intracellular domains that influence HCV infectivity without affecting receptor binding and stimulation of HCV entry induced by HDL/SR-BI interaction. Conversely, we identified positions of SR-BI ectodomain that, by altering HCV binding, inhibit entry. Finally, we characterized alternative ectodomain determinants that, by reducing SR-BI cholesterol uptake and efflux functions, abolish HDL-mediated infection-enhancement. Altogether, we demonstrate that SR-BI is an essential HCV entry factor. Moreover, our results highlight specific SR-BI determinants required during HCV entry and physiological lipid transfer functions hijacked by HCV to favor infection.

  17. 10 Years of Car-2-X Communication - a Success Story?

    Science.gov (United States)

    Wischhof, Lars; Ebner, André

    2012-05-01

    For more than ten years, car-2-x communication has been a major topic of research in the scientific community and an important development focus for the automotive industry. First, this article takes a retrospective look at the evolution of car-2-x and the two different communication paradigms: decentralized car-2-car communication and centralized cellular solutions. Afterwards, a comparison of their technical advantages and limitations is presented, respectively. The result shows that in order to implement safety-relevant applications, car-2-car communication has strong advantages compared to cellular technologies but requires high market penetration. However, its introduction solely for safety applications is difficult since the required penetration will not be achieved until several years after initial deployment. Therefore, car-2-car communication must provide a benefit to the customer, even in the phase of market introduction. For this purpose, the article outlines an approach called SODAD (Segment-Oriented Data Abstraction and Dissemination). It offers a possibility to introduce decentralized vehicular applications with early customer benefit, in order to enable safety applications based on car-2-car communication on a long term.

  18. ERK controls epithelial cell death receptor signalling and cellular FLICE-like inhibitory protein (c-FLIP) in ulcerative colitis

    DEFF Research Database (Denmark)

    Seidelin, Jakob Benedict; Coskun, Mehmet; Vainer, Ben;

    2013-01-01

    Intestinal epithelial cell (IEC) death signalling through the Fas receptor is impaired in active ulcerative colitis (UC). This is possibly due to the activation of cytoprotective pathways resulting in limitation of the tissue injury secondary to inflammation. We hypothesized that inflammatory sig...

  19. The Influence of Receptor-Mediated Interactions on Reaction-Diffusion Mechanisms of Cellular Self-organisation

    Czech Academy of Sciences Publication Activity Database

    Klika, Václav; Baker, R. E.; Headon, D.; Gaffney, E. A.

    2012-01-01

    Roč. 74, č. 4 (2012), s. 935-957. ISSN 0092-8240 Institutional research plan: CEZ:AV0Z20760514 Keywords : reaction-diffusion * receptor-mediated patterning * turing models Subject RIV: BO - Biophysics Impact factor: 2.023, year: 2012 http://www.springerlink.com/content/9713544x6871w4n6/?MUD=MP

  20. Intelligent Car System

    CERN Document Server

    Siddique, Qasim

    2012-01-01

    In modern life the road safety has becomes the core issue. One single move of a driver can cause horrifying accident. The main goal of intelligent car system is to make communication with other cars on the road. The system is able to control to speed, direction and the distance between the cars the intelligent car system is able to recognize traffic light and is able to take decision according to it. This paper presents a framework of the intelligent car system. I validate several aspect of our system using simulation.

  1. Intelligent Car System

    OpenAIRE

    Qasim Siddique

    2009-01-01

    In modern life the road safety has becomes the core issue. One single move of a driver can cause horrifying accident. The main goal of intelligent car system is to make communication with other cars on the road. The system is able to control to speed, direction and the distance between the cars the intelligent car system is able to recognize traffic light and is able to take decision according to it. This paper presents a framework of the intelligent car system. I validate several aspect of o...

  2. Intelligent Car System

    Directory of Open Access Journals (Sweden)

    Qasim Siddique

    2009-01-01

    Full Text Available In modern life the road safety has becomes the core issue. One single move of a driver can cause horrifying accident. The main goal of intelligent car system is to make communication with other cars on the road. The system is able to control to speed, direction and the distance between the cars the intelligent car system is able to recognize traffic light and is able to take decision according to it. This paper presents a framework of the intelligent car system. I validate several aspect of our system using simulation.

  3. Studies of cell-surface glorin receptors, glorin degradation, and glorin-induced cellular responses during development of Polysphondylium violaceum.

    Science.gov (United States)

    De Wit, R J; van Bemmelen, M X; Penning, L C; Pinas, J E; Calandra, T D; Bonner, J T

    1988-12-01

    The chemoattractant mediating cell aggregation in the slime mold Polysphondylium violaceum is N-propionyl-gamma-L-glutamyl-L-ornithine-delta-lactam ethylester (glorin). Here we examine the binding properties of tritiated glorin to intact P. violaceum cells. Scatchard analysis of binding data yielded slightly curvilinear plots with Kd values in the range of 20 and 100 nM. The number of glorin receptors increased from 35,000 in the vegetative stage to 45,000 per cell during aggregation. Later, during culmination receptor numbers decreased to undetectable levels (less than 1000). The receptor binding kinetics show binding equilibrium within 30 s at 0 degrees C, and ligand dissociation occurs from two kinetically distinct receptors whose half-times were 2 s for 72% of the bound glorin and 28 s for the remainder. The enzymatic degradation of glorin did not affect binding data during incubations of up to 1 min at 0 degrees C. Two glorinase activities were observed. An ornithine delta-lactam cleaving activity with a Km of ca. 10(-4) M and a propionic acid removing activity (Km 10(-5) M), both of which were detected mainly on the cell surface. Cleavage of the lactam occurred at a higher rate than removal of propionic acid. Lactam-cleaved glorin showed no chemotactic activity nor did it bind to cell-surface glorin receptors. Cell-surface-bound glorinase activity and glorin-induced cGMP synthesis were developmentally regulated, peaking at aggregation. In the most sensitive stage half-maximal responses (cGMP synthesis, chemotaxis, light-scattering) were elicited in the 10-100 nM range. Neither cAMP synthesis nor glorin-induced glorin synthesis was observed. Guanine nucleotides specifically modulated glorin receptor binding on isolated membranes, and, conversely, glorin modulated GTP gamma S binding to membrane preparations. Our results support the notion that glorin mediates chemotactic cell aggregation in P. violaceum acting via cell-surface receptors, G-proteins, and c

  4. Establishing guidelines for CAR-T cells: challenges and considerations.

    Science.gov (United States)

    Wang, Wei; Qin, Di-Yuan; Zhang, Bing-Lan; Wei, Wei; Wang, Yong-Sheng; Wei, Yu-Quan

    2016-04-01

    T cells, genetically modified by chimeric antigen receptors (CAR-T), are endowed with specificity to a desired antigen and are cytotoxic to cells expressing the targeted antigen. CAR-T-based cancer immunotherapy is a promising therapy for curing hematological malignancy, such as acute lymphoid leukemia, and is promising for extending their efficacy to defeat solid tumors. To date, dozens of different CAR-T cells have been evaluated in clinical trials to treat tumors; this necessitates the establishment of guidelines for the production and application of CAR-T cells. However, it is challenging to standardize CAR-T cancer therapy because it involves a combination of gene therapy and cell therapy. In this review, we compare the existing guidelines for CAR-T cells and discuss the challenges and considerations for establishing guidance for CAR-T-based cancer immunotherapy. PMID:26965523

  5. An Amusing Car Accident

    Institute of Scientific and Technical Information of China (English)

    倪俊

    2001-01-01

    @@ It was about midnight. My son was riding in the back seat with a friend of his in a car driven by a Chinese schoolmate, when a police car suddenly approached from behind with its siren sounding ominously. The driver immediately stopped his car by the roadside and stepped out to see what was happening. Just at that moment, he seemed to hear a policeman shouting to him: “Back your car!” (Actually, his order was: “Go back into your car!”) Then the student set about backing his car. In a flurry, he went so far as to bump into the police car, which made the cops very much alarmed.

  6. CAR-T Cell Therapy for Lymphoma.

    Science.gov (United States)

    Ramos, Carlos A; Heslop, Helen E; Brenner, Malcolm K

    2016-01-01

    Lymphomas arise from clonal expansions of B, T, or NK cells at different stages of differentiation. Because they occur in the immunocyte-rich lymphoid tissues, they are easily accessible to antibodies and cell-based immunotherapy. Expressing chimeric antigen receptors (CARs) on T cells is a means of combining the antigen-binding site of a monoclonal antibody with the activating machinery of a T cell, enabling antigen recognition independent of major histocompatibility complex restriction, while retaining the desirable antitumor properties of a T cell. Here, we discuss the basic design of CARs and their potential advantages and disadvantages over other immune therapies for lymphomas. We review current clinical trials in the field and consider strategies to improve the in vivo function and safety of immune cells expressing CARs. The ultimate driver of CAR development and implementation for lymphoma will be the demonstration of their ability to safely and cost-effectively cure these malignancies. PMID:26332003

  7. Regulating CAR T Cells: A Remote Control Approach.

    Science.gov (United States)

    2016-09-01

    Researchers have synthesized small organic molecules called adaptors that have a tumor-specific ligand on one end and FITC on the other. Instead of engineering a different chimeric antigen receptor (CAR) on T cells for each unique tumor antigen, these antigen-specific adaptors can be used to bridge FITC-binding CAR T and tumor cells. PMID:27412488

  8. Connected Car: Quantified Self becomes Quantified Car

    OpenAIRE

    Melanie Swan

    2015-01-01

    The automotive industry could be facing a situation of profound change and opportunity in the coming decades. There are a number of influencing factors such as increasing urban and aging populations, self-driving cars, 3D parts printing, energy innovation, and new models of transportation service delivery (Zipcar, Uber). The connected car means that vehicles are now part of the connected world, continuously Internet-connected, generating and transmitting data, which on the one hand can be hel...

  9. CAR2 - Czech Database of Car Speech

    Directory of Open Access Journals (Sweden)

    P. Sovka

    1999-12-01

    Full Text Available This paper presents new Czech language two-channel (stereo speech database recorded in car environment. The created database was designed for experiments with speech enhancement for communication purposes and for the study and the design of a robust speech recognition systems. Tools for automated phoneme labelling based on Baum-Welch re-estimation were realised. The noise analysis of the car background environment was done.

  10. The influence of receptor-mediated interactions on reaction-diffusion mechanisms of cellular self-organisation.

    Science.gov (United States)

    Klika, Václav; Baker, Ruth E; Headon, Denis; Gaffney, Eamonn A

    2012-04-01

    Understanding the mechanisms governing and regulating self-organisation in the developing embryo is a key challenge that has puzzled and fascinated scientists for decades. Since its conception in 1952 the Turing model has been a paradigm for pattern formation, motivating numerous theoretical and experimental studies, though its verification at the molecular level in biological systems has remained elusive. In this work, we consider the influence of receptor-mediated dynamics within the framework of Turing models, showing how non-diffusing species impact the conditions for the emergence of self-organisation. We illustrate our results within the framework of hair follicle pre-patterning, showing how receptor interaction structures can be constrained by the requirement for patterning, without the need for detailed knowledge of the network dynamics. Finally, in the light of our results, we discuss the ability of such systems to pattern outside the classical limits of the Turing model, and the inherent dangers involved in model reduction. PMID:22072186

  11. Cellular uptake of saposin (SAP) precursor and lysosomal delivery by the low density lipoprotein receptor-related protein (LRP).

    OpenAIRE

    Hiesberger, T; Hüttler, S; Rohlmann, A; Schneider, W; Sandhoff, K.; Herz, J.

    1998-01-01

    Sphingolipid activator proteins SAP-A, -B, -C and -D (also called saposins) are generated by proteolytic processing from a 73 kDa precursor and function as obligatory activators of lysosomal enzymes involved in glycosphingolipid metabolism. Although the SAP precursor can be recognized by the mannose-6-phosphate (M-6-P) receptor and shuttled directly from the secretory pathway to the lysosome, a substantial fraction of newly synthesized precursor is secreted from the cell where it may particip...

  12. Effect of Chlamydia pneumoniae on Cellular ATP Content in Mouse Macrophages: Role of Toll-Like Receptor 2

    Science.gov (United States)

    Yaraei, Kambiz; Campbell, Lee Ann; Zhu, Xiaodong; Liles, W. Conrad; Kuo, Cho-chou; Rosenfeld, Michael E.

    2005-01-01

    Chlamydiae are obligate intracellular gram-negative bacteria and are dependent on the host cell for ATP. Thus, chlamydial infection may alter the intracellular levels of ATP and affect all energy-dependent processes within the cell. We have shown that both live C. pneumoniae and inactivated C. pneumoniae induce markers of cell death prior to completion of the bacterial growth cycle. As depletion of ATP could account for the observed increase in cell death, the effects of C. pneumoniae on ATP concentrations within mouse macrophages were investigated. Live, heat-killed, and UV-inactivated C. pneumoniae cultures (at multiplicities of infection [MOIs] of 0.01, 0.1, and 1.0) were incubated with mouse bone marrow macrophages isolated from C57BL/6J mice and mice deficient in Toll-like receptors. Treatment of the macrophages with both live and inactivated C. pneumoniae increased the ATP content of the cells. In cells infected with live C. pneumoniae, the increase was inversely proportional to the MOI. In cells treated with inactivated C. pneumoniae, the increase in ATP content was smaller than that induced by infection with live organisms and was proportional to the MOI. The increase in ATP content early in the developmental cycle was independent of the growth of C. pneumoniae, while sustained induction required live organisms. The capacity of C. pneumoniae to increase the ATP content was ablated in macrophages deficient in expression of either Toll-like receptor 2 or the Toll-like receptor accessory protein MyD88. In contrast, no effect was observed in macrophages lacking expression of Toll-like receptor 4. PMID:15972526

  13. The bradykinin B2 receptor induces multiple cellular responses leading to the proliferation of human renal carcinoma cell lines

    International Nuclear Information System (INIS)

    The vasoactive peptide bradykinin (BK) acts as a potent growth factor for normal kidney cells, but there have been few studies on the role of BK in renal cell carcinomas. In this study, we tested the hypothesis that BK also acts as a mitogen in kidney carcinomas, and explored the effects of BK in human renal carcinoma A498 cells. The presence of mRNAs for BK B1 and BK B2 receptors in A498 cells was demonstrated by reverse transcription–polymerase chain reaction. To study BK signaling pathways, we employed fluorescent measurements of intracellular Ca2+, measured changes in extracellular pH as a reflection of Na+/H+ exchange (NHE) with a Cytosensor microphysiometer, and assessed extracellular signal-regulated kinase (ERK) activation by Western blotting. Exposure to 100 nM of BK resulted in the rapid elevation of intracellular Ca2+, caused a ≥30% increase in NHE activity, and a ≥300% increase in ERK phosphorylation. All BK signals were blocked by HOE140, a BK B2 receptor antagonist, but not by a B1 receptor antagonist. Inhibitor studies suggest that BK-induced ERK activation requires phospholipase C and protein kinase C activities, and is Ca2+/calmodulin-dependent. The amiloride analog 5-(N-methyl-N-isobutyl)-amiloride (MIA) blocked short-term NHE activation and inhibited ERK phosphorylation, suggesting that NHE is critical for ERK activation by BK. BK induced an approximately 40% increase in the proliferation of A498 cells as assessed by bromodeoxyuridine uptake. This effect was blocked by the ERK inhibitor PD98059, and was dependent on NHE activity. We conclude that BK exerts mitogenic effects in A498 cells via the BK B2 receptor activation of growth-associated NHE and ERK

  14. Sodium-Dependent myo-Inositol Transporter 1 Is a Cellular Receptor for Mus cervicolor M813 Murine Leukemia Virus

    OpenAIRE

    Hein, Sibyll; Prassolov, Vladimir; Zhang, Yuanming; Ivanov, Dmitry; Löhler, Jürgen; Susan R Ross; Stocking, Carol

    2003-01-01

    Retrovirus infection is initiated by binding of the surface (SU) portion of the viral envelope glycoprotein (Env) to specific receptors on cells. This binding triggers conformational changes in the transmembrane portion of Env, leading to membrane fusion and cell entry, and is thus a major determinant of retrovirus tissue and species tropism. The M813 murine leukemia virus (MuLV) is a highly fusogenic gammaretrovirus, isolated from Mus cervicolor, whose host range is limited to mouse cells. T...

  15. Free-fatty acid receptor-4 (GPR120): Cellular and molecular function and its role in metabolic disorders.

    Science.gov (United States)

    Moniri, Nader H

    2016-06-15

    Over the last decade, a subfamily of G protein-coupled receptors that are agonized by endogenous and dietary free-fatty acids (FFA) has been discovered. These free-fatty acid receptors include FFA2 and FFA3, which are agonized by short-chained FFA, as well as FFA1 and FFA4, which are agonized by medium-to-long chained FFA. Ligands for FFA1 and FFA4 comprise the family of long chain polyunsaturated omega-3 fatty acids including α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), suggesting that many of the long-known beneficial effects of these fats may be receptor mediated. In this regard, FFA4 has gathered considerable interest due to its role in ameliorating inflammation, promoting insulin sensitization, and regulating energy metabolism in response to FFA ligands. The goal of this review is to summarize the body of evidence in regard to FFA4 signal transduction, its mechanisms of regulation, and its functional role in a variety of tissues. In addition, recent endeavors toward discovery of small molecules that modulate FFA4 activity are also presented. PMID:26827942

  16. Helix 11 Dynamics is Critical for Constitutive Androstane Receptor Activity

    OpenAIRE

    Wright, Edward; Busby, Scott A.; Wisecarver, Sarah; Vincent, Jeremy; Griffin, Patrick R.; Fernandez, Elias J.

    2011-01-01

    The constitutive androstane receptor (CAR) transactivation can occur in the absence of exogenous ligand and this activity is enhanced by agonists TCPOBOP and meclizine. We use biophysical and cell-based assays to show that increased activity of CAR(TCPOBOP) relative to CAR(meclizine) corresponds to a higher affinity of CAR(TCPOBOP) for the steroid receptor coactivator-1. Additionally, steady-state fluorescence spectra suggest conformational differences between CAR(TCPOBOP):RXR and CAR(meclizi...

  17. The bradykinin B2 receptor induces multiple cellular responses leading to the proliferation of human renal carcinoma cell lines

    Directory of Open Access Journals (Sweden)

    Kramarenko II

    2012-07-01

    Full Text Available Inga I Kramarenko1, Thomas A Morinelli1,2, Marlene A Bunni1,2, John R Raymond Sr3, Maria N Garnovskaya11Department of Medicine (Nephrology Division, Medical University of South Carolina, Charleston, SC, USA; 2Medical and Research Services of the Ralph H Johnson Veterans Affairs Medical Center, Charleston, SC, USA; 3Medical College of Wisconsin, Milwaukee, WI, USABackground: The vasoactive peptide bradykinin (BK acts as a potent growth factor for normal kidney cells, but there have been few studies on the role of BK in renal cell carcinomas.Purpose: In this study, we tested the hypothesis that BK also acts as a mitogen in kidney carcinomas, and explored the effects of BK in human renal carcinoma A498 cells.Methods: The presence of mRNAs for BK B1 and BK B2 receptors in A498 cells was demonstrated by reverse transcription–polymerase chain reaction. To study BK signaling pathways, we employed fluorescent measurements of intracellular Ca2+, measured changes in extracellular pH as a reflection of Na+/H+ exchange (NHE with a Cytosensor microphysiometer, and assessed extracellular signal-regulated kinase (ERK activation by Western blotting.Results: Exposure to 100 nM of BK resulted in the rapid elevation of intracellular Ca2+, caused a ≥30% increase in NHE activity, and a ≥300% increase in ERK phosphorylation. All BK signals were blocked by HOE140, a BK B2 receptor antagonist, but not by a B1 receptor antagonist. Inhibitor studies suggest that BK-induced ERK activation requires phospholipase C and protein kinase C activities, and is Ca2+/calmodulin-dependent. The amiloride analog 5-(N-methyl-N-isobutyl-amiloride (MIA blocked short-term NHE activation and inhibited ERK phosphorylation, suggesting that NHE is critical for ERK activation by BK. BK induced an approximately 40% increase in the proliferation of A498 cells as assessed by bromodeoxyuridine uptake. This effect was blocked by the ERK inhibitor PD98059, and was dependent on NHE activity

  18. Costimulation Engages the Gear in Driving CARs.

    Science.gov (United States)

    Abken, Hinrich

    2016-02-16

    In this issue of Immunity,Kawalekar et al. (2016) find that costimulation by a chimeric antigen receptor (CAR) can control T cell metabolism and balance the response toward long-lived memory or short-lived effector cells. The results provide a rationale of how to tune cancer immunotherapy more effectively in a hostile tumor environment. PMID:26885852

  19. CD19 CAR-targeted T cells induce long-term remission and B Cell Aplasia in an immunocompetent mouse model of B cell acute lymphoblastic leukemia.

    Directory of Open Access Journals (Sweden)

    Marco L Davila

    Full Text Available Although many adults with B cell acute lymphoblastic leukemia (B-ALL are induced into remission, most will relapse, underscoring the dire need for novel therapies for this disease. We developed murine CD19-specific chimeric antigen receptors (CARs and an immunocompetent mouse model of B-ALL that recapitulates the disease at genetic, cellular, and pathologic levels. Mouse T cells transduced with an all-murine CD3ζ/CD28-based CAR that is equivalent to the one being used in our clinical trials, eradicate B-ALL in mice and mediate long-term B cell aplasias. In this model, we find that increasing conditioning chemotherapy increases tumor eradication, B cell aplasia, and CAR-modified T cell persistence. Quantification of recipient B lineage cells allowed us to estimate an in vivo effector to endogenous target ratio for B cell aplasia maintenance. In mice exhibiting a dramatic B cell reduction we identified a small population of progenitor B cells in the bone marrow that may serve as a reservoir for long-term CAR-modified T cell stimulation. Lastly, we determine that infusion of CD8+ CAR-modified T cells alone is sufficient to maintain long-term B cell eradication. The mouse model we report here should prove valuable for investigating CAR-based and other therapies for adult B-ALL.

  20. The Ability of Thyroid Hormone Receptors to Sense T4 as an Agonist Depends on Receptor Isoform and on Cellular Cofactors

    OpenAIRE

    Schroeder, Amy; Jimenez, Robyn; Young, Briana; Privalsky, Martin L.

    2014-01-01

    T4 (3,5,3′,5′-tetraiodo-l-thyronine) is classically viewed as a prohormone that must be converted to the T3 (3,5,3′-triiodo-l-thyronine) form for biological activity. We first determined that the ability of reporter genes to respond to T4 and to T3 differed for the different thyroid hormone receptor (TR) isoforms, with TRα1 generally more responsive to T4 than was TRβ1. The response to T4 vs T3 also differed dramatically in different cell types in a manner that could not be attributed to diff...

  1. EDA-containing cellular fibronectin induces fibroblast differentiation through binding to alpha4beta7 integrin receptor and MAPK/Erk 1/2-dependent signaling.

    Science.gov (United States)

    Kohan, Martin; Muro, Andres F; White, Eric S; Berkman, Neville

    2010-11-01

    Fibroblast differentiation is an essential step during wound healing and fibrosis. Fibronectin (FN) is a major component of the extracellular matrix and occurs in two main forms: plasma and cellular FN. The latter includes the alternatively spliced domain A (EDA). Although EDA-containing cellular fibronectin (EDA-FN) is associated with fibroblast differentiation, how EDA-FN promotes differentiation is incompletely understood. In this study, we investigate the mechanism by which EDA-FN contributes to fibroblast differentiation with emphasis on the characterization of the EDA-FN receptor. We show that EDA-FN increases α-SMA expression (immunofluorescence), collagen deposition, cell contractility, and focal adhesion kinase (FAK) activation (immunoblotting); whereas plasma FN, a form lacking EDA, shows no effect. Primary lung fibroblasts constitutively express α(4)β(7) integrin receptor (FACS and RT-PCR). Blocking of α(4)β(7) reduces fibroblast adhesion to EDA-FN and inhibits α-SMA expression, collagen deposition, and FAK activation induced by EDA-FN. Using recombinant EDA-containing peptides, we demonstrate that the EDA segment is sufficient to induce fibroblast differentiation via binding to α(4)β(7). EDA-FN induces MAPK-Erk1/2 activation and inhibition of MEK1/2 attenuates EDA-FN-induced α-SMA expression. Our findings demonstrate that EDA-FN induces fibroblast differentiation by a mechanism that involves binding of EDA to α(4)β(7) integrin followed by activation of FAK and MAPK-associated signaling pathways. PMID:20643910

  2. Endocrine Disrupters in Human Blood and Breast Milk: Extraction Methodologies, Cellular Uptake and Effect on Key Nuclear Receptor Functions

    DEFF Research Database (Denmark)

    Hjelmborg, Philip Sebastian

    2010-01-01

    ) was incubated in parallel with the DDT-LDL mixture. RAP is a 40-kDa protein that blocks the lipoprotein receptors. Paper II. Extraction of EDCs from serum was achieved using solid phase extraction (SPE) together with high performance liquid chromatography (HPLC) that utilises that the retention of EDCs are less...... the level of endocrine disrupting activity in the sample. Paper IV. Breast milk was extracted using SPE and these extracts were further processed using polyethylene membranes in a dialytic setup (MDE extraction). The purpose of the dialysis was to reduce the content of lipids in the raw SPE extracts because...

  3. Breaking car use habits

    DEFF Research Database (Denmark)

    Thøgersen, John; Møller, Berit Thorup

    2008-01-01

    Based on calls for innovative ways of reducing car traffic and research indicating that car driving is often the result of habitual decision-making and choice processes, this paper reports on a field experiment designed to test a tool aimed to entice drivers to skip the habitual choice of the car...... and consider using-or at least trying-public transport instead. About 1,000 car drivers participated in the experiment either as experimental subjects, receiving a free one-month travelcard, or as control subjects. As predicted, the intervention had a significant impact on drivers' use of public transport...... and it also neutralized the impact of car driving habits on mode choice. However, in the longer run (i.e., four months after the experiment) experimental subjects did not use public transport more than control subjects. Hence, it seems that although many car drivers choose travel mode habitually, their final...

  4. Electric Car Special

    Energy Technology Data Exchange (ETDEWEB)

    Zoethout, T.; Belin, H.; Verwijs, H.; Nicola, S.; De Saint Jacob, Y.; Gatermann, R.

    2009-09-15

    In six articles, two columns and two interviews a part of this issue is dedicated to electric car developments: about winners and losers in the electric car race; a unique business model to rolling out the electric car by the electric battery company Better Place and the automobile industry Renault Nissan; interview with entrepreneur Shai Agassi of the Indian company Better Place; the development of electric cars in Germany; interview with Jean-Jacques Chanaron, an economist specialising in innovation management and a firm believer in electric cars; start of mass production of electric vehicles at the Japanese Nissan automobile industry; the constraints in Sweden in developing fuel-efficient automobiles; plans for 1 million electric or hybrid cars by 2025 in the Netherlands.

  5. Fc Gamma Receptor 3B (FCGR3Bc.233C>A-rs5030738) Polymorphism Modifies the Protective Effect of Malaria Specific Antibodies in Ghanaian Children

    DEFF Research Database (Denmark)

    Adu, Bright; Jepsen, Micha Phill Grønholm; Gerds, Thomas A;

    2014-01-01

    Immunoglobulin G (IgG) cross-linking with Fc gamma receptor IIIB (FcγRIIIB) triggers neutrophil degranulation, releasing reactive oxygen species with high levels associated with protection against malaria. The FCGR3B-c.233C>A polymorphism thought to influence the interaction between IgG and FcγRI....../AC individuals compared with 233CC children. This genotype related effect modification may significantly influence malaria sero-epidemiological and vaccine trial studies....

  6. Phorbol ester promotes a sustained down-regulation of endothelin receptors and cellular responses to endothelin in human vascular smooth muscle cells.

    Science.gov (United States)

    Resink, T J; Scott-Burden, T; Weber, E; Bühler, F R

    1990-02-14

    The effect of phorbol ester pretreatment of human vascular smooth muscle cells (hVSMC) was studied with respect to regulation of endothelin (ET)-receptor binding and cellular responses to ET. The capacity of hVSMC to bind ET was decreased (by approximately 50% at maximum) after phorbol exposure, and this reductive effect was both rapid (t 1/2 approximately 10 min.) and sustained (for up to 24 hrs. of chronic phorbol exposure). Phorbol pretreatment inhibited both inositol phosphate and diacylclycerol production responses of hVSMC to ET in a manner that was time-dependent and sustained. Phorbol pretreatment also produced a persistent reduction in the ability of ET to release isotopically-labelled arachidonic and/or its metabolites from hVSMC, but importantly ionomycin-stimulated release was similarly negatively affected. Furthermore, ET-induced accumulation of the phospholipase A2/phospholipase B-derived inositol phospholipid metabolite, glycerophosphoinositol, was not different between control and phorbol-treated hVMSC. The mechanism whereby phorbol exerts differential, but notably sustained inhibitory effects on ET-promoted signal transduction pathways are thus complex and illustrative of the selectivity of protein kinase C in regulating cellular responses. PMID:2154974

  7. Microfluidic CARS cytometry

    OpenAIRE

    Wang, Han-Wei; Bao, Ning; Le, Thuc T.; Lu, Chang; Cheng, Ji-Xin

    2008-01-01

    Coherent anti-stokes Raman scattering (CARS) flow cytometry was demonstrated by combining a laser-scanning CARS microscope with a polydimethylsiloxane (PDMS) based microfluidic device. Line-scanning across the hydrodynamically focused core stream was performed for detection of flowing objects. Parameters were optimized by utilizing polystyrene beads as flowing particles. Population measurements of adipocytes isolated from mouse fat tissues demonstrated the viability of microfluidic CARS cytom...

  8. Buying a New Car?

    Institute of Scientific and Technical Information of China (English)

    Paul; Maghielse

    2000-01-01

    You read it here first, folks: a car buying processthat first counsels its readers not to buy a car! Why?Because, no matter what mystical incantations a carsalesperson may whisper in your ear, cars are notinvestments. Certainly, there are a few exceptions to that rule,but in general. vehicles are what the accountantsamong us call depreciating assets. Think of a vehiclepurchase in comparison with the other big-ticketpurchases we make during our lifetimes. Buying a

  9. The insulin receptor with phenylalanine replacing tyrosine-1146 provides evidence for separate signals regulating cellular metabolism and growth

    International Nuclear Information System (INIS)

    The authors have studied the function of a mutant insulin receptor (IR) molecule in which Try-1146, one of the first autophosphorylation sites in the β subunit, was replaced with phenylalanine (IRF1146). Autophosphorylation of the partially purified IRF1146 was reduced 60-70% when compared to the wild-type IR but was still stimulated by insulin. The phosphotransferase activity of the dephospho form of both the IR and IRF1146 toward exogenous substrates was stimulated 3- to 4-fold by insulin. However, the wild-type IR was activated 12-fold by autophosphorylation, whereas the IRF1146 was activated only 2-fold. When the IRF1146 was expressed in Chinese hamster ovary (CHO) cells, [125I]-insulin binding was normal, whereas autophosphorylation was reduced 80% when compared to cells expressing the wild-type IR. Endogeneous substrates of the insulin receptor kinase were not detected during insulin stimulation of CHO cells expressing the IRF1146. These data suggest that activation of the IR tyrosine kinase can be resolved into two components: the first is dependent on insulin binding and the second is dependent on the subsequent insulin-stimulated autophosphorylation cascade. Thus, at least two signal transduction pathways diverging from the IR are implicated in the mechanism of insulin action

  10. Sodium-Dependent myo-Inositol Transporter 1 Is a Cellular Receptor for Mus cervicolor M813 Murine Leukemia Virus

    Science.gov (United States)

    Hein, Sibyll; Prassolov, Vladimir; Zhang, Yuanming; Ivanov, Dmitry; Löhler, Jürgen; Ross, Susan R.; Stocking, Carol

    2003-01-01

    Retrovirus infection is initiated by binding of the surface (SU) portion of the viral envelope glycoprotein (Env) to specific receptors on cells. This binding triggers conformational changes in the transmembrane portion of Env, leading to membrane fusion and cell entry, and is thus a major determinant of retrovirus tissue and species tropism. The M813 murine leukemia virus (MuLV) is a highly fusogenic gammaretrovirus, isolated from Mus cervicolor, whose host range is limited to mouse cells. To delineate the molecular mechanisms of its restricted host range and its high fusogenic potential, we initiated studies to characterize the cell surface protein that mediates M813 infection. Screening of the T31 mouse-hamster radiation hybrid panel for M813 infectivity localized the receptor gene to the distal end of mouse chromosome 16. Expression of one of the likely candidate genes (slc5a3) within this region in human cells conferred susceptibility to both M813 infection and M813-induced fusogenicity. slc5a3 encodes sodium myo-inositol transporter 1 (SMIT1), thus adding another sodium-dependent transporter to the growing list of proteins used by MuLVs for cell entry. Characterization of SMIT1 orthologues in different species identified several amino acid variations within two extracellular loops that may restrict susceptibility to M813 infection. PMID:12719585

  11. The Influence of Receptor-Mediated Interactions on Reaction-Diffusion Mechanisms of Cellular Self-organisation

    KAUST Repository

    Klika, Václav

    2011-11-10

    Understanding the mechanisms governing and regulating self-organisation in the developing embryo is a key challenge that has puzzled and fascinated scientists for decades. Since its conception in 1952 the Turing model has been a paradigm for pattern formation, motivating numerous theoretical and experimental studies, though its verification at the molecular level in biological systems has remained elusive. In this work, we consider the influence of receptor-mediated dynamics within the framework of Turing models, showing how non-diffusing species impact the conditions for the emergence of self-organisation. We illustrate our results within the framework of hair follicle pre-patterning, showing how receptor interaction structures can be constrained by the requirement for patterning, without the need for detailed knowledge of the network dynamics. Finally, in the light of our results, we discuss the ability of such systems to pattern outside the classical limits of the Turing model, and the inherent dangers involved in model reduction. © 2011 Society for Mathematical Biology.

  12. Car stickers for 2012

    CERN Document Server

    GS Department

    2011-01-01

    The 2012 car stickers are now available. Holders of blue car stickers will receive by internal mail their 2012 car stickers as of 5 December. Holders of red car stickers are kindly requested to come to the Registration Service (Building 55,1st floor) to renew their 2011 stickers. This service is open from Monday to Friday from 7.30 am to 5.30 pm non-stop. Documents related to the vehicles concerned are mandatory. Reception and Access Control Service – GS/IS/SIS General Infrastructure Services Department

  13. Car stickers for 2011

    CERN Document Server

    GS Department

    2010-01-01

    The 2011 car stickers are now available. Holders of blue car stickers will receive their 2011 car stickers by internal mail as of 15 December.   Holders of red car stickers are kindly requested to come to the Registration Service (Building 55,1st floor) to renew their 2011 stickers. This service is open from Monday to Friday from 7.30 am to 5.30 pm non-stop. Documents for the vehicles concerned must be presented. Reception and Access Control Service – GS/ISG/SIS General Infrastructure Services Department

  14. A Monosaccharide Residue Is Sufficient to Maintain Mouse and Human IgG Subclass Activity and Directs IgG Effector Functions to Cellular Fc Receptors

    Directory of Open Access Journals (Sweden)

    Daniela Kao

    2015-12-01

    Full Text Available Immunoglobulin G (IgG glycosylation modulates antibody activity and represents a major source of heterogeneity within antibody preparations. Depending on their glycosylation pattern, individual IgG glycovariants present in recombinant antibody preparations may trigger effects ranging from enhanced pro-inflammatory activity to increased anti-inflammatory activity. In contrast, reduction of IgG glycosylation beyond the central mannose core is generally believed to result in impaired IgG activity. However, this study reveals that a mono- or disaccharide structure consisting of one N-acetylglucosamine with or without a branching fucose residue is sufficient to retain the activity of the most active human and mouse IgG subclasses in vivo and further directs antibody activity to cellular Fcγ receptors. Notably, the activity of minimally glycosylated antibodies is not predicted by in vitro assays based on a monomeric antibody-Fcγ-receptor interaction analysis, whereas in vitro assay systems using immune complexes are more suitable to predict IgG activity in vivo.

