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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. 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.

  3. 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.

  4. 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.

  5. 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...

  6. Chimeric Antigen Receptor T Cell (Car T Cell Therapy In Hematology

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    Pinar Ataca

    2015-12-01

    Full Text Available It is well demonstrated that immune system can control and eliminate cancer cells. Immune-mediated elimination of tumor cells has been discovered and is the basis of both cancer vaccines and cellular therapies including hematopoietic stem cell transplantation (HSCT. Adoptive T cell transfer has been improved to be more specific and potent and cause less off-target toxicities. Currently, there are two forms of engineered T cells being tested in clinical trials: T cell receptor (TCR and chimeric antigen receptor (CAR modified T cells. On July 1, 2014, the United States Food and Drug Administration granted ‘breakthrough therapy’ designation to anti-CD19 CAR T cell therapy. Many studies were conducted to evaluate the beneficiaries of this exciting and potent new treatment modality. This review summarizes the history of adoptive immunotherapy, adoptive immunotherapy using CARs, the CAR manufacturing process, preclinical-clinical studies, effectiveness and drawbacks of this strategy.

  7. 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.

  8. 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

  9. Isoform-specific expression of the Coxsackie and adenovirus receptor (CAR in neuromuscular junction and cardiac intercalated discs

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    Karpati George

    2004-11-01

    Full Text Available Abstract Background The Coxsackie and adenovirus receptor (CAR has a restricted expression pattern in the adult. In skeletal muscle, although CAR is expressed in immature fibers, its transcript levels are barely detectable in mature muscle. This is in contrast to the robust expression observed in the heart. However, both heart and skeletal muscle are susceptible to infection with the Coxsackie B virus which utilizes primarily CAR for cellular internalization. The specific point of viral entry in skeletal and heart muscle remains unknown. Results Using antibodies directed against the extracellular and the cytoplasmic domains of CAR, we show CAR in normal human and mouse skeletal muscle to be a novel component of the neuromuscular junction. In cardiac muscle, CAR immunoreactivity is observed at the level of intercalated discs. We demonstrate a single isoform of CAR to be expressed exclusively at the human neuromuscular junction whereas both predominant CAR isoforms are expressed at the intercalated discs of non-diseased human heart. Conclusion The localization of CAR to these important junctional complexes suggests that CAR may play both a structural and a regulatory role in skeletal and cardiac muscle, and that these complexes may serve as a point of entry for Coxsackie B virus.

  10. Cellular trafficking of nicotinic acetylcholine receptors

    Institute of Scientific and Technical Information of China (English)

    Paul A ST JOHN

    2009-01-01

    Nicotinic acetylcholine receptors (nAChRs) play critical roles throughout the body. Precise regulation of the cellular location and availability of nAChRs on neurons and target cells is critical to their proper function. Dynamic, post-translational regulation of nAChRs, particularly control of their movements among the different compartments of cells, is an important aspect of that regulation. A combination of new information and new techniques has the study of nAChR trafficking poised for new breakthroughs.

  11. 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

  12. Ortho-Aminoazotoluene activates mouse Constitutive Androstane Receptor (mCAR) and increases expression of mCAR target genes

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    Smetanina, Mariya A.; Pakharukova, Mariya Y.; Kurinna, Svitlana M.; Dong, Bingning; Hernandez, Juan P.; Moore, David D.; Merkulova, Tatyana I.

    2011-01-01

    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. PMID:21672546

  13. Cysteinyl-Leukotriene Receptors and Cellular Signals

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    G. Enrico Rovati

    2007-01-01

    Full Text Available Cysteinyl-leukotrienes (cysteinyl-LTs exert a range of proinflammatory effects, such as constriction of airways and vascular smooth muscle, increase of endothelial cell permeability leading to plasma exudation and edema, and enhanced mucus secretion. They have proved to be important mediators in asthma, allergic rhinitis, and other inflammatory conditions, including cardiovascular diseases, cancer, atopic dermatitis, and urticaria. The classification into subtypes of the cysteinyl-LT receptors (CysLTRs was based initially on binding and functional data, obtained using the natural agonists and a wide range of antagonists. CysLTRs have proved remarkably resistant to cloning. However, in 1999 and 2000, the CysLT1R and CysLT2R were successfully cloned and both shown to be members of the G-protein coupled receptors (GPCRs superfamily. Molecular cloning has confirmed most of the previous pharmacological characterization and identified distinct expression patterns only partially overlapping. Recombinant CysLTRs couple to the Gq/11 pathway that modulates inositol phospholipids hydrolysis and calcium mobilization, whereas in native systems, they often activate a pertussis toxin-insensitive Gi/o-protein, or are coupled promiscuously to both G-proteins. Interestingly, recent data provide evidence for the existence of an additional receptor subtype that seems to respond to both cysteinyl-LTs and uracil nucleosides, and of an intracellular pool of CysLTRs that may have roles different from those of plasma membrane receptors. Finally, a cross-talk between the cysteinyl-LT and the purine systems is being delineated. This review will summarize recent data derived from studies on the molecular and cellular pharmacology of CysLTRs.

  14. 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.

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

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    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

  16. 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.

  17. 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.

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

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    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

  19. 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)

  20. 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.

  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. 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

  3. 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.

  4. Differences in Gene Regulation by Dual Ligands of Nuclear Receptors Constitutive Androstane Receptor (CAR) and Pregnane X Receptor (PXR) in HepG2 Cells Stably Expressing CAR/PXR.

    Science.gov (United States)

    Kanno, Yuichiro; Tanuma, Nobuaki; Yazawa, Saki; Zhao, Shuai; Inaba, Miki; Nakamura, Satoshi; Nemoto, Kiyomitsu; Inouye, Yoshio

    2016-08-01

    The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) regulate various genes involved in xenobiotics and drug metabolism. In many cases, CAR/PXR share ligands termed dual ligands of CAR/PXR. It is difficult to investigate the effect of CAR/PXR dual ligands in cell lines because CAR and PXR expression is scarcely detected in cultured cell lines. Here, we established a tetracycline-inducible human CAR and stably human PXR-overexpressing HepG2 cell line (HepTR/hCAR/hPXR) to examine CAR/PXR dual ligands. In the present study, we investigated the regulation of CYP2B6, CYP2C9, CYP3A4, and UDP-glucuronosyl transferase, which are target genes of CAR/PXR, by dual ligands of CAR/PXR in two transfectants. Activation of CAR and PXR in cells treated with a high dose of CITCO [6-(4-chlorophenyl)-imidazo(2,1-b)thiazole-5-carbaldehyde] or cotreated with rifampicin and tetracycline resulted in synergistic enhancement of CYP3A4, but not CYP2B6, CYP2C9, or UGT1A1, mRNA expression in HepTR/hCAR/hPXR cells. In contrast, this synergistic effect was not observed in HepTR/hCAR cells. These observations were also demonstrated in human primary hepatocytes. Taken together, our results suggest that dual ligands of CAR/PXR show distinct gene regulation patterns by cross-talk between CAR and PXR. Furthermore, the two newly established cell lines are useful tools to investigate dual ligands of CAR/PXR.

  5. 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.

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

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    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. Monitoring intra-cellular lipid metabolism in macrophages by Raman- and CARS-microscopy

    Science.gov (United States)

    Matthäus, Christian; Bergner, Gero; Krafft, Christoph; Dietzek, Benjamin; Lorkowski, Stefan; Popp, Jürgen

    2010-04-01

    Monocyte-derived macrophages play a key role in lipid metabolism in vessel wall tissues. Macrophages can take up lipids by various mechanisms. As phagocytes, macrophages are important for the decomposition of lipid plaques within arterial walls that contribute to arteriosclerosis. Of special interest are uptake dynamics and intra-cellular fate of different individual types of lipids as, for example, fatty acids, triglycerides or free and esterified cholesterol. Here we utilize Raman microscopy to image the metabolism of such lipids and follow subsequent storage or degradation patterns. The combination of optical microscopy with Raman spectroscopy allows visualization at the diffraction limit of the employed laser light and biochemical characterization through the associated spectral information. Relatively long measuring times, due to the weakness of Raman scattering can be overcome by non-linear effects such as coherent anti-Stokes Raman scattering (CARS). With this contribution we introduce first results to monitor the incorporation of lipid components into individual cells employing Raman and CARS microscopy.

  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 roles of nuclear receptors CAR and PXR in hepatic energy metabolism.

    Science.gov (United States)

    Konno, Yoshihiro; Negishi, Masahiko; Kodama, Susumu

    2008-01-01

    Nuclear receptors constitutive active/androstane receptor (CAR) and pregnane X receptor (PXR) were originally characterized as transcription factors regulating the hepatic genes that encode drug metabolizing enzymes. Recent works have now revealed that these nuclear receptors also play the critical roles in modulating hepatic energy metabolism. While CAR and PXR directly bind to their response sequences phenobarbital-responsive enhancer module (PBREM) and xenobiotic responsive enhancer module (XREM) in the promoter of target genes to increase drug metabolism, the receptors also cross talk with various hormone responsive transcription factors such as forkhead box O1 (FoxO1), forkhead box A2 (FoxA2), cAMP-response element binding protein, and peroxisome proliferator activated receptor gamma coactivator 1alpha (PGC 1alpha) to decrease energy metabolism through down-regulating gluconeogenesis, fatty acid oxidation and ketogenesis and up-regulating lipogenesis. In addition, CAR modulates thyroid hormone activity by regulating type 1 deiodinase in the regenerating liver. Thus, CAR and PXR are now placed at the crossroad where both xenobiotics and endogenous stimuli co-regulate liver function.

  11. Studying Nuclear Receptor Complexes in the Cellular Environment.

    Science.gov (United States)

    Schaufele, Fred

    2016-01-01

    The ligand-regulated structure and biochemistry of nuclear receptor complexes are commonly determined by in vitro studies of isolated receptors, cofactors, and their fragments. However, in the living cell, the complexes that form are governed not just by the relative affinities of isolated cofactors for the receptor but also by the cell-specific sequestration or concentration of subsets of competing or cooperating cofactors, receptors, and other effectors into distinct subcellular domains and/or their temporary diversion into other cellular activities. Most methods developed to understand nuclear receptor function in the cellular environment involve the direct tagging of the nuclear receptor or its cofactors with fluorescent proteins (FPs) and the tracking of those FP-tagged factors by fluorescence microscopy. One of those approaches, Förster resonance energy transfer (FRET) microscopy, quantifies the transfer of energy from a higher energy "donor" FP to a lower energy "acceptor" FP attached to a single protein or to interacting proteins. The amount of FRET is influenced by the ligand-induced changes in the proximities and orientations of the FPs within the tagged nuclear receptor complexes, which is an indicator of the structure of the complexes, and by the kinetics of the interaction between FP-tagged factors. Here, we provide a guide for parsing information about the structure and biochemistry of nuclear receptor complexes from FRET measurements in living cells.

  12. 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.

  13. 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

  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. Cellular prion protein and NMDA receptor modulation: protecting against excitotoxicity

    Directory of Open Access Journals (Sweden)

    Stefanie A.G. Black

    2014-08-01

    Full Text Available Although it is well established that misfolding of the cellular prion protein (PrPC into the beta-sheet-rich, aggregated scrapie conformation (PrPSc causes a variety of transmissible spongiform encephalopathies (TSEs, the physiological roles of PrPC are still incompletely understood. There is accumulating evidence describing the roles of PrPC in neurodegeneration and neuroinflammation. Recently, we identified a functional regulation of NMDA receptors by PrPC that involves formation of a physical protein complex between these proteins. Excessive NMDA receptor activity during conditions such as ischemia mediates enhanced Ca2+ entry into cells and contributes to excitotoxic neuronal death. In addition, NMDA receptors and/or PrPC play critical roles in neuroinflammation and glial cell toxicity. Inhibition of NMDA receptor activity protects against PrPSc-induced neuronal death. Moreover, in mice lacking PrPC, infarct size is increased after focal cerebral ischemia, and absence of PrPC increases susceptibility of neurons to NMDA receptor-dependent death. Recently, PrPC was found to be a receptor for oligomeric beta-amyloid (Abeta peptides, suggesting a role for PrPC in Alzheimer’s disease. Our recent findings suggest that Abeta peptides enhance NMDA receptor current by perturbing the normal copper- and PrPC-dependent regulation of these receptors. Here, we review evidence highlighting a role for PrPC in preventing NMDA receptor-mediated excitotoxicity and inflammation. There is a need for more detailed molecular characterization of PrPC-mediated regulation of NMDA receptors, such as determining which NMDA receptor subunits mediate pathogenic effects upon loss of PrPC-mediated regulation and identifying PrPC binding site(s on the receptor. This knowledge will allow development of novel therapeutic interventions for not only TSEs, but also for Alzheimer’s disease and other neurodegenerative disorders involving dysfunction of PrPC.

  16. ONE-DIMENSIONAL CELLULAR AUTOMATON MODEL OF TRAFFIC FLOW BASED ON CAR-FOLLOWING IDEA

    Institute of Scientific and Technical Information of China (English)

    董力耘; 薛郁; 戴世强

    2002-01-01

    An improved one-dimensional CA (Cellular Automaton) traffic model was proposed to describe the highway traffic under the periodic boundary conditions. This model was based on the idea of the car-following model, which claims that the motion of a vehicle at one time step depends on both its headway and the synchronous motion of the front vehicle,thus including indirectly the influence of its sub-neighboring vehicle. In addition, the socalled safety distance was introduced to consider the deceleration behavior of vehicles and the stochastic factor was taken into account by introducing the deceleration probability.Meanwhile, the conditional deceleration in the model gives a better description of the phenomena observed on highways. It is found that there exists the metastability and hysteresis effect of traffic flow in the neighborhood of critical density under different initial conditions.Since this model gives a reasonable depiction of the motion of a single vehicle, it is easy to be extended to the case of traffic flow under the control of traffic lights in cities.

  17. 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…

  18. 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 based...... at which selective categorical sensing may occur. Categorical sensing can be seen as the cellular capacity for identifying and ordering complex patterns of mixed signals out of a contextual matrix, i.e., the recognition of meaningful patterns out of ubiquitous signals. In this context, redundancy...... be another level of quality control that may help maintaining GPCRs rather stable throughout evolution. We propose here receptor oligomerization to be a basic molecular mechanism controlling GPCRs redundancy in many different cell types, and the plasma membrane as the first hierarchical cell structure...

  19. Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T cells.

    Science.gov (United States)

    Pinz, K; Liu, H; Golightly, M; Jares, A; Lan, F; Zieve, G W; Hagag, N; Schuster, M; Firor, A E; Jiang, X; Ma, Y

    2016-03-01

    Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro. CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs.

  20. Estrogen activation of the nuclear orphan receptor CAR (constitutive active receptor) in induction of the mouse Cyp2b10 gene.

    Science.gov (United States)

    Kawamoto, T; Kakizaki, S; Yoshinari, K; Negishi, M

    2000-11-01

    The nuclear orphan receptor CAR (constitutively active receptor or constitutive androstane receptor) can be activated in response to xenochemical exposure, such as activation by phenobarbital of a response element called NR1 found in the CYP2B gene. Here various steroids were screened for potential endogenous chemicals that may activate CAR, using the NR1 enhancer and Cyp2b10 induction in transfected HepG2 cell and/or in mouse primary hepatocytes as the experimental criteria. 17beta-Estradiol and estrone activated NR1, whereas estriol, estetrol, estradiol sulfate, and the synthetic estrogen diethylstilbestrol did not. On the other hand, progesterone and androgens repressed NR1 activity in HepG2 cells, and the repressed NR1 activity was fully restored by estradiol. Moreover, estrogen treatment elicited nuclear accumulation of CAR in the mouse livers, as well as primary hepatocytes, and induced the endogenous Cyp2b10 gene. Ovariectomy did not affect either the basal or induced level of CAR in the nucleus of the female livers, while castration slightly increased the basal and greatly increased the induced levels in the liver nucleus of male mice. Thus, endogenous estrogen appears not to regulate CAR in female mice, whereas endogenous androgen may be the repressive factor in male mice. Estrogen at pharmacological levels is an effective activator of CAR in both female and male mice, suggesting a biological and/or toxicological role of this receptor in estrogen metabolism. In addition to mouse CAR, estrogens activated rat CAR, whereas human CAR did not respond well to the estrogens under the experimental conditions. PMID:11075820

  1. 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...

  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. 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.

  4. The liver X receptor : Control of cellular lipid homeostasis and beyond Implications for drug design

    NARCIS (Netherlands)

    Oosterveer, Maaike H.; Grefhorst, Aldo; Groen, Albert K.; Kuipers, Folkert

    2010-01-01

    Liver X receptor (LXR) alpha and beta are nuclear receptors that control cellular metabolism. LXRs modulate the expression of genes involved in cholesterol and lipid metabolism in response to changes in cellular cholesterol status. Because of their involvement in cholesterol homeostasis, LXRs have e

  5. 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

  6. 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.

  7. 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

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. 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...

  13. 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...

  14. 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.

  15. Molecular and cellular designs of insect taste receptor system

    Directory of Open Access Journals (Sweden)

    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.

  16. 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

  17. 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.

  18. 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...

  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. 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.

  1. Cellular expression of the neurokinin 1 receptor in the human antrum.

    Science.gov (United States)

    Smith, V C; Sagot, M A; Wong, H; Buchan, A M

    2000-03-15

    The localization of the neurokinin 1 receptor in rat and guinea pig gastrointestinal tract has been extensively studied but not in human tissues. The present study used antibodies to characterize the cellular expression of neurokinin 1 receptors in human antrum. Cryostat sections (40-80 microm) were immunostained for the neurokinin 1 receptor double labeled with substance P, von Willebrand's factor, c-kit, fibronectin, S-100, serotonin, gastrin and somatostatin. Neurokinin 1 receptor-immunoreactivity was observed on neurons within the myenteric and submucosal plexuses surrounded by substance P-immunoreactive fibers and on von Willebrand's factor-immunoreactive endothelial cells lining blood vessels throughout the antral wall. c-Kit-immunoreactive interstitial cells of Cajal and gastrin cells were co-stained by the monoclonal neurokinin 1 receptor antibody. Finally, there was no evidence for the presence of the neurokinin 1 receptor on fibroblasts, Schwann, somatostatin, serotonin or smooth muscle cells. This study clearly demonstrates an expanded cellular expression of the neurokinin 1 receptor in the human antrum.

  2. Protease activated receptor-1 regulates macrophage-mediated cellular senescence : a risk for idiopathic pulmonary fibrosis

    NARCIS (Netherlands)

    Lin, Cong; Rezaee, Farhad; Waasdorp, Maaike; Shi, Kun; van der Poll, Tom; Borensztajn, Keren; Spek, C. Arnold

    2015-01-01

    Idiopathic pulmonary fibrosis (IPF) is a destructive disease in part resulting from premature or mature cellular aging. Protease-activated receptor-1 (PAR-1) recently emerged as a critical component in the context of fibrotic lung diseases. Therefore, we aimed to study the role of macrophages in PAR

  3. 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.

  4. 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

    different from that elicited by FGF-2. In contrast to FGF-induced degradation of endocytic FGFR1, NCAM promotes the stabilization of the receptor, which is recycled to the cell surface in a Rab11- and Src-dependent manner. In turn, FGFR1 recycling is required for NCAM-induced sustained activation of various...... 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 specific cellular response. Besides introducing a further level of complexity in the regulation of FGFR1 function, our findings highlight the link of FGFR recycling with sustained signaling and cell migration and the critical role of these events in dictating the cellular response evoked by receptor...

  5. 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.

