30 research outputs found

    p19/Arf and p53 suppress sentinel lymph node lymphangiogenesis and carcinoma metastasis.

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    The ability of tumor cells to metastasize is increasingly viewed as an interaction between the primary tumor and host tissues. Deletion of the p19/Arf or p53 tumor suppressor genes accelerates malignant progression and metastatic spread of 7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced squamous cell carcinomas, providing a model system to address mechanisms of metastasis. Here, we show that benign pre-metastatic papillomas from wild-type mice trigger lymphangiogenesis within draining lymph nodes, whereas there is no growth of primary tumor lymphatic vessels. Lymph node lymphangiogenesis is greatly accelerated in papilloma-bearing p19/Arf- or p53-deficient mice, which coincides with the greater propensity of these tumors to progress to carcinomas and to metastasize. The extent of accumulation of B cells within the tumor-draining lymph nodes of wild-type mice predicted the level of lymph node lymphangiogenesis and metastatic potential. Arf or p53 deficiency strongly accelerated lymph node immune cell accumulation, in a manner that was associated with the extent of lymph node lymphatic sinus growth. This immune cell accumulation and lymph node lymphangiogenesis phenotype identifies host anti-tumor responses that could drive metastatic spread of cancers via the lymphatics

    Elevated Rates of Sister Chromatid Exchange at Chromosome Ends

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    Chromosome ends are known hotspots of meiotic recombination and double-strand breaks. We monitored mitotic sister chromatid exchange (SCE) in telomeres and subtelomeres and found that 17% of all SCE occurs in the terminal 0.1% of the chromosome. Telomeres and subtelomeres are significantly enriched for SCEs, exhibiting rates of SCE per basepair that are at least 1,600 and 160 times greater, respectively, than elsewhere in the genome

    Human Subtelomeric WASH Genes Encode a New Subclass of the WASP Family

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    Subtelomeres are duplication-rich, structurally variable regions of the human genome situated just proximal of telomeres. We report here that the most terminally located human subtelomeric genes encode a previously unrecognized third subclass of the Wiskott-Aldrich Syndrome Protein family, whose known members reorganize the actin cytoskeleton in response to extracellular stimuli. This new subclass, which we call WASH, is evolutionarily conserved in species as diverged as Entamoeba. We demonstrate that WASH is essential in Drosophila. WASH is widely expressed in human tissues, and human WASH protein colocalizes with actin in filopodia and lamellipodia. The VCA domain of human WASH promotes actin polymerization by the Arp2/3 complex in vitro. WASH duplicated to multiple chromosomal ends during primate evolution, with highest copy number reached in humans, whose WASH repertoires vary. Thus, human subtelomeres are not genetic junkyards, and WASH's location in these dynamic regions could have advantageous as well as pathologic consequences

    Design, Development & Functional Validation of Magnets system in support of 42 GHz Gyrotron in India

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    A multi institutional initiative is underway towards the development of 42 GHz, 200 kW gyrotron system in India under the frame work of Department of Science and Technology, Government of India. Indigenous realization comprising of design, fabrication, prototypes and functional validations of an appropriate Magnet System is one of the primary technological objective of these initiatives. The 42 GHz gyrotron magnet system comprises of a warm gun magnet, a NbTi/Cu based high homogenous superconducting cavity magnet and three warm collector magnets. The superconducting cavity magnet has been housed inside a low loss cryostat. The magnet system has been designed in accordance with gyrotron physics and engineering considerations respecting highly homogenous spatial field profile as well as maintaining steep gradient as per the compression and velocity ratios between the emission and resonator regions. The designed magnet system further ensures the co-linearity of the magnetic axis with that of the beam axis with custom winding techniques apart from a smooth collection of beam with the collector magnet profiles. The designed magnets have been wound after several R & D validations. The superconducting magnet has been housed inside a low loss designed cryostat with in-built radial and axial alignment flexibilities to certain extent. The cryostat further houses liquid helium port, liquid nitrogen ports, current communication ports, ports for monitoring helium level and other instrumentations apart from over-pressure safety intensive burst disks etc. The entire magnet system comprising of warm and superconducting magnets has been installed and integrated in the Gyrotron test set-up. The magnet system has been aligned in both warm and when the superconducting cavity magnet is cold. The integrated geometric axes have been experimentally ensured as well as the field profiles have been measured with the magnets being charged. Under experimental conditions, all magnets including the superconducting magnet have been charged to their nominal values with appropriate protection measures against the quench. This is the first time in India that a gyrotron specific magnet system with superconducting magnet has been realized

    Seismic performance evaluation of circular reinforced concrete bridge piers retrofitted with fibre reinforced polymer

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    A large number of researchers around the globe are currently conducting investigations on the use of fibre-reinforced polymer (FRP) for strengthening of reinforced concrete (RC) bridge piers. It has been observed that such strengthening technique can be a cost-effective method for restoring and increasing the strength and ductility of piers damaged during catastrophic events, like earthquakes. Material properties, amount of longitudinal and transverse steel, external confinement, axial load and shear span-depth ratio affect the lateral load capacity, ductility and failure mode of retrofitted bridge piers under seismic load. These parameters are considerably different in the pre-1970 code designed RC bridge piers compared to the current seismically designed bridges. This research investigates the effect of different factors and their interactions on the limit states of FRP-confined seismically deficient RC circular bridge piers using factorial design method. Nonlinear static pushover analyses of the non-seismically designed FRP retrofitted circular bridge piers are conducted in order to determine the sequence of different limit states such as yielding of reinforcement, and concrete crushing along with ductility capacity of the piers. In addition, nonlinear reverse cyclic, and dynamic time-history analyses are carried out in order to determine the lateral load carrying capacity, flexural ductility, and hysteretic behavior of such retrofitted piers. Fragility curves are developed for the FRP retrofitted RC bridge piers considering different limit states of displacement ductility as the demand parameter. The incremental dynamic analysis is conducted by considering 20 ground motion records to investigate the nonlinear dynamic behavior of the retrofitted piers. The fragility curves are described using lognormal distribution functions with two parameters developed as a function of peak ground acceleration. The impact of various parameters is evaluated on the bridge pier fragility curve based on the theory of probability. This study shows that the shear span-depth ratio, the yield strength of reinforcement, longitudinal reinforcement ratio, axial load and FRP confinement significantly affect the lateral load capacity, ductility and the failure mode of the retrofitted bridge piers under seismic load.Applied Science, Faculty ofEngineering, School of (Okanagan)Graduat
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