  15. Cellular uptake of the antitumor agent Dp44mT occurs via a carrier/receptor-mediated mechanism.

    Science.gov (United States)

    Merlot, Angelica M; Pantarat, Namfon; Menezes, Sharleen V; Sahni, Sumit; Richardson, Des R; Kalinowski, Danuta S

    2013-12-01

    The chelator di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT) shows potent and selective anticancer and antimetastatic activity. However, the mechanism by which it is initially transported into cells to induce cytotoxicity is unknown. Hence, the current investigation examined the cellular uptake of ¹⁴C-Dp44mT relative to two structurally related ligands, namely the aroylhydrazone ¹⁴C-pyridoxal isonicotinoyl hydrazone (¹⁴C-PIH) and the thiosemicarbazone (¹⁴C-2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (¹⁴C-Bp4eT). In marked contrast to the cellular uptake of ¹⁴C-PIH and ¹⁴C-Bp4eT, which were linear as a function of concentration, ¹⁴C-Dp44mT uptake was saturable using SK-N-MC neuroepithelioma cells (Bmax, 4.28 × 10⁷ molecules of chelator/cell; and Kd, 2.45 μM). Together with the fact that ¹⁴C-Dp44mT uptake was temperature-dependent and significantly (P complex [Fe(¹⁴C-Dp44mT)₂] was not saturable as a function of concentration and was much greater than the ligand alone, indicating an alternate mode of transport. Studies examining the tissue distribution of ¹⁴C-Dp44mT injected intravenously into a mouse tumor model demonstrated the ¹⁴C label was primarily identified in the excretory system. Collectively, these findings examining the mechanism of Dp44mT uptake and its distribution and excretion have clinical implications for its bioavailability and uptake in vivo. PMID:24085840

  16. Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells.

    Science.gov (United States)

    Frigault, Matthew J; Lee, Jihyun; Basil, Maria Ciocca; Carpenito, Carmine; Motohashi, Shinichiro; Scholler, John; Kawalekar, Omkar U; Guedan, Sonia; McGettigan, Shannon E; Posey, Avery D; Ang, Sonny; Cooper, Laurence J N; Platt, Jesse M; Johnson, F Brad; Paulos, Chrystal M; Zhao, Yangbing; Kalos, Michael; Milone, Michael C; June, Carl H

    2015-04-01

    This study compared second-generation chimeric antigen receptors (CAR) encoding signaling domains composed of CD28, ICOS, and 4-1BB (TNFRSF9). Here, we report that certain CARs endow T cells with the ability to undergo long-term autonomous proliferation. Transduction of primary human T cells with lentiviral vectors encoding some of the CARs resulted in sustained proliferation for up to 3 months following a single stimulation through the T-cell receptor (TCR). Sustained numeric expansion was independent of cognate antigen and did not require the addition of exogenous cytokines or feeder cells after a single stimulation of the TCR and CD28. Results from gene array and functional assays linked sustained cytokine secretion and expression of T-bet (TBX21), EOMES, and GATA-3 to the effect. Sustained expression of the endogenous IL2 locus has not been reported in primary T cells. Sustained proliferation was dependent on CAR structure and high expression, the latter of which was necessary but not sufficient. The mechanism involves constitutive signaling through NF-κB, AKT, ERK, and NFAT. The propagated CAR T cells retained a diverse TCR repertoire, and cellular transformation was not observed. The CARs with a constitutive growth phenotype displayed inferior antitumor effects and engraftment in vivo. Therefore, the design of CARs that have a nonconstitutive growth phenotype may be a strategy to improve efficacy and engraftment of CAR T cells. The identification of CARs that confer constitutive or nonconstitutive growth patterns may explain observations that CAR T cells have differential survival patterns in clinical trials. PMID:25600436

  17. Epidermal Growth Factor Receptor mediated cellular and subcellular targeted delivery of Iron oxide core-Titanium dioxide shell nanoparticles

    Science.gov (United States)

    Yuan, Ye

    TiO2 nanomaterials can carry a multitude of therapeutic and diagnostic agents and the semiconductor properties of TiO2 allow for the production of cytotoxic reactive oxygen species following photoactivation. However, the delivery of these nanomaterials to specific cancer cells and specific subcellular organelles within these cells can have a substantial impact on the efficacy and safety of TiO2 nanoparticle therapeutics. Targeting cell surface receptors that are overexpressed by cancer cells is one strategy to improve the specificity of nanoparticle delivery. Therefore we decided to target the Epidermal Growth Factor Receptor (EGFR) because ligand- binding induces rapid receptor endocytosis and ligand-bound EGFR can translocate to the nucleus of cancer cells. To create NPs that can bind EGFR, we identified a peptide derived from the B-loop of Epidermal Growth Factor (EGF) that has been shown to bind and activate EGFR and conjugated it to the surface of Fe3O4 core-TiO2 shell NPs to produce B-loop NCs. We then devised a pulldown assay to show that B-loop NCs, but not bare NPs or NCs carrying a scrambled B-loop peptide, can bind and extract EGFR from HeLa cell protein extracts. Interestingly, B-loop NCs can also pulldown importin-beta, a protein that can transport EGFR to the nucleus. Furthermore, we used flow cytometry and fluorescently labeled NPs to show that B-loop peptides can significantly improve the internalization of NPs by EGFR-expressing HeLa cells. We determined that B-loop NCs can bind EGFR on the membrane of HeLa cells and that these NCs can be transported to the nucleus, by using a combination of confocal microscopy and X-ray Fluorescence Microscopy (XFM) to indirectly and directly track the subcellular distribution of NCs. Finally, we demonstrate how the Bionanoprobe, a novel high-resolution XFM apparatus that can scan whole-mounted, frozen-hydrated cells at multiple angles can be used to verify the subcellular distribution of B-loop NCs.

  18. Comparative genomic analysis of buffalo (Bubalus bubalis NOD1 and NOD2 receptors and their functional role in in-vitro cellular immune response.

    Directory of Open Access Journals (Sweden)

    Biswajit Brahma

    Full Text Available Nucleotide binding and oligomerization domain (NOD-like receptors (NLRs are innate immune receptors that recognize bacterial cell wall components and initiate host immune response. Structure and function of NLRs have been well studied in human and mice, but little information exists on genetic composition and role of these receptors in innate immune system of water buffalo--a species known for its exceptional disease resistance. Here, a comparative study on the functional domains of NOD1 and NOD2 was performed across different species. The NOD mediated in-vitro cellular responses were studied in buffalo peripheral blood mononuclear cells, resident macrophages, mammary epithelial, and fibroblast cells. Buffalo NOD1 (buNOD1 and buNOD2 showed conserved domain architectures as found in other mammals. The domains of buNOD1 and buNOD2 showed analogy in secondary and tertiary conformations. Constitutive expressions of NODs were ubiquitous in different tissues. Following treatment with NOD agonists, peripheral lymphocytes showed an IFN-γ response along-with production of pro-inflammatory cytokines. Alveolar macrophages and mammary epithelial cells showed NOD mediated in-vitro immune response through NF-κB dependent pathway. Fibroblasts showed pro-inflammatory cytokine response following agonist treatment. Our study demonstrates that both immune and non-immune cells could generate NOD-mediated responses to pathogens though the type and magnitude of response depend on the cell types. The structural basis of ligand recognition by buffalo NODs and knowledge of immune response by different cell types could be useful for development of non-infective innate immune modulators and next generation anti-inflammatory compounds.

  19. Cellular distribution of 111In-LDTPA galactose BSA in normal and asialoglycoprotein receptor-deficient mouse liver

    International Nuclear Information System (INIS)

    111In-LDTPA galactose BSA (bovine serum albumin) was used to evaluate the asialoglycoprotein receptor (ASGPR) system in both normal and ASGPR-deficient mice. The radiolabeled glycoprotein had complete liver uptake in both normal and ASGPR-deficient mice. Metabolism and hepatic cell-type distribution studies were performed. The normal mouse excreted greater than 60% of the hepatic activity, while the ASGPR-deficient mouse excreted less than 40% of the hepatic activity. 111In-LDTPA galactose BSA was metabolized to 111In-LDTPA-L-lysine in both mouse types. Normal mice showed 70% of the radioactivity in the hepatocyte, whereas the homozygous ASGPR-deficient mouse had equal activity in the hepatocyte and the hepatic endothelial cell

  20. Detailed Study of the Interaction between Human Herpesvirus 6B Glycoprotein Complex and Its Cellular Receptor, Human CD134

    OpenAIRE

    Tang, Huamin; Wang, Junjie; Mahmoud, Nora F.; Mori, Yasuko

    2014-01-01

    Recently, we identified a novel receptor, CD134, which interacts with the human herpesvirus 6B (HHV-6B) glycoprotein (g)H/gL/gQ1/gQ2 complex and plays a key role in the entry of HHV-6B into target cells. However, details of the interaction between the HHV-6B gH/gL/gQ1/gQ2 complex and CD134 were unknown. In this study, we identified a cysteine-rich domain (CRD), CDR2, of CD134 that is critical for binding to the HHV-6B glycoprotein complex and HHV-6B infection. Furthermore, we found that the e...

  1. Prostaglandin A2 enhances cellular insulin sensitivity via a mechanism that involves the orphan nuclear receptor NR4A3.

    Science.gov (United States)

    Zhu, X; Walton, R G; Tian, L; Luo, N; Ho, S-R; Fu, Y; Garvey, W T

    2013-03-01

    We have previously reported that members of the NR4A family of orphan nuclear receptors can augment insulin's ability to stimulate glucose transport in adipocytes. In the current study, we endeavored to test for an insulin-sensitizing effect in muscle cells and to identify a potential transactivator. Lentiviral constructs were used to engineer both hyperexpression and shRNA silencing of NR4A3 in C2C12 myocytes. The NR4A3 hyper-expression construct led to a significant increase in glucose transport rates in the presence of maximal insulin while the NR4A3 knock-down exhibited a significant reduction in insulin-stimulated glucose transport rates. Consistently, insulin-mediated AKT phosphorylation was increased by NR4A3 hyperexpression and decreased following shRNA NR4A3 suppression. Then, we examined effects of prostaglandin A2 (PGA2) on insulin action and NR4A3 transactivation. PGA2 augmented insulin-stimulated glucose uptake in C2C12 myocytes and AKT phosphorylation after 12-h treatment, without significant effects on basal transport or basal AKT phosphorylation. More importantly, we demonstrated that PGA2 led to a greater improvement in insulin-stimulated glucose rates in NR4A3 overexpressing C2C12 myocytes, when compared with Lac-Z controls stimulated with insulin and PGA2. Moreover, the sensitizing effect of PGA2 was significantly diminished in NR4A3 knockdown myocytes compared to scramble controls. These results show for the first time that: (i) PGA2 augments insulin action in myocytes as manifested by enhanced stimulation of glucose transport and AKT phosphorylation; and (ii) the insulin sensitizing effect is dependent upon the orphan nuclear receptor NR4A3. PMID:23104421

  2. Treatment of metastatic renal cell carcinoma (mRCC) with CAIX CAR-engineered T-cells-a completed study overview.

    Science.gov (United States)

    Lamers, Cor H J; Klaver, Yarne; Gratama, Jan W; Sleijfer, Stefan; Debets, Reno

    2016-06-15

    We studied safety and proof of concept of a phase I/II trial with chimeric antigen receptor (CAR) T-cells in patients with metastatic renal cell carcinoma (mRCC). The CAR was based on the G250 mAb that recognized an epitope of carboxy-anhydrase-IX (CAIX). Twelve patients with CAIX+ mRCC were treated in three cohorts with a maximum of 10 daily infusions of 2×10(7) to 2×10(9) CAR T-cells. Circulating CAR T-cells were transiently detectable in all patients and maintained antigen-specific immune functions following their isolation post-treatment. Blood cytokine profiles mirrored CAR T-cell presence and in vivo activity. Unfortunately, patients developed anti-CAR T-cell antibodies and cellular immune responses. Moreover, CAR T-cell infusions induced liver enzyme disturbances reaching CTC grades 2-4, which necessitated cessation of treatment in four out of eight patients (cohort 1+2). Examination of liver biopsies revealed T-cell infiltration around bile ducts and CAIX expression on bile duct epithelium, adding to the notion of on-target toxicity. No such toxicities were observed in four patients that were pretreated with G250 mAb (cohort 3). The study was stopped due to the advent of competing treatments before reaching therapeutic or maximum tolerated dose in cohort 3. No clinical responses have been recorded. Despite that, from this trial numerous recommendations for future trials and their immune monitoring could be formulated, such as choice of the target antigen, format and immunogenicity of receptor and how the latter relates to peripheral T-cell persistence. PMID:27284065

  3. PXR- and CAR-mediated herbal effect on human diseases.

    Science.gov (United States)

    Xu, Chenshu; Huang, Min; Bi, Huichang

    2016-09-01

    The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are two members of the nuclear receptor superfamily that regulate a broad range of genes involved in drug metabolism and transport. A variety of naturally occurring compounds present in herbal medicines were identified as ligands of PXR and CAR. Recently, accumulative evidences have revealed the PXR- and CAR-mediated herbal effect against multiple human diseases, including inflammatory bowel disease (IBD), cholestatic liver disease, and jaundice. The current review summarized the recent progress in identifying the expanding libraries of herbal medicine as ligands for PXR and CAR. Moreover, the potential for herbal medicines as promising therapeutic agents which were mainly regulated through PXR/CAR signaling pathways was also discussed. The discovery of herbal medicines as modulators of PXR and CAR, and their PXR- and CAR-mediated effect on human diseases will provide a basis for rational drug design, and eventually be explored as a novel therapeutic approach against human diseases. This article is part of a Special Issue entitled: Xenobiotic nuclear receptors: New Tricks for An Old Dog, edited by Dr. Wen Xie. PMID:26906544

  4. The Electric Cars Challenge

    Science.gov (United States)

    Roman, Harry T.

    2011-01-01

    Over 100 years ago, the great inventor Thomas Edison warned that gasoline cars would pollute the environment and lead to gasoline shortages. He preferred the use of clean electric vehicles. He also put his money where his mouth was and developed an entirely new alkaline storage battery system for his beloved cars, the nickel-iron storage battery.…

  5. Calcium and adenosine triphosphate control of cellular pathology: asparaginase-induced pancreatitis elicited via protease-activated receptor 2.

    Science.gov (United States)

    Peng, Shuang; Gerasimenko, Julia V; Tsugorka, Tatiana; Gryshchenko, Oleksiy; Samarasinghe, Sujith; Petersen, Ole H; Gerasimenko, Oleg V

    2016-08-01

    Exocytotic secretion of digestive enzymes from pancreatic acinar cells is elicited by physiological cytosolic Ca(2+) signals, occurring as repetitive short-lasting spikes largely confined to the secretory granule region, that stimulate mitochondrial adenosine triphosphate (ATP) production. By contrast, sustained global cytosolic Ca(2+) elevations decrease ATP levels and cause necrosis, leading to the disease acute pancreatitis (AP). Toxic Ca(2+) signals can be evoked by products of alcohol and fatty acids as well as bile acids. Here, we have investigated the mechanism by which l-asparaginase evokes AP. Asparaginase is an essential element in the successful treatment of acute lymphoblastic leukaemia, the most common type of cancer affecting children, but AP is a side-effect occurring in about 5-10% of cases. Like other pancreatitis-inducing agents, asparaginase evoked intracellular Ca(2+) release followed by Ca(2+) entry and also substantially reduced Ca(2+) extrusion because of decreased intracellular ATP levels. The toxic Ca(2+) signals caused extensive necrosis. The asparaginase-induced pathology depended on protease-activated receptor 2 and its inhibition prevented the toxic Ca(2+) signals and necrosis. We tested the effects of inhibiting the Ca(2+) release-activated Ca(2+) entry by the Ca(2+) channel inhibitor GSK-7975A. This markedly reduced asparaginase-induced Ca(2+) entry and also protected effectively against the development of necrosis.This article is part of the themed issue 'Evolution brings Ca(2+) and ATP together to control life and death'. PMID:27377732

  6. Cellular uptake of PLGA nanoparticles targeted with anti-amyloid and anti-transferrin receptor antibodies for Alzheimer's disease treatment.

    Science.gov (United States)

    Loureiro, Joana A; Gomes, Bárbara; Fricker, Gert; Coelho, Manuel A N; Rocha, Sandra; Pereira, Maria Carmo

    2016-09-01

    During the last few decades, relevant efforts have been reported to design nanocarriers for drug transport through the blood brain barrier (BBB). New drugs, such as peptide iAβ5, capable to inhibit the aggregates associated with Alzheimeŕs disease (AD) are being tested but the most frequent drawback is to reach the brain in the desired concentrations due to the low BBB permeability-surface area. Our approach, as a proof of concept to improve drug transport through the BBB, is based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles with surface functionalized with anti-transferrin receptor monoclonal antibody (OX26) and anti-Aβ (DE2B4) to deliver encapsulated iAβ5 into the brain. Porcine brain capillary endothelial cells (PBCECs) were used as a BBB model to evaluate the system efficacy and toxicity. The uptake of immune nanoparticles with a controlled delivery of the peptide iAβ5 was substantially increased compared to the nanoparticles (NPs) without monoclonal antibody functionalization. PMID:27131092

  7. At-Line Cellular Screening Methodology for Bioactives in Mixtures Targeting the α7-Nicotinic Acetylcholine Receptor.

    Science.gov (United States)

    Otvos, Reka A; Mladic, Marija; Arias-Alpizar, Gabriela; Niessen, Wilfried M A; Somsen, Govert W; Smit, August B; Kool, Jeroen

    2016-06-01

    The α7-nicotinic acetylcholine receptor (α7-nAChR) is a ligand-gated ion channel expressed in different regions of the central nervous system (CNS). The α7-nAChR has been associated with Alzheimer's disease, epilepsy, and schizophrenia, and therefore is extensively studied as a drug target for the treatment of these diseases. Important sources for new compounds in drug discovery are natural extracts. Since natural extracts are complex mixtures, identification of the bioactives demands the use of analytical techniques to separate a bioactive from inactive compounds. This study describes screening methodology for identifying bioactive compounds in mixtures acting on the α7-nAChR. The methodology developed combines liquid chromatography (LC) coupled via a split with both an at-line calcium (Ca(2+))-flux assay and high-resolution mass spectrometry (MS). This allows evaluation of α7-nAChR responses after LC separation, while parallel MS enables compound identification. The methodology was optimized for analysis of agonists and positive allosteric modulators, and was successfully applied to screening of the hallucinogen mushroom Psilocybe Mckennaii The crude mushroom extract was analyzed using both reversed-phase and hydrophilic interaction liquid chromatography. Matching retention times and peak shapes of bioactives found with data from the parallel MS measurements allowed rapid pinpointing of accurate masses corresponding to the bioactives. PMID:26738519

  8. Cellular receptor for 125I-labeled tumor necrosis factor: specific binding, affinity labeling, and relationship to sensitivity

    International Nuclear Information System (INIS)

    Tumor necrosis factor (TNF) is a proteinaceous toxin shed by stimulated myeloid cells. Murine TNF was radioiodinated to a specific activity of 1 mCi/nmol (1 Ci = 37 GBq) of monomer. 125I-labeled TNF (125-TNF) retained complete cytotoxic activity and it was immunochemically identical to the native toxin in a quantitative immunoprecipitation assay. It could be shown by competition binding that 125I-TNF bound to intact L929 cells with a specificity equal to that of native toxin. The conditions of time, temperature, and concentration involved in equilibrium specific binding to intact cells were studied in detail. J774.1 cells, the source of the toxin, demonstrated similar binding but were not sensitive to 125I-TNF cytotoxicity. Normal lymphoid organ cell suspensions and two human tumorigenic cell lines were not sensitive and failed to demonstrate specific binding. 125I-TNF, covalently cross-linked to its receptor on sensitive L-M cells with disuccinimidyl suberate, was isolated and analyzed by sodium dodecyl sulfate/polyacrylamide gel electrophoresis and autoradiography. Two specific bands were identified. The presence of the binding site appears to be necessary but not sufficient to explain the sensitivity of cells to the cytotoxic action of TNF

  9. Regulation of humoral and cellular gut immunity by lamina propria dendritic cells expressing Toll-like receptor 5.

    Science.gov (United States)

    Uematsu, Satoshi; Fujimoto, Kosuke; Jang, Myoung Ho; Yang, Bo-Gie; Jung, Yun-Jae; Nishiyama, Mika; Sato, Shintaro; Tsujimura, Tohru; Yamamoto, Masafumi; Yokota, Yoshifumi; Kiyono, Hiroshi; Miyasaka, Masayuki; Ishii, Ken J; Akira, Shizuo

    2008-07-01

    The intestinal cell types responsible for defense against pathogenic organisms remain incompletely characterized. Here we identify a subset of CD11c(hi)CD11b(hi) lamina propria dendritic cells (LPDCs) that expressed Toll-like receptor 5 (TLR5) in the small intestine. When stimulated by the TLR5 ligand flagellin, TLR5(+) LPDCs induced the differentiation of naive B cells into immunoglobulin A-producing plasma cells by a mechanism independent of gut-associated lymphoid tissue. In addition, by a mechanism dependent on TLR5 stimulation, these LPDCs promoted the differentiation of antigen-specific interleukin 17-producing T helper cells and type 1 T helper cells. Unlike spleen DCs, the LPDCs specifically produced retinoic acid, which, in a dose-dependent way, supported the generation and retention of immunoglobulin A-producing cells in the lamina propria and positively regulated the differentiation interleukin 17-producing T helper cells. Our findings demonstrate unique properties of LPDCs and the importance of TLR5 for adaptive immunity in the intestine. PMID:18516037

  10. Calcium and adenosine triphosphate control of cellular pathology: asparaginase-induced pancreatitis elicited via protease-activated receptor 2

    Science.gov (United States)

    Peng, Shuang; Gerasimenko, Julia V.; Tsugorka, Tatiana; Gryshchenko, Oleksiy; Samarasinghe, Sujith; Gerasimenko, Oleg V.

    2016-01-01

    Exocytotic secretion of digestive enzymes from pancreatic acinar cells is elicited by physiological cytosolic Ca2+ signals, occurring as repetitive short-lasting spikes largely confined to the secretory granule region, that stimulate mitochondrial adenosine triphosphate (ATP) production. By contrast, sustained global cytosolic Ca2+ elevations decrease ATP levels and cause necrosis, leading to the disease acute pancreatitis (AP). Toxic Ca2+ signals can be evoked by products of alcohol and fatty acids as well as bile acids. Here, we have investigated the mechanism by which l-asparaginase evokes AP. Asparaginase is an essential element in the successful treatment of acute lymphoblastic leukaemia, the most common type of cancer affecting children, but AP is a side-effect occurring in about 5–10% of cases. Like other pancreatitis-inducing agents, asparaginase evoked intracellular Ca2+ release followed by Ca2+ entry and also substantially reduced Ca2+ extrusion because of decreased intracellular ATP levels. The toxic Ca2+ signals caused extensive necrosis. The asparaginase-induced pathology depended on protease-activated receptor 2 and its inhibition prevented the toxic Ca2+ signals and necrosis. We tested the effects of inhibiting the Ca2+ release-activated Ca2+ entry by the Ca2+ channel inhibitor GSK-7975A. This markedly reduced asparaginase-induced Ca2+ entry and also protected effectively against the development of necrosis. This article is part of the themed issue ‘Evolution brings Ca2+ and ATP together to control life and death’. PMID:27377732

  11. Expression and cellular distribution of transient receptor potential vanilloid 4 in cortical tubers of the tuberous sclerosis complex.

    Science.gov (United States)

    Chen, Xin; Yang, Meihua; Sun, Feiji; Liang, Chao; Wei, Yujia; Wang, Lukang; Yue, Jiong; Chen, Bing; Li, Song; Liu, Shiyong; Yang, Hui

    2016-04-01

    Cortical tubers in patients with tuberous sclerosis complex (TSC) are highly associated with intractable epilepsy. Recent evidence has shown that transient receptor potential vanilloid 4 (TRPV4) has direct effects on both neurons and glial cells. To understand the role of TRPV4 in pathogenesis of cortical tubers, we investigated the expression patterns of TRPV4 in cortical tubers of TSC compared with normal control cortex (CTX). We found that TRPV4 was clearly up-regulated in cortical tubers at the protein levels. Immunostaining indicated that TRPV4 was specially distributed in abnormal cells, including dysplastic neurons (DNs) and giant cells (GCs). In addition, double immunofluorescent staining revealed that TRPV4 was localized on neurofilament proteins (NF200) positive neurons and glial fibrillary acidic portein (GFAP) positive reactive astrocytes. Moreover, TRPV4 co-localized with both glutamatergic and GABAergic neurons. Furthermore, protein levels of protein kinase C (PKC), but not protein kinase A (PKA), the important upstream factors of the TRPV4, were significantly increased in cortical tubers. Taken together, the overexpression and distribution patterns of TRPV4 may be linked with the intractable epilepsy caused by TSC. PMID:26874068

  12. City Car = The City Car / Andres Sevtshuk

    Index Scriptorium Estoniae

    Sevtshuk, Andres, 1981-

    2008-01-01

    Massachusettsi Tehnoloogiainstituudi (MIT) meedialaboratooriumi juures tegutseva Targa Linna Grupi (Smart City Group) ja General Motorsi koostööna sündinud kaheistmelisest linnasõbralikust elektriautost City Car. Nimetatud töögrupi liikmed (juht William J. Mitchell, töögruppi kuulus A. Sevtshuk Eestist)

  13. Der Coxsackievirus- und Adenovirus-Rezeptor (CAR) in Umstrukturierungsprozessen des embryonalen und adulten Herzens

    OpenAIRE

    Freiberg, Fabian

    2013-01-01

    The Coxsackievirus- and Adenovirus-Receptor (CAR) is a multifunctional protein that localizes to the tight junctions of epithelial cells and to the intercalated discs between cardiomyocytes. Via its extracellular domain CAR mediates the binding and internalization of Coxsackie- and Adenoviruses as well as homophilic and heterophilic interactions with other cells. The cytoplasmic tail links CAR to intracellular signaling cascades and the cytoskeleton. CAR is highly expressed in the developing ...

  14. Chimeric antigen receptor T cell therapy: 25years in the making.

    Science.gov (United States)

    Gill, Saar; Maus, Marcela V; Porter, David L

    2016-05-01

    Chimeric antigen receptor (CAR) T cell therapy of cancer is generating enormous enthusiasm. Twenty-five years after the concept was first proposed, major advances in molecular biology, virology, and good manufacturing practices (GMP)-grade cell production have transformed antibody-T cell chimeras from a scientific curiosity to a fact of life for academic cellular immunotherapy researchers and, increasingly, for patients. In this review, we explain the preclinical concept, outline how it has been translated to the clinic, and draw lessons from the first years of CAR T cell therapy for the practicing clinician. PMID:26574053

  15. Restoration of the cellular secretory milieu overrides androgen dependence of in vivo generated castration resistant prostate cancer cells overexpressing the androgen receptor.

    Science.gov (United States)

    Patki, Mugdha; Huang, Yanfang; Ratnam, Manohar

    2016-07-22

    It is believed that growth of castration resistant prostate cancer (CRPC) cells is enabled by sensitization to minimal residual post-castrate androgen due to overexpression of the androgen receptor (AR). Evidence is derived from androgen-induced colony formation in the absence of cell-secreted factors or from studies involving forced AR overexpression in hormone-dependent cells. On the other hand, standard cell line models established from CRPC patient tumors (e.g., LNCaP and VCaP) are hormone-dependent and require selection pressure in castrated mice to re-emerge as CRPC cells and the resulting tumors then tend to be insensitive to the androgen antagonist enzalutamide. Therefore, we examined established CRPC model cells produced by castration of mice bearing hormone-dependent cell line xenografts including CRPC cells overexpressing full-length AR (C4-2) or co-expressing wtAR and splice-variant AR-V7 that is incapable of ligand binding (22Rv1). In standard colony formation assays, C4-2 cells were shown to be androgen-dependent and sensitive to enzalutamide whereas 22Rv1 cells were incapable of colony formation under identical conditions. However, both C4-2 and 22Rv1 cells formed colonies in conditioned media derived from the same cells or from HEK293 fibroblasts that were proven to lack androgenic activity. This effect was (i) not enhanced by androgen, (ii) insensitive to enzalutamide, (iii) dependent on AR (in C4-2) and on AR-V7 and wtAR (in 22Rv1) and (iv) sensitive to inhibitors of several signaling pathways, similar to androgen-stimulation. Therefore, during progression to CRPC in vivo, coordinate cellular changes accompanying overexpression of AR may enable cooperation between hormone-independent activity of AR and actions of cellular secretory factors to completely override androgen-dependence and sensitivity to drugs targeting hormonal factors. PMID:27179779

  16. Cellular Uptake and Cytotoxic Effect of Epidermal Growth Factor Receptor Targeted and Plitidepsin Loaded Co-Polymeric Polymersomes on Colorectal Cancer Cell Lines.

    Science.gov (United States)

    Goñi-de-Cerio, Felipe; Thevenot, Julie; Oliveira, Hugo; Pérez-Andrés, Encarnación; Berra, Edurne; Masa, Marc; Suárez-Merino, Blanca; Lecommandoux, Sébastien; Heredia, Pedro

    2015-11-01

    Encapsulating chemotherapy drugs in targeted nanodelivery systems is one of the most promising approaches to tackle cancer disease, avoiding side effects of common treatment. In the last decade, several nanocarriers with different nature have been tested, but polypeptide-based copolymers have attracted considerable attention for their biocompatibility, controlled and slow biodegradability as well as their low toxicity. In this work, we synthesized, characterized and evaluated poly(trimethylene carbonate)-bock-poly(L-glutamic acid) derived polymersomes, targeted to epidermal growth factor receptor (EGFR), loaded with plitidepsin and ultimately tested in HT29 and LS174T colorectal cancer cell lines for specificity and efficacy. Furthermore, morphology, physico-chemical properties and plitidepsin loading were carefully investigated. A thorough in vitro cytotoxicity analysis of the unloaded polymersomes was carried out for biocompatibility check, studying viability, cell membrane asymmetry and reactive oxygen species levels. Those cytotoxicity assays showed good biocompatibility for plitidepsin-unloaded polymersomes. Cellular uptake and cytotoxic effect of EGFR targeted and plitidepsin loaded polymersome indicated that colorectal cancer cell lines were.more sensitive to anti-EGFR-drug-loaded than untargeted drug-loaded polymersomes. Also, in both cell lines, the use of untargeted polymersomes greatly reduced plitidepsin cytotoxicity as well as the cellular uptake, indicating that the use of this targeted nanocarrier is a promising approach to tackle colorectal cancer disease and avoid the undesired effects of the usual treatment. Furthermore, in vivo assays support the in vitro conclusions that EGFR targeted polymersomes could be a good drug delivery system. This work provides a proof of concept for the use of encapsulated targeted drugs as future therapeutic treatments for cancer. PMID:26554161

  17. Characterization of transferrin receptor-mediated endocytosis and cellular iron delivery of recombinant human serum transferrin from rice (Oryza sativa L.

    Directory of Open Access Journals (Sweden)

    Zhang Deshui

    2012-11-01

    Full Text Available Abstract Background Transferrin (TF plays a critical physiological role in cellular iron delivery via the transferrin receptor (TFR-mediated endocytosis pathway in nearly all eukaryotic organisms. Human serum TF (hTF is extensively used as an iron-delivery vehicle in various mammalian cell cultures for production of therapeutic proteins, and is also being explored for use as a drug carrier to treat a number of diseases by employing its unique TFR-mediated endocytosis pathway. With the increasing concerns over the risk of transmission of infectious pathogenic agents of human plasma-derived TF, recombinant hTF is preferred to use for these applications. Here, we carry out comparative studies of the TFR binding, TFR-mediated endocytosis and cellular iron delivery of recombinant hTF from rice (rhTF, and evaluate its suitability for biopharmaceutical applications. Result Through a TFR competition binding affinity assay with HeLa human cervic carcinoma cells (CCL-2 and Caco-2 human colon carcinoma cells (HTB-37, we show that rhTF competes similarly as hTF to bind TFR, and both the TFR binding capacity and dissociation constant of rhTF are comparable to that of hTF. The endocytosis assay confirms that rhTF behaves similarly as hTF in the slow accumulation in enterocyte-like Caco-2 cells and the rapid recycling pathway in HeLa cells. The pulse-chase assay of rhTF in Caco-2 and HeLa cells further illustrates that rice-derived rhTF possesses the similar endocytosis and intracellular processing compared to hTF. The cell culture assays show that rhTF is functionally similar to hTF in the delivery of iron to two diverse mammalian cell lines, HL-60 human promyelocytic leukemia cells (CCL-240 and murine hybridoma cells derived from a Sp2/0-Ag14 myeloma fusion partner (HB-72, for supporting their proliferation, differentiation, and physiological function of antibody production. Conclusion The functional similarity between rice derived rhTF and native hTF in

  18. The Electric Car Challenge.

    Science.gov (United States)

    Diehl, Brian E.

    1997-01-01

    Describes the Electric Car Challenge during which students applied methods of construction to build lightweight, strong vehicles that were powered by electricity. The activity required problem solving, sheet metal work, electricity, design, and construction skills. (JOW)

  19. Car-use habits

    DEFF Research Database (Denmark)

    Møller, Berit Thorup; Thøgersen, John

    2008-01-01

    It is often claimed that many drivers use their private car rather habitually. The claim gains credibility from the fact that travelling to many everyday destinations fulfils all the prerequisites for habit formation: it is recurring, performed under stable circumstances and produces rewarding...... consequences. Since the decision is made quite automatically and only one choice alternative is considered (the habitually chosen one), behaviour guided by habit is difficult to change. The implications of car use habits for converting drivers to commuters using public transportation is analysed based on a...... do so, car use habit, and the interaction between the two, confirms the theory-derived hypothesis that car use habits act as an obstacle to the transformation of intentions to commute by public transportation into action....