  6. The Aryl Hydrocarbon Receptor Relays Metabolic Signals to Promote Cellular Regeneration.

    Science.gov (United States)

    Casado, Fanny L

    2016-01-01

    While sensing the cell environment, the aryl hydrocarbon receptor (AHR) interacts with different pathways involved in cellular homeostasis. This review summarizes evidence suggesting that cellular regeneration in the context of aging and diseases can be modulated by AHR signaling on stem cells. New insights connect orphaned observations into AHR interactions with critical signaling pathways such as WNT to propose a role of this ligand-activated transcription factor in the modulation of cellular regeneration by altering pathways that nurture cellular expansion such as changes in the metabolic efficiency rather than by directly altering cell cycling, proliferation, or cell death. Targeting the AHR to promote regeneration might prove to be a useful strategy to avoid unbalanced disruptions of homeostasis that may promote disease and also provide biological rationale for potential regenerative medicine approaches. PMID:27563312

  7. BRAF and MEK inhibition variably affect GD2-specific chimeric antigen receptor (CAR) T-cell function in vitro.

    Science.gov (United States)

    Gargett, Tessa; Fraser, Cara K; Dotti, Gianpietro; Yvon, Eric S; Brown, Michael P

    2015-01-01

    Cancer immunotherapy has long been used in the treatment of metastatic melanoma, and an anti-CTLA-4 monoclonal antibody treatment has recently been approved by the US Food and Drug Administration. Targeted therapies such as small molecule kinase inhibitors targeting deregulated mitogen-activated protein kinase (MAPK) signaling have markedly improved melanoma control in up to 50% of metastatic disease patients and have likewise been recently approved. Combination therapies for melanoma have been proposed as a way to exploit the high-level but short-term responses associated with kinase inhibitor therapies and the low-level but longer-term responses associated with immunotherapy. Cancer immunotherapy now includes adoptive transfer of autologous tumor-specific chimeric antigen receptor (CAR) T cells and this mode of therapy is a candidate for combination with small molecule drugs. This paper describes CART cells that target GD2-expressing melanoma cells and investigates the effects of approved MAPK pathway-targeted therapies for melanoma [vemurafenib (Vem), dabrafenib (Dab), and trametinib (Tram)] on the viability, activation, proliferation, and cytotoxic T lymphocyte activity of these CAR T cells, as well as on normal peripheral blood mononuclear cells. We report that, although all these drugs lead to inhibition of stimulated T cells at high concentrations in vitro, only Vem inhibited T cells at concentrations equivalent to reported plasma concentrations in treated patients. Although the combination of Dab and Tram also resulted in inhibition of T-cell effector functions at some therapeutic concentrations, Dab itself had little adverse effect on CAR T-cell function. These findings may have implications for novel therapeutic combinations of adoptive CAR T-cell immunotherapy and MAPK pathway inhibitors.

  8. 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.

  9. 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 proliferation...... recruitment. This complex is crucial for FGFR2b recycling and responses, given that FGF-10 stimulation of either FGFR2b_Y734F mutant- or SH3BP4-depleted cells switches the receptor endocytic route to degradation, resulting in decreased breast cancer cell migration and the inhibition of epithelial branching...

  10. 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.

  11. Xenobiotic-induced hepatocyte proliferation associated with constitutive active/androstane receptor (CAR or peroxisome proliferator-activated receptor α (PPARα is enhanced by pregnane X receptor (PXR activation in mice.

    Directory of Open Access Journals (Sweden)

    Ryota Shizu

    Full Text Available Xenobiotic-responsive nuclear receptors pregnane X receptor (PXR, constitutive active/androstane receptor (CAR and peroxisome proliferator-activated receptor α (PPARα play pivotal roles in the metabolic functions of the liver such as xenobiotics detoxification and energy metabolism. While CAR or PPARα activation induces hepatocyte proliferation and hepatocarcinogenesis in rodent models, it remains unclear whether PXR activation also shows such effects. In the present study, we have investigated the role of PXR in the xenobiotic-induced hepatocyte proliferation with or without CAR activation by 1,4-bis[2-(3,5-dichloropyridyloxy]benzene (TCPOBOP and phenobarbital, or PPARα activation by Wy-14643 in mice. Treatment with TCPOBOP or phenobarbital increased the percentage of Ki-67-positive nuclei as well as mRNA levels of cell proliferation-related genes in livers as expected. On the other hand, treatment with the PXR activator pregnenolone 16α-carbonitrile (PCN alone showed no such effects. Surprisingly, PCN co-treatment significantly augmented the hepatocyte proliferation induced by CAR activation with TCPOBOP or phenobarbital in wild-type mice but not in PXR-deficient mice. Intriguingly, PXR activation also augmented the hepatocyte proliferation induced by Wy-14643 treatment. Moreover, PCN treatment increased the RNA content of hepatocytes, suggesting the induction of G0/G1 transition, and reduced mRNA levels of Cdkn1b and Rbl2, encoding suppressors of cell cycle initiation. Our present findings indicate that xenobiotic-induced hepatocyte proliferation mediated by CAR or PPARα is enhanced by PXR co-activation despite that PXR activation alone does not cause the cell proliferation in mouse livers. Thus PXR may play a novel and unique role in the hepatocyte/liver hyperplasia upon exposure to xenobiotics.

  12. 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

  13. 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

  14. 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.

  15. 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...

  16. Extrasynaptic glutamate receptor activation as cellular bases for dynamic range compression in pyramidal neurons

    Directory of Open Access Journals (Sweden)

    Katerina D Oikonomou

    2012-08-01

    Full Text Available Repetitive synaptic stimulation overcomes the ability of astrocytic processes to clear glutamate from the extracellular space, allowing some dendritic segments to become submerged in a pool of glutamate. This dynamic arrangement activates extrasynaptic NMDA receptors located on dendritic shafts. We used voltage-sensitive and calcium-sensitive dyes to probe dendritic function in this glutamate-rich location. An excess of glutamate in the extrasynaptic space was achieved either by repetitive synaptic stimulation or by glutamate iontophoresis onto the dendrites of pyramidal neurons. Two successive activations of synaptic inputs produced a typical NMDA spike, whereas five successive synaptic inputs produced characteristic plateau potentials, reminiscent of cortical UP states. While NMDA spikes were coupled with brief calcium transients highly restricted to the glutamate input site, the dendritic plateau potentials were accompanied by calcium influx along the entire dendritic branch. Once initiated, the glutamate-mediated dendritic plateau potentials could not be interrupted by negative voltage pulses. Activation of extrasynaptic NMDA receptors in cellular compartments void of spines is sufficient to initiate and support plateau potentials. The only requirement for sustained depolarizing events is a surplus of free glutamate near a group of extrasynaptic receptors. Highly nonlinear dendritic spikes (plateau potentials are summed in a highly sublinear fashion at the soma, revealing the cellular bases of signal compression in cortical circuits. Extrasynaptic NMDA receptors provide pyramidal neurons with a function analogous to a dynamic range compression in audio engineering. They limit or reduce the volume of loud sounds (i.e. strong glut. inputs and amplify quiet sounds (i.e. glutamatergic inputs that barely cross the dendritic threshold for local spike initiation. Our data also explain why consecutive cortical UP states have uniform amplitudes in a

  17. 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

  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.

    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

  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; 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

  20. Activation of Constitutive Androstane Receptor (CAR) in Mice Results in Maintained Biliary Excretion of Bile Acids Despite a Marked Decrease of Bile Acids in Liver.

    Science.gov (United States)

    Lickteig, Andrew J; Csanaky, Iván L; Pratt-Hyatt, Matthew; Klaassen, Curtis D

    2016-06-01

    Activation of Constitutive Androstane Receptor (CAR) protects against bile acid (BA)-induced liver injury. This study was performed to determine the effect of CAR activation on bile flow, BA profile, as well as expression of BA synthesis and transport genes. Synthetic CAR ligand 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) was administered to mice for 4 days. BAs were quantified by UPLC-MS/MS (ultraperformance liquid chromatography-tandem mass spectrometry). CAR activation decreases total BAs in livers of male (49%) and female mice (26%), largely attributable to decreases of the 12α-hydroxylated BA taurocholic acid (T-CA) (males (M) 65%, females (F) 45%). Bile flow in both sexes was increased by CAR activation, and the increases were BA-independent. CAR activation did not alter biliary excretion of total BAs, but overall BA composition changed. Excretion of muricholic (6-hydroxylated) BAs was increased in males (101%), and the 12α-OH proportion of biliary BAs was decreased in both males (37%) and females (28%). The decrease of T-CA in livers of males and females correlates with the decreased mRNA of the sterol 12α-hydroxylase Cyp8b1 in males (71%) and females (54%). As a response to restore BAs to physiologic concentrations in liver, mRNA of Cyp7a1 is upregulated following TCPOBOP (males 185%, females 132%). In ilea, mRNA of the negative feedback regulator Fgf15 was unaltered by CAR activation, indicating biliary BA excretion was sufficient to maintain concentrations of total BAs in the small intestine. In summary, the effects of CAR activation on BAs in male and female mice are quite similar, with a marked decrease in the major BA T-CA in the liver.

  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. 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.

  3. 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.

  4. 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+.

  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. 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.

  7. 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.

  8. 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

  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. Active macropinocytosis induction by stimulation of epidermal growth factor receptor and oncogenic Ras expression potentiates cellular uptake efficacy of exosomes.

    Science.gov (United States)

    Nakase, Ikuhiko; Kobayashi, Nahoko Bailey; Takatani-Nakase, Tomoka; Yoshida, Tetsuhiko

    2015-06-03

    Exosomes are approximately 100-nm vesicles that consist of a lipid bilayer of cellular membranes secreted in large quantities from various types of normal and disease-related cells. Endocytosis has been reported as a major pathway for the cellular uptake of exosomes; however, the detailed mechanisms of their cellular uptake are still unknown. Here, we demonstrate the active induction of macropinocytosis (accompanied by actin reorganisation, ruffling of plasma membrane, and engulfment of large volumes of extracellular fluid) by stimulation of cancer-related receptors and show that the epidermal growth factor (EGF) receptor significantly enhances the cellular uptake of exosomes. We also demonstrate that oncogenic K-Ras-expressing MIA PaCa-2 cells exhibit intensive macropinocytosis that actively transports extracellular exosomes into the cells compared with wild-type K-Ras-expressing BxPC-3 cells. Furthermore, encapsulation of the ribosome-inactivating protein saporin with EGF in exosomes using our simple electroporation method produces superior cytotoxicity via the enhanced cellular uptake of exosomes. Our findings contribute to the biological, pharmaceutical, and medical research fields in terms of understanding the macropinocytosis-mediated cellular uptake of exosomes with applications for exosomal delivery systems.

  12. Endothelin-1 activation of ETB receptors leads to a reduced cellular proliferative rate and an increased cellular footprint

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Jamie L.; Taylor, Linda; Polgar, Peter, E-mail: peterp@bu.edu

    2012-06-10

    Endothelin-1 (ET-1) is a vasoactive peptide which signals through two G-protein coupled receptors, endothelin receptor A (ETA) and B (ETB). We determined that ET-1 activation of its ETB receptor in stably cDNA transfected CHO cells leads to a 55% reduction in cell number by end-point cell counting and a 35% decrease in cell growth by a real-time cell-substrate impedance-based assay after 24 h of cell growth. When CHO ETB cells were synchronized in the late G1 cell cycle phase, ET-1 delayed their S phase progression compared to control by 30% as determined by [{sup 3}H]-thymidine incorporation. On the other hand, no such delay was observed during late G2/M to G1 transit when cells were treated with ET-1 after release from mitotic arrest. Using the cell-substrate impedance-based assay, we observed that ET-1 induces opposing morphological changes in CHO ETA and CHO ETB cells with ETB causing an increase in the cell footprint and ETA a decrease. Likewise, in pulmonary artery smooth muscle cells, which express both ETA and ETB receptors, ET-1 induces an ETA-dependent contraction and an ETB dependent dilation. These results are shedding light on a possible beneficial role for ETB in diseases involving ET-1 dysfunction such as pulmonary hypertension. -- Highlights: Black-Right-Pointing-Pointer ET- hinders cell proliferation in CHO cells transfected with ETB. Black-Right-Pointing-Pointer ET-1 also decreases the rate of DNA synthesis in CHO ETB cells. Black-Right-Pointing-Pointer JNK and PI3K appear to be involved in this reduction of DNA synthesis. Black-Right-Pointing-Pointer ETB activation in CHO ETB cells and hSMCs leads to dilatory morphological changes. Black-Right-Pointing-Pointer In CHO ETA and hSMCs, ETA activation leads to constrictive morphological changes.

  13. 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

  14. 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

  15. 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.

  16. 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...

  17. 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 ...

  18. 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.

  19. Identification and characterization of cellular receptors for the growth regulator, oncostatin M

    Energy Technology Data Exchange (ETDEWEB)

    Linsley, P.S.; Bolton-Hanson, M.; Horn, D.; Malik, N.; Kallestad, J.C.; Ochs, V.; Zarling, J.M.; Shoyab, M.

    1989-03-15

    Oncostatin M is a polypeptide growth regulator produced by activated T cells and phorbol ester-treated U937 cells. To identify specific cellular receptors for this factor, we have characterized the binding of 125I-labeled oncostatin M to a variety of normal and malignant mammalian cells. Recombinant oncostatin M was labeled with 125I with full retention of growth inhibitory activity on A375 melanoma cells. 125I-Oncostatin M bound to sensitive cells in a time- and temperature-dependent fashion. Binding was specifically inhibited by unlabeled native or recombinant oncostatin M, but not by other polypeptide growth factors tested. Binding to human leukemic and normal blood cells was generally less than to nonhematopoietic cells. With four different cell lines, maximal growth inhibition by oncostatin M was achieved at less than maximal binding site occupancy. Scatchard graphs of direct binding data were curvilinear and indicated that 125I-oncostatin M bound with higher apparent affinity at lower 125I-oncostatin M concentrations. Using a two binding site model, affinity constants of Kd1 = 11 +/- 11 pM and Kd2 = 1000 +/- 380 pM were extrapolated from binding data with A375 cells, and values of Kd1 = 3 +/- 2 pM and Kd2 = 400 +/- 44 pM from A549 cells. The major 125I-oncostatin M binding species in a number of mammalian cell lines was identified by chemical cross-linking as a specific protein(s) of Mr = 150,000-160,000. 125I-Oncostatin M was internalized (t1/2 = 30 min) and degraded subsequent to binding to a responsive cell line.

  20. 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.

  1. 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.

  2. 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.

  3. 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

  4. 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.

  5. Immunohistochemical detection of estrogen receptor alpha in pituitary adenomas and its correlation with cellular replication.

    Science.gov (United States)

    Pereira-Lima, Julia F S; Marroni, Caroline P; Pizarro, Cristina B; Barbosa-Coutinho, Ligia M; Ferreira, Nelson P; Oliveira, Miriam C

    2004-03-01

    With the aim of evaluating the relationship between pituitary tumorigenesis and the presence of estrogen receptor-alpha (ERalpha) by immunohistochemistry (IH) and their relevance to patients' clinical presentation, hormonal phenotypes of adenomas, preoperative neuroimaging findings, and the index of cellular replication MIB-1, a study was conducted with material from 91 women and 67 men with pituitary adenomas. The patients had acromegaly (29.7%), Cushing's disease (14.6%), hyperprolactinemic syndrome (20.9%), and clinically nonfunctioning tumors (34.8%). Of the patients, 14.6% had microadenomas, 52.5% had macroadenomas with or without suprasellar growth, 28.5% had invasive macroadenomas and in 4.4% the adenoma was not visualized. IH showed that 43 were positive for growth hormone (GH), 16 for corticotropin (ACTH), 18 for prolactin (PRL), 18 for PRL+GH, 6 for luteinizing hormone (LH) and follicle-stimulating hormone (FSH), 15 had a plurihormonal reaction, and 42 had nonfunctioning adenomas. The presence of ERalpha was positive in 9/158 adenomas with a median value for the percentage of labeled cells of 42.89%, and in 6/16 controls (autopsy samples) with a median value for the percentage of labeled cells of 0.024%. ERalpha was significantly more prevalent in controls than in patients with adenomas (37.5 versus 5.7%; p = 0.001); however, the mean ERalpha concentration in adenomas was significantly greater than in controls (42.89 versus 0.024%; p < 0.001). No significant difference in the concentration of ERalpha was found across the clinical presentations, hormonal phenotypes or findings of preoperative CT. Among the ERalpha-positive adenomas, ERalpha values were significantly greater in invasive macroadenomas (80%) than in microadenomas (3.33%). MIB-1 values did not differ significantly between ERalpha-positive and -negative adenomas, nor did the correlation between ERalpha values and the MIB-1 index attain significance in the total sample, even when only ERalpha

  6. 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...

  7. 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.

  8. 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.

  9. Distinct cellular and subcellular distributions of G protein-coupled receptor kinase and arrestin isoforms in the striatum.

    Directory of Open Access Journals (Sweden)

    Evgeny Bychkov

    Full Text Available G protein-coupled receptor kinases (GRKs and arrestins mediate desensitization of G protein-coupled receptors (GPCR. Arrestins also mediate G protein-independent signaling via GPCRs. Since GRK and arrestins demonstrate no strict receptor specificity, their functions in the brain may depend on their cellular complement, expression level, and subcellular targeting. However, cellular expression and subcellular distribution of GRKs and arrestins in the brain is largely unknown. We show that GRK isoforms GRK2 and GRK5 are similarly expressed in direct and indirect pathway neurons in the rat striatum. Arrestin-2 and arrestin-3 are also expressed in neurons of both pathways. Cholinergic interneurons are enriched in GRK2, arrestin-3, and GRK5. Parvalbumin-positive interneurons express more of GRK2 and less of arrestin-2 than medium spiny neurons. The GRK5 subcellular distribution in the human striatal neurons is altered by its phosphorylation: unphosphorylated enzyme preferentially localizes to synaptic membranes, whereas phosphorylated GRK5 is found in plasma membrane and cytosolic fractions. Both GRK isoforms are abundant in the nucleus of human striatal neurons, whereas the proportion of both arrestins in the nucleus was equally low. However, overall higher expression of arrestin-2 yields high enough concentration in the nucleus to mediate nuclear functions. These data suggest cell type- and subcellular compartment-dependent differences in GRK/arrestin-mediated desensitization and signaling.

  10. 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.

  11. 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.

  12. 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

  13. 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;

    2008-01-01

    (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...

  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...... acid compositions derived from cDNA sequence and amino acid analysis shows that a polypeptide of medium hydrophobicity is excised from the COOH terminus of the nascent u-PAR. A similar proteolytic processing has been reported for other proteins that are linked to the plasma membrane by a glycosyl...

  15. 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...

  16. 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...

  17. 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...

  18. 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

  19. 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...

  20. Bovine adenovirus serotype 3 utilizes sialic acid as a cellular receptor for virus entry.

    Science.gov (United States)

    Li, Xiaoxin; Bangari, Dinesh S; Sharma, Anurag; Mittal, Suresh K

    2009-09-30

    Bovine adenovirus serotype 3 (BAd3) and porcine adenovirus serotype 3 (PAd3) entry into the host cells is independent of Coxsackievirus adenovirus receptor and integrins. The role of sialic acid in BAd3 and PAd3 entry was investigated. Removal of sialic acid by neuraminidase, or blocking sialic acid by wheat germ agglutinin lectin significantly inhibited BAd3, but not PAd3, transduction of Madin-Darby bovine kidney cells. Maackia amurensis agglutinin or Sambucus nigra (elder) agglutinin treatment efficiently blocked BAd3 transduction suggesting that BAd3 utilized alpha(2,3)-linked and alpha(2,6)-linked sialic acid as a cell receptor. BAd3 transduction of MDBK cells was sensitive to sodium periodate, bromelain, or trypsin treatment indicating that the receptor sialoconjugate was a glycoprotein rather than a ganglioside. To determine sialic acid-containing cell membrane proteins that bind to BAd3, virus overlay protein binding assay (VOPBA) was performed and showed that sialylated cell membrane proteins in size of approximately 97 and 34 kDa bind to BAd3. The results suggest that sialic acid serves as a primary receptor for BAd3.