  20. Cars submerged in water.

    OpenAIRE

    2010-01-01

    Crashes in which cars are submerged in deep water or in a ditch are often complicated and serious. Considering their severity and the fact that approximately half the fatalities in this crash type are not due to drowning but to injury, preventive measures are to be preferred above measures that have to assist the vehicle occupants to escape from a car submerged in water. An adequate road design, barrier constructions in road bends and shoulder surfacing, and education and information can redu...

  1. Composing for Cars

    OpenAIRE

    Parkinson, Adam; Tanaka, Atau

    2013-01-01

    The authors report on composing a piece for RoadMusic, an interactive music project which generates and manipulates music for the passengers and driver in a car, using sensor information gathered from the surroundings and from the movements of the car. We present a literature review which brings together related works in the diverse fields of Automotive UI, musical mappings, generative music and sonification. We then describe our strategies for composing for this novel system, and the uni...

  2. Competition and Car Longevity

    OpenAIRE

    Macauley, Molly; Hamilton, Bruce

    1998-01-01

    We examine determinants of the nearly 30 percent increase in the average age of domestically produced, registered automobiles since the mid-1960s. We find that very little of the increase in car longevity is attributable to improvements in the inherent durability of cars. Rather, we find that the temporal pattern of longevity improvement is highly correlated with the level of market concentration in the auto industry. In particular, we argue that the arrival of competition in the industry led...

  3. Engineering CAR-T Cells: Design Concepts

    Science.gov (United States)

    Srivastava, Shivani; Riddell, Stanley R.

    2016-01-01

    Despite being empirically designed based on a simple understanding of TCR signaling, T cells engineered with chimeric antigen receptors (CARs) have been remarkably successful in treating patients with advanced refractory B cell malignancies. However, many challenges remain in improving the safety and efficacy of this therapy and extending it toward the treatment of epithelial cancers. Other aspects TCR signaling beyond those directly provided by CD3ζ and CD28 phosphorylation strongly influence a T cell’s ability to differentiate and acquire full effector functions. Here, we discuss how the principles of TCR recognition, including spatial constraints, Kon/Koff rates, and synapse formation, along with in-depth analysis of CAR signaling might be applied to develop safer and more effective synthetic tumor targeting receptors. PMID:26169254

  4. A Zebrafish Coxsackievirus and Adenovirus Receptor Homologue Interacts with Coxsackie B Virus and Adenovirus

    OpenAIRE

    Petrella, JenniElizabeth; Cohen, Christopher J.; Gaetz, Jedidiah; Bergelson, Jeffrey M.

    2002-01-01

    In this study, a zebrafish homologue of the coxsackievirus and adenovirus receptor (CAR) protein was identified. Although the extracellular domain of zebrafish CAR (zCAR) is less than 50% identical to that of human CAR (hCAR), zCAR mediated infection of transfected cells by both adenovirus type 5 and coxsackievirus B3. CAR residues interacting deep within the coxsackievirus canyon are highly conserved in zCAR and hCAR, which is consistent with the idea that receptor contacts within the canyon...

  5. Dynamic imaging for CAR-T-cell therapy.

    Science.gov (United States)

    Emami-Shahri, Nia; Papa, Sophie

    2016-04-15

    Chimaeric antigen receptor (CAR) therapy is entering the mainstream for the treatment of CD19(+)cancers. As is does we learn more about resistance to therapy and the role, risks and management of toxicity. In solid tumour CAR therapy research the route to the clinic is less smooth with a wealth of challenges facing translating this, potentially hugely valuable, therapeutic option for patients. As we strive to understand our successes, and navigate the challenges, having a clear understanding of how adoptively transferred CAR-T-cells behavein vivoand in human trials is invaluable. Harnessing reporter gene imaging to enable detection and tracking of small numbers of CAR-T-cells after adoptive transfer is one way by which we can accomplish this. The compatibility of certain reporter gene systems with tracers available routinely in the clinic makes this approach highly useful for future appraisal of CAR-T-cell success in humans. PMID:27068944

  6. Targeting the molecular and cellular interactions of the bone marrow niche in immunologic disease.

    Science.gov (United States)

    Brozowski, Jaime M; Billard, Matthew J; Tarrant, Teresa K

    2014-02-01

    Recent investigations have expanded our knowledge of the regulatory bone marrow (BM) niche, which is critical in maintaining and directing hematopoietic stem cell (HSC) self-renewal and differentiation. Osteoblasts, mesenchymal stem cells (MSCs), and CXCL12-abundant reticular (CAR) cells are niche components in close association with HSCs and have been more clearly defined in immune cell function and homeostasis. Importantly, cellular inhabitants of the BM niche signal through G protein-coupled surface receptors (GPCRs) for various appropriate immune functions. In this article, recent literature on BM niche inhabitants (HSCs, osteoblasts, MSCs, CAR cells) and their GPCR mechanistic interactions are reviewed for better understanding of the BM cells involved in immune development, immunologic disease, and current immune reconstitution therapies. PMID:24408534

  7. A Mechanism to Enhance Cellular Responsivity to Hormone Action: Krüppel-Like Factor 9 Promotes Thyroid Hormone Receptor-β Autoinduction During Postembryonic Brain Development.

    Science.gov (United States)

    Hu, Fang; Knoedler, Joseph R; Denver, Robert J

    2016-04-01

    Thyroid hormone (TH) receptor (TR)-β (trb) is induced by TH (autoinduced) in Xenopus tadpoles during metamorphosis. We previously showed that Krüppel-like factor 9 (Klf9) is rapidly induced by TH in the tadpole brain, associates in chromatin with the trb upstream region in a developmental stage and TH-dependent manner, and forced expression of Klf9 in the Xenopus laevis cell line XTC-2 accelerates and enhances trb autoinduction. Here we investigated whether Klf9 can promote trb autoinduction in tadpole brain in vivo. Using electroporation-mediated gene transfer, we transfected plasmids into premetamorphic tadpole brain to express wild-type or mutant forms of Klf9. Forced expression of Klf9 increased baseline trb mRNA levels in thyroid-intact but not in goitrogen-treated tadpoles, supporting that Klf9 enhances liganded TR action. As in XTC-2 cells, forced expression of Klf9 enhanced trb autoinduction in tadpole brain in vivo and also increased TH-dependent induction of the TR target genes klf9 and thbzip. Consistent with our previous mutagenesis experiments conducted in XTC-2 cells, the actions of Klf9 in vivo required an intact N-terminal region but not a functional DNA binding domain. Forced expression of TRβ in tadpole brain by electroporation-mediated gene transfer increased baseline and TH-induced TR target gene transcription, supporting a role for trb autoinduction during metamorphosis. Our findings support that Klf9 acts as an accessory transcription factor for TR at the trb locus during tadpole metamorphosis, enhancing trb autoinduction and transcription of other TR target genes, which increases cellular responsivity to further TH action on developmental gene regulation programs. PMID:26886257

  8. Car use within the household

    DEFF Research Database (Denmark)

    de Borger, Bruno; Mulalic, Ismir; Rouwendal, Jan

    2013-01-01

    In this paper we study the demand for car kilometres in two-car households, focusing on the substitution between cars in response to fuel price changes. We use a large sample of detailed Danish data on two-car households to estimate—for each car owned by the household—own and cross-price effects...... of increases in fuel costs per kilometre. The empirical results show that failure to capture substitution between cars within the household can result in substantial misspecification biases. Ignoring substitution, we estimate fuel price elasticities of –0.81 and -0.65 for the primary and secondary cars...... efficient car, finding partial support for the underlying hypothesis. More importantly, the results of this extended model emphasize the importance of behavioural differences related to the position of the most fuel efficient car in the household, suggesting that households’ fuel efficiency choices...

  9. Connected Car: Quantified Self becomes Quantified Car

    Directory of Open Access Journals (Sweden)

    Melanie Swan

    2015-02-01

    Full Text Available The automotive industry could be facing a situation of profound change and opportunity in the coming decades. There are a number of influencing factors such as increasing urban and aging populations, self-driving cars, 3D parts printing, energy innovation, and new models of transportation service delivery (Zipcar, Uber. The connected car means that vehicles are now part of the connected world, continuously Internet-connected, generating and transmitting data, which on the one hand can be helpfully integrated into applications, like real-time traffic alerts broadcast to smartwatches, but also raises security and privacy concerns. This paper explores the automotive connected world, and describes five killer QS (Quantified Self-auto sensor applications that link quantified-self sensors (sensors that measure the personal biometrics of individuals like heart rate and automotive sensors (sensors that measure driver and passenger biometrics or quantitative automotive performance metrics like speed and braking activity. The applications are fatigue detection, real-time assistance for parking and accidents, anger management and stress reduction, keyless authentication and digital identity verification, and DIY diagnostics. These kinds of applications help to demonstrate the benefit of connected world data streams in the automotive industry and beyond where, more fundamentally for human progress, the automation of both physical and now cognitive tasks is underway.

  10. Car stickers for 2009

    CERN Multimedia

    TS Department

    2008-01-01

    All members of the personnel holding a valid contract (except owners of cars with green or CD plates) can come to the Registration Service (Building 55, 1st floor) to obtain their 2009 car sticker, Mondays to Fridays from 7.30 a.m. to 4.00 p.m. non-stop. Please ensure you bring with you the documents relating to the vehicles(s) concerned. If you only wish to register one vehicle, you can obtain the 2009 sticker using the request form on the Web (via internet Explorer only). NB: This notice only applies to members of the personnel who obtained one or several blue car stickers for 2008. Reception and Access Control Service – TS/FM

  11. Distortionary Company Car Taxation: Deadweight Losses through Increased Car Ownership

    OpenAIRE

    Jos N. van Ommeren; Gutierrez-i-Puigarnau, Eva

    2011-01-01

    This discussion paper led to a publication in Empirical Economics 2013, 45(3), 1189-1204. We analyse the effects of distortionary company car taxation through increased household carownership for the Netherlands. We use several identification strategies and demonstrate thatfor about 20 percent of households company car possession increases car ownership. Theannual welfare loss of distortionary company taxation through increased car ownership isgenerally rather small, maximally €120 per compan...

  12. The market for gasoline cars and diesel cars

    International Nuclear Information System (INIS)

    In Europe the tax tariff is much lower for diesel fuel than for gasoline. This benefit is used by manufacturers to increase the price of diesel-fueled cars, which limits the possibility to control the use of diesel cars by means of a fiscal policy (tax incidence). Attention is paid to the impact of fiscal advantages for diesel cars on the purchasing behavior of the consumer and the pricing policy (price discrimination) of the car manufacturers. 1 ref

  13. French Professional Car Language

    OpenAIRE

    Veslav Kuranovič

    2011-01-01

    In this scientific article is presented french professional car language, also it is analysed a problem of teaching professional language at the technical university. It is presented lot of methods which help student to acquire language skills and also it is presented importance of dialog between student and teacher. Psychology and pedagogy are 2 sciences strong related in teacher’s work.

  14. Modeling the Mousetrap Car

    Science.gov (United States)

    Jumper, William D.

    2012-01-01

    Many high school and introductory college physics courses make use of mousetrap car projects and competitions as a way of providing an engaging hands-on learning experience incorporating Newton's laws, conversion of potential to kinetic energy, dissipative forces, and rotational mechanics. Presented here is a simple analytical and finite element…

  15. Autonomous Car Path Optimalization

    OpenAIRE

    Vladyka, V.

    2015-01-01

    This paper deals with path search and optimalisation of model car in unknown space. All data from sensors are processed in real-time onboard at ARM Cortex M4 microcontroller. Model’s main sensor is line-scan camera.

  16. Cars submerged in water.

    NARCIS (Netherlands)

    2010-01-01

    Crashes in which cars are submerged in deep water or in a ditch are often complicated and serious. Considering their severity and the fact that approximately half the fatalities in this crash type are not due to drowning but to injury, preventive measures are to be preferred above measures that have

  17. Cellular localization of kinin B1 receptor in the spinal cord of streptozotocin-diabetic rats with a fluorescent [Nα-Bodipy]-des-Arg9-bradykinin

    Directory of Open Access Journals (Sweden)

    Gaudreau Pierrette

    2009-03-01

    Full Text Available Abstract Background The kinin B1 receptor (B1R is upregulated by pro-inflammatory cytokines, bacterial endotoxins and hyperglycaemia-induced oxidative stress. In animal models of diabetes, it contributes to pain polyneuropathy. This study aims at defining the cellular localization of B1R in thoracic spinal cord of type 1 diabetic rats by confocal microscopy with the use of a fluorescent agonist, [Nα-Bodipy]-des-Arg9-BK (BdABK and selective antibodies. Methods Diabetes was induced by streptozotocin (STZ; 65 mg/kg, i.p.. Four days post-STZ treatment, B1R expression was confirmed by quantitative real-time PCR and autoradiography. The B1R selectivity of BdABK was determined by assessing its ability to displace B1R [125I]-HPP-desArg10-Hoe140 and B2R [125I]-HPP-Hoe 140 radioligands. The in vivo activity of BdABK was also evaluated on thermal hyperalgesia. Results B1R was increased by 18-fold (mRNA and 2.7-fold (binding sites in the thoracic spinal cord of STZ-treated rats when compared to control. BdABK failed to displace the B2R radioligand but displaced the B1R radioligand (IC50 = 5.3 nM. In comparison, IC50 values of B1R selective antagonist R-715 and B1R agonist des-Arg9-BK were 4.3 nM and 19 nM, respectively. Intraperitoneal BdABK and des-Arg9-BK elicited dose-dependent thermal hyperalgesia in STZ-treated rats but not in control rats. The B1R fluorescent agonist was co-localized with immunomarkers of microglia, astrocytes and sensory C fibers in the spinal cord of STZ-treated rats. Conclusion The induction and up-regulation of B1R in glial and sensory cells of the spinal cord in STZ-diabetic rats reinforce the idea that kinin B1R is an important target for drug development in pain processes.

  18. Do calcium-mediated cellular signalling pathways, prostaglandin E2 (PGE2), estrogen or progesterone receptor antagonists, or bacterial endotoxins affect bovine placental function in vitro?

    Science.gov (United States)

    Weems, Y S; Randel, R D; Carstens, G E; Welsh, T H; Weems, C W

    2004-04-01

    .05). Concentrations of PGE2 in media at 4 and 8 h were lower (P or = 0.05). PGF2alpha was increased (P < or = 0.05) by RU-486 at 8h and no other treatment affected PGF2alpha at 4 or 8 h (P < or = 0.05). In conclusion, modulators of cellular calcium signalling pathways given alone do not affect bovine placental progesterone secretion at the days studied and progesterone receptor-mediated events appear to suppress placental progesterone, PGF2alpha, and PGE2 secretion in cattle. In addition, PGE2 does not appear to regulate bovine placental progesterone secretion when the corpus luteum is functional and bacterial endotoxin does not appear to affect bovine placental secretion of PGF2alpha or PGE2. PMID:15287156

  19. Car boots: layers and drawers

    NARCIS (Netherlands)

    Van Kasteren, J.

    2003-01-01

    The car boot of practically any car appears to be pretty low on the list of items the manufacturer considers important.The world of glossy, state of the art and high-tech design seems to come to a halt behind the rear seat. Designers at Audi, the German car manufacturers, were well aware that this p

  20. Our Car as Power Plant

    NARCIS (Netherlands)

    Van Wijk, A.J.M.; Verhoef, L.

    2014-01-01

    Fuel cell cars can provide more efficient and cleaner transportation. However, we use our cars for transportation only 5% of the time. When parked, the fuel cell in the car can produce electricity from hydrogen, which is cleaner and more efficient than the current electricity system, generating usef

  1. receptores

    Directory of Open Access Journals (Sweden)

    Salete Regina Daronco Benetti

    2006-01-01

    Full Text Available Se trata de un estudio etnográfico, que tuvo lo objetivo de interpretar el sistema de conocimiento y del significado atribuidos a la sangre referente a la transfusión sanguínea por los donadores y receptores de un banco de sangre. Para la colecta de las informaciones se observaron los participantes y la entrevista etnográfica se realizó el análisis de dominio, taxonómicos y temáticos. Los dominios culturales fueron: la sangre es vida: fuente de vida y alimento valioso; creencias religiosas: fuentes simbólicas de apoyos; donación sanguínea: un gesto colaborador que exige cuidarse, gratifica y trae felicidad; donación sanguínea: fuente simbólica de inseguridad; estar enfermo es una condición para realizar transfusión sanguínea; transfusión sanguínea: esperanza de vida; Creencias populares: transfusión sanguínea como riesgo para la salud; donadores de sangre: personas benditas; donar y recibir sangre: como significado de felicidad. Temática: “líquido precioso que origina, sostiene, modifica la vida, provoca miedo e inseguridad”.

  2. Comparative Genomic Analysis of Buffalo (Bubalus bubalis) NOD1 and NOD2 Receptors and Their Functional Role in In-Vitro Cellular Immune Response

    OpenAIRE

    Brahma, Biswajit; Kumar, Sushil; De, Bidhan Chandra; Mishra, Purusottam; Patra, Mahesh Chandra; Gaur, Deepak; Chopra, Meenu; Gautam, Devika; Mahanty, Sourav; Malik, Hrudananda; Malakar, Dhruba; Datta, Tirtha Kumar; De, Sachinandan

    2015-01-01

    Nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) are innate immune receptors that recognize bacterial cell wall components and initiate host immune response. Structure and function of NLRs have been well studied in human and mice, but little information exists on genetic composition and role of these receptors in innate immune system of water buffalo—a species known for its exceptional disease resistance. Here, a comparative study on the functional domains of NOD1 and...

  3. The calcium-sensing receptor-dependent regulation of cell-cell adhesion and keratinocyte differentiation requires Rho and Filamin A

    OpenAIRE

    Tu, Chia-Ling; Chang, Wenhan; Bikle, Daniel D.

    2011-01-01

    Extracellular Ca2+ (Ca2+o) acting through the calcium-sensing receptor (CaR) induces E-cadherin mediated cell-cell adhesion and cellular signals mediating cell differentiation in epidermal keratinocytes. Previous studies indicate that the CaR regulates cell-cell adhesion through the Fyn/Src tyrosine kinases. Here we investigate whether Rho GTPase is a part of the CaR-mediated signaling cascade regulating cell adhesion and differentiation. Suppressing endogenous Rho A expression by small inter...

  4. Epigenetic Methylation of Parathyroid CaR and VDR Promoters in Experimental Secondary Hyperparathyroidism

    OpenAIRE

    Jacob Hofman-Bang; Eva Gravesen; Klaus Olgaard; Ewa Lewin

    2012-01-01

    Secondary hyperparathyroidism (s-HPT) in uremia is characterized by decreased expression in the parathyroids of calcium sensing (CaR) and vitamin D receptors (VDR). Parathyroid hormone (PTH) is normalized despite low levels of CaR and VDR after experimental reversal of uremia. The expression of CaR in parathyroid cultures decreases rapidly. Methylation of promoter regions is often detected during epigenetic downregulation of gene expression. Therefore, using an experimental rat model, we exam...

  5. Cellular automata

    CERN Document Server

    Codd, E F

    1968-01-01

    Cellular Automata presents the fundamental principles of homogeneous cellular systems. This book discusses the possibility of biochemical computers with self-reproducing capability.Organized into eight chapters, this book begins with an overview of some theorems dealing with conditions under which universal computation and construction can be exhibited in cellular spaces. This text then presents a design for a machine embedded in a cellular space or a machine that can compute all computable functions and construct a replica of itself in any accessible and sufficiently large region of t

  6. New developments in clinical CARS

    Science.gov (United States)

    Weinigel, Martin; Breunig, Hans Georg; Kellner-Höfer, Marcel; Bückle, Rainer; Darvin, Maxim; Lademann, Juergen; König, Karsten

    2013-02-01

    We combined two-photon fluorescence and coherent anti-Stokes Raman scattering (CARS) imaging in a clinical hybrid multiphoton tomograph for in vivo imaging of human skin. The clinically approved TPEF/CARS system provides simultaneous imaging of endogenous fluorophores and non-fluorescent lipids. The Stokes laser for the two-beam configuration of CARS is based on spectral broadening of femtosecond laser pulses in a photonic crystal fiber (PCF). We report on the highly flexible medical TPEF/CARS tomograph MPTflex®-CARS with an articulated arm and first in vivo measurements on human skin.

  7. CAR ACCESS USING MULTIMODAL BIOMETRICS

    OpenAIRE

    Catalin LUPU

    2010-01-01

    This paper presents the use of multimodal biometrics in order to identify or to verify a person that wants to start the engine of a car. First of all, a fingerprint sensor is posted on the car’s door, one on the steering wheel, a camera for iris recognition on the car's main mirror, and finally a microphone for voice recognition. There are two possibilities: if the person is identified as the car owner or a known user, then he/she can take control over the car; if it’s an intruder, the car ca...

  8. CERN car stickers 2005

    CERN Multimedia

    Reception and Access Control Service - TS Department

    2004-01-01

    Please note that the car stickers for 2005 are now available. If you have not received the new one by internal mail, you should go along in person to the Registration Service (bldg. 55 - 1st floor), open non-stop from 7:30 to 16:30, taking with you your 2004 sticker and the log-book of your vehicle. Thank you for your collaboration. Reception and Access Control Service - TS Department.

  9. Magnetic Cellular Switches

    OpenAIRE

    Overby, Darryl R.; Alenghat, Francis J.; Montoya-Zavala, Martín; Bei, HuCheng; Oh, Philmo; Karavitis, John; Ingber, Donald E.

    2004-01-01

    This paper focuses on the development of magnetic cellular switches to enable magnetic control of intracellular functions in living mammalian cells, including receptor signal transduction and gene transcription. Our approach takes advantage of the mechanosensitivity of adenosine 3′,5′-monophosphate (cAMP) induction and downstream transcription controlled by the cAMP regulatory element (CRE) to engineer gene constructs that optically report gene expression in living cells. We activate transcri...

  10. p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38

    Science.gov (United States)

    Hori, Takeshi; Moore, Rick

    2016-01-01

    Nuclear receptor constitutive androstane receptor (CAR, NR1I3), which regulates hepatic drug and energy metabolisms as well as cell growth and death, is sequestered in the cytoplasm as its inactive form phosphorylated at threonine 38. CAR activators elicit dephosphorylation, and nonphosphorylated CAR translocates into the nucleus to activate its target genes. CAR was previously found to require p38 mitogen-activated protein kinase (MAPK) to transactivate the cytochrome P450 2B (CYP2B) genes. Here we have demonstrated that p38 MAPK forms a complex with CAR, enables it to bind to the response sequence, phenobarbital-responsive enhancer module (PBREM), within the CYP2B promoter, and thus recruits RNA polymerase II to activate transcription. Subsequently, p38 MAPK elicited rephosphorylation of threonine 38 to inactivate CAR and exclude it from the nucleus. Thus, nuclear p38 MAPK exerted dual regulation by sequentially activating and inactivating CAR-mediated transcription through phosphorylation of threonine 38. PMID:27074912

  11. p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38.

    Science.gov (United States)

    Hori, Takeshi; Moore, Rick; Negishi, Masahiko

    2016-06-01

    Nuclear receptor constitutive androstane receptor (CAR, NR1I3), which regulates hepatic drug and energy metabolisms as well as cell growth and death, is sequestered in the cytoplasm as its inactive form phosphorylated at threonine 38. CAR activators elicit dephosphorylation, and nonphosphorylated CAR translocates into the nucleus to activate its target genes. CAR was previously found to require p38 mitogen-activated protein kinase (MAPK) to transactivate the cytochrome P450 2B (CYP2B) genes. Here we have demonstrated that p38 MAPK forms a complex with CAR, enables it to bind to the response sequence, phenobarbital-responsive enhancer module (PBREM), within the CYP2B promoter, and thus recruits RNA polymerase II to activate transcription. Subsequently, p38 MAPK elicited rephosphorylation of threonine 38 to inactivate CAR and exclude it from the nucleus. Thus, nuclear p38 MAPK exerted dual regulation by sequentially activating and inactivating CAR-mediated transcription through phosphorylation of threonine 38. PMID:27074912

  12. Deciphering the roles of the constitutive androstane receptor in energy metabolism

    OpenAIRE

    Yan, Jiong; Chen, Baian; Lu, Jing; Xie, Wen

    2014-01-01

    The constitutive androstane receptor (CAR) is initially defined as a xenobiotic nuclear receptor that protects the liver from injury. Detoxification of damaging chemicals is achieved by CAR-mediated induction of drug-metabolizing enzymes and transporters. More recent research has implicated CAR in energy metabolism, suggesting a therapeutic potential for CAR in metabolic diseases, such as type 2 diabetes and obesity. A better understanding of the mechanisms by which CAR regulates energy metab...

  13. Different cellular sources and different roles of adenosine: A1 receptor-mediated inhibition through astrocytic-driven volume transmission and synapse-restricted A2A receptor-mediated facilitation of plasticity

    OpenAIRE

    Cunha, Rodrigo A.

    2008-01-01

    Adenosine is a prototypical neuromodulator, which mainly controls excitatory transmission through the activation of widespread inhibitory A1 receptors and synaptically located A2A receptors. It was long thought that the predominant A1 receptor-meditated modulation by endogenous adenosine was a homeostatic process intrinsic to the synapse. New studies indicate that endogenous extracellular adenosine is originated as a consequence of the release of gliotransmitters, namely ATP, which sets a glo...

  14. Car monitoring information systems

    Directory of Open Access Journals (Sweden)

    Alica KALAŠOVÁ

    2008-01-01

    Full Text Available The objective of this contribution is to characterize alternatives of information systems used for managing, processing and evaluation of information related to company vehicles. Especially we focus on logging, transferring and processing of on-road vehicle movement information in inland and international transportation. This segment of company information system has to monitor the car movement – actively or passively – according to demand of the company and after the processing it has to evaluate and give the complex monitoring of a situation of all the company vehicles to the controller.

  15. Car stickers for 2010

    CERN Multimedia

    GS Department

    The 2010 car stickers are now available. Holders of blue stickers will receive their 2010 stickers through the internal mail from 1st December onwards. Holders of red stickers are required to go to the Registration Service (Building 55, first floor), which is open non-stop from 7.30 a.m. to 4.00 p.m. Mondays to Fridays, in order to obtain their new stickers. They will be asked to present documents relating to the vehicles concerned. Owners of vehicles registered on green and CD plates should disregard this message. Reception and Access Control Service – GS/SEM/LS

  16. DECREASED APOPTOSIS DURING CAR-MEDIATED HEPATOPROTECTION AGAINST LITHOCHOLIC ACID-INDUCED LIVER INJURY IN MICE

    OpenAIRE

    Beilke, Lisa D.; Aleksunes, Lauren M.; Olson, Erik R.; Besselsen, David G; Klaassen, Curtis D.; Dvorak, Katerina; Cherrington, Nathan J.

    2009-01-01

    Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver against bile acid-induced toxicity and it may have a role in cell death via apoptosis by altering expression of Bcl-2 family proteins such as myeloid cell leukemia-1 (Mcl-1). Our aim was to determine if activation of CAR reduces hepatocellular apoptosis during cholestasis as a mechanism of hepatoprotection. CAR+/+ (WT) and CAR−/−...

  17. Product declaration for cars

    International Nuclear Information System (INIS)

    This reports for the Swiss Federal Office of Energy (SFOE) presents the results of a study made on the possible ways of declaring product information on cars. The basic elements of such a declaration are discussed and a recommendation for an energy label for cars is presented. The report discusses the fundamental questions posed such as how long a label should be valid, if comparisons should be made and if it is to be based on CO2-emissions or on fuel consumption. Also, the criteria to be used for comparisons - such as vehicle weight, size or power - are looked at and methods of classification are examined along with data fundamentals. Further, the expectations placed on the product declarations with respect to their energetic and economic impact are discussed. The design of the label and the legislature on which it is based are discussed and initial reactions of the automobile industry are noted. The report is rounded off by a discussion of the effects of the declaration in relation to other instruments that have been proposed

  18. D-serine deficiency attenuates the behavioral and cellular effects induced by the hallucinogenic 5-HT(2A) receptor agonist DOI

    DEFF Research Database (Denmark)

    Santini, Martin A; Balu, Darrick T; Puhl, Matthew D;

    2014-01-01

    , the serine racemase knockout (SRKO) mouse, to explore the role of glutamatergic transmission in regulating 5-HT2AR-mediated cellular and behavioral responses. SRKO mice treated with the 5-HT2AR agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI) showed a clearly diminished HTR and lower induction of c-fos m...

  19. 49 CFR 174.615 - Cleaning cars.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Cleaning cars. 174.615 Section 174.615... Requirements for Division 6.1 (Poisonous) Materials § 174.615 Cleaning cars. (a) (b) After Division 6.1 (poisonous) materials are unloaded from a rail car, that car must be thoroughly cleaned unless the car...

  20. Clinical Translational Research of Chimeric Antigen Receptor-T (CAR-T) Cells for the Treatment of Relapsed and Refractory B-cell Lymphoma/Leukemia——Review%利用嵌合抗原受体的T细胞(CAR-T)治疗复发和难治B细胞淋巴瘤/白血病的转化医学研究

    Institute of Scientific and Technical Information of China (English)

    袁顺宗; 苏航

    2014-01-01

    B细胞淋巴瘤/白血病是恶性淋巴瘤中最常见的亚型,其复发和难治常常是导致治疗失败的主要原因.长期以来,手术、放疗、化疗和姑息治疗等作为传统的抗肿瘤治疗模式,挽救了许多患者的生命,但每年仍然有大量患者因肿瘤不治而死亡.B细胞淋巴瘤/白血病,尤其是表达CD20的成熟B细胞淋巴瘤/白血病,在利妥昔单抗问世之后,其治愈率有了大幅度的上升,然而仍然有近20%-40%患者因复发和难治而去世.近5年来,随着可特异性识别B细胞表面CD19的嵌合抗原受体的T细胞(CAR-T)的发展,尤其是CD19 CAR-T细胞免疫治疗在针对复发和难治B细胞淋巴瘤的临床试验中取得了非常显著的疗效,CAR-T细胞免疫治疗便逐渐受到广大研究者和临床学家的重视,包括我国在内的全球多家医疗机构纷纷注册和开展了针对B细胞淋巴瘤/白血病的临床试验.本文就CD19 CAR-T细胞在治疗B细胞淋巴瘤/白血病过程中的发展历史,在前进行中的主要的临床试验和已经证实的主要潜在不良反应作一综述.

  1. CD19-targeted CAR T-cell therapeutics for hematologic malignancies: interpreting clinical outcomes to date.

    Science.gov (United States)

    Park, Jae H; Geyer, Mark B; Brentjens, Renier J

    2016-06-30

    Adoptive transfer of T cells genetically modified to express chimeric antigen receptors (CARs) targeting CD19 has produced impressive results in treating patients with B-cell malignancies. Although these CAR-modified T cells target the same antigen, the designs of CARs vary as well as several key aspects of the clinical trials in which these CARs have been studied. It is unclear whether these differences have any impact on clinical outcome and treatment-related toxicities. Herein, we review clinical results reflecting the investigational use of CD19-targeted CAR T-cell therapeutics in patients with B-cell hematologic malignancies, in light of differences in CAR design and production, and outline the limitations inherent in comparing outcomes between studies. PMID:27207800

  2. Decreased apoptosis during CAR-mediated hepatoprotection against lithocholic acid-induced liver injury in mice.

    Science.gov (United States)

    Beilke, Lisa D; Aleksunes, Lauren M; Olson, Erik R; Besselsen, David G; Klaassen, Curtis D; Dvorak, Katerina; Cherrington, Nathan J

    2009-07-10

    Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver against bile acid-induced toxicity and it may have a role in cell death via apoptosis by altering expression of Bcl-2 family proteins such as myeloid cell leukemia-1 (Mcl-1). Our aim was to determine if activation of CAR reduces hepatocellular apoptosis during cholestasis as a mechanism of hepatoprotection. CAR(+/+) (WT) and CAR(-/-) (CAR-null) mice were pre-treated with compounds known to activate CAR prior to induction of intrahepatic cholestasis using the secondary bile acid lithocholic acid (LCA). Pre-treatment with the CAR activators phenobarbital (PB) and TCPOBOP (TC), as well as the non-CAR activator pregnenolone 16alpha-carbontrile (PCN), protected against LCA-induced liver injury in WT mice, whereas liver injury was more extensive without CAR (CAR-null). Unexpectedly, expression of anti-apoptotic Mcl-1 and Bcl-x(L) was not increased in hepatoprotected mice. Compared to unprotected groups, apoptosis was decreased in hepatoprotected mice as evidenced by the absence of cleaved caspase 3 (cCasp3). In contrast to the cytoplasmic localization in the injured livers (LCA and oltipraz), Mcl-1 protein was localized in the nucleus of hepatoprotected livers to potentially promote cell survival. This study demonstrates that although apoptosis is reduced in hepatoprotected mice pre-treated with CAR and non-CAR activators; hepatoprotection is not directly a result of CAR-induced Mcl-1 expression. PMID:19433268

  3. Energy Use of Passenger Cars

    DEFF Research Database (Denmark)

    Jørgensen, Kaj

    1998-01-01

    Analysis of the Danish sale and stock of passenger cars, focusing particularly on aspects influencing energy use. The project has tracked the development of vehicle weight, power and fuel economy for both the sale of new cars (from 1980 to 1997)and the stock. In addition, the energy use for...

  4. Panorama 2014 - Car-sharing

    International Nuclear Information System (INIS)

    Car-sharing is a new mode of transportation that consists of multiple users sharing the same vehicle. This type of service is expanding with the arrival of larger players, such as traditional car rental companies, automotive manufacturers, and large firms specializing in transportation. This new mode of transportation offers real potential and is currently finding its users, in France and worldwide. (author)

  5. Optimization Of Car Rim

    Directory of Open Access Journals (Sweden)

    Mr. Sushant K. Bawne

    2015-10-01

    Full Text Available The essential of car wheel rim is to provide a firm base on which to fit the tyre. Its dimensions, shape should be suitable to adequately accommodate the particular tyre required for the vehicle. In this project a tyre of car wheel rim belonging to the disc wheel category is considered. Design is an important industrial activity which influences the quality of the product. The wheel rim is modeled by using modeling software catiav5r17. By using this software the time spent in producing the complex 3- D models and the risk involved in the design and manufacturing process can be easily minimized. So the modeling of the wheel rim is made by using CATIA. Later this CATIA modal is imported to ANSYS WORKBENCH 14.5 for analysis work. ANSYS WORKBENCH 14.5 is the latest software used for simulating the different forces, pressure acting on the component and also calculating and viewing the results. By using ANSYS WORKBENCH 14.5 software reduces the time compared with the method of mathematical calculations by a human. ANSYS WORKBENCH 14.5 static structural analysis work is carried out by considered three different materials namely aluminum alloy ,magnesium alloy and structural steel and their relative performances have been observed respectively. In addition to wheel rim is subjected to modal analysis, a part of dynamic analysis is carried out its performance is observed. In this analysis by observing the results of both static and dynamic analysis obtained magnesium alloy is suggested as best material.

  6. 49 CFR 172.330 - Tank cars and multi-unit tank car tanks.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Tank cars and multi-unit tank car tanks. 172.330..., TRAINING REQUIREMENTS, AND SECURITY PLANS Marking § 172.330 Tank cars and multi-unit tank car tanks. (a... material— (1) In a tank car unless the following conditions are met: (i) The tank car must be marked...

  7. 49 CFR 1247.1 - Annual Report of Cars Loaded and Cars Terminated.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 9 2010-10-01 2010-10-01 false Annual Report of Cars Loaded and Cars Terminated... TRANSPORTATION BOARD, DEPARTMENT OF TRANSPORTATION (CONTINUED) ACCOUNTS, RECORDS AND REPORTS REPORT OF CARS LOADED AND CARS TERMINATED § 1247.1 Annual Report of Cars Loaded and Cars Terminated. Beginning with...

  8. Inhibition of Macrophage CD36 Expression and Cellular Oxidized Low Density Lipoprotein (oxLDL) Accumulation by Tamoxifen: A PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR (PPAR)γ-DEPENDENT MECHANISM.

    Science.gov (United States)

    Yu, Miao; Jiang, Meixiu; Chen, Yuanli; Zhang, Shuang; Zhang, Wenwen; Yang, Xiaoxiao; Li, Xiaoju; Li, Yan; Duan, Shengzhong; Han, Jihong; Duan, Yajun

    2016-08-12

    Macrophage CD36 binds and internalizes oxidized low density lipoprotein (oxLDL) to facilitate foam cell formation. CD36 expression is activated by peroxisome proliferator-activated receptor γ (PPARγ). Tamoxifen, an anti-breast cancer medicine, has demonstrated pleiotropic functions including cardioprotection with unfully elucidated mechanisms. In this study, we determined that treatment of ApoE-deficient mice with tamoxifen reduced atherosclerosis, which was associated with decreased CD36 and PPARγ expression in lesion areas. At the cellular level, we observed that tamoxifen inhibited CD36 protein expression in human THP-1 monocytes, THP-1/PMA macrophages, and human blood monocyte-derived macrophages. Associated with decreased CD36 protein expression, tamoxifen reduced cellular oxLDL accumulation in a CD36-dependent manner. At the transcriptional level, tamoxifen decreased CD36 mRNA expression, promoter activity, and the binding of the PPARγ response element in CD36 promoter to PPARγ protein. Tamoxifen blocked ligand-induced PPARγ nuclear translocation and CD36 expression, but it increased PPARγ phosphorylation, which was due to that tamoxifen-activated ERK1/2. Furthermore, deficiency of PPARγ expression in macrophages abolished the inhibitory effect of tamoxifen on CD36 expression or cellular oxLDL accumulation both in vitro and in vivo Taken together, our study demonstrates that tamoxifen inhibits CD36 expression and cellular oxLDL accumulation by inactivating the PPARγ signaling pathway, and the inhibition of macrophage CD36 expression can be attributed to the anti-atherogenic properties of tamoxifen. PMID:27358406

  9. AAP Updates Recommendations on Car Seats

    Science.gov (United States)

    ... Size Email Print Share AAP Updates Recommendations on Car Seats Page Content Article Body Children should ride ... of approved car safety seats. Healthy Children Radio: Car Seat Safety Dennis Durbin, MD, FAAP, lead author ...

  10. Co-Expansion of Cytokine-Induced Killer Cells and Vγ9Vδ2 T Cells for CAR T-Cell Therapy.

    Science.gov (United States)

    Du, Shou-Hui; Li, Zhendong; Chen, Can; Tan, Wee-Kiat; Chi, Zhixia; Kwang, Timothy Weixin; Xu, Xue-Hu; Wang, Shu

    2016-01-01

    Gamma delta (γδ) T cells and cytokine-induced killer (CIK) cells, which are a heterogeneous population of T lymphocytes and natural killer T (NKT) cells, have been separately expanded ex vivo and shown to be capable of targeting and mediating cytotoxicity against various tumor cells in a major histocompatibility complex-unrestricted manner. However, the co-expansion and co-administration of these immune cells have not been explored. In this study we describe an efficient method to expand simultaneously both CIK and Vγ9Vδ2 T cells, termed as CIKZ cells, from human peripheral blood mononuclear cells (PBMCs) using Zometa, interferon-gamma (IFN-γ), interleukin 2 (IL-2), anti-CD3 antibody and engineered K562 feeder cells expressing CD64, CD137L and CD86. A 21-day culture of PBMCs with this method yielded nearly 20,000-fold expansion of CIKZ cells with γδ T cells making up over 20% of the expanded population. The expanded CIKZ cells exhibited antitumor cytotoxicity and could be modified to express anti-CD19 chimeric antigen receptor (CAR), anti-CEA CAR, and anti-HER2 CAR to enhance their specificity and cytotoxicity against CD19-, CEA-, or HER2-positive tumor cells. The tumor inhibitory activity of anti-CD19 CAR-modified CIKZ cells was further demonstrated in vivo in a Raji tumor mouse model. The findings herein substantiate the feasibility of co-expanding CIK and γδ cells for adoptive cellular immunotherapy applications such as CAR T-cell therapy against cancer. PMID:27598655

  11. Cellular Automata

    OpenAIRE

    Bagnoli, Franco

    1998-01-01

    An introduction to cellular automata (both deterministic and probabilistic) with examples. Definition of deterministic automata, dynamical properties, damage spreading and Lyapunov exponents; probabilistic automata and Markov processes, nonequilibrium phase transitions, directed percolation, diffusion; simulation techniques, mean field. Investigation themes: life, epidemics, forest fires, percolation, modeling of ecosystems and speciation. They represent my notes for the school "Dynamical Mod...

  12. The car and crime: critical perspectives.

    OpenAIRE

    Groombridge, Nic

    1997-01-01

    This thesis critically examines the literature on joyriding, car crime, motor projects and masculinities. Fieldwork in motor projects combined with the methods of cultural studies locates car crime within a gendered car culture. Thus motor projects are seen to 'work' within that gendered car culture but a longer term solution to car crime is to be found in 'green' transport policies and changes in gender relations. Theoretically it recognises the reality of car crime and also the reality of t...

  13. Application of Monte Carlo-based statistical significance determinations to the Beta Cephei stars V400 Car, V401 Car, V403 Car and V405 Car

    OpenAIRE

    Engelbrecht, C. A.; Frescura, F. A. M.; Frank, B. S.

    2009-01-01

    We have used Lomb-Scargle periodogram analysis and Monte Carlo significance tests to detect periodicities above the 3-sigma level in the Beta Cephei stars V400 Car, V401 Car, V403 Car and V405 Car. These methods produce six previously unreported periodicities in the expected frequency range of excited pulsations: one in V400 Car, three in V401 Car, one in V403 Car and one in V405 Car. One of these six frequencies is significant above the 4-sigma level. We provide statistical significances for...

  14. Inhibition of HIV Env binding to cellular receptors by monoclonal antibody 2G12 as probed by Fc-tagged gp120

    Directory of Open Access Journals (Sweden)

    Wilson Ian A

    2006-07-01

    Full Text Available Abstract During natural HIV infection, an array of host receptors are thought to influence virus attachment and the kinetics of infection. In this study, to probe the interactions of HIV envelope (Env with various receptors, we assessed the inhibitory properties of various anti-Env monoclonal antibodies (mAbs in binding assays. To assist in detecting Env in attachment assays, we generated Fc fusions of full-length wild-type gp120 and several variable loop-deleted gp120s. Through investigation of the inhibition of Env binding to cell lines expressing CD4, CCR5, DC-SIGN, syndecans or combinations thereof, we found that the broadly neutralizing mAb, 2G12, directed to a unique carbohydrate epitope of gp120, inhibited Env-CCR5 binding, partially inhibited Env-DC-SIGN binding, but had no effect on Env-syndecan association. Furthermore, 2G12 inhibited Env attachment to primary monocyte-derived dendritic cells, that expressed CD4 and CCR5 primary HIV receptors, as well as DC-SIGN, and suggested that the dual activities of 2G12 could be valuable in vivo for inhibiting initial virus dissemination and propagation.

  15. Clinical multiphoton and CARS microscopy

    Science.gov (United States)

    Breunig, H. G.; Weinigel, M.; Darvin, M. E.; Lademann, J.; König, K.

    2012-03-01

    We report on clinical CARS imaging of human skin in vivo with the certified hybrid multiphoton tomograph CARSDermaInspect. The CARS-DermaInspect provides simultaneous imaging of non-fluorescent intradermal lipid and water as well as imaging of two-photon excited fluorescence from intrinsic molecules. Two different excitation schemes for CARS imaging have been realized: In the first setup, a combination of fs oscillator and optical parametric oscillator provided fs-CARS pump and Stokes pulses, respectively. In the second setup a fs oscillator was combined with a photonic crystal fiber which provided a broadband spectrum. A spectral range out of the broadband-spectrum was selected and used for CARS excitation in combination with the residual fs-oscillator output. In both setups, in addition to CARS, single-beam excitation was used for imaging of two-photon excited fluorescence and second harmonic generation signals. Both CARS-excitation systems were successfully used for imaging of lipids inside the skin in vivo.

  16. Future cars: the electric option

    OpenAIRE

    Shukla, AK; Avery, NR; Muddle, BC

    1999-01-01

    Global economic, environmental and political issues are pushing car manufacturers to consider electric power systems as an alternative to the current spark ignition engine. In this article, we analyse the power and energy requirements of a modern car and conclude that a viable electric car could be operated with a 50 kW polymer electrolyte fuel cell (PEFC) stack to provide power for cruising and climbing, coupled in parallel with a 30 kW supercapacitor or battery bank to supply additional sho...

  17. Our Car as Power Plant

    OpenAIRE

    Van Wijk, A.J.M.; Verhoef, L.

    2014-01-01

    Fuel cell cars can provide more efficient and cleaner transportation. However, we use our cars for transportation only 5% of the time. When parked, the fuel cell in the car can produce electricity from hydrogen, which is cleaner and more efficient than the current electricity system, generating useful ‘waste’ products in the form of heat and fresh water. The produced electricity, heat and fresh water can be fed into the respective grids or be used directly in our house, office or the school o...

  18. CERN CAR STICKERS

    CERN Multimedia

    Service Accueil et Controle d'Accès; ST Division

    1999-01-01

    In accordance with Operational Circular n¡ 2, paragraph 21, CERN car stickers are to be renewed. The new stickers are now available and will be valid for a year.Youare therefore requested:either to obtain them from the distribution points for new stickers (see below); or to send us the application form below, duly completed, via the internal mail; or to complete the application form directly via the Web at the address: http://cern.ch/registration-stickers. Each vehicle has to carry a sticker and needs a separate application form.Vehicles bearing CERN diplomatic plates (CD07, 431K and CD series) do not need a sticker for access to the CERN areas.Thank you.List of distribution points:Registration Service (bldg 55 1st floor), open from 07h30 to 16h30. Building 33 (entrance hall), open from 08h00 to 18h00. Building 120 (ground floor), outside working hours.Name Surname CERN identification number Vehicle registration plates Country issuing the plates Vehicle ma...

  19. CERN CAR CLUB

    CERN Multimedia

    Automobile club

    2009-01-01

    You are cordially invited to the next General Assembly of the CERN Car Club Tuesday 12 January 2010 at 5:45pm Bldg. 593 / room 11 As the end of 2009 is approaching, it is time to think about renewing your subscription. Therefore next time you are on the CERN-Meyrin site or at the Post Office counter don’t forget to fill in the payment slip to continue to be a part of our large family. The fee remains unchanged: 50 CHF. For those of you who are regular users of our equipment and who know of all the advantages that the club is in a position to offer, it seems pointless to give details, we are sure that many of you have made use of them and are satisfied. We remind you everyone working on CERN site is entitled to become a member of our club, this includes industrial support personnel and staff of companies which have a contract with CERN. If you are not yet a member, come and visit us! We will be happy to welcome you and show you the facilities, or you can visit our web site. The use of the club&...

  20. Opa binding to cellular CD66 receptors mediates the transcellular traversal of Neisseria gonorrhoeae across polarized T84 epithelial cell monolayers.

    Science.gov (United States)

    Wang, J; Gray-Owen, S D; Knorre, A; Meyer, T F; Dehio, C

    1998-11-01

    We have analysed the capacity of the 11 phase-variable, opacity-associated (Opa) proteins encoded by Neisseria gonorrhoeae MS11 to mediate traversal across polarized monolayers of the human colonic carcinoma T84 cell line. Gonococci expressing either the heparan sulphate proteoglycan (HSPG) binding Opa protein (Opa50) or no Opa protein (Opa-) did not interact with the apical pole of T84 monolayers, whereas the 10 variant Opa proteins previously shown to bind CD66 receptors were found to mediate efficient gonococcal adherence and transepithelial traversal. Consistent with this, T84 cells were shown by reverse transcriptase-polymerase chain reaction (RT-PCR) and immunoblotting to co-express CD66a (BGP), CD66c (NCA) and CD66e (CEA). The recruitment of CD66 receptors by Opa-expressing gonococci indicates their involvement in mediating adherence to the surface of T84 cells, and these bacterial interactions could be inhibited completely using polyclonal antibodies cross-reacting with all of the CD66 proteins co-expressed on T84 cells. Consistent results were obtained when Opa proteins were expressed in Escherichia coli, suggesting that the Opa-CD66 interaction is sufficient to mediate bacterial traversal. Transcytosis of Opa-expressing N. gonorrhoeae or E. coli did not disrupt the barrier function of infected monolayers, as indicated by a sustained transepithelial electrical resistance (TEER) throughout the course of infection, and confocal laser scanning and electron microscopy both suggest a transcellular rather than a paracellular route of traversal across the monolayers. Parallels between the results seen here and previous work done with organ cultures confirm that T84 monolayers provide a valid model for studying neisserial interactions with the mucosal surface, and suggest that CD66 receptors contribute to this process in vivo. PMID:9822830

  1. Opposing Regulation of Cytochrome P450 Expression by CAR and PXR in Hypothyroid Mice

    OpenAIRE

    Park, Young Joo; Lee, Eun Kyung; Lee, Yoon Kwang; Park, Do Joon; Jang, Hak Chul; Moore, David D.

    2012-01-01

    Clinical hypothyroidism affects various metabolic processes including drug metabolism. CYP2B and CYP3A are important cytochrome P450 drug metabolizing enzymes that are regulated by the xenobiotic receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2). We evaluated the regulation of the hepatic expression of CYPs by CAR and PXR in the hypothyroid state induced by a low-iodine diet containing 0.15% propylthiouracil. Expression of Cyp3a11 was suppressed in h...

  2. Human platelets express CAR with localization at the sites of intercellular interaction

    Directory of Open Access Journals (Sweden)

    Othman Maha

    2011-09-01

    Full Text Available Abstract Adenovirus has a wide tissue tropism. The virus attaches to the surface of cells via the fiber protein knob binding to the Coxsackie and Adenovirus receptor known as CAR. Virus entry inside cells is facilitated by integrins αVβ3 and αVβ5. Mice platelets are shown to be the predominant Ad binding blood cell type and the virus is documented inside platelets. CAR was identified on human platelets in one study yet contradicted in another. The presence of CAR appears to be the most reasonable initial step for virus entry into platelets and is a key to the understanding of platelet adenovirus interaction. This study aimed to re investigate the presence of CAR on human platelets. Platelets were tested by indirect immune-fluorescence using rabbit H-300 polyclonal anti-CAR antibody and goat anti-rabbit IgG F(ab'2 Texas Red antibodies, alongside with CAR positive and negative controls. Platelets were found to express CAR on their surface and in contrast to the previous study only 3.5 ± 1.9% of the tested platelets did express CAR. In addition, CAR was seen within intracellular aggregates localized at the sites of cell-cell contacts indicating that CAR expression might be upregulated in response to platelet stimulation. We confirm the presence of CAR on human platelets, we provide explanation to some of the discrepancies in this regards and we add that this receptor is localized at the sites of intercellular interaction.

  3. Cars Are Hot in Beijing

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    MANY Chinese have long dreamedabout the joy of driving. However, in thepast only professional drivers had theopportunity as most cars were stateowned and it was too expensive forindividuals to buy their own.

  4. CHINA ACCOUNTING REVIEW(CAR)

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    China Accounting Review(CAR)is a new accounting journal in Chinese,spon- sored by Peking University,Tsinghua University,Beijing National Accounting Insti- tute and ten more universities,and published by the Peking University Press.

  5. Car Safety for Special Children.

    Science.gov (United States)

    Holland, Suzanne Hauser

    1983-01-01

    Various car seats, harnesses, and vests that can be used with handicapped children are described. Suggestions are also made for improvment when existing equipment is not appropriate. A list of resources on the topic is also provided. (CL)

  6. CAR T Cell Therapy: A Game Changer in Cancer Treatment.

    Science.gov (United States)

    Almåsbak, Hilde; Aarvak, Tanja; Vemuri, Mohan C

    2016-01-01

    The development of novel targeted therapies with acceptable safety profiles is critical to successful cancer outcomes with better survival rates. Immunotherapy offers promising opportunities with the potential to induce sustained remissions in patients with refractory disease. Recent dramatic clinical responses in trials with gene modified T cells expressing chimeric antigen receptors (CARs) in B-cell malignancies have generated great enthusiasm. This therapy might pave the way for a potential paradigm shift in the way we treat refractory or relapsed cancers. CARs are genetically engineered receptors that combine the specific binding domains from a tumor targeting antibody with T cell signaling domains to allow specifically targeted antibody redirected T cell activation. Despite current successes in hematological cancers, we are only in the beginning of exploring the powerful potential of CAR redirected T cells in the control and elimination of resistant, metastatic, or recurrent nonhematological cancers. This review discusses the application of the CAR T cell therapy, its challenges, and strategies for successful clinical and commercial translation. PMID:27298832

  7. CAR T Cell Therapy: A Game Changer in Cancer Treatment

    Science.gov (United States)

    Almåsbak, Hilde; Aarvak, Tanja; Vemuri, Mohan C.

    2016-01-01

    The development of novel targeted therapies with acceptable safety profiles is critical to successful cancer outcomes with better survival rates. Immunotherapy offers promising opportunities with the potential to induce sustained remissions in patients with refractory disease. Recent dramatic clinical responses in trials with gene modified T cells expressing chimeric antigen receptors (CARs) in B-cell malignancies have generated great enthusiasm. This therapy might pave the way for a potential paradigm shift in the way we treat refractory or relapsed cancers. CARs are genetically engineered receptors that combine the specific binding domains from a tumor targeting antibody with T cell signaling domains to allow specifically targeted antibody redirected T cell activation. Despite current successes in hematological cancers, we are only in the beginning of exploring the powerful potential of CAR redirected T cells in the control and elimination of resistant, metastatic, or recurrent nonhematological cancers. This review discusses the application of the CAR T cell therapy, its challenges, and strategies for successful clinical and commercial translation. PMID:27298832

  8. Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK/ERK signaling pathway via cellular receptors

    International Nuclear Information System (INIS)

    Dysregulation of mitogen-activated protein kinase (MAPK) signaling pathways by various viruses has been shown to be responsible for viral pathogenicity. The molecular mechanism by which hepatitis C virus (HCV) infection caused human liver diseases has been investigated on the basis of abnormal intracellular signal events. Current data are very limited involved in transmembrane signal transduction triggered by HCV E2 protein. Here we explored regulation of the MAPK/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway by E2 expressed in Chinese hamster oval cells. In human hepatoma Huh-7 cells, E2 specifically activated the MAPK/ERK pathway including downstream transcription factor ATF-2 and greatly promoted cell proliferation. CD81 and low density lipoprotein receptor (LDLR) on the cell surface mediated binding of E2 to Huh-7 cells. The MAPK/ERK activation and cell proliferation driven by E2 were suppressed by blockage of CD81 as well as LDLR. Furthermore, pretreatment with an upstream kinase MEK1/2 inhibitor U0126 also impaired the MAPK/ERK activation and cell proliferation induced by E2. Our results suggest that the MAPK/ERK signaling pathway triggered by HCV E2 via its receptors maintains survival and growth of target cells

  9. Vibration issues in passenger car

    OpenAIRE

    Rafał BURDZIK; Konieczny, Łukasz

    2014-01-01

    Vibration phenomena occurring in vehicles are very relevant for safety and comfort. Passenger car must be considered as a multi-technical system in which there are non-linear phenomena. Therefore, vibrations occurring in vehicles should be analyzed in many points of car structure and relate them to other criteria analysis. The paper presents examples of the results of vibration and their distribution at selected points during laboratory research and road tests.

  10. Vibration issues in passenger car

    Directory of Open Access Journals (Sweden)

    Rafał BURDZIK

    2014-09-01

    Full Text Available Vibration phenomena occurring in vehicles are very relevant for safety and comfort. Passenger car must be considered as a multi-technical system in which there are non-linear phenomena. Therefore, vibrations occurring in vehicles should be analyzed in many points of car structure and relate them to other criteria analysis. The paper presents examples of the results of vibration and their distribution at selected points during laboratory research and road tests.

  11. High-affinity FRβ-specific CAR T cells eradicate AML and normal myeloid lineage without HSC toxicity.

    Science.gov (United States)

    Lynn, R C; Feng, Y; Schutsky, K; Poussin, M; Kalota, A; Dimitrov, D S; Powell, D J

    2016-06-01

    Acute myeloid leukemia (AML) is an aggressive malignancy, and development of new treatments to prolong remissions is warranted. Chimeric antigen receptor (CAR) T-cell therapies appear promising but on-target, off-tumor recognition of antigen in healthy tissues remains a concern. Here we isolated a high-affinity (HA) folate receptor beta (FRβ)-specific single-chain variable fragment (2.48 nm KD) for optimization of FRβ-redirected CAR T-cell therapy for AML. T cells stably expressing the HA-FRβ CAR exhibited greatly enhanced antitumor activity against FRβ(+) AML in vitro and in vivo compared with a low-affinity FRβ CAR (54.3 nm KD). Using the HA-FRβ immunoglobulin G, FRβ expression was detectable in myeloid-lineage hematopoietic cells; however, expression in CD34(+) hematopoietic stem cells (HSCs) was nearly undetectable. Accordingly, HA-FRβ CAR T cells lysed mature CD14(+) monocytes, while HSC colony formation was unaffected. Because of the potential for elimination of mature myeloid lineage, mRNA CAR electroporation for transient CAR expression was evaluated. mRNA-electroporated HA-FRβ CAR T cells retained effective antitumor activity in vitro and in vivo. Together, our results highlight the importance of antibody affinity in target protein detection and CAR development and suggest that transient delivery of potent HA-FRβ CAR T cells is highly effective against AML and reduces the risk for long-term myeloid toxicity. PMID:26898190

  12. Welfare Effects of Distortionary Company Car Taxation

    NARCIS (Netherlands)

    Gutiérrez-i-Puigarnau, Eva; Ommeren, van Jos

    2007-01-01

    In Europe, company cars are offered by employers as fringe benefits to their employees at a lower price than employees pay in the car market, mainly due to favourable taxation of company cars. We analyse the welfare effects of favourable taxation of company cars for the Netherlands. The estimated an

  13. 49 CFR 231.6 - Flat cars.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Flat cars. 231.6 Section 231.6 Transportation... TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.6 Flat cars. (Cars with sides 12 inches or less above the floor may be equipped the same as flat cars.) (a) Hand brakes—(1) Number. Same as specified...

  14. 49 CFR 1037.2 - Cars.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 8 2010-10-01 2010-10-01 false Cars. 1037.2 Section 1037.2 Transportation Other... GENERAL RULES AND REGULATIONS BULK GRAIN AND GRAIN PRODUCTS-LOSS AND DAMAGE CLAIMS § 1037.2 Cars. A car is... railroad-leased cars....

  15. Art Cars: Transformations of the Mundane

    Science.gov (United States)

    Stienecker, Dawn

    2010-01-01

    The automobile itself is often understood as an extension of oneself, where individuals may manipulate the interior and exterior of cars and trucks, decorating them through detailing, stickers, custom colors, and so on. Others go further and change their cars into unique works of art called art cars. Such cars break away from the banality of mass…

  16. 49 CFR 215.203 - Restricted cars.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Restricted cars. 215.203 Section 215.203..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Restricted Equipment § 215.203 Restricted cars. (a) This section restricts the operation of any railroad freight car that is— (1) More than...

  17. Cellular resilience.

    Science.gov (United States)

    Smirnova, Lena; Harris, Georgina; Leist, Marcel; Hartung, Thomas

    2015-01-01

    Cellular resilience describes the ability of a cell to cope with environmental changes such as toxicant exposure. If cellular metabolism does not collapse directly after the hit or end in programmed cell death, the ensuing stress responses promote a new homeostasis under stress. The processes of reverting "back to normal" and reversal of apoptosis ("anastasis") have been studied little at the cellular level. Cell types show astonishingly similar vulnerability to most toxicants, except for those that require a very specific target, metabolism or mechanism present only in specific cell types. The majority of chemicals triggers "general cytotoxicity" in any cell at similar concentrations. We hypothesize that cells differ less in their vulnerability to a given toxicant than in their resilience (coping with the "hit"). In many cases, cells do not return to the naive state after a toxic insult. The phenomena of "pre-conditioning", "tolerance" and "hormesis" describe this for low-dose exposures to toxicants that render the cell more resistant to subsequent hits. The defense and resilience programs include epigenetic changes that leave a "memory/scar" - an alteration as a consequence of the stress the cell has experienced. These memories might have long-term consequences, both positive (resistance) and negative, that contribute to chronic and delayed manifestations of hazard and, ultimately, disease. This article calls for more systematic analyses of how cells cope with toxic perturbations in the long-term after stressor withdrawal. A technical prerequisite for these are stable (organotypic) cultures and a characterization of stress response molecular networks. PMID:26536287

  18. Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice

    Energy Technology Data Exchange (ETDEWEB)

    Park, Young Joo [Department of Internal Medicine, Seoul National University College of Medicine (Korea, Republic of); Seoul National University Bundang Hospital, Seoul (Korea, Republic of); Lee, Eun Kyung [Department of Internal Medicine, Seoul National University College of Medicine (Korea, Republic of); Lee, Yoon Kwang [Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030 (United States); Park, Do Joon; Jang, Hak Chul [Department of Internal Medicine, Seoul National University College of Medicine (Korea, Republic of); Moore, David D., E-mail: moore@bcm.edu [Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030 (United States)

    2012-09-01

    Clinical hypothyroidism affects various metabolic processes including drug metabolism. CYP2B and CYP3A are important cytochrome P450 drug metabolizing enzymes that are regulated by the xenobiotic receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2). We evaluated the regulation of the hepatic expression of CYPs by CAR and PXR in the hypothyroid state induced by a low-iodine diet containing 0.15% propylthiouracil. Expression of Cyp3a11 was suppressed in hypothyroid C57BL/6 wild type (WT) mice and a further decrement was observed in hypothyroid CAR{sup −/−} mice, but not in hypothyroid PXR{sup −/−} mice. In contrast, expression of Cyp2b10 was induced in both WT and PXR{sup −/−} hypothyroid mice, and this induction was abolished in CAR{sup −/−} mice and in and CAR{sup −/−} PXR{sup −/−} double knockouts. CAR mRNA expression was increased by hypothyroidism, while PXR expression remained unchanged. Carbamazepine (CBZ) is a commonly used antiepileptic that is metabolized by CYP3A isoforms. After CBZ treatment of normal chow fed mice, serum CBZ levels were highest in CAR{sup −/−} mice and lowest in WT and PXR{sup −/−} mice. Hypothyroid WT or PXR{sup −/−} mice survived chronic CBZ treatment, but all hypothyroid CAR{sup −/−} and CAR{sup −/−} PXR{sup −/−} mice died, with CAR{sup −/−}PXR{sup −/−} mice surviving longer than CAR{sup −/−} mice (12.3 ± 3.3 days vs. 6.3 ± 2.1 days, p = 0.04). All these findings suggest that hypothyroid status affects xenobiotic metabolism, with opposing responses of CAR and PXR and their CYP targets that can cancel each other out, decreasing serious metabolic derangement in response to a xenobiotic challenge. -- Highlights: ► Hypothyroid status activates CAR in mice and induces Cyp2b10 expression. ► Hypothyroid status suppresses PXR activity in mice and represses Cyp3a11 expression. ► These responses balance each other out in normal mice.

  19. Design of chimeric antigen receptors with integrated controllable transient functions

    OpenAIRE

    Alexandre Juillerat; Alan Marechal; Jean-Marie Filhol; Julien Valton; Aymeric Duclert; Laurent Poirot; Philippe Duchateau

    2016-01-01

    The ability to control T cells engineered to permanently express chimeric antigen receptors (CARs) is a key feature to improve safety. Here, we describe the development of a new CAR architecture with an integrated switch-on system that permits to control the CAR T-cell function. This system offers the advantage of a transient CAR T-cell for safety while letting open the possibility of multiple cytotoxicity cycles using a small molecule drug.

  20. Design of chimeric antigen receptors with integrated controllable transient functions.

    Science.gov (United States)

    Juillerat, Alexandre; Marechal, Alan; Filhol, Jean-Marie; Valton, Julien; Duclert, Aymeric; Poirot, Laurent; Duchateau, Philippe

    2016-01-01

    The ability to control T cells engineered to permanently express chimeric antigen receptors (CARs) is a key feature to improve safety. Here, we describe the development of a new CAR architecture with an integrated switch-on system that permits to control the CAR T-cell function. This system offers the advantage of a transient CAR T-cell for safety while letting open the possibility of multiple cytotoxicity cycles using a small molecule drug. PMID:26750734

  1. [Current status and future development of CAR-T gene therapy].

    Science.gov (United States)

    Ozawa, Keiya

    2015-10-01

    Adoptive T-cell therapy using chimeric antigen receptor (CAR) technology is a novel approach to cancer immuno-gene therapy. CARs are hybrid proteins consisting of a target-antigen-specific single-chain antibody fragment fused to intracellular T-cell activation domains (CD28 or CD137/CD3ζ receptor). CAR-expressing engineered T lymphocytes can directly recognize and kill tumor cells in an HLA independent manner. In the United States, promising results have been obtained in clinical trials of adoptive immuno-gene therapy using CD19-CAR-T lymphocytes for the treatment of refractory B-cell malignancies, including chronic lymphocytic leukemia (CLL), acute lymphoblastic leukemia (ALL), and malignant lymphoma. PMID:26458458

  2. Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts.

    Science.gov (United States)

    Cartellieri, M; Feldmann, A; Koristka, S; Arndt, C; Loff, S; Ehninger, A; von Bonin, M; Bejestani, E P; Ehninger, G; Bachmann, M P

    2016-01-01

    The adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide 'proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo. PMID:27518241

  3. New concepts in calcium-sensing receptor pharmacology and signalling

    OpenAIRE

    Ward, Donald T.; Riccardi, Daniela

    2012-01-01

    The calcium-sensing receptor (CaR) is the key controller of extracellular calcium (Ca2+o) homeostasis via its regulation of parathyroid hormone (PTH) secretion and renal Ca2+ reabsorption. The CaR-selective calcimimetic drug Cinacalcet stimulates the CaR to suppress PTH secretion in chronic kidney disease and represents the world's first clinically available receptor positive allosteric modulator (PAM). Negative CaR allosteric modulators (NAMs), known as calcilytics, can increase PTH secretio...

  4. Car sharing à la carte

    CERN Multimedia

    Anaïs Schaeffer

    2012-01-01

    Do you want to make your commute to CERN easier, while saving money at the same time? Would you prefer not to spend a quarter of an hour crawling round the CERN car parks looking for a space? If so, read on: this article might well be of great interest to you.   We would like to draw your attention to a well established, albeit sadly under-used, method of transport: car sharing. To promote car-sharing, the GS Department has stepped in to call on the services of the Swiss firm Green Monkeys which specialises in this user-friendly and intelligent transport scheme. The company’s slogan is:  “Car-sharing as you want, when you want and as much as you want”. The principle is very straightforward. To use this car-sharing facility, you simply complete your free online registration with Green Monkeys, providing the following details: your journey, departure time, arrival time and days of the week, and indicating whether you are a passenger or driver or both. &a...

  5. Substitution between Cars within the Household

    DEFF Research Database (Denmark)

    de Borger, Bruno; Mulalic, Ismir; Rouwendal, Jan

    In this paper we study the demand for car kilometres in two-car households, focusing on the substitution between cars in response to fuel price changes. We use a large sample of detailed Danish data on two-car households to estimate—for each car owned by the household—own and cross-price effects of...... increases in fuel costs per kilometre. The empirical results show that failure to capture substitution between cars within the household can result in substantial misspecification biases. Ignoring substitution, we estimate fuel price elasticities of –0.81 and -0.65 for the primary and secondary cars...... efficient car, finding partial support for the underlying hypothesis. More importantly, the results of this extended model emphasize the importance of behavioural differences related to the position of the most fuel efficient car in the household, suggesting that households’ fuel efficiency choices are...

  6. One smart card, one less car

    Energy Technology Data Exchange (ETDEWEB)

    Fenton, B.

    2003-06-30

    A system of car-sharing in Bremen, Germany, a membership-based structure of car-sharing that gives members access to a network of cars stationed throughout the city on a pay-per-trip basis, and without the hassles of car ownership, is discussed. The car-sharing scheme is combined with the city's transit system by means of a smart card that serves both as a pass for the city's transit system and as an electronic key to the cars in the car-sharing system. Future plans include to use the card also as a method of payment for taxis, and organizers are also working with the municipal government to get support for having car-sharing included in the city's official plan. At present, car-sharing stations are simply reserved parking spots for one or more cars, however, future stations are envisaged to include parking for up to five cars, a computer to book cars, direct access to keys using the smart card, parking for bicycles, and information about car-sharing stations, bus, trams, as well as bike and walking routes. Similar, if somewhat more modest, car-sharing schemes are also available in several cities in Canada, including Halifax, Quebec City, Montreal, Toronto, Calgary, Edmonton and Vancouver.

  7. High-Mobility-Group A-Like CarD Binds to a DNA Site Optimized for Affinity and Position and to RNA Polymerase To Regulate a Light-Inducible Promoter in Myxococcus xanthus

    OpenAIRE

    García-Heras, Francisco; Abellón-Ruiz, Javier; Murillo, Francisco J.; Padmanabhan, S.; Elías-Arnanz, Montserrat

    2013-01-01

    The CarD-CarG complex controls various cellular processes in the bacterium Myxococcus xanthus including fruiting body development and light-induced carotenogenesis. The CarD N-terminal domain, which defines the large CarD_CdnL_TRCF protein family, binds to CarG, a zinc-associated protein that does not bind DNA. The CarD C-terminal domain resembles eukaryotic high-mobility-group A (HMGA) proteins, and its DNA binding AT hooks specifically recognize the minor groove of appropriately spaced AT-r...

  8. Differences between disease-associated endoplasmic reticulum aminopeptidase 1 (ERAP1) isoforms in cellular expression, interactions with tumour necrosis factor receptor 1 (TNF-R1) and regulation by cytokines.