  1. 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

  2. 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

  3. 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.

  4. 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

  5. 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...

  6. 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

  7. 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

  8. 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.

  9. 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

  10. 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.

  11. 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...

  12. Beyond the antigen receptor: editing the genome of T-cells for cancer adoptive cellular therapies

    Directory of Open Access Journals (Sweden)

    Angharad eLloyd

    2013-08-01

    Full Text Available Recent early-stage clinical trials evaluating the adoptive transfer of patient CD8+ T-cells re-directed with antigen receptors recognising tumours have shown very encouraging results. These reports provide strong support for further development of the therapeutic concept as a curative cancer treatment. In this respect combining the adoptive transfer of tumour-specific T-cells with therapies that increase their anti-tumour capacity is viewed as a promising strategy to improve treatment outcome. The ex-vivo genetic engineering step that underlies T-cell re-direction offers a unique angle to combine antigen receptor delivery with the targeting of cell intrinsic pathways that restrict T-cell effector functions. Recent progress in genome editing technologies such as protein- and RNA-guided endonucleases raise the possibility of disrupting gene expression in T-cells in order to enhance effector functions or to bypass tumour immune suppression. This approach would avoid the systemic administration of compounds that disrupt immune homeostasis, potentially avoiding autoimmune adverse effects, and could improve the efficacy of T-cell based adoptive therapies.

  13. 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.

  14. 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。

  15. 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

  16. 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

  17. Utero-placental cellular and nuclear expression of bradykinin B2 receptors in normal and preeclamptic pregnancies.

    Science.gov (United States)

    Valdés, Gloria; Acuña, Stephanie; Munizaga, Alejandro; Soto, Gloria X; Figueroa, Carlos D

    2016-01-01

    The bradykinin type 2 receptor (B2R), main effector of the pleiotropic kallikrein-kinin system (KKS), has been localized in the key sites related to placentation in human, rat and guinea pig utero-placental units. The present study was directed to characterize the content, the cellular and subcellular localization of B2R in the villi and basal plate of placentas from normal and preeclamptic pregnancies by means of western blotting, immunohistochemistry and immunoelectron microscopy. The protein content of B2R was demonstrated in both placental zones. The villous placenta of normal and preeclamptic pregnancies expressed B2R in syncytiotrophoblast and fetal endothelium; the basal plate displayed B2R in extravillous trophoblasts and decidual cells. Lastly, immunogold electron microscopy revealed B2R in fetal endothelium, syncytiotrophoblast, extravillous cytotrophoblasts and decidual cells; in all cell types the receptor was mainly located in the cytosol and nucleus. The protein content of placental homogenates and the immunoreactivity in the different cells types did not differ between both study groups; however the abundance of nuclear immunogold B2R positive beads in extravillous trophoblasts was greater in the normal than in the preeclamptic placentas. The purpose of describing nuclear B2R in the utero-placental unit, and its increment in normal extravillous trophoblasts, is to stimulate the study of the functional pathways that may be relevant to understand the local role of the B2R in normal and preeclamptic gestation. PMID:26955769

  18. Identification and molecular characterization of cellular factors required for glucocorticoid receptor-mediated mRNA decay

    Science.gov (United States)

    Park, Ok Hyun; Park, Joori; Yu, Mira; An, Hyoung-Tae; Ko, Jesang; Kim, Yoon Ki

    2016-01-01

    Glucocorticoid (GC) receptor (GR) has been shown recently to bind a subset of mRNAs and elicit rapid mRNA degradation. However, the molecular details of GR-mediated mRNA decay (GMD) remain unclear. Here, we demonstrate that GMD triggers rapid degradation of target mRNAs in a translation-independent and exon junction complex-independent manner, confirming that GMD is mechanistically distinct from nonsense-mediated mRNA decay (NMD). Efficient GMD requires PNRC2 (proline-rich nuclear receptor coregulatory protein 2) binding, helicase ability, and ATM-mediated phosphorylation of UPF1 (upstream frameshift 1). We also identify two GMD-specific factors: an RNA-binding protein, YBX1 (Y-box-binding protein 1), and an endoribonuclease, HRSP12 (heat-responsive protein 12). In particular, using HRSP12 variants, which are known to disrupt trimerization of HRSP12, we show that HRSP12 plays an essential role in the formation of a functionally active GMD complex. Moreover, we determine the hierarchical recruitment of GMD factors to target mRNAs. Finally, our genome-wide analysis shows that GMD targets a variety of transcripts, implicating roles in a wide range of cellular processes, including immune responses.

  19. 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

  20. 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

  1. 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.

  2. 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.

  3. Cellular pattern formation by SCRAMBLED, a leucine-rich repeat receptor-like kinase in Arabidopsis.

    Science.gov (United States)

    Kwak, Su-Hwan; Schiefelbein, John

    2008-02-01

    The appropriate specification of distinct cell types is important for generating the proper tissues and bodies of multicellular organisms. In the root epidermis of Arabidopsis, cell fate determination is accomplished by a transcriptional regulatory circuit that is influenced by positional signaling. A leucine-rich repeat receptor-like kinase, SCRAMBLED (SCM), has been shown to be responsible for the position-dependent aspect of this epidermal pattern. In a recent report, we find that SCM affects the transcriptional regulatory network by down-regulating the WEREWOLF (WER) MYB gene expression in a set of epidermal cells located in a specific position. We also find that SCM and the SCM-related SRF1 and SRF3 are not required for embryonic epidermal patterning and that SRF1 and SRF3 do not act redundantly with SCM. This suggests that distinct positional signaling mechanisms exist for embryonic and post-embryonic epidermal patterning. In this addendum, we discuss the implications of our recent findings and extend our working model for epidermal cell pattering.

  4. 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

  5. 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

  6. TRPV4 is necessary for trigeminal irritant pain and functions as a cellular formalin receptor.

    Science.gov (United States)

    Chen, Yong; Kanju, Patrick; Fang, Quan; Lee, Suk Hee; Parekh, Puja K; Lee, Whasil; Moore, Carlene; Brenner, Daniel; Gereau, Robert W; Wang, Fan; Liedtke, Wolfgang

    2014-12-01

    Detection of external irritants by head nociceptor neurons has deep evolutionary roots. Irritant-induced aversive behavior is a popular pain model in laboratory animals. It is used widely in the formalin model, where formaldehyde is injected into the rodent paw, eliciting quantifiable nocifensive behavior that has a direct, tissue-injury-evoked phase, and a subsequent tonic phase caused by neural maladaptation. The formalin model has elucidated many antipain compounds and pain-modulating signaling pathways. We have adopted this model to trigeminally innervated territories in mice. In addition, we examined the involvement of TRPV4 channels in formalin-evoked trigeminal pain behavior because TRPV4 is abundantly expressed in trigeminal ganglion (TG) sensory neurons, and because we have recently defined TRPV4's role in response to airborne irritants and in a model for temporomandibular joint pain. We found TRPV4 to be important for trigeminal nocifensive behavior evoked by formalin whisker pad injections. This conclusion is supported by studies with Trpv4(-/-) mice and TRPV4-specific antagonists. Our results imply TRPV4 in MEK-ERK activation in TG sensory neurons. Furthermore, cellular studies in primary TG neurons and in heterologous TRPV4-expressing cells suggest that TRPV4 can be activated directly by formalin to gate Ca(2+). Using TRPA1-blocker and Trpa1(-/-) mice, we found that both TRP channels co-contribute to the formalin trigeminal pain response. These results imply TRPV4 as an important signaling molecule in irritation-evoked trigeminal pain. TRPV4-antagonistic therapies can therefore be envisioned as novel analgesics, possibly for specific targeting of trigeminal pain disorders, such as migraine, headaches, temporomandibular joint, facial, and dental pain, and irritation of trigeminally innervated surface epithelia.

  7. The molecular, cellular and clinical consequences of targeting the estrogen receptor following estrogen deprivation therapy.

    Science.gov (United States)

    Fan, Ping; Maximov, Philipp Y; Curpan, Ramona F; Abderrahman, Balkees; Jordan, V Craig

    2015-12-15

    During the past 20 years our understanding of the control of breast tumor development, growth and survival has changed dramatically. The once long forgotten application of high dose synthetic estrogen therapy as the first chemical therapy to treat any cancer has been resurrected, refined and reinvented as the new biology of estrogen-induced apoptosis. High dose estrogen therapy was cast aside once tamoxifen, from its origins as a failed "morning after pill", was reinvented as the first targeted therapy to treat any cancer. The current understanding of the mechanism of estrogen-induced apoptosis is described as a consequence of acquired resistance to long term antihormone therapy in estrogen receptor (ER) positive breast cancer. The ER signal transduction pathway remains a target for therapy in breast cancer despite "antiestrogen" resistance, but becomes a regulator of resistance. Multiple mechanisms of resistance come into play: Selective ER modulator (SERM) stimulated growth, growth factor/ER crosstalk, estrogen-induced apoptosis and mutations of ER. But it is with the science of estrogen-induced apoptosis that the next innovation in women's health will be developed. Recent evidence suggests that the glucocorticoid properties of medroxyprogesterone acetate blunt estrogen-induced apoptosis in estrogen deprived breast cancer cell populations. As a result breast cancer develops during long-term hormone replacement therapy (HRT). A new synthetic progestin with estrogen-like properties, such as the 19 nortestosterone derivatives used in oral contraceptives, will continue to protect the uterus from unopposed estrogen stimulation but at the same time, reinforce apoptosis in vulnerable populations of nascent breast cancer cells.

  8. 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

  9. 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.

  10. Clean cars

    Energy Technology Data Exchange (ETDEWEB)

    Piffaretti, M.

    2008-07-01

    This well-illustrated presentation made at the Swiss 2008 research conference on traffic by the Protoscar company takes a look at research, design, engineering and communication topics in the area of 'clean cars'. The present situation with electrically driven and hybrid-drive cars is reviewed and the chances and problems of the present-day vehicles are examined. New developments and a number of vehicles that should be on the market in the period from 2012 to 2015 are presented. Also, 'clean' specialist vehicles such as trucks and buses are reviewed. Battery systems and associated problems and new developments are looked at. The promotion scheme in Mendrisio, Switzerland is reviewed. Bottom-up and top-down approaches are discussed and future market developments are looked at, as are promotional activities in various countries.

  11. 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!

  12. 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

  13. Chimeric Antigen Receptor T Cell Therapy in Hematology.

    Science.gov (United States)

    Ataca, Pınar; Arslan, Önder

    2015-12-01

    It is well demonstrated that the immune system can control and eliminate cancer cells. Immune-mediated elimination of tumor cells has been discovered and is the basis of both cancer vaccines and cellular therapies including hematopoietic stem cell transplantation. Adoptive T cell transfer has been improved to be more specific and potent and to cause less off-target toxicity. Currently, there are two forms of engineered T cells being tested in clinical trials: T cell receptor (TCR) and chimeric antigen receptor (CAR) modified T cells. On 1 July 2014, the United States Food and Drug Administration granted 'breakthrough therapy' designation to anti-CD19 CAR T cell therapy. Many studies were conducted to evaluate the benefits of this exciting and potent new treatment modality. This review summarizes the history of adoptive immunotherapy, adoptive immunotherapy using CARs, the CAR manufacturing process, preclinical and clinical studies, and the effectiveness and drawbacks of this strategy.

  14. 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...

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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

  20. 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

  1. 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...

  2. Women and Cars

    Institute of Scientific and Technical Information of China (English)

    1996-01-01

    JUST a decade ago, private cars were far too luxurious for Chinese people; most of them never even dreamed of having a car. In the Chinese language, a car is called "jiao che", which literally means "sedan automobile." The fact that a car is referred to as a sedan, a luxury only available to officials in old China, reveals Chinese people’s idea that cars are separated by an impassable gulf from ordinary people.

  3. 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

  4. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Magno, Aaron L. [Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009 (Australia); Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia 6009 (Australia); Ingley, Evan [Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009 (Australia); Brown, Suzanne J. [Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia 6009 (Australia); Conigrave, Arthur D. [School of Molecular Bioscience, University of Sydney, New South Wales 2000 (Australia); Ratajczak, Thomas [Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009 (Australia); Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia 6009 (Australia); Ward, Bryan K., E-mail: bryanw@cyllene.uwa.edu.au [Western Australian Institute for Medical Research and Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009 (Australia); Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Hospital Avenue, Nedlands, Western Australia 6009 (Australia)

    2011-09-09

    Highlights: {yields} A yeast two-hybrid screen revealed testin bound to the calcium-sensing receptor. {yields} The second zinc finger of LIM domain 1 of testin is critical for interaction. {yields} Testin bound to a region of the receptor tail important for cell signalling. {yields} Testin and receptor interaction was confirmed in mammalian (HEK293) cells. {yields} 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.

  6. 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

  7. 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.

  8. Loss of progesterone receptor-mediated actions induce preterm cellular and structural remodeling of the cervix and premature birth.

    Directory of Open Access Journals (Sweden)

    Steven M Yellon

    Full Text Available A decline in serum progesterone or antagonism of progesterone receptor function results in preterm labor and birth. Whether characteristics of premature remodeling of the cervix after antiprogestins or ovariectomy are similar to that at term was the focus of the present study. Groups of pregnant rats were treated with vehicle, a progesterone receptor antagonist (onapristone or mifepristone, or ovariectomized on day 17 postbreeding. As expected, controls given vehicle delivered at term while rats delivered preterm after progesterone receptor antagonist treatment or ovariectomy. Similar to the cervix before term, the preterm cervix of progesterone receptor antagonist-treated rats was characterized by reduced cell nuclei density, decreased collagen content and structure, as well as a greater presence of macrophages per unit area. Thus, loss of nuclear progesterone receptor-mediated actions promoted structural remodeling of the cervix, increased census of resident macrophages, and preterm birth much like that found in the cervix at term. In contrast to the progesterone receptor antagonist-induced advance in characteristics associated with remodeling, ovariectomy-induced loss of systemic progesterone did not affect hypertrophy, extracellular collagen, or macrophage numbers in the cervix. Thus, the structure and macrophage census in the cervix appear sufficient for premature ripening and birth to occur well before term. With progesterone receptors predominantly localized on cells other than macrophages, the findings suggest that interactions between cells may facilitate the loss of progesterone receptor-mediated actions as part of a final common mechanism that remodels the cervix in certain etiologies of preterm and with parturition at term.

  9. 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.

  10. 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

  11. 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.

  12. 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

  13. 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....

  14. 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...

  15. 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.

  16. 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

  17. 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

    -products from incineration plants, plastic additives, technical industry products, pesticides from the farming industry and detergent degradation products. Many of these substances can interfere with the hormonal system in organisms. The common name for these compounds is endocrine disrupters (EDCs). Some EDCs...... are persistent to degradation and are also called persistent organic pollutants (POPs). Endocrine disrupters are compounds that can interfere with an organism’s hormone system by interacting with the hormone receptors. Many of an organism’s body functions are controlled by interactions between hormones...... and hormone receptors and disturbance of these interactions can result in diseases and malfunctions. Compounds that exhibit endocrine disrupting properties have been linked to many diseases including genital malformations, neurological disorders, reproductive problems, insulin resistance and cancers. All...

  18. 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...

  19. 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...

  20. 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

  1. 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.

  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. 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.

  4. 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.

  5. 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

  6. 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.

  7. 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...

  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. 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

  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. 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

  13. 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

    2003-05-01

    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.

  14. 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

  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. 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.

  17. 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.

  18. 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...... compared with 233CC children. This genotype related effect modification may significantly influence malaria sero-epidemiological and vaccine trial studies....

  19. 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...

  20. Cellular distribution of {sup 111}In-LDTPA galactose BSA in normal and asialoglycoprotein receptor-deficient mouse liver

    Energy Technology Data Exchange (ETDEWEB)

    Deal, Kim A.; Cristel, Michael E.; Welch, Michael J

    1998-05-01

    {sup 111}In-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. {sup 111}In-LDTPA galactose BSA was metabolized to {sup 111}In-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.

  1. 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.

  2. 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

  3. 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.

  4. 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...

  5. 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

  6. Car stickers for 2012

    CERN Multimedia

    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

  7. Car stickers for 2011

    CERN Multimedia

    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

  8. 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

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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.…

  16. 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

  17. The Expression Pattern of the Pre-B Cell Receptor Components Correlates with Cellular Stage and Clinical Outcome in Acute Lymphoblastic Leukemia

    Science.gov (United States)

    Chen, Dongfeng; Zheng, Junxiong; Gerasimcik, Natalija; Lagerstedt, Kristina; Sjögren, Helene; Abrahamsson, Jonas; Fogelstrand, Linda; Mårtensson, Inga-Lill

    2016-01-01

    Precursor-B cell receptor (pre-BCR) signaling represents a crucial checkpoint at the pre-B cell stage. Aberrant pre-BCR signaling is considered as a key factor for B-cell precursor acute lymphoblastic leukemia (BCP-ALL) development. BCP-ALL are believed to be arrested at the pre-BCR checkpoint independent of pre-BCR expression. However, the cellular stage at which BCP-ALL are arrested and whether this relates to expression of the pre-BCR components (IGHM, IGLL1 and VPREB1) is still unclear. Here, we show differential protein expression and copy number variation (CNV) patterns of the pre-BCR components in pediatric BCP-ALL. Moreover, analyzing six BCP-ALL data sets (n = 733), we demonstrate that TCF3-PBX1 ALL express high levels of IGHM, IGLL1 and VPREB1, and are arrested at the pre-B stage. By contrast, ETV6-RUNX1 ALL express low levels of IGHM or VPREB1, and are arrested at the pro-B stage. Irrespective of subtype, ALL with high levels of IGHM, IGLL1 and VPREB1 are arrested at the pre-B stage and correlate with good prognosis in high-risk pediatric BCP-ALL (n = 207). Our findings suggest that BCP-ALL are arrested at different cellular stages, which relates to the expression pattern of the pre-BCR components that could serve as prognostic markers for high-risk pediatric BCP-ALL patients. PMID:27611867

  18. P2X7 Cell Death Receptor Activation and Mitochondrial Impairment in Oxaliplatin-Induced Apoptosis and Neuronal Injury: Cellular Mechanisms and In Vivo Approach.