    Science.gov (United States)

    Yousaf, N; Low, W Y; Onipinla, A; Mein, C; Caulfield, M; Munroe, P B; Chernajovsky, Y

    2015-05-01

    Endoplasmic reticulum aminopeptidase 1 (ERAP1) processes peptides for major histocompatibility complex (MHC) class I presentation and promotes cytokine receptor ectodomain shedding. These known functions of ERAP1 may explain its genetic association with several autoimmune inflammatory diseases. In this study, we identified four novel alternatively spliced variants of ERAP1 mRNA, designated as ΔExon-11, ΔExon-13, ΔExon-14 and ΔExon-15. We also observed a rapid and differential modulation of ERAP1 mRNA levels and spliced variants in different cell types pretreated with lipopolysaccharide (LPS). We have studied three full-length allelic forms of ERAP1 (R127-K528, P127-K528, P127-R528) and one spliced variant (ΔExon-11) and assessed their interactions with tumour necrosis factor receptor 1 (TNF-R1) in transfected cells. We observed variation in cellular expression of different ERAP1 isoforms, with R127-K528 being expressed at a much lower level. Furthermore, the cellular expression of full-length P127-K528 and ΔExon-11 spliced variant was enhanced significantly when co-transfected with TNF-R1. Isoforms P127-K528, P127-R528 and ΔExon-11 spliced variant associated with TNF-R1, and this interaction occurred in a region within the first 10 exons of ERAP1. Supernatant-derived vesicles from transfected cells contained the full-length and ectodomain form of soluble TNF-R1, as well as carrying the full-length ERAP1 isoforms. We observed marginal differences between TNF-R1 ectodomain levels when co-expressed with individual ERAP1 isoforms, and treatment of transfected cells with tumour necrosis factor (TNF), interleukin (IL)-1β and IL-10 exerted variable effects on TNF-R1 ectodomain cleavage. Our data suggest that ERAP1 isoforms may exhibit differential biological properties and inflammatory mediators could play critical roles in modulating ERAP1 expression, leading to altered functional activities of this enzyme. PMID:25545008

  9. Substitution between cars within the household

    DEFF Research Database (Denmark)

    De Borger, Bruno; Mulalic, Ismir; Rouwendal, Jan

    The purpose of this paper is to study to what extent two-car households substitute the use of their less fuel efficient car by the use of their more fuel efficient car after an increase in fuel prices. Based on a simple theoretical framework we use a large sample of detailed Danish data on two-car...... households to estimate, for each car owned by the household, own and cross-price effects of increases in fuel costs per kilometer. The empirical results point at important substitution effects, so that models that estimate responses to fuel prices on the implicit or explicit assumption of one car per...

  10. Car car cars:车库梦想

    Institute of Scientific and Technical Information of China (English)

    2014-01-01

    在曾经关于南京摇滚大集合的专题中我们介绍过这支年轻而有趣的乐队,当时他们刚刚开始,最令人印象深刻是男吉他+女鼓手的车库摇滚乐队配置,今年,他们在近一年的辗转与坚持中,越来越多地参与到南京、北京和更多城市的演出中,同时独立发行了乐队的首张同名EP。Car Car Cars的名字和他们热衷的车库风格鲜明地联系在一起,而除了对于风格上的暗示,这个名字与他们最初组建时一直在一间废弃的驾校模拟器教室排练有很大关系。“里面有很多那种模驾练习机嘛,当时就想取一个和“车”有关的乐队名字应该很酷,就叫CAR CAR CARS吧!”酷的不只有名字,Car Car Cars由兄妹二人组成,主唱兼吉他手小汤是年轻的哥哥。鼓手是漂亮的妹妹,这种无意间造就的话题性让人有意无意地联系统The White Stripes。除了外型、配置上的天生抢眼,Car Car Cars这一年中的数场演出,也展示了他们凌厉的台风与属于车库的狂野,首张EP一上来就使用了同期录音的方式,展示了很多惊喜,虽然也不可避免地了一些些遗憾。在进一步的发展中。克服了创作、表现力的一些进阶困难之后,Car Car Cars完全有实力为风格趋于过份统一的国内年轻摇滚圈添上与众不同的一笔。

  11. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition.

    Science.gov (United States)

    Cherkassky, Leonid; Morello, Aurore; Villena-Vargas, Jonathan; Feng, Yang; Dimitrov, Dimiter S; Jones, David R; Sadelain, Michel; Adusumilli, Prasad S

    2016-08-01

    Following immune attack, solid tumors upregulate coinhibitory ligands that bind to inhibitory receptors on T cells. This adaptive resistance compromises the efficacy of chimeric antigen receptor (CAR) T cell therapies, which redirect T cells to solid tumors. Here, we investigated whether programmed death-1-mediated (PD-1-mediated) T cell exhaustion affects mesothelin-targeted CAR T cells and explored cell-intrinsic strategies to overcome inhibition of CAR T cells. Using an orthotopic mouse model of pleural mesothelioma, we determined that relatively high doses of both CD28- and 4-1BB-based second-generation CAR T cells achieved tumor eradication. CAR-mediated CD28 and 4-1BB costimulation resulted in similar levels of T cell persistence in animals treated with low T cell doses; however, PD-1 upregulation within the tumor microenvironment inhibited T cell function. At lower doses, 4-1BB CAR T cells retained their cytotoxic and cytokine secretion functions longer than CD28 CAR T cells. The prolonged function of 4-1BB CAR T cells correlated with improved survival. PD-1/PD-1 ligand [PD-L1] pathway interference, through PD-1 antibody checkpoint blockade, cell-intrinsic PD-1 shRNA blockade, or a PD-1 dominant negative receptor, restored the effector function of CD28 CAR T cells. These findings provide mechanistic insights into human CAR T cell exhaustion in solid tumors and suggest that PD-1/PD-L1 blockade may be an effective strategy for improving the potency of CAR T cell therapies. PMID:27454297

  12. Structure of the Murine Constitutive Androstane Receptor Complexed to Androstenol: A Molecular Basis for Inverse Agonism

    OpenAIRE

    Shan, Li; Vincent, Jeremy; Brunzelle, Joseph S.; Dussault, Isabelle; Lin, Min; Ianculescu, Irina; Sherman, Mark A.; Forman, Barry M.; Fernandez, Elias J.

    2004-01-01

    The nuclear receptor CAR is a xenobiotic responsive transcription factor that plays a central role in the clearance of drugs and bilirubin while promoting cocaine and acetaminophen toxicity. In addition, CAR has established a “reverse” paradigm of nuclear receptor action where the receptor is active in the absence of ligand and inactive when bound to inverse agonists. We now report the crystal structure of murine CAR bound to the inverse agonist androstenol. Androstenol binds within the ligan...

  13. Big Car,More Costly?

    Institute of Scientific and Technical Information of China (English)

    Liu Jiangwen

    2008-01-01

    @@ Latest story Current story on car consumption tax is performing in China.Consumption tax is levied on goods on the basis of value-added tax (VAT).A small number of commodities are chosen to impose consumption tax.which is usually seen in the production sector.

  14. Recharging Emission-Free Cars

    Institute of Scientific and Technical Information of China (English)

    CORRIE; DOSH

    2008-01-01

    New York dealership begins sales of China-made electric vehicles In the 2006 documentary Who Killed the Electric Car?, Director Chris Paine showed how auto manufacturers, the oil industry, government officials and consumers suppressed the development of allelectric, emission-free vehicles. Now, with

  15. The Speeding Car Design Challenge

    Science.gov (United States)

    Roman, Harry T.

    2009-01-01

    All too often, one reads about high-speed police chases in pursuit of stolen cars that result in death and injury to people and innocent bystanders. Isn't there another way to accomplish the apprehension of the thieves that does not put people at such great risk? This article presents a classroom challenge to use technology to remotely shutdown…

  16. Passenger car market encountered depression

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    <正>Passenger vehicle registrations in April-typically one of the hot seasons for passenger vehicle registrations-showed a poor performance in 2008. All the body types saw low growth for the second time this year except SUVs. The Passenger car market (including sedan, hatchback, coupe, roadster

  17. Restoring a Classic Electric Car

    Science.gov (United States)

    Kraft, Thomas E.

    2012-01-01

    One hundred years ago, automobiles were powered by steam, electricity, or internal combustion. Female drivers favored electric cars because, unlike early internal-combustion vehicles, they did not require a crank for starting. Nonetheless, internal-combustion vehicles came to dominate the industry and it's only in recent years that the electrics…

  18. Automated Car Park Management System

    Science.gov (United States)

    Fabros, J. P.; Tabañag, D.; Espra, A.; Gerasta, O. J.

    2015-06-01

    This study aims to develop a prototype for an Automated Car Park Management System that will increase the quality of service of parking lots through the integration of a smart system that assists motorist in finding vacant parking lot. The research was based on implementing an operating system and a monitoring system for parking system without the use of manpower. This will include Parking Guidance and Information System concept which will efficiently assist motorists and ensures the safety of the vehicles and the valuables inside the vehicle. For monitoring, Optical Character Recognition was employed to monitor and put into list all the cars entering the parking area. All parking events in this system are visible via MATLAB GUI which contain time-in, time-out, time consumed information and also the lot number where the car parks. To put into reality, this system has a payment method, and it comes via a coin slot operation to control the exit gate. The Automated Car Park Management System was successfully built by utilizing microcontrollers specifically one PIC18f4550 and two PIC16F84s and one PIC16F628A.

  19. Inflation Rates, Car Devaluation, and Chemical Kinetics

    Science.gov (United States)

    Pogliani, Lionello; Berberan-Santos, Màrio N.

    1996-10-01

    The inflation rate problem of a modern economy shows quite interesting similarities with chemical kinetics and especially with first-order chemical reactions. In fact, capital devaluation during periods of rather low inflation rates or inflation measured over short periods shows a dynamics formally similar to that followed by first-order chemical reactions and they can thus be treated by the aid of the same mathematical formalism. Deviations from this similarity occurs for higher inflation rates. The dynamics of price devaluation for two different types of car, a compact car and a luxury car, has been followed for seven years long and it has been established that car devaluation is a process that is formally similar to a zeroth-order chemical kinetic process disregarding the type of car, if car devaluation is much faster than money devaluation. In fact, expensive cars devaluate with a faster rate than inexpensive cars.

  20. Clustering nuclear receptors in liver regeneration identifies candidate modulators of hepatocyte proliferation and hepatocarcinoma.

    Directory of Open Access Journals (Sweden)

    Michele Vacca

    Full Text Available BACKGROUND & AIMS: Liver regeneration (LR is a valuable model for studying mechanisms modulating hepatocyte proliferation. Nuclear receptors (NRs are key players in the control of cellular functions, being ideal modulators of hepatic proliferation and carcinogenesis. METHODS & RESULTS: We used a previously validated RT-qPCR platform to profile modifications in the expression of all 49 members of the NR superfamily in mouse liver during LR. Twenty-nine NR transcripts were significantly modified in their expression during LR, including fatty acid (peroxisome proliferator-activated receptors, PPARs and oxysterol (liver X receptors, Lxrs sensors, circadian masters RevErbα and RevErbβ, glucocorticoid receptor (Gr and constitutive androxane receptor (Car. In order to detect the NRs that better characterize proliferative status vs. proliferating liver, we used the novel Random Forest (RF analysis to selected a trio of down-regulated NRs (thyroid receptor alpha, Trα; farsenoid X receptor beta, Fxrβ; Pparδ as best discriminators of the proliferating status. To validate our approach, we further studied PPARδ role in modulating hepatic proliferation. We first confirmed the suppression of PPARδ both in LR and human hepatocellular carcinoma at protein level, and then demonstrated that PPARδ agonist GW501516 reduces the proliferative potential of hepatoma cells. CONCLUSIONS: Our data suggest that NR transcriptome is modulated in proliferating liver and is a source of biomarkers and bona fide pharmacological targets for the management of liver disease affecting hepatocyte proliferation.

  1. ANALYSIS OF MODERN CAR BODY STRAIGHTENING METHODS

    Directory of Open Access Journals (Sweden)

    Arhun, Sch.

    2013-01-01

    Full Text Available The analysis of modern car body panels straightening methods is carried out. There have been described both traditional and alternative methods of car body panels straightening. The urgency of magnetic pulse teсhnology dignment is grounded. The main advantages of magnetic pulse teсhno-logy of car body straightening are defernined.

  2. Bayesian calibration of car-following models

    NARCIS (Netherlands)

    Van Hinsbergen, C.P.IJ.; Van Lint, H.W.C.; Hoogendoorn, S.P.; Van Zuylen, H.J.

    2010-01-01

    Recent research has revealed that there exist large inter-driver differences in car-following behavior such that different car-following models may apply to different drivers. This study applies Bayesian techniques to the calibration of car-following models, where prior distributions on each model p

  3. Determining the Air Drag on a Car.

    Science.gov (United States)

    Farr, John E.

    1983-01-01

    Students' cars and wristwatches are used as "apparatus" to introduce and demonstrate Newton's second law of motion. Forces acting on cars are discussed and typical student data (for different makes of cars) are provided. Data could also be used in discussions of work, horsepower, efficiency, and energy cost. (JN)

  4. 49 CFR 174.57 - Cleaning cars.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Cleaning cars. 174.57 Section 174.57... and Loading Requirements § 174.57 Cleaning cars. All hazardous material which has leaked from a package in any rail car or on other railroad property must be carefully removed....

  5. Car Ownership and Private Car Use A Microeconometric Analysis Based on Norwegian Data

    OpenAIRE

    Dag G. Wetterwald

    1994-01-01

    In this paper we analyze household's car ownership and private car use decisions in a model proposed by de Jong (1990). The model, which incorporates variable and fixed costs of car use, can be used to predict the effects of changes in policy measures on the car stock and aggregate use. The model is estimated on Norwegian household data for 1985.

  6. Entwurfskonzept einer Car2Car-Multiband-Dachantenne

    Science.gov (United States)

    Wang, Y.; Reit, M.; Mathis, W.

    2012-09-01

    Due to the vastly increasing use of wireless services in the car, such as WiFi, Car2Car and LTE, the requirements on bandwidth and radiation pattern of the roof antenna systems become more challenging. In this work, a design concept for multi-band roof antenna systems is presented. We aim to get a higher bandwidth and an almost circular radiation pattern on the horizontal plane. Moreover, the antenna length is considered in order to fulfill the requirements set by construction ECE-regulations (ECE, 2010). The applicability of the design concept is not limited to multi-band roof antennas, it can also be used for a general wideband antenna design. For illustration of this concept, a multi-band roof antenna with a bandwidth of 780 MHz to 5.9 GHz and a near circular radiation pattern with an average gain of G = 3 dBi (at 5.9 GHz) on the horizontal plane is designed. The simulation and measurement results are presented.

  7. ARM7 Based Smart Car Security System.

    OpenAIRE

    J.R. Shaikh, S. M. Kate

    2012-01-01

    The main aim of this project is to offer an advance security system in CAR, which consists of a face detection subsystem, a GPS module, a GSM module and a control platform. The face detection subsystem can detect faces in cars during the period in which nobody should be in the car, and make an alarm loudly or soundlessly. The other modules transmit necessary information to users and help to keep eyes on cars all the time, even when the car is lost.In todays world, many new techniques such as ...

  8. Human Receptor Activation by Aroclor 1260, a Polychlorinated Biphenyl Mixture

    OpenAIRE

    Wahlang, Banrida; Falkner, K. Cameron; Clair, Heather B.; Al-Eryani, Laila; Prough, Russell A.; States, J. Christopher; Coslo, Denise M.; Omiecinski, Curtis J.; Cave, Matthew C.

    2014-01-01

    Polychlorinated biphenyls (PCBs) are persistent environmental toxicants, present in 100% of U.S. adults and dose-dependently associated with obesity and non-alcoholic fatty liver disease (NAFLD). PCBs are predicted to interact with receptors previously implicated in xenobiotic/energy metabolism and NAFLD. These receptors include the aryl hydrocarbon receptor (AhR), pregnane xenobiotic receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptors (PPARs), ...

  9. 49 CFR 215.121 - Defective car body.

    Science.gov (United States)

    2010-10-01

    ..., DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Car Bodies § 215.121 Defective car body. A railroad may not place or continue in service a car, if: (a) Any portion of... 49 Transportation 4 2010-10-01 2010-10-01 false Defective car body. 215.121 Section...

  10. Car insurance information management system

    OpenAIRE

    SUN, Yu

    2015-01-01

    A customer information system is a typical information management system. It involves three aspects, the backstage database establishment, the application development and the system maintenance. A car insurance information management system is based on browser/server structure. Microsoft SQL Server establishes the backstage database. Active Server Pages, from Microsoft as well is used as the interface layer. The objective of this thesis was to apply ASP to the dynamic storage of a web page...

  11. Thermoelectric Air Cooling For Cars

    Directory of Open Access Journals (Sweden)

    Manoj S. Raut

    2012-05-01

    Full Text Available India is the second most populous country in the world with over 1.21billion people (estimated for April, 2011,more than sixth of the world’s population. India is projected to be world’s most populous country by 2025,surpassing china, its population exceeding 1.6 billion people by 2050.Comparing with the population there are 2.65 million cars sold in India as of march 2011.According to the society of Indian automotive manufacturer, annual car sales are projected to increase up to 5 million vehicles by 2015 and more than a 9 million by 2020.By 2050,the country is expected to top of the world in car volumes with approximately 611 million vehicles on the nation’s roads.The above data shows that, as the population increase the no. of vehicles also increase. Today, an automobile is a necessity for everyone. For a long or short journey people need car regard to thesafety, environment and most important comfort. Owing to these reasons, many vehicles are equipped with heating, ventilating and air conditioning system. In today’s world, no one feel comfortable in a vehicle without HVAC system. Therefore, HVAC becomes an integral part of human life. Today’s present HVAC system is very efficient and reliable but it has some demerits. It has been observed during the last two decades that the O3 –layer is slowly destroyed because of the refrigerant (CFC and HFC used for the refrigeration and air –conditioning purposes. The common refrigerant used is HFC’s which are leaked and slowly climb into the atmosphere. When they reach to O3 layer they act on O3 –molecules and the layer of O3 is destroyed.

  12. Servicing a Connected Car Service

    OpenAIRE

    Svensson, Benjamin; Varnai, Kristian

    2015-01-01

    Increased wireless connectivity to vehicles invites both existing and new digital methods of attack, requiring the high prioritisation of security throughout the development of not just the vehicle, but also the services provided for it. This report examines such a connected car service used by thousands of customers every day and evaluates it from a security standpoint. The methods used for this evaluation include both direct testing of vulnerabilities, as well as the examination of design c...

  13. Substitution between cars within the household

    DEFF Research Database (Denmark)

    De Borger, Bruno; Mulalic, Ismir; Rouwendal, Jan

    2016-01-01

    In this paper we study the demand for car kilometres in two-car households, focusing on the substitution between cars of different fuel efficiency in response to fuel price changes. We use a large sample of detailed Danish data on two-car households to estimate – for each car owned by the household...... – own and cross-price effects of increases in fuel costs per kilometre. The empirical results show that failure to capture substitution between cars within the household can result in substantial misspecification biases. Ignoring substitution, the basic model yielded fuel price elasticities of 0.98 and...... 1.41 for the primary and secondary cars, respectively. Accounting for substitution effects, these figures reduce to, respectively, 0.32 and 0.45. Consistent with substitution behaviour, we find that the fuel price elasticity of fuel demand exceeds the elasticity of kilometre demands with respect to...

  14. Coordinated Roles of Pregnane X Receptor and Constitutive Androstane Receptor in Autoinduction of Voriconazole Metabolism in Mice

    OpenAIRE

    Ohbuchi, Masato; Yoshinari, Kouichi; Kaneko, Hayato; Matsumoto, Satoru; Inoue, Akiko; Kawamura, Akio; Usui, Takashi; Yamazoe, Yasushi

    2013-01-01

    The antifungal efficacy of voriconazole (VRC) differs among host species, with potent efficacy in humans but less in rodents. We investigated the possible involvement of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the species-specific efficacy of VRC through pharmacokinetic analyses using genetically modified mice and primary human hepatocytes. VRC (30 mg/kg) was orally administered to wild-type, Pxr-null, Car-null, and Pxr- and Car-null (Pxr/Car-null) mice for 7 d...

  15. Phagocytosis, a cellular immune response in insects

    Directory of Open Access Journals (Sweden)

    C Rosales

    2011-06-01

    Full Text Available Insects like many other organisms are exposed to a wide range of infectious agents. Defense against these agents is provided by innate immune systems, which include physical barriers, humoral responses, and cellular responses. The humoral responses are characterized by the production of antimicrobial peptides, while the cellular defense responses include nodulation, encapsulation, melanization and phagocytosis. The phagocytic process, whereby cells ingest large particles, is of fundamental importance for insects’ development and survival. Phagocytic cells recognize foreign particles through a series of receptors on their cell membrane for pathogen-associated molecules. These receptors in turn initiate a series of signaling pathways that instruct the cell to ingest and eventually destroy the foreign particle. This review describes insect innate humoral and cellular immune functions with emphasis on phagocytosis. Recent advances in our understanding of the phagocytic cell types in various insect species; the receptors involved and the signaling pathways activated during phagocytosis are discussed.

  16. CAR-mediated repression of Foxo1 transcriptional activity regulates the cell cycle inhibitor p21 in mouse livers

    International Nuclear Information System (INIS)

    Highlights: • CAR activation decreased the level of Foxo1 in mouse livers. • CAR activation decreased the level of p21 in mouse livers. • CAR activation inhibited Foxo1 transcriptional activity in mouse livers. - Abstract: 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), an agonist of constitutive androstane receptor (CAR), is a well-known strong primary chemical mitogen for the mouse liver. Despite extensive investigation of the role of CAR in the regulation of cell proliferation, our knowledge of the intricate mediating mechanism is incomplete. In this study, we demonstrated that long-term CAR activation by TCPOBOP increased liver-to-body weight ratio and decreased tumour suppressor Foxo1 expression and transcriptional activity, which were correlated with reduced expression of genes regulated by Foxo1, including the cell-cycle inhibitor Cdkn1a(p21), and upregulation of the cell-cycle regulator Cyclin D1. Moreover, we demonstrated the negative regulatory effect of TCPOBOP-activated CAR on the association of Foxo1 with the target Foxo1 itself and Cdkn1a(p21) promoters. Thus, we identified CAR-mediated repression of cell cycle inhibitor p21, as mediated by repression of FOXO1 expression and transcriptional activity. CAR-FOXO1 cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments

  17. The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone

    OpenAIRE

    Kos, Claudine H; Karaplis, Andrew C.; Peng, Ji-Bin; Hediger, Matthias A; Goltzman, David; Mohammad, Khalid S.; Guise, Theresa A.; Pollak, Martin R.

    2003-01-01

    The extracellular calcium-sensing receptor (CaR; alternate gene names, CaR or Casr) is a membrane-spanning G protein–coupled receptor. CaR is highly expressed in the parathyroid gland, and is activated by extracellular calcium (Ca2+o). Mice homozygous for null mutations in the CaR gene (CaR–/–) die shortly after birth because of the effects of severe hyperparathyroidism and hypercalcemia. A wide variety of functions have been attributed to CaR. However, the lethal CaR-deficient phenotype has ...

  18. Toxicities of chimeric antigen receptor T cells: recognition and management.

    Science.gov (United States)

    Brudno, Jennifer N; Kochenderfer, James N

    2016-06-30

    Chimeric antigen receptor (CAR) T cells can produce durable remissions in hematologic malignancies that are not responsive to standard therapies. Yet the use of CAR T cells is limited by potentially severe toxicities. Early case reports of unexpected organ damage and deaths following CAR T-cell therapy first highlighted the possible dangers of this new treatment. CAR T cells can potentially damage normal tissues by specifically targeting a tumor-associated antigen that is also expressed on those tissues. Cytokine release syndrome (CRS), a systemic inflammatory response caused by cytokines released by infused CAR T cells can lead to widespread reversible organ dysfunction. CRS is the most common type of toxicity caused by CAR T cells. Neurologic toxicity due to CAR T cells might in some cases have a different pathophysiology than CRS and requires different management. Aggressive supportive care is necessary for all patients experiencing CAR T-cell toxicities, with early intervention for hypotension and treatment of concurrent infections being essential. Interleukin-6 receptor blockade with tocilizumab remains the mainstay pharmacologic therapy for CRS, though indications for administration vary among centers. Corticosteroids should be reserved for neurologic toxicities and CRS not responsive to tocilizumab. Pharmacologic management is complicated by the risk of immunosuppressive therapy abrogating the antimalignancy activity of the CAR T cells. This review describes the toxicities caused by CAR T cells and reviews the published approaches used to manage toxicities. We present guidelines for treating patients experiencing CRS and other adverse events following CAR T-cell therapy. PMID:27207799

  19. CARS

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    Mercury Mariner混合动力车是一款豪华紧凑型SUV,它采用混合动力发动机,无级变速和全驱动驾驶,续航里程达640公里。如果您是一位不喜欢走寻常路的人,那么这款车型先进的导航系统以及出色的稳定性控制定会给带来惊喜。

  20. CARS

    Institute of Scientific and Technical Information of China (English)

    李啸龙

    2011-01-01

    MINI COUNTRYMAN成为国内空客A380首航专用引导车 10月17日,来自中国南方航空公司的国内首架空客A380于北京首都国际机场起飞,经过近2000km、3个小时的航程,成功降落在广州白云国际机场,3辆MINI COUNTRYMAN引导着这一架“空中巨无霸”精准停机入位。

  1. CARS

    Institute of Scientific and Technical Information of China (English)

    李啸龙

    2011-01-01

    MINI COUNTRYMAN成为国内空客A380首航专用引导车10月17日,来自中国南方航空公司的国内首架空客A380于北京首都国际机场起飞,经过近2000km、3个小时的航程,成功降落在广州白云国际机场,3辆MINI COUNTRYMAN引导着这一架“空中巨无霸”精准停机入位。

  2. In vivo hyperspectral CARS and FWM microscopy of carotenoid accumulation in H. Pluvialis

    Science.gov (United States)

    Slepkov, Aaron D.; Barlow, Aaron M.; Ridsdale, Andrew; McGinn, Patrick J.; Stolow, Albert

    2014-02-01

    Coherent anti-Stokes Raman scattering (CARS) and four-wave-mixing (FWM) microscopy are a related pair of powerful nonlinear optical characterization tools. These techniques often yield strong signals from concentrated samples, but because of their quadratic dependence on concentration, they are not typically employed for imaging or identifying dilute cellular constituents. We report here that, depending on the excitation wavelengths employed, both CARS and degenerate-FWM signals from carotenoid accumulations in alga cysts can be exceptionally large, allowing for low-power imaging of astaxanthin (AXN) deposits in Haematococcus pluvialis microalga. By use of a broadband laser pulse scheme for CARS and FWM, we are able to simultaneously collect strong intrinsic two-photon-excitation fluorescence signals from cellular chlorophyll in vivo. We show that CARS signals from astaxanthin (AXN) samples in vitro strictly follow the expected quadratic dependence on concentration, and we demonstrate the collection of wellresolved CARS spectra in the fingerprint region with sensitivity below 2mM. We suggest that multimodal nonlinear optical microscopy is sufficiently sensitive to AXN and chlorophyll concentrations that it will allow for non-invasive monitoring of carotenogenesis in live H. pluvialis microalgae.

  3. Switch-mediated activation and retargeting of CAR-T cells for B-cell malignancies.

    Science.gov (United States)

    Rodgers, David T; Mazagova, Magdalena; Hampton, Eric N; Cao, Yu; Ramadoss, Nitya S; Hardy, Ian R; Schulman, Andrew; Du, Juanjuan; Wang, Feng; Singer, Oded; Ma, Jennifer; Nunez, Vanessa; Shen, Jiayin; Woods, Ashley K; Wright, Timothy M; Schultz, Peter G; Kim, Chan Hyuk; Young, Travis S

    2016-01-26

    Chimeric antigen receptor T (CAR-T) cell therapy has produced impressive results in clinical trials for B-cell malignancies. However, safety concerns related to the inability to control CAR-T cells once infused into the patient remain a significant challenge. Here we report the engineering of recombinant antibody-based bifunctional switches that consist of a tumor antigen-specific Fab molecule engrafted with a peptide neo-epitope, which is bound exclusively by a peptide-specific switchable CAR-T cell (sCAR-T). The switch redirects the activity of the bio-orthogonal sCAR-T cells through the selective formation of immunological synapses, in which the sCAR-T cell, switch, and target cell interact in a structurally defined and temporally controlled manner. Optimized switches specific for CD19 controlled the activity, tissue-homing, cytokine release, and phenotype of sCAR-T cells in a dose-titratable manner in a Nalm-6 xenograft rodent model of B-cell leukemia. The sCAR-T-cell dosing regimen could be tuned to provide efficacy comparable to the corresponding conventional CART-19, but with lower cytokine levels, thereby offering a method of mitigating cytokine release syndrome in clinical translation. Furthermore, we demonstrate that this methodology is readily adaptable to targeting CD20 on cancer cells using the same sCAR-T cell, suggesting that this approach may be broadly applicable to heterogeneous and resistant tumor populations, as well as other liquid and solid tumor antigens. PMID:26759369

  4. Piracy on the molecular level: human herpesviruses manipulate cellular chemotaxis.

    Science.gov (United States)

    Cornaby, Caleb; Tanner, Anne; Stutz, Eric W; Poole, Brian D; Berges, Bradford K

    2016-03-01

    Cellular chemotaxis is important to tissue homeostasis and proper development. Human herpesvirus species influence cellular chemotaxis by regulating cellular chemokines and chemokine receptors. Herpesviruses also express various viral chemokines and chemokine receptors during infection. These changes to chemokine concentrations and receptor availability assist in the pathogenesis of herpesviruses and contribute to a variety of diseases and malignancies. By interfering with the positioning of host cells during herpesvirus infection, viral spread is assisted, latency can be established and the immune system is prevented from eradicating viral infection. PMID:26669819

  5. Diesel cars in the United States

    Energy Technology Data Exchange (ETDEWEB)

    1978-06-01

    The purpose of this study was to develop a better understanding of the causes of the recent increased interest in diesel cars, thereby providing insight into the related behavior of institutions and individuals. This knowledge may improve the formulation of federal policies for diesel, electric, and other more energy-efficient car systems. The study describes developments in the diesel car field over the past few years, and discusses the present status of diesel cars. Historical data were assembled on diesel car sales and on parameters that might have affected the sales. Information is included on the following items related to diesel cars: buyers preferences and why; fuel economy and availability; energy conservation potential; and exhaust emissions, their control and air pollution effects. (LCL)

  6. Wooing the Chinese Car-Buyer

    Institute of Scientific and Technical Information of China (English)

    MATTHEW PLOWRIGHT; CHRISTINE TSANG

    2008-01-01

    @@ Zhu Ce is a 22-year old salesman at Beijing's largest car market, North Asia Car Market, or Beiya Cheshi (北亚车市). He has been working there a few months, and on average makes about IO sales a month. But Zhu knows next to nothing about cars. He doesn't own one himself, and his employers simply provided him with a small information pamphlet by way of training.

  7. Modeling human learning involved in car driving

    OpenAIRE

    Wewerinke, P.H.

    1994-01-01

    In this paper, car driving is considered at the level of human tracking and maneuvering in the context of other traffic. A model analysis revealed the most salient features determining driving performance and safety. Learning car driving is modelled based on a system theoretical approach and based on a neural network approach. The aim of this research is to assess the relative merit of both approaches to describe human learning behavior in car driving specifically and in operating dynamic sys...

  8. High affinity FRβ-specific CAR T cells eradicate AML and normal yeloid lineage without HSC toxicity

    Science.gov (United States)

    Lynn, Rachel C; Feng, Yang; Schutsky, Keith; Poussin, Mathilde; Kalota, Anna; Dimitrov, Dimiter S; Powell, Daniel J

    2016-01-01

    Acute myeloid leukemia (AML) is an aggressive malignancy, and development of new treatments to prolong remissions is warranted. Chimeric antigen receptor (CAR) T-cell therapies appear promising but on-target, off-tumor recognition of antigen in healthy tissues remains a concern. Here, we isolated a high affinity (HA) folate receptor beta (FRβ)-specific scFv (2.48nM KD) for optimization of FRβ-redirected CAR T-cell therapy for AML. T-cells stably expressing the HA-FRβ CAR exhibited greatly enhanced antitumor activity against FRβ+ AML in vitro and in vivo compared to a low affinity (LA) FRβ CAR (54.3nM KD). Using the HA-FRβ IgG, FRβ expression was detectable in myeloid-lineage hematopoietic cells; however, expression in CD34+ hematopoietic stem cells (HSCs) was nearly undetectable. Accordingly, HA-FRβ CAR T-cells lysed mature CD14+ monocytes, while HSC colony formation was unaffected. Because of the potential for elimination of mature myeloid lineage, mRNA CAR electroporation for transient CAR expression was evaluated. mRNA-electroporated HA-FRβ CAR T-cells retained effective anti-tumor activity in vitro and in vivo. Together, our results highlight the importance of antibody affinity in target protein detection and CAR development and suggest that transient delivery of potent HA-FRβ CAR T-cells is highly effective against AML and reduces the risk for long-term myeloid toxicity. PMID:26898190

  9. Constitutive Androstane Receptor-Mediated Changes in Bile Acid Composition Contributes to Hepatoprotection from Lithocholic Acid-Induced Liver Injury in MiceS⃞

    OpenAIRE

    Beilke, Lisa D.; Aleksunes, Lauren M.; Holland, Ricky D; Besselsen, David G; Beger, Rick D.; Klaassen, Curtis D.; Cherrington, Nathan J.

    2009-01-01

    Pharmacological activation of the constitutive androstane receptor (CAR) protects the liver during cholestasis. The current study evaluates how activation of CAR influences genes involved in bile acid biosynthesis as a mechanism of hepatoprotection during bile acid-induced liver injury. CAR activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR knockout (CAR-null) mice ...

  10. Development of a safe car seat

    OpenAIRE

    Malnarič, Vili; Zupanc, Mirko; Drenovec, Mitja

    2015-01-01

    Here we present a list and order of actions to be taken for the successful development and industrialization of a safe car seat. During the seat's development, its safety role in the car has to be considered. With respect to this, the procedures defining the safety characteristics of the products have to be taken into account. The development stages for a safe car seat are merged within three phases, as follows: the preparation of the starting pointsfor the development of a safe car seat, the...

  11. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity.