    Directory of Open Access Journals (Sweden)

    France Massicot

    Full Text Available Limited information is available regarding the cellular mechanisms of oxaliplatin-induced painful neuropathy during exposure of patients to this drug. We therefore determined oxidative stress in cultured cells and evaluated its occurrence in C57BL/6 mice. Using both cultured neuroblastoma (SH-SY5Y and macrophage (RAW 264.7 cell lines and also brain tissues of oxaliplatin-treated mice, we investigated whether oxaliplatin (OXA induces oxidative stress and apoptosis. Cultured cells were treated with 2-200 µM OXA for 24 h. The effects of pharmacological inhibitors of oxidative stress or inflammation (N-acetyl cysteine, ibuprofen, acetaminophen were also tested. Inhibitors were added 30 min before OXA treatment and then in combination with OXA for 24 h. In SH-SY5Y cells, OXA caused a significant dose-dependent decrease in viability, a large increase in ROS and NO production, lipid peroxidation and mitochondrial impairment as assessed by a drop in mitochondrial membrane potential, which are deleterious for the cell. An increase in levels of negatively charged phospholipids such as cardiolipin but also phosphatidylserine and phosphatidylinositol, was also observed. Additionally, OXA caused concentration-dependent P2X7 receptor activation, increased chromatin condensation and caspase-3 activation associated with TNF-α and IL-6 release. The majority of these toxic effects were equally observed in Raw 264.7 which also presented high levels of PGE2. Pretreatment of SH-SY5Y cells with pharmacological inhibitors significantly reduced or blocked all the neurotoxic OXA effects. In OXA-treated mice (28 mg/kg cumulated dose significant cold hyperalgesia and oxidative stress in the tested brain areas were shown. Our study suggests that targeting P2X7 receptor activation and mitochondrial impairment might be a potential therapeutic strategy against OXA-induced neuropathic pain.

  19. 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)

  20. 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

  1. 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

  2. Breaking car use habits

    DEFF Research Database (Denmark)

    Thøgersen, John; Møller, Berit Thorup

    2008-01-01

    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...

  3. 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)

  4. CAR: no longer forgotten?

    Directory of Open Access Journals (Sweden)

    Toby Lanzer

    2007-07-01

    Full Text Available The international community is waking up to the strategic importance of the Central African Republic (CAR in the crisis over Darfur. Will current interest endure long enough to help the people of CARCAR beyond the immediate future?

  5. TANK CAR CONSTRUCTION REFINMENT

    Directory of Open Access Journals (Sweden)

    A. N. Soberzhansjkyj

    2010-06-01

    Full Text Available The increase of volume and load-carrying capacity of tank cars is an urgent task for improving the efficiency of transportation of liquid bulk cargoes. Variants of the constructive and technical approaches, which allow increasing the specified indices, are considered. After the analysis the most rational constructive scheme meeting the modern requirements for tank cars and allowing to raise their productivity is chosen.

  6. 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...

  7. 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...

  8. 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

  9. Assessment of cellular estrogenic activity based on estrogen receptor-mediated reduction of soluble-form catechol-O-methyltransferase (COMT expression in an ELISA-based system.

    Directory of Open Access Journals (Sweden)

    Philip Wing-Lok Ho

    Full Text Available Xenoestrogens are either natural or synthetic compounds that mimic the effects of endogenous estrogen. These compounds, such as bisphenol-A (BPA, and phthalates, are commonly found in plastic wares. Exposure to these compounds poses major risk to human health because of the potential to cause endocrine disruption. There is huge demand for a wide range of chemicals to be assessed for such potential for the sake of public health. Classical in vivo assays for endocrine disruption are comprehensive but time-consuming and require sacrifice of experimental animals. Simple preliminary in vitro screening assays can reduce the time and expense involved. We previously demonstrated that catechol-O-methyltransferase (COMT is transcriptionally regulated by estrogen via estrogen receptor (ER. Therefore, detecting corresponding changes of COMT expression in estrogen-responsive cells may be a useful method to estimate estrogenic effects of various compounds. We developed a novel cell-based ELISA to evaluate cellular response to estrogenicity by reduction of soluble-COMT expression in ER-positive MCF-7 cells exposed to estrogenic compounds. In contrast to various existing methods that only detect bioactivity, this method elucidates direct physiological effect in a living cell in response to a compound. We validated our assay using three well-characterized estrogenic plasticizers - BPA, benzyl butyl phthalate (BBP, and di-n-butyl phthalate (DBP. Cells were exposed to either these plasticizers or 17β-estradiol (E2 in estrogen-depleted medium with or without an ER-antagonist, ICI 182,780, and COMT expression assayed. Exposure to each of these plasticizers (10(-9-10(-7M dose-dependently reduced COMT expression (p<0.05, which was blocked by ICI 182,780. Reduction of COMT expression was readily detectable in cells exposed to picomolar level of E2, comparable to other in vitro assays of similar sensitivity. To satisfy the demand for in vitro assays targeting different

  10. 犬瘟热病毒细胞受体研究进展%Research Progress in Cellular Receptors of Canine Distemper Virus

    Institute of Scientific and Technical Information of China (English)

    徐淑娟; 史一; 崔健; 赵建军

    2016-01-01

    Canine distemper virus (CDV ) a wide host range of the virus ,can cause severe symptoms in animal .The study confirmed that CDV had two major cellular receptors ,signaling lymphocyte activation molecule (SLAM ) and cell adhesion molecule 4 (Nectin-4 ) .When the virus enters the upper respiratory tract of animals express slam lymphocytes and CDV hemagglutinin (H) protein interactions ,the envelope and host cell fusion caused the virus to enter cells to initiate virus infection process .With the blood circulation through the mucosal epithelial cells in a wide range of infected cells infected with Nectin -4 expression of the epithelial tissues and organs ,and ultimately through the respiratory tract and digestive tract epithelial cells to release viral particles caused by the spread of disease .The presence of these two receptors is an important factor in the CDV cross species infection .In this paper ,the latest research progress in the domestic and international and the author's work ,the above problems are summarized and discussed .%犬瘟热病毒(Canine distemper virus ,CDV )是一种宿主广泛的病原,能引起患病动物的严重呼吸道和消化道症状。CDV具有信号淋巴细胞激活分子(SLAM )和细胞粘附分子4(Nectin-4)2种主要受体。当病毒进入动物上呼吸道后,表达SLAM的淋巴细胞与CDV血凝素(H )蛋白相互作用,以囊膜与宿主细胞融合的方式使病毒进入细胞,启动病毒感染过程,随血液循环通过黏膜上皮细胞淋巴细胞浸润的方式广泛地感染体内表达Nectin-4的上皮组织和器官,最终通过呼吸道和消化道上皮细胞释放病毒粒子造成疾病的传播。CDV与该2种受体的相互作用是病毒跨物种间感染的重要基础。本文就国内、外最新研究进展并结合作者的工作,对上述问题进行了综述和探讨。

  11. Effects of different transferrin forms on transferrin receptor expression, iron uptake, and cellular proliferation of human leukemic HL60 cells. Mechanisms responsible for the specific cytotoxicity of transferrin-gallium

    Energy Technology Data Exchange (ETDEWEB)

    Chitambar, C.R.; Seligman, P.A.

    1986-12-01

    We have previously shown that human leukemic cells proliferate normally in serum-free media containing various transferrin forms, but the addition of transferrin-gallium leads to inhibition of cellular proliferation. Because gallium has therapeutic potential, the effects of transferrin-gallium on leukemic cell proliferation, transferrin receptor expression, and cellular iron utilization were studied. The cytotoxicity of gallium is considerably enhanced by its binding to transferrin and cytotoxicity can be reversed by transferrin-iron but not by other transferrin forms. Exposure to transferrin-gallium leads to a marked increase in cell surface transferrin binding sites, but despite this, cellular /sup 59/Fe incorporation is inappropriately low. Although shunting of transferrin-gallium to another cellular compartment has not been ruled out, other studies suggest that transferrin-gallium impairs intracellular release of /sup 59/Fe from transferrin by interfering with processes responsible for intracellular acidification. These studies, taken together, demonstrate that inhibition of cellular iron incorporation by transferrin-gallium is a prerequisite for inhibition of cellular proliferation.

  12. 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

  13. 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

  14. The phosphorylated C-terminus of cAR1 plays a role in cell-type-specific gene expression and STATa tyrosine phosphorylation.

    Science.gov (United States)

    Briscoe, C; Moniakis, J; Kim, J Y; Brown, J M; Hereld, D; Devreotes, P N; Firtel, R A

    2001-05-01

    cAMP receptors mediate some signaling pathways via coupled heterotrimeric G proteins, while others are G-protein-independent. This latter class includes the activation of the transcription factors GBF and STATa. Within the cellular mounds formed by aggregation of Dictyostelium, micromolar levels of cAMP activate GBF function, thereby inducing the transcription of postaggregative genes and initiating multicellular differentiation. Activation of STATa, a regulator of culmination and ecmB expression, results from cAMP receptor-dependent tyrosine phosphorylation and nuclear localization, also in mound-stage cells. During mound development, the cAMP receptor cAR1 is in a low-affinity state and is phosphorylated on multiple serine residues in its C-terminus. This paper addresses possible roles of cAMP receptor phosphorylation in the cAMP-mediated stimulation of GBF activity, STATa tyrosine phosphorylation, and cell-type-specific gene expression. To accomplish this, we have expressed cAR1 mutants in a strain in which the endogenous cAMP receptors that mediate postaggregative gene expression in vivo are deleted. We then examined the ability of these cells to undergo morphogenesis and induce postaggregative and cell-type-specific gene expression and STATa tyrosine phosphorylation. Analysis of cAR1 mutants in which the C-terminal tail is deleted or the ligand-mediated phosphorylation sites are mutated suggests that the cAR1 C-terminus is not essential for GBF-mediated postaggregative gene expression or STATa tyrosine phosphorylation, but may play a role in regulating cell-type-specific gene expression and morphogenesis. A mutant receptor, in which the C-terminal tail is constitutively phosphorylated, exhibits constitutive activation of STATa tyrosine phosphorylation in pulsed cells in suspension and a significantly impaired ability to induce cell-type-specific gene expression. The constitutively phosphorylated receptor also exerts a partial dominant negative effect on

  15. CAR siRNA 对睾丸支持细胞上皮屏障通透性的影响及机制%Effects of coxsackie-adenovirus′receptor siRNA on the permeability of Sertoli cell epithelial barrier and its related mechanism

    Institute of Scientific and Technical Information of China (English)

    李兴旺; 赵艳玲

    2014-01-01

    目的:观察柯萨奇病毒-腺病毒受体(CAR)siRNA对睾丸支持细胞上皮屏障通透性的影响,并探讨其机制。方法采用睾丸支持细胞原代双室培养方法制备睾丸支持细胞上皮屏障,细胞培养3 d后分为CAR siRNA组、对照组,分别转染CAR siRNA、无同源性非靶向双链RNA。转染后第2天,分别采用RT-PCR和Western blotting法检测睾丸支持细胞中CAR mRNA、蛋白表达;采用Millicell-ERS电阻系统测量双室模型内外室的电位差;采用免疫荧光细胞化学染色法检测支持细胞的Occludin蛋白,荧光显微镜下观察Occludin分布情况;采用Western blotting法检测支持细胞中总Occludin蛋白量、与早期内涵体抗原1(EEA1)抗体结合的Occludin蛋白。结果 CAR siRNA组与对照组CAR mRNA相对表达量分别为0.122±0.013、0.429±0.039,CAR 蛋白相对表达量分别为0.142±0.041、0.532±0.022,两组比较,P均<0.05。 CAR siRNA组与对照组TER分别为(37±2.5)、(50±3.0)ohm· cm2,两组比较,P<0.05。 CAR siRNA组与对照组Occludin蛋白相对表达量分别为0.164±0.025、0.143±0.031,两组比较,P>0.05。对照组Occludin呈蜂巢样沿细胞膜线状分布;CAR siRNA组Occludin分布较紊乱,细胞膜处减少,线性分布破坏,细胞质内增多。 CAR siRNA组、对照组细胞中与EEA1结合的Occludin蛋白量分别为1.332±0.018、1.000±0.015,两组比较,P<0.05。结论 CAR siRNA能增加睾丸支持细胞上皮屏障通透性,其机制可能与其诱导Occludin蛋白内吞增强而分布改变有关。%Objective To investigate the effect of coxsackie-adenovirus receptor(CAR) siRNA on the permeability of Sertoli cell epithelial barrier and its related mechanism.Methods By using two-compartment primary culture system, Sertoli cell epithelial barrier was established.After 3 days of culture, the cells were divided into control and

  16. Remote Controlled CARs: Towards a Safer Therapy for Leukemia.

    Science.gov (United States)

    June, Carl H

    2016-08-01

    Genetic engineering of patient T cells with chimeric antigen receptors (CAR T cells) provides a powerful tool for inducing remissions in patients with various cancers derived from B cells. Challenges stemming from the inability to control the CAR T cells once given pose significant safety concerns. An article in Cancer Immunology Research presents an approach to circumvent this issue. Cancer Immunol Res; 4(8); 643. ©2016 AACRSee article by Sakemura et al., p. 658.

  17. Aerodynamics of Race Cars

    Science.gov (United States)

    Katz, Joseph

    2006-01-01

    Race car performance depends on elements such as the engine, tires, suspension, road, aerodynamics, and of course the driver. In recent years, however, vehicle aerodynamics gained increased attention, mainly due to the utilization of the negative lift (downforce) principle, yielding several important performance improvements. This review briefly explains the significance of the aerodynamic downforce and how it improves race car performance. After this short introduction various methods to generate downforce such as inverted wings, diffusers, and vortex generators are discussed. Due to the complex geometry of these vehicles, the aerodynamic interaction between the various body components is significant, resulting in vortex flows and lifting surface shapes unlike traditional airplane wings. Typical design tools such as wind tunnel testing, computational fluid dynamics, and track testing, and their relevance to race car development, are discussed as well. In spite of the tremendous progress of these design tools (due to better instrumentation, communication, and computational power), the fluid dynamic phenomenon is still highly nonlinear, and predicting the effect of a particular modification is not always trouble free. Several examples covering a wide range of vehicle shapes (e.g., from stock cars to open-wheel race cars) are presented to demonstrate this nonlinear nature of the flow field.

  18. 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...

  19. 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.

  20. 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

  1. 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

  2. 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

  3. Efficacy and toxicity management of CAR-T cell immunotherapy: A matter of responsiveness control or tumor-specificity?

    DEFF Research Database (Denmark)

    Alonso-Camino, Vanesa; Harwood, Seandean Lykke; Alvarez-Méndez, Ana M;

    2016-01-01

    Chimeric antigen receptor (CAR)-expressing T cells have demonstrated potent clinical efficacy in patients with hematological malignancies. However, the use of CAR-T cells targeting solid tumor-associated antigens (TAAs) has been limited by organ toxicities related to activation of T cell effector...... functions through the CAR. Most existing CARs recognize TAAs, which are also found in normal tissues. CAR-T cell-mediated destruction of normal tissues constitutes a major roadblock to CAR-T cell therapy, and must be avoided or mitigated. There is a broad range of strategies for modulating antigen...

  4. 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

  5. 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.

  6. 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…

  7. 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”.

  8. 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...

  9. 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

  10. 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

  11. 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

  12. 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...

  13. 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.

  14. 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 survey undertaken in the Copenhagen area. The study reveals that a relatively low percentage of drivers (10-20%) consider commuting by public transportation in the near future, which is hardly a surprise. A hierarchical analysis, where reported use of public transportation is regressed on intentions...

  15. 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.

  16. Usability of car stereo.

    Science.gov (United States)

    Razza, Bruno Montanari; Paschoarelli, Luis Carlos

    2012-01-01

    Automotive sound systems vary widely in terms of functions and way of use between different brands and models what can bring difficulties and lack of consistency to the user. This study aimed to analyze the usability of car stereo commonly found in the market. Four products were analyzed by task analysis and after use reports and the results indicate serious usability issues with respect to the form of operation, organization, clarity and quality of information, visibility and readability, among others.

  17. 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...

  18. 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...

  19. 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

  20. Individual differences in ethanol locomotor sensitization are associated with dopamine D1 receptor intra-cellular signaling of DARPP-32 in the nucleus accumbens.

    Directory of Open Access Journals (Sweden)

    Karina Possa Abrahao

    Full Text Available In mice there are clear individual differences in the development of behavioral sensitization to ethanol, a progressive potentiation of its psychomotor stimulant effect. Variability in the behavioral responses to ethanol has been associated with alcohol preference. Here we investigated if the functional hyperresponsiveness of D1 receptors observed in ethanol sensitized mice leads to an increased activation of DARPP-32, a central regulatory protein in medium spiny neurons, in the nucleus accumbens - a brain region known to play a role in drug reinforcement. Swiss Webster mice received ethanol (2.2 g/kg/day or saline i.p. administrations for 21 days and were weekly evaluated regarding their locomotor activity. From those treated with ethanol, the 33% with the highest levels of locomotor activity were classified as "sensitized" and the 33% with the lowest levels as "non-sensitized". The latter presented similar locomotor levels to those of saline-treated mice. Different subgroups of mice received intra-accumbens administrations of saline and, 48 h later, SKF-38393, D1 receptor agonist 0.1 or 1 µg/side. Indeed, sensitized mice presented functional hyperresponsiveness of D1 receptors in the accumbens. Two weeks following the ethanol treatment, other subgroups received systemic saline or SKF 10 mg/kg, 20 min before the euthanasia. The nucleus accumbens were dissected for the Western Blot analyses of total DARPP-32 and phospho-Thr34-DARPP-32 expression. D1 receptor activation induced higher phospho-Thr34-DARPP-32 expression in sensitized mice than in non-sensitized or saline. The functionally hyperresponsiveness of D1 receptors in the nucleus accumbens is associated with an increased phospho-Thr34-DARPP-32 expression after D1 receptor activation. These data suggest that an enduring increase in the sensitivity of the dopamine D1 receptor intracellular pathway sensitivity represents a neurobiological correlate associated with the development of

  1. 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.

  2. Car stickers for 2010

    CERN Document Server

    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

  3. Lighting innovations in concept cars

    Science.gov (United States)

    Berlitz, Stephan; Huhn, Wolfgang

    2005-02-01

    Concept cars have their own styling process. Because of the big media interest they give a big opportunity to bring newest technology with styling ideas to different fairgrounds. The LED technology in the concept cars Audi Pikes Peak, Nuvolari and Le Mans will be explained. Further outlook for the Audi LED strategy starting with LED Daytime Running Lamp will be given. The close work between styling and technical engineers results in those concept cars and further technical innovations based on LED technologies.

  4. Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy.

    Science.gov (United States)

    Yeku, Oladapo O; Brentjens, Renier J

    2016-04-15

    Chimaeric antigen receptor (CAR) T-cells are T-cells that have been genetically modified to express an artificial construct consisting of a synthetic T-cell receptor (TCR) targeted to a predetermined antigen expressed on a tumour. Coupling the T-cell receptor to a CD3ζ signalling domain paved the way for first generation CAR T-cells that were efficacious against cluster of differentiation (CD)19-expressing B-cell malignancies. Optimization with additional signalling domains such as CD28 or 4-1BB in addition to CD3ζ provided T-cell activation signal 2 and further improved the efficacy and persistence of these second generation CAR T-cells. Third generation CAR T-cells which utilize two tandem costimulatory domains have also been reported. In this review, we discuss a different approach to optimization of CAR T-cells. Through additional genetic modifications, these resultant armored CAR T-cells are typically modified second generation CAR T-cells that have been further optimized to inducibly or constitutively secrete active cytokines or express ligands that further armor CAR T-cells to improve efficacy and persistence. The choice of the 'armor' agent is based on knowledge of the tumour microenvironment and the roles of other elements of the innate and adaptive immune system. Although there are several variants of armored CAR T-cells under investigation, here we focus on three unique approaches using interleukin-12 (IL-12), CD40L and 4-1BBL. These agents have been shown to further enhance CAR T-cell efficacy and persistence in the face of a hostile tumour microenvironment via different mechanisms.

  5. 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

    Both the serotonin and glutamate systems have been implicated in the pathophysiology of schizophrenia, as well as in the mechanism of action of antipsychotic drugs. Psychedelic drugs act through the serotonin 2A receptor (5-HT2AR), and elicit a head-twitch response (HTR) in mice, which directly c...