    Science.gov (United States)

    Jacoby, Elad; Nguyen, Sang M; Fountaine, Thomas J; Welp, Kathryn; Gryder, Berkley; Qin, Haiying; Yang, Yinmeng; Chien, Christopher D; Seif, Alix E; Lei, Haiyan; Song, Young K; Khan, Javed; Lee, Daniel W; Mackall, Crystal L; Gardner, Rebecca A; Jensen, Michael C; Shern, Jack F; Fry, Terry J

    2016-01-01

    Adoptive immunotherapy using chimeric antigen receptor (CAR) expressing T cells targeting the CD19 B lineage receptor has demonstrated marked success in relapsed pre-B-cell acute lymphoblastic leukaemia (ALL). Persisting CAR-T cells generate sustained pressure against CD19 that may drive unique mechanisms of resistance. Pre-B ALL originates from a committed pre-B cell or an earlier progenitor, with potential to reprogram into other hematopoietic lineages. Here we report changes in lineage markers including myeloid conversion in patients following CD19 CAR therapy. Using murine ALL models we study the long-term effects of CD19 CAR-T cells and demonstrate partial or complete lineage switch as a consistent mechanism of CAR resistance depending on the underlying genetic oncogenic driver. Deletion of Pax5 or Ebf1 recapitulates lineage reprogramming occurring during CD19 CAR pressure. Our findings establish lineage switch as a mechanism of CAR resistance exposing inherent plasticity in genetic subtypes of pre-B-cell ALL. PMID:27460500

  12. Heterodyne effect in Hybrid CARS

    Science.gov (United States)

    Wang, Xi; Zhang, Aihua; Zhi, Miaochan; Sokolov, Alexei; Welch, George; Scully, Marlan

    2009-10-01

    We study the interaction between the resonant Raman signal and non-Raman field, either the concomitant nonresonant four-wave-mixing (FWM) background or an applied external field, in our recently developed scheme of coherent Anti-Stokes Raman scattering, a hybrid CARS. Our technique combines instantaneous coherent excitation of several characteristic molecular vibrations with subsequent probing of these vibrations by an optimally shaped, time-delayed, narrowband laser pulse. This pulse configuration mitigates the non-resonant FWM background while maximizing the Raman-resonant signal, and allows rapid and highly specific detection even in the presence of multiple scattering. We apply this method to non-invasive monitoring of blood glucose levels. Under certain conditions we find that the measured signal is linearly proportional to the glucose concentration due to optical interference with the residual background light, which allows reliable detection of spectral signatures down to medically-relevant glucose levels. We also study the interference between the CARS field and an external field (the local oscillator) by controlling their relative phase and amplitude. This control allows direct observation of the real and imaginary components of the third-order nonlinear susceptibility (χ^(3)) of the sample. We demonstrate that the heterodyne method can be used to amplify the signal and thus increase detection sensitivity.

  13. MMS Based Car Security System

    Directory of Open Access Journals (Sweden)

    Surendra Sot

    2013-03-01

    Full Text Available In This paper “MMS Based Car Security System” is being proposed to solve the issue. It introduces the integration between monitoring and tracking system. Both elements are very crucial in order to have a powerful security system. The system can send SMS and MMS to the owner to have fast response especially if the car is nearby. This paper focuses on using MMS and SMS technology. As soon as there is intrusion detected, first the SMS is sent to master user and the picture of the intruder will be sent via local GSM/GPRS service provider to user (and / or police mail ID. The implementation and testing results show the success of prototype in sending MMS to owner within 30 seconds. The timing and results are suitable to owner and police to take suitable action against intruder. User can also control the module using command. User has to send different SMS to module while configuration of module for master. Master user can be change as per need, only master user can make changes in to the module.

  14. Car-to-car safety broadcast with interference using Raptor codes

    OpenAIRE

    Abdullah, NF; Doufexi, A; Piechocki, RJ

    2011-01-01

    Car-to-car safety applications that demand real-time and reliable communications in vehicular ad hoc networks (VANETs) requires a new paradigm of coding techniques. In this paper, we propose a novel coding approach using a systematic Raptor code for car-to- car post-crash warning broadcast applications. A cross-layer simulator model is developed to evaluate the performance of Raptor codes against repetition codes using also multiple antennas spatial diversity techniques. The end-to-end delay ...

  15. Viral Engineering of Chimeric Antigen Receptor Expression on Murine and Human T Lymphocytes.

    Science.gov (United States)

    Hammill, Joanne A; Afsahi, Arya; Bramson, Jonathan L; Helsen, Christopher W

    2016-01-01

    The adoptive transfer of a bolus of tumor-specific T lymphocytes into cancer patients is a promising therapeutic strategy. In one approach, tumor specificity is conferred upon T cells via engineering expression of exogenous receptors, such as chimeric antigen receptors (CARs). Here, we describe the generation and production of both murine and human CAR-engineered T lymphocytes using retroviruses. PMID:27581020

  16. An improved car-following model considering velocity fluctuation of the immediately ahead car

    Science.gov (United States)

    Yu, Shaowei; Huang, Mengxing; Ren, Jia; Shi, Zhongke

    2016-05-01

    To better describe car-following behaviors in the adaptive cruise control strategy and further increase roadway traffic mobility and reduce fuel consumptions, the linkage between velocity fluctuation of the immediately ahead car and the following car's acceleration or deceleration is explored with respect to the measured car-following data by employing the gray correlation analysis theory and then an improved car-following model considering velocity fluctuation of the immediately ahead car on basis of the full velocity difference model is proposed. Numerical simulations are carried out and the effects of velocity fluctuation of the immediately ahead car on each car's velocity, acceleration, vehicular gap, fuel consumptions and the total fuel consumptions of the whole car-following system with different time window lengths are investigated in detail. The results show that velocity fluctuation of the immediately ahead car has significant effects on car-following behaviors and fuel consumptions, and that considering velocity fluctuation of the immediately ahead car in designing the adaptive cruise control system can improve traffic flow stability and reduce fuel consumptions.

  17. An improved car-following model with two preceding cars' average speed

    Science.gov (United States)

    Yu, Shao-Wei; Shi, Zhong-Ke

    2015-01-01

    To better describe cooperative car-following behaviors under intelligent transportation circumstances and increase roadway traffic mobility, the data of three successive following cars at a signalized intersection of Jinan in China were obtained and employed to explore the linkage between two preceding cars' average speed and car-following behaviors. The results indicate that two preceding cars' average velocity has significant effects on the following car's motion. Then an improved car-following model considering two preceding cars' average velocity was proposed and calibrated based on full velocity difference model and some numerical simulations were carried out to study how two preceding cars' average speed affected the starting process and the traffic flow evolution process with an initial small disturbance, the results indicate that the improved car-following model can qualitatively describe the impacts of two preceding cars' average velocity on traffic flow and that taking two preceding cars' average velocity into account in designing the control strategy for the cooperative adaptive cruise control system can improve the stability of traffic flow, suppress the appearance of traffic jams and increase the capacity of signalized intersections.

  18. Generation of CAR T Cells for Adoptive Therapy in the Context of Glioblastoma Standard of Care

    Science.gov (United States)

    Riccione, Katherine; Suryadevara, Carter M.; Snyder, David; Cui, Xiuyu; Sampson, John H.; Sanchez-Perez, Luis

    2016-01-01

    Adoptive T cell immunotherapy offers a promising strategy for specifically targeting and eliminating malignant gliomas. T cells can be engineered ex vivo to express chimeric antigen receptors specific for glioma antigens (CAR T cells). The expansion and function of adoptively transferred CAR T cells can be potentiated by the lymphodepletive and tumoricidal effects of standard of care chemotherapy and radiotherapy. We describe a method for generating CAR T cells targeting EGFRvIII, a glioma-specific antigen, and evaluating their efficacy when combined with a murine model of glioblastoma standard of care. T cells are engineered by transduction with a retroviral vector containing the anti-EGFRvIII CAR gene. Tumor-bearing animals are subjected to host conditioning by a course of temozolomide and whole brain irradiation at dose regimens designed to model clinical standard of care. CAR T cells are then delivered intravenously to primed hosts. This method can be used to evaluate the antitumor efficacy of CAR T cells in the context of standard of care. PMID:25741761

  19. Paralleled comparison of vectors for the generation of CAR-T cells.

    Science.gov (United States)

    Qin, Di-Yuan; Huang, Yong; Li, Dan; Wang, Yong-Sheng; Wang, Wei; Wei, Yu-Quan

    2016-09-01

    T-lymphocytes genetically engineered with the chimeric antigen receptor (CAR-T) have shown great therapeutic potential in cancer treatment. A variety of preclinical researches and clinical trials of CAR-T therapy have been carried out to lay the foundation for future clinical application. In these researches, several gene-transfer methods were used to deliver CARs or other genes into T-lymphocytes, equipping CAR-modified T cells with a property of recognizing and attacking antigen-expressing tumor cells in a major histocompatibility complex-independent manner. Here, we summarize the gene-transfer vectors commonly used in the generation of CAR-T cell, including retrovirus vectors, lentivirus vectors, the transposon/transposase system, the plasmid-based system, and the messenger RNA electroporation system. The following aspects were compared in parallel: efficiency of gene transfer, the integration methods in the modified T cells, foreground of scale-up production, and application and development in clinical trials. These aspects should be taken into account to generate the optimal CAR-gene vector that may be suitable for future clinical application. PMID:27333595

  20. Approaches to augment CAR T-cell therapy by targeting the apoptotic machinery.

    Science.gov (United States)

    Karlsson, Hannah

    2016-04-15

    Chimaeric antigen receptor (CAR) T-cells have shown impressive results in patients with B-cell leukaemia. Yet, in patients with lymphoma durable responses are still rare and heavy preconditioning required. Apoptosis resistance is considered a hallmark of cancer, often conveyed by a halted apoptosis signalling. Tumours regularly skew the balance of the components of the apoptotic machinery either through up-regulating anti-apoptotic proteins or silencing pro-apoptotic ones. Malignant B-cells frequently up-regulate anti-apoptotic B-cell lymphoma 2 (Bcl-2) family proteins leading to therapy resistance. CAR T-cells kill tumour cells via apoptosis induction and their efficacy may be affected by the level of Bcl-2 family proteins. Hence, there is an interesting possibility to increase the effect of CAR T-cell therapy by combining it with apoptosis inhibitor blockade agents. Compounds that inhibit Bcl-2, B-cell lymphoma extra large (Bcl-xL) and Bcl-2-like protein 2 (Bcl-w), can restore execution of apoptosis in tumour cells or sensitize them to other apoptosis-dependent treatments. Hence, there is a great interest to combine such agents with CAR T-cell therapy to potentiate the effect of CAR T-cell killing. This review will focus on the potential of targeting the apoptotic machinery to sensitize tumour cells to CAR T-cell killing. PMID:27068942

  1. Silver Cars Are the Safest on the Road

    Institute of Scientific and Technical Information of China (English)

    蒋保平

    2007-01-01

    <正>Silver cars are much less likely to be involved in a serious crash than cars of other colours,suggests a new study of over 1,000 cars.People driving in silver cars were 50 per cent less likely to suffer serious injury in a crash compared with drivers of white cars,the research in New Zealand found.

  2. 49 CFR 180.507 - Qualification of tank cars.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Qualification of tank cars. 180.507 Section 180... QUALIFICATION AND MAINTENANCE OF PACKAGINGS Qualification and Maintenance of Tank Cars § 180.507 Qualification of tank cars. (a) Each tank car marked as meeting a “DOT” specification or any other tank car...

  3. Expression of CAR in SW480 and HepG2 cells during G1 is associated with cell proliferation

    International Nuclear Information System (INIS)

    Constitutive androstane receptor (CAR) is a transcription factor to regulate the expression of several genes related to drug-metabolism. Here, we demonstrate that CAR protein accumulates during G1 in human SW480 and HepG2 cells. After the G1/S phase transition, CAR protein levels decreased, and CAR was hardly detected in cells by the late M phase. CAR expression in both cell lines was suppressed by RNA interference-mediated suppression of CDK4. Depletion of CAR by RNA interference in both cells and by hepatocyte growth factor treatment in HepG2 cells resulted in decreased MDM2 expression that led to p21 upregulation and repression of HepG2 cell growth. Thus, our results demonstrate that CAR expression is an early G1 event regulated by CDK4 that contributes to MDM2 expression; these findings suggest that CAR may influence the expression of genes involved in not only the metabolism of endogenous and exogenous substances but also in the cell proliferation

  4. Systemic treatment with CAR-engineered T cells against PSCA delays subcutaneous tumor growth and prolongs survival of mice

    International Nuclear Information System (INIS)

    Adoptive transfer of T cells genetically engineered with a chimeric antigen receptor (CAR) has successfully been used to treat both chronic and acute lymphocytic leukemia as well as other hematological cancers. Experimental therapy with CAR-engineered T cells has also shown promising results on solid tumors. The prostate stem cell antigen (PSCA) is a protein expressed on the surface of prostate epithelial cells as well as in primary and metastatic prostate cancer cells and therefore a promising target for immunotherapy of prostate cancer. We developed a third-generation CAR against PSCA including the CD28, OX-40 and CD3 ζ signaling domains. T cells were transduced with a lentivirus encoding the PSCA-CAR and evaluated for cytokine production (paired Student’s t-test), proliferation (paired Student’s t-test), CD107a expression (paired Student’s t-test) and target cell killing in vitro and tumor growth and survival in vivo (Log-rank test comparing Kaplan-Meier survival curves). PSCA-CAR T cells exhibit specific interferon (IFN)-γ and interleukin (IL)-2 secretion and specific proliferation in response to PSCA-expressing target cells. Furthermore, the PSCA-CAR-engineered T cells efficiently kill PSCA-expressing tumor cells in vitro and systemic treatment with PSCA-CAR-engineered T cells significantly delays subcutaneous tumor growth and prolongs survival of mice. Our data confirms that PSCA-CAR T cells may be developed for treatment of prostate cancer

  5. Reduced Mechanical Stretch Induces Enhanced Endothelin B Receptor-mediated Contractility via Activation of Focal Adhesion Kinase and Extra Cellular-regulated Kinase 1/2 in Cerebral Arteries from Rat

    DEFF Research Database (Denmark)

    Rasmussen, Marianne N P; Spray, Stine; Skovsted, Gry F;

    2016-01-01

    Cerebral ischaemia results in enhanced endothelin B (ETB ) receptor-mediated contraction and receptor protein expression in the affected cerebrovascular smooth muscle cells (SMC). Organ culture of cerebral arteries is a method to induce similar alterations in ETB receptor expression. We hypothesize......-mediated contractility via triggering of an early mechanosensitive signalling pathway involving ERK1/2 and FAK signalling. A mechanism likely to be an initiating factor for the increased ETB receptor-mediated contractility found after cerebral ischaemia. This article is protected by copyright. All rights reserved....

  6. TNFα promotes CAR-dependent migration of leukocytes across epithelial monolayers

    Science.gov (United States)

    Morton, Penny E.; Hicks, Alexander; Ortiz-Zapater, Elena; Raghavan, Swetavalli; Pike, Rosemary; Noble, Alistair; Woodfin, Abigail; Jenkins, Gisli; Rayner, Emma; Santis, George; Parsons, Maddy

    2016-01-01

    Trans-epithelial migration (TEpM) of leukocytes during inflammation requires engagement with receptors expressed on the basolateral surface of the epithelium. One such receptor is Coxsackie and Adenovirus Receptor (CAR) that binds to Junctional Adhesion Molecule-like (JAM-L) expressed on leukocytes. Here we provide the first evidence that efficient TEpM of monocyte-derived THP-1 cells requires and is controlled by phosphorylation of CAR. We show that TNFα acts in a paracrine manner on epithelial cells via a TNFR1-PI3K-PKCδ pathway leading to CAR phosphorylation and subsequent transmigration across cell junctions. Moreover, we show that CAR is hyper-phosphorylated in vivo in acute and chronic lung inflammation models and this response is required to facilitate immune cell recruitment. This represents a novel mechanism of feedback between leukocytes and epithelial cells during TEpM and may be important in controlling responses to pro-inflammatory cytokines in pathological settings. PMID:27193388

  7. TNFα promotes CAR-dependent migration of leukocytes across epithelial monolayers.

    Science.gov (United States)

    Morton, Penny E; Hicks, Alexander; Ortiz-Zapater, Elena; Raghavan, Swetavalli; Pike, Rosemary; Noble, Alistair; Woodfin, Abigail; Jenkins, Gisli; Rayner, Emma; Santis, George; Parsons, Maddy

    2016-01-01

    Trans-epithelial migration (TEpM) of leukocytes during inflammation requires engagement with receptors expressed on the basolateral surface of the epithelium. One such receptor is Coxsackie and Adenovirus Receptor (CAR) that binds to Junctional Adhesion Molecule-like (JAM-L) expressed on leukocytes. Here we provide the first evidence that efficient TEpM of monocyte-derived THP-1 cells requires and is controlled by phosphorylation of CAR. We show that TNFα acts in a paracrine manner on epithelial cells via a TNFR1-PI3K-PKCδ pathway leading to CAR phosphorylation and subsequent transmigration across cell junctions. Moreover, we show that CAR is hyper-phosphorylated in vivo in acute and chronic lung inflammation models and this response is required to facilitate immune cell recruitment. This represents a novel mechanism of feedback between leukocytes and epithelial cells during TEpM and may be important in controlling responses to pro-inflammatory cytokines in pathological settings. PMID:27193388

  8. Car Stopping Distance on a Tabletop

    Science.gov (United States)

    Haugland, Ole Anton

    2013-01-01

    Stopping distances in car braking can be an intriguing topic in physics teaching. It illustrates some basic principles of physics, and sheds valuable light on students' attitude towards aggressive driving. Due to safety considerations, it can be difficult to make experiments with actual car braking. (Contains 2 figures.)

  9. Environmental impact of scrapping old cars

    NARCIS (Netherlands)

    Wee, Bert van; Moll, Henri C.; Dirks, Jessica

    2000-01-01

    Many countries introduced scrapping programs in the 90s, partly legitimated by environmental impact reductions. However, reducing the age of the current car fleet may result in an increase of life-cycle CO2 emissions. This will probably also be true for cars to be produced in future unless fuel effi

  10. Rear-facing car seat (image)

    Science.gov (United States)

    A rear-facing car seat position is recommended for a child who is very young. Extreme injury can occur in an accident because ... child. In a frontal crash a rear-facing car seat is best, because it cradles the head, ...

  11. A Radio-Controlled Car Challenge

    Science.gov (United States)

    Roman, Harry T.

    2010-01-01

    Watching a radio-controlled car zip along a sidewalk or street has become a common sight. Within this toy are the basic ingredients of a mobile robot, used by industry for a variety of important and potentially dangerous tasks. In this challenge, students consider modifying an of-the-shelf, radio-controlled car, adapting it for a robotic task.

  12. CERN car stickers for 2014

    CERN Multimedia

    2013-01-01

    The stickers on your vehicles will cease to be valid at the end of 2013. We kindly request that you inform us as soon as possible if you no longer own a vehicle that is in our records. In particular, please inform the CERN Registration Service (Building 55, first floor) if you receive a sticker for a vehicle that you no longer own.   Stickers for 2014 are valid immediately and can be displayed as soon as you receive them. The Guards Service will continue to allow cars displaying a 2013 sticker into the CERN site until no later than 31 January 2014. After that date, the Guards Service will be obliged to deny access to any vehicles not displaying a valid sticker. Please see Operational Circular No. 2 for more details. We wish you a pleasant day and happy holidays, GS/DI security and access control service

  13. Reactions of Met-Cars

    International Nuclear Information System (INIS)

    A new class of metal-carbon complexes, termed metallo-carbohedrenes (Met-Cars), have been discovered to form in a plasma reactor in which early transition metals are vaporized into a stream carrying small hydrocarbon molecules. The initial discovery involved the species Ti8c12+, while subsequent studies revealed the stability of the anion and, most importantly, the neutral species. Subsequent investigations show that similar molecules, predicted to have a pentagonal dodecahedral structure, can also be formed with vanadium, hafnium, and zirconium. In the case of the latter, more recent investigations have displaced an interesting growth pattern. In particular, pentagonal dodecahedrons with dangling carbon atoms can undergo further growth, adding at least a second and third cage. The latest results on the properties and reactivities of these new cage-like molecular clusters will be discussed

  14. Modelling and optimization of car-to-car compatibility - Modellierung und optimierung von pkw-pkw-kompatibilität

    NARCIS (Netherlands)

    Mooi, H.G.; Nastic, T.; Huibers, J.H.A.M.

    1999-01-01

    In this paper simple and more detailed MADYMO multibody models were used to simulate the car structure for improving the car-to-car compatibility of the whole car fleet. As a first step, survey studies were performed to develop a method for the optimization of car design with respect to frontal and

  15. Wellcome Prize Lecture. Cell surface, ion-sensing receptors.

    Science.gov (United States)

    Riccardi, Daniela

    2002-07-01

    Changes in extracellular calcium (Ca(2+)o) concentration ([Ca2+]o) affect kidney function both under basal and hormone-stimulated conditions. The molecular identification of an extracellular Ca(2+)-sensing receptor (CaR) has confirmed a direct role of Ca(2+)o on parathyroid and kidney function (i.e. independent of calciotropic hormones) as a modulator of Ca2+ homeostasis. In addition, evidence accumulated over the last 10 years has shown that CaR is also expressed in regions outside the calcium homeostatic system where its role is largely undefined but seems to be linked to regulation of local ionic homeostasis. The parathyroid and kidney CaRs are 1081 and 1079 amino acids long, respectively, and belong to the type III family of G protein-coupled receptors (GPCRs), which includes other CaRs, metabotropic glutamate receptors and putative vomeronasal organ receptors. For the CaR, its low (millimolar) affinity for Ca2+, its positive cooperativity and its large ion-sensing extracellular domain, indicate that the receptor is more sensitive to changes in net cationic charge rather than to a specific ligand. Mg2+, trivalent cations of the lanthanide series and polyvalent cations such as spermine and aminoglycoside antibiotics can all activate the receptor in vitro with EC50 values in the micromolar range for trivalent and polyvalent cations or in the millimolar range for Ca2+ and Mg2+. In addition to true CaR agonists, CaR sensitivity to Ca(2+)o is also susceptible to allosteric modulation by ionic strength, L-amino acids and by pharmacological agents. This review will address endogenous and exogenous CaR agonists, the role of the receptor in the calcium homeostatic system and some speculation on possible role(s) of the CaR in regions not involved in mineral ion homeostasis. PMID:12392104

  16. Study on Performances of Car-following Models Induced by Motions of a Leading Car

    Institute of Scientific and Technical Information of China (English)

    2005-01-01

    This paper investigated the performances of a well-known car-following model with numerical simulations in describing the deceleration process induced by the motion of a leading car. A leading car with a pre-specified speed profile was used to test the above model. The results show that this model is to some extent deficient in performing the process aforementioned. Modifications of the model to overcome these deficiencies were demonstrated and a modified car-following model was proposed accordingly. Furthermore, the delay time of car motion of the new model were studied.

  17. The kinematic advantage of electric cars

    Science.gov (United States)

    Meyn, Jan-Peter

    2015-11-01

    Acceleration of a common car with with a turbocharged diesel engine is compared to the same type with an electric motor in terms of kinematics. Starting from a state of rest, the electric car reaches a distant spot earlier than the diesel car, even though the latter has a better specification for engine power and average acceleration from 0 to 100 km h-1. A three phase model of acceleration as a function of time fits the data of the electric car accurately. The first phase is a quadratic growth of acceleration in time. It is shown that the tenfold higher coefficient for the first phase accounts for most of the kinematic advantage of the electric car.

  18. Dual-tip-enhanced ultrafast CARS nanoscopy

    CERN Document Server

    Ballmann, Charles W; Sinyukov, Alexander M; Sokolov, Alexei V; Voronine, Dmitri V

    2013-01-01

    Coherent anti-Stokes Raman scattering (CARS) and, in particular, femtosecond adaptive spectroscopic techniques (FAST CARS) have been successfully used for molecular spectroscopy and microscopic imaging. Recent progress in ultrafast nanooptics provides flexibility in generation and control of optical near fields, and holds promise to extend CARS techniques to the nanoscale. In this theoretical study, we demonstrate ultrafast subwavelentgh control of coherent Raman spectra of molecules in the vicinity of a plasmonic nanostructure excited by ultrashort laser pulses. The simulated nanostructure design provides localized excitation sources for CARS by focusing incident laser pulses into subwavelength hot spots via two self-similar nanolens antennas connected by a waveguide. Hot-spot-selective dual-tip-enhanced CARS (2TECARS) nanospectra of DNA nucleobases are obtained by simulating optimized pump, Stokes and probe near fields using tips, laser polarization- and pulse-shaping. This technique may be used to explore ...

  19. Evaluation of damaged tank car structural integrity

    International Nuclear Information System (INIS)

    To assess the safety of moving a damaged tank car, it is necessary to know the sizes and shapes of cracks, the stresses associated with moving the tank car, and the fracture toughness of the material used to fabricate the tank car. This report provides the results and recommendations for the research related to the examination of nondestructive evaluation techniques and measurements of the mechanical properties of deformed steel plate; Evaluation of computer codes to identify those capable of performing a large displacement inelastic analysis; Two 1/5-scale-model tank cars, representing damaged tank cars that were hydroburst to failure; and Preliminary tests conducted using more interferometry for determining residual stresses of rail components. 24 refs., 37 figs., 4 tabs

  20. Entertainment and Pacification System For Car Seat

    Science.gov (United States)

    Elrod, Susan Vinz (Inventor); Dabney, Richard W. (Inventor)

    2006-01-01

    An entertainment and pacification system for use with a child car seat has speakers mounted in the child car seat with a plurality of audio sources and an anti-noise audio system coupled to the child car seat. A controllable switching system provides for, at any given time, the selective activation of i) one of the audio sources such that the audio signal generated thereby is coupled to one or more of the speakers, and ii) the anti-noise audio system such that an ambient-noise-canceling audio signal generated thereby is coupled to one or more of the speakers. The controllable switching system can receive commands generated at one of first controls located at the child car seat and second controls located remotely with respect to the child car seat with commands generated by the second controls overriding commands generated by the first controls.

  1. GD2-specific CAR T Cells Undergo Potent Activation and Deletion Following Antigen Encounter but can be Protected From Activation-induced Cell Death by PD-1 Blockade.

    Science.gov (United States)

    Gargett, Tessa; Yu, Wenbo; Dotti, Gianpietro; Yvon, Eric S; Christo, Susan N; Hayball, John D; Lewis, Ian D; Brenner, Malcolm K; Brown, Michael P

    2016-06-01

    Chimeric antigen receptor (CAR) T cells have shown great promise in the treatment of hematologic malignancies but more variable results in the treatment of solid tumors and the persistence and expansion of CAR T cells within patients has been identified as a key correlate of antitumor efficacy. Lack of immunological "space", functional exhaustion, and deletion have all been proposed as mechanisms that hamper CAR T-cell persistence. Here we describe the events following activation of third-generation CAR T cells specific for GD2. CAR T cells had highly potent immediate effector functions without evidence of functional exhaustion in vitro, although reduced cytokine production reversible by PD-1 blockade was observed after longer-term culture. Significant activation-induced cell death (AICD) of CAR T cells was observed after repeated antigen stimulation, and PD-1 blockade enhanced both CAR T-cell survival and promoted killing of PD-L1(+) tumor cell lines. Finally, we assessed CAR T-cell persistence in patients enrolled in the CARPETS phase 1 clinical trial of GD2-specific CAR T cells in the treatment of metastatic melanoma. Together, these data suggest that deletion also occurs in vivo and that PD-1-targeted combination therapy approaches may be useful to augment CAR T-cell efficacy and persistence in patients. PMID:27019998

  2. Loss of CAR promotes migration and proliferation of HaCaT cells, and accelerates wound healing in rats via Src-p38 MAPK pathway

    Science.gov (United States)

    Su, Linlin; Fu, Lanqing; Li, Xiaodong; Zhang, Yue; Li, Zhenzhen; Wu, Xue; Li, Yan; Bai, Xiaozhi; Hu, Dahai

    2016-01-01

    The coxsackie and adenovirus receptor (CAR) is a cell adhesion molecule mostly localized to cell-cell contacts in epithelial and endothelial cells. CAR is known to regulate tumor progression, however, its physiological role in keratinocyte migration and proliferation, two essential steps in re-epithelialization during wound healing, has less been investigated. Here we showed that CAR was predominantly expressed in the epidermis of human skin, CAR knockdown by RNAi significantly accelerated HaCaT cell migration and proliferation. In addition, knockdown of CAR in vitro increased p-Src, p-p38, and p-JNK protein levels; however, Src inhibitor PP2 prevented the increase of p-Src and p-p38 induced by CAR RNAi, but not p-JNK, and decelerated cell migration and proliferation. More intriguingly, in vivo CAR RNAi on the skin area surrounding the wounds on rat back visually accelerated wound healing and re-epithelialization process, while treatment with PP2 or p38 inhibitor SB203580 obviously inhibited these effects. By contrast, overexpressing CAR in HaCaT cells significantly decelerated cell migration and proliferation. Above results demonstrate that suppression of CAR could accelerate HaCaT cell migration and proliferation, and promote wound healing in rat skin, probably via Src-p38 MAPK pathway. CAR thus might serve as a novel therapeutic target for facilitating wound healing. PMID:26804208

  3. Study Finds Hybrid Cars Greener Than Hydrogen Cars

    Institute of Scientific and Technical Information of China (English)

    励蓓蓓

    2003-01-01

    选注者言:最近,我也加入了“驾车一族”,我的小别克让我饱尝“飞驰”之乐。因此,我也更关心汽车的前景。本文向我们透露了许多研发新型汽车的最新消息。美国布什政府对研发氢燃料电池驱动的汽车的费用投入达12亿美元。但是,此消息刚刚宣布,MIT的研究就提出氢燃料电池驱动的汽车的不足:…uses sub-stantial energy and emits greenhouse gases.一种更环保更科学的汽车(hybrid cars/复合车)在日本的丰田和本田公司已经被投入生产。

  4. Will Brazil's cars go on the wagon?

    International Nuclear Information System (INIS)

    The use of ethanol as an alternative fuel for cars in Brazil, may shortly be reduced. Falling world oil prices have meant that ethanol, derived from sugar cane, following a fourteen year research program, has ceased to be a financially viable replacement for petrol. Although about a third of Brazil's cars are at present powered by ethanol, only substantial government subsidies could reinstate this fuel despite its reduced pollutant status. Government officials now predict that ethanol will become merely a petrol additive and production of ethanol cars will have stopped by the year 2000. (UK)

  5. Piecewise linear car-following modeling

    CERN Document Server

    Farhi, Nadir

    2011-01-01

    We present a traffic model which extends the linear car-following model as well as the min-plus traffic model (a model based on the min-plus algebra). A discrete-time car-dynamics describing the traffic on a 1-lane road without passing is interpreted as a dynamic programming equation of a stochastic optimal control problem of a Markov chain. This variational formulation permits to characterize the stability of the car-dynamics and to calculte the stationary regimes when they exist. The model is based on a piecewise linear approximation of the fundamental traffic diagram.

  6. Charging electric cars from solar energy

    OpenAIRE

    Liang, Xusheng; Tanyi, Elvis; Zou, Xin

    2016-01-01

    Before vehicles were heavily relied on coal, fossil fuels and wind for power.  Now, they are rapidly being replaced by electric vehicles and or plug-in hybrid electric cars. But these electric cars are still faced with the problem of energy availability because they rely on energy from biomass, hydro power and wind turbines for power generation. The abundance of solar radiation and its use as solar energy as a power source in driving these rapidly increasing electric cars is not only an impor...

  7. The Stylistic Analysis of car ads languages

    Institute of Scientific and Technical Information of China (English)

    张伟苹

    2014-01-01

    Automotive advertising language is mix of phonetics, vocabulary, rhetoric, syntax, and discourse language etc., and owning a strong promotional effect which can functioned as a bridge between language expression and promotion system for es-sential products and consumers. As a kind of the commercial advertising, car advertising with its own unique language features not only for product considerably, but also enriches the advertising language. In order to analysis the car ads, this article draws at-tention from the aspects of the phonetics, vocabulary, rhetoric and syntax features, and aims to get a further and better analysis or understanding of the car ads Languages.

  8. PC-based car license plate reader

    Science.gov (United States)

    Hwang, Chung-Mu; Shu, Shyh-Yeong; Chen, Wen-Yu; Chen, Yie-Wern; Wen, Kuang-Pu

    1992-11-01

    A car license plate reader (CLPR) using fuzzy inference and neural network algorithm has been developed in Industrial Technology Research Institute (ITRI) and installed in highway toll stations to identify stolen cars. It takes an average of 0.7 seconds to recognize a car license plate by using a PC with 80486-50 CPU. The recognition rate of the system is about 97%. The techniques of CLPR include vehicle sensing, image grab control, optic pre- processing, lighting, and optic character recognition (OCR). The CLPR can be used in vehicle flow statistics, the checking of stolen vehicles, automatic charging systems in parking lots or garage management, and so on.

  9. Electric cars as mobile power storage systems

    International Nuclear Information System (INIS)

    This article discusses the use of electric cars as a means of optimising the use of renewable energy sources. Charging the cars' batteries during periods when cheap electricity prices prevail and then using excess capacity to supply the mains with electricity during periods of peak demand is discussed. The possible use of wind for power generation is discussed and a system proposed by a leading supplier of electrical apparatus and systems is examined. Two examples of electric cars and associated power chains are looked at and tests in everyday practice are described

  10. DIAGNOSTICS OF A MODERN CAR

    Directory of Open Access Journals (Sweden)

    Khrapov Y. N.

    2016-04-01

    Full Text Available The article presents a technical diagnostics of a car as a complex of goals and tasks connected with trouble-shooting of mechanisms and systems in order to eliminate them. We have considered the stages of computer diagnostics of different automobile systems such as diagnosing the engine, the brake system, steering and suspension. We have analyzed their components, the ways of troubleshooting and elimination recommendations. The article presents the main troubles transferred from the electronic control unit. The article also presents the stages of diagnosing the engine including external examination, listening to abnormal noises, checking the operating fluids and the engine management system, diagnosing the basic engine systems and checking the cylinders being filled. The article contains the list of main troubles and their reasons. One can also see diagnosing the brake system, its defects and remedies. The article presents diagnostics and repair of the suspender and graphics describing the check of the dismantled shock strut at the stand and tests of the shock strut without being dismantled. We have analyzed computer diagnostics and the problems it solves

  11. Behavioral and Cellular Pharmacology Characterization of 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-(isoquinoline-3′-carboxamido)morphinan (NAQ) as a Mu Opioid Receptor Selective Ligand

    OpenAIRE

    Zhang, Yan; Braithwaite, Amanda; Yuan, Yunyun; Streicher, John M.; Bilsky, Edward J.

    2014-01-01

    Mu opioid receptor (MOR) selective antagonists and partial agonists have been used for the treatment of opioid abuse and addiction. Our recent efforts on the identification of MOR antagonists have provided several novel leads displaying interesting pharmacological profiles. Among them, 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α-[(3'-isoquinolyl)acetamido]morphinan (NAQ) showed sub-nanomolar binding affinity to the MOR with significant selectivity over the delta opioid receptor (DOR) a...