  6. 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...

  7. Progression to metastatic stage in a cellular model of prostate cancer is associated with methylation of the androgen receptor gene and transcriptional suppression of the insulin-like growth factor-I receptor gene

    OpenAIRE

    Schayek, Hagit; Bentov, Itay; Sun, Shihua; Plymate, Stephen R; Werner, Haim

    2010-01-01

    The progression of prostate cancer from an organ-confined, androgen-sensitive disease to a metastatic one is associated with dysregulation of androgen receptor (AR)-regulated target genes and with a decrease in insulin-like growth factor-I receptor (IGF1R) expression. DNA methylation of CpG islands is an epigenetic mechanism associated with gene silencing. Recent studies have demonstrated that methylation occurs early in prostate carcinogenesis and, furthermore, may contribute to androgen ind...

  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. 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.

  10. 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

  11. Cellular Telephone

    Institute of Scientific and Technical Information of China (English)

    杨周

    1996-01-01

    Cellular phones, used in automobiles, airliners, and passenger trains, are basically low-power radiotelephones. Calls go through radio transmitters that are located within small geographical units called cells. Because each cell’s signals are too weak to interfere with those of other cells operating on the same fre-

  12. The attractiveness of car use

    NARCIS (Netherlands)

    Bleijenberg, A.N.

    2012-01-01

    Understanding the driving forces behind car use is necessary for the development of effective transport policies. The high door-to-door speed of the car in comparison with other travel modes forms its main attractiveness. And speed is the main engine for mobility growth, which is not easy to curb. P

  13. 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...

  14. 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)

  15. 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.

  16. 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.

  17. 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...

  18. 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...

  19. 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

  20. Single-step concentration and purification of adenoviruses by coxsackievirus-adenovirus receptor-binding capture and elastin-like polypeptide-mediated precipitation.

    Science.gov (United States)

    Wu, Qian; Liu, Wenjun; Xu, Bi; Zhang, Xinyu; Xia, Xiaoli; Sun, Huaichang

    2016-02-01

    A single-step method for quick concentration and purification of adenoviruses (Ads) was established by combining coxsackievirus and adenovirus receptor (CAR)-binding capture with elastin-like polypeptide (ELP)-mediated precipitation. The soluble ELP-CAR fusion protein was expressed in vector-transformed E. coli and purified to high purity by two rounds of inverse transition cycling (ITC). After demonstration of the specific binding of fusion protein, a recombinant Ad (rAd), namely rAd/GFP, was pulled down from the culture medium and extract of rAd-transduced cells using ELP-CAR protein, with recovery of 76.2 % and 73.3 %, respectively. The rAd was eluted from the ELP-CAR protein and harvested by one round of ITC, with recoveries ranging from 30.6 % to 34.5 % (virus titration assay). Both ELP-CAR-bound and eluted rAds were able to transduce CAR-positive cells, but not CAR-negative cells (fluorescent microscopy). A further viral titration assay showed that the ELP-CAR-bound rAd/GFP had significantly lower transduction efficiency than the eluted rAd, and there was less of a decrease when tested in the presence of fetal bovine serum. In addition, rAd/GFP was efficiently recovered from the "spiked" PBS and tap water with recovery of ~74 % or ~60 %. This work demonstrates the usefulness of the ELP-CAR-binding capture method for concentration and/or purification of Ads in cellular and environmental samples.

  1. Med1 subunit of the mediator complex in nuclear receptor-regulated energy metabolism, liver regeneration, and hepatocarcinogenesis.

    Science.gov (United States)

    Jia, Yuzhi; Viswakarma, Navin; Reddy, Janardan K

    2014-01-01

    Several nuclear receptors regulate diverse metabolic functions that impact on critical biological processes, such as development, differentiation, cellular regeneration, and neoplastic conversion. In the liver, some members of the nuclear receptor family, such as peroxisome proliferator-activated receptors (PPARs), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), liver X receptor (LXR), pregnane X receptor (PXR), glucocorticoid receptor (GR), and others, regulate energy homeostasis, the formation and excretion of bile acids, and detoxification of xenobiotics. Excess energy burning resulting from increases in fatty acid oxidation systems in liver generates reactive oxygen species, and the resulting oxidative damage influences liver regeneration and liver tumor development. These nuclear receptors are important sensors of exogenous activators as well as receptor-specific endogenous ligands. In this regard, gene knockout mouse models revealed that some lipid-metabolizing enzymes generate PPARα-activating ligands, while others such as ACOX1 (fatty acyl-CoA oxidase1) inactivate these endogenous PPARα activators. In the absence of ACOX1, the unmetabolized ACOX1 substrates cause sustained activation of PPARα, and the resulting increase in energy burning leads to hepatocarcinogenesis. Ligand-activated nuclear receptors recruit the multisubunit Mediator complex for RNA polymerase II-dependent gene transcription. Evidence indicates that the Med1 subunit of the Mediator is essential for PPARα, PPARγ, CAR, and GR signaling in liver. Med1 null hepatocytes fail to respond to PPARα activators in that these cells do not show induction of peroxisome proliferation and increases in fatty acid oxidation enzymes. Med1-deficient hepatocytes show no increase in cell proliferation and do not give rise to liver tumors. Identification of nuclear receptor-specific coactivators and Mediator subunits should further our understanding of the complexities of metabolic

  2. CD11b/CD18 (Mac-1) is a novel surface receptor for extracellular double-stranded RNA to mediate cellular inflammatory responses.

    Science.gov (United States)

    Zhou, Hui; Liao, Jieying; Aloor, Jim; Nie, Hui; Wilson, Belinda C; Fessler, Michael B; Gao, Hui-Ming; Hong, Jau-Shyong

    2013-01-01

    During viral infection, extracellular dsRNA is a potent signaling molecule that activates many innate immune cells, including macrophages. TLR3 is a well-known receptor for extracellular dsRNA, and internalization of extracellular dsRNA is required for endosomal TLR3 activation. Preserved inflammatory responses of TLR3-deficient macrophages to extracellular dsRNA strongly support a TLR3-independent mechanism in dsRNA-mediated immune responses. The present study demonstrated that CD11b/CD18 (Mac-1 [macrophage-1 Ag]), a surface integrin receptor, recognized extracellular dsRNA and induced macrophage immune responses. CD11b deficiency reduced inflammatory cytokine induction elicited by polyinosinic:polycytidylic acid (poly I:C; a synthetic dsRNA) in mouse sera and livers, as well as in cultured peritoneal macrophages. dsRNA-binding assay and confocal immunofluorescence showed that Mac-1, especially the CD11b subunit, interacted and colocalized with poly I:C on the surface of macrophages. Further mechanistic studies revealed two distinct signaling events following dsRNA recognition by Mac-1. First, Mac-1 facilitated poly I:C internalization through the activation of PI3K signaling and enhanced TLR3-dependent activation of IRF3 in macrophages. Second, poly I:C induced activation of phagocyte NADPH oxidase in a TLR3-independent, but Mac-1-dependent, manner. Subsequently, phagocyte NADPH oxidase-derived intracellular reactive oxygen species activated MAPK and NF-κB pathways. Our results indicate that extracellular dsRNA activates Mac-1 to enhance TLR3-dependent signaling and to trigger TLR3-independent, but Mac-1-dependent, inflammatory oxidative signaling, identifying a novel mechanistic basis for macrophages to recognize extracellular dsRNA to regulate innate immune responses. This study identifies Mac-1 as a novel surface receptor for extracellular dsRNA and implicates it as a potential therapeutic target for virus-related inflammatory diseases.

  3. 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.

  4. Pervasive Adaptation in Car Crowds

    Science.gov (United States)

    Ferscha, Alois; Riener, Andreas

    Advances in the miniaturization and embedding of electronics for microcomputing, communication and sensor/actuator systems, have fertilized the pervasion of technology into literally everything. Pervasive computing technology is particularly flourishing in the automotive domain, exceling the “smart car”, embodying intelligent control mechanics, intelligent driver assistance, safety and comfort systems, navigation, tolling, fleet management and car-to-car interaction systems, as one of the outstanding success stories of pervasive computing. This paper raises the issue of the socio-technical phenomena emerging from the reciprocal interrelationship between drivers and smart cars, particularly in car crowds. A driver-vehicle co-model (DVC-model) is proposed, expressing the complex interactions between the human driver and the in-car and on-car technologies. Both explicit (steering, shifting, overtaking), as well as implicit (body posture, respiration) interactions are considered, and related to the drivers vital state (attentive, fatigue, distracted, aggressive). DVC-models are considered as building blocks in large scale simulation experiments, aiming to analyze and understand adaptation phenomena rooted in the feed-back loops among individual driver behavior and car crowds.

  5. Loss of α1,6-fucosyltransferase suppressed liver regeneration: implication of core fucose in the regulation of growth factor receptor-mediated cellular signaling.

    Science.gov (United States)

    Wang, Yuqin; Fukuda, Tomohiko; Isaji, Tomoya; Lu, Jishun; Gu, Wei; Lee, Ho-Hsun; Ohkubo, Yasuhito; Kamada, Yoshihiro; Taniguchi, Naoyuki; Miyoshi, Eiji; Gu, Jianguo

    2015-02-05

    Core fucosylation is an important post-translational modification, which is catalyzed by α1,6-fucosyltransferase (Fut8). Increased expression of Fut8 has been shown in diverse carcinomas including hepatocarcinoma. In this study, we investigated the role of Fut8 expression in liver regeneration by using the 70% partial hepatectomy (PH) model, and found that Fut8 is also critical for the regeneration of liver. Interestingly, we show that the Fut8 activities were significantly increased in the beginning of PH (~4d), but returned to the basal level in the late stage of PH. Lacking Fut8 led to delayed liver recovery in mice. This retardation mainly resulted from suppressed hepatocyte proliferation, as supported not only by a decreased phosphorylation level of epidermal growth factor (EGF) receptor and hepatocyte growth factor (HGF) receptor in the liver of Fut8(-/-) mice in vivo, but by the reduced response to exogenous EGF and HGF of the primary hepatocytes isolated from the Fut8(-/-) mice. Furthermore, an administration of L-fucose, which can increase GDP-fucose synthesis through a salvage pathway, significantly rescued the delayed liver regeneration of Fut8(+/-) mice. Overall, our study provides the first direct evidence for the involvement of Fut8 in liver regeneration.

  6. 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...

  7. 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...

  8. 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&...

  9. 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...

  10. 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.

  11. Enhanced toxicity and cellular uptake of methotrexate-conjugated nanoparticles in folate receptor-positive cancer cells by decorating with folic acid-conjugated d-α-tocopheryl polyethylene glycol 1000 succinate.

    Science.gov (United States)

    Junyaprasert, Varaporn Buraphacheep; Dhanahiranpruk, Sirithip; Suksiriworapong, Jiraphong; Sripha, Kittisak; Moongkarndi, Primchanien

    2015-12-01

    Folic acid-conjugated d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS-FOL) decorated methotrexate (MTX)-conjugated nanoparticles were developed for targeted delivery of MTX to folate receptor-expressed tumor cells. The synthesis of TPGS-FOL followed 3-step process. Firstly, the terminal hydroxyl group of TPGS was converted to sulfonyl chloride using mesyl chloride in comparison with nosyl and tosyl chlorides. The highest conversion efficiency and yield were obtained by mesyl chloride due to the formation of higher reactive intermediate in a presence of triethylamine. Secondly, the substitution of sulfonyl group by sodium azide produced considerably high yield with conversion efficiency of over 90%. Lastly, the coupling reaction of azido-substituted TPGS and propargyl folamide by click reaction resulted in 96% conjugation efficiency without polymer degradation. To fabricate the folate receptor-targeted nanoparticles, 10 and 20%mol MTX-conjugated PEGylated poly(ϵ-caprolactone) nanoparticles were decorated with TPGS-FOL. The size and size distribution of MTX-conjugated nanoparticles relatively increased with %MTX. The MTX release from the nanoparticles was accelerated in acidic medium with an increase of %MTX but retarded in physiological pH medium. The decoration of TPGS-FOL onto the nanoparticles slightly enlarged the size and size distribution of the nanoparticles; however, it did not affect the surface charge. The cytotoxicity and cellular uptake of MCF-7 cells demonstrated that 10% MTX-conjugated nanoparticles and FOL-decorated nanoparticles possessed higher toxicity and uptake efficiency than 20% MTX-conjugated nanoparticles and undecorated nanoparticles, respectively. The results indicated that FOL-10% MTX-conjugated nanoparticles exhibited potential targeted delivery of MTX to folate receptor-expressed cancer cells.

  12. Plastic cars for developing nations

    Energy Technology Data Exchange (ETDEWEB)

    Ashley, S.

    1997-11-01

    Plastic automobiles may have passed a milestone on the long road to commercial reality with the development of Composite Concept Vehicle (CCV) from Chrysler Corp. in Auburn Hills, Mich. This basic compact car--so basic it could be called bare bones--is built by attaching an injection-molded thermoplastic polyester body onto a tubular steel chassis. The 1,200-pound CCV, which is expected to require one-third the labor and investment needed to build a conventional small car, was designed for new buyers in the emerging economies of China, India, and Southeast Asia. If commercialized, the car would likely cost about $6,000--halfway between a motorcycle and an entry-level auto. The small car was unveiled in September 1996 at the Frankfurt Auto Show in Germany.

  13. 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.

  14. 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.

  15. 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

  16. Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma

    DEFF Research Database (Denmark)

    Posey, Avery D; Schwab, Robert D; Boesteanu, Alina C;

    2016-01-01

    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 antige...

  17. 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

  18. 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.

  19. 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

  20. 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...

  1. 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....

  2. 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…

  3. 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...

  4. 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.

  5. Receptor for advanced glycation end products plays a more important role in cellular survival than in neurite outgrowth during retinoic acid-induced differentiation of neuroblastoma cells.

    Science.gov (United States)

    Sajithlal, Gangadharan; Huttunen, Henri; Rauvala, Heikki; Munch, Gerald

    2002-03-01

    The receptor for advanced glycation end products (RAGE), a member of the immunoglobulin superfamily, is known to interact with amphoterin. This interaction has been proposed to play a role in neurite outgrowth and process elongation during neurodifferentiation. However, there is as yet no direct evidence of the relevance of this pathway to neurodifferentiation under physiological conditions. In this study we have investigated a possible role of RAGE and amphoterin in the retinoic acid-induced differentiation of neuroblastoma cells. The functional inactivation of RAGE by dominant negative and antisense strategies showed that RAGE is not required for process outgrowth or differentiation, although overexpression of RAGE accelerates the elongation of neuritic processes. Using the antisense strategy, amphoterin was shown to be essential for process outgrowth and differentiation, suggesting that amphoterin may interact with other molecules to exert its effect in this context. Interestingly, the survival of the neuroblastoma cells treated with retinoic acid was partly dependent on the expression of RAGE, and inhibition of RAGE function partially blocked the increase in anti-apoptotic protein Bcl-2 following retinoic acid treatment. Based on these results we propose that a combination therapy using RAGE blockers and retinoic acid may prove as a useful approach for chemotherapy for the treatment of neuroblastoma.

  6. [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

  7. Efficacy and toxicity management of CAR-T-cell immunotherapy: a matter of responsiveness control or tumour-specificity?

    Science.gov (United States)

    Alonso-Camino, Vanesa; Harwood, Seandean Lykke; Álvarez-Méndez, Ana; Alvarez-Vallina, Luis

    2016-04-15

    Chimaeric antigen receptor (CAR)-expressing T-cells have demonstrated potent clinical efficacy in patients with haematological malignancies. However, the use of CAR-T-cells targeting solid tumour-associated antigens (TAAs) has been limited by organ toxicities related to activation of T-cell effector functions through the CAR. Most existing CARs recognize TAAs, which are also found in normal tissues. CAR-T-cell-mediated destruction of normal tissues constitutes a major roadblock to CAR-T-cell therapy, and must be avoided or mitigated. There is a broad range of strategies for modulating antigen responsiveness of CAR-T-cells, with varying degrees of complexity. Some of them might ameliorate the acute and chronic toxicities associated with current CAR constructs. However, further embellishments to CAR therapy may complicate clinical implementation and possibly create new immunogenicity issues. In contrast, the development of CARs targeting truly tumour-specific antigens might circumvent on-target/off-tumour toxicities without adding additional complexity to CAR-T-cell therapies, but these antigens have been elusive and may require novel selection strategies for their discovery.

  8. 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

  9. 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

  10. Design review of gondola car

    Directory of Open Access Journals (Sweden)

    S. V. Myamlin

    2014-12-01

    Full Text Available Purpose. To ensure the constantly growing volume of freight transportations it is necessary to introduce the innovation rolling stock. It should have the best technical and economic parameters in comparison with the existing fleet. Gondola car is the most popular type of railway freight car. Designs of the modern gondolas are based on many years of operating experience and numerous tests carried out by design and research organizations in the field of car building. To improve the body structure of gondolas it is necessary to perform a review of the existing structures and to identify the trends in their improvement. Methodology. The works on improvement the designs of produced gondolas are held by many engineering organizations in almost all industrialized countries. Analysis of the existing body designs of gondola cars is possible by analyzing the research in the field of transport engineering, namely patents, scientific articles, producers catalogues and so on. Findings. When analyzing it was determined that there are gondolas of different designs, but the most common are the gondolas with a solid floor and unloading hatches, the covers of which form the floor of gondola design. An effective method for reducing the gondola empty weight and increasing the body volume is also the use of aluminum alloy instead of steel. Results of the improvement analysis of the gondola bodies` designs showed that the creation of the modern gondola car requires from designers and scientists the implementation of scientific and technical solutions providing the increase of carrying capacity and the body volume, reduction of the gondolas empty weight, increase in repair intervals while improving the strength and dynamic qualities at the same time. Originality. For the first time the gondolas designs were analyzed, their advantages and disadvantages were considered and the trends in improvement of the given structures of gondola cars were determined. Practical value

  11. 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...

  12. 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

  13. 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...

  14. 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.

  15. 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...

  16. 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。

  17. 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...

  18. 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.

  19. 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

  20. 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.

  1. About Oil, Cars and Comrades

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    The last century was the century of oil, cars and electricity. Crude oil was probably the critical raw material for the industrial development of the United States, England, Germany and the like from the late 19th century to the beginning of the 21 st. Amazing amounts of riches were made. Those who called

  2. 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…

  3. 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

  4. 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

  5. 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.

  6. Augmentation of CAR T-cell Trafficking and Antitumor Efficacy by Blocking Protein Kinase A Localization.

    Science.gov (United States)

    Newick, Kheng; O'Brien, Shaun; Sun, Jing; Kapoor, Veena; Maceyko, Steven; Lo, Albert; Puré, Ellen; Moon, Edmund; Albelda, Steven M

    2016-06-01

    Antitumor treatments based on the infusion of T cells expressing chimeric antigen receptors (CAR T cells) are still relatively ineffective for solid tumors, due to the presence of immunosuppressive mediators [such as prostaglandin E2 (PGE2) and adenosine] and poor T-cell trafficking. PGE2 and adenosine activate protein kinase A (PKA), which then inhibits T-cell receptor (TCR) activation. This inhibition process requires PKA to localize to the immune synapse via binding to the membrane protein ezrin. We generated CAR T cells that expressed a small peptide called the "regulatory subunit I anchoring disruptor" (RIAD) that inhibits the association of PKA with ezrin, thus blunting the negative effects of PKA on TCR activation. After exposure to PGE2 or adenosine in vitro, CAR-RIAD T cells showed increased TCR signaling, released more cytokines, and showed enhanced killing of tumor cells compared with CAR T cells. When injected into tumor-bearing mice, the antitumor efficacy of murine and human CAR-RIAD T cells was enhanced compared with that of CAR T cells, due to resistance to tumor-induced hypofunction and increased T-cell infiltration of established tumors. Subsequent in vitro assays showed that both mouse and human CAR-RIAD cells migrated more efficiently than CAR cells did in response to the chemokine CXCL10 and also had better adhesion to various matrices. Thus, the intracellular addition of the RIAD peptide to adoptively transferred CAR T cells augments their efficacy by increasing their effector function and by improving trafficking into tumor sites. This treatment strategy, therefore, shows potential clinical application for treating solid tumors. Cancer Immunol Res; 4(6); 541-51. ©2016 AACR.