  12. Human receptor activation by aroclor 1260, a polychlorinated biphenyl mixture.

    Science.gov (United States)

    Wahlang, Banrida; Falkner, K Cameron; Clair, Heather B; Al-Eryani, Laila; Prough, Russell A; States, J Christopher; Coslo, Denise M; Omiecinski, Curtis J; Cave, Matthew C

    2014-08-01

    Polychlorinated biphenyls (PCBs) are persistent environmental toxicants, present in 100% of U.S. adults and dose-dependently associated with obesity and non-alcoholic fatty liver disease (NAFLD). PCBs are predicted to interact with receptors previously implicated in xenobiotic/energy metabolism and NAFLD. These receptors include the aryl hydrocarbon receptor (AhR), pregnane xenobiotic receptor (PXR), constitutive androstane receptor (CAR), peroxisome proliferator-activated receptors (PPARs), liver-X-receptor (LXRα), and farnesoid-X-receptor (FXR). This study evaluates Aroclor 1260, a PCB mixture with congener composition mimicking that of human adipose tissue, and selected congeners, as potential ligands for these receptors utilizing human hepatoma-derived (HepG2) and primate-derived (COS-1) cell lines, and primary human hepatocytes. Aroclor 1260 (20 μg/ml) activated AhR, and PCB 126, a minor component, was a potent inducer. Aroclor 1260 activated PXR in a simple concentration-dependent manner at concentrations ≥10 μg/ml. Among the congeners tested, PCBs 138, 149, 151, 174, 183, 187, and 196 activated PXR. Aroclor 1260 activated CAR2 and CAR3 variants at lower concentrations and antagonize CAR2 activation by the CAR agonist, CITCO, at higher concentrations (≥20 μg/ml). Additionally, Aroclor 1260 induced CYP2B6 in primary hepatocytes. At subtoxic doses, Aroclor 1260 did not activate LXR or FXR and had no effect on LXR- or FXR-dependent induction by the agonists T0901317 or GW4064, respectively. Aroclor 1260 (20 μg/ml) suppressed PPARα activation by the agonist nafenopin, although none of the congeners tested demonstrated significant inhibition. The results suggest that Aroclor 1260 is a human AhR, PXR and CAR3 agonist, a mixed agonist/antagonist for CAR2, and an antagonist for human PPARα. PMID:24812009

  13. Binarity of the LBV HR Car

    CERN Document Server

    Rivinius, Th; de Wit, W J; Mehner, A; Martayan, Ch; Guieu, S; Bouquin, J -B Le

    2014-01-01

    VLTI/AMBER and VLTI/PIONIER observations of the LBV HR Car show an interferometric signature that could not possibly be explained by an extended wind, more or less symmetrically distributed around a single object. Instead, observations both in the Br$\\gamma$ line and the H-band continuum are best explained by two point sources (or alternatively one point source and one slightly extended source) at about 2 mas separation and a contrast ratio of about 1:5. These observations establish that HR Car is a binary, but further interpretation will only be possible with future observations to constrain the orbit. Under the assumption that the current separation is close to the maximum one, the orbital period can be estimated to be of the order of 5 years, similar as in the $\\eta$ Car system. This would make HR Car the second such LBV binary.

  14. 100-Car Naturalistic Driving Study Fact Sheet

    OpenAIRE

    Box, Sherri

    2005-01-01

    The 100-Car Naturalistic Driving Study was recently completed by the Virginia Tech Transportation Institute (VTTI) and sponsored by the National Highway Traffic Safety Administration (NHTSA), Virginia Tech, Virginia Department of Transportation (VDOT), and Virginia Transportation Research Council (VTRC).

  15. Ultrafast CARS with Improved Spectral Resolution

    Directory of Open Access Journals (Sweden)

    Lochbrunner S.

    2013-03-01

    Full Text Available Molecular vibrations are investigated by time and frequency resolved CARS applying ultrafast excitation and picosecond probing for high spectral resolution. Enhanced spectral structure and beating phenomena are demonstrated for coalescing Raman bands.

  16. Computer Security: your car, my control

    CERN Multimedia

    Stefan Lueders, Computer Security Team

    2015-01-01

    We have discussed the Internet of Things (IoT) and its security implications already in past issues of the CERN Bulletin, for example in “Today’s paranoia, tomorrow’s reality” (see here). Unfortunately, tomorrow has come. At this years's Black Hat conference researchers presented their findings on how easily your car can be hacked and controlled remotely. Sigh.   While these researchers have just shown that they can wirelessly hijack a Jeep Cherokee, others have performed similar studies with SmartCars, Fords, a Tesla, a Corvette, BMWs, Chryslers and Mercedes! With the increasing computerisation of cars, the engine management system, air conditioning, anti-lock braking system, electronic stability programme, etc. are linked to the infotainment, navigation and communication systems, opening the door for these vehicles to be hacked remotely. The now prevalent Bluetooth connection with smartphones is one entry vector to attack your car remotely...

  17. Humanitarian reform: a view from CAR

    Directory of Open Access Journals (Sweden)

    Toby Lanzer

    2007-12-01

    Full Text Available As the Humanitarian Coordinator in the Central AfricanRepublic (CAR, it is my job to ensure that the UN andhumanitarian organisations work together to meet needsas efficiently as we can.

  18. Red, Yellow, and Green: A psychological perspective on car purchase and implications for subsequent car use

    OpenAIRE

    Nayum, Alim

    2016-01-01

    ABSTRACT - Red, Yellow, and Green: A psychological perspective on car purchase and implications for subsequent car use - Research on consumer behaviors having high impact on natural resources and the environment is considered important for developing measures for a sustainable future. This thesis focuses on one of such consumer behaviors – purchases and use of new passenger cars. The primary aim of the thesis is to examine the effects of socio-psychological factors in ...

  19. Post-Car World: Why Laugh at Change? Definitions of the Car and Potential Changes

    OpenAIRE

    Rigal, Alexandre; Rudler, Jade

    2014-01-01

    Far from the sirens of Modernism and the models founded on a standard vision of humanity, the scope of the Post-Car World research project is pluralistic. This project, funded by the Fonds National (Synergia), aims to create urban planning scenarios, focusing on the role of the car. Originally based on our investigation of people’s relationship with the car, the plurality of practices and their possible (and desired) alternatives will likewise enhance these scenarios. This plurality of views ...

  20. New Strategies for the Treatment of Solid Tumors with CAR-T Cells

    Science.gov (United States)

    Zhang, Hao; Ye, Zhen-long; Yuan, Zhen-gang; Luo, Zheng-qiang; Jin, Hua-jun; qian, Qi-jun

    2016-01-01

    Recent years, we have witnessed significant progresses in both basic and clinical studies regarding novel therapeutic strategies with genetically engineered T cells. Modification with chimeric antigen receptors (CARs) endows T cells with tumor specific cytotoxicity and thus induce anti-tumor immunity against malignancies. However, targeting solid tumors is more challenging than targeting B-cell malignancies with CAR-T cells because of the histopathological structure features, specific antigens shortage and strong immunosuppressive environment of solid tumors. Meanwhile, the on-target/off-tumor toxicity caused by relative expression of target on normal tissues is another issue that should be reckoned. Optimization of the design of CAR vectors, exploration of new targets, addition of safe switches and combination with other treatments bring new vitality to the CAR-T cell based immunotherapy against solid tumors. In this review, we focus on the major obstacles limiting the application of CAR-T cell therapy toward solid tumors and summarize the measures to refine this new cancer therapeutic modality. PMID:27194949

  1. Travel Time Estimation Using Floating Car Data

    CERN Document Server

    Sevlian, Raffi

    2010-01-01

    This report explores the use of machine learning techniques to accurately predict travel times in city streets and highways using floating car data (location information of user vehicles on a road network). The aim of this report is twofold, first we present a general architecture of solving this problem, then present and evaluate few techniques on real floating car data gathered over a month on a 5 Km highway in New Delhi.

  2. Notice of car park and road closures

    CERN Multimedia

    2006-01-01

    The arrival of one of the end caps of the CMS Tracker in Building 186 will result in the temporary closure of the following car parks: Building186: south entrance Building 613 Building 28 Building181: south entrance Building 600 Building 31 Route Oppenheimer The car parks concerned will be closed from Sunday 22 October until the evening of Monday 23 October. Thank you for your cooperation. PH-CMT Group Tel. 164569

  3. Notice of car park and road closures

    CERN Multimedia

    2006-01-01

    The arrival of one of the end caps of the CMS Tracker in Building 186 will result in the temporary closure of the following car parks: Building186: south entrance Building 613 Building 28 Building181: south entrance Building 600 Building 31 Route Oppenheimer The car parks concerned will be closed from Monday 30 October until the evening of Tuesday 31 October. Thank you for your cooperation. PH-CMT Group Tel. 164569

  4. Issue 5: High Interest in Hybrid Cars

    OpenAIRE

    Ong, Paul M.; Haselhoff, Kim

    2005-01-01

    This SCS Fact Sheet provides information on the level of interest in purchasing hybrid automobiles—vehicles that combine gasoline and electric motors to increase fuel mileage and reduce air pollution. A significant minority stated that they are willing to pay more for such a car, with the proportion varying by income and ethnicity. Not surprisingly, those drivers who commute to work and those with environmental concerns are more likely to pay the additional cost for a hybrid car.

  5. Autonomous Guided Car Using a Fuzzy Controller

    OpenAIRE

    Olivares Mendez, Miguel Angel; Campoy, Pascual; Mellado-Bataller, Ignacio; Mondragon, Ivan; Martinez, Carol; Sanchez-Lopez, Joseluis

    2013-01-01

    The goal of the work described in this paper is to develop a visual line guided system for being used on-board an Autonomous Guided Vehicle (AGV) commercial car, controlling the steering and using just the visual information of a line painted below the car. In order to implement the control of the vehicle, a Fuzzy Logic controller has been implemented, that has to be robust against curvature changes and velocity changes. The only input information for the controller is th...

  6. Implementation of Endomorphisms of the CAR Algebra

    OpenAIRE

    Binnenhei, Carsten

    1997-01-01

    The implementation of non-surjective Bogoliubov transformations in Fock states over CAR algebras is investigated. Such a transformation is implementable by a Hilbert space of isometries if and only if the well-known Shale-Stinespring condition is met. In this case, the dimension of the implementing Hilbert space equals the square root of the Watatani index of the associated inclusion of CAR algebras, and both are determined by the Fredholm index of the corresponding one-particle operator. Exp...

  7. Without wheels: alternatives to the private car

    Energy Technology Data Exchange (ETDEWEB)

    Bendixson, T.

    1975-01-01

    Alternatives to private cars are examined in a response to the need for new transportation strategies. It is believed that there is no single panacea for the problem, and both existing technologies (trains, buses, taxis, bicycles, and cars) and new technologies (driverless vehicles, electronic guidance systems, and moving sidewalks) are considered. New concepts in town planning and life style that could reduce travel needs are examined, and various current urban experiments are detailed. (PMA)

  8. Tunable narrow band filter for CARS microscopy

    International Nuclear Information System (INIS)

    In this letter we present an approach to CARS microscopy, which compromises between fast acquisition rates and the amount of chemical information obtained. By using a light modulator as tunable filter in concert with narrowband pump and broadband Stokes pulses, we demonstrate an experimental arrangement, which allows for fast electronic switching between CARS images recorded at different Raman resonances without the need for any optical adjustment

  9. Driving Cars by Means of Genetic Algorithms

    OpenAIRE

    Sáez, Yago; Pérez, Diego; Sanjuan, Óscar; Isasi, Pedro

    2008-01-01

    The techniques and the technologies supporting Automatic Vehicle Guidance are an important issue. Automobile manufacturers view automatic driving as a very interesting product with motivating key features which allow improvement of the safety of the car, reducing emission or fuel consumption or optimizing driver comfort during long journeys. Car racing is an active research field where new advances in aerodynamics, consumption and engine power are critical each season. Our proposal is to rese...

  10. Blue Car, Red Car: Developing Efficiency in Online Interpretation of Adjective-Noun Phrases

    OpenAIRE

    Fernald, Anne; Thorpe, Kirsten; Marchman, Virginia A.

    2010-01-01

    Two experiments investigated the development of fluency in interpreting adjective-noun phrases in 30- and 36-month-old English-learning children. Using online processing measures, children’s gaze patterns were monitored as they heard the familiar adjective/noun phrases (e.g. blue car) in visual contexts where the adjective was either informative (e.g. blue car paired with red car or red house) or uninformative (e.g. blue car paired with blue house). Thirty-six-month-olds processed adjective-n...

  11. A model of car ownership and use incorporating quality choice and ownership of multiple cars

    OpenAIRE

    Rouwendal, Jan; Pommer, John

    2003-01-01

    In this paper we develop and estimate a discrete-continuous model for car ownership and use that incorporates quality choice and the decision to own multiple cars. The basic model, used for instance in De Jong (1991), treats all cars as being equal (no differences in quality) and only considers ownership of a single car. In order to introduce quality into the model we assume that the marginal utility of driving is increased by a latent variable (interpreted as quality) that is related to the ...

  12. PLC Based Automatic Multistoried Car Parking System

    Directory of Open Access Journals (Sweden)

    Swanand S .Vaze

    2014-12-01

    Full Text Available This project work presents the study and design of PLC based Automatic Multistoried Car Parking System. Multistoried car parking is an arrangement which is used to park a large number of vehicles in least possible place. For making this arrangement in a real plan very high technological instruments are required. In this project a prototype of such a model is made. This prototype model is made for accommodating twelve cars at a time. Availability of the space for parking is detected by optical proximity sensor which is placed on the pallet. A motor controlled elevator is used to lift the cars. Elevator status is indicated by LED which is placed on ground floor. Controlling of the platforms and checking the vacancies is done by PLC. For unparking of car, keyboard is interfaced with the model for selection of required platform. Automation is done to reduce requirement of space and also to reduce human errors, which in-turn results in highest security and greatest flexibility. Due to these advantages, this system can be used in hotels, railway stations, airports where crowding of car is more.

  13. 36 CFR 1192.109 - Between-car barriers.

    Science.gov (United States)

    2010-07-01

    ... 36 Parks, Forests, and Public Property 3 2010-07-01 2010-07-01 false Between-car barriers. 1192... Commuter Rail Cars and Systems § 1192.109 Between-car barriers. Where vehicles operate in a high-platform, level-boarding mode, and where between-car bellows are not provided, devices or systems shall...

  14. Modelling strategic responses to car and fuel taxation

    NARCIS (Netherlands)

    Heijnen, P.; Kooreman, P.

    2006-01-01

    We develop a model to analyse the interactions between actors involved in car and fuel taxation: consumers, car producers, fuel producers and the government. Heterogeneous consumers choose between two versions of a car that differ in engine type (diesel or gasoline). Car manufacturers and fuel produ

  15. 49 CFR 231.21 - Tank cars without underframes.

    Science.gov (United States)

    2010-10-01

    ... inches. (3) Location. One safety railing at each end of car shall extend horizontally across car not less... car at center. (ii) The safety railing shall enclose the operating platform, manway and fittings used... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD SAFETY APPLIANCE STANDARDS § 231.21 Tank cars...

  16. Premium small car demand,not rising in China

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    <正>A growing number of worldwide car makers are focusing on making premium or luxury small cars. These cars ensure sales income, stabilize their market share and they are a good reflection of a civic-oriented society. But why these kinds of cars are unable to create market demand in China where resources supply is tougher than in most countries.

  17. 49 CFR 215.119 - Defective freight car truck.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Defective freight car truck. 215.119 Section 215... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Freight Car Components Suspension System § 215.119 Defective freight car truck. A railroad may not place or continue in service...

  18. 30 CFR 56.19079 - Blocking mine cars.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Blocking mine cars. 56.19079 Section 56.19079... Hoisting Procedures § 56.19079 Blocking mine cars. Where mine cars are hoisted by cage or skip, means for blocking cars shall be provided at all landings and also on the cage....

  19. 30 CFR 57.19079 - Blocking mine cars.

    Science.gov (United States)

    2010-07-01

    ... 30 Mineral Resources 1 2010-07-01 2010-07-01 false Blocking mine cars. 57.19079 Section 57.19079... Hoisting Procedures § 57.19079 Blocking mine cars. Where mine cars are hoisted by cage or skip, means for blocking cars shall be provided at all landings and also on the cage....

  20. 49 CFR 215.303 - Stenciling of restricted cars.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Stenciling of restricted cars. 215.303 Section 215... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD FREIGHT CAR SAFETY STANDARDS Stenciling § 215.303 Stenciling of restricted cars. (a) Each restricted railroad freight car that is described in § 215.205(a)...

  1. 19 CFR 151.26 - Molasses in tank cars.

    Science.gov (United States)

    2010-04-01

    ... 19 Customs Duties 2 2010-04-01 2010-04-01 false Molasses in tank cars. 151.26 Section 151.26....26 Molasses in tank cars. When molasses is imported in tank cars, the importer shall file with the... sugars or the character of the molasses in the different cars....

  2. 49 CFR 223.15 - Requirements for existing passenger cars.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Requirements for existing passenger cars. 223.15... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION SAFETY GLAZING STANDARDS-LOCOMOTIVES, PASSENGER CARS AND CABOOSES Specific Requirements § 223.15 Requirements for existing passenger cars. (a) Passenger cars built...

  3. 49 CFR 218.80 - Movement of occupied camp cars.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Movement of occupied camp cars. 218.80 Section 218... ADMINISTRATION, DEPARTMENT OF TRANSPORTATION RAILROAD OPERATING PRACTICES Protection of Occupied Camp Cars § 218.80 Movement of occupied camp cars. Occupied cars may not be humped or flat switched unless coupled...

  4. REMOTE CONTROLLED CAR HEATER USING A RASPBERRY PI

    OpenAIRE

    Loukola, Petrik

    2015-01-01

    In this thesis, the goal was to design and implement a technology with which the user can control the car heaters and monitor the car temperature via Wi-Fi network and web browser. The idea for this project came from the Finnish cold climate. Winters in Finland can be very cold and if the car owners want to drive their cars, it is recommended to preheat the car engine and interior before driving the car. This will make driving safer, the car will make less pollution, better for the engines li...

  5. Are weeds hitchhiking a ride on your car? A systematic review of seed dispersal on cars.

    Directory of Open Access Journals (Sweden)

    Michael Ansong

    Full Text Available When traveling in cars, we can unintentionally carry and disperse weed seed; but which species, and where are they a problem? To answer these questions, we systematically searched the scientific literature to identify all original research studies that assess seed transported by cars and listed the species with seed on/in cars. From the 13 studies that fit these criteria, we found 626 species from 75 families that have seed that can be dispersed by cars. Of these, 599 are listed as weeds in some part of the world, with 439 listed as invasive or naturalized alien species in one or more European countries, 248 are invasive/noxious weeds in North America, 370 are naturalized alien species in Australia, 167 are alien species in India, 77 are invasive species in China and 23 are declared weeds/invaders in South Africa. One hundred and one are classified as internationally important environmental weeds. Although most (487 were only recorded once, some species such as Chenopodium album, Poa pratensis and Trifolium repens were common among studies. Perennial graminoids seem to be favoured over annual graminoids while annual forbs are favoured over perennial forbs. Species characteristics including seed size and morphology and where the plants grew affected the probability that their seed was transported by cars. Seeds can be found in many different places on cars including under the chassis, front and rear bumpers, wheel wells and rims, front and back mudguards, wheel arches, tyres and on interior floor mats. With increasing numbers of cars and expanding road networks in many regions, these results highlight the importance of cars as a dispersal mechanism, and how it may favour invasions by some species over others. Strategies to reduce the risk of seed dispersal by cars include reducing seed on cars by mowing road verges and cleaning cars.

  6. Research progress of application of immunotherapy by chimeric antigen receptor-engineered T cells%嵌合抗原受体修饰的T细胞免疫治疗研究进展

    Institute of Scientific and Technical Information of China (English)

    李伟; 于慧杰

    2015-01-01

    The technique of chimeric antigen receptor-engineered T cells (CAR-T) is combined single chain antibody and T-cell activation modification and has specific and durable killing effect on tumors.It had achieved stunning results on clinical trials of B lymphocytic leukemias,B lymphomas and solid tumors.Meanwhile it also had potential risk on the off target effects,cytokine release syndrome,graft versus host disease and so on.This paper briefly reviews the principal of CAR-T cellular mechanism,advantages and clinical applications.%嵌合抗原受体修饰的T细胞(CAR-T细胞)是将单链抗体技术和T细胞活化基序结合应用的一种新的免疫治疗技术,具有特异、持久的肿瘤杀伤效应,在B淋巴细胞白血病、B淋巴瘤及实体瘤的临床试验中取得了令人震惊的效果,但也存在着脱靶效应、细胞因子释放综合征、移植物抗宿主病等潜在的风险.文章就CAR-T细胞原理、优势、临床应用等方面进行简要综述.

  7. 49 CFR 180.519 - Periodic retest and inspection of tank cars other than single-unit tank car tanks.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Periodic retest and inspection of tank cars other than single-unit tank car tanks. 180.519 Section 180.519 Transportation Other Regulations Relating to... of Tank Cars § 180.519 Periodic retest and inspection of tank cars other than single-unit tank...

  8. 49 CFR 231.8 - Tank cars without side sills and tank cars with short side sills and end platforms.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 4 2010-10-01 2010-10-01 false Tank cars without side sills and tank cars with... APPLIANCE STANDARDS § 231.8 Tank cars without side sills and tank cars with short side sills and end platforms. (a) Hand brakes—(1) Number. Same as specified for “Box and other house cars” (see §...

  9. 49 CFR 173.319 - Cryogenic liquids in tank cars.

    Science.gov (United States)

    2010-10-01

    ... subchapter for a DOT-113C120W tank car apply to a DOT-113D120W tank car. (49 U.S.C. 1803, 1804, 1808; 49 CFR... 49 Transportation 2 2010-10-01 2010-10-01 false Cryogenic liquids in tank cars. 173.319 Section... cars. (a) General requirements. (1) A tank car containing a flammable cryogenic liquid may not...

  10. Modelling cellular behaviour

    Science.gov (United States)

    Endy, Drew; Brent, Roger

    2001-01-01

    Representations of cellular processes that can be used to compute their future behaviour would be of general scientific and practical value. But past attempts to construct such representations have been disappointing. This is now changing. Increases in biological understanding combined with advances in computational methods and in computer power make it possible to foresee construction of useful and predictive simulations of cellular processes.

  11. Nigramide J is a novel potent inverse agonist of the human constitutive androstane receptor.

    Science.gov (United States)

    Kanno, Yuichiro; Tanuma, Nobuaki; Yatsu, Tomofumi; Li, Wei; Koike, Kazuo; Inouye, Yoshio

    2014-02-01

    The constitutive androstane receptor (CAR, NR1I3) is very important for drug development and for understanding pharmacokinetic drug-drug interactions. We screened by mammalian one hybrid assay among natural compounds to discover novel ligands of human constitutive androstane receptor (hCAR). hCAR transcriptional activity was measured by luciferase assay and mRNA levels of CYP2B6 and CYP3A4 in HepTR-hCAR cells and human primary hepatocytes were measured by real-time RT-PCR. Nigramide J (NJ) whose efficacy is comparable to those of hitherto known inverse agonists such as clotrimazole, PK11195, and ethinylestradiol. NJ is a naturally occurring cyclohexane-type amide alkaloid that was isolated from the roots of Piper nigrum. The suppressive effect of NJ on the CAR-dependent transcriptional activity was found to be species specific, in the descending order of hCAR, rat CAR, and mouse CAR. The unliganded hCAR-dependent transactivation of reporter and endogenous genes was suppressed by NJ at concentrations higher than 5 μmol/L. The ligand-binding cavity of hCAR was shared by NJ and CITCO, because they were competitive in the binding to hCAR. NJ interfered with the interaction of hCAR with coactivator SRC-1, but not with its interaction with the corepressor NCoR1. Furthermore, NJ is agonist of human pregnane X receptor (hPXR). NJ is a dual ligand of hCAR and hPXR, being an agonist of hPXR and an inverse agonist of hCAR. PMID:25505573

  12. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy.

    Science.gov (United States)

    Gardner, Rebecca; Wu, David; Cherian, Sindhu; Fang, Min; Hanafi, Laïla-Aïcha; Finney, Olivia; Smithers, Hannah; Jensen, Michael C; Riddell, Stanley R; Maloney, David G; Turtle, Cameron J

    2016-05-19

    Administration of lymphodepletion chemotherapy followed by CD19-specific chimeric antigen receptor (CAR)-modified T cells is a remarkably effective approach to treating patients with relapsed and refractory CD19(+) B-cell malignancies. We treated 7 patients with B-cell acute lymphoblastic leukemia (B-ALL) harboring rearrangement of the mixed lineage leukemia (MLL) gene with CD19 CAR-T cells. All patients achieved complete remission (CR) in the bone marrow by flow cytometry after CD19 CAR-T-cell therapy; however, within 1 month of CAR-T-cell infusion, 2 of the patients developed acute myeloid leukemia (AML) that was clonally related to their B-ALL, a novel mechanism of CD19-negative immune escape. These reports have implications for the management of patients with relapsed and refractory MLL-B-ALL who receive CD19 CAR-T-cell therapy. PMID:26907630

  13. Pollutants Characterization of Car Wash Wastewater

    Directory of Open Access Journals (Sweden)

    Hashim Nor Haslina

    2016-01-01

    Full Text Available The huge quantity of water consumed per car during washing cars yields the untreated effluents discharged to the stormwater system. Wastewater samples from snow car wash and two full hand service car wash station were analyzed for pH and the presence of PO43-,TP, O&G, alkalinity, TSS, NO3-, NO2-, COD and surfactant in accordance Standard Method of Water and Wastewater 2012. Two full hand wash service stations and one station of snow foam service were investigated in this study. Amongst the stations, snow foam car wash station indicates the highest concentration of PO43-, TP, O&G, TSS, COD and surfactant with the average value of 10.18 ± 0.87 mg/L, 30.93 ± 0.31 mg/L , 85.00 ± 0.64 mg/L 325.0 ± 0.6 mg/L, 485.0 ± 0.3 mg/L and 54.00 ± 2.50 mg/L as MBAS, respectively. Whereas, in parameters characterization in different stages throughout the car wash process, O&G was found to be the highest in pre soak stage, PO43-, TP, TSS and COD in washing stage and NO3- and NO2- in rinse stage. All parameters were compared to Environmental Quality (Industrial Effluent Regulations, 2009. There is a strong need to study on the characterization of car wash water in order to suggest the suitable treatment need for this type of wastewater.

  14. The Aldo-Keto Reductase Akr1b7 Gene Is a Common Transcriptional Target of Xenobiotic Receptors Pregnane X Receptor and Constitutive Androstane Receptor

    OpenAIRE

    Liu, Ming-Jie; Takahashi, Yuki; Wada, Taira; He, Jinhan; Gao, Jie; Tian, Yanan; Li, Song; Xie, Wen

    2009-01-01

    Aldo-keto reductase (AKR) family 1, member 7 (AKR1B7), a member of the AKR superfamily, has been suggested to play an important role in the detoxification of lipid peroxidation by-products. The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are xenosensors postulated to alleviate xeno- and endobiotic chemical insults. In this study, we show that the mouse Akr1b7 is a shared transcriptional target of PXR and CAR in the liver and i...

  15. Gasoline-powered series hybrid cars cause lower life cycle carbon emissions than battery cars

    Science.gov (United States)

    Meinrenken, Christoph; Lackner, Klaus S.

    2012-02-01

    Battery cars powered by grid electricity promise reduced life cycle green house gas (GHG) emissions from the automotive sector. Such scenarios usually point to the much higher emissions from conventional, internal combustion engine cars. However, today's commercially available series hybrid technology achieves the well known efficiency gains in electric drivetrains (regenerative breaking, lack of gearbox) even if the electricity is generated onboard, from conventional fuels. Here, we analyze life cycle GHG emissions for commercially available, state-of the-art plug-in battery cars (e.g. Nissan Leaf) and those of commercially available series hybrid cars (e.g., GM Volt, at same size and performance). Crucially, we find that series hybrid cars driven on (fossil) gasoline cause fewer emissions (126g CO2eq per km) than battery cars driven on current US grid electricity (142g CO2eq per km). We attribute this novel finding to the significant incremental emissions from plug-in battery cars due to losses during grid transmission and battery dis-/charging, and manufacturing larger batteries. We discuss crucial implications for strategic policy decisions towards a low carbon automotive sector as well as relative land intensity when powering cars by biofuel vs. bioelectricity.

  16. Gasoline-powered serial hybrid cars cause lower life cycle carbon emissions than battery cars

    Science.gov (United States)

    Meinrenken, Christoph J.; Lackner, Klaus S.

    2011-04-01

    Battery cars powered by grid electricity promise reduced life cycle green house gas (GHG) emissions from the automotive sector. Such scenarios usually point to the much higher emissions from conventional, internal combustion engine cars. However, today's commercially available serial hybrid technology achieves the well known efficiency gains from regenerative breaking, lack of gearbox, and light weighting - even if the electricity is generated onboard, from conventional fuels. Here, we analyze emissions for commercially available, state-of the-art battery cars (e.g. Nissan Leaf) and those of commercially available serial hybrid cars (e.g., GM Volt, at same size and performance). Crucially, we find that serial hybrid cars driven on (fossil) gasoline cause fewer life cycle GHG emissions (126g CO2e per km) than battery cars driven on current US grid electricity (142g CO2e per km). We attribute this novel finding to the significant incremental life cycle emissions from battery cars from losses during grid transmission, battery dis-/charging, and larger batteries. We discuss crucial implications for strategic policy decisions towards a low carbon automotive sector as well as relative land intensity when powering cars by biofuel vs. bioelectricity.

  17. Forecasting U.S. Car Sales and Car Registrations in Japan: Rationality, Accuracy and Herding

    DEFF Research Database (Denmark)

    Stadtmann, Georg; Rülke, Jan; Pierdzioch, Christian

    2011-01-01

    We analyze forecasts of car sales in the U.S. and forecasts of car registrations in Japan. We document a substantial heterogeneity of forecasts, and we show that, based on traditional criteria, forecasts are neither rational nor unbiased. We also report that forecasters anti-herd, that is...

  18. Crystallographic analysis of murine constitutive androstane receptor ligand-binding domain complexed with 5α-androst-16-en-3α-ol

    International Nuclear Information System (INIS)

    The purification and structure determination of the murine constitutive androstane receptor bound to its inverse agonist/antagonist androstenol is described. The constitutive androstane receptor (CAR) is a member of the nuclear receptor superfamily. In contrast to classical nuclear receptors, which possess small-molecule ligand-inducible activity, CAR exhibits constitutive transcriptional activity in the apparent absence of ligand. CAR is among the most important transcription factors; it coordinately regulates the expression of microsomal cytochrome P450 genes and other drug-metabolizing enzymes. The murine CAR ligand-binding domain (LBD) was coexpressed with the steroid receptor coactivator protein (SRC-1) receptor-interacting domain (RID) in Escherichia coli. The mCAR LBD subunit was purified away from SRC-1 by affinity, anion-exchange and size-exclusion chromatography, crystallized with androstenol and the structure of the complex determined by molecular replacement

  19. Cloning and characterization of R-PTP-kappa, a new member of the receptor protein tyrosine phosphatase family with a proteolytically cleaved cellular adhesion molecule-like extracellular region

    DEFF Research Database (Denmark)

    Jiang, Y P; Wang, H; D'Eustachio, P; Musacchio, J M; Schlessinger, J; Sap, J

    1993-01-01

    We describe a new member of the receptor protein tyrosine phosphatase family, R-PTP-kappa, cDNA cloning predicts that R-PTP-kappa is synthesized from a precursor protein of 1,457 amino acids. Its intracellular domain displays the classical tandemly repeated protein tyrosine phosphatase homology, ...

  20. Nonlinear optical methods for cellular imaging and localization.

    Science.gov (United States)

    McVey, A; Crain, J

    2014-07-01

    Of all the ways in which complex materials (including many biological systems) can be explored, imaging is perhaps the most powerful because delivering high information content directly. This is particular relevant in aspects of cellular localization where the physical proximity of molecules is crucial in biochemical processes. A great deal of effort in imaging has been spent on enabling chemically selective imaging so that only specific features are revealed. This is almost always achieved by adding fluorescent chemical labels to specific molecules. Under appropriate illumination conditions only the molecules (via their labels) will be visible. The technique is simple and elegant but does suffer from fundamental limitations: (1) the fluorescent labels may fade when illuminated (a phenomenon called photobleaching) thereby constantly decreasing signal contrast over the course of image acquisition. To combat photobleaching one must reduce observation times or apply unfavourably low excitation levels all of which reduce the information content of images; (2) the fluorescent species may be deactivated by various environmental factors (the general term is fluorescence quenching); (3) the presence of fluorescent labels may introduce unexpected complications or may interfere with processes of interest (4) Some molecules of interest cannot be labelled. In these circumstances we require a fundamentally different strategy. One of the most promising alternative is based on a technique called Coherent Anti-Stokes Raman scattering (CARS). CARS is a fundamentally more complex process than is fluorescence and the experimental procedures and optical systems required to deliver high quality CARS images are intricate. However, the rewards are correspondingly very high: CARS probes the chemically distinct vibrations of the constituent molecules in a complex system and is therefore also chemically selective as are fluorescence-based methods. Moreover,the potentially severe problems of

  1. Car accidents and number of stopped cars due to road blockage on a one-lane highway

    OpenAIRE

    Boccara, N.; Fuks, H.; Zeng, Q.

    1997-01-01

    Within the framework of a simple model of car traffic on a one-lane highway, we study the probability for car accidents to occur when drivers do not respect the safety distance between cars, and, as a result of the blockage during the time $T$ necessary to clear the road, we determine the number of stopped cars as a function of car density. We give a simple theory in good agreement with our numerical simulations.

  2. Decentralized Cooperation Strategies in Two-Dimensional Traffic of Cellular Automata

    International Nuclear Information System (INIS)

    We study the two-dimensional traffic of cellular automata using computer simulation. We propose two type of decentralized cooperation strategies, which are called stepping aside (CS-SA) and choosing alternative routes (CS-CAR) respectively. We introduce them into an existing two-dimensional cellular automata (CA) model. CS-SA is designed to prohibit a kind of ping-pong jump when two objects standing together try to move in opposite directions. CS-CAR is designed to change the solution of conflict in parallel update. CS-CAR encourages the objects involved in parallel conflicts choose their alternative routes instead of waiting. We also combine the two cooperation strategies (CS-SA-CAR) to test their combined effects. It is found that the system keeps on a partial jam phase with nonzero velocity and flow until the density reaches one. The ratios of the ping-pong jump and the waiting objects involved in conflict are decreased obviously, especially at the free phase. And the average flow is improved by the three cooperation strategies. Although the average travel time is lengthened a bit by CS-CAR, it is shorten by CS-SA and CS-SA-CAR. In addition, we discuss the advantage and applicability of decentralized cooperation modeling.

  3. Car Safety System Using Fuzzy Logic

    Directory of Open Access Journals (Sweden)

    M. Al-Hadidi

    2008-01-01

    Full Text Available Nowadays everybody can recognize the huge increasing of car numbers on roads. Day after day, this increasing may be an indicator for changing and development. This put a lot of challenges on people and governments. One of these challenges is car accidents and there bad effects. The main aim of our proposal is to help our society to decrease car accidents by designing a system which makes the drivers pay more attention and worn them before an accident takes place. The designed system consists basically of three general circuits, which complete each others. The first circuit consists of microcontroller, power source, speaker and switches needed. The second circuit, the ultrasonic transmitter and receiver circuit which measures the distance between the car and any thing in front of it. Finally, the third circuit, the opto-coupler circuit, its function to determine the current speed of the car. The characteristics of this system include flexibility and effectiveness of implementation. It’s cheap and it has low power consumption with a small size. The system records all the changes surrounded the driver environment, then process them using a fuzzy microcontroller which worn the driver of expected dangers through an output devices which lead the driver to take all necessary measures to avoid the accident.

  4. The old-new car sticker

    CERN Multimedia

    2000-01-01

    You have had the same car sticker for ten years and have been driving in and out of CERN every day. Suddenly one morning the guard stops you and tells you need a new one. Hmmm ?! “There were 60 000 stickers in circulation in Geneva and we could not control wether the sticker had been distributed to the right person”, saysa Claude Ducastel, responsible for Entrance Security. “So to solve this problem, last year DSU decided to change Operational Circular N°2 and introduce new car stickers that will be changed every year.” Three types of car stickers were introduced: blue, green and red. The blue one is for staff members whose contract is for one year or more. It indicates the plate number of the car. The green one is for staff members whose contract is for less than one year. It indicates the plate number of the car and the date the contract of the employee terminates. It also has a big L for "Limited". The red one is for enterprise subcontractors whose contracts finish at the end of the year. If ...

  5. Computer assisted radiology and surgery. CARS 2010

    Energy Technology Data Exchange (ETDEWEB)

    Anon.

    2010-06-15

    The conference proceedings include contributions to the following topics: (1) CARS Clinical Day: minimally invasive spiral surgery, interventional radiology; (2) CARS - computer assisted radiology and surgery: ophthalmology, stimulation methods, new approaches to diagnosis and therapy; (3) Computer assisted radiology 24th International congress and exhibition: computer tomography and magnetic resonance, digital angiographic imaging, digital radiography, ultrasound, computer assisted radiation therapy, medical workstations, image processing and display; (4) 14th Annual conference of the International Society for computer aided surgery; ENT-CMF head and neck surgery computer-assisted neurosurgery, cardiovascular surgery, image guided liver surgery, abdominal and laparoscopic surgery, computer-assisted orthopedic surgery, image processing and visualization, surgical robotics and instrumentation, surgical modeling, simulation and education; (5) 28th International EuroPACS meeting: image distribution and integration strategies, planning and evaluation, telemedicine and standards, workflow and data flow in radiology; (6) 11th CARS/SPIE/EuroPACS joint workshop on surgical PACS and the digital operating, management and assessment of OR systems and integration; (7) 12th International workshop on computer-aided diagnosis: special session on breast CAD, special session on thoracic CAD, special session on abdominal brain, lumbar spine CAD; (8) 16th computed Maxillofacial imaging congress: computed maxillofacial imaging in dental implantology, orthodontics and dentofacial orthopedics; approaches to 3D maxillofacial imaging; surgical navigation; (9) 2nd EuroNOTES/CARS workshop on NOTES: an interdisciplinary challenge; (10) 2nd EPMA/CARS workshop on personalized medicine and ICT.; (11)poster sessions.

  6. Computer assisted radiology and surgery. CARS 2010

    International Nuclear Information System (INIS)

    The conference proceedings include contributions to the following topics: (1) CARS Clinical Day: minimally invasive spiral surgery, interventional radiology; (2) CARS - computer assisted radiology and surgery: ophthalmology, stimulation methods, new approaches to diagnosis and therapy; (3) Computer assisted radiology 24th International congress and exhibition: computer tomography and magnetic resonance, digital angiographic imaging, digital radiography, ultrasound, computer assisted radiation therapy, medical workstations, image processing and display; (4) 14th Annual conference of the International Society for computer aided surgery; ENT-CMF head and neck surgery computer-assisted neurosurgery, cardiovascular surgery, image guided liver surgery, abdominal and laparoscopic surgery, computer-assisted orthopedic surgery, image processing and visualization, surgical robotics and instrumentation, surgical modeling, simulation and education; (5) 28th International EuroPACS meeting: image distribution and integration strategies, planning and evaluation, telemedicine and standards, workflow and data flow in radiology; (6) 11th CARS/SPIE/EuroPACS joint workshop on surgical PACS and the digital operating, management and assessment of OR systems and integration; (7) 12th International workshop on computer-aided diagnosis: special session on breast CAD, special session on thoracic CAD, special session on abdominal brain, lumbar spine CAD; (8) 16th computed Maxillofacial imaging congress: computed maxillofacial imaging in dental implantology, orthodontics and dentofacial orthopedics; approaches to 3D maxillofacial imaging; surgical navigation; (9) 2nd EuroNOTES/CARS workshop on NOTES: an interdisciplinary challenge; (10) 2nd EPMA/CARS workshop on personalized medicine and ICT.; (11)poster sessions.

  7. Dual-tip-enhanced ultrafast CARS nanoscopy

    International Nuclear Information System (INIS)

    Coherent anti-Stokes Raman scattering (CARS) and, in particular, femtosecond adaptive spectroscopic techniques (FAST CARS) have been successfully used for molecular spectroscopy and microscopic imaging. Recent progress in ultrafast nano-optics provides flexibility in generation and control of optical near fields, and holds promise to extend CARS techniques to the nanoscale. In this theoretical study, we demonstrate ultrafast subwavelentgh control of coherent Raman spectra of molecules in the vicinity of a plasmonic nanostructure excited by ultrashort laser pulses. The simulated nanostructure design provides localized excitation sources for CARS by focusing incident laser pulses into subwavelength hot spots via two self-similar nanolens antennas connected by a waveguide. Hot-spot-selective dual-tip-enhanced CARS (2TECARS) nanospectra of DNA nucleobases are obtained by simulating optimized pump, Stokes and probe near fields using tips, laser polarization- and pulse-shaping. This technique may be used to explore ultrafast energy and electron transfer dynamics in real space with nanometre resolution. (paper)

  8. ENERGY EFFICIENT AUTOMATED CAR PARKING SYSTEM

    Directory of Open Access Journals (Sweden)

    V. Sumathi

    2013-06-01

    Full Text Available Due to a rapid increase in the number of vehicles, the need for parking spaces is on rise. It is important to park the cars in close proximity to avoid traffic congestion and use a parking areaefficiently. Current car parking management systems utilize human personnel to find available parking areas or use a video based system that collects the information in the form of images and tracks available parking slots. This paper describes an alternative energy efficient system which allots a unique parking ‘slot’ for every incoming car. The parking area has a number of ‘slots’ to park which are prioritized in such a way that the available slot nearest to the entry is allotted to every incoming car. The driver has to park in that particular slot allotted without searching for a vacant space thus reducing the time for parking and making an efficient use of available space. The System additionally makes efficient use ofenergy by switching the lights in the parking area ON only when a car is in motion. The application is developed on LPC1343 ARM processor and tested on a miniature prototype. The results suggest that it isa robust system and can be implemented in real time with an option to increase the number of parking slots as required.

  9. Coxsackievirus and adenovirus receptor expression in human endometrial adenocarcinoma: possible clinical implications

    Directory of Open Access Journals (Sweden)

    Sfiniadakis Ioannis K

    2008-06-01

    Full Text Available Abstract The coxsackievirus and adenovirus receptor (CAR is a crucial receptor for the entry of both coxsackie B viruses and adenoviruses into host cells. CAR expression on tumor cells was reported to be associated with their sensitivity to adenoviral infection, while it was considered as a surrogate marker for monitoring and/or predicting the outcome of adenovirus-mediated gene therapy. The aim of the present study was to evaluate the clinical significance of CAR expression in endometrial adenocarcinoma. CAR expression was assessed immunohistochemically in tumoral samples of 41 endometrial adenocarcinoma patients and was statistically analyzed in relation to various clinicopathological parameters, tumor proliferative capacity and patient survival. CAR positivity was noted in 23 out of 41 (56% endometrial adenocarcinoma cases, while high CAR expression in 8 out of 23 (35% positive ones. CAR intensity of immunostaining was classified as mild in 11 (48%, moderate in 10 (43% and intense in 2 (9% out of the 23 positive cases. CAR positivity was significantly associated with tumor histological grade (p = 0.036, as well differentiated tumors more frequently demonstrating no CAR expression. CAR staining intensity was significantly associated with tumor histological type (p = 0.016, as tumors possessing squamous elements presented more frequently intense CAR immunostaining. High CAR expression showed a trend to be correlated with increased tumor proliferative capacity (p = 0.057. Patients with tumors presenting moderate or intense CAR staining intensity were characterized by longer survival times than those with mild one; however, this difference did not reach statistical significance. These data reveal, for the first time, the expression of CAR in clinical material obtained from patients with endometrial adenocarcinoma in relation to important clinicopathological parameters for their management. As CAR appears to modulate the proliferation and

  10. Cellular host responses to gliomas.

    Directory of Open Access Journals (Sweden)

    Joseph Najbauer

    Full Text Available BACKGROUND: Glioblastoma multiforme (GBM is the most aggressive type of malignant primary brain tumors in adults. Molecular and genetic analysis has advanced our understanding of glioma biology, however mapping the cellular composition of the tumor microenvironment is crucial for understanding the pathology of this dreaded brain cancer. In this study we identified major cell populations attracted by glioma using orthotopic rodent models of human glioma xenografts. Marker-specific, anatomical and morphological analyses revealed a robust influx of host cells into the main tumor bed and tumor satellites. METHODOLOGY/PRINCIPAL FINDINGS: Human glioma cell lines and glioma spheroid orthotopic implants were used in rodents. In both models, the xenografts recruited large numbers of host nestin-expressing cells, which formed a 'network' with glioma. The host nestin-expressing cells appeared to originate in the subventricular zone ipsilateral to the tumor, and were clearly distinguishable from pericytes that expressed smooth muscle actin. These distinct cell populations established close physical contact in a 'pair-wise' manner and migrated together to the deeper layers of tumor satellites and gave rise to tumor vasculature. The GBM biopsy xenografts displayed two different phenotypes: (a low-generation tumors (first in vivo passage in rats were highly invasive and non-angiogenic, and host nestin-positive cells that infiltrated into these tumors displayed astrocytic or elongated bipolar morphology; (b high-generation xenografts (fifth passage had pronounced cellularity, were angiogenic with 'glomerulus-like' microvascular proliferations that contained host nestin-positive cells. Stromal cell-derived factor-1 and its receptor CXCR4 were highly expressed in and around glioma xenografts, suggesting their role in glioma progression and invasion. CONCLUSIONS/SIGNIFICANCE: Our data demonstrate a robust migration of nestin-expressing host cells to glioma, which

  11. Efficiency of cellular information processing

    CERN Document Server

    Barato, Andre C; Seifert, Udo

    2014-01-01

    We show that a rate of conditional Shannon entropy reduction, characterizing the learning of an internal process about an external process, is bounded by the thermodynamic entropy production. This approach allows for the definition of an informational efficiency that can be used to study cellular information processing. We analyze three models of increasing complexity inspired by the E. coli sensory network, where the external process is an external ligand concentration jumping between two values. We start with a simple model for which ATP must be consumed so that a protein inside the cell can learn about the external concentration. With a second model for a single receptor we show that the rate at which the receptor learns about the external environment can be nonzero even without any dissipation inside the cell since chemical work done by the external process compensates for this learning rate. The third model is more complete, also containing adaptation. For this model we show inter alia that a bacterium i...

  12. Heterogeneous cellular networks

    CERN Document Server

    Hu, Rose Qingyang

    2013-01-01

    A timely publication providing coverage of radio resource management, mobility management and standardization in heterogeneous cellular networks The topic of heterogeneous cellular networks has gained momentum in industry and the research community, attracting the attention of standardization bodies such as 3GPP LTE and IEEE 802.16j, whose objectives are looking into increasing the capacity and coverage of the cellular networks. This book focuses on recent progresses,  covering the related topics including scenarios of heterogeneous network deployment, interference management i

  13. Cellular Reflectarray Antenna

    Science.gov (United States)

    Romanofsky, Robert R.

    2010-01-01

    The cellular reflectarray antenna is intended to replace conventional parabolic reflectors that must be physically aligned with a particular satellite in geostationary orbit. These arrays are designed for specified geographical locations, defined by latitude and longitude, each called a "cell." A particular cell occupies nominally 1,500 square miles (3,885 sq. km), but this varies according to latitude and longitude. The cellular reflectarray antenna designed for a particular cell is simply positioned to align with magnetic North, and the antenna surface is level (parallel to the ground). A given cellular reflectarray antenna will not operate in any other cell.

  14. Noise mapping inside a car cabin

    DEFF Research Database (Denmark)

    Knudsen, Kim; Sjøj, Sidsel Marie Nørholm; Jacobsen, Finn;

    The mapping of noise is of considerable interest in the car industry where a good noise mapping can make it much easier to identify the sources that generate the noise and eventually reduce the individual contributions to the noise. The methods used for this purpose include delay-and-sum beamform......The mapping of noise is of considerable interest in the car industry where a good noise mapping can make it much easier to identify the sources that generate the noise and eventually reduce the individual contributions to the noise. The methods used for this purpose include delay......-and-sum beamforming and spherical harmonics beamforming. These methods have a poor spatial esolution at low frequencies, and since much noise generated in cars is dominated by low frequencies the methods are not optimal. In the present paper the mapping is done by solving an inverse problem with a transfer matrix...

  15. Neu1 sialidase and matrix metalloproteinase-9 cross-talk regulates nucleic acid-induced endosomal TOLL-like receptor-7 and -9 activation, cellular signaling and pro-inflammatory responses.

    Science.gov (United States)

    Abdulkhalek, Samar; Szewczuk, Myron R

    2013-11-01

    The precise mechanism(s) by which intracellular TOLL-like receptors (TLRs) become activated by their ligands remains unclear. Here, we report a molecular organizational G-protein coupled receptor (GPCR) signaling platform to potentiate a novel mammalian neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B GPCR, all of which form a tripartite complex with TLR-7 and -9. siRNA silencing Neu1, MMP-9 and neuromedin-B GPCR in RAW-blue macrophage cells significantly reduced TLR7 imiquimod- and TLR9 ODN1826-induced NF-κB (NF-κB-pSer(536)) activity. Tamiflu, specific MMP-9 inhibitor, neuromedin B receptor specific antagonist BIM23127, and the selective inhibitor of whole heterotrimeric G-protein complex BIM-46174 significantly block nucleic acid-induced TLR-7 and -9 MyD88 recruitment, NF-κB activation and proinflammatory TNFα and MCP-1 cytokine responses. For the first time, Neu1 clearly plays a central role in mediating nucleic acid-induced intracellular TLR activation, and the interactions involving NMBR-MMP9-Neu1 cross-talk constitute a novel intracellular TLR signaling platform that is essential for NF-κB activation and pro-inflammatory responses. PMID:23827939

  16. Traffic jam dynamics in stochastic cellular automata

    Energy Technology Data Exchange (ETDEWEB)

    Nagel, K. [Los Alamos National Lab., NM (United States)]|[Santa Fe Inst., NM (United States); Schreckenberg, M. [Univ. Duisburg (Germany)

    1995-09-01

    Simple models for particles hopping on a grid (cellular automata) are used to simulate (single lane) traffic flow. Despite their simplicity, these models are astonishingly realistic in reproducing start-stop-waves and realistic fundamental diagrams. One can use these models to investigate traffic phenomena near maximum flow. A so-called phase transition at average maximum flow is visible in the life-times of jams. The resulting dynamic picture is consistent with recent fluid-dynamical results by Kuehne/Kerner/Konhaeuser, and with Treiterer`s hysteresis description. This places CA models between car-following models and fluid-dynamical models for traffic flow. CA models are tested in projects in Los Alamos (USA) and in NRW (Germany) for large scale microsimulations of network traffic.

  17. Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma.

    Science.gov (United States)

    Posey, Avery D; Schwab, Robert D; Boesteanu, Alina C; Steentoft, Catharina; Mandel, Ulla; Engels, Boris; Stone, Jennifer D; Madsen, Thomas D; Schreiber, Karin; Haines, Kathleen M; Cogdill, Alexandria P; Chen, Taylor J; Song, Decheng; Scholler, John; Kranz, David M; Feldman, Michael D; Young, Regina; Keith, Brian; Schreiber, Hans; Clausen, Henrik; Johnson, Laura A; June, Carl H

    2016-06-21

    Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells. PMID:27332733

  18. Scientists Explain Catalysis Neutralizing Car's Tail Gas

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    @@ The neutralization of the car's tail gas is a problem of practical importance in the eyes of both experimental and theoretical physicists. Recently, a group of CAS scientists join hands with the Queen's University of Belfast in the UK to make advances in exploring the process of CO oxidation in a bid to reduce the air pollution caused by the car's exhaust gas. The work has been supported by the "National 973Program" and the CAS Foundation for Overseas Studies. On March 4,its result was published by the Internet edition of the Journal of the American Chemical Society.

  19. Shady Car Dealings and Taxing Work Practices

    DEFF Research Database (Denmark)

    Boll, Karen

    2014-01-01

    The empirical focus of this article is a ten-month ethnography of a tax audit process led by the Danish Tax and Customs Administration. The tax audit concerns a number of shady car dealings from which taxable income is not reported. This article focuses on the process whereby the tax administration...... succeeds in making some of these car dealings visible. This article draws inspiration from interpretative tax studies that consider taxation as an organisational, institutional, social and cultural phenomenon. Complementing those studies’ approaches, the present study draws both on Latour’s concept...

  20. The 2009 Simulated Car Racing Championship

    DEFF Research Database (Denmark)

    Loiacono, Daniele; Lanzi, Pier Luca; Togelius, Julian;

    2011-01-01

    In this paper, we overview the 2009 Simulated Car Racing Championship-an event comprising three competitions held in association with the 2009 IEEE Congress on Evolutionary Computation (CEC), the 2009 ACM Genetic and Evolutionary Computation Conference (GECCO), and the 2009 IEEE Symposium....... The organizers provide short summaries of the other competitors. Finally, we summarize the championship results, followed by a discussion about what the organizers learned about 1) the development of high-performing car racing controllers and 2) the organization of scientific competitions....

  1. Event marketing in car industry : case: Carfest

    OpenAIRE

    Häme, Erkki

    2013-01-01

    Car importer companies compete on the pages of newspapers and magazines with who has the nicest and most clever advertisement on their new car models. The industry uses quite basic means of marketing – including TV and Radio. Event marketing means to have an event and market your product through that. It needs involvement from the potential customer – not only browsing the magazine or listening to the radio. The main objective in this thesis was to find out whether a SMB can organize...

  2. Audi cars Sponsored to Summer Davos

    Institute of Scientific and Technical Information of China (English)

    You Wanlong

    2009-01-01

    @@ During the upcoming Summer Davos in Asia this year,it is not only the grand affair to Dalian city,but also for the Audi cars,as the exclusive vehicle sunnlier for the event The Vehicle Handover Ceremony of the Faw Volkswagen Audi was held at Xinghai Square,Dalian,China,September 3,2009. Faw Volkswa,vehicle sponsor of the Summer Davos 2009,provides a total of 85 new Audi cars to be running for the distinguished guests during the meeting.

  3. ANALYSIS OF TOWING HOOKS OF CARS

    Directory of Open Access Journals (Sweden)

    K. Turgut YÜKSEL

    2005-02-01

    Full Text Available Towing hooks generally are assembled to vehicles as accessory. They are used to tow caravans and trailers having no engine, which provide accommodation and haulage of loads, respectively. So, the transport capacity of cars is increased safely. Towing hooks require different constructive structures due to different chassis or monocoque body of each car type; hence they are to be manufactured and assembled in small- or middle-size factories as per order. In this study, three different constructions of towing hook are modelled and structurally analysed. The results obtained are compared with each other to improve the structural strength.

  4. T cells expressing VHH-directed oligoclonal chimeric HER2 antigen receptors

    DEFF Research Database (Denmark)

    Jamnani, Fatemeh Rahimi; Rahbarizadeh, Fatemeh; Shokrgozar, Mohammad Ali;

    2014-01-01

    Adoptive cell therapy with engineered T cells expressing chimeric antigen receptors (CARs) originated from antibodies is a promising strategy in cancer immunotherapy. Several unsuccessful trials, however, highlight the need for alternative conventional binding domains and the better combination of...... costimulatory endodomains for CAR construction to improve the effector functions of the engineered T cells. Camelid single-domain antibodies (VHHs), which are the smallest single domain antibodies, can endow great targeting ability to CAR-engineered T cells....

  5. Perancangan dan Implementasi Kontroler PID untuk Pengaturan Autonomous Car-Following Car

    Directory of Open Access Journals (Sweden)

    Andreas Parluhutan Bonor Sinaga

    2014-03-01

    Full Text Available Pengiriman logistik ke daerah-daerah rawan bencana merupakan hal yang sangat sulit dilakukan, tentunya diperlukan pengetahuan mengenai kondisi medan jalan. Salah satu dampak yang utama adalah sulitnya melakukan manuver dalam pengendalian performansi  truk logistik yang pada umumnya berupa truk-truk gandeng. Untuk membantu pengemudi truk dalam berkendara pada kondisi tersebut, dirancang sebuah prototype mobil mandiri (Autonomous Car yang mampu melakukan manuver-manuver pergerakan secara sendirinya, salah satu manuver tersebut ialah Following Car.  Dalam Tugas Akhir ini perancangan sistem yang akan dilakukan dengan  memodelkan  dua buah kendaraan mobil RC (remote control yang bertindak sebagai  follower dan leader car. Pengoperasian dari  following car dilakukan dengan memodifikasi dari kendaraan RC-1, sedangkan RC-2 bertindak sebagai leader car yang dikondisikan secara manual. Dengan penerapan kontroler PID pada implementasi sistem didapatkan penurunan time settling menjadi 2,7 Detik dan peningkatan error steady state sebesar 2,44%. Pada implementasi diberikan kecepatan leader secara acak, dengan implementasi kontroler PID, kondisi jarak antara autonomous car dengan leader car masih dalam range keadaan ideal pada set point.

  6. Demand for mini cars and large cars; decay effects, and gasoline demand in Japan

    International Nuclear Information System (INIS)

    This article explains why: (a) consumers underinvest in new car fuel economy by opting to buy large vehicles; (b) macro shifts in vehicle classes have occurred in the last decades; and how (c) the effects of vehicle fuel economy and shifts in vehicle type influence the growth path of gasoline demand, which is the key to designing effective energy efficiency goals for transport. From 2008, 1.9 EXJ (Exajoules) of energy were consumed in Japan by private vehicles producing 124 MtCO2 emissions. For the period 1980 to 2008, we estimated: (1) gasoline demand for three vehicle sizes; (2) vehicle sales; (3) new car fuel economy changes (the ‘real’ technical change); and (4) vehicle stocks. Using a data sample for 1980–2008 we found that: (a) in the short term consumers buy fuel economy, that is sales of mini and small cars increase, but this is not sustained in the long term: and (b) consumers increasingly traded in their cars for larger cars. A further finding was that gasoline demand is projected to increase to 2.3 EXJ by 2035, even with a growing number of mini cars. The policy implication is clear: Japan’s policy to reduce oil dependency to 80% by 2030 is in peril as long as buyers prefer larger cars and drive ever longer distances.

  7. Cellular oncogenes in neoplasia.

    OpenAIRE

    Chan, V T; McGee, J O

    1987-01-01

    In recent years cellular homologues of many viral oncogenes have been identified. As these genes are partially homologous to viral oncogenes and are activated in some tumour cell lines they are termed "proto-oncogenes". In tumour cell lines proto-oncogenes are activated by either quantitative or qualitative changes in gene structure: activation of these genes was originally thought to be a necessary primary event in carcinogenesis, but activated cellular oncogenes, unlike viral oncogenes, do ...

  8. Cellular Cardiomyoplasty: Clinical Application

    OpenAIRE

    Chachques, J. (J.); Acar, C; J. Herreros; Trainini, J. (Jorge); Prosper, F.; D’Attellis, N. (N.); Fabiani, J. N.; Carpentier, A

    2004-01-01

    Myocardial regeneration can be induced with the implantation of a variety of myogenic and angiogenic cell types. More than 150 patients have been treated with cellular cardiomyoplasty worldwide, 18 patients have been treated by our group. Cellular cardiomyoplasty seems to reduce the size and fibrosis of infarct scars, limit postischemic remodelling, and restore regional myocardial contractility. Techniques for skeletal myoblasts culture and ex vivo expansion using auto...

  9. Car Age, Taxation, Scrappage Premiums and the ELV Directive

    OpenAIRE

    Sandström, F. Mikael

    2003-01-01

    A chain of replacement model is used to examine the effects of automobile taxes and of a scrappage premium on the life length of cars, and on the size of the car fleet. The predictions of the model are tested on data on the scrappage of cars in Sweden 1989-2002. The theoretical model predicts that increased taxes on the purchase of cars should increase the life length of cars, and reduce the number of cars. A scrappage premium would have the opposite effects. Changes in periodic taxes would h...

  10. Coordinated roles of pregnane X receptor and constitutive androstane receptor in autoinduction of voriconazole metabolism in mice.

    Science.gov (United States)

    Ohbuchi, Masato; Yoshinari, Kouichi; Kaneko, Hayato; Matsumoto, Satoru; Inoue, Akiko; Kawamura, Akio; Usui, Takashi; Yamazoe, Yasushi

    2013-03-01

    The antifungal efficacy of voriconazole (VRC) differs among host species, with potent efficacy in humans but less in rodents. We investigated the possible involvement of pregnane X receptor (PXR) and constitutive androstane receptor (CAR) in the species-specific efficacy of VRC through pharmacokinetic analyses using genetically modified mice and primary human hepatocytes. VRC (30 mg/kg) was orally administered to wild-type, Pxr-null, Car-null, and Pxr- and Car-null (Pxr/Car-null) mice for 7 days. Hepatic VRC metabolism was significantly increased by VRC administration, and the elimination rates of plasma VRC were much higher on day 7 than on day 1 in wild-type mice. This autoinduction was also observed in Pxr-null and Car-null mice but not in Pxr/Car-null mice, suggesting coordinated roles of PXR and CAR in the autoinduction of VRC metabolism in mice. Hepatic Cyp3a11 mRNA levels were increased by VRC administration, hepatic metabolic activities for VRC were correlated with CYP3A activities, and the induced VRC metabolism was inhibited by ketoconazole (a CYP3A inhibitor). In primary human hepatocytes, VRC barely increased mRNA levels of CYP3A4 and CYP2B6 (human PXR/CAR target genes) at its therapeutic concentrations. In conclusion, these results suggest that VRC is metabolized mainly by CYP3A11 in mouse livers and that PXR- and CAR-mediated CYP3A11 induction, namely, autoinduction of VRC metabolism, is a primary reason for the ineffectiveness of VRC in mice. A limited ability of VRC to activate human PXR/CAR at its clinical concentration might explain the VRC efficacy in humans. Therefore, the ability to activate PXR/CAR might determine the VRC efficacy in different mammalian species. PMID:23274663

  11. Where sustainable transport and social exclusion meet: households without cars and car dependence in Great Britain

    OpenAIRE

    Mattioli, G.

    2014-01-01

    A secondary analysis of the British National Travel Survey for the years 2002–2010 shows that the composition of the group of carless households is a good indicator of the level of car dependence in a local area: indeed, while non-car ownership in peripheral and rural areas very often correspond to a marginal socio-demographic situation, this is less and less true as one moves towards larger urban areas. Similarly, while in sparse areas most households without cars are either virtually immobi...

  12. Protein-Protein Interactions at the Adrenergic Receptors

    OpenAIRE

    Cotecchia, Susanna; Stanasila, Laura; Diviani, Dario

    2012-01-01

    The adrenergic receptors are among the best characterized G protein-coupled receptors (GPCRs) and knowledge on this receptor family has provided several important paradigms about GPCR function and regulation. One of the most recent paradigms initially supported by studies on adrenergic receptors is that both βarrestins and G protein-coupled receptors themselves can act as scaffolds binding a variety of proteins and this can result in growing complexity of the receptor-mediated cellular effect...

  13. Cytokines as cellular communicators

    Directory of Open Access Journals (Sweden)

    R. Debets

    1996-01-01

    Full Text Available Cytokines and their receptors are involved in the pathophysiology of many diseases. Here we present a detailed review on cytokines, receptors and signalling routes, and show that one important lesson from cytokine biology is the complex and diverse regulation of cytokine activity. The activity of cytokines is controlled at the level of transcription, translation, storage, processing, posttranslational modification, trapping, binding by soluble proteins, and receptor number and/or function. Translation of this diverse regulation in strategies aimed at the control of cytokine activity will result in the development of more specific and selective drugs to treat diseases.

  14. Perceptions and attitudes of car owners on innovative automobiles

    International Nuclear Information System (INIS)

    To abate the detrimental effects of transport a transition is foreseen from the conventional fossil cars to energy-sustainable cars. A successful transition requires a major behavioral change of car consumers who need to make choices about new options for transport with uncertain costs and benefits compared to their current car. This paper examines consumers' perceptions about innovative cars and considerations for buying or not buying innovative cars (hybrid, electric, plug-in electric, hydrogen, flexifuel). In this study an on-line questionnaire on attitudes, interests and social norms regarding innovative cars was conducted among 339 Dutch respondents who recently bought a new car. To obtain in-depth understanding of the answers, a follow-up study was conducted consisting of two focus groups with a sample of survey participants. These focus groups respectively concentrated on respondents' perceptions of innovative cars, and on the personality traits of the 'typical' innovative car driver. The results of the survey shows that the attitude towards innovative cars are strongly influenced by affective aspects (such as comfort and pleasant) and to a (much) smaller extent by environmental considerations. The results of the focus groups confirm these findings. According to the participants the price of the car is decisive whereby environmental concerns play no role. The design and image of the car are important. In addition, it appears that the familiarity with (and thus the knowledge about) the innovative cars is still very limited (with the exception of the hybrid car). This point of view stresses the importance of the way in which innovative cars are positioned thereby affecting the image (social norms) people will have regarding these cars.

  15. Opposing regulation of cytochrome P450 expression by CAR and PXR in hypothyroid mice

    International Nuclear Information System (INIS)

    Clinical hypothyroidism affects various metabolic processes including drug metabolism. CYP2B and CYP3A are important cytochrome P450 drug metabolizing enzymes that are regulated by the xenobiotic receptors constitutive androstane receptor (CAR, NR1I3) and pregnane X receptor (PXR, NR1I2). We evaluated the regulation of the hepatic expression of CYPs by CAR and PXR in the hypothyroid state induced by a low-iodine diet containing 0.15% propylthiouracil. Expression of Cyp3a11 was suppressed in hypothyroid C57BL/6 wild type (WT) mice and a further decrement was observed in hypothyroid CAR−/− mice, but not in hypothyroid PXR−/− mice. In contrast, expression of Cyp2b10 was induced in both WT and PXR−/− hypothyroid mice, and this induction was abolished in CAR−/− mice and in and CAR−/− PXR−/− double knockouts. CAR mRNA expression was increased by hypothyroidism, while PXR expression remained unchanged. Carbamazepine (CBZ) is a commonly used antiepileptic that is metabolized by CYP3A isoforms. After CBZ treatment of normal chow fed mice, serum CBZ levels were highest in CAR−/− mice and lowest in WT and PXR−/− mice. Hypothyroid WT or PXR−/− mice survived chronic CBZ treatment, but all hypothyroid CAR−/− and CAR−/− PXR−/− mice died, with CAR−/−PXR−/− mice surviving longer than CAR−/− mice (12.3 ± 3.3 days vs. 6.3 ± 2.1 days, p = 0.04). All these findings suggest that hypothyroid status affects xenobiotic metabolism, with opposing responses of CAR and PXR and their CYP targets that can cancel each other out, decreasing serious metabolic derangement in response to a xenobiotic challenge. -- Highlights: ► Hypothyroid status activates CAR in mice and induces Cyp2b10 expression. ► Hypothyroid status suppresses PXR activity in mice and represses Cyp3a11 expression. ► These responses balance each other out in normal mice. ► Hypothyroidism sensitizes CAR null mice to toxic effects of carbamazepine.

  16. The integrin αvβ6: a novel target for CAR T-cell immunotherapy?

    Science.gov (United States)

    Whilding, Lynsey M; Vallath, Sabari; Maher, John

    2016-04-15

    Immunotherapy of cancer using chimeric antigen receptor (CAR) T-cells is a rapidly expanding field. CARs are fusion molecules that couple the binding of a tumour-associated cell surface target to the delivery of a tailored T-cell activating signal. Re-infusion of such genetically engineered T-cells to patients with haematological disease has demonstrated unprecedented response rates in Phase I clinical trials. However, such successes have not yet been observed using CAR T-cells against solid malignancies and this is, in part, due to a lack of safe tumour-specific targets. The αvβ6 integrin is strongly up-regulated in multiple solid tumours including those derived from colon, lung, breast, cervix, ovaries/fallopian tube, pancreas and head and neck. It is associated with poorer prognosis in several cancers and exerts pro-tumorigenic activities including promotion of tumour growth, migration and invasion. By contrast, physiologic expression of αvβ6 is largely restricted to wound healing. These attributes render this epithelial-specific integrin a highly attractive candidate for targeting using immunotherapeutic strategies such as CAR T-cell adoptive immunotherapy. This mini-review will discuss the role and expression of αvβ6 in cancer, as well as its potential as a therapeutic target. PMID:27068939

  17. What Happens at a Car Wash?

    Science.gov (United States)

    Gallick, Barbara; Lee, Lisa

    2010-01-01

    A class of 3- to 5-year-old children in a child care center in the midwestern United States chose to study a car wash as a group project. This article discusses how the project evolved, describes the three phases of the project, and provides the teachers' reflections on the project. Photos taken during the project and children's sketches are…

  18. Attention-Grabbing Train Car Advertisements

    Directory of Open Access Journals (Sweden)

    Motoi Ogura,

    2014-01-01

    Full Text Available Younger people have changed the way they access information in recent years, increasing the number of opportunities to take advantage of transit advertising. Train car advertising in particular boasts a high contact rate and extended length of contact. This study seeks to understand the correlations between passenger information and riding conditions when it comes to train car advertising (hanging posters, above-window posters, and sticker ads in order to discover the ideal way to advertise inside passenger trains. Specifically, the study first tries to find the correlations among three factors: (1 whether or not passengers pay attention to train car advertisements, (2 basic passenger information (age and gender, and (3 riding conditions (riding time, average number of trips, etc.. Once data on riding conditions is collected, it is then grouped using a cluster analysis and Quantification Theory Type III in order to establish the relationship of the data to passenger attention towards train advertisements once again. Then, in order to conduct an in-depth analysis, a Categorical Automatic Interaction Detector (CAID analysis is done on each group, using passengers pay attention to train advertisements as the objective variable and basic passenger information as the explanatory variable. The results of the CAID analysis are then used to study the format of existing and future train car advertisements.

  19. The second French car; Der zweite Franzose

    Energy Technology Data Exchange (ETDEWEB)

    Wiedemann, Karsten

    2012-02-15

    The Flence Z.E. is the second electric-powered car that French manufacturer Renault presented within a short period of time. The limousine has a roomy passenger compartment but little space for luggage. Refuelling is possible by battery exchange within just a few minutes, but not in Germany.

  20. Floating car data for traffic monitoring

    DEFF Research Database (Denmark)

    Torp, Kristian; Lahrmann, Harry Spaabæk

    2005-01-01

    This paper describes a complete prototype system that uses Floating Car Data (FCD) for both automatic and manual detection of queues in traffic. The system is developed under EU’s Tempo program. The systems consists of small hardware units placed in mobile traffic report units (we use taxis...