  7. 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.

  8. 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.

  9. 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....

  10. 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

  11. Phenobarbital and Insulin Reciprocate Activation of the Nuclear Receptor Constitutive Androstane Receptor through the Insulin Receptor.

    Science.gov (United States)

    Yasujima, Tomoya; Saito, Kosuke; Moore, Rick; Negishi, Masahiko

    2016-05-01

    Phenobarbital (PB) antagonized insulin to inactivate the insulin receptor and attenuated the insulin receptor downstream protein kinase B (AKT)-forkhead box protein O1 and extracellular signal-regulated kinase 1/2 signals in mouse primary hepatocytes and HepG2 cells. Hepatic AKT began dephosphorylation in an early stage of PB treatment, and blood glucose levels transiently increased in both wild-type and constitutive androstane receptor (CAR) knockout (KO) mice. On the other hand, blood glucose levels increased in wild-type mice, but not KO mice, in later stages of PB treatment. As a result, PB, acting as an insulin receptor antagonist, elicited CAR-independent increases and CAR-dependent decreases of blood glucose levels at these different stages of treatment, respectively. Reciprocally, insulin activation of the insulin receptor repressed CAR activation and induction of its target CYP2B6 gene in HepG2 cells. Thus, PB and insulin cross-talk through the insulin receptor to regulate glucose and drug metabolism reciprocally.

  12. 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.

  13. 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), ...

  14. The cellular RNA export receptor TAP/NXF1 is required for ICP27-mediated export of herpes simplex virus 1 RNA, but the TREX complex adaptor protein Aly/REF appears to be dispensable.

    Science.gov (United States)

    Johnson, Lisa A; Li, Ling; Sandri-Goldin, Rozanne M

    2009-07-01

    Herpes simplex virus 1 (HSV-1) protein ICP27 has been shown to shuttle between the nucleus and cytoplasm and to bind viral RNA during infection. ICP27 was found to interact with the cellular RNA export adaptor protein Aly/REF, which is part of the TREX complex, and to relocalize Aly/REF to viral replication sites. ICP27 is exported to the cytoplasm through the export receptor TAP/NXF1, and ICP27 must be able to interact with TAP/NXF1 for efficient export of HSV-1 early and late transcripts. We examined the dynamics of ICP27 movement and its localization with respect to Aly/REF and TAP/NXF1 in living cells during viral infection. Recombinant viruses with a yellow fluorescent protein (YFP) tag on the N or C terminus of ICP27 were constructed. While the N-terminally tagged ICP27 virus behaved like wild-type HSV-1, the C-terminally tagged virus was defective in viral replication and gene expression, and ICP27 was confined to the nucleus, suggesting that the C-terminal YFP tag interfered with ICP27's C-terminal interactions, including the interaction with TAP/NXF1. To assess the role of Aly/REF and TAP/NXF1 in viral RNA export, these factors were knocked down using small interfering RNA. Knockdown of Aly/REF had little effect on the export of ICP27 or poly(A)(+) RNA during infection. In contrast, a decrease in TAP/NXF1 levels severely impaired export of ICP27 and poly(A)(+) RNA. We conclude that TAP/NXF1 is essential for ICP27-mediated export of RNA during HSV-1 infection, whereas Aly/REF may be dispensable.

  15. 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.

  16. 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...

  17. 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...

  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. The insect cellular immune response

    Institute of Scientific and Technical Information of China (English)

    Michael R. Strand

    2008-01-01

    The innate immune system of insects is divided into humoral defenses that include the production of soluble effector molecules and cellular defenses like phagocytosis and encapsulation that are mediated by hemocytes. This review summarizes current understanding of the cellular immune response. Insects produce several terminally differentiated types of hemocytes that are distinguished by morphology, molecular and antigenic markers, and function. The differentiated hemocytes that circulate in larval or nymphal stage insects arise from two sources: progenitor cells produced during embryogenesis and mesodermally derived hematopoietic organs. Regulation of hematopoiesis and hemocyte differentiation also involves several different signaling pathways. Phagocytosis and encapsulation require that hemocytes first recognize a given target as foreign followed by activation of downstream signaling and effector responses. A number of humoral and cellular receptors have been identified that recognize different microbes and multicellular parasites. In turn, activation of these receptors stimulates a number of signaling pathways that regulate different hemocyte functions. Recent studies also identify hemocytes as important sources of a number of humoral effector molecules required for killing different foreign invaders.

  20. Cellular: Toward personal communications

    Science.gov (United States)

    Heffernan, Stuart

    1991-09-01

    The cellular industry is one of the fastest growing segment of the telecommunications industry. With an estimated penetration rate of 20 percent in the near future, cellular is becoming an ubiquitous telecommunications service in the U.S. In this paper we will examine the major advancements in the cellular industry: customer equipment, cellular networks, engineering tools, customer support, and nationwide seamless service.

  1. 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。

  2. 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。

  3. 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。

  4. Prediction of future car forms based on historical trends

    Directory of Open Access Journals (Sweden)

    Bijendra Kumar

    2016-09-01

    Full Text Available Cars are one of the most important products that affects our daily life. Manufacturers of cars are inclined to know factors that affect the sales of cars and how to influence them. Car is a very competitive product whose technology is already matured. Thus, purchase decisions of a car depend on factors such as, aesthetics, ergonomics, features available and price. Exterior form and colour of a car are the most important factors that influence likeness of the car. We did a case study on car aesthetics (form, colour, shape, and user focus with more than 500 car advertisements over the past 70 years, appearing in various car magazines. Results show that form of cars has changed from sharp to smooth over the years, and white colour cars are becoming more popular. Additionally, car size is becoming smaller and increasingly focused towards family. Thus, manufacturers are recommended to develop compact, efficient and hybrid cars.

  5. MODERN ELECTRIC CARS OF TESLA MOTORS COMPANY

    Directory of Open Access Journals (Sweden)

    O. F. Vynakov

    2016-08-01

    Full Text Available This overview article shows the advantages of a modern electric car as compared with internal combustion cars by the example of the electric vehicles of Tesla Motors Company. It (в смысле- статья describes the history of this firm, provides technical and tactical characteristics of three modifications of electric vehicles produced by Tesla Motors. Modern electric cars are not less powerful than cars with combustion engines both in speed and acceleration amount. They are reliable, economical and safe in operation. With every year the maximum range of an electric car is increasing and its battery charging time is decreasing.Solving the problem of environmental safety, the governments of most countries are trying to encourage people to switch to electric cars by creating subsidy programs, lending and abolition of taxation. Therefore, the advent of an electric vehicle in all major cities of the world is inevitable.

  6. 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

  7. 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.

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. 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...... ETB receptor agonist sarafotoxin 6c. The involvement of extracellular regulated kinase (ERK) 1/2 and focal adhesion kinase (FAK) were studied by their specific inhibitors U0126 and PF-228, respectively. Compared to their stretched counterparts, un-stretched MCA segments showed a significantly...

  13. Car driver casualty rates in Great Britain by type of car.

    Science.gov (United States)

    Broughton, Jeremy

    2008-07-01

    Since 1989, the British STATS19 national road accident reporting system has included the Vehicle Registration Mark (VRM). This allows the basic vehicle record to be augmented with details such as the date of first registration and codes that specify the vehicle's make and model. In order to examine the influence of car type upon the driver casualty rate, this paper groups car models into six types, ranging from 'Minis and Superminis' to '4x4s and people carriers (pc)'. Exploratory analyses of data from accidents that occurred between 2001 and 2005 show that the driver casualty rate falls markedly with size of car. In car-car collisions, the rate also rises markedly with the size of the other car. The car's year of first registration also influences the casualty rate, and represents the influence of changes in the characteristics of new cars. Statistical models are fitted to identify the separate influences on a driver's risk of injury in a car-car collision of the type and registration year of the driver's car and the type and registration year of the other car in the collision. The analysis is extended to include collisions with other vehicles such as lorries and buses. PMID:18606288

  14. 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.

  15. The influence of positionality in car-purchasing behaviour on the downsizing of new cars

    NARCIS (Netherlands)

    Hoen, Anco; Geurs, Karst T.

    2011-01-01

    This paper presents results from stated choice experiments looking at the influence of positionality in peoples’ choices of passenger cars in the Netherlands. It provides evidence that cars are positional goods and that selected car attributes such as size, engine capacity and interior add to their

  16. CAR T Cells Targeting Podoplanin Reduce Orthotopic Glioblastomas in Mouse Brains.

    Science.gov (United States)

    Shiina, Satoshi; Ohno, Masasuke; Ohka, Fumiharu; Kuramitsu, Shunichiro; Yamamichi, Akane; Kato, Akira; Motomura, Kazuya; Tanahashi, Kuniaki; Yamamoto, Takashi; Watanabe, Reiko; Ito, Ichiro; Senga, Takeshi; Hamaguchi, Michinari; Wakabayashi, Toshihiko; Kaneko, Mika K; Kato, Yukinari; Chandramohan, Vidyalakshmi; Bigner, Darell D; Natsume, Atsushi

    2016-03-01

    Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults with a 5-year overall survival rate of less than 10%. Podoplanin (PDPN) is a type I transmembrane mucin-like glycoprotein, expressed in the lymphatic endothelium. Several solid tumors overexpress PDPN, including the mesenchymal type of GBM, which has been reported to present the worst prognosis among GBM subtypes. Chimeric antigen receptor (CAR)-transduced T cells can recognize predefined tumor surface antigens independent of MHC restriction, which is often downregulated in gliomas. We constructed a lentiviral vector expressing a third-generation CAR comprising a PDPN-specific antibody (NZ-1-based single-chain variable fragment) with CD28, 4-1BB, and CD3ζ intracellular domains. CAR-transduced peripheral blood monocytes were immunologically evaluated by calcein-mediated cytotoxic assay, ELISA, tumor size, and overall survival. The generated CAR T cells were specific and effective against PDPN-positive GBM cells in vitro. Systemic injection of the CAR T cells into an immunodeficient mouse model inhibited the growth of intracranial glioma xenografts in vivo. CAR T-cell therapy that targets PDPN would be a promising adoptive immunotherapy to treat mesenchymal GBM.

  17. 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

  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. 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.

  20. 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...

  1. Cancer T cell immunotherapy with bispecific antibodies and chimeric antigen receptors.

    Science.gov (United States)

    Lacher, Markus D; Provenzano, Maurizio

    2013-09-01

    Solid tumors contain several different types of malignant cells. This cellular heterogeneity complicates therapy for at least two reasons. First, each subpopulation may respond differently to a given treatment. Second, cancer cells are plastic, and thus may convert from a therapy-sensitive to a therapy-resistant cell type represented by another subpopulation. Therefore, successful therapies will have to target numerous malignant cell types, not just the rapidly proliferating cells as most standard treatments do. Immunotherapies with T cells engineered to recognize cancer cells via bispecific antibodies (bsAbs) or chimeric antigen receptors (CARs) are particularly promising approaches with potential to ablate both dividing and non/slow-dividing subpopulations of cancer cells. Here, we discuss several patents associated with exceptionally effective bsAbs of the tandem single-chain variable fragment (taFv) class and untangle a part of the complex network of patents directly or indirectly related to CARs. Furthermore, we speculate on the future of bsAbs and CARs for both treatment and prevention of solid tumors such as prostate cancer. PMID:23688207

  2. 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

  3. 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

  4. 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.

  5. 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

  6. 49 CFR 174.110 - Car magazine.

    Science.gov (United States)

    2010-10-01

    ... 49 Transportation 2 2010-10-01 2010-10-01 false Car magazine. 174.110 Section 174.110...) Materials § 174.110 Car magazine. When specially authorized by the carrier, Division 1.1 or 1.2 (explosive... packages of Class 1 (explosive) materials are placed in a “magazine” box made of sound lumber not less...

  7. 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.)

  8. 75 FR 10567 - Commerce Acquisition Regulation (CAR)

    Science.gov (United States)

    2010-03-08

    ... proposed rule published on October 13, 2009 in the Federal Register (74 FR 52541). The document is also... Commerce 48 CFR Chapter 13 Commerce Acquisition Regulation (CAR); Final Rule #0;#0;Federal Register / Vol... Chapter 13 RIN 0605-AA26 Commerce Acquisition Regulation (CAR) AGENCY: Department of Commerce...

  9. 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, ...

  10. 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

  11. 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

  12. 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.

  13. 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

  14. 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

  15. 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 ...

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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

  1. RNA-Seq reveals common and unique PXR- and CAR-target gene signatures in the mouse liver transcriptome.

    Science.gov (United States)

    Cui, Julia Yue; Klaassen, Curtis D

    2016-09-01

    The pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known xenobiotic-sensing nuclear receptors with overlapping functions. However, there lacks a quantitative characterization to distinguish between the PXR and CAR target genes and signaling pathways in the liver. The present study performed a transcriptomic comparison of the PXR- and CAR-targets using RNA-Seq in livers of adult wild-type mice that were treated with the prototypical PXR ligand PCN (200mg/kg, i.p. once daily for 4days in corn oil) or the prototypical CAR ligand TCPOBOP (3mg/kg, i.p., once daily for 4days in corn oil). At the given doses, TCPOBOP differentially regulated many more genes (2125) than PCN (212), and 147 of the same genes were differentially regulated by both chemicals. As expected, the top pathways differentially regulated by both PCN and TCPOBOP were involved in xenobiotic metabolism, and they also up-regulated genes involved in retinoid metabolism, but down-regulated genes involved in inflammation and iron homeostasis. Regarding unique pathways, PXR activation appeared to overlap with the aryl hydrocarbon receptor signaling, whereas CAR activation appeared to overlap with the farnesoid X receptor signaling, acute-phase response, and mitochondrial dysfunction. The mRNAs of differentially regulated drug-processing genes (DPGs) partitioned into three patterns, namely TCPOBOP-induced, PCN-induced, as well as TCPOBOP-suppressed gene clusters. The cumulative mRNAs of the differentially regulated DPGs, phase-I and -II enzymes, as well as efflux transporters were all up-regulated by both PCN and TCPOBOPOP, whereas the cumulative mRNAs of the uptake transporters were down-regulated only by TCPOBOP. The absolute mRNA abundance in control and receptor-activated conditions was examined in each DPG category to predict the contribution of specific DPG genes in the PXR/CAR-mediated pharmacokinetic responses. The preferable differential regulation by TCPOBOP in the

  2. Isoform-specific regulation and localization of the coxsackie and adenovirus receptor in human airway epithelia.

    Directory of Open Access Journals (Sweden)

    Katherine J D A Excoffon

    Full Text Available Adenovirus is an important respiratory pathogen. Adenovirus fiber from most serotypes co-opts the Coxsackie-Adenovirus Receptor (CAR to bind and enter cells. However, CAR is a cell adhesion molecule localized on the basolateral membrane of polarized epithelia. Separation from the lumen of the airways by tight junctions renders airway epithelia resistant to inhaled adenovirus infection. Although a role for CAR in viral spread and egress has been established, the mechanism of initial respiratory infection remains controversial. CAR exists in several protein isoforms including two transmembrane isoforms that differ only at the carboxy-terminus (CAR(Ex7 and CAR(Ex8. We found low-level expression of the CAR(Ex8 isoform in well-differentiated human airway epithelia. Surprisingly, in contrast to CAR(Ex7, CAR(Ex8 localizes to the apical membrane of epithelia where it augments adenovirus infection. Interestingly, despite sharing a similar class of PDZ-binding domain with CAR(Ex7, CAR(Ex8 differentially interacts with PICK1, PSD-95, and MAGI-1b. MAGI-1b appears to stoichiometrically regulate the degradation of CAR(Ex8 providing a potential mechanism for the apical localization of CAR(Ex8 in airway epithelial. In summary, apical localization of CAR(Ex8 may be responsible for initiation of respiratory adenoviral infections and this localization appears to be regulated by interactions with PDZ-domain containing proteins.

  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. The benefits of improved car secondary safety.

    Science.gov (United States)

    Broughton, Jeremy

    2003-07-01

    The term 'secondary safety' refers to the protection that a vehicle provides its occupants when involved in an accident. This paper studies information from the British database of road accident reports between 1980 and 1998, to estimate the reduction in the number of occupant casualties over these years which may be attributed to improvements to secondary safety in cars. The paper shows that the proportion of driver casualties who are killed or seriously injured (KSI) is lower for modern cars than for older cars. The reduction of this proportion is used to assess the improvement in secondary safety. Statistical models are developed to represent the proportion with 'year of first registration' as one of the independent variables, although only an incomplete assessment of the benefits of improved secondary safety can be made with the available data. The assessment compares the number of casualties that would have been expected if secondary safety had remained at the level found in cars first registered in 1980 with the actual casualty numbers. It is estimated that improved secondary safety reduced the number of drivers KSI by at least 19.7% in 1998, in comparison with what might have occurred if all cars had had that lower level of secondary safety. This figure relates to all cars on the road in 1998, and rises to 33%, when confined to the most modern cars (those which were first registered in 1998).

  5. Characterizing drug-metabolizing enzymes and transporters that are bona fide CAR-target genes in mouse intestine

    Directory of Open Access Journals (Sweden)

    Shinhee Park

    2016-09-01

    Full Text Available Intestine is responsible for the biotransformation of many orally-exposed chemicals. The constitutive androstane receptor (CAR/Nr1i3 is known to up-regulate many genes encoding drug-metabolizing enzymes and transporters (drug-processing genes/DPGs in liver, but less is known regarding its effect in intestine. Sixty-day-old wild-type and Car−/− mice were administered the CAR-ligand TCPOBOP or vehicle once daily for 4 days. In wild-type mice, Car mRNA was down-regulated by TCPOBOP in liver and duodenum. Car−/− mice had altered basal intestinal expression of many DPGs in a section-specific manner. Consistent with the liver data (Aleksunes and Klaassen, 2012, TCPOBOP up-regulated many DPGs (Cyp2b10, Cyp3a11, Aldh1a1, Aldh1a7, Gsta1, Gsta4, Gstm1-m4, Gstt1, Ugt1a1, Ugt2b34, Ugt2b36, and Mrp2–4 in specific sections of small intestine in a CAR-dependent manner. However, the mRNAs of Nqo1 and Papss2 were previously known to be up-regulated by TCPOBOP in liver but were not altered in intestine. Interestingly, many known CAR-target genes were highest expressed in colon where CAR is minimally expressed, suggesting that additional regulators are involved in regulating their expression. In conclusion, CAR regulates the basal expression of many DPGs in intestine, and although many hepatic CAR-targeted DPGs were bona fide CAR-targets in intestine, pharmacological activation of CAR in liver and intestine are not identical.

  6. 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

  7. Multimodal CARS microscopy of structured carbohydrate biopolymers

    Science.gov (United States)

    Slepkov, Aaron D.; Ridsdale, Andrew; Pegoraro, Adrian F.; Moffatt, Douglas J.; Stolow, Albert

    2010-01-01

    We demonstrate the utility of multimodal coherent anti-Stokes Raman scattering (CARS) microscopy for the study of structured condensed carbohydrate systems. Simultaneous second-harmonic generation (SHG) and spectrally-scanned CARS microscopy was used to elucidate structure, alignment, and density in cellulose cotton fibers and in starch grains undergoing rapid heat-moisture swelling. Our results suggest that CARS response of the O-H stretch region (3000 cm−1–3400 cm−1), together with the commonly-measured C-H stretch (2750 cm−1–2970 cm−1) and SHG provide potentially important structural information and contrast in these materials. PMID:21258555

  8. 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.

  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. 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...

  11. REPAIR TECHNOLOGY IMPROVEMENT OF SPECIALIZED FREIGHT CARS

    Directory of Open Access Journals (Sweden)

    V. M. Bubnov

    2016-02-01

    Full Text Available Purpose. The volume of cargo transportation demands the introduction of a new generation of cars that would be able to provide all the needs of carriers. But this is impossible without the implementation of renovation repair facilities with the introduction of new technologies and modernization of the repair process. Repair of rolling stock is a key factor that must proceed with the establishment of new cars, as not all of the inventions may be repaired in car-repair depots, most of which are obsolete. The purpose is to analyze the possibility of increasing the efficiency of the repair process by introducing new repair technologies or improving the existing ones. It will improve not only the quality of the repair, but also its rate. Methodology. Works on improving the designs of freight cars are held by many design organizations in almost all industrialized countries. It makes repair organizations (depots and car-repair plants to upgrade the repair process. Achievements of-this goal is possible by improving the technology renovation and reorganization through the use of flexible flow technologies, which to date are the most effective in the repair of rolling stock. Findings. When performing the analysis it was determined that there are different designs of cars. More of cars are all-purpose and their repair does not cause difficulties for car-repair business. However, the number of specialized cars is also significant, and the technology of their repair should be improved. One of the reasons is that many models, such as tank wagons for the carriage of sulfur, are intended for the carriage of dangerous goods and their failure at the time of motion is not permitted. Originality. Firstly the authors have defined direction at improving technologies of repair specialized cars. Practical value. Actual improvement in the construction of cars is to improve the existing repair facilities. In addition, the repair technology using nowadays when repairing

  12. 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.

  13. 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

  14. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies.

    Science.gov (United States)

    Romanski, Annette; Uherek, Christoph; Bug, Gesine; Seifried, Erhard; Klingemann, Hans; Wels, Winfried S; Ottmann, Oliver G; Tonn, Torsten

    2016-07-01

    Many B-cell acute and chronic leukaemias tend to be resistant to killing by natural killer (NK) cells. The introduction of chimeric antigen receptors (CAR) into T cells or NK cells could potentially overcome this resistance. Here, we extend our previous observations on the resistance of malignant lymphoblasts to NK-92 cells, a continuously growing NK cell line, showing that anti-CD19-CAR (αCD19-CAR) engineered NK-92 cells can regain significant cytotoxicity against CD19 positive leukaemic cell lines and primary leukaemia cells that are resistant to cytolytic activity of parental NK-92 cells. The 'first generation' CAR was generated from a scFv (CD19) antibody fragment, coupled to a flexible hinge region, the CD3ζ chain and a Myc-tag and cloned into a retrovirus backbone. No difference in cytotoxic activity of NK-92 and transduced αCD19-CAR NK-92 cells towards CD19 negative targets was found. However, αCD19-CAR NK-92 cells specifically and efficiently lysed CD19 expressing B-precursor leukaemia cell lines as well as lymphoblasts from leukaemia patients. Since NK-92 cells can be easily expanded to clinical grade numbers under current Good Manufactoring Practice (cGMP) conditions and its safety has been documented in several phase I clinical studies, treatment with CAR modified NK-92 should be considered a treatment option for patients with lymphoid malignancies.

  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. Car-following models of vehicular traffic

    Institute of Scientific and Technical Information of China (English)

    翁彦琳; 吴铁军

    2002-01-01

    The Car-following model is a kind of microscopic simulation model for vehicular traffic, which describe the one-by-one following behaviors of vehides in the same traffic lane. As a common traffic phenomenon, following behavior is of great importance in the micro-study of intelligent traffic control.Compared with other traffic-flow models, car-following model embodies the human factors and feflects the real traffic sit-uation in a better way. This paper gives a systematic review of the development and actuality of car-following models by introducing and analyzing in detail the advantages and disavantages of GHR model, OV model,CA model and fuzzy-logic model. In addition, local stability and asymptotic stability of car-following models are discussed in this paper.

  17. 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.

  18. 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.

  19. Car-following models of vehicular traffic

    Institute of Scientific and Technical Information of China (English)

    翁彦琳; 吴铁军

    2002-01-01

    The Car-following models is a kind of microscopic simulation model f or vehicular traffic, which describe the one-by-one following behaviors of v ehicles in the same traffic lane. As a common traffic phenomenon, following behavior is of great importance in the micro-study of intelligent traffic control. Compared with other traffic-flow models, car-following model embodies the human factors a nd reflects the real traffic situation in a better way. This paper gives a syste matic review of the development and actuality of car-following models by introd u cing and analyzing in detail the advantages and disadvantages of GHR model, OV m odel, CA model and fuzzy-logic model. In addition, local stability and asymptot ic stability of car-following models are discussed in this paper.

  20. 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...

  1. 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 ...

  2. 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 ...

  3. 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

  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. 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.

  6. 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)

  7. 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

  8. 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

  9. 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

  10. The Goods Upstairs Car Innovative Design

    Science.gov (United States)

    Wang, Feng-Lan; Zhang, Bo; Gao, Bo; Liu, Yan-Xin; Gao, Bo

    2016-05-01

    The design is a new kind of cars used for loading goods when you upstairs. The cars -- ones are very safe and convenient --consist of body, chassis, bottom, round, object, stage, upstairs, train wheels, handles, storage tank, security fence etc. The design, composed of combination of each structure, achieves the purpose of loading goods and even some large potted plants when you go upstairs or downstairs very flatly.

  11. 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.

  12. Possible Relevance of Receptor-Receptor Interactions between Viral- and Host-Coded Receptors for Viral-Induced Disease

    Directory of Open Access Journals (Sweden)

    Luigi F. Agnati

    2007-01-01

    Full Text Available It has been demonstrated that some viruses, such as the cytomegalovirus, code for G-protein coupled receptors not only to elude the immune system, but also to redirect cellular signaling in the receptor networks of the host cells. In view of the existence of receptor-receptor interactions, the hypothesis is introduced that these viral-coded receptors not only operate as constitutively active monomers, but also can affect other receptor function by interacting with receptors of the host cell. Furthermore, it is suggested that viruses could also insert not single receptors (monomers, but clusters of receptors (receptor mosaics, altering the cell metabolism in a profound way. The prevention of viral receptor-induced changes in host receptor networks may give rise to novel antiviral drugs that counteract viral-induced disease.

  13. 49 CFR 215.119 - Defective freight car truck.

    Science.gov (United States)

    2010-10-01

    ... 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 a... 49 Transportation 4 2010-10-01 2010-10-01 false Defective freight car truck. 215.119 Section...

  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. 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.

  16. 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....

  17. 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....

  18. 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)...

  19. 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....

  20. 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...

  1. 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...

  2. 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.

  3. Reversible quantum cellular automata

    CERN Document Server

    Schumacher, B

    2004-01-01

    We define quantum cellular automata as infinite quantum lattice systems with discrete time dynamics, such that the time step commutes with lattice translations and has strictly finite propagation speed. In contrast to earlier definitions this allows us to give an explicit characterization of all local rules generating such automata. The same local rules also generate the global time step for automata with periodic boundary conditions. Our main structure theorem asserts that any quantum cellular automaton is structurally reversible, i.e., that it can be obtained by applying two blockwise unitary operations in a generalized Margolus partitioning scheme. This implies that, in contrast to the classical case, the inverse of a nearest neighbor quantum cellular automaton is again a nearest neighbor automaton. We present several construction methods for quantum cellular automata, based on unitaries commuting with their translates, on the quantization of (arbitrary) reversible classical cellular automata, on quantum c...

  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. 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.

  6. Complement-dependent cellular cytotoxicity: lymphoblastoid lines that activate complement component 3 (C3) and express C3 receptors have increased sensitivity to lymphocyte-mediated lysis in the presence of fresh human serum.

    Science.gov (United States)

    Ramos, O F; Sármay, G; Klein, E; Yefenof, E; Gergely, J

    1985-08-01

    Lymphocyte-mediated lysis of cells of the Raji, Daudi, Jijoye, and Bjab lines was elevated when fresh human serum was added to the assay. A higher proportion of effector-target conjugates was observed in the presence of human serum. In similar experiments lysis of 1301, Rael, and P3HR-1 cells was unaltered. All cell lines activated the alternative pathway of complement but they varied in the expression of receptors for complement component 3 (C3) and in the ability to fix the C3 cleavage products on their membrane. The enhancement of lysis in the presence of human serum occurred only with those cells that bound C3. This characteristic was correlated to the expression of C3 receptors. Analysis of the nature of the deposited C3 was performed with Raji cells. Raji cells exposed to human serum bound C3b as indicated by the immunoadherence test. The C3b was further processed to C3bi, because the immunoadherence declined with time and conjugate formation increased with Daudi cells, which carry the C3 receptors CR2 and CR3. This suggests that in the lytic assay lymphocytes with C3bi receptors are recruited in the presence of human serum. We assume that the bridge of C3 molecules between targets and effectors increases the avidity of their interaction. PMID:3895232

  7. 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

  8. 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...

  9. 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.

  10. 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 §...

  11. 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

  12. 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...

  13. Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.

    Science.gov (United States)

    Boice, Michael; Salloum, Darin; Mourcin, Frederic; Sanghvi, Viraj; Amin, Rada; Oricchio, Elisa; Jiang, Man; Mottok, Anja; Denis-Lagache, Nicolas; Ciriello, Giovanni; Tam, Wayne; Teruya-Feldstein, Julie; de Stanchina, Elisa; Chan, Wing C; Malek, Sami N; Ennishi, Daisuke; Brentjens, Renier J; Gascoyne, Randy D; Cogné, Michel; Tarte, Karin; Wendel, Hans-Guido

    2016-10-01

    The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM((P37-V202))) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development, and our study illustrates the use of CAR-T cells as "micro-pharmacies" able to deliver an anti-cancer protein.

  14. 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

  15. 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.

  16. Decentralized Cooperation Strategies in Two-Dimensional Traffic of Cellular Automata

    Institute of Scientific and Technical Information of China (English)

    方峻; 覃征; 陈喜群; 冷彪; 徐朝晖; 江子能

    2012-01-01

    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.

  17. Melatonin and breast cancer: cellular mechanisms, clinical studies and future perspectives

    OpenAIRE

    Grant, Stephen G.; Melan, Melissa A.; Latimer, Jean J.; Witt-Enderby, Paula A.

    2009-01-01

    Recent studies have suggested that the pineal hormone melatonin may protect against breast cancer, and the mechanisms underlying its actions are becoming clearer. Melatonin works through receptors and distinct second messenger pathways to reduce cellular proliferation and to induce cellular differentiation. In addition, independently of receptors melatonin can modulate oestrogen-dependent pathways and reduce free-radical formation, thus preventing mutation and cellular toxicity. The fact that...

  18. 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.

  19. 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.

  20. 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...

  1. 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

  2. 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...

  3. 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

  4. 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.

  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. 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)

  7. 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 ...

  8. 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.

  9. Nanostructured cellular networks.

    Science.gov (United States)

    Moriarty, P; Taylor, M D R; Brust, M

    2002-12-01

    Au nanocrystals spin-coated onto silicon from toluene form cellular networks. A quantitative statistical crystallography analysis shows that intercellular correlations drive the networks far from statistical equilibrium. Spin-coating from hexane does not produce cellular structure, yet a strong correlation is retained in the positions of nanocrystal aggregates. Mechanisms based on Marangoni convection alone cannot account for the variety of patterns observed, and we argue that spinodal decomposition plays an important role in foam formation.

  10. 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...

  11. Parametric design of air powered car

    Energy Technology Data Exchange (ETDEWEB)

    Sundar, T.M.; Kumar, B.P.; Suresh, R. [Tamilnadu College of Engineering, Coimbatore (India). Dept. of Mechanical Engineering

    2006-07-01

    An air-powered car was described with particular reference to its thermodynamic properties. The car was based on an external combustion engine. Air suction occurred in a piston and cylinder assembly through an air vent, where it was then compressed to higher pressures. The compressed air then entered a multi-stage reciprocating single-acting air compressor where the air was further compressed. Power for the compressor was provided by a double-battery system and a relay circuit to trigger the battery connection. Compressed air was stored in a compressed air tank and controlled by valves. The valves were controlled by a contour profile of an overhead camshift. Design specifications were included for the cylinder and cylinder liner; the pistons; the connecting rod; crank; valve gear mechanism; and the compressor. Results of the thermodynamic analysis indicated that the air-powered car is technologically feasible. 7 refs., 3 tabs., 1 fig.

  12. 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...

  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. 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

  15. Occupant safety in modern passenger cars.

    Science.gov (United States)

    Fildes, B N; Vulcan, A P; Lenard, J

    1992-06-01

    A study was undertaken recently for the Federal Office of Road Safety in Australia of 150 modern vehicle crashes where at least one of the vehicle occupants was admitted to hospital. The types of injuries sustained by occupants of modern Australian passenger cars involved in road crashes (including points of contact within the vehicle) were assessed to provide direction for future improvements in occupant protection. Seat belt performance in all seating positions was of particular interest. While the limited number of cases did not permit a full and detailed statistical analysis of these data, the findings nevertheless show there is scope for improving occupant protection for drivers and passengers of modern passenger cars.

  16. 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...

  17. Islamic Mobility : Car Culture in Modern Malaysia

    OpenAIRE

    Fischer, Johan

    2016-01-01

    In a modern and respectable middle-class suburb outside Kuala Lumpur, the overtness of cars evokes intense speculation about the nature of the make-up of covert middle-class homes and the formation of Malay Muslim identities more generally. I argue that the more ‘Islamic’ cultures of consumption assert themselves in modern Malaysia, the more the growing Malay Muslim middle class is split between desiring cars as positional commodities, on the one hand, and claims for piety through consumption...

  18. 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.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. 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...

  4. Complement-dependent cellular cytotoxicity: lymphoblastoid lines that activate complement component 3 (C3) and express C3 receptors have increased sensitivity to lymphocyte-mediated lysis in the presence of fresh human serum.

    OpenAIRE

    Ramos, O F; Sármay, G; Klein, E.; Yefenof, E; Gergely, J.

    1985-01-01

    Lymphocyte-mediated lysis of cells of the Raji, Daudi, Jijoye, and Bjab lines was elevated when fresh human serum was added to the assay. A higher proportion of effector-target conjugates was observed in the presence of human serum. In similar experiments lysis of 1301, Rael, and P3HR-1 cells was unaltered. All cell lines activated the alternative pathway of complement but they varied in the expression of receptors for complement component 3 (C3) and in the ability to fix the C3 cleavage prod...

  5. Epstein-Barr virus/complement fragment C3d receptor (CR2) reacts with p53, a cellular antioncogene-encoded membrane phosphoprotein: detection by polyclonal anti-idiotypic anti-CR2 antibodies.

    OpenAIRE

    Barel, M; Fiandino, A; Lyamani, F; Frade, R

    1989-01-01

    Epstein-Barr virus and the C3d fragment of the third component of complement are specific extracellular ligands for complement receptor type 2 (CR2). However, intracellular proteins that react specifically with CR2 and are involved in post-membrane signals remain unknown. We recently prepared polyclonal anti-idiotypic anti-CR2 antibodies (Ab2) by using the highly purified CR2 molecule as original immunogen. We showed that Ab2 contained anti-idiotypic specificities that mimicked extracellular ...

  6. Current status and regulatory perspective of chimeric antigen receptor-modified T cell therapeutics.

    Science.gov (United States)

    Kim, Mi-Gyeong; Kim, Dongyoon; Suh, Soo-Kyung; Park, Zewon; Choi, Min Joung; Oh, Yu-Kyoung

    2016-04-01

    Chimeric antigen receptor-modified T cells (CAR-T) have emerged as a new modality for cancer immunotherapy due to their potent efficacy against terminal cancers. CAR-Ts are reported to exert higher efficacy than monoclonal antibodies and antibody-drug conjugates, and act via mechanisms distinct from T cell receptor-engineered T cells. These cells are constructed by transducing genes encoding fusion proteins of cancer antigen-recognizing single-chain Fv linked to intracellular signaling domains of T cell receptors. CAR-Ts are classified as first-, second- and third-generation, depending on the intracellular signaling domain number of T cell receptors. This review covers the current status of CAR-T research, including basic proof-of-concept investigations at the cell and animal levels. Currently ongoing clinical trials of CAR-T worldwide are additionally discussed. Owing to the lack of existing approved products, several unresolved concerns remain with regard to safety, efficacy and manufacturing of CAR-T, as well as quality control issues. In particular, the cytokine release syndrome is the major side-effect impeding the successful development of CAR-T in clinical trials. Here, we have addressed the challenges and regulatory perspectives of CAR-T therapy. PMID:26895243

  7. 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.

  8. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases.

    Science.gov (United States)

    Chen, Xilin; Han, Jianfeng; Chu, Jianhong; Zhang, Lingling; Zhang, Jianying; Chen, Charlie; Chen, Luxi; Wang, Youwei; Wang, Hongwei; Yi, Long; Elder, J Bradley; Wang, Qi-En; He, Xiaoming; Kaur, Balveen; Chiocca, E Antonio; Yu, Jianhua

    2016-05-10

    Breast cancer brain metastases (BCBMs) are common in patients with metastatic breast cancer and indicate a poor prognosis. These tumors are especially resistant to currently available treatments due to multiple factors. However, the combination of chimeric antigen receptor (CAR)-modified immune cells and oncolytic herpes simplex virus (oHSV) has not yet been explored in this context. In this study, NK-92 cells and primary NK cells were engineered to express the second generation of EGFR-CAR. The efficacies of anti-BCBMs of EGFR-CAR NK cells, oHSV-1, and their combination were tested in vitro and in a breast cancer intracranial mouse model. In vitro, compared with mock-transduced NK-92 cells or primary NK cells, EGFR-CAR-engineered NK-92 cells and primary NK cells displayed enhanced cytotoxicity and IFN-γ production when co-cultured with breast cancer cell lines MDA-MB-231, MDA-MB-468, and MCF-7. oHSV-1 alone was also capable of lysing and destroying these cells. However, a higher cytolytic effect of EGFR-CAR NK-92 cells was observed when combined with oHSV-1 compared to the monotherapies. In the mice intracranially pre-inoculated with EGFR-expressing MDA-MB-231 cells, intratumoral administration of either EGFR-CAR-transduced NK-92 cells or oHSV-1 mitigated tumor growth. Notably, the combination of EGFR-CAR NK-92 cells with oHSV-1 resulted in more efficient killing of MDA-MB-231 tumor cells and significantly longer survival of tumor-bearing mice when compared to monotherapies. These results demonstrate that regional administration of EGFR-CAR NK-92 cells combined with oHSV-1 therapy is a potentially promising strategy to treat BCBMs.

  9. 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.

  10. Epigenetics and Cellular Metabolism

    Science.gov (United States)

    Xu, Wenyi; Wang, Fengzhong; Yu, Zhongsheng; Xin, Fengjiao

    2016-01-01

    Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well. PMID:27695375

  11. Architected Cellular Materials

    Science.gov (United States)

    Schaedler, Tobias A.; Carter, William B.

    2016-07-01

    Additive manufacturing enables fabrication of materials with intricate cellular architecture, whereby progress in 3D printing techniques is increasing the possible configurations of voids and solids ad infinitum. Examples are microlattices with graded porosity and truss structures optimized for specific loading conditions. The cellular architecture determines the mechanical properties and density of these materials and can influence a wide range of other properties, e.g., acoustic, thermal, and biological properties. By combining optimized cellular architectures with high-performance metals and ceramics, several lightweight materials that exhibit strength and stiffness previously unachievable at low densities were recently demonstrated. This review introduces the field of architected materials; summarizes the most common fabrication methods, with an emphasis on additive manufacturing; and discusses recent progress in the development of architected materials. The review also discusses important applications, including lightweight structures, energy absorption, metamaterials, thermal management, and bioscaffolds.

  12. Epigenetics and Cellular Metabolism

    Science.gov (United States)

    Xu, Wenyi; Wang, Fengzhong; Yu, Zhongsheng; Xin, Fengjiao

    2016-01-01

    Living eukaryotic systems evolve delicate cellular mechanisms for responding to various environmental signals. Among them, epigenetic machinery (DNA methylation, histone modifications, microRNAs, etc.) is the hub in transducing external stimuli into transcriptional response. Emerging evidence reveals the concept that epigenetic signatures are essential for the proper maintenance of cellular metabolism. On the other hand, the metabolite, a main environmental input, can also influence the processing of epigenetic memory. Here, we summarize the recent research progress in the epigenetic regulation of cellular metabolism and discuss how the dysfunction of epigenetic machineries influences the development of metabolic disorders such as diabetes and obesity; then, we focus on discussing the notion that manipulating metabolites, the fuel of cell metabolism, can function as a strategy for interfering epigenetic machinery and its related disease progression as well.

  13. Cellular uptake of steroid carrier proteins – mechanisms and implications

    OpenAIRE

    Willnow, T E; Nykjaer, A

    2009-01-01

    Abstract Steroid hormones are believed to enter cells solely by free diffusion through the plasma membrane. However, recent studies suggest the existence of cellular uptake pathways for carrier-bound steroids. Similar to the clearance of cholesterol via lipoproteins, these pathways involve the recognition of carrier proteins by endocytic receptors on the surface of target cells, followed by internalization and cellular delivery of the bound sterols. Here, we discuss the emerging co...

  14. 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…

  15. Picasso, Car Classics, and the Engineers.

    Science.gov (United States)

    Wosk, Julie H.

    1982-01-01

    Describes a college course which introduces engineering and business students to abstract art. Students study the relationships between abstract styles in painting and abstract styles in twentieth-century architecture and industrial design. The relevance of abstract design principles is shown by referring students to "Car and Driver" magazine. (AM)

  16. Colleges Drive Research on Electric Cars

    Science.gov (United States)

    Basken, Paul

    2009-01-01

    As the General Motors Corporation shuts assembly plants and veers toward bankruptcy, the lonely remnants of one of its top technological achievements--the first modern mass-produced electric car--lie scattered across a few dozen American college campuses. GM produced and leased to customers more than 1,000 "EV1" automobiles beginning in 1996. In…

  17. What Are Behind The Electric Car Heat?

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    Is the world's auto industry going to change greatly in the future 3-5 years so that ICEs will fade out?Will this electric car heat repeat itselfjust like it did in the history? The Chinese government issued pro- grams in Jan 2009 to cheer up the auto industrv.The plans include enacting new energy vehicle strategy,industrializing

  18. 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...

  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. The Hottest Craze of Private Car

    Institute of Scientific and Technical Information of China (English)

    DougLubbes; 王赣湘

    2004-01-01

    Automobile is, I suppose, the hottest craze in China nowadays: one has only to go to one of the important exhibitions of cars in Shanghai,Beijing and Guangzhou or any other large city,to see this. Rich and poor, young and old, one can see them all there, enquiring and watching

  1. 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.

  2. Design And Development of Aerosolar Car

    Directory of Open Access Journals (Sweden)

    Someswara Rao K

    2013-08-01

    Full Text Available This paper reports the design and development of aerosolar car. A aerosolar car is a vehicle, which is powered by wind and sun’s energy. This car is a light weight, low power vehicle designed. They have limited seating (two people, they have very little cargo capacity, and they can be driven during the days and Nights also by using dynamo motor attachment on the front of the vehicle. It does, however, offer an excellent opportunity to develop future technologies that can be applied to practical applications. The main components of an Aerosolar car are its solar arrays & alternators which collect the energy from the sun & wind respectively and convert it into electrical energy. The process of combining these mechanical and electrical components is not an easy task especially at the design stage because of the individual part specific characteristic and function. Since the development cost is one of the major constraints for this project, the sustainable design concept was implemented. Suitable parts which can be easily recycled and re-used, with desired functions that contribute to vehicle optimum performance are properly selected.

  3. Anastomose carótido-basilar

    Directory of Open Access Journals (Sweden)

    Ricardo Reixach-Granés

    1965-09-01

    Full Text Available O autor relata um caso de anastomose carótido-basilar por persistência da artéria trigeminal, demonstrado angiogràficamente. O paciente apresentou hemiplegia súbita e era portador de transtornos mentais de tipo deficitário. A pneumencefalografia evidenciou atrofia do parênquima cerebral do lado da anomalia.

  4. Business Class in a race car

    NARCIS (Netherlands)

    Wassink, J.

    2008-01-01

    It's not a car, it's not a bus, it's not a truck, and it's not even a super stretch limousine. What is being built in Delft is the much-discussed Superbus, which is to travel from door to door, reaching speeds of 250 kilometres per hour. This summer this new form of public transport is to enter serv

  5. Cellular membrane trafficking of mesoporous silica nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Fang, I-Ju [Iowa State Univ., Ames, IA (United States)

    2012-01-01

    This dissertation mainly focuses on the investigation of the cellular membrane trafficking of mesoporous silica nanoparticles. We are interested in the study of endocytosis and exocytosis behaviors of mesoporous silica nanoparticles with desired surface functionality. The relationship between mesoporous silica nanoparticles and membrane trafficking of cells, either cancerous cells or normal cells was examined. Since mesoporous silica nanoparticles were applied in many drug delivery cases, the endocytotic efficiency of mesoporous silica nanoparticles needs to be investigated in more details in order to design the cellular drug delivery system in the controlled way. It is well known that cells can engulf some molecules outside of the cells through a receptor-ligand associated endocytosis. We are interested to determine if those biomolecules binding to cell surface receptors can be utilized on mesoporous silica nanoparticle materials to improve the uptake efficiency or govern the mechanism of endocytosis of mesoporous silica nanoparticles. Arginine-glycine-aspartate (RGD) is a small peptide recognized by cell integrin receptors and it was reported that avidin internalization was highly promoted by tumor lectin. Both RGD and avidin were linked to the surface of mesoporous silica nanoparticle materials to investigate the effect of receptor-associated biomolecule on cellular endocytosis efficiency. The effect of ligand types, ligand conformation and ligand density were discussed in Chapter 2 and 3. Furthermore, the exocytosis of mesoporous silica nanoparticles is very attractive for biological applications. The cellular protein sequestration study of mesoporous silica nanoparticles was examined for further information of the intracellular pathway of endocytosed mesoporous silica nanoparticle materials. The surface functionality of mesoporous silica nanoparticle materials demonstrated selectivity among the materials and cancer and normal cell lines. We aimed to determine

  6. Children in Hot Cars Result in Fatal Consequences

    Medline Plus

    Full Text Available ... Health Tips » Holiday and Seasonal Children in Hot Cars Result in Fatal Consequences Emergency physicians are warning ... it bluntly, leaving your child in a hot car is like leaving your child in a lit ...

  7. Children in Hot Cars Result in Fatal Consequences

    Science.gov (United States)

    ... Health Tips » Holiday and Seasonal Children in Hot Cars Result in Fatal Consequences Emergency physicians are warning ... it bluntly, leaving your child in a hot car is like leaving your child in a lit ...

  8. 1,4-Naphthoquinones: From Oxidative Damage to Cellular and Inter-Cellular Signaling

    Directory of Open Access Journals (Sweden)

    Lars-Oliver Klotz

    2014-09-01

    Full Text Available Naphthoquinones may cause oxidative stress in exposed cells and, therefore, affect redox signaling. Here, contributions of redox cycling and alkylating properties of quinones (both natural and synthetic, such as plumbagin, juglone, lawsone, menadione, methoxy-naphthoquinones, and others to cellular and inter-cellular signaling processes are discussed: (i naphthoquinone-induced Nrf2-dependent modulation of gene expression and its potentially beneficial outcome; (ii the modulation of receptor tyrosine kinases, such as the epidermal growth factor receptor by naphthoquinones, resulting in altered gap junctional intercellular communication. Generation of reactive oxygen species and modulation of redox signaling are properties of naphthoquinones that render them interesting leads for the development of novel compounds of potential use in various therapeutic settings.

  9. 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...

  10. Effect of interferences on indoor visible light car-to-car communication systems

    Science.gov (United States)

    Kim, Jong-Young; Park, Bong-Seok; Choi, Hyun-Sik; Kim, So Eun; Moon, Inkyu; Lee, Chung Ghiu

    2016-04-01

    We report the effect of interferences on visible light car-to-car communication system. The interferences from floor reflections and fluorescent lamps are taken into account for indoor car-to-car visible light communication (VLC) systems. The system is composed of a white LED lamp as a VLC transmitter and a photo-receiver with an appropriate optical filter as a VLC receiver. The signal power distribution patterns are measured and analyzed at a transmission distance, considering the positions of the transmitter and receiver. Generally, the light from fluorescent lamps in indoor environment affects the DC level of the received signal power, which is more significant at higher receiver positions. The measurements show that the indoor VLC communication performance can be varied depending on floor reflections. Also, the fluorescent ceiling illuminations affect the DC level change of the received VLC signal waveforms.

  11. The role of complement receptor type 1 (CR1, CD35) in determining the cellular distribution of opsonized immune complexes between whole blood cells: kinetic analysis of the buffering capacity of erythrocytes

    DEFF Research Database (Denmark)

    Nielsen, C H; Matthiesen, S H; Lyng, I;

    1997-01-01

    , in a CR1-dependent manner, a progressive uptake via CR2 by the B cells. CR1 was the dominant receptor in the early IC-uptake by B cells as well as PMN and monocytes, since CR1-blockade inhibited the initial IC-uptake by these populations in a preparation of isolated leucocytes suspended in serum...... to E. Moreover, E are efficient processors of IC-attached C3b/iC3b fragments to C3dg as indicated by a pronounced enhancement by E of IC-uptake via CR2 on B cells. We propose that this mechanism may play a role in preventing phagocyte activation via CR3....

  12. PROGRESS ON THE ANTHRAX TOXIN AND THE CELLULAR CLONE RECEPTOR FOR ANTHRAX TOXIN%炭疽毒素及其克隆受体的研究进展

    Institute of Scientific and Technical Information of China (English)

    刘承宜; 李艳玲; 段锐; 李燕; 蔡雄伟; 黄平

    2002-01-01

    综述炭疽毒素研究的最新进展.炭疽毒素由3种蛋白组成:致死因子(Lethal factor,LF),水肿因子(edema factor,EF)和保护性抗原(protective antigen,PA).本文主要讲述了炭疽毒素的关键致病因子--致死因子(LF)的结构和功能,炭疽毒素受体(anthrax toxin receptor,ATR)的结构及其特征性功能基团,介绍了通过基因互补对ATR进行克隆的方法,并讨论了ATR和ATR的cDNA克隆在炭疽治疗的可能应用.

  13. 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;

    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......, separated from the transmembrane segment by an uncharacteristically large juxta-membrane region. The extracellular domain of the R-PTP-kappa precursor protein contains an immunoglobulin-like domain and four fibronectin type III-like repeats, preceded by a signal peptide and a region of about 150 amino acids...... with similarity to the Xenopus A5 antigen, a putative neuronal recognition molecule (S. Takagi, T. Hsrata, K. Agata, M. Mochii, G. Eguchi, and H. Fujisawa, Neuron 7:295-307, 1991). Antibodies directed against the intra- and extracellular domains reveal that the R-PTP-kappa precursor protein undergoes proteolytic...

  14. Study concerning the loads over driver's chests in car crashes with cars of the same or different generation

    Science.gov (United States)

    Ispas, N.; Năstăsoiu, M.

    2016-08-01

    Reducing occupant injuries for cars involves in traffic accidents is a main target of today cars designers. Known as active or passive safety, many technological solutions were developing over the time for an actual better car's occupant safety. In the real world, in traffic accidents are often involved cars from different generations with various safety historical solutions. The main aim of these papers are to quantify the influences over the car driver chest loads in cases of same or different generation of cars involved in side car crashes. Both same and different cars generations were used for the study. Other goal of the paper was the study of in time loads conformity for diver's chests from both cars involved in crash. The paper's experimental results were obtained by support of DSD, Dr. Steffan Datentechnik GmbH - Linz, Austria. The described tests were performed in full test facility of DSD Linz, in “Easter 2015 PC-Crash Seminar”. In all crashes we obtaining results from both dummy placed in impacted and hits car. The novelty of the paper are the comparisons of data set from each of driver (dummy) of two cars involved in each of six experimental crashes. Another novelty of this paper consists in possibilities to analyse the influences of structural historical cars solutions over deformation and loads in cases of traffic accidents involved. Paper's conclusions can be future used for car passive safety improvement.

  15. The 37/67kDa laminin receptor (LR) inhibitor, NSC47924, affects 37/67kDa LR cell surface localization and interaction with the cellular prion protein

    Science.gov (United States)

    Sarnataro, Daniela; Pepe, Anna; Altamura, Gennaro; De Simone, Imma; Pesapane, Ada; Nitsch, Lucio; Montuori, Nunzia; Lavecchia, Antonio; Zurzolo, Chiara

    2016-01-01

    The 37/67 kDa laminin receptor (LR) is a non-integrin protein, which binds both laminin-1 of the extracellular matrix and prion proteins, that hold a central role in prion diseases. The 37/67 kDa LR has been identified as interactor for the prion protein (PrPC) and to be required for pathological PrP (PrPSc) propagation in scrapie-infected neuronal cells, leading to the possibility that 37/67 kDa LR-PrPC interaction is related to the pathogenesis of prion diseases. A relationship between 37/67 kDa LR and PrPC in the presence of specific LR inhibitor compounds has not been investigated yet. We have characterized the trafficking of 37/67 kDa LR in both neuronal and non-neuronal cells, finding the receptor on the cell surface and nuclei, and identified the 67 kDa LR as the almost exclusive isoform interacting with PrPC. Here, we show that the treatment with the 37/67 kDa LR inhibitor, NSC47924, affects both the direct 37/67 kDa LR-PrPC interaction in vitro and the formation of the immunocomplex in live cells, inducing a progressive internalization of 37/67 kDa LR and stabilization of PrPC on the cell surface. These data reveal NSC47924 as a useful tool to regulate PrPC and 37/67 kDa LR trafficking and degradation, representing a novel small molecule to be tested against prion diseases. PMID:27071549

  16. Structure of the murine constitutive androstane receptor complexed to androstenol: a molecular basis for inverse agonism

    Energy Technology Data Exchange (ETDEWEB)

    Shan, L.; Vincent, J.; Brunzelle, J.S.; Dussault, I.; Lin, M.; Ianculescu, I.; Sherman, M.A.; Forman, B.M.; Fernandez, E. (Tennesse)

    2010-03-08

    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 ligand binding pocket, but unlike many nuclear receptor ligands, it makes no contacts with helix H12/AF2. The transition from constitutive to basal activity (androstenol bound) appears to be associated with a ligand-induced kink between helices H10 and H11. This disrupts the previously predicted salt bridge that locks H12 in the transcriptionally active conformation. This mechanism of inverse agonism is distinct from traditional nuclear receptor antagonists thereby offering a new approach to receptor modulation.

  17. Vertical Marketing as a Model of Cooperation Between Car Manufacturers and Car Trade

    OpenAIRE

    Zeljko Sudaric

    2011-01-01

    The last element of the marketing mix is the distribution and marketing channels in the automotive industry, which determine how cars will arrive at customers and end users through sales and distribution activities. Car manufacturers, regardless of how their product was excellent, must provide this value to its customers carefully selecting partners in the channel, because if its agents have poor sales in comparison to the competition the value of the product is irrelevant and unworthy. For t...

  18. Customer Relationship Management In Car Service Industry With Reference To Car Dealers In Coimbatore

    OpenAIRE

    Sathish, M; Balamurugan, R N; Sharma, Surinder Nath; Karthikeyan, Dr.P.

    2013-01-01

    The usefulness of the car is based on the customers expectation. The expectation is not only up to the purchase of the car, it continues in after sales service. Some of the general expectations of every customer include being reminded for periodical service, pick up & drop, nominal charges, etc. It indicates that for retaining customer, it would be necessary to fulfill his maximum expectations.With structured questionnaire, the co-ordinal discussions were done with the personnels managing the...

  19. Cellular factors implicated in filovirus entry.

    Science.gov (United States)

    Bhattacharyya, Suchita; Hope, Thomas J

    2013-01-01

    Although filoviral infections are still occurring in different parts of the world, there are no effective preventive or treatment strategies currently available against them. Not only do filoviruses cause a deadly infection, but they also have the potential of being used as biological weapons. This makes it imperative to comprehensively study these viruses in order to devise effective strategies to prevent the occurrence of these infections. Entry is the foremost step in the filoviral replication cycle and different studies have reported the involvement of a myriad of cellular factors including plasma membrane components, cytoskeletal proteins, endosomal components, and cytosolic factors in this process. Signaling molecules such as the TAM family of receptor tyrosine kinases comprising of Tyro3, Axl, and Mer have also been implicated as putative entry factors. Additionally, filoviruses are suggested to bind to a common receptor and recent studies have proposed T-cell immunoglobulin and mucin domain 1 (TIM-1) and Niemann-Pick C1 (NPC1) as potential receptor candidates. This paper summarizes the existing literature on filoviral entry with a special focus on cellular factors involved in this process and also highlights some fundamental questions. Future research aimed at answering these questions could be very useful in designing novel antiviral therapeutics. PMID:23365575

  20. Cellular Factors Implicated in Filovirus Entry

    Directory of Open Access Journals (Sweden)

    Suchita Bhattacharyya

    2013-01-01

    Full Text Available Although filoviral infections are still occurring in different parts of the world, there are no effective preventive or treatment strategies currently available against them. Not only do filoviruses cause a deadly infection, but they also have the potential of being used as biological weapons. This makes it imperative to comprehensively study these viruses in order to devise effective strategies to prevent the occurrence of these infections. Entry is the foremost step in the filoviral replication cycle and different studies have reported the involvement of a myriad of cellular factors including plasma membrane components, cytoskeletal proteins, endosomal components, and cytosolic factors in this process. Signaling molecules such as the TAM family of receptor tyrosine kinases comprising of Tyro3, Axl, and Mer have also been implicated as putative entry factors. Additionally, filoviruses are suggested to bind to a common receptor and recent studies have proposed T-cell immunoglobulin and mucin domain 1 (TIM-1 and Niemann-Pick C1 (NPC1 as potential receptor candidates. This paper summarizes the existing literature on filoviral entry with a special focus on cellular factors involved in this process and also highlights some fundamental questions. Future research aimed at answering these questions could be very useful in designing novel antiviral therapeutics.